Crystalline EDG-2 receptor antagonist and method for manufacturing it

Abstract

This invention provides crystals useful for preparing pharmaceutical compositions for the treatment of diseases or conditions that benefit from administration of EDG-2 receptor antagonist compounds. [Solution] A crystalline form 1 of 2-(4-methoxy-3-(3-methylphenethoxy)benzamide)-2,3-dihydro-1H-indene-2-carboxylic acid is provided.

Description

[Technical Field]

[0001] cross reference This application claims the interests of U.S. Provisional Patent Application No. 63 / 072,848, filed on 31 August 2020, and U.S. Provisional Patent Application No. 63 / 227,279, filed on 29 July 2021, which are incorporated herein by reference in their entirety.

[0002] This specification describes crystalline forms of endothelial differentiation gene 2 (EDG-2) antagonist compounds and their pharmaceutical compositions, as well as methods of use thereof in the treatment of diseases or conditions for which treatment with an EDG-2 antagonist compound is beneficial. [Background technology]

[0003] EDG-2 (also known as lysophosphatidic acid receptor 1, LPA1 receptor, or LPAR1) is a member of the G protein-coupled receptor family of endometrial membrane proteins that are important for lipid signaling. LPA1 receptor antagonists are useful in treating diseases or conditions such as atherosclerosis, myocardial infarction, and heart failure, in which abnormal LPA signaling is a contributing factor. [Overview of the Initiative]

[0004] This disclosure relates to various solid-state forms of 2-(4-methoxy-3-(3-methylphenethoxy)benzamide)-2,3-dihydro-1H-indene-2-carboxylic acid, an LPA1 receptor antagonist, and methods for producing them. Such forms of 2-(4-methoxy-3-(3-methylphenethoxy)benzamide)-2,3-dihydro-1H-indene-2-carboxylic acid are useful for modulating the activity of the LPA1 receptor in mammals from which such activity is beneficial.

[0005] In some embodiments, crystalline form 1 of 2-(4-methoxy-3-(3-methylphenethoxy)benzamide)-2,3-dihydro-1H-indene-2-carboxylic acid (compound I) is described herein. In some embodiments, crystalline form 1 of compound I is substantially the same as the X-ray powder diffraction (XRPD) pattern shown in Figure 1, measured using Cu(Kα) rays, or an X-ray powder diffraction (XRPD) pattern derived using Cu(Kα) rays with peaks at 5.2±0.2°²-theta, 9.0±0.2°²-theta, 14.4±0.2°²-theta, and 17.7±0.2°²-theta, measured using Cu(Kα) rays, or approximately 1739.6 cm². -1 A Fourier transform IR spectroscopy (FTIR) pattern with a peak at 293K,

[0006] [Table 1] The unit cell parameters are substantially equal to those shown in Figure 4, or the solid state is substantially the same as those shown in Figure 4. 13 Solid states characterized by carbon nuclear magnetic resonance (ssNMR) spectra, or resonances (δc) at 23.35, 124.43, 126.78, 127.42, and 136.47 ppm. 13 It is characterized by having a carbon nuclear magnetic resonance (ssNMR) spectrum, or a combination thereof.

[0007] In some embodiments, crystalline form 2 of 2-(4-methoxy-3-(3-methylphenethoxy)benzamide)-2,3-dihydro-1H-indene-2-carboxylic acid (compound I) is further described herein. In some embodiments, crystalline form 2 of compound I is measured using Cu(Kα) radiation and is substantially the same as the X-ray powder diffraction (XRPD) pattern shown in Figure 6, or measured using Cu(Kα) radiation and is an X-ray powder diffraction (XRPD) pattern with peaks at 5.6±0.2°²-theta, 7.6±0.2°²-theta, 9.4±0.2°²-theta, 15.5±0.2°²-theta, and 16.3±0.2°²-theta, or a Fourier transform IR spectroscopy (FTIR) pattern with a peak at approximately 1731.7 cm⁻¹, or at 293 K,

[0008] [Table 2] The unit cell parameters are substantially equal to those shown in Figure 8, or the solid state is substantially the same as those shown in Figure 8. 13 Solid states characterized by carbon nuclear magnetic resonance (ssNMR) spectra, or resonances (δc) at 20.59, 126.39, 128.34, and 137.69 ppm. 13 It is characterized by having a carbon nuclear magnetic resonance (ssNMR) spectrum, or a combination thereof.

[0009] In some embodiments, crystalline form 3 of 2-(4-methoxy-3-(3-methylphenethoxy)benzamide)-2,3-dihydro-1H-indene-2-carboxylic acid (compound I) is further described herein. In some embodiments, crystalline form 3 of compound I is substantially the same as the X-ray powder diffraction (XRPD) pattern shown in Figure 10, measured using Cu(Kα) rays, or an X-ray powder diffraction (XRPD) pattern with peaks at 4.2±0.2°²-theta, 6.8±0.2°²-theta, 15.1±0.2°²-theta, 25.0±0.2°²-theta, 25.5±0.2°²-theta, and 26.4±0.2°²-theta, measured using Cu(Kα) rays, or approximately 1722.0 cm². -1A Fourier transform IR spectroscopy (FTIR) pattern having a peak at, or a solid state substantially the same as that shown in FIG. 12 13 A solid state characterized by a Carbon nuclear magnetic resonance (ssNMR) spectrum, or resonances (δc) at 64.56, 67.67, 122.99, and 126.71 ppm 13 Characterized by having a Carbon nuclear magnetic resonance (ssNMR) spectrum, or a combination thereof.

[0010] In some embodiments, crystalline form 4 of 2-(4-methoxy-3-(3-methylphenethoxy)benzamide)-2,3-dihydro-1H-indene-2-carboxylic acid (Compound I) is further described herein. In some embodiments, crystalline form 4 of Compound I has an X-ray powder diffraction (XRPD) pattern substantially the same as that shown in FIG. 13, measured using Cu(Kα) radiation, or a Fourier transform IR spectroscopy (FTIR) pattern having a peak at about 1743.9 cm -1 Characterized by having a peak at, or a combination thereof.

[0011] In some embodiments, the amorphous phase of 2-(4-methoxy-3-(3-methylphenethoxy)benzamide)-2,3-dihydro-1H-indene-2-carboxylic acid (Compound I) is further described herein, and the amorphous phase has an XRPD pattern indicative of lack of crystallinity, and / or a solid state substantially the same as that shown in FIG. 16 13 Characterized by having a Carbon nuclear magnetic resonance (ssNMR) spectrum.

[0012] In some embodiments, pharmaceutical compositions comprising crystalline form compound I and at least one pharmaceutically acceptable excipient are further described herein. For example, in some embodiments, pharmaceutical compositions comprising crystalline form 1 and at least one pharmaceutically acceptable excipient are further described herein. In some embodiments, the pharmaceutical composition is formulated for oral administration to mammals. In some embodiments, the pharmaceutical composition is formulated for oral administration to mammals in the form of tablets, pills, capsules, suspensions, or solutions. In some embodiments, the pharmaceutical composition is in solid form. In some embodiments, the pharmaceutical composition is in the form of tablets, pills, or capsules. In some embodiments, the pharmaceutical composition is substantially free of impurities of compound I. In some embodiments, the pharmaceutical composition contains less than about 1% w / w of impurities of compound I. In some embodiments, the impurities of compound I include one or more decomposition products of compound I, one or more intermediates used in the synthesis of compound I, or a combination thereof. In some embodiments, the impurities of compound I include one or more intermediates used in the synthesis of compound I.

[0013] In some embodiments, compound I:

[0014] [ka] The process for the preparation of is described herein, and compound I is (1) Equation 7:

[0015] [ka] (In the formula, M + is Na + , K + , or Li + To provide compounds where M-OH is NaOH, KOH, or LiOH, Formula 6:

[0016] [ka] (In the formula, R 2 C1-C 20 Alkyl, C1-C 20 Alkenil, C3-C 10 Cycloalkyl, or C3-C 10 A step of contacting a compound (which is a cycloalkenyl) with a hydroxide reagent having the formula M-OH in a suitable solvent, (2) To provide compound I, the compound of formula 7 is brought into contact with a suitable organic acid in a suitable solvent. include.

[0017] Other purposes, features, and advantages of the compounds, methods, and compositions described herein will become apparent from the detailed descriptions that follow. However, since various variations and modifications within the spirit and scope of this disclosure will become apparent to those skilled in the art from the modes for carrying out the invention, it should be understood that the modes for carrying out the invention and specific examples are given only as examples, while illustrating specific embodiments. [Brief explanation of the drawing]

[0018] [Figure 1] This figure shows the X-ray powder diffraction (XRPD) pattern of Form 1. [Figure 2] This figure shows a differential scanning calorimetry (DSC) thermogram of Form 1. [Figure 3] This figure shows the thermogravimetric analysis (TGA) pattern of form 1. [Figure 4] This figure shows the 13-carbon NMR spectrum of the solid state of form 1. [Figure 5] This is a diagram showing the molecular structure of form 1. [Figure 6] This figure shows the X-ray powder diffraction (XRPD) pattern of Form 2. [Figure 7] This figure shows a differential scanning calorimetry (DSC) thermogram of form 2. [Figure 8] This figure shows the 13-carbon NMR spectrum of the solid state in form 2. [Figure 9] This is a diagram showing the molecular structure of form 2. [Figure 10] This figure shows the X-ray powder diffraction (XRPD) pattern of form 3. [Figure 11] This figure shows a differential scanning calorimetry (DSC) thermogram of form 3. [Figure 12] This figure shows the 13-carbon NMR spectrum of the solid state in form 3. [Figure 13] This figure shows the X-ray powder diffraction (XRPD) pattern of form 4. [Figure 14] This figure shows a differential scanning calorimetry (DSC) thermogram of form 4. [Figure 15] These figures represent Fourier transform infrared spectroscopy (FTIR) pattern overlays of forms 1, 2, 3, and 4. [Figure 16] This figure shows the 13Carbon NMR spectrum of the amorphous solid state. [Figure 17] This figure shows the XRPD pattern of Form 1 obtained using a Malvern Panalytical Empyrean diffractometer. [Figure 18] This figure shows the XRPD pattern of form 2 obtained using a Malvern Panalytical Empyrean diffractometer. [Figure 19] This figure shows the XRPD pattern of form 1 obtained using the Stoe Stadi P, G.52.SYS.S072 diffractometer. [Figure 20] This figure shows the XRPD pattern of form 2 obtained using the Stoe Stadi P, G.52.SYS.S072 diffractometer. [Figure 21] This figure shows XRPD pattern overlays of form 1 (upper XRPD) and form 2 (lower XRPD), obtained using the Stoe Stadi P, G.52.SYS.S072 diffractometer. [Figure 22] This figure shows the XRPD pattern of form 1 obtained using a PANalytical X'Pert PRO MPD diffractometer. [Figure 23]This figure shows the XRPD pattern of type 2 obtained using a PANalytical X'Pert PRO MPD diffractometer. [Figure 24] This figure shows a comparison of the XRPD patterns of Form 1 (upper XRPD) and Form 2 (lower XRPD), with the Form 2 peak used to quantify Form 2 in Form 1 highlighted. [Figure 25] This figure shows the XRPD overlay of the calibration standard used during the development of the XRPD limit test for measuring Form 2 in Form 1 drug raw materials. [Figure 26] This figure shows the calibration curve used during the development of the XRPD limit test for measuring Form 2 in Form 1 drug raw materials. [Figure 27] This is a diagram showing the Raman spectrum of form 1. [Figure 28] This figure shows the Raman spectrum of form 2. [Modes for carrying out the invention]

[0019] 2-(4-methoxy-3-(3-methylphenethoxy)benzamide)-2,3-dihydro-1H-indene-2-carboxylic acid (compound I) is a potent and selective LPA1 receptor antagonist. The LPA1 receptor is activated by lysophosphatidic acid (LPA). LPA1 receptor antagonists are useful in treating diseases or conditions such as atherosclerosis, myocardial infarction, and heart failure, in which abnormal LPA signaling is a contributing factor.

[0020] Compound I Compound I is a potent, selective, orally available LPA1 receptor antagonist useful for the treatment of various diseases or conditions, including fibrotic diseases or conditions as described herein. In vivo, Compound I transformed skin thickening, significantly inhibited myofibroblast differentiation, and reduced collagen content in a mouse model of dermatofibrosis. Mechanistic investigations indicated that the anti-fibrotic effect of LPA1 blockade may be partially mediated by inhibition of the Wnt signaling pathway. In a clinical setting, Compound I demonstrated good tolerability, target engagement, and improved endpoints in patients with diffuse cutaneous systemic sclerosis (dcSSc) (Y. Allanore et al. Arthritis & Rheumatology, Vol. 70, No. 10, October 2018, pp. 1634-1643).

[0021] The preparation and use of Compound I are described previously (see WO 2009 / 135590, US 8,362,073, US 8,445,530, US 8,802,720, and US 9,328,071, which are referred to in their entirety).

[0022] Compound I refers to 2-(4-methoxy-3-(3-methylphenethoxy)benzamide)-2,3-dihydro-1H-indene-2-carboxylic acid, and its chemical structure is as follows:

[0023] [ka] It holds.

[0024] In some embodiments provided herein, compound I is crystalline.

[0025] In some embodiments provided herein, compound I is a single crystalline form. In some embodiments provided herein, compound I is a single crystalline form that substantially does not contain any other crystalline forms. In some embodiments, the crystalline solid form is a single solid-state form, e.g., crystalline form 1. In some embodiments, “substantially not containing” means less than about 10% w / w, less than about 9% w / w, less than about 8% w / w, less than about 7% w / w, less than about 6% w / w, less than about 5% w / w, less than about 4% w / w, less than about 3% w / w, less than about 2.5% w / w, less than about 2% w / w, less than about 1.5% w / w, less than about 1% w / w, less than about 0.75% w / w, less than about 0.50% w / w, less than about 0.25% w / w, less than about 0.10% w / w, or less than about 0.05% w / w of any other crystalline forms (e.g., form 2) in a sample of crystalline form 1. In some embodiments, "substantially absent" means an amount that is undetectable (e.g., by XRPD analysis).

[0026] In some embodiments, the crystallinity of the solid state is determined by X-ray powder diffraction (XRPD). In some embodiments, the crystallinity of the solid state is determined by solid-state NMR. In some embodiments, the crystallinity of the solid state is determined by Fourier transform infrared spectroscopy (FTIR).

[0027] Crystal form of compound I 1 In one embodiment, crystalline form 1 of 2-(4-methoxy-3-(3-methylphenethoxy)benzamide)-2,3-dihydro-1H-indene-2-carboxylic acid is provided herein. Several embodiments provide compositions comprising crystalline form 1 of 2-(4-methoxy-3-(3-methylphenethoxy)benzamide)-2,3-dihydro-1H-indene-2-carboxylic acid. In some embodiments, crystalline form 1 of 2-(4-methoxy-3-(3-methylphenethoxy)benzamide)-2,3-dihydro-1H-indene-2-carboxylic acid is, • The X-ray powder diffraction (XRPD) pattern, measured using Cu(Kα) radiation, is substantially the same as that shown in Figure 1. X-ray powder diffraction (XRPD) patterns derived using Cu(Kα) radiation, with peaks at 5.2±0.2°²-theta, 9.0±0.2°²-theta, 14.4±0.2°²-theta, and 17.7±0.2°²-theta, measured using Cu(Kα) radiation. Approximately 1739.6cm -1 Fourier transform IR spectroscopy (FTIR) pattern with a peak, • At 293K,

[0028] [Table 3] The unit cell parameter is substantially equal to this. • Substantially the same solid state as shown in Figure 4 13 Carbon nuclear magnetic resonance (ssNMR) spectrum, Solid states characterized by resonance (δc) at 23.35, 124.43, 126.78, 127.42, and 136.47 ppm. 13 Carbon nuclear magnetic resonance (ssNMR) spectrum, or • These combinations It is characterized by having the following features.

[0029] In some embodiments, crystalline form 1 of 2-(4-methoxy-3-(3-methylphenethoxy)benzamide)-2,3-dihydro-1H-indene-2-carboxylic acid (compound I) has an X-ray powder diffraction (XRPD) pattern measured using Cu(Kα) radiation, with peaks at 5.2±0.2°²-theta, 9.0±0.2°²-theta, 14.4±0.2°²-theta, and 17.7±0.2°²-theta.

[0030] In some embodiments, the crystalline form 1 of compound I is measured using Cu(Kα) radiation, with X-ray powder diffraction (XRPD) patterns showing peaks at 5.2±0.2°²-theta, 9.0±0.2°²-theta, 14.4±0.2°²-theta, and 17.7±0.2°²-theta, and approximately 1739.6 cm². -1 It has a Fourier transform IR spectroscopy (FTIR) pattern with a peak at [location].

[0031] In some embodiments, the crystalline form 1 of compound I has an X-ray powder diffraction (XRPD) pattern measured using Cu(Kα) rays, with peaks at 5.2±0.2°²-theta, 9.0±0.2°²-theta, 14.4±0.2°²-theta, and 17.7±0.2°²-theta, and a differential scanning calorimetry (DSC) thermogram with three endothermic events having a starting point and peak at approximately 198.5°C and a peak at approximately 200.4°C, a starting point and a peak at approximately 204.8°C and a peak at approximately 205.8°C, and a starting point and a peak at approximately 213.9°C and a peak at approximately 216.3°C.

[0032] In some embodiments, the crystalline form 1 of compound I is characterized by an X-ray powder diffraction (XRPD) pattern with peaks at 5.2±0.2°²-theta, 9.0±0.2°²-theta, 14.4±0.2°²-theta, and 17.7±0.2°²-theta, measured using Cu(Kα) radiation, and resonances (δc) at approximately 23.35 ppm, 124.43 ppm, 126.78 ppm, 127.42 ppm, and 136.47 ppm in the solid state. 13 It has a carbon nuclear magnetic resonance (ssNMR) spectrum.

[0033] In some embodiments, the crystalline form 1 of compound I is characterized by an X-ray powder diffraction (XRPD) pattern with peaks at 5.2±0.2°²-theta, 9.0±0.2°²-theta, 14.4±0.2°²-theta, and 17.7±0.2°²-theta, measured using Cu(Kα) radiation, and resonances (δc) at approximately 23.35 ppm, 124.43 ppm, 126.78 ppm, 127.42 ppm, and 136.47 ppm in the solid state. 13 It includes a carbon nuclear magnetic resonance (ssNMR) spectrum and a differential scanning calorimetry (DSC) thermogram with three endothermic events: a starting point and peak at approximately 198.5°C and 200.4°C, a starting point and peak at approximately 204.8°C and 205.8°C, and a starting point and peak at approximately 213.9°C and 216.3°C.

[0034] In some embodiments, crystalline form 1 of compound I has substantially the same X-ray powder diffraction (XRPD) pattern as shown in Figure 1, measured using Cu(Kα) radiation.

[0035] In some embodiments, the crystalline form 1 of compound I has substantially the same X-ray powder diffraction (XRPD) pattern as shown in Figure 1, measured using Cu(Kα) radiation, and substantially the same differential scanning calorimetry (DSC) thermogram as shown in Figure 2.

[0036] In some embodiments, the crystalline form 1 of compound I exhibits substantially the same X-ray powder diffraction (XRPD) pattern as shown in Figure 1, measured using Cu(Kα) radiation, and approximately 1739.6 cm⁻¹. -1 It has a Fourier transform IR spectroscopy (FTIR) pattern with a peak at approximately 1739.6 cm⁻¹. In some embodiments, the crystalline form 1 of compound I has substantially the same X-ray powder diffraction (XRPD) pattern as shown in Figure 1, measured using Cu(Kα) rays, and approximately 1739.6 cm⁻¹. -1 It has a Fourier transform IR spectroscopy (FTIR) pattern with a peak at [location], and a differential scanning calorimetry (DSC) thermogram that is substantially the same as that shown in Figure 2.

