Salt forms of RXR agonists, their polymorphs, and their uses

Abstract

Provided herein are salts and solid forms of (2E,4E)-3-methyl-5-((1S,2S)-2-methyl-2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)cyclopropyl)penta-2,4-dienoic acid, including the tris salt form of (2E,4E)-3-methyl-5-((1S,2S)-2-methyl-2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)cyclopropyl)penta-2,4-dienoic acid, polymorphs thereof, methods for preparing said compounds, and methods of using them.

Description

[Technical field]

[0001] (Related Applications) This application claims priority to U.S. Provisional Patent Application No. 63 / 320,159, filed March 15, 2022, which is incorporated herein by reference in its entirety.

[0002] (Technical field) The present disclosure generally describes (2E,4E)-3-methyl-5-((1S,2S)-2-methyl-2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)cyclopropyl)penta-2,4-dienoic acid (Compound 1) in the form of a tris salt, a diethylamine salt, a lysine salt, a glycine salt, a choline salt, an ammonium salt, a magnesium salt, a calcium salt, a potassium salt, or a sodium salt. The present disclosure also generally describes (2E,4E)-3-methyl-5-((1S,2S)-2-methyl-2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)cyclopropyl)penta-2,4-dienoic acid (Compound 1) in the form of a tris(hydroxymethyl)aminomethane (tris) salt and its polymorphic forms. Compositions comprising such forms are also described, including pharmaceutical compositions in general and formulations for specific routes of administration. Therapeutic or prophylactic uses of such forms and compositions are also described, either as monotherapy or in combination with one or more other active pharmaceutical agents, including thyroid hormones or neurotrophic factors. [Background technology]

[0003] Compound 1 and its synthetic preparation are described in U.S. Patent Nos. 5,917,082 and 10,590,059, the entire contents of each of which are incorporated herein by reference. Its chemical structure is shown below.

[0004] [ka]

[0005] Compound 1 is a potent and selective clinical stage retinoid X receptor (RXR) agonist that is brain penetrant and promotes differentiation of oligodendrocyte precursor cells and is also a clinical stage experimental therapeutic for a variety of diseases including prostate, lung, and other cancers. RXR regulates functions related to differentiation, cytostasis, apoptosis, and metastasis. Preclinical studies with RXR antagonists, rexinoids, suggest that selective activation of RXR may be useful for the treatment of a variety of diseases related to biochemical functions regulated by RXR.

[0006] Compound 1, which contains a carboxylic acid moiety, is lipophilic. Although useful in certain contexts, this characteristic limits the methods of formulating compound 1. What is needed, therefore, are novel salts and polymorphic forms of compound 1 to access methods of formulating a compound that is otherwise unavailable, at least in part due to its lipophilicity, and to improve its therapeutic utility. Summary of the Invention [Means for solving the problem]

[0007] Provided herein are salt forms, including the tris salt, of Compound 1 and polymorphic forms thereof, compositions comprising one or more salt forms thereof, uses thereof, methods for preparing them, and kits containing them. [Brief description of the drawings]

[0008] [Figure 1] X-ray powder diffraction (XRPD) trace of the tris salt form A of compound 1. [Diagram 2] Differential scanning calorimetry (DSC) trace of the Tris salt form A of compound 1. [Diagram 3] Thermogravimetric analysis (TGA) trace of the tris salt form A of compound 1. [Figure 4] XRPD trace of the Tris salt form B of compound 1. [Diagram 5] DSC trace of the Tris salt form B of compound 1. [Figure 6]TGA trace of the Tris salt form B of compound 1. [Figure 7] XRPD traces of the Tris salt forms A / B / C / D / E of compound 1. [Figure 8A] DSC / TGA trace of the Tris salt form A of compound 1. [Figure 8B] DSC / TGA trace of the Tris salt form B of compound 1. [Figure 8C] DSC / TGA trace of the Tris salt form C of compound 1. [Figure 8D] DSC / TGA trace of the tris salt form D of compound 1. [Figure 9A] XRPD traces of Compound 1 and the sodium (Na) salt Form A of Compound 1: Compound 1 (free acid); and the Na salt Form A (from evaporation of methanol). [Figure 9B] XRPD traces of the sodium (Na) salt form A / B of Compound 1: Na salt form A (from acetonitrile); and Na salt form B (from isopropanol). [Figure 9C] XRPD traces of the sodium (Na) salt forms C / D of compound 1: Na salt form C (with ethyl acetate); and Na salt form D (with acetone-H2O 5:1). [Figure 10A] DSC / TGA trace of the sodium (Na) salt form A of compound 1. [Figure 10B] DSC / TGA trace of the sodium (Na) salt form B of compound 1. [Figure 10C] DSC / TGA trace of the sodium (Na) salt form C of compound 1. [Figure 10D] DSC / TGA trace of the sodium (Na) salt form D of compound 1. [Figure 11] XRPD traces of potassium (K) salt forms A / B / C / D / E of compound 1: K salt form A (from ACN); K salt form B (from THF); K salt form C (from evaporation of methanol); K salt form D (from evaporation of isopropanol); and K salt form E (from acetone-HO 5:1). [Figure 12A] DSC / TGA trace of potassium (K) salt form A of compound 1. [Figure 12B] DSC / TGA trace of potassium (K) salt form B of compound 1. [Figure 12C] DSC / TGA trace of potassium (K) salt form C of compound 1. [Figure 12D] DSC / TGA trace of the potassium (K) salt form D of compound 1. [Figure 12E] DSC / TGA trace of potassium (K) salt form E of compound 1. [Figure 13A] XRPD traces of diethylamine (DEA) salt forms A / C of compound 1: DEA salt form A (from acetonitrile); DEA salt form A (from evaporation of methanol); and DEA salt form C (from isopropanol). [Figure 13B] XRPD traces of diethylamine (DEA) salt form B of compound 1: DEA salt form B (with acetone-H2O 5:1); DEA salt form B (with ethyl acetate); and DEA salt form B (with tetrahydrofuran). [Figure 14A] DSC / TGA trace of the diethylamine salt form A of compound 1. [Figure 14B] DSC / TGA trace of the diethylamine salt form B of compound 1. [Figure 14C] DSC / TGA trace of the diethylamine salt form C of compound 1. [Figure 15A] XRPD traces of lysine and lysine salt forms A / B / C of compound 1: lysine; lysine salt form A (by evaporation of methanol); lysine salt form B (by acetonitrile); and lysine salt form C (by isopropanol). [Figure 15B] XRPD traces of lysine and the D-form lysine salts of compound 1: Lysine D-form (with tetrahydrofuran); Lysine D-form (with ethyl acetate); and Lysine D-form (with acetone-H2O 5:1). [Figure 16A] DSC / TGA trace of Form A lysine salt of compound 1. [Figure 16B] DSC / TGA trace of the B-form lysine salt of compound 1. [Figure 16C] DSC / TGA trace of the Form C lysine salt of compound 1. [Figure 16D] DSC / TGA trace of the D-lysine salt of compound 1. [Figure 17] XRPD traces of glycine and glycine salt Form A of compound 1: glycine; and glycine salt Form A (with acetonitrile). [Figure 18] XRPD traces of ammonium (NH4) salt A / B / C / D forms of compound 1: NH4 salt form A (with acetonitrile); NH4 salt form B (with isopropanol); NH4 salt form C (with tetrahydrofuran); and NH4 salt form D (with ethyl acetate). [Figure 19A] DSC / TGA trace of the ammonium salt form A of compound 1. [Figure 19B] DSC / TGA trace of the ammonium salt form B of compound 1. [Figure 19C] DSC / TGA trace of the ammonium salt form C of compound 1. [Figure 19D] DSC / TGA trace of the ammonium salt form D of compound 1. [Figure 20] XRPD traces of the magnesium (Mg) salt form A / B of compound 1: Mg salt form A (with methanol); and Mg salt form B (with acetonitrile). [Figure 21A] DSC / TGA trace of the magnesium salt form A of compound 1. [Figure 21B] DSC / TGA trace of the magnesium salt form B of compound 1. [Figure 22] XRPD traces of the calcium (Ca) salt Form A of Compound 1: calcium acetate; and Ca salt Form A (with methanol). [Diagram 23] DSC / TGA trace of the calcium salt form A of compound 1. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0009] It has been discovered that salt forms, including the tris salt form of Compound 1, have certain advantages over the corresponding Compound 1, i.e., Compound 1 as a free acid. The chemical structure of Compound 1 as a tris salt form is shown below. When used medically, tris is sometimes referred to as tromethamine or THAM. The tris salt form of Compound 1 can be prepared, for example, by combining equimolar amounts of Compound 1 and tris in a suitable solvent, such as an alcoholic or aqueous solvent, to prepare a solution, and then evaporating the solvent. Salt forms with other cations can be prepared similarly.

[0010] [ka]

[0011] It was also discovered that compound 1 as a tris salt has a dynamic aqueous solubility that is approximately an order of magnitude higher, or even higher, than compound 1 (see Table 1).

[0012] [Table 1]

[0013] It has also been discovered that the Tris salt of Compound 1 can be prepared in one or more solid forms. In some embodiments, the solid form is a crystalline solid form. In some embodiments, the solid form is anhydrous. In some embodiments, the solid form is a hydrate. In some embodiments, the hydrate is a hemihydrate, monohydrate, or dihydrate, e.g., (Compound 1)(Tris)(HO), respectively. 0.5 , (Compound 1)(Tris)(H2O), or (Compound 1)(Tris)(H2O)2.

