Crystalline forms of LPA1 antagonist

Abstract

Described herein are 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 Compound (A); and preparation thereof. Also disclosed are pharmaceutical compositions comprising the LPA1 antagonists, methods of treating interstitial lung disease using the LPA1 antagonists. # imgabs0 #

Description

Cross - Reference to Related Applications

[0001] This application claims the benefit of priority of U.S. Provisional Application No. 63 / 477,000, filed on December 23, 2022, which is hereby incorporated by reference in its entirety. Technical Field

[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. This disclosure also relates to the preparation of the crystalline forms, its pharmaceutical compositions, and methods of using the LPA1 antagonist for treating fibrotic diseases or conditions, including interstitial lung diseases. Background Art

[0003] Interstitial lung diseases (ILDs) are a heterogeneous group of lung disorders classified together based on imaging or histopathology by shared clinical features, parenchymal lung scarring (fibrosis), and / or inflammation with different patterns of lung injury. ILDs can be caused by identifiable etiologies 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, and typically fatal lung disease of unknown etiology, characterized by worsening dyspnea due to scarring in the lungs, cough, loss of lung function, and necessarily having a pathologic and radiographic pattern called usual interstitial pneumonia (UIP) (Meltzer et al., Orphanet J. Rare Dis. 2008, 3:8). In addition to IPF, some patients with other forms of ILD develop a progressive fibrotic phenotype, characterized by worsening respiratory symptoms, worsening lung function, radiographic fibrosis progression, and early death.

[0004] To date, two approved therapies (pirfenidone and nintedanib) have significantly reduced lung function decline in patients with IPF, and both appear to have a modest effect on progression-free survival (Noble et al., Lancet 2011, 377(9779), 1760-1769; King et al., N. Engl. J. Med. 2014, 370(22), 2083-2092; Richeldi et al., New Engl J Med 2014, 370(22), 2071-2082). However, many patients still progress despite treatment. Another treatment option is lung transplantation, which has been shown to improve survival in carefully selected patients but has complications (Kistler et al., BMC Pulmonary Med. 2014;14:139). Despite these advances, there remains a large unmet need for safe, well-tolerated, and effective therapies for IPF that improve lung function, delay disease progression, and reduce mortality.

[0005] Due to clinical and pathophysiological similarities between IPF and other forms of progressive pulmonary fibrosis (PPF), it has been shown that, regardless of etiology, such disorders share common pathological mechanisms that lead to progressive pulmonary fibrosis and may therefore respond to treatment similarly to IPF (Raghu et al., Am. J. Respir. Crit. Care Med. 2022, 205, e18–e47; du Bois et al., Am. J. Respir. Crit. Care Med. 2012, 186, 712–715; Flaherty et al., N. Engl. J. Med. 2019, 381(18), 1718–1727). Indeed, in the recently published INBUILD trial, patients with PPF of diverse etiologies were treated with nintedanib or placebo. Compared with patients receiving placebo, patients treated with nintedanib had slower progression of pulmonary fibrosis, as demonstrated by a lower annual rate of decline in forced vital capacity (FVC) over a 52-week study period (Flaherty et al., N. Engl. J. Med. 2019, 381(18), 1718–1727). The absolute treatment effect in the PPF study was similar in magnitude to the absolute treatment effect observed in the pivotal INPULSIS trial that led to the approval of nintedanib for the treatment of IPF. In addition, the IMPULSIS and INBUILD trials demonstrated that patients with IPF and PPF were similar with respect to the rate of decline in FVC. Based on data from the INBUILD trial, health authorities have also approved nintedanib for patients with PPF. Nevertheless, since many patients are unable to tolerate nintedanib due to gastrointestinal side effects and because some patients may still progress despite treatment with nintedanib, there remains an unmet need for well-tolerated, effective therapies for PPF (Flaherty et al., N. Engl. J. Med. 2019, 381(18), 1718–1727).

[0006] Overall, patients with non-IPF (progressive pulmonary fibrosis (PPF)) who exhibit disease progression have a high unmet need for effective and tolerable treatment. Fibrotic diseases such as these can be mediated by LPA, which signals via six LPA receptors (LPA 1-6 ). Signaling via LPA1 appears to be fundamental in the pathogenesis of fibrotic diseases.

[0007] U.S. Patent Application Publication No. 2017 / 0360759 (PCT Application Publication No. WO 2017 / 223016) discloses certain antagonists of lysophosphatidic acid (LPA) receptors for use in treating LPA-dependent or LPA-mediated disorders 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 U.S. Patent Application Publication No. 2017 / 0360759.

[0009] Compound A is an effective LPA1 antagonist in vitro (LPA1 K b = 6.9 nM in CHO cells overexpressing human LPA1 and LPA1 K b = 5.9 nM in normal human lung fibroblasts). Compound A is currently in clinical development as a therapy for IPF and PF-ILD. This disclosure provides methods of using Compound A to treat interstitial lung diseases. BRIEF DESCRIPTION OF THE DRAWINGS

[0010] Figure 1 Shows the powder X-ray diffraction (PXRD) pattern of Form A.

[0011] Figure 2 Shows the differential scanning calorimetry (DSC) thermogram of Form A.

[0012] Figure 3 Shows the thermogravimetric analysis (TGA) thermogram of Form A.

[0013] Figure 4 Shows the water sorption isotherm of Form A. SUMMARY OF THE INVENTION

[0014] In some aspects, this disclosure provides a crystalline Form A of Compound A:

[0015] In some aspects, the crystal form is characterized by at least one of the following: a) A single crystal structure having unit cell parameters substantially equal to the following: Crystal system, space group triclinic, P1 Unit cell dimensions α = 92.8 ± 1.0° β = 95.5 ± 1.0° γ = 93.0 ± 1.0° Volume Density (calculated value) 1.239 g / cm 3 Temperature Room temperature wherein the measurement of the single crystal structure is carried out 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 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 (obtained at room temperature and ); d) A powder x-ray diffraction pattern 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 (obtained at room temperature and ); e) A differential scanning calorimetry thermogram substantially similar to that shown in Figure 2 ; f) A differential scanning calorimetry thermogram having an endotherm starting at about 152 °C; and / or g) A thermogravimetric analysis thermogram substantially similar to that shown in Figure 3 ;

[0016] In some aspects, the crystalline form A has a single crystal structure with unit cell parameters substantially equal to the following: Crystal system, space group triclinic, P1 Unit cell dimensions α = 92.8 ± 1.0° β = 95.5 ± 1.0° γ = 93.0 ± 1.0° Volume Density (calculated value): 1.239 g / cm 3 Temperature: room temperature wherein the measurement of the single crystal structure was carried out at room temperature.

[0017] In some aspects, crystalline form A is characterized by being substantially the same as the powder X-ray diffraction pattern shown in Figure 1 ...

[0018] In some aspects, crystalline form A is characterized by a powder X-ray diffraction pattern 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 (obtained at room temperature and ...).

[0019] In some aspects, form A has a powder X-ray diffraction pattern 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 (obtained at room temperature and ...).

[0020] In some aspects, form A has a powder X-ray diffraction pattern 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 (obtained at room temperature and ...).

[0021] In some aspects, crystalline form A is characterized by a powder X-ray diffraction pattern 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 (obtained at room temperature and ...).

[0022] In some aspects, form A has a powder X-ray diffraction pattern 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 (obtained at room temperature and obtained below. In some aspects, crystalline Form A is characterized by a differential scanning calorimetry thermogram that is substantially similar to that shown in Figure 2 the following.

[0023] In some aspects, crystalline Form A is characterized by an endothermic differential scanning calorimetry thermogram that begins at about 152 °C.

[0024] In some aspects, crystalline Form A is characterized by a thermogravimetric analysis thermogram that is substantially similar to that shown in Figure 3 the following.

[0025] In some aspects, the crystalline form is in a substantially pure form.

[0026] In some aspects, the present disclosure provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and crystalline Form A as described in claims 1-10, alone or in combination with another therapeutic agent.

