Crystalline forms of LPA1 antagonists

Abstract

Compound (A) Described herein is the LPA1 antagonist (1S,3S)-3-((2-methyl-6-(1-methyl-5-(((methyl(propyl)carbamoyl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid, including crystalline forms of TIFF2025542317000009.tif31165 and preparations thereof. Pharmaceutical compositions containing the LPA1 antagonists, and methods of using the LPA1 antagonists for the treatment of interstitial lung disease, are also disclosed.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of priority to U.S. Provisional Patent Application No. 63 / 477,000, filed December 23, 2022, which is incorporated herein by reference in its entirety.

[0002] Described herein is the LPA1 antagonist (1S,3S)-3-((2-methyl-6-(1-methyl-5-(((methyl(propyl)carbamoyl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid, including crystalline forms. The disclosure also relates to preparations of the crystalline forms, pharmaceutical compositions thereof, and methods of using the LPA1 antagonists in the treatment of fibrotic diseases or conditions, including interstitial lung disease. [Background technology]

[0003] Interstitial lung diseases (ILDs) are a heterogeneous group of lung disorders classified together based on common clinical features: parenchymal lung scarring (fibrosis) and / or inflammation with various patterns of lung damage by imaging or histopathology. ILDs can arise from identifiable causes, such as underlying systemic autoimmune diseases (e.g., systemic sclerosis or rheumatoid arthritis), environmental exposures (e.g., asbestos or silica), or drug toxicity, but are often idiopathic in nature. Idiopathic pulmonary fibrosis (IPF), one of the more common and most devastating types of ILD, is a chronic, progressive, typically fatal lung disease of unknown etiology characterized by worsening dyspnea, cough, and loss of lung function due to scarring in the lungs, and must have a pathological and radiological pattern known as usual interstitial pneumonia (UIP) (Non-Patent Document 1). Besides IPF, some patients with other forms of ILD develop a progressive fibrotic phenotype characterized by respiratory symptoms, worsening lung function, progressive fibrosis on imaging, and early mortality.

[0004] To date, two approved treatments, pirfenidone and nintedanib, significantly reduce the decline in lung function in patients with IPF, and both appear to modestly impact progression-free survival (Non-Patent Document 2, Non-Patent Document 3, Non-Patent Document 4). However, many patients progress despite treatment. Another treatment option, lung transplantation, has been shown to improve mortality in carefully selected patients, but not without complications (Non-Patent Document 5). Despite these advances, there remains a significant unmet need for safe, well-tolerated, and effective IPF therapies that improve lung function, delay disease progression, and reduce mortality.

[0005] Because of the clinical and pathophysiological similarities between IPF and other forms of progressive pulmonary fibrosis (PPF), it has been suggested that such disorders, regardless of their cause, share common pathobiological mechanisms, resulting in progressive pulmonary fibrosis and therefore may have similar treatment responses to IPF (Non-Patent Document 6, Non-Patent Document 7, Non-Patent Document 8). Indeed, in the recently published INBUILD trial, patients with PPF of various etiologies were treated with nintedanib or placebo. Patients treated with nintedanib experienced slower progression of pulmonary fibrosis than patients receiving placebo, as demonstrated by a lower annual rate of decline in forced vital capacity (FVC) over the 52-week study period (Non-Patent Document 8). The absolute treatment effect in the PPF trial was similar in magnitude to that observed in the pivotal IMPULSIS trial, which led to the approval of nintedanib for the treatment of IPF. Furthermore, the IMPULSIS and INBUILD trials demonstrated that IPF and PPF patients were similar in terms of FVC decline. Based on data from the INBUILD trial, health authorities have also approved nintedanib for patients with PPF. Nevertheless, many patients cannot tolerate nintedanib due to gastrointestinal side effects, and some patients may progress despite treatment with nintedanib, so there remains an unmet need for an effective, well-tolerated treatment for PPF (Non-Patent Document 8).

[0006] Overall, there is a high unmet need for effective and tolerable treatments for patients with non-IPF, progressive pulmonary fibrosis (PPF) who present with disease progression. Fibrotic diseases such as these are characterized by the activation of six LPA receptors (LPA). 1~6 This can be mediated by LPA1, which signals through LPA1. Signaling through LPA1 appears to be fundamental in the pathogenesis of fibrotic diseases.

[0007] Patent Document 1 (Patent Document 2) discloses specific antagonists of lysophosphatidic acid (LPA) receptors for use in treating LPA-dependent or LPA-mediated conditions or diseases, such as fibrosis of various organs, including the lung.

[0008] The compound (1S,3S)-3-((2-methyl-6-(1-methyl-5-(((methyl(propyl)carbamoyl)-oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (hereinafter referred to as "Compound A") is described in Patent Document 1. [ka] [Prior art documents] [Patent documents]

[0009] [Patent Document 1] US Patent Application Publication No. 2017 / 0360759 [Patent Document 2] International Publication No. 2017 / 223016 Brochure [Non-patent literature]

[0010] [Non-Patent Document 1] Meltzer et al.,Orphanet J.Rare Dis.2008,3:8 [Non-patent document 2] Noble et al.,Lancet 2011,377 (9779),1760-1769 [Non-patent document 3] King et al.,N.Engl.J.Med.2014,370(22),2083-2092 [Non-patent document 4] Richeldi et al.,New Engl J Med 2014,370(22),2071-2082 [Non-patent document 5] Kistler et al.,BMC Pulmonary Med.2014;14:139 [Non-patent document 6] Raghu et al.,Am.J.Respir.Crit.Care Med.2022,205,e18-e47 [Non-Patent Document 7] du Bois et al.,Am.J.Respir.Crit.Care Med.2012,186,712-715 [Non-patent document 8] Flaherty et al.,N.Engl.J.Med.2019,381(18),1718-1727 Summary of the Invention [Means for solving the problem]

[0011] Compound A is a potent LPA1 antagonist in vitro (LPA1K in CHO cells overexpressing human LPA1). b = 6.9 nM, and LPA1K in normal human lung fibroblasts b =5.9 nM). Compound A is currently in clinical development for the treatment of IPF and PF-ILD. The present disclosure provides methods of treating interstitial lung disease using Compound A. [Brief explanation of the drawings]

[0012] [Figure 1] 1 shows the powder X-ray diffraction (PXRD) pattern of Form A. [Figure 2]1 shows a differential scanning calorimetry (DSC) thermogram of Form A. [Figure 3] 1 shows a thermogravimetric analysis (TGA) thermogram of Form A. [Figure 4] 1 shows the moisture sorption isotherm of Form A. DETAILED DESCRIPTION OF THE INVENTION

[0013] In some embodiments, the present disclosure provides a compound A: [ka] The present invention provides crystalline form A of the compound of formula (I).

[0014] In some embodiments, the crystalline form is a) a single crystal structure, Crystal system, space group triclinic system, P1 Unit cell dimensions a=6.53±0.10Å α=92.8±1.0° b=13.06±0.10Å β=95.5±1.0° c=14.04±0.10Å γ=93.0±1.0° Volume 1189(20)Å 3 Density (calculation) 1.239g / cm 3 temperature room temperature and the measurements of the single crystal structure are at room temperature. b) a powder X-ray diffraction pattern substantially the same as that shown in Figure 1; c) a powder X-ray diffraction pattern (obtained at room temperature and CuKα λ=1.5418 Å) comprising two or more peaks at 2θ values ​​selected from 6.4±0.2, 6.8±0.2, 9.6±0.2, 13.6±0.2, 15.7±0.2, 18.2±0.2, 19.9±0.2, 21.6±0.2, 24.8±0.2, and 26.8±0.2; d) a powder X-ray diffraction pattern (obtained at room temperature and CuKα λ=1.5418 Å) comprising three or more peaks at 2θ values ​​selected from 6.4±0.2, 6.8±0.2, 9.6±0.2, 13.6±0.2, 14.1±0.2, 14.5±0.2, 14.7±0.2, 15.7±0.2, 18.2±0.2, 18.7±0.2, 19.2±0.2, 19.9±0.2, 20.5±0.2, 21.6±0.2, 22.5±0.2, 23.1±0.2, 24.1±0.2, 24.8±0.2, 25.6±0.2, 26.8±0.2, 27.1±0.2, and 27.8±0.2; e) A differential scanning calorimetry thermogram substantially similar to that shown in Figure 2; f) a differential scanning calorimetry thermogram with an endotherm onset at about 152°C, and / or g) Thermogravimetric analysis thermogram substantially similar to that shown in Figure 3 It is characterized by at least one of the following:

[0015] In some embodiments, crystalline form A is a single crystalline structure having Crystal system, space group triclinic system, P1 Unit cell dimensions a=6.53±0.10Å α=92.8±1.0° b=13.06±0.10Å β=95.5±1.0° c=14.04±0.10Å γ=93.0±1.0° Volume 1189(20)Å 3 Density (calculation) 1.239g / cm 3 temperature room temperature and the measurements of the single crystal structure are at room temperature.

[0016] In some embodiments, crystalline Form A is characterized by a powder X-ray diffraction pattern substantially the same as that shown in FIG.

[0017] In some embodiments, crystalline form A is characterized by a powder X-ray diffraction pattern (obtained at room temperature and CuKα λ=1.5418 Å) comprising two or more peaks at 2θ values ​​selected from 6.4±0.2, 6.8±0.2, 9.6±0.2, 13.6±0.2, 15.7±0.2, 18.2±0.2, 19.9±0.2, 21.6±0.2, 24.8±0.2, and 26.8±0.2.

[0018] In some embodiments, Form A has an X-ray powder diffraction pattern (obtained at room temperature and CuKα λ=1.5418 Å) comprising two or more peaks at 2θ values ​​selected from 6.4±0.2, 6.8±0.2, 13.6±0.2, 15.7±0.2, and 21.6±0.2.

