LPA1 antagonists for treating interstitial lung disease

Abstract

The present disclosure relates to methods of treating interstitial lung disease by administering (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 (an LPA1 antagonist).

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of priority to U.S. Provisional Patent Application No. 63 / 476,992, filed December 23, 2022, and U.S. Provisional Patent Application No. 63 / 519,692, filed August 15, 2023, the entire contents of each of which are hereby incorporated by reference.

[0002] The present disclosure relates to methods of treating interstitial lung disease by administering (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 (an LPA1 antagonist). [Background technology]

[0003] Interstitial lung diseases (ILDs) are a heterogeneous group of lung disorders classified together based on shared 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 radiographic pattern known as usual interstitial pneumonia (UIP) (Non-Patent Document 1). Beyond 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 etiology, 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 with respect to 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 a well-tolerated and effective treatment for PPF (Non-Patent Document 8).

[0006] Overall, there is a high unmet need for effective and tolerable treatments for patients with IPF and non-IPF, PPF, who present with disease progression. Fibrotic diseases such as these involve 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 the treatment of 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]

[0009] 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.

[0010] The present disclosure provides methods of treating interstitial lung disease using Compound A. [Prior art documents] [Patent documents]

[0011] [Patent Document 1] US Patent Application Publication No. 2017 / 0360759 [Patent Document 2] PCT Application Publication Number: International Publication No. 2017 / 223016 Pamphlet [Non-patent literature]

[0012] [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 [Brief explanation of the drawings]

[0013] [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 (differential scanning calorimetry, TGA) thermogram of Form A. [Figure 4] 1 shows the moisture sorption isotherm of Form A. [Figure 5] An overview of the phase 2 trial is shown below. [Figure 6] Figure 1 shows the percent change in ppFVC in patients treated with placebo or Compound A. [Figure 7] Figure 1 shows the change in FVC (mL) in patients treated with placebo or Compound A. [Figure 8] Absolute change from baseline (mL) in FVC in patients treated with placebo or Compound A is shown. [Figure 9] Figure 1 shows the percent change in ppFVC with basal use of antifibrotic agents in patients treated with placebo or Compound A. [Figure 10] Figure 1 shows the change from baseline in ppFVC percentage (primary estimand) in PPF subjects treated with placebo or Compound A. [Figure 11] Figure 1 shows the change from baseline (mL) (primary estimand) in FVC in PPF subjects treated with placebo or Compound A. [Figure 12] Figure 1 shows the change from baseline in ppFVC percentage (primary estimand) in PPF subjects treated with UIP with placebo or Compound A. [Figure 13] Figure 1 shows the change from baseline (mL) (primary estimand) in FVC in PPF subjects without UIP treatment with placebo or Compound A. [Figure 14] Figure 1 shows the percent change in ppFVC in PPF subjects with and without UIP treatment with placebo or Compound A. [Figure 15] 1 shows the change from baseline in ppFVC percentage (primary estimand) in PPF subjects receiving antifibrotic agents treated with placebo or Compound A. [Figure 16] Figure 1 shows the change from baseline in ppFVC percentage (primary estimand) in PPF subjects not taking antifibrotic agents treated with placebo or Compound A. Summary of the Invention [Means for solving the problem]

[0014] In some embodiments, the disclosure provides a method of treating interstitial lung disease, the method comprising administering to a subject in need thereof about 120 mg / day of Compound A: [ka] or an equivalent amount of a pharmaceutically acceptable salt thereof. In some embodiments, Compound A, or a pharmaceutically acceptable salt thereof, is administered once daily.

[0015] In some embodiments, Compound A, or a pharmaceutically acceptable salt thereof, is administered twice daily. In some embodiments, about 60 mg of Compound A, or an equivalent amount of a pharmaceutically acceptable salt thereof, is administered twice daily. In some embodiments, Compound A, or a pharmaceutically acceptable salt thereof, is administered orally. In some embodiments, Compound A, or a pharmaceutically acceptable salt thereof, is administered as a tablet.

[0016] In some embodiments, the subject being treated is simultaneously treated with one or more therapies for interstitial lung disease. In some embodiments, one or more therapies is pirfenidone. In some embodiments, one or more therapies is nindanib.

[0017] In some embodiments, Compound A or a pharmaceutically acceptable salt thereof is administered to a subject with food. In some embodiments, Compound A or a pharmaceutically acceptable salt thereof is administered to a subject without food.

[0018] In some embodiments, the interstitial lung disease is idiopathic pulmonary fibrosis (IPF). In some embodiments, the interstitial lung disease is progressive pulmonary fibrosis (PPF).

[0019] In some embodiments, Compound A is: a) unit cell parameters substantially equal to the crystalline system; space group triclinic, 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 (calculated value) 1.239g / cm 3 temperature room temperature A single crystal structure having Measurements of the single crystal structure are at room temperature, single crystal structure; 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) containing 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) containing 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 with an onset of about 152°C, and / or g) Thermogravimetric analysis thermogram substantially similar to that shown in Figure 3 The present invention includes crystalline forms characterized by at least one of the following:

[0020] In some embodiments, the subject experiences a smaller decrease in forced vital capacity (FVC) after the treatment period when compared to untreated subjects. In some embodiments, the subject experiences a longer time to the first disease progression event after the treatment period than untreated subjects, and the first disease progression event is absolute percentage of predicted forced vital capacity (ppFVC) ≥ 10% from baseline; acute exacerbation of pulmonary fibrosis; Respiratory hospitalization lung transplant; and Selected from all-cause mortality.

[0021] 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 an absolute predicted forced vital capacity (ppFVC) decline of 10% or more from baseline; acute exacerbation of pulmonary fibrosis; Pulmonary fibrosis-related hospitalization; and All-cause mortality is selected from.

[0022] In some embodiments, subjects 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.

[0023] In some embodiments, the disclosure provides a method for treating interstitial lung disease using about 120 mg / day of Compound A: [ka] or an equivalent amount of a pharmaceutically acceptable salt thereof.

[0024] In some embodiments, the disclosure provides a method for treating interstitial lung disease using about 120 mg / day of Compound A: [ka] or an equivalent amount of a pharmaceutically acceptable salt thereof. In some embodiments, the interstitial lung disease is idiopathic pulmonary fibrosis (IPF). In some embodiments, the interstitial lung disease is progressive pulmonary fibrosis (PPF). DETAILED DESCRIPTION OF THE INVENTION

[0025] The present disclosure provides a method of treating interstitial lung disease, the method comprising administering to a subject in need thereof about 120 mg / day of Compound A: [ka] or an equivalent amount of a pharmaceutically acceptable salt thereof.

[0026] In order that this description may be more readily understood, certain terms are first defined. Further definitions are set forth throughout the detailed description.

[0027] 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 "included," 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.

[0028] All measurements are subject to experimental error and are within the scope of the present invention.

[0029] 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%.

[0030] 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.

[0031] 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.

[0032] 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.

[0033] 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.

[0034] As used herein, the term "BP" refers to blood pressure, the term "SBP" refers to systolic blood pressure, and the term "DBP" refers to diastolic blood pressure.