[0027] In some aspects, the crystalline form described herein is used to treat interstitial lung disease. In some aspects, the interstitial lung disease is idiopathic pulmonary fibrosis (IPF). In some aspects, the interstitial lung disease is progressive pulmonary fibrosis (PPF). DETAILED DESCRIPTION

[0028] The present disclosure provides crystalline Compound A: Methods for preparing and using its crystalline compounds.

[0029] To make the present specification easier to understand, certain terms are first defined. Additional definitions are set forth throughout the detailed description. I. DEFINITIONS

[0030] Unless otherwise specified, the following terms used in this application (including the specification and claims) have the definitions given below. It must be noted that as used in the 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 spectrometry, NMR, HPLC, protein chemistry, biochemistry, recombinant DNA technology, and pharmacology are employed unless otherwise indicated. Additionally, the use of the term "including" and other forms such as "include", "includes", and "included" is non-restrictive. The section headings used herein are for organizational purposes only and should not be construed as limiting the subject matter described.

[0031] All measurement results are affected by experimental errors and are within the spirit of the present invention.

[0032] The names used herein to characterize a particular form (e.g., "Form A") should not be considered restrictive with respect to any other substance having similar or identical physical and chemical characteristics, but rather it should be understood that the name is merely an identifier that should be interpreted in light of the characterization information also presented herein.

[0033] As used throughout the specification and claims, the term "about" when used in connection with a numerical value means an interval of accuracy familiar and acceptable to those skilled in the art. Such an interval of accuracy is ±10%.

[0034] As used herein, the term "acceptable" with respect to a formulation, composition, or ingredient means that it has no continuing adverse effect on the overall health of the subject being treated.

[0035] The terms "administration of" and / or "administering" a compound or composition should be understood to mean providing the compound or composition described herein to one or more subjects.

[0036] As used herein, "amorphous" refers to a solid form of molecules, atoms, and / or ions that is not crystalline. An amorphous solid does not exhibit a distinct X-ray diffraction pattern.

[0037] As used herein, the term "antagonist" refers to a molecule, such as a compound, that reduces, inhibits, or blocks the action of another molecule or the activity of a receptor site. Antagonists include, but are not limited to, competitive antagonists, non-competitive antagonists, uncompetitive antagonists, partial agonists, and inverse agonists.

[0038] As used herein, terms such as "co-administration" are intended to encompass the administration of selected therapeutic agents to a single subject and are intended to include treatment regimens in which the agents are administered by the same or different routes of administration or at the same or different times.

[0039] As used herein, the term "DSC" refers to differential scanning calorimetry. The term "TGA" refers to thermogravimetric analysis.

[0040] As used herein, the term "effective amount" or "therapeutically effective amount" means an amount of an agent or compound administered that will, to some extent, alleviate one or more symptoms of the disease or disorder being treated. The result can be a reduction and / or amelioration of the signs, symptoms, or causes of the disease, or any other desired alteration of a biological system. For example, an "effective amount" for therapeutic use is the amount of a composition comprising a compound as disclosed herein that is required to provide a clinically significant reduction in the symptoms of the disease. Techniques such as dose escalation studies can be used to determine the appropriate "effective" amount in any individual case.

[0041] As used herein, the phrase "pharmaceutically acceptable" refers to those compounds, materials, compositions, and / or dosage forms that, within the scope of reasonable medical judgment, are suitable for contact with the tissues of humans and animals without excessive toxicity, irritation, allergic response, or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0042] As used herein, "polymorph" refers to a crystalline form having the same chemical structure but a different spatial arrangement of molecules and / or ions that form the crystal.

[0043] The term "room temperature" generally means about 22 °C, but can vary up to 7 °C above or below.

[0044] The term "subject" encompasses mammals. Examples of mammals include, but are not limited to, 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.

[0045] As used herein, when used in reference to a crystal form, "substantially pure" means a compound having the following purity: greater than 90 weight %, based on the weight of the compound, including greater than 90 weight %, 91 weight %, 92 weight %, 93 weight %, 94 weight %, 95 weight %, 96 weight %, 97 weight %, 98 weight %, and 99 weight %, and also including a crystal form of Compound A equal to about 100 weight %. The remaining material includes one or more other forms of the compound and / or reaction impurities and / or processing impurities resulting from its preparation. For example, a crystal form of Compound A can be considered substantially pure because it has a purity greater than 90 weight %, as measured by means known and generally accepted in the art at the time, where the remaining less than 10 weight % of the material includes one or more other forms of Compound A and / or reaction impurities and / or processing impurities.

[0046] When the term "substantially identical" is used in reference to a PXRD or XRPD pattern, it should be understood that the measured peak positions for a given crystalline form of the same compound will vary within the error bounds. It should also be understood that the intensity of the peaks can vary between different PXRD scans of the same crystalline form of the same compound. The relative intensities of the different peaks are not intended to limit the comparison of different PXRD scans.

[0047] As used herein, the terms "treat", "treating", or "treatment" include alleviating, reducing, or ameliorating at least one symptom of a disease or disorder, preventing additional symptoms, inhibiting the disease or disorder (e.g., arresting the development of the disease or disorder), relieving the disease or disorder, causing regression of the disease or disorder, alleviating the condition caused by the disease or disorder, or prophylactically and / or therapeutically halting the symptoms of the disease or disorder. II. Compound A

[0048] Compound A is described in U.S. Patent Application Publication No. 2017 / 0360759.

[0049] In the preparation of pharmaceutical compositions, such forms of the active ingredient are sought that have a balance of desired properties (e.g., such as dissolution rate, solubility, bioavailability, and / or storage stability). For example, such forms of the active ingredient are sought that have sufficient solubility, bioavailability, and storage stability to prevent the conversion of a sufficiently soluble and bioavailable form during the manufacture, preparation, and / or storage of the pharmaceutical composition into another form having an undesired solubility and / or bioavailability profile. In addition, such forms of the active ingredient may also be sought that allow for the separation and / or purification of the active ingredient, for example, during the preparation process.

[0050] The present invention provides at least one form of Compound A that unexpectedly provides a balance of the properties sought in a pharmaceutical composition.

[0051] Compound A (including polymorphs and amorphous phases) and methods of using Compound A, preferably anhydrous Compound A, are described herein.

[0052] In some aspects, the present disclosure provides crystalline anhydrous Compound A.

[0053] 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, the crystalline Form A of Compound A is a pure crystalline form.

[0054] In some aspects, Compound A includes the crystalline form "Form A". When dissolved, the crystalline form of Compound A loses its crystalline structure and is thus referred to as a solution of Compound A. However, all forms of the present invention can be used to prepare liquid formulations in which the drug is dissolved or suspended. In addition, the crystalline Form A of Compound A can be incorporated into solid formulations.

[0055] As used herein, a PXRD (powder x-ray diffraction) or XRPD (x-ray powder diffraction) pattern that "comprises" or has multiple peaks selected from a specified set of peaks is intended to include a PXRD pattern that has additional peaks not included in the specified set of peaks. For example, a PXRD pattern that comprises 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 a PXRD pattern that has: (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 A, B, C, D, E, F, G, and H peaks.

[0056] In some aspects, Form A is characterized by a single crystal structure having unit cell parameters that are substantially equal to the following: Crystal system, triclinic, P1 Unit cell dimensions α = 92.8 ± 1.0° β = 95.5 ± 1.0° γ = 93.0 ± 1.0° Volume Density (calculated) 1.239 g / cm 3 Temperature room temperature wherein the measurement of the single crystal structure is carried out at room temperature.

[0057] In some aspects, Form A has a powder x-ray diffraction pattern that is substantially the same as that shown in Figure 1 the following.

