Pharmaceutical formulations and administration schedules of HIPPO-YAP pathway modulators

Abstract

Provided herein are pharmaceutical formulations of a therapeutically effective amount of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl) phenoxy)-2-naphthamide in a solid dosage form. Also provided herein are methods of treating cancer comprising a pharmaceutical formulation of a therapeutically effective amount of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl) phenoxy)-2-naphthamide in a solid dosage form.

Description

[0001] Cross-references This application claims the benefit of U.S. Provisional Application No. 63 / 496,235, filed April 14, 2023, which is incorporated herein by reference in its entirety. Background Technology

[0002] YAP and TAZ are transcriptional coactivators of the Hippo pathway network and regulate cell proliferation, migration, and apoptosis. Inhibition of the Hippo pathway promotes YAP / TAZ translocation to the nucleus, where YAP / TAZ interacts with transcriptional enhancer association domain (TEAD) transcription factors, coactivating target gene expression and promoting cell proliferation. Overactivation of YAP and TAZ and / or mutations in one or more members of the Hippo pathway network are associated with many cancers. This article describes inhibitors associated with one or more members of the Hippo pathway network, such as inhibitors of YAP / TAZ or inhibitors regulating the interaction between YAP / TAZ and TEAD. Summary of the Invention

[0003] In one aspect, this article provides a pharmaceutical formulation in solid dosage form comprising a therapeutically effective amount of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide. In some embodiments, the pharmaceutical formulation may be used to treat cancer.

[0004] In another aspect, this document provides a method for treating cancer in a subject by administering the pharmaceutical preparation described herein to that subject in need. In some embodiments, the method of treating cancer includes, for example, administering a pharmaceutical preparation in a solid dosage form comprising a therapeutically effective amount of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide and the excipients disclosed herein. In some embodiments, the method of treating cancer includes, for example, administering a pharmaceutical preparation in a solid dosage form comprising a therapeutically effective amount of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide and the excipients disclosed herein, wherein the pharmaceutical preparation is administered according to the dosing schedule described herein.

[0005] In one aspect, this document discloses a pharmaceutical formulation in solid dosage form comprising: (a) (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide of about 20% w / w to about 50% w / w; (b) a first filler of about 15% w / w to about 40% w / w; (c) a second filler of about 15% w / w to about 40% w / w; (d) a first lubricant of about 1% w / w to about 10% w / w; (e) a second lubricant of about 0.1% w / w to about 1% w / w; (f) a disintegrant of about 1% w / w to about 5% w / w; and (g) a flow aid of about 0.1% w / w to about 2% w / w. In some embodiments, the pharmaceutical formulation comprises about 25% w / w to about 45% w / w of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide. In some embodiments, the pharmaceutical formulation comprises about 30% w / w to about 40% w / w of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide. In some embodiments, the pharmaceutical formulation comprises about 37% w / w of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide. In some embodiments, the amount of (R)-N-(1-hydroxypropyl-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, the amount of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, or 200 mg. In some embodiments, the amount of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is 25 mg, 50 mg, 100 mg, 125 mg, or 150 mg. In some embodiments, the amount of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is 25 mg, 50 mg, or 100 mg. In some embodiments, the amount of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is 25 mg. In some embodiments, the amount of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is 50 mg. In some embodiments, the amount of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is 100 mg.In some embodiments, the pharmaceutical formulation comprises a first filler of about 20% w / w to about 35% w / w. In some embodiments, the pharmaceutical formulation comprises a first filler of about 25% w / w to about 30% w / w. In some embodiments, the pharmaceutical formulation comprises a first filler of about 27% w / w. In some embodiments, the pharmaceutical formulation comprises a second filler of about 20% w / w to about 35% w / w. In some embodiments, the pharmaceutical formulation comprises a second filler of about 25% w / w to about 30% w / w. In some embodiments, the pharmaceutical formulation comprises a second filler of about 27% w / w. 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 (Starch1500). In some embodiments, the first filler is lactose. In some embodiments, the lactose is lactose monohydrate. In some embodiments, the second filler is mannitol. In some embodiments, the mannitol is mannitol 200SD. In some embodiments, the pharmaceutical formulation comprises a first lubricant of about 3% w / w to about 7% w / w. In some embodiments, the pharmaceutical formulation comprises a first lubricant of about 5% w / w. In some embodiments, the pharmaceutical formulation comprises a second lubricant of about 0.3% w / w to about 0.7% w / w. In some embodiments, the pharmaceutical formulation comprises a second lubricant of about 0.5% w / w. In some embodiments, about 0.3% w / w of the second lubricant is within the particles, and about 0.2% w / w of the second lubricant is outside the particles. In some embodiments, the first and second lubricants are independently selected from sodium lauryl ether sulfate, sodium lauryl sulfate, magnesium stearate, stearic acid, sodium stearate, calcium stearate, ammonium lauryl sulfate, and sodium stearate 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 comprises a disintegrant of about 2% w / w to about 4% w / w. In some embodiments, the pharmaceutical formulation comprises about 3% w / w of a disintegrant. In some embodiments, the disintegrant is selected from povidone, crospovidone, hydroxypropyl methylcellulose, croscarmellose sodium, carboxymethyl cellulose, hydroxypropyl cellulose, and poly(vinyl alcohol). In some embodiments, the disintegrant is croscarmellose sodium. In some embodiments, the pharmaceutical formulation comprises about 0.5% w / w to about 1.5% w / w of a flow aid. In some embodiments, the pharmaceutical formulation comprises about 1% w / w of a flow aid. In some embodiments, the flow aid is selected from silicates, silica, and talc. In some embodiments, the flow aid is silica. In some embodiments, the silica is colloidal silica.

[0006] On the other hand, this article discloses a pharmaceutical formulation in solid dosage form comprising: (a) about 37% w / w (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide; (b) about 26.7% w / w lactose monohydrate; (c) about 26.7% w / w mannitol; (d) about 5% w / w sodium dodecyl sulfate; (e) about 0.5% w / w magnesium stearate; (f) about 3% w / w croscarmellose sodium; and (g) about 1% w / w colloidal silica.

[0007] In some embodiments, the pharmaceutical formulation disclosed herein has a half-life of at least 3 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 12 to 15 days. In some embodiments, the pharmaceutical formulation has a half-life of 12 days. In some embodiments, the solid dosage form is selected from powders, tablets, chewable disintegrating tablets, chewable tablets, capsules, gelcapsule tablets, effervescent powders, rapidly disintegrating tablets, abuse prevention tablets, modified release tablets, modified release capsules, and aqueous suspensions made from powders. 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 comprises gelatin and titanium dioxide. In some embodiments, the hard gelatin capsule also comprises 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 capsule. In some embodiments, the solid dosage form is a dry granulation mixture.

[0008] In another aspect, this document discloses methods for treating cancer in subjects of need, including administering the disclosed pharmaceutical preparations to the subject. 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 aspect, this document discloses a method for treating cancer in a subject of need, comprising administering to the subject of need a therapeutically effective amount of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide, wherein the therapeutically effective amount of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is administered daily for at least three days. In some embodiments, the therapeutically effective amount of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is administered in the form of an oral formulation. In some embodiments, the therapeutically effective amount of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is administered in a capsule. In some embodiments, the therapeutically effective dose of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is at least 25 mg daily. In some embodiments, the therapeutically effective dose of (R)-N-(1-hydroxypropyl-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 daily. In some embodiments, the therapeutically effective dose of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, or 200 mg daily. In some embodiments, the therapeutically effective dose of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is 25 mg, 50 mg, 100 mg, 125 mg, 150 mg, or 200 mg daily. In some embodiments, the therapeutically effective dose of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is 25 mg daily. In some embodiments, the therapeutically effective dose of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is 50 mg daily. In some embodiments, the therapeutically effective dose of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is 100 mg daily. In some embodiments, the therapeutically effective dose of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is administered daily for at least one week.In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is administered daily for at least two weeks. In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is administered daily for at least three weeks. In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is administered in three-week cycles, wherein the therapeutically effective amount is administered daily for one week, followed by a two-week period without administration. In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is administered in a three-week cycle, wherein the therapeutically effective amount is administered daily for one week, followed by a two-week period without administration, wherein the therapeutically effective amount of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is administered in 200 mg. In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is administered in a four-week cycle, wherein the therapeutically effective amount of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is administered daily for one week, followed by a three-week period without administration. In some implementations, a therapeutically effective amount of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is administered in a four-week cycle, wherein the therapeutically effective amount of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is administered daily for one week, followed by a three-week period without administration, wherein the therapeutically effective amount of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is administered in the form of 150 mg. In some implementations, a therapeutically effective amount of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is administered in a three-week cycle, wherein the therapeutically effective amount of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is administered daily for two weeks, followed by a week without administration.In some implementations, a therapeutically effective amount of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is administered in a three-week cycle, wherein the therapeutically effective amount of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is administered daily for two weeks, followed by a week without administration, wherein the therapeutically effective amount of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is administered in 200 mg. In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is administered in a four-week cycle, wherein the therapeutically effective amount of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is administered daily for two weeks, followed by a two-week period without administration. In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is administered in a four-week cycle, wherein the therapeutically effective amount of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is administered daily for two weeks, followed by a two-week period without administration, wherein the therapeutically effective amount of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is administered in 100 mg. In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is administered in a four-week cycle, wherein the therapeutically effective amount of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is administered daily for two weeks, followed by a two-week period without administration, wherein the therapeutically effective amount of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is administered in 200 mg. In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is administered daily for 15 days, followed by weekly administration for three weeks. In some embodiments, the therapeutically effective dose of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is 50 mg once daily for 15 days, followed by 50 mg weekly for three weeks. In some embodiments, the therapeutically effective dose of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is 100 mg once daily for 15 days, followed by 100 mg weekly for three weeks.In some implementations, the therapeutically effective dose of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is 50 mg once daily for 15 days, followed by 100 mg once weekly for three weeks.

[0010] In another aspect, this article discloses a method for treating cancer in subjects of need, comprising administering 100 mg of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide daily to the subject of need for two weeks, followed by a two-week period without administration of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide. In some embodiments, a method for treating cancer in a subject of need includes administering 100 mg of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide daily to the subject of need for two weeks, followed by a two-week period without administration of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide, and also includes administering 50 mg of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide daily to the subject of need for two weeks in four-week cycles, followed by a two-week period without administration of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide administered in at least two cycles.

[0011] In another aspect, this article discloses a method for treating cancer in subjects of need, comprising administering 100 mg of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide daily to the subject of need for two weeks, followed by a two-week period without administration of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide, followed by a four-week cycle of administering 50 mg of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide daily for two weeks, followed by a two-week period without administration of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide, wherein the 50 mg of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is administered for at least two cycles. In some embodiments, 50 mg of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is administered over at least four cycles. In some embodiments, 50 mg of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is administered over at least eight cycles. In some embodiments, 50 mg of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is administered over at least twelve cycles. In some embodiments, 50 mg of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is administered over at least twenty-four cycles.

[0012] In some implementations, a therapeutically effective amount of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is administered in at least two cycles. In some implementations, the cancer is mesothelioma, hepatocellular carcinoma, meningioma, malignant peripheral nerve schwannoma, 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] Incorporation All publications, patents and patent applications mentioned in this specification are incorporated herein by reference to the extent that each individual publication, patent or patent application is specifically and individually cited and incorporated herein by reference. Attached Figure Description

[0014] Various aspects of this disclosure are set forth in detail in the appended claims. A better understanding of the features and advantages of the invention will be gained by referring to the following detailed description and accompanying drawings, which illustrate embodiments utilizing the principles of the invention, in which: Figure 1 A schematic diagram of the Hippo signaling network is shown. Dark gray shaded Hippo pathway components represent those that inhibit YAP / TAZ activity. Light gray shaded Hippo pathway components represent those that promote YAP / TAZ activity. Pointed and blunt arrows represent activation and inhibition interactions, respectively. Abbreviations: α-CAT (α-catenin), AJUB (Ajuba), AMOT (Angiomotin), β-TRCP (protein containing β-transduction repeat sequence), CK1 (casein kinase 1), CRB (Crumbs), E-CAD (E-cadherin), EX (extended), GPCR (G protein-coupled receptor), HIPK (homology-interacting protein kinase), KIBRA (kidney / brain), LATS (large tumor suppressor), LGL (larval giant lethal gene), MASK (multi-anchor protein single KH), MER (Membrane-like protein (Merlin)), MOB (Mps one binder), MST (mammal sterility 20), PALS (Lin-7 associated protein), PATJ (Pals1 associated tight junction protein), PP2A (protein phosphatase 2A), PTPN14 (protein tyrosine phosphatase non-receptor type 14), RASSF (Ras-related factor), SAV (Salvador), SCRIB (Scribble), SIK (salt-inducible kinase), TAO (a protein of 101 amino acids), TAZ (a transcriptional coactivator with a PDZ binding motif), TEAD (TEA domain protein), VGL4 (Vestigial-like 4), WBP2 (WW domain binding protein 2), YAP (Yes-related protein), ZO (closed band), ZYX (pigmentin).

