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

[0002] This disclosure provides a solid form of a compound that may alter, modulate, or inhibit the RXRa and/or PPARy pathways and methods of treating cancers, particularly cancers in which agents that target the RXRa and/or PPARy pathways are known to be useful.

[0003] Muscle-invasive bladder cancer (MIBC) is an aggressive, potentially lethal disease with limited therapeutic options. Although chemotherapies and immunotherapies are approved for treatment of locally advanced or metastatic bladder cancer, the majority of patients will either not respond or present only a short duration of response (Seiler et al., 2017 Eur Urology, Robertson et al., 2017 Cell). This suggests that additional efforts are needed to identify novel therapies that can benefit those patients currently not responding to existing standard-of-care (SoC) therapies.

[0004] Recent work has revealed that not all advanced bladder cancers are created equal. Deep gene expression and genomic analysis has revealed 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), with unique tumor intrinsic and microenvironmental characteristics. Much like luminal breast and prostate cancers, luminal bladder cancer tends to be slower growing, less immune infiltrated, and less responsive to both chemotherapies and immunotherapies (Robertson et al., 2017 Cell). As only suboptimal therapies are currently available for luminal disease, a concerted effort is required to identify and exploit novel luminal lineage-specific therapeutic nodes.

[0005] Genomic alterations in the RXRa/ PPARy pathway in a large fraction of luminal bladder cancer, including recurrent mutations in RXRa at serine 427 (S427F/Y), hotspot mutations in PPARy at threonine 475 (T475M), and amplification/overexpression of PPARy (Guo et al., 2013 Nature Genetics,' Van Allen et al., 2014 Cancer Discovery) are evident. These genomic alterations enhance PPARy/RXRa-dependent transcription programs in MIBC (Halstead et al., 2017 eLife; Korpal et al., 2017 Nat Communications; Goldstein et al., 2017 Cancer Research). Additionally, only PPARy ^active luminal bladder cancer cell lines show reduced proliferation following genetic/pharmacological inhibition of PPARy (Halstead et al., 2017 eLife; Goldstein et al, 2017 Cancer Research). Accordingly, this pathway activation is associated with dependence on RXRa/ PPARy for growth. Subsequent analysis of the functional role of PPARy in luminal cells has revealed a critical role in promoting energy production through enhancing glucose and lipid metabolism (Liu et al., 2019 Nat Communications) which may contribute to the observed dependence on PPARy in genomically altered luminal cells.

[0006] In addition to this tumor-intrinsic role played by PPARy in PPARy altered luminal bladder cancer, recent studies suggest that activated PPARy/RXRa suppresses inflammatory cytokine expression and immune cell infiltration (Korpal et al., 2017 Nat Communications; Kardos et al., 2016 JCI Insight). Several clinical datasets and an in vivo tumor model indicate that PPARy ^High /RXRa ^s427F/Y impairs CD8 ⁺ T cell infiltration and confers partial resistance to immune checkpoint inhibitors. Knockdown of PPARy or RXRa and pharmacological inhibition of PPARy significantly increases cytokine expression and may suggest therapeutic approaches to reviving immunosurvcillancc and sensitivity to immunotherapies (Korpal et al., 2017 Nat Communications). Collectively, these studies suggest PPARy acts as a tumor cell-intrinsic “immuno-oncogene” that functions by promoting tumor cell growth, enhancing energy production, and increasing tumor cell survival through immunosuppression.

[0007] “Compound I” as used herein may be described using its name according to ACD/Name software which is (7S)-4-{ [5-(5-fluoro-2-methoxypyridin-4-yl)-lff-pyrazol-3-yl]carbony l}-A-[(lr,4S)-4- hydroxy-4-(trifluoromethyl)cyclohexyl]-4-azaspiro[2.5]octane -7-carboxamide, and/or as (S)-4-(5-(5- fluoro-2-methoxypyridin-4-yl)-lH-pyrazole-3-carbonyl)-N-((lr ,4S)-4-hydroxy-4- (trifluoromethyl)cyclohexyl)-4-azaspiro[2.5]octane-7-carboxa mide. The structure of Compound I may be depicted as:

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

[0009] One aspect of the present disclosure provides a new solid state form, Form A, of Compound I, which can be employed in the treatment of cancers in which agents that target the RXRa and/or PPARy pathways are known to be useful.

[0010] Another aspect of the disclosure provides methods of 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, the methods of treatment include administration of at least one additional active agent to the subject in need thereof, either in the same pharmaceutical composition as Form A of Compound I, or as separate compositions.

[0012] Also provided are methods of modulating PPARy, comprising administering to a subject in need thereof, Form A of Compound I, or a pharmaceutical composition comprising the same.

Brief Description of the Drawings

[0013] FIG. 1 depicts an XRPD diffractogram of Form A of Compound I.

[0014] FIG. 2 depicts a solid state ¹³ C SSNMR spectrum of Form A of Compound I.

[0015] FIG. 3 depicts a TGA/DSC thermogram of Form A of Compound I.

[0016] FIG. 4 depicts a Raman spectrum of Form A of Compound I.

[0017] FIG. 5 depicts an adsorption and desorption isotherm of Form A of Compound I. [0018] FIG. 6 depicts the crystal structure of Form A of Compound I.

Definitions

[0019] The term “compound,” when referring to a compound of this disclosure, refers to a collection of molecules having an identical chemical structure unless otherwise indicated as a collection of stereoisomers (for example, a collection of racemates, a collection of cis/trans stereoisomers, or a collection of (E) and (Z) stereoisomers), except that there may be isotopic variation among the constituent atoms of the molecules. Thus, it will be clear to those of skill in the art that a compound represented by a particular chemical structure containing indicated deuterium atoms, will also contain lesser amounts of isotopologues having hydrogen atoms at one or more of the designated deuterium positions in that structure. The relative amount of such isotopologues in a compound of this disclosure will depend upon a number of factors including the isotopic purity of reagents used to make the compound and the efficiency of incorporation of isotopes in the various synthesis steps used to prepare the compound. However, as set forth above the relative amount of such isotopologues in toto will be less than 49.9% of the compound. Tn other embodiments, the relative amount of such isotopologues in toto will 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.

[0020] Non-limiting, examples of suitable solvents that may be used in this disclosure include, but are not limited to, water, methanol (MeOH), ethanol (EtOH), dichloromethane or “methylene chloride” (CH2CI2), toluene, acetonitrile (McCN), dimethylformamide (DMF), dimethyl sulfoxide (DMSO), methyl acetate (MeOAc), ethyl acetate (EtOAc), heptanes, isopropyl acetate (IP Ac), tert-butyl acetate (t-BuOAc), isopropyl alcohol (IP A), tetrahydrofuran (THF), 2-methyl tetrahydrofuran (2-MeTHF), methyl ethyl ketone (MEK), tert-butanol, diethyl ether (Et2O), methyl-tert-butyl ether (MTBE), 1,4-dioxane, and A-methyl pyrrolidone (NMP).

[0021] Non-limiting, examples of suitable bases that may be used in this disclosure include, but are not limited to, l,8-diazabicyclo[5.4.0]undec-7-ene (DBU), potassium tert-butoxide (KOtBu), potassium carbonate (K2CO3), A-methylmorpholine (NMM), triethylamine (EtsN; TEA), diisopropyl-ethyl amine (i- PnEtN; DIPEA), pyridine, potassium hydroxide (KOH), sodium hydroxide (NaOH), lithium hydroxide (LiOH) and sodium methoxide (NaOMe; NaOCHj).

[0022] The terms “about” and “approximately”, when used in connection with doses, amounts, or weight percent of ingredients of a composition or a dosage form, include the value of a specified dose, amount, or weight percent or a range of the dose, amount, or weight percent that is recognized by one of ordinary skill in the art to provide a pharmacological effect equivalent to that obtained from the specified dose, amount, or weight percent.

[0023] “Treatment,” “treat,” or “treating” cancer refers to reversing, alleviating, and/or delaying the progression of a cancer as described herein.

[0024] “Subject”, as used herein, means an animal subject, such as a mammalian subject, and particularly human beings. [0025] “Pharmaceutically acceptable carrier” as used herein refers to a nontoxic carrier, adjuvant, or vehicle that does not destroy the pharmacological activity of the compound with which it is formulated. Pharmaceutically acceptable carriers, adjuvants or vehicles that may be used in the compositions of this 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, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, cyclodextrins, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene- polyoxypropylene-block polymers, polyethylene glycol and wool fat.

[0026] The terms “patient” and “subject” are used interchangeably and refer to an animal including a human.

[0027] The terms "effective dose" and “effective amount” are used interchangeably herein and refer to that amount of compound that produces the desired effect for which it is administered. The exact amount of an effective dose will depend on the purpose of the treatment and will be ascertainable by one skilled in the art using known techniques (see, e.g., Lloyd (1999) The Art, Science and Technology of Pharmaceutical Compounding).

[0028] Form A of Compound I may be administered once daily, twice daily, or three times daily, for example, for the treatment of FSGS. In some embodiments, Form A of Compound I is administered once daily. In some embodiments, Form A of Compound I is administered twice daily. In some embodiments, Form A of Compound I is administered three times daily.

[0029] As used herein, the term “ambient conditions” means room temperature, open air condition and uncontrolled humidity condition.

[0030] As used herein, the terms “crystalline form” and “Form” interchangeably refer to a crystal structure (or polymorph) having a particular molecular packing arrangement in the crystal lattice. Crystalline forms can be identified and distinguished from each other by one or more characterization techniques including, for example, X-ray powder 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). Accordingly, as used herein, the terms “crystalline Form A of Compound I” refers to a unique crystalline form that can be identified and distinguished from other crystalline forms of Compound I by one or more characterization techniques including, for example, XRPD, SXRD, SSNMR, Raman, DSC, and/or TGA. In some embodiments, the novel crystalline Form A of is characterized by an X-ray powder diffractogram having one or more signals at one or more specified two-theta values (° 20).

[0031] As used herein, the term “SSNMR” refers to the analytical characterization method of solid state nuclear magnetic resonance. SSNMR spectra can be recorded at ambient conditions on any magnetically active isotope present in the sample. The typical examples of active isotopes for small molecule active pharmaceutical ingredients include H, ² H, ¹³ C, ¹⁹ F, ³¹ P, ¹⁵ N, ¹⁴ N, ³⁵ C1, ⁿ B, ⁷ Li, ¹⁷ 0, ²³ Na, ⁷⁹ Br, and ¹⁹⁵ Pt.

