Crystalline forms of RIPK1 inhibitors

Abstract

Crystalline forms of receptor-interacting protein-1 kinase (RIPK1) inhibitors are provided. [Solution] Formula: TIFF2026035824000013.tif28128 The present invention provides a crystalline compound of the formula:

Description

[Technical Field]

[0001] The present invention relates to certain novel crystalline forms of the receptor-interacting protein-1 kinase (RIPK1) inhibitor (S)-5-benzyl-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide, pharmaceutical compositions containing the crystalline forms, methods of using the crystalline forms to treat physiological disorders such as inflammatory and autoimmune diseases, and methods useful for their synthesis. [Background technology]

[0002] RIP1 is a serine / threonine protein kinase that belongs to the tyrosine kinase-like family and is involved in innate immune signaling. RIP1 plays a central role in regulating cell signaling, and its role in programmed cell death has been implicated in various autoimmune and inflammatory diseases, such as inflammatory bowel disease, psoriasis, rheumatoid arthritis, and other diseases and / or conditions associated with inflammation and / or necrotic cell death.

[0003] WO 2019 / 213447 discloses kinase inhibitor compounds, such as RIPK1 inhibitor compounds, useful for treating inflammatory diseases, including, for example, the RIPK1 inhibitor (S)-5-benzyl-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide. Summary of the Invention

[0004] Crystalline forms of (S)-5-benzyl-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide are desired. Additionally, novel crystalline forms of (S)-5-benzyl-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide that offer improved solid-state stability are desired. Additionally, novel crystalline forms of (S)-5-benzyl-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide that offer improved solid-state stability for enhanced utilization in the preparation and manufacture of pharmaceutical formulations with improved stability are desired. The present invention provides crystalline compounds that address one or more of these needs.

[0005] Thus, in one embodiment, the present invention provides crystalline (S)-5-benzyl-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide.

[0006] In certain embodiments, the present invention further provides anhydrous, crystalline (S)-5-benzyl-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide.

[0007] In one embodiment, the present invention further provides crystalline (S)-5-benzyl-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide Anhydrous Form A, characterized by an X-ray powder diffraction (XRPD) pattern using CuKα radiation comprising a peak at a 2θ diffraction angle of 17.5° and one or more peaks at 9.7°, 14.4°, 15.4°, 17.0°, or 17.9°, with a diffraction angle tolerance of ±0.2 degrees.

[0008] In a further embodiment, the present invention provides crystalline (S)-5-benzyl-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide Anhydrous Form B, characterized by an XRPD pattern using CuKα radiation containing a peak at a 2-theta diffraction angle of 18.1° and one or more peaks at 9.9°, 11.5°, 12.2°, 14.7°, or 16.5°, with a diffraction angle tolerance of ±0.2 degrees.

[0009] In a further embodiment, the present invention provides crystalline (S)-5-benzyl-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide monoethanol solvate Form C, characterized by an XRPD pattern using CuKα radiation containing a peak at a 6.8° 2θ diffraction angle and one or more peaks at 4.9°, 9.9°, 13.6°, or 18.4°, with a diffraction angle tolerance of ±0.2 degrees.

[0010] In certain embodiments, the present invention provides a method for producing a pharmaceutical composition comprising: a) an X-ray powder diffraction pattern using CuKα radiation containing a peak at a 2θ diffraction angle of 7.0° and one or more peaks at 11.2°, 17.4°, or 19.5°, with a diffraction angle tolerance of ±0.2 degrees; and b) Contains peaks referenced to the upfield resonance of adamantane (δ=29.5 ppm) at 168.5, 159.7, 157.4, 156.0, 149.5, 138.5, 136.6, 129.7, 129.1, 127.5, 126.6, 123.5, 121.9, 98.5, 79.8, 77.2, 65.8, 49.1, 36.4, 34.9, 32.5, and 30.5 ppm (each ±0.2 ppm). 13 C solid-state NMR spectra The present invention provides crystalline (S)-5-benzyl-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide anhydrate Form D, characterized by at least one of:

