Solid forms of PPAR gamma regulators and methods of using the same

Abstract

A solid form of a compound capable of altering, modulating, or inhibiting the RXRα and / or PPARγ pathway, and a method of treating cancer, particularly cancer known to be useful for agents that target the RXRα and / or PPARγ pathway are provided. 【Solution】The present disclosure provides a novel solid state A form of Compound I, a composition containing the same, and methods of use thereof, including use in the treatment of cancer, particularly cancer known to be useful for agents that target the RXRα and / or PPARγ pathway. JPEG2025516478000044.jpg33149

Description

Technical Field

[0001] This application claims priority to U.S. Provisional Patent Application No. 63 / 364,402, filed on May 9, 2022, the contents of which are hereby incorporated by reference in their entirety.

[0002] The present disclosure provides solid forms of compounds that can alter, modulate, or inhibit the RXRα and / or PPARγ pathways, and methods of treating cancer, particularly cancer known to be useful for agents that target the RXRα and / or PPARγ pathways.

Background Art

[0003] Muscle-invasive bladder cancer (MIBC) is a highly malignant disease that can be lethal, and treatment options are limited. Chemotherapy and immunotherapy are approved for the treatment of locally advanced or metastatic bladder cancer, but the majority of patients may either not respond or only show a very short-term response (Seiler et al., 2017 Eur Urology; Robertson et al., 2017 Cell). This suggests that further efforts are needed to identify novel therapies that can benefit patients who are not currently responding to existing standard of care (SoC) therapies.

[0004] Recent studies have revealed that not all advanced bladder cancers are created equal. Deep gene expression and genomic analyses have identified distinct molecular subtypes of MIBC, including basal and luminal subtypes (Choi et al., 2014 Cancer Cell; Kardos et al., 2016 JCI Insight; Kamoun et al., 2020 Eur Urology), which possess unique tumor-intrinsic and microenvironmental characteristics. Similar to luminal breast and prostate cancers, luminal bladder cancers tend to grow slowly, have low immune infiltration, and exhibit low response rates to both chemotherapy and immunotherapy (Robertson et al., 2017 Cell). Currently, there is a lack of optimal therapies for luminal disease, and a coordinated effort is needed to identify and exploit novel luminal subtype-specific therapeutic nodes.

[0005] In the majority of luminal bladder cancers, genomic alterations in the RXRα / PPARγ pathway are prominent, including recurrent mutations at serine 427 of RXRα (S427F / Y), a hotspot mutation at threonine 475 of PPARγ (T475M), and amplification / overexpression of PPARγ (Guo et al., 2013 Nature Genetics; Van Allen et al., 2014 Cancer Discovery). These genomic alterations enhance the PPARγ / RXRα-dependent transcriptional program in MIBC (Halstead et al., 2017 eLife; Korpal et al., 2017 Nat Communications; Goldstein et al., 2017 Cancer Research). Additionally, growth reduction is shown after genetic / pharmacological inhibition of PPARγ, which activeOnly luminal bladder cancer cell lines (Halstead et al., 2017 eLife; Goldstein et al., 2017 Cancer Research). Thus, activation of this pathway is associated with growth being dependent on RXRα / PPARγ. Analysis of the functional role of PPARγ in subsequent luminal cells has revealed a decisive role in promoting energy production through enhanced glucose and lipid metabolism (Liu et al., 2019 Nat Communications), which may contribute to the observed dependence on PPARγ in genomically altered luminal cells.

[0006] In addition to this tumor-specific role of PPARγ in luminal bladder cancer with altered PPARγ, recent studies have suggested that activated PPARγ / RXRα suppresses inflammatory cytokine expression and immune cell infiltration (Korpal et al., 2017 Nat Communications; Kardos et al., 2016 JCI Insight). From several clinical datasets and in vivo tumor models, it has been pointed out that PPARγ High / RXRα S427F / Y weakens CD8 + T cell infiltration and confers partial resistance to immune checkpoint inhibitors. Knockdown of PPARγ or RXRα and pharmacological inhibition of PPARγ significantly increase cytokine expression, suggesting a therapeutic approach to restore sensitivity to immune surveillance and immunotherapy (Korpal et al., 2017 Nat Communications). In summary, these studies suggest that PPARγ functions as a tumor cell-intrinsic "immune-oncogene" that promotes tumor cell growth, enhances energy production, and increases tumor cell survival through immunosuppression. Summary of the Invention Means for Solving the Problems

[0007] "Compound I", as used herein, is described by its name based on the ACD / Name software, i.e., (7S)-4-{[5-(5-fluoro-2-methoxypyridin-4-yl)-1H-pyrazol-3-yl]carbonyl}-N-[(1r,4S)-4-hydroxy-4-(trifluoromethyl)cyclohexyl]-4-azaspiro[2.5]octane-7-carboxamide, and / or may be described as (S)-4-(5-(5-fluoro-2-methoxypyridin-4-yl)-1H-pyrazole-3-carbonyl)-N-((1r,4S)-4-hydroxy-4-(trifluoromethyl)cyclohexyl)-4-azaspiro[2.5]octane-7-carboxamide. The structure of Compound I is [Chemical formula] and can be illustrated as

[0008] Compound I and its preparation method are disclosed as Compound 169B in U.S. Provisional Patent Application No. 63 / 11,354, U.S. Patent Application No. 17 / 521,666, and PCT / US2021 / 058473, all of which were filed on November 9, 2020, November 8, 2021, respectively; the entire contents of each of which are incorporated herein by reference.

[0009] One aspect of the present disclosure provides a novel solid state form, Form A, of Compound I that can be utilized in the treatment of cancer, where it is known that agents targeting the RXRα and / or PPARγ pathways are useful.

[0010] Another aspect of the present disclosure provides a method for treating cancer, comprising administering to a subject in need thereof Form A of Compound I or a pharmaceutical composition comprising the same.

[0011] In some embodiments, this treatment method includes administering to a subject in need thereof at least one additional active agent either in the same pharmaceutical composition as Form A of Compound I or as a separate composition.

[0012] Also provided is a method for modulating PPARγ, which comprises administering to a subject in need thereof the A form of Compound I or a pharmaceutical composition comprising the same.

Brief Description of the Drawings

[0013]

Figure 1

Figure 2

Figure 3

Figure 4

Figure 5

Figure 6

Modes for Carrying Out the Invention

[0014] Definitions When referring to the compounds of the present disclosure, the term "compound" refers to a group of molecules having the same chemical structure as a group of stereoisomers (e.g., a group of racemates, a group of cis / trans stereoisomers, or a group of (E) and (Z) stereoisomers), provided that there may be isotopic changes between the constituent atoms of the molecule. Thus, it will be apparent to those skilled in the art that a compound represented by a particular chemical structure containing the indicated deuterium atoms may also contain in lesser amounts isotopic substitutes having hydrogen atoms at one or more of the designated deuterium positions in said structure. The relative amounts of such isotopic substitutes in the compounds of the present disclosure will depend on several factors, including the isotopic purity of the reagents used in the preparation of the compounds and the isotopic incorporation efficiency in the various synthetic steps used in the preparation of the compounds. However, as indicated above, the relative amount of such isotopic substitutes as a whole may be less than 49.9% of the compound. In other embodiments, the relative amount of such isotopic substitutes as a whole may be less than 47.5%, less than 40%, less than 32.5%, less than 25%, less than 17.5%, less than 10%, less than 5%, less than 3%, less than 1%, or less than 0.5% of the compound.

[0015] Non-limiting examples of suitable solvents that can be used in the present disclosure include, but are not limited to, water, methanol (MeOH), ethanol (EtOH), dichloromethane or "methylene chloride" (CH 2 Cl 2 ), toluene, acetonitrile (MeCN), dimethylformamide (DMF), dimethyl sulfoxide (DMSO), methyl acetate (MeOAc), ethyl acetate (EtOAc), heptanes, isopropyl acetate (IPAc), tert-butyl acetate (t-BuOAc), isopropyl alcohol (IPA), tetrahydrofuran (THF), 2-methyltetrahydrofuran (2-MeTHF), methyl ethyl ketone (MEK), tert-butanol, diethyl ether (Et 2 O), methyl tert-butyl ether (MTBE), 1,4-dioxane, and N-methylpyrrolidone (NMP).

[0016] Non-limiting examples of suitable bases that can be used in the present disclosure include, but are not limited to, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), potassium tert-butoxide (KOtBu), potassium carbonate (K 2 CO 3 ), N-methylmorpholine (NMM), triethylamine (Et 3 N; TEA), diisopropylethylamine (i-Pr 2 EtN; DIPEA), pyridine, potassium hydroxide (KOH), sodium hydroxide (NaOH), lithium hydroxide (LiOH), and sodium methoxide (NaOMe; NaOCH 3 ).

[0017] When used in connection with the dosage, amount, or weight percentage of a component of a composition or dosage form, the terms “about” and “approximately” include values or ranges of dosages, amounts, or weight percentages that are recognized by those skilled in the art to provide a pharmacological effect equivalent to that obtained from the specifically recited dosage, amount, or weight percentage.

[0018] “Treatment,” “treating,” or “treatment” of cancer refers to causing regression of, reducing, and / or delaying the progression of cancer as described herein.

[0019] “Subject,” as used herein, means an animal subject, particularly a human, such as a mammalian subject.

[0020] "Pharmaceutically acceptable carrier", as used herein, refers to a non-toxic carrier, adjuvant, or vehicle that does not impair the pharmacological activity of the compounds formulated therewith. Pharmaceutically acceptable carriers, adjuvants or vehicles that may be used in the compositions of the present disclosure include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose substances, polyethylene glycol, cyclodextrins, sodium carboxymethyl cellulose, polyacrylates, waxes, polyethylene-polyoxypropylene block polymers, polyethylene glycol and lanolin.

[0021] The terms "patient" and "subject" are used interchangeably and refer to animals including humans.

[0022] The terms "effective dose" and "effective amount" are used interchangeably herein and refer to the amount of a compound that produces the desired effect when administered. The exact amount of the effective dose will depend on the purpose of the treatment and can be ascertained by techniques known to those of ordinary skill in the art (see, e.g., Lloyd (1999) The Art, Science and Technology of Pharmaceutical Compounding).