[0037] In some embodiments, the crystalline form 1 of compound I exhibits substantially the same X-ray powder diffraction (XRPD) pattern as shown in Figure 1, measured using Cu(Kα) radiation, and substantially the same solid state as shown in Figure 4. 13 It has a carbon nuclear magnetic resonance (ssNMR) spectrum. In some embodiments, the crystalline form 1 of compound I has substantially the same X-ray powder diffraction (XRPD) pattern as shown in Figure 1, measured using Cu(Kα) radiation, and substantially the same solid state as shown in Figure 4. 13 The image shows a carbon nuclear magnetic resonance (ssNMR) spectrum and a differential scanning calorimetry (DSC) thermogram that is substantially the same as the one shown in Figure 2.

[0038] In some embodiments, the crystalline form 1 of 2-(4-methoxy-3-(3-methylphenethoxy)benzamide)-2,3-dihydro-1H-indene-2-carboxylic acid (compound I) is at 293K.

[0039] [Table 4] It has unit cell parameters that are substantially equivalent to those of the other.

[0040] In some embodiments, the crystalline form 1 of compound I is substantially the same solid state as that shown in Figure 4. 13 It is characterized by having a carbon nuclear magnetic resonance (ssNMR) spectrum. In some embodiments, the crystalline form 1 of compound I is substantially the same as the solid state shown in Figure 4. 13 Carbon nuclear magnetic resonance (ssNMR) spectrum, and approximately 1739.6 cm⁻¹ -1 It is characterized by having a Fourier transform IR spectroscopy (FTIR) pattern with a peak at [location]. In some embodiments, the crystalline form 1 of compound I is substantially the same as the solid state shown in Figure 4. 13 It is characterized by having a carbon nuclear magnetic resonance (ssNMR) spectrum and a differential scanning calorimetry (DSC) thermogram that is substantially the same as that shown in Figure 2.

[0041] In some embodiments, the crystalline form 1 of compound I is a solid state characterized by resonance (δc) at approximately 23.35 ppm, approximately 124.43 ppm, approximately 126.78 ppm, approximately 127.42 ppm, and approximately 136.47 ppm. 13 It is characterized by having a carbon nuclear magnetic resonance (ssNMR) spectrum.

[0042] In some embodiments, the crystalline form 1 of compound I is a solid state characterized by resonance (δc) at approximately 23.35 ppm, approximately 124.43 ppm, approximately 126.78 ppm, approximately 127.42 ppm, and approximately 136.47 ppm. 13It is characterized by having a carbon nuclear magnetic resonance (ssNMR) spectrum and a differential scanning calorimetry (DSC) thermogram that is substantially the same as that shown in Figure 2.

[0043] In some embodiments, the crystalline form 1 of compound I is a solid state characterized by resonance (δc) at approximately 23.35 ppm, approximately 124.43 ppm, approximately 126.78 ppm, approximately 127.42 ppm, and approximately 136.47 ppm. 13 Carbon nuclear magnetic resonance (ssNMR) spectrum and approximately 1739.6 cm⁻¹ -1 It is characterized by having a Fourier transform IR spectroscopy (FTIR) pattern with a peak at [location].

[0044] In some embodiments, the crystalline form 1 of compound I is approximately 1739.6 cm². -1 It is characterized by having a Fourier transform IR spectroscopy (FTIR) pattern with a peak at [a certain point]. In some embodiments, the crystalline form 1 of compound I is approximately 1739.6 cm². -1 It is characterized by having a Fourier transform IR spectroscopy (FTIR) pattern with a peak at a certain point, and a differential scanning calorimetry (DSC) thermogram that is substantially the same as that shown in Figure 2.

[0045] In some embodiments, the crystalline form 1 of compound I is approximately 1739.6 cm². -1 It is characterized by having a Fourier transform IR spectroscopy (FTIR) pattern with a peak at [location], and a differential scanning calorimetry (DSC) thermogram with three endothermic events having a starting point at approximately 198.5°C and a peak at approximately 200.4°C, a starting point at approximately 204.8°C and a peak at approximately 205.8°C, and a starting point at approximately 213.9°C and a peak at approximately 216.3°C.

[0046] In some embodiments, crystalline form 1 of compound I has a DSC thermogram substantially the same as that shown in Figure 2. In some embodiments, crystalline form 1 has a DSC thermogram with one or more endothermic events having a starting point of about 198.5°C and a peak at about 200.4°C, a starting point of about 204.8°C and a peak at about 205.8°C, and / or a starting point of about 213.9°C and a peak at about 216.3°C. In some embodiments, crystalline form 1 has a DSC thermogram with three endothermic events having a starting point of about 198.5°C and a peak at about 200.4°C, a starting point of about 204.8°C and a peak at about 205.8°C, and a starting point of about 213.9°C and a peak at about 216.3°C.

[0047] In some embodiments, crystalline form 1 of 2-(4-methoxy-3-(3-methylphenethoxy)benzamide)-2,3-dihydro-1H-indene-2-carboxylic acid has substantially the same TGA pattern as that shown in Figure 3. In some embodiments, crystalline form 1 has a TGA pattern with a 15.4% w / w decrease at approximately 287.9°C to approximately 298.9°C. In some embodiments, crystalline form 1 has a TGA pattern with a weight loss of less than 1% at up to 200°C.

[0048] In some embodiments, crystalline form 1 of compound I has reversible moisture absorption (approximately -0.1% w / w) at relative humidity (RH) of 0 to 95%. In some embodiments, crystalline form 1 of compound I does not have reversible moisture absorption at relative humidity (RH) of 0 to 95%. In some embodiments, crystalline form 1 of compound I has reversible moisture absorption of <1% w / w at relative humidity (RH) of 0 to 95%. In some embodiments, crystalline form 1 of compound I has reversible moisture absorption of approximately -0.1% w / w at relative humidity (RH) of 0 to 95%.

[0049] In some embodiments, the crystalline form 1 of compound I is approximately 1739.6 cm². -1 Use the FTIR spectrum that has a peak at [location].

[0050] In some embodiments, the crystalline form 1 of compound I is 1730 cm². -1 ±2cm -1 It has a Raman spectrum with a peak at [location].

[0051] In some embodiments, crystalline form 1 of 2-(4-methoxy-3-(3-methylphenethoxy)benzamide)-2,3-dihydro-1H-indene-2-carboxylic acid shows no change in FTIR after storage at 75% RH and 80°C for 7 days.

[0052] In some embodiments, crystalline form 1 of compound I has a crystal structure characterized by atomic coordinates substantially as shown in Table 2, and the crystal structure is measured at 293 K. In some embodiments, crystalline form 1 has a crystal structure characterized by having unit cell parameters substantially equal to a=6.521(6) Å, b=10.548(9) Å, c=17.453(15) Å, α=104.080(16)°, β=92.430(16)°, γ=101.081(17)°, and a triclinic space group = P1 (Z=2), and the crystal structure is measured at 293 K. In some embodiments, crystalline form 1 has a crystal structure characterized by unit cell parameters substantially equal to a=6.521(6)Å, b=10.548(9)Å, c=17.453(15)Å, α=104.080(16)°, β=92.430(16)°, γ=101.081(17)°, and a triclinic space group = P1(Z=2), and the crystal structure is measured at 293K and is characterized substantially by atomic coordinates as shown in Table 2.

[0053] In some embodiments, crystalline form 1 of compound I has substantially the same ssNMR spectrum as that shown in Figure 4. In some embodiments, crystalline form 1 has an ssNMR spectrum characterized by resonances (δc) at 23.35, 124.43, 126.78, 127.42, and 136.47 ppm. In some embodiments, crystalline form 1 has an ssNMR spectrum further characterized by resonances (δc) at 54.41, 65.40, 138.94, 142.61, 148.68, 152.19, and 174.59 ppm. In some embodiments, crystalline form 1 has an ssNMR spectrum characterized by resonances (δc) at 23.35, 36.40, 44.12, 45.70, 54.41, 65.40, 71.58, 110.97, 114.45, 121.00, 124.43, 126.78, 127.42, 131.27, 136.47, 138.94, 142.61, 148.68, 152.19, 172.07, and 174.59 ppm.

[0054] In some embodiments, crystalline form 1 of compound I transforms into crystalline form 2 when slurryed in a solvent at a temperature of 60°C or higher. In some embodiments, crystalline form 1 transforms into crystalline form 2 when slurryed in MEK or 1-pentanol at a temperature of 60°C or 70°C. In some embodiments, the transformation of morphology is determined by FTIR.

[0055] In some embodiments, the crystalline form 1 of compound I is anhydrous.

[0056] Crystal morphology of compound I 2 Furthermore, crystalline form 2 of 2-(4-methoxy-3-(3-methylphenethoxy)benzamide)-2,3-dihydro-1H-indene-2-carboxylic acid is also provided herein. Some embodiments provide compositions comprising crystalline form 2 of 2-(4-methoxy-3-(3-methylphenethoxy)benzamide)-2,3-dihydro-1H-indene-2-carboxylic acid. In some embodiments, crystalline form 2 of 2-(4-methoxy-3-(3-methylphenethoxy)benzamide)-2,3-dihydro-1H-indene-2-carboxylic acid is, • The X-ray powder diffraction (XRPD) pattern, measured using Cu(Kα) radiation, is substantially the same as that shown in Figure 6. X-ray powder diffraction (XRPD) patterns measured using Cu(Kα) radiation, with peaks at 5.6±0.2°²-theta, 7.6±0.2°²-theta, 9.4±0.2°²-theta, 15.5±0.2°²-theta, and 16.3±0.2°²-theta. ·Approx. 1731.7cm -1 Fourier transform IR spectroscopy (FTIR) pattern with a peak, • At 293K,

[0057] [Table 5] The unit cell parameter is substantially equal to this. • Substantially the same solid state as shown in Figure 8 13 Carbon nuclear magnetic resonance (ssNMR) spectrum, Solid states characterized by resonance (δc) at 20.59, 126.39, 128.34, and 137.69 ppm. 13 Carbon nuclear magnetic resonance (ssNMR) spectra, or combinations thereof. It is characterized by having the following features.

[0058] In some embodiments, the crystalline form 2 of compound I is characterized by having substantially the same X-ray powder diffraction (XRPD) pattern as shown in Figure 6, measured using Cu(Kα) radiation.

[0059] In some embodiments, the crystalline form 2 of compound I exhibits a substantially identical XRPD pattern to that shown in Figure 6, measured using Cu(Kα) radiation, and approximately 1731.7 cm². -1 It is characterized by having a Fourier transform IR spectroscopy (FTIR) pattern with a peak at a certain point.

[0060] In some embodiments, the crystalline form 2 of compound I has substantially the same XRPD pattern as shown in Figure 6, measured using Cu(Kα) radiation, and substantially the same solid state as shown in Figure 8. 13 It is characterized by having a carbon nuclear magnetic resonance (ssNMR) spectrum.

[0061] In some embodiments, the crystalline form 2 of compound I is characterized by having substantially the same XRPD pattern as shown in Figure 6 and substantially the same differential scanning calorimetry (DSC) thermogram as shown in Figure 7, measured using Cu(Kα) radiation.

[0062] In some embodiments, the crystalline form 2 of compound I, 2-(4-methoxy-3-(3-methylphenethoxy)benzamide)-2,3-dihydro-1H-indene-2-carboxylic acid (compound I), is characterized by having an X-ray powder diffraction (XRPD) pattern measured using Cu(Kα) radiation, with peaks at 5.6±0.2°²-theta, 7.6±0.2°²-theta, 9.4±0.2°²-theta, 15.5±0.2°²-theta, and 16.3±0.2°²-theta.

[0063] In some embodiments, the crystalline form 2 of compound I is characterized by having an XRPD pattern measured using Cu(Kα) radiation, with peaks at 5.6±0.2°²-theta, 7.6±0.2°²-theta, 9.4±0.2°²-theta, 15.5±0.2°²-theta, and 16.3±0.2°²-theta, and a differential scanning calorimetry (DSC) thermogram with an endothermic event having an initiation point of approximately 215.3°C and a peak at approximately 216.4°C.

[0064] In some embodiments, the crystalline form 2 of compound I was measured using Cu(Kα) radiation and exhibited an XRPD pattern with peaks at 5.6±0.2°²-theta, 7.6±0.2°²-theta, 9.4±0.2°²-theta, 15.5±0.2°²-theta, and 16.3±0.2°²-theta, and approximately 1731.7 cm². -1 It is characterized by having a Fourier transform IR spectroscopy (FTIR) pattern with a peak at [location].

[0065] In some embodiments, the crystalline form 2 of compound I is characterized by an XRPD pattern with peaks at 5.6±0.2°²-theta, 7.6±0.2°²-theta, 9.4±0.2°²-theta, 15.5±0.2°²-theta, and 16.3±0.2°²-theta, measured using Cu(Kα) radiation, and resonances (δc) at 20.59, 126.39, 128.34, and 137.69 ppm in the solid state. 13 It is characterized by having a carbon nuclear magnetic resonance (ssNMR) spectrum.

[0066] In some embodiments, the crystalline form 2 of 2-(4-methoxy-3-(3-methylphenethoxy)benzamide)-2,3-dihydro-1H-indene-2-carboxylic acid (compound I) is at 293K.

[0067] [Table 6] It is characterized by having unit cell parameters that are substantially equal to those of the other.

[0068] In some embodiments, the crystalline form 2 of compound I is substantially the same solid state as that shown in Figure 8. 13 It is characterized by having a carbon nuclear magnetic resonance (ssNMR) spectrum.

[0069] In some embodiments, the crystalline form 2 of compound I is substantially the same solid state as that shown in Figure 8. 13 Carbon nuclear magnetic resonance (ssNMR) spectrum and approximately 1731.7 cm⁻¹-1 It is characterized by having a Fourier transform IR spectroscopy (FTIR) pattern with a peak at [location].

[0070] In some embodiments, the crystalline form 2 of compound I is a solid state characterized by resonance (δc) at 20.59, 126.39, 128.34, and 137.69 ppm. 13 It is characterized by having a carbon nuclear magnetic resonance (ssNMR) spectrum.

[0071] In some embodiments, the crystalline form 2 of compound I is a solid state characterized by resonance (δc) at 20.59, 126.39, 128.34, and 137.69 ppm. 13 It is characterized by having a carbon nuclear magnetic resonance (ssNMR) spectrum and a differential scanning calorimetry (DSC) thermogram with an endothermic event having a starting point of approximately 215.3°C and a peak of approximately 216.4°C.

[0072] In some embodiments, the crystalline form 2 of compound I is a solid state characterized by resonance (δc) at 20.59, 126.39, 128.34, and 137.69 ppm. 13 Carbon nuclear magnetic resonance (ssNMR) spectrum and approximately 1731.7 cm⁻¹ -1 It is characterized by having a Fourier transform IR spectroscopy (FTIR) pattern with a peak at [location].

[0073] In some embodiments, the crystalline form 2 of compound I is approximately 1739.6 cm². -1 It is characterized by having a Fourier transform IR spectroscopy (FTIR) pattern with a peak at a certain point.

[0074] In some embodiments, the crystalline form 2 of compound I is 1725 cm². -1 ±2cm -1 It has a Raman spectrum with a peak at [location].

[0075] In some embodiments, the crystalline form 2 has a TGA pattern with a weight loss of less than 1% at up to 200°C.

[0076] In some embodiments, crystalline form 2 of compound I has a DSC thermogram substantially identical to that shown in Figure 7. In some embodiments, crystalline form 2 has a DSC thermogram with an endothermic event having an initiation point of about 215°C and a peak at about 216.4°C.

[0077] In some embodiments, the crystalline form 2 of compound I is approximately 1731.7 cm². -1 Use the FTIR spectrum that has a peak at [location].

[0078] In some embodiments, the crystalline form 2 of compound I shows no change in FTIR after being stored at 75% RH and 80°C for 7 days.

[0079] In some embodiments, crystalline form 2 of compound I has a crystal structure characterized substantially by atomic coordinates as shown in Table 4, and the crystal structure is measured at 293 K. In some embodiments, crystalline form 2 has a crystal structure characterized by having unit cell parameters substantially equal to a=6.2823(10) Å, b=23.285(4) Å, c=31.614(6) Å, α=90.00°, β=90.00°, γ=90.00°, and an orthorhombic space group = Pbca(Z=8), and the crystal structure is measured at 293 K. In some embodiments, crystalline form 2 has a crystal structure characterized by unit cell parameters substantially equal to a=6.2823(10)Å, b=23.285(4)Å, c=31.614(6)Å, α=90.00°, β=90.00°, γ=90.00°, and an orthorhombic space group = Pbca(Z=8), and the crystal structure is measured at 293K and is characterized substantially by atomic coordinates as shown in Table 4.

[0080] In some embodiments, crystalline form 2 of compound I has substantially the same ssNMR spectrum as that shown in Figure 8. In some embodiments, crystalline form 2 has an ssNMR spectrum characterized by resonances (δc) at 20.59, 126.39, 128.34, and 137.69 ppm. In some embodiments, crystalline form 2 has an ssNMR spectrum further characterized by resonances (δc) at 55.25, 66.34, 136.78, 141.73, 149.44, 153.68, and 175.49 ppm. In some embodiments, crystalline form 2 has an ssNMR spectrum characterized by resonances (δc) at 20.59, 37.04, 44.03, 46.84, 55.25, 66.34, 71.74, 111.25, 116.90, 122.48, 123.63, 126.39, 128.34, 131.33, 136.78, 137.69, 141.73, 149.44, 153.68, 172.82, and 175.49 ppm.

[0081] In some embodiments, crystalline form 2 of compound I is converted to crystalline form 1 when slurryed in a solvent at a temperature of 50°C or below. In some embodiments, crystalline form 2 is converted to crystalline form 1 when slurryed in MEK or methanol at 40°C or 50°C. In some embodiments, crystalline form 2 is converted to crystalline form 1 when slurryed in MEK at room temperature (approximately 25°C). In some embodiments, the morphological conversion is determined by FTIR.

[0082] Crystal form of compound I 3 Furthermore, crystalline form 3 of 2-(4-methoxy-3-(3-methylphenethoxy)benzamide)-2,3-dihydro-1H-indene-2-carboxylic acid is also provided herein. Some embodiments provide compositions comprising crystalline form 3 of 2-(4-methoxy-3-(3-methylphenethoxy)benzamide)-2,3-dihydro-1H-indene-2-carboxylic acid. In some embodiments, crystalline form 3 of 2-(4-methoxy-3-(3-methylphenethoxy)benzamide)-2,3-dihydro-1H-indene-2-carboxylic acid is, • The X-ray powder diffraction (XRPD) pattern, measured using Cu(Kα) radiation, is substantially the same as that shown in Figure 10. X-ray powder diffraction (XRPD) patterns measured using Cu(Kα) radiation, with peaks at 4.2±0.2°²-theta, 6.8±0.2°²-theta, 15.1±0.2°²-theta, 25.0±0.2°²-theta, 25.5±0.2°²-theta, and 26.4±0.2°²-theta. ·Approx. 1722.0cm -1 Fourier transform IR spectroscopy (FTIR) pattern with a peak, • Substantially the same solid state as shown in Figure 12 13 Carbon nuclear magnetic resonance (ssNMR) spectrum, Solid states characterized by resonance (δc) at 64.56, 67.67, 122.99, and 126.71 ppm. 13 Carbon nuclear magnetic resonance (ssNMR) spectrum, or • These combinations It is characterized by having the following features.

[0083] In some embodiments, the crystalline form 3 of compound I is characterized by having substantially the same X-ray powder diffraction (XRPD) pattern as shown in Figure 10, measured using Cu(Kα) radiation.

[0084] In some embodiments, the crystalline form 3 of compound I is characterized by having substantially the same XRPD pattern as shown in Figure 10 and substantially the same differential scanning calorimetry (DSC) thermogram as shown in Figure 11, measured using Cu(Kα) radiation.

[0085] In some embodiments, the crystalline form 3 of compound I exhibits a substantially identical XRPD pattern to that shown in Figure 10, measured using Cu(Kα) radiation, and approximately 1722.0 cm². -1 It is characterized by having a Fourier transform IR spectroscopy (FTIR) pattern with a peak at a certain point.

[0086] In some embodiments, the crystalline form 3 of compound I, 2-(4-methoxy-3-(3-methylphenethoxy)benzamide)-2,3-dihydro-1H-indene-2-carboxylic acid (compound I), is characterized by having an X-ray powder diffraction (XRPD) pattern measured using Cu(Kα) radiation, with peaks at 4.2±0.2°²-theta, 6.8±0.2°²-theta, 15.1±0.2°²-theta, 25.0±0.2°²-theta, 25.5±0.2°²-theta, and 26.4±0.2°²-theta.

