Crystals of nitrogen-containing heterocyclic compounds that have Nrf2 activating activity.

Abstract

The present invention provides a crystal of a low molecular weight compound which has Nrf2 activation effect, a crystal of a salt of the compound, or a crystal of a solvate of the compound or the salt.　The present invention specifically provides a crystal of a compound represented by any one of formulae (1) to (5), a crystal of a salt of the compound, or a crystal of a solvate of the compound or the salt.

Description

[Technical Field]

[0001] This invention relates to nitrogen-containing heterocyclic compounds having Nrf2 activating properties, or their salts, or crystals of solvates thereof. It also relates to pharmaceuticals and pharmaceutical compositions containing these as active ingredients. [Background technology]

[0002] Nrf2 is a regulatory factor for a group of genes involved in various biological defenses and is a transcription factor that is activated in response to oxidative stress. Under normal conditions, Nrf2 binds to Keap1, undergoes ubiquitination, and is degraded by the proteasome pathway. However, under stress, it escapes degradation by being released from Keap1 and translocates to the nucleus. Subsequently, Nrf2 forms a heterodimer with small Maf group factors and binds to antioxidant response elements (AREs), inducing the transcription of downstream molecules.

[0003] Nrf2 activation exhibits a wide range of pharmacological effects, including antioxidant, anti-inflammatory, anti-fibrotic, and anti-apoptotic effects, and is thought to have protective effects against various diseases. Specific examples of diseases include neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease, Friedreich's ataxia, and amyotrophic lateral sclerosis; lung diseases such as idiopathic pulmonary fibrosis, acute respiratory distress syndrome, chronic obstructive pulmonary disease, pulmonary arterial hypertension, and asthma; kidney diseases such as chronic kidney disease and acute kidney injury; ophthalmic diseases such as uveitis, glaucoma, and age-related macular degeneration; liver diseases such as non-alcoholic steatohepatitis; and immune and inflammatory diseases such as multiple sclerosis, rheumatoid arthritis, and ulcerative colitis (Non-patent documents 3-7). In fact, bardoxolone methyl (CDDO-Me, Patent Document 1), a compound that induces Nrf2 activation, has undergone clinical trials targeting various chronic kidney diseases. Furthermore, RTA-408 (omaveloxolone, Patent Document 2) has been approved by the FDA for the treatment of Friedreich's ataxia, etc. Dimethyl fumarate (Patent Document 3) is used as a treatment for multiple sclerosis. However, these compounds are covalently bound to Keap1. Concerns have been reported about the risk of heart failure due to the interaction of the covalent binding site of bardoxolone methyl with non-target proteins (Non-Patent Document 8).

[0004] To date, compounds such as those described in Patent Document 4 have been reported as Nrf2 activators. However, clinical development has not yet been reached, and there is a need for the development of non-covalent Nrf2 activators that are expected to reduce interactions with non-target proteins (Non-Patent Documents 1-3). [Prior art documents] [Patent Documents]

[0005] [Patent Document 1] International Publication No. 1999 / 065478 [Patent Document 2] International Publication No. 2014 / 176415 [Patent Document 3] International Publication No. 2016 / 090154 [Patent Document 4] International Publication No. 2020 / 165776 [Non-Patent Document]

[0006] [Non-Patent Document 1] Med Chem Commun, 2017, 8, 286-294. [Non-Patent Document 2] Medicinal Chemistry Research,2020,29,846-867. [Non-Patent Document 3] Nature Reviews Drug Discovery,2019,18,295-317. [Non-Patent Document 4] Oxydative Medicine and Cellular Longevity,2019,ArticleID9372182,1-20. [Non-Patent Document 5] Neurodegenr Dis Manag,2017,7,97-100. [Non-Patent Document 6] Oxydative Medicine and Cellular Longevity,2019,ArticleID7090534,1-17. [Non-Patent Document 7] Oxydative Medicine and Cellular Longevity,2020,ArticleID9410952,1-22. [Non-Patent Document 8] Am J Nephrol,2014,39,499-508 [Summary of the Invention] [Problems to be Solved by the Invention]

[0007] The object of the present invention is to provide low molecular weight compounds, salts thereof, or crystals of solvates thereof that have the ability to activate Nrf2 and reduce interactions with non-target proteins due to covalent bonding. Furthermore, the object is to provide preventive or therapeutic agents for various diseases, such as neurodegenerative diseases, lung diseases, and kidney diseases, containing these compounds as active ingredients. [Means for solving the problem]

[0008] The inventors of the present invention diligently conducted research to solve the aforementioned problems and discovered that compounds represented by formulas (1) to (5), or their salts or solvates, which have significantly different chemical structures from known Nrf2 activators, possess excellent Nrf2 activating properties. They also found crystals of the compounds represented by formulas (1) to (5), or their salts or solvates, thus completing the present invention.