[0032] As used herein, the term “XRPD” refers to the analytical characterization method of X-ray powder diffraction. XRPD patterns can be recorded at ambient conditions in transmission or reflection geometry using a diffractometer.

[0033] As used herein, the terms “X-ray powder diffractogram,” “X-ray powder diffraction pattern,” “XRPD pattern” interchangeably refer to an experimentally obtained pattern plotting signal positions (on the abscissa) versus signal intensities on the ordinate). For an amorphous material, an X-ray powder diffractogram may include one or more broad signals; and for a crystalline material, an X-ray powder diffractogram may include one or more signals, each identified by its angular value as measured in degrees 20 (° 20), depicted on the abscissa of an X-ray powder diffractogram, which may be expressed as “a signal at ... degrees two-theta,” “a signal at [a] two-theta value(s) of ...” and/or “a signal at at least ... two-theta value(s) chosen from ....”

[0034] A “signal” or “peak” as used herein refers to a point in the XRPD pattern where the intensity as measured in counts is at a local maximum. One of ordinary skill in the art would recognize that one or more signals (or peaks) in an XRPD pattern may overlap and may, for example, not be apparent to the naked eye. Indeed, one of ordinary skill in the art would recognize that some art-recognized methods are capable of and suitable for determining whether a signal exists in a pattern, such as Rietveld refinement. [0035] As used herein, “a signal at .. . degrees two-theta,” “a signal at [a] two-theta value[] of ...” and/or “a signal at at least .. . two-theta value(s) chosen from ....” refer to X-ray reflection positions as measured and observed in X-ray powder diffraction experiments (° 20).

[0036] The repeatability of the angular values is in the range of ± 0.2° 20, i.e., the angular value can be at the recited angular value + 0.2 degrees two-theta, the angular value - 0.2 degrees two-theta, or any value between those two end points (angular value + 0.2 degrees two-theta and angular value - 0.2 degrees two-theta).

[0037] The terms “signal intensities” and “peak intensities” interchangeably refer to relative signal intensities within a given X-ray powder diffractogram. Factors that can affect the relative signal or peak intensities include sample thickness and preferred orientation (e.g., the crystalline particles are not distributed randomly).

[0038] The term “X-ray powder diffractogram having a signal at .. . two-theta values” as used herein refers to an XRPD pattern that contains X-ray reflection positions as measured and observed in X-ray powder diffraction experiments (° 20).

[0039] As used herein, an X-ray powder diffractogram is “substantially similar to that in [a particular] Figure” when at least 90%, such as at least 95%, at least 98%, or at least 99%, of the signals in the two diffractograms overlap. In determining “substantial similarity,” one of ordinary skill in the art will understand that there may be variation in the intensities and/or signal positions in XRPD diffractograms even for the same crystalline form. Thus, those of ordinary skill in the art will understand that the signal positions in XRPD diffractograms (in degrees two-theta (° 29) referred to herein) generally mean that value reported is ± 0.2 degrees 29 of the reported value, an art-recognized variance.

[0040] As used herein, an SSNMR spectrum is “substantially similar to that in [a particular] Figure” when at least 90%, such as at least 95%, at least 98%, or at least 99%, of the signals in the two spectra overlap. In determining “substantial similarity,” one of ordinary skill in the art will understand that there may be variation in the intensities and/or signal positions in SSNMR spectra even for the same crystalline form. Thus, those of ordinary skill in the art will understand that the signal positions in SSNMR spectra (in ppm) referred to herein generally mean that value reported is ±0.2 ppm of the reported value, an art- recognized variance.

[0041] As used herein, a crystalline form is “substantially pure” when it accounts for an amount by weight equal to or greater than 90% of the sum of all solid form(s) in a sample as determined by a method in accordance with the art, such as quantitative XRPD. In some embodiments, the solid form is "substantially pure" when it accounts for an amount by weight equal to or greater than 95% of the sum of all solid form(s) in a sample. In some embodiments, the solid form is "substantially pure" when it accounts for an amount by weight equal to or greater than 99% of the sum of all solid form(s) in a sample. [0042] As used herein, the term “DSC” refers to the analytical method of Differential Scanning Calorimetry.

[0043] As used herein, the term “TG A” refers to the analytical method of Thermo Gravimetric (or thermogravimetric) Analysis.

[0044] 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.

[0045] Disclosed herein is 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 an X-ray powder diffractogram substantially similar to that in FIG. 1. In some embodiments, Form A of Compound I is characterized by an X-ray powder diffractogram having a signal at at least one two-theta value chosen 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 an X-ray powder diffractogram having a signal at at least two two-theta values chosen 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 an X-ray powder diffractogram having a signal at at least one two-theta value chosen 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 an X-ray powder diffractogram having a signal at at least two two-theta values chosen 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 an X-ray powder diffractogram having a signal at at least one two-theta value chosen 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 an X-ray powder diffractogram having a signal at at least two two-theta values chosen 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 an X-ray powder diffractogram having a signal at at least one two-theta value chosen from 14.8 ± 0.2, 18.5 + 0.2, and 19.4 ± 0.2. In some embodiments, Form A of Compound I is characterized by an X-ray powder diffractogram having a signal at at least two two-theta values chosen from 14.8 ± 0.2, 18.5 ± 0.2, and 19.4 + 0.2.

[0046] In some embodiments, Form A of Compound I is characterized by an X-ray powder diffractogram having a signal at at least three two-theta values chosen 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 an X-ray powder diffractogram having a signal at at least four two-theta values chosen 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 an X-ray powder diffractogram having a signal at at least five two-theta values chosen 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 an X-ray powder diffractogram having a signal at at least six two-theta values chosen 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 an X-ray powder diffractogram having a signal at at least seven two-theta values chosen 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 an X-ray powder diffractogram having a signal at at least eight two-theta values chosen 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 an X- ray powder diffractogram having a signal at at least nine two-theta values chosen 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.

[0047] In some embodiments, Form A of Compound I is characterized by an X-ray powder diffractogram having a signal 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 an X-ray powder diffractogram having a signal 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 an X-ray powder diffractogram having a signal 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 an X-ray powder diffractogram having a signal at 14.8 ± 0.2, 18.5 ± 0.2, and 19.4 + 0.2.

[0048] In some embodiments, disclosed herein is a composition comprising Form A of Compound I. In some embodiments, disclosed herein is a composition comprising Compound I in substantially pure Form A. In some embodiments, disclosed herein is a composition comprising at least one active compound consisting essentially of Compound I in Form A. [0049] In some embodiments, Form A of Compound I is characterized by a TGA/DSC substantially similar to that in FIG. 3. In some embodiments, Form A of Compound I is characterized by a DSC having an onset of around 240 °C.

[0050] In some embodiments, Form A of Compound I is characterized by a ¹³ C SSNMR spectrum having a signal at at least one ppm value chosen 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. In some embodiments, Form A of Compound I is characterized by a ¹³ C SSNMR spectrum having a signal at at least two ppm values chosen 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. In some embodiments, Form A of Compound I is characterized by a ¹³ C SSNMR spectrum having a signal at at least three ppm values chosen 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. Tn some embodiments, Form A of Compound I is characterized by a ¹³ C SSNMR spectrum having a signal at at least four ppm values chosen 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. In some embodiments, Form A of Compound I is characterized by a ¹³ C SSNMR spectrum having a signal at at least five ppm values chosen 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. In some embodiments, Form A is characterized by a ¹³ C SSNMR spectrum having a signal at at least six ppm values chosen 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. In some embodiments, Form A of Compound I is characterized by a ¹³ C SSNMR spectrum having a signal at at least seven ppm values chosen 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. In some embodiments, Form A of Compound I is characterized by a ^l3 C SSNMR spectrum having a signal at at least eight ppm values chosen 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. In some embodiments, Form A of Compound I is characterized by a ¹³ C SSNMR spectrum having a signal at at least nine ppm values chosen 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. In some embodiments, Form A of Compound I is characterized by a ¹³ C SSNMR spectrum 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.

[0051] Tn some embodiments, Form A of Compound 1 is characterized by a Raman spectrum having a signal at at least one cm value chosen from 579.1 + 2 cm L 741.3 + 2 cm _: 863.7 + 2 cm 1066.6 + 2 cm ’, 1262.2 + 2 cm , 1352.7 + 2 cm ’, 1405.3 + 2 cm ’, 1509.0 + 2 cm , 1568.9 + 2 cm and 1630.2 + 2 cm In some embodiments, Form A of Compound I is characterized by a Raman spectrum having a signal at at least two cm value chosen from 579.1 + 2 cm 741.3 ± 2 cm 863.7 ± 2 cm 1066.6 ± 2 cm" ¹ , 1262.2 + 2 cm- ¹ , 1352.7 + 2 cm- ¹ , 1405.3 ± 2 cm L 1509.0 ± 2 cm . 1568.9 ± 2 cm-’, and 1630.2 ± 2 cm ¹ . In some embodiments, Form A of Compound I is characterized by a Raman spectrum having a signal at at least three cm ¹ value chosen from 579.1 ± 2 cm ¹ , 741.3 ± 2 cm ¹ , 863.7 ± 2 cm ¹ , 1066.6 + 2 enr 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 . In some embodiments, Form A of Compound I is characterized by a Raman spectrum having a signal at at least four cm ¹ value chosen from 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 . 1568.9 ± 2 cm-’, and 1630.2 ± 2 cm ¹ . In some embodiments, Form A of Compound I is characterized by a Raman spectrum having a signal at at least five cm ¹ value chosen from 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 . 1568.9 ± 2 cm-’, and 1630.2 ± 2 cm ¹ . In some embodiments, Form A of Compound I is characterized by a Raman spectrum having a signal at at least six cm ¹ value chosen from 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 . 1568.9 ± 2 cm- ¹ , and 1630.2 ± 2 cm ¹ . In some embodiments, Form A of Compound I is characterized by a Raman spectrum having a signal at at least seven cm-’ value chosen from 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 j 1509.0 ± 2 cm . 1568.9 ± 2 cm- ¹ , and 1630.2 ± 2 cm ¹ . In some embodiments, Form A of Compound I is characterized by a Raman spectrum having a signal at at least eight cm ¹ value chosen from 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 j 1509.0 ± 2 cm . 1568.9 ± 2 cm- ¹ , and 1630.2 ± 2 cm ¹ . In some embodiments, Form A of Compound I is characterized by a Raman spectrum having a signal at at least nine cm ¹ value chosen from 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 j 1509.0 ± 2 cm . 1568.9 ± 2 cm- ¹ , and 1630.2 ± 2 cm ¹ . In some embodiments, Form A of Compound I is characterized by a Raman spectrum having signals at 579.1 ± 2 cm- ¹ , 741.3 ± 2 cm . 863.7 ± 2 cm . 1066.6 ± 2 cm" ¹ , 1262.2 ± 2 cm j 1352.7 ± 2 cm- ¹ , 1405.3 + 2 cm- ¹ , 1509.0 + 2 cm- ¹ , 1568.9 ± 2 cm L and 1630.2 ± 2 cm- ¹ .