[0087] In some embodiments, the crystalline form 3 of compound I is characterized by having an XRPD pattern measured using Cu(Kα) radiation, with peaks at 4.2±0.2°²-theta, 6.8±0.2°²-theta, 15.1±0.2°²-theta, 25.0±0.2°²-theta, 25.5±0.2°²-theta, and 26.4±0.2°²-theta, and a differential scanning calorimetry (DSC) with one or more endothermic events having an onset point of about 204.2°C and a peak at about 205.3°C and / or an onset point of about 213.6°C and a peak at about 215.8°C.

[0088] In some embodiments, the crystalline form 3 of compound I was measured using Cu(Kα) radiation and exhibited an XRPD pattern with peaks at 4.2±0.2°²-theta, 6.8±0.2°²-theta, 15.1±0.2°²-theta, 25.0±0.2°²-theta, 25.5±0.2°²-theta, and 26.4±0.2°²-theta, and approximately 1722.0 cm². -1 It is characterized by having a Fourier transform IR spectroscopy (FTIR) pattern with a peak at a certain point.

[0089] In some embodiments, the crystalline form 3 of compound I is approximately 1722.0 cm². -1 It is characterized by having a Fourier transform IR spectroscopy (FTIR) pattern with a peak at a certain point.

[0090] In some embodiments, the crystalline form 3 of compound I is substantially the same solid state as that shown in Figure 12. 13It is characterized by having a carbon nuclear magnetic resonance (ssNMR) spectrum.

[0091] In some embodiments, the crystalline form 3 of compound I is a solid state characterized by resonance (δc) at 64.56, 67.67, 122.99, and 126.71 ppm. 13 It is characterized by having a carbon nuclear magnetic resonance (ssNMR) spectrum.

[0092] In some embodiments, crystalline morphology 3 has a TGA pattern with a weight loss of less than 1% at a maximum temperature of 200°C.

[0093] In some embodiments, crystalline form 3 of compound I has substantially the same X-ray powder diffraction (XRPD) pattern as that shown in Figure 11. In some embodiments, crystalline form 3 has a DSC thermogram with one or more endothermic events having an initiation point of about 204.2°C and a peak at about 205.3°C, and / or an initiation point of about 213.6°C and a peak at about 215.8°C. In some embodiments, crystalline form 3 has a DSC thermogram with two endothermic events having an initiation point of about 204.2°C and a peak at about 205.3°C, and an initiation point of about 213.6°C and a peak at about 215.8°C.

[0094] In some embodiments, crystalline form 3 is approximately 1722.0 cm². -1 It has an FTIR spectrum with a peak. In some embodiments, the crystalline form 3 of 2-(4-methoxy-3-(3-methylphenethoxy)benzamide)-2,3-dihydro-1H-indene-2-carboxylic acid shows no change in FTIR after being stored at 75% RH and 80°C for 7 days.

[0095] In some embodiments, crystalline form 3 of compound I has substantially the same ssNMR spectrum as that shown in Figure 12. In some embodiments, crystalline form 3 has an ssNMR spectrum characterized by resonances (δc) at 64.56, 67.67, 122.99, and 126.71 ppm. In some embodiments, crystalline form 3 has an ssNMR spectrum further characterized by resonances (δc) at 110.33, 146.87, 150.90, and 176.47 ppm. In some embodiments, crystalline form 3 has an ssNMR spectrum characterized by resonances (δc) at 43.81, 46.00, 54.01, 64.56, 67.67, 109.22, 110.33, 119.58, 122.99, 126.71, 139.68, 140.34, 143.63, 144.25, 146.87, 150.90, 168.32, and 176.47 ppm. In some embodiments, crystalline form 3 has an ssNMR spectrum characterized by resonances (δc) at 21.72, 22.23, 43.81, 46.00, 54.01, 64.56, 67.67, 109.22, 110.33, 119.58, 122.99, 126.71, 130.28, 138.46, 139.68, 140.34, 143.63, 144.25, 146.87, 150.90, 168.32, and 176.47 ppm.

[0096] In some embodiments, crystalline form 3 of compound I is converted to crystalline form 1 when slurryed in a solvent at room temperature (approximately 25°C). In some embodiments, crystalline form 3 is converted to crystalline form 1 when slurryed in methanol, MEK, methyl-THF, or ethyl acetate at room temperature (approximately 25°C). In some embodiments, the conversion of forms is determined by FTIR.

[0097] Crystal morphology of compound I (4) Furthermore, crystalline form 4 of 2-(4-methoxy-3-(3-methylphenethoxy)benzamide)-2,3-dihydro-1H-indene-2-carboxylic acid is also provided herein. Several embodiments provide compositions comprising crystalline form 4 of 2-(4-methoxy-3-(3-methylphenethoxy)benzamide)-2,3-dihydro-1H-indene-2-carboxylic acid. In some embodiments, crystalline form 4 of 2-(4-methoxy-3-(3-methylphenethoxy)benzamide)-2,3-dihydro-1H-indene-2-carboxylic acid has substantially the same X-ray powder diffraction (XRPD) pattern as shown in Figure 13, substantially the same differential scanning calorimetry (DSC) thermogram as shown in Figure 14, approximately 1743.9 cm⁻¹ -1 It is characterized by having a Fourier transform IR spectroscopy (FTIR) pattern with a peak, or a combination thereof.

[0098] In some embodiments, the crystalline form 4 of 2-(4-methoxy-3-(3-methylphenethoxy)benzamide)-2,3-dihydro-1H-indene-2-carboxylic acid has substantially the same XRPD pattern as that shown in Figure 13.

[0099] In some embodiments, the crystalline form 4 of 2-(4-methoxy-3-(3-methylphenethoxy)benzamide)-2,3-dihydro-1H-indene-2-carboxylic acid has substantially the same differential scanning calorimetry (DSC) thermogram as shown in Figure 14.

[0100] In some embodiments, crystalline form 4 is approximately 1743.9 cm². -1 Use the FTIR spectrum that has a peak at [location].

[0101] In some embodiments, the crystalline form 4 has a TGA pattern with a weight loss of less than 1% at a maximum temperature of 200°C.

[0102] Amorphous phase of compound I Furthermore, an amorphous phase of 2-(4-methoxy-3-(3-methylphenethoxy)benzamide)-2,3-dihydro-1H-indene-2-carboxylic acid (Compound I) is also provided herein. Several embodiments provide compositions comprising an amorphous phase of 2-(4-methoxy-3-(3-methylphenethoxy)benzamide)-2,3-dihydro-1H-indene-2-carboxylic acid. In some embodiments, the amorphous phase of 2-(4-methoxy-3-(3-methylphenethoxy)benzamide)-2,3-dihydro-1H-indene-2-carboxylic acid (Compound I) is characterized by having an XRPD pattern indicating a lack of crystallinity. In some embodiments, the amorphous phase of 2-(4-methoxy-3-(3-methylphenethoxy)benzamide)-2,3-dihydro-1H-indene-2-carboxylic acid (Compound I) is substantially the same solid state as shown in Figure 16. 13 It is characterized by having a carbon nuclear magnetic resonance (ssNMR) spectrum.

[0103] synthesis The compounds described herein are synthesized using standard synthetic techniques or in combination with the methods described herein, using methods known in the art. Unless otherwise specified, conventional methods such as mass spectrometry, NMR, and HPLC are employed.

[0104] For example, the compounds are prepared using standard organic chemistry techniques, such as those described in March's Advanced Organic Chemistry, 6th Edition, John Wiley and Sons, Inc. Alternative reaction conditions for the synthetic transformations described herein, including variations in solvent, reaction temperature, reaction time, and various chemical reagents and other reaction conditions, may also be utilized.

[0105] In the reactions described, it may be necessary to protect reactive functional groups, such as hydroxyl or amino groups, and these are desired in the final product to avoid unnecessary involvement in the reaction. Detailed descriptions of techniques applicable to the generation and removal of protecting groups are provided in Greene and Wuts, Protective Groups in Organic Synthesis, 3rd Ed., John Wiley & Sons, New York, NY, 1999, and Kocienski, Protective Groups, Thieme Verlag, New York, NY, 1994 (incorporated herein by reference).

[0106] Synthesis of compound I As outlined in Schemes 1-3, a method for synthesizing compound I is disclosed herein.

[0107] [ka]

[0108] In short, in some embodiments, the primary alcohol of the compound of formula 1 is converted to a leaving group, yielding the compound of formula 2. In some embodiments, the compound of formula 2 is reacted with the phenol compound of formula 3 and then saponified to yield compound 4.

[0109] [ka]

[0110] In short, in some embodiments, acidic compound 4 undergoes an amide bond formation reaction with the compound of formula 5, yielding the compound of formula 6.

[0111] [ka]

[0112] Briefly, the compound of formula 6 undergoes a saponification reaction with NaOH, KOH, or LiOH, resulting in the salt of formula 7. The salt of formula 7 is acidified with a suitable organic acid to provide compound I.

[0113] As disclosed herein, for the variables in Scheme 3, LG is a suitable leaving group, and R 1 is C1-C 20 alkyl, C1-C 20 alkenyl, C3-C 10 cycloalkyl, or C3-C 10 cycloalkenyl, and R 2 is C1-C 20 alkyl, C1-C 20 alkenyl, C3-C 10 cycloalkyl, or C3-C 10 cycloalkenyl, and also M + is defined as Na + , K + , or Li + .

[0114] i n some embodiments, LG is halogen, sulfonate, or sulfate. In some embodiments, LG is Cl, Br, I, mesylate, tosylate, or triflate. In some embodiments, LG is Cl, Br, I, -OTf, -OT, or -OM. In some embodiments, LG is halogen. In some embodiments, LG is Cl, Br, or I. In some embodiments, LG is Br or I. In some embodiments, LG is sulfonate. In some embodiments, LG is mesylate, tosylate, or triflate. In some embodiments, LG is -OTf, -OT, or -OM. In some embodiments, LG is -OM.

[0115] In some embodiments, R 1 is C1-C 10 alkyl, C1-C 10 alkenyl, C3-C 10 cycloalkyl, or C3-C 10It is a cycloalkenyl. In some embodiments, R 1 is C1-C 20 alkyl or C1-C 20 alkenyl. In some embodiments, R 1 is C1-C 10 alkyl or C1-C 10 alkenyl. In some embodiments, R 1 is C1-C6 alkyl or C1-C6 alkenyl. In some embodiments, R 1 is C1-C6 alkyl. In some embodiments, R 1 is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, isoamyl, pentyl, hexyl, heptyl, octyl, nonyl, terpenyl, bornyl, allyl, linalyl, or geranyl. In some embodiments, R 1 is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, isoamyl, pentyl, or hexyl. In some embodiments, R[[ID=2J]] 1 is methyl or ethyl. In some embodiments, R 1 is methyl.

[0116] In some embodiments, R 2 is C1-C 10 alkyl, C1-C 10 alkenyl, C3-C 10 cycloalkyl, or C3-C 10 cycloalkenyl. In some embodiments, R 2 is C1-C 20 alkyl or C1-C 20 alkenyl. In some embodiments, R 2 is C1-C 10 alkyl or C1-C 10 alkenyl. In some embodiments, R 2 is C1-C6 alkyl or C1-C6 alkenyl. In some embodiments, R 2 is C1-C6 alkyl. In some embodiments, R 2R is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, isoamyl, pentyl, hexyl, heptyl, octyl, nonyl, terpenyl, bornyl, allyl, linalyl, or geranyl. In some embodiments, R 2 R is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, isoamyl, pentyl, or hexyl. In some embodiments, R 2 is methyl or ethyl. In some embodiments, R 2 It is methyl.

[0117] In some embodiments, the compound of formula 7 is not isolated between reaction steps 4 and 5. In some embodiments, steps 4 and 5 are carried out in the same reaction vessel. In some embodiments, compound I is crystallized from the reaction mixture to provide crystalline form 1 of compound I.

[0118] Step 1: Synthesis of the compound in formula 2 In some embodiments, the alcohol-OH group of the compound of formula 1 is converted to a leaving group by treatment with a suitable reagent in a suitable solvent, yielding the compound of formula 2.

[0119] In some embodiments, suitable reagents are halogenating agents, sulfonating agents, or sulfonyl chlorides.

[0120] In some embodiments, the suitable reagent is a halogenating agent. In such embodiments, LG is a halogen. In some embodiments, LG is Cl, Br, or I. In some embodiments, LG is Br or I. In some embodiments, LG is Cl or Br. In some embodiments, LG is Br. In some embodiments, the suitable reagent is SOCl2, PBr3, or PCl3, etc. In some embodiments, the suitable reagent is PBr3.

[0121] In some embodiments, the suitable reagent is a sulfonating agent. In such embodiments, LG is a sulfate.

[0122] In some embodiments, a suitable reagent is sulfonyl chloride. In such embodiments, LG is a sulfonate. In some embodiments, a suitable reagent is tosyl chloride, mesyl chloride, or trifuryl chloride, etc. In such embodiments, LG is tosylate, mesylate, or triflate, respectively. In some embodiments, a suitable reagent is mesyl chloride. In such embodiments, LG is mesylate.

[0123] In some embodiments, suitable solvents are acetonitrile, dimethylformamide, diethyl ether, ethanol, tetrahydrofuran, isopropyl alcohol, 1,4-dioxane, toluene, water, or a combination thereof. In some embodiments, the suitable solvent is toluene.

[0124] In some embodiments, the reaction takes place at a low temperature. In some embodiments, the reaction takes place at a temperature lower than the ambient temperature. In some embodiments, the reaction takes place at a temperature of about 0°C to about 20°C. In some embodiments, the reaction takes place at about 5°C.

[0125] In some embodiments, step 1 further comprises a suitable base. In some embodiments, suitable bases include pyridine, N-methylmorpholine, triethylamine, diisopropylethylamine, sec-butylamine, 1,2,2,6,6-pentamethylpiperidine, tributylamine, and 1,8-diazabicyclo[5.4.0]undeca-7-ene (DBU). In some embodiments, the suitable base is triethylamine.

[0126] In some embodiments, the compound of formula 2 is compound 2a:

[0127] [ka] That is the case.

[0128] Step 2: Synthesis of the compound of formula 4 In some embodiments, the compound of formula 2 is reacted with a suitable base and the compound of formula 3 in a suitable solvent (step 2a), followed by saponification (step 2b) to provide the compound of formula 4.

[0129] In some embodiments, the suitable base for step 2a is an amine base. In some embodiments, the suitable base is a tertiary amine base. In some embodiments, suitable bases include triethylamine, diisopropylethylamine, 1,2,2,6,6-pentamethylpiperidine, tributylamine, 1,8-diazabicycloundec-7-ene (DBU), etc. In other embodiments, the suitable base is an inorganic base. In some embodiments, suitable bases include NaHCO3, NaOAc, KOAc, Ba(OH)2, Li2CO3, Na2CO3, K2CO3, Cs2CO3, Na3PO4, K3PO4, CsF, etc. In some embodiments, the suitable base is K2CO3.

[0130] In some embodiments, suitable solvents are acetonitrile, dimethylformamide, diethyl ether, ethanol, tetrahydrofuran, isopropyl alcohol, 1,4-dioxane, toluene, water, or a combination thereof. In some embodiments, a suitable solvent is ethanol.

[0131] In some embodiments, the reaction in step 2a is carried out at a high temperature. In some embodiments, the reaction is carried out at the reflux temperature of the reaction mixture. In some embodiments, the reaction is carried out at the boiling point of the solvent used. In some embodiments, the solvent is ethanol and the reaction is carried out at about 78-80°C. In some embodiments, the reaction is carried out below the boiling point of the solvent used. In some embodiments, the reaction is carried out at a temperature of about 60°C to about 80°C. In some embodiments, the reaction is carried out at about 65°C.

[0132] In some embodiments, step 2a further comprises a phase transfer catalyst. In some embodiments, the phase transfer catalyst is tetrabutylammonium bromide, benzyltriethylammonium chloride, methyltricaprylammonium chloride, methyltributylammonium chloride, or methyltrioctylammonium chloride. In some embodiments, step 2a further comprises tetrabutylammonium bromide.

[0133] In some embodiments, the saponification in step 2b proceeds using a hydroxide reagent. In some embodiments, the hydroxide reagent is added directly to the reaction mixture in step 2a.

[0134] In some embodiments, the hydroxide reagent is NaOH, KOH, or LiOH. In some embodiments, the hydroxide reagent is NaOH or KOH. In some embodiments, the hydroxide reagent is KOH. In some embodiments, the hydroxide reagent in step 2b is provided as an aqueous solution. In some embodiments, the hydroxide reagent is about 0.1 M, about 0.5 M, about 1.0 M, about 2.0 M, about 5.0 M, about 10 M, or concentrated aqueous potassium hydroxide. In some embodiments, the hydroxide reagent is about 45% aqueous potassium hydroxide.

[0135] In some embodiments, the saponification in step 2b is carried out at a high temperature. In some embodiments, the saponification is carried out at a temperature of about 60°C to about 80°C. In some embodiments, the saponification is carried out at about 65°C.

[0136] In some embodiments, the reaction mixture is acidified to provide compound 4.

[0137] In some embodiments, the compound of formula 3 is compound 3a:

[0138] [ka] That is the case.

[0139] Step 3: Synthesis of the compound of formula 6 In some embodiments, acidic compound 4 is reacted with the amine of the compound of formula 5 to yield the amide compound of formula 6 under amide bond formation conditions.

[0140] In some embodiments, amide formation proceeds in a suitable reagent, a suitable base, and a suitable solvent. In some embodiments, suitable reagents include BOP, PyBOP, HATU, HBTU, and pivaloyl chloride. In some embodiments, suitable bases include N-methylmorpholine, triethylamine, diisopropylethylamine, sec-butylamine, 1,2,2,6,6-pentamethylpiperidine, tributylamine, and 1,8-diazabicyclo[5.4.0]undeca-7-ene (DBU). In some embodiments, suitable solvents include acetonitrile, dimethylformamide, diethyl ether, ethanol, tetrahydrofuran, isopropyl alcohol, 1,4-dioxane, toluene, or a combination thereof.

[0141] In other embodiments, the acid of compound 4 is converted to an acid chloride using a suitable reagent in a suitable solvent before reacting with the compound of formula 5. In some embodiments, suitable reagents include PCl5, PCl3, SOCl2, oxalyl chloride (C2O2Cl2), phosgene (COCl2), triphosgene (C3O3Cl6), etc. In some embodiments, the suitable reagent is SOCl2. In some embodiments, the reaction further includes the use of N-methylpyrrolidone (NMP), dimethylformamide (DMF), dimethylammonium (chloromethylene) chloride (Vilsmeier reagent), or an analogue of the Vilsmeier reagent. In some embodiments, the reaction further includes the use of N-methylpyrrolidone (NMP). In some such embodiments, NMP is used in catalytic amounts, e.g., less than 0.2, less than 0.1, or less than 0.05 equivalents. In some embodiments, the reaction contains about 0.05 equivalents of NMP. In some embodiments, the amide bond formation reaction proceeds in an acid chloride, a suitable base, and a suitable solvent. In some embodiments, suitable bases include N-methylmorpholine, triethylamine, diisopropylethylamine, sec-butylamine, 1,2,2,6,6-pentamethylpiperidine, tributylamine, and 1,8-diazabicyclo[5.4.0]undeca-7-ene (DBU). In some embodiments, the suitable base is triethylamine. In some embodiments, the suitable solvent is acetonitrile, dimethylformamide, diethyl ether, ethanol, tetrahydrofuran, isopropyl alcohol, 1,4-dioxane, toluene, or a combination thereof. In some embodiments, the suitable solvent is toluene.

[0142] In some embodiments, the reaction in step 3 is carried out at a high temperature. In some embodiments, the reaction in step 3 is carried out at a temperature of about 50°C to about 60°C. In some embodiments, the reaction in step 3 is carried out at ambient temperature.