[0023] Form A of Compound I may be administered once, twice, or three times a day, for example, for the treatment of FSGS. In some embodiments, Form A of Compound I is administered once a day. In some embodiments, Form A of Compound I is administered twice a day. In some embodiments, Form A of Compound I is administered three times a day.

[0024] As used herein, the term "ambient conditions" means room temperature, outside air conditions, and uncontrolled humidity conditions.

[0025] As used herein, the terms "crystalline form" and "form" are used interchangeably and refer to a crystal structure (or polymorph) having a specific molecular packing arrangement in the crystal lattice. Crystalline forms can be identified and distinguished from one another by one or more characterization techniques including, for example, powder X-ray diffraction (XRPD), single crystal X-ray diffraction (SXRD), solid state nuclear magnetic resonance (SSNMR), Raman spectroscopy (Raman), differential scanning calorimetry (DSC), and / or thermogravimetric analysis (TGA). Thus, as used herein, the term "Form A crystalline form of Compound I" refers to a unique crystalline form that can be identified by one or more characterization techniques including, for example, XRPD, SXRD, SSNMR, Raman, DSC, and / or TGA and distinguished from other crystalline forms of Compound I. In some embodiments, the novel Form A crystalline form is characterized by a powder X-ray diffractogram having one or more signals at one or more specified 2θ values (°2θ).

[0026] As used herein, the term "SSNMR" refers to an analytical characterization method for solid state nuclear magnetic resonance. SSNMR spectra can be recorded under ambient conditions for any magnetically active isotope present in the sample. Typical examples of active isotopes for small molecule pharmaceutical active ingredients include 1 H, 2 H, 13 C, 19 F, 31 P, 15 N, 14 N, 35 Cl, 11 B, 7 Li, 17 O, 23 Na, 79 Br, and 195 Pt.

[0027] As used herein, the term "XRPD" refers to an analytical characterization method of powder X-ray diffraction. The XRPD pattern can be recorded using a diffractometer in a transmission or reflection geometry configuration under ambient conditions.

[0028] As used herein, the terms "powder X-ray diffractogram", "powder X-ray diffraction pattern", "XRPD pattern" are used synonymously to refer to an experimentally obtained pattern that plots signal intensity (on the vertical axis) against signal position (on the horizontal axis). For amorphous materials, the powder X-ray diffractogram may include one or more broad signals; for crystalline materials, the powder X-ray diffractogram may include one or more signals identified by their angular values as measured in degrees 2θ (°2θ) on the horizontal axis of the powder X-ray diffractogram, which can be expressed as "signal at... degrees 2θ", "signal at the 2θ value of...", and / or "signal at at least... 2θ values selected from...".

[0029] "Signal" or "peak", as used herein, refers to the point of maximum intensity when measured in counts in the XRPD pattern. One of ordinary skill in the art will recognize that one or more signals (or peaks) in the XRPD pattern may overlap and that there may be signals that are not visible to the naked eye, for example. In fact, one of ordinary skill in the art will recognize that some methods recognized in the art, such as the Rietveld refinement method, are capable of determining whether a signal is present in the pattern and are suitable for that determination.

[0030] As used herein, "signal at... degrees 2θ", "signal at the 2θ value of...", and / or "signal at at least... 2θ values selected from..." refer to the X-ray reflection position when measured and observed in a powder X-ray diffraction experiment (°2θ).

[0031] The reproducibility of the angle value is in the range of ±0.2° 2θ. That is, the angle value can be the stated angle value + 0.2 degrees 2θ, the angle value - 0.2 degrees 2θ, or any value between these two endpoints (angle value + 0.2 degrees 2θ to angle value - 0.2 degrees 2θ).

[0032] The terms "signal intensity" and "peak intensity" are used synonymously to refer to the relative signal intensity within a given powder X-ray diffractogram. Factors that can affect the relative signal or peak intensity include sample thickness and preferred orientation (e.g., the crystal grains are not randomly distributed).

[0033] The term "powder X-ray diffractogram having a signal at... 2θ value" as used herein refers to an XRPD pattern that includes the X-ray reflection positions when measured and observed in a powder X-ray diffraction experiment (°2θ).

[0034] As used herein, a powder X-ray diffractogram is "substantially the same as that of [a particular] figure" when at least 90%, for example at least 95%, at least 98%, or at least 99% of the signals in two diffractograms overlap. In determining "substantially the same or not", one of ordinary skill in the art will understand that even for the same crystal form, there may be differences in the intensity and / or signal position in the XRPD diffractogram. Thus, one of ordinary skill in the art will understand that the signal position in the XRPD diffractogram (in degrees 2θ (°2θ) units as referred to herein) generally means that the reported value is ±0.2 degrees 2θ, which is the amount of variation recognized in the art from that reported value.

[0035] As used herein, an SSNMR spectrum is "substantially the same as that of [a particular] figure" when at least 90%, such as at least 95%, at least 98%, or at least 99% of the signals in two spectra overlap. In determining "substantially the same or not", one of ordinary skill in the art will understand that even for the same crystal form, there may be differences in the intensity and / or signal position in the SSNMR spectrum. Thus, one of ordinary skill in the art will understand that the signal position (in ppm) in the SSNMR spectrum referred to herein generally means that the reported value is ±0.2 ppm from the reported value which is the amount of variation recognized in the art.

[0036] As used herein, a crystal form is "substantially pure" when it occupies an amount of 90% or more by weight relative to the total of all one or more solid forms in a sample when determined by a method in the art such as quantitative XRPD. In some embodiments, a solid form is "substantially pure" when it occupies an amount of 95% or more by weight relative to the total of all one or more solid forms in a sample. In some embodiments, a solid form is "substantially pure" when it occupies an amount of 99% or more by weight relative to the total of all one or more solid forms in a sample.

[0037] As used herein, the term "DSC" refers to an analytical method of differential scanning calorimetry.

[0038] As used herein, the term "TGA" refers to an analytical method of thermogravimetric (or thermogravimetric) analysis.

[0039] As used herein, the term "room temperature" refers to a temperature in the range of 15°C to 30°C, or in some embodiments 20°C to 25°C.

[0040] This specification discloses a novel Form A of Compound I. In some embodiments, Form A of Compound I is substantially pure. In some embodiments, Form A is characterized by a powder X-ray diffractogram that is substantially the same as that of Figure 1. In some embodiments, Form A of Compound I is characterized by a powder X-ray diffractogram having signals at at least one 2θ value selected from 14.8 ± 0.2, 15.9 ± 0.2, 17.5 ± 0.2, 18.5 ± 0.2, 19.4 ± 0.2, 20.0 ± 0.2, 20.7 ± 0.2, 21.0 ± 0.2, 22.6 ± 0.2, and 27.2 ± 0.2. In some embodiments, Form A of Compound I is characterized by a powder X-ray diffractogram having signals at at least two 2θ values selected from 14.8 ± 0.2, 15.9 ± 0.2, 17.5 ± 0.2, 18.5 ± 0.2, 19.4 ± 0.2, 20.0 ± 0.2, 20.7 ± 0.2, 21.0 ± 0.2, 22.6 ± 0.2, and 27.2 ± 0.2. In some embodiments, Form A of Compound I is characterized by a powder X-ray diffractogram having signals at at least one 2θ value selected from 14.8 ± 0.2, 17.5 ± 0.2, 18.5 ± 0.2, 19.4 ± 0.2, 20.0 ± 0.2, 21.0 ± 0.2, and 22.6 ± 0.2. In some embodiments, Form A of Compound I is characterized by a powder X-ray diffractogram having signals at at least two 2θ values selected from 14.8 ± 0.2, 17.5 ± 0.2, 18.5 ± 0.2, 19.4 ± 0.2, 20.0 ± 0.2, 21.0 ± 0.2, and 22.6 ± 0.2. In some embodiments, Form A of Compound I is characterized by a powder X-ray diffractogram having signals at at least one 2θ value selected from 14.8 ± 0.2, 18.5 ± 0.2, 19.4 ± 0.2, 21.0 ± 0.2, and 22.6 ± 0.2. In some embodiments, Form A of Compound I is characterized by a powder X-ray diffractogram having signals at at least two 2θ values selected from 14.8 ± 0.2, 18.5 ± 0.2, 19.4 ± 0.2, 21.0 ± 0.2, and 22.6 ± 0.2.In some embodiments, the Form A of Compound I is characterized by a powder X-ray diffractogram having signals at at least one 2θ value selected from 14.8±0.2, 18.5±0.2, and 19.4±0.2. In some embodiments, the Form A of Compound I is characterized by a powder X-ray diffractogram having signals at at least two 2θ values selected from 14.8±0.2, 18.5±0.2, and 19.4±0.2.

[0041] In some embodiments, Form A of Compound I is characterized by a powder X-ray diffractogram having signals at at least 3 2θ values selected from 14.8±0.2, 15.9±0.2, 17.5±0.2, 18.5±0.2, 19.4±0.2, 20.0±0.2, 20.7±0.2, 21.0±0.2, 22.6±0.2, and 27.2±0.2. In some embodiments, Form A of Compound I is characterized by a powder X-ray diffractogram having signals at at least 4 2θ values selected from 14.8±0.2, 15.9±0.2, 17.5±0.2, 18.5±0.2, 19.4±0.2, 20.0±0.2, 20.7±0.2, 21.0±0.2, 22.6±0.2, and 27.2±0.2. In some embodiments, Form A of Compound I is characterized by a powder X-ray diffractogram having signals at at least 5 2θ values selected from 14.8±0.2, 15.9±0.2, 17.5±0.2, 18.5±0.2, 19.4±0.2, 20.0±0.2, 20.7±0.2, 21.0±0.2, 22.6±0.2, and 27.2±0.2. In some embodiments, Form A of Compound I is characterized by a powder X-ray diffractogram having signals at at least 6 2θ values selected from 14.8±0.2, 15.9±0.2, 17.5±0.2, 18.5±0.2, 19.4±0.2, 20.0±0.2, 20.7±0.2, 21.0±0.2, 22.6±0.2, and 27.2±0.2. In some embodiments, Form A of Compound I is characterized by a powder X-ray diffractogram having signals at at least 7 2θ values selected from 14.8±0.2, 15.9±0.2, 17.5±0.2, 18.5±0.2, 19.4±0.2, 20.0±0.2, 20.7±0.2, 21.0±0.2, 22.6±0.2, and 27.2±0.2. In some embodiments, Form A of Compound I is characterized by a powder X-ray diffractogram having signals at at least 8 2θ values selected from 14.8±0.2, 15.9±0.2, 17.5±0.2, 18.5±0.2, 19.4±0.2, 20.0±0.2, 20.7±0.2, 21.0±0.2, 22.6±0.2, and 27.2±0.2.In some embodiments, Form A of Compound I is characterized by a powder X-ray diffractogram having signals at at least nine 2θ values selected from 14.8 ± 0.2, 15.9 ± 0.2, 17.5 ± 0.2, 18.5 ± 0.2, 19.4 ± 0.2, 20.0 ± 0.2, 20.7 ± 0.2, 21.0 ± 0.2, 22.6 ± 0.2, and 27.2 ± 0.2.

