Synthesis of HIPPO-YAP path modulators and their polymorphs

Abstract

The preparation of Hippo-YAP pathway modulators and chemical intermediates used in the synthesis process is described herein. Polymorphs of the Hippo-YAP pathway modulators are also described herein.

Description

[Technical Field]

[0001] cross reference This application claims the benefit of U.S. Provisional Application No. 63 / 492,440, filed on 27 March 2023, which is incorporated herein by reference in its entirety. [Background technology]

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

[0003] The preparation of the Hippo-YAP pathway modulator and chemical intermediates used in the synthesis process is described herein. The process for the synthesis of the Hippo-YAP pathway modulator is described herein, and the Hippo-YAP pathway modulator is (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide) (compound (I)).

[0004] In one embodiment, (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide (compound (I))

[0005] [ka] A process of synthesizing, Compound D

[0006]

Chem.

[0007] Some embodiments relate to Compound D

[0008]

Chem.

[0009]

Chem.

[0010] Some embodiments relate to Compound C

[0011]

Chem.

[0012]

Chem.

[0013] Some embodiments relate to Compound B

[0014]

Chemical formula

[0015]

Chemical formula

[0016]

Chemical formula

[0017] [Chemical Formula] are further contacted. In some embodiments, the solvent is selected from ethyl acetate, dichloromethane, tetrahydrofuran, diethyl ether, dimethylformamide, dimethyl sulfoxide, methanol, ethanol, acetone, acetonitrile, 1,4-dioxane, hexane, and methyl tert-butyl ether. In some embodiments, the solvent is 1,4-dioxane.

[0018] In another aspect, a crystalline form of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide or a solvate thereof is described herein.

[0019] One embodiment is a crystalline form of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide having the following characteristics, (a) an X-ray powder diffraction (XRPD) pattern substantially the same as that shown in Figure 2, (b) An X-ray powder diffraction (XRPD) pattern having characteristic peaks at 8.1° 2-θ, 16.2° 2-θ, 18.6° 2-θ, 18.8° 2-θ, 19.4° 2-θ, 20.0° 2-θ, 23.9° 2-θ, 24.2° 2-θ, and 28.4° 2-θ, (c) A DSC thermogram substantially similar to that shown in Figure 3, (d) A DSC thermogram having an endotherm starting at about 140°C, (e) A thermogravimetric analysis (TGA) substantially similar to that shown in Figure 4, or (f) A combination of these is a crystalline form, Form 1, having at least one of these.

[0020] Some embodiments are crystalline forms of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide having an X-ray powder diffraction (XRPD) pattern substantially the same as that shown in Figure 2.

[0021] Some embodiments are crystalline forms of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide having an X-ray powder diffraction (XRPD) pattern having characteristic peaks at 8.1° 2-θ, 16.2° 2-θ, 18.6° 2-θ, 18.8° 2-θ, 19.4° 2-θ, 20.0° 2-θ, 23.9° 2-θ, 24.2° 2-θ, and 28.4° 2-θ.

[0022] Some embodiments are crystalline (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide, Form 1, having a DSC thermogram substantially similar to that shown in Figure 3.

[0023] Some embodiments are crystalline (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide, Form 1, having a DSC thermogram having an endotherm starting at about 140°C.

[0024] Some embodiments are Form 1 of crystalline (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide having a thermogravimetric analysis (TGA) substantially similar to that shown in FIG. 4.

[0025] Some embodiments are Form 1 of crystalline (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide, characterized by having the following properties: (a) an X-ray powder diffraction (XRPD) pattern substantially the same as that shown in FIG. 2; (b) an X-ray powder diffraction (XRPD) pattern having characteristic peaks at 8.1° 2-θ, 16.2° 2-θ, 18.6° 2-θ, 18.8° 2-θ, 19.4° 2-θ, 20.0° 2-θ, 23.9° 2-θ, 24.2° 2-θ, and 28.4° 2-θ; (c) a DSC thermogram substantially similar to that shown in FIG. 3; (d) a DSC thermogram having an endotherm starting at about 140° C; and (e) a thermogravimetric analysis (TGA) substantially similar to that shown in FIG. 4.

[0026] Some embodiments are Form 1 of crystalline (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide obtained from ethanol.

[0027] Some embodiments are pharmaceutical compositions comprising Form No. 1 of crystalline (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide and a pharmaceutically acceptable excipient.

[0028] Some embodiments are methods of treating cancer in a subject that requires treatment of cancer, the method comprising administering to the subject in need thereof a therapeutically effective amount of crystalline (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide, Form 1. Some embodiments are methods of treating cancer in a subject that requires treatment of cancer, the method comprising administering to the subject in need thereof a therapeutically effective amount of crystalline (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide, wherein the cancer is selected from mesothelioma, hepatocellular carcinoma, meningioma, malignant peripheral nerve sheath tumor, schwannoma, lung cancer, bladder cancer, dermatofibrosarcoma protuberans, prostate cancer, pancreatic cancer, glioblastoma, endometrial adenocarcinoma, anaplastic thyroid carcinoma, gastric adenocarcinoma, esophageal adenocarcinoma, ovarian cancer, ovarian serous adenocarcinoma, melanoma, and breast cancer.

[0029] Some embodiments are methods of treating polycystic kidney or hepatic fibrosis in a subject that requires treatment of polycystic kidney or hepatic fibrosis, the method comprising administering to the subject in need thereof a therapeutically effective amount of crystalline (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide, Form 1.

[0030] Incorporation by reference All publications, patents, and patent applications mentioned herein are hereby incorporated by reference as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. BRIEF DESCRIPTION OF THE DRAWINGS

[0031] Various aspects of the disclosure are described in detail in the appended claims. A better understanding of the features and advantages of the disclosure will be obtained by reference to the following detailed description that describes exemplary embodiments in which the principles of the disclosure are utilized and the accompanying drawings. [Figure 1]Figure 1 shows a schematic diagram of the Hippo signaling network. The Hippo pathway components shaded in dark gray indicate the components that inhibit YAP / TAZ activity. The Hippo pathway components shaded in light gray indicate the components that promote YAP / TAZ activity. The pointed arrows and blunt arrows indicate activation interactions and inhibitory interactions, respectively. Abbreviations: α-CAT (α-catenin), AJUB (Ajuba), AMOT (angiomotin), β-TRCP (β-transducin repeat-containing protein), CK1 (casein kinase 1), CRB (crumbs), E-CAD (E-cadherin), EX (expansion), GPCR (G protein-coupled receptor), HIPK (homeodomain-interacting protein kinase), KIBRA (kidney brain), LATS (large tumor suppressor), LGL (lethal giant larvae), MASK (multiankyrin single KH), MER (Merlin), MOB (Mps1 binder), MST (mammalian sterile 20-like), PALS (protein associated with Lin-7), 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 (1000 and 1 amino acid protein), TAZ (transcriptional activator with PDZ-binding motif), TEAD (TEA domain protein), VGL4 (Vestigial-like 4), WBP2 (WW domain-binding protein 2), YAP (Yes-associated protein), ZO (zonula occludens), ZYX (zyxin). [Figure 2] Figure 2 shows the X-ray powder diffraction (XRPD) pattern of crystalline (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide) (Compound (I)), Form 1. [Figure 3] Figure 3 shows the differential scanning calorimetry (DSC) thermogram of crystalline (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide) (Compound (I)), Form 1. [Figure 4]Figure 4 shows the thermogravimetric analysis (TGA) thermogram of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide) (Compound (I)), Form 1. [Figure 5] Figure 5 shows the dynamic vapor sorption (DVS) analysis of crystalline (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide) (Compound (I)), Form 1. MODE FOR CARRYING OUT THE INVENTION

[0032] Hippo Signaling Network The Hippo signaling network (also known as the Salvador / Warts / Hippo (SWH) pathway) is a master regulator of cell proliferation, cell death, and cell differentiation. In some embodiments, the main function of the Hippo signaling pathway 7 is to negatively regulate the transcriptional coactivator Yes-associated protein (YAP) and its paralog, the transcriptional coactivator with PDZ-binding motif (TAZ; also known as WWTR1) (Figure 1). The Hippo kinase cascade phosphorylates and inhibits YAP / TAZ by promoting its cytoplasmic retention and degradation, thereby inhibiting the growth-promoting functions regulated under YAP / TAZ control. In the non-phosphorylated / dephosphorylated state, YAP, also known as YAP1 or YAP65, is transported to the nucleus together with TAZ, where it interacts with the TEAD family of transcription factors to upregulate genes that promote proliferation and migration and inhibit apoptosis. In some examples, the unregulated upregulation of these genes involved in proliferation, migration, and anti-apoptosis leads to cancer development. In some examples, overexpression of YAP / TAZ is associated with cancer. Compound (I) disclosed herein is an inhibitor of one or more proteins included in or related to the Hippo pathway shown in Figure 1.