[0052] Another aspect of the disclosure provides pharmaceutical compositions 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.

[0053] A pharmaceutical composition may further comprise at least one pharmaceutically acceptable carrier. In some embodiments, the at least one pharmaceutically acceptable carrier is chosen from pharmaceutically acceptable vehicles and pharmaceutically acceptable adjuvants. In some embodiments, the at least one pharmaceutically acceptable is chosen from pharmaceutically acceptable fillers, disintegrants, surfactants, binders, lubricants.

[0054] It will also be appreciated that a pharmaceutical composition of this disclosure can be employed in combination therapies; that is, the pharmaceutical compositions described herein can further include at least one additional active therapeutic agent. Alternatively, a pharmaceutical composition comprising Form A of Compound I can be administered as a separate composition concurrently with, prior to, or subsequent to, 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 as a separate composition concurrently with, prior to, or subsequent to, a composition comprising at least one other active therapeutic agent.

[0055] As described above, pharmaceutical compositions disclosed herein may optionally further comprise at least one pharmaceutically acceptable carrier. The at least one pharmaceutically acceptable carrier may be chosen from adjuvants and vehicles. The at least one pharmaceutically acceptable carrier, as used herein, includes any and all solvents, diluents, other liquid vehicles, dispersion aids, suspension aids, surface active agents, isotonic agents, thickening agents, emulsifying agents, preservatives, solid binders, and lubricants, as suited to 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 discloses various carriers used in formulating pharmaceutical compositions and known techniques for the preparation thereof. Except insofar as any conventional carrier is incompatible with the compounds of this disclosure, such as by producing any undesirable biological effect or otherwise interacting in a deleterious manner with any other component(s) of the pharmaceutical composition, its use is contemplated to be within the scope of this disclosure. 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), buffer 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, polyvinyl pyrrolidone, poly acrylates, waxes, polycthylcnc-polyoxypropylcnc-block polymers, wool fat, 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), powdered tragacanth, 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, releasing agents, coating agents, sweetening agents, flavoring agents, perfuming agents, preservatives, and antioxidants. [0056] In some embodiments, Compound I is a crystalline solid consisting of 1 % to 99% Form A relative to the total weight of the crystalline solid Compound I. In some embodiments, the crystalline solid consists of 2% to 99% Form A relative to the total weight of the crystalline solid Compound I. In some embodiments, the crystalline solid consists of 5% to 99% Form A relative to the total weight of the crystalline solid Compound I. In some embodiments, the crystalline solid consists of 10% to 99% Form A relative to the total weight of the crystalline solid Compound I. In some embodiments, the crystalline solid consists of 15% to 99% Form A relative to the total weight of the crystalline solid Compound I. In some embodiments, the crystalline solid consists of 20% to 99% Form A relative to the total weight of the crystalline solid Compound I. In some embodiments, the crystalline solid consists of 25% to 99% Form A relative to the total weight of the crystalline solid Compound I. In some embodiments, the crystalline solid consists of 30% to 99% Form A relative to the total weight of the crystalline solid Compound I. In some embodiments, the crystalline solid consists of 35% to 99% Form A relative to the total weight of the crystalline solid Compound I. In some embodiments, the crystalline solid consists of 45% to 99% Form A relative to the total weight of the crystalline solid Compound I. In some embodiments, the crystalline solid consists of 50% to 99% Form A relative to the total weight of the crystalline solid Compound I. In some embodiments, the crystalline solid consists of 55% to 99% Form A relative to the total weight of the crystalline solid Compound I. In some embodiments, the crystalline solid consists of 60% to 99% Form A relative to the total weight of the crystalline solid Compound I. In some embodiments, the crystalline solid consists of 65% to 99% Form A relative to the total weight of the crystalline solid Compound I. In some embodiments, the crystalline solid consists of 70% to 99% Form A relative to the total weight of the crystalline solid Compound I. In some embodiments, the crystalline solid consists of 75% to 99% Form A relative to the total weight of the crystalline solid Compound I. In some embodiments, the crystalline solid consists of 80% to 99% Form A relative to the total weight of the crystalline solid Compound I. In some embodiments, the crystalline solid consists of 85% to 99% Form A relative to the total weight of the crystalline solid Compound I. In some embodiments, the crystalline solid consists of 90% to 99% Form A relative to the total weight of the crystalline solid Compound I. In some embodiments, the crystalline solid consists of 95% to 99% Form A relative to the total weight of the crystalline solid Compound I.

[0057] In some embodiments, methods of treating cancer comprise administering to a subject in need thereof, Form A of Compound I or a pharmaceutical composition comprising the same.

[0058] In some embodiments, the methods of treatment include administration of at least one additional active agent to the subject in need thereof, either in the same pharmaceutical composition as Form A of Compound I, or as separate compositions.

[0059] In some embodiments, methods of modulating PPARy comprise administering to a subject in need thereof, Form A of Compound I, or a pharmaceutical composition comprising the same.

Non-limiting Exemplary Embodiments

Embodiment 1: Form A of (7S)-4-{ [5-(5-fluoro-2-methoxypyridin-4-yl)-l/7-pyrazol-3-yl]carbony l }-N- [(lr,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)-lH-pyrazole-3-carb onyl)-N-((lr,4S)-4-hydroxy-4- (trifluoromethyl)cyclohexyl)-4-azaspiro[2.5]octane-7-carboxa mide) (i.e. Form A of Compound I: Compound I).

Embodiment 2: Form A according to embodiment 1, characterized by an X-ray powder diffractogram substantially similar to that in FIG. 1.

Embodiment 3: Form A according to embodiment 1, characterized by an X-ray powder diffractogram having a signal at at least one two-theta value chosen 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.

Embodiment 4: Form A according to embodiment 1, characterized by an X-ray powder diffractogram having a signal at at least two two-theta values chosen 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.

Embodiment 5: Form A according to embodiment 1, characterized by an X-ray powder diffractogram having a signal at at least two two-theta values chosen 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.

Embodiment 6: Form A according to embodiment 1, characterized by an X-ray powder diffractogram having a signal at at least two two-theta values chosen from 14.8 ± 0.2, 18.5 ± 0.2, 19.4 ± 0.2, 21.0 ± 0.2, and 22.6 + 0.2.

Embodiment 7 : Form A according to embodiment 1 , characterized by an X-ray powder diffractogram having a signal at at least two two-theta values chosen from 14.8 ± 0.2, 18.5 ± 0.2, and 19.4 ± 0.2. Embodiment 8 : Form A according to embodiment 1 , characterized by an X-ray powder diffractogram having a signal at at least three two-theta values chosen 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.

Embodiment 9: Form A according to embodiment 1, characterized by an X-ray powder diffractogram having a signal at at least four two-theta values chosen 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.

Embodiment 10: Form A according to embodiment 1, characterized by an X-ray powder diffractogram having a signal at at least five two-theta values chosen 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.

Embodiment 11 : Form A according to embodiment 1 , characterized by an X-ray powder diffractogram having a signal 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.

Embodiment 12: Form A according to embodiment 1, characterized by an X-ray powder diffractogram having a signal 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. Embodiment 13: Form A according to embodiment 1, characterized by an X-ray powder diffractogram having a signal at 14.8 ± 0.2, 18.5 + 0.2, 19.4 ± 0.2, 21.0 ± 0.2, and 22.6 + 0.2.

Embodiment 14: Form A according to embodiment 1, characterized by an X-ray powder diffractogram having a signal at 14.8 ± 0.2, 18.5 + 0.2, and 19.4 ± 0.2.

Embodiment 15: Form A according to embodiment 1, characterized by a ¹³ C SSNMR spectrum having a signal at at least five ppm values chosen 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.

Embodiment 16: Form A according to embodiment 1, characterized by a ¹³ C SSNMR spectrum having a signal at at least four ppm values chosen 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.

Embodiment 17: Form A according to embodiment 1, characterized by a ¹³ C SSNMR spectrum having a signal at at least three ppm values chosen 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.

Embodiment 18: Form A according to embodiment 1, characterized by a ¹³ C SSNMR spectrum having a signal at at least two ppm values chosen 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.

Embodiment 19: Form A according to embodiment 1, characterized by a ¹³ C SSNMR spectrum having a signal at at least one ppm value chosen 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.

Embodiment 20: Form A according to embodiment 1, characterized by a ¹³ C SSNMR spectrum 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.

Embodiment 21 : Form A according to embodiment 1, characterized by a ¹³ C SSNMR spectrum 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.

Embodiment 22: Form A according to embodiment 1, characterized by a ¹³ C SSNMR spectrum 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.

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

Embodiment 24: Form A according to embodiment 1, characterized by a TGA/DSC substantially similar to that in FIG. 3.

Embodiment 25: Form A according to embodiment 1, characterized by a Raman substantially similar to that in FIG. 4. Embodiment 26: Form A according to embodiment 1, characterized by a Raman spectrum having a signal at at least one ppm value chosen from 579.1 ± 2 cm , 741.3 ± 2 cm . 863.7 ± 2 cm 1066.6 + 2 cm

1262.2 + 2 cm- ¹ , 1352.7 + 2 cm . 1405.3 + 2 cm L 1509.0 + 2 cm . 1568.9 + 2 cm L and 1630.2 + 2 cm ^-1 .