[0042] In some embodiments, Form A of Compound I is characterized by a powder X-ray diffractogram having signals at 14.8 ± 0.2, 15.9 ± 0.2, 17.5 ± 0.2, 18.5 ± 0.2, 19.4 ± 0.2, 20.0 ± 0.2, 20.7 ± 0.2, 21.0 ± 0.2, 22.6 ± 0.2, and 27.2 ± 0.2. In some embodiments, Form A of Compound I is characterized by a powder X-ray diffractogram having signals at 14.8 ± 0.2, 17.5 ± 0.2, 18.5 ± 0.2, 19.4 ± 0.2, 20.0 ± 0.2, 21.0 ± 0.2, and 22.6 ± 0.2. In some embodiments, Form A of Compound I is characterized by a powder X-ray diffractogram having signals at 14.8 ± 0.2, 18.5 ± 0.2, 19.4 ± 0.2, 21.0 ± 0.2, and 22.6 ± 0.2. In some embodiments, Form A of Compound I is characterized by a powder X-ray diffractogram having signals at 14.8 ± 0.2, 18.5 ± 0.2, and 19.4 ± 0.2.

[0043] In some embodiments, compositions comprising Form A of Compound I are disclosed herein. In some embodiments, compositions comprising substantially pure Form A of Compound I are disclosed herein. In some embodiments, compositions comprising at least one active compound consisting essentially of Form A of Compound I are disclosed herein.

[0044] In some embodiments, Form A of Compound I is characterized by a TGA / DSC substantially similar to that of FIG. 3. In some embodiments, Form A of Compound I is characterized by a DSC having an extrapolated onset temperature of about 240 °C.

[0045] In some embodiments, Form A of Compound I has signals at at least one ppm value selected from 41.4 ± 0.2 ppm, 43.7 ± 0.2 ppm, 47.7 ± 0.2 ppm, 54.8 ± 0.2 ppm, 70.1 ± 0.2 ppm, 127.2 ± 0.2 ppm, 134.3 ± 0.2 ppm, 148.9 ± 0.2 ppm, 161.2 ± 0.2 ppm, and 179.0 ± 0.2 ppm 13 characterized by a 13C SSNMR spectrum. In some embodiments, Form A of Compound I has signals at at least two ppm values selected from 41.4 ± 0.2 ppm, 43.7 ± 0.2 ppm, 47.7 ± 0.2 ppm, 54.8 ± 0.2 ppm, 70.1 ± 0.2 ppm, 127.2 ± 0.2 ppm, 134.3 ± 0.2 ppm, 148.9 ± 0.2 ppm, 161.2 ± 0.2 ppm, and 179.0 ± 0.2 ppm 13 characterized by a 13C SSNMR spectrum. In some embodiments, Form A of Compound I has signals at at least three ppm values selected from 41.4 ± 0.2 ppm, 43.7 ± 0.2 ppm, 47.7 ± 0.2 ppm, 54.8 ± 0.2 ppm, 70.1 ± 0.2 ppm, 127.2 ± 0.2 ppm, 134.3 ± 0.2 ppm, 148.9 ± 0.2 ppm, 161.2 ± 0.2 ppm, and 179.0 ± 0.2 ppm 13 characterized by a 13C SSNMR spectrum. In some embodiments, Form A of Compound I has signals at at least four ppm values selected from 41.4 ± 0.2 ppm, 43.7 ± 0.2 ppm, 47.7 ± 0.2 ppm, 54.8 ± 0.2 ppm, 70.1 ± 0.2 ppm, 127.2 ± 0.2 ppm, 134.3 ± 0.2 ppm, 148.9 ± 0.2 ppm, 161.2 ± 0.2 ppm, and 179.0 ± 0.2 ppm 13It is characterized by a 13C SSNMR spectrum. In some embodiments, Form A of Compound I has signals at at least 5 ppm values selected from 41.4 ± 0.2 ppm, 43.7 ± 0.2 ppm, 47.7 ± 0.2 ppm, 54.8 ± 0.2 ppm, 70.1 ± 0.2 ppm, 127.2 ± 0.2 ppm, 134.3 ± 0.2 ppm, 148.9 ± 0.2 ppm, 161.2 ± 0.2 ppm, and 179.0 ± 0.2 ppm 13 It is characterized by a 13C SSNMR spectrum. In some embodiments, Form A has signals at at least 6 ppm values selected from 41.4 ± 0.2 ppm, 43.7 ± 0.2 ppm, 47.7 ± 0.2 ppm, 54.8 ± 0.2 ppm, 70.1 ± 0.2 ppm, 127.2 ± 0.2 ppm, 134.3 ± 0.2 ppm, 148.9 ± 0.2 ppm, 161.2 ± 0.2 ppm, and 179.0 ± 0.2 ppm 13 It is characterized by a 13C SSNMR spectrum. In some embodiments, Form A of Compound I has signals at at least 7 ppm values selected from 41.4 ± 0.2 ppm, 43.7 ± 0.2 ppm, 47.7 ± 0.2 ppm, 54.8 ± 0.2 ppm, 70.1 ± 0.2 ppm, 127.2 ± 0.2 ppm, 134.3 ± 0.2 ppm, 148.9 ± 0.2 ppm, 161.2 ± 0.2 ppm, and 179.0 ± 0.2 ppm 13 It is characterized by a 13C SSNMR spectrum. In some embodiments, Form A of Compound I has signals at at least 8 ppm values selected from 41.4 ± 0.2 ppm, 43.7 ± 0.2 ppm, 47.7 ± 0.2 ppm, 54.8 ± 0.2 ppm, 70.1 ± 0.2 ppm, 127.2 ± 0.2 ppm, 134.3 ± 0.2 ppm, 148.9 ± 0.2 ppm, 161.2 ± 0.2 ppm, and 179.0 ± 0.2 ppm 13It is characterized by a 13C SSNMR spectrum. In some embodiments, Form A of Compound I has signals at at least 9 ppm values selected from 41.4 ± 0.2 ppm, 43.7 ± 0.2 ppm, 47.7 ± 0.2 ppm, 54.8 ± 0.2 ppm, 70.1 ± 0.2 ppm, 127.2 ± 0.2 ppm, 134.3 ± 0.2 ppm, 148.9 ± 0.2 ppm, 161.2 ± 0.2 ppm, and 179.0 ± 0.2 ppm 13 It is characterized by a 13C SSNMR spectrum. In some embodiments, Form A of Compound I has signals at 41.4 ± 0.2 ppm, 43.7 ± 0.2 ppm, 47.7 ± 0.2 ppm, 54.8 ± 0.2 ppm, 70.1 ± 0.2 ppm, 127.2 ± 0.2 ppm, 134.3 ± 0.2 ppm, 148.9 ± 0.2 ppm, 161.2 ± 0.2 ppm, and 179.0 ± 0.2 ppm 13 It is characterized by a 13C SSNMR spectrum.