[0033] Compound In some embodiments, the Hippo-YAP pathway modulators described herein are (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide (Compound (I)) or its co-crystals. Compound (I) has the following structure.

[0034]

Chemical formula

[0035] In some embodiments, the intermediate in the synthesis of Compound (I) is

[0036]

Chemical formula

[0037] Further forms of the compound Isomers In some embodiments, the compounds described herein exist as geometric isomers. In some embodiments, the compounds described herein have one or more double bonds. The compounds presented herein include all cis, trans, syn, anti, entgegen(I) and tuzamen(Z) isomers, as well as their corresponding mixtures. In some situations, the compounds exist as tautomers. The compounds described herein include all possible tautomers in the formulas described herein. In some situations, the compounds described herein have one or more chiral centers, each center existing in either an R or S configuration. The compounds described herein include all diastereomer, enantiomer, and epimer forms, as well as their corresponding mixtures. In further embodiments of the compounds and methods provided herein, mixtures of enantiomers and / or diastereoisomers resulting from a single preparation step, combination, or interconversion are useful for the applications described herein. In some embodiments, the compounds described herein are prepared as their individual stereoisomers by reacting a racemic mixture of the compounds with an optically active resolving agent to form pairs of diastereoisomer compounds, separating the diastereomers, and recovering the optically pure enantiomers. In some embodiments, dissociable complexes (e.g., crystalline diastereomer salts) are disclosed herein. In some embodiments, the diastereomers have different physical properties (e.g., melting point, boiling point, solubility, reactivity, etc.) and are separated by utilizing these differences. In some embodiments, the diastereomers are separated by chiral chromatography or, preferably, by separation / resolving techniques based on differences in solubility. In some embodiments, the optically pure enantiomers are then recovered together with the resolving agent by any practical means that do not result in racemization.

[0038] labeled compound In some embodiments, the compounds described herein exist in isotopically labeled forms. In some embodiments, the methods disclosed herein include methods of treating a disease by administering such isotopically labeled compounds. In some embodiments, the methods disclosed herein include methods of treating a disease by administering such isotopically labeled compounds as a pharmaceutical composition. Thus, in some embodiments, the compounds disclosed herein include isotopically labeled compounds, which are identical to those listed herein except that one or more atoms are replaced by atoms having an atomic mass or mass number different from the atomic mass or mass number normally found in nature. In some embodiments, examples of isotopes incorporated into the compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, for example, 17 H, 3 H, 13 C, 14 C, 15 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F, and 36 Cl. Compounds described herein containing the above isotopes and / or other isotopes of other atoms, as well as their metabolites, pharmaceutically acceptable salts, esters, prodrugs, solvates, hydrates, or derivatives are within the scope of the present disclosure. Certain isotopically labeled compounds, for example, 3 H and 14 C, etc., incorporated with radioactive isotopes are useful in drug and / or substrate tissue distribution assays. Tritiation, i.e., 3 H and carbon-14, i.e., 14 C isotopes are particularly preferred due to the ease of their preparation and detectability. Further, deuterium, i.e., 2Substitution with heavy isotopes such as 1H results in certain therapeutic benefits arising from greater metabolic stability, such as an increased in vivo half-life or a reduced required dose. In some embodiments, isotope-labeled compounds, their pharmaceutically acceptable salts, esters, prodrugs, solvates, hydrates, or derivatives are prepared by any suitable method.

[0039] Pharmaceutically acceptable salts In some embodiments, the compounds described herein exist as pharmaceutically acceptable salts thereof. In some embodiments, the methods disclosed herein include methods for treating a disease by administering such pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods for treating a disease by administering such pharmaceutically acceptable salts as a pharmaceutical composition.

[0040] In some embodiments, the compounds described herein have an acidic or basic group and therefore react with several inorganic or organic bases, as well as either inorganic or organic acids, to form pharmaceutically acceptable salts. In some embodiments, these salts are prepared either in situ during the final isolation and purification of the compounds of this disclosure, or by separately reacting the purified compound in its free form with a suitable acid or base and isolating the salts thus formed.

[0041] solvate In some embodiments, the compounds described herein exist as solvates. This disclosure provides methods for treating diseases by administering such solvates. This disclosure further provides methods for treating diseases by administering such solvates as pharmaceutical compositions.

[0042] Solvates contain either stoichiometric or non-stoichiometric amounts of solvent and, in some embodiments, are formed during a crystallization process using a pharmaceutically acceptable solvent such as water or ethanol. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. In some embodiments, solvates of the compounds described herein are conveniently prepared or formed during the processes described herein. As just one example, hydrates of the compounds described herein are conveniently prepared by recrystallization from aqueous / organic solvent mixtures using organic solvents, but not limited to dioxane, tetrahydrofuran, or methanol. In some embodiments, the compounds provided herein exist in both unsolvated and solvated forms. Generally, the solvated form is considered equivalent to the unsolvated form for the purposes of the compounds and methods provided herein.

[0043] Preparation of compound (I) The compounds used in the reactions described herein are prepared starting from commercially available chemicals and / or compounds described in the chemical literature, according to organic synthesis techniques known to those skilled in the art."Commercially available chemicals" include Acros Organics (Pittsburgh, Pennsylvania), Aldrich Chemical (Milwaukee, Wisconsin, including Sigma Chemical and Fluka), Apin Chemicals Ltd. (Milton Park, UK), Avocado Research (Lancashire, UK), BDH Inc. (Toronto, Canada), Bionet (Cornwall, UK), Chemservice Inc. (Westchester, Pennsylvania), Crescent Chemical Co. (Hauppauge, New York), Eastman Organic Chemicals, Eastman Kodak Company (Rochester, New York), Fisher Scientific Co. (Pittsburgh, Pennsylvania), Fisons Chemicals (Leicestershire, UK), Frontier Scientific (Logan, Utah), ICN Biomedicals, Inc. (Costa Mesa, California), Key Organics (Cornwall, UK), Lancaster Synthesis (Wyndham, New Hampshire), and Maybridge Chemical Co. Ltd. (UK). It is obtained from standard commercial sources including Cornwall, Parish Chemical Co. (Olem, Utah), Pfaltz & Bauer, Inc. (Waterbury, Connecticut), Polyorganix (Houston, Texas), Pierce Chemical Co. (Rockford, Illinois), Riedel de Haen AG (Hannover, Germany), Spectrum Quality Product, Inc. (New Brunswick, New Jersey), TCI America (Portland, Oregon), Trans World Chemicals, Inc. (Rockville, Maryland), and Wako Chemicals USA, Inc. (Richmond, Virginia).