[0035] 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 agents are administered by the same or different routes of administration or at the same or different times.

[0036] As used herein, the term "DSC" refers to differential scanning calorimetry. The term "TGA" refers to thermogravimetric analysis.

[0037] The term "effective amount" or "therapeutically effective amount," as used herein, refers 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.

[0038] 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.

[0039] 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.

[0040] The term "room temperature" generally means approximately 22°C, but can vary 7°C above or below.

[0041] The terms "subject" and "participant" are used interchangeably and include 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 aspect, the mammal is a human.

[0042] 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 contains one or more other forms of the compound and / or reaction and / or processing impurities resulting from its preparation. For example, a crystalline form of Compound A can be considered substantially pure in that it has 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 containing one or more other forms of the compound and / or reaction and / or processing impurities.

[0043] When the term "substantially matches" is used in reference to a PXRD or XRPD pattern, it should be understood that measurements of peak positions for a given crystalline form of the same compound will vary within a margin of error. It should also be 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.

[0044] 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.

[0045] II. Compound A Compound A is described in U.S. Patent Application Publication No. 2017 / 0360759. [ka]

[0046] 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 can be used to prepare liquid formulations in which the drug is dissolved or suspended. Additionally, crystalline Form A of Compound A can be incorporated into solid formulations.

[0047] 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.

[0048] In some embodiments, Form A has a single crystalline structure with unit cell parameters substantially equal to the crystalline system Space group triclinic, 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 (calculated value) 1.239 g / cm 3 temperature room temperature A single crystal structure having The single crystal structure measurements are at room temperature and are characterized by a single crystal structure.

[0049] In some embodiments, Form A has a powder X-ray diffraction pattern substantially the same as that shown in FIG.

[0050] In some embodiments, Form A has 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. In some embodiments, Form A has a powder x-ray diffraction (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, 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 (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, 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.

[0051] In some embodiments, Form A has 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. 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, 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 a powder x-ray diffraction pattern (obtained 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.

[0052] 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.

[0053] In some embodiments, Form A has a differential scanning calorimetry thermogram substantially similar to that shown in FIG.

[0054] In some embodiments, Form A has a differential scanning calorimetry thermogram with an onset endotherm at about 152°C.

[0055] In some embodiments, Form A has a thermogravimetric analysis thermogram substantially similar to that shown in FIG.

[0056] 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 ingredients, as well as any product that results directly or indirectly from the combination of specified amounts of specified ingredients. Such terms, in connection with pharmaceutical compositions, are intended to encompass a product comprising one or more active and inactive ingredients 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 ingredients, or from the dissociation of one or more ingredients, or from any other type of reaction or interaction of one or more ingredients. Thus, pharmaceutical compositions of the present invention encompass any composition made by admixing a compound of the present invention with a pharmaceutically acceptable carrier. By "pharmaceutically acceptable carrier" it is meant that the carrier, diluent, or excipient is compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.

[0057] In some embodiments, the compositions of the present disclosure are suitable for oral administration. These compositions may include 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.

[0058] 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 tablets, sugar-coated tablets, or film-coated tablets. Enteric-coated tablets are compressed tablets coated with a substance that is resistant to stomach acid but dissolves or disintegrates in the intestine, protecting 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 protecting the tablets from oxidation. Film-coated tablets are compressed tablets coated 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. Multilayer compressed tablets are compressed tablets made by more than one compression cycle, including multilayer tablets and compression-coated or dry-coated tablets.

[0059] 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.

[0060] 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 cracking. 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.

[0061] 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, 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 semisolid dosage forms include, but are not limited to, solutions and suspensions in propylene carbonate, vegetable oils, triglycerides, and combinations thereof. Capsules can also be coated as known to those skilled in the art to modify or sustain dissolution of the active ingredient.

[0062] 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 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 containing 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.

[0063] In some aspects, compositions of the present disclosure for oral administration may also be provided in the form of liposomes, micelles, microspheres, or nanosystems.

[0064] In some embodiments, the compositions of the present disclosure can 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 can include, but are not limited to, diluents, sweeteners, humectants, 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.

[0065] 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.

[0066] In certain aspects, the compositions of the present disclosure can be formulated as immediate or modified release dosage forms, including delayed-, extended-, pulsed-, controlled-, targeted-, and programmed-release forms.

[0067] The compositions of the present disclosure may include other 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.

[0068] 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.

[0069] Compound A, or a pharmaceutically acceptable salt thereof, 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.

[0070] 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. Moreover, when desired or necessary, suitable binders, lubricants, disintegrants, glidants, flavoring agents, and coloring agents can also be incorporated into the mixture.

[0071] In still 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).

[0072] 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 may contain from 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 unit.

[0073] In some aspects, the present disclosure provides pharmaceutical compositions comprising Compound A, as described herein, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.

[0074] In some aspects, the present disclosure provides a pharmaceutical formulation for oral administration, comprising: (a) about 5% to about 40% by weight of Compound A; (b) about 30% to about 90% by weight of a diluent or mixture of diluents; (c) from about 0% to about 2% by weight of a glidant; (d) about 2% to about 10% by weight of a disintegrant; and (e) about 0.25 wt % to about 4 wt % of a lubricant The present invention provides a pharmaceutical formulation comprising:

[0075] 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.

[0076] 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) from about 0% to about 2% by weight of a glidant; (d) about 2% to about 10% by weight of a disintegrant; and (e) about 0.25 wt % to about 4 wt % of a lubricant The present invention provides a pharmaceutical formulation comprising:

[0077] 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.

[0078] 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.

[0079] 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.

[0080] 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.

[0081] 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. In some aspects, the surfactant is sodium lauryl sulfate.

[0082] 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.

[0083] In some aspects, provided herein is a pharmaceutical formulation for oral administration, comprising: (a) about 5% to about 40% by weight of Compound A; (b) about 15% to about 70% by weight microcrystalline cellulose and about 15% to about 70% by weight anhydrous lactose; (c) about 0% to about 2% by weight of silicon dioxide; (d) about 2% to about 6% by weight of croscarmellose sodium; and (e) about 0.25% to about 1.5% by weight of magnesium stearate A pharmaceutical formulation is provided comprising:

[0084] 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.

[0085] 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 microcrystalline cellulose and about 25% to about 70% by weight anhydrous lactose; (c) about 0% to about 2% by weight of silicon dioxide; (d) about 2% to about 6% by weight of croscarmellose sodium; and (e) about 0.25% to about 1.5% by weight of magnesium stearate A pharmaceutical formulation is provided comprising:

[0086] 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.

[0087] [Table 1]

[0088] [Table 2]

[0089] In some embodiments, pharmaceutical compositions for oral administration may be pre-formulated by direct compression or granulation (dry, wet or melt granulation).

[0090] 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-hydroxy-sn-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.

[0091] 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 various biological responses.

[0092] 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.

[0093] Activation of LPA receptors (LPA1, LPA2, LPA3, LPA4, LPA5, and LPA6) mediates 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 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), and nuclear factor kB. These include, but are not limited to, NF-kB (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 achieved endpoint 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.