[0011] In one embodiment, the present invention provides c) an X-ray powder diffraction pattern using CuKα radiation containing a peak at a 2θ diffraction angle of 7.0° and one or more peaks at 11.2°, 16.9°, 17.4°, or 19.5°, with a diffraction angle tolerance of ±0.2 degrees; and d) Contains peaks referenced to the upfield resonance of adamantane (δ=29.5 ppm) at 168.5, 159.7, 157.4, 156.0, 149.5, 138.5, 136.6, 129.7, 129.1, 127.5, 126.6, 123.5, 121.9, 98.5, 79.8, 77.2, 65.8, 49.1, 36.4, 34.9, 32.5, and 30.5 ppm (each ±0.2 ppm). 13 C solid-state NMR spectra The present invention provides crystalline (S)-5-benzyl-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide anhydrate Form D, characterized by at least one of:

[0012] In one embodiment, the present invention provides e) an X-ray powder diffraction pattern using CuKα radiation containing a peak at a 2θ diffraction angle of 7.0° and one or more peaks at 11.2°, 15.1°, 16.9°, 17.4°, or 19.5°, with a diffraction angle tolerance of ±0.2 degrees; and f) Contains peaks referenced to the upfield resonance of adamantane (δ=29.5 ppm) at 168.5, 159.7, 157.4, 156.0, 149.5, 138.5, 136.6, 129.7, 129.1, 127.5, 126.6, 123.5, 121.9, 98.5, 79.8, 77.2, 65.8, 49.1, 36.4, 34.9, 32.5, and 30.5 ppm (each ±0.2 ppm). 13 C solid-state NMR spectra The present invention provides crystalline (S)-5-benzyl-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide anhydrate Form D, characterized by at least one of:

[0013] In one embodiment, the present invention further provides a method of treating an inflammatory disease in a patient in need thereof, comprising administering to the patient an effective amount of crystalline (S)-5-benzyl-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide. In one embodiment, the present invention further provides a method of treating an autoimmune disease in a patient in need thereof, comprising administering to the patient an effective amount of crystalline (S)-5-benzyl-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide. In one embodiment, the present invention further provides a method of treating atopic dermatitis in a patient in need thereof, comprising administering to the patient an effective amount of crystalline (S)-5-benzyl-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide. In one embodiment, the present invention further provides a method of treating inflammatory bowel disease in a patient in need thereof, comprising administering to the patient an effective amount of crystalline (S)-5-benzyl-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide.In one embodiment, the present invention further provides a method of treating rheumatoid arthritis in a patient in need thereof, comprising administering to the patient an effective amount of crystalline (S)-5-benzyl-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide. In one embodiment, the present invention also provides a method of treating psoriasis in a patient in need thereof, comprising administering to the patient an effective amount of crystalline (S)-5-benzyl-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide. In one embodiment, the present invention also provides a method of treating systemic lupus erythematosus in a patient in need thereof, comprising administering to the patient an effective amount of crystalline (S)-5-benzyl-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide. In one embodiment, the present invention also provides a method of treating gout in a patient in need thereof, comprising administering to the patient an effective amount of crystalline (S)-5-benzyl-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide.In one embodiment, the present invention also provides a method of treating cutaneous lupus erythematosus in a patient in need thereof, comprising administering to the patient an effective amount of crystalline (S)-5-benzyl-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide. In one embodiment, the present invention also provides a method of treating lupus nephritis in a patient in need thereof, comprising administering to the patient an effective amount of crystalline (S)-5-benzyl-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide.

[0014] In one embodiment of the above method of treatment, the crystalline (S)-5-benzyl-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide is a crystalline anhydrate. In a further embodiment of the above method of treatment, the crystalline (S)-5-benzyl-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide is Form D crystalline anhydrate.