[0014] In addition, it was found that the tris salt of compound 1 has a difference in thermodynamic solubility in certain solvents at room temperature, as shown in Table 2. For example, the solubility of compound 1 in methanol is lower than that of the tris salt A of compound 1 in methanol, while the solubility of compound 1 in ethanol, isopropanol, or butanol is higher than that of the tris salt A of compound 1 in ethanol, isopropanol, or butanol. Surprisingly, the thermodynamic solubility of compound 1 in water at room temperature is higher than that of the tris salt A of compound 1. Furthermore, the tris salt A of compound 1 and the corresponding free acid (compound 1) have low or undetectable kinetic solubility in artificial gastric fluid, but the kinetic solubility of the tris salt A of compound 1 is significantly higher in artificial small intestinal fluid, whereas the kinetic solubility of compound 1 is not (see Table 1).

[0015] It has also been found that solid forms of additional salts of Compound 1 can be prepared. For example, crystalline forms of the sodium (Na), potassium (K), diethylamine, lysine, ammonium, magnesium (Mg), or calcium (Ca) salts of Compound 1 have been prepared. See Figures 7-23 for XRPD, DSC, and TGA traces of the Tris salt Form C / D, the Na salt Form A / B / C / D, the K salt Form A / B / C / D / E, the diethylamine salt Form A / B / C, the lysine salt Form A / B / C / D, the ammonium salt Form A / B / C / D, the Mg salt Form A / B / C / D, and the Ca salt Form A / B / C of Compound 1, and Table 2a for the corresponding endothermic transitions. The glycine and choline salts of Compound 1 were prepared as amorphous solid forms. See Table 2 for thermodynamic solubility data. The methods and uses described herein also apply to these amorphous and crystalline solid forms. For example, when reference is made to the Tris salt of Compound 1, the corresponding alternative salt forms may be contemplated instead of the Tris salt form.

[0016] [Table 2]

[0017] [Table 2a]

[0018] definition Certain terms, whether used alone or as part of a phrase or other term, are defined below.

[0019] The articles "a" and "an" refer to one or to more than one of the grammatical object of the article.

[0020] Numerical values ​​relating to measurements are subject to measurement errors that give limits to their precision. Therefore, all numerical values ​​provided herein should be understood as being modified by the term "about" unless otherwise specified. Thus, the last decimal point of a numerical value provided herein indicates its degree of precision. If no other error is given, the maximum error is ascertained by applying the rounding convention to the last decimal point or to the last significant digit when no decimals exist in the numerical value provided.

[0021] The term "amelioration" refers to a reduction in the severity of at least one indicator of a condition or disease, such as a slowing or retardation of the progression of one or more indicators of a condition or disease. The severity of an indicator may be determined by subjective or objective measures known to those skilled in the art.

[0022] The terms "composition" and "pharmaceutical composition" refer to a mixture of at least one compound described herein and a pharma- ceutical acceptable carrier. The pharmaceutical composition facilitates administration of the compound to a patient or subject. There are multiple techniques for administering the compound, including, but not limited to, intravenous administration, oral administration, aerosol administration, parenteral administration, ophthalmic administration, nasal administration, pulmonary administration, and topical administration.

[0023] The terms "effective amount" and "therapeutically effective amount" refer to an amount of a therapeutic compound, such as a compound described herein, that is effective to produce a desired therapeutic effect in a subject, either as a single dose or as part of a series of doses. In general, a therapeutically effective amount can be estimated initially in cell culture assays or in mammalian models, such as non-human primates, mice, rabbits, dogs, or pigs. Animal models may also be used to determine appropriate concentration ranges and routes of administration. Such information can be used to determine useful dosages and routes of administration in non-human and human subjects.

[0024] The term "pharmaceutical acceptable carrier" refers to a pharmaceutical acceptable material, composition, or carrier, such as a liquid filler, solid filler, stabilizer, dispersant, suspending agent, diluent, excipient, thickener, solvent, or encapsulating material, which is involved in the delivery or transport of at least one compound described herein into or to a patient so that it may perform its intended function. A given carrier must be "acceptable" in the sense of being compatible with the other ingredients of a particular formulation containing the compound described herein and not harmful to the patient. Other ingredients that may be included in the pharmaceutical compositions described herein are known in the art and are described, for example, in "Remington's Pharmaceutical Sciences" (Genaro (Ed.), Mack Publishing Co., 1985), the entire contents of which are incorporated herein by reference.

[0025] The term "refractory disease" refers to a disease that continues to progress during treatment with a pharmaceutical ingredient other than the compounds provided herein, a disease that is partially responsive to other treatments, or a disease that is transiently responsive to other treatments. This term may be applied to each of the diseases referred to herein.

[0026] The term "treatment" or "treating" refers to the application of one or more specific procedures used to ameliorate a disease. "Prophylactic" treatment refers to slowing the rate of progression of the disease or condition being treated, delaying the onset of the disease or condition, or reducing the severity of its onset.

[0027] The recitation of ranges of values ​​herein is merely intended to serve as a shorthand method for individually referencing each individual value falling within the range. Unless otherwise indicated herein, each individual value is incorporated herein as if it were individually set forth herein. All methods described herein can be performed in any suitable order unless otherwise indicated herein or clearly contradicted by context. Any examples or exemplary language used herein (e.g., "such as") are merely intended to better describe the subject matter described and do not limit the scope of the claimed subject matter. No language in this specification should be construed as indicating any non-claimed element essential to practicing the subject matter described.

[0028] Groupings of alternative elements or embodiments of the present disclosure should not be construed as limitations. Each group member may be referenced and claimed individually or in any combination with other members of the group or other components found herein. Furthermore, the mentioned members of a group may be included in or excluded from another mentioned group for reasons of convenience or patentability. When such inclusions or exclusions are made, the specification shall be deemed to include the groups modified to satisfy all Markush group descriptions used in the appended claims.

[0029] Throughout this specification, references are made to patents and printed publications, each of which is incorporated herein by reference in its entirety.

[0030] It should be understood that the embodiments of the present disclosure are illustrative, and thus, the present disclosure is not limited to that precisely as shown and described.

[0031] compound In some embodiments, provided herein are tris salts and polymorphs thereof (e.g., solid, amorphous, and crystalline forms) of Compound 1. The tris salt forms of Compound 1 may be included in any composition, including liquid, gel, syrup, powder, or solid forms.

[0032] Each polymorph described herein can be uniquely identified by a number of different analytical parameters, alone or in combination, including X-ray diffraction (XRD) patterning (e.g., X-ray powder diffraction (XRPD)), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), or melting point (MP), to name a few.

[0033] The tris salt forms of Compound 1 used herein are useful in various methods for preparing pharmaceutical compositions comprising one or more salt forms. Thus, the salts and polymorphs provided herein, as well as compositions comprising them, are useful for modulating RXR, and thus for treating diseases associated with RXR modulation.

[0034] Broadly, provided herein is a tris salt form of Compound 1. In some embodiments, the salt form is a solid salt form. In some embodiments, the solid salt form is a crystalline salt form.

[0035] In some embodiments, the crystalline salt form is Form A. In some embodiments, Form A is an anhydrous form. In some embodiments, Form A is characterized by data including one or more of the following: a. one or more XRPD signals at 3.8, 7.6, 11.3, 18.1, or 19.6±0.2 degrees in terms of two theta (2θ); b. one or more XRPD signals at 10.1, 12.0, 19.0, or 24.3±0.2 degrees in terms of two theta (2θ); c. DSC thermogram with an endothermic transition at 154±3°C; d. TGA trace shown in Figure 3.

[0036] In some embodiments, the crystalline salt form is Form B, and in some embodiments, Form B is a hydrate form. In some embodiments, Form B is characterized by data including one or more of the following: a. one or more XRPD signals at 3.9, 11.5, 18.3, 19.9, or 23.2±0.2 degrees in terms of 2θ; b. one or more XRPD signals at 19.9, 23.2, or 26.9±0.2 degrees in terms of 2θ; c. A DSC thermogram containing an endothermic transition at 150±3°C; or d. TGA trace as in Figure 6.

[0037] In some embodiments, the crystalline salt form is characterized by data comprising one, two, three or more XRPD signals, relative to 2θ, selected from the Type A signals of Table 4 with at least one corresponding Type B signal of Table 5 ±0.2°. In some embodiments, the crystalline salt form comprises an XRPD profile substantially as shown in Figure 1. In some embodiments, the crystalline salt form comprises an XRPD profile substantially as shown in Figure 4. In some embodiments, the crystalline salt form comprises at least 50% of the XRPD signals of Table 4, relative to 2θ, ±0.2°. In some embodiments, the crystalline salt form comprises at least 50% of the XRPD signals of Table 5, relative to 2θ, ±0.2°.

[0038] In some embodiments, the compositions provided herein comprise a mixture of Form A and Form B salts. In some embodiments, the compositions comprise multiple polymorphs of the tris salt form of Compound 1, optionally comprising greater than or equal to 80, 90, 95, 99, 99.5, or 99.9% by weight of Form A. In some embodiments, the compositions comprise multiple polymorphs of the tris salt form of Compound 1, optionally comprising greater than or equal to 80, 90, 95, 99, 99.5, or 99.9% by weight of Form B.