[0094] 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 acyltransferase, such as endophilin. The LPA concentration in human serum is estimated to be 1–5 μM. Serum LPA is bound 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 different effects.

[0095] LPA1 (previously called VZG-1 / EDG-2 / mrec1.3) binds two types of G proteins: G i / o , G q , and G 12 / 13 Through activation of these G proteins, LPA mediates the following: 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.

[0096] In adult mice, widespread expression of LPA1 was observed, with distinct localization in the testes, brain, heart, lungs, small intestine, stomach, spleen, thymus, and skeletal muscle. Similarly, human tissues also express LPA1; it is present in the brain, heart, lungs, placenta, colon, small intestine, prostate, testes, ovaries, pancreas, spleen, kidneys, skeletal muscle, and thymus.

[0097] 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.

[0098] As used herein, the term "LPA-mediated" refers to a condition or disorder that may occur in the absence of LPA, but can occur in the presence of LPA.

[0099] 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 recruitment of fibroblasts, 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.

[0100] 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 kidney disease (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, e.g., These include, but are not limited to, conditions 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, radiation-induced head and neck fibrosis, corneal scarring (e.g., LASIK (laser refractive surgery), corneal transplantation, 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.

[0101] 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, blisters. respiratory disorders selected from the group consisting of: sexual disorders, 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, Sokapnic 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 These include urinary bladder inflammation, 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 1 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.

[0102] Currently, there are two approved treatments for interstitial lung disease: nintedanib and perfenidone, and several compounds are currently under development. In certain embodiments of the present disclosure, the subject receiving Compound A or a pharmaceutically acceptable salt thereof is receiving concurrent treatment with one or more therapies for interstitial lung disease. In some embodiments, the one or more therapies are selected from nintedanib and perfenidone.

[0103] In certain embodiments, the subject is administered about 100 mg to about 150 mg of Compound A per day, or an equivalent amount of a pharmaceutically acceptable salt thereof. In some embodiments, the subject is administered about 110 mg to about 130 mg of Compound A per day, or an equivalent amount of a pharmaceutically acceptable salt thereof. 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, or an equivalent amount of a pharmaceutically acceptable salt thereof. In some embodiments, the subject is administered about 120 mg of Compound A per day, or an equivalent amount of a pharmaceutically acceptable salt thereof.

[0104] In some embodiments, the subject is administered Compound A, or a pharmaceutically acceptable salt thereof, once daily. In some embodiments, the subject is administered Compound A, or a pharmaceutically acceptable salt thereof, twice daily. In some embodiments, the subject is administered Compound A, or a pharmaceutically acceptable salt thereof, three times daily. In some embodiments, the subject is administered Compound A, or a pharmaceutically acceptable salt thereof, four times daily. In some embodiments, the subject is administered Compound A, or a pharmaceutically acceptable salt thereof, five times daily.

[0105] In some embodiments, subjects are administered 120 mg of Compound A, or an equivalent amount of a pharmaceutically acceptable salt thereof, once daily. In some embodiments, subjects are administered 60 mg of Compound A, or an equivalent amount of a pharmaceutically acceptable salt thereof, twice daily. In some embodiments, subjects are administered 40 mg of Compound A, or an equivalent amount of a pharmaceutically acceptable salt thereof, three times daily. In some embodiments, subjects are administered 30 mg of Compound A, or an equivalent amount of a pharmaceutically acceptable salt thereof, four times daily. In some embodiments, subjects are administered 24 mg of Compound A, or an equivalent amount of a pharmaceutically acceptable salt thereof, five times daily.

[0106] In some embodiments, the subject is administered Compound A, or a pharmaceutically acceptable salt thereof, with food. In some embodiments, the subject is administered Compound A, or a pharmaceutically acceptable salt thereof, without food.

[0107] In some embodiments, subjects administered Compound A, or a pharmaceutically acceptable salt thereof, 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, or a pharmaceutically acceptable salt thereof, experience a smaller decrease in forced vital capacity 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 over the subject's face and having the subject forcibly inhale and exhale as much as possible while measurements are collected.

[0108] 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, or a pharmaceutically acceptable salt thereof, have a longer time to first disease progression after a treatment period than untreated subjects. In some embodiments, the first disease progression event is an absolute percentage predicted forced vital capacity (ppFVC) of 10% or more from baseline. An absolute or relative decline in predicted FVC% of 10% or more is associated with mortality. In some embodiments, subjects treated with Compound A, or a pharmaceutically acceptable salt thereof, have a longer time to an absolute percentage predicted forced vital capacity (ppFVC) of 10% or more from baseline than untreated subjects.

[0109] 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, or a pharmaceutically acceptable salt thereof, have a longer time to an acute exacerbation of pulmonary fibrosis than untreated subjects.

[0110] In some embodiments, the first disease progression event is respiratory hospitalization, hi some embodiments, subjects treated with Compound A, or a pharmaceutically acceptable salt thereof, have a longer time to respiratory hospitalization than untreated subjects.

[0111] In some embodiments, the first disease progression event is a pulmonary fibrosis-related hospitalization. In some embodiments, subjects treated with Compound A, or a pharmaceutically acceptable salt thereof, have a longer time to pulmonary fibrosis-related hospitalization than untreated subjects.

[0112] In some embodiments, the first disease progression event is lung transplantation. In some embodiments, subjects treated with Compound A, or a pharmaceutically acceptable salt thereof, have a longer time to lung transplantation than untreated subjects.

[0113] In some embodiments, the first disease progression event is mortality. In some embodiments, subjects treated with Compound A, or a pharmaceutically acceptable salt thereof, have a longer time to all-cause mortality than untreated subjects.

[0114] 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) ≥ 10% from baseline; acute exacerbation of pulmonary fibrosis; respiratory hospitalization; lung transplant; and All-cause mortality is selected from.

[0115] 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 an absolute predicted forced vital capacity (ppFVC) decline of 10% or more from baseline; acute exacerbation of pulmonary fibrosis; Pulmonary fibrosis-related hospitalization; and All-cause mortality is selected from.

[0116] 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, or a pharmaceutically acceptable salt thereof, 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]

[0117] 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.

[0118] 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.

[0119] 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.

[0120] Seed crystals can be added to any crystallization mixture to promote crystallization. Seeding can be used to control the growth of a particular polymorph or to control the particle size distribution of the crystalline product. Therefore, calculation of the amount of seed required can be performed using the methods described in, for example, "Programmed Cooling of Batch Crystallizers", It depends on the size of the available seeds and the desired size of the average product particle, as described in J. W. Mullin and J. Nyvlt, Chemical Engineering Science, 1971, 26, 369-377. Generally, small size seeds are required to effectively control the growth of crystals in the batch. Small size 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., change to amorphous or another polymorph).

[0121] 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, and 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.

[0122] The presence of two or more polymorphs in a sample can be determined by techniques such as powder X-ray diffraction (PXRD), or by 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 two or more polymorphs 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).

[0123] 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 a 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 measurement for the target form is compared with a simulated profile representing the pure powder material, characterized as a set of 2q values ​​(usually four or more).