[0044] Methods known to those skilled in the art can be identified through various reference books and databases. Suitable references and papers that detail the synthesis of reactants useful in the preparation of the compounds described herein, or provide references to papers describing the preparations, include, for example, “Synthetic Organic Chemistry”, John Wiley & Sons, Inc., New York; SRSandler et al., “Organic Functional Group Preparations”, 2nd Ed., Academic Press, New York, 1983; HOHouse, “Modern Synthetic Reactions”, 2nd Ed., WABenjamin, Inc. Menlo Park, Calif. 1972; TLGilchrist, “Heterocyclic Chemistry”, 2nd Ed., John Wiley & Sons, New York, 1992; J. March, “Advanced Organic Chemistry: Reactions, Mechanisms and Structure”, 4th Ed., Wiley Interscience, New York, 1992. Further suitable references and papers that detail the synthesis of reactants useful in the preparation of the compounds described herein, or provide references to papers describing the preparation, include, for example, Fuhrhop, J. and Penzlin G., “Organic Synthesis: Concepts, Methods, Starting Materials”, Second, Revised and Enlarged Edition (1994), John Wiley & Sons, ISBN: 3 527-29074-5; Hoffman, RV, “Organic Chemistry, An Intermediate Text” (1996), Oxford University Press, ISBN 0-19-509618-5; and Larock, RC.“Comprehensive Organic Transformations: A Guide to Functional Group Preparations” 2nd Edition (1999) Wiley-VCH, ISBN: 0-471-19031-4; March, J. “Advanced Organic Chemistry: Reactions, Mechanisms, and Structure” 4th Edition (1992) John Wiley & Sons, ISBN: 0-471-60180-2; Otera, J. (editor) “Modern Carbonyl Chemistry” (2000) Wiley-VCH, ISBN: 3-527-29871-1; Patai, S. “Patai’s 1992 Guide to the Chemistry of Functional Groups” (1992) Interscience ISBN: 0-471-93022-9; Solomons, T.W.G. “Organic Chemistry” 7th Edition (2000) John Wiley & Sons, ISBN: 0-471-19095-0; Stowell, J.C., “Intermediate Organic Chemistry” 2nd Edition (1993) Wiley-Interscience, ISBN: 0-471-57456-2; “Industrial Organic Chemicals: Starting Materials and Intermediates: An Ullmann’s Encyclopedia” (1999) John Wiley & Sons, ISBN: 3-527-29645-X, in 8 volumes; “Organic Reactions” (1942-2000) John Wiley & Sons, in over 55 volumes; and “Chemistry of Functional Groups” John Wiley & Sons, in 73 volumes.

[0045] In some cases, specific and similar reactants are identified through an index of known chemicals prepared by the American Chemical Society's Chemical Abstract Service, which is available in most public and university libraries, as well as through online databases (for more details, contact the American Chemical Society, Washington, D.C., Washington). Chemicals that are known but not commercially available in catalogs are prepared by custom chemical synthesis houses, and many standard chemical supply houses (e.g., those listed above) offer custom synthesis services. A reference for the preparation and selection of pharmaceutical salts of the compounds described herein is PHStahl & CGWermuth, “Handbook of Pharmaceutical Salts”, Verlag Helvetica Chimica Acta, Zurich, 2002.

[0046] In some embodiments, the compounds disclosed herein are prepared as described in the Examples section.

[0047] In some embodiments, (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide) (compound (I))

[0048] [ka] A process for synthesizing compound D

[0049] [ka] A process comprising contacting with (R)-2-aminopropan-1-ol in the presence of a solvent is described herein. It is described. In some embodiments, the solvent is 2-methyl-THF.

[0050] Some embodiments of compound D

[0051] [ka] However, compound C

[0052] [ka] This is a process for synthesizing (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide (compound (I)) by a process comprising contacting with a chlorinating agent in the presence of a solvent. In some embodiments, the chlorinating agent is thionyl chloride. In some embodiments, the solvent is 2-methyl-THF.

[0053] Some embodiments of compound C

[0054] [ka] However, compound B

[0055] [ka] This is a process for synthesizing (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide (compound (I)), which is prepared by a process comprising contacting with a base in the presence of a solvent. In some embodiments, the base is an inorganic base. In some embodiments, the base is selected from NaOH, KOH, and CsOH. In some embodiments, the base is NaOH. In some embodiments, the base is KOH. In some embodiments, the base is CsOH. In some embodiments, the base is CS2CO3. In some embodiments, the base is K2CO3. In some embodiments, the base is Na2CO3. In some embodiments, the base is NaHCO3. In some embodiments, the solvent is a mixture of 2-methyl-THF and water.

[0056] Some embodiments of compound B

[0057] [ka] but,

[0058] [ka] In the presence of a catalyst, a base, and a solvent,

[0059] [ka] This is a process for synthesizing (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide (compound (I)) prepared by a process including contact with . In some embodiments, the catalyst is CuI. In some embodiments, the catalyst is N,N-dimethylglycine. In some embodiments, the base is an organic base. In some embodiments, the organic base is selected from piperidine, 1,8-diazabicyclo[5.4.0]undeca-7-ene, N,N-diisopropylethylamine, and triethylamine. In some embodiments, the organic base is piperidine. In some embodiments, the organic base is 1,8-diazabicyclo[5.4.0]undeca-7-ene. In some embodiments, the organic base is N,N-diisopropylethylamine. In some embodiments, the organic base is triethylamine. In some embodiments, the base is an inorganic base. In some embodiments, the inorganic base is selected from NaOH, KOH, CsOH, Cs2CO3, K2CO3, Na2CO3, or NaHCO3. In some embodiments, the inorganic base is K2CO3. In some embodiments, the base is NaOH. In some embodiments, the base is KOH. In some embodiments, the base is CsOH. In some embodiments, the base is CS2CO3. In some embodiments, the base is K2CO3. In some embodiments, the base is Na2CO3. In some embodiments, the base is NaHCO3. In some embodiments, compounds A1 and A2 are,

[0060] [ka] Further contact occurs. In some embodiments, the solvent is selected from ethyl acetate, dichloromethane, tetrahydrofuran, diethyl ether, dimethylformamide, dimethyl sulfoxide, methanol, ethanol, acetone, acetonitrile, 1,4-dioxane, hexane, and methyl tert-butyl ether. In some embodiments, the solvent is 1,4-dioxane. In some embodiments, the solvent is ethyl acetate. In some embodiments, the solvent is dichloromethane. In some embodiments, the solvent is tetrahydrofuran. In some embodiments, the solvent is diethyl ether. In some embodiments, the solvent is dimethylformamide. In some embodiments, the solvent is dimethyl sulfoxide. In some embodiments, the solvent is methanol. In some embodiments, the solvent is ethanol. In some embodiments, the solvent is acetone. In some embodiments, the solvent is acetonitrile. In some embodiments, the solvent is hexane. In some embodiments, the solvent is methyl tert-butyl ether.

[0061] Some embodiments of compound B

[0062] [ka] but,

[0063] [ka] This is done in the presence of a catalyst, a phosphine ligand, a base, and a solvent.

[0064] [ka] This is a process for synthesizing (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide (compound (I)) prepared by a process including contact with . In some embodiments, the catalyst is an allyl palladium (II) chloride dimer. In some embodiments, the phosphine ligand is RockPhos. In some embodiments, the base is an inorganic base. In some embodiments, the base is CS2CO3. In some embodiments, the solvent is selected from ethyl acetate, dichloromethane, tetrahydrofuran, diethyl ether, dimethylformamide, dimethyl sulfoxide, methanol, ethanol, acetone, acetonitrile, 1,4-dioxane, hexane, and methyl tert-butyl ether.

[0065] In some embodiments of the process for synthesizing (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide (compound (I)) as described herein, compound (I) is synthesized substantially pure. In certain embodiments, the substantially pure compound (I) is substantially free of impurities. In certain embodiments, the purity of the substantially pure compound (I) is about 95% or higher, about 96% or higher, about 97% or higher, about 98% or higher, about 98.5% or higher, about 99% or higher, about 99.5% or higher, or about 99.8% or higher.