[0019] In some embodiments, Form A has an X-ray powder diffraction pattern (obtained at room temperature and CuKα λ=1.5418 Å) comprising three or more peaks at 2θ values ​​selected from 6.4±0.2, 6.8±0.2, 13.6±0.2, 15.7±0.2, and 21.6±0.2.

[0020] In some embodiments, crystalline Form A is characterized by a powder X-ray diffraction pattern (obtained at room temperature and CuKα λ=1.5418 Å) comprising three or more peaks at 2θ values ​​selected from 6.4±0.2, 6.8±0.2, 9.6±0.2, 13.6±0.2, 14.1±0.2, 14.5±0.2, 14.7±0.2, 15.7±0.2, 18.2±0.2, 18.7±0.2, 19.2±0.2, 19.9±0.2, 20.5±0.2, 21.6±0.2, 22.5±0.2, 23.1±0.2, 24.1±0.2, 24.8±0.2, 25.6±0.2, 26.8±0.2, 27.1±0.2, and 27.8±0.2.

[0021] In some embodiments, Form A has a powder X-ray diffraction pattern (obtained at room temperature and CuKα λ=1.5418 Å) comprising four or more peaks at 2θ values ​​selected from 6.4±0.2, 6.8±0.2, 13.6±0.2, 15.7±0.2, and 21.6±0.2. In some embodiments, crystalline Form A is characterized by a differential scanning calorimetry thermogram substantially similar to that shown in FIG.

[0022] In some embodiments, crystalline Form A is characterized by a differential scanning calorimetry thermogram with an endotherm at an onset of about 152°C.

[0023] In some embodiments, crystalline Form A is characterized by a thermogravimetric analysis thermogram substantially similar to that shown in FIG.

[0024] In some embodiments, the crystalline form is a substantially pure form.

[0025] In some aspects, the present disclosure provides pharmaceutical compositions comprising a pharmaceutically acceptable carrier and crystalline Form A according to claims 1-10, alone or in combination with another therapeutic agent.

[0026] In some embodiments, the crystalline forms described herein are used to treat interstitial lung disease. In some embodiments, the interstitial lung disease is idiopathic pulmonary fibrosis (IPF). In some embodiments, the interstitial lung disease is progressive pulmonary fibrosis (PPF).

[0027] The present disclosure provides crystalline Compound A: [ka] and discloses methods for preparing and using the crystalline compounds.

[0028] In order that this description may be more readily understood, certain terms are first defined. Additional definitions are set forth throughout the detailed description.

[0029] I. Definition Unless otherwise stated, the following terms used in this application, including the specification and claims, have the definitions set forth below. It should be noted that as used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Conventional methods of mass spectroscopy, NMR, HPLC, protein chemistry, biochemistry, recombinant DNA techniques, and pharmacology are employed unless otherwise indicated. Furthermore, the use of other forms such as "include," "includes," and "including" is not intended to be limiting. The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.

[0030] All measurements are subject to experimental error and are within the scope of the present invention.

[0031] The designations used herein to characterize a particular form, e.g., "Form A," should not be considered as limitations on any other substance having similar or identical physical and chemical characteristics; rather, the designation should be understood as a mere identifier that should be interpreted in accordance with the characterization information also presented herein.

[0032] The term "about," when used in connection with numerical values ​​throughout this specification and claims, indicates an interval of accuracy well known and accepted by those skilled in the art. Such interval of accuracy is ±10%.

[0033] The term "acceptable" as used herein with respect to a formulation, composition, or ingredient means that it does not have any lasting adverse effects on the general health of the subject being treated.

[0034] The terms "administration" and / or "administering" a compound or composition should be understood to mean providing a compound or composition described herein to one or more subjects.

[0035] As used herein, "amorphous" refers to a solid form of molecules, atoms, and / or ions that is not crystalline. Amorphous solids do not exhibit distinct X-ray diffraction patterns.

[0036] The term "antagonist," as used herein, refers to a molecule, such as a compound, that reduces, inhibits, or prevents the action of another molecule or the activity of a receptor site. Antagonists include, but are not limited to, competitive antagonists, noncompetitive antagonists, uncompetitive antagonists, partial agonists, and inverse agonists.

[0037] As used herein, the term "co-administration" and the like is meant to encompass the administration of selected therapeutic agents to a single subject, and is intended to include therapeutic regimens in which the agents are administered by the same or different routes of administration or at the same or different times.

[0038] As used herein, the term "DSC" refers to differential scanning calorimetry. The term "TGA" refers to thermogravimetric analysis.

[0039] The terms "effective amount" or "therapeutically effective amount," as used herein, refer to a sufficient quantity of an agent or compound being administered to relieve to some extent one or more of the symptoms of the disease or condition being treated. The result can be reduction and / or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. For example, an "effective amount" for therapeutic use is the quantity of a composition comprising a compound disclosed herein that is required to provide a clinically significant reduction in a disease symptom. An appropriate "effective" amount in any individual case can be determined using techniques, such as a dose escalation study.

[0040] As used herein, the phrase "pharmaceutically acceptable" refers to compounds, materials, compositions and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication commensurate with a reasonable benefit / risk ratio.

[0041] As used herein, "polymorph" refers to crystalline forms that have the same chemical structure but differ in the spatial arrangement of the molecules and / or ions that form the crystals.

[0042] The term "room temperature" generally means approximately 22°C, but can vary up to 7°C above or below.

[0043] The term "subject" includes mammals. Examples of mammals include humans, chimpanzees, apes, monkeys, cows, horses, sheep, goats, pigs, rabbits, dogs, cats, rodents, rats, mice, guinea pigs, etc. In one embodiment, the mammal is a human.

[0044] As used herein, "substantially pure," when used in reference to a crystalline form, refers to a compound having a purity of greater than 90% by weight of the crystalline form of Compound A, based on the weight of the compound, including purities of greater than 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99% by weight of the crystalline form of Compound A, and including purities of greater than about 100% by weight of the crystalline form of Compound A. The remaining material comprises other forms of the compound and / or reaction and / or processing impurities resulting from its preparation. For example, a crystalline form of Compound A may be considered substantially pure in having a purity of greater than 90% by weight, as measured by means known and generally accepted in the art, with the remaining less than 10% by weight of the material comprising other forms of the compound and / or reaction and / or processing impurities.

[0045] When the term "substantially matches" is used in reference to a PXRD or XRPD pattern, it is understood that measurements of peak positions for a given crystalline form of the same compound will vary within a margin of error. It is also understood that the intensities of peaks may vary between different PXRD scans of the same crystalline form of the same compound. The relative intensities of different peaks are not meant to be limited to comparisons of different PXRD scans.

[0046] The terms "treat," "treating," or "treatment," as used herein, include alleviating, reducing, or ameliorating at least one symptom of a disease or condition, preventing further symptoms, arresting the onset of a disease or condition, relieving the disease or condition, causing regression of a disease or condition, alleviating pathology caused by a disease or condition, or prophylactically and / or therapeutically arresting the symptoms of a disease or condition.

[0047] II. Compound A Compound A is described in U.S. Patent Application Publication No. 2017 / 0360759. [ka]

[0048] In preparing pharmaceutical compositions, a form of an active ingredient is sought that has a balance of desired properties, such as, for example, dissolution rate, solubility, bioavailability, and / or storage stability. For example, a form of an active ingredient is sought that has sufficient solubility, bioavailability, and storage stability to prevent conversion of a sufficiently soluble and bioavailable form to another form with an undesirable solubility and / or bioavailability profile during the manufacture, preparation, and / or storage of the pharmaceutical composition. In addition, a form of the active ingredient may also be sought that allows for isolation and / or purification of the active ingredient, for example, during a preparative process.

[0049] The present invention surprisingly provides at least one form of Compound A that provides the balance of properties desired in a pharmaceutical composition.

[0050] Described herein are polymorphic and amorphous phases and methods of use thereof, preferably anhydrous Compound A.

[0051] In some embodiments, the present disclosure provides crystalline anhydrous Compound A.

[0052] In some aspects, the present disclosure provides a crystalline anhydrous form of Compound A, designated Form A. In some embodiments, Compound A is provided as a crystalline material comprising Form A. In some embodiments, crystalline Form A of Compound A is a pure crystalline form.

[0053] In some embodiments, Compound A comprises a crystalline form "Form A." Upon dissolution, the crystalline form of Compound A loses its crystalline structure and is therefore referred to as a solution of Compound A. However, all forms of the present invention may be used to prepare liquid formulations in which the drug is dissolved or suspended. In addition, crystalline Form A of Compound A may be incorporated into solid formulations.

[0054] As used herein, a PXRD (X-ray powder diffraction) or XRPD (X-ray powder diffraction) pattern that "comprises" or has peaks selected from a particular set of peaks is intended to include PXRD patterns that have additional peaks not included in the particular set of peaks. For example, a PXRD pattern that includes four or more, preferably five or more, peaks at 2θ values ​​selected from A, B, C, D, E, F, G, and H is intended to include PXRD patterns that have (a) four or more, preferably five or more, peaks at 2θ values ​​selected from A, B, C, D, E, F, G, and H, and (b) zero or more peaks that are not one of the peaks A, B, C, D, E, F, G, and H.

[0055] In some embodiments, Form A is a single crystalline structure having Crystal system, space group triclinic system, P1 Unit cell dimensions a=6.53±0.10Å α=92.8±1.0° b=13.06±0.10Å β=95.5±1.0° c=14.04±0.10Å γ=93.0±1.0° Volume 1189(20)Å 3 Density (calculation) 1.239g / cm 3 temperature room temperature and the measurements of the single crystal structure are at room temperature.

[0056] In some embodiments, Form A has a powder X-ray diffraction pattern substantially the same as that shown in FIG.