[0009] In other words, in one aspect of the present invention, the following invention is provided. [A1] The following formula (1) [ka] A compound represented by, or a salt thereof, or a crystal of a solvate thereof. [A2] The crystal described in [A1], wherein the crystal is a solvate crystal of the compound represented by formula (1). [A3] The crystal according to [A1] or [A2], wherein the solvate crystal is a hydrate crystal. [A4] The crystal according to [A3], wherein the hydrate crystal is a type 1A crystal having at least one peak selected from the group consisting of diffraction angles (2θ values) of 6.0°, 9.3°, 9.7°, 10.4°, 11.9°, 12.9°, 15.3°, 15.9°, 16.4°, and 16.8° (±0.2°) as determined by powder X-ray diffraction. [A4-1] The crystal according to [A3], wherein the hydrate crystal is a type 1A crystal having at least three peaks selected from the group consisting of diffraction angles (2θ values) of 6.0°, 9.3°, 9.7°, 10.4°, 11.9°, 12.9°, 15.3°, 15.9°, 16.4°, and 16.8° (±0.2°) as determined by powder X-ray diffraction. [A4-2] The crystal according to [A3], wherein the hydrate crystal is a type 1A crystal having at least five peaks selected from the group consisting of diffraction angles (2θ values) of 6.0°, 9.3°, 9.7°, 10.4°, 11.9°, 12.9°, 15.3°, 15.9°, 16.4°, and 16.8° (±0.2°) as determined by powder X-ray diffraction. [A4-3] The crystal according to [A3], wherein the hydrate crystal is a type 1A crystal having at least seven peaks selected from the group consisting of diffraction angles (2θ values) of 6.0°, 9.3°, 9.7°, 10.4°, 11.9°, 12.9°, 15.3°, 15.9°, 16.4°, and 16.8° (±0.2°) as determined by powder X-ray diffraction. [A4-4] The crystal described in [A3], wherein the hydrate crystal is a type 1A crystal containing peaks at 6.0°, 9.3°, 9.7°, 10.4°, 11.9°, 12.9°, 15.3°, 15.9°, 16.4°, and 16.8° (±0.2°) as diffraction angles (2θ values) determined by powder X-ray diffraction. [A5] The crystal according to [A3], wherein the hydrate crystal is a 1G type crystal having at least one peak selected from the group consisting of diffraction angles (2θ values) of 8.8°, 9.2°, 10.4°, 12.7°, 13.4°, 15.8°, 16.9°, 17.3°, 18.3°, and 18.9° (±0.2°) as determined by powder X-ray diffraction. [A5-1] The crystal according to [A3], wherein the hydrate crystal is a 1G type crystal having at least three peaks selected from the group consisting of diffraction angles (2θ values) of 8.8°, 9.2°, 10.4°, 12.7°, 13.4°, 15.8°, 16.9°, 17.3°, 18.3°, and 18.9° (±0.2°) as determined by powder X-ray diffraction. [A5-2] The crystal according to [A3], wherein the hydrate crystal is a 1G type crystal having at least five peaks selected from the group consisting of diffraction angles (2θ values) of 8.8°, 9.2°, 10.4°, 12.7°, 13.4°, 15.8°, 16.9°, 17.3°, 18.3°, and 18.9° (±0.2°) as determined by powder X-ray diffraction. [A5-3] The crystal according to [A3], wherein the hydrate crystal is a 1G type crystal having at least seven peaks selected from the group consisting of diffraction angles (2θ values) of 8.8°, 9.2°, 10.4°, 12.7°, 13.4°, 15.8°, 16.9°, 17.3°, 18.3°, and 18.9° (±0.2°) as determined by powder X-ray diffraction. [A5-4] The crystal described in [A3], wherein the hydrate crystal is a 1G type crystal containing peaks at 8.8°, 9.2°, 10.4°, 12.7°, 13.4°, 15.8°, 16.9°, 17.3°, 18.3°, and 18.9° (±0.2°) as diffraction angles (2θ values) determined by powder X-ray diffraction. [A6] The crystal according to [A3], wherein the hydrate crystal is a 1G type crystal having at least one peak selected from the group consisting of diffraction angles (2θ values) of 8.9°, 9.3°, 10.5°, 12.8°, 13.5°, 15.9°, 17.0°, 17.4°, 18.4°, and 19.0° (±0.2°) as determined by powder X-ray diffraction. [A6-1] The crystal according to [A3], wherein the hydrate crystal is a 1G type crystal having at least three peaks selected from the group consisting of diffraction angles (2θ values) of 8.9°, 9.3°, 10.5°, 12.8°, 13.5°, 15.9°, 17.0°, 17.4°, 18.4°, and 19.0° (±0.2°) as determined by powder X-ray diffraction. [A6-2] The crystal according to [A3], wherein the hydrate crystal is a 1G type crystal having at least five peaks selected from the group consisting of diffraction angles (2θ values) of 8.9°, 9.3°, 10.5°, 12.8°, 13.5°, 15.9°, 17.0°, 17.4°, 18.4°, and 19.0° (±0.2°) as determined by powder X-ray diffraction. [A6-3] The crystal according to [A3], wherein the hydrate crystal is a 1G type crystal having at least seven peaks selected from the group consisting of diffraction angles (2θ values) of 8.9°, 9.3°, 10.5°, 12.8°, 13.5°, 15.9°, 17.0°, 17.4°, 18.4°, and 19.0° (±0.2°) as determined by powder X-ray diffraction. [A6-4] The crystal described in [A3], wherein the hydrate crystal is a 1G type crystal containing peaks at 8.9°, 9.3°, 10.5°, 12.8°, 13.5°, 15.9°, 17.0°, 17.4°, 18.4°, and 19.0° (±0.2°) as diffraction angles (2θ values) determined by powder X-ray diffraction. [A7] The crystal according to any one of [A6] to [A6-4], wherein the diffraction angle (2θ value) is the diffraction angle (2θ value) of a hydrate crystal stored at a temperature of 34°C and 60% relative humidity for 5 minutes. [A8] The crystal according to [A3], wherein the hydrate crystal is a 1J type crystal having at least one peak selected from the group consisting of diffraction angles (2θ values) of 9.7°, 10.5°, 13.1°, 15.0°, 16.2°, 16.6°, 17.6°, 18.9°, 19.3°, and 20.8° (±0.2°) as determined by powder X-ray diffraction. [A8-1] The crystal according to [A3], wherein the hydrate crystal is a 1J type crystal having at least three peaks selected from the group consisting of diffraction angles (2θ values) of 9.7°, 10.5°, 13.1°, 15.0°, 16.2°, 16.6°, 17.6°, 18.9°, 19.3°, and 20.8° (±0.2°) as determined by powder X-ray diffraction. [A8-2] The crystal according to [A3], wherein the hydrate crystal is a 1J type crystal having at least five peaks selected from the group consisting of diffraction angles (2θ values) of 9.7°, 10.5°, 13.1°, 15.0°, 16.2°, 16.6°, 17.6°, 18.9°, 19.3°, and 20.8° (±0.2°) as determined by powder X-ray diffraction. [A8-3] The crystal according to [A3], wherein the hydrate crystal is a 1J type crystal having at least seven peaks selected from the group consisting of diffraction angles (2θ values) of 9.7°, 10.5°, 13.1°, 15.0°, 16.2°, 16.6°, 17.6°, 18.9°, 19.3°, and 20.8° (±0.2°) as determined by powder X-ray diffraction. [A8-4] The crystal described in [A3], wherein the hydrate crystal is a 1J type crystal containing peaks at 9.7°, 10.5°, 13.1°, 15.0°, 16.2°, 16.6°, 17.6°, 18.9°, 19.3°, and 20.8° (±0.2°) as diffraction angles (2θ values) determined by powder X-ray diffraction. [A9] The crystal according to any one of [A8] to [A8-4], wherein the diffraction angle (2θ value) is the diffraction angle (2θ value) of a hydrate crystal stored at a temperature of 34°C and 30% relative humidity for 15 minutes. [A10] The crystal described in [A1], wherein the crystal is a nonsolvate crystal of the compound represented by formula (1). [A11] The crystal according to [A1] or [A10], wherein the nonsolvate crystal is a 1H-type crystal having at least one peak selected from the group consisting of diffraction angles (2θ values) of 12.3°, 15.1°, 15.9°, 16.2°, 16.5°, 16.9°, 17.5°, 17.8°, 18.5°, and 19.7° (±0.2°) as determined by powder X-ray diffraction. [A11-1] The crystal according to [A1] or [A10], wherein the nonsolvate crystal is a 1H-type crystal having at least three peaks selected from the group consisting of diffraction angles (2θ values) of 12.3°, 15.1°, 15.9°, 16.2°, 16.5°, 16.9°, 17.5°, 17.8°, 18.5°, and 19.7° (±0.2°) as determined by powder X-ray diffraction. [A11-2] The crystal according to [A1] or [A10], wherein the nonsolvate crystal is a 1H-type crystal having at least five peaks selected from the group consisting of diffraction angles (2θ values) of 12.3°, 15.1°, 15.9°, 16.2°, 16.5°, 16.9°, 17.5°, 17.8°, 18.5°, and 19.7° (±0.2°) as determined by powder X-ray diffraction. [A11-3] The crystal according to [A1] or [A10], wherein the nonsolvate crystal is a 1H-type crystal having at least seven peaks selected from the group consisting of diffraction angles (2θ values) of 12.3°, 15.1°, 15.9°, 16.2°, 16.5°, 16.9°, 17.5°, 17.8°, 18.5°, and 19.7° (±0.2°) as determined by powder X-ray diffraction. [A11-4] The crystal according to [A1] or [A10], wherein the nonsolvate crystal is a 1H-type crystal containing peaks at 12.3°, 15.1°, 15.9°, 16.2°, 16.5°, 16.9°, 17.5°, 17.8°, 18.5°, and 19.7° (±0.2°) as diffraction angles (2θ values) determined by powder X-ray diffraction. [A12] The crystal according to any one of [A11] to [A11-4], wherein the diffraction angle (2θ value) is the diffraction angle (2θ value) of a water nonsolvate crystal stored at a temperature of 34°C and 0% relative humidity for 60 minutes. [A13] The crystal according to [A1] or [A2], wherein the crystal is a 1K type crystal having at least one peak selected from the group consisting of diffraction angles (2θ values) of 9.5°, 11.3°, 16.3°, 16.6°, 17.6°, 18.4°, 19.1°, 19.9°, 21.0°, and 21.9° (±0.2°) as determined by powder X-ray diffraction. [A13-1] The crystal according to [A1] or [A2], wherein the crystal is a 1K type crystal having at least three peaks selected from the group consisting of diffraction angles (2θ values) of 9.5°, 11.3°, 16.3°, 16.6°, 17.6°, 18.4°, 19.1°, 19.9°, 21.0°, and 21.9° (±0.2°) as determined by powder X-ray diffraction. [A13-2] The crystal according to [A1] or [A2], wherein the crystal is a 1K type crystal having at least five peaks selected from the group consisting of diffraction angles (2θ values) of 9.5°, 11.3°, 16.3°, 16.6°, 17.6°, 18.4°, 19.1°, 19.9°, 21.0°, and 21.9° (±0.2°) as determined by powder X-ray diffraction. [A13-3] The crystal according to [A1] or [A2], wherein the crystal is a 1K type crystal having at least seven peaks selected from the group consisting of diffraction angles (2θ values) of 9.5°, 11.3°, 16.3°, 16.6°, 17.6°, 18.4°, 19.1°, 19.9°, 21.0°, and 21.9° (±0.2°) as determined by powder X-ray diffraction. [A13-4] The crystal according to [A1] or [A2], wherein the crystal is a 1K type crystal containing peaks at 9.5°, 11.3°, 16.3°, 16.6°, 17.6°, 18.4°, 19.1°, 19.9°, 21.0°, and 21.9° (±0.2°) as diffraction angles (2θ values) determined by powder X-ray diffraction. [B1] The following formula (2) [ka] A compound represented by, or a salt thereof, or a crystal of a solvate thereof. [B2] The crystal described in [B1], wherein the crystal is a nonsolvate crystal of the compound represented by formula (2). [B3] The crystal according to [B1] or [B2], wherein the nonsolvate crystal is a 3A type crystal having at least one peak selected from the group consisting of 10.4°, 12.6°, 15.1°, 15.9°, 16.6°, 17.1°, 18.4°, 19.6°, 19.9°, and 20.6° (±0.2°) as diffraction angles (2θ values) by powder X-ray diffraction. [B3-1] The crystal according to [B1] or [B2], wherein the nonsolvate crystal is a 3A type crystal having at least three peaks selected from the group consisting of diffraction angles (2θ values) of 10.4°, 12.6°, 15.1°, 15.9°, 16.6°, 17.1°, 18.4°, 19.6°, 19.9°, and 20.6° (±0.2°) as determined by powder X-ray diffraction. [B3-2] The crystal according to [B1] or [B2], wherein the nonsolvate crystal is a 3A type crystal having at least five peaks selected from the group consisting of diffraction angles (2θ values) of 10.4°, 12.6°, 15.1°, 15.9°, 16.6°, 17.1°, 18.4°, 19.6°, 19.9°, and 20.6° (±0.2°) as determined by powder X-ray diffraction. [B3-3] The crystal according to [B1] or [B2], wherein the nonsolvate crystal is a 3A type crystal having at least seven peaks selected from the group consisting of diffraction angles (2θ values) of 10.4°, 12.6°, 15.1°, 15.9°, 16.6°, 17.1°, 18.4°, 19.6°, 19.9°, and 20.6° (±0.2°) as determined by powder X-ray diffraction. [B3-4] The crystal according to [B1] or [B2], wherein the nonsolvate crystal is a 3A type crystal containing peaks at 10.4°, 12.6°, 15.1°, 15.9°, 16.6°, 17.1°, 18.4°, 19.6°, 19.9°, and 20.6° (±0.2°) as diffraction angles (2θ values) determined by powder X-ray diffraction. [B4] The crystal according to [B1] or [B2], wherein the nonsolvate crystal is a 3C type crystal having at least one peak selected from the group consisting of diffraction angles (2θ values) of 7.9°, 8.5°, 8.8°, 9.2°, 10.4°, 11.4°, 12.0°, 13.1°, 15.2°, and 15.7° (±0.2°) as determined by powder X-ray diffraction. [B4-1] The crystal according to [B1] or [B2], wherein the nonsolvate crystal is a 3C type crystal having at least three peaks selected from the group consisting of diffraction angles (2θ values) of 7.9°, 8.5°, 8.8°, 9.2°, 10.4°, 11.4°, 12.0°, 13.1°, 15.2°, and 15.7° (±0.2°) as determined by powder X-ray diffraction. [B4-2] The crystal according to [B1] or [B2], wherein the nonsolvate crystal is a 3C type crystal having at least five peaks selected from the group consisting of diffraction angles (2θ values) of 7.9°, 8.5°, 8.8°, 9.2°, 10.4°, 11.4°, 12.0°, 13.1°, 15.2°, and 15.7° (±0.2°) as determined by powder X-ray diffraction. [B4-3] The crystal according to [B1] or [B2], wherein the nonsolvate crystal is a 3C type crystal having at least seven peaks selected from the group consisting of diffraction angles (2θ values) of 7.9°, 8.5°, 8.8°, 9.2°, 10.4°, 11.4°, 12.0°, 13.1°, 15.2°, and 15.7° (±0.2°) as determined by powder X-ray diffraction. [B4-4] The crystal according to [B1] or [B2], wherein the nonsolvate crystal is a 3C type crystal containing peaks of 7.9°, 8.5°, 8.8°, 9.2°, 10.4°, 11.4°, 12.0°, 13.1°, 15.2°, and 15.7° (±0.2°) as diffraction angles (2θ values) determined by powder X-ray diffraction. [B5] The crystal described in [B1], wherein the crystal is a solvate crystal of the compound represented by formula (2). [B6] The crystal according to [B1] or [B5], wherein the crystal is a 3D type crystal having at least one peak selected from the group consisting of diffraction angles (2θ values) of 6.6°, 7.3°, 10.9°, 11.8°, 13.9°, 17.1°, 17.5°, 18.3°, 19.3°, and 22.0° (±0.2°) as determined by powder X-ray diffraction. [B6-1] The crystal according to [B1] or [B5], wherein the crystal is a 3D type crystal having at least three peaks selected from the group consisting of diffraction angles (2θ values) of 6.6°, 7.3°, 10.9°, 11.8°, 13.9°, 17.1°, 17.5°, 18.3°, 19.3°, and 22.0° (±0.2°) as determined by powder X-ray diffraction. [B6-2] The crystal according to [B1] or [B5], wherein the crystal is a 3D type crystal having at least five peaks selected from the group consisting of diffraction angles (2θ values) of 6.6°, 7.3°, 10.9°, 11.8°, 13.9°, 17.1°, 17.5°, 18.3°, 19.3°, and 22.0° (±0.2°) as determined by powder X-ray diffraction. [B6-3] The crystal according to [B1] or [B5], wherein the crystal is a 3D type crystal having at least seven peaks selected from the group consisting of diffraction angles (2θ values) of 6.6°, 7.3°, 10.9°, 11.8°, 13.9°, 17.1°, 17.5°, 18.3°, 19.3°, and 22.0° (±0.2°) as determined by powder X-ray diffraction. [B6-4] The crystal according to [B1] or [B5], wherein the crystal is a 3D type crystal containing peaks of 6.6°, 7.3°, 10.9°, 11.8°, 13.9°, 17.1°, 17.5°, 18.3°, 19.3°, and 22.0° (±0.2°) as diffraction angles (2θ values) determined by powder X-ray diffraction. [B7] The crystal according to [B1] or [B5], wherein the crystal is a 3B type crystal having at least one peak selected from the group consisting of diffraction angles (2θ values) of 7.4°, 14.0°, 14.6°, 15.5°, 17.1°, 18.1°, 19.8°, 21.8°, 22.4°, and 24.1° (±0.2°) as determined by powder X-ray diffraction. [B7-1] The crystal according to [B1] or [B5], wherein the crystal is a 3B type crystal having at least three peaks selected from the group consisting of diffraction angles (2θ values) of 7.4°, 14.0°, 14.6°, 15.5°, 17.1°, 18.1°, 19.8°, 21.8°, 22.4°, and 24.1° (±0.2°) as determined by powder X-ray diffraction. [B7-2] The crystal according to [B1] or [B5], wherein the crystal is a 3B type crystal having at least five peaks selected from the group consisting of diffraction angles (2θ values) of 7.4°, 14.0°, 14.6°, 15.5°, 17.1°, 18.1°, 19.8°, 21.8°, 22.4°, and 24.1° (±0.2°) as determined by powder X-ray diffraction. [B7-3] The crystal according to [B1] or [B5], wherein the crystal is a 3B type crystal having at least seven peaks selected from the group consisting of diffraction angles (2θ values) of 7.4°, 14.0°, 14.6°, 15.5°, 17.1°, 18.1°, 19.8°, 21.8°, 22.4°, and 24.1° (±0.2°) as determined by powder X-ray diffraction. [B7-4] The crystal according to [B1] or [B5], wherein the crystal is a 3B type crystal containing peaks of 7.4°, 14.0°, 14.6°, 15.5°, 17.1°, 18.1°, 19.8°, 21.8°, 22.4°, and 24.1° (±0.2°) as diffraction angles (2θ values) determined by powder X-ray diffraction. [C1] The following formula (3) [ka] A compound represented by, or a salt thereof, or a crystal of a solvate thereof. The crystal described in [C1], wherein the crystal [C2] is a nonsolvate crystal of the compound represented by formula (3). [C3] The crystal according to [C1] or [C2], wherein the nonsolvate crystal is a 2B type crystal having at least one peak selected from the group consisting of 7.2°, 7.6°, 13.4°, 14.5°, 16.0°, 16.6°, 17.3°, 19.9°, 20.6°, and 22.4° (±0.2°) as diffraction angles (2θ values) by powder X-ray diffraction. [C3-1] The crystal according to [C1] or [C2], wherein the nonsolvate crystal is a 2B type crystal having at least three peaks selected from the group consisting of diffraction angles (2θ values) of 7.2°, 7.6°, 13.4°, 14.5°, 16.0°, 16.6°, 17.3°, 19.9°, 20.6°, and 22.4° (±0.2°) as determined by powder X-ray diffraction. [C3-2] The crystal according to [C1] or [C2], wherein the nonsolvate crystal is a 2B type crystal having at least five peaks selected from the group consisting of diffraction angles (2θ values) of 7.2°, 7.6°, 13.4°, 14.5°, 16.0°, 16.6°, 17.3°, 19.9°, 20.6°, and 22.4° (±0.2°) as determined by powder X-ray diffraction. [C3-3] The crystal according to [C1] or [C2], wherein the nonsolvate crystal is a 2B type crystal having at least seven peaks selected from the group consisting of diffraction angles (2θ values) of 7.2°, 7.6°, 13.4°, 14.5°, 16.0°, 16.6°, 17.3°, 19.9°, 20.6°, and 22.4° (±0.2°) as determined by powder X-ray diffraction. [C3-4] The crystal according to [C1] or [C2], wherein the nonsolvate crystal is a 2B type crystal containing peaks at 7.2°, 7.6°, 13.4°, 14.5°, 16.0°, 16.6°, 17.3°, 19.9°, 20.6°, and 22.4° (±0.2°) as diffraction angles (2θ values) determined by powder X-ray diffraction. [C4] The crystal according to [C1] or [C2], wherein the nonsolvate crystal is a 2A type crystal having at least one peak selected from the group consisting of diffraction angles (2θ values) of 7.5°, 10.0°, 10.7°, 13.7°, 14.6°, 15.1°, 16.8°, 17.4°, 18.0°, and 18.5° (±0.2°) as determined by powder X-ray diffraction. [C4-1] The crystal according to [C1] or [C2], wherein the nonsolvate crystal is a 2A type crystal having at least three peaks selected from the group consisting of diffraction angles (2θ values) of 7.5°, 10.0°, 10.7°, 13.7°, 14.6°, 15.1°, 16.8°, 17.4°, 18.0°, and 18.5° (±0.2°) as determined by powder X-ray diffraction. [C4-2] The crystal according to [C1] or [C2], wherein the nonsolvate crystal is a 2A type crystal having at least five peaks selected from the group consisting of diffraction angles (2θ values) of 7.5°, 10.0°, 10.7°, 13.7°, 14.6°, 15.1°, 16.8°, 17.4°, 18.0°, and 18.5° (±0.2°) as determined by powder X-ray diffraction. [C4-3] The crystal according to [C1] or [C2], wherein the nonsolvate crystal is a 2A type crystal having at least seven peaks selected from the group consisting of diffraction angles (2θ values) of 7.5°, 10.0°, 10.7°, 13.7°, 14.6°, 15.1°, 16.8°, 17.4°, 18.0°, and 18.5° (±0.2°) as determined by powder X-ray diffraction. [C4-4] The crystal according to [C1] or [C2], wherein the nonsolvate crystal is a 2A type crystal containing peaks at 7.5°, 10.0°, 10.7°, 13.7°, 14.6°, 15.1°, 16.8°, 17.4°, 18.0°, and 18.5° (±0.2°) as diffraction angles (2θ values) determined by powder X-ray diffraction. [C5] The nonsolvate crystal is a 2C-type crystal having at least one peak selected from the group consisting of 7.2°, 9.9°, 14.5°, 15.3°, 15.7°, 17.2°, 17.6°, 18.0°, 19.1°, and 19.8° (±0.2°) as diffraction angles (2θ values) determined by powder X-ray diffraction, as described in [C1] or [C2]. [C5-1] The crystal according to [C1] or [C2], wherein the nonsolvate crystal is a 2C-type crystal having at least three peaks selected from the group consisting of diffraction angles (2θ values) of 7.2°, 9.9°, 14.5°, 15.3°, 15.7°, 17.2°, 17.6°, 18.0°, 19.1°, and 19.8° (±0.2°) as determined by powder X-ray diffraction. [C5-2] The crystal according to [C1] or [C2], wherein the nonsolvate crystal is a 2C-type crystal having at least five peaks selected from the group consisting of diffraction angles (2θ values) of 7.2°, 9.9°, 14.5°, 15.3°, 15.7°, 17.2°, 17.6°, 18.0°, 19.1°, and 19.8° (±0.2°) as determined by powder X-ray diffraction. [C5-3] The crystal according to [C1] or [C2], wherein the nonsolvate crystal is a 2C-type crystal having at least seven peaks selected from the group consisting of diffraction angles (2θ values) of 7.2°, 9.9°, 14.5°, 15.3°, 15.7°, 17.2°, 17.6°, 18.0°, 19.1°, and 19.8° (±0.2°) as determined by powder X-ray diffraction. [C5-4] The crystal according to [C1] or [C2], wherein the nonsolvate crystal is a 2C-type crystal containing peaks at 7.2°, 9.9°, 14.5°, 15.3°, 15.7°, 17.2°, 17.6°, 18.0°, 19.1°, and 19.8° (±0.2°) as diffraction angles (2θ values) determined by powder X-ray diffraction. [C6] The crystal according to [C1] or [C2], wherein the nonsolvate crystal is a 2F type crystal having at least one peak selected from the group consisting of 7.3°, 9.9°, 11.4°, 14.5°, 15.3°, 16.4°, 16.8°, 17.2°, 17.7°, and 18.1° (±0.2°) as diffraction angles (2θ values) by powder X-ray diffraction. [C6-1] The crystal according to [C1] or [C2], wherein the nonsolvate crystal is a 2F type crystal having at least three peaks selected from the group consisting of diffraction angles (2θ values) of 7.3°, 9.9°, 11.4°, 14.5°, 15.3°, 16.4°, 16.8°, 17.2°, 17.7°, and 18.1° (±0.2°) as determined by powder X-ray diffraction. [C6-2] The crystal according to [C1] or [C2], wherein the nonsolvate crystal is a 2F type crystal having at least five peaks selected from the group consisting of diffraction angles (2θ values) of 7.3°, 9.9°, 11.4°, 14.5°, 15.3°, 16.4°, 16.8°, 17.2°, 17.7°, and 18.1° (±0.2°) as determined by powder X-ray diffraction. [C6-3] The crystal according to [C1] or [C2], wherein the nonsolvate crystal is a 2F type crystal having at least seven peaks selected from the group consisting of diffraction angles (2θ values) of 7.3°, 9.9°, 11.4°, 14.5°, 15.3°, 16.4°, 16.8°, 17.2°, 17.7°, and 18.1° (±0.2°) as determined by powder X-ray diffraction. [C6-4] The crystal according to [C1] or [C2], wherein the nonsolvate crystal is a 2F type crystal containing peaks at 7.3°, 9.9°, 11.4°, 14.5°, 15.3°, 16.4°, 16.8°, 17.2°, 17.7°, and 18.1° (±0.2°) as diffraction angles (2θ values) determined by powder X-ray diffraction. [D1] The following formula (4) [ka] A compound represented by, or a salt thereof, or a crystal of a solvate thereof. The crystal described in [D1], wherein the crystal [D2] is a solvate crystal of the compound represented by formula (4). [D3] The crystal according to [D1] or [D2], wherein the solvate crystal is a hydrate crystal. [D4] The crystal according to [D3], wherein the hydrate crystal is a 5A type crystal having at least one peak selected from the group consisting of diffraction angles (2θ values) of 7.4°, 8.8°, 9.5°, 10.4°, 12.2°, 15.5°, 16.6°, 17.1°, 17.5°, and 18.1° (±0.2°) as determined by powder X-ray diffraction. [D4-1] The crystal according to [D3], wherein the hydrate crystal is a 5A type crystal having at least three peaks selected from the group consisting of diffraction angles (2θ values) of 7.4°, 8.8°, 9.5°, 10.4°, 12.2°, 15.5°, 16.6°, 17.1°, 17.5°, and 18.1° (±0.2°) as determined by powder X-ray diffraction. [D4-2] The crystal according to [D3], wherein the hydrate crystal is a 5A type crystal having at least five peaks selected from the group consisting of diffraction angles (2θ values) of 7.4°, 8.8°, 9.5°, 10.4°, 12.2°, 15.5°, 16.6°, 17.1°, 17.5°, and 18.1° (±0.2°) as determined by powder X-ray diffraction. [D4-3] The crystal according to [D3], wherein the hydrate crystal is a 5A type crystal having at least seven peaks selected from the group consisting of diffraction angles (2θ values) of 7.4°, 8.8°, 9.5°, 10.4°, 12.2°, 15.5°, 16.6°, 17.1°, 17.5°, and 18.1° (±0.2°) as determined by powder X-ray diffraction. [D4-4] The crystal described in [D3], wherein the hydrate crystal is a 5A type crystal containing peaks at 7.4°, 8.8°, 9.5°, 10.4°, 12.2°, 15.5°, 16.6°, 17.1°, 17.5°, and 18.1° (±0.2°) as diffraction angles (2θ values) determined by powder X-ray diffraction. [D5] The crystal described in [D3], wherein the hydrate crystal is a 5A type crystal containing peaks at 7.4°, 8.8°, and 9.5° (±0.2°) as diffraction angles (2θ values) determined by powder X-ray diffraction. [D6] The crystal according to [D3], wherein the hydrate crystal is a 5A type crystal having at least one peak selected from the group consisting of diffraction angles (2θ values) of 7.4°, 8.8°, 9.5°, 10.8°, 12.7°, 16.0°, 16.8°, 17.3°, 17.9°, and 19.2° (±0.2°) as determined by powder X-ray diffraction. [D6-1] The crystal according to [D3], wherein the hydrate crystal is a 5A type crystal having at least three peaks selected from the group consisting of diffraction angles (2θ values) of 7.4°, 8.8°, 9.5°, 10.8°, 12.7°, 16.0°, 16.8°, 17.3°, 17.9°, and 19.2° (±0.2°) as determined by powder X-ray diffraction. [D6-2] The crystal according to [D3], wherein the hydrate crystal is a 5A type crystal having at least five peaks selected from the group consisting of diffraction angles (2θ values) of 7.4°, 8.8°, 9.5°, 10.8°, 12.7°, 16.0°, 16.8°, 17.3°, 17.9°, and 19.2° (±0.2°) as determined by powder X-ray diffraction. [D6-3] The crystal according to [D3], wherein the hydrate crystal is a 5A type crystal having at least seven peaks selected from the group consisting of diffraction angles (2θ values) of 7.4°, 8.8°, 9.5°, 10.8°, 12.7°, 16.0°, 16.8°, 17.3°, 17.9°, and 19.2° (±0.2°) as determined by powder X-ray diffraction. [D6-4] The crystal described in [D3], wherein the hydrate crystal is a 5A type crystal containing peaks at 7.4°, 8.8°, 9.5°, 10.8°, 12.7°, 16.0°, 16.8°, 17.3°, 17.9°, and 19.2° (±0.2°) as diffraction angles (2θ values) determined by powder X-ray diffraction. [D7] The crystal according to any one of [D6] to [D6-4], wherein the diffraction angle (2θ value) is the diffraction angle (2θ value) of a hydrate crystal stored for 1 hour at a temperature of 25°C and 10% relative humidity. [D8] The crystal according to [D3], wherein the hydrate crystal is a 5A type crystal having at least one peak selected from the group consisting of diffraction angles (2θ values) of 7.4°, 8.8°, 9.5°, 10.5°, 12.2°, 15.6°, 16.6°, 17.1°, 17.3°, and 17.5° (±0.2°) as determined by powder X-ray diffraction. [D8-1] The crystal according to [D3], wherein the hydrate crystal is a 5A type crystal having at least three peaks selected from the group consisting of diffraction angles (2θ values) of 7.4°, 8.8°, 9.5°, 10.5°, 12.2°, 15.6°, 16.6°, 17.1°, 17.3°, and 17.5° (±0.2°) as determined by powder X-ray diffraction. [D8-2] The crystal according to [D3], wherein the hydrate crystal is a 5A type crystal having at least five peaks selected from the group consisting of diffraction angles (2θ values) of 7.4°, 8.8°, 9.5°, 10.5°, 12.2°, 15.6°, 16.6°, 17.1°, 17.3°, and 17.5° (±0.2°) as determined by powder X-ray diffraction. [D8-3] The crystal according to [D3], wherein the hydrate crystal is a 5A type crystal having at least seven peaks selected from the group consisting of diffraction angles (2θ values) of 7.4°, 8.8°, 9.5°, 10.5°, 12.2°, 15.6°, 16.6°, 17.1°, 17.3°, and 17.5° (±0.2°) as determined by powder X-ray diffraction. [D8-4] The crystal described in [D3], wherein the hydrate crystal is a 5A type crystal containing peaks at 7.4°, 8.8°, 9.5°, 10.5°, 12.2°, 15.6°, 16.6°, 17.1°, 17.3°, and 17.5° (±0.2°) as diffraction angles (2θ values) determined by powder X-ray diffraction. [D9] The crystal according to any one of [D8] to [D8-4], wherein the diffraction angle (2θ value) is the diffraction angle (2θ value) of a hydrate crystal stored for 1 hour at a temperature of 25°C and 20% relative humidity. [D10] The crystal according to [D3], wherein the hydrate crystal is a 5A type crystal having at least one peak selected from the group consisting of diffraction angles (2θ values) of 7.4°, 8.8°, 9.5°, 10.5°, 12.2°, 15.5°, 16.4°, 16.6°, 17.1°, and 17.6° (±0.2°) as determined by powder X-ray diffraction. [D10-1] The crystal according to [D3], wherein the hydrate crystal is a 5A type crystal having at least three peaks selected from the group consisting of diffraction angles (2θ values) of 7.4°, 8.8°, 9.5°, 10.5°, 12.2°, 15.5°, 16.4°, 16.6°, 17.1°, and 17.6° (±0.2°) as determined by powder X-ray diffraction. [D10-2] The crystal according to [D3], wherein the hydrate crystal is a 5A type crystal having at least five peaks selected from the group consisting of diffraction angles (2θ values) of 7.4°, 8.8°, 9.5°, 10.5°, 12.2°, 15.5°, 16.4°, 16.6°, 17.1°, and 17.6° (±0.2°) as determined by powder X-ray diffraction. [D10-3] The crystal according to [D3], wherein the hydrate crystal is a 5A type crystal having at least seven peaks selected from the group consisting of diffraction angles (2θ values) of 7.4°, 8.8°, 9.5°, 10.5°, 12.2°, 15.5°, 16.4°, 16.6°, 17.1°, and 17.6° (±0.2°) as determined by powder X-ray diffraction. [D10-4] The crystal described in [D3], wherein the hydrate crystal is a 5A type crystal containing peaks at 7.4°, 8.8°, 9.5°, 10.5°, 12.2°, 15.5°, 16.4°, 16.6°, 17.1°, and 17.6° (±0.2°) as diffraction angles (2θ values) determined by powder X-ray diffraction. [D11] The crystal according to any one of [D10] to [D10-4], wherein the diffraction angle (2θ value) is the diffraction angle (2θ value) of a hydrate crystal stored for 1 hour at a temperature of 25°C and 30% relative humidity. [D12] The crystal according to [D3], wherein the hydrate crystal is a 5A type crystal having at least one peak selected from the group consisting of diffraction angles (2θ values) of 7.4°, 8.8°, 9.5°, 10.3°, 12.2°, 15.4°, 16.3°, 16.6°, 17.0°, and 17.6° (±0.2°) as determined by powder X-ray diffraction. [D12-1] The crystal according to [D3], wherein the hydrate crystal is a 5A type crystal having at least three peaks selected from the group consisting of diffraction angles (2θ values) of 7.4°, 8.8°, 9.5°, 10.3°, 12.2°, 15.4°, 16.3°, 16.6°, 17.0°, and 17.6° (±0.2°) as determined by powder X-ray diffraction. [D12-2] The crystal according to [D3], wherein the hydrate crystal is a 5A type crystal having at least five peaks selected from the group consisting of diffraction angles (2θ values) of 7.4°, 8.8°, 9.5°, 10.3°, 12.2°, 15.4°, 16.3°, 16.6°, 17.0°, and 17.6° (±0.2°) as determined by powder X-ray diffraction. [D12-3] The crystal according to [D3], wherein the hydrate crystal is a 5A type crystal having at least seven peaks selected from the group consisting of diffraction angles (2θ values) of 7.4°, 8.8°, 9.5°, 10.3°, 12.2°, 15.4°, 16.3°, 16.6°, 17.0°, and 17.6° (±0.2°) as determined by powder X-ray diffraction. [D12-4] The crystal described in [D3], wherein the hydrate crystal is a 5A type crystal containing peaks at 7.4°, 8.8°, 9.5°, 10.3°, 12.2°, 15.4°, 16.3°, 16.6°, 17.0°, and 17.6° (±0.2°) as diffraction angles (2θ values) determined by powder X-ray diffraction. [D13] The crystal according to any one of [D12] to [D12-4], wherein the diffraction angle (2θ value) is the diffraction angle (2θ value) of a hydrate crystal stored for 1 hour at a temperature of 25°C and 60% relative humidity. [D14] The crystal according to [D3], wherein the hydrate crystal is a 5E type crystal having at least one peak selected from the group consisting of diffraction angles (2θ values) of 9.2°, 10.6°, 11.9°, 13.7°, 15.0°, 15.8°, 16.6°, 17.1°, 18.5°, and 19.2° (±0.2°) as determined by powder X-ray diffraction. [D14-1] The crystal according to [D3], wherein the hydrate crystal is a 5E type crystal having at least three peaks selected from the group consisting of diffraction angles (2θ values) of 9.2°, 10.6°, 11.9°, 13.7°, 15.0°, 15.8°, 16.6°, 17.1°, 18.5°, and 19.2° (±0.2°) as determined by powder X-ray diffraction. [D14-2] The crystal according to [D3], wherein the hydrate crystal is a 5E type crystal having at least five peaks selected from the group consisting of diffraction angles (2θ values) of 9.2°, 10.6°, 11.9°, 13.7°, 15.0°, 15.8°, 16.6°, 17.1°, 18.5°, and 19.2° (±0.2°) as determined by powder X-ray diffraction. [D14-3] The crystal according to [D3], wherein the hydrate crystal is a 5E type crystal having at least seven peaks selected from the group consisting of diffraction angles (2θ values) of 9.2°, 10.6°, 11.9°, 13.7°, 15.0°, 15.8°, 16.6°, 17.1°, 18.5°, and 19.2° (±0.2°) as determined by powder X-ray diffraction. [D14-4] The crystal described in [D3], wherein the hydrate crystal is a 5E type crystal containing peaks at 9.2°, 10.6°, 11.9°, 13.7°, 15.0°, 15.8°, 16.6°, 17.1°, 18.5°, and 19.2° (±0.2°) as diffraction angles (2θ values) determined by powder X-ray diffraction. [D15] The crystal described in [D3], wherein the hydrate crystal is a 5J type crystal containing peaks at 7.3°, 9.0°, 9.6°, 10.8°, 12.2°, 15.7°, 16.6°, and 17.3° (±0.2°) as diffraction angles (2θ values) determined by powder X-ray diffraction. [D16] The crystal according to [D3], wherein the hydrate crystal is a 5J type crystal having at least one peak selected from the group consisting of 7.3°, 9.0°, 9.6°, 10.9°, 12.3°, 15.9°, 16.6°, 17.1°, and 17.5° (±0.2°) as diffraction angles (2θ values) by powder X-ray diffraction. [D16-1] The crystal according to [D3], wherein the hydrate crystal is a 5J type crystal having at least three peaks selected from the group consisting of diffraction angles (2θ values) of 7.3°, 9.0°, 9.6°, 10.9°, 12.3°, 15.9°, 16.6°, 17.1°, and 17.5° (±0.2°) as determined by powder X-ray diffraction. [D16-2] The crystal according to [D3], wherein the hydrate crystal is a 5J type crystal having at least five peaks selected from the group consisting of diffraction angles (2θ values) of 7.3°, 9.0°, 9.6°, 10.9°, 12.3°, 15.9°, 16.6°, 17.1°, and 17.5° (±0.2°) as determined by powder X-ray diffraction. [D16-3] The crystal according to [D3], wherein the hydrate crystal is a 5J type crystal having at least seven peaks selected from the group consisting of diffraction angles (2θ values) of 7.3°, 9.0°, 9.6°, 10.9°, 12.3°, 15.9°, 16.6°, 17.1°, and 17.5° (±0.2°) as determined by powder X-ray diffraction. [D16-4] The crystal described in [D3], wherein the hydrate crystal is a 5J type crystal containing peaks at 7.3°, 9.0°, 9.6°, 10.9°, 12.3°, 15.9°, 16.6°, 17.1°, and 17.5° (±0.2°) as diffraction angles (2θ values) determined by powder X-ray diffraction. [D17] The crystal according to any one of [D16] to [D16-4], wherein the diffraction angle (2θ value) is the diffraction angle (2θ value) of a hydrate crystal stored for 1 hour at a temperature of 25°C and 30% relative humidity. [D18] The crystal according to [D3], wherein the hydrate crystal is a 5J type crystal having at least one peak selected from the group consisting of 7.3°, 8.9°, 9.6°, 10.8°, 12.2°, 15.7°, 16.3°, 16.6°, 17.0°, and 17.3° (±0.2°) as diffraction angles (2θ values) by powder X-ray diffraction. [D18-1] The crystal according to [D3], wherein the hydrate crystal is a 5J type crystal having at least three peaks selected from the group consisting of diffraction angles (2θ values) of 7.3°, 8.9°, 9.6°, 10.8°, 12.2°, 15.7°, 16.3°, 16.6°, 17.0°, and 17.3° (±0.2°) as determined by powder X-ray diffraction. [D18-2] The crystal according to [D3], wherein the hydrate crystal is a 5J type crystal having at least five peaks selected from the group consisting of diffraction angles (2θ values) of 7.3°, 8.9°, 9.6°, 10.8°, 12.2°, 15.7°, 16.3°, 16.6°, 17.0°, and 17.3° (±0.2°) as determined by powder X-ray diffraction. [D18-3] The crystal according to [D3], wherein the hydrate crystal is a 5J type crystal having at least seven peaks selected from the group consisting of diffraction angles (2θ values) of 7.3°, 8.9°, 9.6°, 10.8°, 12.2°, 15.7°, 16.3°, 16.6°, 17.0°, and 17.3° (±0.2°) as determined by powder X-ray diffraction. [D18-4] The crystal described in [D3], wherein the hydrate crystal is a 5J type crystal containing peaks at 7.3°, 8.9°, 9.6°, 10.8°, 12.2°, 15.7°, 16.3°, 16.6°, 17.0° and 17.3° (±0.2°) as diffraction angles (2θ values) determined by powder X-ray diffraction. [D19] The crystal according to any one of [D18] to [D18-4], wherein the diffraction angle (2θ value) is the diffraction angle (2θ value) of a hydrate crystal stored for 1 hour at a temperature of 25°C and 40% relative humidity. [D20] The crystal according to [D3], wherein the hydrate crystal is a 5J type crystal having at least one peak selected from the group consisting of diffraction angles (2θ values) of 7.3°, 8.9°, 9.6°, 10.7°, 12.1°, 15.6°, 16.2°, 16.6°, 16.9° and 17.2° (±0.2°) as determined by powder X-ray diffraction. [D20-1] The crystal according to [D3], wherein the hydrate crystal is a 5J type crystal having at least three peaks selected from the group consisting of diffraction angles (2θ values) of 7.3°, 8.9°, 9.6°, 10.7°, 12.1°, 15.6°, 16.2°, 16.6°, 16.9° and 17.2° (±0.2°) as determined by powder X-ray diffraction. [D20-2] The crystal according to [D3], wherein the hydrate crystal is a 5J type crystal having at least five peaks selected from the group consisting of diffraction angles (2θ values) of 7.3°, 8.9°, 9.6°, 10.7°, 12.1°, 15.6°, 16.2°, 16.6°, 16.9° and 17.2° (±0.2°) as determined by powder X-ray diffraction. [D20-3] The crystal according to [D3], wherein the hydrate crystal is a 5J type crystal having at least seven peaks selected from the group consisting of diffraction angles (2θ values) of 7.3°, 8.9°, 9.6°, 10.7°, 12.1°, 15.6°, 16.2°, 16.6°, 16.9° and 17.2° (±0.2°) as determined by powder X-ray diffraction. [D20-4] The crystal described in [D3], wherein the hydrate crystal is a 5J type crystal containing peaks at 7.3°, 8.9°, 9.6°, 10.7°, 12.1°, 15.6°, 16.2°, 16.6°, 16.9° and 17.2° (±0.2°) as diffraction angles (2θ values) determined by powder X-ray diffraction. [D21] The crystal according to any one of [D20] to [D20-4], wherein the diffraction angle (2θ value) is the diffraction angle (2θ value) of a hydrate crystal stored for 1 hour at a temperature of 25°C and a relative humidity of 50-60%. [D22] The crystal according to [D3], wherein the hydrate crystal is a 5J type crystal having at least one peak selected from the group consisting of diffraction angles (2θ values) of 7.2°, 8.9°, 9.5°, 10.6°, 12.0°, 15.5°, 16.1°, 16.6°, and 17.1° (±0.2°) as determined by powder X-ray diffraction. [D22-1] The crystal according to [D3], wherein the hydrate crystal is a 5J type crystal having at least three peaks selected from the group consisting of diffraction angles (2θ values) of 7.2°, 8.9°, 9.5°, 10.6°, 12.0°, 15.5°, 16.1°, 16.6°, and 17.1° (±0.2°) as determined by powder X-ray diffraction. [D22-2] The crystal according to [D3], wherein the hydrate crystal is a 5J type crystal having at least five peaks selected from the group consisting of diffraction angles (2θ values) of 7.2°, 8.9°, 9.5°, 10.6°, 12.0°, 15.5°, 16.1°, 16.6°, and 17.1° (±0.2°) as determined by powder X-ray diffraction. [D22-3] The crystal according to [D3], wherein the hydrate crystal is a 5J type crystal having at least seven peaks selected from the group consisting of diffraction angles (2θ values) of 7.2°, 8.9°, 9.5°, 10.6°, 12.0°, 15.5°, 16.1°, 16.6°, and 17.1° (±0.2°) as determined by powder X-ray diffraction. [D22-4] The crystal described in [D3], wherein the hydrate crystal is a 5J type crystal containing peaks at 7.2°, 8.9°, 9.5°, 10.6°, 12.0°, 15.5°, 16.1°, 16.6°, and 17.1° (±0.2°) as diffraction angles (2θ values) determined by powder X-ray diffraction. [D23] The crystal according to any one of [D22] to [D22-4], wherein the diffraction angle (2θ value) is the diffraction angle (2θ value) of a hydrate crystal stored for 1 hour at a temperature of 25°C and a relative humidity of 70% or more. [D24] The crystal described in [D1], wherein the crystal is a nonsolvate crystal of the compound represented by formula (4). The crystal according to [D1] or [D24], wherein the crystal is a 5C type crystal having at least one peak selected from the group consisting of diffraction angles (2θ values) of 7.3°, 9.7°, 12.1°, 14.8°, 15.2°, 15.7°, 16.6°, and 17.7° (±0.2°) as determined by powder X-ray diffraction. [D25-1] The crystal according to [D1] or [D24], wherein the crystal is a 5C type crystal having at least three peaks selected from the group consisting of diffraction angles (2θ values) of 7.3°, 9.7°, 12.1°, 14.8°, 15.2°, 15.7°, 16.6°, and 17.7° (±0.2°) as determined by powder X-ray diffraction. [D25-2] The crystal according to [D1] or [D24], wherein the crystal is a 5C type crystal having at least five peaks selected from the group consisting of diffraction angles (2θ values) of 7.3°, 9.7°, 12.1°, 14.8°, 15.2°, 15.7°, 16.6°, and 17.7° (±0.2°) as determined by powder X-ray diffraction. [D25-3] The crystal according to [D1] or [D24], wherein the crystal is a 5C type crystal having at least seven peaks selected from the group consisting of diffraction angles (2θ values) of 7.3°, 9.7°, 12.1°, 14.8°, 15.2°, 15.7°, 16.6°, and 17.7° (±0.2°) as determined by powder X-ray diffraction. [D25-4] The crystal according to [D1] or [D24], wherein the crystal is a 5C type crystal containing peaks at 7.3°, 9.7°, 12.1°, 14.8°, 15.2°, 15.7°, 16.6°, and 17.7° (±0.2°) as diffraction angles (2θ values) determined by powder X-ray diffraction. [D26] The crystal according to [D1] or [D24], wherein the nonsolvate crystal is a 5D type crystal having at least one peak selected from the group consisting of 11.3°, 13.1°, 13.8°, 14.9°, 15.9°, 16.1°, 16.7°, 17.5°, 18.1°, and 18.5° (±0.2°) as diffraction angles (2θ values) by powder X-ray diffraction. [D26-1] The crystal according to [D1] or [D24], wherein the nonsolvate crystal is a 5D type crystal having at least three peaks selected from the group consisting of diffraction angles (2θ values) of 11.3°, 13.1°, 13.8°, 14.9°, 15.9°, 16.1°, 16.7°, 17.5°, 18.1°, and 18.5° (±0.2°) as determined by powder X-ray diffraction. [D26-2] The crystal according to [D1] or [D24], wherein the nonsolvate crystal is a 5D type crystal having at least five peaks selected from the group consisting of diffraction angles (2θ values) of 11.3°, 13.1°, 13.8°, 14.9°, 15.9°, 16.1°, 16.7°, 17.5°, 18.1°, and 18.5° (±0.2°) as determined by powder X-ray diffraction. [D26-3] The crystal according to [D1] or [D24], wherein the nonsolvate crystal is a 5D type crystal having at least seven peaks selected from the group consisting of diffraction angles (2θ values) of 11.3°, 13.1°, 13.8°, 14.9°, 15.9°, 16.1°, 16.7°, 17.5°, 18.1°, and 18.5° (±0.2°) as determined by powder X-ray diffraction. [D26-4] The crystal according to [D1] or [D24], wherein the nonsolvate crystal is a 5D type crystal containing peaks at 11.3°, 13.1°, 13.8°, 14.9°, 15.9°, 16.1°, 16.7°, 17.5°, 18.1°, and 18.5° (±0.2°) as diffraction angles (2θ values) determined by powder X-ray diffraction. [D27] The crystal according to [D1] or [D2], wherein the crystal is a 5G type crystal having at least one peak selected from the group consisting of diffraction angles (2θ values) of 9.4°, 11.0°, 13.4°, 15.0°, 16.1°, 17.8°, 18.1°, 19.7°, 20.8°, and 22.0° (±0.2°) as determined by powder X-ray diffraction. [D27-1] The crystal according to [D1] or [D2], wherein the crystal is a 5G type crystal having at least three peaks selected from the group consisting of diffraction angles (2θ values) of 9.4°, 11.0°, 13.4°, 15.0°, 16.1°, 17.8°, 18.1°, 19.7°, 20.8°, and 22.0° (±0.2°) as determined by powder X-ray diffraction. [D27-2] The crystal according to [D1] or [D2], wherein the crystal is a 5G type crystal having at least five peaks selected from the group consisting of diffraction angles (2θ values) of 9.4°, 11.0°, 13.4°, 15.0°, 16.1°, 17.8°, 18.1°, 19.7°, 20.8°, and 22.0° (±0.2°) as determined by powder X-ray diffraction. [D27-3] The crystal according to [D1] or [D2], wherein the crystal is a 5G type crystal having at least seven peaks selected from the group consisting of diffraction angles (2θ values) of 9.4°, 11.0°, 13.4°, 15.0°, 16.1°, 17.8°, 18.1°, 19.7°, 20.8°, and 22.0° (±0.2°) as determined by powder X-ray diffraction. [D27-4] The crystal according to [D1] or [D2], wherein the crystal is a 5G type crystal containing peaks at 9.4°, 11.0°, 13.4°, 15.0°, 16.1°, 17.8°, 18.1°, 19.7°, 20.8°, and 22.0° (±0.2°) as diffraction angles (2θ values) determined by powder X-ray diffraction. [E1] The following formula (5) [ka] A compound represented by, or a salt thereof, or a crystal of a solvate thereof. The crystal described in [E1], wherein the crystal [E2] is a solvate crystal of the compound represented by formula (5). [E3] The crystal according to [E1] or [E2], wherein the solvate crystal is a hydrate crystal. [E4] The crystal according to [E3], wherein the hydrate crystal is a 4B type crystal having at least one peak selected from the group consisting of diffraction angles (2θ values) of 7.7°, 13.3°, 14.0°, 15.4°, 16.2°, 17.9°, 18.2°, 18.5°, 19.1°, and 20.6° (±0.2°) as determined by powder X-ray diffraction. [E4-1] The crystal according to [E3], wherein the hydrate crystal is a 4B type crystal having at least three peaks selected from the group consisting of diffraction angles (2θ values) of 7.7°, 13.3°, 14.0°, 15.4°, 16.2°, 17.9°, 18.2°, 18.5°, 19.1°, and 20.6° (±0.2°) as determined by powder X-ray diffraction. [E4-2] The crystal according to [E3], wherein the hydrate crystal is a 4B type crystal having at least five peaks selected from the group consisting of diffraction angles (2θ values) of 7.7°, 13.3°, 14.0°, 15.4°, 16.2°, 17.9°, 18.2°, 18.5°, 19.1°, and 20.6° (±0.2°) as determined by powder X-ray diffraction. [E4-3] The crystal according to [E3], wherein the hydrate crystal is a 4B type crystal having at least seven peaks selected from the group consisting of diffraction angles (2θ values) of 7.7°, 13.3°, 14.0°, 15.4°, 16.2°, 17.9°, 18.2°, 18.5°, 19.1°, and 20.6° (±0.2°) as determined by powder X-ray diffraction. [E4-4] The crystal described in [E3], wherein the hydrate crystal is a 4B type crystal containing peaks at 7.7°, 13.3°, 14.0°, 15.4°, 16.2°, 17.9°, 18.2°, 18.5°, 19.1°, and 20.6° (±0.2°) as diffraction angles (2θ values) determined by powder X-ray diffraction. [E5] The crystal according to [E1] or [E2], wherein the crystal is a 4A type crystal having at least one peak selected from the group consisting of diffraction angles (2θ values) of 11.5°, 11.8°, 15.7°, 17.2°, 17.5°, 18.1°, 19.5°, 20.3°, 20.5°, and 21.2° (±0.2°) as determined by powder X-ray diffraction. [E5-1] The crystal according to [E1] or [E2], wherein the crystal is a 4A type crystal having at least three peaks selected from the group consisting of diffraction angles (2θ values) of 11.5°, 11.8°, 15.7°, 17.2°, 17.5°, 18.1°, 19.5°, 20.3°, 20.5°, and 21.2° (±0.2°) as determined by powder X-ray diffraction. [E5-2] The crystal according to [E1] or [E2], wherein the crystal is a 4A type crystal having at least five peaks selected from the group consisting of diffraction angles (2θ values) of 11.5°, 11.8°, 15.7°, 17.2°, 17.5°, 18.1°, 19.5°, 20.3°, 20.5°, and 21.2° (±0.2°) as determined by powder X-ray diffraction. [E5-3] The crystal according to [E1] or [E2], wherein the crystal is a 4A type crystal having at least seven peaks selected from the group consisting of diffraction angles (2θ values) of 11.5°, 11.8°, 15.7°, 17.2°, 17.5°, 18.1°, 19.5°, 20.3°, 20.5°, and 21.2° (±0.2°) as determined by powder X-ray diffraction. [E5-4] The crystal according to [E1] or [E2], wherein the crystal is a 4A type crystal containing peaks at 11.5°, 11.8°, 15.7°, 17.2°, 17.5°, 18.1°, 19.5°, 20.3°, 20.5°, and 21.2° (±0.2°) as diffraction angles (2θ values) determined by powder X-ray diffraction. [F1] The following formulas (1) to (5) [ka] A compound represented by any of the following, or a salt thereof, or a crystal of a solvate thereof. The crystal described in [F1] is a crystal of a compound or salt thereof or a solvate thereof, as described in any of [F2], [A1] to [A13-4], [B1] to [B7-4], [C1] to [C6-4], [D1] to [D27-4], and [E1] to [E5-4]. A pharmaceutical composition comprising any of the compounds listed in [G1], [A1] to [A13-4], [B1] to [B7-4], [C1] to [C6-4], [D1] to [D27-4], [E1] to [E5-4], and [F1] to [F2], or a salt thereof, or a crystal of a solvate thereof. [G2] The pharmaceutical composition described in [G1] for the prevention and / or treatment of neurodegenerative diseases, lung diseases, or kidney diseases. [G3] A method for the prevention and / or treatment of neurodegenerative diseases, lung diseases, or kidney diseases, comprising administering an effective amount of any of the compounds listed in [A1] to [A13-4], [B1] to [B7-4], [C1] to [C6-4], [D1] to [D27-4], [E1] to [E5-4], and [F1] to [F2], or a salt thereof or a crystal of a solvate thereof, to a patient. [G4] A compound or salt thereof or a crystal of a solvate thereof, as described in any of [A1] to [A13-4], [B1] to [B7-4], [C1] to [C6-4], [D1] to [D27-4], [E1] to [E5-4], and [F1] to [F2], for use in the prevention and / or treatment of neurodegenerative diseases, lung diseases, or kidney diseases. [G5] Use of any of the compounds described in [A1] to [A13-4], [B1] to [B7-4], [C1] to [C6-4], [D1] to [D27-4], [E1] to [E5-4], and [F1] to [F2], or salts thereof or crystals of solvates thereof, for the manufacture of pharmaceutical compositions for the prevention and / or treatment of neurodegenerative diseases, lung diseases, or kidney diseases. A pharmaceutical composition obtained by mixing a compound or a salt thereof, or a crystal of a solvate thereof, described in any of [G6], [A1] to [A13-4], [B1] to [B7-4], [C1] to [C6-4], [D1] to [D27-4], [E1] to [E5-4], and [F1] to [F2] with a pharmaceutically acceptable carrier or medium. A pharmaceutical composition obtained by dissolving a compound or salt thereof, or a crystal of a solvate thereof, described in any of [G7], [A1] to [A13-4], [B1] to [B7-4], [C1] to [C6-4], [D1] to [D27-4], [E1] to [E5-4], and [F1] to [F2] in a pharmaceutically acceptable carrier or medium. [H1] The following equations (1) to (5) [ka] A method for producing a pharmaceutical composition containing a compound represented by any one of the following, a salt thereof, or a solvate thereof as an active ingredient, The manufacturing method comprising the step of mixing a compound or a salt thereof or a crystal of a solvate thereof, as described in any of [A1] to [A13-4], [B1] to [B7-4], [C1] to [C6-4], [D1] to [D27-4], and [E1] to [E5-4], with a pharmaceutically acceptable carrier or medium. [H2] The method according to [H1], wherein the crystals of the compound, its salt, or its solvate are solvate crystals of the compound. [H3] The method according to [H2], wherein the solvate crystal is a hydrate crystal. [H4] The method according to [H1], wherein the crystals of the compound, its salt, or its solvate are non-solvate crystals of the compound. [H5] The method according to any one of [H1] to [H4], wherein the step of mixing the compound or a salt thereof or crystals thereof with a pharmaceutically acceptable carrier or medium is the step of dissolving the compound or a salt thereof or crystals thereof in a pharmaceutically acceptable carrier or medium. [H6] The following equations (1) to (5) [ka] A method for producing a pharmaceutical composition containing a compound represented by any one of the following, a salt thereof, or a solvate thereof as an active ingredient, The manufacturing method comprising the step of mixing the aforementioned compound or a salt thereof or a solvate thereof with a pharmaceutically acceptable carrier or medium. The method according to [H6], wherein the compound represented by any of formulas (1) to (5), a salt thereof, or a solvate thereof is a solvate of the compound represented by any of formulas (1) to (5). [H8] The method according to [H7], wherein the solvate is a hydrate. The method according to [H6], wherein the compound represented by any of formulas (1) to (5), a salt thereof, or a solvate thereof is a non-solvate of the compound represented by any of formulas (1) to (5). [H10] The method according to any one of [H6] to [H9], wherein the step of mixing the compound or a salt thereof or a solvate thereof with a pharmaceutically acceptable carrier or medium is the step of dissolving the compound or a salt thereof or a solvate thereof in a pharmaceutically acceptable carrier or medium. In the above numbering scheme, the numbers referenced by dependent clauses include their sub-numbers unless otherwise specified. For example, [A4] referenced in a dependent clause includes [A4], as well as its sub-numbers [A4-1], [A4-2], [A4-3], and [A4-4]. The same applies to other numbering schemes. [Effects of the Invention]