[0046] In some embodiments, Form A of Compound I has a Raman spectrum characterized by signals at at least one cm−1 value selected from 579.1 ± 2 cm−1 -1 , 741.3 ± 2 cm−1 -1 , 863.7 ± 2 cm−1 -1 , 1066.6 ± 2 cm−1 -1 , 1262.2 ± 2 cm−1 -1 , 1352.7 ± 2 cm−1 -1 , 1405.3 ± 2 cm−1 -1 , 1509.0 ± 2 cm−1 -1 , 1568.9 ± 2 cm−1 -1 , and 1630.2 ± 2 cm−1 -1 In some embodiments, Form A of Compound I has a Raman spectrum characterized by signals at 579.1 ± 2 cm−1 -1 -1 , 741.3 ± 2 cm−1 -1 , 863.7 ± 2 cm−1 -1 , 1066.6 ± 2 cm−1 -1 , 1262.2 ± 2 cm−1 -1 , 1352.7 ± 2 cm−1 -1 , 1405.3 ± 2 cm−1 -1 , 1509.0 ± 2 cm−1 -1 , 1568.9 ± 2 cm−1 -1 ​, and 1630.2 ± 2 cm -1 at least two cm selected from -1 characterized by a Raman spectrum having signals at the values. In some embodiments, Form A of Compound I is 579.1 ± 2 cm -1 , 741.3 ± 2 cm -1 , 863.7 ± 2 cm -1 , 1066.6 ± 2 cm -1 , 1262.2 ± 2 cm -1 , 1352.7 ± 2 cm -1 , 1405.3 ± 2 cm -1 , 1509.0 ± 2 cm -1 , 1568.9 ± 2 cm -1 , and 1630.2 ± 2 cm -1 at least three cm selected from -1 characterized by a Raman spectrum having signals at the values. In some embodiments, Form A of Compound I is 579.1 ± 2 cm -1 , 741.3 ± 2 cm -1 , 863.7 ± 2 cm -1 , 1066.6 ± 2 cm -1 , 1262.2 ± 2 cm -1 , 1352.7 ± 2 cm -1 , 1405.3 ± 2 cm -1 , 1509.0 ± 2 cm -1 , 1568.9 ± 2 cm -1 , and 1630.2 ± 2 cm -1 at least four cm selected from -1 characterized by a Raman spectrum having signals at the values. In some embodiments, Form A of Compound I is 579.1 ± 2 cm -1 , 741.3 ± 2 cm -1 , 863.7 ± 2 cm -1 , 1066.6 ± 2 cm -1 , 1262.2 ± 2 cm -1 , 1352.7 ± 2 cm -1 , 1405.3 ± 2 cm -1 , 1509.0 ± 2 cm -1 , 1568.9 ± 2 cm -1 , and 1630.2 ± 2 cm -1 at least five cm selected from -1It is characterized by a Raman spectrum having signals at the values. In some embodiments, Form A of Compound I has signals at 579.1 ± 2 cm -1 、741.3 ± 2 cm -1 、863.7 ± 2 cm -1 、1066.6 ± 2 cm -1 、1262.2 ± 2 cm -1 、1352.7 ± 2 cm -1 、1405.3 ± 2 cm -1 、1509.0 ± 2 cm -1 、1568.9 ± 2 cm -1 、and 1630.2 ± 2 cm -1 and is characterized by a Raman spectrum having signals at at least 6 cm -1 values selected therefrom. In some embodiments, Form A of Compound I has signals at 579.1 ± 2 cm -1 、741.3 ± 2 cm -1 、863.7 ± 2 cm -1 、1066.6 ± 2 cm -1 、1262.2 ± 2 cm -1 、1352.7 ± 2 cm -1 、1405.3 ± 2 cm -1 、1509.0 ± 2 cm -1 、1568.9 ± 2 cm -1 、and 1630.2 ± 2 cm -1 and is characterized by a Raman spectrum having signals at at least 7 cm -1 values selected therefrom. In some embodiments, Form A of Compound I has signals at 579.1 ± 2 cm -1 、741.3 ± 2 cm -1 、863.7 ± 2 cm -1 、1066.6 ± 2 cm -1 、1262.2 ± 2 cm -1 、1352.7 ± 2 cm -1 、1405.3 ± 2 cm -1 、1509.0 ± 2 cm -1 、1568.9 ± 2 cm -1 、and 1630.2 ± 2 cm -1 and is characterized by a Raman spectrum having signals at at least 8 cm -1 values selected therefrom. In some embodiments, Form A of Compound I has signals at 579.1 ± 2 cm-1 , 741.3 ± 2 cm -1 , 863.7 ± 2 cm -1 , 1066.6 ± 2 cm -1 , 1262.2 ± 2 cm -1 , 1352.7 ± 2 cm -1 , 1405.3 ± 2 cm -1 , 1509.0 ± 2 cm -1 , 1568.9 ± 2 cm -1 , and at least nine cm selected from 1630.2 ± 2 cm -1 characterized by a Raman spectrum having signals at the values. In some embodiments, Form A of Compound I is 579.1 ± 2 cm -1 , 741.3 ± 2 cm -1 , 741.3 ± 2 cm -1 , 863.7 ± 2 cm -1 , 1066.6 ± 2 cm -1 , 1262.2 ± 2 cm -1 , 1352.7 ± 2 cm -1 , 1405.3 ± 2 cm -1 , 1509.0 ± 2 cm -1 , 1568.9 ± 2 cm -1 , and 1630.2 ± 2 cm -1 characterized by a Raman spectrum having signals at the values.

[0047] Another aspect of the present disclosure provides a pharmaceutical composition comprising Form A of Compound I. In some embodiments, the pharmaceutical composition comprising Form A of Compound I is administered to a patient in need thereof.

[0048] The pharmaceutical composition may further comprise at least one pharmaceutically acceptable carrier. In some embodiments, the at least one pharmaceutically acceptable carrier is selected from pharmaceutically acceptable vehicles and pharmaceutically acceptable adjuvants. In some embodiments, the at least one pharmaceutically acceptable one is selected from pharmaceutically acceptable fillers, disintegrants, surfactants, binders, lubricants.

[0049] It will also be understood that the pharmaceutical compositions of the present disclosure can be utilized in combination therapies; that is, the pharmaceutical compositions described herein can further comprise at least one additional active therapeutic agent. Alternatively, a pharmaceutical composition comprising Form A of Compound I can be administered simultaneously with, prior to, or subsequent to, as a separate composition, a composition comprising at least one other active therapeutic agent. In some embodiments, a pharmaceutical composition comprising Form A of Compound I can be administered simultaneously with, prior to, or subsequent to, as a separate composition, a composition comprising at least one other active therapeutic agent.

[0050] As described above, the pharmaceutical compositions disclosed herein may optionally further comprise at least one pharmaceutically acceptable carrier. The at least one pharmaceutically acceptable carrier may be selected from excipients and vehicles. As used herein, the at least one pharmaceutically acceptable carrier includes any and all solvents, diluents, other liquid media, dispersion aids, suspension aids, surfactants, isotonic agents, thickening agents, emulsifying agents, preservatives, solid binders, and lubricants as are appropriate for the particular dosage form desired. Remington: The Science and Practice of Pharmacy, 21st edition, 2005, ed. D. B. Troy, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and J. C. Boylan, 1988 to 1999, Marcel Dekker, New York disclose various carriers used in the formulation of pharmaceutical compositions and their known preparation techniques. The use of any conventional carrier is contemplated to be within the scope of the present disclosure so long as it does not become incompatible with the compounds of the present disclosure, such as by producing any undesirable biological effects or otherwise interacting in a detrimental manner with any other one or more components of the pharmaceutical composition.Non-limiting examples of suitable pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (such as human serum albumin), buffering substances (such as phosphates, glycine, sorbic acid, and potassium sorbate), partial glyceride mixtures of saturated vegetable fatty acids, water, salts, and electrolytes (such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, and zinc salts), colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene block polymers, lanolin, sugars (such as lactose, glucose, and sucrose), starches (such as corn starch and potato starch), cellulose and its derivatives (such as sodium carboxymethyl cellulose, ethyl cellulose, and cellulose acetate), tragacanth powder, malt, gelatin, talc, excipients (such as cocoa butter and suppository waxes), oils (such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil), glycols (such as propylene glycol and polyethylene glycol), esters (such as ethyl oleate and ethyl laurate), agar, buffering agents (such as magnesium hydroxide and aluminum hydroxide), alginic acid, pyrogen-free water, isotonic saline, Ringer's solution, ethyl alcohol, phosphate buffer solutions, non-toxic compatible lubricants (such as sodium lauryl sulfate and magnesium stearate), coloring agents, release agents, coating agents, sweetening agents, flavoring agents, fragrances, preservatives, and antioxidants.

[0051] In some embodiments, Compound I is a crystalline solid consisting of 1% to 99% of Form A, based on the total weight of the crystalline solid Compound I. In some embodiments, the crystalline solid consists of 2% to 99% of Form A, based on the total weight of the crystalline solid Compound I. In some embodiments, the crystalline solid consists of 5% to 99% of Form A, based on the total weight of the crystalline solid Compound I. In some embodiments, the crystalline solid consists of 10% to 99% of Form A, based on the total weight of the crystalline solid Compound I. In some embodiments, the crystalline solid consists of 15% to 99% of Form A, based on the total weight of the crystalline solid Compound I. In some embodiments, the crystalline solid consists of 20% to 99% of Form A, based on the total weight of the crystalline solid Compound I. In some embodiments, the crystalline solid consists of 25% to 99% of Form A, based on the total weight of the crystalline solid Compound I. In some embodiments, the crystalline solid consists of 30% to 99% of Form A, based on the total weight of the crystalline solid Compound I. In some embodiments, the crystalline solid consists of 35% to 99% of Form A, based on the total weight of the crystalline solid Compound I. In some embodiments, the crystalline solid consists of 45% to 99% of Form A, based on the total weight of the crystalline solid Compound I. In some embodiments, the crystalline solid consists of 50% to 99% of Form A, based on the total weight of the crystalline solid Compound I. In some embodiments, the crystalline solid consists of 55% to 99% of Form A, based on the total weight of the crystalline solid Compound I. In some embodiments, the crystalline solid consists of 60% to 99% of Form A, based on the total weight of the crystalline solid Compound I. In some embodiments, the crystalline solid consists of 65% to 99% of Form A, based on the total weight of the crystalline solid Compound I. In some embodiments, the crystalline solid consists of 70% to 99% of Form A, based on the total weight of the crystalline solid Compound I. In some embodiments, the crystalline solid consists of 75% to 99% of Form A, based on the total weight of the crystalline solid Compound I. In some embodiments, the crystalline solid consists of 80% to 99% of Form A, based on the total weight of the crystalline solid Compound I. In some embodiments, the crystalline solid consists of 85% to 99% of Form A, based on the total weight of the crystalline solid Compound I. In some embodiments, the crystalline solid consists of 90% to 99% of Form A, based on the total weight of the crystalline solid Compound I.In some embodiments, the crystalline solid consists of 95% to 99% of Form A, based on the total weight of the crystalline solid compound I.

[0052] In some embodiments, a method of treating cancer comprises administering to a subject in need thereof Form A of compound I or a pharmaceutical composition comprising the same.

[0053] In some embodiments, the method of treatment comprises administering to a subject in need thereof at least one additional active agent, either in the same pharmaceutical composition as Form A of compound I or as a separate composition.

[0054] In some embodiments, a method of modulating PPARγ comprises administering to a subject in need thereof Form A of compound I or a pharmaceutical composition comprising the same.

[0055] Non-limiting exemplary embodiments Embodiment 1: Form A of (7S)-4-{[5-(5-fluoro-2-methoxypyridin-4-yl)-1H-pyrazol-3-yl]carbonyl}-N-[(1r,4S)-4-hydroxy-4-(trifluoromethyl)cyclohexyl]-4-azaspiro[2.5]octane-7-carboxamide (i.e., Form A of (S)-4-(5-(5-fluoro-2-methoxypyridin-4-yl)-1H-pyrazole-3-carbonyl)-N-((1r,4S)-4-hydroxy-4-(trifluoromethyl)cyclohexyl)-4-azaspiro[2.5]octane-7-carboxamide) (i.e., Form A of compound I:

Chemical formula

[0056] Embodiment 2: The Form A according to Embodiment 1, characterized by a powder X-ray diffractogram substantially the same as that of FIG. 1.