[0015] Figure 2 A schematic diagram of the Hippo signaling pathway regulated by the Gα protein is shown.

[0016] Figure 3 The design of the Phase 1 clinical trial is shown, including the primary enrollment eligibility criteria, dose escalation, and dose expansion.

[0017] Figures 4A-4C The pharmacokinetics of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide are shown: mean plasma C max (ng / mL) and dosage (mg) Figure 4A Mean plasma AUC last With dosage (mg) ( Figure 4B); and the average concentration (ng / mL) on day 15 versus time (hours) ( Figure 4C ). Detailed Implementation

[0018] Hippo signal transmission 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 implementations, the primary function of the Hippo signaling pathway is to negatively regulate the transcriptional coactivator Yes-associated protein (YAP) and its paralogs, the transcriptional coactivator TAZ (also known as WWTR1) with a PDZ-binding motif. Figure 1 The Hippo kinase cascade phosphorylates and inhibits YAP / TAZ by promoting cytoplasmic retention and degradation of YAP / TAZ, thereby suppressing growth-promoting functions regulated under YAP / TAZ control. In their unphosphorylated / dephosphorylated state, YAP (also known as YAP1 or YAP65) is transported to the nucleus along with TAZ, where they interact with the TEAD transcription factor family, upregulating genes that promote proliferation and migration and inhibiting apoptosis. In some cases, dysregulation of these genes involved in proliferation, migration, and anti-apoptosis leads to cancer development. In some cases, overexpression of YAP / TAZ is associated with cancer.

[0019] Other key members of the Hippo signaling pathway include serine / threonine kinases MST1 / 2 (in Drosophila). Hippo / Hpo Homologous compounds), Lats1 / 2 ( Warts / Wts (homophores) and its adaptor protein Sav1 ( Salvador / Sav (homogeneous compounds) and Mob (MOBKL1A and MOBKL1B); Mats (homologous) Figure 1 Typically, MST1 / 2 kinases complex with the scaffold protein Sav1, which in turn phosphorylates and activates Lats1 / 2 kinases. Lats1 / 2 is also activated by the scaffold protein Mob. The activated Lats1 / 2 then phosphorylates and inactivates YAP or its paralog TAZ. Phosphorylation of YAP / TAZ leads to their nuclear export, retention in the cytoplasm, and degradation by the ubiquitin-proteasome system.

[0020] In some cases, Lats1 / 2 phosphorylates YAP at the [HXRXXS] common motif. YAP contains five [HXRXXS] common motifs, where X represents any amino acid residue. In some cases, Lats1 / 2 phosphorylates YAP at one or more common motifs. In some cases, Lats1 / 2 phosphorylates YAP at all five common motifs. In some cases, Lats1 / 2 phosphorylates YAP at the S127 amino acid position. Phosphorylation of YAP at S127 promotes 14-3-3 protein binding and leads to cytoplasmic segregation of YAP. Mutations at the S127 position of YAP thereby disrupt its interaction with 14-3-3, subsequently promoting nuclear translocation.

[0021] Additional phosphorylation occurs at the S381 amino acid position of YAP. Phosphorylation at the S381 position of YAP and at the corresponding site in TAZ triggers further phosphorylation events in both proteins induced by the CK1δ / ε degradation motif, which then signals interaction with the β-TRCP E3 ubiquitin ligase, leading to polyubiquitination and degradation of YAP.

[0022] In some cases, Lats1 / 2 phosphorylates TAZ at the [HXRXXS] common motif. TAZ contains four [HXRXXS] common motifs, where X represents any amino acid residue. In some cases, Lats1 / 2 phosphorylates TAZ at one or more common motifs. In some cases, Lats1 / 2 phosphorylates TAZ at all four common motifs. In some cases, Lats1 / 2 phosphorylates TAZ at the S89 amino acid position. Phosphorylation of TAZ at S89 promotes 14-3-3 protein binding and leads to cytoplasmic segregation of TAZ. Mutations at the S89 position of TAZ thereby disrupt its interaction with 14-3-3, subsequently promoting nuclear translocation.

[0023] In some implementations, phosphorylated YAP / TAZ accumulates in the cytoplasm and undergoes SCF treatment. β-TRCPMediated ubiquitination and subsequent proteasome degradation. In some cases, the complex containing Skp, hysteresis protein, and F-box (SCF complex) is a multi-protein E3 ubiquitin ligase complex containing F-box family members (e.g., Cdc4), Skp1 (a bridging protein), and RBX1 (which contains a small RING Finger domain that interacts with E2-ubiquitin conjugates). In some cases, the F-box family contains more than 40 members, with exemplary members including protein 1A (FBXW1A, βTrCP1, Fbxw1, hsSlimb, plkappaBalpha-E3 receptor subunit) containing F-box / WD repeat sequences and S-phase kinase-associated protein 2 (SKP2). In some embodiments, the SCF complex (e.g., SCF) βTrCP1 It interacts with E1 ubiquitin activator and E2 ubiquitin conjugate to catalyze ubiquitin transfer to YAP / TAZ substrates. Exemplary E1 ubiquitin activators include enzymes encoded by the following genes: UBA1, UBA2, UBA3, UBA5, UBA5, UBA7, ATG7, NAE1 and SAE1 Exemplary E2 ubiquitin conjugates include enzymes encoded by the following 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 implementations, ubiquitinated YAP / TAZ further undergoes degradation via the 26S proteasome.

[0024] In some implementations, the Hippo pathway is regulated upstream by regulators from several different families. Figure 1 In some cases, the Hippo pathway is regulated by G proteins and their coupled receptors, the Crumbs complex, regulators upstream of MST kinases, and adhesion junctions.

[0025] Interaction between YAP / TAZ and TEAD In some implementations, unphosphorylated and / or dephosphorylated YAP / TAZ accumulates in the cell nucleus. Within the nucleus, YAP / TAZ interacts with transcription factors of the TEAD family (e.g., TEAD1, TEAD2, TEAD3, or TEAD4) to activate genes involved in anti-apoptosis and proliferation, such as... CTFG , Cyr61 and FGF1 .

[0026] 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.

[0027] G-protein / GPCR-mediated YAP / TAZ regulation In some implementations, the Hippo pathway is regulated by proteins from the G protein-coupled receptor (GPCR) and the G protein (also known as guanine nucleotide-binding protein) family. Figure 2 G proteins are molecular switches that transmit extracellular stimuli into the cell via GPCRs. In some cases, two types of G proteins exist: monomeric small GTPases and heterotrimeric G protein complexes. In some cases, the latter type of complex consists of alpha (G...) α ), beta (G β ) and gamma (G γ Subunit composition. In some cases, there are several types of G. α Subunit: G q / 11 α, G 12 / 13 α, G i / o α (G inhibitory, G other) and G s α (G stimulation).

[0028] In some cases, G i α (G inhibition), G o α (G other), G q / 11 α and G 12 / 13 α-coupled GPCRs activate YAP / TAZ and promote nuclear translocation. In other cases, G... s α (G-stimulatory)-coupled GPCRs inhibit YAP / TAZ activity, leading to YAP / TAZ degradation.

[0029] In some cases, G i α (G inhibition), G o α (G other), G q / 11 α and G 12 / 13 α-coupled GPCRs activate YAP / TAZ by inhibiting Lats1 / 2 activity. In contrast, G... s In some implementations, α induces Lats1 / 2 activity, thereby promoting YAP / TAZ degradation.

[0030] G q family G q α (also known as G) q / 11 Proteins are involved in the inositol triphosphate (IP3) signaling pathway and in the extraction of calcium (Ca) from intracellular storage by activating phospholipase C (PLC). 2+Release. Activated PLCs hydrolyze phosphatidylinositol 4,5-bisphosphate (PIP2) into diacylglycerol (DAG) and IP3. In some cases, for muscle cells, IP3 then diffuses through the cytoplasm into the ER or sarcoplasmic reticulum (SR), where it binds to the inositol triphosphate receptor (InsP3R), which is a Ca2+ receptor. 2+ Channel. In some cases, this binding triggers Ca. 2+ The opening of the channel increases Ca. 2+ Release into the cytoplasm.

[0031] In some implementations, with G q α-interacting GPCRs include, but are not limited to, 5-HT2 and 5-HT3 receptors (5-HT receptors); α-1 adrenergic receptors; angiotensin type 1 receptors 1A and 1B; angiotensin II receptor type 1; calcitonin receptors; histamine H1 receptors; metabotropic glutamate receptors, group I; muscarinic receptors M1, M3 and M5; and trace amine-associated receptor 1.

[0032] In some cases, there are several types of G q α: G q G q / 11 G q / 14 and G q / 15 G q Proteins are composed of GNAQ Encoding. G q / 11 Depend on GNA11 Encoding. G q / 14 Depend on GNA14 Encoding. G q / 15 Depend on GNA15 coding.

[0033] In some cases, G q Mutations or modifications to the α gene are associated with cancer. In fact, research shows that G... q Mutations in α promote the development of uveal melanoma (UM). In some cases, approximately 80% of UM cases have been detected in α. GNAQ and / or GNA11 It contains mutations.

[0034] In some cases, G q Mutations or modifications of the α gene are associated with congenital disorders. In some cases, G has been observed in congenital disorders such as port-wine stains and / or Sturge-Weber syndrome. q Mutations in alpha. In some cases, approximately 92% of port-wine stain cases are due to... GNAQ The mutation is present. In some cases, approximately 88% of Sturge-Weber syndrome cases are due to this mutation. GNAQIt contains mutations.

[0035] G 12 / 13 family G 12 / 13 α regulates actin cytoskeleton remodeling and modulates cellular processes through guanine nucleotide exchange factor (GEF). GEF is involved in the activation of small GTPases, which act as molecular switches in various intracellular signaling pathways. Examples of small GTPases include the Ras-associated GTPase superfamily (e.g., the Rho family, such as Cdc42), which are involved in cell differentiation, proliferation, cytoskeleton organization, vesicle transport, and nuclear transport.

[0036] In some implementations, with G 12 / 13 α-interacting GPCRs include, but are not limited to, purinergic 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 acids (e.g., LPA1, LPA2, LPA3); angiotensin II (AT1); and serotonin (5-HT). 2c And 5-HT4); somatostatin (SST5); endothelin (ET) A and ET B Cholecystokinin (CCK1); angiotensin receptor; D5 dopamine receptor; fMLP formyl peptide receptor; GAL2 glycopeptide receptor; EP3 prostaglandin receptor; A1 adenosine receptor; α1 adrenergic receptor; BB2 bufotenoid receptor; B2 bradykinin receptor; calcium receptor; KSHV-ORF74 chemokine receptor; NK1 tachykinin receptor; and thyroid-stimulating hormone (TSH) receptor.

[0037] In some cases, G 12 / 13 α is further subdivided into those composed of... GNA12 and GNA13 Encoded G 12 and G 13 type.

[0038] G i / o family G i / o α (G inhibitory, G other) (also known as G) i / G0 or G i The protein inhibits the production of 3',5'-cyclic AMP (cAMP) from adenosine triphosphate (ATP) by inhibiting adenylate cyclase activity, which converts ATP into cAMP.

[0039] In some implementations, with G i α-interacting GPCRs include, but are not limited to, 5-HT1 and 5-HT5 serotonin receptor (5-HT receptor) types; muscarinic acetylcholine receptors, such as M2 and M4; adenosine receptors, such as A1 and A3; and adrenergic receptors, such as α-receptors. 2A α 2B and α 2C apelin receptor; calcium receptor; cannabinoid receptors CB1 and CB2; chemokine CXCR4 receptor; 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 melatonin receptor type 3 (MT3); niacin receptors, such as NIACR1 and NIACR2; opioid receptors, such as δ, κ, μ, and nociceptive peptide 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-associated receptor 8.

[0040] In some cases, there are several types of G i α: G i α1, G i α2, G i α3, G i α4, G o α, G t G gust and G z G i α1 by GNAI1 Encoding. G i α2 by GNAI2 Encoding. G i α3 by GNAI3 Encoding. G o α, i.e., a o Subunit, by GNAO1 Encoding. G t Depend on GNAT1 and GNAT2 Encoding. G gust Depend on GNAT3 Encoding. G z Depend on GNAZ coding.

[0041] G s family G s α (also known as G-stimulatory G) s alpha subunit or G s The protein activates the cAMP-dependent pathway by activating adenylate cyclase, which converts adenosine triphosphate (ATP) into 3',5'-cyclic AMP (cAMP) and pyrophosphate. In some embodiments, it is associated with G... s α-interacting GPCRs include, but are not limited to, 5-HT4, 5-HT6, and 5-HT7 receptors (5-HT receptors); adrenocorticotropic hormone receptors (ACTH receptors) (also known as melanocortin receptor 2 or MC2R); and adenosine receptor type A. 2a and A 2b Arginine angiotensin 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; follicle-stimulating hormone receptor (FSH-receptor); gastric inhibitory peptide receptor; glucagon receptor; histamine H2 receptor; luteinizing hormone / human chorionic gonadotropin receptor; melanocorticoid receptors, such as MC1R, MC2R, MC3R, MC4R, and MC5R; parathyroid hormone receptor 1; prostaglandin receptor types D2 and I2; secretin receptor; thyroid-stimulating hormone receptor; trace amine-associated receptor 1; and box jellyfish opsin.