[0015] In one embodiment, the present invention further provides crystalline (S)-5-benzyl-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide for use in therapy. In one embodiment, the present invention provides crystalline (S)-5-benzyl-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide for use in the treatment of inflammatory diseases. In one embodiment, the present invention provides crystalline (S)-5-benzyl-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide for use in the treatment of autoimmune diseases. In one embodiment, the present invention provides crystalline (S)-5-benzyl-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide for use in the treatment of atopic dermatitis. In one embodiment, the present invention provides crystalline (S)-5-benzyl-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide for use in the treatment of rheumatoid arthritis. In one embodiment, the present invention provides crystalline (S)-5-benzyl-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide for use in the treatment of inflammatory bowel disease.In one embodiment, the present invention provides crystalline (S)-5-benzyl-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide for use in the treatment of psoriasis. In one embodiment, the present invention provides crystalline (S)-5-benzyl-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide for use in the treatment of systemic lupus erythematosus. In one embodiment, the present invention provides crystalline (S)-5-benzyl-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide for use in the treatment of gout. In one embodiment, the present invention provides crystalline (S)-5-benzyl-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide for use in the treatment of cutaneous lupus erythematosus. In one embodiment, the present invention provides crystalline (S)-5-benzyl-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide for use in the treatment of lupus nephritis.

[0016] In one embodiment of the above therapeutic use, the crystalline (S)-5-benzyl-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide is a crystalline anhydrate. In a further embodiment of the above therapeutic use, the crystalline (S)-5-benzyl-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide is Form D crystalline anhydrate.

[0017] In one embodiment, the present invention also provides the use of crystalline (S)-5-benzyl-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide for the manufacture of a medicament for the treatment of an inflammatory disease. In one embodiment, the present invention provides the use of crystalline (S)-5-benzyl-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide for the manufacture of a medicament for the treatment of an autoimmune disease. In one embodiment, the present invention provides the use of crystalline (S)-5-benzyl-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide for the manufacture of a medicament for the treatment of atopic dermatitis. In one embodiment, the present invention provides the use of crystalline (S)-5-benzyl-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide for the manufacture of a medicament for the treatment of rheumatoid arthritis. In one embodiment, the present invention further provides the use of crystalline (S)-5-benzyl-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide for the manufacture of a medicament for the treatment of inflammatory bowel disease.In one embodiment, the present invention further provides the use of crystalline (S)-5-benzyl-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide for the manufacture of a medicament for the treatment of psoriasis. In one embodiment, the present invention also provides the use of crystalline (S)-5-benzyl-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide for the manufacture of a medicament for the treatment of systemic lupus erythematosus. In one embodiment, the present invention also provides the use of crystalline (S)-5-benzyl-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide for the manufacture of a medicament for the treatment of gout. In one embodiment, the present invention also provides the use of crystalline (S)-5-benzyl-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide for the manufacture of a medicament for the treatment of cutaneous lupus erythematosus. In one embodiment, the present invention also provides the use of crystalline (S)-5-benzyl-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide for the manufacture of a medicament for the treatment of lupus nephritis.

[0018] In one embodiment of the above medicament, the crystalline (S)-5-benzyl-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide is a crystalline anhydrate. In a further embodiment of the above medicament, the crystalline (S)-5-benzyl-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide is Form D crystalline anhydrate.

[0019] In one embodiment, the present invention further provides a pharmaceutical composition comprising crystalline (S)-5-benzyl-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide, together with one or more pharmaceutically acceptable carriers, diluents, or excipients. In one embodiment, the present invention further provides a pharmaceutical composition comprising the crystalline anhydrate (S)-5-benzyl-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide, together with one or more pharmaceutically acceptable carriers, diluents, or excipients. In one embodiment, the present invention further provides a method for preparing a pharmaceutical composition, comprising mixing crystalline (S)-5-benzyl-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide with one or more pharmaceutically acceptable carriers, diluents, or excipients. In one embodiment, the present invention also encompasses a method for synthesizing crystalline (S)-5-benzyl-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide.