[0143] In some embodiments, the compound of formula 5 is methyl 2-amino-2,3-dihydro-1H-indene-2-carboxylate (compound 5a):

[0144] [ka] It is the hydrochloride salt of [the substance].

[0145] In some embodiments, the compound of formula 6 is compound 6a:

[0146] [ka] That is the case.

[0147] Step 4: Synthesis of the compound in formula 7 (saponification) In some embodiments, the compound of formula 6 undergoes a saponification reaction to yield the compound of formula 7. In some embodiments, saponification proceeds by contacting the compound of formula 6 with a hydroxide reagent having formula M-OH in a suitable solvent to yield the compound of formula 7.

[0148] In some embodiments, the hydroxide reagent is NaOH, KOH, or LiOH. In some embodiments, the hydroxide reagent is NaOH or KOH. In some embodiments, the hydroxide reagent is NaOH, and M + is Na + In some embodiments, the hydroxide reagent is provided as an aqueous solution. In some embodiments, the hydroxide reagent is an aqueous solution of sodium hydroxide of about 0.1 M, about 0.5 M, about 1.0 M, about 2.0 M, about 5.0 M, about 10 M, or a concentrated aqueous solution. In some embodiments, the hydroxide reagent is an aqueous solution of sodium hydroxide of about 1.0 M.

[0149] In some embodiments, suitable solvents for the saponification reaction are tetrahydrofuran, methanol, ethanol, ethylene glycol, acetonitrile, water, or a combination thereof. In some embodiments, a suitable solvent is a mixture of methanol and water.

[0150] In some embodiments, the saponification process is carried out at a high temperature. In some embodiments, the saponification process is carried out at a temperature of approximately 50°C to approximately 70°C. In some embodiments, the saponification process is carried out at a temperature of approximately 60°C.

[0151] In some embodiments, the saponification process is carried out for at least 1 hour, at least 2 hours, at least 3 hours, or longer. In some embodiments, the saponification process is carried out for about 1 hour, about 2 hours, or about 3 hours. In some embodiments, the saponification process is carried out for about 3 hours.

[0152] In some embodiments, the compound of formula 7 is compound 7a:

[0153] [ka] That is the case.

[0154] In some embodiments, the compound of formula 7 is not isolated before step 5. In some such embodiments, steps 4 and 5 are carried out in the same reaction vessel. In some such embodiments, the reaction mixture of step 4 is cooled to room temperature before proceeding to step 5. In some such embodiments, the reaction mixture of step 4 is cooled to room temperature before the addition of the organic acid. In some such embodiments, the reaction mixture of step 4 is cooled to 20°C before the addition of the organic acid.

[0155] Step 5: Synthesis of the compound (acidification) In some embodiments, the salt of formula 7 undergoes an acidification reaction to provide a free acid compound I. In some embodiments, the acidification proceeds by contacting the compound of formula 7 with a suitable acid in a suitable solvent to provide compound I. In some embodiments, the acidification proceeds by contacting the compound of formula 7 with a suitable organic acid in a suitable solvent to provide compound I.

[0156] In some embodiments, suitable solvents for the acidification reaction are tetrahydrofuran, methanol, ethanol, ethylene glycol, acetonitrile, water, or a combination thereof. In some embodiments, a suitable solvent is a mixture of methanol and water. In some embodiments, the compound of formula 7 is not isolated from the saponification reaction, and the acidification reaction proceeds in the same vessel and the same solvent as the saponification reaction.

[0157] In some embodiments, acidification is carried out using a suitable organic acid. In some embodiments, suitable organic acids include 1-hydroxy-2-naphthoic acid, 2,2-dichloroacetic acid, 2-hydroxyethanesulfonic acid, 2-oxoglutaric acid, 4-acetamidobenzoic acid, 4-aminosalicylic acid, acetic acid, adipic acid, ascorbic acid (L), aspartic acid (L), benzenesulfonic acid, benzoic acid, camphoric acid (+), campho-10-sulfonic acid (+), capric acid (decanoic acid), caproic acid (hexanoic acid), caprylic acid (octanoic acid), carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecyl sulfate, ethane-1,2-disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galactaric acid, and gentisic acid. These include glucoheptonic acid (D), gluconic acid (D), glucuronic acid (D), glutamic acid, glutaric acid, glycerophosphate, glycolic acid, hippuric acid, isobutyric acid, lactic acid (DL), lactobionic acid, lauric acid, maleic acid, malic acid (-L), malonic acid, mandelic acid (DL), methanesulfonic acid, naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid, nicotinic acid, oleic acid, oxalic acid, palmitic acid, pamoic acid, phosphoric acid, propionic acid, pyroglutamic acid (-L), salicylic acid, sebacic acid, stearic acid, succinic acid, tartaric acid (+L), thiocyanic acid, toluenesulfonic acid (p), or undecylenic acid. In some embodiments, suitable organic acids include lactic acid, acetic acid, formic acid, citric acid, oxalic acid, malic acid, and tartaric acid. In some embodiments, the suitable organic acid is citric acid. In some embodiments, the suitable organic acid is provided as an aqueous solution. In some embodiments, the suitable organic acid is aqueous citric acid in concentrations of about 0.1 M, about 0.5 M, about 1.0 M, about 1.5 M, or about 2.0 M. In some embodiments, the suitable organic acid is aqueous citric acid in a concentration of about 1.0 M.

[0158] In some embodiments, the pH of the solution after the addition of a suitable organic acid is about 6 to about 9. In some embodiments, the pH of the solution after the addition of a suitable organic acid is about 7 to about 8. In some embodiments, the pH of the solution after the addition of a suitable organic acid is about 7.0, about 7.1, about 7.2, about 7.3, about 7.4, about 7.5, about 7.6, about 7.7, about 7.8, about 7.9, or about 8. In some embodiments, the pH of the solution after the addition of a suitable organic acid is about 7.5.

[0159] crystallization In some embodiments, compound I is isolated and recrystallized.

[0160] In some embodiments, compound I is crystallized directly from the reaction mixture.

[0161] In some embodiments, the reaction mixture is cooled to promote crystallization. In some embodiments, the reaction mixture is cooled to about 0°C to about 10°C. In some embodiments, the reaction mixture is cooled to about 10°C. In some embodiments, the reaction mixture is cooled rapidly. In other embodiments, the reaction mixture is cooled over time. In some embodiments, the reaction mixture is cooled for about 1 hour, 2 hours, 3 hours, 4 hours, or longer. In some embodiments, the cooled mixture is kept at a low temperature for about 1 hour, 2 hours, 3 hours, 4 hours, or longer.

[0162] In some embodiments, the reaction mixture is cooled from 20°C to 10°C for about 3 hours. In some such embodiments, the reaction mixture is maintained at approximately 1°C for about 1 hour.

[0163] In some embodiments, the reaction mixture is seeded with pure crystalline form 1 before cooling to promote crystallization. In some such embodiments, the reaction mixture is seeded with about 1% w / w, about 2% w / w, about 3% w / w, about 4% w / w, or about 5% w / w pure crystalline form 1. In some such embodiments, the reaction mixture is seeded with about 2% w / w pure crystalline form 1.

[0164] In some embodiments, compound I is isolated as crystalline form 1. In some embodiments, the isolated compound I is isolated as crystalline form 1 and shows no evidence of other forms.

[0165] In some embodiments, compound I is synthesized as outlined in Scheme 4.

[0166] [ka]

[0167] In short, in some embodiments, the compound of formula 1 is treated with MsCl and a suitable base (e.g., Et3N) to yield compound 2a. In some embodiments, compound 2a is reacted with compound 3a, followed by saponification to yield compound 4. In some embodiments, the acidic compound 4 undergoes an amide bond formation reaction with compound 5a to yield compound 6a. In some embodiments, compound 6a undergoes a saponification reaction with a suitable hydroxide reagent (e.g., NaOH, KOH, or LiOH), and the resulting salt is acidified with a suitable organic acid to provide compound I. In some embodiments, compound I is crystallized as described herein.

[0168] In some embodiments, the compounds and solid-state forms described herein are synthesized as outlined in the examples.

[0169] A pharmaceutical composition of the compound 2-(4-methoxy-3-(3-methylphenethoxy)benzamide)-2,3-dihydro-1H-inden-2-carboxylic acid (Compound I) substantially free of impurities is described herein. In some embodiments, the pharmaceutical composition is substantially free of impurities of Compound I. In some embodiments, the pharmaceutical composition contains less than about 1% w / w of impurities of Compound I. In some embodiments, the pharmaceutical composition contains less than about 1% w / w, less than about 0.75% w / w, less than about 0.50% w / w, less than about 0.25% w / w, less than about 0.20% w / w, less than about 0.15% w / w, less than about 0.10% w / w, or less than about 0.05% w / w of impurities of Compound I. In some embodiments, the amount of impurities of Compound I is undetectable. In some embodiments, the amount of impurities of Compound I is undetectable by NMR, HPLC, etc.

[0170] In some embodiments, the impurities of Compound I include one or more degradation products of Compound I. In some embodiments, the impurities of Compound I include one or more intermediates used in the synthesis of Compound I. In some embodiments, the impurities of Compound I are

[0171] [Chemical formula] selected from or a combination thereof.

[0172] As used herein, "pharmaceutically acceptable" refers to materials such as carriers or diluents which do not inhibit the biological activity or properties of the compound, are relatively non-toxic, i.e., the material is administered to an individual without causing undesirable biological effects or interacting in a harmful manner with any of the components of the composition in which it is contained.

[0173] The term "pharmaceutically acceptable salt" refers to a therapeutically active drug in the cationic form combined with a suitable anion, or, in alternative embodiments, a therapeutically active drug consisting of the anionic form combined with a suitable cation. (Handbook of Pharmaceutical Salts: Properties, Selection and Use. International Union of Pure and Applied Chemistry, Wiley-VCH 2002. SMBerge, LDBighley, D.C. Monkhouse, J. Pharm. Sci. 1977, 66, 1-19. PHStahl and C.G. Wermuth, editors, Handbook of Pharmaceutical Salts: Properties, Selection and Use, Weinheim / Zurich: Wiley-VCH / VHCA, 2002.) Pharmaceutical salts are typically more soluble than nonionic species, rapidly soluble in gastric and intestinal fluids, and therefore useful in solid dosage forms. Furthermore, since its solubility is often influenced by pH, selective dissolution in one or another part of the digestive tract is possible, and this ability can be manipulated as a form of delayed-release and sustained-release behavior. In addition, since salt-forming molecules can be in equilibrium with a neutral form, their passage through biological membranes can be regulated.

[0174] In some embodiments, a pharmaceutically acceptable salt of compound I is obtained by reacting compound I with a base. In some embodiments, the base is an inorganic base. In such situations, the acidic proton of compound I is replaced with a metal ion, such as lithium, sodium, potassium, magnesium, or calcium. Acceptable inorganic bases used to form a salt with compound I include, but are not limited to, calcium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydroxide, lithium hydroxide, and the like. In some embodiments, the compounds provided herein are prepared as sodium salts, calcium salts, potassium salts, or magnesium salts. In some embodiments, a sodium salt of compound I is described herein.

[0175] References to pharmaceutically acceptable salts should be understood to include solvated forms. In some embodiments, solvates include either stoichiometric or nonstoichiometric solvents and are formed during crystallization processes using pharmaceutically acceptable solvents such as water and ethanol. Hydrates are formed when the solvent is water, or alkoxides are formed when the solvent is alcohol. Solvates of the compounds described herein are conveniently prepared or formed during the processes described herein. In addition, the compounds provided herein may optionally exist in both solvated and non-solvated forms.

[0176] Therapeutic agents that can be administered to mammals, such as humans, must be prepared in accordance with regulatory guidelines. These government-regulated guidelines are called Good Manufacturing Practice (GMP) regulations for the manufacture and quality control of pharmaceuticals and quasi-drugs. GMP guidelines outline acceptable levels of contamination of active therapeutic agents, such as the amount of residual solvent in the final product. Preferred solvents are suitable for use in GMP facilities and do not contradict industrial safety concerns. Solvent categories are defined, for example, in the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH), Impurities: Guidelines for Residual Solvents, Q3C(R3) (November 2005).

[0177] Solvents are classified into three classes. Class 1 solvents are toxic and should be avoided. Class 2 solvents are those whose use is restricted during the manufacture of therapeutic agents. Class 3 solvents are potentially low-toxicity and pose a low risk to human health. Data for Class 3 solvents indicate low toxicity in acute or short-term studies and negative results in genotoxicity tests.

[0178] Class 1 solvents to be avoided include benzene, carbon tetrachloride, 1,2-dichloroethane, 1,1-dichloroethene, and 1,1,1-trichloroethane.

[0179] Examples of Class 2 solvents include acetonitrile, chlorobenzene, chloroform, cyclohexane, 1,2-dichloroethene, dichloromethane, 1,2-dimethoxyethane, N,N-dimethylacetamide, N,N-dimethylformamide, 1,4-dioxane, 2-ethoxyethanol, ethylene glycol, formamide, hexane, methanol, 2-methoxyethanol, methyl butyl ketone, methylcyclohexane, N-methylpyrrolidine, nitromethane, pyridine, sulfolane, tetralin, toluene, 1,1,2-trichloroethene, and xylene.

[0180] Low-toxicity Class 3 solvents include acetic acid, acetone, anisole, 1-butanol, 2-butanol, butyl acetate, tert-butyl methyl ether (MTBE), cumene, dimethyl sulfoxide, ethanol, ethyl acetate, ethyl ether, ethyl formate, formic acid, heptane, isobutyl acetate, isopropyl acetate, methyl acetate, 3-methyl-1-butanol, methyl ethyl ketone, methyl isobutyl ketone, 2-methyl-1-propanol, pentane, 1-pentanol, 1-propanol, 2-propanol, propyl acetate, and tetrahydrofuran.

[0181] Residual solvents in active pharmaceutical ingredients (APIs) originate from the API's manufacturing process. In some cases, the solvent may not be completely removed by the actual manufacturing technique. The appropriate selection of solvents for API synthesis can enhance yield and determine properties such as crystal form, purity, and solubility. Therefore, the solvent is a parameter of significant importance in the synthesis process.

[0182] In some embodiments, the composition containing compound I contains an organic solvent(s). In some embodiments, the composition containing compound I contains a residual amount of an organic solvent(s). In some embodiments, the composition containing compound I contains a residual amount of a Class 3 solvent. In some embodiments, the Class 3 solvent is selected from the group consisting of acetic acid, acetone, anisole, 1-butanol, 2-butanol, butyl acetate, tert-butyl methyl ether, cumene, dimethyl sulfoxide, ethanol, ethyl acetate, ethyl ether, ethyl formate, formic acid, heptane, isobutyl acetate, isopropyl acetate, methyl acetate, 3-methyl-1-butanol, methyl ethyl ketone, methyl isobutyl ketone, 2-methyl-1-propanol, pentane, 1-pentanol, 1-propanol, 2-propanol, propyl acetate, and tetrahydrofuran. In some embodiments, the Class 3 solvent is selected from ethyl acetate, isopropyl acetate, tert-butyl methyl ether, heptane, isopropanol, and ethanol.

[0183] In some embodiments, the composition containing compound I contains a detectable amount of an organic solvent. In some embodiments, the organic solvent is a Class 3 solvent.

[0184] In other embodiments, the composition comprises compound I, and the composition comprises a detectable amount of solvent less than about 1%, the solvent being selected from acetone, 1,2-dimethoxyethane, acetonitrile, ethyl acetate, tetrahydrofuran, methanol, ethanol, heptane, or 2-propanol. In further embodiments, the composition comprises compound I, and the composition comprises a detectable amount of solvent less than about 5000 ppm. Furthermore, in even further embodiments, the composition comprises compound I, and the detectable amount of solvent is less than about 5000 ppm, less than about 4000 ppm, less than about 3000 ppm, less than about 2000 ppm, less than about 1000 ppm, less than about 500 ppm, or less than about 100 ppm.

[0185] The methods and formulations described herein include the use of N-oxides (where appropriate) or pharmaceutically acceptable salts of compounds having the structures disclosed herein, as well as the use of active metabolites of these compounds having the same type of activity.

[0186] In some embodiments, the organic radical (e.g., alkyl group, aromatic ring) of the compounds disclosed herein is sensitive to various metabolic reactions. By incorporating appropriate substituents into the organic radical, this metabolic pathway is reduced, minimized, or eliminated. In certain embodiments, suitable substituents for reducing or eliminating the sensitivity of the aromatic ring to metabolic reactions include, for example, halogens, deuterium, alkyl groups, haloalkyl groups, or deuterated alkyl groups.

[0187] In another embodiment, the compounds described herein may be isotoped (e.g., with radioisotopes) or labeled by other means including, but not limited to, the use of a chromophore or fluorescent portion, a bioluminescent label, or a chemiluminescent label.

[0188] Apart from the fact that one or more atoms are replaced with atoms having atomic masses or mass numbers different from those commonly found in nature, the compounds described herein include isotope-labeled compounds that are identical to those enumerated in the various formulas and structures presented herein. Examples of isotopes that can be incorporated into these compounds include, for example, 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 17 O, 35 S, 18 F, 36 Cl, 123 I, 124 I, 125 I, 131 I, 32 P, and 33Examples of isotopes include hydrogen, carbon, nitrogen, oxygen, sulfur, fluorine, chlorine, iodine, and phosphorus, such as P. In one embodiment, isotope-labeled compounds as described herein, for example, 3 H and 14 Compounds incorporating radioactive isotopes such as 13C are useful in drug and / or substrate tissue distribution assays. In one embodiment, substitution with isotopes such as deuterium yields specific therapeutic benefits resulting from greater metabolic stability, such as increased in vivo half-life or alteration of metabolic pathways to reduce undesirable metabolites, or reduced dosage requirements.

[0189] In some embodiments, one or more hydrogen atoms on compound I are substituted with deuterium. In some embodiments, deuterium substitution results in certain therapeutic benefits due to greater metabolic stability, such as an increased in vivo half-life or reduced dosage requirements.

[0190] In one aspect, the structure:

[0191] [ka] Compounds having the formula are described, where R is independently selected from hydrogen, deuterium, or pharmaceutically acceptable salts thereof.

[0192] In some embodiments, the compounds disclosed herein have one or more stereocenters, each of which independently exists in either the R or S configuration. For example, in some embodiments, if one stereocenter is present, the compounds disclosed herein exist in the R configuration. In other embodiments, if one stereocenter is present, the compounds disclosed herein exist in the S configuration. In some embodiments, if two stereocenters are present, the compounds disclosed herein exist in the RR configuration. In some embodiments, if two stereocenters are present, the compounds disclosed herein exist in the RS configuration. In some embodiments, if two stereocenters are present, the compounds disclosed herein exist in the SS configuration. In some embodiments, if two stereocenters are present, the compounds disclosed herein exist in the SR configuration.

[0193] The compounds presented herein include, in addition to all diastereomers, individual enantiomers, atropisomers, and epimeric forms thereof, their appropriate mixtures. The compounds and methods provided herein include all cis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers, and their appropriate mixtures.

[0194] Individual stereoisomers can be obtained as needed by methods such as stereoselective synthesis and / or separation of stereoisomers by chiral chromatography columns, or separation of diastereomers by non-chiral or chiral chromatography columns, or crystallization and recrystallization in a suitable solvent or mixture of solvents. In certain embodiments, the compounds disclosed herein are prepared as their individual stereoisomers by reacting a racemic mixture of the compounds with an optically active resolving agent to form a pair of diastereomer isomer compounds / salts, separating the diastereomers and recovering the optically pure enantiomers. In some embodiments, the decomposition of individual enantiomers of the compounds disclosed herein is carried out using covalent diastereomer derivatives of the compounds described herein. In other embodiments, the diastereomers of the compounds disclosed herein are separated by separation / decomposition techniques based on differences in solubility. In other embodiments, the separation of stereoisomers disclosed herein is carried out by chromatography, or by separation by formation of diastereomer salts and recrystallization, or by chromatography, or any combination thereof. Jean Jacques, Andre Collet, Samuel H. Wilen, “Enantiomers, Racemates and Resolutions”, John Wiley and Sons, Inc., 1981. In some embodiments, stereoisomers are obtained by stereoselective synthesis.

