Crystal morphology of RIPK1 inhibitors

Abstract

The present invention relates to a compound of formula: The present invention provides a crystalline compound represented by TIFF2024544273000014.tif28128, which is useful for treating autoimmune and inflammatory diseases, such as atopic dermatitis, rheumatoid arthritis, and psoriasis.

Description

Technical Field

[0001] The present invention relates to a specific novel crystal form 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, which is an inhibitor of receptor-interacting protein-1 kinase (“RIPK1”), a pharmaceutical composition containing the crystal form, a method of using the crystal form for treating physiological disorders such as inflammatory diseases and autoimmune diseases, and a method useful for its synthesis.

Background Art

[0002] RIP1 belongs to the tyrosine kinase-like family and is a serine / threonine protein kinase involved in innate immune signaling. RIP1 plays a central role in the regulation of cell signaling, and its role in programmed cell death is related to 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 the treatment of inflammatory diseases, including (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] A crystalline form of (S)-5-benzyl-N-(7-(3-hydroxy-3-methylbuta-1-in-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-1,2,4-triazole-3-carboxamide is desired. Furthermore, a novel crystalline form of (S)-5-benzyl-N-(7-(3-hydroxy-3-methylbuta-1-in-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-1,2,4-triazole-3-carboxamide is desired to provide improved solid stability. In addition, there is a desire for novel crystalline forms of (S)-5-benzyl-N-(7-(3-hydroxy-3-methylbuta-1-in-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-1,2,4-triazole-3-carboxamide that provide improved solid stability for enhanced use in the preparation and manufacture of pharmaceutical formulations having improved stability. The present invention provides crystalline compounds that address one or more of these needs.

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

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

[0007] In one embodiment, the present invention further provides a crystalline (S)-5-benzyl-N-(7-(3-hydroxy-3-methylbuta-1-in-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-1,2,4-triazole-3-carboxamide anhydride form A, characterized by an X-ray powder diffraction (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.

[0008] In a further embodiment, the present invention provides a crystalline (S)-5-benzyl-N-(7-(3-hydroxy-3-methylbuta-1-in-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-1,2,4-triazole-3-carboxamide anhydride form B, characterized by 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.

[0009] In a further embodiment, the present invention provides a crystalline (S)-5-benzyl-N-(7-(3-hydroxy-3-methylbuta-1-in-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-1,2,4-triazole-3-carboxamide monoethanol solvate form C, characterized by an XRPD pattern using CuKα radiation that includes a peak at a 2θ diffraction angle of 6.8° 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 is a) An X-ray powder diffraction 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°, wherein the tolerance of the diffraction angle is ±0.2 degrees, and b) Includes peaks referenced to the high-field resonance (δ=29.5 ppm) of adamantane 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 present invention provides crystalline (S)-5-benzyl-N-(7-(3-hydroxy-3-methylbuta-1-in-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-1,2,4-triazole-3-carboxamide anhydride form D, characterized by at least one of the following.

[0011] In one embodiment, the present invention is c) An X-ray powder diffraction pattern using CuKα radiation that includes 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 tolerance of the diffraction angle is ±0.2 degrees, and d) Includes peaks referenced to the high-field resonance (δ=29.5 ppm) of adamantane 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 present invention provides crystalline (S)-5-benzyl-N-(7-(3-hydroxy-3-methylbuta-1-in-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-1,2,4-triazole-3-carboxamide anhydride form D, characterized by at least one of the following.

[0012] In one embodiment, the present invention is e) An X-ray powder diffraction pattern using CuKα radiation that includes 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 tolerance of the diffraction angle is ±0.2 degrees, and f) Includes peaks referenced to the high-field resonance (δ=29.5 ppm) of adamantane 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 present invention provides crystalline (S)-5-benzyl-N-(7-(3-hydroxy-3-methylbuta-1-in-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-1,2,4-triazole-3-carboxamide anhydride form D, characterized by at least one of the following.

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

[0014] In one embodiment of the above treatment method, crystalline (S)-5-benzyl-N-(7-(3-hydroxy-3-methylbuta-1-in-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-1,2,4-triazole-3-carboxamide is a crystalline anhydride. In a further embodiment of the above treatment method, crystalline (S)-5-benzyl-N-(7-(3-hydroxy-3-methylbuta-1-in-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-1,2,4-triazole-3-carboxamide is a crystalline anhydride of form D.

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

[0016] In one embodiment of the therapeutic use described above, crystalline (S)-5-benzyl-N-(7-(3-hydroxy-3-methylbuta-1-in-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-1,2,4-triazole-3-carboxamide is a crystalline anhydride. In a further embodiment of the therapeutic use described above, crystalline (S)-5-benzyl-N-(7-(3-hydroxy-3-methylbuta-1-in-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-1,2,4-triazole-3-carboxamide is a crystalline anhydride of form D.