Embodiment 27 : Form A according to embodiment 1 , characterized by a Raman spectrum having a signal at at least two ppm values chosen from 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 1509.0 ± 2 cm . 1568.9 ± 2 cm and 1630.2 ± 2 cm- ¹ .

Embodiment 28: Form A according to embodiment 1, characterized by a Raman spectrum having a signal at at least three ppm values chosen from 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 1509.0 + 2 cm . 1568.9 + 2 cm and 1630.2 + 2 cm- ¹ .

Embodiment 29: Form A according to embodiment 1, characterized by a Raman spectrum having a signal at at least four ppm values chosen from 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 1509.0 + 2 cm . 1568.9 + 2 cm and 1630.2 + 2 cm- ¹ .

Embodiment 30: Form A according to embodiment 1, characterized by a Raman spectrum having a signal at at least five ppm values chosen from 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 .

Embodiment 31 : Form A according to embodiment 1 , characterized by a Raman spectrum having a signal at 579.1 + 2 cm" ¹ , 741.3 ± 2 cm . 863.7 + 2 cm- ¹ , 1066.6 + 2 cm- ¹ , 1262.2 + 2 cm- ¹ , 1352.7 ± 2 cm .

1405.3 + 2 cm- ¹ , 1509.0 ± 2 cm . 1568.9 + 2 and 1630.2 + 2 cm- ¹ .

Embodiment 32: Form A according to embodiment 1, characterized by a Raman spectrum having a signal at 741.3 + 2 cm- ¹ , 863.7 ± 2 cm . 1066.6 ± 2 cm , 1352.7 + 2 cm" ¹ , 1405.3 + 2 cm ’, 1509.0 + 2 cm- ¹ , and 1630.2 + 2 cm- ¹ .

Embodiment 33: Form A of Compound I according to embodiment 1, characterized by a Raman spectrum having a signal at 741.3 + 2 cm ^-1 , 863.7 + 2 cm ^-1 , 1352.7 + 2 cm ^-1 , 1405.3 + 2 cm ^-1 , and 1630.2 + 2 cm ^-1 . Embodiment 34: Form A according to embodiment 1, characterized by a Raman spectrum having a signal at 863.7 + 2 cm- ¹ , 1405.3 + 2 cm- ¹ , and 1630.2 + 2 cm- ¹ .

Embodiment 35 : A pharmaceutical composition comprising Form A according to any one of embodiments 1 to 34 and a pharmaceutically acceptable carrier.

Embodiment 36: A method for treating and/or preventing cancer comprising administering to a subject in need thereof an effective amount of Form A according to any one of embodiments 1 to 34 or a pharmaceutical composition according to embodiment 35.

Embodiment 37: The method according to embodiment 36, wherein the cancer is chosen from bladder cancers, breast cancers, prostate cancers, and cancers having altered RXRa and/or PPARy pathways. Embodiment 38: The method according to any one of embodiments 36 and 37, wherein the cancer is bladder cancer.

Embodiment 39: The method according to any one of embodiments 37 to 38, wherein the bladder cancer is chosen from advanced bladder cancers, luminal bladder cancers, and basal bladder cancers.

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

Embodiment 41 : A use of Form A of (75)-4-{ [5-(5-fluoro-2-methoxypyridin-4-yl)-17f-pyrazol-3- yl]carbonyl}-A-[(lr,4S)-4-hydroxy-4-(trifluoromethyl)cyclohe xyl]-4-azaspiro[2.5]octane-7-carboxamide according to any one of embodiments 1 to 34 and pharmaceutical compositions according to embodiment 35 in treating and/or preventing cancer.

Embodiment 42: A method of preparing Form A of (7S)-4-{ [5-(5-fhioro-2-methoxypyridin-4-yl)-l//- pyrazol-3-ylJcarbonyl}-7V-[(lr,45)-4-hydroxy-4-(trifIuoromet hyl)cyclohexylJ-4-azaspiro[2.5Joctane-7- carboxamide comprising mixing (75)-4-{ [5-(5-fluoro-2-methoxypyridin-4-yl)-lH-pyrazol-3-yl]carbonyl }-A ^r -[(lr,4S)-4- hydroxy-4-(trifluoromethyl)cyclohexyl]-4-azaspiro[2.5]octane -7-carboxamide with acetonitrile at room temperature, and stirring said mixture at room temperature for at least 24 hours.

EXAMPLES

[0060] In order that the disclosure described herein may be more fully understood, the following examples are set forth. It should be understood that these examples are for illustrative purposes only and are not to be construed as limiting this disclosure in any manner.

[0061] Methods of preparation and structure of Compound I are reported in U.S. Provisional Application No. 63/11,354 filed on November 9, 2020, U.S. Application No. 17/521,666, and PCT International Application No. PCT/US2021/058473, both of which were filed on November 8, 2021; the contents of each of which are incorporated herein by reference.

Synthesis of Compound I

[0062] Tert-butyl 7-(((lr,4r)-4-hydroxy-4-(trifluoromethyl)cyclohexyl)carbamoy l)-4- azaspiro[2.5]octane-4-carboxylate

[0063] HATU (447.0 mg, 1.18 mmol) and (lr,4r)-4-amino-l-(trifluoromethyl)cyclohexan-l-ol (226.0 mg, 1.23 mmol, CAS#: 1408075-09-1, Enamine Ltd.) were added to a stirred mixture of 4-(tert- butoxycarbonyl)-4-azaspiro[2.5]octane-7-carboxylic acid (300.0 mg, 1 .18 mmol) and DTPEA (0.62 mL, 3.53 mmol) in DMF (6.00 mL) at 0 °C. The resulting mixture was stirred at 25 °C for 1 h. The reaction mixture was diluted with EtOAc, water, then extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous NazSO i, filtered, and the solvent was evaporated. The residue was purified by silica gel column chromatography eluting with 60-100% EtOAc/hexanes to afford the diastereomeric mixtures of the title compound (494.0 mg) as an oil, containing residual solvent. LCMS (ESI): [M+Na] ⁺ : 443.4.

[0064] iV-((lr,4r)-4-Hydroxy-4-(trifluori>methyl)eyclohexyl)-4-a zaspiro[2.5]octane-7- carboxamide

[0065] TFA (3.00 mL) was added to a solution of tert-butyl 7-(((lr,4r)-4-hydroxy-4- (trifluoromethyl)cyclohexyl)carbamoyl)-4-azaspiro[2.5]octane -4-carboxylate (494.0 mg, 1.18 mmol) in DCM (5.00 mL). The reaction mixture was stirred at 25 °C for 8 h. The reaction mixture was concentrated under reduced pressure and purified by reverse phase column chromatography (using the following conditions: C18 Column, 0% - 20% MeCN/water (0.1% formic acid)) to obtain the title compound (534.0 nig) as a solid mixture of diastereomers, containing residual solvent. LCMS (ESI): [M+H] ⁺ : 322.3.

[0066] Methyl 5-bromo-l-((2-(trimethylsilyl)ethoxy)methyl)-lff-pyrazole-3- carboxylate

[0067] SEM-C1 (2.85 mL, 16.10 mmol) was added dropwise to a stirred solution of methyl 5-bromo- 17/-pyrazole-3-carboxylate (3.00 g, 14.63 mmol) and K2CO3 (2.23 g, 16.10 mmol) in DMF (40.00 mL) at 0 °C. The reaction mixture was then stirred at 25 °C for 2 h. The solution was diluted with EtOAc and water, then extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous NihSO,, filtered, and the solvent was evaporated. The residue was purified by silica gel column chromatography (EtOAc/Hexane, 0/100 to 10/90 v/v) to obtain the title compound (3.49 g) as an oil. LCMS (ESI): [M+H] ⁺ : 337.0.

[0068] Methyl 5-(5-fluoro-2-methoxypyridin-4-yl)-l-((2-(trimcthylsilyl)cth oxy)methyl)-lZ7- pyrazolc-3-carboxylate

[0069] Pd(dppf)C12 (0.44 g, 0.60 mmol) and K2CO3 (1.24 g, 8.95 mmol) were added to a stirred solution of methyl 5-bromo-l-((2-(trimethylsilyl)ethoxy)methyl)-l/f-pyrazole-3- carboxylate (1.0 g, 2.98 mmol) and (5-fluoro-2-methoxypyridin-4-yl)boronic acid (0.61 g, 3.58 mmol) in water (2.00 mL) and 1,4-dioxane (8.00 mL). The reaction mixture was stirred at 100 °C for 15 h under nitrogen atmosphere. The reaction mixture was then cooled to 25 °C and diluted with EtOAc and water. The organic layer was washed with brine, dried over anhydrous Na2SC>4, filtered, and the solvent was evaporated. The residue was purified by silica gel column chromatography (EtOAc/Hexane, 5/95 to 25/75 v/v) to obtain the title compound (765.0 mg) as an oil. LCMS (ESI): [M+H] ⁺ : 382.2.

[0070] 5-(5-fluoro-2-methoxypyridin-4-yl)-l-((2-(trimethylsilyl)eth oxy)methyl)-l/7-pyrazole-3- carboxylic acid

[0071] 1 M aqueous solution of lithium hydroxide (2.21 mL, 2.21 mmol) was added to a stirred solution of methyl 5-(5-fluoro-2-methoxypyridin-4-yl)-l-((2-(trimethylsilyl)eth oxy)methyl)-l/f-pyrazole-3- carboxylate (281.0 mg, 0.74 mmol) in water (2.00 mL) and THF (8.00 mL). The reaction mixture was stirred at 25 °C for 7 h. The pH of the mixture was then adjusted to 1 by the addition of aqueous HC1 (1 M). The solution was concentrated, and the residue was purified by silica gel column chromatography (EtOAc/Hexane, 30/70 to 50/50 v/v) to obtain the title compound (264.0 mg) as a solid. LCMS (ESI): 369.4 [M+H] ⁺ .

[0072] Methyl 5-(5-fluoro-2-methoxypyridin-4-yl)-lH-pyrazole-3-carboxylate

[0073] TFA (10.00 mL) was added to a stirred solution of methyl 5-(5-fluoro-2-methoxypyridin-4-yl)- l-((2-(trimethylsilyl)ethoxy)methyl)-17/-pyrazole-3-carboxyl ate (10.00 g, 26.21 mmol) in DCM (10.00 mL). The resulting mixture was stirred at 25 °C for 4 h, then the solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM/MeOH, 12/1 v/v) to obtain the title compound (7.00 g) as an oil. LCMS (ESI): [M+H] ⁺ : 252.1.