[0057] Embodiment 3: The A form according to Embodiment 1, characterized by a powder X-ray diffractogram having signals at at least one 2θ value selected from 14.8 ± 0.2, 15.9 ± 0.2, 17.5 ± 0.2, 18.5 ± 0.2, 19.4 ± 0.2, 20.0 ± 0.2, 20.7 ± 0.2, 21.0 ± 0.2, 22.6 ± 0.2, and 27.2 ± 0.2.

[0058] Embodiment 4: The A form according to Embodiment 1, characterized by a powder X-ray diffractogram having signals at at least two 2θ values selected from 14.8 ± 0.2, 15.9 ± 0.2, 17.5 ± 0.2, 18.5 ± 0.2, 19.4 ± 0.2, 20.0 ± 0.2, 20.7 ± 0.2, 21.0 ± 0.2, 22.6 ± 0.2, and 27.2 ± 0.2.

[0059] Embodiment 5: The A form according to Embodiment 1, characterized by a powder X-ray diffractogram having signals at at least two 2θ values selected from 14.8 ± 0.2, 17.5 ± 0.2, 18.5 ± 0.2, 19.4 ± 0.2, 20.0 ± 0.2, 21.0 ± 0.2, and 22.6 ± 0.2.

[0060] Embodiment 6: The A form according to Embodiment 1, characterized by a powder X-ray diffractogram having signals at at least two 2θ values selected from 14.8 ± 0.2, 18.5 ± 0.2, 19.4 ± 0.2, 21.0 ± 0.2, and 22.6 ± 0.2.

[0061] Embodiment 7: The A form according to Embodiment 1, characterized by a powder X-ray diffractogram having signals at at least two 2θ values selected from 14.8 ± 0.2, 18.5 ± 0.2, and 19.4 ± 0.2.

[0062] Embodiment 8: The A form according to Embodiment 1, characterized by a powder X-ray diffractogram having signals at at least three 2θ values selected from 14.8 ± 0.2, 15.9 ± 0.2, 17.5 ± 0.2, 18.5 ± 0.2, 19.4 ± 0.2, 20.0 ± 0.2, 20.7 ± 0.2, 21.0 ± 0.2, 22.6 ± 0.2, and 27.2 ± 0.2.

[0063] Embodiment 9: An A form according to Embodiment 1, characterized by a powder X-ray diffractogram having signals at at least four 2θ values selected from 14.8±0.2, 15.9±0.2, 17.5±0.2, 18.5±0.2, 19.4±0.2, 20.0±0.2, 20.7±0.2, 21.0±0.2, 22.6±0.2, and 27.2±0.2.

[0064] Embodiment 10: An A form according to Embodiment 1, characterized by a powder X-ray diffractogram having signals at at least five 2θ values selected from 14.8±0.2, 15.9±0.2, 17.5±0.2, 18.5±0.2, 19.4±0.2, 20.0±0.2, 20.7±0.2, 21.0±0.2, 22.6±0.2, and 27.2±0.2.

[0065] Embodiment 11: An A form according to Embodiment 1, characterized by a powder X-ray diffractogram having signals at 14.8±0.2, 15.9±0.2, 17.5±0.2, 18.5±0.2, 19.4±0.2, 20.0±0.2, 20.7±0.2, 21.0±0.2, 22.6±0.2, and 27.2±0.2.

[0066] Embodiment 12: An A form according to Embodiment 1, characterized by a powder X-ray diffractogram having signals at 14.8±0.2, 17.5±0.2, 18.5±0.2, 19.4±0.2, 20.0±0.2, 21.0±0.2, and 22.6±0.2.

[0067] Embodiment 13: An A form according to Embodiment 1, characterized by a powder X-ray diffractogram having signals at 14.8±0.2, 18.5±0.2, 19.4±0.2, 21.0±0.2, and 22.6±0.2.

[0068] Embodiment 14: An A form according to Embodiment 1, characterized by a powder X-ray diffractogram having signals at 14.8±0.2, 18.5±0.2, and 19.4±0.2.

[0069] Embodiment 15: Having signals at at least five ppm values selected from 41.4 ± 0.2 ppm, 43.7 ± 0.2 ppm, 47.7 ± 0.2 ppm, 54.8 ± 0.2 ppm, 70.1 ± 0.2 ppm, 127.2 ± 0.2 ppm, 134.3 ± 0.2 ppm, 148.9 ± 0.2 ppm, 161.2 ± 0.2 ppm, and 179.0 ± 0.2 ppm 13 Form A according to Embodiment 1, characterized by a 13C SSNMR spectrum

[0070] Embodiment 16: Having signals at at least four ppm values selected from 41.4 ± 0.2 ppm, 43.7 ± 0.2 ppm, 47.7 ± 0.2 ppm, 54.8 ± 0.2 ppm, 70.1 ± 0.2 ppm, 127.2 ± 0.2 ppm, 134.3 ± 0.2 ppm, 148.9 ± 0.2 ppm, 161.2 ± 0.2 ppm, and 179.0 ± 0.2 ppm 13 Form A according to Embodiment 1, characterized by a 13C SSNMR spectrum

[0071] Embodiment 17: Having signals at at least three ppm values selected from 41.4 ± 0.2 ppm, 43.7 ± 0.2 ppm, 47.7 ± 0.2 ppm, 54.8 ± 0.2 ppm, 70.1 ± 0.2 ppm, 127.2 ± 0.2 ppm, 134.3 ± 0.2 ppm, 148.9 ± 0.2 ppm, 161.2 ± 0.2 ppm, and 179.0 ± 0.2 ppm 13 Form A according to Embodiment 1, characterized by a 13C SSNMR spectrum

[0072] Embodiment 18: Having signals at at least two ppm values selected from 41.4 ± 0.2 ppm, 43.7 ± 0.2 ppm, 47.7 ± 0.2 ppm, 54.8 ± 0.2 ppm, 70.1 ± 0.2 ppm, 127.2 ± 0.2 ppm, 134.3 ± 0.2 ppm, 148.9 ± 0.2 ppm, 161.2 ± 0.2 ppm, and 179.0 ± 0.2 ppm 13 Form A according to Embodiment 1, characterized by a 13C SSNMR spectrum

[0073] Embodiment 19: having a signal at at least one ppm value selected from 41.4 ± 0.2 ppm, 43.7 ± 0.2 ppm, 47.7 ± 0.2 ppm, 54.8 ± 0.2 ppm, 70.1 ± 0.2 ppm, 127.2 ± 0.2 ppm, 134.3 ± 0.2 ppm, 148.9 ± 0.2 ppm, 161.2 ± 0.2 ppm, and 179.0 ± 0.2 ppm 13 Form A according to Embodiment 1, characterized by a 13C SSNMR spectrum.

[0074] Embodiment 20: having a signal at 41.4 ± 0.2 ppm, 43.7 ± 0.2 ppm, 47.7 ± 0.2 ppm, 54.8 ± 0.2 ppm, 70.1 ± 0.2 ppm, 127.2 ± 0.2 ppm, 134.3 ± 0.2 ppm, 148.9 ± 0.2 ppm, 161.2 ± 0.2 ppm, and 179.0 ± 0.2 ppm 13 Form A according to Embodiment 1, characterized by a 13C SSNMR spectrum.

[0075] Embodiment 21: having a signal at 41.4 ± 0.2 ppm, 54.8 ± 0.2 ppm, 70.1 ± 0.2 ppm, 127.2 ± 0.2 ppm, 134.3 ± 0.2 ppm, 148.9 ± 0.2 ppm, and 161.2 ± 0.2 ppm 13 Form A according to Embodiment 1, characterized by a 13C SSNMR spectrum.

[0076] Embodiment 22: having a signal at 41.4 ± 0.2 ppm, 54.8 ± 0.2 ppm, 70.1 ± 0.2 ppm, 134.3 ± 0.2 ppm, and 148.9 ± 0.2 ppm 13 Form A according to Embodiment 1, characterized by a 13C SSNMR spectrum.

[0077] Embodiment 23: having a signal at 54.8 ± 0.2 ppm, 70.1 ± 0.2 ppm, and 148.9 ± 0.2 ppm 13 Form A of Compound I according to Embodiment 1, characterized by a 13C SSNMR spectrum.

[0078] Embodiment 24: Form A as described in embodiment 1, characterized by a TGA / DSC substantially similar to that in FIG.

[0079] Embodiment 25: Form A according to embodiment 1, characterized by a Raman spectrum substantially similar to that of FIG.

