Crystal of nitrogen-containing heterocyclic compound having nrf2 activation effect

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

Crystals of nitrogen-containing heterocyclic compounds with Nrf2 activation activity

[0001] The present invention relates to a crystal of a nitrogen-containing heterocyclic compound or a salt thereof, or a solvate thereof, which has Nrf2 activation activity, and also to a medicament and a pharmaceutical composition containing the compound or salt as an active ingredient.

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

[0003] Activation of Nrf2 exerts a wide range of pharmacological effects, including antioxidant, anti-inflammatory, anti-fibrotic, and anti-apoptotic effects, and is believed to have a protective effect 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; pulmonary diseases such as idiopathic pulmonary fibrosis, acute respiratory distress syndrome, chronic obstructive pulmonary disease, pulmonary arterial hypertension, and asthma; renal diseases such as chronic kidney disease and acute kidney injury; ophthalmological diseases such as uveitis, glaucoma, and age-related macular degeneration; liver diseases such as nonalcoholic steatohepatitis; and immune / inflammatory diseases such as multiple sclerosis, rheumatoid arthritis, and ulcerative colitis (Non-Patent Documents 3 to 7). Bardoxolone methyl (CDDO-Me, Patent Document 1), a compound that has been shown to induce Nrf2 activation, is currently undergoing clinical trials in various chronic kidney diseases. Furthermore, RTA-408 (omaveloxolone, Patent Document 2) has been approved by the FDA for the treatment of Friedreich's ataxia and other conditions. Dimethyl fumarate (Patent Document 3) is used as a therapeutic agent for multiple sclerosis. However, these compounds covalently bind to Keap1. Concerns have been raised about the risk of heart failure due to interactions between the covalent binding site of bardoxolone methyl and 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, they have not yet reached clinical development, 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 to 3).

[0005] International Publication No. WO 1999 / 065478 International Publication No. WO 2014 / 176415 International Publication No. WO 2016 / 090154 International Publication No. WO 2020 / 165776

[0006] Med Chem Commun, 2017, 8, 286-294. Medicinal Chemistry Research, 2020, 29, 846-867. Nature Reviews Drug Discovery, 2019, 18, 295-317. Oxydative Medicine and Cellular Longevity, 2019, Article ID9372182, 1-20. Neurodegenr Dis Manag, 2017, 7, 97-100. Oxydative Medicine and Cellular Longevity, 2019, Article ID7090534, 1-17. Oxydative Medicine and Cellular Longevity, 2020, Article ID9410952, 1-22. Am J Nephrol, 2014, 39, 499-508

[0007] The present invention aims to provide a low molecular weight compound, a salt thereof, or a crystal of a solvate thereof that has the ability to activate Nrf2 and exhibits reduced interaction with non-target proteins due to covalent bonding, as well as to provide a preventive or therapeutic agent for various diseases, such as neurodegenerative diseases, pulmonary diseases, and renal diseases, containing the compound or salt as an active ingredient.

[0008] The present inventors have conducted extensive research to solve these problems and have discovered that compounds represented by formulas (1) to (5), or salts thereof, or solvates thereof, which have chemical structures significantly different from those of known Nrf2 activators, have excellent Nrf2 activating effects, and have also discovered crystals of the compounds represented by formulas (1) to (5), or salts thereof, or solvates thereof, thereby completing the present invention.