[0058] In some aspects, Form A has a powder x-ray diffraction pattern that comprises two or more peaks at 2θ values selected from the following: 6.4 ± 0.2, 6.8 ± 0.2, 13.6 ± 0.2, 15.7 ± 0.2, and 21.6 ± 0.2 (obtained at room temperature and the following). In some aspects, Form A has a powder x-ray diffraction pattern that comprises three or more peaks at 2θ values selected from the following: 6.4 ± 0.2, 6.8 ± 0.2, 13.6 ± 0.2, 15.7 ± 0.2, and 21.6 ± 0.2 (obtained at room temperature and the following). In some aspects, Form A has a powder x-ray diffraction pattern that comprises four or more peaks at 2θ values selected from the following: 6.4 ± 0.2, 6.8 ± 0.2, 13.6 ± 0.2, 15.7 ± 0.2, and 21.6 ± 0.2 (obtained at room temperature and the following).

[0059] In some aspects, Form A has a powder X-ray diffraction pattern having 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 (obtained at room temperature and under). In some aspects, Form A has a powder X-ray diffraction having 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 (obtained at room temperature and under). In some aspects, Form A has a powder X-ray diffraction having 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 (obtained at room temperature and under).

[0060] In some aspects, Form A has a powder X-ray diffraction pattern having 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 (obtained at room temperature and under). In some aspects, Form A has a powder X-ray diffraction pattern having 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 (obtained at room temperature and Obtained under). In some aspects, Form A has a powder X-ray diffraction pattern with 5 or more peaks at 2θ values selected from the following: 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 (at room temperature and Obtained under).

[0061] In some aspects, Form A has a Figure 2 Differential scanning calorimetry thermogram that is substantially similar to that shown in

[0062] In some aspects, Form A has a differential scanning calorimetry thermogram with an endotherm starting at about 152 °C.

[0063] In some aspects, Form A has a Figure 3 Thermogravimetric analysis thermogram that is substantially similar to that shown in

[0064] In some aspects, crystalline Form A is characterized by at least one of the following: a) A single crystal structure having unit cell parameters substantially equal to the following: Crystal system, triclinic, P1 Unit cell dimensions α = 92.8 ± 1.0° β = 95.5 ± 1.0° γ = 93.0 ± 1.0° Volume Density (calculated) 1.239 g / cm 3 Temperature Room temperature Wherein the measurement of the single crystal structure is carried out 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 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 (obtained at room temperature and obtained); d) A powder X-ray diffraction pattern 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 (obtained at room temperature and obtained); e) A differential scanning calorimetry thermogram substantially similar to that shown in Figure 2 ; f) A differential scanning calorimetry thermogram having an endotherm starting at about 152 °C; and / or g) A thermogravimetric analysis thermogram substantially similar to that shown in Figure 3 .

[0065] In some aspects, crystalline form A is characterized by at least one of the following: a) A single crystal structure having unit cell parameters substantially equal to the following: Crystal system, triclinic, P1 Unit cell dimensions α = 92.8 ± 1.0 ° β = 95.5 ± 1.0 ° γ = 93.0 ± 1.0 ° Volume Density (calculated) 1.239 g / cm 3 Temperature Room temperature wherein the measurement of the single crystal structure is carried out 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 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 (obtained at room temperature and below); d) A powder X-ray diffraction pattern 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 (obtained at room temperature and below); e) A differential scanning calorimetry thermogram substantially similar to that shown in Figure 2 ; f) A differential scanning calorimetry thermogram having an endotherm starting at about 152 °C; and / or g) A thermogravimetric analysis thermogram substantially similar to that shown in Figure 3 ; h) A water adsorption isotherm substantially similar to that shown in Figure 4 ; and / or i) Non-hygroscopic.

[0066] In some aspects, crystalline form A is characterized by a water adsorption isotherm substantially as shown in Figure 4 ;

[0067] 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.

[0068] In some aspects, crystalline form A of compound A is substantially pure. In some aspects, based on the weight of crystalline form A of compound A, the crystalline compound A contains at least about 90 wt.%, preferably at least about 95 wt.%, more preferably at least about 99 wt.% of form A.

[0069] In some embodiments, crystalline form A is obtained from tetrahydrofuran (THF).

[0070] In some embodiments, crystalline form A is obtained from dichloromethane (DCM).

[0071] In some embodiments, crystalline Form A is obtained from tetrahydrofuran (THF) / water.

[0072] In some embodiments, crystalline Form A is obtained from 2-methyl THF / heptane.

[0073] In some embodiments, crystalline Form A is obtained by dissolving in tert-amyl alcohol (t-AmOH), then adding DCM and water, separating and concentrating the DCM layer, then adding ethyl acetate (EtOAc) to the concentrated DCM layer, heating until completely dissolved, cooling, aging the resulting slurry, filtering, washing the wet filter cake with EtOAc, and drying under vacuum.

[0074] In some embodiments, crystalline Form A is obtained by dissolving in tert-amyl alcohol (t-AmOH), then adding 2-propanol (IPA) and concentrating under vacuum, repeating the addition / concentration cycle, adding water and heating the solution, then cooling, then seeding with Form A, then adding water, aging the resulting slurry, cooling, aging the slurry, filtering, washing the wet filter cake with a mixture of water:IPA:t-AmOH, and drying under vacuum.

[0075] In some embodiments, crystalline Form A is anhydrous.

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

[0077] In some embodiments, crystalline Compound A, preferably Form A, is administered orally.

[0078] The present invention includes the use of crystalline Compound A, preferably Form A, for use in therapy, for use in formulating a medicament for the treatment of ILD. III. Compositions

[0079] In some aspects, the present disclosure provides compositions comprising Compound A. In some aspects, the present disclosure provides compositions comprising a crystalline form of Compound A. In some aspects, the present disclosure provides compositions comprising Form A of Compound A. As used herein, the term "composition" is intended to encompass a product comprising a specified amount of specified ingredients, as well as any product directly or indirectly resulting from the combination of the specified amounts of the specified ingredients. Such term with respect to pharmaceutical compositions is intended to encompass a product comprising one or more active ingredients and one or more inert ingredients constituting a carrier, as well as any product directly or indirectly resulting from the combination, complexation or aggregation of any two or more ingredients, or from the dissociation of one or more ingredients, or from other types of reactions or interactions of one or negligible ingredients. Thus, the pharmaceutical compositions of the present invention encompass any composition prepared by mixing the compounds of the present invention with a pharmaceutically acceptable carrier. With respect to "pharmaceutically acceptable carrier", it means a carrier, diluent or excipient that is compatible with the other ingredients of the formulation and harmless to its recipient.

[0080] In some aspects, 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, lingual and sublingual administration. Suitable oral dosage forms include, but are not limited to, tablets, capsules, pills, troches, lozenges, pastilles, cachets, pellets, medicated chewing gums, granules, bulk powders, effervescent or non-effervescent powders or granules, solutions, emulsions, suspensions, solutions, wafers, sprinkles, elixirs, syrups or any combination thereof. In some aspects, the compositions of the present disclosure suitable for oral administration are in the form of tablets or capsules. In some aspects, the compounds of the present disclosure may be in the form of capsules. In some aspects, the capsules may be immediate-release capsules.

[0081] The compositions of the present disclosure can be in the form of compressed tablets, developed tablets, chewable lozenges, rapidly dissolving tablets, multi-compressed tablets, or enteric-coated tablets, sugar-coated tablets or film-coated tablets. Enteric-coated tablets are compressed tablets coated with a substance that resists the action of gastric acid but dissolves or disintegrates in the intestine to protect the active ingredient from the acidic environment of the stomach. 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 can be beneficial in masking unpleasant tastes or odors and in protecting the tablets from oxidation. Film-coated tablets are compressed tablets covered with a thin layer or film of a water-soluble material. Film coatings include, but are not limited to, hydroxyethyl cellulose, sodium carboxymethyl cellulose, polyethylene glycol 4000, and cellulose acetate phthalate. Film coatings can impart the same general characteristics as sugar coatings. Multi-compressed tablets are compressed tablets prepared by more than one compression cycle, including multi-layer tablets and compression-coated tablets or dry-coated tablets.

[0082] In some aspects, the compounds of the present disclosure can be in the form of tablets. In some aspects, the compounds of the present disclosure can be in the form of compressed tablets. In some aspects, the compounds of the present disclosure can be in the form of film-coated compressed tablets. In some aspects, the compositions of the present disclosure can be in the form of film-coated compressed tablets.