[0039] Tris salts of compound 1 described herein may also be prepared as isotopically labeled compounds in which one or more atoms are replaced with an atom having the same atomic number but an atomic mass or mass number different from the atomic mass or mass number predominantly found in nature. Examples of isotopes suitable for inclusion in the compounds described herein include: 2 H, 3 H, 11 C. 13 C. 14 C. 36 Cl, 18 F, 123 I, 125 I, 13 N, 15 N, 15 O. 17 O. 18 O. 32 P, and 35 In some embodiments, isotope-labeled compounds are useful for drug or substrate tissue distribution studies. In another embodiment, substitution with heavier isotopes such as deuterium provides greater metabolic stability (e.g., increased in vivo half-life or reduced dosage). In yet another embodiment, 11 C. 18 F, 15 O and 13 Substitution with positron emitting isotopes, such as N, is useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy. Isotopically labeled compounds are prepared by any suitable method or technique in which an appropriate isotopically labeled reagent is substituted for a non-labeled reagent employed in other methods.

[0040] In some embodiments, the solid forms provided herein are prepared as particles or as compressed solids. In some embodiments, these solid forms are coated. In some embodiments, the particles comprise an average particle size of about 10 microns or less. In some embodiments, the particles comprise an average particle size of about 2 microns or less. In some embodiments, the particles comprise an average particle size of about 10 to 20 microns or more. In some embodiments, the solid forms or particles provided herein are formulated as a suspension in a liquid or as a dry powder for aerosol administration.

[0041] In some embodiments, the solid form is at least about 75, 80, 85, 90, 95, or 100% by weight of the particle.

[0042] In some embodiments, the particle comprises a particle surface, the particle surface comprises a coating on at least a portion of the particle surface. In some embodiments, the coating comprises a film coating. In some embodiments, the particle comprises a film coating with a polymer or copolymer to form a microcapsule that may be used to form a chewable taste-masked granule. In some embodiments, the coating comprises a polymer or copolymer. In some embodiments, the coating comprises one or more of cellulose acetate phthalate, cellulose acetate trimerate, ethyl cellulose, glycol, hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose phthalate, methacrylic acid copolymer, high molecular weight polyethylene, polyvinyl alcohol, polyvinylpyrrolidone, starch, or shellac. In some embodiments, the coating comprises a sugar. In some embodiments, the coating comprises a sugar coating. In some embodiments, the particles described herein are sugar coated. In some embodiments, the particles described herein are not sugar coated. In some embodiments, the coating comprises an enteric coating. In some embodiments, the coating is an extended release coating. In some embodiments, the coating is a sustained release coating. In some embodiments, the coating comprises a controlled release coating. In some embodiments, the coating is a delayed release coating. In some embodiments, the particles described herein may comprise a second coating layered over the first coating. In some embodiments, the coating is stable at less than about pH 7. In some embodiments, the coating is stable at less than about pH 5.5. In some embodiments, the coating is stable in an acidic environment.In some embodiments, the coating is stable in gastric fluids and unstable in intestinal fluids.

[0043] In some embodiments, a dosage form comprising a plurality of particles comprises coated particles, where the coating is selected, independently for each particle, from the coatings described herein. Thus, in some embodiments, the plurality of particles may comprise a mixture of enteric coated particles and sustained release coated particles.

[0044] In some embodiments, the particles described herein are encapsulated within a coating.

[0045] In some embodiments of the particles described herein, the coating is no greater than 25% by weight of the coated particle.

[0046] In some embodiments, the particles described herein are provided as a composition comprising a plurality of particles, which may comprise one or more carriers. In some embodiments, the plurality of particles is encapsulated in a capsule, a compression coating, a film coating, or a powder coating. In some embodiments, the particle or particles are spray coated, either as a powder, a compressed powder, or a tablet. In some embodiments, the plurality of particles is a loose powder in an ingestible capsule. In some embodiments, the plurality of particles is compressed into a friable solid.

[0047] In some embodiments, a dosage form is provided that includes the particles, compositions, or pharmaceutical compositions described herein. In some embodiments, the dosage form includes a plurality of particles as a powder or as a compressed powder. In some embodiments, the dosage form includes a plurality of particles in a suspension. As described above, the particles may be coated.

[0048] In some embodiments, the solid form, particle, composition, or pharmaceutical composition described herein is contained in at least one container.

[0049] composition In some embodiments, a composition is provided that includes a tris salt form of Compound 1 described herein.

[0050] In some embodiments, a pharmaceutical composition is provided that includes a tris salt form of Compound 1 described herein and a pharma- ceutically acceptable carrier.

[0051] In some embodiments of the compositions provided herein, the compositions further comprise a thyroid hormone. In some embodiments of the compositions provided herein, the compositions further comprise a therapeutically effective amount of a thyroid hormone.

[0052] In some embodiments of the compositions provided herein, the compositions further comprise a neurotrophic factor. In some embodiments of the compositions provided herein, the compositions further comprise a therapeutically effective amount of a neurotrophic factor.

[0053] In some embodiments, the neurotrophic factor is a GLP agonist, BDNF, GDNF, NGF, NT-3, bFGF, CNTF, NT-4 / 5, IGF, or insulin, or a mimetic thereof, or a combination of two or more thereof. In some embodiments, the GLP agonist is independently selected from semaglutide, dulaglutide, exenatide, liraglutide, or lixisenatide.

[0054] method In some embodiments, a method for treating a disease in a subject in need of treatment is provided, comprising administering to the subject a therapeutically effective amount of a compound described herein.In some embodiments, the disease is an RXR-related disease.RXR affects a variety of cellular processes, including cell proliferation, immune response, lipid and glucose metabolism, and neuropathy.In some embodiments, the disease comprises neurodegeneration.In some embodiments, the neurodegeneration comprises age-related neurodegeneration.In some embodiments, the disease comprises hypoxic brain injury, retinopathy, glaucoma, type II diabetes, Huntington's disease, migraine, chronic pain, or alopecia areata.

[0055] In some embodiments, there is provided a method of promoting hair growth in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound described herein.

[0056] In some embodiments, the subject has a refractory disease. In some embodiments, the refractory disease comprises a refractory cancer.

[0057] In some embodiments, the refractory disease comprises a thyroid hormone resistant disease.

[0058] In some embodiments, the refractory disease comprises a neurotrophic factor resistant disease.

[0059] In some embodiments of the methods provided herein, the methods further comprise administering a therapeutically effective amount of a thyroid hormone.

[0060] In some embodiments of the methods provided herein, the methods further comprise administering a therapeutically effective amount of a neurotrophic factor.

[0061] In some embodiments, the neurotrophic factor is a GLP agonist, BDNF, GDNF, NGF, NT-3, bFGF, CNTF, NT-4 / 5, IGF, or insulin, or a mimic thereof, or a combination of two or more thereof. In some embodiments, the neurotrophic factor is GDNF, or a GDNF mimic, and the CNS disease is Parkinson's disease. In some embodiments, the neurotrophic factor is GDNF, or a GDNF mimic, and the CNS disease is multiple sclerosis. In some embodiments, the neurotrophic factor is GDNF, or a GDNF mimic, and the CNS disease is amyotrophic lateral sclerosis. In some embodiments, the neurotrophic factor is GDNF, or a GDNF mimic, and the CNS disease is Alzheimer's disease. In some embodiments, the neurotrophic factor is BDNF, and the CNS disease is Alzheimer's disease. In some embodiments, the neurotrophic factor is insulin or an insulin-like growth factor, and the CNS disease is Alzheimer's disease. In some embodiments, the neurotrophic factor is BDNF and the CNS disease is multiple sclerosis. In some embodiments, the neurotrophic factor is BDNF and the CNS disease is stroke, nervous system trauma, aging, or dementia. In some embodiments, the neurotrophic factor is BDNF, or GDNF, or insulin, or a mimic thereof, or a combination of two or more thereof, and the CNS disease is age-related CNS neurodegeneration. In some embodiments, the neurotrophic factor is IGF, or a mimic thereof, and the CNS disease is Parkinson's disease, or Alzheimer's disease, or amyotrophic lateral sclerosis, or multiple sclerosis, or age-related neurodegeneration. In some embodiments, the neurotrophic factor or mimic is administered by oral, parenteral, nasal, or topical route, or by controlled release.

[0062] In some embodiments of the methods provided herein, the disease is selected from a nervous system disease, a muscle disease, a cell proliferation disease (e.g., a cancer or tumor), or an autoimmune disease. In some embodiments, the cancer is a non-solid cancer (e.g., a liquid cancer, e.g., a blood cancer). In some embodiments, the cancer or tumor is a solid cancer or tumor.