[0020] As used herein, the terms "treating," "treatment," or "treat" include suppressing, slowing, arresting, or ameliorating the progression or severity of an existing condition or disorder.

[0021] As used herein, the term "patient" refers to a mammal, particularly a human.

[0022] As used herein, the term "effective amount" refers to an amount or dose of a compound of the present invention or a pharmaceutically acceptable salt thereof that, when administered in single or multiple doses to a patient, provides the desired effect in the patient being diagnosed or treated.

[0023] Effective amounts can be determined by those skilled in the art by using known techniques and observing the results obtained under similar circumstances. In determining the effective amount for a patient, several factors are considered by the attending physician, including but not limited to the patient's species; its size, age, and general health; the specific disease or disorder involved; the extent or involvement or severity of the disease or disorder; the response of the individual patient; the specific compound administered; the mode of administration; the bioavailability characteristics of the administered preparation; the selected dosing regimen; the use of concomitant medications; and other relevant circumstances.

[0024] The compounds of the present invention are preferably formulated as pharmaceutical compositions to be administered by any route that makes the compounds bioavailable, including oral, transdermal, and parenteral routes. More preferably, such compositions are for oral administration. Such pharmaceutical compositions and methods for their preparation are well known in the art (see, for example, Remington: The Science and Practice of Pharmacy, A. Adejare, Editor, 23 nd Edition, published 2020, Elsevier Science).

[0025] Certain abbreviations are defined as follows: "MIBK" refers to methyl isobutyl ketone, "EtOAc" refers to ethyl acetate, "EtOH" refers to ethanol, "DMSO" refers to dimethyl sulfoxide, "RT" refers to room temperature, "HPLC" refers to high performance liquid chromatography, "XRPD" refers to X-ray powder diffraction, "mL" refers to milliliter, "nm" refers to nanometer or nanometer, "rpm" means revolutions per minute, and "min" refers to minutes.

[0026] The name "(S)-5-benzyl-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide" corresponds to the structure of Formula I below. [ka] The amorphous form of the compound of Formula I, (S)-5-benzyl-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide, can be prepared by procedures known to those skilled in the art, such as those taught in WO 2019 / 213447. The following examples further illustrate the invention. Example 1

[0027] Preparation of crystalline (S)-5-benzyl-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide anhydrous, Form D [ka] Amorphous (S)-5-benzyl-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide (316.3 mg) was suspended in a mixture of acetone / n-heptane (1:2, v / v, 3 mL). The suspension was stirred at room temperature for about 3 days. The solid was isolated by centrifugation (10,000 rpm, 2 minutes) and then dried under vacuum at room temperature for about 1 day to provide the title compound. Crystalline (S)-5-benzyl-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide anhydrate Form D was found to be the most thermodynamically stable crystalline form in the temperature range of room temperature to 50°C compared to the other identified Forms A, B, and C. Example 2

[0028] Preparation of crystalline (S)-5-benzyl-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide anhydrate, Form A Amorphous (S)-5-benzyl-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide (approximately 15 mg) was suspended in MIBK / n-heptane (1:1, v / v, 0.3 mL) in an HPLC vial. The suspension was magnetically stirred at room temperature for 4 days, after which the remaining solid was isolated to give the title compound. Example 3

[0029] Preparation of crystalline (S)-5-benzyl-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide anhydrous, Form B Amorphous (S)-5-benzyl-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide (approximately 15 mg) was suspended in EtOAc / n-heptane (1:1, v / v, 0.3 mL) in an HPLC vial. After magnetic stirring of the suspension at room temperature for 4 days, the remaining solid was isolated to give the title compound. Example 4

[0030] Preparation of crystalline (S)-5-benzyl-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide monoethanol solvate, Form C Crystalline (S)-5-benzyl-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide (53.0 mg) was dissolved in a mixture of EtOH / HO (1:1, v / v, 3 mL) to give a clear solution at approximately 75 °C. The solution was hot filtered through a preheated syringe filter (0.45 μm GHP) into a clean vial and cooled to 2-8 °C in three steps (44 °C, room temperature, then placed in a refrigerator). After holding the sample at 2-8 °C for 5 days, needle-like aggregates formed in the solution, which were isolated by decanting the liquid to give the title compound. The wet solid was analyzed by XRPD.