[0042] In some cases, there are two types of G. s α: G s and G olf G s Depend on GNAS Encoding. G olf Depend on GNAL coding.

[0043] Other modifiers of the Hippo signaling network In some implementations, another regulator of the Hippo signaling pathway is the Crumbs (Crb) complex. The Crumbs complex is a key regulator of cell polarity and cell shape. In some cases, the Crumbs complex contains transmembrane CRB proteins that assemble into multi-protein complexes that function in cell polarity. In others, the CRB complex recruits members of the angioactin (AMOT) adaptor protein family, which interact with components of the Hippo pathway. In still others, studies have shown that AMOT binds directly to YAP, promoting YAP phosphorylation and inhibiting its nuclear localization.

[0044] In some cases, other 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 kinase and the cell polar kinase PAR-1.

[0045] In some cases, other regulators of the Hippo signaling pathway include adhesion molecules. In some cases, E-cadherin (E-cad) inhibits YAP nuclear localization and activity by modulating MST activity. In some embodiments, the E-cad-associated protein α-catenin regulates YAP by isolating the YAP / 14-3-3 complex in the cytoplasm. In other cases, members of the Ajuba protein family interact with Lats1 / 2 kinase activity, thereby preventing YAP / TAZ inactivation.

[0046] In some implementations, other proteins that interact directly or indirectly with YAP / TAZ include, but are not limited to, membrane-like protein (Merlin), procadherin Fat 1, 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.

[0047] In some embodiments, the compounds described herein are inhibitors of transcriptional coactivators with a PDZ-binding motif / Yes-associated protein transcriptional coactivator (TAZ / YAP). In some embodiments, the compounds described herein increase phosphorylation of TAZ / YAP or decrease dephosphorylation of TAZ / YAP. In some embodiments, the compounds increase ubiquitination of TAZ / YAP or decrease deubiquitination of TAZ / YAP.

[0048] In some embodiments, the compounds disclosed herein are inhibitors of one or more proteins covered by or associated with the Hippo pathway. In some cases, said one or more proteins include... Figure 1 and / or Figure 2The protein shown. 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 an inhibitor of the following proteins: G q α-family proteins, such as G q G q / 11 G q / 14 and G q / 15 G 12 / 13 α-family proteins, such as G 12 and G 13 ; or G i α-family proteins, such as G i α1, G i α2, G i α3, G i α4, G o α, G t G gust and G z In some implementations, the inhibitor of the Hippo pathway is G... q Inhibitors of the Hippo pathway. In some implementations, the inhibitor of the Hippo pathway is G... q / 11 Inhibitors of the Hippo pathway. In some implementations, the inhibitor of the Hippo pathway is G... q / 14 Inhibitors of the Hippo pathway. In some implementations, the inhibitor of the Hippo pathway is G... q / 15 Inhibitors of the Hippo pathway. In some implementations, the inhibitor of the Hippo pathway is G... 12 Inhibitors of the Hippo pathway. In some implementations, the inhibitor of the Hippo pathway is G... 13 Inhibitors of the Hippo pathway. In some implementations, the inhibitor of the Hippo pathway is G... i Inhibitors of α1. In some implementations, the inhibitor of the Hippo pathway is G... i Inhibitors of α2. In some implementations, the inhibitor of the Hippo pathway is G... i Inhibitors of α3. In some implementations, the inhibitor of the Hippo pathway is G... i Inhibitors of α4. In some implementations, the inhibitor of the Hippo pathway is G... o An inhibitor of α. In some implementations, the inhibitor of the Hippo pathway is G... t Inhibitors of the Hippo pathway. In some implementations, the inhibitor of the Hippo pathway is G... gust Inhibitors of the Hippo pathway. In some implementations, the inhibitor of the Hippo pathway is G... z Inhibitors.

[0049] In some embodiments, the inhibitor of the Hippo pathway is an inhibitor of the core protein of the Hippo pathway. In some embodiments, the inhibitor of the Hippo pathway is an inhibitor of Sav1. In some embodiments, the inhibitor of the Hippo pathway is an inhibitor of Mob. In some embodiments, the inhibitor of the Hippo pathway is an inhibitor of YAP. In some embodiments, the inhibitor of the Hippo pathway is an inhibitor of TAZ. In some embodiments, the inhibitor of the Hippo pathway is an inhibitor of TEAD.

[0050] In some embodiments, the inhibitors of the Hippo pathway are inhibitors of proteins associated with ubiquitination and proteasome degradation pathways. In some embodiments, the inhibitors of the Hippo pathway are inhibitors of proteasome degradation pathway proteins (e.g., the 26S proteasome).

[0051] In some embodiments, the inhibitor of the Hippo pathway is an inhibitor of proteins from the Ras protein superfamily. In some embodiments, the inhibitor of the Hippo pathway is an inhibitor of proteins from the Rho protein family. In some embodiments, the inhibitor of the Hippo pathway is an inhibitor of Cdc42.

[0052] Cdc42 is a member of the Ras superfamily of small GTPases. Specifically, Cdc42 belongs to the Rho family of GTPases, whose members are involved in a variety of key 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, it is activated by guanine nucleotide exchange factor (GEF). In some cases, inhibitors of Cdc42 are the compounds disclosed herein.

[0053] In some embodiments, the inhibitor of the Hippo pathway is an inhibitor of deubiquitinating enzymes. In some embodiments, the inhibitor of the Hippo pathway is an inhibitor of cysteine ​​proteases or metalloproteinases. In some embodiments, the inhibitor of the Hippo pathway is an inhibitor of ubiquitin-specific proteases. 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.

[0054] compound The compound (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide disclosed herein refers to a compound having the following structure: .

[0055] pharmaceutical preparations (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide and at least one pharmaceutically acceptable excipient are in the form of a solid dosage form.

[0056] In one aspect, this application discloses a pharmaceutical preparation in solid dosage form, comprising: (a) (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide, approximately 20% w / w to approximately 50% w / w; (b) A first filler of about 15% w / w to about 40% w / w; (c) A second filler of approximately 15% w / w to approximately 40% w / w; (d) A first lubricant of about 1% w / w to about 10% w / w; (e) A second lubricant of about 0.1% w / w to about 1% w / w; (f) a disintegrant of about 1% w / w to about 5% w / w; and (g) A flow aid of about 0.1% w / w to about 2% w / w.

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

[0058] In some embodiments, the pharmaceutical formulation comprises about 20% w / w (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide. In some embodiments, the pharmaceutical formulation comprises about 25% w / w (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide. In some embodiments, the pharmaceutical formulation comprises about 30% w / w (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide. In some embodiments, the pharmaceutical formulation comprises about 35% w / w (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide. In some embodiments, the pharmaceutical formulation comprises about 37% w / w (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide. In some embodiments, the pharmaceutical formulation comprises about 40% w / w (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide. In some embodiments, the pharmaceutical formulation comprises about 45% w / w (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide. In some embodiments, the pharmaceutical formulation comprises about 50% w / w (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide.

[0059] In some embodiments, the pharmaceutical formulation comprises 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-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide. In some embodiments, the pharmaceutical formulation comprises about 25 mg, about 50 mg, about 100 mg, about 125 mg, about 150 mg, or about 200 mg of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide. In some embodiments, the pharmaceutical formulation comprises about 25 mg, about 50 mg, about 100 mg, about 150 mg, or about 200 mg of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide. In some embodiments, the pharmaceutical formulation comprises about 25 mg, about 50 mg, or about 100 mg of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide.

[0060] In some embodiments, the pharmaceutical formulation comprises about 25 mg of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide. In some embodiments, the pharmaceutical formulation comprises about 50 mg of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide. In some embodiments, the pharmaceutical formulation comprises about 75 mg of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide. In some embodiments, the pharmaceutical formulation comprises about 100 mg of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide. In some embodiments, the pharmaceutical formulation comprises about 125 mg of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide. In some embodiments, the pharmaceutical formulation comprises about 150 mg of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide. In some embodiments, the pharmaceutical formulation comprises about 175 mg of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide. In some embodiments, the pharmaceutical formulation comprises about 200 mg of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide. In some embodiments, the pharmaceutical formulation comprises about 300 mg of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide. In some embodiments, the pharmaceutical formulation comprises about 400 mg of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide.

[0061] In some aspects, the fillers disclosed herein increase the volume of the 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 comprises about 25% w / w of a first filler. In some embodiments, the pharmaceutical formulation comprises about 26% w / w of a first filler. In some embodiments, the pharmaceutical formulation comprises about 27% w / w of a first filler. In some embodiments, the pharmaceutical formulation comprises about 28% w / w of a first filler. In some embodiments, the pharmaceutical formulation comprises about 29% w / w of a first filler. In some embodiments, the pharmaceutical formulation comprises about 30% w / w of a first filler. In some embodiments, the pharmaceutical formulation comprises about 35% w / w of a first filler. In some embodiments, the pharmaceutical formulation comprises about 40% w / w of a first filler.

[0062] 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 comprises about 26% w / w of a second filler. In some embodiments, the pharmaceutical formulation comprises about 27% w / w of a second filler. In some embodiments, the pharmaceutical formulation comprises about 28% w / w of a second filler. In some embodiments, the pharmaceutical formulation comprises about 29% w / w of a second filler. In some embodiments, the pharmaceutical formulation comprises about 30% w / w of a second filler. In some embodiments, the pharmaceutical formulation comprises about 35% w / w of a second filler. In some embodiments, the pharmaceutical formulation comprises about 40% w / w of a second filler.

[0063] 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).

[0064] 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, the 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, the mannitol is mannitol 200 SD. In some embodiments, the first filler is mannitol 200 SD. 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).

[0065] 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, the 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, the mannitol is mannitol 200 SD. In some embodiments, the second filler is mannitol 200 SD. 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).

[0066] In some aspects, the lubricants disclosed herein are compounds that prevent, reduce, or inhibit material adhesion or friction. 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 comprises about 1% w / w to about 7% w / w of a first lubricant. In some embodiments, the pharmaceutical formulation comprises about 1% w / w to about 6% w / w of a first lubricant. In some embodiments, the pharmaceutical formulation comprises about 1% w / w to about 5% w / w of a first lubricant. In some embodiments, the pharmaceutical formulation comprises about 2% w / w to about 8% w / w of a first lubricant. In some embodiments, the pharmaceutical formulation comprises about 3% w / w to about 7% w / w of a first lubricant. In some embodiments, the pharmaceutical formulation comprises about 3% w / w to about 6% w / w of a first lubricant. In some embodiments, the pharmaceutical formulation comprises about 4% w / w to about 6% w / w of a first lubricant. In some embodiments, the pharmaceutical formulation comprises about 1% w / w of a first lubricant. In some embodiments, the pharmaceutical formulation comprises about 2% w / w of a first lubricant. In some embodiments, the pharmaceutical formulation comprises about 3% w / w of a first lubricant. In some embodiments, the pharmaceutical formulation comprises about 3.5% w / w of a first lubricant. In some embodiments, the pharmaceutical formulation comprises about 4% w / w of a first lubricant. In some embodiments, the pharmaceutical formulation comprises about 4.5% w / w of a first lubricant. In some embodiments, the pharmaceutical formulation comprises about 5% w / w of a first lubricant. In some embodiments, the pharmaceutical formulation comprises about 5.5% w / w of a first lubricant. In some embodiments, the pharmaceutical formulation comprises about 6% w / w of a first lubricant. In some embodiments, the pharmaceutical formulation comprises about 6.5% w / w of a first lubricant. In some embodiments, the pharmaceutical formulation comprises about 7% w / w of a first lubricant. In some embodiments, the pharmaceutical formulation comprises about 8% w / w of a first lubricant. In some embodiments, the pharmaceutical formulation comprises about 9% w / w of a first lubricant. In some embodiments, the pharmaceutical formulation comprises about 10% w / w of a first lubricant.

[0067] 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 comprises about 0.1% w / w to about 0.6% w / w of a second lubricant. In some embodiments, the pharmaceutical formulation comprises about 0.1% w / w to about 0.5% w / w of a second lubricant. In some embodiments, the pharmaceutical formulation comprises about 0.3% w / w to about 0.7% w / w of a second lubricant. In some embodiments, the pharmaceutical formulation comprises about 0.4% w / w to about 0.7% w / w of a second lubricant. In some embodiments, the pharmaceutical formulation comprises about 0.5% w / w to about 0.7% w / w of a second lubricant. In some embodiments, the pharmaceutical formulation comprises about 0.3% w / w to about 0.6% w / w of a second lubricant. In some embodiments, the pharmaceutical formulation comprises about 0.4% w / w to about 0.6% w / w of a second lubricant. In some embodiments, the pharmaceutical formulation comprises about 0.5% w / w to about 0.6% w / w of a second lubricant. In some embodiments, the pharmaceutical formulation comprises about 0.1% w / w of a second lubricant. In some embodiments, the pharmaceutical formulation comprises about 0.2% w / w of a second lubricant. In some embodiments, the pharmaceutical formulation comprises about 0.3% w / w of a second lubricant. In some embodiments, the pharmaceutical formulation comprises about 0.4% w / w of a second lubricant. In some embodiments, the pharmaceutical formulation comprises about 0.5% w / w of a second lubricant. In some embodiments, the pharmaceutical formulation comprises about 0.6% w / w of a second lubricant. In some embodiments, the pharmaceutical formulation comprises about 0.7% w / w of a second lubricant. In some embodiments, the pharmaceutical formulation comprises about 0.8% w / w of a second lubricant. In some embodiments, the pharmaceutical formulation comprises about 0.9% w / w of a second lubricant. In some embodiments, the pharmaceutical formulation comprises about 1% w / w of a second lubricant.