[0063] In some embodiments, the nervous system disease is relapsing / remitting, primary progressive, and secondary progressive forms of multiple sclerosis (MS), diffuse white matter damage in premature infants, neuromyelitis optica, acute disseminated encephalomyelitis, Marburg multiple sclerosis, diffuse myeloclastic sclerosis (Schilder's disease), Baroconcentric sclerosis, sporadic sclerosis, optic neuritis, transverse myelitis, amyotrophic lateral sclerosis (ALS), leukodystrophies (multiple variants, e.g., adrenoleukodystrophy, adrenomyeloneuropathy). , Parkinson's disease, Alzheimer's disease, progressive supranuclear palsy, stroke, seizure disorders, CNS trauma including traumatic brain injury and traumatic spinal cord injury, radiation-induced neuroinflammation, radiation somnolence syndrome, Devic's disease, inflammatory demyelinating diseases, CNS neuropathy, central pontomyelolysis, dorsal Tabb's disease (syphilitic myelopathy), progressive multifocal leukoencephalopathy, leukodystrophies, depression, schizophrenia, epilepsy, dementia, cancer, AIDS, chronic kidney disease, and cachexia associated with old age.

[0064] In some embodiments, the central nervous system disease is a demyelination-related disease such as multiple sclerosis, radiation-induced central nervous system inflammation, Alzheimer's disease, or Parkinson's disease.

[0065] In some embodiments, the nervous system disease is a peripheral nervous system disease, such as Guillain-Barre syndrome, acute inflammatory demyelinating polyneuropathy, chronic inflammatory demyelinating polyneuropathy, demyelinating diabetic neuropathy, progressive inflammatory neuropathy, drug- or toxin-induced neuropathy such as chemotherapy-induced neuropathy or organophosphate-induced neuropathy, anti-MAG peripheral neuropathy, Charcot-Marie-Tooth disease, or copper deficiency.

[0066] In some embodiments, the muscle disease is a muscle wasting disease. In some embodiments, the muscle disease is a muscle wasting disease. In some embodiments, the muscle disease is a muscle wasting disease. In some embodiments, the muscle disease is a muscle wasting disease. In some embodiments, the muscle disease is a muscle wasting disease. In some embodiments, the muscle disease is a muscle wasting disease. In some embodiments, the muscle disease is a muscle wasting disease. In some embodiments, the muscle disease is a muscle wasting disease. In some embodiments, the muscle disease is a muscle wasting disease. In some embodiments, the muscle disease is a muscle wasting disease. - selected from Dryfs muscular dystrophy (EDMD), facioscapulohumeral muscular dystrophy (FSHD), fibromyalgia, fibrositis, limb-girdle muscular dystrophy (LGMD), McArdle syndrome, muscular dystrophy, muscle fatigue, myasthenia gravis, myofascial pain syndrome, myopathy, myotonia, myotonic muscular dystrophy type 1, myotonic muscular dystrophy type 2, nemaline myopathy, oculopharyngeal muscular dystrophy (OCM), myoglobinuria, paramyotonia congenita (Eulenberg disease), polymyositis, rhabdomyolysis, sarcoglycanopathy, or spasticity.

[0067] In some embodiments, the muscle disease is a myopathy, such as dermatomyositis, inclusion body myositis, or polymyositis.

[0068] In some embodiments, the muscle disease is caused by cancer, HIV / AIDS, COPD, chronic steroid use, fibromyalgia, or a skeletal myopathy.

[0069] In certain embodiments for treating an autoimmune disease, the method includes treating acute disseminated encephalomyelitis (ADEM), Addison's disease, allergies, allergic rhinitis, antiphospholipid syndrome (APS), arthritis, asthma, acquired immune deficiency syndrome (AIDS), autoimmune hemolytic anemia, autoimmune hepatitis, autoimmune inner ear disease, bullous pemphigoid, celiac disease, Chagas disease, chronic obstructive pulmonary disease (COPD), type 1 diabetes mellitus (IDDM), endometriosis, gastrointestinal diseases, glomerulonephritis, Goodpasture's syndrome, Graves' disease, Guillain-Barré syndrome, and others. Treating an autoimmune disease selected from the group consisting of Barre syndrome (GBS), Hashimoto's thyroiditis, sweat gland abscess, idiopathic thrombocytopenic purpura, interstitial nephritis, interstitial cystitis, lupus, morphea, multiple sclerosis (MS), myasthenia gravis, myopathy, myositis, narcolepsy, neuromyotonia, pemphigus vulgaris, pernicious anemia, primary biliary cirrhosis, psoriasis, psoriatic arthritis, pulmonary fibrosis, relapsing disseminated encephalomyelitis, rheumatic fever, schizophrenia, scleroderma, Sjogren's syndrome, skin disease, tenosynovitis, uveitis, vasculitis, or vitiligo.

[0070] In certain embodiments, the disease does not include multiple sclerosis, ie, the subject being treated does not have or has not been diagnosed as having multiple sclerosis.

[0071] In certain embodiments, the arthritis is monoarthritis, oligoarthritis, polyarthritis, osteoarthritis, rheumatoid arthritis, juvenile idiopathic arthritis, septic arthritis, spondyloarthropathy, gout, pseudogout, or Still's disease.

[0072] In some embodiments, the gastrointestinal disease is irritable bowel disease or inflammatory bowel disease, hi other embodiments, the inflammatory bowel disease is Crohn's disease or ulcerative colitis.

[0073] In some embodiments, the lupus is discoid lupus erythematosus, drug-induced lupus erythematosus, lupus nephritis, neonatal lupus, subacute cutaneous lupus erythematosus, or systemic lupus erythematosus.

[0074] In some embodiments, the autoimmune disease is a myopathy with an autoimmune component, such as dermatomyositis, inclusion body myositis, or polymyositis.

[0075] In some embodiments, the skin disorder is dermatitis, eczema, hidradenitis pustular, psoriasis, rosacea, or scleroderma.

[0076] In some embodiments, the vasculitis is Buerger's disease, cerebral vasculitis, Churg-Strauss arteritis, cryoglobulinemia, essential cryoglobulinemic vasculitis, giant cell arteritis, golfer's vasculitis, Henoch-Schonlein purpura, hypersensitivity vasculitis, Kawasaki disease, microscopic polyarteritis / polyangiitis, polyarteritis nodosa, polymyalgia rheumatica (PMR), rheumatoid vasculitis, Takayasu's arteritis, or Wegener's granulomatosis.

[0077] In some embodiments, the autoimmune disease is multiple sclerosis, psoriasis, rheumatoid arthritis, glomerulonephritis, pulmonary fibrosis, interstitial nephritis, or inflammatory bowel disease.

[0078] Although the methods described herein refer to the compounds described herein, it should be understood that the compounds may also be used in conjunction with these methods in the form of compositions or pharmaceutical compositions.

[0079] The actual dosage of the active ingredient (e.g., a compound of the formulae provided herein), composition, or pharmaceutical composition provided herein may be varied to obtain an amount of the active ingredient that is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, and which is not toxic to the patient.

[0080] In particular, the selected dosage level depends on various factors, including the activity of the specific compound employed, the administration time, the excretion rate of the compound, the duration of treatment, other drugs, compounds or materials used in combination with the compound, the age, sex, weight, condition, general health, and previous medical history of the patient being treated, and factors as known in the art.A physician, such as a physician or veterinarian, having ordinary skill in the art may easily determine and prescribe the effective amount of pharmaceutical composition required.For example, a physician or veterinarian may start the dose of the compound employed in the pharmaceutical composition at a level lower than the level required to achieve the desired therapeutic effect, and gradually increase the dose until the desired effect is achieved.

[0081] Administration of the compounds, compositions, or combinations disclosed herein can be by any acceptable form, including, but not limited to, oral administration in any acceptable form, such as, for example, tablets, liquids, capsules, powders, etc.; topical administration in any acceptable form, such as, for example, drops, sprays, creams, gels, or ointments, etc.; buccal, nasal, and / or inhalation administration in any acceptable form; rectal administration in any acceptable form; vaginal administration in any acceptable form; intravascular administration in any acceptable form, such as, for example, intravenous bolus injection, intravenous infusion, intra-arterial bolus injection, intra-arterial infusion, and catheter infusion into the vascular system; These include various enteral or parenteral approaches selected from, for example, peri- and intra-tissue administration in any acceptable form, such as intraperitoneal injection, intramuscular injection, subcutaneous injection, subcutaneous infusion, intraocular injection, retinal injection, or subretinal or epidural injection; intravesical administration in any acceptable form, such as, for example, catheter infusion; and administration by placement devices, such as, for example, implants, stents, patches, pellets, catheters, osmotic pumps, suppositories, bioerodible delivery systems, non-bioerodible delivery systems, or another implanted sustained or slow release system.

[0082] The compounds, compositions, or combinations disclosed herein can be administered to a mammal using a variety of routes. The routes of administration include, but are not limited to, oral, nasal, rectal, vaginal, parenteral, buccal, sublingual, or topical. In some embodiments, the oral or nasal route of administration is an oral inhalation route or a nasal inhalation route of administration. The compounds for use as described herein may be formulated for administration by any suitable route to achieve the particular method of application. In some embodiments, the routes of administration suitable for treating demyelination-related diseases disclosed herein include both local and systemic administration. Local administration results in significantly more delivery of the compound, composition, or combination to a particular site compared to the entire body of the mammal, whereas systemic administration results in delivery of the compound, composition, or combination to essentially the entire body of the individual. The routes of administration suitable for or for treating demyelination-related diseases as disclosed herein also include both central and peripheral administration. Central administration essentially results in delivery of the compound, composition or combination to the central nervous system of an individual, and includes, for example, intranasal administration, intrathecal administration, epidural administration, as well as cranial injections or implants. In some embodiments, central administration is used to administer the compounds, compositions, or combinations described herein.