[0010] The present invention provides compounds or salts thereof, or crystals of solvates thereof, that have Nrf2 activating activity and can be used as preventive or therapeutic agents for various diseases, such as neurodegenerative diseases, lung diseases, and kidney diseases. [Brief explanation of the drawing]

[0011] [Figure 1] The results of powder X-ray diffraction measurements of the crystals obtained in Example 2-1-1 are shown. The vertical axis represents diffraction intensity, and the horizontal axis represents the diffraction angle 2θ (°). [Figure 2] The results of the TG-DTA measurement of the crystals obtained in Example 2-1-1 are shown. In (A), the vertical axis is weight change and the horizontal axis is temperature. In (B), the vertical axis is heat flow and the horizontal axis is temperature. The + marks and temperatures indicated on the graph in (B) represent the melting point or other transition point. [Figure 3] The results of powder X-ray diffraction measurements of the crystals obtained in Example 2-1-3 are shown. The vertical axis represents diffraction intensity, and the horizontal axis represents the diffraction angle 2θ (°). [Figure 4] The results of TG-DTA measurements of the crystals obtained in Example 2-1-3 are shown. In (A), the vertical axis is weight change and the horizontal axis is temperature. In (B), the vertical axis is heat flow and the horizontal axis is temperature. The + marks and temperatures indicated on the graph in (B) represent the melting point or other transition point. [Figure 5] The results of powder X-ray diffraction measurements under humidity-controlled conditions obtained in Example 2-1-4 are shown. The vertical axis represents diffraction intensity, and the horizontal axis represents diffraction angle 2θ (°). The relative humidity (RH) for each pattern is shown in the figure. The broad peak around 6.4° is due to the measurement device. [Figure 6] The results of powder X-ray diffraction measurements of the crystals obtained in Example 2-1-5 are shown. The vertical axis represents diffraction intensity, and the horizontal axis represents the diffraction angle 2θ (°). [Figure 7] The crystal structure of the 1G-type crystal described in Example 2-1-6 is shown. [Figure 8] The results of powder X-ray diffraction measurements of the crystals obtained in Example 2-2-2 are shown. The vertical axis represents diffraction intensity, and the horizontal axis represents the diffraction angle 2θ (°). [Figure 9]The results of powder X-ray diffraction measurements of the crystals obtained in Example 2-2-4 are shown. The vertical axis represents diffraction intensity, and the horizontal axis represents the diffraction angle 2θ (°). [Figure 10] The results of the TG-DTA measurement of the crystals obtained in Example 2-2-4 are shown. In (A), the vertical axis is weight change and the horizontal axis is temperature. In (B), the vertical axis is heat flow and the horizontal axis is temperature. The + marks and temperatures indicated on the graph in (B) represent the melting point or other transition point. [Figure 11] The results of powder X-ray diffraction measurements of the crystals obtained in Example 2-2-5 are shown. The vertical axis represents diffraction intensity, and the horizontal axis represents the diffraction angle 2θ (°). [Figure 12] The results of the TG-DTA measurement of the crystals obtained in Example 2-2-5 are shown. In (A), the vertical axis is weight change and the horizontal axis is temperature. In (B), the vertical axis is heat flow and the horizontal axis is temperature. The + marks and temperatures indicated on the graph in (B) represent the melting point or other transition point. [Figure 13] The results of powder X-ray diffraction measurements of the crystals obtained in Example 2-2-6 are shown. The vertical axis represents diffraction intensity, and the horizontal axis represents the diffraction angle 2θ (°). [Figure 14] The results of the TG-DTA measurement of the crystals obtained in Example 2-2-6 are shown. In (A), the vertical axis is weight change and the horizontal axis is temperature. In (B), the vertical axis is heat flow and the horizontal axis is temperature. The + marks and temperatures indicated on the graph in (B) represent the melting point or other transition point. [Figure 15] The results of powder X-ray diffraction measurements of the crystals obtained in Example 2-3-1 before vacuum drying are shown. The vertical axis represents diffraction intensity, and the horizontal axis represents the diffraction angle 2θ (°). [Figure 16] The results of powder X-ray diffraction measurements of the vacuum-dried crystals obtained in Example 2-3-1 are shown. The vertical axis represents diffraction intensity, and the horizontal axis represents the diffraction angle 2θ (°). [Figure 17] The results of the TG-DTA measurement of the crystals obtained in Example 2-3-1 are shown. In (A), the vertical axis is weight change and the horizontal axis is temperature. In (B), the vertical axis is heat flow and the horizontal axis is temperature. The + marks and temperatures indicated on the graph in (B) represent the melting point or other transition point. [Figure 18]The results of powder X-ray diffraction measurements of the crystals obtained in Example 2-3-2 are shown. The vertical axis represents diffraction intensity, and the horizontal axis represents the diffraction angle 2θ (°). [Figure 19] The results of powder X-ray diffraction measurements of the crystals obtained in Example 2-3-3 are shown. The vertical axis represents diffraction intensity, and the horizontal axis represents the diffraction angle 2θ (°). [Figure 20] The results of the TG-DTA measurement of the crystals obtained in Example 2-3-3 are shown. In (A), the vertical axis is weight change and the horizontal axis is temperature. In (B), the vertical axis is heat flow and the horizontal axis is temperature. The + marks and temperatures indicated on the graph in (B) represent the melting point or other transition point. [Figure 21] The results of powder X-ray diffraction measurements of the crystals obtained in Example 2-4-1 are shown. The vertical axis represents diffraction intensity, and the horizontal axis represents the diffraction angle 2θ (°). [Figure 22] The crystal structure of the 4B type crystal described in Example 2-4-2 is shown. [Figure 23] The results of powder X-ray diffraction measurements of the crystals obtained in Example 2-4-3 are shown. The vertical axis represents diffraction intensity, and the horizontal axis represents the diffraction angle 2θ (°). [Figure 24] The results of the TG-DTA measurement of the crystals obtained in Example 2-4-3 are shown. In (A), the vertical axis is weight change and the horizontal axis is temperature. In (B), the vertical axis is heat flow and the horizontal axis is temperature. The + marks and temperatures indicated on the graph in (B) represent the melting point or other transition point. [Figure 25] The results of powder X-ray diffraction measurements of the crystals obtained in Example 2-5-2 are shown. The vertical axis represents diffraction intensity, and the horizontal axis represents the diffraction angle 2θ (°). [Figure 26] The results of the TG-DTA measurement of the crystals obtained in Example 2-5-2 are shown. In (A), the vertical axis is weight change and the horizontal axis is temperature. In (B), the vertical axis is heat flow and the horizontal axis is temperature. The + marks and temperatures indicated on the graph in (B) represent the melting point or other transition point. [Figure 27] The results of powder X-ray diffraction measurements of the crystals obtained in Example 2-5-3 before vacuum drying are shown. The vertical axis represents diffraction intensity, and the horizontal axis represents the diffraction angle 2θ (°). [Figure 28]The results of TG-DTA measurements of the crystals obtained in Example 2-5-3 before vacuum drying are shown. In (A), the vertical axis is weight change and the horizontal axis is temperature. In (B), the vertical axis is heat flow and the horizontal axis is temperature. The + marks and temperatures indicated on the graph in (B) represent the melting point or other transition point. [Figure 29] The results of powder X-ray diffraction measurements of the vacuum-dried crystals obtained in Example 2-5-3 are shown. The vertical axis represents diffraction intensity, and the horizontal axis represents the diffraction angle 2θ (°). [Figure 30] The results of powder X-ray diffraction measurements under each humidity condition obtained in Example 2-5-4 are shown. The vertical axis represents diffraction intensity, and the horizontal axis represents the diffraction angle 2θ (°). The relative humidity (RH) for each pattern is shown in the figure. [Figure 31] The results of powder X-ray diffraction measurements (first and second measurements) under a relative humidity (RH) of 60% obtained in Example 2-5-4 are shown. The vertical axis represents diffraction intensity, and the horizontal axis represents the diffraction angle 2θ (°). The RH and measurement timing for each pattern are shown in the figure. The broad peak around 6.4° is due to the measurement device. [Figure 32] The results of powder X-ray diffraction measurements of the crystals obtained in Example 2-5-5 are shown. The vertical axis represents diffraction intensity, and the horizontal axis represents the diffraction angle 2θ (°). [Figure 33] The results of powder X-ray diffraction measurements of the crystals obtained in Example 2-5-6 are shown. The vertical axis represents diffraction intensity, and the horizontal axis represents the diffraction angle 2θ (°). [Figure 34] The crystal structure of the 5A type crystal described in Example 2-5-6 is shown. [Figure 35] The results of powder X-ray diffraction measurements under 5% relative humidity conditions obtained in Example 2-5-8 are shown. The vertical axis represents diffraction intensity, and the horizontal axis represents the diffraction angle 2θ (°). The broad peak around 6.4° is due to the measurement device. [Figure 36] The results of representative powder X-ray diffraction measurements under each humidity condition obtained in Example 2-5-9 are shown. The vertical axis represents diffraction intensity, and the horizontal axis represents the diffraction angle 2θ (°). The relative humidity (RH) for each pattern is shown in the figure. The broad peak around 6.4° is due to the measurement device. [Modes for carrying out the invention]

[0012] The present invention will be described in detail below, including definitions of symbols, terms, etc. used herein, and embodiments of the present invention.

[0013] In one embodiment, the present invention relates to crystals of compounds represented by formulas (1) to (5), salts thereof, or solvates thereof. Specifically, examples of crystals of this compound include non-solvate crystals or solvate crystals of this compound, or non-solvate crystals or solvate crystals of salts thereof. Specifically, examples of solvate crystals include hydrate crystals, acetone hydrate crystals, dimethyl sulfoxide (DMSO) hydrate crystals, dimethylformamide (DMF) hydrate crystals, acetonitrile hydrate crystals, tetrahydrofuran hydrate crystals, methyl ethyl ketone hydrate crystals, methyl isobutyl ketone hydrate crystals, ethyl acetate hydrate crystals, heptane hydrate crystals, polyethylene glycol (PEG) hydrate crystals, 2-propanol hydrate crystals, methanol hydrate crystals, or ethanol hydrate crystals, with hydrate crystals being preferred.

[0014] The compounds described herein may be salts thereof or solvates thereof. Furthermore, in this specification, "compound or salt thereof or solvate thereof" includes compounds, salts of compounds, solvates of compounds, and solvates of salts of compounds. Salts of compounds include, for example, hydrochlorides; hydrobroms; hydroiodides; phosphates; phosphonates; sulfates; sulfonates such as methanesulfonates and p-toluenesulfonates; carboxylates such as acetates, citrates, malates, tartrates, succinates, and salicylates; or alkali metal salts such as sodium salts and potassium salts; alkaline earth metal salts such as magnesium salts and calcium salts; and ammonium salts such as ammonium salts, alkylammonium salts, dialkylammonium salts, trialkylammonium salts, and tetraalkylammonium salts. These salts are produced, for example, by contacting a compound with an acid or a base. In this specification, a solvate refers to a compound that, together with a solvent, forms a molecular group, and is not particularly limited as long as it is a solvate formed with a solvent that is permissible to ingest in conjunction with the administration of a drug. Examples include not only solvates with a single solvent such as hydrates, alcoholic dihydrates (ethanolic dihydrate, methanolic dihydrate, 1-propanolic dihydrate, 2-propanolic dihydrate, etc.), and dimethyl sulfoxide, but also compounds in which one molecule of a compound forms solvates with multiple solvents, or compounds in which one molecule of a compound forms solvates with multiple types of solvents. If the solvent is water, it is called a hydrate. Hydrates are preferred as solvates of the compounds of the present invention, and specifically, examples of such hydrates include 1-10 hydrates, preferably 1-5 hydrates, and more preferably 1-3 hydrates.

[0015] In powder X-ray diffraction, the diffraction angle 2θ is the diffraction peak measured using CuKα or CuKα1 radiation. Crystals of these solvates that are further identified by the diffraction angle 2θ in powder X-ray diffraction are sometimes called "Type 1A crystals" of the hydrates shown below, for example, but are also sometimes simply called "Type 1A".

[0016] In the notation of diffraction angles 2θ, if "(±0.2°)" is written at the end of the listed diffraction angles 2θ, it means that a range of ±0.2° is acceptable for each listed diffraction angle 2θ.

[0017] In one embodiment, the hydrate crystal of the compound of formula (1) is a type 1A crystal that, in powder X-ray diffraction, contains at least one of the following peaks at a diffraction angle of 2θ. 6.0°, 9.3°, 9.7°, 10.4°, 11.9°, 12.9°, 15.3°, 15.9°, 16.4°, and 16.8° (±0.2°)

[0018] In one embodiment, the hydrate crystal of the compound of formula (1) is a type 1A crystal that, in powder X-ray diffraction, contains at least three of the following peaks at a diffraction angle of 2θ. 6.0°, 9.3°, 9.7°, 10.4°, 11.9°, 12.9°, 15.3°, 15.9°, 16.4°, and 16.8° (±0.2°)

[0019] In one embodiment, the hydrate crystal of the compound of formula (1) is a type 1A crystal that, in powder X-ray diffraction, contains at least five of the following peaks at a diffraction angle of 2θ. 6.0°, 9.3°, 9.7°, 10.4°, 11.9°, 12.9°, 15.3°, 15.9°, 16.4°, and 16.8° (±0.2°)

[0020] In one embodiment, the hydrate crystal of the compound of formula (1) is a type 1A crystal that, in powder X-ray diffraction, contains at least seven of the following peaks at a diffraction angle of 2θ. 6.0°, 9.3°, 9.7°, 10.4°, 11.9°, 12.9°, 15.3°, 15.9°, 16.4°, and 16.8° (±0.2°).

[0021] In one embodiment, the hydrate crystal of the compound of formula (1) is a type 1A crystal that, in powder X-ray diffraction, contains the following peak at a diffraction angle of 2θ. 6.0°, 9.3°, 9.7°, 10.4°, 11.9°, 12.9°, 15.3°, 15.9°, 16.4°, and 16.8° (±0.2°)

[0022] In one embodiment, the hydrate crystal of the compound of formula (1) is a 1G type crystal that, in powder X-ray diffraction, contains at least one of the following peaks at a diffraction angle of 2θ. 8.8°, 9.2°, 10.4°, 12.7°, 13.4°, 15.8°, 16.9°, 17.3°, 18.3°, and 18.9° (±0.2°)

[0023] In one embodiment, the hydrate crystal of the compound of formula (1) is a 1G type crystal that, in powder X-ray diffraction, contains at least three of the following peaks at a diffraction angle of 2θ. 8.8°, 9.2°, 10.4°, 12.7°, 13.4°, 15.8°, 16.9°, 17.3°, 18.3°, and 18.9° (±0.2°)

[0024] In one embodiment, the hydrate crystal of the compound of formula (1) is a 1G type crystal that, in powder X-ray diffraction, contains at least five of the following peaks at a diffraction angle of 2θ. 8.8°, 9.2°, 10.4°, 12.7°, 13.4°, 15.8°, 16.9°, 17.3°, 18.3°, and 18.9° (±0.2°)

[0025] In one embodiment, the hydrate crystal of the compound of formula (1) is a 1G type crystal that, in powder X-ray diffraction, contains at least seven of the following peaks at a diffraction angle of 2θ. 8.8°, 9.2°, 10.4°, 12.7°, 13.4°, 15.8°, 16.9°, 17.3°, 18.3°, and 18.9° (±0.2°)

[0026] In one embodiment, the hydrate crystal of the compound of formula (1) is a 1G type crystal that, in powder X-ray diffraction, contains the following peak at a diffraction angle of 2θ. 8.8°, 9.2°, 10.4°, 12.7°, 13.4°, 15.8°, 16.9°, 17.3°, 18.3°, and 18.9° (±0.2°)

[0027] In one embodiment, the hydrate crystal of the compound of formula (1) is a 1G type crystal that, in powder X-ray diffraction, contains at least one of the following peaks at a diffraction angle of 2θ. The diffraction angles (2θ values) below are preferably those of the hydrate crystal stored at a temperature of 34°C and 60% relative humidity for 5 minutes. 8.9°, 9.3°, 10.5°, 12.8°, 13.5°, 15.9°, 17.0°, 17.4°, 18.4°, and 19.0° (±0.2°)

[0028] In one embodiment, the hydrate crystal of the compound of formula (1) is a 1G type crystal that, in powder X-ray diffraction, contains at least three of the following peaks at a diffraction angle of 2θ. The diffraction angles (2θ values) below are preferably those of the hydrate crystal stored at a temperature of 34°C and 60% relative humidity for 5 minutes. 8.9°, 9.3°, 10.5°, 12.8°, 13.5°, 15.9°, 17.0°, 17.4°, 18.4°, and 19.0° (±0.2°)

[0029] In one embodiment, the hydrate crystal of the compound of formula (1) is a 1G type crystal that, in powder X-ray diffraction, contains at least five of the following peaks at a diffraction angle of 2θ. The diffraction angles (2θ values) below are preferably those of the hydrate crystal stored at a temperature of 34°C and 60% relative humidity for 5 minutes. 8.9°, 9.3°, 10.5°, 12.8°, 13.5°, 15.9°, 17.0°, 17.4°, 18.4°, and 19.0° (±0.2°)

[0030] In one embodiment, the hydrate crystal of the compound of formula (1) is a 1G type crystal that, in powder X-ray diffraction, contains at least seven of the following peaks at a diffraction angle of 2θ. The diffraction angles (2θ values) below are preferably those of the hydrate crystal stored at a temperature of 34°C and 60% relative humidity for 5 minutes. 8.9°, 9.3°, 10.5°, 12.8°, 13.5°, 15.9°, 17.0°, 17.4°, 18.4°, and 19.0° (±0.2°)

[0031] In one embodiment, the hydrate crystal of the compound of formula (1) is a 1G type crystal that includes the following peak at a diffraction angle of 2θ in powder X-ray diffraction. The diffraction angle (2θ value) below is preferably the diffraction angle (2θ value) of the hydrate crystal stored at a temperature of 34°C and 60% relative humidity for 5 minutes. 8.9°, 9.3°, 10.5°, 12.8°, 13.5°, 15.9°, 17.0°, 17.4°, 18.4°, and 19.0° (±0.2°)

[0032] In one embodiment, the hydrate crystal of the compound of formula (1) is a 1J type crystal that, in powder X-ray diffraction, contains at least one of the following peaks at a diffraction angle of 2θ. Note that the diffraction angle (2θ value) below may be the diffraction angle (2θ value) of the hydrate crystal stored at a temperature of 34°C and 30% relative humidity for 15 minutes. 9.7°, 10.5°, 13.1°, 15.0°, 16.2°, 16.6°, 17.6°, 18.9°, 19.3°, and 20.8° (±0.2°)