[0068] In some embodiments, for 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 of the second lubricant is extragranular. In some embodiments, for 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 of the second lubricant is extragranular. In some embodiments, for 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 of the second lubricant is extragranular. In some embodiments, for 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 of the second lubricant is extragranular. In some embodiments, for a pharmaceutical formulation containing about 0.5% w / w of a second lubricant, about 0.4% w / w of the second lubricant is intraparticle and about 0.1% w / w of the second lubricant is extraparticle. In some embodiments, for a pharmaceutical formulation containing about 0.5% w / w of a second lubricant, about 0.5% w / w of the second lubricant is intraparticle and about 0% w / w of the second lubricant is extraparticle.

[0069] In some embodiments, the first lubricant and the second lubricant are independently selected from sodium lauryl ether sulfate, sodium dodecyl sulfate, magnesium stearate, stearic acid, sodium stearate, calcium stearate, ammonium dodecyl sulfate, and sodium stearate fumarate.

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

[0071] In some embodiments, the second lubricant is selected from sodium lauryl ether sulfate, sodium lauryl sulfate, magnesium stearate, stearic acid, sodium stearate, calcium stearate, ammonium lauryl sulfate, and sodium stearate fumarate. In some embodiments, the second lubricant is sodium lauryl ether 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 stearate fumarate.

[0072] In some aspects, the disintegrants disclosed herein facilitate the rupture 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 comprises about 3% w / w to about 4% w / w of the disintegrant. In some embodiments, the pharmaceutical formulation contains about 1% w / w of disintegrant. In some embodiments, the pharmaceutical formulation also contains about 2% w / w of disintegrant. In some embodiments, the pharmaceutical formulation also contains about 2.5% w / w of disintegrant. In some embodiments, the pharmaceutical formulation also contains about 3% w / w of disintegrant. In some embodiments, the pharmaceutical formulation also contains about 3.5% w / w of disintegrant. In some embodiments, the pharmaceutical formulation also contains about 4% w / w of disintegrant. In some embodiments, the pharmaceutical formulation also contains about 5% w / w of disintegrant.

[0073] In some embodiments, the disintegrant is selected from povidone, crospovidone, hydroxypropyl methylcellulose, crospovidone sodium carboxymethyl cellulose, carboxymethyl cellulose, hydroxypropyl cellulose, and poly(vinyl alcohol). In some embodiments, the disintegrant is povidone. In some embodiments, the disintegrant is crospovidone. In some embodiments, the disintegrant is hydroxypropyl methylcellulose. In some embodiments, the disintegrant is crospovidone sodium carboxymethyl cellulose. In some embodiments, the disintegrant is carboxymethyl cellulose. In some embodiments, the disintegrant is hydroxypropyl cellulose. In some embodiments, the disintegrant is poly(vinyl alcohol).

[0074] In some aspects, the flow aids 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 aid. In some embodiments, the pharmaceutical formulation comprises about 0.2% w / w to about 2% w / w of the flow aid. In some embodiments, the pharmaceutical formulation comprises about 0.3% w / w to about 2% w / w of the flow aid. In some embodiments, the pharmaceutical formulation comprises about 0.4% w / w to about 2% w / w of the flow aid. In some embodiments, the pharmaceutical formulation comprises about 0.5% w / w to about 2% w / w of the flow aid. In some embodiments, the pharmaceutical formulation comprises about 0.6% w / w to about 2% w / w of the flow aid. In some embodiments, the pharmaceutical formulation comprises about 0.7% w / w to about 2% w / w of the flow aid. In some embodiments, the pharmaceutical formulation comprises about 0.8% w / w to about 2% w / w of the flow aid. In some embodiments, the pharmaceutical formulation comprises about 0.9% w / w to about 2% w / w of a flow aid. In some embodiments, the pharmaceutical formulation comprises about 1% w / w to about 2% w / w of a flow aid. In some embodiments, the pharmaceutical formulation comprises about 0.1% w / w to about 1.9% w / w of a flow aid. In some embodiments, the pharmaceutical formulation comprises about 0.1% w / w to about 1.8% w / w of a flow aid. In some embodiments, the pharmaceutical formulation comprises about 0.1% w / w to about 1.7% w / w of a flow aid. In some embodiments, the pharmaceutical formulation comprises about 0.1% w / w to about 1.6% w / w of a flow aid. In some embodiments, the pharmaceutical formulation comprises about 0.1% w / w to about 1.5% w / w of a flow aid. In some embodiments, the pharmaceutical formulation comprises about 0.1% w / w to about 1.4% w / w of a flow aid. In some embodiments, the pharmaceutical formulation comprises about 0.1% w / w to about 1.3% w / w of a flow aid. In some embodiments, the pharmaceutical formulation comprises about 0.1% w / w to about 1.2% w / w of a flow aid. In some embodiments, the pharmaceutical formulation comprises about 0.1% w / w to about 1.1% w / w of a flow aid. In some embodiments, the pharmaceutical formulation comprises about 0.3% w / w to about 1.7% w / w of a flow aid. In some embodiments, the pharmaceutical formulation comprises about 0.5% w / w to about 1.5% w / w of a flow aid. In some embodiments, the pharmaceutical formulation comprises about 0.7% w / w to about 1.3% w / w of a flow aid. In some embodiments, the pharmaceutical formulation comprises about 0.9% w / w to about 1.1% w / w of a flow aid. In some embodiments, the pharmaceutical formulation comprises about 1% w / w to about 1.5% w / w of a flow aid. In some embodiments, the pharmaceutical formulation comprises about 0.5% w / w to about 1% w / w of a flow aid. In some embodiments, the pharmaceutical formulation comprises about 0.1% w / w of a flow aid. In some implementations, the pharmaceutical formulation contains approximately 0.2% w / w of a flow aid.In some embodiments, the pharmaceutical formulation contains about 0.3% w / w of a flow aid. In some embodiments, the pharmaceutical formulation contains about 0.4% w / w of a flow aid. In some embodiments, the pharmaceutical formulation contains about 0.5% w / w of a flow aid. In some embodiments, the pharmaceutical formulation contains about 0.6% w / w of a flow aid. In some embodiments, the pharmaceutical formulation contains about 0.7% w / w of a flow aid. In some embodiments, the pharmaceutical formulation contains about 0.8% w / w of a flow aid. In some embodiments, the pharmaceutical formulation contains about 0.9% w / w of a flow aid. In some embodiments, the pharmaceutical formulation contains about 1% w / w of a flow aid. In some embodiments, the pharmaceutical formulation contains about 1.1% w / w of a flow aid. In some embodiments, the pharmaceutical formulation contains about 1.2% w / w of a flow aid. In some embodiments, the pharmaceutical formulation contains about 1.3% w / w of a flow aid. In some embodiments, the pharmaceutical formulation contains about 1.4% w / w of a flow aid. In some embodiments, the pharmaceutical formulation contains about 1.5% w / w of a flow aid. In some embodiments, the pharmaceutical formulation contains about 1.6% w / w of a flow aid. In some embodiments, the pharmaceutical formulation contains about 1.7% w / w of a flow aid. In some embodiments, the pharmaceutical formulation contains about 1.8% w / w of a flow aid. In some embodiments, the pharmaceutical formulation contains about 1.9% w / w of a flow aid. In some embodiments, the pharmaceutical formulation contains about 2% w / w of a flow aid.

[0075] In some embodiments, the flow aid is selected from silicates, silica, and talc. In some embodiments, the flow aid is a silicate. In some embodiments, the flow aid is silica. In some embodiments, the silica is colloidal silica. In some embodiments, the flow aid is colloidal silica. In some embodiments, the flow aid is talc.

[0076] In some embodiments, this document discloses pharmaceutical formulations in solid dosage form, comprising: (a) Approximately 37% w / w of (R)-N-(1-hydroxypropyl-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 dodecyl sulfate; (e) Approximately 0.5% w / w magnesium stearate; (f) Approximately 3% w / w of croscarmellose sodium; and (g) Approximately 1% w / w of colloidal silica.

[0077] In some embodiments, the half-life of the drug formulation is at least 1 day. In some embodiments, the half-life of the drug formulation is at least 2 days. In some embodiments, the half-life of the drug formulation is at least 3 days. In some embodiments, the half-life of the drug formulation is at least 4 days. In some embodiments, the half-life of the drug formulation is at least 5 days. In some embodiments, the half-life of the drug formulation is at least 6 days. In some embodiments, the half-life of the drug formulation is at least 7 days. In some embodiments, the half-life of the drug formulation is at least 8 days. In some embodiments, the half-life of the drug formulation is at least 9 days. In some embodiments, the half-life of the drug formulation is at least 10 days. In some embodiments, the half-life of the drug formulation is at least 11 days. In some embodiments, the half-life of the drug formulation is at least 12 days. In some embodiments, the half-life of the drug formulation is at least 13 days. In some embodiments, the half-life of the drug formulation is at least 14 days. In some embodiments, the half-life of the drug formulation is at least 15 days.

[0078] In some embodiments, the half-life of the drug formulation is 1 to 20 days. In some embodiments, the half-life of the drug formulation is 2 to 19 days. In some embodiments, the half-life of the drug formulation is 3 to 18 days. In some embodiments, the half-life of the drug formulation is 4 to 17 days. In some embodiments, the half-life of the drug formulation is 5 to 16 days. In some embodiments, the half-life of the drug formulation is 6 to 15 days. In some embodiments, the half-life of the drug formulation is 7 to 15 days. In some embodiments, the half-life of the drug formulation is 8 to 15 days. In some embodiments, the half-life of the drug formulation is 9 to 15 days. In some embodiments, the half-life of the drug formulation is 10 to 15 days. In some embodiments, the half-life of the drug formulation is 11 to 15 days. In some embodiments, the half-life of the drug formulation is 12 to 15 days.

[0079] In some embodiments, the half-life of the drug formulation is 1 day. In some embodiments, the half-life of the drug formulation is 2 days. In some embodiments, the half-life of the drug formulation is 3 days. In some embodiments, the half-life of the drug formulation is 4 days. In some embodiments, the half-life of the drug formulation is 5 days. In some embodiments, the half-life of the drug formulation is 6 days. In some embodiments, the half-life of the drug formulation is 7 days. In some embodiments, the half-life of the drug formulation is 8 days. In some embodiments, the half-life of the drug formulation is 9 days. In some embodiments, the half-life of the drug formulation is 10 days. In some embodiments, the half-life of the drug formulation is 11 days. In some embodiments, the half-life of the drug formulation is 12 days. In some embodiments, the half-life of the drug formulation is 13 days. In some embodiments, the half-life of the drug formulation is 14 days. In some embodiments, the half-life of the drug formulation is 15 days. In some embodiments, the half-life of the drug formulation is 16 days. In some embodiments, the half-life of the drug formulation is 17 days. In some embodiments, the half-life of the drug formulation is 18 days. In some embodiments, the half-life of the drug formulation is 19 days. In some embodiments, the half-life of the drug formulation is 20 days.

[0080] Dosage form In some embodiments, the pharmaceutical formulations described herein comprising (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide are incorporated into a solid unit dosage form. The term "solid unit dosage form" refers to a dosage form intended to be swallowed as a single unit, selected from the following: powders, tablets, chewable disintegrating tablets, chewable tablets, capsules, sac-type tablets, effervescent powders, rapidly disintegrating tablets, abuse prevention tablets, modulated-release tablets, modulated-release sac-type tablets, modulated-release capsules, and aqueous suspensions made from powders.

[0081] 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 disintegrating tablet. In some embodiments, the solid dosage form is a chewable tablet. In some embodiments, the solid dosage form is a capsule. In some embodiments, the solid dosage form is a capsule-type tablet. 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 an adjusted-release tablet. In some embodiments, the solid dosage form is an adjusted-release capsule. In some embodiments, the solid dosage form is an adjusted-release capsule. In some embodiments, the solid dosage form is an aqueous suspension made from a powder.

[0082] In some embodiments, the capsule disclosed herein is a hard gelatin capsule. In some embodiments, the hard gelatin capsule comprises gelatin and titanium dioxide. In some embodiments, the hard gelatin capsule is gelatin. In some embodiments, the hard gelatin capsule is titanium dioxide. In some embodiments, the capsule is gelatin. In some embodiments, the capsule is titanium dioxide.