[0066] In some embodiments, the impurity in the synthesis process described herein is bis((R)-2-(5-(4-(trifluoromethyl)phenoxy)-2-naphthamidopropyl)sulfite having the following structure:

[0067] [ka] In certain embodiments, the substantially pure compound (I) is substantially free of bis((R)-2-(5-(4-(trifluoromethyl)phenoxy)-2-naphthamido)propyl) sulfite. In certain embodiments, the substantially pure compound (I) contains less than 0.5% of bis((R)-2-(5-(4-(trifluoromethyl)phenoxy)-2-naphthamido)propyl) sulfite. In certain embodiments, the substantially pure compound (I) contains less than 0.4% of bis((R)-2-(5-(4-(trifluoromethyl)phenoxy)-2-naphthamido)propyl) sulfite. In certain embodiments, the substantially pure compound (I) contains less than 0.3% of bis((R)-2-(5-(4-(trifluoromethyl)phenoxy)-2-naphthamido)propyl) sulfite. In certain embodiments, substantially pure compound (I) contains less than 0.2% bis((R)-2-(5-(4-(trifluoromethyl)phenoxy)-2-naphthamido)propyl) sulfite. In certain embodiments, substantially pure compound (I) contains less than 0.15% bis((R)-2-(5-(4-(trifluoromethyl)phenoxy)-2-naphthamido)propyl) sulfite. In certain embodiments, substantially pure compound (I) contains less than 0.1% bis((R)-2-(5-(4-(trifluoromethyl)phenoxy)-2-naphthamido)propyl) sulfite. In certain embodiments, substantially pure compound (I) contains less than 0.05% bis((R)-2-(5-(4-(trifluoromethyl)phenoxy)-2-naphthamido)propyl) sulfite.

[0068] In some embodiments, the impurity in the synthesis process described herein is 5-(4-(trifluoromethyl)phenoxy)-2-naphthoic acid (protonated compound C) having the following structure.

[0069] [ka] In certain embodiments, substantially pure compound (I) is substantially free of 5-(4-(trifluoromethyl)phenoxy)-2-naphthoic acid. In certain embodiments, substantially pure compound (I) contains less than 0.5% of 5-(4-(trifluoromethyl)phenoxy)-2-naphthoic acid. In certain embodiments, substantially pure compound (I) contains less than 0.4% of 5-(4-(trifluoromethyl)phenoxy)-2-naphthoic acid. In certain embodiments, substantially pure compound (I) contains less than 0.3% of 5-(4-(trifluoromethyl)phenoxy)-2-naphthoic acid. In certain embodiments, substantially pure compound (I) contains less than 0.2% of 5-(4-(trifluoromethyl)phenoxy)-2-naphthoic acid. In certain embodiments, substantially pure compound (I) contains less than 0.15% of 5-(4-(trifluoromethyl)phenoxy)-2-naphthoic acid. In certain embodiments, the substantially pure compound (I) contains less than 0.1% 5-(4-(trifluoromethyl)phenoxy)-2-naphthoic acid. In certain embodiments, the substantially pure compound (I) contains less than 0.05% 5-(4-(trifluoromethyl)phenoxy)-2-naphthoic acid.

[0070] Crystal morphology The identification and selection of the solid form of a pharmaceutical compound is complex, given that changes in solid form can affect various physical and chemical properties, which can offer advantages or disadvantages in processing, formulation, stability, bioavailability, storage, and handling (e.g., transportation), among other important pharmaceutical properties. Useful pharmaceutical solids include crystalline and amorphous solids, depending on the product and its mode of administration. Amorphous solids are characterized by the lack of long-range structural order, while crystalline solids are characterized by structural periodicity. The desired class of pharmaceutical solid depends on the specific application; amorphous solids are sometimes selected based on, for example, enhanced solubility profiles, while crystalline solids may be preferred for properties such as, for example, physical or chemical stability.

[0071] Whether crystalline or amorphous, the solid forms of pharmaceutical compounds include monocomponent and multicomponent solids. Monocomponent solids are essentially composed of the pharmaceutical compound or active ingredient in the absence of other compounds. The diversity among monocomponent crystalline materials can potentially arise from polymorphism, with multiple three-dimensional configurations existing for a given pharmaceutical compound.

[0072] In particular, if crystalline forms of compounds exist, it is impossible to predict a priori how to successfully prepare them (e.g., Braga and Grepioni, 2005, “Making crystals from crystals: a green route to crystal engineering and polymorphism,” Chem.Commun.:3635-3645 (with regard to crystal engineering, if the instructions are not very precise and / or other external factors affect the process, the results can be unpredictable); Jones et al., 2006, “Pharmaceutical Cocrystals: An Emerging Approach to Physical Property Enhancement,” MRS Bulletin 31:875-879 (currently, it is generally impossible to computationally predict the number of observable polymorphs of the simplest molecules); Price, 2004, “The computational prediction of pharmaceutical crystal structures and polymorphism,” Advanced Drug Delivery Reviews 56:301-319 (“Price”); and Bernstein, 2004, “Crystal Structure Prediction and Polymorphism,” ACA Transactions See 39:14-23 (Crystal structure, and the ability to predict far fewer polymorphic forms, still requires a great deal of learning and practice before one can state this ability with any degree of confidence).

[0073] Various possible solid forms create potential diversity in the physical and chemical properties of a given pharmaceutical compound. The discovery and selection of solid forms are crucial in the development of effective, stable, and marketable pharmaceuticals.

[0074] Crystalline Compound (I), Form 1 In some embodiments, compound (I) is crystalline. In some embodiments, compound (I) is crystalline and anhydrous. In some embodiments, compound (I) is crystalline and hydrated. In some embodiments, compound (I) is crystalline and monohydrate. In some embodiments, the crystalline compound (I) is characterized by having at least one of the following properties. (a) A substantially the same X-ray powder diffraction (XRPD) pattern as shown in Figure 2, (b) X-ray powder diffraction (XRPD) patterns with characteristic peaks at 8.1°²-θ, 16.2°²-θ, 18.6°²-θ, 18.8°²-θ, 19.4°²-θ, 20.0°²-θ, 23.9°²-θ, 24.2°²-θ, and 28.4°²-θ. (c) A DSC thermogram substantially similar to the one shown in Figure 3, (d) DSC thermogram with endothermic properties starting at approximately 140°C. (e) Thermogravimetric analysis (TGA) substantially similar to that shown in Figure 4, or (f) These combinations.

[0075] In some embodiments, form 1 of crystalline compound (I) is characterized by having at least two properties selected from (a) to (f). In some embodiments, form 1 of crystalline compound (I) is characterized by having at least three properties selected from (a) to (f). In some embodiments, form 1 of crystalline compound (I) is characterized by having at least four properties selected from (a) to (f). In some embodiments, form 1 of crystalline compound (I) is characterized by having at least five properties selected from (a) to (f).

[0076] In some embodiments, crystalline compound (I), form 1 has a substantially identical X-ray powder diffraction (XRPD) pattern to that shown in Figure 2. In some embodiments, crystalline compound (I), form 1 has an X-ray powder diffraction (XRPD) pattern with characteristic peaks at 8.1°²-θ, 16.2°²-θ, 18.6°²-θ, 18.8°²-θ, 19.4°²-θ, 20.0°²-θ, 23.9°²-θ, 24.2°²-θ, and 28.4°²-θ. In some embodiments, crystalline compound (I), form 1 has a DSC thermogram substantially identical to that shown in Figure 3. In some embodiments, crystalline compound (I), form 1 has a DSC thermogram with endothermic properties starting at approximately 140°C. In some embodiments, crystalline compound (I), form 1 has a thermogravimetric analysis (TGA) thermogram substantially identical to that shown in Figure 4. In some embodiments, form 1 of crystalline compound (I) is anhydrous. In some embodiments, form 1 of crystalline compound (I) is obtained from ethanol. In some embodiments, form 1 of crystalline compound (I) is obtained from solvent systems such as those shown in Tables 2, 3, 4, 5, 6, or 7 described herein. In some embodiments, form 1 of crystalline compound (I) is solvated. In some embodiments, form 1 of crystalline compound (I) is not solvated.

[0077] Preparation of crystalline compound (I), form 1 In some embodiments, crystalline compound (I), form 1, is prepared as outlined in the examples. Note that the solvent, temperature, and other reaction conditions presented herein may vary.