[0124] Other means of characterizing forms, such as solid state nuclear magnetic resonance (SSNMR), differential scanning calorimetry, thermogravimetry, FT-Raman, and FT-IR, can be used. 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.

[0125] 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.

[0126] 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.

[0127] 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.

[0128] 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.

[0129] Example 1E A solution of Compound A in tert-amyl alcohol (t-AmOH) was concentrated under vacuum to 4 L / kg, followed by charging 15 L / kg of DCM and 10 L / kg of water. The layers were separated, and the DCM layer was concentrated under vacuum to 4 L / kg. 8-10 L / kg of ethyl acetate (EtOAc) was charged to the DCM layer, followed by concentration under vacuum to 4 L / kg. An additional 8-10 L / kg of EtOAc was charged, followed by concentration under vacuum to 4 L / kg. 6-8 L / kg of EtOAc was charged and warmed 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 of EtOAc and dried under vacuum at 55-60°C to obtain Form A solid.

[0130] Example 1F A 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 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 50-60°C to give Form A solid.

[0131] 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 about 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 a solid of Form A.

[0132] Analytical data for crystalline Compound A described herein was obtained using the following procedures.

[0133] 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 crystals were at room temperature during data collection.

[0134] 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 (GMSheldrick, SHELXTL v6.14, Bruker AXS, Madison, WI USA). The structure refinement was performed using the Σw(|F o |-|F c |) 2 where 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.

[0135] 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.

[0136] 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.

[0137] Thermogravimetric analysis (TGA) TGA thermograms were obtained using a TA Instruments Q500 thermogravimetric analyzer at 60 mL / min for samples in Al pans under a 40 mL / min N purge for the balance. TGA thermograms were obtained at 15° C. / min.

[0138] 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 for 35 minutes, or when a maximum rate of 600 minutes was achieved.

[0139] Example 2. A randomized, placebo-controlled, double-blind, single and multiple ascending dose study of the safety, pharmacokinetics, and exploratory pharmacodynamics of oral administration of Compound A in healthy participants The study was conducted in three parts with 112 healthy male and female participants, including 24 Japanese participants. Female participants were not of childbearing potential. This study was designed to evaluate the safety and tolerability, PK, and exploratory PD of Compound A oral suspension. Parts A and B (Cohort B1 only) enrolled healthy participants and were conducted at sites in the Netherlands. Part B (Cohorts B2-B5) enrolled healthy non-Japanese participants and was conducted at sites in the United Kingdom (UK). Part C enrolled healthy Japanese participants and was conducted at the same site in the UK.

[0140] Part A was a fasted SAD study with six sequential dose-escalation cohorts (3 mg, 10 mg, 30 mg, 100 mg, 150 mg, or 250 mg) of eight healthy participants each (six active plus two placebo). Eligible participants in Part A (excluding participants in Cohort A7 [food effect (FE) / pH cohort]) received a single dose of study drug (Compound A or placebo) under fasting conditions. Cohorts A1 through A6 used sentinel dosing (one active plus one placebo, followed 48 hours later by the remaining participants in the cohort [five active plus one placebo]). However, in Cohort A6 (250 mg), a dose-limiting event was observed in the sentinel participant, so only two sentinel participants were dosed before further enrollment was discontinued. In addition to the six ascending dose cohorts, a cohort of six healthy participants (Cohort A7; six active, 100 mg Compound A) was included to evaluate the effects of food and pH on the bioavailability of Compound A in a three-period, open-label, fixed-sequence, crossover design (FE / pH cohort).

[0141] Part B was a MAD study with a planned number of six sequential dose-escalation cohorts (10 mg QD, 30 mg QD, 30 mg BID, 60 mg BID, 125 mg BID, and ≤250 mg BID) of eight healthy participants each (six active drug + two placebo) in the fasted state. However, Cohort B6 (≤250 mg BID) was discontinued due to insufficient safety and PK data at doses up to 125 mg BID. Eligible participants received study drug (Compound A or placebo) orally for 14 days.

[0142] Part C was a multi-agent controlled trial of three sequential dose-escalation cohorts (30 mg BID, 60 mg BID, and 90 mg BID) of eight healthy Japanese participants each (six active drug and two placebo). Eligible participants in cohorts C1-C3 received the study drug (Compound A or placebo) orally for 14 days.

[0143] Physical examinations, vital sign measurements (including orthostasis testing in Cohort A6, Cohorts B3-B5, and Cohorts C1-C3 at selected time points), 12-lead electrocardiograms (ECGs), and clinical laboratory assessments were performed at selected time points throughout the study. Additionally, Holter monitoring was performed for the first 24 hours after dosing on Day 1 in Part A (but not in the FE / pH cohorts) and for the first 24 hours after dosing on Days 1 and 14 in Parts B and C. Participants were closely monitored for adverse events (AEs). Blood samples were collected for up to 14 days (follow-up visits) after the (last) study drug administration for PK analysis. Additionally, blood and urine samples were collected for exploratory biomarker evaluation and for biobanking of samples for potential analyses. For potential PK analysis, urine was collected for up to 96 hours after administration of a single dose of Compound A or placebo in the SAD part, and for up to 24 hours after administration of the first (morning) dose of study drug on Day 1 in the MAD part, and for up to 24 hours after administration of the last (morning) dose of study drug on Day 14.

[0144] Compound A was generally safe and well tolerated after single and multiple oral dose administration to healthy participants. Compound A was generally associated with a reversible reduction in blood pressure (BP), which peaked 4-8 hours after administration and was not associated with significant changes in heart rate. The BP reduction was largely asymptomatic.

[0145] In the SAD cohort, Compound A dose-dependently, reversibly, and largely asymptomatically reduced SBP and DBP with minimal effect on heart rate. Changes in blood pressure are shown in Tables 3 and 4 below.

[0146] [Table 3]

[0147] [Table 4]

[0148] In the MAD cohort, reversible reductions in mean SBP and DBP occurred in all groups except the placebo QD group, which showed no change in BP. In the QD group, reductions generally occurred in a Compound A dose-dependent manner. In the BID group, both placebo and Compound A treatments reduced BP, with no clear difference between the placebo and Compound A groups. There was no clear change in the magnitude of BP reduction with repeated administration over the 14-day treatment period. In the Japanese MAD cohort, reversible reductions in mean BP occurred in all groups, including placebo. There was no clear Compound A dose-dependent trend toward reduced BP. Blood pressure changes can be seen in Tables 5 to 7 below.

[0149] [Table 5]

[0150] [Table 6]

[0151] [Table 7]

[0152] Example 3. A randomized, placebo-controlled, double-blind, single and multiple ascending dose study of the safety, tolerability, and pharmacokinetics of oral administration of Compound A in healthy Chinese participants. A single dose of 60 mg and multiple doses of 60 mg BID were selected for this Chinese PK bridging study, which provides clinically relevant doses of PK, safety, and tolerability. It investigates the effects of genetic variations in genes related to drug absorption, distribution, metabolism, excretion, and transport on the PK of Compound A in healthy Chinese participants.

[0153] Single dose On Day 1, eligible subjects will be randomized in a 3:1 ratio to receive a single oral dose of Compound A or matching placebo. Participants will fast for at least 10 hours prior to dosing, and will remain fasted until at least 4 hours after dosing.