[0083] In some embodiments, the hard gelatin capsules disclosed herein also comprise FD&C Red 40 and FD&C Blue 1. In some embodiments, the hard gelatin capsules disclosed herein also comprise FD&C Red 40. In some embodiments, the hard gelatin capsules disclosed herein also comprise FD&C Blue 1.

[0084] In some implementations, the solid dosage form is a dry granulation mixture.

[0085] method In some embodiments, this disclosure provides a method for treating cancer in a subject of need, including administering a pharmaceutical preparation disclosed herein to the subject.

[0086] In some embodiments, this disclosure provides a method for treating cancer in a subject of need, comprising administering to the subject a pharmaceutical formulation disclosed herein, the pharmaceutical formulation comprising a therapeutically effective amount of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide and at least one pharmaceutically acceptable excipient.

[0087] In some embodiments, the cancer is mesothelioma, hepatocellular carcinoma, meningioma, malignant peripheral schwannoma, 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. 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 schwannoma. 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 cancer. In some embodiments, the cancer is gastric adenocarcinoma. In some embodiments, the cancer is esophageal adenocarcinoma. In some implementations, the cancer is ovarian cancer. In some implementations, the cancer is serous adenocarcinoma of the ovary. In some implementations, the cancer is melanoma. In some implementations, the cancer is breast cancer.

[0088] In some embodiments, this application provides a method for treating cancer in a subject of need, comprising administering to the subject a therapeutically effective amount of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide, wherein the therapeutically effective amount of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is administered daily for at least three days. In some embodiments, the therapeutically effective amount of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is administered daily for at least four days. In some embodiments, the therapeutically effective amount of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is administered daily for at least five days. In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is administered daily for at least six days. In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is administered daily for at least seven days. In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is administered daily for at least eight days. In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is administered daily for at least nine days. In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is administered daily for at least 10 days. In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is administered daily for at least 11 days. In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is administered daily for at least 12 days. In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is administered daily for at least 13 days. In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is administered daily for at least 14 days. In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is administered daily for at least 15 days.In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is administered daily for at least one week. In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is administered daily for at least two weeks. In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is administered daily for at least three weeks.

[0089] In some implementations, a therapeutically effective amount of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is administered in the form of an oral formulation.

[0090] In some implementations, a therapeutically effective amount of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is administered in capsule form.

[0091] In some embodiments, the therapeutically effective dose of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is at least 10 mg daily. In some embodiments, the therapeutically effective dose of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is at least 15 mg daily. In some embodiments, the therapeutically effective dose of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is at least 20 mg daily. In some embodiments, the therapeutically effective dose of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is at least 25 mg daily. In some embodiments, the therapeutically effective dose of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is at least 50 mg daily. In some embodiments, the therapeutically effective dose of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is at least 75 mg daily. In some embodiments, the therapeutically effective dose of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is at least 100 mg daily. In some embodiments, the therapeutically effective dose of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is at least 125 mg daily. In some embodiments, the therapeutically effective dose of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is at least 150 mg daily. In some embodiments, the therapeutically effective dose of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is at least 175 mg daily. In some embodiments, the therapeutically effective dose of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is at least 200 mg daily. In some embodiments, the therapeutically effective dose of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is at least 225 mg daily. In some embodiments, the therapeutically effective dose of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is at least 250 mg daily. In some embodiments, the therapeutically effective dose of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is at least 275 mg daily. In some embodiments, the therapeutically effective dose of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is at least 300 mg daily.In some embodiments, the therapeutically effective dose of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is at least 325 mg daily. In some embodiments, the therapeutically effective dose of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is at least 350 mg daily. In some embodiments, the therapeutically effective dose of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is at least 375 mg daily. In some embodiments, the therapeutically effective dose of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is at least 400 mg daily.

[0092] In some embodiments, the therapeutically effective dose of (R)-N-(1-hydroxypropyl-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 daily. In some embodiments, the therapeutically effective dose of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is 25 mg, 50 mg, 100 mg, 125 mg, 150 mg, or 200 mg daily.

[0093] In some embodiments, the therapeutically effective dose of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is 25 mg daily. In some embodiments, the therapeutically effective dose of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is 50 mg daily. In some embodiments, the therapeutically effective dose of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is 75 mg daily. In some embodiments, the therapeutically effective dose of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is 100 mg daily. In some embodiments, the therapeutically effective dose of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is 125 mg daily. In some embodiments, the therapeutically effective dose of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is 150 mg daily. In some embodiments, the therapeutically effective dose of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is 175 mg daily. In some embodiments, the therapeutically effective dose of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is 200 mg daily. In some embodiments, the therapeutically effective dose of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is 250 mg daily. In some embodiments, the therapeutically effective dose of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is 300 mg daily. In some embodiments, the therapeutically effective dose of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is 350 mg daily. In some embodiments, the therapeutically effective dose of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is 400 mg daily.

[0094] In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is administered daily. In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is administered daily for at least one week. In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is administered daily for one week. In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is administered daily for at least two weeks. In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is administered daily for two weeks. In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is administered daily for at least three weeks. In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is administered daily for three weeks. In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is administered daily for four weeks.

[0095] In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is administered in a three-week cycle, wherein the therapeutically effective amount of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is administered daily for one week, followed by a two-week period without administration. In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is administered in a three-week cycle, wherein the therapeutically effective amount of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is 200 mg administered daily for one week, followed by a two-week period without administration. In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is administered in a three-week cycle, wherein the therapeutically effective amount of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is 150 mg daily for one week, followed by a two-week period without administration. In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is administered in a three-week cycle, wherein the therapeutically effective amount of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is 100 mg daily for one week, followed by a two-week period without administration. In some implementations, a therapeutically effective amount of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is administered in a three-week cycle, wherein the therapeutically effective amount of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is 50 mg daily for one week, followed by a two-week period without administration.

[0096] In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is administered in a three-week cycle, wherein the therapeutically effective amount of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is administered daily for two weeks, followed by a week without administration. In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is administered in a three-week cycle, wherein the therapeutically effective amount of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is 200 mg daily for two weeks, followed by a week without administration. In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is administered in a three-week cycle, wherein the therapeutically effective amount of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is 150 mg daily for two weeks, followed by a week without administration. In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is administered in a three-week cycle, wherein the therapeutically effective amount of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is 100 mg daily for two weeks, followed by a week without administration. In some implementations, a therapeutically effective amount of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is administered in a three-week cycle, wherein the therapeutically effective amount of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is 50 mg daily for two weeks, followed by a week without administration.

[0097] In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is administered in a four-week cycle, wherein the therapeutically effective amount of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is administered daily for one week, followed by a three-week period without administration. In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is administered in a four-week cycle, wherein the therapeutically effective amount of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is 200 mg administered daily for one week, followed by a three-week period without administration. In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is administered in a four-week cycle, wherein the therapeutically effective amount of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is 150 mg daily for one week, followed by a three-week period without administration. In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is administered in a four-week cycle, wherein the therapeutically effective amount of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is 100 mg daily for one week, followed by a three-week period without administration. In some implementations, a therapeutically effective amount of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is administered in a four-week cycle, wherein the therapeutically effective amount of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is 50 mg daily for one week, followed by a three-week period without administration.

[0098] In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is administered in a four-week cycle, wherein the therapeutically effective amount of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is administered daily for two weeks, followed by a two-week period without administration. In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is administered in a four-week cycle, wherein the therapeutically effective amount of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is 200 mg administered daily for two weeks, followed by a two-week period without administration. In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is administered in a four-week cycle, wherein the therapeutically effective amount of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is 150 mg daily for two weeks, followed by a two-week period without administration. In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is administered in a four-week cycle, wherein the therapeutically effective amount of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is 100 mg daily for two weeks, followed by a two-week period without administration. In some implementations, a therapeutically effective amount of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is administered in a four-week cycle, wherein the therapeutically effective amount of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is 50 mg daily for two weeks, followed by a two-week period without administration.

[0099] In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is administered in a four-week cycle, wherein the therapeutically effective amount of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is administered daily for three weeks, followed by a week without administration. In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is administered in a four-week cycle, wherein the therapeutically effective amount of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is 200 mg administered daily for three weeks, followed by a week without administration. In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is administered in a four-week cycle, wherein the therapeutically effective amount of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is 150 mg daily for three weeks, followed by a week without administration. In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is administered in a four-week cycle, wherein the therapeutically effective amount of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is 100 mg daily for three weeks, followed by a week without administration. In some implementations, a therapeutically effective amount of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is administered in a four-week cycle, wherein the therapeutically effective amount of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is 50 mg daily for three weeks, followed by a week without administration.

[0100] In some embodiments, the therapeutically effective dose of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is 25 mg once daily for two weeks, followed by 100 mg weekly. In some embodiments, the therapeutically effective dose of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is 50 mg once daily for two weeks, followed by 100 mg weekly. In some embodiments, the therapeutically effective dose of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is 75 mg once daily for two weeks, followed by 100 mg weekly. In some implementations, the therapeutically effective dose of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is 100 mg once daily for two weeks, followed by 100 mg once weekly.

[0101] In some embodiments, a therapeutically effective dose of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is administered daily for 15 days, followed by weekly administration for three weeks. In some embodiments, a therapeutically effective dose of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is 50 mg administered daily for 15 days, followed by weekly administration for three weeks. In some embodiments, a therapeutically effective dose of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is 100 mg administered daily for 15 days, followed by weekly administration for three weeks. In some implementations, the therapeutically effective dose of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is 50 mg once daily for 15 days, followed by 100 mg once weekly for three weeks.

[0102] In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is administered over at least one cycle. In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is administered over at least two cycles. In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is administered over at least three cycles. In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is administered over at least four cycles. In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is administered over at least five cycles. In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is administered over at least six cycles. In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is administered over at least seven cycles. In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is administered over at least eight cycles. In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is administered over at least nine cycles. In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is administered over at least ten cycles. In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is administered for at least 11 cycles. In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is administered for at least 12 cycles. In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is administered for at least 18 cycles. In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is administered for at least 24 cycles. In some implementations, a therapeutically effective amount of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is administered over at least 36 cycles.In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is administered over at least 48 cycles. In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is administered over at least 60 cycles.

[0103] In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is administered in one cycle. In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is administered in two cycles. In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is administered in three cycles. In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is administered in four cycles. In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is administered in five cycles. In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is administered over six cycles. In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is administered over seven cycles. In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is administered over eight cycles. In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is administered over nine cycles. In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is administered over ten cycles. In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is administered for 11 cycles. In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is administered for 12 cycles. In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is administered for 18 cycles. In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is administered for 24 cycles. In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is administered for 30 cycles. In some implementations, a therapeutically effective amount of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is administered in 36 cycles.In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is administered over 48 cycles. In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is administered over 60 cycles. In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is administered over 72 cycles. In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is administered over 84 cycles. In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is administered over 96 cycles. In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is administered over 108 cycles. In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is administered over 120 cycles.

[0104] In some embodiments, 100 mg of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is administered daily for two weeks, followed by a two-week period without administration. In some embodiments, 100 mg of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is administered daily for two weeks, followed by a two-week period without administration, and then 50 mg of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is administered daily for two weeks in four-week cycles, followed by a two-week period without administration, wherein the 50 mg of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is administered in at least two cycles. In some embodiments, 50 mg of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is administered over at least four cycles. In some embodiments, 50 mg of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is administered over at least eight cycles. In some embodiments, 50 mg of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is administered over at least twelve cycles. In some embodiments, 50 mg of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is administered over at least 24 cycles. In some embodiments, 50 mg of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is administered for at least 36 cycles. In some embodiments, 50 mg of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is administered for at least 48 cycles. In some embodiments, 50 mg of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is administered for at least 60 cycles.

[0105] In some embodiments, 50 mg of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is administered in one cycle. In some embodiments, 50 mg of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is administered in two cycles. In some embodiments, 50 mg of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is administered in three cycles. In some embodiments, 50 mg of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is administered in four cycles. In some embodiments, 50 mg of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is administered in five cycles. In some embodiments, 50 mg of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is administered over six cycles. In some embodiments, 50 mg of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is administered over seven cycles. In some embodiments, 50 mg of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is administered over eight cycles. In some embodiments, 50 mg of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is administered over nine cycles. In some embodiments, 50 mg of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is administered over ten cycles. In some embodiments, 50 mg of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is administered over 11 cycles. In some embodiments, 50 mg of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is administered over 12 cycles. In some embodiments, 50 mg of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is administered over 18 cycles. In some embodiments, 50 mg of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is administered over 24 cycles. In some embodiments, 50 mg of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is administered over 30 cycles. In some embodiments, 50 mg of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is administered over 36 cycles.In some embodiments, 50 mg of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is administered over 48 cycles. In some embodiments, 50 mg of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is administered over 60 cycles. In some embodiments, 50 mg of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is administered over 72 cycles. In some embodiments, 50 mg of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is administered over 84 cycles. In some embodiments, 50 mg of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is administered over 96 cycles. In some embodiments, 50 mg of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is administered over 108 cycles. In some embodiments, 50 mg of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is administered over 120 cycles.

[0106] Other implementations provided herein include combinations of one or more of the specific implementations described above.