[0080] Embodiment 26: 579.1 ± 2 cm -1 , 741.3±2cm -1 , 863.7±2cm -1 , 1066.6±2cm -1 , 1262.2±2cm -1 , 1352.7±2cm -1 , 1405.3±2cm -1 , 1509.0±2cm -1 , 1568.9±2cm -1 , and 1630.2±2cm -1 2. Form A according to embodiment 1, characterized by a Raman spectrum having a signal at at least one ppm value selected from:

[0081] Embodiment 27: 579.1 ± 2 cm -1 , 741.3±2cm -1 , 863.7±2cm -1 , 1066.6±2cm -1 , 1262.2±2cm -1 , 1352.7±2cm -1 , 1405.3±2cm -1 , 1509.0±2cm -1 , 1568.9±2cm -1 , and 1630.2±2cm -1 2. Form A according to embodiment 1, characterized by a Raman spectrum having signals at at least two ppm values ​​selected from:

[0082] Embodiment 28: 579.1 ± 2 cm -1 , 741.3±2cm -1 , 863.7±2cm -1 , 1066.6±2cm -1 , 1262.2±2cm -1 , 1352.7±2cm -1, 1405.3 ± 2 cm -1 , 1509.0 ± 2 cm -1 , 1568.9 ± 2 cm -1 , and 1630.2 ± 2 cm -1 A form according to Embodiment 1, characterized by a Raman spectrum having signals at at least three ppm values selected from

[0083] Embodiment 29: 579.1 ± 2 cm -1 , 741.3 ± 2 cm -1 , 863.7 ± 2 cm -1 , 1066.6 ± 2 cm -1 , 1262.2 ± 2 cm -1 , 1352.7 ± 2 cm -1 , 1405.3 ± 2 cm -1 , 1509.0 ± 2 cm -1 , 1568.9 ± 2 cm -1 , and 1630.2 ± 2 cm -1 A form according to Embodiment 1, characterized by a Raman spectrum having signals at at least four ppm values selected from

[0084] Embodiment 30: 579.1 ± 2 cm -1 , 741.3 ± 2 cm -1 , 863.7 ± 2 cm -1 , 1066.6 ± 2 cm -1 , 1262.2 ± 2 cm -1 , 1352.7 ± 2 cm -1 , 1405.3 ± 2 cm -1 , 1509.0 ± 2 cm -1 , 1568.9 ± 2 cm -1 , and 1630.2 ± 2 cm -1 A form according to Embodiment 1, characterized by a Raman spectrum having signals at at least five ppm values selected from

[0085] Embodiment 31: 579.1 ± 2 cm -1 , 741.3 ± 2 cm -1 , 863.7 ± 2 cm -1 , 1066.6 ± 2 cm -1 , 1262.2 ± 2 cm -1, 1352.7 ± 2 cm -1 , 1405.3 ± 2 cm -1 , 1509.0 ± 2 cm -1 , 1568.9 ± 2 cm -1 , and a Raman spectrum having signals at 1630.2 ± 2 cm, the A form according to Embodiment 1. -1

[0086] Embodiment 32: 741.3 ± 2 cm -1 , 863.7 ± 2 cm -1 , 1066.6 ± 2 cm -1 , 1352.7 ± 2 cm -1 , 1405.3 ± 2 cm -1 , 1509.0 ± 2 cm -1 , and a Raman spectrum having signals at 1630.2 ± 2 cm, the A form according to Embodiment 1. -1

[0087] Embodiment 33: 741.3 ± 2 cm -1 , 863.7 ± 2 cm -1 , 1352.7 ± 2 cm -1 , 1405.3 ± 2 cm -1 , and a Raman spectrum having signals at 1630.2 ± 2 cm, the A form of Compound I according to Embodiment 1. -1

[0088] Embodiment 34: 863.7 ± 2 cm -1 , 1405.3 ± 2 cm -1 , and a Raman spectrum having signals at 1630.2 ± 2 cm, the A form according to Embodiment 1. -1

[0089] Embodiment 35: A pharmaceutical composition comprising the A form according to any one of Embodiments 1 to 34 and a pharmaceutically acceptable carrier.

[0090] Embodiment 36: A method for treating and / or preventing cancer, comprising administering to a subject in need thereof an effective amount of the A form according to any one of Embodiments 1 to 34 or the pharmaceutical composition according to Embodiment 35.​​​​

[0091] Embodiment 37: The method according to embodiment 36, wherein the cancer is selected from bladder cancer, breast cancer, prostate cancer, and cancer with altered RXRα and / or PPARγ pathways.

[0092] Embodiment 38: The method according to embodiment 36 or 37, wherein the cancer is bladder cancer.

[0093] Embodiment 39: The method according to any one of embodiments 37 or 38, wherein the bladder cancer is selected from advanced bladder cancer, luminal bladder cancer, and basal cell bladder cancer.

[0094] Embodiment 40: The method according to any one of embodiments 36 to 39, wherein the cancer is chemotherapy-resistant cancer and / or immunotherapy-resistant cancer.

[0095] Embodiment 41: Use of the A form of (7S)-4-{[5-(5-fluoro-2-methoxypyridin-4-yl)-1H-pyrazol-3-yl]carbonyl}-N-[(1r,4S)-4-hydroxy-4-(trifluoromethyl)cyclohexyl]-4-azaspiro[2.5]octane-7-carboxamide according to any one of embodiments 1 to 34 and the pharmaceutical composition according to embodiment 35 in the treatment and / or prevention of cancer.

[0096] Embodiment 42: A method for preparing the A form of (7S)-4-{[5-(5-fluoro-2-methoxypyridin-4-yl)-1H-pyrazol-3-yl]carbonyl}-N-[(1r,4S)-4-hydroxy-4-(trifluoromethyl)cyclohexyl]-4-azaspiro[2.5]octane-7-carboxamide, comprising mixing (7S)-4-{[5-(5-fluoro-2-methoxypyridin-4-yl)-1H-pyrazol-3-yl]carbonyl}-N-[(1r,4S)-4-hydroxy-4-(trifluoromethyl)cyclohexyl]-4-azaspiro[2.5]octane-7-carboxamide with acetonitrile at room temperature, and stirring the mixture at room temperature for at least 24 hours A method comprising

Example

[0097] To more fully understand the disclosure described herein, the following examples are provided. It should be understood that these examples are for illustrative purposes only and should not be construed as limiting the disclosure in any way.

[0098] The method of preparation and structure of Compound I are reported in U.S. Provisional Patent Application No. 63 / 11,354, filed November 9, 2020, U.S. Patent Application No. 17 / 521,666, filed November 8, 2021, and PCT / US2021 / 058473, both of which are incorporated herein by reference in their entirety.

[0099] Synthesis of Compound I tert-Butyl 7-(((1r,4r)-4-hydroxy-4-(trifluoromethyl)cyclohexyl)carbamoyl)-4-azaspiro[2.5]octane-4-carboxylate

Chemical formula

[0100] N-((1r,4r)-4-Hydroxy-4-(trifluoromethyl)cyclohexyl)-4-azaspiro[2.5]octane-7-carboxamide

Chemical Structure

[0101] Methyl 5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-3-carboxylate

Chemical Structure

[0102] Methyl 5-(5-fluoro-2-methoxypyridin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-3-carboxylate

Chemical Structure

[0103] 5-(5-Fluoro-2-methoxypyridin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-3-carboxylic acid

Chem.

[0104] Methyl 5-(5-fluoro-2-methoxypyridin-4-yl)-1H-pyrazole-3-carboxylate

Chem.

[0105] 5-(5-Fluoro-2-methoxypyridin-4-yl)-1H-pyrazole-3-carboxylic acid

Chem.

[0106] Alternative synthetic method of 5-(5-fluoro-2-methoxypyridin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-3-carboxylic acid Methyl 5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-3-carboxylate and methyl 3-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-5-carboxylate

Chem.

[0107] Methyl 5-(5-fluoro-2-methoxypyridin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-3-carboxylate

Chemical Structure

[0108] 5-(5-Fluoro-2-methoxypyridin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-3-carboxylic acid

Chemical Structure

[0109] 4-(5-(5-Fluoro-2-methoxypyridin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-3-carbonyl)-N-((1r,4r)-4-hydroxy-4-(trifluoromethyl)cyclohexyl)-4-azaspiro[2.5]octane-7-carboxamide

Chemical Structure

[0110] (7R)-4-{[5-(5-Fluoro-2-methoxypyridin-4-yl)-1H-pyrazol-3-yl]carbonyl}-N-[(1r,4R)-4-hydroxy-4-(trifluoromethyl)cyclohexyl]-4-azaspiro[2.5]octane-7-carboxamide and (7S)-4-{[5-(5-Fluoro-2-methoxypyridin-4-yl)-1H-pyrazol-3-yl]carbonyl}-N-[(1r,4S)-4-hydroxy-4-(trifluoromethyl)cyclohexyl]-4-azaspiro[2.5]octane-7-carboxamide

Chemical Structure

[0111] A solid mixture of diastereomers (80.0 mg) was separated using Chiral-Prep-HPLC. Column: CHIRALPAK IA column Column dimensions: 2 × 25 cm, 5 μm Mobile phase: hexane (8 mM NH3·MeOH):EtOH = 50:50, held for 15 minutes Flow rate: 18 mL / min Detection: 220 / 254 nm

[0112] The first eluting diastereomer (26.3 mg) was obtained as a solid, and the retention time was 4.59 minutes. 1 1H NMR (300 MHz, DMSO-d 6 ) δ 14.09 - 13.85 (m, 1H), 8.29 - 8.23 (m, 1H), 7.82 (s, 1H), 7.32 (d, 1H), 7.04 (s, 1H), 5.70 (s, 1H), 4.56 - 4.49 (m, 1H), 3.91 - 3.76 (m, 4H), 2.86 - 2.70 (m, 2H), 2.22 - 2.16 (m, 1H), 1.83 - 1.72 (m, 5H), 1.56 - 1.46 (m, 5H), 1.30 - 0.43 (m, 5H). LCMS (ESI): [M+H] + : 540.2.

[0113] The second eluting diastereomer (28.3 mg) was obtained as a solid, and the retention time was 8.06 minutes. 1 1H NMR (300 MHz, DMSO-d 6 ) δ 14.00 (s, 1H), 8.27 (d, 1H), 7.82 (d, 1H), 7.33 (d, 1H), 7.03 (d, 1H), 5.71 (s, 1H), 4.44 (br s, 1H), 3.91 - 3.80 (m, 4H), 3.38 - 3.33 (m, 1H), 2.90 - 2.76 (m, 1H), 2.21 (s, 1H), 1.83 - 1.71 (m, 5H), 1.56 - 1.46 (m, 5H), 1.29 - 1.00 (m, 1H), 0.99 - 0.80 (m, 2H), 0.78 - 0.61 (m, 2H). LCMS (ESI): [M+H] + : 540.2.

[0114] Alternative synthesis of Compound I Synthesis of (S)-4-[5-(5-Fluoro-2-methoxypyridin-4-yl)-1H-pyrazole-3-carbonyl]-4-azaspiro[2.5]octane-7-carboxylic acid and (R)-4-(5-(5-Fluoro-2-methoxypyridin-4-yl)-1H-pyrazole-3-carbonyl)-4-azaspiro[2.5]octane-7-carboxylic acid

Chem.

Chem.

[0115] Methyl 4-[5-(5-Fluoro-2-methoxypyridin-4-yl)-1H-pyrazole-3-carbonyl]-4-azaspiro[2.5]octane-7-carboxylate

Chem.