[0074] 5-(5-Fluoro-2-methoxypyridin-4-yl)-lfl-pyrazole-3-carboxylic acid

[0075] LiOHH2O (1.67 g, 39.80 mmol) was added to a stirred solution of methyl 5-(5-fluoro-2- methoxypyridin-4-yl)-l//-pyrazole-3-carboxylate (5.00 g, 19.90 mmol) in THF (8.00 mL), MeOH (8.00 mL) and HzO (8.00 mL). The resulting mixture was stirred at 60 °C for 14 h., then the solution was concentrated under reduced pressure. The pH of the solution was adjusted to 3 by the addition of aqueous HC1 (1 M). The precipitated solids were collected by filtration and washed with water, then dried under pressure to obtain the title compound (4.50 g) as a solid. H NMR (300 MHz, DMSO-cfc) 5 14.37 (s, 1H), 8.28 (s, 1H), 7.32 (s, 1H), 7.20 (s, 1H), 3.87 (s, 3H). LCMS (ESI): [M+H] ⁺ : 238.0.

[0076] Alternative method of synthesis of 5-(5-fluoro-2-methoxypyridin-4-yl)-l-((2-

(trimethylsilyl)ethoxy)methyl)-lZ7-pyrazole-3-carboxylic acid

[0077] Methyl 5-bronio-l-((2-(triniethylsilyl)ethoxy)methyl)-lff-pyrazole- 3-carboxylate and methyl 3-bromo-l-((2-(trimethylsilyl)ethoxy)methyl)-lEf-pyrazole-5- carboxylate

[0078] Two batches were carried out in parallel. Dichloromethane (2.50 L) was added to a 5.00 L of jacket flask equipped with overhead stirrer, addition funnel and thermometer, Nz balloon at 0 °C. 3. Methyl 5-bromo- 1 H-pyrazole-3 -carboxylate (500.00 g, 2.44 mol) was added to the flask at 0 °C. DIPEA (630.00 g, 4.88 mol) and SEM-C1 (610.00 kg, 3.66 mol) were added to the flask at 0 °C. The resulting mixture was purged with N2 for 3 times and was stirred at 0 to 20 °C for 12 h under N2. Two batches were combined and the reaction mixture was poured into H2O (8.00 L), extracted with dichloromethane (4.00 L x 2). The combined organic layer was washed with brine (5.00 L), dried over Na2SC>4, filtered and the filtrate was concentrated in vacuum. The residue was purified by silica gel column chromatography eluting with petroleum ether/ethyl acetate (5/1 v/v) to obtain the title compounds (1.03 kg) as a solid. *H NMR (400 MHz, CDCh) 3 6.92 (s, 1H), 5.83 (s, 2H), 3.94 (s, 3H), 3.64 (t, 2H), 0.91 - 0.95 (m, 2H), 2.70 - 1.75 (t, 1H), 1.73 - 1.74 (m, 4H), 1.48 - 1.55 (m, 6H), 1.43 (s, 9H), 1.18 - 1.19 (m, 1H), 0.00 (s, 9H). LCMS: [M+H] ⁺ : 279.

[0079] Methyl 5-(5-fluoro-2-methoxypyridin-4-yl)-l-((2-(trimethylsilyl)eth oxy)methyl)-H/- pyrazole-3-carboxylate

[0080] Two batches were carried out in parallel. Methanol (2.50 L) was added to a 5.00 L of jacket flask equipped with overhead stirrer, addition funnel and thermometer, N2 balloon at 25 °C. Methyl 5- bromo-l-((2-(trimethylsilyl)ethoxy)methyl)-17/-pyrazole-3-ca rboxylate and methyl 3-bromo-l-((2- ( trimethylsilyl )ethoxy)methyl )- 1 H-pyrazole-5 -carboxylate (517.00 g, 1.54 mol) was added to the flask at 25 °C. DIPEA (399.00 g, 3.08 mol) was added to the flask at 0 °C and (5-fluoro-2-methoxypyridin-4- yl)boronic acid (277.00 g, 1.62 mol) was added to the flask at 25 °C. P(tBu)3Pd G2 (39.50 g, 77.10 mmol) was added to the flask at 25 °C and the resulting mixture was purged with N2 for 3 times. The reaction mixture was stirred at 65 °C for 2 h under N2. Two batches were combined and the reaction mixture was poured into H2O (3.00 L), extracted with ethyl acetate (3.00 L x 2). The combined organic layer was washed with brine (4.00 L), dried over Na2SC>4, filtered and the filtrate was concentrated in vacuum. The residue was purified by silica gel column chromatography eluting with petroleum ether/ethyl acetate (30/1 to 5/1 v/v) to obtain the title compound (1.15 kg) as a solid. ’H NMR (400 MHz, CDCh) <> 8.09 (d, 1H), 7.40 (t, 2H), 5.92 (s, 2H), 3.95 (d, 6H), 3.66 (t, 2H), 0.92 (t, 2H), 0.03 (s, 9H). LCMS: [M+H] ⁺ : 382.4.

[0081] 5-(5-fluoro-2-methoxypyridin-4-yl)-l-((2-(trimethylsilyl)eth oxy)methyl)-l/7-pyrazole-3- carboxylic acid

[0082] Two batches were carried out in parallel. THF (1.80 L) and H2O (1.80 L) were added to a 5.00 L of jacket flask equipped with overhead stirrer, addition funnel and thermometer, Nz balloon etc at 25 °C. Methyl 5-(5-fluoro-2-methoxypyridin-4-yl)-l-((2-(trimethylsilyl)eth oxy)methyl)-177-pyrazole-3- carboxylate (576.00 g, 1.51 mol) and LiOH.HzO (127.00 g, 3.02 mol) were added to the flask at 25 °C. The reaction mixture was stirred at 25 °C for 2 h under Nz. Two batches were combined and the reaction mixture was adjusted to pH=4, extracted with ethyl acetate (500 mL x 2). The combined organic layer was washed with brine (500 mL), dried over NazSCL, filtered and the filtrate was concentrated in vacuum. The residue was triturated with petroleum ether/ethyl acetate (10/1 v/v, 100 mL) at 25 °C for 0.5 h and concentrated to obtain the title compound (1.01 kg) as a solid. *H NMR (400 MHz, MeOD) 3 8.07 (d, 1H), 7.33 (d, 1H), 7.23 (d, 1H), 6.00 (s, 2H), 3.92 (s, 3H), 3.67 (t, 2H), 0.88 (t, 2H), 0.04 (s, 9H). LCMS: [M+H] ⁺ : 368.1.

[0083] 4-(5-(5-Fluoro-2-methoxypyridin-4-yl)-l-((2-(trimethylsilyl) ethoxy)methyl)-l//-pyrazole- 3-carbonyl)-A ^, -((lr,4r)-4-hydroxy-4-(trifluoromethyl)cyclohexyl)-4-a zaspiro[2.5]octane-7- carboxamide

[0084] HATU (103.0 mg, 0.27 mmol) and A-((lr,4r)-4-hydroxy-4-(trifluoromethyl)cyclohexyl)-4- azaspiro[2.5]octane-7-carboxamide (164.0 mg, 0.36 mmol) were added to a stirred solution of 5-(5- fluoro-2-methoxypyridin-4-yl)-l-((2-(trimethylsilyl)ethoxy)m ethyl)-177-pyrazole-3-carboxylic acid (100.0 mg, 0.27 mmol) and DIPEA (0.19 mL, 1.09 mmol) in DMF (6.00 mL). The resulting mixture was stirred at 25 °C for 16 h. The reaction mixture was diluted with EtOAc and water, then extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous NazSOi, filtered, and the solvent was evaporated. The residue was purified by silica gel column chromatography eluting with 70% - 100% EtOAc/hexanes to afford the title compound (153.0 mg) as a solid mixture of diastereomers. LCMS (ESI): [M+H] ⁺ : 670.6.

[0085] (7/?)-4-{[5-(5-Fluoro-2-methoxypyridin-4-yl)-lH-pyrazol-3-yl ]carbonyl}-A-[( lr,4/?)-4- hydroxy-4-(trifluoromethyl)cydohexyl]-4-azaspiro[2.5]octane- 7-carboxamide and (7S)-4-{[5-(5- fluoro-2-methoxypyridin-4-yl)-l//-pyrazol-3-yl]carbonyl}-jV- [(lr,4S)-4-hydroxy-4- (trifluoromethyl)cyclohexyl]-4-azaspiro[2.5]octane-7-carboxa mide [0086] TFA (3.00 mL) was added to a stirred solution of 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-carboxa mide (89.0 mg, 0.13 mmol) in DCM (3.00 mL). The resulting mixture was stirred at 25 °C for 1 h. The reaction mixture was concentrated and purified by silica gel column chromatography eluting with 0% – 10% MeOH/DCM to obtain (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-carboxa mide (Compound I) (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-carboxa mide (62.0 mg,) as a solid mixture of diastereomers. ¹ H NMR (400 MHz, CD3OD) δ 8.12 (d, 1 H), 7.27 (br d, 1 H), 7.10 (br s, 1 H), 4.89 – 4.95 (m, 1 H), 4.39 – 4.71 (m, 1 H), 3.93 (s, 4 H), 2.91 (br d, 1 H), 2.21 – 2.61 (m, 1 H), 1.56 – 2.01 (m, 10 H), 1.14 – 1.40 (m, 2 H), 0.81 – 1.10 (m, 2 H), 0.73 (br s, 2 H). LCMS (ESI): [M+H] ⁺ : 540.2. [0087] The solid mixture of diastereomers (80.0 mg) was separated using Chiral-Prep-HPLC. [0088] Column: CHIRALPAK IA column [0089] Column dimension: 2 × 25 cm, 5 µm [0090] Mobile Phase: hexanes (8 mM NH3·MeOH):EtOH=50:50 hold for 15 min [0091] Flow rate: 18 mL/min [0092] Detection: 220/254 nm [0093] The first eluting diastereomer (26.3 mg) was obtained as a solid and had a retention time of 4.59 min. [0094] ¹ H NMR (300 MHz, DMSO-d6) 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. [0095] The second eluting diastereomer (28.3 mg) was obtained as a solid and had a retention time of 8.06 min. [0096] ¹ H NMR (300 MHz, DMSO-d6) 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. Alternative synthesis of Compound I [0097] Synthesis of (S)-4-[5-(5-fluoro-2-methoxypyridin-4-yl)-1H-pyrazole-3-carb onyl]-4- azaspiro[2.5]octane-7-carboxylic acid & (R)-4-(5-(5-fluoro-2-methoxypyridin-4-yl)-1H-pyrazole-3- carbonyl)-4-azaspiro[2.5]octane-7-carboxylic acid