[0107] disease cancer In some embodiments, the pharmaceutical formulations and methods disclosed herein can be used to treat cancer. In some embodiments, this document provides a pharmaceutical formulation and method for treating cancer in a subject of need, comprising administering to the subject of need a pharmaceutical formulation comprising a pharmaceutically effective amount of the (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide disclosed herein. In some embodiments, this document provides a pharmaceutical formulation for treating cancer in a subject of need, the treatment comprising administering to the subject of need a pharmaceutically effective amount of the (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide disclosed herein in the manufacture of a medicament for treating cancer. In some embodiments, this document provides the use of a pharmaceutical formulation comprising a pharmaceutically effective amount of the (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide disclosed herein in the manufacture of a medicament for treating cancer.

[0108] In some embodiments, cancer is mediated by activation of the transcriptional coactivator / Yes-associated protein transcriptional coactivator (TAZ / YAP) with a PDZ-binding motif. In some embodiments, cancer is mediated by regulating the interaction between YAP / TAZ and TEAD. In some embodiments, the cancer is characterized by a mutated Gα-protein. In some embodiments, the mutated Gα-protein is selected from G12, G13, Gq, G11, Gi, Go, and Gs. In some embodiments, the mutated Gα-protein is G12. In some embodiments, the mutated Gα-protein is G13. In some embodiments, the mutated Gα-protein is Gq. In some embodiments, the mutated Gα-protein is G11. In some embodiments, the mutated Gα-protein is Gi. In some embodiments, the mutated Gα-protein is Go. In some embodiments, the mutated Gα-protein is Gs.

[0109] In some implementations, cancer is a solid tumor. In some cases, cancer is a hematologic malignancy. In some cases, a solid tumor is a sarcoma or carcinoma. In some cases, a solid tumor is a sarcoma. In some cases, a solid tumor is carcinoma.

[0110] Exemplary sarcomas include, but are not limited to, small vesicular rhabdomyosarcoma, soft tissue alveolar sarcoma, ameloblastoma, angiosarcoma, chondrosarcoma, chordoma, clear cell sarcoma of soft tissue, dedifferentiated liposarcoma, desmoid fibroma, connective tissue proliferative small round cell tumor, embryonal rhabdomyosarcoma, epithelioid fibrosarcoma, epithelioid hemangioendothelioma, epithelioid sarcoma, sensory neuroblastoma, Ewing sarcoma, extrarenal rhabdomyosarcoma, extraosseous myxoid chondrosarcoma, extraosseous osteosarcoma, fibrosarcoma, giant cell tumor, hemangiopericytoma, infantile fibrosarcoma, inflammatory myofibroblastic tumor, Kaposi's sarcoma, bone leiomyosarcoma, and liposarcoma. Tumors, osteoliposarcoma, malignant fibrous histiocytoma (MFH), malignant mesenchymal tumor, malignant peripheral nerve sheath tumor, mesenchymal chondrosarcoma, myxoid fibrosarcoma, myxoid liposarcoma, myxoid inflammatory fibroblastic sarcoma, tumors with perivascular epithelioid cell differentiation, osteosarcoma, periosteal osteosarcoma, tumors with perivascular epithelioid cell differentiation, periosteal osteosarcoma, pleomorphic liposarcoma, pleomorphic rhabdomyosarcoma, PNET / extraosseous Ewing tumor, rhabdomyosarcoma, round cell liposarcoma, small cell osteosarcoma, solitary fibroma, synovial sarcoma, and capillary dilatational osteosarcoma.

[0111] Exemplary cancers include, but are not limited to, adenocarcinoma, squamous cell carcinoma, adenosquamous carcinoma, anaplastic carcinoma, large cell carcinoma, small cell carcinoma, anal cancer, appendix cancer, cholangiocarcinoma (i.e., bile duct epithelial carcinoma), bladder cancer, brain tumor, breast cancer, cervical cancer, colon cancer, cancer of unknown primary origin (CUP), esophageal cancer, eye cancer, fallopian tube cancer, gastrointestinal cancer, kidney cancer, liver cancer, lung cancer, medulloblastoma, melanoma, oral cancer, ovarian cancer, pancreatic cancer, parathyroid disease, penile cancer, pituitary adenoma, prostate cancer, rectal cancer, skin cancer, stomach cancer, testicular cancer, laryngeal cancer, thyroid cancer, uterine cancer, vaginal cancer, and vulvar cancer. In some cases, liver cancer is primary liver cancer.

[0112] In some cases, the cancer may be 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 sarcoma, head and neck cancer, prostate cancer, or meningioma. In some cases, the cancer may be 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 sarcoma, head and neck cancer, prostate cancer, or meningioma. In some cases, the cancer may be uveal melanoma, mesothelioma, esophageal cancer, or liver cancer. In some cases, the cancer may be uveal melanoma. In some cases, the cancer may be mesothelioma. In some cases, the cancer may be esophageal cancer. In some cases, the cancer may be liver cancer. In some cases, the cancer may be primary liver cancer.

[0113] In some cases, cancer is a hematologic malignancy. In some implementations, a hematologic malignancy is leukemia, lymphoma, myeloma, non-Hodgkin lymphoma, Hodgkin lymphoma, T-cell malignancy, or B-cell malignancy. In some cases, a hematologic malignancy is a T-cell malignancy. Exemplary T-cell malignancies include, but are not limited to, peripheral T-cell lymphoma (PTCL-NOS), anaplastic large cell lymphoma, angioimmunoblastic lymphoma, cutaneous T-cell lymphoma, adult T-cell leukemia / lymphoma (ATLL), blastic NK-cell lymphoma, enteropathy-type T-cell lymphoma, hepatosplenic γ-δ T-cell lymphoma, lymphoblastic lymphoma, nasal NK / T-cell lymphoma, and treatment-related T-cell lymphoma.

[0114] In some cases, hematologic 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 implementations, the 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 high-grade B-cell lymphoma, primary mediastinal B-cell lymphoma (PMBL), immunoblastic large cell lymphoma, precursor B-lymphoblastic lymphoma, B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma, splenic marginal zone lymphoma, plasma cell myeloma, plasmacytoma, mediastinal (thymic) large B-cell lymphoma, intravascular large B-cell lymphoma, primary exudative lymphoma, or lymphomatoid granulomatosis.

[0115] In some cases, cancer is recurrent or refractory cancer. In some implementations, recurrent or refractory cancer is a recurrent or refractory solid tumor. In some implementations, a recurrent or refractory solid tumor is a recurrent or refractory sarcoma or a recurrent or refractory carcinoma. In some implementations, recurrent or refractory cancer includes adenocarcinoma, squamous cell carcinoma, adenosquamous carcinoma, anaplastic carcinoma, large cell carcinoma, small cell carcinoma, anal cancer, appendix cancer, bile duct cancer (i.e., bile duct epithelial carcinoma), bladder cancer, brain tumor, breast cancer, cervical cancer, colon cancer, cancer of unknown origin (CUP), esophageal cancer, eye cancer, fallopian tube cancer, gastrointestinal cancer, kidney cancer, liver cancer, lung cancer, medulloblastoma, melanoma, oral cancer, ovarian cancer, pancreatic cancer, parathyroid disease, penile cancer, pituitary adenoma, prostate cancer, rectal cancer, skin cancer, stomach cancer, testicular cancer, laryngeal cancer, thyroid cancer, uterine cancer, vaginal cancer, and vulvar cancer.

[0116] In some cases, recurrent or refractory cancers are 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 sarcoma, head and neck cancer, prostate cancer, and meningioma. In some cases, recurrent or refractory cancers are 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 sarcoma, head and neck cancer, prostate cancer, or meningioma. In some cases, recurrent or refractory cancers are 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, it is recurrent or refractory mesothelioma. In some cases, it is recurrent or refractory esophageal cancer. In some cases, it is recurrent or refractory liver cancer. In some cases, it is recurrent or refractory primary liver cancer.

[0117] In some implementations, relapsed or refractory cancer is a relapsed or refractory hematologic malignancy. In some implementations, relapsed or refractory hematologic malignancies are relapsed or refractory leukemia, relapsed or refractory lymphoma, relapsed or refractory myeloma, relapsed or refractory non-Hodgkin lymphoma, relapsed or refractory Hodgkin lymphoma, relapsed or refractory T-cell malignancy, or relapsed or refractory B-cell malignancy. In some cases, relapsed or refractory hematologic malignancies are relapsed or refractory T-cell malignancies. In some cases, relapsed or refractory hematologic malignancies are relapsed or refractory B-cell malignancies, such as chronic lymphocytic leukemia (CLL), small lymphocytic leukemia (SLL), high-risk CLL, or non-CLL / SLL lymphoma. In some implementations, the 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 high-grade B-cell lymphoma, primary mediastinal B-cell lymphoma (PMBL), immunoblastic large cell lymphoma, precursor B-lymphoblastic lymphoma, B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma, splenic marginal zone lymphoma, plasma cell myeloma, plasmacytoma, mediastinal (thymic) large B-cell lymphoma, intravascular large B-cell lymphoma, primary exudative lymphoma, or lymphomatoid granulomatosis.

[0118] In some cases, cancer is metastatic cancer. In some cases, metastatic cancer is a metastatic solid tumor. In some cases, metastatic solid tumors are metastatic sarcomas or metastatic carcinomas. In some implementations, metastatic cancer includes adenocarcinoma, squamous cell carcinoma, adenosquamous carcinoma, anaplastic carcinoma, large cell carcinoma, small cell carcinoma, anal cancer, appendix cancer, bile duct cancer (i.e., bile duct epithelial carcinoma), bladder cancer, brain tumor, breast cancer, cervical cancer, colon cancer, cancer of unknown primary origin (CUP), esophageal cancer, eye cancer, fallopian tube cancer, gastrointestinal cancer, kidney cancer, liver cancer, lung cancer, medulloblastoma, melanoma, oral cancer, ovarian cancer, pancreatic cancer, parathyroid disease, penile cancer, pituitary adenoma, prostate cancer, rectal cancer, skin cancer, stomach cancer, testicular cancer, laryngeal cancer, thyroid cancer, uterine cancer, vaginal cancer, and vulvar cancer.

[0119] In some cases, the 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 sarcoma, head and neck cancer, prostate cancer, and meningioma. In some implementations, the 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 sarcoma, head and neck cancer, prostate cancer, or meningioma. In some implementations, the metastatic cancer is metastatic uveal melanoma, mesothelioma, esophageal cancer, or liver cancer. In some cases, the metastatic cancer is metastatic uveal melanoma. In some cases, the metastatic cancer is metastatic mesothelioma. In some cases, the metastatic cancer is metastatic esophageal cancer. In some cases, the metastatic cancer is metastatic liver cancer. In other cases, the metastatic cancer is metastatic primary liver cancer.

[0120] In some cases, the metastatic cancer is a metastatic hematologic malignancy. In some implementations, the metastatic hematologic 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, the metastatic hematologic malignancy is a metastatic T-cell malignancy. In some cases, the metastatic hematologic malignancy is a metastatic B-cell malignancy, such as chronic lymphocytic leukemia (CLL), small lymphocytic leukemia (SLL), high-risk CLL, or non-CLL / SLL lymphoma. In some implementations, the 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 high-grade B-cell lymphoma, primary mediastinal B-cell lymphoma (PMBL), immunoblastic large cell lymphoma, precursor B-lymphoblastic lymphoma, B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma, splenic marginal zone lymphoma, plasma cell myeloma, plasmacytoma, mediastinal (thymic) large B-cell lymphoma, intravascular large B-cell lymphoma, primary exudative lymphoma, or lymphomatoid granulomatosis.

[0121] In some cases, cancer is mesothelioma, hepatocellular carcinoma, meningioma, malignant peripheral nerve sheath tumor, Schwann cell tumor, lung cancer, bladder cancer, neurofibroma of the skin, prostate cancer, pancreatic cancer, glioblastoma, endometrial adenosquamous carcinoma, anaplastic thyroid carcinoma, gastric adenocarcinoma, esophageal adenocarcinoma, ovarian cancer, ovarian serous adenocarcinoma, melanoma, or breast cancer.

[0122] Non-cancer indications In some embodiments, the pharmaceutical formulations and methods disclosed herein can be used to treat polycystic kidney disease. In some embodiments, the pharmaceutical formulations and methods disclosed herein can be used to treat liver fibrosis. In some embodiments, this document provides a method for treating polycystic kidney disease in a subject of need, comprising administering to the subject of need a therapeutically effective amount of the disclosed compound or a pharmaceutically acceptable salt thereof. In some embodiments, this document provides a compound for treating polycystic kidney disease in a subject of need, the treatment comprising administering to the subject of need a therapeutically effective amount of the disclosed compound or a pharmaceutically acceptable salt thereof. In some embodiments, this document provides the use of the disclosed compound or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating polycystic kidney disease. In some embodiments, this document provides a method for treating liver fibrosis in a subject of need, comprising administering to the subject of need a therapeutically effective amount of the disclosed compound or a pharmaceutically acceptable salt thereof. In some embodiments, this document provides a compound for treating liver fibrosis in a subject of need, the treatment comprising administering to the subject of need a therapeutically effective amount of the disclosed compound or a pharmaceutically acceptable salt thereof. In some embodiments, this document provides the use of the disclosed compound or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating liver fibrosis.