[0057] In some embodiments, Form A has an X-ray powder diffraction pattern (obtained at room temperature and CuKα λ=1.5418 Å) comprising two or more peaks at 2θ values ​​selected from 6.4±0.2, 6.8±0.2, 13.6±0.2, 15.7±0.2, and 21.6±0.2. In some embodiments, Form A has an X-ray powder diffraction pattern (obtained at room temperature and CuKα λ=1.5418 Å) comprising three or more peaks at 2θ values ​​selected from 6.4±0.2, 6.8±0.2, 13.6±0.2, 15.7±0.2, and 21.6±0.2. In some embodiments, Form A has an X-ray powder diffraction pattern (obtained at room temperature and CuKα λ=1.5418 Å) comprising four or more peaks at 2θ values ​​selected from 6.4±0.2, 6.8±0.2, 13.6±0.2, 15.7±0.2, and 21.6±0.2.

[0058] In some embodiments, Form A has an X-ray powder diffraction pattern (obtained at room temperature and CuKα λ=1.5418 Å) comprising two or more peaks at 2θ values ​​selected from 6.4±0.2, 6.8±0.2, 9.6±0.2, 13.6±0.2, 15.7±0.2, 18.2±0.2, 19.9±0.2, 21.6±0.2, 24.8±0.2, and 26.8±0.2. In some embodiments, Form A has a powder X-ray diffraction (taken at room temperature and CuKα λ=1.5418 Å) comprising three or more peaks at 2θ values ​​selected from 6.4±0.2, 6.8±0.2, 9.6±0.2, 13.6±0.2, 15.7±0.2, 18.2±0.2, 19.9±0.2, 21.6±0.2, 24.8±0.2, and 26.8±0.2. In some embodiments, Form A has a powder X-ray diffraction (taken at room temperature and CuKα λ=1.5418 Å) comprising four or more peaks at 2θ values ​​selected from 6.4±0.2, 6.8±0.2, 9.6±0.2, 13.6±0.2, 15.7±0.2, 18.2±0.2, 19.9±0.2, 21.6±0.2, 24.8±0.2, and 26.8±0.2.

[0059] In some embodiments, Form A has an X-ray powder diffraction pattern (taken at room temperature and CuKα λ=1.5418 Å) comprising three or more peaks at 2θ values ​​selected from 6.4±0.2, 6.8±0.2, 9.6±0.2, 13.6±0.2, 14.1±0.2, 14.5±0.2, 14.7±0.2, 15.7±0.2, 18.2±0.2, 18.7±0.2, 19.2±0.2, 19.9±0.2, 20.5±0.2, 21.6±0.2, 22.5±0.2, 23.1±0.2, 24.1±0.2, 24.8±0.2, 25.6±0.2, 26.8±0.2, 27.1±0.2, and 27.8±0.2. In some embodiments, Form A has an X-ray powder diffraction pattern (taken at room temperature and CuKα λ=1.5418 Å) comprising four or more peaks at 2θ values ​​selected from 6.4±0.2, 6.8±0.2, 9.6±0.2, 13.6±0.2, 14.1±0.2, 14.5±0.2, 14.7±0.2, 15.7±0.2, 18.2±0.2, 18.7±0.2, 19.2±0.2, 19.9±0.2, 20.5±0.2, 21.6±0.2, 22.5±0.2, 23.1±0.2, 24.1±0.2, 24.8±0.2, 25.6±0.2, 26.8±0.2, 27.1±0.2, and 27.8±0.2. In some embodiments, Form A has an X-ray powder diffraction pattern (taken at room temperature and CuKα λ=1.5418 Å) comprising five or more peaks at 2θ values ​​selected from 6.4±0.2, 6.8±0.2, 9.6±0.2, 13.6±0.2, 14.1±0.2, 14.5±0.2, 14.7±0.2, 15.7±0.2, 18.2±0.2, 18.7±0.2, 19.2±0.2, 19.9±0.2, 20.5±0.2, 21.6±0.2, 22.5±0.2, 23.1±0.2, 24.1±0.2, 24.8±0.2, 25.6±0.2, 26.8±0.2, 27.1±0.2, and 27.8±0.2.

[0060] In some embodiments, Form A has a differential scanning calorimetry thermogram substantially similar to that shown in FIG.

[0061] In some embodiments, Form A has a differential scanning calorimetry thermogram with an endotherm onset at about 152°C.

[0062] In some embodiments, Form A has a thermogravimetric analysis thermogram substantially similar to that shown in FIG.

[0063] In some embodiments, crystalline form A is a) a single crystal structure, Crystal system, space group triclinic system, P1 Unit cell dimensions a=6.53±0.10Å α=92.8±1.0° b=13.06±0.10Å β=95.5±1.0° c=14.04±0.10Å γ=93.0±1.0° Volume 1189(20)Å 3 Density (calculation) 1.239g / cm 3 temperature room temperature and the measurements of the single crystal structure are at room temperature. b) a powder X-ray diffraction pattern substantially the same as that shown in Figure 1; c) a powder X-ray diffraction pattern (obtained at room temperature and CuKα λ=1.5418 Å) comprising two or more peaks at 2θ values ​​selected from 6.4±0.2, 6.8±0.2, 9.6±0.2, 13.6±0.2, 15.7±0.2, 18.2±0.2, 19.9±0.2, 21.6±0.2, 24.8±0.2, and 26.8±0.2; d) a powder X-ray diffraction pattern (obtained at room temperature and CuKα λ=1.5418 Å) comprising three or more peaks at 2θ values ​​selected from 6.4±0.2, 6.8±0.2, 9.6±0.2, 13.6±0.2, 14.1±0.2, 14.5±0.2, 14.7±0.2, 15.7±0.2, 18.2±0.2, 18.7±0.2, 19.2±0.2, 19.9±0.2, 20.5±0.2, 21.6±0.2, 22.5±0.2, 23.1±0.2, 24.1±0.2, 24.8±0.2, 25.6±0.2, 26.8±0.2, 27.1±0.2, and 27.8±0.2; e) A differential scanning calorimetry thermogram substantially similar to that shown in Figure 2; f) a differential scanning calorimetry thermogram with an endotherm onset at about 152°C, and / or g) Thermogravimetric analysis thermogram substantially similar to that shown in Figure 3 It is characterized by at least one of the following:

[0064] In some embodiments, crystalline form A is a) a single crystal structure, Crystal system, space group triclinic system, P1 Unit cell dimensions a=6.53±0.10Å α=92.8±1.0° b=13.06±0.10Å β=95.5±1.0° c=14.04±0.10Å γ=93.0±1.0° Volume 1189(20)Å 3 Density (calculation) 1.239g / cm 3 temperature room temperature and the measurements of the single crystal structure are at room temperature. b) a powder X-ray diffraction pattern substantially the same as that shown in Figure 1; c) a powder X-ray diffraction pattern (obtained at room temperature and CuKα λ=1.5418 Å) comprising two or more peaks at 2θ values ​​selected from 6.4±0.2, 6.8±0.2, 9.6±0.2, 13.6±0.2, 15.7±0.2, 18.2±0.2, 19.9±0.2, 21.6±0.2, 24.8±0.2, and 26.8±0.2; d) a powder X-ray diffraction pattern (obtained at room temperature and CuKα λ=1.5418 Å) comprising three or more peaks at 2θ values ​​selected from 6.4±0.2, 6.8±0.2, 9.6±0.2, 13.6±0.2, 14.1±0.2, 14.5±0.2, 14.7±0.2, 15.7±0.2, 18.2±0.2, 18.7±0.2, 19.2±0.2, 19.9±0.2, 20.5±0.2, 21.6±0.2, 22.5±0.2, 23.1±0.2, 24.1±0.2, 24.8±0.2, 25.6±0.2, 26.8±0.2, 27.1±0.2, and 27.8±0.2; e) A differential scanning calorimetry thermogram substantially similar to that shown in Figure 2; f) a differential scanning calorimetry thermogram with an endotherm onset at about 152°C, and / or g) a thermogravimetric analysis thermogram substantially similar to that shown in Figure 3; h) a moisture sorption isotherm substantially similar to that shown in Figure 4, and / or i) Non-hygroscopic It is characterized by at least one of the following:

[0065] In some embodiments, crystalline Form A is characterized by a moisture sorption isotherm substantially as shown in FIG.

[0066] In some aspects, the present invention describes a pharmaceutical composition comprising a therapeutically effective amount of crystalline Form A of Compound A and a pharmaceutically acceptable carrier.

[0067] In some embodiments, crystalline Form A of Compound A is substantially pure. In some embodiments, crystalline Compound A contains at least about 90% by weight, preferably at least about 95% by weight, and more preferably at least about 99% Form A, based on the weight of crystalline Form A of Compound A.

[0068] In some embodiments, crystalline Form A was obtained from tetrahydrofuran (THF).

[0069] In some embodiments, crystalline Form A was obtained from dichloromethane (DCM).

[0070] In some embodiments, crystalline Form A was obtained from tetrahydrofuran (THF) / water.

[0071] In some embodiments, crystalline Form A was obtained from 2-methyl THF / heptane.

[0072] In some embodiments, crystalline Form A was obtained by dissolving in tert-amyl alcohol (t-AmOH), followed by adding DCM and water, separating and concentrating the DCM layer, then adding ethyl acetate (EtOAc) to the concentrated DCM layer and heating until complete dissolution and then cooling, aging the resulting slurry, filtering, washing the wet cake with EtOAc, and drying under vacuum.

[0073] In some embodiments, crystalline Form A was prepared by dissolving in tert-amyl alcohol (t-AmOH), followed by dosing with 2-propanol (IPA) and concentrating under vacuum, repeating the dosing / concentration cycle, dosing with water and heating the solution, followed by cooling to grow the Form A seed, followed by adding water, aging and cooling the resulting slurry, aging and filtering the slurry, washing the wet cake with a mixture of water:IPA:t-AmOH, and drying under vacuum.