[0098] Methyl 4-[5-(5-fluoro-2-methoxypyridin-4-yl)-l-[[2-

(trimethylsilyl)ethoxy]methyl]pyrazole-3-carbonyl]-4-azas piro[2.5]octane-7-carboxylate

[0099] Methyl 4-azaspiro[2.5]octane-7-carboxylate hydrochloride (6.77 g, 32.9 mmol, CAS#: 2253630-26-9, Enamine Ltd.), HATU (13.66 g, 35.9 mmol) and DIPEA (11.61 g, 89.8 mmol) were added to a stirred solution of 5-(5-fluoro-2-methoxypyridin-4-yl)-l-((2-(trimethylsilyl)eth oxy)methyl)-177- pyrazole-3-carboxylic acid (11.0 g, 29.9 mmol) in DMF (30.00 mL). The resulting mixture was stirred at 25 °C for 1 h. The solution was diluted with EtOAc and washed with water. The organic layer was concentrated under reduced pressure to result in a residue that was purified via silica gel chromatography (EtOAc/petroleum ether, 1/3 v/v) to obtain of the title compound (14 g) as an oil. LCMS (ESI): 519.2 [M+H] ⁺

[00100] Methyl 4-[5-(5-fluoro-2-methoxypyridin-4-yl)-lH-pyrazole-3-carbonyl ]-4- azaspiro[2.5]octane-7-carboxylate

[00101] TFA (60.00 mL) was added to a stirred solution of methyl 4-[5-(5-fluoro-2-methoxypyridin-4- yl)-l-[[2-(trimethylsilyl)ethoxy]methyl]pyrazole-3-carbonyl] -4-azaspiro[2.5]octane-7 -carboxylate (13.00 g, 25.1 mmol) in DCM (30.00 mL). The resulting mixture was stirred at 25 °C for 14 h. The solution was concentrated under reduced pressure. The residue was purified via silica gel chromatography (EtOAc/petroleum ether, 3/1 v/v) to obtain the title compound (9.65 g) as a white solid. LCMS (ESI):389.2 [M+H] ⁺

[00102] Methyl (S’)-4-|5-(5-fliioro-2-methoxypyridin-4-yl)-l//-pyrazole-3 -carbonyl|-4- azaspiro[2.5]octane-7-carboxylate and methyl (/?)-4-(5-(5-fluoro-2-methoxypyridin-4-yl)-lH- pyrazole-3-carbonyl)-4-azaspiro[2.5]octane-7-carboxylate [00103] Methyl 4-[5-(5-fhioro-2-methoxypyridin-4-yl)-l//-pyrazole-3-carbony l]-4- azaspiro[2.5]octane-7-carboxylate (5.54 g) was purified by Prep-SFC with the following conditions:

Column: CHIRALPAK IG column

Column dimension: 30x250 mm, 5 pm

Mobile Phase A: CO2; Mobile Phase B: IP A

Flow rate: 23 mL/min

Gradient: 50% B

Detection: 220 nm;

Injection Volume: 4.8 mL;

[00104] Methyl (>S)-4-[5-(5-fliioro-2-methoxypyridin-4-yl)-l//-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 min. LCMS (ESI): 389.1 [M+H] ⁺ .

[00105] Methyl (Z?)-4-(5-(5-fluoro-2-methoxypyridin-4-yl)-l.H-pyrazole-3-ca rbonyl)-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 min. LCMS (ESI): 389.1 [M+H] ⁺ .

[00106] (>S')-4-[5-(5-fluoro-2-methoxypyridin-4-yl)-lEf-pyrazole- 3-carbonyl]-4- azaspiro[2.5]octane-7 -carboxylic acid

[00107] LiOH.HjO (0.56 g, 13.4 mmol) was added to a stirred solution of methyl (5)-4-[5-(5-fluoro-2- methoxypyridin-4-yl)-l/f-pyrazole-3-carbonyl]-4-azaspiro[2.5 ]octane-7-carboxylate (2.6 g, 6.69 mmol, 1.00 equiv) 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 h. The solution was concentrated under reduced pressure to remove MeOH and THF, as much as possible, then acidified to pH 3 with HC1 (1 M), then the solution was extracted with EtOAc. The organic layers were combined and concentrated under reduced pressure to obtain the title compound (2.50 g) as a solid. LCMS (ESI):375.2 [M+H] ⁺

[00108] (R)-4-(5-(5-fluoro-2-methoxypyridin-4-yl)-l.H-pyrazole-3-car bonyl)-4- azaspiro[2.5]octane-7 -carboxylic acid

[00109] LiOH.H2O (497.0 mg, 11.84 mmol) was added to a stirred solution of methyl (R)-4-(5-(5- fluoro-2-methoxypyridin-4-yl)-127-pyrazole-3-carbonyl)-4-aza spiro[2.5]octane-7-carboxylate (2.30 g, 5.92 mmol) in THF (5.00 mL), MeOH (5.00 mL), water (5.00 mL). The resulting mixture was stirred at 25 °C for 1 h. The resulting mixture was concentrated under reduced pressure to remove McOH and THF. The mixture was acidified to pH 3 with HC1 (1 M). The aqueous layer was extracted with EtOAc. The organic layers were combined and concentrated under reduced pressure to obtain the title compound (2.20 g) as a solid. LCMS (ESI): 375.1 [M+H] ⁺ .

[00110] (S)-4-(5-(5-fluoro-2-methoxypyridin-4-yl)-lEf-pyrazole-3-car bonyl)-N-((lr,45)-4- hydroxy-4-(trifluoromethyl)cydohexyl)-4-azaspiro[2.5]octane- 7-carboxamide (Compound I)

[00111] HOBt (2.44 g, 18.03 mmol) and EDCI (3.46 g, 18.00 mmol) were added to a stirred solution of (S)-4-[5-(5-fluoro-2-methoxypyridin-4-yl)-17/-pyrazole-3-car bonyl]-4-azaspiro[2.5]octane-7- carboxylic acid (4.50 g, 12.02 mmol) in DMF (20.00 mL). The resulting mixture was stirred at 25 °C for 30 min. Then (lr,4r)-4-aniino-l-(trifluoromethyl)cyclohexan-l-ol hydrochloride (3.17 g, 14.42 mmol, CAS#: 2137056-98-3, Enamine Ltd.) and DIPEA (7.77 g, 60.10 mmol) were added to the resulting mixture. The resulting mixture was stirred at 25 °C for 14 h. The solution was diluted with EtOAc and washed with water. The organic layer was concentrated under reduced pressure. The residue was purified by reverse phase column chromatography (using the following conditions: Column: C18 column; Mobile Phase A: Water (10 mM NH4HCO3), Mobile Phase B: MeCN; Gradient: 5% B to 40% B in 30 min; Flow rate: 40 mL/min; Detector, UV 220/254 ran) to obtain the title compound (4.91 g). *H NMR (400 MHz, DMSO-c/g) 6 14.18 - 13.81 (m, 1H), 8.23 (d, 1H), 7.81 (d, 1H), 7.30 (d, 1H), 7.02 (br s, 1H), 5.69 (s, 1H), 4.64 - 4.32 (m, 1H), 3.87 - 3.84 (m, 4H), 3.36 - 3.34 (m, 1H), 2.90 - 2.75 (m, 1H), 2.27 - 2.08 (m, 1H), 1.79 - 1.70 (m, 5H), 1.56 - 1.45 (m, 5H), 1.25 - 0. 80 (m, 2H), 0.68 - 0.44 (m, 3H). LCMS (ESI): [M+H] ⁺ : 540.45.

Alternative synthesis of Compound I

[00112] 4-Benzyl-7-(((tert-butyldiphenylsilyl)oxy)methyl)-4-azaspiro [2.5]octane

[00113] THF (30.00 L) was added to a 50.0 L of the flask equipped with stirrer, addition funnel and thermometer, Nz protection at 5 °C. (4-Benzyl-4-azaspiro[2.5]octan-7-yl)methanol (3.00 kg, 12.90 mol) was added to the flask at 5 °C. Imidazole (2.21 kg, 32.40 mol) was added to the flask at 5 °C. /m-butyl- chloro-diphenyl-silane (4.28 kg, 15.60 mol) was added to the flask at 5 "C. The reaction mixture was stirred at 5 to 25 °C for 12 h under Nj. The reaction mixture was poured into HjO (10.00 L), extracted with ethyl acetate (10.00 L x 2). The combined organic layer was washed with brine (10.00 L), dried over Na2SC>4, filtered and the filtrate was concentrated in vacuum. The residue was purified by silica gel column chromatography eluting with petroleum ether/ethyl acetate (10/1 v/v) to obtain the title compound (5.50 kg) as an oil and which was directly used to next step. [00114] Tert-butyl 7-(((tert-butyldiphenylsilyl)oxy)methyl)-4-azaspiro[2.5]octa ne-4-carboxylate