[0009] That is, in one aspect of the present invention, the following invention is provided: [A1] A compound represented by the following formula (1): or a crystal of a compound represented by formula (1), or a salt thereof, or a solvate thereof. [A2] The crystal according to [A1], wherein the crystal is a solvate crystal of a 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 1A type crystal comprising at least one peak selected from the group consisting 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 a diffraction angle (2θ value) in powder X-ray diffraction. [A4-1] The crystal according to [A3], wherein the hydrate crystal is a 1A type crystal having at least three peaks selected from the group consisting 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 diffraction angles (2θ values) in powder X-ray diffraction. [A4-2] The crystal according to [A3], wherein the hydrate crystal is a 1A type crystal having at least five peaks selected from the group consisting 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 diffraction angles (2θ values) in powder X-ray diffraction. [A4-3] The crystal according to [A3], wherein the hydrate crystal is a 1A type crystal containing at least seven peaks selected from the group consisting 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 diffraction angles (2θ values) in powder X-ray diffraction. [A4-4] The crystal according to [A3], wherein the hydrate crystal is a 1A type 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) in 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 8.8°, 9.2°, 10.4°, 12.7°, 13.4°, 15.8°, 16.9°, 17.3°, 18.3°, and 18.9° (±0.2°) as a diffraction angle (2θ value) 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 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) in 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 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) in 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 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) in powder X-ray diffraction. [A5-4] The crystal according to [A3], wherein the hydrate crystal is a 1G-type crystal having 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) in 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 8.9°, 9.3°, 10.5°, 12.8°, 13.5°, 15.9°, 17.0°, 17.4°, 18.4°, and 19.0° (±0.2°) as a diffraction angle (2θ value) in 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 8.9°, 9.3°, 10.5°, 12.8°, 13.5°, 15.9°, 17.0°, 17.4°, 18.4°, and 19.0° (±0.2°) as a diffraction angle (2θ value) in 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 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) in 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 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) in powder X-ray diffraction. [A6-4] The crystal according to [A3], wherein the hydrate crystal is a 1G-type crystal having peaks at the following diffraction angles (2θ values) in powder X-ray diffraction: 8.9°, 9.3°, 10.5°, 12.8°, 13.5°, 15.9°, 17.0°, 17.4°, 18.4°, and 19.0° (±0.2°). [A7] The crystal according to any of [A6] to [A6-4], wherein the diffraction angles (2θ values) are those of the hydrate crystal stored at 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 9.7°, 10.5°, 13.1°, 15.0°, 16.2°, 16.6°, 17.6°, 18.9°, 19.3°, and 20.8° (±0.2°) as a diffraction angle (2θ value) in 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 9.7°, 10.5°, 13.1°, 15.0°, 16.2°, 16.6°, 17.6°, 18.9°, 19.3°, and 20.8° (±0.2°) as a diffraction angle (2θ value) in powder X-ray diffraction. [A8-2] The crystal according to [A3], wherein the hydrate crystal is a 1J-type crystal containing at least five peaks selected from the group consisting 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 diffraction angles (2θ values) in powder X-ray diffraction.[A8-3] The crystal according to [A3], wherein the hydrate crystal is a 1J-type crystal containing at least seven peaks selected from the group consisting 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 diffraction angles (2θ values) in powder X-ray diffraction. [A8-4] The crystal according to [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) in powder X-ray diffraction. [A9] The crystal according to any one of [A8] to [A8-4], wherein the diffraction angle (2θ value) is that of a hydrate crystal stored at a temperature of 34°C and 30% relative humidity for 15 minutes. [A10] The crystal according to [A1], wherein the crystal is a non-solvate crystal of the compound represented by formula (1). [A11] The crystal according to [A1] or [A10], wherein the non-solvate crystal is a 1H-type crystal comprising at least one peak selected from the group consisting 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 a diffraction angle (2θ value) by powder X-ray diffraction. [A11-1] The crystal according to [A1] or [A10], wherein the non-solvate crystal is a 1H-type crystal containing at least three peaks selected from the group consisting 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 diffraction angles (2θ values) in powder X-ray diffraction. [A11-2] The crystal according to [A1] or [A10], wherein the non-solvate crystal is a 1H-type crystal containing at least five peaks selected from the group consisting 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 diffraction angles (2θ values) in powder X-ray diffraction.