[0074] In some embodiments, crystalline form A is anhydrous.

[0075] In some embodiments, crystalline Compound A, preferably Form A, is administered to a human.

[0076] In some embodiments, crystalline Compound A, preferably Form A, is orally administered to a human.

[0077] The present invention includes the use of crystalline Compound A, preferably Form A, for use in a pharmaceutical formulation for treating ILD.

[0078] III. Composition In some embodiments, the disclosure provides a composition comprising Compound A. In some embodiments, the disclosure provides a composition comprising a crystalline form of Compound A. In some embodiments, the disclosure provides a composition comprising Form A of Compound A. As used herein, the term "composition" is intended to encompass a product comprising specified amounts of specified components, as well as any product that results directly or indirectly from the combination of specified amounts of specified components. Such terms, in connection with pharmaceutical compositions, are intended to encompass products comprising active and inactive components that comprise the carrier, as well as any product that results directly or indirectly from the combination, complexation, or aggregation of any two or more components, or the dissociation of one or more components, or any other type of reaction or interaction of one or more components. Thus, pharmaceutical compositions of the present invention encompass any composition made by mixing a compound of the present invention with a pharmaceutically acceptable carrier. By "pharmaceutically acceptable carrier" is meant that the carrier, diluent, or excipient is compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.

[0079] In some embodiments, the compositions of the present disclosure are suitable for oral administration. These compositions may comprise solid, semi-solid, gel matrix, or liquid dosage forms suitable for oral administration. As used herein, oral administration includes buccal administration, lingual administration, and sublingual administration. Suitable oral dosage forms include, but are not limited to, tablets, capsules, pills, troches, lozenges, pastilles, sachets, pellets, medicated chewing gum, granules, bulk powders, effervescent or non-effervescent powders or granules, solutions, emulsions, suspensions, solutions, wafers, sprinkles, elixirs, syrups, or any combination thereof. In some embodiments, the compositions of the present disclosure suitable for oral administration are in the form of tablets or capsules. In some embodiments, the compounds of the present disclosure may be in the form of capsules. In some embodiments, the capsules may be immediate-release capsules.

[0080] The compositions of the present disclosure may be in the form of compressed tablets, molded tablets, chewable tablets, fast-dissolving tablets, multi-layer compressed tablets, or enteric-coated, sugar-coated, or film-coated tablets. Enteric-coated tablets are compressed tablets that are resistant to stomach acid but are coated with a substance that protects the active ingredient from the acidic stomach environment so that it dissolves or disintegrates in the intestine. Enteric coatings include, but are not limited to, fatty acids, fats, phenyl salicylate, waxes, shellac, ammoniated shellac, and cellulose acetate phthalate. Sugar-coated tablets are compressed tablets surrounded by a sugar coating, which may be beneficial for masking unpleasant tastes or odors and protecting the tablets from oxidation. Film-coated tablets are compressed tablets that are covered with a thin layer or film of a water-soluble material. Film coatings include, but are not limited to, hydroxyethylcellulose, sodium carboxymethylcellulose, polyethylene glycol 4000, and cellulose acetate phthalate. Film coatings can have the same general characteristics as sugar coatings. Multi-layer compressed tablets are compressed tablets made by two or more compression cycles, including multi-layer tablets and compression-coated or dry-coated tablets.

[0081] In some embodiments, the compounds of the present disclosure can be in the form of tablets. In some embodiments, the compounds of the present disclosure can be in the form of compressed tablets. In some embodiments, the compounds of the present disclosure can be in the form of film-coated compressed tablets. In some embodiments, the compositions of the present disclosure can be in the form of film-coated compressed tablets.

[0082] In some embodiments, the compositions of the present disclosure can be prepared by fluid bed granulation, combining a compound of the present disclosure with one or more pharmaceutically acceptable carriers, vehicles, and / or excipients. In some embodiments, the compositions of the present disclosure can be prepared by a fluid bed granulation process, which can provide tablet formulations with good flowability, good compressibility, rapid dissolution, good stability, and / or minimal to no cracks. In some embodiments, the fluid bed granulation process can enable the preparation of formulations with high drug loading, for example, greater than 70% or greater than 75% of the compound of the present disclosure.

[0083] In some embodiments, the compositions of the present disclosure may be in the form of soft or hard capsules, which may be made of gelatin, methylcellulose, starch, and / or calcium alginate. Hard gelatin capsules, also known as dry-fill capsules (DFCs), may contain two sections, one sliding over the other, thus completely enclosing the active ingredient. Soft elastic capsules (SECs) are soft, spherical shells, such as gelatin shells, plasticized by adding glycerin, sorbitol, or similar polyols. In some embodiments, soft gelatin shells may contain preservatives to prevent microbial growth. Suitable preservatives include, but are not limited to, those described herein, including methylparaben and propylparaben, sorbic acid, and combinations thereof. The liquid, semi-solid, and solid dosage forms provided herein may be encapsulated in capsules. Suitable liquid and semi-solid dosage forms include, but are not limited to, solutions and suspensions of propylene carbonate, vegetable oils, triglycerides, and combinations thereof. The capsules may also be coated as known to those skilled in the art to modify or sustain dissolution of the active ingredient.

[0084] In some embodiments, the compositions of the present disclosure may be in liquid or semisolid dosage forms, such as emulsions, solutions, suspensions, elixirs, and syrups. In some embodiments, emulsions may be two-phase systems in which one liquid is dispersed in the form of small globules throughout another liquid, which may be oil-in-water or water-in-oil. Emulsions may contain a pharmaceutically acceptable non-aqueous liquid or solvent, an emulsifier, and a preservative. Suspensions may contain a pharmaceutically acceptable suspending agent and a preservative. Hydroalcoholic solutions may include, for example, pharmaceutically acceptable acetals, such as di-(lower alkyl) acetals of lower alkyl aldehydes (the term "lower" refers to alkyls having 1 to 6 carbon atoms), such as acetaldehyde diethyl acetal, and water-miscible solvents having one or more hydroxyl groups, such as propylene glycol and ethanol. Elixirs may be clear, sweetened, hydroalcoholic solutions. Syrups may be concentrated aqueous solutions of a sugar, such as sucrose, and may contain a preservative. For a liquid dosage form, the solution, for example, in a polyethylene glycol, may be diluted with a sufficient quantity of a pharmaceutically acceptable liquid carrier, e.g., water, to be measured conveniently for administration.

[0085] In some aspects, compositions of the present disclosure for oral administration may also be provided in the form of liposomes, micelles, microspheres, or nanosystems.

[0086] In some embodiments, the compositions of the present disclosure may be provided as non-effervescent or effervescent granules and powders to be reconstituted into a liquid dosage form. Pharmaceutically acceptable carriers and excipients used in non-effervescent granules or powders may include, but are not limited to, diluents, sweeteners, humectants, and mixtures thereof. Pharmaceutically acceptable carriers and excipients used in effervescent granules or powders may include, but are not limited to, organic acids, carbon dioxide sources, and mixtures thereof.

[0087] Coloring and flavoring agents can be used in all of the above dosage forms. Additionally, flavoring and sweetening agents can be particularly useful in the formation of chewable tablets and lozenges.

[0088] In certain aspects, the compositions of the present disclosure may be formulated as immediate or modified release dosage forms, including delayed-, extended-, pulsed-, controlled-, targeted-, and programmed-release forms.

[0089] The compositions of the present disclosure may include additional active ingredients that do not confer therapeutic or prophylactic efficacy on the composition and / or may include substances that enhance or supplement the efficacy of the composition.

[0090] In certain embodiments, Compound A or a pharmaceutically acceptable salt and / or solvate thereof is administered orally. In some embodiments, Compound A or a pharmaceutically acceptable salt and / or solvate thereof may be administered in a capsule. In some embodiments, Compound A or a pharmaceutically acceptable salt and / or solvate thereof may be administered in a tablet.

[0091] Compound A is typically administered in admixture with a suitable pharmaceutical diluent, excipient, or carrier (collectively referred to herein as a pharmaceutical carrier) appropriately selected for the intended form of administration, i.e., oral tablet, capsule, elixir, syrup, etc., and consistent with conventional pharmaceutical practice.

[0092] For example, for oral administration in the form of a tablet or capsule, the active drug ingredient can be combined with a non-toxic, pharmaceutically acceptable, inert oral carrier such as lactose, sucrose, dextrose, dextrate, glucose, maltodextrin, mannitol, xylitol, sorbitol, cyclodextrin, calcium phosphate, calcium sulfate, starch, modified starch, methylcellulose, microcrystalline cellulose, microcellulose, talc, etc., and for oral administration in liquid form, it can be combined with a non-toxic, pharmaceutically acceptable, inert oral carrier such as ethanol, glycerol, water, etc. Furthermore, when desired or necessary, suitable binders, lubricants, disintegrants, glidants, flavoring agents, and coloring agents can also be incorporated into the mixture.

[0093] In yet other embodiments, a film coating is provided around the Compound A formulation using standard coating procedures such as those described in Remingon's Pharmaceutical Sciences, 20th Edition (2000).

[0094] Dosage forms (pharmaceutical compositions) suitable for administration may contain from about 1 milligram to about 300 milligrams of active ingredient per dosage unit. In such pharmaceutical compositions, the active ingredient will typically be present in an amount of from about 0.5 to 95% by weight, based on the total weight of the composition. In some embodiments, dosage forms suitable for administration may contain from about 10 to about 240 milligrams of active ingredient per dosage unit. In some embodiments, dosage forms suitable for administration can contain about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, or about 240 mg of active ingredient per dosage form.