[0083] In some aspects, the compositions of the present disclosure can be prepared by fluidized bed granulation of the compounds of the present disclosure with one or more pharmaceutically acceptable carriers, vehicles, and / or excipients. In some aspects, the compositions of the present disclosure can be prepared by a fluidized bed granulation method and can provide tablet formulations with good flowability, good compressibility, rapid dissolution, good stability, and / or minimal to no capping. In some aspects, the fluidized bed granulation method can allow the preparation of formulations with a high drug loading (such as more than 70% or more than 75% of the compounds of the present disclosure).

[0084] In some aspects, the compositions of the present disclosure can be in the form of soft gelatin capsules or hard gelatin capsules, which can be made of gelatin, methylcellulose, starch, and / or calcium alginate. Hard gelatin capsules (also known as dry-filled capsules (DFC)) can consist of two parts that slide over one another to completely enclose the active ingredient. Soft elastic capsules (SEC) are soft spherical shells (such as gelatin shells) that are plasticized by the addition of glycerol, sorbitol, or similar polyols. In some aspects, the soft gelatin shell can contain preservatives to prevent the growth of microorganisms. 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 can be encapsulated in capsules. Suitable liquid and semi-solid dosage forms include, but are not limited to, solutions and suspensions in propylene carbonate, vegetable oils, triglycerides, and combinations thereof. As is known to those skilled in the art, capsules can also be coated to alter or maintain the dissolution of the active ingredient.

[0085] In some aspects, the compositions of the present disclosure can be in liquid or semi-solid dosage forms, including emulsions, solutions, suspensions, elixirs, and syrups. In some aspects, an emulsion can be a two-phase system in which one liquid is dispersed throughout the other in the form of small spheres, which can be water-in-oil or oil-in-water. The emulsion can contain a pharmaceutically acceptable non-aqueous liquid or solvent, an emulsifier, and a preservative. A suspension can contain a pharmaceutically acceptable suspending agent and a preservative. An aqueous alcoholic solution can contain a pharmaceutically acceptable acetal, such as a di-(lower alkyl) acetal of a lower alkyl aldehyde (the term "lower" means an alkyl group having from 1 to 6 carbon atoms), such as acetaldehyde diethyl acetal; and a water-miscible solvent having one or more hydroxyl groups, such as propylene glycol and ethanol. An elixir can be a clear solution, a sweetened solution, and an aqueous alcoholic solution. A syrup can be a concentrated aqueous solution of sugar (e.g., sucrose) and can contain a preservative. For liquid dosage forms, for example, a solution in polyethylene glycol can be diluted with a sufficient amount of a pharmaceutically acceptable liquid carrier (e.g., water) to facilitate measurement for administration.

[0086] In some aspects, the compositions of the present disclosure for oral administration can also be provided in the form of liposomes, micelles, microspheres, or nano-systems.

[0087] In some aspects, the compositions of the present disclosure can be provided as non-effervescent or effervescent granules and powders to be reconstituted into liquid dosage forms. Pharmaceutically acceptable carriers and excipients used in non-effervescent granules or powders can include, but are not limited to, diluents, sweeteners, wetting agents, and mixtures thereof. Pharmaceutically acceptable carriers and excipients used in effervescent granules or powders can include, but are not limited to, organic acids, carbon dioxide sources, and mixtures thereof.

[0088] Colorants and flavorants can be used in all of the above dosage forms. In addition, flavorants and sweeteners can be used especially in the formation of chewable tablets and lozenges.

[0089] In some aspects, the compositions of the present disclosure can be formulated as immediate-release dosage forms or modified-release dosage forms, including delayed-release, extended-release, pulsatile-release, controlled-release, targeted-release, and programmed-release forms.

[0090] The compositions of the present disclosure can include another active ingredient that does not impair the therapeutic or prophylactic efficacy of the composition and / or can include substances that enhance or supplement the efficacy of the composition.

[0091] In some aspects, Compound A or a pharmaceutically acceptable salt and / or solvate thereof can be administered orally. In some aspects, Compound A or a pharmaceutically acceptable salt and / or solvate thereof can be administered in capsules. In some aspects, Compound A or a pharmaceutically acceptable salt and / or solvate thereof can be administered in tablets.

[0092] Typically, Compound A is administered as a mixture with a suitable pharmaceutical diluent, excipient, or carrier (collectively referred to herein as pharmaceutical carriers), which are appropriately selected relative to the intended dosage form (i.e., oral tablets, capsules, elixirs, syrups, etc.) and consistent with conventional pharmaceutical practice.

[0093] For example, for oral administration in the form of tablets or capsules, the active pharmaceutical ingredient can be combined with an orally non-toxic pharmaceutically acceptable inert carrier (such as lactose, sucrose, dextrose, dextrates, glucose, maltodextrin, mannitol, xylitol, sorbitol, cyclodextrin, calcium phosphate, calcium sulfate, starch, modified starch, methylcellulose, microcrystalline cellulose, microcellulose, talc, etc.); for oral administration in liquid form, the oral pharmaceutical ingredient can be combined with any orally non-toxic pharmaceutically acceptable inert carrier (such as ethanol, glycerol, water, etc.). In addition, suitable binders, lubricants, disintegrants, glidants, flavorants, and colorants can also be incorporated into the mixture when desired or necessary.

[0094] In still other aspects, using standard coating procedures, such as those described in Remingon's Pharmaceutical Sciences, 20th Edition (2000), a film coating can be provided around the formulation of Compound A.

[0095] Dosage forms (pharmaceutical compositions) suitable for administration can contain from about 1 mg to about 300 mg of active ingredient per dosage unit. In these pharmaceutical compositions, the active ingredient will generally be present in an amount of about 0.5% - 95% by weight, based on the total weight of the composition. In some aspects, dosage forms suitable for administration can contain from about 10 to about 240 mg of active ingredient per dosage unit. In some aspects, dosage forms suitable for administration can contain about 10, about 20, about 30, about 40, about 50, about 60, about 70, about 80, about 90, about 100, about 110, about 120, about 130, about 140, about 150, about 160, about 170, about 180, about 190, about 200, about 210, about 220, about 230 or about 240 mg of active ingredient per dosage unit.

[0096] In some aspects, the present disclosure provides pharmaceutical compositions that comprise Compound A as described herein and at least one pharmaceutically acceptable carrier.

[0097] In some aspects, the present disclosure provides a pharmaceutical formulation for oral administration, the pharmaceutical formulation comprising: (a) about 5 wt% to 40 wt% of Compound A; (b) about 30 wt% to about 90 wt% of a diluent or mixture of diluents; (c) about 0 wt% to about 2 wt% of a glidant; (d) about 2 wt% to about 10 wt% of a disintegrant; and (e) about 0.25 wt% to about 4 wt% of a lubricant.

[0098] In some aspects, the Compound A of the pharmaceutical formulation comprises crystalline Form A. In some aspects, the pharmaceutical formulation for oral administration is a tablet.

[0099] In some aspects, the present disclosure provides a pharmaceutical formulation for oral administration, the pharmaceutical formulation comprising: (a) about 10 wt% to 30 wt% of Compound A; (b) about 40 wt% to about 85 wt% of a diluent or mixture of diluents; (c) about 0 wt% to about 2 wt% of a glidant; (d) about 2 wt% to about 10 wt% of a disintegrant; and (e) about 0.25 wt% to about 4 wt% of a lubricant.

[0100] In some aspects, the Compound A of the pharmaceutical formulation comprises crystalline Form A. In some aspects, the pharmaceutical formulation for oral administration is a tablet.

[0101] In some aspects, the diluents described herein are selected from lactose, sucrose, dextrose, glucose binders, 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 diluent mixture is selected from microcrystalline cellulose and anhydrous lactose.

[0102] As used herein, the term "glidant" refers to a substance that improves the flowability of a powder (such as by reducing interparticle friction) when added to the powder. In some aspects, the glidants described herein are selected from silica, silicon dioxide, CAB-0-SILM-SP, AEROSIL, talc, starch, magnesium aluminum silicate, and combinations thereof. In some aspects, the glidant is silicon dioxide.