[0195] The separation of individual enantiomers of a racemic mixture can be performed using chiral supercritical fluid chromatography (SFC) or chiral high-performance liquid chromatography (HPLC). In some embodiments, the enantiomers described herein are separated from each other using chiral SFC or chiral HPLC. In some embodiments, compounds disclosed herein that contain one or more chiral centers (e.g., compounds disclosed herein that contain partially trans-octahydro-1H-pyrido[3,4-b]morpholine-6-yl) are separated into individual enantiomers using chiral SFC or chiral HPLC. Various conditions and suitable columns are available.

[0196] The Daicel polysaccharide chiral stationary phase (CSP) is present in the column used for chiral SFC separation. In some embodiments, Daicel analysis-immobilized and coated CHIRALPAK and CHIRALCEL HPLC columns may be used for SFC analysis.

[0197] In some embodiments, screening for the suitability of using an SFC column is performed with four main stationary phases (CHIRALPAK IA, IB, IC, and ID) and four main coated columns (CHIRALPAK AD and AS and CHIRALCEL OD and OJ) with various concentrations of organic modifiers. A variety of column phases are available, but are not limited to, OD and OJ, OX and OZ chlorinated phases, and a series of complementary cellulose-based CHIRALCEL phases including OA, OB, OC, OF, OG, and OK.

[0198] Non-limiting examples of chiral selectors intended for use in the separation of enantiomers include amylostris(3,5-dimethylphenylcarbamate), cellulose tris(3,5-dimethylphenylcarbamate), cellulose tris(3,5-dichlorophenylcarbamate), amylostris(3-chlorophenylcarbamate), amylostris(3,5-dichlorophenylcarbamate), amylostris(3-chloro,4-methylphenylcarbamate), amylostris((S)-alpha-methylbenzylcarbamate), amylostris(5-chloro-2-methylphenylcarbamate), cellulose tris(4-methylbenzoate), cellulose tris(4-chloro-3-methylphenylcarbamate), and cellulose tris(3-chloro-4-methylphenylcarbamate).

[0199] Non-limiting examples of chiral columns intended for use in the separation of enantiomers include CHIRALPAK IA SFC, CHIRALPAK AD-H SFC, CHIRALPAK IB SFC, CHIRALCEL OD-H SFC, CHIRALPAK IC SFC, CHIRALPAK ID SFC, CHIRALPAK IE SFC, CHIRALPAK IF SFC, CHIRALPAK AZ-H SFC, CHIRALPAK AS-H SFC, CHIRALPAK AY-H SFC, CHIRALCEL OJ-H SFC, CHIRALCEL OX-H SFC, and CHIRALCEL OZ-H SFC.

[0200] In additional or further embodiments, the compounds described herein are metabolized upon administration to an organism in need, thereby producing metabolites which are then used to produce desired effects, including the desired therapeutic effect.

[0201] The “metabolites” of the compounds disclosed herein are derivatives of the compounds formed during the metabolism of the compounds. The term “active metabolite” refers to the biologically active derivatives of a compound formed when a compound is metabolized. As used herein, the term “metabolized” refers to the totality of processes (including, but not limited to, hydrolysis and enzyme-catalyzed reactions) in which a particular substance is transformed by an organism. Thus, enzymes can bring about specific structural changes in compounds. For example, cytochrome P450 catalyzes a variety of oxidation and reduction reactions, while uridine diphosphate glucuronyltransferase catalyzes the transfer of activated glucuronic acid molecules to aromatic alcohols, aliphatic alcohols, carboxylic acids, amines, and free sulfhydryl groups. The metabolites of the compounds disclosed herein are optionally identified by either administration of the compounds to a host and analysis of tissue samples from the host, or by in vitro incubation of the compounds using hepatocytes and analysis of the resulting compounds.

[0202] Unless otherwise specified, the following terms used in this application have the definitions given below. In addition to the term "including," the use of other forms such as "include," "includes," and "included" is not limited to this application. Section headings used herein are for structural purposes only and are not to be construed as limiting the subject matter described herein.

[0203] The terms "halo," or alternatively "halogen" or "halide," refer to fluoro, chloro, bromo, or iodine. In some embodiments, the halo is fluoro, chloro, or bromo.

[0204] The term “single bond” refers to a chemical bond between two atoms or two substructures, where the atoms linked by the bond are considered to be part of a larger substructure. In one embodiment, when the groups described herein form a single bond, the referenced group is absent, thereby allowing the formation of a single bond between the remaining specified groups.

[0205] The term "part" refers to a specific segment or functional group of a molecule. A chemical part is often understood as a chemical substance embedded in or attached to a molecule.

[0206] The term “acceptable” in relation to a formulation, composition, or component means, when used herein, that it does not have a persistent or harmful effect on the health condition of the subject being treated.

[0207] The term "modulate," as used herein, means to interact with a target directly or indirectly in order to alter its activity. Alterations to target activity include, but are not limited to, enhancing, inhibiting, limiting, or expanding the target's activity.

[0208] The term "modulator," as used herein, refers to a molecule that interacts with a target, either directly or indirectly. Interactions include, but are not limited to, interactions between agonists, partial agonists, inverse agonists, antagonists, degradants, or combinations thereof. In some embodiments, the modulator is an agonist.

[0209] As used herein, terms such as “administer,” “administering,” and “administration” refer to methods that may be used to enable the delivery of a compound or composition to a desired site of biological action. These methods include, but are not limited to, oral routes, intraduodenal routes, parenteral infusion (including intravenous, subcutaneous, intraperitoneal, intramuscular, intravascular, or intravenous infusion), topical administration, and rectal administration. Those skilled in the art will be familiar with the administration techniques that may be utilized with the compounds and methods described herein. In some embodiments, the compounds and compositions described herein are administered orally.

[0210] When used herein, terms such as "simultaneous administration" are intended to encompass the administration of selected therapeutic agents to a single patient and include treatment regimens in which the therapeutic agents are administered via the same or different routes of administration, or at the same or different times.

[0211] As used herein, the terms “effective dose” or “therapeutically effective dose” refer to a sufficient amount of an administered drug or compound that alleviates, to some extent, one or more symptoms of the disease or illness being treated. Results include a reduction and / or mitigation of the signs, symptoms, or causes of the disease, or other desired changes in the biological system. For example, an “effective dose” for therapeutic use is the amount of a composition containing a compound as disclosed herein that is required to clinically significantly reduce disease symptoms. The appropriate “effective” dose in any individual case is determined at will using techniques such as dose-escalation studies.

[0212] As used herein, the terms “enhance” or “enhancing” mean increasing or extending a desired effect in either efficacy or duration. Therefore, with respect to enhancing the effect of a therapeutic agent, “enhance” refers to the ability to increase or extend the effect of another therapeutic agent on a system in either potency or duration. As used herein, “enhancing effective dose” refers to an amount sufficient to enhance the effect of another therapeutic agent on a desired system.

[0213] As used herein, the term “pharmaceutical combination” means a product resulting from a mixture or combination of one or more active ingredients, and includes both fixed and unfixed combinations of active ingredients. The term “fixed combination” means that the active ingredients, e.g., the compounds disclosed herein or their pharmaceutically acceptable salts, and the adjuvants, are both administered to the patient simultaneously in the form of a single entity or dosage. The term “unfixed combination” means that the active ingredients, e.g., the compounds disclosed herein or their pharmaceutically acceptable salts, and the adjuvants, are administered to the patient as separate entities simultaneously, concurrently, or sequentially, without any specific intervening time constraints, and such administrations provide the patient’s body with effective levels of two compounds. The latter term also applies to cocktail therapies, e.g., the administration of three or more active ingredients.

[0214] The terms "product" and "kit" are used as synonyms.

[0215] The terms “subject” or “patient” encompass mammals. Examples of mammals include, but are not limited to, members of any mammalian classification, including humans, non-human primates such as chimpanzees, other apes and monkey species, domesticated animals such as cattle, horses, sheep, goats and pigs, pet animals such as rabbits, dogs and cats, and rodents such as rats, mice and guinea pigs. In one aspect of experimental animals, the mammal is a human.

[0216] As used herein, the terms “treat,” “treating,” or “treatment” include, whether preventive or / or therapeutic, alleviating, reducing or improving at least one symptom of a disease or illness, preventing additional symptoms, inhibiting a disease or illness, for example, stopping the progression of a disease or illness, reducing a disease or illness, causing regression of a disease or illness, alleviating a condition caused by a disease or illness, or stopping the symptoms of a disease or illness.

[0217] Pharmaceutical composition In some embodiments, the compounds described herein are formulated into pharmaceutical compositions. The pharmaceutical compositions are formulated in a conventional manner using one or more pharmaceutically acceptable inert components that facilitate the treatment of the active compound into a preparation for pharmaceutical use. The appropriate formulation depends on the selected route of administration. Summaries of the pharmaceutical compositions described herein can be found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995), Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975, Liberman, H.A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, NY, 1980, and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins 1999), which are incorporated herein by reference for such disclosures.

[0218] In some embodiments, the compounds described herein are administered alone or in combination with pharmaceutically acceptable carriers, excipients, or diluents in pharmaceutical compositions. Administration of the compounds and compositions described herein may be achieved by methods that enable delivery of the compounds to the site of action.

[0219] In some embodiments, pharmaceutical compositions suitable for oral administration are presented as individual units such as capsules, cachets, or tablets, each containing a predetermined amount of the active ingredient; as powders or granules; as solutions or suspensions in aqueous or non-aqueous liquids; or as oil-in-water or water-in-oil liquid emulsions. In some embodiments, the active ingredient is presented as a bolus, lick, or paste.

[0220] Pharmaceutical compositions for oral use include tablets, gelatin-based press-fit capsules, gelatin-based soft-seal capsules, and plasticizers such as glycerol or sorbitol. Tablets may be produced by compression or molding, optionally with one or more minor components. Compressed tablets may be prepared by compressing the active ingredient in a free-flowing form such as powder or granules using appropriate machinery, optionally mixed with a binder, inert diluent or lubricant, surfactant, or dispersant. Molded tablets may be produced by molding a mixture of powder compounds moistened with an inert liquid diluent using appropriate machinery. In some embodiments, tablets are coated or scored and formulated to result in delayed or controlled release of the active ingredient therein. All formulations for oral administration must be in a dosage suitable for such administration. Press-fit capsules may contain the active ingredient in combination with a filler such as lactose, a binder such as starch, and / or a lubricant such as talc or magnesium stearate, and optionally a stabilizer. In soft capsules, the active compound may be dissolved or suspended in a suitable liquid, such as fatty oil, liquid paraffin, or liquid polyethylene glycol. In some embodiments, stabilizers are added. The sugar-coated tablet core is given a suitable coating. For this purpose, a concentrated sugar solution may be used, which may optionally contain gum arabic, talc, polyvinylpyrrolidone, carbol gel, polyethylene glycol, and / or titanium dioxide, lacquer solution, and a suitable organic solvent or solvent mixture. Dyes or pigments may be added to the tablet or sugar-coated tablet coating for identification or to characterize various combinations of doses of the active compound.

[0221] In particular, please understand that, in addition to the components mentioned above, the compounds and compositions described herein include other conventional agents in the art, taking into consideration the type of formulation in question, and for example, those suitable for oral administration may include flavorings.

[0222] Medication methods and treatment regimens In one embodiment, the compounds disclosed herein, or pharmaceutically acceptable salts thereof, are used to prepare drugs for the treatment of diseases or illnesses in mammals that benefit from the modulation of LPA1 agonists. A method for treating any of the diseases or illnesses described herein in a mammal requiring such treatment comprises administering a therapeutically effective dose to a mammal a pharmaceutical composition comprising at least one of the compounds disclosed herein, or a pharmaceutically acceptable salt thereof, an active metabolite, a prodrug, or a pharmaceutically acceptable solvate thereof.

[0223] In certain embodiments, compositions containing the compounds described herein are administered for prophylactic and / or therapeutic purposes. In certain therapeutic uses, the compositions are administered to a patient already suffering from a disease or illness in an amount sufficient to cure or at least partially block at least one of the symptoms of the disease or illness. The effective amount for this use depends on the severity and course of the disease or illness, previous treatments, the patient's health status, weight, and response to the drug, as well as the judgment of the treating physician. The therapeutically effective amount is determined by methods including, but not limited to, dose escalation and / or dose determination clinical trials.

[0224] The amount of a given drug corresponding to such a quantity will vary depending on factors such as the specific compound, the disease state and severity of the subject or host requiring treatment, and their identity (e.g., weight, sex), but nevertheless, it will be determined according to the specific drug being administered, the route of administration, the disease being treated, and the specific environment surrounding the case, including the subject or host being treated.

[0225] However, generally, the range of doses used for the treatment of adult humans is typically 0.01 mg to 2000 mg per day. In one embodiment, the desired dose is conveniently presented as a single dose or as divided doses administered simultaneously or at appropriate intervals, for example, two, three, four times, or more subdoses per day.

[0226] In one embodiment, the appropriate daily dose of the compounds disclosed herein or their pharmaceutically acceptable salts described herein is approximately 0.01 to approximately 50 mg / kg per kg of body weight. In some embodiments, the daily dose or the amount of active ingredient in the dosage form may be less or more than the range shown herein, based on many variables relating to the individual treatment regimen. In various embodiments, the daily dose and unit dose may be modified, but are not limited, depending on many variables, including the activity of the compound used, the disease or illness being treated, the mode of administration, the requirements of the individual subject, the severity of the disease or illness being treated, and the judgment of the healthcare professional.

[0227] In any of the embodiments described herein, in further embodiments, an effective amount of the compound disclosed herein or a pharmaceutically acceptable salt thereof is administered (a) systemically to a mammal and / or (b) orally to a mammal.

[0228] In some embodiments, compound I or a pharmaceutically acceptable salt thereof is administered in doses selected from about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, and about 400 mg. In some embodiments, the above dose is administered once daily. In some embodiments, the above dose is administered twice daily.

[0229] Products and Kits In certain embodiments, kits and products for use with one or more methods described herein are disclosed herein. In some embodiments, additional components of the kit include a carrier, package, or container partitioned to receive one or more containers such as vials, tubes, etc., each of which contains one of the distinct elements used in the methods described herein. Suitable containers include, for example, bottles, vials, plates, syringes, and test tubes. In one embodiment, the container is formed from a variety of materials such as glass or plastic.

[0230] The products provided herein include packaging materials. Examples of pharmaceutical packaging materials include, but are not limited to, bottles, tubes, bags, containers, and packaging materials suitable for the selected formulation and intended mode of use.

[0231] For example, a container may contain one or more compounds described herein. Such a kit may optionally include an identification mark or label, or instructions for its use in the manner described herein.

[0232] The kit typically includes a label listing the contents and / or instructions for use, and accompanying documentation with instructions for use. A set of instructions is also usually included.

[0233] In one embodiment, the label is on or attached to the container. In one embodiment, the label is on the container if the letters, numbers, or other markings forming the label are affixed, molded, or engraved onto the container itself, and the label is attached to the container if it is present, for example, as an accompanying document, in the receptacle or carrier that holds the container. In one embodiment, the label is used to indicate that the contents are to be used for a specific therapeutic purpose. The label also indicates how to use the contents, for example, by the method described herein. [Examples]

[0234] Abbreviation Aq or aq: Water-based ACN or MeCN: Acetonitrile DCM: Dichloromethane DSC: Differential Scanning Calorimetry DVS: Dynamic Water Vapor Adsorption Et: Ethyl alkyl: ethyl acetate EtOH: Ethanol equiv or eq.: equivalent FTIR: Fourier Transform Infrared Spectroscopy h or hr: time hrs: hours HPLC: High-Performance Liquid Chromatography LC-MS or LCM or Lc / MS: Liquid Chromatography-Mass Spectrometry M: Mole MEK: Methyl ethyl ketone Me: Methyl MeOH: methanol MeTHF or methyl THF: 2-methyltetrahydrofuran mins or min: minutes NaOH: Sodium hydroxide NMR: nuclear magnetic resonance measurement Rh: Relative humidity rt or RT: Room temperature SCXRD: Single-crystal X-ray diffraction ssNMR: Solid State Nuclear Magnetic Resonance TGA: Thermogravimetric analysis THF: Tetrahydrofuran vol: Typically used as volume for the reaction amount or ratio of a solvent. w / w: weight ratio XRPD: X-ray Powder Diffraction

[0235] The following examples are provided for illustrative purposes only and are not intended to limit the scope of the claims provided herein.

[0236] Example 1: Preparation of 2-(4-methoxy-3-(3-methylphenethoxy)benzamide)-2,3-dihydro-1H-indene-2-carboxylic acid (Compound I) The preparation of compound I has been previously described (see WO 2009 / 135590, US 8,362,073, US 8,445,530, US 8,802,720, US 9,328,071, each of which is referred to in whole).

[0237] Form 2 was provided by the preparation of compound I as previously described.

[0238] Example 1a: Preparation of 2-(4-methoxy-3-(3-methylphenethoxy)benzamide)-2,3-dihydro-1H-indene-2-carboxylic acid (Compound I, Form 1) Compound I (Form 2) was suspended in THF (using the minimum amount of THF (5v / w)) and stirred at approximately 22°C for approximately 5 to 7 days. The container or solid was not washed with any further solvent. Compound I (Form 1) was obtained. Conversion from Form 2 to Form 1 did not occur for approximately 2 to 4 days.

[0239] Example 1a: Alternative preparation of 2-(4-methoxy-3-(3-methylphenethoxy)benzamide)-2,3-dihydro-1H-indene-2-carboxylic acid (Compound I, Form 1)) Alternative preparations of compound I are described here.

[0240] [ka]

[0241] a) Saponification: Methyl 2-(4-methoxy-3-(3-methylphenethoxy)benzamide)-2,3-dihydro-1H-indene-2-carboxylate (6a, 10 g, 22 mmol, 1 eq) was dissolved in methanol (164 mL, 1.64 vol) and heated to 50°C with stirring. Aqueous NaOH (1 M, 26 mL, 1.21 eq) was added to the solution, which was stirred for 30 minutes, and then water (3 mL, 0.3 vol) was added. The reaction was stirred at 60°C for 3 hours, at which point the complete reaction of 6a was shown by LC-MS. The reaction mixture was cooled to 20°C and filtered to remove insoluble material. The pH of the obtained solution was 13.2.

[0242] b) Acidification / crystallization: The solution was acidified to pH 7.5 using 1 M citric acid (aq). Crystals of Form 1 (2% by mass) were seeded into the solution and cooled to 10°C for more than 3 hours, then maintained at 10°C for 1 hour. The resulting suspension was filtered, and the solid was washed with 1:1 water:methanol (2 × 5 vol), then with methanol (2 × 5 vol). The solid was dried in a vacuum oven at 40°C to produce compound I (9.2 g, 95%, Form 1 according to XRPD).

[0243] Example 2: Preparation of solid form - Evaporation from solvent at room temperature Compound I was dissolved in various solvents at room temperature (approximately 25°C) to provide a solution of Compound I at a maximum concentration of 10 mg / mL. The raw materials used in these experiments were mixtures of polymorphs 1, 2, and 3.

[0244] The maximum concentration used in this series of experiments was 10 mg / mL. Solubility was highest in THF, at >10 mg / mL. Solubility of 4–6 mg / mL was observed in acetone and MEK, while methanol showed a solubility of approximately 2–3 mg / mL. Solubility was estimated to be less than 2 mg / mL for 1-butanol, butyl acetate, hexane, ethanol, ethyl acetate, isobutyl alcohol, 1-pentanol, isopropanol, acetonitrile, dichloromethane, chloroform, and water.

[0245] When a solubility of 2 mg / mL or higher was observed, the solution was filtered at 25°C and evaporated to isolate the solid.

[0246] The crystal form determination for each sample is recorded in the table below.

[0247] [Table 7]

[0248] Samples prepared by evaporation from low-to-medium polar solvents (acetone, MEK, THF) demonstrated the presence of pure Form 1. Samples prepared from a more polar solvent (methanol) demonstrated the presence of both Form 1 and Form 2. The correlation between the presence of Form 2 and the more polar solvent was consistent with observations from other isolation methods.

[0249] TGA results for all samples showed a weight loss of less than 1.0% at a maximum temperature of 200°C.