[0095] In some aspects, the present disclosure provides pharmaceutical compositions comprising Compound A, as described herein, and at least one pharmaceutically acceptable carrier.

[0096] In some aspects, the present disclosure provides a pharmaceutical formulation for oral administration, comprising: (a) about 5% by weight to about 40% by weight of compound A; (b) about 30% to about 90% by weight of a diluent or mixture of diluents; (c) about 0% to about 2% by weight of a glidant; (d) about 2% by weight to about 10% by weight of a disintegrant; (e) about 0.25 wt % to about 4 wt % of a lubricant; The present invention provides a pharmaceutical formulation comprising:

[0097] In some embodiments, Compound A of the pharmaceutical formulation comprises crystalline Form A. In some embodiments, the pharmaceutical formulation for oral administration is a tablet.

[0098] In some aspects, the present disclosure provides a pharmaceutical formulation for oral administration, comprising: (a) about 10% by weight to about 30% by weight of compound A; (b) about 40% to about 85% by weight of a diluent or mixture of diluents; (c) about 0% to about 2% by weight of a glidant; (d) about 2% by weight to about 10% by weight of a disintegrant; (e) about 0.25 wt % to about 4 wt % of a lubricant; The present invention provides a pharmaceutical formulation comprising:

[0099] In some embodiments, Compound A of the pharmaceutical formulation comprises crystalline Form A. In some embodiments, the pharmaceutical formulation for oral administration is a tablet.

[0100] In some aspects, the diluents described herein are selected from lactose, sucrose, dextrose, dextrate, glucose, maltodextrin, mannitol, xylitol, sorbitol, cyclodextrin, calcium phosphate, calcium sulfate, starch, modified starch, methylcellulose, microcrystalline cellulose, microcellulose, talc, and combinations thereof. In some aspects, the diluent or mixture of diluents is selected from microcrystalline cellulose and anhydrous lactose.

[0101] As used herein, the term "glidant" refers to a substance that, when added to a powder, improves the flowability of the powder, such as by reducing interparticle friction. In some embodiments, the glidant described herein is selected from silica, silicon dioxide, CAB-O-SILM-SP, AEROSIL, talc, magnesium aluminum silicate, and combinations thereof. In some embodiments, the glidant is silicon dioxide.

[0102] In some embodiments, the disintegrant described herein is selected from natural starch, pregelatinized starch, sodium starch, methylcrystalline cellulose, methylcellulose, croscarmellose, croscarmellose sodium, cross-linked sodium carboxymethylcellulose, cross-linked carboxymethylcellulose, cross-linked croscarmellose, cross-linked starches such as sodium starch glycolate, cross-linked polymers such as crospovidone, cross-linked polyvinylpyrrolidone, sodium alginate, clays, gums, and combinations thereof. In some embodiments, the disintegrant is croscarmellose sodium.

[0103] In some aspects, the surfactant described herein is selected from sodium lauryl sulfate, sorbitan monooleate, polyoxyethylene sorbitan monooleate, polysorbates, polaxomers, bile salts, glyceryl monostearate, copolymers of ethylene oxide, propylene oxide, and combinations thereof, hi some aspects, the surfactant is sodium lauryl sulfate.

[0104] In some aspects, the lubricant described herein is selected from stearic acid, calcium hydroxide, talc, corn starch, sodium stearyl fumarate, stearic acid, sodium oleate, sodium stearate, sodium benzoate, sodium acetate, sodium chloride, magnesium stearate, zinc stearate, waxes, and combinations thereof, hi some aspects, the lubricant is magnesium stearate.

[0105] In some aspects, provided herein is a pharmaceutical formulation for oral administration, comprising: (a) about 5% by weight to about 40% by weight of compound A; (b) about 15% to about 70% by weight of microcrystalline cellulose and about 15% to about 70% by weight of anhydrous lactose; (c) about 0% to about 2% by weight of silicon dioxide; (d) about 2% to about 6% by weight of croscarmellose sodium; (e) about 0.25% by weight to about 1.5% by weight of magnesium stearate; A pharmaceutical formulation comprising:

[0106] In some embodiments, Compound A of the pharmaceutical formulation comprises crystalline Form A. In some embodiments, the pharmaceutical formulation for oral administration is a tablet.

[0107] In some aspects, provided herein is a pharmaceutical formulation for oral administration, comprising: (a) about 10% by weight to about 30% by weight of compound A; (b) about 25% to about 70% by weight of microcrystalline cellulose and about 25% to about 70% by weight of anhydrous lactose; (c) about 0% to about 2% by weight of silicon dioxide; (d) about 2% to about 6% by weight of croscarmellose sodium; (e) about 0.25% by weight to about 1.5% by weight of magnesium stearate; A pharmaceutical formulation comprising:

[0108] In some embodiments, Compound A of the pharmaceutical formulation comprises crystalline Form A. In some embodiments, the pharmaceutical formulation for oral administration is a tablet. In some embodiments, the tablet can be prepared using the ingredients provided in Table 1 and / or Table 2.

[0109] [Table 1]

[0110] [Table 2]

[0111] In some embodiments, pharmaceutical compositions for oral administration may be preformed by direct compression or granulation (dry, wet, or melt granulation).

[0112] In some embodiments, the pharmaceutical composition further comprises an additional therapeutic agent, such as pirfenidone, nintedanib, thalidomide, carlumab, FG-3019, fresolimumab, interferon alpha, lecithinized superoxide dismutase, sintuzumab, tanzisertib, tralokinumab, hu3G9, AM-152, IFN-gamma-1b, IW-001, PRM-151, PXS-25, pentoxifylline / N-acetyl-cysteine, pentoxifylline / and further comprising one or more additional antifibrotic agents selected from vitamin E, salbutamol sulfate, [Sar9,Met(O2)11]-substance P, pentoxifylline, mercaptan amine bitartrate, obeticholic acid, aramchol, GFT-505, eicosapentaenoic acid ethyl ester, metformin, metreleptin, muromonab-CD3, oltipraz, IMM-124-E, MK-4074, PX-102, RO-5093151.

[0113] IV. Treatment Methods The present disclosure provides a method for treating interstitial lung disease by administering Compound A, an LPA1 antagonist. Lysophospholipids are membrane-derived bioactive lipid mediators. Examples of lysophospholipids include, but are not limited to, lysophosphatidic acid (1-acyl-2-hydroxysn-glycero-3-phosphate, LPA), sphingosine 1-phosphate (S1P), lysophosphatidylcholine (LPC), and sphingosylphosphorylcholine (SPC). Lysophospholipids affect fundamental cellular functions, including cell proliferation, differentiation, survival, migration, adhesion, invasion, and morphogenesis. These functions influence many biological processes, including neurogenesis, angiogenesis, wound healing, immunity, and carcinogenesis.

[0114] LPA acts in an autocrine and paracrine manner through a set of specific G protein-coupled receptors (GPCRs). Binding of LPA to its cognate GPCRs (LPA1, LPA2, LPA3, LPA4, LPA5, and LPA6) activates intracellular signaling pathways to generate a variety of biological responses.

[0115] Lysophospholipids, such as LPA, are quantitatively smaller lipid species compared to their major phospholipid counterparts (e.g., phosphatidylcholine, phosphatidylethanolamine, and sphingomyelin). LPA acts as a biological effector molecule, exerting diverse physiological actions, including, but not limited to, effects on blood pressure, platelet activation, and smooth muscle contraction, as well as various cellular actions, including cell proliferation, cell rounding, neurite retraction, actin stress fiber formation, and cell migration. The effects of LPA are primarily receptor-mediated.

[0116] LPA receptors (LPA1, LPA2, LPA3, LPA4, LPA5, and LPA6) mediate various downstream signaling cascades, including mitogen-activated protein kinase (MAPK) activation, adenylyl cyclase (AC) inhibition / activation, and phospholipase C (PLC) activation / Ca upregulation. 2+These include, but are not limited to, mobilization, arachidonic acid release, Akt / PKB activation and activation of small GTPases, Rho, Rock, Rac and Ras. Other pathways affected by LPA receptor activation include, but are not limited to, cyclic adenosine monophosphate (cAMP), cell division cycle 42 / GTP-binding protein (Cdc42), proto-oncogene serine / threonine-protein kinase Raf (c-RAF), proto-oncogene tyrosine-protein kinase Src (c-src), extracellular signal-regulated kinase (ERK), focal adhesion kinase (FAK), guanine nucleotide exchange factors (GEFs), glycogen synthase kinase 3b (GSK3b), c-jun amino-terminal kinase (JNK), MEK, myosin light chain II (MLCII), nuclear factor kappa B (NF-kB), N-methyl-D-aspartate (NMDA) receptor activation, phosphatidylinositol 3-kinase (PI3K), protein kinase A (PKA), protein kinase C (PKC), and ras-related C3 botulinum toxin substrate 1 (RAC1). The actual pathway and the endpoint achieved depend on various variables, including receptor usage, cell type, receptor or signaling protein expression level, and LPA concentration. Nearly all mammalian cells, tissues, and organs co-express several LPA receptor subtypes, indicating that LPA receptors signal in a cooperative manner. LPA1, LPA2, and LPA3 share high amino acid sequence similarity.

[0117] LPA is produced by activated platelets, activated adipocytes, neurons, and other cell types. Serum LPA is produced by multiple enzymatic pathways involving monoacylglycerol kinase, phospholipase A1, secretory phospholipase A2, and lysophospholipase D (lysoPLD), including autotaxin. LPA degradation involves several enzymes: lysophospholipase, lipid phosphate phosphatase, and LPA acyltransferases such as endophilin. The LPA concentration in human serum is estimated to be 1-5 μM. Serum LPA binds to albumin, low-density lipoprotein, or other proteins, which may protect LPA from rapid degradation. Naturally occurring LPA species with different acyl chain lengths and saturations include 1-palmitoyl (16:0), 1-palmitoleoyl (16:1), 1-stearoyl (18:0), 1-oleoyl (18:1), 1-linoleoyl (18:2), and 1-arachidonyl (20:4) LPA. Small alkyl LPAs have similar biological activity to acyl LPAs, and different LPA species activate different LPA receptor subtypes with varying effects.