[0123] Congenital diseases In some embodiments, the pharmaceutical formulations and methods disclosed herein can be used to treat congenital diseases. In some embodiments, this document provides a method of treating a congenital disease in a subject of need, comprising administering to the subject a therapeutically effective amount of the disclosed compound or a pharmaceutically acceptable salt thereof. In some embodiments, this document provides a compound for treating a congenital disease in a subject of need, the treatment comprising administering to the subject a therapeutically effective amount of the disclosed compound or a pharmaceutically acceptable salt thereof. In some embodiments, this document provides the use of the disclosed compound or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating a congenital disease. In some embodiments, the congenital disease is mediated by activation of a transcriptional coactivator / Yes-related protein transcriptional coactivator (TAZ / YAP) having a PDZ-binding motif. In some embodiments, the congenital disease is characterized by a mutated Gα-protein. In some embodiments, the mutated Gα-protein is selected from G12, G13, Gq, G11, Gi, Go, and Gs. In some embodiments, the mutated Gα-protein is G12. In some embodiments, the mutated Gα-protein is G13. In some embodiments, the mutated 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.

[0124] In some implementations, congenital diseases are the result of genetic abnormalities, intrauterine environment, morphogenesis-related errors, infections, epigenetic modifications on the parental lineage, or chromosomal abnormalities. Exemplary congenital diseases include, but are not limited to, Sturge-Weber syndrome, port-wine stain, Holt-Oram syndrome, abdominal wall defects, Becker muscular dystrophy (BMD), biotinylate deficiency, Charcot-Marie-Tooth (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 ataxia, galactosemia, hemoglobinopathies, 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 arthroophthalmos), spinal muscular atrophy, and trisomy 18. In some embodiments, the congenital disease is Sturge-Weber syndrome or port-wine stain. In some embodiments, the congenital disease is Sturge-Weber syndrome. In some implementations, the congenital condition is port-wine stain.

[0125] definition Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the claimed subject matter pertains. It should be understood that the foregoing general description and the following detailed description are merely illustrative and exemplary and do not limit any of the claimed subject matter.

[0126] In this application, unless otherwise expressly stated, the use of the singular form includes the plural form. It must be noted that, unless the context clearly indicates otherwise, the singular forms “a,” “an,” and “the” used in this specification and the appended claims include indicators of the plural form. For example, the term “a sample” includes multiple samples, including mixtures thereof. In this application, unless otherwise stated, the use of “or” means “and / or.” Furthermore, the use of the term “comprising” and other forms such as “include,” “includes,” and “included” does not constitute limitation.

[0127] As used herein, various embodiments may be presented in scope. It should be understood that scope descriptions are provided for convenience and brevity only and should not be construed as a strict limitation on the scope of this disclosure. Therefore, a scope description should be considered as having specifically disclosed all possible sub-scopes and individual values ​​within those scopes. For example, a description of a scope such as 1 to 6 should be considered as having specifically disclosed sub-scopes such as 1 to 3, 1 to 4, 1 to 5, 2 to 4, 2 to 6, 3 to 6, etc., and individual values ​​within those scopes, such as 1, 2, 3, 4, 5, and 6. This provision applies regardless of the width of the scope.

[0128] As used herein, in some implementations, ranges and quantities are expressed as “about” a specific value or range. “About” also includes precise quantities. Therefore, “about 5 µL” means both “about 5 µL” and “5 µL”. Typically, the term “about” includes quantities expected to be within experimental error.

[0129] The chapter titles used in this article are for organizational purposes only and should not be construed as limiting the topics described.

[0130] As used herein, the terms “individual,” “object,” and “patient” mean any mammal. In some embodiments, the mammal is a human. In some embodiments, the mammal is a non-human. None of these terms require or limit a situation characterized by care (e.g., long-term or intermittent) provided by a healthcare worker (e.g., a physician, registered nurse, nurse practitioner, physician assistant, caregiver, or hospice worker).

[0131] As used in this specification and the appended claims, unless otherwise stated, the following terms shall have the meanings described below.

[0132] The terms "optional" or "optionally" mean that the event or situation described below may or may not occur, and that the description includes both the possibility that the event or situation occurs and the possibility that it does not occur. For example, "optionally substituted aryl" means that the aryl group may or may not be substituted, and that the description includes both substituted and unsubstituted aryl groups.

[0133] As used herein, the terms “formulation” and “composition” are used interchangeably and refer to a mixture of two or more compounds, elements, or molecules. In some respects, the terms “formulation” and “composition” can be used to refer to a mixture of one or more active agents with a carrier or other excipient.

[0134] As used herein, the terms "treatment," "management," "relief," or "improvement" are used interchangeably. These terms refer to the means of achieving a beneficial or desired outcome (including, but not limited to, therapeutic and / or preventive benefits). A "therapeutic benefit" refers to the elimination or improvement of an underlying condition that is being treated. Alternatively, a therapeutic benefit may be achieved by the eradication or improvement of one or more physical symptoms associated with the underlying condition, resulting in an observed improvement in a patient, even if, in some embodiments, the patient is suffering from the underlying condition. For preventive benefits, in some embodiments, the composition is administered to a patient at risk of developing a specific disease, or to a patient who reports one or more physical symptoms of a disease, even if the disease has not yet been diagnosed.

[0135] As used herein, the term "effective amount" or "therapeutic effective amount" refers to an adequate amount of an administered agent or compound that will, to a certain extent, alleviate one or more symptoms of the disease or condition being treated. The result may be a reduction and / or alleviation of the signs, symptoms, or cause of the disease, or any other desired biological systemic change. For example, an "effective amount" for therapeutic use is the amount of a composition comprising a compound disclosed herein that clinically provides significant relief from disease. An appropriate "effective" amount in any individual case can be determined using techniques such as dose escalation studies.

[0136] The terms “active agent,” “active pharmaceutical agent,” “drug,” “active ingredient,” and their variants are used interchangeably to refer to an agent or substance that has measurable specific or selective physiological activity when applied to a subject in a significant or effective amount.

[0137] While not intended to be bound by any particular theory, certain solid forms are characterized by physical properties (e.g., stability, solubility, and dissolution rate) suitable for pharmaceutical and therapeutic dosage forms. Furthermore, while not wishing to be bound by any particular theory, certain solid forms are characterized by physical properties (e.g., density, compressibility, hardness, morphology, pyrolysis, viscosity, solubility, hygroscopicity, electrical properties, thermal behavior, solid-state reactivity, physical stability, and chemical stability) that influence specific processes (e.g., production, filtration, washing, drying, grinding, mixing, tableting, flowability, dissolution, formulation, and lyophilization), making certain solid forms suitable for the manufacture of solid dosage forms. These properties can be determined using specific analytical chemistry techniques, including solid-state analytical techniques as described herein and known in the art (e.g., X-ray diffraction, microscopy, spectroscopy, and thermal analysis).

[0138] Example The following illustrative examples represent implementations of the stimuli, systems, and methods described herein and are not intended to be limiting in any way.

[0139] This disclosure relates to (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide, as described in U.S. Patent No. 11,420,935, which is hereby incorporated herein by reference in its entirety.

[0140] Example 1. Preparation of pharmaceutical products Dosage form (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is supplied in 25 mg and 100 mg capsules. Hard gelatin capsules are filled with a dry granulation mixture of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide and excipients for solid oral dosage forms. 25 mg dose strength is No. 4 off-white capsules. 100 mg dose strength is No. 0 Swedish orange capsules.

[0141] formula The quantitative formulation and function of each component of the capsule are shown in Table 1.

[0142] Table 1

[0143] The quantitative formulation of the capsule shell is shown in Table 2. All excipients and components in the capsule shell comply with pharmacopoeia standards and are generally considered safe. The drug does not contain any novel excipients.

[0144] Table 2

[0145] Containers and capping types for dosage forms (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide 25 mg capsules are packaged in 50-count 75 cc white round HDPE bottles with sensor seal and child-safe caps. (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide 100 mg capsules are packaged in 25-count 75 cc white round HDPE bottles with sensor seal and child-safe caps.

[0146] Example 2 – Clinical Trial Figure 3 The experimental design of the Phase I clinical trial is shown, including the primary enrollment eligibility criteria, the dose escalation in Part 1, and the dose expansion in Part 2. Part 2 begins with the first patient recruited from the first expansion cohort, with a 4-week cycle of 100 mg / day for 2 weeks followed by a 2-week stop.

[0147] The baseline characteristics of cohorts 1-12 in Part 1 of the Phase 1 clinical trial are shown in Table 3.

[0148] Table 3

[0149] Table 4 shows detailed dosage and dosing schedule information for (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide used in Part 1 of the Phase 1 clinical trial.

[0150] Table 4

[0151] *Due to the more rapid onset of proteinuria, the dose was reduced by the safety review committee for all patients in the ongoing 200 mg cohort.

[0152] Overall, such as Figures 4A-4C As shown, (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide was administered orally and then exposed according to the dose ratio. Figure 4A In this study, when the dose level of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide was high, the mean C between day 1 and day 15 was [missing information]. max The differences in values ​​became even greater when the mean AUC was measured on day 1 and day 15 with different doses. last At the same time, similar patterns were also discovered. Figure 4BFurthermore, (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide has a very long half-life up to day 15, approximately seven times that of day 1. Figure 4C Even under intermittent dosing schedules, (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide provides continuous exposure.

[0153] Example 3 – Non-clinical pharmacology Main pharmacodynamics (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide exhibits a high-affinity direct interaction with TEAD proteins, significantly altering the melting temperature of purified recombinant TEAD1, TEAD2, TEAD3, and TEAD4 proteins in a thermal shift assay (TSA). (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide dose-dependently and potently inhibits YAP-TEAD transcriptional activity in a TEAD-responsive element-driven reporter gene assay, with a mean IC50 value of [missing value]. 50 The concentration was 4.9 nM, and it had no effect on reporter genes driven by the thymidine kinase (TK) promoter at micromolar concentrations.

[0154] In cell-based TEAD (via transfection overexpression) palmitoylation assays, (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide potently inhibited palmitoylation of TEAD1 and TEAD3 proteins, weakly inhibited palmitoylation of TEAD2, and did not inhibit palmitoylation of TEAD4. Acyl-PEGylation gel translocation (APEGS) assays in the human dermatoma cell line NCI-H2373 (which contains a homologous deletion of the NF2 gene) showed that (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide exhibited similar TEAD selectivity for endogenous TEAD proteins.

[0155] TEAD proteins are highly conserved among humans and other mammalian species due to sequence homology. Using a cell-based assay of endogenous TEAD palmitoylation, empirical evidence showed that (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide inhibits TEAD palmitoylation in rat, rhesus, cynomolgus, and canine cells with activity similar to that in human cells. These data support the selection of rats and cynomolgus monkeys for the toxicological evaluation of the safety of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide.

[0156] In some implementations, frequent genetic alterations of Hippo-YAP-TEAD pathway components are observed in malignant mesotheliomas, leading to constitutive YAP activation in more than 70% of malignant mesotheliomas. Importantly, YAP, in synergy with TEAD transcription factors, has been shown to be functionally essential for the proliferation and anchorage-independent growth of malignant mesothelioma cells. (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide was found to potently inhibit the proliferation of NF2-deficient (NCI-H226) and NF2-mutant (NCI-H2052, NCI-H2373) mesothelioma cell lines, but not NF2 wild-type mesothelioma cell lines (NCI-H28, NCI-H2452). Further testing of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide in a group of 26 mesothelioma cell lines demonstrated the selectivity of the compound, as it exhibited potent efficacy in NF2-deficient or NF2-mutant / Merlin-negative mesothelioma cell lines, but its activity decreased to 1 / 100 to 1 / 1000 in NF2-wild-type / Merlin-positive mesothelioma cells.

[0157] In some implementations, CTGF and CYR61 are among the most characteristic target genes of YAP-TEAD. (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide significantly downregulated the expression of pathway target genes CTGF and CYR61 in mouse NF2-deficient NCI-H226 tumors in a dose-dependent manner.

[0158] Several NF2-deficient mesothelioma and NSCLC cell lines, including NCI-H2052, NCI-H2373, NCI-H226, ACC-MESO-1, and LOU-NH9, were attempted to establish cell line-derived xenograft models (CDX) for in vivo evaluation of the antitumor efficacy of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthylamide. However, except for NCI-H226, no tumors grew well in mice. When the tumor reached approximately 107 mm... 3 At that time, treatment was initiated on NCI-H226 tumor-bearing mice.

[0159] In some embodiments, (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide significantly inhibited NCI-H226 tumor growth in mice in a dose-dependent manner. In the NCI-H226 CDX model, (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide exhibited strong antitumor activity when administered orally once daily at 3 mg / kg and 10 mg / kg (tumor growth inhibition rate (TGI) = 80%, p = 0.00257 and 90%, p = 1.95e-05, respectively). At 1 mg / kg daily, (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide resulted in partial inhibition of tumor growth (TGI = 32%). No adverse effects on body weight were observed during long-term treatment with (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide for 50 days of daily administration.