[0116] (S)-Methyl 4-[5-(5-fluoro-2-methoxypyridin-4-yl)-1H-pyrazole-3-carbonyl]-4-azaspiro[2.5]octane-7-carboxylate and (R)-methyl 4-(5-(5-fluoro-2-methoxypyridin-4-yl)-1H-pyrazole-3-carbonyl)-4-azaspiro[2.5]octane-7-carboxylate

Chemical Structure

[0117] (S)-Methyl 4-[5-(5-fluoro-2-methoxypyridin-4-yl)-1H-pyrazole-3-carbonyl]-4-azaspiro[2.5]octane-7-carboxylate. The second eluting enantiomer (2.29 g) was obtained as a solid. The second eluting enantiomer had a retention time of 14.29 minutes. LCMS (ESI): 389.1 [M+H] + .

[0118] (R)-Methyl 4-(5-(5-fluoro-2-methoxypyridin-4-yl)-1H-pyrazole-3-carbonyl)-4-azaspiro[2.5]octane-7-carboxylate. The first eluting enantiomer (2.42 g) was obtained as a solid. The first eluting enantiomer had a retention time of 8.25 minutes. LCMS (ESI): 389.1 [M+H] + .

[0119] (S)-4-[5-(5-fluoro-2-methoxypyridin-4-yl)-1H-pyrazole-3-carbonyl]-4-azaspiro[2.5]octane-7-carboxylic acid [Chemical formula] LiOH.H 2 O (0.56 g, 13.4 mmol) was added to a stirred solution of (S)-methyl 4-[5-(5-fluoro-2-methoxypyridin-4-yl)-1H-pyrazole-3-carbonyl]-4-azaspiro[2.5]octane-7-carboxylate (2.6 g, 6.69 mmol, 1.00 equivalent) in a mixture of THF (10.00 mL), MeOH (10.00 mL), and water (10.00 mL) at 0 °C. The resulting mixture was stirred at 25 °C for 2 hours. The solution was concentrated under reduced pressure to remove as much MeOH and THF as possible, then acidified to pH 3 with HCl (1 M), and then the solution was extracted with EtOAc. The combined organic layers were concentrated under reduced pressure to give the title compound (2.50 g) as a solid. LCMS (ESI): 375.2 [M+H] +

[0120] (R)-4-(5-(5-Fluoro-2-methoxypyridin-4-yl)-1H-pyrazole-3-carbonyl)-4-azaspiro[2.5]octane-7-carboxylic acid

Chem.

[0121] (S)-4-(5-(5-Fluoro-2-methoxypyridin-4-yl)-1H-pyrazole-3-carbonyl)-N-((1r,4S)-4-hydroxy-4-(trifluoromethyl)cyclohexyl)-4-azaspiro[2.5]octane-7-carboxamide (Compound I)

Chem.

[0122] Alternative synthesis of Compound I 4-Benzyl-7-(((tert-butyldiphenylsilyl)oxy)methyl)-4-azaspiro[2.5]octane

Chemical Structure

[0123] tert-Butyl 7-(((tert-butyldiphenylsilyl)oxy)methyl)-4-azaspiro[2.5]octane-4-carboxylate

Chemical formula

[0124] tert-Butyl 7-(hydroxymethyl)-4-azaspiro[2.5]octane-4-carboxylate

Chem.

[0125] 4-(tert-Butoxycarbonyl)-4-azaspiro[2.5]octane-7-carboxylic acid

Chem.

[0126] tert-Butyl 7-(((1r,4r)-4-hydroxy-4-(trifluoromethyl)cyclohexyl)carbamoyl)-4-azaspiro[2.5]octane-4-carboxylate

Chem.

[0127] N - ((1r,4r) - 4 - hydroxy - 4 - (trifluoromethyl)cyclohexyl) - 4 - azaspiro[2.5]octane - 7 - carboxamide hydrochloride

Chemical formula

[0128] 4-(5-(5-Fluoro-2-methoxypyridin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-3-carbonyl)-N-((1r,4r)-4-hydroxy-4-(trifluoromethyl)cyclohexyl)-4-azaspiro[2.5]octane-7-carboxamide

Chem.

[0129] 4-(5-(5-Fluoro-2-methoxypyridin-4-yl)-1H-pyrazole-3-carbonyl)-N-((1r,4r)-4-hydroxy-4-(trifluoromethyl)cyclohexyl)-4-azaspiro[2.5]octane-7-carboxamide

Chem.

[0130] (7S)-4-{[5-(5-Fluoro-2-methoxypyridin-4-yl)-1H-pyrazol-3-yl]carbonyl}-N-[(1r,4S)-4-hydroxy-4-(trifluoromethyl)cyclohexyl]-4-azaspiro[2.5]octane-7-carboxamide (Compound I)

Chemical Structure

[0131] Equipment: Waters SFC prep 350 Column: DAICEL CHIRALPAK IG (250 mm × 50 mm, 10 μm) Mobile phase A: CO 2 Mobile phase B: EtOH Gradient: B 55% Flow rate: 200 mL / min Back pressure: 100 bar Column temperature: 35 °C Wavelength: 220 nm Cycle time: approximately 12.2 minutes Sample preparation: 1150 g of the compound was dissolved in 4700 ml of ethanol Injection: 15 mL per injection

[0132] Compound I (411.00 g) was obtained as a solid, and the retention time was 21.69 minutes.

[0133] 1 H NMR (400 MHz, DMSO-d 6 ) δ 14.0 (br s, 1H), 8.26 (s, 1H), 7.82 (d, 1H), 7.32 (d, 1H), 7.03 (s, 1H), 5.68 (s, 1H), 4.47 - 4.34 (m, 1H), 3.87 (s, 3H), 3.83 (s, 1H) 2.79 (s, 1H), 2.20 - 2.10 (m, 1H), 1.78 - 1.50 (m, 11H), 1.08 - 0.98 (m, 3H), 0.89 - 0.65 (m, 2H). LCMS: [M+H] + 540.1.

[0134] Crystallization of Compound I into Form A Acetonitrile (0.6 mL) was added to Compound I (597 mg), and the resulting solution was stirred at room temperature for 3 days. The precipitate was collected by filtration to obtain Compound I (Form A, 544 mg).

[0135] Powder X-ray diffraction The powder X-ray diffractogram of Form A of Compound I (Figure 1) was obtained under the following conditions: Instrument: SmartLab (Rigaku) X-ray source: CuKα (45 kV, 200 mA) Optical system: Converging beam optical element Solar slit: 2.5° Detector: D / teX Ultra 250 detector (1D semiconductor detection system) Mode: Transmission Scan range: 3° to 40° Step size: 0.01° Scan speed: 5° / min Sample holder: Mylar (trademark) film The peak is listed in Table 1 below.

[0136]

Table 1

[0137]

Table 2

[0138] Solid-state NMR 13 For 13C SSNMR spectroscopy, the A form of compound (I) was loaded into a 7 mm rotor. The solid state of the sample 13 13C SSNMR spectra were obtained under the following conditions: Instrument: Avance 400 MHz (BRUKER) 7 mm-CPMAS probe (BRUKER) Nucleus measured: 13C (100.6238359 MHz) Pulse mode: CPTOSS measurement Rotation frequency: 5000 Hz Pulse repetition time: 5 s

[0139] Contact time: 1 msec Number of scans: 10240 Of the A form of compound I 13 13C CPMAS (Figure 2) was obtained at room temperature with 5 kHz rotation using the carbonyl carbon of glycine adamantane at 176.03 ppm as a reference. The peaks are listed in Table 2 below.

[0140]

Table 3

[0141] Thermogravimetric analysis and differential scanning calorimetry Thermogravimetric analysis and differential scanning calorimetry of Form A of Compound I were measured using a METTLER TOLEDO TGA / DSC 3+.

[0142] Approximately 3 mg of the crystalline (Form A) sample was accurately weighed and placed in an aluminum pan, and then the analysis was carried out under the following conditions. Atmosphere: Nitrogen gas flow rate 50 mL / min Reference pan: Empty aluminum pan Heating rate: 10 °C / min Sampling interval: 1 second Temperature range: 25 - 300 °C The DSC curve thermogram (Figure 3) shows one endotherm at approximately 240 °C (extrapolated onset temperature).

[0143] Raman spectroscopy For Raman spectroscopy, 50 - 100 mg of Form A of Compound I was filled in a plastic bag. The Raman spectrum of the sample was obtained under the following conditions. Instrument: TRS100 Raman (Agilent) Laser wavelength: 830 nm Laser output: 0.65 W Exposure time: 1.000 second Scan number: 10 times Laser spot size: 4 mm Collection size: Medium The Raman spectrum (Figure 4) was obtained. The wavenumbers are listed in Table 3 below.

[0144] [Table 4]

[0145] Hygroscopicity Weighed 10.88 mg of Form A of Compound I into a sampling cup and placed the sampling cup in an isothermal chamber at 25°C. The relative humidity (RH) was controlled from 0% to 95% using a gravimetric vapor adsorption system, and the sample weight at each RH stage was measured at predetermined time intervals (for example, every 2 minutes). The weight changes at each RH stage were evaluated stepwise and then finally determined according to the following criteria. The maximum weight change for each measurement was less than 0.002% (w / w) per minute. Refer to Figure 5.

[0146] Single crystal X-ray diffraction Dissolved 3.24 mg of Form A of Compound I in 600 μL of MEK (methyl ethyl ketone). Put 200 μL of this solution into another glass vial, and then stored this vial in a fixed container with 2 mL of c-hexane at room temperature for 2 days (MEK / c-hexane vapor diffusion method). Colorless crystals were collected.

[0147] Dispersed the colorless single crystal blocks (0.1×0.1×0.01 mm) found in the crystallization solution in Parabar 10312 liquid and mounted them on Dual-Thickness MicroMounts (trademark) (MiTeGen). Diffraction data were collected at -160°C by the ω-axis oscillation method using multilayer mirror monochromated Cu-Kα radiation with XtaLAB PRO P200 MM007HF (Rigaku). The single crystal X-ray diffractogram of Compound I was obtained under the conditions described in Table 4.