[0078] In another embodiment, crystalline compound (I), form 1 is substantially pure. In a particular embodiment, substantially pure crystalline compound (I), form 1 substantially does not contain other solid forms, such as amorphous solids. In a particular embodiment, the purity of substantially pure crystalline compound (I), form 1 is about 95% or higher, about 96% or higher, about 97% or higher, about 98% or higher, about 98.5% or higher, about 99% or higher, about 99.5% or higher, or about 99.8% or higher.

[0079] Suitable solvent Therapeutic agents that can be administered to mammals such as humans must be prepared in accordance with regulatory guidelines. Such government regulatory guidelines are called Good Manufacturing Practices (GMP). GMP guidelines outline, for example, acceptable levels of contamination of active therapeutic agents, such as the amount of residual solvent in the final product. In some embodiments, the solvents disclosed herein are suitable for use in GMP facilities and meet industrial safety concerns. Solvent categories are defined, for example, in the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH), “Impurities: Guidelines for Residual Solvents Q3C(R6),” (October 2016).

[0080] Solvents are classified into three classes. Class 1 solvents are toxic and should be avoided. Class 2 solvents are solvents whose use is restricted during the manufacture of therapeutic drugs. Class 3 solvents are solvents with a low potential for toxicity and a low risk to human health. Data for Class 3 solvents indicate that they have low toxicity in acute or short-term studies and are negative in genotoxicity studies.

[0081] The Class 1 solvents to be avoided include benzene, carbon tetrachloride, 1,2-dichloroethane, 1,1-dichloroethene, and 1,1,1-trichloroethane.

[0082] Examples of Class 2 solvents are as follows: acetonitrile, chlorobenzene, chloroform, cumene, cyclohexane, 1,2-dichloroethene, dichloromethane, 1,2-dimethoxyethane, N,N-dimethylacetamide, N,N-dimethylformamide, 1,4-dioxane, 2-ethoxyethanol, ethylene glycol, formamide, hexane, methanol, 2-methoxyethanol, methyl butyl ketone, methylcyclohexane, methyl isobutyl ketone, N-methylpyrrolidone, nitromethane, pyridine, sulfolane, tetrahydrofuran, tetralin, toluene, 1,1,2-trichloroethene, and xylene.

[0083] Examples of low-toxicity Class 3 solvents include acetic acid, acetone, anisole, 1-butanol, 2-butanol, butyl acetate, tert-butyl methyl ether (MTBE), dimethyl sulfoxide, ethanol, ethyl acetate, ethyl ether, ethyl formate, formic acid, heptane, isobutyl acetate, isopropyl acetate, methyl acetate, 3-methyl-1-butanol, methyl ethyl ketone, 2-methyl-1-propanol, pentane, 1-pentanol, 1-propanol, 2-propanol, propyl acetate, and triethylamine.

[0084] Residual solvents in active pharmaceutical ingredients (APIs) originate from the API's manufacture. In some cases, the solvent cannot be completely removed by practical manufacturing techniques. The appropriate selection of solvents for API synthesis can increase yield or determine characteristics such as crystalline form, purity, and solubility. Therefore, the solvent is a crucial parameter in the synthesis process.

[0085] In some embodiments, the composition containing form 1 of compound (I) contains an organic solvent. In some embodiments, the composition containing form 1 of compound (I) contains a residual amount of organic solvent. In some embodiments, the composition containing form 1 of compound (I) contains a residual amount of class 3 solvent. In some embodiments, the organic solvent is a class 3 solvent. In some embodiments, the class 3 solvent is selected from the group consisting of acetic acid, acetone, anisole, 1-butanol, 2-butanol, butyl acetate, tert-butyl methyl ether (MTBE), dimethyl sulfoxide, ethanol, ethyl acetate, ethyl ether, ethyl formate, formic acid, heptane, isobutyl acetate, isopropyl acetate, methyl acetate, 3-methyl-1-butanol, methyl ethyl ketone, 2-methyl-1-propanol, pentane, 1-pentanol, 1-propanol, 2-propanol, propyl acetate, and triethylamine. In some embodiments, the class 3 solvent is selected from the group consisting of acetone, ethyl acetate, isopropyl acetate, tert-butyl methyl ether, heptane, isopropanol, and ethanol.

[0086] In some embodiments, the composition comprising form 1 of compound (I) comprises a residual amount of class 2 solvent. In some embodiments, the organic solvent is a class 2 solvent. In some embodiments, the class 2 solvent is selected from the group consisting of acetonitrile, chlorobenzene, chloroform, cumene, cyclohexane, 1,2-dichloroethene, dichloromethane, 1,2-dimethoxyethane, N,N-dimethylacetamide, N,N-dimethylformamide, 1,4-dioxane, 2-ethoxyethanol, ethylene glycol, formamide, hexane, methanol, 2-methoxyethanol, methyl butyl ketone, methylcyclohexane, methyl isobutyl ketone, N-methylpyrrolidone, nitromethane, pyridine, sulfolane, tetrahydrofuran, tetralin, toluene, 1,1,2-trichloroethene, and xylene. In some embodiments, the class 2 solvent is selected from the group consisting of acetonitrile, tetrahydrofuran, and toluene. In some embodiments, the class 2 solvent is acetonitrile.

[0087] In some embodiments, the composition comprising compound (I), form 1, contains a residual amount of solvent for which no suitable toxicological data was found. In some embodiments, the organic solvent is a solvent for which no suitable toxicological data was found. In some embodiments, the solvent is selected from the group consisting of 2-butanone and 2-methyltetrahydrofuran.

[0088] Pharmaceutical composition In certain embodiments, crystalline compound (I), form 1 described herein, is administered as a pure chemical substance. In other embodiments, crystalline compound (I), form 1 described herein, is combined with a selected route of administration and a pharmaceutically appropriate or acceptable carrier (also referred to herein as a pharmaceutically appropriate (or acceptable) excipient, a physiologically appropriate (or acceptable) excipient, or a physiologically appropriate (or acceptable) carrier) selected based on standard pharmacovigilance, such as Remington: The Science and Practice of Pharmacy (Gennaro, 21st Ed. Mack Pub. Co., Easton, PA (2005)) (the disclosure thereof is incorporated herein by reference in its entirety).

[0089] method In some embodiments, form 1 of the crystalline compound (I) disclosed herein is useful for treating cancer. In some embodiments, a method for treating cancer in a subject requiring treatment of cancer is provided herein, comprising the step of administering a therapeutically effective amount of form 1 of the crystalline compound (I) to a subject requiring treatment of cancer. In some embodiments, a compound for use in treating cancer in a subject requiring treatment of cancer is provided herein, the compound comprising administering a therapeutically effective amount of form 1 of the crystalline compound (I) to a subject requiring treatment of cancer. In some embodiments, the use of form 1 of the crystalline compound (I) disclosed herein in the manufacture of a pharmacopoeia for treating cancer is provided herein.

[0090] In some embodiments, cancer is mediated by activation of a transcriptional coactivator by a PDZ-binding motif / Yes-associated protein transcriptional coactivator (TAZ / YAP). In some embodiments, cancer is mediated by modulation of the interaction between YAP / TAZ and TEAD. In some embodiments, cancer is characterized by a mutant Ga protein. In some embodiments, the mutant Ga protein is selected from G12, G13, Gq, G11, Gi, Go, and Gs. In some embodiments, the mutant Ga protein is G12. In some embodiments, the mutant Ga protein is G13. In some embodiments, the mutant Ga protein is Gq. In some embodiments, the mutant Ga protein is G11. In some embodiments, the mutant Ga protein is Gi. In some embodiments, the mutant Ga protein is Go. In some embodiments, the mutant Ga protein is Gs.

[0091] In some embodiments, cancer is a solid tumor. In some examples, cancer is a hematological malignancy. In some examples, the solid tumor is a sarcoma or carcinoma. In some examples, the solid tumor is a sarcoma. In some examples, the solid tumor is a carcinoma.