[0154] Multiple doses On days 5-10, subjects will receive Compound A BID or matching placebo. On day 11, subjects will receive the morning dose (final dose) of Compound A or matching placebo.

[0155] On days 5 and 11, participants will fast for at least 10 hours prior to administration of the morning dose, and participants will remain fasted until at least 4 hours after administration.

[0156] Participants will also receive fasted doses in the mornings of days 6-10, but will be given breakfast approximately two hours after dosing on these days.

[0157] In the evenings of days 5-10, participants will receive a second oral dose of Compound A or placebo 12 hours after the morning dose. The evening dose will be administered approximately 2 hours after the start of dinner.

[0158] The test treatments are administered with 240 mL of water.

[0159] Example 4: A multicenter, randomized, placebo-controlled, double-blind, phase 2 study of the efficacy, safety, and tolerability of Compound A in participants with pulmonary fibrosis Safety and efficacy topline data from the final analysis of the IPF cohort in the Phase 2 study support the continued development of Compound A in both IPF and PPF. A schematic overview of both cohorts of the study is shown in Figure 5.

[0160] Example 4A: IPF Cohort A total of 278 participants with IPF were randomized, and 276 participants were treated at the data cutoff for the final analysis (August 4, 2022). Male and female participants aged 40 years or older with IPF and a forced vital capacity (ppFVC) of 40% or greater and a predicted pulmonary pulmonary carbon dioxide (DLCO) of 25% or greater, diagnosed within 7 years of screening, with centrally assessed chest HRRT obtained at screening consistent with UIP or probable UIP, or with a lung biopsy consistent with UIP, were eligible for study participation. The mean baseline ppFVC for all subjects was 76.5%. In the primary IPF cohort, participants were randomized (1:1:1) to receive 30 mg or 60 mg of Compound A or placebo (PBO) twice daily for 26 weeks. Participants were stratified by standard of care (SoC) IPF (pirfenidone vs. nintedanib vs. none) and by region at randomization (Japan vs. rest of the world).

[0161] The primary objective of the study was to determine the percent change in ppFVC from baseline to week 26. The primary objective was evaluated in two estimand frameworks to address the concurrent event of dose reduction to 10 mg BID or matching PBO if prespecified low BP criteria were met. The primary estimand was employed to estimate the treatment effect when a dose reduction was implemented. A supplemental estimand was employed to estimate the treatment effect without a dose reduction.

[0162] Of the 276 treated participants who contributed to these analyses, 90% (n=248) completed the 26-week treatment period, and 10% (n=28) discontinued treatment. Treatment discontinuation due to TEAEs was evenly balanced across treatment groups (PBO: 9.8%; 30 mg: 9.9%; 60 mg: 6.5%).

[0163] Table 8 shows the baseline demographic and clinical characteristics of the subject population in the IPF cohort.

[0164] [Table 8]

[0165] Summary results are presented in Tables 9-12, and further results from the final analysis from the IPF cohort are presented below.

[0166] Main Estimand: Analytical strategy: The primary objective was to assess the efficacy of Compound A 30 mg or 60 mg twice daily compared with PBO in IPF participants meeting the enrollment criteria, regardless of SoC use. The percent decline in ppFVC from baseline to week 26 was compared using the difference between each dose and PBO as a population-level summary, regardless of dose reduction or treatment discontinuation for any reason (treatment policy strategy).

[0167] Primary efficacy outcome: In the overall population, the 60 mg dose group demonstrated a favorable treatment response at week 26, measured as the rate of decline in ppFVC and the rate of decline in FVC (mL), when compared with PBO under both the primary and supplemental estimand frameworks (Table 8). The 30 mg dose group demonstrated no efficacy (data not shown).

[0168] In the overall population, the 60 mg dose demonstrated a treatment difference in the rate of decline in ppFVC of 1.45 ± 0.81 (mean ± standard error of the mean [SEM]) [95% Cl −0.133, 3.028], corresponding to an overall relative decline of 54% when compared with the decline slope for PBO (−2.67 ± 0.57).

[0169] When analyzing the rate of decline in FVC (mL) (adjusted for age, sex, and height as measured by the difference in slope in the 60 mg arm [-54.3 ± 20.76] by the difference in slope in the PBO arm [-101.2 ± 20.45]), the 60 mg dose corresponded to a relative treatment difference of 46.9 mL compared with PBO (46.9 ± 29.14 (mean ± SEM) [95% CI -10.3, 104.1]).

[0170] Subgroup analysis of basal SoC (SoC vs. no treatment) showed a favorable response for the primary endpoint in the 60 mg group in contrast to the PBO group.

[0171] Among subjects with basal SoC (68% of the total population), the 60 mg dose demonstrated a treatment difference (mean ± SEM) of 1.22 ± 0.87 versus PBO [95% Cl − 0.486, 2.929], corresponding to a relative treatment benefit of 39% compared with PBO.

[0172] Among those not on basal SoC (32% of the total population), the 60 mg dose showed a treatment difference (mean ± SEM) of 2.01 ± 1.7 vs. PBO, corresponding to a relative treatment benefit of 113% when compared with [95% Cl − 1.327, 5.355].

[0173] Supplementary Estimand: Analytical Strategy: A supplemental estimate for the primary objective was to assess the efficacy of Compound A 30 mg or 60 mg twice daily without dose reduction compared with PBO in IPF subjects meeting enrollment criteria, regardless of SoC use. The percent decline in ppFVC from baseline to week 26 was compared using the difference between each dose and PBO as a population-level summary, regardless of treatment discontinuation for any reason (treat-to-treat strategy). In the event of dose reduction, data collected after the dose reduction would not be considered relevant to the treatment effect of interest and would therefore be treated as missing (subtherapeutic strategy).

[0174] Dose reduction to Compound A 10 mg BID vs. adapted PBO occurred due to protocol-defined low BP criteria in 18 (6.5%) participants, and was evenly distributed across arms (PBO: 5 (5.4%); 30 mg: 7 (7.7%); 60 mg: 6 (6.5%)).

[0175] In the overall population, the 60 mg dose showed a treatment difference in the rate of decline in ppFVC of 1.77 ± 0.82 (mean ± SEM) [95% CI 0.162, 3.370], corresponding to an overall relative decline of 62% when compared with the decline slope for PBO (-2.84 ± 0.57).

[0176] When analyzing FVC (mL) (adjusted for age, sex, and height as measured by the difference in slope in the PBO arm [-108.7 ± 20.58] and the 60 mg dose [-47.2 ± 20.92]), the 60 mg dose corresponds to a relative treatment difference of 61.4 mL compared with PBO.

[0177] Subgroup analysis of basal SoC (SoC vs. no treatment) showed a favorable response for the primary endpoint in the 60 mg group in contrast to the PBO group.

[0178] Among subjects on basal SoC (68% of the total population), the 60 mg dose demonstrated a treatment difference (mean ± SEM) versus PBO for the primary endpoint (percent change in ppFVC) of 1.41 ± 0.89 [95% CI −0.341, 3.151], corresponding to a relative treatment benefit of 44% compared with PBO.