[0160] In some implementations, NCI-H2373 is a human dermatoma cell line containing a homozygous deletion of the NF2 gene. This cell line does not grow tumors well in mice. To obtain an in vivo model for a second working study to evaluate the antitumor efficacy of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide in long-term treatment, NCI-H2373 tumors were serially passaged in mice to obtain the NCI-H2373-Tu-P2 cell line, which was confirmed to be genetically associated with NCI-H2373 by short tandem repeat (STR) profiling. The efficacy of NCI-H2373 was then studied by implanting the NCI-H2373-Tu-P2 tumor fragment into mice, and when the tumor reached approximately 75–190 mm... 3 Treatment was initiated at that time. (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide resulted in dose-dependent tumor growth inhibition with no adverse effects on body weight.

[0161] When the average tumor size reaches approximately 152 mm 3 The in vivo efficacy of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide was also tested in an NF2-deficient NSCLC PDX model (LU-01-0407). Daily oral administration of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide at 30 mg / kg resulted in tumor growth inhibition (TGI=71%, p=0.015). No significant weight loss was observed during the 54-day study period.

[0162] In vivo efficacy studies were conducted using the NF2-deficient mesothelioma NCI-H226 CDX model to determine the effectiveness of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide with intermittent administration. This was performed when the tumor reached approximately 90-120 mm in size. 3 Different dose levels of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide were administered using different dosing schedules. Significant tumor growth inhibition and durable tumor response were observed with both 30 mg / kg, 7-day continuous / 14-day stop-dosing schedules and 30 mg / kg, 14-day continuous / 14-day stop-dosing schedules of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide intermittent dosing regimens (TGI = 92% and 95%, respectively). During the 93-day study period, both 30 mg / kg (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide intermittent dosing regimens inhibited tumor growth (TGI = 92% and 95%, respectively). Significant tumor growth inhibition and durable tumor response (TGI = 84% and 84%, respectively) were also observed in (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide administered at 10 mg / kg on 7-day continuous / 7-day stop-dose and 14-day continuous / 14-day stop-dose schedules. In contrast, the baseline group receiving 3 mg / kg daily began to show increased tumor growth after approximately 60 days (TGI eventually decreased to 72%). Furthermore, unlike tumor-bearing mice receiving (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide daily at 3 mg / kg, tumor-bearing mice receiving 10 mg / kg or 30 mg / kg with intermittent discontinuation of the drug continued to gain body weight, similar to tumor-bearing mice receiving the mediator. Therefore, intermittent administration of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide at higher doses appears to avoid the potential adverse effects of weight gain in long-term treatment of tumor-bearing mice while maintaining the effectiveness of tumor growth inhibition.

[0163] To identify other genes regulated by (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide for potential use as biomarkers for PD, formalin-fixed paraffin-embedded (FFPE) tumor samples collected 4 h after the third daily dose were analyzed using the NanoString nCounter gene expression assay (Canopy Biosciences) with a 768-gene human metabolic pathway assay. The gene with the largest fold change in (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide expression at 3 mg / kg and 10 mg / kg was IL6. The downregulation of IL6 expression was dose-dependent and correlated with 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 crucial for YAP-promoted IL-6 transcription. Therefore, in addition to the well-characterized pathway target genes CTGF and CYR61, IL-6 can also be used as a PD biomarker by measuring transcript levels before and after treatment. Furthermore, since IL-6 is a secreted cytokine, its circulating expression level can be monitored by ELISA analysis of plasma or serum samples.

[0164] Summarize (1) Indications and usage In one respect, (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide can be used to treat solid tumors with NF2 mutations or other YAP activation mechanisms, including malignant pleural mesothelioma.

[0165] (2) Dosage and administration (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide may be available in 25 or 100 mg capsules for oral administration to treat solid tumors with NF2 mutations or other YAP activation mechanisms, including malignant pleural mesothelioma.

[0166] Although preferred embodiments of the invention have been shown and described herein, it will be apparent to those skilled in the art that such embodiments are provided by way of example only. Many variations, modifications, and substitutions will now occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments of the invention described herein may be employed in the practice of the invention. The following claims are intended to define the scope of the invention and thereby cover the methods and structures within the scope of these claims and their equivalents.

Claims

1. A pharmaceutical preparation in solid dosage form, said pharmaceutical preparation comprising: (a) (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide, approximately 20% w / w to approximately 50% w / w; (b) A first filler of about 15% w / w to about 40% w / w; (c) A second filler of approximately 15% w / w to approximately 40% w / w; (d) A first lubricant of about 1% w / w to about 10% w / w; (e) A second lubricant of about 0.1% w / w to about 1% w / w; (f) a disintegrant of about 1% w / w to about 5% w / w; and (g) A flow aid of about 0.1% w / w to about 2% w / w.

2. The pharmaceutical formulation according to claim 1, wherein the pharmaceutical formulation comprises about 25% w / w to about 45% w / w of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide.

3. The pharmaceutical formulation according to claim 1 or 2, wherein the pharmaceutical formulation comprises about 30% w / w to about 40% w / w of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide.

4. The pharmaceutical formulation according to any one of claims 1 to 3, wherein the pharmaceutical formulation comprises about 37% w / w (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide.

5. The pharmaceutical preparation according to any one of claims 1 to 4, wherein the amount of (R)-N-(1-hydroxypropyl-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.

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

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

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

12. The pharmaceutical formulation according to any one of claims 1 to 11, wherein the pharmaceutical formulation comprises about 20% w / w to about 35% w / w of the first filler.

13. The pharmaceutical formulation according to any one of claims 1 to 12, wherein the pharmaceutical formulation comprises about 25% w / w to about 30% w / w of the first filler.

14. The pharmaceutical formulation according to any one of claims 1 to 13, wherein the pharmaceutical formulation comprises about 27% w / w of the first filler.

15. The pharmaceutical formulation according to any one of claims 1 to 14, wherein the pharmaceutical formulation comprises about 20% w / w to about 35% w / w of the second filler.

16. The pharmaceutical formulation according to any one of claims 1 to 15, wherein the pharmaceutical formulation comprises about 25% w / w to about 30% w / w of the second filler.

17. The pharmaceutical formulation according to any one of claims 1 to 16, wherein the pharmaceutical formulation comprises about 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 formulation according to any one of claims 1 to 20, wherein the second filler is mannitol.

22. The pharmaceutical formulation of claim 21, wherein the mannitol is mannitol 200 SD.

23. The pharmaceutical formulation according to any one of claims 1 to 22, wherein the pharmaceutical formulation comprises about 3% w / w to about 7% w / w of the first lubricant.

24. The pharmaceutical formulation according to any one of claims 1 to 23, wherein the pharmaceutical formulation comprises about 5% w / w of the first lubricant.

25. The pharmaceutical formulation according to any one of claims 1 to 24, wherein the pharmaceutical formulation comprises about 0.3% w / w to about 0.7% w / w of the second lubricant.

26. The pharmaceutical formulation according to any one of claims 1 to 25, wherein the pharmaceutical formulation comprises about 0.5% w / w of the second lubricant.

27. The pharmaceutical formulation of claim 26, wherein about 0.3% w / w of the second lubricant is intraparticle and about 0.2% w / w of the second lubricant is extraparticle.

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 lauryl ether sulfate, sodium dodecyl sulfate, magnesium stearate, stearic acid, sodium stearate, calcium stearate, ammonium dodecyl sulfate, and sodium stearate fumarate.

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

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

31. The pharmaceutical formulation according to any one of claims 1 to 30, wherein the pharmaceutical formulation comprises about 2% w / w to about 4% w / w of the disintegrant.

32. The pharmaceutical formulation according to any one of claims 1 to 31, wherein the pharmaceutical formulation comprises about 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, hydroxypropyl methylcellulose, crospovidone sodium carboxymethyl cellulose, carboxymethyl cellulose, hydroxypropyl cellulose and poly(vinyl alcohol).

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

35. The pharmaceutical formulation according to any one of claims 1 to 34, wherein the pharmaceutical formulation comprises about 0.5% w / w to about 1.5% w / w of the gliding agent.

36. The pharmaceutical formulation according to any one of claims 1 to 35, wherein the pharmaceutical formulation comprises about 1% w / w of the gliding agent.

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

38. The pharmaceutical formulation according to any one of claims 1 to 37, wherein the flow aid is silica.

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

40. A pharmaceutical preparation in a solid dosage form, said pharmaceutical preparation comprising: (a) Approximately 37% w / w of (R)-N-(1-hydroxypropyl-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 dodecyl sulfate; (e) Approximately 0.5% w / w magnesium stearate; (f) Approximately 3% w / w of croscarmellose sodium; and (g) Approximately 1% w / w of colloidal silica.

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

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

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

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

45. The pharmaceutical preparation according to any one of claims 1 to 44, wherein the solid dosage form is selected from powders, tablets, chewable disintegrating tablets, chewable tablets, capsules, capsule-shaped tablets, effervescent powders, rapidly disintegrating tablets, abuse prevention tablets, modulated-release tablets, modulated-release capsules, modulated-release capsules, and aqueous suspensions made from powders.

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 of claim 47, wherein the hard gelatin capsule comprises gelatin and titanium dioxide.

49. The pharmaceutical formulation according to claim 47 or claim 48, wherein the hard gelatin capsule further comprises FD&C Red 40 and FD&C Blue 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 capsule or tablet.

52. The pharmaceutical formulation according to any one of claims 1 to 51, wherein the solid dosage form is a dry granulation mixture.

53. A method for treating cancer in a subject of need, the method comprising administering to the subject a pharmaceutical preparation according to 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, anaplastic thyroid carcinoma, gastric adenocarcinoma, esophageal adenocarcinoma, ovarian cancer, ovarian serous adenocarcinoma, melanoma, or breast cancer.

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

56. The method of claim 55, wherein the therapeutically effective amount of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is administered in the form of an oral formulation.

57. The method according to claim 55 or claim 56, wherein the therapeutically effective amount of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide 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-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is at least 25 mg daily.

59. The method according to any one of claims 55 to 58, wherein the therapeutically effective amount of (R)-N-(1-hydroxypropyl-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 daily.

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

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

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

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

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

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

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

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

68. The method according to any one of claims 55 to 67, wherein the therapeutically effective amount of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide 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-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide 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-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide 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-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is applied in a three-week cycle, wherein the therapeutically effective amount is applied daily for one week and then not applied for two weeks.

72. The method according to any one of claims 55 to 61, wherein the therapeutically effective amount of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is administered in a three-week cycle, wherein the therapeutically effective amount is administered daily for one week and then not administered for two weeks, wherein the therapeutically effective amount of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide 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-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is applied in a four-week cycle, wherein the therapeutically effective amount of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is applied daily for one week, and then not applied for the next three weeks.

74. The method according to any one of claims 55 to 61, wherein the therapeutically effective amount of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is administered in a four-week cycle, wherein the therapeutically effective amount of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is administered daily for one week, followed by a three-week period without administration, wherein the therapeutically effective amount of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is administered in the form of 150 mg.

75. The method according to any one of claims 55 to 67, wherein the therapeutically effective amount of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is administered in a three-week cycle, wherein the therapeutically effective amount of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is administered daily for two weeks, followed by a week without administration.

76. The method according to any one of claims 55 to 61, wherein the therapeutically effective amount of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is administered in a three-week cycle, wherein the therapeutically effective amount of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is administered daily for two weeks, followed by a week without administration, wherein the therapeutically effective amount of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide 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-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is applied in a four-week cycle, wherein the therapeutically effective amount of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is applied daily for two weeks, followed by a two-week period without application.

78. The method according to any one of claims 55 to 61, wherein the therapeutically effective amount of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is administered in a four-week cycle, wherein the therapeutically effective amount of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is administered daily for two weeks, followed by a two-week period without administration, wherein the therapeutically effective amount of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide 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-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is administered in a four-week cycle, wherein the therapeutically effective amount of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is administered daily for two weeks, followed by a two-week period without administration, wherein the therapeutically effective amount of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide 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-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide 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-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is applied daily for 15 days, and then weekly for three weeks.

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

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

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

85. A method for treating cancer in a subject of need, the method comprising administering 100 mg of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide to the subject of need daily for two weeks, followed by a two-week period without administration of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide.

86. The method of claim 85, further comprising administering 50 mg of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide daily to the subject of need for two weeks at a cycle length of four weeks, followed by a two-week period without administration, wherein the 50 mg of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is administered in at least two cycles.

87. A method for treating cancer in a subject of need, the method comprising administering 100 mg of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide daily to the subject of need for two weeks, followed by a two-week period without administration of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide, followed by a two-week period without administration of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide, wherein the 50 mg of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is administered to the subject of need in at least two cycles.

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

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

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

91. The method according to claim 86 or 87, wherein the 50 mg of (R)-N-(1-hydroxypropyl-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is administered in at least twenty-four 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, anaplastic thyroid carcinoma, gastric adenocarcinoma, esophageal adenocarcinoma, ovarian cancer, ovarian serous adenocarcinoma, melanoma, or breast cancer.

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