[A11-3] The crystal according to [A1] or [A10], wherein the non-solvate crystal is a 1H type crystal comprising at least seven peaks selected from the group consisting 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 diffraction angles (2θ values) in powder X-ray diffraction. [A11-4] The crystal according to [A1] or [A10], wherein the non-solvate crystal is a 1H type crystal comprising peaks 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 diffraction angles (2θ values) in powder X-ray diffraction. [A12] The crystal according to any one of [A11] to [A11-4], wherein the diffraction angle (2θ value) is that of a water non-solvate 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 containing at least one peak selected from the group consisting 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 a diffraction angle (2θ value) 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 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) in 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 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) in 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 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) in powder X-ray diffraction. [A13-4] The crystal according to [A1] or [A2], wherein the crystal is a 1K type crystal having 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) in powder X-ray diffraction. [B1] The crystal represented by the following formula (2): [B2] The crystal according to [B1], wherein the crystal is a non-solvate crystal of a compound represented by formula (2). [B3] The crystal according to [B1] or [B2], wherein the non-solvate crystal is a type 3A crystal comprising 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 a diffraction angle (2θ value) in powder X-ray diffraction. [B3-1] The crystal according to [B1] or [B2], wherein the non-solvate crystal is a 3A type crystal containing at least three peaks 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) in powder X-ray diffraction. [B3-2] The crystal according to [B1] or [B2], wherein the non-solvate crystal is a 3A type crystal containing at least five peaks 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) in powder X-ray diffraction. [B3-3] The crystal according to [B1] or [B2], wherein the non-solvate crystal is a 3A type crystal comprising at least seven peaks 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) in powder X-ray diffraction. [B3-4] The crystal according to [B1] or [B2], wherein the non-solvate crystal is a 3A type crystal comprising 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) in powder X-ray diffraction.[B4] The crystal according to [B1] or [B2], wherein the non-solvate crystal is a 3C type crystal comprising at least one peak selected from the group consisting 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) in powder X-ray diffraction. [B4-1] The crystal according to [B1] or [B2], wherein the non-solvate crystal is a 3C type crystal comprising at least three peaks selected from the group consisting 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) in powder X-ray diffraction. [B4-2] The crystal according to [B1] or [B2], wherein the non-solvate crystal is a 3C type crystal containing at least five peaks selected from the group consisting 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) in powder X-ray diffraction. [B4-3] The crystal according to [B1] or [B2], wherein the non-solvate crystal is a 3C type crystal containing at least seven peaks selected from the group consisting 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) in powder X-ray diffraction. [B4-4] The crystal according to [B1] or [B2], wherein the non-solvate crystal is a 3C type crystal containing peaks at 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°) in powder X-ray diffraction. [B5] The crystal according to [B1], wherein the crystal is a solvate crystal of the compound represented by formula (2). [B6] The crystal according to [B1] or [B5] is a 3D-type crystal containing at least one peak selected from the group consisting 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 a diffraction angle (2θ value) by powder X-ray diffraction.[B6-1] The crystal according to [B1] or [B5], wherein the crystal is a 3D crystal having at least three peaks selected from the group consisting 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) in powder X-ray diffraction. [B6-2] The crystal according to [B1] or [B5], wherein the crystal is a 3D crystal having at least five peaks selected from the group consisting 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) in powder X-ray diffraction. [B6-3] The crystal according to [B1] or [B5], wherein the crystal is a 3D crystal containing at least seven peaks selected from the group consisting 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) in powder X-ray diffraction. [B6-4] The crystal according to [B1] or [B5], wherein the crystal is a 3D crystal containing peaks at 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) in powder X-ray diffraction. [B7] The crystal according to [B1] or [B5], wherein the crystal is a 3B type crystal containing at least one peak selected from the group consisting 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 a diffraction angle (2θ value) in powder X-ray diffraction. [B7-1] The crystal according to [B1] or [B5], wherein the crystal is a 3B type crystal containing at least three peaks selected from the group consisting 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 a diffraction angle (2θ value) in powder X-ray diffraction.