[0103] In some aspects, the disintegrants described herein are selected from natural starch, pregelatinized starch, sodium starch glycolate, methylcellulose crystalline, methylcellulose, cross-linked carboxymethylcellulose, sodium cross-linked carboxymethylcellulose, sodium cross-linked carboxymethylcellulose, cross-linked carboxymethylcellulose, cross-linked cross-linked carboxymethylcellulose, cross-linked starch (such as sodium starch glycolate), cross-linked polymers (such as crospovidone, cross-linked polyvinylpyrrolidone), sodium alginate, clay, gums, and combinations thereof. In some aspects, the disintegrant is sodium cross-linked carboxymethylcellulose.

[0104] In some aspects, the surfactants described herein are selected from sodium lauryl sulfate, sorbitan monooleate, polyoxyethylene sorbitan monooleate, polysorbate, poloxamer, bile salts, glyceryl monostearate, copolymers of ethylene oxide and propylene oxide, and combinations thereof. In some aspects, the surfactant is sodium lauryl sulfate.

[0105] In some aspects, the lubricants described herein are 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. In some aspects, the lubricant is magnesium stearate.

[0106] In some aspects, provided herein is a pharmaceutical formulation for oral administration, the pharmaceutical formulation comprising: (a) from about 5 wt% to about 40 wt% of Compound A; (b) from about 15 wt% to about 70 wt% of microcrystalline cellulose and from about 15 wt% to about 70 wt% of anhydrous lactose; (c) from about 0 wt% to about 2 wt% of silicon dioxide; (d) from about 2 wt% to about 6 wt% of sodium cross-linked carboxymethylcellulose; and (e) from about 0.25 wt% to about 1.5 wt% of magnesium stearate.

[0107] In some aspects, Compound A of the pharmaceutical formulation comprises crystalline Form A. In some aspects, the pharmaceutical formulation for oral administration is a tablet.

[0108] In some aspects, provided herein is a pharmaceutical formulation for oral administration, the pharmaceutical formulation comprising: (a) from about 10 wt% to 30 wt% of Compound A; (b) from about 25 wt% to about 70 wt% of microcrystalline cellulose and from about 25 wt% to about 70 wt% of anhydrous lactose; (c) from about 0 wt% to about 2 wt% of silicon dioxide; (d) from about 2 wt% to about 6 wt% of croscarmellose sodium; and (e) from about 0.25 wt% to about 1.5 wt% of magnesium stearate.

[0109] In some aspects, Compound A of the pharmaceutical formulation comprises crystalline Form A. In some aspects, the pharmaceutical formulation for oral administration is a tablet. In some aspects, the tablet can be prepared with the components provided in Table 1 and / or Table 2. Table 1 Table 2

[0110] In some aspects, the pharmaceutical composition for oral administration can be prepared by direct compression or granulation (dry granulation, wet granulation or melt granulation).

[0111] In some embodiments, the pharmaceutical composition further comprises one or more additional therapeutic agents. In some embodiments, the pharmaceutical composition further comprises one or more additional anti-fibrotic agents selected from the following: pirfenidone, nintedanib, thalidomide, carlumab, FG-3019, fresolimumab, interferon α, polyethylene glycol superoxide dismutase, simtuzumab, tanzisertib, tralokinumab, hu3G9, AM-152, IFN-γ-1b, IW-001, PRM-151, PXS-25, pentoxifylline / N-acetyl-cysteine, pentoxifylline / vitamin E, salbutamol sulfate, [Sar9,Met(O2)11]-substance P, pentoxifylline, mercaptoethylamine bitartrate, obeticholic acid, aramchol, GFT-505, eicosapentaenoic acid ethyl ester, metformin, metreleptin, muromonab-CD3, oltipraz, IMM-124-E, MK-4074, PX-102, RO-5093151. IV. Methods of Treatment

[0112] The present disclosure provides a method of treating interstitial lung disease by administering Compound A (an LPA1 antagonist). Lysophospholipids are membrane-derived bioactive lipid mediators. Lysophospholipids include, but are not limited to, lysophosphatidic acid (1-acyl-2-hydroxy-sn-glycerol-3-phosphate; LPA), sphingosine-1-phosphate (S1P), lysophosphatidylcholine (LPC), and sphingosylphosphorylcholine (SPC). Lysophospholipids affect fundamental cellular functions, which include cell proliferation, differentiation, survival, migration, adhesion, invasion, and morphogenesis. These functions affect many biological processes, which include neurogenesis, angiogenesis, wound healing, immunity, and carcinogenesis.

[0113] LPA acts in an autocrine and paracrine manner through several groups of specific G protein-coupled receptors (GPCRs). Binding of LPA to its cognate GPCRs (LPA1, LPA2, LPA3, LPA4, LPA5, LPA6) activates intracellular signaling pathways to produce a variety of biological responses.

[0114] Lysophospholipids (such as LPA) are minor lipid species in number compared to their major phospholipid counterparts (e.g., phosphatidylcholine, phosphatidylethanolamine, and sphingomyelin). LPA has a role as a bioactive molecule and has a variety of physiological effects (such as, but not limited to, effects on blood pressure, platelet activation, and smooth muscle contraction) and a variety of cellular effects (which include cell growth, cell rounding, neurite retraction, and actin stress fiber formation, as well as cell migration). The effects of LPA are mainly receptor-mediated.

[0115] Activation of LPA receptors (LPA1, LPA2, LPA3, LPA4, LPA5, LPA6) by LPA mediates a series of downstream signaling cascades. These include but are not limited to mitogen-activated protein kinase (MAPK) activation, adenylyl cyclase (AC) inhibition / activation, phospholipase C (PLC) activation / Ca 2+ 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 protein 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 factor (GEF), glycogen synthase kinase 3b (GSK3b), c-jun N-terminal kinase (JNK), MEK, myosin light chain II (MLC II), nuclear factor kB (NF-kB), N-methyl-D-aspartic acid (NMDA) receptor activation, phosphatidylinositol 3-kinase (PI3K), protein kinase A (PKA), protein kinase C (PKC), ras-related C3 botulinum toxin substrate 1 (RAC1). The actual pathways and the endpoints achieved depend on a series of variables, which include receptor usage, cell type, expression levels of the receptor or signaling proteins, and LPA concentration. Almost all mammalian cells, tissues, and organs co-express several LPA receptor subtypes, suggesting that LPA receptors signal in a collaborative manner. LPA1, LPA2, and LPA3 have high amino acid sequence similarity.

[0116] LPA is produced by activated platelets, activated adipocytes, neuronal cells, and other cell types. Serum LPA is generated through multiple enzymatic pathways involving monoacylglycerol kinase, phospholipase A1, secreted phospholipase A2, and lysophospholipase D (lysoPLD) (including autotaxin). Several enzymes are involved in LPA degradation: lysophospholipase, lipid phosphate phosphatase, and LPA acyltransferase such as endophilin. The concentration of LPA 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. LPA molecular species with different acyl chain lengths and saturations are naturally occurring, including 1-palmitoyl (16:0), 1-palmitoleoyl (16:1), 1-stearoyl (18:0), 1-oleoyl (18:1), 1-linoleoyl (18:2), and 1-arachidonoyl (20:4) LPA. The less abundant alkyl LPA has biological activities similar to those of acyl LPA, and different LPA species activate LPA receptor subtypes with different potencies.

[0117] LPA1 (previously known as VZG-1 / EDG-2 / mrec1.3) couples to the following three types of G proteins: G i / o , G q , and G 12 / 13 . By activating these G proteins, LPA induces a series of cellular responses through LPA1, including but not limited to: cell proliferation, serum response element (SRE) activation, mitogen-activated protein kinase (MAPK) activation, adenylyl cyclase (AC) inhibition, phospholipase C (PLC) activation, Ca 2+ mobilization, Akt activation, and Rho activation.