[0017] In one embodiment, the present invention also provides the use of crystalline (S)-5-benzyl-N-(7-(3-hydroxy-3-methylbuta-1-in-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-1,2,4-triazole-3-carboxamide for the manufacture of pharmaceuticals for the treatment of inflammatory diseases. In one embodiment, the present invention also provides the use of crystalline (S)-5-benzyl-N-(7-(3-hydroxy-3-methylbuta-1-in-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-1,2,4-triazole-3-carboxamide for the manufacture of pharmaceuticals for the treatment of autoimmune diseases. In one embodiment, the present invention provides the use of crystalline (S)-5-benzyl-N-(7-(3-hydroxy-3-methylbuta-1-in-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-1,2,4-triazole-3-carboxamide for the manufacture of a pharmaceutical 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-methylbuta-1-in-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-1,2,4-triazole-3-carboxamide for the manufacture of a pharmaceutical 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-methylbuta-1-in-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-1,2,4-triazole-3-carboxamide for the manufacture of pharmaceuticals 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-methylbuta-1-in-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-1,2,4-triazole-3-carboxamide for the manufacture of a pharmacopoeia 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-methylbuta-1-in-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-1,2,4-triazole-3-carboxamide for the manufacture of a pharmacopoeia 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-methylbuta-1-in-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-1,2,4-triazole-3-carboxamide for the manufacture of a pharmaceutical 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-methylbuta-1-in-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-1,2,4-triazole-3-carboxamide for the manufacture of a pharmaceutical 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-methylbuta-1-in-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-1,2,4-triazole-3-carboxamide for the manufacture of a pharmaceutical for the treatment of lupus nephritis.

[0018] In one embodiment of the above pharmaceutical, crystalline (S)-5-benzyl-N-(7-(3-hydroxy-3-methylbuta-1-in-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-1,2,4-triazole-3-carboxamide is a crystalline anhydride. In a further embodiment of the above pharmaceutical, crystalline (S)-5-benzyl-N-(7-(3-hydroxy-3-methylbuta-1-in-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-1,2,4-triazole-3-carboxamide is a crystalline anhydride of form D.

[0019] In one embodiment, the present invention further provides a pharmaceutical composition comprising crystalline (S)-5-benzyl-N-(7-(3-hydroxy-3-methylbuta-1-in-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-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 (S)-5-benzyl-N-(7-(3-hydroxy-3-methylbuta-1-in-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-1,2,4-triazole-3-carboxamide, which is a crystalline anhydride, 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-methylbuta-1-in-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-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-methylbuta-1-in-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-1,2,4-triazole-3-carboxamide.

[0020] As used herein, the terms “to treat,” “to cure,” or “to treat” include slowing, delaying, preventing, or improving the progression or severity of an existing condition or disorder.

[0021] As used herein, the term “patient” refers to a mammal, in particular a human.

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

[0023] An effective amount can be determined by one of ordinary skill in the art 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 species of the patient; its size, age, and general health; the specific disease or disorder involved; the degree 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 preparation administered; the dosing regimen selected; the use of concomitant medications; and other related circumstances.

[0024] The compounds of the invention are preferably formulated as pharmaceutical compositions for administration by any route that makes the compound bioavailable, including oral, transdermal, and parenteral routes. More preferably, such compositions are for oral administration. Such pharmaceutical compositions and methods for preparing them are well known in the art. (See, e.g., 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, "rpm" means revolutions per minute, and "min" refers to minute.

[0026] The name "(S)-5-benzyl-N-(7-(3-hydroxy-3-methylbuta-1-in-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-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-methylbuta-1-in-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-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 International Publication No. 2019 / 213447. The present invention will be further illustrated by the following examples. [Example 1]

[0027] Preparation of crystalline (S)-5-benzyl-N-(7-(3-hydroxy-3-methylbuta-1-in-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-1,2,4-triazole-3-carboxamide anhydride, form D [ka] Amorphous (S)-5-benzyl-N-(7-(3-hydroxy-3-methylbuta-1-in-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-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 approximately 3 days. The solid was isolated by centrifugation (10,000 rpm, 2 minutes), and then dried under vacuum at room temperature for approximately 1 day to obtain the title compound. Crystalline (S)-5-benzyl-N-(7-(3-hydroxy-3-methylbuta-1-in-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-1,2,4-triazole-3-carboxamide anhydride 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-methylbuta-1-in-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-1,2,4-triazole-3-carboxamide anhydride, form A Amorphous (S)-5-benzyl-N-(7-(3-hydroxy-3-methylbuta-1-in-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-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, and the remaining solid was isolated to obtain the title compound. [Example 3]