[0179] Among those not eligible for basal SoC (32% of the total population), the 60 mg dose demonstrated a treatment difference (mean ± SEM) versus PBO for the primary endpoint (percent change in ppFVC) of 2.55 ± 1.73 [95% CI −0.84, 5.948], corresponding to a relative treatment benefit of 123% compared with PBO.

[0180] Subgroup analyses of participants enrolled while on stable baseline SoC (defined as either nintedanib or pirfenidone) (68% of the overall population) and those enrolled without SoC (no SoC, 32% of the overall population) showed favorable efficacy with 60 mg compared with PBO (Table 8).

[0181] Subgroup analysis based on gender revealed different rates of decline (data not shown).

[0182] [Table 9]

[0183] [Table 10]

[0184] Further data for the IPF cohort are shown in Figures 6-9. As shown in Figure 6, in the treatment-directed strategy, the percent change in ppFVC over 26 weeks in patients with IPF was -2.7% for placebo, compared to -2.8% and -1.2% for the 30 mg and 60 mg Compound A arms, respectively. The treatment difference between the 60 mg arm and placebo was 1.4% (95% Cl, -0.1 to 3.0), a relative decline of 54% (Figure 6A). When the subtherapeutic strategy was used, the percent change in ppFVC was -2.8% for placebo, compared to -3.2% and -1.1% for the 30 mg and 60 mg Compound A arms, respectively. The treatment difference between the 60 mg Compound A arm and placebo was 1.8% (95% Cl, 0.2 to 3.4), a relative decline of 62% (Figure 6B). In Bayesian analyses, the posterior probability of a positive treatment difference for 60 mg Compound A versus placebo was greater than 95% under both estimand strategies.

[0185] The percent change in FVC (mL) for the IPF cohort is shown in Figure 7, and the absolute change in FVC is shown in Figure 8. The adjusted mean treatment difference in absolute change in FVC (mL) between the 60 mg Compound A and placebo arms at week 26 was 45.5 mL (Figure 8A).

[0186] Figure 9 shows the percent change in ppFVC for subjects with and without basal antifibrotic treatment in the IPF cohort. Treatment differences in percent change in ppFVC were consistent between both groups (Figures 9A and 9B).

[0187] Summary of efficacy results: The 30 mg dose group did not demonstrate efficacy compared with PBO in the overall SoC and non-SoC populations (data not shown). - The 60 mg dose group demonstrated a good treatment response to PBO in the overall population with and without SoC, and for the subgroup of participants at baseline SoC, as well as for participants without SoC. - These results demonstrate that Compound A has a favorable effect on FVC compared with PBO when used alone or in combination with background therapy with nintedanib or pirfenidone.

[0188] In general, overall adverse events in subjects with at least one TEAE were observed more frequently in the PBO group (Table 11). Discontinuations due to TEAEs were evenly balanced across treatment groups (PBO: 9.8%; 30 mg: 9.9%; 60 mg: 6.5%).

[0189] [Table 11]

[0190] Safety rating: - In general, overall safety events were more common in the PBO group. Treatment-emergent adverse events (TEAEs): PBO: 74 cases (80.4%); 30 mg: 69 cases (75.8%); 60 mg: 69 cases (74.2%) - Adverse Events of Special Interest (AESI): PBO: 19 cases (20.7%); 30 mg: 18 cases (19.8%); 60 mg: 9 cases (9.7%) Treatment-emergent serious adverse events (TESAEs): PBO: 16 cases (17.4%); 30 mg: 10 cases (11.0%); 60 mg: 10 cases (10.8%) - Discontinuation due to TEAEs: PBO: 9 cases (9.8%); 30 mg: 9 cases (9.9%); 60 mg: 6 cases (6.5%) - TEAEs related to study treatment PBO: 20 cases (21.7%); 30 mg: 23 cases (25.3%); 60 mg: 25 cases (26.9%) - No major organ systems or preferred time period reported for treatment discontinuation - Total deaths: 13 PBO: 4 cases (4.4%); 30 mg: 4 cases (4.4%); 60 mg: 5 cases (5.4%). Causes of death were as follows: 9 due to disease progression; 3 due to pneumonia; 1 due to congestive heart failure. TEAE-related deaths: Nine (3.3%) participants died during the study or within 28 days of the last dose of treatment. PBO: 2 cases (2.2%); 30 mg: 3 cases (3.3%); 60 mg: 4 cases (4.3%). Four additional participants died beyond the 28-day TEAE period.

[0191] Blood Pressure Monitoring: Based on pre-specified low BP safety monitoring and protocol-specified criteria, participants at 60 mg had the least frequent orthostatic intolerance, orthostatic hypotension, or pre-specified symptomatic or asymptomatic low BP criteria.

[0192] In the overall population, the following orthostatic intolerance, orthostatic hypotension, or symptomatic or asymptomatic low BP events were observed: - Orthostatic intolerance observed in 19 (6.9%) participants. · PBO: 7 people (7.6%); 30 mg: 10 people (11.0%); 60 mg: 2 people (2.2%) Orthostatic hypotension was observed with asymptomatic low BP in 54 (19.6%) participants. Note that orthostatic hypotension was defined as a fall in SBP of 20 mmHg or more or DBP of 10 mmHg or more, assuming an upright position from either supine or sitting to standing. · PBO: 19 people (20.7%); 30 mg: 21 people (23.1%); 60 mg: 14 people (15.1%) - Orthostatic hypotension observed with symptomatic low BP in 21 (7.5%) participants. · PBO: 7 people (7.6%); 30mg: 9 people (9.9%), 60mg: 5 people (5.4%) - Asymptomatic hypotension was observed in 59 (21.4%) participants. · PBO: 20 people (21.7%); 30 mg: 22 people (24.2%); 60 mg: 17 people (18.3%) - Symptomatic hypotension was observed in 27 (9.8%) participants. · PBO: 10 people (10.9%); 30 mg: 11 people (12.1%); 60 mg: 6 people (6.5%) Dose reduction to Compound A 10 mg BID vs. adapted PBO occurred due to protocol-defined low BP criteria (shown below) in 18 (6.5%) participants, and was evenly distributed across arms: PBO: 5 (5.4%); 30 mg: 7 (7.7%); 60 mg: 6 (6.5%).

[0193] Asymptomatic hypotension criteria The patient experiences one of the following, confirmed by retest within 15 minutes: Systolic blood pressure when sitting is less than 85mmHg Diastolic blood pressure when sitting is less than 55mmHg Orthostatic hypotension

[0194] Symptomatic hypotension criteria Patients will experience symptoms that, in the investigator's opinion, may be related to hypotension and confirmed by re-examination within 15 minutes, including at least one of the following: Systolic blood pressure when sitting is less than 100mmHg or diastolic blood pressure when sitting is less than 60mmHg A decrease in systolic blood pressure while sitting of 20mmHg or more since the previous visit, or a decrease in diastolic blood pressure while sitting of 10mmHg or more since the previous visit Orthostatic hypotension Orthostatic tachycardia

[0195] Based on the protocol's pre-specified BP monitoring and low BP criteria, these data indicated that Compound A 60 mg twice daily (BID) was not associated with any increased risk of orthostatic intolerance, orthostatic hypotension, orthostatic tachycardia, or symptomatic or asymptomatic low BP when compared with PBO (Table 12). However, post-dose decreases in SBP were observed with 30 mg and 60 mg on Day 1 of dosing. A mean post-dose decrease from baseline to nadir in sitting SBP was observed 2 hours after dosing (PBO: -2.1 mmHg; Compound A 30 mg: -10.5 mmHg; Compound A 60 mg: -14.1 mmHg). These decreases were not associated with any clinical sequelae and were essentially self-limiting.