[00115] MeOH (20.00 F) was added to a 50.0 L of the flask equipped with stirrer, addition funnel and thermometer, Nz protection at 20 to 30 °C. 4-Benzyl-7-(((tert-butyldiphenylsilyl)oxy)methyl)-4- azaspiro[2.5]octane (1 .00 kg, 2.13 mol) was added to the flask at 20 to 30 °C in one portion and Pd/C (100.00 g, 213.00 mmol, 10.0% purity) was added to the flask at 20 to 30 °C in several portions under N2. HCOOH (1.02 kg, 21.30 mol) was added to the flask at 20 to 30 °C under N2. The mixture was stirred at 50 to 55 °C for 1 h. The mixture was filtered through Celite and the filtrated cake was washed with MeOH (5.00 L x 2). The mixture was adjusted the pH to 7 to 8 with NaHCCh solution (10.00 L) and extracted with ethyl acetate (10.0 L x 2), the combined organic layers were washed with brine (10.0 L x 2), and dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue of 1.30 kg. THF (6.50 L) and H2O (3.90 L) were added to a 50.0 L of jacket flask with overhead stirrer, addition funnel and thermometer, N2 balloon etc at 20 to 30 °C. The residue (1.30 kg) was added to the flask at 20 to 30 °C in one portion and NaHCCh (447.00 g, 5.32 mol) was added to the flask at 20 to 30 °C. BOC2O (697.00 g, 3.19 mol) was added to the flask dropwise at 10 to 20 °C. The mixture was stirred at 20 to 30 °C for 1.5 h. H2O (10.0 L) was added to the reaction mixture and extracted with MTBE (10.0 L x 2), the combined organic layers were washed with brine (10.0 L x 2), and dried over Na2SC>4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography eluting with petroleum ether/ethyl acetate (1/1 v/v) to obtain the title compound (810.00 g) as a solid. *H NMR (400 MHz, CDCh) 5 7.66 (d, 4H), 7.29 - 7.45 (m, 6H), 4.03 (d, 1H), 3.51 (d, 2H), 2.90 (t, 1H), 1.98 - 2.07 (m, 1H), 1.72 - 1.75 (m, 2H), 1.48 (s, 9H), 1.26 - 1.29 (m, 2 H), 1.08 (s, 9H), 1.00 - 1.06 (m, 1H), 0.83 - 0.99 (m, 1H), 0.50 - 0.52 (m, 1H), 0.39 - 0.40 (m, 1H). LCMS: [M+H] ⁺ : 380.1.

[00116] Tert-butyl 7-(hydroxymethyl)-4-azaspiro[2.5]octane-4-carboxylate

[00117] THF (24.00 L) was added to a 50.0 L of the flask with stirrer, addition funnel and thermometer, N2 protection at 20 °C. Tert-butyl 7-(((rert-butyldiphenylsilyl)oxy)methyl)-4- azaspiro[2.5]octane-4-carboxylate (3.10 kg, 6.46 mol) was added to the flask at 20 °C at one portion. TBAF (1.00 M, 6.46 L) was added to the flask at 20 °C and the resulting mixture was stirred at 20 °C for 2 h. The mixture was poured into H2O (10.00 F), extracted with ethyl acetate (10.00 E x 2). The combined organic layer was washed with brine (5.00 L), dried over NajSO,. filtered and the filtrate was concentrate in vacuum. The residue was purified by silica gel column chromatography eluting with petroleum ether/ethyl acetate (3/1 v/v) to obtain the title compound (1.45 kg) as an oil. H NMR (400 MHz, DMSO-*) 6 4.43 (t, 1H), 3.83 - 3.86 (m, 1H), 3.21 - 3.24 (m, 2H), 1.75 - 1.99 (m, 1H), 1.65 - 1.70 (m, 1H), 1.39 (t, 1H), 1.18 (s, 9H), 1.00 - 1.06 (m, 1 H) 0.37 – 0.38 (m, 1H), 0.33 – 0.35 (m, 1H). [00118] 4-(tert-butoxycarbonyl)-4-azaspiro[2.5]octane-7-carboxylic acid _[00119] Five batches were carried out in parallel. MeCN (1.10 L) and H ₂ O (1.10 L) were added to a 5.00 L of jacket flask with overhead stirrer, addition funnel and thermometer, N ₂ balloon at 10 °C. Tert- butyl 7-(hydroxymethyl)-4-azaspiro[2.5]octane-4-carboxylate (284.00 g, 1.18 mol) was added to the flask at 10 °C. TEMPO (74.00 g, 470.00 mmol) was added to the flask at 10 °C in one portion and PhI(OAc)2 (947.00 g, 2.94 mol) was slowly added to the reaction at 10 °C in ten portions under N2. The mixture was stirred at 25 °C for 12 h under N2. Five batches were combined and the reaction mixture was slowly added to saturated Na ₂ SO ₃ solution (8.00 L) and stirred at 20 °C for 0.5 h. Then saturated K ₂ CO ₃ solution was added and adjusted to pH = 11. The mixture was extracted with petroleum ether (3.00 L × 2) and 1N HCl (approximately 20.0 L) was added to the aqueous solution and adjusted to pH = 3. The mixture was extracted with DCM (5.00 L × 3) and the combined organic layer was concentrated in vacuum. The residue was crystallized from (heptanes, 2.00 L, 20 °C) and the mixture was filtered and the filtrate cake was washed with heptanes (300 mL × 2). The residue was collected and concentrated in vacuum to obtain the title compound (1.40 kg, 4.47 mol) as a solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.2 (br s, 1H), 3.81 (d, 1H), 2.91 (t, 1H), 2.60 (t, 1H), 1.75 - 1.78 (m, 2H), 1.23 - 1.26 (m, 10H), 0.81 - 0.82 (m, 1H), 0.51 - 0.79 (m, 1H), .0.47 - 0.49 (m, 2H). LCMS: [M–100] ⁺ : 156.6. [00120] Tert-butyl 7-(((1r,4r)-4-hydroxy-4-(trifluoromethyl)cyclohexyl)carbamoy l)-4- azaspiro[2.5]octane-4-carboxylate [00121] Four batches were carried out in parallel. DCM (3.20 L) was added to a 5.00 L of jacket flask equipped with overhead stirrer, addition funnel and thermometer, N ₂ balloon.4-(tert-butoxycarbonyl)-4- azaspiro[2.5]octane-7-carboxylic acid (317.00g, 1.24 mol) was added to the flask at 0 °C. DIPEA (321.00 g, 2.48 mol), EDCI (297.00 g, 1.55 mol), and HOBt (209.00 g, 1.55 mol) were added to the flask at 0 °C. (1r,4r)-4-amino-1-(trifluoromethyl)cyclohexan-1-ol (239.00 g, 1.30 mol) was added to the flask at 0 °C and the resulting mixture was purged with N2 for 3 times. The reaction mixture was stirred at 0 to 25 °C for 2 h under N ₂ . Four batches were combined and the reaction was poured into H ₂ O (10.00 L), extracted with ethyl acetate (10.0 L x 2). The combined organic layer was washed with brine (10.00 L), dried over Na ₂ SO ₄ , filtered and the filtrate was concentrated in vacuum. The residue was purified by silica gel column chromatography eluting with petroleum ether/ethyl acetate (1/2 v/v) to obtain the title compound (1.55 kg) as a solid. *H NMR (400 MHz, DMSO-dg) 8 7.74 (d, 1H), 5.77 (s, 1H), 3.80 - 3.88 (m, 2H), 2.78 - 2.88 (m, 1H), 2.70 - 2.70 (m, 1H), 2.70 - 1.75 (t, 1H), 1.73 - 1.74 (m, 4H), 1.48 - 1.55 (m, 6H), 1.43 (s, 9H), 1.18 - 1.19 (m, 1H), 0.80 - 0.81 (m, 1H), 0.79 - 0.81 (m, 1H), 0.46 - 0.48 (m, 2H).

[00122] 2V-((lr,4r)-4-hydroxy-4-(trifluoromethyl)cyclohexyl)-4-azasp iro[2.5]<jctane-7- carboxamide hydrochloride

[00123] Ethyl acetate (10.00 L) was added to a 30.0 L flask equipped with stirrer, addition funnel and thermometer, N- protection. Tert-butyl 7-(((lr,4r)-4-hydroxy-4-(trifluoromethyl)cyclohexyl)carbamoy l)- 4-azaspiro[2.5]octane-4-carboxylate (1.50 kg, 3.57 mol) was added to the flask at 0 °C. The reaction mixture was purged with N ₃ for 3 times. HCl/dioxane (4.00 M, 2.50 L) was added to the flask at 0 °C. The reaction was stirred at 0 to 20 °C for 1 h under N ₃ . The reaction mixture was concentrated under vacuum to obtain the title compound (1.40 kg) as a solid and was directly used to next step. H NMR (400 MHz, DMSO-d ₆ ) 8 9.43 (s, 2H), 7.94 (d, 1H), 5.37 (br s, 1H), 3.81 (s, 1H), 3.42 - 3.44 (m, 1H), 2.80 - 2.90 (m, 1H), 2.51 - 2.64 (m, 1H), 2.10 - 2.13 (m, 1H), 1.78 - 1.83 (s, 6H), 1.74 - 1.78 (m, 4H), 1.49 (d, 1H), 1.03 - 1.05 (m, 2H), 0.70 - 0.73 (m, 2H).

[00124] 4-(5-(5-fluoro-2-methoxypyridin-4-yl)-l-((2-(trimethylsilyl) ethoxy)methyl)-l//-pyrazole- 3-carbonyl)-A ⁷ -((lr,4r)-4-hydroxy-4-(trifluoromethyl)cyclohexyl)-4-a zaspiro[2.5]octane-7- carboxamide