[0148] Determined the structure of Form A using single crystal X-ray diffraction (SXRD). Summarized the results in Tables 4 to 7. These results demonstrate that Form A is anhydrous. Refer to Figure 6.

[0149]

Table 5

[0150]

Table 6

[0151]

Table 7

[0152]

Table 8

[0153]

Table 9

[0154]

Table 10

[0155] Measurement of Co-R peptide recruitment to PPARγ by TR-FRET assay His for the assay was expressed and purified according to Korpal, M., et al., Evasion of immunosurveillance by genomic alterations of PPARgamma / RXRalpha in bladder cancer. Nature communications, 2017.8(1):p.103 6 -TEV-PPARγ-(234-505) protein was expressed and purified.

[0156] The assay buffer contained 50 mM potassium chloride (Sigma), 50 mM HEPES pH 7.4 (Teknova), 2 mM DTT (Boston Bioproducts), 0.1 mg / mL bovine γ-globulin (Sigma), and 0.001% Pluronic F-127 (Thermo Fisher). His 6The 2× working stock of -PPARγ-(234-505) was diluted with assay buffer to a final concentration of 10 nM. The 2× detection solution contained anti-6xHis-terbium antibody (CisBio) and FITC-labeled Co-R peptide (SMRT-ID2, supplier New England Peptide) at final concentrations of 5 and 200 nM, respectively.

[0157] Using an acoustic dispenser, 4 nL of compound or DMSO at a maximum final concentration of 20 μM was dispensed from an 11-point master dose response (MDR) source plate into a 384-well assay plate (Corning, 3820). In these assay plates, the positive control in column 24 contained 500 nM (final concentration) T0070907, and the negative control in column 23 contained the same volume of DMSO. Next, 5 μL of the 2× protein working stock or control was added to the plate and incubated at room temperature for 20 minutes. The addition of reagents was performed using either a Combi (Thermo) or Mantis (Formulatrix) pipetting device. After incubation, 5 μL of the 2× detection solution was subsequently added. The plate was covered, centrifuged, and incubated for an additional 1 hour. TR-FRET data were recorded using an Envision plate reader (Perkin Elmer) with settings recommended by Thermo Fisher. The TR-FRET signal for the reaction rate was normalized using the TR-FRET signals of the FITC-Co-R peptide mobilization of the positive and negative controls to determine the assay Z' prime. The experiment was performed in triplicate and analyzed using GraphPad Prism 7.

[0158] The results of this assay are reported in Table 8.

[0159]

Table 11

Claims

1. (7S)-4-{[5-(5-fluoro-2-methoxypyridine-4-yl)-1H-pyrazole-3-yl]carbonyl}-N-[(1r,4S)-4-hydroxy-4-(trifluoromethyl)cyclohexyl]-4-azaspiro[2.5]octane-7-carboxamide A form (i.e., (S)-4-(5-(5-fluoro-2-methoxypyridine-4-yl)-1H-pyrazole-3-carbonyl)-N-((1r,4S)-4-hydroxy-4-(trifluoromethyl)cyclohexyl)-4-azaspiro[2.5]octane-7-carboxamide A form) (i.e., compound I: 【Chemistry 1】 (Type A).

2. Type A according to claim 1, characterized by a powder X-ray diffractogram substantially similar to that of Figure 1.

3. Type A according to claim 1, characterized by a powder X-ray diffractogram having a signal at at least one 2θ value selected from 14.8±0.2, 15.9±0.2, 17.5±0.2, 18.5±0.2, 19.4±0.2, 20.0±0.2, 20.7±0.2, 21.0±0.2, 22.6±0.2, and 27.2±0.

2.

4. Type A according to claim 1, characterized by a powder X-ray diffractogram having signals at at least two 2θ values ​​selected from 14.8±0.2, 17.5±0.2, 18.5±0.2, 19.4±0.2, 20.0±0.2, 21.0±0.2, and 22.6±0.

2.

5. Type A according to claim 1, characterized by a powder X-ray diffractogram having signals at at least two 2θ values ​​selected from 14.8±0.2, 18.5±0.2, 19.4±0.2, 21.0±0.2, and 22.6±0.

2.

6. Type A according to claim 1, characterized by a powder X-ray diffractogram having signals at at least two 2θ values ​​selected from 14.8±0.2, 18.5±0.2, and 19.4±0.

2.

7. Type A according to claim 1, characterized by a powder X-ray diffractogram having signals at 14.8±0.2, 15.9±0.2, 17.5±0.2, 18.5±0.2, 19.4±0.2, 20.0±0.2, 20.7±0.2, 21.0±0.2, 22.6±0.2, and 27.2±0.

2.

8. Type A according to claim 1, characterized by a powder X-ray diffractogram having signals at 14.8±0.2, 17.5±0.2, 18.5±0.2, 19.4±0.2, 20.0±0.2, 21.0±0.2, and 22.6±0.

2.

9. Type A according to claim 1, characterized by a powder X-ray diffractogram having signals at 14.8±0.2, 18.5±0.2, 19.4±0.2, 21.0±0.2, and 22.6±0.

2.

10. Type A according to claim 1, characterized by a powder X-ray diffractogram having signals at 14.8±0.2, 18.5±0.2, and 19.4±0.

2.

11. The signal is present at at least one ppm value selected from 41.4±0.2 ppm, 43.7±0.2 ppm, 47.7±0.2 ppm, 54.8±0.2 ppm, 70.1±0.2 ppm, 127.2±0.2 ppm, 134.3±0.2 ppm, 148.9±0.2 ppm, 161.2±0.2 ppm, and 179.0±0.2 ppm. １３ Type A according to claim 1, characterized by a C SSN NMR spectrum.

12. Signals are present at 41.4±0.2 ppm, 43.7±0.2 ppm, 47.7±0.2 ppm, 54.8±0.2 ppm, 70.1±0.2 ppm, 127.2±0.2 ppm, 134.3±0.2 ppm, 148.9±0.2 ppm, 161.2±0.2 ppm, and 179.0±0.2 ppm. １３ Type A according to claim 1, characterized by a C SSN NMR spectrum.

13. Signals are present at 41.4±0.2 ppm, 54.8±0.2 ppm, 70.1±0.2 ppm, 127.2±0.2 ppm, 134.3±0.2 ppm, 148.9±0.2 ppm, and 161.2±0.2 ppm. １３ Type A according to claim 1, characterized by a C SSN NMR spectrum.

14. Signals are present at 41.4±0.2 ppm, 54.8±0.2 ppm, 70.1±0.2 ppm, 134.3±0.2 ppm, and 148.9±0.2 ppm. １３ Type A according to claim 1, characterized by a C SSN NMR spectrum.

15. Signals are present at 54.8 ± 0.2 ppm, 70.1 ± 0.2 ppm, and 148.9 ± 0.2 ppm. １３ A form of compound I according to claim 1, characterized by a C SSN NMR spectrum.

16. Type A according to claim 1, characterized by a TGA / DSC substantially the same as that of Figure 3.

17. Type A according to claim 1, characterized by a Raman curve substantially similar to that of Figure 4.

18. 579.1 ± 2 cm －１ , 741.3 ± 2 cm －１ , 863.7 ± 2 cm －１ , 1066.6 ± 2 cm －１ , 1262.2 ± 2 cm －１ , 1352.7 ± 2 cm －１ , 1405.3 ± 2 cm －１ , 1509.0 ± 2 cm －１ , 1568.9 ± 2 cm －１ , and a Raman spectrum having a signal at at least one wavenumber selected from 1630.2 ± 2 cm －１ The A form according to claim 1, characterized by

19. 579.1 ± 2 cm －１ 741.3±2cm －１ 863.7±2cm －１ , 1066.6±2cm －１ , 1262.2±2cm －１ , 1352.7±2cm －１ , 1405.3±2cm －１ , 1509.0±2cm －１ , 1568.9±2cm －１ , and 1630.2±2cm －１ The A-type according to claim 1, characterized by a Raman spectrum having a signal.

20. 741.3 ± 2 cm －１ 863.7±2cm －１ , 1066.6±2cm －１ , 1352.7±2cm －１ , 1405.3±2cm －１ , 1509.0±2cm －１ , and 1630.2±2cm －１ The A-type according to claim 1, characterized by a Raman spectrum having a signal.

21. 741.3 ± 2 cm －１ 863.7±2cm －１ , 1352.7±2cm －１ , 1405.3±2cm －１ , and 1630.2±2cm －１ The A form of compound I according to claim 1, characterized by a Raman spectrum having a signal.

22. 863.7 ± 2 cm －１ , 1405.3±2cm －１ , and 1630.2±2cm －１ The A-type according to claim 1, characterized by a Raman spectrum having a signal.

23. A pharmaceutical composition comprising type A as described in any one of claims 1 to 22 and a pharmaceutically acceptable carrier.

24. A pharmaceutical composition according to claim 23 for treating and / or preventing cancer.

25. The pharmaceutical composition according to claim 24, wherein the cancer is selected from bladder cancer, breast cancer, prostate cancer, and cancers in which the RXRα and / or PPARγ pathways are altered.

26. The pharmaceutical composition according to claim 25, wherein the cancer is bladder cancer.

27. The pharmaceutical composition according to claim 26, wherein the bladder cancer is selected from advanced bladder cancer, luminal bladder cancer, and basal cell-like bladder cancer.

28. The pharmaceutical composition according to claim 24, wherein the cancer is a chemotherapy-resistant cancer and / or an immunotherapy-resistant cancer.

29. A method for preparing form A of (7S)-4-{[5-(5-fluoro-2-methoxypyridine-4-yl)-1H-pyrazole-3-yl]carbonyl}-N-[(1r,4S)-4-hydroxy-4-(trifluoromethyl)cyclohexyl]-4-azaspiro[2.5]octane-7-carboxamide, (7S)-4-{[5-(5-fluoro-2-methoxypyridine-4-yl)-1H-pyrazole-3-yl]carbonyl}-N-[(1r,4S)-4-hydroxy-4-(trifluoromethyl)cyclohexyl]-4-azaspiro[2.5]octane-7-carboxamide is mixed with acetonitrile at room temperature, and Stir the mixture at room temperature for at least 24 hours. A method that includes this.

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