[0118] Widespread expression of LPA1 has been observed in adult mice, specifically present in the testis, brain, heart, lung, small intestine, stomach, spleen, thymus, and skeletal muscle. Similarly, human tissues also express LPA1; it is present in the brain, heart, lung, placenta, colon, small intestine, prostate, testis, ovary, pancreas, spleen, kidney, skeletal muscle, and thymus.

[0119] As used herein, the term "LPA-dependent" refers to a condition or disorder that does not occur or does not occur to the same extent in the absence of LPA.

[0120] As used herein, the term "LPA-mediated" refers to a condition or disorder that may occur in the absence of LPA but should occur in the presence of LPA.

[0121] As used herein, the terms "fibrosis" and "fibrotic disease" refer to conditions associated with abnormal accumulation of cells and / or fibronectin and / or collagen and / or increased fibroblast recruitment, and include, but are not limited to, fibrosis of a single organ or tissue (such as the heart, kidney, liver, joints, lungs, pleural tissue, peritoneal tissue, skin, cornea, retina, musculoskeletal, and gastrointestinal tract), such as idiopathic pulmonary fibrosis, scleroderma, and chronic kidney disease.

[0122] Exemplary diseases, disorders, or conditions involving fibrosis include, but are not limited to: lung diseases associated with fibrosis, such as idiopathic pulmonary fibrosis, pulmonary fibrosis secondary to systemic inflammatory diseases (such as rheumatoid arthritis, scleroderma, lupus), cryptogenic fibrosing alveolitis, 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 that induced by bacterial pneumonia, trauma, viral pneumonia, ventilator use, non-pulmonary sepsis, and aspiration); chronic kidney disease associated with injury / fibrosis (renal fibrosis), such as glomerulonephritis secondary to systemic inflammatory diseases (such as lupus and scleroderma), diabetes, glomerulonephritis, focal segmental glomerulosclerosis, IgA nephropathy, hypertension, allograft, and hereditary nephritis (Alport); intestinal fibrosis, such as scleroderma and radiation-induced intestinal fibrosis; liver fibrosis, such as cirrhosis, alcohol-induced liver fibrosis, non-alcoholic steatohepatitis (NASH), bile duct injury, primary biliary cirrhosis, infection or virus-induced liver fibrosis (e.g., chronic HCV infection), and autoimmune hepatitis; head and neck fibrosis, such as radiation-induced; corneal scarring, such as LASIK (laser-assisted in situ keratomileusis), corneal transplantation, and trabeculectomy; hypertrophic scars and keloids, such as burn-induced or surgical; and other fibrotic diseases, such as sarcoidosis, scleroderma, spinal cord injury / fibrosis, myelofibrosis, vascular restenosis, atherosclerosis, arteriosclerosis, Wegener's granulomatosis, mixed connective tissue disease, and Peyronie's disease.

[0123] 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 passage fibrosis, sinusitis, neutrophil-mediated inflammation, and fibroblast-mediated fibrosis, skin disorders (including skin proliferative or inflammatory disorders, such as atopic dermatitis, bullous disorders, collagen diseases, psoriasis, psoriatic lesions, dermatitis, contact dermatitis, eczema, rosacea, wound healing, scars, hypertrophic scars, keloids, Kawasaki disease, rosacea, Sjogren-Larsson syndrome ( - Larsson Syndrome) and urticaria), respiratory diseases (including 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, etc. isocapnic 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), and inflammatory / immune disorders (including psoriasis, rheumatoid arthritis, vasculitis, inflammatory bowel disease, dermatitis, osteoarthritis, asthma, inflammatory muscle diseases, allergic rhinitis, vaginitis, interstitial cystitis, scleroderma, eczema, allograft or xenograft (organ, bone marrow, stem cells and other cells and tissues) graft rejection, graft-versus-host disease, lupus erythematosus, inflammatory diseases, type I diabetes, pulmonary fibrosis, dermatomyositis, Sjogren's syndrome, thyroiditis (e.g., Hashimoto's thyroiditis and autoimmune thyroiditis), myasthenia gravis, autoimmune hemolytic anemia, multiple sclerosis, cystic fibrosis, chronic recurrent hepatitis, primary biliary cirrhosis, allergic conjunctivitis and atopic dermatitis).

[0124] There are currently two approved treatments for interstitial lung disease: nintedanib and pirfenidone, but several compounds are currently being developed. In certain aspects of the present disclosure, subjects receiving Compound A are undergoing concomitant treatment with one or more therapies for interstitial lung disease. In some aspects, one or more therapies are selected from nintedanib and pirfenidone.

[0125] In certain aspects, about 100 mg to about 150 mg of Compound A is administered to the subject daily. In some aspects, about 110 mg to about 130 mg of Compound A is administered to the subject daily. In some aspects, about 100, about 105, about 110, about 115, about 120, about 125, about 130, about 135, about 140, about 145 or about 150 mg of Compound A is administered to the subject daily. In some aspects, about 120 mg of Compound A is administered to the subject daily.

[0126] In some aspects, Compound A is administered to the subject once daily. In some aspects, Compound A is administered to the subject twice daily. In some aspects, Compound A is administered to the subject three times daily. In some aspects, Compound A is administered to the subject four times daily. In some aspects, Compound A is administered to the subject five times daily.

[0127] In some aspects, 120 mg is administered to the subject once daily. In some aspects, a 60 mg dose of Compound A is administered to the subject twice daily. In some aspects, a 40 mg dose of Compound A is administered to the subject three times daily. In some aspects, a 30 mg dose of Compound A is administered to the subject four times daily. In some aspects, a 24 mg dose is administered to the subject five times daily.

[0128] In some aspects, Compound A is administered to the subject with food. In some aspects, Compound A is administered to the subject without food.

[0129] In some aspects, compared to untreated subjects, subjects administered Compound A experience slower disease progression. In some aspects, disease progression is measured by a decrease in the forced vital capacity (FVC) of the subject. In some aspects, compared to untreated subjects, subjects treated with Compound A experience a smaller decrease in forced vital capacity (FVC) after the treatment period. FVC is the amount of air that a subject can forcefully exhale from his / her lungs after breathing in as deeply as possible. A spirometry test is typically used to measure FVC, which involves placing a special mask on the subject's face and having the subject inhale and exhale as forcefully as possible while collecting the measurements.

[0130] In some aspects, disease progression can be measured by the time it takes for the subject to experience a disease progression event. In some aspects, compared to untreated subjects, subjects administered Compound A experience a longer time to the first disease progression event after the treatment period. In some aspects, the first disease progression event is an absolute predicted percent forced vital capacity (ppFVC) relative to baseline ≥ 10%. An absolute or relative decrease in predicted FVC% ≥ 10% is associated with death. In some aspects, compared to untreated subjects, subjects treated with Compound A experience a longer time to an absolute predicted percent forced vital capacity (ppFVC) relative to baseline ≥ 10%.

[0131] In some aspects, the first disease progression event is an acute exacerbation (e.g., sudden worsening) of his / her pulmonary fibrosis. In some aspects, compared to untreated subjects, subjects treated with Compound A experience a longer time to an acute exacerbation of pulmonary fibrosis.

[0132] In some aspects, the first disease progression event is a respiratory hospitalization. In some aspects, compared to untreated subjects, subjects treated with Compound A experience a longer time to a respiratory hospitalization.

[0133] In some aspects, the first disease progression event is a lung transplant. In some aspects, compared to untreated subjects, subjects treated with Compound A experience a longer time to a lung transplant.

[0134] In some aspects, the first disease progression event is death. In some aspects, compared to untreated subjects, subjects treated with Compound A experience a longer time to all-cause death.

[0135] In some aspects, compared to untreated subjects, subjects experience a longer time to the first disease progression event after the treatment period, where the first disease progression event is selected from: Absolute predicted forced vital capacity percentage (ppFVC) relative to baseline ≥ 10%; Acute exacerbation of pulmonary fibrosis; Respiratory hospitalization; Lung transplantation; and All-cause death.