[0033] In one embodiment, the hydrate crystal of the compound of formula (1) is a 1J type crystal that, in powder X-ray diffraction, contains at least three of the following peaks at a diffraction angle of 2θ. Note that the diffraction angles (2θ values) below may be those of the hydrate crystal stored at a temperature of 34°C and 30% relative humidity for 15 minutes. 9.7°, 10.5°, 13.1°, 15.0°, 16.2°, 16.6°, 17.6°, 18.9°, 19.3°, and 20.8° (±0.2°)

[0034] In one embodiment, the hydrate crystal of the compound of formula (1) is a 1J type crystal that, in powder X-ray diffraction, contains at least five of the following peaks at a diffraction angle of 2θ. Note that the diffraction angles (2θ values) below may be those of the hydrate crystal stored at a temperature of 34°C and 30% relative humidity for 15 minutes. 9.7°, 10.5°, 13.1°, 15.0°, 16.2°, 16.6°, 17.6°, 18.9°, 19.3°, and 20.8° (±0.2°)

[0035] In one embodiment, the hydrate crystal of the compound of formula (1) is a 1J type crystal that, in powder X-ray diffraction, contains at least seven of the following peaks at a diffraction angle of 2θ. Note that the diffraction angles (2θ values) below may be those of the hydrate crystal stored at a temperature of 34°C and 30% relative humidity for 15 minutes. 9.7°, 10.5°, 13.1°, 15.0°, 16.2°, 16.6°, 17.6°, 18.9°, 19.3°, and 20.8° (±0.2°)

[0036] In one embodiment, the hydrate crystal of the compound of formula (1) is a 1J type crystal that contains the following peak at a diffraction angle of 2θ in powder X-ray diffraction. Note that the diffraction angle (2θ value) below may be the diffraction angle (2θ value) of the hydrate crystal stored at a temperature of 34°C and 30% relative humidity for 15 minutes. 9.7°, 10.5°, 13.1°, 15.0°, 16.2°, 16.6°, 17.6°, 18.9°, 19.3°, and 20.8° (±0.2°)

[0037] In one embodiment, the nonsolvate crystal of the compound of formula (1) is a 1H-type crystal that, in powder X-ray diffraction, contains at least one of the following peaks at a diffraction angle of 2θ. Note that the diffraction angle (2θ value) below may be the diffraction angle (2θ value) of the nonsolvate crystal stored at a temperature of 34°C and 0% relative humidity for 60 minutes. 12.3°, 15.1°, 15.9°, 16.2°, 16.5°, 16.9°, 17.5°, 17.8°, 18.5°, and 19.7° (±0.2°)

[0038] In one embodiment, the nonsolvate crystal of the compound of formula (1) is a 1H-type crystal that, in powder X-ray diffraction, contains at least three of the following peaks at a diffraction angle of 2θ. Note that the diffraction angles (2θ values) below may be those of the nonsolvate crystal stored at 34°C and 0% relative humidity for 60 minutes. 12.3°, 15.1°, 15.9°, 16.2°, 16.5°, 16.9°, 17.5°, 17.8°, 18.5°, and 19.7° (±0.2°)

[0039] In one embodiment, the nonsolvate crystal of the compound of formula (1) is a 1H-type crystal that, in powder X-ray diffraction, contains at least five of the following peaks at a diffraction angle of 2θ. Note that the diffraction angles (2θ values) below may be those of the nonsolvate crystal stored at 34°C and 0% relative humidity for 60 minutes. 12.3°, 15.1°, 15.9°, 16.2°, 16.5°, 16.9°, 17.5°, 17.8°, 18.5°, and 19.7° (±0.2°)

[0040] In one embodiment, the nonsolvate crystal of the compound of formula (1) is a 1H-type crystal that, in powder X-ray diffraction, contains at least seven of the following peaks at a diffraction angle of 2θ. Note that the diffraction angles (2θ values) below may be those of the nonsolvate crystal stored at 34°C and 0% relative humidity for 60 minutes. 12.3°, 15.1°, 15.9°, 16.2°, 16.5°, 16.9°, 17.5°, 17.8°, 18.5°, and 19.7° (±0.2°)

[0041] In one embodiment, the nonsolvate crystal of the compound of formula (1) is a 1H-type crystal that includes the following peak at a diffraction angle of 2θ in powder X-ray diffraction. Note that the diffraction angle (2θ value) below may be the diffraction angle (2θ value) of the nonsolvate crystal stored at a temperature of 34°C and 0% relative humidity for 60 minutes. 12.3°, 15.1°, 15.9°, 16.2°, 16.5°, 16.9°, 17.5°, 17.8°, 18.5°, and 19.7° (±0.2°)

[0042] In one embodiment, the crystal of the compound of formula (1) is a 1K type crystal that, in powder X-ray diffraction, contains at least one of the following peaks at a diffraction angle of 2θ. 9.5°, 11.3°, 16.3°, 16.6°, 17.6°, 18.4°, 19.1°, 19.9°, 21.0°, and 21.9° (±0.2°)

[0043] In one embodiment, the crystal of the compound of formula (1) is a 1K type crystal that, in powder X-ray diffraction, contains at least three of the following peaks at a diffraction angle of 2θ. 9.5°, 11.3°, 16.3°, 16.6°, 17.6°, 18.4°, 19.1°, 19.9°, 21.0°, and 21.9° (±0.2°)

[0044] In one embodiment, the crystal of the compound of formula (1) is a 1K type crystal that, in powder X-ray diffraction, contains at least five of the following peaks at a diffraction angle of 2θ. 9.5°, 11.3°, 16.3°, 16.6°, 17.6°, 18.4°, 19.1°, 19.9°, 21.0°, and 21.9° (±0.2°)

[0045] In one embodiment, the crystal of the compound of formula (1) is a 1K type crystal that, in powder X-ray diffraction, contains at least seven of the following peaks at a diffraction angle of 2θ. 9.5°, 11.3°, 16.3°, 16.6°, 17.6°, 18.4°, 19.1°, 19.9°, 21.0°, and 21.9° (±0.2°)

[0046] In one embodiment, the crystal of the compound of formula (1) is a 1K type crystal that, in powder X-ray diffraction, contains the following peak at a diffraction angle of 2θ. 9.5°, 11.3°, 16.3°, 16.6°, 17.6°, 18.4°, 19.1°, 19.9°, 21.0°, and 21.9° (±0.2°)

[0047] In one embodiment, the nonsolvate crystal of the compound of formula (2) is a 3A type crystal that, in powder X-ray diffraction, contains at least one of the following peaks at a diffraction angle of 2θ. 10.4°, 12.6°, 15.1°, 15.9°, 16.6°, 17.1°, 18.4°, 19.6°, 19.9°, and 20.6° (±0.2°)

[0048] In one embodiment, the nonsolvate crystal of the compound of formula (2) is a 3A type crystal that, in powder X-ray diffraction, contains at least three of the following peaks at a diffraction angle of 2θ. 10.4°, 12.6°, 15.1°, 15.9°, 16.6°, 17.1°, 18.4°, 19.6°, 19.9°, and 20.6° (±0.2°)

[0049] In one embodiment, the nonsolvate crystal of the compound of formula (2) is a 3A type crystal that, in powder X-ray diffraction, contains at least five of the following peaks at a diffraction angle of 2θ. 10.4°, 12.6°, 15.1°, 15.9°, 16.6°, 17.1°, 18.4°, 19.6°, 19.9°, and 20.6° (±0.2°)

[0050] In one embodiment, the nonsolvated crystal of the compound of formula (2) is a 3A type crystal that, in powder X-ray diffraction, contains at least seven of the following peaks at a diffraction angle of 2θ. 10.4°, 12.6°, 15.1°, 15.9°, 16.6°, 17.1°, 18.4°, 19.6°, 19.9°, and 20.6° (±0.2°)

[0051] In one embodiment, the nonsolvated crystal of the compound of formula (2) is a 3A type crystal that, in powder X-ray diffraction, contains the following peak at a diffraction angle of 2θ. 10.4°, 12.6°, 15.1°, 15.9°, 16.6°, 17.1°, 18.4°, 19.6°, 19.9°, and 20.6° (±0.2°)

[0052] In one embodiment, the nonsolvate crystal of the compound of formula (2) is a 3C-type crystal that, in powder X-ray diffraction, contains at least one of the following peaks at a diffraction angle of 2θ. 7.9°, 8.5°, 8.8°, 9.2°, 10.4°, 11.4°, 12.0°, 13.1°, 15.2°, and 15.7° (±0.2°)

[0053] In one embodiment, the nonsolvated crystal of the compound of formula (2) is a 3C-type crystal that, in powder X-ray diffraction, contains at least three of the following peaks at a diffraction angle of 2θ. 7.9°, 8.5°, 8.8°, 9.2°, 10.4°, 11.4°, 12.0°, 13.1°, 15.2°, and 15.7° (±0.2°)

[0054] In one embodiment, the nonsolvated crystal of the compound of formula (2) is a 3C-type crystal that, in powder X-ray diffraction, contains at least five of the following peaks at a diffraction angle of 2θ. 7.9°, 8.5°, 8.8°, 9.2°, 10.4°, 11.4°, 12.0°, 13.1°, 15.2°, and 15.7° (±0.2°)

[0055] In one embodiment, the nonsolvated crystal of the compound of formula (2) is a 3C-type crystal that, in powder X-ray diffraction, contains at least seven of the following peaks at a diffraction angle of 2θ. 7.9°, 8.5°, 8.8°, 9.2°, 10.4°, 11.4°, 12.0°, 13.1°, 15.2°, and 15.7° (±0.2°)

[0056] In one embodiment, the nonsolvated crystal of the compound of formula (2) is a 3C-type crystal that, in powder X-ray diffraction, has the following peak at a diffraction angle of 2θ. 7.9°, 8.5°, 8.8°, 9.2°, 10.4°, 11.4°, 12.0°, 13.1°, 15.2°, and 15.7° (±0.2°)

[0057] In one embodiment, the crystal of the compound of formula (2) is a 3D type crystal that, in powder X-ray diffraction, contains at least one of the following peaks with diffraction angle 2θ. 6.6°, 7.3°, 10.9°, 11.8°, 13.9°, 17.1°, 17.5°, 18.3°, 19.3°, and 22.0° (±0.2°)

[0058] In one embodiment, the crystal of the compound of formula (2) is a 3D type crystal that, in powder X-ray diffraction, has at least three of the following peaks at a diffraction angle of 2θ. 6.6°, 7.3°, 10.9°, 11.8°, 13.9°, 17.1°, 17.5°, 18.3°, 19.3°, and 22.0° (±0.2°)

[0059] In one embodiment, the crystal of the compound of formula (2) is a 3D type crystal that, in powder X-ray diffraction, has at least five of the following peaks at a diffraction angle of 2θ. 6.6°, 7.3°, 10.9°, 11.8°, 13.9°, 17.1°, 17.5°, 18.3°, 19.3°, and 22.0° (±0.2°)

[0060] In one embodiment, the crystal of the compound of formula (2) is a 3D crystal that, in powder X-ray diffraction, has at least seven of the following peaks at a diffraction angle of 2θ. 6.6°, 7.3°, 10.9°, 11.8°, 13.9°, 17.1°, 17.5°, 18.3°, 19.3°, and 22.0° (±0.2°)

[0061] In one embodiment, the crystal of the compound of formula (2) is a 3D type crystal that includes the following peak at a diffraction angle of 2θ in powder X-ray diffraction. 6.6°, 7.3°, 10.9°, 11.8°, 13.9°, 17.1°, 17.5°, 18.3°, 19.3°, and 22.0° (±0.2°)

[0062] In one embodiment, the crystal of the compound of formula (2) is a 3B type crystal that, in powder X-ray diffraction, contains at least one of the following peaks at a diffraction angle of 2θ. 7.4°, 14.0°, 14.6°, 15.5°, 17.1°, 18.1°, 19.8°, 21.8°, 22.4°, and 24.1° (±0.2°)

[0063] In one embodiment, the crystal of the compound of formula (2) is a 3B type crystal that, in powder X-ray diffraction, has at least three of the following peaks at a diffraction angle of 2θ. 7.4°, 14.0°, 14.6°, 15.5°, 17.1°, 18.1°, 19.8°, 21.8°, 22.4°, and 24.1° (±0.2°)

[0064] In one embodiment, the crystal of the compound of formula (2) is a 3B type crystal that, in powder X-ray diffraction, has at least five of the following peaks at a diffraction angle of 2θ. 7.4°, 14.0°, 14.6°, 15.5°, 17.1°, 18.1°, 19.8°, 21.8°, 22.4°, and 24.1° (±0.2°)

[0065] In one embodiment, the crystal of the compound of formula (2) is a 3B type crystal that, in powder X-ray diffraction, has at least seven of the following peaks at a diffraction angle of 2θ. 7.4°, 14.0°, 14.6°, 15.5°, 17.1°, 18.1°, 19.8°, 21.8°, 22.4°, and 24.1° (±0.2°)

[0066] In one embodiment, the crystal of the compound of formula (2) is a 3B type crystal that, in powder X-ray diffraction, has the following peak at a diffraction angle of 2θ. 7.4°, 14.0°, 14.6°, 15.5°, 17.1°, 18.1°, 19.8°, 21.8°, 22.4°, and 24.1° (±0.2°)

[0067] In one embodiment, the nonsolvate crystal of the compound of formula (3) is a 2B type crystal that, in powder X-ray diffraction, contains at least one of the following peaks at a diffraction angle of 2θ. 7.2°, 7.6°, 13.4°, 14.5°, 16.0°, 16.6°, 17.3°, 19.9°, 20.6°, and 22.4° (±0.2°)

[0068] In one embodiment, the nonsolvate crystal of the compound of formula (3) is a 2B type crystal that, in powder X-ray diffraction, contains at least three of the following peaks at a diffraction angle of 2θ. 7.2°, 7.6°, 13.4°, 14.5°, 16.0°, 16.6°, 17.3°, 19.9°, 20.6°, and 22.4° (±0.2°)

[0069] In one embodiment, the nonsolvated crystal of the compound of formula (3) is a 2B type crystal that, in powder X-ray diffraction, contains at least five of the following peaks at a diffraction angle of 2θ. 7.2°, 7.6°, 13.4°, 14.5°, 16.0°, 16.6°, 17.3°, 19.9°, 20.6°, and 22.4° (±0.2°)

[0070] In one embodiment, the nonsolvated crystal of the compound of formula (3) is a 2B-type crystal that, in powder X-ray diffraction, contains at least seven of the following peaks at a diffraction angle of 2θ. 7.2°, 7.6°, 13.4°, 14.5°, 16.0°, 16.6°, 17.3°, 19.9°, 20.6°, and 22.4° (±0.2°)

[0071] In one embodiment, the nonsolvated crystal of the compound of formula (3) is a 2B type crystal that, in powder X-ray diffraction, contains the following peak at a diffraction angle of 2θ. 7.2°, 7.6°, 13.4°, 14.5°, 16.0°, 16.6°, 17.3°, 19.9°, 20.6°, and 22.4° (±0.2°)

[0072] In one embodiment, the nonsolvate crystal of the compound of formula (3) is a 2A type crystal that, in powder X-ray diffraction, contains at least one of the following peaks at a diffraction angle of 2θ. 7.5°, 10.0°, 10.7°, 13.7°, 14.6°, 15.1°, 16.8°, 17.4°, 18.0°, and 18.5° (±0.2°)

[0073] In one embodiment, the nonsolvated crystal of the compound of formula (3) is a 2A type crystal that, in powder X-ray diffraction, contains at least three of the following peaks at a diffraction angle of 2θ. 7.5°, 10.0°, 10.7°, 13.7°, 14.6°, 15.1°, 16.8°, 17.4°, 18.0°, and 18.5° (±0.2°)

[0074] In one embodiment, the nonsolvate crystal of the compound of formula (3) is a 2A type crystal that, in powder X-ray diffraction, contains at least five of the following peaks at a diffraction angle of 2θ. 7.5°, 10.0°, 10.7°, 13.7°, 14.6°, 15.1°, 16.8°, 17.4°, 18.0°, and 18.5° (±0.2°)

[0075] In one embodiment, the nonsolvated crystal of the compound of formula (3) is a 2A type crystal that, in powder X-ray diffraction, contains at least seven of the following peaks at a diffraction angle of 2θ. 7.5°, 10.0°, 10.7°, 13.7°, 14.6°, 15.1°, 16.8°, 17.4°, 18.0°, and 18.5° (±0.2°)

[0076] In one embodiment, the nonsolvated crystal of the compound of formula (3) is a 2A type crystal that, in powder X-ray diffraction, contains the following peak at a diffraction angle of 2θ. 7.5°, 10.0°, 10.7°, 13.7°, 14.6°, 15.1°, 16.8°, 17.4°, 18.0°, and 18.5° (±0.2°)

[0077] In one embodiment, the nonsolvated crystal of the compound of formula (3) is a 2C-type crystal that, in powder X-ray diffraction, contains at least one of the following peaks at a diffraction angle of 2θ. 7.2°, 9.9°, 14.5°, 15.3°, 15.7°, 17.2°, 17.6°, 18.0°, 19.1°, and 19.8° (±0.2°)

[0078] In one embodiment, the nonsolvated crystal of the compound of formula (3) is a 2C-type crystal that, in powder X-ray diffraction, contains at least three of the following peaks at a diffraction angle of 2θ. 7.2°, 9.9°, 14.5°, 15.3°, 15.7°, 17.2°, 17.6°, 18.0°, 19.1°, and 19.8° (±0.2°)

[0079] In one embodiment, the nonsolvated crystal of the compound of formula (3) is a 2C-type crystal that, in powder X-ray diffraction, contains at least five of the following peaks at a diffraction angle of 2θ. 7.2°, 9.9°, 14.5°, 15.3°, 15.7°, 17.2°, 17.6°, 18.0°, 19.1°, and 19.8° (±0.2°)

[0080] In one embodiment, the nonsolvated crystal of the compound of formula (3) is a 2C-type crystal that, in powder X-ray diffraction, contains at least seven of the following peaks at a diffraction angle of 2θ. 7.2°, 9.9°, 14.5°, 15.3°, 15.7°, 17.2°, 17.6°, 18.0°, 19.1°, and 19.8° (±0.2°)

[0081] In one embodiment, the nonsolvated crystal of the compound of formula (3) is a 2C-type crystal that, in powder X-ray diffraction, contains the following peak at a diffraction angle of 2θ. 7.2°, 9.9°, 14.5°, 15.3°, 15.7°, 17.2°, 17.6°, 18.0°, 19.1°, and 19.8° (±0.2°)

[0082] In one embodiment, the nonsolvated crystal of the compound of formula (3) is a 2F-type crystal that, in powder X-ray diffraction, contains at least one of the following peaks at a diffraction angle of 2θ. 7.3°, 9.9°, 11.4°, 14.5°, 15.3°, 16.4°, 16.8°, 17.2°, 17.7°, and 18.1° (±0.2°)

[0083] In one embodiment, the nonsolvated crystal of the compound of formula (3) is a 2F-type crystal that, in powder X-ray diffraction, has at least three of the following peaks at a diffraction angle of 2θ. 7.3°, 9.9°, 11.4°, 14.5°, 15.3°, 16.4°, 16.8°, 17.2°, 17.7°, and 18.1° (±0.2°)

[0084] In one embodiment, the nonsolvate crystal of the compound of formula (3) is a 2F type crystal that, in powder X-ray diffraction, has at least five of the following peaks at a diffraction angle of 2θ. 7.3°, 9.9°, 11.4°, 14.5°, 15.3°, 16.4°, 16.8°, 17.2°, 17.7°, and 18.1° (±0.2°)

[0085] In one embodiment, the nonsolvated crystal of the compound of formula (3) is a 2F-type crystal that, in powder X-ray diffraction, contains at least seven of the following peaks at a diffraction angle of 2θ. 7.3°, 9.9°, 11.4°, 14.5°, 15.3°, 16.4°, 16.8°, 17.2°, 17.7°, and 18.1° (±0.2°)

[0086] In one embodiment, the nonsolvated crystal of the compound of formula (3) is a 2F-type crystal that, in powder X-ray diffraction, has the following peak at a diffraction angle of 2θ. 7.3°, 9.9°, 11.4°, 14.5°, 15.3°, 16.4°, 16.8°, 17.2°, 17.7°, and 18.1° (±0.2°)

[0087] In one embodiment, the hydrate crystal of the compound of formula (4) is a 5A type crystal that, in powder X-ray diffraction, contains at least one of the following peaks at a diffraction angle of 2θ. 7.4°, 8.8°, 9.5°, 10.4°, 12.2°, 15.5°, 16.6°, 17.1°, 17.5°, and 18.1° (±0.2°)

[0088] In one embodiment, the hydrate crystal of the compound of formula (4) is a 5A type crystal that, in powder X-ray diffraction, has at least three of the following peaks at a diffraction angle of 2θ. 7.4°, 8.8°, 9.5°, 10.4°, 12.2°, 15.5°, 16.6°, 17.1°, 17.5°, and 18.1° (±0.2°)

[0089] In one embodiment, the hydrate crystal of the compound of formula (4) is a 5A type crystal that, in powder X-ray diffraction, contains at least five of the following peaks at a diffraction angle of 2θ. 7.4°, 8.8°, 9.5°, 10.4°, 12.2°, 15.5°, 16.6°, 17.1°, 17.5°, and 18.1° (±0.2°)

[0090] In one embodiment, the hydrate crystal of the compound of formula (4) is a 5A type crystal that, in powder X-ray diffraction, contains at least seven of the following peaks at a diffraction angle of 2θ. 7.4°, 8.8°, 9.5°, 10.4°, 12.2°, 15.5°, 16.6°, 17.1°, 17.5°, and 18.1° (±0.2°)

[0091] In one embodiment, the hydrate crystal of the compound of formula (4) is a 5A type crystal that, in powder X-ray diffraction, contains the following peak at a diffraction angle of 2θ. 7.4°, 8.8°, 9.5°, 10.4°, 12.2°, 15.5°, 16.6°, 17.1°, 17.5°, and 18.1° (±0.2°)

[0092] In one embodiment, the hydrate crystal of the compound of formula (4) is a 5A type crystal that, in powder X-ray diffraction, contains the following peak at a diffraction angle of 2θ. 7.4°, 8.8°, and 9.5° (±0.2°)

[0093] In one embodiment, the hydrate crystal of the compound of formula (4) is a 5A type crystal that, in powder X-ray diffraction, contains at least one of the following peaks at a diffraction angle of 2θ. Note that the diffraction angle (2θ value) below may be the diffraction angle (2θ value) of the hydrate crystal stored at a temperature of 25°C and 10% relative humidity for 1 hour. 7.4°, 8.8°, 9.5°, 10.8°, 12.7°, 16.0°, 16.8°, 17.3°, 17.9°, and 19.2° (±0.2°)

[0094] In one embodiment, the hydrate crystal of the compound of formula (4) is a 5A type crystal that, in powder X-ray diffraction, contains at least three of the following peaks at a diffraction angle of 2θ. Note that the diffraction angles (2θ values) below may be those of the hydrate crystal stored for 1 hour at a temperature of 25°C and 10% relative humidity. 7.4°, 8.8°, 9.5°, 10.8°, 12.7°, 16.0°, 16.8°, 17.3°, 17.9°, and 19.2° (±0.2°)

[0095] In one embodiment, the hydrate crystal of the compound of formula (4) is a 5A type crystal that, in powder X-ray diffraction, contains at least five of the following peaks at a diffraction angle of 2θ. Note that the diffraction angles (2θ values) below may be those of the hydrate crystal stored for 1 hour at a temperature of 25°C and 10% relative humidity. 7.4°, 8.8°, 9.5°, 10.8°, 12.7°, 16.0°, 16.8°, 17.3°, 17.9°, and 19.2° (±0.2°)

[0096] In one embodiment, the hydrate crystal of the compound of formula (4) is a 5A type crystal that, in powder X-ray diffraction, contains at least seven of the following peaks at a diffraction angle of 2θ. Note that the diffraction angles (2θ values) below may be those of the hydrate crystal stored for 1 hour at a temperature of 25°C and 10% relative humidity. 7.4°, 8.8°, 9.5°, 10.8°, 12.7°, 16.0°, 16.8°, 17.3°, 17.9°, and 19.2° (±0.2°)

[0097] In one embodiment, the hydrate crystal of the compound of formula (4) is a 5A type crystal that includes the following peak at a diffraction angle of 2θ in powder X-ray diffraction. Note that the diffraction angle (2θ value) below may be the diffraction angle (2θ value) of the hydrate crystal stored at a temperature of 25°C and 10% relative humidity for 1 hour. 7.4°, 8.8°, 9.5°, 10.8°, 12.7°, 16.0°, 16.8°, 17.3°, 17.9°, and 19.2° (±0.2°)

[0098] In one embodiment, the hydrate crystal of the compound of formula (4) is a 5A type crystal that, in powder X-ray diffraction, contains at least one of the following peaks at a diffraction angle of 2θ. Note that the diffraction angle (2θ value) below may be the diffraction angle (2θ value) of the hydrate crystal stored for 1 hour at a temperature of 25°C and 20% relative humidity. 7.4°, 8.8°, 9.5°, 10.5°, 12.2°, 15.6°, 16.6°, 17.1°, 17.3°, and 17.5° (±0.2°)

[0099] In one embodiment, the hydrate crystal of the compound of formula (4) is a 5A type crystal that, in powder X-ray diffraction, contains at least three of the following peaks at a diffraction angle of 2θ. Note that the diffraction angles (2θ values) below may be those of the hydrate crystal stored for 1 hour at a temperature of 25°C and 20% relative humidity. 7.4°, 8.8°, 9.5°, 10.5°, 12.2°, 15.6°, 16.6°, 17.1°, 17.3°, and 17.5° (±0.2°)

[0100] In one embodiment, the hydrate crystal of the compound of formula (4) is a 5A type crystal that, in powder X-ray diffraction, contains at least five of the following peaks at a diffraction angle of 2θ. Note that the diffraction angles (2θ values) below may be those of the hydrate crystal stored for 1 hour at a temperature of 25°C and 20% relative humidity. 7.4°, 8.8°, 9.5°, 10.5°, 12.2°, 15.6°, 16.6°, 17.1°, 17.3°, and 17.5° (±0.2°)

[0101] In one embodiment, the hydrate crystal of the compound of formula (4) is a 5A type crystal that, in powder X-ray diffraction, contains at least seven of the following peaks at a diffraction angle of 2θ. Note that the diffraction angles (2θ values) below may be those of the hydrate crystal stored for 1 hour at a temperature of 25°C and 20% relative humidity. 7.4°, 8.8°, 9.5°, 10.5°, 12.2°, 15.6°, 16.6°, 17.1°, 17.3°, and 17.5° (±0.2°)

[0102] In one embodiment, the hydrate crystal of the compound of formula (4) is a 5A type crystal that includes the following peak at a diffraction angle of 2θ in powder X-ray diffraction. Note that the diffraction angle (2θ value) below may be the diffraction angle (2θ value) of the hydrate crystal stored for 1 hour at a temperature of 25°C and 20% relative humidity. 7.4°, 8.8°, 9.5°, 10.5°, 12.2°, 15.6°, 16.6°, 17.1°, 17.3°, and 17.5° (±0.2°)

[0103] In one embodiment, the hydrate crystal of the compound of formula (4) is a 5A type crystal that, in powder X-ray diffraction, contains at least one of the following peaks at a diffraction angle of 2θ. Note that the diffraction angle (2θ value) below may be the diffraction angle (2θ value) of the hydrate crystal stored for 1 hour at a temperature of 25°C and 30% relative humidity. 7.4°, 8.8°, 9.5°, 10.5°, 12.2°, 15.5°, 16.4°, 16.6°, 17.1°, and 17.6° (±0.2°)