[00125] Four batches were carried out in parallel. DMF (3.00 L) was added a 5.00 L of jacket flask equipped with overhead stirrer, addition funnel and thermometer, Nz balloon at 0 °C. 7V-((lr,4r)-4- hydroxy-4-(trifluoromethyl)cyclohexyl)-4-azaspiro[2.5]octane -7-carboxamide hydrochloride (317.00 g, 863.00 mmol) was added to the flask at 0 °C. DIPEA (502.00 g, 3.88 mol), EDCI (298.00 g, 1.55 mol), and HOBt (209.00 g, 1 .55 mol) were added to the flask at 0 °C. The reaction mixture was stirred at 0 °C and purged with Nz. 5-(5-fluoro-2-methoxypyridin-4-yl )- 1 -((2-(trimethylsilyl)ethoxy)methyl )- 1 H- pyrazole-3-carboxylic acid (Intermediate 506, 370.00 g, 1.04 mol) was added to the flask at 0 °C and the resulting mixture was stirred at 0 to 30 °C for 12 h under N ₃ . Four batches were combined and the reaction mixture was poured into H2O (10.00 L), extracted with ethyl acetate (10.00 L x 2). The combined organic layer was washed with brine (10.00 L), dried over Na2SO4, filtered and the filtrate was concentrated in vacuum. The residue was purified by silica gel column chromatography eluting with petroleum ether/ethyl acetate (1/2 v/v) to obtain the title compound (1.50 kg) as an oil. ¹ H NMR (400 MHz, DMSO- d6) δ 8.31 (d, 1H), 7.86 (s, 1H), 7.33 (d, 1H), 7.08 (s, 1H), 5.81 - 5.80 (m, 1H), 5.49 (d, 1H), 3.93 (s, 3H), 3.92 - 3.89 (m, 1H), 3.63 - 3.61 (m, 2H), 2.98 - 2.96 (m, 1H), 2.06 - 2.02 (m, 1H), 1.85 - 1.25 (m, 11H), 1.23 (t, 3H), 1.23 - 0.64 (m, 6H), 0.00 (s, 9H). LCMS: [M+H] ⁺ : 670.2. [00126] 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-carboxa mide [00127] Three batche s added to a 10 L of the flask equipped with stirrer, addition funnel and thermometer, N2 protection at 20 °C.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 (500 g, 747 mmol, 1.00 eq) was added to the flask at 20 °C under N ₂ . TFA (1.28 kg, 11.20 mol) was added to the flask at 20 °C. The reaction mixture was stirred at 20 to 25 °C for 2 h under N2. Three batches were combined and the reaction mixture was poured into NaHCO3 (10.00 L), extracted with ethyl acetate (10.0 L x 2). The combined organic layer was concentrated under vacuum. The resulting 1.20 kg of residue was dissolved into methanol (3.00 L) and NH3.H2O (1.00 L) was slowly added dropwise at 5 to 10 °C and the mixture was stirred for 1 h. The mixture was poured into sat. NaCl (2.00 L) solution, extracted with ethyl acetate (4.00 L x 2), the combined organic layer was dried over Na ₂ SO ₄ , filtered and the filtrate was concentrated under vacuum. The residue was crystallized from (MTBE, 2.00 L, 25 °C), the mixture was filtered and the filtrate cake was washed with MTBE (300 mL x 2). The filtrate cake was collected and concentrated under vacuum to obtain the title compound (970.00 g) as a solid. ¹ H NMR (400 MHz, DMSO-d6) δ 14.0 (br s, 1H), 8.27 (s, 1H), 7.81 (d, 1H), 7.32 (d, 1H), 7.03 (s, 1H), 4.37 – 4.34 (m, 1H), 3.88 (s, 3H), 3.83 (s, 1H) 2.79 (s,1H), 2.20 – 2.10 (m, 1H), 1.79 – 1.50 (m, 11H), 1.08 – 0.98 (m, 3H), 0.89 – 0.65 (m, 2H). LCMS: [M+H] ⁺ : 540.1. [00128] (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) [00129] 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-carboxa mide (1.15 kg, 2.13 mol) was separated using Prep-SFC. [00130] Instrument: Waters SFC prep 350 [00131] Column: DAICEL CHIRALPAK IG (250 mm × 50 mm, 10 µm) [00132] Mobile phase A: CO2 [00133] Mobile phase B: EtOH [00134] Gradient: B 55% [00135] Flow rate: 200 mL/min [00136] Back pressure: 100 bar [00137] Column temperature: 35 °C [00138] Wavelength: 220 nm [00139] Cycle time: approximately 12.2 min [00140] Sample preparation: 1150 g compound was dissolved in 4700 ml ethanol [00141] Injection: 15 mL per injection [00142] Compound I (411.00 g) was obtained as a solid and had a retention time of 21.69 min. [00143] ¹ H NMR (400 MHz, DMSO-d6) 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. Crystallization to Form A of Compound I [00144] To Compound I (597 mg) was added acetonitrile (0.6 mL), and the resulting solution was stirred at room temperature for 3 days. The precipitates were cropped by filtration to afford Compound I (Form A, 544 mg). X-Ray Powder Diffraction [00145] The X-ray powder diffractogram of Form A of Compound I (Figure 1) was acquired under the following conditions: [00146] Equipment: SmartLab (Rigaku) [00147] X-ray source: CuKα (45 kV, 200 mA) [00148] Optical system: Convergent beam optics [00149] Soller slit: 2.5° [00150] Detector: D/teX Ultra 250 detector (1D semiconductor detection system) [00151] Mode: Transmission [00152] Scan range: from 3° to 40° [00153] Step size: 0.01° [00154] Scan speed: 5°/min [00155] Sample holder: Mylar ^TM film [00156] The peaks are listed in Table 1 below.

Table 1. Peak list from powder X-ray powder diffraction diffractogram of Form A

Solid State NMR

[00157] Form A of Compound (I) was packed into a 7 mm rotor for ¹³ C SSNMR spectroscopy. The solid-state ¹³ C SSNMR spectrum of the sample was obtained under the following conditions: [00158] Instrument: Avance 400 MHz (BRUKER) 7mm - CPMAS probe (BRUKER)

[00159] Measurement nucleus: 13C (100.6238359 MHz)

[00160] Pulse mode: CPTOSS measurement

[00161] Rotational frequency: 5000 Hz

[00162] Pulse repetition time: 5 sec

[00163] Contact time: 1 msec

[00164] Number of scans: 10240 [00165] The ¹³ C CPMAS of Form A of Compound I (Figure 2) was acquired at room temperature with 5 kHz spinning and using as a reference carbonyl carbon of glycine adamantane 176.03 ppm. The peaks are listed in Table 2 below.

Thermogravimetric Analysis & Differential Scanning Calorimetry Analysis

[00166] Thermal gravimetric analysis and differential scanning calorimetry analysis of Form A of Compound I was measured using a METTLER TOLEDO TGA/DSC 3+.

[00167] Approximately 3 mg of the crystal (Form A) sample was accurately weighed into an aluminum pan and then the analysis was performed under the following conditions.

[00168] Atmosphere: nitrogen gas flow of 50 mL/minute

[00169] Reference pan: empty aluminum pan

[00170] Heating rate: 10 °C/minute

[00171] Sampling interval: 1 second

[00172] Temperature range: 25 to 300 °C

[00173] The DSC curve thermogram (Figure 3) shows one endotherm around 240 °C (onset temperature).

Raman Spectroscopy

[00174] 50 - 100 mg of Form A of Compound I was packed into a plastic bag for Raman spectroscopy.

The Raman spectrum of the sample was obtained under the following conditions.

[00175] Instrument: TRS100 Raman (Agilent)

[00176] Laser wavelength: 830 nm

[00177] Laser power: 0.65 W

[00178] Exposure time: 1.000 sec

[00179] Number of scans: 10 [00180] Laser spot size: 4 mm

[00181] Collection size: Medium

[00182] The Raman spectrum (Figure 4) was acquired and the wave numbers are listed in Table 3 below.

Hygroscopicity

[00183] Form A of Compound I (10.88 mg) was weighed into a sampling cup and the sampling cup was placed inside an isothermal chamber at 25°C. The relative humidity (RH) was controlled from 0% to 95% using a gravimetric vapor sorption system and the sample weight at each RH stage was measured within a predetermined interval of time (e.g. every 2 minutes). The weight change at each RH stage was evaluated in a stepwise manner, and then was finally determined under the following criteria. The maximum weight change for each measurement is less than 0.002% (w/w) in 1 minute. See Figure 5.

Single Crystal X-Ray Diffraction

[00184] Form A of Compound I (3.24 mg) was dissolved in 600 uL of MEK (methyl ethyl ketone). 200 pL of this solution was put in another glass vial and then this vial was stored in fixed container with 2 mL of c-hexane at room temperature for 2 days (MEK/c-hexane vapor diffusion method). A colorless crystal was collected.

[00185] A colorless block single crystal (0.1 x 0.1 x 0.01 mm) found in crystallization solution was dispersed in liquid Parabar 10312 and was mounted on a Dual-Thickness MicroMountsTM (MiTeGen). Diffraction data was collected at -160 °C on XtaLAB PRO P200 MM007HF (Rigaku) with co axis oscillation method using multi-layer mirror monochromated Cu-Ka radiation. The Single Crystal X-ray diffractogram of Compound I was acquired under the conditions described in Table 4.

[00186] Single crystal X-ray diffraction (SXRD) was used to determine the structure of Form A and the results are summarized in Tables 4 to 7. The results demonstrate that Form A is anhydrous. See Figure 6. [0060] TR-FRET assay to measure Co-R Peptide Recruitment to PPARy

[0061] The His6-TEV-PPARy-(234-505) protein for assay was expressed and purified according to Korpal, M., et al., Evasion of immuno surveillance by genomic alterations of PPARgamma/RXRalpha in bladder cancer. Nature communications, 2017. 8(1): p. 103.

[0062] The assay buffer was comprised of 50 mM Potassium Chloride (Sigma), 50 mM HEPES pH 7.4 (Teknova), 2 mM DTT (Boston Bioproducts), 0.1 mg/mL bovine gamma-globulin (Sigma), and 0.001% Plutonic F-127 (Thermo Fisher). A 2x working stock of Hiss-PPARy-(234-505) was diluted to a final concentration of 10 nM in assay buffer. The 2x detection solution contained anti-6xHis-Terbium antibody (CisBio) and F1TC labeled Co-R peptide (SMRT-1D2 from New England Peptide) at final concentrations of 5 and 200 nM respectively.

[0063] An acoustic dispenser delivered 4 nL of compound or DMSO from an 11-point master dose response (MDR) source plate into 384 well assay plates (Corning, 3820), with top final concentration of 20 pM. In these assay plates, the positive control in column 24 contained 500 nM (final) T0070907 and the negative control in column 23 contained an identical volume of DMSO. Then, 5 pL of 2x protein working stock or controls were added to the plate and incubated for 20 minutes at room temperature. Reagents additions were performed with either a Combi (Thermo) or Mantis (Formulatrix) pipetting device. The incubation was followed by addition of 5 pL of the 2x detection solution. Plates were covered, centrifuged, and incubated for an additional hour. The TR-FRET data was recorded with an Envision plate reader (Perkin Elmer), using settings recommended by Thermo Fisher. The TR-FRET signal of the positive and negative control’ s recruitment of FITC-Co-R peptide was used to normalize the TR-FRET signal to percent response and to determine the assay Z prime. Experiments were performed in triplicate and analyzed in GraphPad Prism 7.

[0064] Results of the assay are reported in Table 8.

Table 8. Biological Assay Results