[0031] X-ray powder diffraction conditions for Examples 1 to 3 XRPD analysis was performed on a PANalytical X'Pert3 X-ray powder diffractometer. The XRPD measurement conditions used are listed in Table 1.

[0032] Table 1. Measurement conditions for XRPD analysis [Table 1]

[0033] Table 2. XRPD peaks of crystalline (S)-5-benzyl-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide anhydrate, form D. [Table 2]

[0034] Crystalline (S)-5-benzyl-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide anhydrate Form D is characterized by an XRPD pattern having the diffraction peaks (2θ values) set forth in Table 2, specifically an XRPD pattern using CuKα radiation that includes a peak at a 2θ diffraction angle of 7.0° and one or more peaks at 11.2°, 17.4°, or 19.5°, with a diffraction angle tolerance of ±0.2 degrees.

[0035] Crystalline (S)-5-benzyl-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide anhydrate Form D is further characterized by an XRPD pattern using CuKα radiation having diffraction peaks (2θ values) as set forth in Table 2, specifically including a peak at a 7.0° 2θ diffraction angle and one or more peaks at 11.2°, 16.9°, 17.4°, or 19.5°, with a diffraction angle tolerance of ±0.2 degrees.

[0036] Crystalline (S)-5-benzyl-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide anhydrate Form D is further characterized by an XRPD pattern using CuKα radiation having diffraction peaks (2θ values) as set forth in Table 2, specifically including a peak at a 2θ diffraction angle of 7.0° and one or more peaks at 11.2°, 15.1°, 16.9°, 17.4°, or 19.5°, with a diffraction angle tolerance of ±0.2 degrees.

[0037] 13 C solid-state NMR ( 13 C ssNMR) Without weighing, a small amount of material was scooped into a 4 mm rotor and compressed to ensure uniform distribution. This was repeated until the rotor was filled. Crystalline (S)-5-benzyl-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide anhydrate Form D 13C ssNMR was acquired at ambient temperature on a Bruker Avance III HD equipped with a Bruker Ultrashield 400WB Plus magnet operating at a frequency of 100.6 MHz. The probe used was a Bruker MAS 4 BL CP BB DVT NP / H. Acquisition parameters were as follows: 15552 scans, 34 ms acquisition time, 2.5 s interpulse delay, 10 kHz MAS frequency, 1.5 ms contact time, and SPINAL 64 decoupling scheme. Data were externally referenced to 29.5 ppm adamantane.

[0038] Representative of crystalline (S)-5-benzyl-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide anhydrate, Form D 13 C ssNMR resonances include 168.5, 159.7, 157.4, 156.0, 149.5, 138.5, 136.6, 129.7, 129.1, 127.5, 126.6, 123.5, 121.9, 98.5, 79.8, 77.2, 65.8, 49.1, 36.4, 34.9, 32.5, and 30.5 ppm (each ±0.2 ppm).

[0039] Table 3. XRPD peaks of crystalline (S)-5-benzyl-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide anhydrate, form A. [Table 3]

[0040] Crystalline (S)-5-benzyl-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide anhydrate Form A is characterized by an XRPD pattern having the diffraction peaks (2θ values) set forth in Table 3, specifically an XRPD pattern using CuKα radiation that includes a peak at a 2θ diffraction angle of 17.5° and one or more peaks at 9.7°, 14.4°, 15.4°, 17.0°, or 17.9°, with a diffraction angle tolerance of ±0.2 degrees.

[0041] Table 4. XRPD peaks of crystalline (S)-5-benzyl-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide anhydrous, form B. [Table 4]

[0042] Crystalline (S)-5-benzyl-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide anhydrate Form B is characterized by an XRPD pattern having the diffraction peaks (2θ values) set forth in Table 4, specifically an XRPD pattern using CuKα radiation that includes a peak at a 2θ diffraction angle of 18.1° and one or more peaks at 9.9°, 11.5°, 12.2°, 14.7°, or 16.5°, with a diffraction angle tolerance of ±0.2 degrees.