[0083] Central administration by nasal route, which targets drug absorption through the vascular plexus of the nasal cavity, is different from administration by nasal inhalation, which delivers drugs via the pulmonary system.The latter usually uses liquid or dry powder aerosols with average particle size of less than 10 microns, and in some embodiments, about 2 microns or less, while central administration is usually achieved using average particle size of 10 to 20 microns or more.Mists and aerosols can be produced using nebulizers, dry powder inhalers, pressurized aerosols, and spray pumps, with the latter being preferred.Central administration by nasal route can also be achieved using nasal drops.

[0084] Peripheral administration results in the delivery of the compound, composition, or combination to essentially any site of an individual other than the central nervous system, and includes any route of administration other than direct administration to the spine or brain. The actual route of administration of the compounds, compositions, or combinations used herein can be determined by those of skill in the art, taking into consideration factors including, but not limited to, the type of demyelination-related disease, the site of the demyelination-related disease, the cause of the demyelination-related disease, the severity of the demyelination-related disease, the desired duration of treatment, the desired degree of relief, the desired duration of relief, the specific compound, composition, or combination, the rate of excretion of the compound, composition, or combination used, the pharmacodynamics of the compound, composition, or combination used, the nature of other compounds included in the composition or combination, the specific route of administration, the specific characteristics, medical history, and risk factors of the individual, such as age, weight, general health, etc., the individual's response to treatment, or a combination thereof. Thus, the effective dosage of the compounds, compositions, or combinations disclosed herein can be readily determined by those of skill in the art by considering all criteria and utilizing their best judgment for the individual.

[0085] In some embodiments, a packaged compound, packaged composition, or packaged pharmaceutical composition is provided that includes a container holding a therapeutically effective amount of a compound described herein and instructions for using the compound according to one or more of the methods provided herein.

[0086] The compounds and related materials can be completed as commercial products by processes commonly performed in the art, such as appropriate sterilization and packaging processes. For example, the materials can be treated with UV / visible light irradiation (200-500 nm), for example with photoinitiators with different absorption wavelengths (e.g., Irgacure 184, 2959), preferably with a water-soluble initiator (e.g., Irgacure 2959). Such irradiation is typically performed for irradiation times of 1-60 minutes, although longer irradiation times may be used depending on the specific method. The materials according to the present disclosure can be finally sterile packaged and packaged (e.g., adding a specific product information leaflet) in a suitable container (e.g., a box) to maintain sterility until the time of use.

[0087] According to further embodiments, the compounds can be provided in kit form in combination with other components necessary for administration of the material to a patient. For example, the disclosed kits for use in the treatment of cancer can further include, for example, administration materials.

[0088] The kits are designed in a variety of forms based on the specific defect they are designed to treat.

[0089] The compounds or compositions provided herein may be prepared and housed in containers for storage at ambient or elevated temperatures. When the compounds or compositions are stored in polyolefin plastic containers compared to polyvinyl chloride plastic containers, discoloration of the compounds or compositions may be reduced, even if the compounds or compositions are dissolved or suspended in a liquid composition (e.g., aqueous or organic liquid solution) or are solid. Without intending to be bound by theory, the containers may reduce exposure of the contents of the container to electromagnetic radiation, whether visible light (e.g., wavelengths of about 380-780 nm) or ultraviolet (UV) light (e.g., wavelengths of about 190-320 nm (UV B light) or about 320-380 nm (UV A light)). Some containers include a second component capable of, or having such capability, reducing exposure of the contents of the container to infrared radiation. Containers that may be used include those made from polyolefins such as polyethylene, polypropylene, polyethylene terephthalate, polycarbonate, polymethylpentene, polybutene, or combinations thereof, particularly polyethylene, polypropylene, or combinations thereof. In some embodiments, the container is a glass container. The container may be placed within a second container, e.g., a container of paper, cardboard, paperboard, metal film, or foil, or a combination thereof, to reduce further exposure of the contents of the container to ultraviolet, visible, or infrared radiation. Compounds and compositions that benefit from reduced discoloration, decomposition, or both during storage include eye drops or implants that include the compounds or compositions provided herein. The compounds or compositions provided herein may require storage for three months or longer, and in some cases may require storage for one year or longer. The container may be any shape suitable for containing the contents, e.g., a bag, a bottle, a box.

[0090] The following examples further illustrate aspects of the present disclosure, but are not meant to be limitations of the teachings or disclosure described herein.

[0091] (Example) Salts of compound 1 were isolated. For example, about 50 mg of the starting free acid (compound 1) and the corresponding base were mixed in about 0.06-8.0 mL of a solvent system with a molar charge ratio of 1:1 (Ca and Mg used a molar ratio of 2:1). After 4 days of magnetic stirring at room temperature, the precipitate was isolated by centrifugation. If no precipitate was observed, the clear solution was transferred and stirred at 5°C for 24 hours to induce crystallization. If no solids were still observed, the clear solution was finally slowly evaporated at room temperature. The isolated solids were dried under vacuum at 40°C for 2 hours before analysis. The various isolated salts of compound 1 were tested for solid-state properties such as solid-state stability, hygroscopicity, crystallinity, morphology (anhydrous, hydrated, or solvate), and solubility in simulated gastric and small intestinal fluids. The tris salt of compound 1 was chosen for further analysis, in part, based on the discovery that it had various improved solid-state properties compared to compound 1.

[0092] Values ​​of 2θ and °C may vary from sample to sample and from instrument to instrument, therefore values ​​reported herein may include variations of ±0.2° for 2θ values ​​and ±3°C for °C values.

[0093] Example 1 Tris Salt Crystallization. Table 3 describes a procedure for preparing crystals of tris salt form A. The X-ray diffraction pattern of the dried product shows that the solid produced is mostly form A, but also shows the characteristic signal of form B at very weak intensity. The DSC curve shows two thermal transitions at 149.3 °C (corresponding to form B from the salt screen) and 153.9 °C (corresponding to form A), confirming the presence of form B in the product. Table 3a describes an alternative procedure for preparing crystals of tris salt form A.

[0094] [Table 3]

[0095] Example 2 Preparation of Form B. Form B can be prepared according to Table 3, where the solvent contains at least 3% water by volume. Form B can also be prepared according to Table 3a.

[0096] [Table 3a]

[0097] Example 3 XRPD analysis. A Panalytical Xpert instrument was used with the following parameters: X-ray tube Cu (Kα); tube voltage 45 kV; tube current 40 mA; scan 2-40 degrees 2θ; 0.01 degree / step; and scan speed 6 degrees / min. The results are shown in Figure 1 and Figure 4.

[0098] Table 4 provides a list of the XRPD signals and relative intensities for the Tris salt Form A of Compound 1. Table 5 provides a list of the XRPD signals and relative intensities for the Tris salt Form B of Compound 1.

[0099] [Table 4]

[0100] [Table 5]

[0101] Example 4 Differential Scanning Calorimetry. A TA Instruments Discovery DSC (DSC-1) instrument was used with the following parameters: ramp 3 °C / min, scan 25-250 °C, N sweep 50 mL / min. The results are shown in Figures 2 and 5.

[0102] Table 6 shows the DSC endothermic transition temperatures of the tris salt form A of Compound 1 and the tris salt form B of Compound 1.

[0103] [Table 6]

[0104] Example 5 Thermogravimetric analysis. A TA Instruments Discovery TGA instrument was used with the following parameters: ramp 10 °C / min, scan 25-250 °C, N sweep 50 mL / min. The results are shown in Figures 3 and 6.

[0105] Example 6 Polarized Light Microscopy. An Olympus BX51 polarized light microscope with the following parameters was used: JENOPTIK ProgRes camera and ProgRes Capture Pro 2.8.8 software.

[0106] Example 7 Dynamic solubility. Dynamic solubility measurements were performed on Compound 1 (free acid) and the Tris salt form A of Compound 1 in water and three biologically relevant media (artificial gastric fluid, fed artificial small intestinal fluid, and fasted artificial small intestinal fluid) at 37°C. The results are shown in Table 1.

[0107] Example 8 Preparation of tris salt Form C of Compound 1 and tris salt Form D of Compound 1 (see Figures 7, 8C and 8D). Forms C and D may be prepared by a procedure similar to that described above for preparing Form A, except that 2-methyltetrahydrofuran is used as the solvent for Form C and methanol is used as the solvent for Form D. Form C may be a 2-MeTHF solvate and Form D may be a methanol solvate, and both may be converted to Form A by heating, for example, at 110°C.