[0250] Acetone: Form 1 No evidence of other polymorphs was observed. DSC scanning revealed three endothermic events between 190 and 220°C. The first endothermic event, at approximately 192–197°C, is attributed to the transformation of morphology 1. The second endothermic event coincides with the recrystallization and melting of morphology 2 (starting point 214°C) following the melting of morphology 3.

[0251] Methyl ethyl ketone (MEK): Form 1 No evidence of other polymorphs was observed. DSC scanning revealed that morphology 2 exhibited endothermic initiation at approximately 190–195°C followed by recrystallization and melting at approximately 213°C.

[0252] THF: Form 1 No evidence of other polymorphs was observed. DSC scanning revealed a transformation of morphology 1 at approximately 190°C, followed by multiple exothermic events (recrystallization), and then melting of morphology 2 at approximately 213°C.

[0253] Methanol: Form 1 + Form 2 XRPD showed evidence for both morphology 1 and morphology 2 at 5–6° and 8.5–9.5° (2-theta). DSC scanning revealed only a single endothermic reaction consistent with the melting point of morphology 2.

[0254] Example 3: Preparation of solid form - Evaporation from solvent at high temperature Compound I was dissolved in various solvents at high temperatures (approximately the boiling point of the solvent) to provide a solution of Compound I with a maximum concentration of 15 mg / mL. The raw materials used in these experiments were a mixture of polymorphs 1, 2, and 3.

[0255] When the concentration of compound I was 2 mg / mL or higher, the solution was filtered at 25°C and evaporated to isolate the solid.

[0256] The crystal form determination and estimated hot solubility of each sample are recorded in the table below.

[0257] [Table 8]

[0258] Higher polar solvents (methanol, ethanol, acetonitrile) were more likely to produce Form 2. Medium polar solvents (acetone, MEK) were more likely to produce Form 1. Mixtures of Form 2 and Form 1 were observed in ethyl acetate, 1-pentanol, and isobutyl alcohol. Pure Form 3 was observed only in chloroform. Experiments with dichloromethane produced oil.

[0259] TGA results for all samples showed a weight loss of less than 1.0% at a maximum temperature of 200°C, with the exception of ethyl acetate (1.5%).

[0260] Acetone: Form 1 No further morphological evidence was observed. DSC scanning revealed weak endothermic activity starting at approximately 190°C, followed by further endothermic / exothermic activity at 200–205°C, and finally endothermic activity at approximately 214°C.

[0261] n-butanol: Form 2 No further morphological evidence was found by XRPD. DSC scanning revealed a single endothermic reaction at 214°C, which was consistent with the melting point of morphology 2.

[0262] Butyl acetate: Form 2 DSC data showed a single endothermic reaction at the melting point (starting point of approximately 215°C) consistent with the presence of Form 2.

[0263] Ethanol: Form 2 No evidence of other forms was observed. DSC scanning revealed a single melting peak at 215°C, consistent with the presence of form 2.

[0264] Ethyl acetate: Form 2 (dominant) + possible form 1 The XRPD pattern appears similar to the reference pattern of morphology 2, but a shoulder is observed between 5 and 6 degrees 2-theta. The location of the shoulder is consistent with the presence of morphology 1. DSC scanning revealed a single melting peak at approximately 213°C.

[0265] Methyl ethyl ketone (MEK): Form 1 No evidence of other forms was observed. DSC scanning indicated that form 1 appears to transform into molten / form 3 (form 3, which melts at approximately 205°C), showing multiple endothermic reactions. A third endothermic reaction was observed at 213°C, indicating that the sample transformed into form 2.

[0266] Isobutyl alcohol: Form 1 + Form 2 XRPD data showed evidence for both morphology 1 and morphology 2 at 5–6°C and 8.5–9.5°C 2-theta. DSC scanning revealed a single endothermic reaction at approximately 214°C.

[0267] 1-Pentanol: Form 1 + Form 2 XRPD patterns showed evidence of both morphology 1 and morphology 2 at 5–6°C and 8.5–9.5°C 2-theta. DSC scanning revealed a single endothermic reaction at approximately 214°C.

[0268] 2-Propanol: Form 1 + Form 2 XRPD revealed a pattern that was largely consistent with morphology 2, along with faint evidence of morphology 3 at 4.2°C 2-theta. DSC scanning showed a single endothermic pattern at approximately 214°C.

[0269] Acetonitrile: Form 2 The XRPD pattern is consistent with morphology 2, and there is no evidence of other morphologies. DSC scanning revealed a single endothermic pattern at approximately 215°C.

[0270] Methanol: Form 2 The XRPD pattern is consistent with morphology 2, and there is no evidence of other morphologies. DSC scanning revealed a single endothermic pattern at approximately 214°C.

[0271] Chloroform: Form 3 The XRPD pattern showed some similarities to the XRPD pattern of form 3, but positive identity necessitated further characterization. The presence of form 3 was confirmed using FTIR.

[0272] Example 4: Preparation of solid form - Conventional recrystallization (slow cooling) at -25°C For recrystallization, we attempted to generate novel morphologies by utilizing both slow cooling (at 25°C) and rapid cooling (rapid cooling to 0°C). High-temperature solutions (see Example 3, evaporation at high temperature) were cooled to 25°C, and the resulting collected solids were analyzed by XRPD.

[0273] The determination of the crystal form of each individual sample isolated by slow cooling is shown in the table below.

[0274] [Table 9]

[0275] Form 2 was primarily observed in methanol and ethanol, the most polar solvents. Form 1 (pure or nearly pure) was most frequently observed, particularly in medium-polar solvents. These solvents include butyl acetate, isobutyl alcohol, 1-pentanol, 2-propanol, and methyl THF. Mixtures of Form 1 and Form 2 were observed in acetone, ethyl acetate, MEK, and acetonitrile.

[0276] TGA results for all samples showed a weight loss of less than 1.0% at a maximum temperature of 200°C.

[0277] Acetone: Form 1 + Form 2 XRPD patterns showed evidence of both morphology 1 and morphology 2 at 5–6 degrees (shoulder) and 8.5–9.5 degrees 2-theta. Characteristic reflections of morphology 2 are evident at 7.2–8.2 degrees 2-theta. DSC scanning revealed weak endothermic heating starting at approximately 190°C, followed by further endothermic heating at approximately 215°C.

[0278] 1-Butanol: Form 1 No further morphological evidence was found by XRPD. DSC scanning revealed endothermic heating (characteristic of morphology 1) starting at approximately 193–200°C, followed by recrystallization and endothermic heating consistent with the melting point of morphology 2 at approximately 215°C.

[0279] Butyl acetate: Form 1 + trace form 3 The XRPD pattern was consistent with morphology 1, but there was a small peak at approximately 4.3 degrees 2-theta suggesting traces of morphology 3. DSC data revealed numerous event characteristics, including morphology 1 transformation (190–198°C), morphology 3 melting (200–205°C), recrystallization, and morphology 2 melting (approximately 215°C).

[0280] Ethanol: Form 2 + Trace Form 1 The XRPD pattern was consistent with morphology 2. Possible trace evidence of morphology 1 was observed at approximately 5.2 degrees 2-theta. DSC scanning revealed a single melting peak at 215°C.

[0281] Ethyl acetate: Form 1 + Form 2 XRPD patterns showed evidence for both morphology 1 and morphology 2 at 5–6 degrees (shoulder) and 8.5–9.5 degrees 2-theta. Characteristic reflections of morphology 2 are evident at 7.2–8.2 degrees 2-theta. DSC scanning revealed a single endothermic reaction at approximately 215°C.

[0282] Methyl ethyl ketone (MEK): Form 1 + Form 2 XRPD patterns showed evidence of both morphology 1 and morphology 2 at 5–6 degrees (shoulder) and 8.5–9.5 degrees 2-theta. Characteristic reflections of morphology 2 are evident at 7.2–8.2 degrees 2-theta. DSC scanning revealed weak endothermic activity at 192–200°C followed by endothermic activity at approximately 216°C.

[0283] Isobutyl alcohol: Form 1 No evidence of other forms was observed. DSC scanning revealed multiple endothermic reactions corresponding to the melting of form 1 transition (190–198°C), the melting of form 3 / transition (200–204°C), and the melting of form 2 (approximately 214°C).

[0284] 1-Pentanol: Form 1 (predominant) XRPD patterns primarily showed patterns consistent with morphology 1. Trace amounts of morphology 2 (reflection at approximately 7.5 degrees 2-theta) may be present. DSC scanning revealed multiple events at 195–205°C associated with melting / conversion of morphology 1, and endothermic events at 215°C consistent with melting of morphology 2.

[0285] 2-Propanol: Form 1 (dominant) XRPD revealed a pattern that was primarily consistent with morphology 1, with faint evidence of 2-theta morphology 2 at 7.4–7.5°C. DSC scanning showed endothermic activity at approximately 194–200°C followed by endothermic activity at 216°C.

[0286] Acetonitrile: Form 1 + Form 2 XRPD showed evidence for both morphology 1 and morphology 2 at 5-6 degrees 2-theta. DSC showed a single endothermic reaction at 214°C.

[0287] Methanol: Form 2 The XRPD pattern matches morphology 2. DSC scanning revealed a single endothermic event at approximately 216°C.

[0288] Methyl THF: Form 1 No further morphological evidence was found using XRPD. DSC scanning revealed endothermic activity at approximately 215°C, followed by endothermic activity at 194–198°C.

[0289] Example 5: Preparation of solid form - Conventional recrystallization (rapid cooling) at -0°C The crystal forms of individual samples isolated by rapid cooling at 0°C are described in the table below.

[0290] [Table 10]

[0291] Isolation of Form 1 is most likely to occur in low-to-medium polar solvents. Form 1 was mainly isolated from acetone, 1-butanol, butyl acetate, MEK, 1-pentanol, and methyl THF. Form 2 was mainly isolated from methanol. XRPD data from samples isolated from isobutyl alcohol and 2-propanol appeared similar to Form 4.

[0292] TGA results for all samples showed a weight loss of less than 1.0% at a maximum temperature of 200°C.

[0293] Acetone: Form 1 The XRPD pattern matched morphology 1. DSC scanning revealed two weak endothermic events at approximately 195–200°C and 200–205°C, followed by a further endothermic event at approximately 216°C.

[0294] 1-Butanol: Form 1 No further morphological evidence was found using XRPD. DSC scanning revealed multiple endothermic properties, including morphology 1 (194–200°C), morphology 3 melting / conversion (203–206°C), and morphology 2 melting (approximately 216°C).

[0295] Butyl acetate: Form 1 No further morphological evidence was found using XRPD. DSC data revealed multiple event characteristics, including transformation to morphology 1 (188–199°C), melting to morphology 3 (203–204°C), recrystallization, and melting to morphology 2 (approximately 216°C).

[0296] Ethanol - Form 1 + Form 2 XRPD patterns showed evidence of both morphology 1 and morphology 2 at 5–6°C and 8.5–9.5°C 2-theta. DSC scanning showed melting of morphology 2 at approximately 215°C, followed by weak endothermic reaction at 195–200°C.

[0297] Ethyl acetate: Form 1 + Form 3 XRPD patterns provided evidence for both morphology 1 (5.3° 2-theta) and morphology 3 (4.2° 2-theta). The characteristic reflection of morphology 3 is evident at 6.5–7.5° 2-theta. DSC scanning revealed multiple endothermic properties, including conversion in morphology 1 (195–199°C), melting / recrystallization in morphology 3 (209–205°C), and melting in morphology 2 (approximately 214°C).

[0298] Methyl ethyl ketone (MEK): Form 1 No further morphological evidence was found by XRPD. DSC scanning revealed weak endothermic / exothermic activity at 195–200°C and again at 202–204°C, and endothermic activity at approximately 214°C.

[0299] Isobutyl alcohol: Form 4 (dominant) The XRPD pattern is similar to the pattern of form 4, but the peaks are less defined. DSC revealed weak exothermic properties at 150–160°C, followed by endothermic properties for form 1 (190–198°C), form 3 (202–206°C), and form 2 (214°C).

[0300] 1-Pentanol: Form 1 No other form of evidence was observed. DSC scanning revealed broad endothermy between 190 and 198°C, weak endothermy between 202 and 205°C, and endothermy at approximately 214°C.

[0301] 2-Propanol: Form 4 + Form 3 XRPD patterns showed similarities to morphology 4, along with evidence of several morphology 3s (4.2 and approximately 7° 2-theta). The peaks appeared less defined than those of morphology 4. DSC showed weak exothermic activity at 140–160°C. Endothermic activity was observed at 188–195°C, 203–205°C, and 215°C.

[0302] Acetonitrile: Form 1 + Form 2 + Form 3 XRPD provided evidence of morphology 1, 2, and 3, with only trace levels of morphology 3 appearing. DSC scanning revealed weak endothermic and exothermic activity between 195 and 205°C, and endothermic activity at approximately 215°C.

[0303] Methanol: Form 2 The XRPD pattern is consistent with morphology 2. A slight shoulder of 5.3 degrees 2-theta may indicate a trace level of morphology 1. DSC revealed weak endothermy at approximately 165°C followed by endothermy at 215°C.

[0304] Methyl THF: Form 1 The XRPD pattern is consistent with morphology 1. DSC scanning revealed the initiation of melting of morphology 1 at 198–199°C, followed by recrystallization and melting of morphology 2 (approximately 214°C).

[0305] Example 6: Preparation of solid form - Isolation by reverse solvent addition The samples were isolated by crystallization via a reverse solvent by adding a THF solution (concentration 25 mg / mL, temperature 25°C) in a 4:1 ratio to several reverse solvents. Therefore, the final concentration of compound I was 5 mg / mL. The crystal form determinations for each sample are shown in the table below.

[0306] [Table 11]

[0307] Form 2 was observed when the reverse solvent was acetonitrile, ethanol-water, and 2-propanol. Form 1 was observed when the weak solvent was water.

[0308] TGA results for all samples showed a weight loss of less than 1.0% at a maximum temperature of 200°C.

[0309] THF / water: form 1 The XRPD pattern was consistent with morphology 1. DSC scanning revealed multiple endothermic reactions (195–198°C, 200–204°C) followed by dissolution at 215°C. The DSC was similar to that of the morphology 1 sample.

[0310] THF / acetonitrile: Form 2 The XRPD pattern matched morphology 2. DSC scanning revealed a single endothermic pattern at approximately 215°C.

[0311] THF / ethyl acetate: Form 1 + Form 2 XRPD patterns showed evidence of both morphology 1 and morphology 2 at 5–6°C and 8.5–9.5°C 2-theta. DSC scanning revealed a single endothermic reaction at approximately 215°C.

[0312] THF / 2-propanol:Form 2 The XRPD pattern matched morphology 2. DSC scanning revealed a single endothermic pattern at approximately 215°C.

[0313] THF / ethanol-water (1:1):Form 2 The XRPD pattern matched morphology 2. DSC scanning revealed a single endothermic pattern at approximately 215°C.

[0314] Example 7: Slurry Stability Study The slurry stability and maturation studies were initially conducted with the aim of identifying the most stable crystalline form at room temperature (25°C).

[0315] In this series of experiments, both individual forms and mixtures of forms were slurryed in multiple solvents for four weeks, followed by filtration and analysis to determine the resulting forms. The first set of experiments included equal amounts of pure forms 1, 2, and 3, and mixtures of these forms. Solvents included methanol, ethyl acetate, MEK, and methyl THF to investigate various solvent polarities. Additional experiments were performed using mixtures of forms 1 and 4 in MEK and methanol.

[0316] Due to its ease of analysis of small amounts, FTIR was used. Interestingly, the carboxylic acid was located at different positions in each polymorph. The results of the first set of experiments, comparing the initial and final forms, are described below.

[0317] [Table 12]

[0318] Pure form 1 remained invariant in each solvent, while pure form 3 and mixtures of the three forms were observed to convert to form 1. Form 2 was observed to convert to form 1 only in MEK, and no change was observed in methanol, methyl THF, or ethyl acetate.

[0319] Further experiments (using Forms 1 and 4) showed that the conversion of Forms 4 and Form 1 mixtures to Form 1 was observed in both methanol and MEK. The dataset clearly showed that Form 1 was the most stable form at room temperature (25°C), while each of the other forms showed conversion in multiple experiments.

[0320] Furthermore, slurry conversion studies were conducted using Forms 1 and 2 at 40–70°C to determine the transition temperatures between the forms. Mixtures of Forms 1 and 2 (1:1 ratio) were slurryed in two different solvents at temperatures of 40°C, 50°C, 60°C, and 70°C, and then analyzed to determine the direction of conversion. Methanol and MEK were used at 40°C and 50°C. MEK and 1-pentanol were used at 60°C and 70°C. The results are summarized below.

[0321] [Table 13]

[0322] The data showed that the transition to morphology 1 occurred at 40–50°C and to morphology 2 at 60–70°C. This dataset suggests that the transition temperature between morphology 1 and morphology 2 lies between 50°C and 60°C, and therefore the two morphologies are enantiotropically related.

[0323] Example 8: X-ray powder diffraction (XRPD) The following diffractometers were used, but other types of diffractometers may also be used. Furthermore, other wavelengths may be used, and conversion to Cu Kα may be possible. In some embodiments, synchrotron radiation X-ray powder diffraction (SR-XRPD) may be used to characterize the crystal morphology.

[0324] "Characteristic peaks" are a subset of observed peaks within a given range, used to distinguish one crystalline polymorph from another (a polymorph that is a crystalline form with the same chemical composition). Characteristic peaks are determined by evaluating, within ±0.2°²-theta, which observed peaks are present in all other known crystalline polymorphs of a compound, if they are present in that compound.

[0325] STOE Stadi-P Transmission Diffraction Meter X-ray powder diffraction was performed using a STOE Stadi-P transmission diffractometer with Cu-Kα1 radiation. A linear position-sensitive detector was used for capillary measurements and samples in flat preparations, while an image plate position-sensitive detector (IP-PSD) was used for temperature-resolved XRPD, humidity-resolved XRPD, and robotic samples in 96-well plates. Measurement data were visualized and evaluated using WinXPOW V2.12 software.

[0326] The 2-theta peak values ​​provided for XRPD are within ±0.2°2-theta.

[0327] Characterization of the solid state morphology of compound I The X-ray powder diffraction pattern of compound I in crystal form 1 is shown in Figure 1. The X-ray powder diffraction pattern of compound I in crystal form 2 is shown in Figure 6. The X-ray powder diffraction pattern of compound I in crystal form 3 is shown in Figure 10. The X-ray powder diffraction pattern of compound I in crystal form 4 is shown in Figure 13.

[0328] Characterization of crystalline form 1 of compound I The X-ray powder diffraction pattern of crystalline form 1 of compound I is shown in Figure 1. Characteristic XRPD peaks include 5.2±0.2°2-theta, 9.0±0.2°2-theta, 14.4±0.2°2-theta, and 17.7±0.2°2-theta.

[0329] Characterization of crystalline form 2 of compound I The X-ray powder diffraction pattern of crystalline form 2 of compound I is shown in Figure 6. Characteristic XRPD peaks include 5.6±0.2°2-theta, 7.6±0.2°2-theta, 8.1±0.2°2-theta, 9.4±0.2°2-theta, 14.9±0.2°2-theta, and 16.3±0.2°2-theta.

[0330] Characterization of crystalline form 3 of compound I The X-ray powder diffraction pattern of crystalline form 3 of compound I is shown in Figure 10. Characteristic XRPD peaks include 4.2±0.2°2-theta, 6.8±0.2°2-theta, 15.1±0.2°2-theta, 25.0±0.2°2-theta, 25.5±0.2°2-theta, and 26.4±0.2°2-theta.

[0331] In some embodiments, measurements of samples prepared independently on different instruments can result in variability greater than ±0.2°²-theta. Samples of independently prepared crystal morphologies 1 and 2 were characterized using three additional diffractometers.

[0332] Malvern Panalytical Empyrean Diffraction Meter Equipment:Malvern Panalytical

[0333] Type: Empyrean with a Pixel 1D detector, copper XRD tube, theta-theta goniometer, and sample changer.