[0043] XRPD conditions for Example 4 XRPD patterns of crystalline solids were obtained on a Bruker D8 Endeavor X-ray powder diffractometer equipped with a CuKα (1.5418 Å) source and Linxeye detector operating at 40 kV and 40 mA. Samples were scanned from 4 to 42° 2θ with a step size of 0.009° 2θ and a scan rate of 0.5 s / step, using a 0.3° primary slit aperture and a 3.9° PSD aperture. The powder was wet packed into a quartz sample holder, and a glass slide was used to obtain a smooth surface. Crystalline form diffraction patterns were collected at ambient temperature and relative humidity. Crystalline peak positions were determined using MDI-Jade v7.9.9. It is well known in the field of crystallography that for any crystalline form, the relative intensities of diffraction peaks can vary due to preferred orientation resulting from factors such as crystal morphology and crystal habit. When preferred orientation effects are present, peak intensities change, but the characteristic peak positions of the crystalline form remain unchanged. See, e.g., The United States Pharmacopeia #23, National Formulary #18, pages 1843-1844, 1995. Furthermore, it is well known in the field of crystallography that for any crystalline form, angular peak positions may vary slightly. For example, peak positions may shift due to variations in the temperature at which the sample is analyzed, sample displacement, or the presence or absence of an internal standard. In this case, a peak position variation of ±0.2 2θ° is estimated to account for these potential variations without precluding unambiguous identification of the indicated crystalline form. Confirmation of a crystalline form can be based on any unique combination of characteristic peaks.

[0044] Table 5. XRPD peaks of crystalline (S)-5-benzyl-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide monoethanol solvate, Form C. [Table 5]

[0045] Crystalline (S)-5-benzyl-N-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide monoethanol solvate, Form C, is characterized by an XRPD pattern having diffraction peaks (2θ values) listed in Table 5, specifically an XRPD pattern using CuKα radiation that includes a peak at a 6.8° 2θ diffraction angle and one or more peaks at 4.9°, 9.9°, 13.6°, or 18.4°, with a diffraction angle tolerance of ±0.2 degrees.

Claims

1. formula: 【Chemistry 1】 A compound represented by the formula: wherein the compound is crystalline.

2. formula: 【Chemistry 2】 The compound represented by the formula:

3. formula: 【Transformation 3】 A compound represented by the formula: a) an X-ray powder diffraction pattern using CuKα radiation comprising a peak at a 2θ diffraction angle of 7.0° and one or more peaks at 11.2°, 17.4°, or 19.5°, wherein the diffraction angle has a tolerance of ±0.2 degrees; and b) Contains peaks referenced to the upfield resonance of adamantane (δ=29.5 ppm) at 168.5, 159.7, 157.4, 156.0, 149.5, 138.5, 136.6, 129.7, 129.1, 127.5, 126.6, 123.5, 121.9, 98.5, 79.8, 77.2, 65.8, 49.1, 36.4, 34.9, 32.5, and 30.5 ppm (each ±0.2 ppm). １３ C solid state NMR spectrum The compound is a crystalline anhydrate characterized by at least one of:

4. formula: 【Chemistry 4】 A compound represented by the formula: a) an X-ray powder diffraction pattern using CuKα radiation comprising a peak at a 2θ diffraction angle of 7.0° and one or more peaks at 11.2°, 16.9°, 17.4°, or 19.5°, wherein the diffraction angle has a tolerance of ±0.2 degrees; and b) Contains peaks referenced to the upfield resonance of adamantane (δ=29.5 ppm) at 168.5, 159.7, 157.4, 156.0, 149.5, 138.5, 136.6, 129.7, 129.1, 127.5, 126.6, 123.5, 121.9, 98.5, 79.8, 77.2, 65.8, 49.1, 36.4, 34.9, 32.5, and 30.5 ppm (each ±0.2 ppm). １３ C solid state NMR spectrum The compound is a crystalline anhydrate characterized by at least one of:

5. formula: 【Transformation 5】 A compound represented by the formula: a) an X-ray powder diffraction pattern using CuKα radiation comprising a peak at a 2θ diffraction angle of 7.0° and one or more peaks at 11.2°, 15.1°, 16.9°, 17.4°, or 19.5°, wherein the diffraction angle has a tolerance of ±0.2 degrees; and b) Contains peaks referenced to the upfield resonance of adamantane (δ=29.5 ppm) at 168.5, 159.7, 157.4, 156.0, 149.5, 138.5, 136.6, 129.7, 129.1, 127.5, 126.6, 123.5, 121.9, 98.5, 79.8, 77.2, 65.8, 49.1, 36.4, 34.9, 32.5, and 30.5 ppm (each ±0.2 ppm). １３ C solid state NMR spectrum The compound is a crystalline anhydrate characterized by at least one of:

6. 3. The crystalline anhydrate of claim 2, characterized by an X-ray powder diffraction pattern using CuKα radiation including a peak at a 2θ diffraction angle of 17.5° and one or more peaks at 9.7°, 14.4°, 15.4°, 17.0°, or 17.9°, wherein the diffraction angle tolerance is ±0.2 degrees.

7. 3. The crystalline anhydrate of claim 2, characterized by an X-ray powder diffraction pattern using CuKα radiation comprising a peak at a 2θ diffraction angle of 18.1° and one or more peaks at 9.9°, 11.5°, 12.2°, 14.7°, or 16.5°, wherein the diffraction angle tolerance is ±0.2 degrees.

8. A method of treating an inflammatory disease in a patient, comprising administering to a patient in need of such treatment an effective amount of a compound according to any one of claims 1 to 7.

9. A method of treating an autoimmune disease in a patient, comprising administering to a patient in need of such treatment an effective amount of a compound according to any one of claims 1 to 7.

10. 10. A method of treating psoriasis in a patient, comprising administering to a patient in need of such treatment an effective amount of a compound according to any one of claims 1 to 7.

11. 10. A method of treating atopic dermatitis in a patient, comprising administering to a patient in need of such treatment an effective amount of a compound according to any one of claims 1 to 7.

12. A method of treating rheumatoid arthritis in a patient, comprising administering to a patient in need of such treatment an effective amount of a compound according to any one of claims 1 to 7.

13. A compound according to any one of claims 1 to 7 for use in therapy.

14. A compound according to any one of claims 1 to 7 for use in the treatment of an inflammatory disease.

15. A compound according to any one of claims 1 to 7 for use in the treatment of an autoimmune disease.

16. A compound according to any one of claims 1 to 7 for use in the treatment of atopic dermatitis.

17. A compound according to any one of claims 1 to 7 for use in the treatment of psoriasis.

18. A compound according to any one of claims 1 to 7 for use in the treatment of rheumatoid arthritis.

19. Use of a compound according to any one of claims 1 to 7 for the manufacture of a medicament for the treatment of an inflammatory disease.

20. Use of a compound according to any one of claims 1 to 7 for the manufacture of a medicament for the treatment of an autoimmune disease.

21. Use of a compound according to any one of claims 1 to 7 for the manufacture of a medicament for the treatment of atopic dermatitis.

22. Use of a compound according to any one of claims 1 to 7 for the manufacture of a medicament for the treatment of psoriasis.

23. Use of a compound according to any one of claims 1 to 7 for the manufacture of a medicament for the treatment of rheumatoid arthritis.

24. A pharmaceutical composition comprising a compound according to any one of claims 1 to 7, together with one or more pharmaceutically acceptable carriers, diluents or excipients.

25. 10. A method for preparing a pharmaceutical composition, comprising mixing a compound according to any one of claims 1 to 7 with one or more pharmaceutically acceptable carriers, diluents, or excipients.

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