[0136] In some aspects, disease progression is measured by changes in the score of the Lung-PF (Lung Fibrosis Quality of Life) questionnaire. The Lung-PF questionnaire assesses the symptoms and quality of life of patients with fibrotic interstitial lung disease (ILD). The scores in its dyspnea and cough domains (the responses to whose items are based on 24-hour recall) range from 0 to 100, with higher scores indicating greater symptom severity (see, for example, Swigris JJ et al. BMJ Open Resp Res [Open Access Journal of BMJ Respiratory Diseases] 2022;9:e001167.doi:10.1136 / bmjresp-2021-001167). In some aspects, compared to untreated subjects, subjects administered Compound A experience a smaller increase in the score of the cough domain as measured by the Lung-PF questionnaire during the treatment period. In some aspects, compared to untreated subjects, subjects experience a smaller increase in the score of dyspnea as measured by the Lung-PF questionnaire during the treatment period. Examples Example 1: Preparation of Crystalline Form A of Compound A

[0137] The crystalline form 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 spray jetting. Techniques for crystallizing or recrystallizing the eutectic form from a solvent mixture include, for example, evaporating the solvent, lowering the temperature of the solvent mixture, seeding the crystal into a supersaturated solvent mixture of the molecule and / or salt, freeze-drying the solvent mixture, and adding an anti-solvent (anti-solvent) to the solvent mixture.

[0138] For crystallization techniques using solvents, the choice 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. Combinations of solvents can be employed. For example, a compound can be dissolved in a first solvent to provide a solution, and then an anti-solvent can be added to reduce the solubility of the compound in the solution and result in the formation of crystals. An anti-solvent is a solvent in which the compound has low solubility.

[0139] In one method of preparing crystals, a compound is suspended and / or stirred in a suitable solvent to obtain a slurry, which can be heated to facilitate dissolution. As used herein, the term "slurry" means a saturated solution of the compound, which may also contain additional amounts of the compound to obtain a heterogeneous mixture of the compound and the solvent at a given temperature.

[0140] Seeds can be added to any crystallization mixture to facilitate crystallization. Seeds can be used to control the growth of a particular polymorph or to control the particle size distribution of the crystallization product. Thus, the calculation of the required amount of seeds depends on the size of the available seeds and the desired size of the average product particles, 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 a batch. Small-sized seeds can be produced by sieving, grinding, or micronizing large crystals, or by microcrystallization of a solution. It should be noted that grinding or micronizing of the crystals does not result in any change in crystallinity with respect to the desired crystal form (i.e., becoming amorphous or becoming another polymorph).

[0141] The cooled crystallization mixture can be filtered under vacuum, and the separated solid can be washed with a suitable solvent (such as a cold recrystallization solvent) and dried under a nitrogen purge to obtain the desired crystalline form. The separated solid can be analyzed by suitable spectroscopic or analytical techniques (such as solid-state nuclear magnetic resonance, differential scanning calorimetry, X-ray powder diffraction, etc.) to ensure the formation of the preferred crystalline form of the product. The resulting crystalline form is typically produced in an amount corresponding to a separation yield of greater than about 70% by weight, preferably greater than 90% by weight, based on the weight of the compound initially employed in the crystallization procedure. If desired, the product can be co-ground or passed through a sieve to deagglomerate the product.

[0142] The presence of more than one polymorph in a sample can be determined by techniques such as powder X-ray diffraction (PXRD) or by techniques such as Raman or infrared spectroscopy, solid-state nuclear magnetic resonance spectroscopy. For example, the presence of additional peaks in the comparison of an experimentally measured PXRD pattern with a simulated PXRD pattern can indicate the presence of more than one polymorph in the sample. The simulated PXRD can be calculated from single crystal X-ray data. See Smith, D.K., “A FORTRAN Program for Calculating X-Ray Powder Diffraction Patterns,” Lawrence Radiation Laboratory, Livermore, California, UCRL-7196 (April 1963).

[0143] The crystalline forms of Compound A according to the present invention can be characterized using a variety of techniques, the operation of which is well known to those of ordinary skill in the art. These forms can be characterized and distinguished using single crystal X-ray diffraction, which is based on the unit cell measurements of single crystals of the form at a fixed analysis temperature. A detailed description of the unit cell is provided in Stout and Jensen, X-Ray Structure Determination: A Practical Guide, Macmillan Co., New York (1968), Chapter 3, which is incorporated herein by reference. Alternatively, the unique arrangement of atoms in the spatial relationships within the lattice can be characterized based on the observed fractional atomic coordinates. Another means of characterizing the crystalline structure is by powder X-ray diffraction analysis (where the diffraction spectrum is compared with a simulated spectrum representative of the pure powder material, both run at the same analysis temperature) and measurement of the subject form (characterized as a series of 2θ values (usually four or more)).

[0144] Other means of characterizing the form can be used, such as solid-state nuclear magnetic resonance (SSNMR), differential scanning calorimetry, thermogravimetric analysis, and FT-Raman and FT-IR. These techniques can also be used in combination to characterize the subject form. In addition to the techniques specifically described herein, the presence of a particular crystalline form can also be determined by other suitable analytical methods. Example 1A

[0145] At 20 °C, 150 mg of Compound A was dissolved in 1.5 mL of tetrahydrofuran (THF). 0.5 mL of this solution was subjected to rapid evaporation using a centrifugal evaporator to produce a solid of Form A. At 20 °C, 0.5 mL of the same solution was subjected to slow evaporation to produce a solid of Form A. Example 1B

[0146] At 20 °C, 200 mg of Compound A was dissolved in 1 mL of dichloromethane (DCM). 0.5 mL of this solution was subjected to rapid evaporation using a centrifugal evaporator to produce a solid of Form A. At 20 °C, 0.5 mL of the same solution was subjected to slow evaporation to produce a solid of Form A. Example 1C

[0147] At 50 °C, 100 mg of Compound A was dissolved in 0.5 mL of THF and stirred at 20 °C. 0.5 mL of water was added to the clear solution, which produced a solid of Form A. Example 1D

[0148] At 50 °C, 100 mg of Compound A was dissolved in 1 mL of 2-methyl THF and stirred at 20 °C. 1 mL of n-heptane was added to the clear solution, which produced a solid of Form A. Example 1E

[0149] A solution of Compound A in tert-amyl alcohol (t-AmOH) was concentrated to 4 L / kg under vacuum, then 15 L / kg of DCM and 10 L / kg of water were added. The layers were separated, and the DCM layer was concentrated to 4 L / kg under vacuum. 8 - 10 L / kg of ethyl acetate (EtOAc) was added to the DCM layer, then it was concentrated to 4 L / kg under vacuum. Another 8 - 10 L / kg of EtOAc was added, then it was concentrated to 4 L / kg under vacuum. 6 - 8 L / kg of EtOAc was added and warmed to 70 °C - 83 °C until completely dissolved. The resulting slurry was cooled to 0 °C - 10 °C over at least 2 hours, followed by aging for at least 12 hours. The slurry was filtered. The wet filter cake was washed with 3 - 5 L / kg of EtOAc and dried at 55 °C - 60 °C under vacuum to produce a solid of Form A. Example 1F

[0150] A solution of compound A in t-AmOH was concentrated to 4 L / kg at 55 °C under vacuum, then 5 L / kg of 2-propanol (IPA) was added and the mixture was concentrated to 4 L / kg at 55 °C under vacuum. This process was repeated two more times with 2 x 5 L / kg of IPA. The batch was cooled to 30 °C, then 1.3 L / kg of water was added and the mixture was heated to 45 °C - 55 °C. The resulting warm solution was filtered finely and cooled to 30 °C. 1 wt% of seed form A was added, followed by 2 L / kg of water. After at least 6 hours, an additional 8.7 L / kg of water was added. 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 successively with 3 L / kg of a water:IPA:t-AmOH mixture (11:3:1 by volume) and 3 L / kg of water and dried under vacuum at 50 °C - 60 °C to give the solid of form A. Example 1G

[0151] To a solution of (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 isopropyl ester (500 mg, 1.025 mmol) in 1:1 THF / MeOH (10 mL) was added aqueous 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 room temperature and the organic volatiles were removed in vacuo. The concentrated solution was washed with EtOAc and then acidified to pH ~6 - 7 (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 yield the solid of form A.