[0334] Characterization of crystalline form 1 of compound I The X-ray powder diffraction pattern of crystalline form 1 of compound I is shown in Figure 17. Characteristic XRPD peaks include 5.2±0.2°2-theta, 9.0±0.2°2-theta, 14.4±0.2°2-theta, and 17.7±0.2°2-theta.

[0335] Characterization of crystalline form 2 of compound I The X-ray powder diffraction pattern of crystalline form 2 of compound I is shown in Figure 18. Characteristic XRPD peaks include 5.6±0.2°2-theta, 7.6±0.2°2-theta, 8.1±0.2°2-theta, 9.4±0.2°2-theta, 14.8±0.2°2-theta, and 16.2±0.2°2-theta.

[0336] Stoe Stadi P, G.52.SYS.S072

[0337] [Table 14]

[0338] Sample preparation: The cylindrical volume, determined by a washer and two foils, was slightly overfilled with a small amount of sample, and then smoothed using two glass slides to obtain a powder disc. This specimen was then fixed in a nickel-coated metal sample holder.

[0339] Characterization of crystalline form 1 of compound I The X-ray powder diffraction pattern of crystalline form 1 of compound I is shown in Figure 19. Characteristic XRPD peaks include 5.2±0.2°2-theta, 9.0±0.2°2-theta, 14.4±0.2°2-theta, and 17.7±0.2°2-theta.

[0340] Characterization of crystalline form 2 of compound I The X-ray powder diffraction pattern of crystalline form 2 of compound I is shown in Figure 20. Characteristic XRPD peaks include 5.5±0.2°2-theta, 7.5±0.2°2-theta, 8.0±0.2°2-theta, 9.4±0.2°2-theta, 14.8±0.2°2-theta, and 16.2±0.2°2-theta.

[0341] The XRPD overlays for Form 1 (upper spectrum) and Form 2 (lower spectrum) are shown in Figure 21.

[0342] PANalytical X'Pert PRO MPD Diffractometer X-ray powder diffraction (XRPD, transmission mode): XRPD patterns were collected using a PANalytical X'Pert PRO MPD diffractometer with incident Cu beams generated using an Optix long-precision focal source. Cu KαX-rays were focused onto the detector via the specimen using an elliptical tilting multilayer mirror. The specimen was sandwiched between 3 μm thick films and analyzed by transmission geometry. Prior to analysis, a silicon specimen (NIST SRM 640f) was analyzed to confirm that the observed position of the Si 111 peak matched the NIST-certified position. Background caused by the atmosphere was minimized using a beam stop, a short scatter-removal extension, and a scatter-removal knife edge. Spreading from axial divergence was minimized using solar slits for the incident and diffracted beams. Diffraction patterns were collected using a scanning position-sensitive detector (X'Celerator) located 240 mm from the specimen and Data Collector software v.5.5.

[0343] X-ray powder diffraction peak identification process: Depending on the instrument used to collect the data and / or intrinsic peak resolution, each peak was rounded to the nearest 0.1° or 0.01°²Θ using a rounding algorithm. The peak positions along the X-axis (°²-theta) in both figures and tables were determined using TRIADS® v2.1.1 software and rounded to one or two significant figures based on the above criteria. The variation in peak positions is given within ±0.2°²-theta, based on the recommendations outlined in the USP discussion on variation in X-ray powder diffraction (USP-NF 2021, Issue 2). <941> Characterization of Crystalline and Partially Crystalline Solids by X-Ray Powder Diffraction (XRPD), 1_GUID-14EBB55E-0D24-45A1-A84F-FE4DCAAEE3E8_1_en-US (official version prior to 2013). In some embodiments, measurements of samples prepared independently on various instruments may result in variability greater than ±0.2°²-theta. For the d-interval list, the wavelength used to calculate the d-interval was 1.5405929 Å, the CuKα1 wavelength (Phys. Rev. A56(6), 4554-4568 (1997)).

[0344] Characterization of crystalline form 1 of compound I The X-ray powder diffraction pattern of crystalline form 1 of compound I is shown in Figure 22. Characteristic XRPD peaks include 5.2±0.2°2-theta, 9.0±0.2°2-theta, 14.4±0.2°2-theta, and 17.7±0.2°2-theta.

[0345] Characterization of crystalline form 2 of compound I The X-ray powder diffraction pattern of crystalline form 2 of compound I is shown in Figure 23. Characteristic XRPD peaks include 5.5±0.2°2-theta, 7.5±0.2°2-theta, 8.0±0.2°2-theta, 9.4±0.2°2-theta, 14.8±0.2°2-theta, and 16.2±0.2°2-theta.

[0346] XRPD limit testing method using PANalytical X'Pert PRO MPD diffractometer The development of a non-limiting method for XRPD limit testing to determine Form 2 in Form 1 drug raw materials is described. Specificity, which is the ability to clearly assess the analyte in the presence of components that may be expected to be present, was evaluated by comparing the XRPD patterns of Form 1 and Form 2. Since several peaks highlighted in Figure 24 can be used to quantify Form 2 (lower spectrum) within Form 1 (upper spectrum), the specificity of Form 2 is good in Form 1 drug raw materials.

[0347] Calibration model generation: Calibration standards containing 0-10% of form 2 in form 1 were prepared by geometrically mixing the components without requiring any additional sample processing.

[0348] [Table 15]

[0349] The XRPD overlay of the calibration standard is shown in Figure 25. Peaks specific to Form 2 are highlighted (using dotted lines), and good linearity was demonstrated based on visual evaluation.

[0350] We developed a spreadsheet to calculate the peak areas at approximately 5.6°, 7.6°, and 8.1°, which are normalized to the total peak area within the range of 4.0–25.5°.

[0351] The calibration curve is shown in Figure 26. The regression statistics, along with the limit of quantification (LOQ) and limit of detection (LOD), are summarized below.

[0352] [Table 16]

[0353] LOD and LOQ were calculated using the following equations. LOD(3.3×σ)= / S LOQ(10×σ)= / S σ is the standard error of the linear regression, and S is the slope of the calibration curve. The LOD and LOQ were calculated to be 1.0% and 2.8% (w / total), respectively.

[0354] Example 9: Differential Scanning Calorimetry (DSC) 9.1 METTLER DSC822e DSC measurements are performed using a METTLER DSC822e (module DSC822e / 700 / 109 / 414935 / 0025). A 40 μl aluminum crucible with a sealed lid and pinhole is used. All measurements are performed with a nitrogen gas flow of 50 mL / min and a typical heating rate of 10 °C / min. Measurement data are evaluated using STARe V8.10 software.

[0355] 9.2 Perkin Elmer Diamond DSC DSC scanning was performed using a Perkin Elmer Diamond DSC. The sample was encapsulated in a perforated aluminum pan to allow residual solvent to be released. Scanning was performed at a rate of 10°C / min from 25 to 240°C. The system was calibrated using indium (MP 156.6°C) and tin (MP 231.9°C) before use.

[0356] Characterization of the solid state morphology of compound I Figure 2 shows the DSC thermogram of crystalline form 1 of compound I.

[0357] Figure 7 shows the DSC thermogram of crystalline form 2 of compound I.

[0358] Figure 11 shows the DSC thermogram of crystalline form 3 of compound I.

[0359] Figure 14 shows the DSC thermogram of crystalline form 4 of compound I.

[0360] The endothermic events observed in differential scanning calorimetry (DSC) thermograms for solid-state morphology are as shown in the table below.

[0361] [Table 17]

[0362] Example 10: Thermogravimetric Analysis (TGA) Method 10.1: METTLER TGA851e Thermogravimetric analysis will be performed using a METTLER TGA851e (module TGA / SDTA851e / SF1100 / 042). Measurements will be performed using a 100 μl aluminum crucible with a sealed lid and hole, with a nitrogen gas flow of 50 mL / min. The measurement data will be evaluated using STARe V8.10 software.

[0363] Method 10.2: Perkin Elmer Pyris System TGA was obtained on any Perkin Elmer Pyris System. Samples were run from 25 to 200°C at a rate of 10°C / min. System accuracy was verified using barium chloride dihydrate.

[0364] Characterization of the solid state morphology of compound I The TGA pattern of crystalline form 1 of compound I is shown in Figure 3.

[0365] The thermogravimetric analysis (TGA) patterns for the solid state are as shown in the table below.

[0366] [Table 18]

[0367] Example 11: Dynamic water vapor adsorption (DVS) Moisture absorption / desorption isotherms are recorded using a DVS-1 from SURFACE MEASUREMENT SYSTEMS. Two cycles are performed at 25°C, raising the relative humidity (RH) from 0% to 95% and then back to 0%. The data is evaluated using DVSWin V.2.15 software.

[0368] The reversible water absorption of form 1 of compound I, as determined by DVS, is less than 1% (approximately -0.1% w / w between 0 and 95% RH).

[0369] Example 12: Fourier Transform Infrared (FTIR) Spectroscopy FTIRs of different solid-state forms of compound I were collected using the Nicolet Magna 750 system. Samples were prepared at a concentration of 1% in KBr and compressed at 10,000 pounds.

[0370] Figure 15 shows partial Fourier transform infrared (FTIR) spectroscopic pattern overlays of crystalline forms 1, 2, 3, and 4 of compound I. The FTIR spectrum of crystalline form 1 is approximately 1739.6 cm⁻¹. -1 It has a peak at [location]. The FTIR spectrum of crystal form 2 is approximately 1731.7 cm⁻¹. -1 It has a peak at [location]. The FTIR spectrum of crystal form 3 is approximately 1722.0 cm⁻¹. -1 It has a peak at [location]. The FTIR spectrum of crystal form 4 is approximately 1743.9 cm⁻¹. -1 It has a peak at [location].

[0371] Example 13: Fourier transform Raman spectroscopy Raman spectra were obtained on a Raman module interfaced to a Nicolet 6700 IR spectrophotometer (Thermo Nicolet) equipped with an indium gallium arsenide (InGaAs) detector. Wavelength matching was performed using sulfur and cyclohexane. Each sample was prepared for analysis by placing the sample in a 13 mm diameter stainless steel cup and leveling the material. The cup was rotated during data acquisition using the Thermo Nicolet's step-and-repeat accessory. Three spectra were collected for each sample, from the outer ring to the inner ring of the sample cup. The samples were irradiated using an Nd:YVO4 laser power of approximately 0.5 W (excitation wavelength of 1064 nm). Each spectrum was collected at 2 cm. -1 The analysis consisted of 512 co-additive scans using the specified spectral resolution. The three spectra of each sample were averaged using Omnic v7.2 (ThermoElectron).

[0372] The variability in Raman peak position is due to the observed sharpness of the picked peaks and 1 cm -1 Data point interval (2cm) -1 Based on data acquisition using the resolution of ±2cm -1 The peaks were given within the given timeframe. Peak picking was performed using Thermo Electron OMNIC software version 7.2. The observed peaks include all Raman peaks for a given form, excluding very weak intensity peaks and broad peaks with incompletely defined maximum values.

[0373] The Raman spectrum of form 1 is shown in Figure 27. The Raman spectrum of form 1 is at 1730 cm⁻¹. -1 ±2cm -1 It has a peak at [location].

[0374] The Raman spectrum of form 2 is shown in Figure 28. The Raman spectrum of form 1 is 1725 cm⁻¹. -1 ±2cm -1 It has a peak at [location].

[0375] Example 14: Solid-state nuclear magnetic resonance (ssNMR) spectroscopy All spectra were obtained using a Bruker DRX500 spectrometer equipped with an 11.7 Tesla magnet and a 4 mm diameter solid-state probe. The following parameters were used:

[0376] [Table 19]

[0377] Using the high-frequency signal of adamantane, all spectra are indirectly referenced to tetramethylsilane. All samples were packed into a 4 mm OD rotor made of zirconia fitted with a Kel-F drive cap. Gaussian convolution was applied to free induction decay before the Fourier transform, with GB = 0.035 and LB = -10.0 Hz.

[0378] Characterization of crystalline form 1 of compound I The ssNMR spectrum of crystalline form 1 of compound I is shown in Figure 4. The resonance characteristics of form 1 are described below. δc / ppm:23.35, 36.40, 44.12, 45.70, 54.41, 65.40, 71.58, 110.97, 114.45, 121.00, 124 .43, 126.78, 127.42, 131.27, 136.47, 138.94, 142.61, 148.68, 152.19, 172.07, 174.59

[0379] Characterization of crystalline form 2 of compound I The ssNMR spectrum of crystalline form 2 of compound I is shown in Figure 8. The resonances characteristic of form 2 are described below. δc / ppm:20.59, 37.04, 44.03, 46.84, 55.25, 66.34, 71.74, 111.25, 116.90, 122.48, 123 .63, 126.39, 128.34, 131.33, 136.78, 137.69, 141.73, 149.44, 153.68, 172.82, 175.49

[0380] Characterization of crystalline form 3 of compound I The ssNMR spectrum of crystalline form 3 of compound I is shown in Figure 12. The resonances characteristic of form 3 are described below. δc / ppm: 21.72 # , 22.23 # , 43.81, 46.00, 54.01, 64.56, 67.67, 109.22, 110.33, 119.58, 122.99, 126.71, 130.28 # , 138.46 # , 139.68, 140.34, 143.63, 144.25, 146.87, 150.90, 168.32, 176.47 # A spread or fragmented signal whose shape or chemical shift may vary.

[0381] Characterization of the amorphous form of compound I The ssNMR spectrum of the amorphous form of compound I is shown in Figure 16.

[0382] Example 15: Stability of solid-state morphology To determine whether interconversion was observed, the physical stability of morphology 1, morphology 2, and morphology 3 was investigated at 80°C / 75%RH. Samples were subjected to stress for one week in open glass vials and then examined by FTIR.

[0383] No changes in the FTIR spectrum were observed in any of the forms, suggesting that these forms are relatively stable in the solid state.

[0384] Example 16: Solubility study The solubility of various polymorphs was determined in phosphate buffer at pH 7.4 at 25°C. Equilibrium values ​​were determined by analyzing the samples as a function of time for each morphology. Analysis of the residual solids of each sample confirmed that the morphology remained unchanged throughout the experiment. Concentration (mg / mL) versus time data for each morphology are described below.

[0385] [Table 20]

[0386] The equilibrium solubility values ​​at 24 hours showed that forms 3 and 4 had more than twice the solubility of form 1. The 24-hour result for form 2 was more than 30% greater than that of form 1.

[0387] It should be noted that the analysis of residual solids did not show polymorphic transformation during the experiment. The data for forms 3 and 4 are equivalents within experimental error.

[0388] Example 17: Single-crystal X-ray diffraction (SCXRD) of crystalline form 1 of compound I. Crystallization of compound I from propyl acetate, sealed in a Lindemann glass capillary, yielding *0.5*0.04*0.02 mm 3 Crystals of this size were obtained. X-ray diffraction data were obtained using a SMART APEX region detector, a cryogenic instrument (model LT 2), and molybdenum K α Acquisition was performed using a Bruker / AXS 3-circle diffractometer with a rotating anode generator, operated at 50kV / 120mA, and measured on a 0.5×5mm scale. 2 The focus was adjusted to high precision. Using the program package SMART V 5.628 (Bruker AXS, 2001), data frames were collected by applying ω-scanning with a step size of 0.3° and an exposure time of 60 seconds. Data processing using the program SAINT+Release6.45 (Bruker AXS, 2003) was performed on 6452 reflections.

[0389]

number

[0390] Using the XL module of SHELXTL 6.14 (Bruker AXS, 2000), the least squares method ((F o 2 -F c 2 ) 2 The structure was refined by minimizing the difference Fourier synthesis map. The position of all H atoms is determined by the difference Fourier synthesis map, S goodness of fit =0.780, R all data =0.2189(|F obs |>4σ, wR2 all data =0.1080, wR2 obs. data R for 1479 reflections using =0.0759 obs. data This was experimentally determined from (=0.0536). The largest unassigned peak in the difference map is Å 3 This corresponds to -0.193 pairs and +0.162 electrons per bond. The mean estimated standard deviation (esd) for CC bonds is 0.005 Å, for OC bonds it is 0.004 Å, for NC bonds it is 0.004 Å, and for CH bonds it is 0.03 Å. The mean esd for CCC bond angles is 0.4, and the CCCC twist angle is 0.5°.

[0391] The crystal structure of crystalline form 1 of compound I was determined at 293K, and a summary of the structural data can be found in Tables 1 and 2. The molecular structure is shown in Figure 5.

[0392] [Table 21]

[0393] [Table 22-1]

[0394] [Table 22-2]

[0395] Example 18: Single-crystal X-ray diffraction (SCXRD) of crystalline form 2 of compound I. Crystallization of compound I from N-methyl-2-pyrrolidone / methanol, sealed in a Lindemann glass capillary, yielded 0.6*0.2*0.2 mm 3 Crystals of this size were obtained. X-ray diffraction data were obtained using a SMART APEX region detector, a cryogenic instrument (model LT 2), and copper-K α Data was acquired using a Bruker / AXS 3-circle diffractometer equipped with a microfocus generator, manipulating a focused beam Montel multilayer optical component (Wiesmann et al., 2007) with an image focus spot diameter of approximately 250 μm at 45 kV / 650 μA. Using the SMART V 5.628 program package (Bruker AXS, 2001), ω-scanning was applied with a step size of 0.3° and an exposure time of 5 seconds to acquire data frames. Data processing using the SAINT+Release 6.45 program (Bruker AXS, 2003) resulted in 23,571 reflections.

[0396]

number

[0397] Using the XL module of SHELXTL 6.14 (Bruker AXS, 2000), the least squares method ((F o 2 -F c2 ) 2 The structure was refined by minimizing the difference Fourier synthesis map. The position of all H atoms is determined by the difference Fourier synthesis map, S goodness of fit =1.039, R all data =0.0490((|F obs |>4σ, wR2 all data =0.1041, wR2 obs. data R for 3283 reflections using =0.0971 obs. data This was experimentally determined from (=0.0379). The largest unassigned peak in the difference map is Å 3 This corresponds to -0.179 pairs and +0.185 electrons per unit. The mean estimated standard deviation (esd) of CC bonds is 0.002 Å, which is 0.002 Å for OC bonds, 0.002 Å for NC bonds, and 0.02 Å for CH bonds. The mean esd of the CCC bond angle is 0.2, which is 0.2° for the CCCC twist angle.

[0398] The crystal structure of crystalline form 2 of compound I was determined at 293K, and a summary of the structural data can be found in Tables 3 and 4. The molecular structure is shown in Figure 9.

[0399] [Table 23]

[0400] [Table 24-1]

[0401] [Table 24-2]

[0402] The experimentally determined powder diffraction pattern is consistent with that calculated from the crystal structure.

[0403] Example A-1: ​​Parenteral pharmaceutical composition To prepare parenteral pharmaceutical compositions suitable for administration by injection (subcutaneous or intravenous), dissolve 1 to 100 mg of compound I, or a pharmaceutically acceptable salt or solvate thereof, in sterile water, and then mix with 10 mL of 0.9% sterile saline. Adjust the pH by optionally adding a suitable buffer solution, along with an optional acid or base. Consolidate the mixture into a unit dosage form suitable for injection.

[0404] Example A-2: Oral solution To prepare a pharmaceutical composition for oral delivery, a sufficient amount of compound I, or a pharmaceutically acceptable salt thereof, is added to water (along with an optional solubilizer, an optional buffer, and taste-masking excipients) to provide a 20 mg / mL solution.

[0405] Example A-3: Oral tablets Tablets are prepared by mixing 20-50% by weight of compound I or a pharmaceutically acceptable salt thereof, 20-50% by weight of microcrystalline cellulose, 1-10% by weight of unsubstituted hydroxypropyl cellulose, and 1-10% by weight of magnesium stearate or other suitable excipients. Tablets are prepared by direct compression. The total weight of the compressed tablets is maintained at 100-500 mg.

[0406] Example A-4: Oral capsule To prepare a pharmaceutical composition for oral delivery, 10 to 500 mg of compound I, or a pharmaceutically acceptable salt thereof, is optionally mixed with starch or other suitable powder blends. The mixture is then incorporated into an oral dosage form, such as a hard gelatin capsule, suitable for oral administration.