[0118] LPA1 (previously called VZG-1 / EDG-2 / mrec1.3) binds three types of G proteins: G i / o , G q and G 12 / 13 Through the activation of these G proteins, LPA induces cell proliferation, serum response element (SRE) activation, mitogen-activated protein kinase (MAPK) activation, adenylyl cyclase (AC) inhibition, phospholipase C (PLC) activation, and Ca 2+ It induces various cellular responses through LPA1, including, but not limited to, recruitment, Akt activation, and Rho activation.

[0119] In adult mice, widespread expression of LPA1 has been observed, with distinct localization in the testes, brain, heart, lungs, small intestine, stomach, spleen, thymus, and skeletal muscle. Similarly, human tissues also express LPA1, with its localization in the brain, heart, lungs, placenta, colon, small intestine, prostate, testes, ovaries, pancreas, spleen, kidneys, skeletal muscle, and thymus.

[0120] The term "LPA-dependent," as used herein, refers to a condition or disorder that does not occur, or does not occur to the same extent, in the absence of LPA.

[0121] As used herein, the term "LPA-mediated" refers to a condition or disorder that can occur in the presence of LPA, although it can also occur in the absence of LPA.

[0122] As used herein, the terms "fibrosis" and "fibrotic disease" refer to pathological conditions associated with abnormal accumulation of cells, and / or fibronectin, and / or collagen and / or increased fibroblast recruitment, and refer to fibrosis of individual organs or tissues, such as the heart, kidney, liver, joints, lung, pleural tissue, abdominal tissue, skin, cornea, retina, musculoskeletal and gastrointestinal tract, including idiopathic pulmonary fibrosis, scleroderma and chronic nephropathy.

[0123] Exemplary diseases, disorders, or conditions involving fibrosis include pulmonary diseases associated with fibrosis, e.g., pulmonary fibrosis secondary to systemic inflammatory diseases such as idiopathic pulmonary fibrosis, rheumatoid arthritis, lupus, idiopathic interstitial pneumonia, radiation-induced fibrosis, chronic obstructive pulmonary disease (COPD), chronic asthma, silicosis, asbestos-induced pulmonary or pleural fibrosis, acute lung injury and acute respiratory distress (including those due to bacterial pneumonia, trauma, viral pneumonia, mechanical ventilation, non-pulmonary sepsis, and aspiration), chronic nephropathy (renal fibrosis) associated with injury or fibrosis, e.g., glomerulonephritis secondary to systemic inflammatory diseases such as lupus and scleroderma, diabetes, glomerulonephritis, focal segmental glomerulosclerosis, IgA nephropathy, hypertension, allografts, and Alport syndrome, gastrointestinal fibrosis, and the like. These include, but are not limited to, diseases such as scleroderma, radiation-induced gastrointestinal fibrosis), liver fibrosis such as cirrhosis, alcoholic liver fibrosis, non-alcoholic steatohepatitis (NASH), cholangiopathy, primary biliary cirrhosis, infectious or virally induced liver fibrosis (e.g., chronic hepatitis C) and autoimmune hepatitis, e.g., radiation-induced head and neck fibrosis, corneal scarring such as LASIK (laser refractive surgery), corneal transplants, trabeculectomy), hypertrophic scars and keloids, e.g., due to burns or surgery, and other fibrotic diseases such as sarcoidosis, scleroderma, spinal cord injury / fibrosis, myelofibrosis, vascular restenosis, arteriosclerosis, arteriosclerosis, Wegener's granulomatosis, mixed connective tissue disease, Peyronie's disease.

[0124] Other diseases, disorders or conditions in which the LPA1 receptor may be involved include atherosclerosis, thrombosis, heart disease, vasculitis, scar tissue formation, restenosis, phlebitis, COPD (chronic obstructive pulmonary disease), pulmonary hypertension, pulmonary fibrosis, pulmonary inflammation, intestinal adhesions, bladder fibrosis and cystitis, nasal fibrosis, sinusitis, neutrophil-mediated inflammation and fibroblast-mediated fibrosis, dermatological disorders including proliferative or inflammatory disorders of the skin, e.g., atopic dermatitis, bullous disorders, Respiratory diseases selected from the group consisting of collagenosis, psoriasis, psoriatic lesions, dermatitis, contact dermatitis, eczema, rosacea, wound healing, scarring, hypertrophic scarring, keloids, Kawasaki disease, rosacea, Sjogren-Larsson syndrome and urticaria, asthma, adult respiratory distress syndrome and allergic (extrinsic) asthma, non-allergic (intrinsic) asthma, acute severe asthma, chronic asthma, clinical asthma, nocturnal asthma, allergen-induced asthma, aspirin-sensitive asthma, exercise-induced asthma, isocapnine hyperventilation, childhood-onset asthma, adult-onset asthma, cough variant asthma, occupational asthma, steroid-resistant asthma, seasonal asthma, seasonal allergic rhinitis, perennial allergic rhinitis, chronic obstructive pulmonary disease including chronic bronchitis or emphysema, pulmonary hypertension, interstitial pulmonary fibrosis and / or airway inflammation and cystic fibrosis, and hypoxia, as well as psoriasis, rheumatoid arthritis, vasculitis, inflammatory bowel disease, dermatitis, osteoarthritis, asthma, inflammatory myopathy, allergic rhinitis, vaginitis, interstitial cystitis, Selected from the group consisting of scleroderma, eczema, allograft or xenograft (organ, bone marrow, stem cells and other cells and tissue) graft rejection, graft versus host disease, lupus erythematosus, inflammatory diseases, type I diabetes, pulmonary fibrosis, dermatomyositis, Sjogren's syndrome, thyroiditis (e.g., Hashimoto's disease and autoimmune thyroiditis), myasthenia gravis, autoimmune hemolytic anemia, multiple sclerosis, cystic fibrosis, chronic relapsing hepatitis, primary biliary cirrhosis, allergic conjunctivitis and atopic dermatitis.

[0125] Currently, there are two approved treatments for interstitial lung disease: nintedanib and perfenidone, and several compounds are currently in development. In certain embodiments of the present disclosure, the subject receiving Compound A is concurrently receiving one or more treatments for interstitial lung disease. In some embodiments, the one or more treatments are selected from nintedanib and perfenidone.

[0126] In certain embodiments, the subject is administered about 100 mg to about 150 mg of Compound A per day. In some embodiments, the subject is administered about 110 mg to about 130 mg of Compound A per day. In some embodiments, the subject is administered about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, about 125 mg, about 130 mg, about 135 mg, about 140 mg, about 145 mg, or about 150 mg of Compound A per day. In some embodiments, the subject is administered about 120 mg of Compound A per day.

[0127] In some embodiments, the subject is administered Compound A once daily. In some embodiments, the subject is administered Compound A twice daily. In some embodiments, the subject is administered Compound A three times daily. In some embodiments, the subject is administered Compound A four times daily. In some embodiments, the subject is administered Compound A five times daily.

[0128] In some embodiments, the subject is administered 120 mg once daily. In some embodiments, the subject is administered Compound A at a dose of 60 mg twice daily. In some embodiments, the subject is administered Compound A at a dose of 40 mg three times daily. In some embodiments, the subject is administered Compound A at a dose of 30 mg four times daily. In some embodiments, the subject is administered Compound A at a dose of 24 mg five times daily.

[0129] In some embodiments, the subject is administered Compound A with food. In some embodiments, the subject is administered Compound A without food.

[0130] In some embodiments, subjects administered Compound A experience slower disease progression than untreated subjects. In some embodiments, disease progression is measured by the subject's decrease in forced vital capacity (FVC). In some embodiments, subjects treated with Compound A experience a smaller decrease in forced vital capacity (FVC) after a treatment period compared to untreated subjects. FVC is the amount of air a subject can forcibly exhale from their lungs after taking the deepest breath they can. FVC is typically measured using a spirometry test, which involves placing a special mask on the subject's face and having the subject forcibly inhale and exhale as much as possible while measurements are collected.

[0131] In some embodiments, disease progression can be measured by the time it takes a subject to experience a disease progression event. In some embodiments, subjects administered Compound A have a longer time to the first disease progression event after a treatment period than untreated subjects. In some embodiments, the first disease progression event is an absolute percentage predicted forced vital capacity (ppFVC) greater than 10% from baseline. An absolute or relative decline in predicted FVC% of 10% or greater is associated with mortality. In some embodiments, subjects treated with Compound A have a longer time to an absolute percentage predicted forced vital capacity (ppFVC) greater than 10% from baseline than untreated subjects.

[0132] In some embodiments, the initial disease progression event is an acute exacerbation (e.g., a sudden worsening) of the patient's pulmonary fibrosis. In some embodiments, subjects treated with Compound A have a longer time to an acute exacerbation of pulmonary fibrosis than untreated subjects.

[0133] In some embodiments, the first disease progression event is respiratory hospitalization. In some embodiments, subjects treated with Compound A have a longer time to respiratory hospitalization than untreated subjects.

[0134] In some embodiments, the first disease progression event is lung transplantation. In some embodiments, subjects treated with Compound A have a longer time to lung transplantation than untreated subjects.

[0135] In some embodiments, the first disease progression event is mortality. In some embodiments, subjects treated with Compound A have a longer time to all-cause mortality than untreated subjects.