[0092] In some cases, cancer is selected from uveal melanoma, mesothelioma, esophageal cancer, liver cancer, breast cancer, hepatocellular carcinoma, lung adenocarcinoma, glioma, colon cancer, colorectal cancer, gastric cancer, medulloblastoma, ovarian cancer, esophageal squamous cell carcinoma, sarcoma, Ewing's sarcoma, head and neck cancer, prostate cancer, and meningioma. In some cases, cancer is uveal melanoma, mesothelioma, esophageal cancer, liver cancer, breast cancer, hepatocellular carcinoma, lung adenocarcinoma, glioma, colon cancer, colorectal cancer, gastric cancer, medulloblastoma, ovarian cancer, esophageal squamous cell carcinoma, sarcoma, Ewing's sarcoma, head and neck cancer, prostate cancer, or meningioma. In some cases, cancer is uveal melanoma, mesothelioma, esophageal cancer, or liver cancer. In some cases, cancer is uveal melanoma. In some cases, cancer is mesothelioma. In some cases, cancer is esophageal cancer. In some cases, cancer is liver cancer. In some cases, the cancer is primary liver cancer.

[0093] In some cases, cancer is a hematological malignancy. In some embodiments, hematological malignancies include leukemia, lymphoma, myeloma, non-Hodgkin lymphoma, Hodgkin lymphoma, T-cell malignancies, or B-cell malignancies. In some cases, the hematological malignancy is a T-cell malignancy.

[0094] In some cases, hematological malignancies are B-cell malignancies.

[0095] In some cases, the cancer is recurrent or refractory.

[0096] In some embodiments, form 1 of crystalline compound (I) is useful for the treatment of polycystic kidney disease. In some embodiments, form 1 of crystalline compound (I) is useful for the treatment of hepatic fibrosis. In some embodiments, form 1 of crystalline compound (I) is useful for the treatment of congenital diseases.

[0097] definition Unless otherwise defined, all technical terms, notations, and other technical and scientific terms or terms used herein are intended to have the same meaning as commonly understood by those skilled in the art in the field relating to the claimed subject matter. Where applicable, terms having a commonly understood meaning are defined herein for clarity and / or for easy reference, and the inclusion of such definitions herein should not necessarily be construed as representing a substantial difference from the generally understood meaning in the art.

[0098] Throughout this application, various embodiments can be presented in scope form. It should be understood that the scope form is merely for convenience and brevity and should not be interpreted as an inflexible limitation to the scope of this disclosure. Therefore, a scope description should be considered to have all possible sub-scopes specifically disclosed, as well as the individual numbers within those scopes. For example, a scope description such as 1-6 should be considered to specifically disclose sub-scopes such as 1-3, 1-4, 1-5, 2-4, 2-6, 3-6, as well as the individual numbers within those scopes, e.g., 1, 2, 3, 4, 5, and 6. This applies regardless of the width of the scope.

[0099] As used herein and in the claims, the singular forms "a," "an," and "the" include plural references unless the context explicitly indicates otherwise. For example, the term "a sample" includes multiple samples, mixtures thereof.

[0100] In this application, the use of “or” means “and / or” unless otherwise stated. Furthermore, the use of the term “including,” as well as other forms such as “include,” “includes,” and “included,” is not limited to these.

[0101] As used herein, in some embodiments, ranges and quantities are expressed as "about" a specific value or range. "About" also includes the exact quantity. Therefore, "about 5 μL" means "about 5 μL" and also "5 μL". Generally, the term "about" includes quantities that are expected to be within experimental error.

[0102] The section headings used herein are for organizational purposes only and should not be interpreted as limiting the subjects described.

[0103] The section headings used herein are for organizational purposes only and should not be interpreted as limiting the subjects described. [Examples]

[0104] The following exemplary embodiments are representative of, and not intended to limit, embodiments of the stimuli, systems, and methods described herein.

[0105] List of abbreviations As used above and throughout this disclosure, the following abbreviations shall be understood to have the following meanings unless otherwise indicated. °C (Celsius) G grams kg (kilogram) μL (microliter) h, hr, hrs time HATU 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxidehexafluorophosphate T3P 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinate-2,4,6-trioxide HPLC (High-Performance Liquid Chromatography) GC Gas Chromatography KF Karl Fischer titration XRPD (X-ray Powder Diffraction) RSM Regulatory Starting Materials Me methyl THF (Tetrahydrofuran) DMF (N,N-dimethylformamide) MeOH methanol

[0106] I. Chemical synthesis Unless otherwise noted, reagents and solvents were used as they were obtained from commercial suppliers. In some embodiments, if there is a discrepancy between the reaction scheme and the written procedure, the written procedure should be followed. Example 1. Synthesis of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide (compound (I))

[0107] [ka]

[0108] Step 1: Preparation of methyl 5-(4-(trifluoromethyl)phenoxy)-2-naphthoate Methyl 5-hydroxy-2-naphthoate (compound A1) (2.8 kg, 1.0 equivalent) and 1-iodo-4-(trifluoromethyl)benzene (compound A2) (4.5 kg, 1.2 equivalents) were combined in 1,4-dioxane (29 kg) with N,N-dimethylglycine (0.45 kg, 0.3 equivalents), cesium carbonate (6.9 kg, 1.5 equivalents), and cuprous iodide (1.54 kg, 0.6 equivalents). This mixture was heated at 95-105°C for approximately 15 hours. The mixture was cooled, and 1,3,5-triazine-2,4,6(1H,3H,5H)-trithion sodium salt (2.2 kg, 0.65 equivalents) was added. The mixture was diluted with 2-methyl-THF (approximately 70 kg) and filtered through diatomaceous earth. This solution was held for the next step.

[0109] Step 1 was repeated using 4.4 kg of methyl 5-hydroxy-2-naphthoate and 7.1 kg of 1-iodo-4-(trifluoromethyl)benzene. The resulting 2-methyl-THF solution of methyl 5-(4-(trifluoromethyl)phenoxy)-2-naphthoate was combined with the solution prepared above, and the combined solution was added to the esterification saponification step described below.

[0110] Step 2: Preparation of sodium 5-(4-(trifluoromethyl)phenoxy)-2-naphthoate The combined methyl 5-(4-(trifluoromethyl)phenoxy)-2-naphthoate 2-methyl-THF solution was washed with aqueous sodium chloride and aqueous ammonium hydroxide, and then the 2-methyl-THF solution was concentrated under vacuum. Sodium hydroxide solution (4.4 kg) and water (71 kg) were added to the concentrate, and after addition, the mixture was stirred at 60-70°C for 10 hours. The solution was concentrated under vacuum, and n-heptane (25 kg) was added. The solution was seeded, and an additional n-heptane (27 kg) was added. The mixture was cooled to 0-5°C, filtered, and dried under vacuum to obtain 8.0 kg of compound C (69% yield in two steps).

[0111] Step 3: Preparation of compound (I) Compound C (8.0 kg, 1.0 equivalent) was combined with 2-methyl-THF (48 kg), thionyl chloride (7.2 kg, 2.7 equivalents), and DMF (0.07 kg, 0.05 equivalents). The reaction mixture was stirred at 20-30°C for 5-10 hours. The mixture was concentrated under vacuum. The residue was dissolved in 2-methyl-THF (46 kg) and concentrated again to remove residual thionyl chloride. Then, an additional 2-methyl-THF (38 kg) was added to the residue, followed by (R)-2-aminopropan-1-ol. The reaction mixture was stirred at 20-30°C for 2-6 hours. The solution was stirred with warm aqueous sodium hydroxide for 5-10 hours. The mixture was cooled to 20-30°C, the layers were separated, and the 2-ME-THF layer was washed with brine. n-heptane was added to the organic layer, and the crude product was filtered. The product was recrystallized from DMF / water. After two recrystallizations, further crystallization was performed from 2-methyl-THF / n-heptane. The solid was recovered by filtration and dried under vacuum to obtain 6.65 kg (yield 76%) of compound (I).