[0407] In another embodiment, 10 to 500 mg of the compound described herein, or a pharmaceutically acceptable salt thereof, is placed in a size 4 capsule or a size 1 capsule (hypromellose or hard gelatin), and the capsule is closed.

[0408] The examples and embodiments described herein are for illustrative purposes only, and various modifications or changes suggested to those skilled in the art should be included within the spirit and scope of this application and the attached claims.

Claims

1. Crystal form 1 of 2-(4-methoxy-3-(3-methylphenethoxy)benzamide)-2,3-dihydro-1H-indene-2-carboxylic acid (compound I), wherein the crystal form 1 is The X-ray powder diffraction (XRPD) pattern, measured using Cu(Kα) radiation, is substantially the same as that shown in Figure 1, or X-ray powder diffraction (XRPD) patterns measured using Cu(Kα) rays, with peaks at 5.2±0.2°²-theta, 9.0±0.2°²-theta, 14.4±0.2°²-theta, and 17.7±0.2°²-theta, or Approximately 1739.6 cm －１ A Fourier transform IR spectroscopy (FTIR) pattern with a peak, or At 293K, Table 1 The unit cell parameter is substantially equal to this. This is essentially the same solid state as shown in Figure 4. １３ Carbon nuclear magnetic resonance (ssNMR) spectrum, or Solid states characterized by resonances (δc) at 23.35, 124.43, 126.78, 127.42, and 136.47 ppm １３ Carbon nuclear magnetic resonance (ssNMR) spectrum, or These combinations A crystal form 1 characterized by having the following characteristics.

2. Crystalline form 1 of 2-(4-methoxy-3-(3-methylphenethoxy)benzamide)-2,3-dihydro-1H-indene-2-carboxylic acid (compound I), having an X-ray powder diffraction (XRPD) pattern with peaks at 5.2±0.2°²-theta, 9.0±0.2°²-theta, 14.4±0.2°²-theta, and 17.7±0.2°²-theta, measured using Cu(Kα) radiation.

3. Crystalline form 1 of 2-(4-methoxy-3-(3-methylphenethoxy)benzamide)-2,3-dihydro-1H-indene-2-carboxylic acid (compound I), having substantially the same X-ray powder diffraction (XRPD) pattern as shown in Figure 1, measured using Cu(Kα) radiation.

4. At 293K, Table 2 Crystal form 1 of 2-(4-methoxy-3-(3-methylphenethoxy)benzamide)-2,3-dihydro-1H-indene-2-carboxylic acid (compound I) having substantially equal unit cell parameters.

5. This is essentially the same solid state as shown in Figure 4. １３ Crystal morphology 1 of 2-(4-methoxy-3-(3-methylphenethoxy)benzamide)-2,3-dihydro-1H-indene-2-carboxylic acid (compound I) having a carbon nuclear magnetic resonance (ssNMR) spectrum.

6. The crystalline form 1 of compound I is substantially the same solid state as that shown in Figure 4. １３ The crystal morphology according to any one of claims 2 to 4, further characterized by having a carbon nuclear magnetic resonance (ssNMR) spectrum.

7. Solid states characterized by resonances (δc) at approximately 23.35 ppm, 124.43 ppm, 126.78 ppm, 127.42 ppm, and 136.47 ppm. １３ Crystal morphology 1 of 2-(4-methoxy-3-(3-methylphenethoxy)benzamide)-2,3-dihydro-1H-indene-2-carboxylic acid (compound I) having a carbon nuclear magnetic resonance (ssNMR) spectrum.

8. The crystalline form 1 of compound I is a solid state characterized by resonance (δc) at approximately 23.35 ppm, approximately 124.43 ppm, approximately 126.78 ppm, approximately 127.42 ppm, and approximately 136.47 ppm. １３ The crystal morphology according to any one of claims 2 to 4, further characterized by having a carbon nuclear magnetic resonance (ssNMR) spectrum.

9. Approximately 1739.6 cm －１ Crystal morphology 1 of 2-(4-methoxy-3-(3-methylphenethoxy)benzamide)-2,3-dihydro-1H-indene-2-carboxylic acid (compound I) having a Fourier transform IR spectroscopy (FTIR) pattern with a peak.

10. The crystalline form 1 of the compound I further has a Fourier transform IR spectroscopy (FTIR) pattern having a peak at about 1739.6 cm －１ The crystalline form according to any one of claims 2 to 10, further characterized in that.

11. The crystal morphology according to any one of claims 1 to 10, further characterized in that the crystal morphology 1 of compound I has substantially the same differential scanning calorimetry (DSC) thermogram as that shown in Figure 2.

12. The crystal morphology according to any one of claims 1 to 10, further characterized in that the crystal morphology 1 of compound I has a differential scanning calorimetry (DSC) thermogram having three endothermic events: one at approximately 198.5°C and a peak at approximately 200.4°C, one at approximately 204.8°C and a peak at approximately 205.8°C, and one at approximately 213.9°C and a peak at approximately 216.3°C.

13. The crystalline form 1 of compound I is anhydrous, according to any one of claims 1 to 12.

14. The crystalline form 1 of compound I substantially does not include the crystalline form 2 of compound I, as described in any one of claims 1 to 13.

15. The crystalline form 1 of compound I includes the crystalline form 2 of compound I at less than 1% w / w, according to any one of claims 1 to 13.

16. Crystal form 2 of 2-(4-methoxy-3-(3-methylphenethoxy)benzamide)-2,3-dihydro-1H-indene-2-carboxylic acid (compound I), wherein the crystal form 2 is The X-ray powder diffraction (XRPD) pattern measured using Cu(Kα) radiation is substantially the same as that shown in Figure 6, or X-ray powder diffraction (XRPD) patterns measured using Cu(Kα) rays, with peaks at 5.6±0.2°²-theta, 7.6±0.2°²-theta, 9.4±0.2°²-theta, 15.5±0.2°²-theta, and 16.3±0.2°²-theta, or Approximately 1731.7cm －１ Fourier transform IR spectroscopy (FTIR) pattern with a peak, Or 293K Table 3 The unit cell parameter is substantially equal to this. This is essentially the same solid state as shown in Figure 8. １３ Carbon nuclear magnetic resonance (ssNMR) spectrum, or Solid states characterized by resonances (δc) at 20.59, 126.39, 128.34, and 137.69 ppm １３ Carbon nuclear magnetic resonance (ssNMR) spectrum, or These combinations Crystal form 2, characterized by having the following characteristics.

17. Crystalline form 2 of 2-(4-methoxy-3-(3-methylphenethoxy)benzamide)-2,3-dihydro-1H-indene-2-carboxylic acid (compound I), characterized by having substantially the same X-ray powder diffraction (XRPD) pattern as shown in Figure 6, measured using Cu(Kα) rays.

18. Crystalline form 2 of 2-(4-methoxy-3-(3-methylphenethoxy)benzamide)-2,3-dihydro-1H-indene-2-carboxylic acid (compound I), characterized by having an X-ray powder diffraction (XRPD) pattern with peaks at 5.6±0.2°²-theta, 7.6±0.2°²-theta, 9.4±0.2°²-theta, 15.5±0.2°²-theta, and 16.3±0.2°²-theta, as measured using Cu(Kα) rays.

19. At 293K, Table 4 Crystal form 2 of 2-(4-methoxy-3-(3-methylphenethoxy)benzamide)-2,3-dihydro-1H-indene-2-carboxylic acid (compound I), characterized by having unit cell parameters substantially equal to those of the other compound.

20. This is essentially the same solid state as shown in Figure 8. １３ Crystal form 2 of 2-(4-methoxy-3-(3-methylphenethoxy)benzamide)-2,3-dihydro-1H-indene-2-carboxylic acid (compound I), characterized by having a carbon nuclear magnetic resonance (ssNMR) spectrum.

21. The crystalline form 2 of compound I is substantially the same solid state as that shown in Figure 8. １３ The crystal morphology according to any one of claims 16 to 19, further characterized by having a carbon nuclear magnetic resonance (ssNMR) spectrum.

22. Solid states characterized by resonances (δc) at 20.59, 126.39, 128.34, and 137.69 ppm １３ Crystalline form 2 of 2-(4-methoxy-3-(3-methylphenethoxy)benzamide)-2,3-dihydro-1H-indene-2-carboxylic acid (compound I) having a carbon nuclear magnetic resonance (ssNMR) spectrum.

23. The crystalline form 2 of compound I is a solid state characterized by resonance (δc) at 20.59, 126.39, 128.34, and 137.69 ppm. １３ The crystal morphology according to any one of claims 16 to 19, further characterized by having a carbon nuclear magnetic resonance (ssNMR) spectrum.

24. Approximately 1731.6 cm －１ Crystal form 2 of 2-(4-methoxy-3-(3-methylphenethoxy)benzamide)-2,3-dihydro-1H-indene-2-carboxylic acid (compound I), characterized by having a Fourier transform IR spectroscopy (FTIR) pattern with a peak.

25. The crystalline form 2 of compound I is approximately 1731.7 cm². －１ The crystal morphology according to any one of claims 16 to 23, further characterized by having a Fourier transform IR spectroscopy (FTIR) pattern with a peak at [location].

26. The crystal morphology according to any one of claims 16 to 25, further characterized in that the crystal morphology 2 of compound I has substantially the same differential scanning calorimetry (DSC) thermogram as that shown in Figure 7.

27. The crystal morphology according to any one of claims 16 to 25, further characterized in that the crystal morphology 2 of compound I has a differential scanning calorimetry (DSC) thermogram with an endothermic event having a start at approximately 215.3°C and a peak at approximately 216.4°C.

28. The crystalline form 2 of compound I is anhydrous, according to any one of claims 16 to 27.

29. Crystal form 3 of 2-(4-methoxy-3-(3-methylphenethoxy)benzamide)-2,3-dihydro-1H-indene-2-carboxylic acid (compound I), where crystal form 3 is The X-ray powder diffraction (XRPD) pattern measured using Cu(Kα) radiation is substantially the same as that shown in Figure 10, or X-ray powder diffraction (XRPD) patterns measured using Cu(Kα) rays, with peaks at 4.2±0.2°²-theta, 6.8±0.2°²-theta, 15.1±0.2°²-theta, 25.0±0.2°²-theta, 25.5±0.2°²-theta, and 26.4±0.2°²-theta, or Approximately 1722.0cm －１ A Fourier transform IR spectroscopy (FTIR) pattern with a peak at, or This is essentially the same solid state as shown in Figure 12. １３ Carbon nuclear magnetic resonance (ssNMR) spectrum, or Solid states characterized by resonances (δc) at 64.56, 67.67, 122.99, and 126.71 ppm １３ Carbon nuclear magnetic resonance (ssNMR) spectrum, or These combinations A crystal form 3 characterized by having the following characteristics.

30. Crystalline form 3 of 2-(4-methoxy-3-(3-methylphenethoxy)benzamide)-2,3-dihydro-1H-indene-2-carboxylic acid (compound I), characterized by having substantially the same X-ray powder diffraction (XRPD) pattern as shown in Figure 10, measured using Cu(Kα) rays.

31. Crystalline form 3 of compound I of 2-(4-methoxy-3-(3-methylphenethoxy)benzamide)-2,3-dihydro-1H-indene-2-carboxylic acid (compound I), characterized by having an X-ray powder diffraction (XRPD) pattern with peaks at 4.2±0.2°²-theta, 6.8±0.2°²-theta, 15.1±0.2°²-theta, 25.0±0.2°²-theta, 25.5±0.2°²-theta, and 26.4±0.2°²-theta, measured using Cu(Kα) rays.

32. Approximately 1722.0cm －１ Crystal form 3 of 2-(4-methoxy-3-(3-methylphenethoxy)benzamide)-2,3-dihydro-1H-indene-2-carboxylic acid (compound I), characterized by having a Fourier transform IR spectroscopy (FTIR) pattern with a peak at [location].

33. The crystalline form 3 of compound I is approximately 1722.0 cm². －１ The crystal morphology according to claim 30 or 31, further characterized by having a Fourier transform IR spectroscopy (FTIR) pattern with a peak at [location].

34. This is essentially the same solid state as shown in Figure 12. １３ Crystal form 3 of 2-(4-methoxy-3-(3-methylphenethoxy)benzamide)-2,3-dihydro-1H-indene-2-carboxylic acid (compound I), characterized by having a carbon nuclear magnetic resonance (ssNMR) spectrum.

35. The crystalline form 3 of compound I is substantially the same solid state as that shown in Figure 12. １３ The crystal morphology according to any one of claims 30 to 33, further characterized by having a carbon nuclear magnetic resonance (ssNMR) spectrum.

36. Solid states characterized by resonances (δc) at 64.56, 67.67, 122.99, and 126.71 ppm １３ Crystal form 3 of 2-(4-methoxy-3-(3-methylphenethoxy)benzamide)-2,3-dihydro-1H-indene-2-carboxylic acid (compound I), characterized by having a carbon nuclear magnetic resonance (ssNMR) spectrum.

37. The crystalline form 3 of compound I is a solid state characterized by resonance (δc) at 64.56, 67.67, 122.99, and 126.71 ppm. １３ The crystal morphology according to any one of claims 30 to 33, further characterized by having a carbon nuclear magnetic resonance (ssNMR) spectrum.

38. The crystal morphology according to any one of claims 29 to 37, further characterized in that the crystal morphology 3 of compound I has substantially the same differential scanning calorimetry (DSC) thermogram as that shown in Figure 11.

39. The method according to any one of claims 27 to 37, wherein the crystalline form 3 of compound I is further characterized by a differential scanning calorimetry (DSC) thermogram having one or more endothermic events having a start at about 204.2°C and a peak at about 205.3°C, and / or a start at about 213.6°C and a peak at about 215.8°C.

40. The crystalline form 3 of compound I is anhydrous, according to any one of claims 29 to 39.

41. Crystal form 4 of 2-(4-methoxy-3-(3-methylphenethoxy)benzamide)-2,3-dihydro-1H-indene-2-carboxylic acid (compound I), wherein the crystal form 4 is The X-ray powder diffraction (XRPD) pattern measured using Cu(Kα) radiation is substantially the same as that shown in Figure 13, or Approximately 1743.9cm －１ A Fourier transform IR spectroscopy (FTIR) pattern with a peak at, or These combinations A crystal form 4 characterized by having the following characteristics.

42. Crystalline form 4 of 2-(4-methoxy-3-(3-methylphenethoxy)benzamide)-2,3-dihydro-1H-indene-2-carboxylic acid (compound I), characterized by having substantially the same X-ray powder diffraction (XRPD) pattern as shown in Figure 13, measured using Cu(Kα) rays.

43. The crystal morphology according to claim 41 or 42, further characterized in that the crystal morphology 4 of compound I has substantially the same differential scanning calorimetry (DSC) thermogram as that shown in Figure 14.

44. The crystalline form 4 of compound I is anhydrous, according to any one of claims 41 to 43.

45. The amorphous phase of 2-(4-methoxy-3-(3-methylphenethoxy)benzamide)-2,3-dihydro-1H-indene-2-carboxylic acid (compound I), wherein the amorphous phase exhibits an XRPD pattern indicating a lack of crystallinity and / or is substantially the same as that shown in Figure 16. １３ An amorphous phase characterized by having a carbon nuclear magnetic resonance (ssNMR) spectrum.

46. A pharmaceutical composition comprising the crystalline form 1 described in any one of claims 1 to 15 and at least one pharmaceutically acceptable excipient.

47. A pharmaceutical composition comprising the crystalline form described in any one of claims 1 to 44 or the amorphous phase described in claim 45 and at least one pharmaceutically acceptable excipient.

48. The pharmaceutical composition according to claim 46 or 47, wherein the pharmaceutical composition is in the form of a solid pharmaceutical composition.

49. The pharmaceutical composition according to claim 48, wherein the pharmaceutical composition is in the form of a tablet, pill, or capsule.

50. The pharmaceutical composition according to any one of claims 46 to 49, wherein the pharmaceutical composition is in the form of a tablet and contains about 50 mg to about 300 mg of crystalline form 1 of compound I.

51. The pharmaceutical composition according to any one of claims 46 to 50, wherein the pharmaceutical composition is in the form of a tablet and contains about 150 mg of compound I in crystalline form 1.

52. The pharmaceutical composition according to any one of claims 46 to 51, wherein the pharmaceutical composition comprises a crystalline form 1 of compound I, and the crystalline form 1 of compound I substantially does not contain a crystalline form 2 of compound I.

53. The pharmaceutical composition according to any one of claims 46 to 51, wherein the pharmaceutical composition comprises a crystalline form 1 of compound I, and the crystalline form 1 of compound I comprises a crystalline form 2 of compound I at less than 1% w / w.

54. The pharmaceutical composition according to any one of claims 46 to 53, wherein the pharmaceutical composition substantially does not contain impurities of compound I.

55. The pharmaceutical composition according to any one of claims 46 to 53, wherein the pharmaceutical composition contains an impurity of compound I in less than about 1% w / w.

56. The pharmaceutical composition according to claim 55, wherein the impurities of compound I include one or more decomposition products of compound I, one or more intermediates used in the synthesis of compound I, or a combination thereof.

57. The pharmaceutical composition according to claim 55, wherein the impurities of compound I include one or more intermediates used in the synthesis of compound I.

58. The impurities in compound I are 【Chemistry 1】 A pharmaceutical composition according to claim 55, or a combination thereof selected.

59. Compound I: 【Chemistry 2】 A process for preparing compounds having the structure, The aforementioned process （１） Formula 7: 【Transformation 3】 (In the formula, M ＋ is Na ＋ _K ＋ , or Li ＋ To provide compounds where M-OH is NaOH, KOH, or LiOH, Formula 6: 【Chemistry 4】 (In the formula, R ２ C １ -C ２０ Alkyl, C １ -C ２０ Alkenil, C ３ -C １０ Cycloalkyl, or C ３ -C １０ A step of contacting a compound (which is a cycloalkenyl) with a hydroxide reagent having the formula M-OH in a suitable solvent, (2) To provide compound I, the step of contacting the compound of formula 7 with a suitable organic acid in a suitable solvent, The process includes.

60. R ２ The process according to claim 59, wherein is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, isoamyl, pentyl, hexyl, heptyl, octyl, nonyl, terpenyl, bornyl, allyl, linalyl, or geranyl.

61. The compound of formula 6 is compound 6a: 【Transformation 5】 The process according to claim 59.

62. The hydroxide reagent in step (1) is NaOH, and the compound of formula 7 is compound 7a: 【Transformation 6】 The process according to any one of claims 59 to 61.

63. The process according to any one of claims 59 to 62, wherein the suitable solvent for step (1) is tetrahydrofuran, methanol, ethanol, ethylene glycol, acetonitrile, water, or a combination thereof, the suitable organic acid for step (2) is lactic acid, acetic acid, formic acid, citric acid, oxalic acid, malic acid, or tartaric acid, and the suitable solvent for step (2) is tetrahydrofuran, methanol, ethanol, ethylene glycol, acetonitrile, water, or a combination thereof, and the pH of the solution after the addition of the organic acid is about 7 to about 8.

64. The process according to any one of claims 59 to 62, wherein the suitable solvent in step (1) is a mixture of methanol and water, and the suitable organic acid in step (2) is citric acid, and the suitable solvent in step (2) is a mixture of methanol and water.

65. Step (1) is carried out at a temperature of approximately 60°C for at least two hours, the process according to any one of claims 59 to 64.

66. The process according to any one of claims 59 to 65, wherein the pH of the solution after the addition of the organic acid is approximately 7.

5.

67. The process according to any one of claims 59 to 66, wherein the compound of formula 7 is not isolated before step (2), and steps (1) and (2) are carried out in the same reaction vessel.

68. The process according to claim 67, wherein the reaction mixture in step (1) is cooled to room temperature before the addition of the organic acid.

69. The process according to any one of claims 59 to 68, comprising the steps of crystallizing compound I from the reaction mixture of step (2), and isolating crystalline form 1 of compound I.

70. The process according to claim 69, wherein the reaction mixture is seeded in the crystalline form 1 of pure compound I.

71. The process according to claim 69 or 70, wherein the reaction mixture in step (2) is cooled to about 10°C.

72. The process of claim 69 or 70, wherein the reaction mixture in step (2) is cooled to about 10°C over about 3 hours.

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