[0196] [Table 12]

[0197] The number of dose reductions (and overall percentage of subjects in the group) in the IPF cohort was 5 (5.4) for placebo, 7 (7.7) for 30 mg Compound A, and 6 (6.5) for 60 mg Compound A.

[0198] The number of dose reductions (and overall percentage of subjects in the group) in the IPF cohort was 5 (5.4) for placebo, 7 (7.7) for 30 mg Compound A, and 6 (6.5) for 60 mg Compound A.

[0199] Example 4B: PPF Cohort A total of 123 participants with PPF were randomized. Participants (aged 21 years or older) were randomized (1:1:1) to receive either 30 mg or 60 mg of Compound A twice daily for 26 weeks. A centrally reviewed HRCT obtained at screening showed parenchymal fibrosis greater than 10% of the lung. (a) ILD progression within 24 months prior to screening, defined as either a decline in relative ppFVC of 10% or more, or a decline in relative ppFVC of 5% to less than 10%, with an increase in the degree of fibrosis on pre-screening chest computed tomography compared to the preceding imaging study, or evidence of symptoms associated with ILD progression, with an increase in the degree of fibrosis on pre-screening chest computed tomography compared to the preceding imaging study; (b) Subjects with interstitial lung disease of various etiologies, excluding connective tissue disease-associated interstitial lung disease (excluding rheumatoid arthritis-associated interstitial lung disease) and sarcoid, were enrolled. Immunosuppressive medications (mycophenolate mofetil, mycophenolic acid, azathioprine, and / or tacrolimus) were permitted only if they had been on stable medication for at least 6 months prior to screening. If patients received the antifibrotic agents pirfenidone or nintedanib, they had to be on a stable dose for at least 3 months prior to screening and during the screening period. If patients did not receive pirfenidone or nintedanib, they had to be naive to both drugs or had not received either drug for 4 weeks prior to Day 1. A total of 47 subjects (38.2%) were receiving antifibrotic drug treatment (with or without immunosuppressive therapy). Of these subjects, 34 were treated with nintedanib and 13 with pirfenidone. Participants were stratified by usual interstitial pneumonia (UIP) pattern (present vs. absent) and background treatment (antifibrotic agents + / - ILD-targeted immunosuppression vs. ILD-targeted immunosuppression alone vs. none). UIP pattern was present in 52% of subjects, and unclassifiable ILD was the most common disease classification.

[0200] The study was not powered to detect statistical significance (no formal tests). The target effect size was not defined in the study design. There were two estimand approaches to analysis: Treatment policy: Effect of treatment with dose reduction as part of the treatment regimen. Subtherapeutic: Effect of treatment without dose reduction.

[0201] Of the 123 treated participants who contributed to these analyses, 90.2% (n=111) completed the 26-week treatment period, and 9.8% (n=12) discontinued treatment (6 (4.9%) discontinued due to adverse events). Treatment discontinuation occurred across treatment groups (PBO: 17.1%; 30 mg: 7.5%; 60 mg: 4.8%). A total of 91 (74%) subjects continued in the 26-week Optional Treatment Extension (OTE).

[0202] The primary efficacy endpoint, the rate of FVC decline (% predicted) from baseline to wk-26 in the PPF cohort, was estimated using a linear mixed-effects model utilizing all FVC time points. This was analyzed under the primary estimand (all data, using the treatment-directed strategy) and the supplemental estimand (all data up to the dose reduction time point, using the treatment-directed strategy). Analyses were performed in the entire population as well as in subgroups without 1) basal antifibrotic treatment, or 2) UIP radiographic pattern (present or absent). Mean baseline ppFVC was 66.7% for the PPF cohort.

[0203] Table 13 shows the baseline demographic and clinical characteristics of the subjects in the PPF cohort, and Table 14 shows their baseline disease characteristics.

[0204] [Table 13]

[0205] [Table 14]

[0206] Summary results are provided in Tables 15-26, and further results from the final analysis from the PPF cohort are provided below.

[0207] [Table 15]

[0208] [Table 16]

[0209] [Table 17]

[0210] Further data for the IPF cohort are presented in Figures 6-16. As shown in Figure 6, the percent change in ppFVC over 26 weeks in patients with PPF was -4.3% for placebo versus -2.7% and -1.1% for the 30 mg and 60 mg Compound A arms, respectively, by treatment strategy. The treatment difference between 60 mg Compound A and placebo was 3.2% (95% Cl, 0.7-5.6), a relative decline of 74% (Figure 6C). When the subtherapeutic strategy was used, the percent change in ppFVC was -4.2% for placebo versus -2.5% and -1.3% for the 30 mg and 60 mg arms, respectively. The treatment difference between 60 mg Compound A and placebo was 2.9% (95% Cl, 0.4-5.5), a relative decline of 69% (Figure 6D).

[0211] The percent change in FVC (mL) for the PPF cohort is shown in Figure 7, and the absolute change in FVC is shown in Figure 8. The adjusted mean treatment difference in absolute change in FVC (mL) between the 60 mg Compound A and placebo arms at Week 26 was 87.4 mL (Figure 8B).

[0212] 10 and 11 show the mean observed change in ppFVC percentage and FVC in the PPF cohort from baseline to week 26. As shown in the figures, both 30 mg and 60 mg show improvement over placebo at week 8, but 30 mg shows a more significant improvement after week 20, while 60 mg maintains improvement over placebo through the end of week 26.

[0213] [Table 18]

[0214] [Table 19]

[0215] [Table 20]

[0216] [Table 21]

[0217] Figures 12 and 13 show the mean observed change from baseline to week 26 in ppFVC percentage and FVC in patients with and without UIP within the PPF cohort, and Figure 14 shows the percent change in ppFVC in PPF patients with and without UIP. As shown in the figures, treatment differences were observed in the PPF cohort, regardless of the presence or absence of a UIP pattern. Acute exacerbations of pulmonary fibrosis were observed in 6 (2%) patients with IPF (placebo: n=2; 30 mg: n=3; 60 mg: n=1) and 3 (2%) patients with PPF, all in the placebo arm.

[0218] [Table 22]

[0219] [Table 23]

[0220] [Table 24]

[0221] [Table 25]

[0222] Figures 15 and 16 show the mean observed change from baseline to week 26 in ppFVC percentage and FVC in patients with and without additional antifibrotic treatment within the PPF cohort, and Figure 9 shows the percent change in ppFVC for subjects with and without basal antifibrotic treatment in PPF patients. Treatment differences in percent change in ppFVC were consistent across basal antifibrotic PPF cohorts (Figures 9C and 9D).