[0104] In one embodiment, the hydrate crystal of the compound of formula (4) is a 5A type crystal that, in powder X-ray diffraction, contains at least three of the following peaks at a diffraction angle of 2θ. Note that the diffraction angles (2θ values) below may be those of the hydrate crystal stored for 1 hour at a temperature of 25°C and 30% relative humidity. 7.4°, 8.8°, 9.5°, 10.5°, 12.2°, 15.5°, 16.4°, 16.6°, 17.1°, and 17.6° (±0.2°)

[0105] In one embodiment, the hydrate crystal of the compound of formula (4) is a 5A type crystal that, in powder X-ray diffraction, contains at least five of the following peaks at a diffraction angle of 2θ. Note that the diffraction angles (2θ values) below may be those of the hydrate crystal stored for 1 hour at a temperature of 25°C and 30% relative humidity. 7.4°, 8.8°, 9.5°, 10.5°, 12.2°, 15.5°, 16.4°, 16.6°, 17.1°, and 17.6° (±0.2°)

[0106] In one embodiment, the hydrate crystal of the compound of formula (4) is a 5A type crystal that, in powder X-ray diffraction, contains at least seven of the following peaks at a diffraction angle of 2θ. Note that the diffraction angles (2θ values) below may be those of the hydrate crystal stored for 1 hour at a temperature of 25°C and 30% relative humidity. 7.4°, 8.8°, 9.5°, 10.5°, 12.2°, 15.5°, 16.4°, 16.6°, 17.1°, and 17.6° (±0.2°)

[0107] In one embodiment, the hydrate crystal of the compound of formula (4) is a 5A type crystal that includes the following peak at a diffraction angle of 2θ in powder X-ray diffraction. Note that the diffraction angle (2θ value) below may be the diffraction angle (2θ value) of the hydrate crystal stored for 1 hour at a temperature of 25°C and 30% relative humidity. 7.4°, 8.8°, 9.5°, 10.5°, 12.2°, 15.5°, 16.4°, 16.6°, 17.1°, and 17.6° (±0.2°)

[0108] In one embodiment, the hydrate crystal of the compound of formula (4) is a 5A type crystal that, in powder X-ray diffraction, contains at least one of the following peaks at a diffraction angle of 2θ. Note that the diffraction angle (2θ value) below may be the diffraction angle (2θ value) of the hydrate crystal stored for 1 hour at a temperature of 25°C and 60% relative humidity. 7.4°, 8.8°, 9.5°, 10.3°, 12.2°, 15.4°, 16.3°, 16.6°, 17.0°, and 17.6° (±0.2°)

[0109] In one embodiment, the hydrate crystal of the compound of formula (4) is a 5A type crystal that, in powder X-ray diffraction, contains at least three of the following peaks at a diffraction angle of 2θ. Note that the diffraction angles (2θ values) below may be those of the hydrate crystal stored for 1 hour at a temperature of 25°C and 60% relative humidity. 7.4°, 8.8°, 9.5°, 10.3°, 12.2°, 15.4°, 16.3°, 16.6°, 17.0°, and 17.6° (±0.2°)

[0110] In one embodiment, the hydrate crystal of the compound of formula (4) is a 5A type crystal that, in powder X-ray diffraction, contains at least five of the following peaks at a diffraction angle of 2θ. Note that the diffraction angles (2θ values) below may be those of the hydrate crystal stored for 1 hour at a temperature of 25°C and 60% relative humidity. 7.4°, 8.8°, 9.5°, 10.3°, 12.2°, 15.4°, 16.3°, 16.6°, 17.0°, and 17.6° (±0.2°)

[0111] In one embodiment, the hydrate crystal of the compound of formula (4) is a 5A type crystal that, in powder X-ray diffraction, contains at least seven of the following peaks at a diffraction angle of 2θ. Note that the diffraction angles (2θ values) below may be those of the hydrate crystal stored for 1 hour at a temperature of 25°C and 60% relative humidity. 7.4°, 8.8°, 9.5°, 10.3°, 12.2°, 15.4°, 16.3°, 16.6°, 17.0°, and 17.6° (±0.2°)

[0112] In one embodiment, the hydrate crystal of the compound of formula (4) is a 5A type crystal that includes the following peak at a diffraction angle of 2θ in powder X-ray diffraction. Note that the diffraction angle (2θ value) below may be the diffraction angle (2θ value) of the hydrate crystal stored for 1 hour at a temperature of 25°C and 60% relative humidity. 7.4°, 8.8°, 9.5°, 10.3°, 12.2°, 15.4°, 16.3°, 16.6°, 17.0°, and 17.6° (±0.2°)

[0113] In one embodiment, the hydrate crystal of the compound of formula (4) is a 5E type crystal that, in powder X-ray diffraction, contains at least one of the following peaks at a diffraction angle of 2θ. 9.2°, 10.6°, 11.9°, 13.7°, 15.0°, 15.8°, 16.6°, 17.1°, 18.5°, and 19.2° (±0.2°)

[0114] In one embodiment, the hydrate crystal of the compound of formula (4) is a 5E type crystal that, in powder X-ray diffraction, has at least three of the following peaks at a diffraction angle of 2θ. 9.2°, 10.6°, 11.9°, 13.7°, 15.0°, 15.8°, 16.6°, 17.1°, 18.5°, and 19.2° (±0.2°)

[0115] In one embodiment, the hydrate crystal of the compound of formula (4) is a 5E type crystal that, in powder X-ray diffraction, contains at least five of the following peaks at a diffraction angle of 2θ. 9.2°, 10.6°, 11.9°, 13.7°, 15.0°, 15.8°, 16.6°, 17.1°, 18.5°, and 19.2° (±0.2°)

[0116] In one embodiment, the hydrate crystal of the compound of formula (4) is a 5E type crystal that, in powder X-ray diffraction, contains at least seven of the following peaks at a diffraction angle of 2θ. 9.2°, 10.6°, 11.9°, 13.7°, 15.0°, 15.8°, 16.6°, 17.1°, 18.5°, and 19.2° (±0.2°)

[0117] In one embodiment, the hydrate crystal of the compound of formula (4) is a 5E type crystal that, in powder X-ray diffraction, contains the following peak at a diffraction angle of 2θ. 9.2°, 10.6°, 11.9°, 13.7°, 15.0°, 15.8°, 16.6°, 17.1°, 18.5°, and 19.2° (±0.2°)

[0118] In one embodiment, the hydrate crystal of the compound of formula (4) is a 5J type crystal that, in powder X-ray diffraction, contains at least one of the following peaks at a diffraction angle of 2θ. 7.3°, 9.0°, 9.6°, 10.8°, 12.2°, 15.7°, 16.6°, and 17.3° (±0.2°)

[0119] In one embodiment, the hydrate crystal of the compound of formula (4) is a 5J type crystal that, in powder X-ray diffraction, contains at least one of the following peaks at a diffraction angle of 2θ. Note that the diffraction angle (2θ value) below may be the diffraction angle (2θ value) of the hydrate crystal stored for 1 hour at a temperature of 25°C and 30% relative humidity. 7.3°, 9.0°, 9.6°, 10.9°, 12.3°, 15.9°, 16.6°, 17.1°, and 17.5° (±0.2°)

[0120] In one embodiment, the hydrate crystal of the compound of formula (4) is a 5J type crystal that, in powder X-ray diffraction, contains at least three of the following peaks at a diffraction angle of 2θ. Note that the diffraction angles (2θ values) below may be those of the hydrate crystal stored for 1 hour at a temperature of 25°C and 30% relative humidity. 7.3°, 9.0°, 9.6°, 10.9°, 12.3°, 15.9°, 16.6°, 17.1°, and 17.5° (±0.2°)

[0121] In one embodiment, the hydrate crystal of the compound of formula (4) is a 5J type crystal that, in powder X-ray diffraction, contains at least five of the following peaks at a diffraction angle of 2θ. Note that the diffraction angles (2θ values) below may be those of the hydrate crystal stored for 1 hour at a temperature of 25°C and 30% relative humidity. 7.3°, 9.0°, 9.6°, 10.9°, 12.3°, 15.9°, 16.6°, 17.1°, and 17.5° (±0.2°)

[0122] In one embodiment, the hydrate crystal of the compound of formula (4) is a 5J type crystal that, in powder X-ray diffraction, contains at least seven of the following peaks at a diffraction angle of 2θ. Note that the diffraction angles (2θ values) below may be those of the hydrate crystal stored for 1 hour at a temperature of 25°C and 30% relative humidity. 7.3°, 9.0°, 9.6°, 10.9°, 12.3°, 15.9°, 16.6°, 17.1°, and 17.5° (±0.2°)

[0123] In one embodiment, the hydrate crystal of the compound of formula (4) is a 5J type crystal that includes the following peak at a diffraction angle of 2θ in powder X-ray diffraction. Note that the diffraction angle (2θ value) below may be the diffraction angle (2θ value) of the hydrate crystal stored for 1 hour at a temperature of 25°C and 30% relative humidity. 7.3°, 9.0°, 9.6°, 10.9°, 12.3°, 15.9°, 16.6°, 17.1°, and 17.5° (±0.2°)

[0124] In one embodiment, the hydrate crystal of the compound of formula (4) is a 5J type crystal that, in powder X-ray diffraction, contains at least one of the following peaks at a diffraction angle of 2θ. Note that the diffraction angle (2θ value) below may be the diffraction angle (2θ value) of the hydrate crystal stored for 1 hour at a temperature of 25°C and 40% relative humidity. 7.3°, 8.9°, 9.6°, 10.8°, 12.2°, 15.7°, 16.3°, 16.6°, 17.0°, and 17.3° (±0.2°)

[0125] In one embodiment, the hydrate crystal of the compound of formula (4) is a 5J type crystal that, in powder X-ray diffraction, contains at least three of the following peaks at a diffraction angle of 2θ. The diffraction angles (2θ values) below are preferably those of the hydrate crystal stored for 1 hour at a temperature of 25°C and 40% relative humidity. 7.3°, 8.9°, 9.6°, 10.8°, 12.2°, 15.7°, 16.3°, 16.6°, 17.0°, and 17.3° (±0.2°)

[0126] In one embodiment, the hydrate crystal of the compound of formula (4) is a 5J type crystal that, in powder X-ray diffraction, contains at least five of the following peaks at a diffraction angle of 2θ. The diffraction angles (2θ values) below are preferably those of the hydrate crystal stored for 1 hour at a temperature of 25°C and 40% relative humidity. 7.3°, 8.9°, 9.6°, 10.8°, 12.2°, 15.7°, 16.3°, 16.6°, 17.0°, and 17.3° (±0.2°)

[0127] In one embodiment, the hydrate crystal of the compound of formula (4) is a 5J type crystal that, in powder X-ray diffraction, contains at least seven of the following peaks at a diffraction angle of 2θ. The diffraction angles (2θ values) below are preferably those of the hydrate crystal stored for 1 hour at a temperature of 25°C and 40% relative humidity. 7.3°, 8.9°, 9.6°, 10.8°, 12.2°, 15.7°, 16.3°, 16.6°, 17.0°, and 17.3° (±0.2°)

[0128] In one embodiment, the hydrate crystal of the compound of formula (4) is a 5J type crystal that includes the following peak at a diffraction angle of 2θ in powder X-ray diffraction. The diffraction angle (2θ value) below is preferably the diffraction angle (2θ value) of the hydrate crystal stored for 1 hour at a temperature of 25°C and 40% relative humidity. 7.3°, 8.9°, 9.6°, 10.8°, 12.2°, 15.7°, 16.3°, 16.6°, 17.0°, and 17.3° (±0.2°)

[0129] In one aspect, the hydrate crystal of the compound of formula (4) is a 5J-type crystal containing at least one of the following peaks as diffraction angle 2θ in powder X-ray diffraction. The following diffraction angles (2θ values) may be the diffraction angles (2θ values) of the hydrate crystal stored at a temperature of 25 °C and a relative humidity of 50 to 60% for 1 hour. 7.3°, 8.9°, 9.6°, 10.7°, 12.1°, 15.6°, 16.2°, 16.6°, 16.9° and 17.2° (±0.2°)

[0130] In one aspect, the hydrate crystal of the compound of formula (4) is a 5J-type crystal containing at least three of the following peaks as diffraction angle 2θ in powder X-ray diffraction. The following diffraction angles (2θ values) may be the diffraction angles (2θ values) of the hydrate crystal stored at a temperature of 25 °C and a relative humidity of 50 to 60% for 1 hour. 7.3°, 8.9°, 9.6°, 10.7°, 12.1°, 15.6°, 16.2°, 16.6°, 16.9° and 17.2° (±0.2°)

[0131] In one aspect, the hydrate crystal of the compound of formula (4) is a 5J-type crystal containing at least five of the following peaks as diffraction angle 2θ in powder X-ray diffraction. The following diffraction angles (2θ values) may be the diffraction angles (2θ values) of the hydrate crystal stored at a temperature of 25 °C and a relative humidity of 50 to 60% for 1 hour. 7.3°, 8.9°, 9.6°, 10.7°, 12.1°, 15.6°, 16.2°, 16.6°, 16.9° and 17.2° (±,0.2°)

[0132] In one aspect, the hydrate crystal of the compound of formula (4) is a 5J-type crystal containing at least seven of the following peaks as diffraction angle 2θ in powder X-ray diffraction. The following diffraction angles (2θ values) may be the diffraction angles (2θ values) of the hydrate crystal stored at a temperature of 25 °C and a relative humidity of 50 to 60% for 1 hour. 7.3°, 8.9°, 9.6°, 10.7°, 12.1°, 15.6°, 16.2°, 16.6°, 16.9° and 17.2° (±0.2°)

[0133] In one embodiment, the hydrate crystal of the compound of formula (4) is a 5J type crystal that includes the following peak at a diffraction angle of 2θ in powder X-ray diffraction. Note that the diffraction angle (2θ value) below may be the diffraction angle (2θ value) of the hydrate crystal stored for 1 hour at a temperature of 25°C and a relative humidity of 50-60%. 7.3°, 8.9°, 9.6°, 10.7°, 12.1°, 15.6°, 16.2°, 16.6°, 16.9°, and 17.2° (±0.2°)

[0134] In one embodiment, the hydrate crystal of the compound of formula (4) is a 5J type crystal that, in powder X-ray diffraction, contains at least one of the following peaks at a diffraction angle of 2θ. Note that the diffraction angle (2θ value) below may be the diffraction angle (2θ value) of the hydrate crystal stored for 1 hour at a temperature of 25°C and a relative humidity of 70% or higher. 7.2°, 8.9°, 9.5°, 10.6°, 12.0°, 15.5°, 16.1°, 16.6°, and 17.1° (±0.2°)

[0135] In one embodiment, the hydrate crystal of the compound of formula (4) is a 5J type crystal that, in powder X-ray diffraction, contains at least three of the following peaks at a diffraction angle of 2θ. Note that the diffraction angle (2θ value) below may be the diffraction angle (2θ value) of the hydrate crystal stored for 1 hour at a temperature of 25°C and a relative humidity of 70% or higher. 7.2°, 8.9°, 9.5°, 10.6°, 12.0°, 15.5°, 16.1°, 16.6°, and 17.1° (±0.2°)

[0136] In one embodiment, the hydrate crystal of the compound of formula (4) is a 5J type crystal that, in powder X-ray diffraction, contains at least five of the following peaks at a diffraction angle of 2θ. Note that the diffraction angles (2θ values) below may be those of the hydrate crystal stored for 1 hour at a temperature of 25°C and a relative humidity of 70% or higher. 7.2°, 8.9°, 9.5°, 10.6°, 12.0°, 15.5°, 16.1°, 16.6°, and 17.1° (±0.2°)

[0137] In one embodiment, the hydrate crystal of the compound of formula (4) is a 5J type crystal that, in powder X-ray diffraction, contains at least seven of the following peaks at a diffraction angle of 2θ. Note that the diffraction angles (2θ values) below may be those of the hydrate crystal stored for 1 hour at a temperature of 25°C and a relative humidity of 70% or higher. 7.2°, 8.9°, 9.5°, 10.6°, 12.0°, 15.5°, 16.1°, 16.6°, and 17.1° (±0.2°)

[0138] In one embodiment, the hydrate crystal of the compound of formula (4) is a 5J type crystal that includes the following peak at a diffraction angle of 2θ in powder X-ray diffraction. Note that the diffraction angle (2θ value) below may be the diffraction angle (2θ value) of the hydrate crystal stored for 1 hour at a temperature of 25°C and a relative humidity of 70% or higher. 7.2°, 8.9°, 9.5°, 10.6°, 12.0°, 15.5°, 16.1°, 16.6°, and 17.1° (±0.2°)

[0139] In one embodiment, the crystal of the compound of formula (4) is a 5C-type crystal that, in powder X-ray diffraction, contains at least one of the following peaks at a diffraction angle of 2θ. 7.3°, 9.7°, 12.1°, 14.8°, 15.2°, 15.7°, 16.6°, and 17.7° (±0.2°)

[0140] In one embodiment, the crystal of the compound of formula (4) is a 5C-type crystal that, in powder X-ray diffraction, has at least three of the following peaks at a diffraction angle of 2θ. 7.3°, 9.7°, 12.1°, 14.8°, 15.2°, 15.7°, 16.6°, and 17.7° (±0.2°)

[0141] In one embodiment, the crystal of the compound of formula (4) is a 5C-type crystal that, in powder X-ray diffraction, has at least five of the following peaks at a diffraction angle of 2θ. 7.3°, 9.7°, 12.1°, 14.8°, 15.2°, 15.7°, 16.6°, and 17.7° (±0.2°)

[0142] In one embodiment, the crystal of the compound of formula (4) is a 5C-type crystal that, in powder X-ray diffraction, has at least seven of the following peaks at a diffraction angle of 2θ. 7.3°, 9.7°, 12.1°, 14.8°, 15.2°, 15.7°, 16.6°, and 17.7° (±0.2°)

[0143] In one embodiment, the crystal of the compound of formula (4) is a 5C-type crystal that, in powder X-ray diffraction, has the following peak at a diffraction angle of 2θ. 7.3°, 9.7°, 12.1°, 14.8°, 15.2°, 15.7°, 16.6°, and 17.7° (±0.2°)

[0144] In one embodiment, the nonsolvated crystal of the compound of formula (4) is a 5D type crystal that, in powder X-ray diffraction, contains at least one of the following peaks at a diffraction angle of 2θ. 11.3°, 13.1°, 13.8°, 14.9°, 15.9°, 16.1°, 16.7°, 17.5°, 18.1°, and 18.5° (±0.2°)

[0145] In one embodiment, the nonsolvated crystal of the compound of formula (4) is a 5D type crystal that, in powder X-ray diffraction, contains at least three of the following peaks at a diffraction angle of 2θ. 11.3°, 13.1°, 13.8°, 14.9°, 15.9°, 16.1°, 16.7°, 17.5°, 18.1°, and 18.5° (±0.2°)

[0146] In one embodiment, the nonsolvate crystal of the compound of formula (4) is a 5D type crystal that, in powder X-ray diffraction, has at least five of the following peaks at a diffraction angle of 2θ. 11.3°, 13.1°, 13.8°, 14.9°, 15.9°, 16.1°, 16.7°, 17.5°, 18.1°, and 18.5° (±0.2°)

[0147] In certain embodiments, the non-solvate crystals of the compound of formula (4) are 5D-type crystals that include at least seven of the following peaks as diffraction angle 2θ in powder X-ray diffraction. 11.3°, 13.1°, 13.8°, 14.9°, 15.9°, 16.1°, 16.7°, 17.5°, 18.1°, and 18.5° (±0.2°)

[0148] In certain embodiments, the non-solvate crystals of the compound of formula (4) are 5D-type crystals that include the following peaks as diffraction angle 2θ in powder X-ray diffraction. 11.3°, 13.1°, 13.8°, 14.9°, 15.9°, 16.1°, 16.7°, 17.5°, 18.1°, and 18.5° (±0.2°)

[0149] In certain embodiments, the crystals of the compound of formula (4) are 5G-type crystals that include at least one of the following peaks as diffraction angle 2θ in powder X-ray diffraction. 9.4°, 11.0°, 13.4°, 15.0°, 16.1°, 17.8°, 18.1°, 19.7°, 20.8°, and 22.0° (±0.2°)

[0150] In certain embodiments, the crystals of the compound of formula (4) are 5G-type crystals that include at least three of the following peaks as diffraction angle 2θ in powder X-ray diffraction. 9.4°, 11.0°, 13.4°, 15.0°, 16.1°, 17.8°, 18.1°, 19.7°, 20.8°, and 22.0° (±0.2°)

[0151] In certain embodiments, the crystals of the compound of formula (4) are 5G-type crystals that include at least five of the following peaks as diffraction angle 2θ in powder X-ray diffraction. 9.4°, 11.0°, 13.4°, 15.0°, 16.1°, 17.8°, 18.1°, 19.7°, 20.8°, and 22.0° (±0.2°)

[0152] In one embodiment, the crystal of the compound of formula (4) is a 5G type crystal that, in powder X-ray diffraction, has at least seven of the following peaks at a diffraction angle of 2θ. 9.4°, 11.0°, 13.4°, 15.0°, 16.1°, 17.8°, 18.1°, 19.7°, 20.8°, and 22.0° (±0.2°)

[0153] In one embodiment, the crystal of the compound of formula (4) is a 5G type crystal that, in powder X-ray diffraction, has the following peak at a diffraction angle of 2θ. 9.4°, 11.0°, 13.4°, 15.0°, 16.1°, 17.8°, 18.1°, 19.7°, 20.8°, and 22.0° (±0.2°)

[0154] In one embodiment, the hydrate crystal of the compound of formula (5) is a 4B type crystal that, in powder X-ray diffraction, contains at least one of the following peaks at a diffraction angle of 2θ. 7.7°, 13.3°, 14.0°, 15.4°, 16.2°, 17.9°, 18.2°, 18.5°, 19.1°, and 20.6° (±0.2°)

[0155] In one embodiment, the hydrate crystal of the compound of formula (5) is a 4B type crystal that, in powder X-ray diffraction, has at least three of the following peaks at a diffraction angle of 2θ. 7.7°, 13.3°, 14.0°, 15.4°, 16.2°, 17.9°, 18.2°, 18.5°, 19.1°, and 20.6° (±0.2°)

[0156] In one embodiment, the hydrate crystal of the compound of formula (5) is a 4B type crystal that, in powder X-ray diffraction, contains at least five of the following peaks at a diffraction angle of 2θ. 7.7°, 13.3°, 14.0°, 15.4°, 16.2°, 17.9°, 18.2°, 18.5°, 19.1°, and 20.6° (±0.2°)

[0157] In one embodiment, the hydrate crystal of the compound of formula (5) is a 4B type crystal that, in powder X-ray diffraction, contains at least seven of the following peaks at a diffraction angle of 2θ. 7.7°, 13.3°, 14.0°, 15.4°, 16.2°, 17.9°, 18.2°, 18.5°, 19.1°, and 20.6° (±0.2°)

[0158] In one embodiment, the hydrate crystal of the compound of formula (5) is a 4B type crystal that, in powder X-ray diffraction, has the following peak at a diffraction angle of 2θ. 7.7°, 13.3°, 14.0°, 15.4°, 16.2°, 17.9°, 18.2°, 18.5°, 19.1°, and 20.6° (±0.2°)

[0159] In one embodiment, the crystal of the compound of formula (5) is a 4A type crystal that, in powder X-ray diffraction, contains at least one of the following peaks at a diffraction angle of 2θ. 11.5°, 11.8°, 15.7°, 17.2°, 17.5°, 18.1°, 19.5°, 20.3°, 20.5°, and 21.2° (±0.2°)

[0160] In one embodiment, the crystal of the compound of formula (5) is a 4A type crystal that, in powder X-ray diffraction, has at least three of the following peaks at a diffraction angle of 2θ. 11.5°, 11.8°, 15.7°, 17.2°, 17.5°, 18.1°, 19.5°, 20.3°, 20.5°, and 21.2° (±0.2°)

[0161] In one embodiment, the crystal of the compound of formula (5) is a 4A type crystal that, in powder X-ray diffraction, contains at least five of the following peaks at a diffraction angle of 2θ. 11.5°, 11.8°, 15.7°, 17.2°, 17.5°, 18.1°, 19.5°, 20.3°, 20.5°, and 21.2° (±0.2°)

[0162] In one embodiment, the crystal of the compound of formula (5) is a 4A type crystal that, in powder X-ray diffraction, has at least seven of the following peaks at a diffraction angle of 2θ. 11.5°, 11.8°, 15.7°, 17.2°, 17.5°, 18.1°, 19.5°, 20.3°, 20.5°, and 21.2° (±0.2°)

[0163] In one embodiment, the crystal of the compound of formula (5) is a 4A type crystal that, in powder X-ray diffraction, has the following peak at a diffraction angle of 2θ. 11.5°, 11.8°, 15.7°, 17.2°, 17.5°, 18.1°, 19.5°, 20.3°, 20.5°, and 21.2° (±0.2°)

[0164] In this specification, the "~" symbol indicating a numerical range includes the values ​​at both ends of the range. For example, "A~B" means a numerical range where A is greater than or equal to B and B is less than or equal to B.

[0165] In this specification, the term "approximately" when used in combination with a number means a range of values ​​within +10% and -10% of that number.

[0166] In this specification, the meaning of the term "and / or" includes any combination of "and" and "or" as appropriate. Specifically, for example, "A, B, and / or C" includes the following seven variations: (i) A, (ii) B, (iii) C, (iv) A and B, (v) A and C, (vi) B and C, (vii) A, B, and C.

[0167] The compounds represented by formulas (1) to (5) can be synthesized by various methods, and may be synthesized by methods well known to those skilled in the art. For example, the compounds represented by formulas (1) to (5) can be synthesized by the method described in Example 1 below.

[0168] <Manufacturing method> The compounds of the present invention, or their salts, or crystals of their solvates, can be produced, for example, by the following methods. Crystals of the compound, its salt, or its solvate can be obtained by adding a solvent suitable for crystallization to the compound, optionally adding seed crystals, and stirring as necessary. The solvent added during crystallization is not particularly limited as long as it is a solvent in which the compound can form crystals, but a solvent that can reduce the solubility of the compound in the solution in which the compound is dissolved is preferred. For example, if crystallization is possible by reducing the solubility of the compound by adding a poor solvent or cooling the solution, a solvent capable of such operations is exemplified. Also, if crystals of the compound can be obtained by keeping crude crystals of the compound suspended in a suspension state for any desired time, a solvent capable of such operations can be used for crystallization. Specific examples of solvents added during crystallization include acetone, water, dimethyl sulfoxide (DMSO), dimethylformamide (DMF), acetonitrile, tetrahydrofuran, methyl ethyl ketone, methyl isobutyl ketone, ethyl acetate, heptane, polyethylene glycol (PEG), 2-propanol, methanol, or ethanol, and mixtures thereof.

[0169] <Pharmaceutical composition> The present invention provides a pharmaceutical composition containing the compound of the present invention, a salt thereof, or crystals of a solvate thereof. The pharmaceutical composition of the present invention can be formulated by introducing a pharmaceutically acceptable carrier in addition to the compound of the present invention, its salt, or a crystal of its solvate, using known methods. For formulation, commonly used excipients, binders, lubricants, colorants, flavoring agents, and, if necessary, stabilizers, emulsifiers, absorption enhancers, surfactants, pH adjusters, preservatives, antioxidants, etc., can be used, and the formulation is carried out by conventional methods using components generally used as raw materials for pharmaceutical formulations. Pharmaceutical formulation allows for the processing of the active ingredients used in a pharmaceutical product into an optimal shape or form, i.e., dosage form, tailored to the method of use and intended purpose, using known methods. Examples of commonly used dosage forms include, but are not limited to, liquid pharmaceutical preparations (liquid formulations) such as injections, suspensions, emulsions, and eye drops, and solid pharmaceutical preparations (solid formulations) such as tablets, powders, granules, coated tablets, capsules, dry syrups, lozenges, and suppositories.