[0029] Preparation of crystalline (S)-5-benzyl-N-(7-(3-hydroxy-3-methylbuta-1-in-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-1,2,4-triazole-3-carboxamide anhydride, form B Amorphous (S)-5-benzyl-N-(7-(3-hydroxy-3-methylbuta-1-in-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-1,2,4-triazole-3-carboxamide (approximately 15 mg) was suspended in ELISA / n-heptane (1:1, v / v, 0.3 mL) in an HPLC vial. The suspension was magnetically stirred at room temperature for 4 days, and the remaining solid was isolated to obtain the title compound. [Example 4]

[0030] Preparation of crystalline (S)-5-benzyl-N-(7-(3-hydroxy-3-methylbuta-1-in-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-1,2,4-triazole-3-carboxamide monoethanol solvate, form C Crystalline (S)-5-benzyl-N-(7-(3-hydroxy-3-methylbuta-1-in-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-1,2,4-triazole-3-carboxamide (53.0 mg) was dissolved in a mixture of EtOH / H2O (1:1, v / v, 3 mL) and heated to approximately 75°C to obtain a clear solution. The solution was passed through a preheated syringe filter (0.45 μm GHP) and thermally filtered into a clean vial, and cooled in three stages to 2-8°C (44°C, room temperature, then refrigerated). After holding the sample at 2-8°C for 5 days, needle-shaped crystal aggregates formed in the solution, and the title compound was obtained by decanting the liquid. The wet solid was analyzed by XRPD.

[0031] X-ray powder diffraction conditions for Examples 1-3 XRPD analysis was performed using 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. Crystalline (S)-5-benzyl-N-(7-(3-hydroxy-3-methylbuta-1-in-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-1,2,4-triazole-3-carboxamide anhydride, XRPD peak of form D. [Table 2]

[0034] Crystalline (S)-5-benzyl-N-(7-(3-hydroxy-3-methylbuta-1-in-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-1,2,4-triazole-3-carboxamide anhydride form D is characterized by an XRPD pattern using CuKα radiation having the diffraction peaks (2θ values) listed in Table 2, specifically including 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-methylbuta-1-in-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-1,2,4-triazole-3-carboxamide anhydride form D is further characterized by an XRPD pattern using CuKα radiation having diffraction peaks (2θ values) as described in Table 2, specifically including 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.

[0036] Crystalline (S)-5-benzyl-N-(7-(3-hydroxy-3-methylbuta-1-in-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-1,2,4-triazole-3-carboxamide anhydride form D is characterized by having diffraction peaks (2θ values) as described 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°, 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 onto a 4mm rotor and compressed to ensure uniform distribution. This was repeated until the rotor was full. Crystalline (S)-5-benzyl-N-(7-(3-hydroxy-3-methylbuta-1-in-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-1,2,4-triazole-3-carboxamide anhydride form D 13C ssNMR was acquired at ambient temperature using a Bruker Avance III HD 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. The acquisition parameters were as follows: 15552 scans, 34 ms acquisition time, 2.5 sec pulse delay, 10 kHz MAS frequency, 1.5 ms contact time, and SPINAL 64 decoupling scheme. The data were externally referenced to 29.5 ppm adamantane.

[0038] Crystalline (S)-5-benzyl-N-(7-(3-hydroxy-3-methylbuta-1-in-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-1,2,4-triazole-3-carboxamide anhydride, a representative form D. 13 The 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. Crystalline (S)-5-benzyl-N-(7-(3-hydroxy-3-methylbuta-1-in-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-1,2,4-triazole-3-carboxamide anhydride, XRPD peak of form A. [Table 3]

[0040] Crystalline (S)-5-benzyl-N-(7-(3-hydroxy-3-methylbuta-1-in-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-1,2,4-triazole-3-carboxamide anhydride form A is characterized by an XRPD pattern using CuKα radiation having the diffraction peaks (2θ values) listed in Table 3, specifically 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°, with a diffraction angle tolerance of ±0.2 degrees.