[0108] Example 9 Salt screening. Sixty salt screening experiments were performed using 10 bases and 6 solvent systems. Specifically, approximately 50 mg of the starting free acid of compound 1 and the corresponding base were mixed in 0.06–8.0 mL of solvent at a 1:1 molar ratio (with the exception of calcium and magnesium, which were in a 2:1 molar ratio). After magnetic stirring at room temperature for 4 days, the precipitate was isolated by centrifugation. If no precipitate was present, the clear solution was transferred to 5 °C and stirred for 24 h to induce crystallization. If no solid was still obtained, the final clear solution was slowly evaporated at room temperature. The isolated solid was vacuum dried at 40 °C for 2 h before analysis. Crystalline salts were obtained as confirmed by XRPD, DSC and TGA, namely Na salt forms A / B / C / D, K salt forms A / B / C / D / E, diethylamine salt forms A / B / C, Tris salt forms A / B, Lysine salt forms A / B / C / D, Ammonium salt forms A / B / C / D, Mg salt forms A / B and Ca salt forms A / B / C, as summarized in Table 7; see Figure 7-23. Tris salt forms C / D were prepared from 2-MeTHF and MeOH, respectively.

[0109] [Table 7]

[0110] In some embodiments, the solid forms provided herein may be described by their respective XRPD signal patterns or portions thereof. For example, the solid forms may be described by one, two, three, four, or five, or six or more XRPD signals ±0.2° 2θ, where each signal is selected from those signals provided in the table herein corresponding to the described solid form. In some embodiments, the signals used to describe the solid forms herein are selected from the signals described herein having at least 100 cts. The description of the XRPD signal patterns of the solid forms described herein may include about 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 95, or 100% of the signals included in the table of XRPD signals provided corresponding to the particular solid form described, and optionally the table of XRPD signals is limited to signals having at least 100 cts. In some embodiments, the signals used herein to describe solid forms are selected from signals having a relative intensity of at least about 0.25, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, or 20%.

[0111] In some embodiments, a solid form provided herein may be described by an XRPD signal pattern that includes an XRPD signal that is not within 0.2° 2θ of another solid form provided herein. For example, a solid form provided herein may include an XRPD signal pattern that includes the following: 2.59±0.2° 2θ (e.g., K-salt C-type), 5.12±0.2° 2θ (e.g., lysine salt type B), 5.47±0.2° 2θ (e.g. Tris salt type C), 8.66±0.2° 2θ (e.g., lysine salt form A), or 39.70±0.2° 2θ (e.g., Tris salt D type) The XRPD signal may be one or more of the following:

[0112] In some embodiments, a solid form provided herein may be described by an XRPD signal pattern that includes an XRPD signal that is not within 0.15° 2θ of another solid form provided herein. For example, a solid form provided herein may include an XRPD signal pattern that includes the following: 2.59±0.15° 2θ (e.g., K-salt C-type), 2.94±0.15° 2θ (e.g., Tris salt type C), 3.12±0.15° 2θ (e.g., lysine salt type B), 4.57±0.15° 2θ (e.g. NH4 salt C type), 4.73±0.15° 2θ (e.g. NH4 salt A type), 5.12±0.15° 2θ (e.g., lysine salt type B), 5.47±0.15° 2θ (e.g. Tris salt type C), 8.66±0.15° 2θ (e.g., lysine salt form A), 26.65±0.15° 2θ (e.g. NH4 salt type A), 35.21±0.15° 2θ (e.g. Tris salt type A), 35.71±0.15° 2θ (e.g. Na salt A type), 37.03±0.15° 2θ (e.g., Na salt form B), or 39.70±0.15° 2θ (e.g. Tris salt D type) The XRPD signal may include one or more of the following:

[0113] In some embodiments, a solid form provided herein may be described by an XRPD signal pattern that includes an XRPD signal that is not within 0.10° 2θ of another solid form provided herein. For example, a solid form provided herein may include the following: 2.59±0.10° 2θ (e.g., K-salt C-type), 2.94±0.10° 2θ (e.g., Tris salt type C), 3.12±0.10° 2θ (e.g., lysine salt type B), 4.57±0.10° 2θ (e.g. NH4 salt C type), 4.73±0.10° 2θ (e.g. NH4 salt type A), 5.12±0.10° 2θ (e.g., lysine salt type B), 5.47±0.10° 2θ (e.g. Tris salt type C), 6.01±0.10° 2θ (e.g. NH4 salt type B), 6.46±0.10° 2θ (e.g. Tris salt type C), 8.26±0.10° 2θ (e.g. starting material), 8.66±0.10° 2θ (e.g., lysine salt form A), 10.44±0.10° 2θ (e.g., lysine salt D-form), 12.16±0.10° 2θ (e.g. DEA salt type C), 12.65±0.10° 2θ (e.g. NH4 salt D type), 14.39±0.10° 2θ (e.g. NH4 salt D type), 24.95±0.10° 2θ (e.g. K salt E type), 26.65±0.10° 2θ (e.g. NH4 salt type A), 30.63±0.10° 2θ (e.g. NH4 salt D type), 32.84±0.10° 2θ (e.g., Tris salt type B), 33.95±0.10° 2θ (e.g. DEA salt type B), 34.07±0.10° 2θ (e.g. Tris salt type B), 35.21±0.10° 2θ (e.g. Tris salt type A), 35.71±0.10° 2θ (e.g. Na salt type A), 36.58±0.10° 2θ (e.g. Na salt C type), 36.71±0.10° 2θ (e.g., lysine salt D-form), 37.03±0.10° 2θ (e.g., Na salt B form), or 39.70±0.10° 2θ (e.g., Tris salt D type) The XRPD signal may include one or more of the following:

[0114] In some embodiments, the solid forms provided herein may be described by an XRPD signal pattern that includes an XRPD signal that is not within 0.2° 2θ of another solid form provided herein when considering an XRPD signal that is greater than 100 ct in height. For example, the solid forms provided herein may include an XRPD signal pattern that includes an XRPD signal that is not within 0.2° 2θ of another solid form provided herein when considering an XRPD signal that is greater than 100 ct in height. 2.59±0.2° 2θ (e.g., K-salt C-type), 5.12±0.2° 2θ (e.g., lysine salt type B), 5.47±0.2° 2θ (e.g. Tris salt type C), 8.66±0.2° 2θ (e.g., lysine salt form A), 32.33±0.2° 2θ (e.g., Tris salt type B), 34.07±0.2° 2θ (e.g. Tris salt type B), 35.05±0.2° 2θ (e.g. Tris salt type B), 36.41±0.2° 2θ (e.g. starting material), 37.61±0.2° 2θ (e.g., Tris salt form D), or 39.70±0.2° 2θ (e.g., Tris salt D type) The XRPD signal may include one or more of the following:

[0115] In some embodiments, a solid form provided herein may be described by an XRPD signal pattern that includes an XRPD signal that is not within 0.15° 2θ of another solid form provided herein when considering an XRPD signal that is greater than 100 ct in height. For example, a solid form provided herein may include an XRPD signal pattern that includes an XRPD signal that is greater than 100 ct in height and that is not within 0.15° 2θ of another solid form provided herein. 2.59±0.15° 2θ (e.g., K-salt C-type), 2.94±0.15° 2θ (e.g., Tris salt type C), 3.12±0.15° 2θ (e.g., lysine salt type B), 4.57±0.15° 2θ (e.g. NH4 salt C type), 4.73±0.15° 2θ (e.g. NH4 salt A type), 5.12±0.15° 2θ (e.g., lysine salt type B), 5.47±0.15° 2θ (e.g. Tris salt type C), 8.45±0.15° 2θ (e.g. Tris salt type C), 8.66±0.15° 2θ (e.g., lysine salt form A), 8.86±0.15° 2θ (e.g. Tris salt type C), 32.33±0.15° 2θ (e.g., Tris salt type B), 32.67±0.15° 2θ (e.g. Tris salt D type), 32.84±0.15° 2θ (e.g. Tris salt type B), 33.53±0.15° 2θ (e.g. Tris salt D type), 34.07±0.15° 2θ (e.g. Tris salt type B), 35.05±0.15° 2θ (e.g. Tris salt type B), 36.41±0.15° 2θ (e.g. starting material), 37.61±0.15° 2θ (e.g., Tris salt D type), 38.91±0.15° 2θ (e.g., Tris salt form D), or 39.70±0.15° 2θ (e.g., Tris salt D type) The XRPD signal may include one or more of the following:

[0116] In some embodiments, the solid forms provided herein may be described by an XRPD signal pattern that includes an XRPD signal that is not within 0.10° 2θ of another solid form provided herein when considering an XRPD signal that is greater than 100 ct in height. For example, the solid forms provided herein may include an XRPD signal pattern that includes an XRPD signal that is not within 0.10° 2θ of another solid form provided herein when considering an XRPD signal that is greater than 100 ct in height. 2.59±0.10° 2θ (e.g., K-salt C-type), 2.94±0.10° 2θ (e.g., Tris salt type C), 3.12±0.10° 2θ (e.g., lysine salt type B), 4.57±0.10° 2θ (e.g. NH4 salt C type), 4.73±0.10° 2θ (e.g. NH4 salt type A), 5.12±0.10° 2θ (e.g., lysine salt type B), 5.47±0.10° 2θ (e.g. Tris salt type C), 6.01±0.10° 2θ (e.g. NH4 salt type B), 6.46±0.10° 2θ (e.g. Tris salt type C), 7.95±0.10° 2θ (e.g. NH4 salt type B), 8.11±0.10° 2θ (e.g. DEA salt type C), 8.26±0.10° 2θ (e.g. starting material), 8.45±0.10° 2θ (e.g., Tris salt type C), 8.66±0.10° 2θ (e.g., lysine salt form A), 8.86±0.10° 2θ (e.g. Tris salt type C), 10.43±0.10° 2θ (e.g., lysine salt D-form), 12.16±0.10° 2θ (e.g. DEA salt type C), 12.65±0.10° 2θ (e.g. NH4 salt D type), 14.39±0.10° 2θ (e.g. NH4 salt D type), 24.95±0.10° 2θ (e.g. K salt E type), 26.21±0.10° 2θ (e.g. NH4 salt A type), 28.18±0.10° 2θ (e.g. NH4 salt D type), 28.92±0.10° 2θ (e.g. Tris salt type C), 29.04±0.10° 2θ (e.g. Tris salt type B), 29.83±0.10° 2θ (e.g. Tris salt type C), 29.97±0.10° 2θ (e.g. Tris salt D type), 32.34±0.10° 2θ (e.g. Tris salt type B), 32.67±0.10° 2θ (e.g. Tris salt D type), 32.84±0.10° 2θ (e.g. Tris salt type B), 33.53±0.10° 2θ (e.g. Tris salt D type), 34.07±0.10° 2θ (e.g. Tris salt type B), 35.05±0.10° 2θ (e.g. Tris salt type B), 36.41±0.10° 2θ (e.g. starting material), 37.61±0.10° 2θ (e.g., Tris salt D type), 38.91±0.10° 2θ (e.g., Tris salt D type), 39.26±0.10° 2θ (e.g., Tris salt D form), or 39.70±0.10° 2θ (e.g. Tris salt D type) The XRPD signal may include one or more of the following:

[0117] Tables 8-37 provide listings of the signals, heights, and relative intensities for some of the XRPD signal patterns of the solid forms identified in Table 7.

[0118] [Table 8a] [Table 8b]

[0119] [Table 9a] [Table 9b]

[0120] [Table 10a] [Table 10b]

[0121] [Table 11a] [Table 11b]

[0122] [Table 12a]

Table 12b

[0123]

Table 13

[0124]

Table 14

[0125]

Table 15

[0126]

Table 16

[0127]

Table 17

[0128]

Table 18

[0129]

Table 19

[0130]

Table 20

[0131]

Table 21

[0132]

Table 22

[0133]

Table 23

[0134]

Table 24

[0135]

Table 25

[0136]

Table 26

[0137]

Table 27

[0138]

Table 28

[0139]

Table 29

[0140]

Table 30

[0141]

Table 31

[0142]

Table 32

[0143] [Table 33]

[0144] [Table 34]

[0145] [Table 35]

[0146] [Table 36]

[0147] [Table 37]

[0148] Unless otherwise noted, all numerical values ​​used in the specification and claims expressing quantities of ingredients, properties such as molecules, reaction conditions, and the like, are understood to be modified by the word "about". As used herein, the terms "about" and "approximately" mean within a range of 10 to 15%, preferably 5 to 10%. Thus, the numerical parameters set forth in the specification and appended claims are, unless otherwise indicated, estimates and may vary depending on the properties desired to be obtained by the present invention. At the very least, and not as an attempt to limit the application of the doctrine of equivalents to the scope of the claims, each numerical parameter should be construed in light of at least the number of reported significant digits and by applying ordinary rounding techniques. Notwithstanding that the numerical ranges and parameters setting forth the broad scope of the invention are estimates, the numerical values ​​set forth in the specific examples are reported as precisely as possible. Numerical values, however, inherently contain certain errors resulting from the standard deviation in their respective testing measurements.

[0149] As used herein in the context of describing the invention (particularly in the context of the claims below), "a," "an," "the," and similar reference words are to be construed to cover the singular and the plural, unless otherwise specified herein or clearly contradicted by context. The recitation of ranges of values ​​herein is intended merely as a shorthand method of individually referring to each value falling within the range. Unless otherwise specified herein, each value is incorporated herein as if individually set forth herein. Unless otherwise specified herein or clearly contradicted by context, all methods described herein can be performed in any suitable order. Any examples provided herein, or the use of exemplary language (e.g., "such as"), are intended merely to more clearly illustrate the invention and are not intended to limit the scope of the invention as otherwise claimed. Nothing in this specification should be construed as indicating an element that is not claimed but is essential to the practice of the invention.

[0150] Groupings of alternative elements or embodiments of the invention disclosed herein are not to be construed as limitations. The elements of each group may be referred to and claimed individually or may be combined in any manner with other elements of the groups or with other elements used in this specification. For reasons of convenience and / or patentability, one or more elements of a group may be included in or deleted from a group. When such inclusion or deletion is made, the specification shall be deemed to include the group as modified to satisfy the description of all Markush groups used in the appended claims.

[0151] Certain embodiments of the present invention are described herein, including the best mode known to the inventors for carrying out the embodiments. Of course, variations on the described embodiments will become apparent to those of ordinary skill in the art upon reading the foregoing description. The inventors expect that such variations will be adopted appropriately by those skilled in the art, and the inventors intend to carry out the embodiments in ways other than as specifically described herein. Accordingly, this invention includes all modifications and equivalents of the subject matter recited in the appended claims as permitted by applicable law. Moreover, all combinations of elements in all possible variations described above are encompassed by this invention, unless otherwise stated herein or clearly contradicted by context.

[0152] Certain embodiments disclosed herein may be further limited in the claims using the language consisting of or consisting essentially of. When used in a claim, whether as filed or added by amendment, the transitional term "consisting of" excludes any component, step, or ingredient not specified in the claim. The transitional term "consisting essentially of" limits the scope of the claim to those materials or steps specified and which do not materially affect the basic novel characteristics. Embodiments of the invention so claimed are inherently or explicitly described and enabled herein.

[0153] Additionally, throughout this specification, numerous references have been made to patents and printed publications. Each of the above cited patents and printed publications is herein individually incorporated by reference in its entirety.

[0154] Finally, it is to be understood that the embodiments of the invention disclosed herein are illustrative of the principles of the invention. Other modifications that may be adopted are within the scope of the invention. Thus, by way of example, and not of limitation, alternative configurations of the invention may be utilized in accordance with the teachings herein. Thus, the invention is not limited to that precisely as shown and described.

[0155] (Additional Note) (Appendix 1) A salt of (2E,4E)-3-methyl-5-((1S,2S)-2-methyl-2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)cyclopropyl)penta-2,4-dienoic acid, which is a tris salt, diethylamine salt, lysine salt, glycine salt, choline salt, ammonium salt, magnesium salt, calcium salt, potassium salt, or sodium salt of (2E,4E)-3-methyl-5-((1S,2S)-2-methyl-2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)cyclopropyl)penta-2,4-dienoic acid.

[0156] (Appendix 2) The salt according to appendix 1, which is (2E,4E)-3-methyl-5-((1S,2S)-2-methyl-2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)cyclopropyl)penta-2,4-dienoic acid mono(tris(hydroxymethyl)aminomethane).

[0157] (Appendix 3) The salt according to appendix 1, which is an anhydrate, hemihydrate, monohydrate or dihydrate of (2E,4E)-3-methyl-5-((1S,2S)-2-methyl-2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)cyclopropyl)penta-2,4-dienoic acid tris(hydroxymethyl)aminomethane.

[0158] (Appendix 4) A solid form of Form A of the salt according to Appendix 2.

[0159] (Appendix 5) 5. A solid form according to claim 4, having an X-ray powder diffraction pattern including a signal at 11.3±0.2° in terms of 2θ.

[0160] (Appendix 6) 5. The solid form of claim 4 having an X-ray powder diffraction pattern comprising signals at 3.8±0.2°, 7.6±0.2°, 11.3±0.2°, 18.1±0.2° and 19.6±0.2° in degrees 2θ.

[0161] (Appendix 7) 5. The solid form of claim 4 having an X-ray powder diffraction pattern substantially as shown in FIG.

[0162] (Appendix 8) 8. The solid form of any one of claims 4 to 7, having a differential scanning calorimetry thermogram comprising an endothermic transition at 154±3° C.

[0163] (Appendix 9) 8. A solid form according to any one of claims 4 to 7, having a differential scanning calorimetry thermogram substantially as shown in Figure 2.

[0164] (Appendix 10) 10. A solid form according to any one of claims 4 to 9, having a thermogravimetric analysis substantially as shown in Figure 3.

[0165] (Appendix 11) A solid form of Form B of the salt according to Appendix 2.

[0166] (Appendix 12) 12. The solid form of claim 11, having an X-ray powder diffraction pattern including a signal at 11.5±0.2 degrees 2θ.

[0167] (Appendix 13) 12. The solid form of claim 11, having an X-ray powder diffraction pattern comprising signals at 3.9±0.2°, 11.5±0.2°, 18.3±0.2°, 19.9±0.2°, and 23.2±0.2° in terms of two theta.

[0168] (Appendix 14) 12. The solid form of claim 11, having an X-ray powder diffraction pattern substantially as shown in FIG.

[0169] (Appendix 15) 15. The solid form of any one of claims 11 to 14, having a differential scanning calorimetry thermogram comprising an endothermic transition at 150±3° C.

[0170] (Appendix 16) 15. A solid form according to any one of claims 11 to 14, having a differential scanning calorimetry thermogram substantially as shown in Figure 5.

[0171] (Appendix 17) 17. A solid form according to any one of claims 11 to 16, having a thermogravimetric analysis substantially as shown in Figure 6.