[0152] The analytical data for the crystalline compound A described herein were obtained using the following procedure. Single crystal

[0153] Single crystal X-ray data were collected on a Bruker X8 Kappa diffractometer equipped with an APEX II CCD detector and a MICROSTAR microfocus rotating anode X-ray generator with monochromated Cu Kα radiation. During data collection, the single crystal was at room temperature.

[0154] Indexing and processing of the intensity data measured with the APEX2 program suite (Bruker AXS, Inc., 5465 East Cheryl Parkway, Madison, Wisconsin 53711, USA). The final cell parameters were determined using the full data set. The structure was solved by direct methods and refined by full-matrix least-squares using the SHELXTL software package (G. M. Sheldrick, SHELXTL v6.14, Bruker, Madison, Wisconsin, USA). Structure refinement involves minimizing the function defined by ∑w(|F o |-|F c |) 2 where w is an appropriate weighting factor based on the error of the observed intensity, F o is the structure factor for the measured reflections, and F c is the structure factor for the calculated reflections. The agreement between the refined crystal structure model and the experimental X-ray diffraction data was evaluated by using the residual factors R = ∑||F o |-|F c || / ∑|F o | and wR = [∑w(|F o |-|F c |) 2 / ∑w|F o |] 1 / 2 . The difference Fourier maps were examined at all refinement stages. All non-hydrogen atoms were refined with anisotropic thermal displacement parameters. Hydrogen atoms were introduced using idealized geometries with isotropic temperature factors and were included in the structure factor calculations with fixed parameters. Powder X-ray diffraction (PXRD)

[0155] PXRD patterns were acquired in the 2θ range of 2 - 40° on a Bruker D8 Advance system using Cu Kα (40 kV / 40 mA) radiation, a step size of 0.03° 2θ, and a LynxEye detector. Configuration on the incident beam side: Mirror, mirror exit slit (0.2 mm), 2.5-degree Soller slit, beam knife. Configuration on the diffracted beam side: anti-scatter slit (8 mm) and 2.5° Soller slit. The sample was flat-fixed on a zero-background silicon wafer. Differential scanning calorimetry (DSC)

[0156] DSC was performed on a TA Instruments Q2000 differential scanning calorimeter equipped with an autosampler and a refrigerated cooling system under a 40 mL / min N2 purge (for Q2000). DSC thermograms were obtained in crimped aluminum pans at 15 °C / min. Thermogravimetric analysis (TGA)

[0157] TGA thermograms were obtained using a TA Instruments Q500 thermogravimetric analyzer under 40 mL / min N2 purge (for the balance) and 60 mL / min (for the sample in the aluminum pan). The TGA thermograms were obtained at 15 °C / min. Water sorption isotherms

[0158] Water sorption isotherms were collected using approximately 270 mg of sample in a 250 μL ceramic pan in a TA Instruments VTI-SA+ vapor sorption analyzer. The sample was dried at 30 °C until a loss rate of 0.005 wt% / min was obtained for 10 minutes. The sample was 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 obtained for 35 minutes or when a maximum of 600 minutes had elapsed.

[0159] It should be understood that the detailed description section, rather than 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 of the exemplary aspects of the present disclosure as contemplated by the inventors, and are therefore not intended to limit the present disclosure and the appended claims in any way.

[0160] The present disclosure has been described above by means of functional building blocks that specify the implementation of the specified functions and their relationships. For ease of description, the boundaries of these functional building blocks have been arbitrarily defined herein. Alternative boundaries may be defined as long as the specified functions and their relationships are properly performed.

[0161] The foregoing description of the specific aspects will so fully reveal the general nature of the present disclosure that others can, by applying knowledge within the scope of the art, readily modify and / or adapt such specific aspects for various applications without undue experimentation and without departing from the general concept of the present disclosure. Accordingly, such adaptations and modifications are intended to be within the meaning and range of equivalents of the disclosed aspects based on the teachings and guidance presented herein. It should be understood that the language or terminology herein is for the purpose of description and not of limitation, and thus the terminology or language of this specification will be interpreted by those skilled in the art in light of the teachings and guidance.

[0162] The breadth and scope of the present disclosure should not be limited by any of the above exemplary aspects, but should be defined only in accordance with the following claims and their equivalents.

Claims

1. Crystal form A of a compound A:

2. The crystal form A according to claim 1, characterized by at least one of the following: a) having a single crystal structure with unit cell parameters substantially equal to the following: Crystal system, space group triclinic, P1 Unit cell dimensions α = 92.8 ± 1.0° β＝95.5±1.0° γ = 93.0 ± 1.0° Volume Density (calculated value) 1.239 g / cm 3 Temperature room temperature wherein the measurement of the single crystal structure is carried out 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 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 (obtained at room temperature and under); d) A powder X-ray diffraction pattern 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 (obtained at room temperature and below); e) a differential scanning calorimetry thermogram substantially similar to that shown in Figure 2; f) having a differential scanning calorimetry thermogram with an endotherm starting at about 152 °C; and / or g) a thermogravimetric analysis thermogram substantially similar to that shown in Figure 3.

3. The crystal form A according to claim 1 or claim 2, wherein the crystal form A has a single crystal structure with unit cell parameters substantially equal to the following: Crystal system, space group triclinic, P1 Unit cell dimensions α = 92.8 ± 1.0° β＝95.5±1.0° γ = 93.0 ± 1.0° Volume Density (calculated value) 1.239 g / cm 3 Temperature room temperature wherein the measurement of the single crystal structure is carried out at room temperature.

4. The crystal form A according to claim 1 or claim 2, wherein the crystal form A is characterized by a powder X-ray diffraction pattern substantially the same as that shown in Figure 1.

5. The crystalline form A as claimed in claim 1 or claim 2, wherein the crystalline form A is characterized by a powder X-ray diffraction pattern comprising two or more peaks at 2θ values selected from the following: 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 (obtained at room temperature and below).

6. The crystalline form A as claimed in claim 1 or claim 2, wherein the crystalline form A is characterized by a powder X-ray diffraction pattern comprising two or more peaks at 2θ values selected from the following: 6.4 ± 0.2, 6.8 ± 0.2, 13.6 ± 0.2, 15.7 ± 0.2, and 21.6 ± 0.2 (obtained at room temperature and below).

7. The crystalline form A as claimed in claim 1 or claim 2, wherein the crystalline form A is characterized by a powder X-ray diffraction pattern comprising three or more peaks at 2θ values selected from the following: 6.4 ± 0.2, 6.8 ± 0.2, 13.6 ± 0.2, 15.7 ± 0.2, and 21.6 ± 0.2 (obtained at room temperature and below).

8. The crystalline form A according to claim 1 or claim 2, wherein the crystalline form A is characterized by a powder X-ray diffraction pattern comprising three or more peaks at 2θ values selected from the following: 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 (obtained at room temperature and below).

9. The crystalline form A according to claim 1 or claim 2, wherein the crystalline form A is characterized by a powder X-ray diffraction pattern comprising 4 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 (obtained at room temperature and below).

10. The crystal form A according to claim 1 or claim 2, wherein the crystal form A is characterized by a differential scanning calorimetry thermogram substantially similar to that shown in Figure 2.

11. The crystal form A according to claim 1 or claim 2, wherein the crystal form A is characterized by having a differential scanning calorimetry thermogram with an endotherm starting at about 152 °C.

12. The crystal form A according to claim 1 or claim 2, wherein the crystal form A is characterized by a thermogravimetric analysis thermogram substantially similar to that shown in Figure 3.

13. The crystal form A according to claims 1-12, in a substantially pure form.

14. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and the crystal form A according to claims 1-13, alone or in combination with another therapeutic agent.

15. The crystal form A according to claims 1-13 and the pharmaceutical composition according to claim 11, for use in the treatment of interstitial lung disease.

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

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

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