[0170] For example, to produce a liquid formulation, the compound of the present invention, its salt, or a crystal of its solvate is mixed with a pharmaceutically acceptable carrier or medium, specifically, a combination of pharmaceutically acceptable additives commonly used in the pharmaceutical field, such as sterile water, physiological saline, vegetable oil, emulsifiers, suspension agents, surfactants, stabilizers, flavoring agents, excipients, vehicles, preservatives, and binders, and then formulated in a unit dose form generally accepted for pharmaceutical production. Alternatively, a solid formulation prepared for liquid formulation can be dissolved as needed by adding a suitable solvent, such as sterile water or physiological saline, before administration.

[0171] Such liquid formulations can also be used parenterally, for example, as sterile solutions with water or other pharmaceutically acceptable liquids, or as injectable suspensions. For example, they can be formulated by mixing them with pharmaceutically acceptable carriers or media, specifically sterile water, physiological saline, vegetable oil, emulsifiers, suspensions, surfactants, stabilizers, flavorings, excipients, vehicles, preservatives, binders, etc., in a unit dose form generally accepted for pharmaceutical practice. Specifically, examples of carriers include light anhydrous silicic acid, lactose, crystalline cellulose, mannitol, starch, carmellose calcium, carmellose sodium, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinyl acetal diethylaminoacetate, polyvinylpyrrolidone, gelatin, medium-chain triglycerides, polyoxyethylene hydrogenated castor oil 60, sucrose, carboxymethylcellulose, corn starch, and inorganic salts. The amount of active ingredient in these formulations should be such that an appropriate volume within the indicated range is obtained. Sterile compositions for injection can be formulated using a vehicle such as distilled water for injection, following standard formulation procedures.

[0172] Examples of aqueous solutions for injection include isotonic solutions containing physiological saline or other adjuvants, such as D-sorbitol, D-mannose, D-mannitol, and sodium chloride. These may be used in combination with appropriate solubilizers, such as alcohol, specifically ethanol, polyalcohols, such as propylene glycol and polyethylene glycol, and nonionic surfactants, such as polysorbate 80 (registered trademark) and HCO-50.

[0173] Examples of oily liquids include sesame oil and soybean oil, and may be used in combination with benzyl benzoate or benzyl alcohol as solubilizers. It may also be combined with buffers such as phosphate buffer or sodium acetate buffer, analgesics such as procaine hydrochloride, stabilizers such as benzyl alcohol or phenol, and antioxidants. The prepared injection solution is usually filled into appropriate ampoules.

[0174] For example, to produce a solid dosage form, the compound of the present invention, or a salt thereof, or a crystal of a solvate thereof, is combined with excipients and, if necessary, pharmaceutically acceptable additives commonly used in the pharmaceutical field, such as binders, disintegrants, lubricants, colorants, and flavoring / odorizing agents, in an appropriate combination. Then, the product is prepared by conventional methods as a tablet, powder, fine granules, granules, coated tablets, capsules, dry syrup, lozenges, suppositories, etc.

[0175] Examples of pharmaceutically acceptable additives used in such solid dosage forms include animal and vegetable oils such as soybean oil, beef tallow, and synthetic glycerides; hydrocarbons such as liquid paraffin, squalane, and solid paraffin; ester oils such as octyldodecyl myristate and isopropyl myristate; higher alcohols such as cetostearyl alcohol and behenyl alcohol; silicone resins; silicone oils; surfactants such as polyoxyethylene fatty acid esters, sorbitan fatty acid esters, glycerin fatty acid esters, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene hydrogenated castor oil, and polyoxyethylene polyoxypropylene block copolymers; water-soluble polymers such as hydroxyethylcellulose, polyacrylic acid, carboxyvinyl polymer, polyethylene glycol, polyvinylpyrrolidone, and methylcellulose; lower alcohols such as ethanol and isopropanol; polyhydric alcohols such as glycerin, propylene glycol, dipropylene glycol, and sorbitol; sugars such as lactose, lactose monohydrate, fructose, and sucrose; inorganic powders such as anhydrous silicic acid, aluminum magnesium silicate, and aluminum silicate, and purified water.

[0176] Examples of excipients include sugars (e.g., lactose, lactose monohydrate, fructose, sucrose, etc.), sugar alcohols (e.g., mannitol, etc.), starches (corn starch, potato starch, wheat starch, rice starch, partially pregelatinized starch, pregelatinized starch, etc.), cellulose (e.g., crystalline cellulose), and inorganic salts (e.g., calcium silicate, anhydrous calcium hydrogen phosphate, precipitated calcium carbonate, etc.).

[0177] Examples of binders include polyvinyl alcohol, polyvinyl ether, methylcellulose, ethylcellulose, gum arabic, tragacanth, gelatin, shellac, hydroxypropyl methylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone, and polypropylene glycol / polyoxyethylene block polymer.

[0178] Examples of disintegrants include croscarmellose sodium, carmellose sodium, hydroxypropyl cellulose, carmellose, carmellose calcium, methylcellulose, crystalline cellulose, sodium lauryl sulfate, povidone, or polysorbate.

[0179] Examples of lubricants include magnesium stearate, calcium stearate, talc, sucrose fatty acid esters, sodium stearyl fumarate, and hydrogenated oils.

[0180] As coloring agents, those permitted for addition to pharmaceuticals are used, while as flavoring and deodorizing agents, cocoa powder, peppermint, aromatic powders, peppermint oil, borneol, cinnamon powder, etc., are used.

[0181] These tablets and granules may, of course, be coated with sugar or other coatings as needed. Furthermore, when manufacturing liquid preparations such as syrups and injectable preparations, the compounds of the present invention, their salts, or crystals of their solvates are formulated by conventional methods with pH adjusters, solvents, isotonic agents, and, if necessary, solubilizers and stabilizers.

[0182] Administration is preferably parenteral, but the method of administration is not limited to parenteral administration. Specific examples of parenteral administration include injectable formulations, nasal administration formulations, pulmonary administration formulations, and transdermal administration formulations. Examples of injectable formulations include intravenous injection, intramuscular injection, intraperitoneal injection, and subcutaneous injection, which can be administered systemically or locally.

[0183] Furthermore, the administration method can be appropriately selected depending on the patient's age and symptoms. The dosage of a pharmaceutical composition containing the compound of the present invention, or its salt or solvate crystals, produced by the method of the present invention, can be selected in the range of 0.0001 mg to 1000 mg per kg of body weight per dose. Alternatively, the dosage can be selected in the range of 0.001 to 100,000 mg / body per patient, but is not necessarily limited to these values. The dosage and administration method will vary depending on the patient's weight, age, symptoms, etc., but a person skilled in the art can select them appropriately.

[0184] In one embodiment, the compounds of the present invention, or their salts or solvates, crystals can be used to activate Nrf2, or to inhibit Keap1 and activate Nrf2.

[0185] In one embodiment, the pharmaceutical composition of the present invention is used for diseases in the subjects described in, for example, Nature Reviews DrugDiscovery, 2019, 18, pp. 295-317, more specifically, for neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease, Friedreich's ataxia, and amyotrophic lateral sclerosis; for lung diseases such as idiopathic pulmonary fibrosis, acute respiratory distress syndrome, chronic obstructive pulmonary disease, pulmonary arterial hypertension, and asthma; for kidney diseases such as chronic kidney disease and acute kidney injury; for ophthalmic diseases such as uveitis, glaucoma, and age-related macular degeneration; for liver diseases such as non-alcoholic steatohepatitis; for immune and inflammatory diseases such as multiple sclerosis, rheumatoid arthritis, and ulcerative colitis; and for head and neck cancers (pharyngeal cancer, laryngeal cancer, tongue cancer, etc.), esophageal cancer, gastric cancer, and colorectal cancer. It can be used to treat or prevent solid cancers such as cecal cancer, colon cancer, rectal cancer, lung cancer (small cell carcinoma, non-small cell carcinoma, etc.), thyroid cancer, breast cancer, gallbladder cancer, pancreatic cancer, liver cancer, prostate cancer, ovarian cancer, uterine cancer (endometrial cancer, cervical cancer, etc.), testicular cancer, renal cell carcinoma, bladder cancer, renal pelvis / ureteral cancer, malignant melanoma, skin cancer, and other solid cancers, as well as cell proliferation disorders exemplified by blood and lymphoid cancers such as leukemia (acute myeloid leukemia, acute lymphoblastic leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia, etc.), malignant lymphoma (Hodgkin's disease, non-Hodgkin lymphoma, etc.), multiple myeloma, and myelodysplastic syndrome.

[0186] In this specification, "subjects" include mammals, and among mammals, humans are preferred.

[0187] The present invention provides a pharmaceutical composition obtained by mixing crystals of the compound of the present invention, a salt thereof, or a solvate thereof with a pharmaceutically acceptable carrier or medium. The present invention also provides a method for producing a pharmaceutical composition containing crystals of the compound of the present invention, a salt thereof, or a solvate thereof as an active ingredient, the method comprising the step of mixing the crystals with a pharmaceutically acceptable carrier or medium.

[0188] The present invention provides a method for producing a pharmaceutical composition containing the compound of the present invention, a salt thereof, or a solvate thereof as an active ingredient, the method comprising the step of mixing the compound, a salt thereof, or a solvate thereof with a pharmaceutically acceptable carrier or medium.

[0189] In this specification, “mixing a compound or its salt or solvate crystals with a pharmaceutically acceptable carrier or medium” includes any of the following: (a) sequentially adding other components to either (1) a compound or its salt or solvate crystals, and (2) a pharmaceutically acceptable carrier or medium; and (b) simultaneously adding (1) and (2). In this specification, “mixing a compound or its salt or solvate crystals with a pharmaceutically acceptable carrier or medium” also includes any of the following: (a') sequentially adding other components to either (1') a compound or its salt or solvate, and (2') a pharmaceutically acceptable carrier or medium; and (b') simultaneously adding (1') and (2'). Here, “mixing” does not require that a homogeneous mixture be obtained when mixing (1) and (2), or (1') and (2'). For example, "mixing" includes "dissolution," "suspension," or "emulsion." [Examples]

[0190] The present invention will be further explained by the following examples and reference examples. All starting materials and reagents were obtained from commercial suppliers or synthesized using known methods. Room temperature (rt) refers to 5 to 35°C. HPLC purification of the compounds was performed using an AutoPurification HPLC / MS System (Waters) and a Trilution (Gilson). 1¹H-NMR spectra were measured with or without Me4Si as an internal standard using the MR400 OneNMR probe (400 MHz, Agilent technology), AVANCE III HD 400 SMART-BBFO probe (400 MHz, Bruker), ECP400 (400 MHz, JEOL), AVANCE III HD 400 SMART-BBFO probe (400 MHz, Bruker), MR400 OneNMR probe (400 MHz, Agilent technology), or AVANCE NEO 400 iProbe (400 MHz, Bruker) (s=singlet, brs=broad singlet, d=doublet, t=triplet, q=quartet, dd=double doublet, ddd=double double doublet, dt=double triplet, td=triple doublet, m=multiplet). NMR data are shown in ppm (parts per million, δ). Mass spectral data were obtained using a Shimadzu Corporation single quadrupole mass spectrometer (LCMS-2020) with ultra-high-performance liquid chromatography (Nexera UC or Nexera) or a Waters Acquity single quadrupole mass spectrometer (SQD or SQD2) with ultra-high-performance liquid chromatography (UPLC or ULC I-Class). Where two retention times are listed, each indicates the retention time for the rotational isomer. Microwave irradiation was performed using an Initiator™ (Biotage).

[0191] [Table 1]

[0192] [Example 1] Synthesis of the compound <Example 1-1> Compound A Methyl 4-[3-(4-bromo-2,6-dichlorobenzoyl)-2,4-dihydro-1,3-benzoxazine-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoate First step Compound A1 tert-butyl N-[(3-bromo-2-hydroxyphenyl)methyl]carbamate [ka] A solution of 3-bromo-2-hydroxybenzaldehyde (5.00 g, 24.9 mmol) and tert-butylcarbamate (8.74 g, 74.6 mmol) in acetonitrile (35.0 mL) was cooled to 0°C. Triethylsilane (11.9 mL, 74.6 mmol) and trifluoroacetic acid (3.81 mL, 49.7 mmol) were added to the reaction mixture. The mixture was stirred at 35°C for 5 hours, then cooled to room temperature. After stirring at room temperature for 15 hours, water was added to the reaction mixture and stirred for 1 hour, then more water was added and stirred for 30 minutes. The reaction mixture was filtered and washed with acetonitrile / water (1 / 2). Further washing with heptane and drying under reduced pressure yielded the title compound (88%, 6.60 g). LCMS: m / z 300 [MH] - HPLC retention time: 1.16 minutes (analysis condition F)

[0193] Second process Compound A2 tert-butyl 8-bromo-2,4-dihydro-1,3-benzoxazine-3-carboxylate [ka] To a solution of tert-butyl N-[(3-bromo-2-hydroxyphenyl)methyl]carbamate (5.00 g, 16.6 mol) in acetonitrile (30.0 mL), 36% formaldehyde aqueous solution (5.06 mL, 66.2 mmol) and formic acid (5.08 mL, 132 mmol) were added, and the mixture was stirred at 56°C for 7 hours. The reaction mixture was cooled to 25°C, water was added, and the mixture was stirred for 30 minutes. Further water was added, and the mixture was stirred for another 30 minutes. The reaction mixture was filtered and washed with acetonitrile / water (1 / 2). The title compound (81%, 4.20 g) was obtained by drying under reduced pressure. LCMS: m / z 214[M-Boc+H] + HPLC retention time: 1.31 minutes (analysis condition F)

[0194] Third step Compound A3 4-Bromo-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid [ka] 4-bromo-2,5-difluorobenzoic acid (3.00 g, 12.7 mmol) and 3-oxa-8-azabicyclo[3.2.1]octane hydrochloride (2.46 g, 16.5 mmol) were suspended in tetrahydrofuran (6.00 mL) solution to which 1 M lithium (bistrimethylsilyl)amide in tetrahydrofuran solution (50.6 mL, 50.6 mmol) was added over 12 minutes at room temperature. The reaction mixture was stirred at room temperature for 5.5 hours, and then allowed to stand at room temperature for 15 hours. 2 M hydrochloric acid was added to the reaction mixture, and it was extracted with ethyl acetate. The aqueous layer was extracted again with ethyl acetate, and the two organic layers were washed together with 20% aqueous ammonium chloride solution and 15% aqueous sodium chloride solution. The washed organic layers were concentrated to obtain the title compound as the crude product. LCMS: m / z 330[M+H] + HPLC retention time: 0.61 min (analysis condition D)

[0195] Fourth step Compound A4 Methyl 4-bromo-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoate [ka] To a solution of 4-bromo-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid (4.18 g, 12.7 mmol) in N,N-dimethylformamide (21.0 mL), potassium carbonate (2.10 g, 15.2 mmol) and iodomethane (1.58 mL, 25.3 mmol) were added, and the mixture was stirred at room temperature for 30 minutes. A 20% aqueous solution of ammonium chloride and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with a 20% aqueous solution of ammonium chloride and concentrated. Methanol was added to the crude product, and the mixture was heated to 60°C, then cooled to room temperature and stirred for 30 minutes. Water was added and the mixture was stirred for 1 hour, then water was added again and the mixture was stirred for another 30 minutes. After filtration, the resulting solid was washed with methanol / water (1 / 1) and dried under reduced pressure to obtain the title compound (55%, 2.38 g). LCMS: m / z 344[M+H] + HPLC retention time: 1.18 minutes (analysis condition F)

[0196] Fifth step Compound A5 tert-butyl 8-[2-fluoro-4-methoxycarbonyl-5-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)phenyl]-2,4-dihydro-1,3-benzoxazine-3-carboxylate [ka] A solution of methyl 4-bromo-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoato (1.21 g, 3.50 mmol) in tetrahydrofuran (5.30 mL) was cooled to -10°C. 2M isopropylmagnesium chloride-tetrahydrofuran solution (1.91 mL, 3.82 mmol) was added, and the mixture was stirred for 1 hour. 2M zinc(II) chloride-2-methyltetrahydrofuran solution (0.955 mL, 1.91 mmol) was added to the reaction mixture. Tert-butyl 8-bromo-2,4-dihydro-1,3-benzoxazine-3-carboxylate (1.00 g, 3.18 mmol) and SPhos Pd G3 (0.0250 g, 0.0320 mmol) were added to the reaction mixture, and the temperature was raised to 45°C, with stirring for 90 minutes. The mixture was cooled to room temperature, and aqueous solutions of ethyl acetate and ammonium chloride were added. Extraction was performed with ethyl acetate. The organic layer was washed with aqueous solutions of N-acetylcysteine ​​and sodium chloride, and concentrated to obtain the crude product. Ethanol was added to the crude product, and the temperature was raised to 80°C to dissolve it. The mixture was cooled to room temperature. Heptane was added, and the mixture was cooled to 0°C. The solid obtained by filtration was washed with ethanol / heptane (1 / 2) and dried under reduced pressure to obtain the title compound (73%, 1.16 g). LCMS: m / z 499[M+H] + HPLC retention time: 1.40 minutes (analysis condition F)

[0197] Sixth step Compound A6 Methyl 4-(3,4-dihydro-2H-1,3-benzoxazine-8-yl)-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoate dihydrochloride [ka] 100 mL of acetonitrile solution was added to 100 mL of tert-butyl 8-[2-fluoro-4-methoxycarbonyl-5-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)phenyl]-2,4-dihydro-1,3-benzoxazine-3-carboxylate (10.0 g, 20.1 mmol), and 25.1 mL of 4 M ethyl hydrochloride solution (100 mmol) was added. The mixture was stirred at room temperature for 2 hours. The title compound (76%, 7.16 g) was obtained as crystals by filtration. LCMS: m / z 399[M+H] + HPLC retention time: 0.75 minutes (analysis condition F)

[0198] Seventh step Compound A7 4-Bromo-2,6-dichlorobenzoyl chloride [ka] To a solution of 4-bromo-2,6-dichlorobenzoic acid (45.5 g, 169 mmol) in toluene (241 mL), thionyl chloride (24.5 mL, 337 mmol) and N,N-dimethylformamide (0.261 mL, 3.37 mmol) were added, and the mixture was stirred at 70°C for 7 hours. The reaction mixture was cooled to room temperature, concentrated, and the resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (99%, 48.0 g). HPLC retention time: 1.48 minutes (analysis condition F) 1 H NMR (400 MHz, CDCl3) δ 7.56 (s, 2H)

[0199] Eighth process Compound A Methyl 4-[3-(4-bromo-2,6-dichlorobenzoyl)-2,4-dihydro-1,3-benzoxazine-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoate [ka] A solution of methyl 4-(3,4-dihydro-2H-1,3-benzoxazin-8-yl)-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoate dihydrochloride (9.22 g, 19.6 mmol) in toluene (92.0 mL) was added with 4-bromo-2,6-dichlorobenzoyl chloride (7.33 g, 25.4 mmol) and pyridine (11.1 mL, 137 mmol), and stirred at 70 °C for 12 hours. Ethyl acetate and 1 M hydrochloric acid were added to the reaction solution for extraction, and the organic layer was washed with a 50% saturated aqueous sodium hydrogen carbonate solution and a 50% saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. After concentration, the obtained residue was triturated with hexane to obtain the title compound (48%, 6.06 g). LCMS: m / z 649 [M+H] + HPLC retention time: 1.42 minutes (analysis condition F)

[0200] <Example 1-2> Compound B Methyl 4-[3-(4-bromo-2,6-dichlorobenzoyl)-2,4-dihydro-1,3-benzoxazine-8-yl]-5-fluoro-2-morpholine-4-ylbenzoate First step Compound B1 4-Bromo-5-fluoro-2-morpholine-4-ylbenzoic acid [Chemical formula] Morpholine (6.98 g, 80.0 mmol) was added to 4-bromo-2,5-difluorobenzoic acid (950 mg, 4.01 mmol), and the mixture was stirred at 100 °C for 24 hours. Ethyl acetate and hydrochloric acid were added to the reaction solution, and after extraction, it was washed with saturated brine. The organic layer was concentrated to obtain the title compound (98%, 1.20 g). LCMS: m / z 304 [M+H] + HPLC retention time: 0.77 minutes (analysis condition H)

[0201] Second step Compound B2 Methyl 4-bromo-5-fluoro-2-morpholine-4-ylbenzoate [Chemical formula] 4-bromo-5-fluoro-2-morpholine-4-ylbenzoic acid (400 mg, 1.32 mmol) was dissolved in dichloromethane (5.00 mL)-methanol (1.00 mL), to which 2M trimethylsilyldiazomethane-hexane solution (1.32 mL, 2.63 mmol) was added and the mixture was stirred at room temperature for 30 minutes. Acetic acid was added to the reaction mixture, and after concentrating the reaction mixture, the reaction mixture was purified by silica gel chromatography (hexane / ethyl acetate) to obtain the title compound (81%, 341 mg). LCMS:m / z 318[M+H] + HPLC retention time: 1.10 minutes (analysis condition H)

[0202] Third step Compound B3 tert-butyl 8-(2-fluoro-4-methoxycarbonyl-5-morpholine-4-ylphenyl)-2,4-dihydro-1,3-benzoxazine-3-carboxylate [ka] A solution of methyl 4-bromo-5-fluoro-2-morpholine-4-ylbenzoate (2.95 g, 9.28 mmol), bis(pinacolato)diborone (2.78 g, 11.0 mmol), potassium acetate (2.48 g, 25.3 mmol), and 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (0.344 g, 0.422 mmol) in 1,4-dioxane (16.9 mL) was stirred at 90°C for 5 hours. The reaction mixture was cooled to room temperature, and tert-butyl 8-bromo-2,4-dihydro-1,3-benzoxazine-3-carboxylate (2.65 g, 8.43 mmol), 1,1'-bis(diphenylphosphin)ferrocene-palladium(II) dichloride dichloromethane complex (0.344 g, 0.422 mmol), potassium carbonate (3.50 g, 25.3 mmol), and water (4.22 mL) were added. The mixture was stirred at 90°C for 3 hours. The reaction mixture was cooled to room temperature, water and ethyl acetate were added, and the mixture was filtered by Celite. The organic layer was washed with brine, dried, and concentrated. The resulting residue was purified by silica gel chromatography (hexane / ethyl acetate) to obtain the title compound (91%, 3.63 g). LCMS: m / z 473[M+H] + HPLC retention time: 1.34 minutes (analysis condition F)

[0203] Fourth step Compound B4 Methyl 4-(3,4-dihydro-2H-1,3-benzoxazine-8-yl)-5-fluoro-2-morpholine-4-ylbenzoato dihydrochloride [ka] To a solution of tert-butyl 8-(2-fluoro-4-methoxycarbonyl-5-morpholine-4-ylphenyl)-2,4-dihydro-1,3-benzoxazine-3-carboxylate (100 mg, 0.212 mmol) in dichloromethane (1.058 mL), a solution of 1,4-dioxane in 4M hydrochloric acid (0.794 mL, 3.17 mmol) was added and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated to obtain the title compound as the crude product. LCMS: m / z 373[M+H] + HPLC retention time: 0.49 minutes (analysis condition D)

[0204] Fifth step Compound B Methyl 4-[3-(4-bromo-2,6-dichlorobenzoyl)-2,4-dihydro-1,3-benzoxazine-8-yl]-5-fluoro-2-morpholine-4-ylbenzoate [ka] A solution of methyl 4-(3,4-dihydro-2H-1,3-benzoxazine-8-yl)-5-fluoro-2-morpholine-4-ylbenzoato dihydrochloride (141 mg, 0.317 mmol) and 4-bromo-2,6-dichlorobenzoyl chloride (137 mg, 0.476 mmol) in dichloromethane (1.585 mL) was cooled to 0°C. N,N-diisopropylethylamine (0.166 mL, 0.951 mmol) was added, and the mixture was stirred at room temperature for 3 hours. Ethanolamine was added to the reaction mixture, and the mixture was purified by reverse-phase column chromatography (acetonitrile / water, 0.1% formic acid) to obtain the title compound (56%, 110 mg). LCMS: m / z 623[M+H] + HPLC retention time: 1.37 minutes (analysis condition F)

[0205] <Examples 1-3> compound 1 4-[3-[2,6-Dichloro-4-[(2R)-2,4-dimethylpiperazine-1-yl]benzoyl]-2,4-dihydro-1,3-benzoxazine-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid First step Compound 1-1 Methyl 4-[3-[2,6-dichloro-4-[(2R)-2,4-dimethylpiperazine-1-yl]benzoyl]-2,4-dihydro-1,3-benzoxazine-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoate [ka] A solution of compound A (20.2 g, 31.1 mmol), (3R)-1,3-dimethylpiperazine (4.61 g, 40.4 mmol), rac-BINAP Pd G4 (938 mg, 0.932 mmol), and cesium carbonate (30.4 g, 93.0 mmol) in 1,4-dioxane (202 mL) was stirred at 80°C for 7.5 hours. (3R)-1,3-dimethylpiperazine (2.48 g, 21.7 mmol) was added, and the reaction mixture was stirred at 100°C for 49 hours. The reaction mixture was filtered through Celite and washed with ethyl acetate. The filtrate was washed with 15% aqueous sodium chloride solution, and the organic layer was concentrated. The resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate / methanol) to obtain the title compound (75%, 15.9 g). LCMS:m / z 683[M+H] + HPLC retention time: 0.89 minutes (analysis condition F)

[0206] Second process compound 1 4-[3-[2,6-Dichloro-4-[(2R)-2,4-dimethylpiperazine-1-yl]benzoyl]-2,4-dihydro-1,3-benzoxazine-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid [ka] To a solution of methyl 4-[3-[2,6-dichloro-4-[(2R)-2,4-dimethylpiperazine-1-yl]benzoyl]-2,4-dihydro-1,3-benzoxazine-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoato (18.6 g, 27.2 mmol) in 1-methylpyrrolidine-2-one (186 mL), 11.9 mL, 95.0 mmol, aqueous potassium hydroxide solution was added and the mixture was stirred at 60°C for 2 hours. Formic acid solution was added to the reaction mixture and purified by reverse-phase column chromatography (acetonitrile / water, 0.1% formic acid) to obtain the title compound (85%, 15.4 g). LCMS: m / z 669[M+H] + HPLC retention time: 0.99 minutes, 1.04 minutes (Analysis conditions B)

[0207] <Examples 1-4> compound 2 4-[3-[2,6-Dichloro-4-[4-(2-methoxyethyl)piperazine-1-yl]benzoyl]-2,4-dihydro-1,3-benzoxazine-8-yl]-5-fluoro-2-morpholine-4-ylbenzoic acid [ka] Compound B (1.72 g, 2.76 mmol), 1-(2-methoxyethyl)piperazine (0.818 ml, 5.51 mmol), [2,2'-bis(diphenylphosphino)-1,1'-binaphthyl]dichloropalladium(II) (65.0 mg, 0.0810 mmol), and cesium carbonate (2.69 g, 8.27 mmol) were heated in toluene (15.0 mL) at 95°C for 2 hours. The reaction mixture was cooled to room temperature and the solvent was concentrated. Dimethyl sulfoxide (5.00 mL), 1,4-dioxane (5.00 mL), and 5M sodium hydroxide aqueous solution (2.76 mL, 13.8 mmol) were added, and the mixture was stirred at 90°C for 1 hour. The reaction mixture was concentrated to remove 1,4-dioxane, formic acid was added, and the reaction mixture was purified by reverse-phase column chromatography (acetonitrile / water, 0.1% formic acid) to obtain the title compound (67%, 1.24 g). LCMS: m / z 673[M+H] + HPLC retention time: 0.77 minutes, 0.82 minutes (Analysis conditions A)

[0208] <Examples 1-5> compound 3 4-[3-[2,6-dichloro-4-(7,7-dimethyl-5,9-dioxa-2-azaspiro[3.5]nonan-2-yl)benzoyl]-2,4-dihydro-1,3-benzoxazine-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid First step Compound 3-1 Benzyl 7,7-dimethyl-5,9-dioxa-2-azaspiro[3,5]nonane-2-carboxylate [ka] To a solution of benzyl 3-oxoazetidine-1-carboxylate (15.0 g, 73.1 mmol) in acetonitrile (300 mL), 2,2-dimethyl-1,3-propanediol (14.5 ml, 146 mmol) and trimethylsilyl trifluoromethanesulfonate (6.60 ml, 36.5 mmol) were added, and the mixture was stirred at 70°C for 7 hours. The reaction mixture was cooled to room temperature and concentrated. The resulting residue was dissolved in ethyl acetate, washed with 5% aqueous sodium bicarbonate and 15% aqueous sodium chloride, and the organic layer was dried over magnesium sulfate and concentrated. The resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (84%, 17.9 g). LCMS:m / z 292[M+H] + HPLC retention time: 1.15 minutes (analysis condition F)

[0209] Second process Compound 3-2 7,7-dimethyl-5,9-dioxa-2-azaspiro[3.5]nonane [ka] To a solution of benzyl 7,7-dimethyl-5,9-dioxa-2-azaspiro[3,5]nonane-2-carboxylate (3.63 g, 12.5 mmol) in 1,4-dioxane (36.3 mL), 20% palladium hydroxide-activated carbon (hydrated) (306 mg, 0.436 mmol) was added, and the mixture was stirred under a hydrogen atmosphere for 14 hours. The reaction mixture was filtered through Celite, washed with 1,4-dioxane, and concentrated to obtain the title compound as the crude product of the 1,4-dioxane solution.