[0172] (Appendix 18) 18. A substantially purified solid form according to any one of claims 4 to 17.

[0173] (Appendix 19) 19. The solid form of any one of claims 4 to 18, which is crystalline.

[0174] (Appendix 20) 20. The solid form of any one of claims 4 to 19, prepared by a process comprising precipitating the solid form from a solution comprising (2E,4E)-3-methyl-5-((1S,2S)-2-methyl-2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)cyclopropyl)penta-2,4-dienoic acid, tris(hydroxymethyl)aminomethane and a solvent.

[0175] (Appendix 21) 21. The solid form of claim 20, wherein the solvent comprises ethanol, isopropanol, butanol, or a combination thereof, and the solvent further comprises 0 to about 1% by volume of water.

[0176] (Appendix 22) A solid form of the salt described in Appendix 1.

[0177] (Appendix 23) 23. A particle comprising a salt according to any one of appendices 1 to 3, or a solid form according to any one of appendices 4 to 22, said particle being optionally coated, micronized, or both.

[0178] (Appendix 24) A pharmaceutical composition comprising a salt according to any one of appendices 1 to 3, a solid form according to any one of appendices 4 to 22, or a particle according to appendices 23, and a pharma- ceutically acceptable carrier.

[0179] (Appendix 25) 24. A pharmaceutical composition comprising a salt according to any one of appendices 1 to 3, a solid form according to any one of appendices 4 to 22, or a particle according to appendices 23, wherein the solid form is present in an amount of at least about 80% by weight in the composition.

[0180] (Appendix 26) 24. A pharmaceutical composition consisting essentially of a salt according to any one of appendices 1 to 3, a solid form according to any one of appendices 4 to 22, or a particle according to appendices 23.

[0181] (Appendix 27) 27. A pharmaceutical composition according to any one of claims 24 to 26, formulated as an oral, parenteral, topical or inhaled dosage form or formulated for oral, parenteral, topical or inhaled administration.

[0182] (Appendix 28) A composition comprising a salt according to any one of appendices 1 to 3, a solid form according to any one of appendices 4 to 22, or a particle according to appendices 23.

[0183] (Appendix 29) precipitating a solid form from a solution comprising (2E,4E)-3-methyl-5-((1S,2S)-2-methyl-2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)cyclopropyl)penta-2,4-dienoic acid, tris(hydroxymethyl)aminomethane and a solvent; the solvent comprises ethanol, isopropanol, butanol, or a combination thereof, the solvent further comprising 0 to about 1% by volume of water; A method for preparing a solid form according to any one of claims 4 to 19 or 22.

[0184] (Appendix 30) A salt form according to any one of claims 1 to 3; A solid form according to any one of appendixes 4 to 22; Particles according to claim 23; A pharmaceutical composition according to any one of claims 24 to 27; or The composition according to claim 28. administering to a subject an effective amount of A method of treating a disease in a subject in need thereof.

[0185] (Appendix 31) 31. The method of claim 30, wherein the disease is a retinoid X receptor associated disease.

[0186] (Appendix 32) 31. The method of claim 30, wherein the disease is selected from a nervous system disease, a muscular disease, a cell proliferation disease, or an autoimmune disease.

[0187] (Appendix 33) 31. The method of claim 30, wherein the disease is selected from cancer or tumor.

Claims

1. A salt of (2E,4E)-3-methyl-5-((1S,2S)-2-methyl-2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene-2-yl)cyclopropyl)penta-2,4-dienoic acid, which is a Tris salt, diethylamine salt, lysine salt, glycine salt, choline salt, ammonium salt, magnesium salt, calcium salt, potassium salt, or sodium salt of (2E,4E)-3-methyl-5-((1S,2S)-2-methyl-2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene-2-yl)cyclopropyl)penta-2,4-dienoic acid.

2. The salt according to claim 1, wherein the salt is (2E,4E)-3-methyl-5-((1S,2S)-2-methyl-2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene-2-yl)cyclopropyl)penta-2,4-dienoic acid mono(tris(hydroxymethyl)aminomethane).

3. The salt according to claim 1, wherein the salt is the anhydrous, hemihydrate, monohydrate or dihydrate of tris(hydroxymethyl)aminomethane (2E,4E)-3-methyl-5-((1S,2S)-2-methyl-2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene-2-yl)cyclopropyl)penta-2,4-dienoate.

4. The solid form of type A of the salt according to claim 2.

5. The solid form according to claim 4, having a powder X-ray diffraction pattern that includes a signal at 11.3 ± 0.2° with respect to 2θ.

6. The solid form according to claim 4, having a powder X-ray diffraction pattern with respect to 2θ including signals at 3.8±0.2°, 7.6±0.2°, 11.3±0.2°, 18.1±0.2° and 19.6±0.2°.

7. The solid form according to claim 4, having substantially the powder X-ray diffraction pattern shown in Figure 1.

8. A solid form according to any one of claims 4 to 7, having a differential scanning calorimetry thermogram that includes an endothermic transition at 154 ± 3°C.

9. A solid form according to any one of claims 4 to 7, having substantially the differential scanning calorimetry thermogram as shown in Figure 2.

10. The solid form according to any one of claims 4 to 7, having substantially the thermogravimetric analysis shown in Figure 3.

11. The solid form of type B of the salt according to claim 2.

12. The solid form according to claim 11, having a powder X-ray diffraction pattern that includes a signal at 11.5 ± 0.2° with respect to 2θ.

13. The solid form according to claim 11, having a powder X-ray diffraction pattern with respect to 2θ including signals at 3.9±0.2°, 11.5±0.2°, 18.3±0.2°, 19.9±0.2°, and 23.2±0.2°.

14. The solid form according to claim 11, having substantially the powder X-ray diffraction pattern shown in Figure 4.

15. The solid form according to any one of claims 11 to 14, having a differential scanning calorimetry thermogram that includes an endothermic transition at 150 ± 3°C.

16. The solid form according to any one of claims 11 to 14, having substantially the differential scanning calorimetry thermogram as shown in Figure 5.

17. The solid form according to any one of claims 11 to 14, wherein the thermogravimetric analysis is substantially as shown in Figure 6.

18. A substantially purified solid form according to any one of claims 4 to 7 or 11 to 14.

19. The solid form according to any one of claims 4 to 7 or 11 to 14, which is crystalline.

20. The solid form according to any one of claims 4 to 7 or 11 to 14, which is prepared by a method comprising precipitating the solid form from a solution containing (2E,4E)-3-methyl-5-((1S,2S)-2-methyl-2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene-2-yl)cyclopropyl)penta-2,4-dienoate tris(hydroxymethyl)aminomethane and a solvent.

21. The solid form according to claim 20, wherein the solvent comprises ethanol, isopropanol, butanol, or a combination thereof, and the solvent further comprises 0 to about 1 volume percent of water.

22. The solid form of the salt according to claim 1.

23. Particles comprising a salt according to any one of claims 1 to 3 or a solid form according to any one of claims 4 to 7, 11 to 14, 21 or 22, wherein the particles are optionally coated, pulverized, or both.

24. A pharmaceutical composition comprising a salt according to any one of claims 1 to 3, a solid form according to any one of claims 4 to 7, 11 to 14, 21 or 22, or particles according to claim 23, and a pharmaceutically acceptable carrier.

25. A pharmaceutical composition comprising a salt according to any one of claims 1 to 3, a solid form according to any one of claims 4 to 7, 11 to 14, 21 or 22, or particles according to claim 23, wherein the solid form is present in the composition in an amount of at least about 80% by weight.

26. A pharmaceutical composition comprising essentially a salt according to any one of claims 1 to 3, a solid form according to any one of claims 4 to 7, 11 to 14, 21 or 22, or particles according to claim 23.

27. The pharmaceutical composition according to claim 24, formulated as an oral, parenteral, topical, or inhalation dosage form, or formulated for oral, parenteral, topical, or inhalation administration.

28. A composition comprising a salt according to any one of claims 1 to 3, a solid form according to any one of claims 4 to 7, 11 to 14, 21 or 22, or particles according to claim 23.

29. The process involves precipitating a solid form from a solution containing (2E,4E)-3-methyl-5-((1S,2S)-2-methyl-2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene-2-yl)cyclopropyl)penta-2,4-dienoate tris(hydroxymethyl)aminomethane and a solvent. The solvent comprises ethanol, isopropanol, butanol, or a combination thereof, and the solvent further comprises 0 to about 1 volume percent of water. A method for preparing a solid form according to any one of claims 4 to 7, 11 to 14, or 22.

30. The form of the salt according to any one of claims 1 to 3; The solid form according to any one of claims 4 to 7, 11 to 14, 21 or 22; Particles according to claim 23; The pharmaceutical composition according to claim 24; or Composition according to claim 28 Including an effective amount of, A pharmaceutical composition for treating a disease in a subject who requires treatment, by administration to the subject.

31. The pharmaceutical composition according to claim 30, wherein the disease is a retinoid X receptor-related disease.

32. The pharmaceutical composition according to claim 30, wherein the disease is selected from a nervous system disorder, a muscle disorder, a cell proliferation disorder, or an autoimmune disorder.

33. The pharmaceutical composition according to claim 30, wherein the disease is selected from cancer or tumor.

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