[0136] In some embodiments, subjects experience a longer time to a first disease progression event after a treatment period than untreated subjects, and the first disease progression event occurs after absolute percentage of predicted forced vital capacity (ppFVC) greater than 10% from baseline; acute exacerbation of pulmonary fibrosis, respiratory hospitalization, Lung transplants, and All-cause mortality is selected from.

[0137] In some embodiments, disease progression is measured by a change in score on the Living with Pulmonary Fibrosis (L-PF) questionnaire. The L-PF questionnaire assesses symptoms and quality of life in patients with fibrotic interstitial lung disease (ILDS). Its dyspnea and cough domains are based on 24-hour recall of item responses and have scores ranging from 0 to 100, with higher scores indicating greater symptom severity (e.g., Swigris JJ, et al. BMJ Open Resp Res 2022;9:e001167.doi:10.1136 / bmjresp 2021:001167). In some embodiments, subjects administered Compound A experience a smaller increase in cough domain score as measured by the Living with Pulmonary Fibrosis (L-PF) questionnaire over the treatment period than untreated subjects. In some embodiments, subjects experience a smaller increase in dyspnea domain score as measured by the Living with Pulmonary Fibrosis (L-PF) questionnaire over the treatment period than untreated subjects. [Example]

[0138] Example 1: Preparation of crystalline form A of Compound A Crystalline forms can be prepared by a variety of methods, including, for example, crystallization or recrystallization from a suitable solvent, sublimation, growth from the melt, solid-state transformation from another phase, crystallization from supercritical fluids, and jet spraying. Techniques for crystallization or recrystallization of co-crystalline forms from solvent mixtures include, for example, evaporation of the solvent, lowering the temperature of the solvent mixture, seeding crystals of a supersaturated solvent mixture of the molecule and / or salt, freeze-drying the solvent mixture, and adding an anti-solvent (counter-solvent) to the solvent mixture.

[0139] For the crystallization technique using solvent, the selection of one or more solvents typically depends on one or more factors, such as the solubility of the compound, the crystallization technique, and the vapor pressure of the solvent.A combination of solvents can be used, for example, a compound can be solubilized in a first solvent to obtain a solution, and then an anti-solvent can be added to reduce the solubility of the compound in the solution, resulting in the formation of crystals.An anti-solvent is a solvent in which the compound has low solubility.

[0140] In one method of preparing crystals, the compound is suspended and / or stirred in a suitable solvent to obtain a slurry, which can be heated to promote dissolution. As used herein, the term "slurry" refers to a saturated solution of the compound, which may also contain additional amounts of the compound to provide a heterogeneous mixture of the compound and the solvent at a given temperature.

[0141] Seed crystals can be added to any crystallization mixture to promote crystallization. Seeding can be used to control the growth of a specific polymorph or to control the particle size distribution of the crystalline product. Therefore, the calculation of the amount of seeds required depends on the available seed size and the desired size of the average product particle, as described, for example, in "Programmed Cooling of Batch Crystallizers," J. W. Mullin and J. Nyvlt, Chemical Engineering Science, 1971, 26, 369-377. Generally, small-sized seeds are required to effectively control the growth of crystals in the batch. Small-sized seeds can be produced by sieving, grinding, or micronizing large crystals or by microcrystallizing a solution. It should be noted that grinding or micronizing crystals does not result in any change in the crystallinity of the desired crystalline form (i.e., to amorphous or another polymorph).

[0142] The cooled crystallization mixture can be filtered under vacuum, and the isolated solid can be washed with a suitable solvent, such as a low-temperature recrystallization solvent, and dried under a nitrogen purge to obtain the desired crystalline form. The isolated solid can be analyzed by suitable spectroscopic or analytical techniques, such as solid-state nuclear magnetic resonance, differential scanning calorimetry, or X-ray powder diffraction, to ensure the formation of the desired crystalline form of the product. The resulting crystalline form is typically produced in an isolated yield of greater than about 70% by weight, preferably greater than 90% by weight, based on the weight of the compound originally utilized in the crystallization procedure. If necessary, the product can be crushed or passed through a mesh screen to separate the product.

[0143] The presence of more than one polymorph in a sample can be determined by techniques such as powder X-ray diffraction (PXRD), Raman spectroscopy, IR spectroscopy, or solid-state nuclear magnetic resonance spectroscopy. For example, the presence of extra peaks in a comparison of an experimentally measured PXRD pattern with a simulated PXRD pattern can indicate the presence of more than one polymorph in a sample. Simulated PXRD can be calculated from single-crystal X-ray data. See Smith, DK, "A FORTRAN Program for Calculating X-Ray Powder Diffraction Patterns," Lawrence Radiation Laboratory, Livermore, California, UCRL-7196 (April 1963).

[0144] The crystalline forms of Compound A according to the present invention can be characterized using various techniques whose operation is well known to those skilled in the art. Forms can be characterized and distinguished using single crystal X-ray diffraction, which is based on unit cell measurements of a single crystal of the form at a given analysis temperature. A detailed description of the unit cell is provided in Stout & Jensen, X-Ray Structure Determination: A Practical Guide, Macmillan Co., New York (1968), Chapter 3, the entire contents of which are incorporated herein by reference. Alternatively, the unique arrangement of atoms in spatial relationship within the crystal lattice can be characterized according to the observed atomic fractional coordinates. Another means of characterizing the crystal structure is by powder X-ray diffraction analysis, where both diffraction profiles are performed at the same analysis temperature, and the measurements for the target form are compared with a simulated profile representing the pure powder material, characterized as a set of 2q values ​​(usually four or more).

[0145] Other means of characterizing forms can be used, such as solid-state nuclear magnetic resonance (SSNMR), differential scanning calorimetry, thermogravimetry, and FT-Raman and FT-IR. These techniques can also be used in combination to characterize the form of interest. In addition to the techniques specifically described herein, the presence of a particular crystalline form can be determined by other suitable analytical methods.

[0146] Example 1A 150 mg of Compound A was dissolved in 1.5 mL of tetrahydrofuran (THF) at 20° C. 0.5 mL of this solution was subjected to flash evaporation using a centrifugal concentrator to obtain a solid of Form A. 0.5 mL of the same solution was slowly evaporated at 20° C. to obtain a solid of Form A.

[0147] Example 1B 200 mg of Compound A was dissolved in 1 mL of dichloromethane (DCM) at 20° C. 0.5 mL of this solution was subjected to flash evaporation using a centrifugal concentrator to obtain a solid of Form A. 0.5 mL of the same solution was slowly evaporated at 20° C. to obtain a solid of Form A.

[0148] Example 1C 100 mg of Compound A was dissolved in 0.5 mL of THF at 50° C. and stirring was continued at 20° C. 0.5 mL of water was added to the clear solution, which gave Form A solid.

[0149] Example 1D 100 mg of Compound A was dissolved in 1 mL of 2-methyl THF at 50° C. and stirring was continued at 20° C. 1 mL of n-heptane was added to the clear solution, which gave Form A solid.

[0150] Example 1E A solution of Compound A in tert-amyl alcohol (t-AmOH) was concentrated under vacuum to 4 L / kg, followed by the addition of 15 L / kg DCM and 10 L / kg water. The layers were separated, and the DCM layer was concentrated under vacuum to 4 L / kg. 8-10 L / kg ethyl acetate (EtOAc) was added to the DCM layer, followed by the addition of another 8-10 L / kg EtOAc, followed by the addition of another 4 L / kg EtOAc, followed by the addition of another 6-8 L / kg EtOAc and the mixture was heated to 70-83°C until complete dissolution. The resulting slurry was cooled to 0-10°C over at least 2 hours and then aged for at least an additional 12 hours. The slurry was filtered. The wet cake was washed with 3-5 L / kg EtOAc and dried under vacuum at 55-60°C to obtain Form A solid.

[0151] Example 1F The solution of Compound A in t-AmOH was concentrated under vacuum at 55°C to 4 L / kg, then charged with 5 L / kg of 2-propanol (IPA) and concentrated under vacuum at 55°C to 4 L / kg. This process was repeated two more times with 2 x 5 L / kg of IPA. The batch was cooled to 30°C, then charged with 1.3 L / kg of water and heated to 45-55°C. The resulting warm solution was polish filtered and cooled to 30°C. 1 wt% Form A seeds were charged, followed by 2 L / kg of water. After at least 6 hours, an additional 8.7 L / kg of water was charged. The resulting slurry was cooled to 20°C over at least 30 minutes, and the slurry was aged for at least 3 hours. The solid was filtered and the wet cake was washed sequentially with 3 L / kg of water: IPA:t-AmOH mixture (11:3:1 by volume) and 3 L / kg of water, and dried under vacuum at 50-60°C to give Form A solid.

[0152] Example 1G To a solution of isopropyl (1S,3S)-3-((2-methyl-6-(1-methyl-5-(((methyl(propyl)carbamoyl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylate (500 mg, 1.025 mmol) in 1:1 THF / MeOH (10 mL) was added LiOH (1.538 mL of a 2 M solution, 3.08 mmol). The reaction mixture was stirred at 50° C. for 1 h, then cooled to RT and the organic volatiles removed in vacuo. The concentrated solution was washed with EtOAc and then acidified to approximately 6-7° C. (1 N aqueous HCl). The aqueous layer was extracted several times with EtOAc. The combined organic extracts were washed with water, dried (MgSO4), and the MgSO4 was filtered off. The EtOAc solution was concentrated in vacuo to give Form A solid.

[0153] Analytical data for crystalline Compound A described herein was obtained using the following procedures.

[0154] Single crystal Single crystal X-ray data were collected using a Bruker X8 Kappa diffractometer equipped with an APEX II CCD detector and a MICROSTAR microfocus rotating anode X-ray generator with monochromatic Cu Kα radiation. The single crystal was at room temperature during data collection.