[0210] Third step Compound 3-3 Methyl 4-[3-[2,6-dichloro-4-(7,7-dimethyl-5,9-dioxa-2-azabispiro[3.5]nonan-2-yl)benzoyl]-2,4-dihydro-1,3-benzoxazine-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoate [ka] Compound A (4.40 g, 6.77 mmol), a 6.58 wt% solution of 7,7-dimethyl-5,9-dioxa-2-azaspiro[3.5]nonane-1,4-dioxane (21.0 g, 8.80 mmol), cesium carbonate (6.61 g, 20.3 mmol), and a 1,4-dioxane solution of rac-BINAP Pd G4 (204 mg, 0.203 mmol) (30.8 mL) were stirred at 60°C for 4.5 hours. The reaction mixture was filtered through Celite and washed with ethyl acetate. The filtrate was washed with a 15% aqueous sodium chloride solution and then extracted. The organic layer was dried over sodium sulfate and concentrated. The resulting residue was mixed with ethyl acetate and hexane, and the title compound (4.96 g) was quantitatively obtained by trituration. LCMS:m / z 726[M+H] + HPLC retention time: 1.48 minutes (analysis condition F)

[0211] Fourth step compound 3 4-[3-[2,6-dichloro-4-(7,7-dimethyl-5,9-dioxa-2-azaspiro[3.5]nonan-2-yl)benzoyl]-2,4-dihydro-1,3-benzoxazine-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid [ka] To a solution of methyl 4-[3-[2,6-dichloro-4-(7,7-dimethyl-5,9-dioxa-2-azabicyclo[3.5]nonan-2-yl)benzoyl]-2,4-dihydro-1,3-benzoxazine-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoato (12.8 g, 17.6 mmol) in tetrahydrofuran (32.0 mL) and methanol (32.0 mL), 8M potassium hydroxide aqueous solution (6.61 mL, 52.8 mmol) was added, and the mixture was stirred at 50°C for 3 hours. The reaction mixture was cooled to room temperature, 1M hydrochloric acid was added, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with 3% N-acetylcysteine ​​aqueous solution and 15% sodium chloride aqueous solution, dried over sodium sulfate, and concentrated. Ethanol was added to the residue, heated at 60°C, and then water was added and the mixture was cooled to room temperature. Further water was added, the resulting solid was filtered, and washed with ethanol / water (1 / 6) to obtain the title compound (88%, 11.0 g). LCMS:m / z 712[M+H] + HPLC retention time: 1.68, 1.72 minutes (Analysis conditions B)

[0212] <Examples 1-6> compound 4 4-[3-[2,6-dichloro-4-(6-methoxy-2-azaspiro[3.3]heptan-2-yl)benzoyl]-2,4-dihydro-1,3-benzoxazine-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid Synthesis method A First step Compound 4-1 2,6-Dichloro-4-(6-methoxy-2-azaspiro[3,3]heptan-2-yl)benzoic acid [ka] 4-bromo-2,6-dichlorobenzoic acid (1.28 g, 4.74 mmol), 6-methoxy-2-azaspiro[3.3]heptane hydrochloride (1.55 g, 9.48 mmol), Xantphos (137 mg, 0.237 mmol), allyl palladium(II) chloride (dimer) (87.0 mg, 0.237 mmol), and trans,trans-1,5-diphenyl-1,4-pentadien-3-one (56.0 mg, 0.237 mmol) were added dropwise to a solution of 1,3-dimethyl-2-imidazolidinone (23.7 mL) with 1 M sodium bis(trimethylsilyl)amide tetrahydrofuran solution (19.0 mL, 19.0 mmol). The reaction mixture was stirred at room temperature for 17 hours, then aqueous formic acid and dimethyl sulfoxide were added, and the mixture was purified by reverse-phase column chromatography (acetonitrile / water, 0.1% formic acid) to obtain the title compound (84%, 1.26 g). LCMS:m / z 316[M+H] + HPLC retention time: 1.01 min (analysis condition F)

[0213] Second process Compound 4-2 Methyl 4-[3-[2,6-dichloro-4-(6-methoxy-2-azaspiro[3.3]heptan-2-yl)benzoyl]-2,4-dihydro-1,3-benzoxazine-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoate [ka] 2,6-Dichloro-4-(6-methoxy-2-azaspiro[3.3]heptan-2-yl)benzoic acid (698 mg, 2.21 mmol) was dissolved in ethyl acetate (14.0 mL) and Ghosez reagent (0.350 mL, 2.65 mmol) was added. The mixture was stirred at room temperature for 30 minutes. 4-Methylmorpholine (1.54 mL, 14.1 mmol) and methyl 4-(3,4-dihydro-2H-1,3-benzoxazin-8-yl)-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoato dihydrochloride (944 mg, 2.01 mmol) were added to the reaction mixture. The reaction mixture was stirred overnight at 50°C, and the solution was cooled to room temperature. 0.5 M sulfuric acid was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium bicarbonate aqueous solution and concentrated to obtain the crude product of the title compound. LCMS:m / z 696[M+H] + HPLC retention time: 3.22 minutes (Analysis conditions J)

[0214] Third step compound 4 4-[3-[2,6-dichloro-4-(6-methoxy-2-azaspiro[3.3]heptan-2-yl)benzoyl]-2,4-dihydro-1,3-benzoxazine-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid [ka] Methyl 4-[3-[2,6-dichloro-4-(6-methoxy-2-azaspiro[3.3]heptan-2-yl)benzoyl]-2,4-dihydro-1,3-benzoxazine-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoato (196 mg, 0.281 mmol) and 8M potassium hydroxide aqueous solution (0.352 mL, 2.81 mmol) were mixed in tetrahydrofuran (0.471 mL) and ethanol (1.57 mL) and stirred at 60°C for 1 hour. After the reaction mixture was cooled to room temperature, aqueous formic acid and dimethyl sulfoxide were added, and the mixture was purified by reverse-phase column chromatography (acetonitrile / water, 0.1% formic acid) to obtain the title compound (95%, 183 mg). LCMS:m / z 682[M+H] + HPLC retention time: 1.58 minutes, 1.61 minutes (Analysis conditions B)

[0215] <Examples 1-7> compound 4 4-[3-[2,6-dichloro-4-(6-methoxy-2-azaspiro[3.3]heptan-2-yl)benzoyl]-2,4-dihydro-1,3-benzoxazine-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid Synthesis method B First step Compound 4-2 Methyl 4-[3-[2,6-dichloro-4-(6-methoxy-2-azaspiro[3.3]heptan-2-yl)benzoyl]-2,4-dihydro-1,3-benzoxazine-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoate [ka] A solution of compound A (12.0 g, 18.5 mmol), 6-methoxy-2-azaspiro[3.3]heptane hydrochloride (4.53 g, 27.7 mmol), rac-BINAP (1.15 g, 1.85 mmol), tris(dibenzylideneacetone)dipalladium(0) (846 mg, 0.923 mmol), and cesium carbonate (30.1 g, 92.0 mmol) in 1-methylpyrrolidine-2-one (84.0 mL) and water (8.39 mL) was stirred at 100°C for 3 hours. The reaction mixture was cooled to room temperature, ethyl acetate and water were added, and the mixture was extracted. The organic layer was washed with aqueous N-acetylcysteine ​​and aqueous sodium chloride, dried over magnesium sulfate, and then concentrated. The resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (12.6 g) as a mixture with ethyl acetate. LCMS:m / z 696[M+H] + HPLC retention time: 3.22 minutes (Analysis conditions J)

[0216] Second process compound 4 4-[3-[2,6-dichloro-4-(6-methoxy-2-azaspiro[3.3]heptan-2-yl)benzoyl]-2,4-dihydro-1,3-benzoxazine-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid [ka] To a solution of methyl 4-[3-[2,6-dichloro-4-(6-methoxy-2-azaspiro[3.3]heptan-2-yl)benzoyl]-2,4-dihydro-1,3-benzoxazine-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoato (12.3 g, 17.6 mmol) in tetrahydrofuran (22.0 mL) / ethanol (22.0 mL), 11.0 mL of 8 M potassium hydroxide aqueous solution (88.0 mmol) was added, and the mixture was stirred at 60°C for 2.5 hours. The reaction mixture was cooled to room temperature, 0.5 M hydrochloric acid and water were added, and the mixture was stirred. The resulting solid was filtered, washed with water, and dried under reduced pressure. The resulting solid was mixed with an ethanol / water (1 / 9) solution, the solution was frozen in a -80°C freezer, and then freeze-dried to obtain the title compound (91%, 10.9 g). LCMS:m / z 682[M+H] + HPLC retention time: 1.58 minutes, 1.61 minutes (Analysis conditions B)

[0217] <Examples 1-8> compound 5 4-[3-[2-chloro-4-[(2R,5R)-2,4,5-trimethylpiperazine-1-yl]benzoyl]-2,4-dihydro-1,3-benzoxazine-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid First step Compound 5-1 (2R,5R)-1,2,5-trimethylpiperazine [ka] A solution of (2R,5R)-1,2,5-trimethylpiperazine dihydrochloride (10.3 g, 51.0 mmol) in tetrahydrofuran (49.6 mL) was mixed with 50% potassium hydroxide aqueous solution (11.4 g, 102 mmol), stirred at room temperature, filtered, and washed with tetrahydrofuran. The filtrate was concentrated to obtain a tetrahydrofuran solution of the title compound. 1H-NMR (400 MHz, DMSO-D6) δ: 5.75 (1H, s), 2.78-2.68 (2H, m), 2.56 (1H, dd, J = 12.0, 4.6 Hz), 2.39-2.36 (1H, m), 2.19 (1H, dd, J = 11.0, 3.4 Hz), 2.13-2.09 (4H, m), 0.99 (3H, d, J = 6.4 Hz), 0.91 (3H, d, J = 6.6 Hz).

[0218] Second process Compound 5-2 2-Chloro-4-[(2R,5R)-2,4,5-trimethylpiperazine-1-yl]benzoic acid [ka] Sodium tert-butoxide (2.78 g, 28.9 mmol) was added to a solution of (2R,5R)-1,2,5-trimethylpiperazine (1.63 g, 12.7 mmol) in tetrahydrofuran (18.4 mL). A solution of 4-bromo-2-chlorobenzoic acid (2.00 g, 8.49 mmol) and rac-BINAP (0.264 g, 0.425 mmol) in 4-methyltetrahydropyran (6.00 mL) was added. In a separate container, allyl palladium(II) chloride (dimer) (0.0780 g, 0.212 mmol) and rac-BINAP (0.264 g, 0.425 mmol) were added to 4-methyltetrahydropyran (4.00 mL) and stirred for 30 minutes. The prepared solutions were added and stirred at 90°C for 2 hours. After cooling the reaction mixture to room temperature, an aqueous solution of N-acetylcysteine ​​was added and the mixture was stirred at 45°C for 3 hours. 6M hydrochloric acid and 4-methyltetrahydropyran were added, and back-extraction was performed. Ethyl acetate was added to the aqueous layer, and back-extraction was performed with an 8M aqueous sodium hydroxide solution. Ammonium sulfate was added to the resulting aqueous layer, and then it was extracted with tetrahydrofuran. The organic layer was concentrated, trifluoroethanol was added, and the mixture was heated to 75°C. Acetonitrile was added and the mixture was stirred at 75°C. After cooling to 25°C, the resulting solid was filtered, washed with acetonitrile, and dried under reduced pressure to obtain the title compound (60%, 1.22 g). LCMS: m / z 283[M+H] + HPLC retention time: 0.33 minutes (analysis condition E)

[0219] Third step Compound 5-3 Methyl 4-(3,4-dihydro-2H-1,3-benzoxazine-8-yl)-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoatomethanesulfonate [ka] A solution of the title compound in acetonitrile was obtained by adding methanesulfonic acid (4.58 mL, 70.6 mmol) to a solution of tert-butyl 8-[2-fluoro-4-methoxycarbonyl-5-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)phenyl]-2,4-dihydro-1,3-benzoxazine-3-carboxylate (7.04 g, 14.1 mmol) in acetonitrile (28.1 mL) and stirring at room temperature for 2 hours.

[0220] Fourth step Compound 5-4 2-Chloro-4-[(2R,5R)-2,4,5-trimethylpiperazine-1-yl]benzoyl chloride [ka] A mixture of 2-chloro-4-[(2R,5R)-2,4,5-trimethylpiperazine-1-yl]benzoic acid (4.99 g, 16.9 mmol) and acetonitrile (42.2 mL) was mixed with Ghosez reagent (3.97 mL, 28.8 mmol) and stirred at room temperature for 1 hour. Methanesulfonic acid (1.19 mL, 18.3 mmol) was added. An acetonitrile solution of the title compound was obtained.

[0221] Fifth step Compound 5-5 Methyl 4-[3-[2-chloro-4-[(2R,5R)-2,4,5-trimethylpiperazine-1-yl]benzoyl]-2,4-dihydro-1,3-benzoxazine-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoate [ka] To the acetonitrile solution of 2-chloro-4-[(2R,5R)-2,4,5-trimethylpiperazine-1-yl]benzoyl chloride obtained in the fourth step, an acetonitrile solution of methyl 4-(3,4-dihydro-2H-1,3-benzoxazine-8-yl)-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoatomethanesulfonate obtained in the third step was added. N,N-diisopropylethylamine (16.0 mL, 92.0 mmol) was added and the mixture was stirred at 25°C for 1 hour. Ethyl acetate and water were added to the reaction mixture, and then water, 15% sodium chloride aqueous solution, 8M sodium hydroxide aqueous solution, and 1M hydrochloric acid were added, and the resulting organic layer was concentrated by extraction. 1M hydrochloric acid and ethyl acetate were added to the resulting residue, and back-extraction was performed. 8M sodium hydroxide aqueous solution and 2M hydrochloric acid were added to the resulting aqueous layer, and it was extracted with 4-methyltetrahydropyran. The organic layer was washed with a 15% aqueous sodium chloride solution, concentrated, and dried under reduced pressure to obtain the title compound (69%, 8.99 g). LCMS: m / z 663[M+H] + HPLC retention time: 0.86 minutes (analysis condition F)

[0222] Sixth step compound 5 4-[3-[2-chloro-4-[(2R,5R)-2,4,5-trimethylpiperazine-1-yl]benzoyl]-2,4-dihydro-1,3-benzoxazine-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid [ka] Methyl 4-[3-[2-chloro-4-[(2R,5R)-2,4,5-trimethylpiperazine-1-yl]benzoyl]-2,4-dihydro-1,3-benzoxazine-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoato (5.74 g, 8.66 mmol) was mixed with tetrahydrofuran (29.3 mL), 4-methyltetrahydropyran (1.38 mL), and methanol (8.61 mL). A 50% aqueous potassium hydroxide solution (1.93 mL, 26.0 mmol) was added, and the mixture was stirred at 25°C for 3 hours. Water and cyclopentyl methyl ether were added to the reaction mixture, and back-extraction was performed. 6M hydrochloric acid was added to the resulting aqueous layer, and it was washed with ethyl acetate. 2-butanone and 8M sodium hydroxide were added to the aqueous layer, and sodium chloride was added. Extraction was performed with 2-butanone, the resulting organic layer was concentrated, filtered, and washed with 2-butanone. The resulting filtrate and washings were concentrated, and acetone was added. Water was added to the resulting solution, and the mixture was stirred at 25°C. The resulting solid was filtered and washed with water. The title compound (83%, 4.67 g) was obtained by drying. LCMS:m / z 649[M+H] + HPLC retention time: 1.13 minutes (Analysis condition B)

[0223] <Examples 1-9> compound 6 4-[3-[4-chloro-6-(7,7-dimethyl-5,9-dioxa-2-azabispiro[3.5]nonan-2-yl)-2-methylpyridine-3-carbonyl]-2,4-dihydro-1,3-benzoxazine-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid First step Compound 6-1 4,6-Dichloro-2-methylpyridine-3-carbonyl chloride [ka] To a suspension of 4,6-dichloro-2-methylnicotinic acid (10.0 g, 48.5 mmol) in dichloromethane (194 mL), oxalyl chloride (5.00 mL, 58.2 mmol) and N,N-dimethylformamide (0.0380 mL, 0.485 mmol) were added, and the mixture was stirred at room temperature for 17 hours. An additional oxalyl chloride (5.00 mL, 58.2 mmol) was added to the reaction mixture, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated to obtain the title compound as the crude product.

[0224] Second process Compound 6-2 Methyl 4-[3-(4,6-dichloro-2-methylpyridine-3-carbonyl)-2,4-dihydro-1,3-benzoxazine-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoate [ka] Using methyl 4-(3,4-dihydro-2H-1,3-benzoxazine-8-yl)-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoato dihydrochloride and 4,6-dichloro-2-methylpyridine-3-carbonyl chloride, the title compound was obtained by the same procedure as for compound B and step 5. However, 4-methylmorpholine was used instead of N,N-diisopropylethylamine. LCMS:m / z 586[M+H] + HPLC retention time: 1.30 minutes (analysis condition F)

[0225] Third step Compound 6-3 Methyl 4-[3-[4-chloro-6-(7,7-dimethyl-5,9-dioxa-2-azabispiro[3.5]nonan-2-yl)-2-methylpyridine-3-carbonyl]-2,4-dihydro-1,3-benzoxazine-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoate [ka] A suspension of methyl 4-[3-(4,6-dichloro-2-methylpyridine-3-carbonyl)-2,4-dihydro-1,3-benzoxazine-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoato (5.00 g, 7.93 mmol), 7,7-dimethyl-5,9-dioxa-2-azaspiro[3.5]nonane (1.31 g, 8.33 mmol), XantPhos Pd G3 (0.376 g, 0.396 mmol), and cesium carbonate (10.3 g, 31.7 mmol) in a 1,4-dioxane (52.9 mL) solution was stirred overnight at 60°C. The reaction mixture was cooled to room temperature, XantPhos Pd G3 (0.376 g, 0.396 mmol) was added, and the mixture was stirred at 60°C for 8 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride aqueous solution, dried over magnesium sulfate, and filtered. The resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (36%, 2.01 g). LCMS:m / z 707[M+H] + HPLC retention time: 1.39 minutes (analysis condition F)

[0226] Fourth step compound 6 4-[3-[4-chloro-6-(7,7-dimethyl-5,9-dioxa-2-azabispiro[3.5]nonan-2-yl)-2-methylpyridine-3-carbonyl]-2,4-dihydro-1,3-benzoxazine-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid [ka] Methyl 4-[3-[4-chloro-6-(7,7-dimethyl-5,9-dioxa-2-azabicyclo[3.5]nonan-2-yl)-2-methylpyridine-3-carbonyl]-2,4-dihydro-1,3-benzoxazine-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoato (5.97 g, 8.44 mmol) was mixed with tetrahydrofuran (16.9 mL) and methanol (16.9 mL), to which 8M potassium hydroxide aqueous solution (3.17 mL, 25.3 mmol) was added and the mixture was stirred at 50°C for 1.5 hours. After adding formic acid aqueous solution to the reaction mixture, the mixture was purified by reverse-phase column chromatography (acetonitrile / water, 0.1% formic acid) to obtain the title compound (91%, 5.33 g). LCMS: m / z 693[M+H] + HPLC retention time: 1.62 minutes, 1.65 minutes (Analysis conditions B)

[0227] <Examples 1-10> compound 7 (2S,3R)-3-[2-[2,6-dichloro-4-(2-methoxyethoxy)benzoyl]-3,4-dihydro-1H-isoquinoline-5-yl]-2-methylbutanoic acid First step Compound 7-1 Ethyl (E)-3-(3,4-dihydroisoquinoline-5-yl)buta-2-enoate [ka] A solution of 5-bromo-3,4-dihydroisoquinoline (500 mg, 2.38 mmol), ethyl (E)-buta-2-enoate (678 mg, 5.94 mmol), dichlorobis(triphenylphosphine)palladium(II) (175 mg, 0.250 mmol), and potassium carbonate (1.15 g, 8.32 mmol) in N,N-dimethylformamide (5.00 mL) was stirred at 120°C for 16 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated to obtain a residue which was purified by reverse-phase column chromatography (acetonitrile / water, 0.1% formic acid) to obtain the title compound (35%, 200 mg). LCMS: m / z 244[M+H] + HPLC retention time: 1.22 minutes (Analysis conditions L)

[0228] Second process Compound 7-2 Ethyl 3-(1,2,3,4-tetrahydroisoquinoline-5-yl)butanoate [ka] A solution of ethyl (E)-3-(3,4-dihydroisoquinoline-5-yl)buta-2-enoate (100 mg, 0.410 mmol) and 10% palladium carbon (20.0 mg) in ethanol (10.0 mL) was stirred under a hydrogen atmosphere for 10 days. The solution was filtered, and the filtrate was concentrated to obtain the title compound as the crude product. LCMS: m / z 248[M+H] + HPLC retention time: 1.35 minutes (Analysis conditions L)

[0229] Third step Compound 7-3 Ethyl 3-(1,2,3,4-tetrahydroisoquinoline-5-yl)butanoatohydrochloride [ka] Ethyl 3-(1,2,3,4-tetrahydroisoquinoline-5-yl)butanoato (500 mg, 2.02 mmol) was dissolved in ethyl acetate (20.0 mL) and hydrochloric acid gas was bubbling at room temperature for 30 minutes. The resulting solid was filtered to obtain the title compound as the crude product. LCMS: m / z 248[M+H] + HPLC retention time: 1.34 minutes (analysis condition K)

[0230] Fourth step Compound 7-4 Ethyl (3R)-3-(1,2,3,4-tetrahydroisoquinoline-5-yl)butanoate [ka] Ethyl 3-(1,2,3,4-tetrahydroisoquinoline-5-yl)butanoato hydrochloride (300 mg) was separated into two stereoisomers by SFC (Chiralpak IBZ × 25 cm, 0.005 mm chiral-PCIB, hexane (0.2% isopropanol) / ethanol (0.2% isopropanol)) to obtain the title compound (47.9 mg) and the isomer (121.2 mg). LCMS:248[M+H] + HPLC retention time: 1.36 minutes (analysis condition K) SFC retention time: 3.19 min (Isomer retention time: 4.90 min) (Analysis conditions: CHIRALPAK IB-3, 0.46 × 15 cm, 3 μm, Hexane (0.2% isopropanol):Ethanol = 70:30, 9.0 min), 25℃, 220 nm)

[0231] Fifth step Compound 7-5 tert-butyl 5-[(2R)-4-ethoxy-4-oxobutan-2-yl]-3,4-dihydro-1H-isoquinoline-2-carboxylate [ka] Ethyl (3R)-3-(1,2,3,4-tetrahydroisoquinoline-5-yl)butanoato (29.0 mg, 0.117 mmol), di-tert-butyl 2carbonate (30.7 mg, 0.141 mmol), and triethylamine (0.0245 mL, 0.176 mmol) in dichloromethane (0.391 mL) were stirred at room temperature for 3 hours. The reaction mixture was poured into 1 M hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated sodium bicarbonate aqueous solution, passed through a phase separator, and the resulting residue was concentrated and purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (74%, 30.2 mg). LCMS:m / z 248[M+H-tBu] + HPLC retention time: 1.40 minutes (analysis condition I)

[0232] Sixth step Compound 7-6 (R)-3-(2-(tert-butoxycarbonyl)-1,2,3,4-tetrahydroisoquinoline-5-yl)butanoic acid [ka] To a solution of tert-butyl 5-[(2R)-4-ethoxy-4-oxobutan-2-yl]-3,4-dihydro-1H-isoquinoline-2-carboxylate (416 mg, 1.20 mmol) in tetrahydrofuran (2.99 mL) and methanol (2.99 mL), 5M aqueous sodium hydroxide (0.718 mL, 1.13 mmol) was added and the mixture was stirred at room temperature for 2 hours. The reaction mixture was then mixed with aqueous hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydroxide, passed through a phase separator, and then concentrated to obtain the title compound as the crude product. LCMS: m / z 342[M+Na] + HPLC retention time: 1.17 minutes (analysis condition I)

[0233] Seventh step Compound 7-7 5-((R)-4-((S)-4-isopropyl-2-oxoxazolidine-3-yl)-4-oxobutan-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylic acid tert-butyl [ka] The crude product of (R)-3-(2-(tert-butoxycarbonyl)-1,2,3,4-tetrahydroisoquinoline-5-yl)butanoic acid and a solution of triethylamine (0.499 mL, 3.59 mmol) in tetrahydrofuran (4.79 mL) were cooled to 0°C, pivaloyl chloride (0.162 mL, 1.32 mmol) was added, and the mixture was stirred at 0°C for 1 hour. (S)-4-isopropyl-2-oxazolidinone (170 mg, 1.32 mmol) and lithium chloride (66.0 mg, 1.56 mmol) were added at 0°C, and the mixture was stirred for 1 hour while increasing the temperature to room temperature. The reaction mixture was concentrated by adding 1 M hydrochloric acid and methanol at 0°C, and then purified by reverse-phase column chromatography (acetonitrile / water, 0.1% formic acid) to obtain the title compound (95%, 490 mg). LCMS: m / z 453[M+Na] + HPLC retention time: 1.41 minutes (analysis condition I)

[0234] Eighth process Compound 7-8 5-((2R,3S)-4-((S)-4-isopropyl-2-oxoxazolidine-3-yl)-3-methyl-4-oxobutan-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylic acid tert-butyl [ka] A solution of 5-((R)-4-((S)-4-isopropyl-2-oxoxazolidine-3-yl)-4-oxobutan-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylic acid tert-butyl (365 mg, 0.848 mmol) in tetrahydrofuran (4.24 mL) was cooled to -78°C, and 1 M sodium bis(trimethylsilyl)amide (1.10 mL, 1.10 mmol) was added dropwise and the mixture was stirred for 1 hour. Iodomethane (0.158 mL, 2.54 mmol) was added and the mixture was stirred for 1 hour, followed by stirring at -40°C for 2 hours. Saturated ammonium chloride aqueous solution was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with saturated sodium bicarbonate aqueous solution and saturated brine, concentrated through a phase separator, and then purified by reverse-phase column chromatography (acetonitrile / water, 0.1% formic acid) to obtain the title compound (70%, 263 mg). LCMS: m / z 467[M+Na] + HPLC retention time: 1.51 minutes (analysis condition G)

[0235] Ninth step Compound 7-9 (4S)-3-[(2S,3R)-2-methyl-3-(1,2,3,4-tetrahydroisoquinoline-5-yl)butanoyl]4-propan-2-yl-1,3-oxazolidine-2-one hydrochloride [ka] 228 mg, 0.513 mmol of tert-butyl 5-[(2R)-4-ethoxy-4-oxobutan-2-yl]-3,4-dihydro-1H-isoquinoline-2-carboxylate was added to a solution of 4M hydrochloric acid-1,4-dioxane (5.00 ml, 20.0 mmol), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated to obtain the title compound as the crude product. LCMS: m / z 345[M+H] + HPLC retention time: 0.73 minutes (analysis condition G)

[0236] Tenth step Compound 7-10 (4S)-3-[(2S,3R)-3-[2-[2,6-dichloro-4-(2-methoxyethoxy)benzoyl]-3,4-dihydro-1H-isoquinoline-5-yl]-2-methylbutanoyl]-4-propan-2-yl-1,3-oxazolidine-2-one [ka] To a solution of 2,6-dichloro-4-(2-methoxyethoxy)benzoic acid (119 mg, 0.448 mmol) in dichloromethane (2.00 ml), oxalyl chloride (0.0710 ml, 0.814 mmol) and N,N-dimethylformamide (0.00315 ml, 0.0410 mmol) were added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated and azeotropically removed with toluene to obtain 2,6-dichloro-4-(2-methoxyethoxy)benzoyl chloride as the crude product. A solution of (4S)-3-[(2S,3R)-2-methyl-3-(1,2,3,4-tetrahydroisoquinoline-5-yl)butanoyl]-4-propan-2-yl-1,3-oxazolidine-2-one hydrochloride (155 mg, 0.407 mmol) in dichloromethane (2.00 ml) was cooled to 0°C, and 2,6-dichloro-4-(2-methoxyethoxy)benzoyl chloride and triethylamine (0.170 ml, 1.22 mmol) were added. The mixture was stirred at room temperature for 30 minutes. The reaction mixture was poured into 1 M hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated sodium bicarbonate aqueous solution, passed through a phase separator, and then concentrated to obtain the title compound as the crude product. LCMS:m / z 591[M+H] + HPLC retention time: 1.39 minutes (analysis condition G)

[0237] Eleventh step compound 7 (2S,3R)-3-[2-[2,6-dichloro-4-(2-methoxyethoxy)benzoyl]-3,4-dihydro-1H-isoquinoline-5-yl]-2-methylbutanoic acid [ka] A solution of (4S)-3-[(2S,3R)-3-[2-[2,6-dichloro-4-(2-methoxyethoxy)benzoyl]-3,4-dihydro-1H-isoquinoline-5-yl]-2-methylbutanoyl]-4-propan-2-yl-1,3-oxazolidine-2-one (241 mg, 0.407 mmol) in tetrahydrofuran (2.17 ml) and water (0.543 ml) was cooled to 0°C, and 34.5% hydrogen peroxide solution (0.281 ml, 2.85 mmol) and lithium hydroxide monohydrate (51.2 mg, 1.22 mmol) were added, and the mixture was stirred at room temperature for 3 hours. Methanol and formic acid were added to the reaction mixture, and the mixture was purified by reverse-phase column chromatography (acetonitrile / water, 0.1% formic acid) to obtain the title compound (96%, 187 mg). LCMS: m / z 480[M+H] + HPLC retention time: 1.07, 1.09 minutes (analysis condition C)

[0238] [Example 2] Method for producing crystals (Example 2-1-1) Compound 1 (28.9 mg) was dissolved in 120 μL of tetrahydrofuran at room temperature. 480 μL of methanol / water = 9 / 1 (v / v) mixed solution was added, and the mixture was stirred for 20 minutes. Further, 600 μL of methanol / water = 9 / 1 (v / v) mixed solution was added, and the mixture was stirred for 4 hours to obtain a suspension. The suspension was filtered and vacuum-dried for 24 hours to obtain 18.8 mg of hydrate type 1A crystalline powder. The results of powder X-ray diffraction measurements of this powder are shown in Figure 1, and representative peaks are shown in Table 2 below. The results of TG-DTA measurements are also shown in Figure 2.