[0112] Recrystallization of compound (I) to achieve the desired crystal form 1 Compound (I) (6.5 kg) was combined with ethanol, and the mixture was heated to 55-60°C and stirred until a clear solution was obtained. The solution was filtered through a polishing filter, and warm water (44 kg) was added to the filtrate over several hours. The mixture was then heated again to 70-80°C for about 30 minutes, then cooled to 55-60°C, seeded, and dried under vacuum to obtain 6.31 kg (95% yield) of compound (I). XRPD analysis confirmed that the product was crystalline compound (I), form 1.

[0113] Example 1A: Alternative synthesis of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide (compound (I))

[0114] [ka]

[0115] II. Characterization of Polymorphs Example 2: X-ray powder diffraction (XRPD) X-ray powder diffraction studies were performed using a Bruker D8 Advance.

[0116] Bruker D8 Advance parameters:

[0117] [Table 1]

[0118] XRPD analysis of compound (I) form 1 (Figure 2) showed that form 1 is a crystal with characteristic peaks at 8.1° 2θ, 16.2° 2θ, 18.6° 2θ, 18.8° 2θ, 19.4° 2θ, 20.0° 2θ, 23.9° 2θ, 24.2° 2θ, and 28.4° 2θ.

[0119] Example 3: Differential Scanning Calorimetry (DSC) DSC studies were performed using the TA Discovery Q2000. A sample (approximately 1 mg) was tested using a sealed aluminum pan with a pinhole. The sample was heated from 30°C to 300°C at a heating rate of 10°C / min.

[0120] DSC analysis of compound (I) form 1 (Figure 3) showed endothermic reactions that began at approximately 140°C.

[0121] Example 4: Thermogravimetric Analysis Solid thermogravimetric analysis was performed using a TA Discovery TGA 5500. The sample (3-5 mg) was placed in an open aluminum pan. The sample was heated from room temperature to 300°C at a heating rate of 10°C / min under 25 mL / mL of N2.

[0122] TGA of compound (I) form 1 (Figure 4) showed a weight loss of approximately 0.15% from 35°C to 130.5°C.

[0123] Example 5: Dynamic Vapor Adsorption (DVS) DVS testing was performed using a DVS Intrinsic (SMS, UK). A 10 mg sample was transferred to the DVS instrument, and the weight change with respect to ambient humidity at 25°C was recorded. The sample was analyzed using the following parameters. -Equilibrium: dm / dt: 0.01% / min. (For minutes (min), 10 minutes, maximum: 180 minutes). - Drying conditions: 120 minutes at 0%RH -RH(%) measurement process: 10% -RH(%) Measurement process range: 40%-0%-95%-0%-40%

[0124] DVS analysis of compound (I) form 1 (Figure 5) showed that form 1 is non-hygroscopic (0.13% weight change from 0 to 80% RH).

[0125] III. Polymorph Screening Example 6: Solubility Test Approximately 2 mg of compound (I) was weighed into a 2 mL glass vial, and then different selected solvents were added to the vial in stages until all solids were dissolved. The experiment was performed by manual dilution combined with visual observation at 25°C and 50°C. The total volume of added solvent was recorded. The results are shown in Table 1.

[0126] [Table 2]

[0127] Example 7: Slurry method at 25°C Approximately 50 mg of compound (I) was weighed into a 2 mL vial, and then 1 mL of each of the following solvents (MTBE, toluene, heptane, H2O, EtOH / H2O(1 / 1), DMF / H2O(1 / 1), DMSO / H2O(1 / 1), 1,4-dioxane / H2O(1 / 1), acetone / H2O(1 / 1), IPA / H2O(1 / 1), ACN / H2O(1 / 1), and THF / H2O(1 / 1)) was added at a target concentration of approximately 50 mg / mL. The suspension was stirred at 25°C (700 rpm) for 2 weeks. After 1 and 2 weeks of slurry, appropriate suspensions were taken out, and the residual solids after centrifugation (8000 rpm, 10 min) were characterized by XRPD. The results are shown in Table 2.

[0128] [Table 3]

[0129] Example 8: Slurry method at 50°C Approximately 50 mg of compound (I) was weighed into a 2 mL vial, and then 1 mL of each of the following solvents (MTBE, toluene, heptane, H2O, EtOH / H2O(1 / 1), DMF / H2O(1 / 1), DMSO / H2O(1 / 1), acetone / H2O(1 / 1), IPA / H2O(1 / 1), ACN / H2O(1 / 1), and THF / H2O(1 / 1)) was added at a target concentration of approximately 50 mg / mL. The suspension was stirred at 50°C (700 rpm) for 2 weeks. After 1 and 2 weeks of slurry analysis, appropriate suspensions were taken out, and the residual solids after centrifugation (8000 rpm, 10 min) were characterized by XRPD. The results are shown in Table 3.

[0130] [Table 4]

[0131] Example 9: Evaporation Method Approximately 50 mg of compound (I) was weighed into a 2 mL vial, and then 0.3 mL of each of two different solvents (acetone, DCM, Ã, EtOH, IPA, MeOH, and THF) was added at a target concentration of approximately 166.7 mg / mL. The solvents were evaporated at 25°C to form crystals. The formed crystals were characterized by XRPD. The results are shown in Table 4.

[0132] [Table 5]

[0133] Example 10: Solvent heating-cooling method Rapid cooling method: Compound (I) was dissolved in various solvents at 60°C to prepare saturated solutions. The solutions were then cooled in an ice bath and maintained at 0°C to rapidly precipitate the solid. The residual solid after centrifugation (8000 rpm, 10 minutes) was characterized by XRPD. The results are shown in Table 5.

[0134] [Table 6]

[0135] Slow cooling method: Compound (I) was dissolved in various solvents at 60°C to prepare saturated solutions. The solutions were then cooled using a temperature-programmed cooling circulator (0.1°C / min) to precipitate the solid at 5°C. The residual solid after centrifugation (8000 rpm, 10 min) was characterized by XRPD. The results are shown in Table 6.

[0136] [Table 7]

[0137] Example 11: Poor Solvent Precipitation Method Approximately 20 mg of compound (I) was dissolved in various solvents at 25°C to prepare saturated solutions, and then a certain amount of poor solvent was added to precipitate the cristol. The residual solid after centrifugation (8000 rpm, 10 minutes) was characterized by XRPD. The results are shown in Table 7.

[0138] [Table 8]

[0139] IV. Biological evaluation Example 12: YAP Reporter Assay HEK293T cells, stably transfected with 8XTBD luciferase reporter and pRLTK in 384-well plates, were treated with the test compounds at 1:3 dilutions and 10 points in 4-well strips, starting at 3 μM (final concentration in the assay plate). After 24 hours of incubation with the compounds at 37°C and 5% CO2, the cells were lysed, and 8XTBD-driven firefly luciferase and control TK-driven sea urchin luciferase activity were measured using the Promega Dual-luciferase Reporter Assay System.

[0140] Reagents: The reagents used in this study are as follows: DMEM: Invitrogen #11960077, Dual-Glo luciferase assay system: Promega-E2980, Puromycin dihydrochloride: Invitrogen-A1113803, 384-well plate: PerkinElmer-6007480, L-GLUTAMINE: Invitrogen-25030164, Hygromycin B: Invitrogen-10687010, and Penicillin-Streptomycin: MERK-TMS-AB2-C

[0141] Culture medium: The culture medium used in this assay was as follows: Culture medium: DMEM 1 μg / mL puromycin 200 μg / mL hygromycin (containing 10% FBS 1 mM L-glutamine), and assay medium: DMEM (containing 10% FBS 1 mM L-glutamine 1×P / S).