[0155] Indexing and processing of the measured intensity data were performed using the APEX2 program suite (Bruker AXS, Inc., 5465 East Cheryl Parkway, Madison, WI 53711 USA). Final unit cell parameters were determined using the complete data set. The structure was solved by direct methods and refined by full-matrix least-squares using the SHELXTL software package (GM Sheldrick, SHELXTL v6.14, Bruker AXS, Madison, WI USA). The refinement of the structure was performed using the Σw(|F o |-|F c |) 2where w is an appropriate weighting factor based on the error in the observed intensity, and F o is the structure factor based on the measured reflection, and F c is the calculated reflection-based structure factor. The agreement between the refined crystal structure model and the experimental X-ray diffraction data is determined by the residual factor R = Σ||F o |-|F c || / Σ|F o | and wR = [Σw(|F o |-|F c |) 2 / Σw|F o |] 1 / 2 The lattice structure was evaluated using the differential Fourier maps. Difference Fourier maps were examined at all stages of refinement. All non-hydrogen atoms were refined using anisotropic thermal displacement parameters. Hydrogen atoms were introduced using idealized geometries with isotropic temperature factors and were included in the structure factor calculations using fixed parameters.

[0156] Powder X-ray diffraction (PXRD) PXRD diffractograms were acquired on a Bruker D8 Advance system using CuKα (40 kV / 40 mA) radiation over a 2θ range of 2 to 40°, a step size of 0.03°2q, and a LynxEye detector. The incident beam configuration was: a Göbel mirror, a mirror exit slit (0.2 mm), a 2.5° Soller slit, and a beam knife. The diffracted beam configuration was: an anti-scatter slit (8 mm) and a 2.5° Soller slit. The sample was mounted flat on a zero-background Si wafer.

[0157] Differential scanning calorimetry (DSC) DSC was performed using a TA Instruments Q2000 differential scanning calorimeter equipped with an autosampler and cooling system under a 40 mL / min N purge for the Q2000. DSC thermograms were acquired at 15°C / min in crimped Al pans.

[0158] Thermogravimetric analysis (TGA) TGA thermograms were obtained using a TA Instruments Q500 thermogravimetric analyzer at 60 mL / min on samples in Al pans under a 40 mL / min N purge on the balance. TGA thermograms were obtained at 15° C. / min.

[0159] Moisture absorption isotherm Moisture sorption isotherms were collected on a TA Instruments VTI-SA+ vapor sorption analyzer using approximately 270 mg of sample in a 250 μL ceramic pan. The sample was dried at 30° C. for 10 minutes until a loss rate of 0.005 wt.% / min was obtained. Samples were tested at 25° C. and 4%, 5%, 15%, 25%, 35%, 45%, 50%, 65%, 75%, 85%, and 95% RH. Equilibrium was reached at each RH when a rate of 0.01 wt.% / min was achieved over 35 minutes or when a maximum rate of 600 minutes was achieved.

[0160] It is understood that the Detailed Description section, and not the Summary and Abstract sections, is intended to be used to interpret the claims. The Summary and Abstract sections may set forth one or more, but not all, exemplary aspects of the present disclosure contemplated by the inventors, and as such are not intended to limit the scope of the present disclosure and the appended claims in any way.

[0161] This disclosure has been described above in terms of functional building blocks that illustrate implementations of specified functions and relationships thereof. The boundaries of these functional building blocks have been arbitrarily defined herein for convenience of description. Alternate boundaries may be defined so long as the specified functions and relationships thereof are appropriately performed.

[0162] The foregoing description of the specified embodiments fully reveals the general nature of the present disclosure so that others can readily modify such specific embodiments and / or adapt them for various uses by applying knowledge within the skill of the art without undue experimentation and without departing from the general concepts of the present disclosure. Such adaptations and modifications are therefore intended to be within the meaning and range of equivalents of the disclosed embodiments, based on the teaching and guidance provided herein. It is to be understood that the phraseology or terminology herein is intended to be descriptive rather than limiting, as the terminology or terminology herein can be interpreted by one of ordinary skill in the art in light of the teaching and guidance.

[0163] The breadth and scope of the present disclosure should not be limited by any of the above-described exemplary aspects, but should be defined only in accordance with the following claims and their equivalents.

Claims

1. Compound A: 【Chemistry 1】 Crystalline form A of

2. a) a single crystal structure, Crystal system, space group triclinic system, P1 Unit cell dimensions a = 6.53 ± 0.10 Å α = 92.8 ± 1.0° b=13.06±0.10Å β=95.5±1.0° c=14.04±0.10Å γ=93.0±1.0° Volume 1189 (20) Å ３ Density (calculated): 1.239 g / cm³ ３ temperature room temperature a single crystal structure having unit cell parameters substantially equal to: b) a powder X-ray diffraction pattern substantially the same as that shown in Figure 1; c) a powder X-ray diffraction pattern (obtained at room temperature and CuKα λ=1.5418 Å) comprising two or more peaks at 2θ values ​​selected from 6.4±0.2, 6.8±0.2, 9.6±0.2, 13.6±0.2, 15.7±0.2, 18.2±0.2, 19.9±0.2, 21.6±0.2, 24.8±0.2, and 26.8±0.2; d) a powder X-ray diffraction pattern (obtained at room temperature and CuKα λ=1.5418 Å) comprising three or more peaks at 2θ values ​​selected from: 6.4±0.2, 6.8±0.2, 9.6±0.2, 13.6±0.2, 14.1±0.2, 14.5±0.2, 14.7±0.2, 15.7±0.2, 18.2±0.2, 18.7±0.2, 19.2±0.2, 19.9±0.2, 20.5±0.2, 21.6±0.2, 22.5±0.2, 23.1±0.2, 24.1±0.2, 24.8±0.2, 25.6±0.2, 26.8±0.2, 27.1±0.2, and 27.8±0.2; e) a differential scanning calorimetry thermogram substantially similar to that shown in Figure 2; f) a differential scanning calorimetry thermogram with an endotherm onset at about 152°C, and / or g) Thermogravimetric analysis thermogram substantially similar to that shown in Figure 3.

2. The crystalline form A of claim 1, characterized by at least one of:

3. A single crystal structure, Crystal system, space group triclinic system, P1 Unit cell dimensions a = 6.53 ± 0.10 Å α = 92.8 ± 1.0° b=13.06±0.10Å β=95.5±1.0° c=14.04±0.10Å γ=93.0±1.0° Volume 1189 (20) Å ３ Density (calculated): 1.239 g / cm³ ３ temperature room temperature 3. The crystalline form A of claim 1 or 2, having a single crystal structure with unit cell parameters substantially equal to:

4. 3. The crystalline form A of claim 1 or 2, characterized by a powder X-ray diffraction pattern substantially the same as that shown in Figure 1.

5. 3. Crystalline form A of claim 1 or 2, characterized by an X-ray powder diffraction pattern (obtained at room temperature and CuKα λ=1.5418 Å) comprising two or more peaks at 2θ values ​​selected from 6.4±0.2, 6.8±0.2, 9.6±0.2, 13.6±0.2, 15.7±0.2, 18.2±0.2, 19.9±0.2, 21.6±0.2, 24.8±0.2 and 26.8±0.

2.

6. 3. Crystalline form A of claim 1 or 2, characterized by a powder X-ray diffraction pattern (obtained at room temperature and CuKα λ=1.5418 Å) comprising two or more peaks at 2θ values ​​selected from 6.4±0.2, 6.8±0.2, 13.6±0.2, 15.7±0.2, and 21.6±0.

2.

7. 3. Crystalline form A of claim 1 or 2, characterized by a powder X-ray diffraction pattern (obtained at room temperature and CuKα λ=1.5418 Å) comprising three or more peaks at 2θ values ​​selected from 6.4±0.2, 6.8±0.2, 13.6±0.2, 15.7±0.2, and 21.6±0.

2.

8. 3. Crystalline form A of claim 1 or 2, characterized by an X-ray powder diffraction pattern (obtained at room temperature and CuKα λ=1.5418 Å) comprising three or more peaks at 2θ values ​​selected from: 6.4±0.2, 6.8±0.2, 9.6±0.2, 13.6±0.2, 14.1±0.2, 14.5±0.2, 14.7±0.2, 15.7±0.2, 18.2±0.2, 18.7±0.2, 19.2±0.2, 19.9±0.2, 20.5±0.2, 21.6±0.2, 22.5±0.2, 23.1±0.2, 24.1±0.2, 24.8±0.2, 25.6±0.2, 26.8±0.2, 27.1±0.2, and 27.8±0.

2.

9. 3. Crystalline form A of claim 1 or 2, characterized by a powder X-ray diffraction pattern (obtained at room temperature and CuKα λ=1.5418 Å) comprising four or more peaks at 2θ values ​​selected from 6.4±0.2, 6.8±0.2, 13.6±0.2, 15.7±0.2, and 21.6±0.

2.

10. 3. Crystalline Form A of claim 1 or 2, characterized by a differential scanning calorimetry thermogram substantially similar to that shown in Figure 2.

11. 3. The crystalline form A of claim 1 or 2, characterized by a differential scanning calorimetry thermogram with an endotherm onset at about 152°C.

12. 3. Crystalline Form A of claim 1 or 2, characterized by a thermogravimetric analysis thermogram substantially similar to that shown in Figure 3.

13. 13. Crystalline form A according to any one of claims 1 to 12 in substantially pure form.

14. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and crystalline form A of any one of claims 1 to 13, alone or in combination with another therapeutic agent.

15. Crystalline form A according to any one of claims 1 to 13 or the pharmaceutical composition according to claim 11 for use in the treatment of interstitial lung diseases.

16. 16. The use of claim 15, wherein the interstitial lung disease is idiopathic pulmonary fibrosis (IPF).

17. 16. The use of claim 15, wherein the interstitial lung disease is progressive pulmonary fibrosis (PPF).

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