[0239] [Table 2]

[0240] (Example 2-1-2) Compound 1 (10.8 mg) was added to a 50 μL mixture of ethanol / water = 1 / 3 (v / v), and the mixture was shaken at 25°C for 13 days to obtain crystals. The obtained crystals were confirmed to be hydrate 1G type crystals by powder X-ray diffraction.

[0241] (Example 2-1-3) Compound 1 (30.3 mg) was dissolved in 120 μL of tetrahydrofuran at room temperature. 120 μL of water was added, and approximately 0.1 mg of the crystals obtained in Example 2-1-2 was added as a seed crystal. After 30 minutes, 60 μL of water was added. After 130 minutes, another 60 μL of water was added. After 50 minutes, 120 μL of water was added. After 150 minutes, another 120 μL of water was added. After 80 minutes, 240 μL of water was added. After 20 hours, the liquid was filtered and dried at room temperature for 24 hours to obtain 27.8 mg of hydrate 1G type crystalline powder. The results of the powder X-ray diffraction measurement of this powder are shown in Figure 3, and the representative peaks are shown in Table 3 below. The results of the TG-DTA measurement are shown in Figure 4.

[0242] [Table 3]

[0243] (Example 2-1-4) Powder X-ray diffraction measurements were performed on 1G-type crystals stored at 34°C and 60% relative humidity for approximately 5 minutes. Then, the relative humidity was changed to 0% and the crystals were stored for approximately 60 minutes, followed by another powder X-ray diffraction measurement. These results confirmed that changing the relative humidity from 60% to 0% caused the 1G-type crystals to transform into the non-solvated 1H-type crystals. Furthermore, the relative humidity was changed to 30% and the crystals were stored for approximately 15 minutes, followed by another powder X-ray diffraction measurement. These results confirmed that changing the relative humidity from 0% to 30% caused the 1H-type crystals to further transform into the hydrated 1J-type crystals. The results of these powder X-ray diffraction measurements are shown in Figure 5, and representative peaks at each humidity level are shown in Table 4 below.

[0244] [Table 4]

[0245] (Example 2-1-5) Compound 1 (5.6 mg) was mixed with acetone (15 μL) and stirred. After 5 minutes, acetone (35 μL) was added. The suspension was filtered to obtain 1K type crystals. The results of powder X-ray diffraction are shown in Figure 6, and representative peaks are shown in Table 5 below.

[0246] [Table 5]

[0247] (Example 2-1-6) Compound 1 (10.5 mg) was dissolved in dimethylformamide (40 μL) at 80°C. Water (20 μL) was added, and a 1G type crystal (0.1 mg) was added as a seed crystal, and the mixture was cooled to room temperature. Then, the mixture was heated to 80°C, water (10 μL) was added, and the mixture was cooled to room temperature. The mixture was then heated again to 80°C and cooled to room temperature. The mixture was heated again to 80°C, water (5 μL) was added, and the mixture was cooled to room temperature. The mixture was then heated again to 80°C and cooled to room temperature. X-ray crystal structure analysis was performed on the obtained crystal. The crystal structure of the obtained 1G type crystal is shown in Figure 7. The parameters characterizing this crystal are shown in Table 6 below.

[0248] [Table 6]

[0249] (Example 2-2-1) Compound 4 (3 mg) was mixed with 2-propanol (15 μL) and shaken for 6 days to obtain crystals. Powder X-ray diffraction confirmed that the obtained crystals were non-solvated 2A type crystals.

[0250] (Example 2-2-2) 3 mg of compound 4 was mixed with 15 μL of ethanol and shaken for 6 days to obtain a non-solvated 2B type crystal. The results of powder X-ray diffraction are shown in Figure 8, and representative peaks are shown in Table 7 below.

[0251] [Table 7]

[0252] (Example 2-2-3) Compound 4 (approximately 5 mg) was dissolved in acetonitrile (100 μL) under reflux conditions, and then cooled to room temperature to obtain crystals. The obtained crystals were confirmed to be 2F-type crystals, which are non-solvated, by powder X-ray diffraction.

[0253] (Example 2-2-4) Compound 4 (146.8 mg) was dissolved in DMSO (1 mL) at 120°C. After cooling to room temperature, 2-propanol (5 mL) was added, and then the crystal obtained in Example 2-2-1 (approximately 0.1 mg) was added as a seed crystal. Another 2-propanol (10 mL) was added, and after stirring for 18 hours, the mixture was filtered and the resulting solid was washed with 2-propanol (2 mL). After vacuum drying for 1 day, 125.3 mg of non-solvated 2A type crystals were obtained. The results of powder X-ray diffraction measurement are shown in Figure 9, and representative peaks are shown in Table 8 below. The results of TG-DTA measurement are shown in Figure 10.

[0254] [Table 8]

[0255] (Example 2-2-5) Compound 4 (105.8 mg) was dissolved in acetonitrile (5 mL) under reflux and cooled to room temperature. This solution was added dropwise to water (15 mL) and stirred overnight to obtain 92.2 mg of a non-solvated 2C-type crystal. The results of powder X-ray diffraction measurements are shown in Figure 11, and representative peaks are shown in Table 9 below. The results of TG-DTA measurements are shown in Figure 12.

[0256] [Table 9]

[0257] (Example 2-2-6) Compound 4 (29.4 mg) was dissolved in acetonitrile (900 μL) under reflux conditions and then cooled to room temperature. The crystal obtained in Example 2-2-3 (approximately 0.1 mg) was added as a seed crystal, and the mixture was stirred for 3 hours. After filtration, the resulting powder was vacuum-dried to obtain 18.9 mg of 2F-type crystals. The results of the powder X-ray diffraction measurement are shown in Figure 13, and representative peaks are shown in Table 10 below. The results of the TG-DTA measurement are shown in Figure 14.

[0258] [Table 10]

[0259] (Example 2-3-1) Compound 3 (approximately 30 mg) was mixed with ethyl acetate (300 μL). After 30 minutes, a portion of the suspension was filtered to obtain 3D-type crystals. The results of the powder X-ray diffraction measurement are shown in Figure 15. The remaining suspension was stirred for another 15 minutes and then filtered. The resulting solid was vacuum-dried overnight to obtain 3B-type crystals. The results of the powder X-ray diffraction measurement are shown in Figure 16. The results of the TG-DTA measurement are shown in Figure 17. Representative peaks from each powder X-ray diffraction measurement are shown in Table 11 below.

[0260] [Table 11]

[0261] (Example 2-3-2) Compound 3 (29.4 mg) was dissolved in ethanol (300 μL) under reflux. After cooling to room temperature and stirring for 16 hours, the suspension was filtered and powder X-ray diffraction was performed. The obtained powder was vacuum dried to obtain non-solvated type 3A crystals. The results of the powder X-ray diffraction measurement are shown in Figure 18, and representative peaks are shown in Table 12 below.

[0262] [Table 12]

[0263] (Example 2-3-3) Compound 3 (approximately 30 mg) was mixed with methanol (300 μL) and stirred at room temperature for approximately 30 minutes. A portion of the resulting suspension was filtered, and powder X-ray diffraction was performed. The remainder was also filtered, and the solid was isolated and vacuum-dried for one day to obtain non-solvated 3C type crystals. The results of the powder X-ray diffraction measurement are shown in Figure 19, and representative peaks are shown in Table 13 below. The results of the TG-DTA measurement are shown in Figure 20.

[0264] [Table 13]

[0265] (Example 2-4-1) Methyl isobutyl ketone (15 μL) was added to compound 6 (3 mg) and shaken for 3 days. Then, heptane (15 μL) was added and shaken for 5 days to obtain type 4A crystals. The results of powder X-ray diffraction measurements are shown in Figure 21, and representative peaks are shown in Table 14 below.

[0266] [Table 14]

[0267] (Example 2-4-2) 3 mg of compound 6 was mixed with water / acetonitrile = 3 / 1 (v / v) (15 μL) and shaken for 8 days to obtain a hydrated 4B-type crystal. The results of single-crystal X-ray crystal structure analysis are shown in Figure 22. The parameters characterizing this crystal are shown in Table 15 below.

[0268] [Table 15]

[0269] (Example 2-4-3) Compound 6 (50.1 mg) was mixed with acetone (200 μL) and heated to 60°C. After cooling to room temperature, water (50 μL) was added. After 5 minutes, water (100 μL) was added. After 10 minutes, water (250 μL) was added. After 5 minutes, water (400 μL) was added. After 5 minutes, water (1200 μL) was added. After 15 minutes, the suspension was filtered and powder X-ray diffraction was performed. The mixture was dried at room temperature under normal pressure for 15 hours to obtain 44.9 mg of type 4B crystals. The results of the powder X-ray diffraction measurement are shown in Figure 23, and representative peaks are shown in Table 16 below. The results of the TG-DTA measurement are shown in Figure 24.

[0270] [Table 16]

[0271] (Example 2-5-1) Compound 5 (5.4 mg) was mixed with PEG400 (15 μL) and heated to 80°C. The mixture was stirred overnight, and water (5 μL) was added. After a further 7 hours, it was cooled to room temperature and stirred for 3 days to obtain crystals. The obtained crystals were confirmed to be hydrate type 5A crystals by powder X-ray diffraction.

[0272] (Example 2-5-2) Compound 5 (30.6 mg) was dissolved in acetone / methyl ethyl ketone = 1 / 2 (v / v) (120 μL). Water (120 μL) was added, and then the crystal obtained in Example 2-5-1 (approximately 0.1 mg) was added as a seed crystal, and the mixture was stirred for 55 minutes. Water (120 μL) was added and the mixture was stirred for 210 minutes. Water (120 μL) was added again and the mixture was stirred for 70 minutes, and then water (240 μL) was added. After stirring for a further 15 hours, the suspension was filtered and dried at room temperature and atmospheric pressure for 7 hours to obtain type 5A crystals (26.7 mg). The results of the powder X-ray diffraction measurement are shown in Figure 25, and the representative peaks are shown in Table 17 below. The results of the TG-DTA measurement are shown in Figure 26.

[0273] [Table 17]

[0274] (Example 2-5-3) Compound 5 (approximately 25 mg) was heated at 110°C for 1 hour. After cooling to room temperature, it was stored at 100% relative humidity for 2 hours to obtain hydrate 5E type crystals. The results of powder X-ray diffraction measurement are shown in Figure 27. The results of TG-DTA measurement are shown in Figure 28. Furthermore, the obtained 5E type crystals were vacuum-dried to obtain non-solvated 5D type crystals. The results of powder X-ray diffraction measurement are shown in Figure 29. Representative peaks from each powder X-ray diffraction measurement are shown in Table 18 below.

[0275] [Table 18]

[0276] (Example 2-5-4) A hydrated 5A-type crystal was stored at 25°C and 95% relative humidity for 1 hour. Then, it was stored at 60% relative humidity for 1 hour, and powder X-ray diffraction measurements were performed (1st measurement). Next, it was stored at 30% relative humidity for 1 hour, and powder X-ray diffraction measurements were performed again. Then, it was stored at 20% relative humidity for 1 hour, and powder X-ray diffraction measurements were performed again. Finally, it was stored at 10% relative humidity for 1 hour, and powder X-ray diffraction measurements were performed again. The results of these powder X-ray diffraction measurements are shown in Figure 30, and the representative peaks at each humidity are shown in Table 19 below. Next, the crystal was stored at 5% relative humidity for 1 hour, and then at 60% relative humidity for 1 hour, and powder X-ray diffraction measurements were performed again (2nd measurement). As shown in Figure 31, the pattern matched that of the initial measurement at 60% relative humidity. This indicates that the 5A-type crystal is a crystalline form in which the peak position fluctuates in response to humidity.

[0277] [Table 19]

[0278] (Example 2-5-5) 5G type crystals were obtained by adding acetone (25 μL) to 5A type crystals (5.0 mg), adding glass beads, and shaking at 2000 rpm for 7 days at room temperature. The results of powder X-ray diffraction measurements are shown in Figure 32, and representative peaks are shown in Table 20 below.

[0279] [Table 20]

[0280] (Example 2-5-6) A methyl ethyl ketone / acetone = 2 / 1 (v / v) mixed solution was prepared. This mixed solution was then mixed with water in a ratio of 65 / 35 (v / v). 30 μL of this solution was mixed with approximately 3 mg each of 5A-type crystals and 5G-type crystals, glass beads were added, and the mixture was shaken at 2000 rpm for one month to obtain a solid. The results of powder X-ray diffraction measurement are shown in Figure 33. This measurement confirmed that the obtained solid was a 5A-type crystal. Single-crystal X-ray structure analysis was also performed under conditions of 25°C and 30% relative humidity. The obtained crystal structure is shown in Figure 34. The parameters characterizing this crystal are shown in Table 21 below.

[0281] [Table 21]

[0282] (Example 2-5-7) To a methyl ethyl ketone solution (1.4 v / w) of compound 5 (850 mg), acetone (1.3 v / w, 1.1 mL) was added, followed by methyl ethyl ketone (1.2 v / w, 1.0 mL). Water (1.6 mL) was added, and a 5A type crystal (8.5 mg) was added as a seed crystal. Further water (1.6 mL) was added over 30 minutes, and the mixture was stirred for 1 hour. Water (3.2 mL) was added, and the mixture was stirred for 21 hours. Further water (3.2 mL) was added over 1 hour, and the mixture was stirred for 3 hours, and further water (3.2 mL) was added over 1 hour, and the mixture was stirred for 17 hours and 30 minutes. Finally, water (3.2 mL) was added over 1 hour, and the mixture was stirred for 23 hours and 30 minutes. The suspension was filtered and washed with water (6.5 v / w, 5.5 mL) to obtain wet crystals (1.1 g). 297.9 mg of wet crystals were dried under a nitrogen stream for approximately 5 hours to obtain dry crystals (269.4 mg). Of the dried crystals, 206.2 mg was further dried under a nitrogen stream for 5 hours and 30 minutes to obtain dried crystals (203.5 mg). Of these, 110.4 mg was further dried under a nitrogen stream for 28 hours to obtain 5A type crystals (110.3 mg).

[0283] (Example 2-5-8) 5A type crystals prepared by the method described in Example 2-5-7 were stored at 25°C at a relative humidity of 5% or 10% for 1 hour, and powder X-ray diffraction measurements were performed. The results confirmed that when the relative humidity was changed to around 10% or lower, the hydrated 5A type crystals transformed into 5C type crystals. The results of the powder X-ray diffraction measurements are shown in Figure 35, and representative peaks are shown in Table 22 below.

[0284] [Table 22]

[0285] (Example 2-5-9) 5C-type crystals prepared by the method described in Example 2-5-8 were stored at 25°C for 1 hour at a relative humidity of approximately 30% or higher, and powder X-ray diffraction measurements were performed at each relative humidity. The results confirmed that changing the relative humidity to approximately 30% or higher caused the 5C-type crystals to transform into the hydrated 5J-type crystals. Furthermore, it was confirmed that the peak position of the powder X-ray diffraction pattern of the 5J-type crystals shifted slightly depending on the relative humidity. The results of the powder X-ray diffraction measurements are shown in Figure 36, and representative peaks are shown in Table 23 below.

[0286] [Table 23]

[0287] [Evaluation of crystals] Powder X-ray diffraction measurements in Example 2 were performed under one of the following conditions. (Measurement method 1) Measurement equipment: SmartLab System, D / Tex Ultra detector (manufactured by Rigaku) Radiation source: CuKα1 tube Voltage: 45 kV Tube current: 200 mA Scanning speed: 5° / min Sampling width: 0.02° (Measurement method 2) Measurement equipment: D8 Discover, 2D VÅNTEC-500 solid state detector (manufactured by Bruker) Source: CuKα Tube voltage / current: 40kV / 40mA or 50kV / 1000μA Measurement range: 5~31° Exposure time: 40-600 seconds

[0288] Powder X-ray diffraction measurements under temperature and humidity control were performed under one of the following conditions. (Measurement method 1) Measurement device: X'pert-pro MPD (manufactured by PANalytical) Radiation source: CuKα tube Voltage: 45 kV Tube current: 40 mA Scanning speed: 0.33° / second Sampling width: 0.026° Number of integrations: 3 (Measurements were repeated 3 times under the above scanning conditions and then integrated) (Measurement method 2) Measurement equipment: SmartLab System, D / Tex Ultra detector, water vapor generator HUM-SL (manufactured by Rigaku Corporation) Source: CuKα1 Tube voltage: 45kV Tube current: 200mA Scanning speed: 2.0° / min Sampling width: 0.02°

[0289] Single-crystal X-ray structural analysis was performed under the following conditions. Measurement device: XtaLAB Synergy Custom with a VariMax Cu diffractometer or Rigaku R-AXIS RAPID-II with a VariMax Cu diffractometer (manufactured by Rigaku Corporation) Source: CuKα Tube voltage / current: 40kV / 30mA Temperature: -180°C or room temperature In all cases, measurements were performed using strategies and exposure times that were considered to yield sufficient diffraction spots for structural analysis. Furthermore, for structural analysis, the initial structure determination was performed using the direct method (SHELXT2014 / 5 or SHELXT2018 / 2), and structural refinement was performed using the full-matrix least-squares method (SHELXL2017 / 1).

[0290] The differential thermal and thermogravimetric simultaneous measurement (TG-DTA) in Example 2 was performed under the following conditions. The onset temperature was determined from the endothermic peak and used as the melting point. Equipment: STA7200RV (manufactured by Hitachi High-Tech Science Co., Ltd.) Measurement atmosphere: Nitrogen Heating conditions: The temperature was increased from 30°C to 350°C at a rate of 10°C / min.

[0291] [Example 3] Measurement of in vitro Nrf2 transcriptional activity in HepG2 cells by ARE-dependent reporter assay The pGL4.37 vector (pARE-Luc, Promega) was transfected into the human hepatocellular carcinoma cell line HepG2, and incubated overnight at 37°C in a humidified atmosphere containing 5% CO2. The cells were detached by trypsin treatment, seeded in a 384-well plate containing the test compound, and incubated at 37°C for 4 hours. Subsequently, Bright-Glo Reagent (Promega) was added, and luciferase activity was measured using an Envision plate reader. The luciferase activity in each well was converted to a reaction rate (%), with the luciferase activity when compound 2 or compound 7 was reacted at a concentration of 3.75 μM set as 100%. A dose-response curve was created for each example compound, and the 50% effective concentration (EC2) was calculated. 50 The following was calculated. The results are shown in Table 24. These results demonstrate that the compounds of the present invention have Nrf2 activating activity in vitro.

[0292] [Table 24] [Industrial applicability]

[0293] The present invention provides low molecular weight compounds having Nrf2 activating activity, or salts thereof, or crystals of solvates thereof. The present invention also provides pharmaceuticals for the prevention and / or treatment of various diseases, such as neurodegenerative diseases, lung diseases, and kidney diseases.

Claims

1. The following formulas (1) to (5) 【Chemistry 1】 A compound represented by any of the following, or a salt thereof, or a crystal of a solvate thereof.

2. The crystal according to claim 1, wherein the crystal is a crystal of a compound represented by formula (4), a salt thereof, or a solvate thereof.

3. The crystal according to claim 1, wherein the crystal is a solvate crystal of the compound.

4. The crystal according to claim 3, wherein the solvate crystal is a hydrate crystal.

5. The crystal according to claim 4, wherein the hydrate crystal is a 1 to 10 hydrate crystal.

6. The crystal according to claim 4, wherein the hydrate crystal is a 1 to 5 hydrate crystal.

7. The crystal according to claim 4, wherein the hydrate crystal is a 1-3 hydrate crystal.

8. The crystal according to claim 1, wherein the crystal is a nonsolvate crystal of the compound.

9. The crystal according to claim 2, wherein the crystal is a hydrate crystal, and the hydrate crystal is a type 5A crystal containing peaks at 7.4°, 8.8°, and 9.5° (±0.2°) as diffraction angles (2θ values) determined by powder X-ray diffraction.

10. The crystal according to claim 2, wherein the crystal is a hydrate crystal, and the hydrate crystal is a type 5A crystal having at least three peaks selected from the group consisting of 7.4°, 8.8°, 9.5°, 10.8°, 12.7°, 16.0°, 16.8°, 17.3°, 17.9°, and 19.2° (±0.2°) as diffraction angles (2θ values) by powder X-ray diffraction, and the diffraction angles (2θ values) are those of a hydrate crystal stored for 1 hour at a temperature of 25°C and 10% relative humidity.

11. The crystal according to claim 2, wherein the crystal is a hydrate crystal, and the hydrate crystal is a 5A type crystal having at least five peaks selected from the group consisting of 7.4°, 8.8°, 9.5°, 10.8°, 12.7°, 16.0°, 16.8°, 17.3°, 17.9°, and 19.2° (±0.2°) as diffraction angles (2θ values) by powder X-ray diffraction, and the diffraction angles (2θ values) are those of a hydrate crystal stored for 1 hour at a temperature of 25°C and 10% relative humidity.

12. The crystal according to claim 2, wherein the crystal is a hydrate crystal, and the hydrate crystal is a type 5A crystal having at least seven peaks selected from the group consisting of 7.4°, 8.8°, 9.5°, 10.8°, 12.7°, 16.0°, 16.8°, 17.3°, 17.9°, and 19.2° (±0.2°) as diffraction angles (2θ values) by powder X-ray diffraction, and the diffraction angles (2θ values) are those of a hydrate crystal stored for 1 hour at a temperature of 25°C and 10% relative humidity.

13. The crystal according to claim 2, wherein the crystal is a hydrate crystal, and the hydrate crystal is a type 5A crystal having peaks of 7.4°, 8.8°, 9.5°, 10.8°, 12.7°, 16.0°, 16.8°, 17.3°, 17.9°, and 19.2° (±0.2°) as diffraction angles (2θ values) determined by powder X-ray diffraction, and the diffraction angles (2θ values) are those of a hydrate crystal stored for 1 hour at a temperature of 25°C and 10% relative humidity.

14. The crystal according to claim 2, wherein the crystal is a hydrate crystal, and the hydrate crystal is a type 5A crystal having peaks of 7.4°, 8.8°, 9.5°, 10.5°, 12.2°, 15.6°, 16.6°, 17.1°, 17.3°, and 17.5° (±0.2°) as diffraction angles (2θ values) determined by powder X-ray diffraction, and the diffraction angles (2θ values) are those of a hydrate crystal stored for 1 hour at a temperature of 25°C and 20% relative humidity.

15. The crystal according to claim 2, wherein the crystal is a hydrate crystal, and the hydrate crystal is a type 5A crystal with diffraction angles (2θ values) of 7.4°, 8.8°, 9.5°, 10.5°, 12.2°, 15.5°, 16.4°, 16.6°, 17.1°, and 17.6° (±0.2°) as measured by powder X-ray diffraction, and the diffraction angles (2θ values) are those of a hydrate crystal stored for 1 hour at a temperature of 25°C and 30% relative humidity.

16. The crystal according to claim 2, wherein the crystal is a hydrate crystal, and the hydrate crystal is a type 5A crystal having peaks of 7.4°, 8.8°, 9.5°, 10.3°, 12.2°, 15.4°, 16.3°, 16.6°, 17.0°, and 17.6° (±0.2°) as diffraction angles (2θ values) determined by powder X-ray diffraction, and the diffraction angles (2θ values) are those of a hydrate crystal stored for 1 hour at a temperature of 25°C and 60% relative humidity.

17. Crystals of the compound or salt thereof, or solvates thereof, according to any one of claims 1 to 16, for use in the prevention and / or treatment of neurodegenerative diseases, lung diseases, or kidney diseases.

18. A pharmaceutical composition comprising a compound or a salt thereof, or a crystal of a solvate thereof, according to any one of claims 1 to 16.

19. The pharmaceutical composition according to claim 18 for the prevention and / or treatment of neurodegenerative diseases, lung diseases, or kidney diseases.

20. The following formulas (1) to (5) 【Chemistry 2】 A method for producing a pharmaceutical composition containing a compound represented by any one of the following, a salt thereof, or a solvate thereof as an active ingredient, The method for producing the compound according to any one of claims 1 to 16, or a salt thereof, or a crystal of a solvate thereof, with a pharmaceutically acceptable carrier or medium.

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