[0041] Table 4. Crystalline (S)-5-benzyl-N-(7-(3-hydroxy-3-methylbuta-1-in-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-1,2,4-triazole-3-carboxamide anhydride, XRPD peak of form B. [Table 4]

[0042] Crystalline (S)-5-benzyl-N-(7-(3-hydroxy-3-methylbuta-1-in-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-1,2,4-triazole-3-carboxamide anhydride form B is characterized by an XRPD pattern using CuKα radiation having the diffraction peaks (2θ values) listed in Table 4, specifically including 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 using a Bruker D8 Endeavor X-ray powder diffractometer equipped with a CuKα (1.5418 Å) source operating at 40 kV and 40 mA and a Linxeye detector. The sample was scanned at 4–42 2θ° with a step size of 0.009 2θ° and a scanning speed of 0.5 sec / step, using a 0.3° primary slit aperture and a 3.9° PSD aperture. The powder was packed moist into a quartz sample holder, and a smooth surface was obtained using a glass slide. Crystal morphology diffraction patterns were collected at ambient temperature and relative humidity. Crystal peak positions were determined using MDI-Jade v7.9.9. In the field of crystallography, it is well known that for any crystal morphology, the relative intensity of diffraction peaks may vary due to preferred orientation resulting from factors such as crystal morphology and crystal habit. When the effect of preferred orientation is present, the peak intensity changes, but the characteristic peak positions of the crystal morphology remain unchanged. For example, see The United States Pharmacopeia #23, National Formulary #18, pages 1843–1844, 1995. Furthermore, in the field of crystallography, it is well known that the angular peak positions may vary slightly for any crystal morphology. For example, peak positions may shift due to variations in the temperature at which the sample is analyzed, displacement of the sample, 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 hindering the clear identification of the indicated crystal morphology. Confirmation of the crystal morphology can be performed based on any unique combination of characteristic peaks.

[0044] Table 5. Crystalline (S)-5-benzyl-N-(7-(3-hydroxy-3-methylbuta-1-in-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-1,2,4-triazole-3-carboxamide monoethanol solvate, XRPD peak of form C. [Table 5]

[0045] Crystalline (S)-5-benzyl-N-(7-(3-hydroxy-3-methylbuta-1-in-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-1,2,4-triazole-3-carboxamide monoethanol solvate, form C is characterized by an XRPD pattern using CuKα radiation having diffraction peaks (2θ values) as described in Table 5, specifically including a peak at a 2θ diffraction angle of 6.8° 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 crystal of a compound represented by , characterized in that the X-ray powder diffraction pattern using CuKα radiation includes peaks at 2θ diffraction angles of 7.0°, 16.9°, and 19.5°, and the tolerance at the said diffraction angles is ±0.2 degrees.

2. formula: 【Chemistry 2】 A crystal of the anhydrous compound represented by , characterized in that the X-ray powder diffraction pattern using CuKα radiation includes peaks at 7.0°, 15.1°, and 19.5° with a 2θ diffraction angle, and the tolerance at the said diffraction angles is ±0.2 degrees.

3. Includes peaks referenced to the high-field resonance (δ = 29.5 ppm) of adamantane 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 The crystal according to claim 2, characterized by a 1C solid-state NMR spectrum.

4. The crystal according to claim 2, characterized in that it is an X-ray powder diffraction pattern using CuKα radiation which further includes one or more peaks at 11.2° or 17.4°, and the tolerance at the diffraction angle is ±0.2 degrees.

5. The crystal according to claim 2, characterized in that it is an X-ray powder diffraction pattern using CuKα radiation, the diffraction pattern having one or more additional peaks at 11.2°, 16.9°, or 17.4°, wherein the tolerance at the diffraction angle is ±0.2 degrees.

6. A pharmaceutical composition comprising the crystal described in any one of claims 1 to 5, for use in therapeutic purposes.

7. A pharmaceutical composition comprising the crystal described in any one of claims 1 to 5, for use in the treatment of inflammatory diseases.

8. A pharmaceutical composition comprising the crystal described in any one of claims 1 to 5 for use in the treatment of an autoimmune disease.

9. A pharmaceutical composition comprising the crystal described in any one of claims 1 to 5, for use in the treatment of atopic dermatitis.

10. A pharmaceutical composition comprising the crystal described in any one of claims 1 to 5 for use in the treatment of psoriasis.

11. A pharmaceutical composition comprising the crystal described in any one of claims 1 to 5, for use in the treatment of rheumatoid arthritis.

12. A pharmaceutical composition comprising the crystal described in any one of claims 1 to 5, for use in the treatment of inflammatory bowel disease.

13. Use of the crystal according to any one of claims 1 to 5 for the manufacture of a pharmaceutical product for the treatment of an inflammatory disease or an autoimmune disease.

14. Use of the crystal according to any one of claims 1 to 5 for the manufacture of a pharmaceutical product for the treatment of atopic dermatitis, psoriasis, rheumatoid arthritis, or inflammatory bowel disease.

15. A pharmaceutical composition comprising the crystal described in any one of claims 1 to 5 together with one or more pharmaceutically acceptable carriers, diluents, or excipients.

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