[0223] [Table 26]

[0224] Summary of adverse events Subjects with at least one treatment-emergent adverse event (TEAE): PBO-24%, 30mg-10%, 60mg-24% Subjects with at least one treatment-emergent serious adverse event (TESAE): PBO-32%, 30mg-10%, 60mg-12% Subjects with at least one TEAE attributed to the investigational medicinal product (IMP): PBO-17%, 30mg-18%, 60mg-26% Seven subjects had adverse events leading to treatment discontinuation Six patients were in the PBO group and one in the 30 mg group (due to hypotension) Three subjects died from TEAEs, all in the PBO group. 1 case of infectious pneumonia, 1 case of PE, and 1 case of respiratory failure Dose-dependent BP findings reaffirm low BP safety risk for Compound A Decreased blood pressure on day 1 of treatment; no clinical effect Dose-dependent low BP threshold ("event"): PBO-24%, 30mg-30%, 60mg-41% ·Dose reduction: PBO-2%, 30mg-15%, 60mg-12% AESI due to low BP: PBO-24%, 30mg-10%, 60mg-24% No significant disparities in significant laboratory abnormalities between treatment groups No hepatobiliary toxicity

[0225] In patients with PPF, the nadir post-dose reduction from baseline in mean sitting systolic blood pressure on Day 1 was -4.2 mmHg for placebo and -10.7 mmHg and -12.7 mmHg for the 30 mg and 60 mg Compound A arms, respectively. Pre-specified blood pressure reduction criteria (shown below) increased in a dose-dependent manner across PPF cohort arms (Table 27).

[0226] Asymptomatic hypotension criteria The patient experiences one of the following, confirmed by retest within 15 minutes: Systolic blood pressure when sitting is less than 85mmHg Diastolic blood pressure when sitting is less than 55mmHg Orthostatic hypotension

[0227] Symptomatic hypotension criteria Patients will experience symptoms that, in the investigator's opinion, may be related to hypotension and confirmed by re-examination within 15 minutes, including at least one of the following: Systolic blood pressure when sitting is less than 100mmHg or diastolic blood pressure when sitting is less than 60mmHg A decrease in systolic blood pressure while sitting of 20mmHg or more since the previous visit, or a decrease in diastolic blood pressure while sitting of 10mmHg or more since the previous visit Orthostatic hypotension Orthostatic tachycardia

[0228] [Table 27]

[0229] Compound A was well tolerated, had no unexpected safety findings, and had an overall profile similar to that seen in the IPF cohort. Other than hypotension, the adverse event profile generally favored the 60 mg group versus placebo.

[0230] In the PPF cohort, there was a dose-dependent decrease in blood pressure on day 1 that was similar in magnitude to that seen in the IPF cohort. Orthostatic hypotension (asymptomatic and symptomatic) was higher in the 60 mg group than in the other groups. There were two cases of syncope and one case of presyncope, all in the placebo group.

[0231] It should be 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 are not intended to limit the scope of the disclosure and the appended claims in any way, as they may set forth one or more, but not all, exemplary aspects of the disclosure contemplated by the inventors.

[0232] This disclosure has been described above in terms of functional building blocks that illustrate the implementation 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.

[0233] The foregoing description of the specified embodiments fully reveals the general nature of the present disclosure so that others can readily modify and / or adapt such specific embodiments 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 used herein is intended to be descriptive rather than limiting, as the terminology or terminology may be interpreted by one of ordinary skill in the art in light of the teaching and guidance.

[0234] 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. 1. A method of treating interstitial lung disease, comprising administering to a subject in need thereof about 120 mg / day of Compound A: 【Chemistry 1】 or an equivalent amount of a pharmaceutically acceptable salt thereof.

2. 10. The method of claim 1, wherein Compound A, or the pharmaceutically acceptable salt thereof, is administered once daily.

3. 10. The method of claim 1, wherein Compound A, or the pharmaceutically acceptable salt thereof, is administered twice daily.

4. 4. The method of claim 3, wherein about 60 mg of Compound A, or an equivalent amount of a pharmaceutically acceptable salt thereof, is administered twice daily.

5. 5. The method of any one of claims 1 to 4, wherein Compound A, or the pharmaceutically acceptable salt thereof, is administered orally.

6. 6. The method of claim 5, wherein Compound A, or the pharmaceutically acceptable salt thereof, is administered as a tablet.

7. 7. The method of any one of claims 1 to 6, wherein the subject is simultaneously treated with one or more therapies for interstitial lung disease.

8. 8. The method of claim 7, wherein the one or more therapies is pirfenidone.

9. 8. The method of claim 7, wherein the one or more therapies is nindanib.

10. 10. The method of any one of claims 1 to 9, wherein Compound A, or the pharmaceutically acceptable salt thereof, is administered with food.

11. 10. The method of any one of claims 1 to 9, wherein Compound A, or the pharmaceutically acceptable salt thereof, is administered without food.

12. The method of any one of claims 1 to 11, wherein the interstitial lung disease is idiopathic pulmonary fibrosis (IPF).

13. The method of any one of claims 1 to 11, wherein the interstitial lung disease is progressive pulmonary fibrosis (PPF).

14. Compound A is selected from the group consisting of: a) unit cell parameters substantially equal to the crystalline system; Space group triclinic, 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 a single crystal structure, wherein said measurement of said single crystal structure is 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=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=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.

14. The method of any one of claims 1 to 13, comprising a crystalline form characterized by at least one of:

15. 15. The method of any one of claims 1-14, wherein the subject experiences a smaller decline in forced vital capacity (FVC) after a treatment period when compared to an untreated subject.

16. the subject experiences a longer time to a first disease progression event after a treatment period than an untreated subject, and the first disease progression event occurs Absolute predicted forced vital capacity (ppFVC) decline of 10% or more from baseline; acute exacerbation of pulmonary fibrosis; pulmonary fibrosis-related hospitalization; and All-cause mortality The method according to any one of claims 1 to 15, wherein the compound is selected from the group consisting of:

17. 17. The method of any one of claims 1-16, wherein the subject experiences a smaller increase in cough domain score as measured by the Living with Pulmonary Fibrosis (L-PF) questionnaire over the treatment period than an untreated subject.

18. 18. The method of any one of claims 1-17, wherein the subject experiences a smaller increase in dyspnea score as measured by the Living with Pulmonary Fibrosis (L-PF) questionnaire over the treatment period than an untreated subject.

19. About 120 mg / day of Compound A for treating interstitial lung disease: 【Chemistry 2】 or an equivalent amount of a pharmaceutically acceptable salt thereof.

20. About 120 mg / day of Compound A in the manufacture of a medicament for treating interstitial lung disease: 【Transformation 3】 or an equivalent amount of a pharmaceutically acceptable salt thereof.

21. 21. The use according to claim 19 or 20, wherein the interstitial lung disease is idiopathic pulmonary fibrosis (IPF).

22. 21. The use according to claim 19 or 20, wherein the interstitial lung disease is progressive pulmonary fibrosis (PPF).

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