[0142] Cell plating: Appropriate media were warmed to 37°C in a water bath: culture medium, assay medium, 1* D-PBS, 0.05% trypsin-EDTA. After removing all media, the cells were trypsinized and then washed with 1× sterile D-PBS, then 2 ml of 0.05% trypsin-EDTA. The cells were then incubated at room temperature for 1 minute. Then 10 ml / 75 cm³ 2 Assay medium was added to each flask. Then, using a 10 ml pipette, the cells were gently resuspended in the medium until the aggregates were completely gone. The cells were then transferred to a 50 ml centrifuge tube and centrifuged at 800 rpm for 5 minutes. The medium was removed and the cells were resuspended in assay medium. Cell density (cells / ml) was counted using aliquots of cells. The cell suspension was then diluted with assay medium in 6 x 10⁶ units. 4 The cell suspension was diluted to a concentration of cells / ml. Then, 50 μl of the cell suspension was seeded into a 384-well plate (PerkinElmer-6007480) in a 3x10⁶ arrangement. 3 Cells were incubated in a 37°C, 5% CO2 incubator in a cell / well format.

[0143] Compound preparation: In the afternoon (3-4 hours of plate incubation), the test compound was added by Echo, starting at 3 μM (final concentration in the assay plate), diluted 1:3, in 10 points, and in a 4-strand configuration. The plate was placed in a 37°C, 5% CO2 incubator for 24 hours.

[0144] Detection: The Dual-Glo luciferase reagent was prepared by transferring the contents of one bottle of Dual-Glo luciferase buffer to one bottle of Dual-Glo luciferase substrate. Mixing was performed by inversion until the substrate was completely dissolved. After mixing, the reagent was dispensed into 15 ml tubes. In the afternoon (24 hours after compound treatment), DMEM+ medium in a 384-well plate was aspirated using a microplate washer.

[0145] Measurement of firefly luciferase activity: 20 μL of Dual-Glo luciferase reagent was added to a 384-well plate. The plate was protected from light to prevent interference with the assay. The plate was shaken for 1 minute, followed by centrifugation at 1000 rpm for 30 seconds. After waiting for at least 10 minutes, firefly luminescence was measured using Envision.

[0146] Measurement of sea urchin luciferase activity: 20 μL of Stop-Glo reagent was added to a 384-well plate. The plate was shaken for 1 minute, then centrifuged at 1000 rpm for 30 seconds. After waiting for at least 10 minutes, sea urchin luminescence was measured by Envision.

[0147] The IC50 for the firefly luciferase activity of compound (I) is ≤0.1 μM.

[0148] Preferred embodiments of the present invention have been shown and described herein, but it will be apparent to those skilled in the art that such embodiments are provided only as examples. Numerous variations, modifications, and substitutions will come to mind to those skilled in the art without departing from the present invention. It should be understood that various alternative forms of the embodiments of the present invention described herein may be adopted when carrying out the present invention. The following claims define the scope of the present invention, and methods and structures within these claims, as well as their equivalents, are intended to be encompassed thereby.

Claims

1. Compound (I) 【Chemistry 1】 A process for synthesizing, Compound D 【Chemistry 2】 A process comprising contacting with (R)-2-aminopropan-1-ol in the presence of a solvent.

2. The process according to claim 1, wherein the solvent is 2-methyl-THF.

3. Compound D 【Transformation 3】 However, compound C 【Chemistry 4】 The process according to claim 1 or 2, wherein the product is prepared by a process comprising contacting it with a chlorinating agent in the presence of a solvent.

4. The process according to claim 3, wherein the chlorinating agent is thionyl chloride.

5. The process according to claim 3 or 4, wherein the solvent is 2-methyl-THF.

6. Compound C 【Transformation 5】 However, compound B 【Transformation 6】 The process according to any one of claims 1 to 5, wherein the product is prepared by a process comprising contacting the product with a base in the presence of a solvent.

7. The process according to claim 6, wherein the base is an inorganic base.

8. The process according to claim 6, wherein the base is selected from NaOH, KOH, and CsOH.

9. The process according to claim 8, wherein the base is NaOH.

10. The process according to any one of claims 6 to 9, wherein the solvent is a mixture of 2-methyl-THF and water.

11. Compound B 【Transformation 7】 but, 【Transformation 8】 In the presence of a catalyst, a base, and a solvent, 【Chemistry 9】 The process according to any one of claims 1 to 10, which is prepared by a process including contacting with

12. The process according to claim 11, wherein the catalyst is CuI and N,N-dimethylglycine.

13. The process according to claim 11 or 12, wherein the base is an organic base.

14. The process according to claim 13, wherein the organic base is selected from piperidine, 1,8-diazabicyclo[5.4.0]undeca-7-ene, N,N-diisopropylethylamine, and triethylamine.

15. The process according to claim 11 or 12, wherein the base is an inorganic base.

16. The inorganic base is NaOH, KOH, CsOH, Cs ２ CO ３ _K ２ CO ３ Na ２ CO ３ , or NaHCO ３ The process according to claim 15, selected from the following.

17. wherein the inorganic base is K ２ CO ３ The process according to claim 16, wherein the inorganic base is K

18. Compound A1 and Compound A2 【Chemistry 10】 The process according to any one of claims 11 to 17, further involving contact with the

19. The process according to any one of claims 11 to 18, wherein the solvent is selected from ethyl acetate, dichloromethane, tetrahydrofuran, diethyl ether, dimethylformamide, dimethyl sulfoxide, methanol, ethanol, acetone, acetonitrile, 1,4-dioxane, hexane, and methyl tert-butyl ether.

20. The process according to claim 19, wherein the solvent is 1,4-dioxane.

21. (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is a crystalline form with the following properties: (a) A substantially the same X-ray powder diffraction (XRPD) pattern as shown in Figure 2, (b) X-ray powder diffraction (XRPD) patterns with characteristic peaks at 8.1°²-θ, 16.2°²-θ, 18.6°²-θ, 18.8°²-θ, 19.4°²-θ, 20.0°²-θ, 23.9°²-θ, 24.2°²-θ, and 28.4°²-θ. (c) A DSC thermogram substantially similar to the one shown in Figure 3, (d) DSC thermogram with endothermic properties starting at approximately 140°C, (e) Thermogravimetric analysis (TGA) substantially similar to that shown in Figure 4, or (f) These combinations A crystalline form having at least one of the following characteristics.

22. The crystal morphology according to claim 21, having substantially the same X-ray powder diffraction (XRPD) pattern as that shown in Figure 2.

23. The crystal morphology according to claim 21, having an X-ray powder diffraction (XRPD) pattern with characteristic peaks at 8.1°²-θ, 16.2°²-θ, 18.6°²-θ, 18.8°²-θ, 19.4°²-θ, 20.0°²-θ, 23.9°²-θ, 24.2°²-θ, and 28.4°²-θ.

24. The crystal morphology according to claim 21, having a DSC thermogram substantially similar to that shown in Figure 3.

25. The crystal morphology according to claim 21, having a DSC thermogram that exhibits endothermic properties starting at approximately 140°C.

26. The crystal morphology according to claim 21, having substantially the same thermogravimetric analysis (TGA) as shown in Figure 4.

27. The crystal morphology according to claim 21, characterized by having properties (a), (b), (c), (d), and (e).

28. The crystalline form according to any one of claims 21 to 27, obtained by recrystallization of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide in ethanol.

29. A pharmaceutical composition comprising a crystalline form according to any one of claims 21 to 28 and a pharmaceutically acceptable excipient.

30. A method for treating cancer in a subject requiring treatment, comprising the step of administering a therapeutically effective amount of a crystalline form described in any one of claims 21 to 28 to the subject requiring treatment.

31. The method according to claim 30, wherein the cancer is selected from mesothelioma, hepatocellular carcinoma, meningioma, malignant peripheral nerve schwannoma, schwannoma, lung cancer, bladder cancer, cutaneous neurofibroma, prostate cancer, pancreatic cancer, glioblastoma, endometrial adenosquamous carcinoma, histologically nonplastic thyroid cancer, gastric adenocarcinoma, esophageal adenocarcinoma, ovarian cancer, ovarian serous adenocarcinoma, melanoma, and breast cancer.

32. A method for treating polycystic kidney disease or hepatic fibrosis in a subject requiring treatment for polycystic kidney disease or hepatic fibrosis, comprising the step of administering a therapeutically effective amount of the crystalline form described in any one of claims 21 to 28 to the subject requiring treatment.

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