[B7-2] The crystal according to [B1] or [B5], wherein the crystal is a 3B type crystal containing at least five peaks selected from the group consisting 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) in powder X-ray diffraction. [B7-3] The crystal according to [B1] or [B5], wherein the crystal is a 3B type crystal containing at least seven peaks selected from the group consisting 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) in powder X-ray diffraction. [B7-4] The crystal according to [B1] or [B5], which is a 3B type crystal containing peaks at 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°) in powder X-ray diffraction. [C1] The crystal of the following formula (3): [C2] The crystal according to [C1], wherein the crystal is a non-solvate crystal of a compound represented by formula (3): [C3] The crystal according to [C1] or [C2], wherein the non-solvate crystal is a type 2B crystal comprising 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 a diffraction angle (2θ value) in powder X-ray diffraction. [C3-1] The crystal according to [C1] or [C2], wherein the non-solvate crystal is a 2B type crystal containing at least three peaks 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) in powder X-ray diffraction. [C3-2] The crystal according to [C1] or [C2], wherein the non-solvate crystal is a 2B type crystal containing at least five peaks 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) in powder X-ray diffraction. [C3-3] The crystal according to [C1] or [C2], wherein the non-solvate crystal is a 2B type crystal comprising at least seven peaks 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) in powder X-ray diffraction. [C3-4] The crystal according to [C1] or [C2], wherein the non-solvate crystal is a 2B type crystal comprising 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) in powder X-ray diffraction. [C4] The crystal according to [C1] or [C2], wherein the non-solvate crystal is a type 2A crystal containing at least one peak selected from the group consisting 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 a diffraction angle (2θ value) in powder X-ray diffraction.[C4-1] The crystal according to [C1] or [C2], wherein the non-solvate crystal is a 2A type crystal containing at least three peaks selected from the group consisting 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 diffraction angles (2θ values) in powder X-ray diffraction. [C4-2] The crystal according to [C1] or [C2], wherein the non-solvate crystal is a 2A type crystal containing at least five peaks selected from the group consisting 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 diffraction angles (2θ values) in powder X-ray diffraction. [C4-3] The crystal according to [C1] or [C2], wherein the non-solvate crystal is a 2A type crystal comprising at least seven peaks selected from the group consisting 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 diffraction angles (2θ values) in powder X-ray diffraction. [C4-4] The crystal according to [C1] or [C2], wherein the non-solvate crystal is a 2A type crystal comprising 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) in powder X-ray diffraction. [C5] The crystal according to [C1] or [C2], wherein the non-solvate crystal is a 2C type crystal comprising 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) in powder X-ray diffraction. [C5-1] The crystal according to [C1] or [C2], wherein the non-solvate crystal is a 2C type crystal comprising at least three peaks 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) in powder X-ray diffraction.[C5-2] The crystal according to [C1] or [C2], wherein the non-solvate crystal is a 2C type crystal containing at least five peaks 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) in powder X-ray diffraction. [C5-3] The crystal according to [C1] or [C2], wherein the non-solvate crystal is a 2C type crystal containing at least seven peaks 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) in powder X-ray diffraction. [C5-4] The crystal according to [C1] or [C2], wherein the non-solvate crystal is a 2C type crystal containing peaks at 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°) by powder X-ray diffraction. [C6] The crystal according to [C1] or [C2], wherein the non-solvate crystal is a 2F type crystal containing 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°) by powder X-ray diffraction. [C6-1] The crystal according to [C1] or [C2], wherein the non-solvate crystal is a 2F type crystal containing at least three peaks 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) in powder X-ray diffraction. [C6-2] The crystal according to [C1] or [C2], wherein the non-solvate crystal is a 2F type crystal containing at least five peaks 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) in powder X-ray diffraction.[C6-3] The crystal according to [C1] or [C2], wherein the non-solvate crystal is a 2F type crystal containing at least seven peaks 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) in powder X-ray diffraction. [C6-4] The crystal according to [C1] or [C2], wherein the non-solvate 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) in powder X-ray diffraction. [D1] The crystal according to the following formula (4): [D2] The crystal according to [D1], wherein the crystal is a solvate crystal of a 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 comprising at least one peak selected from the group consisting 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 a diffraction angle (2θ value) in 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 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) in 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 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) in powder X-ray diffraction. [D4-3] The crystal according to [D3], wherein the hydrate crystal is a 5A type crystal containing at least seven peaks selected from the group consisting 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 diffraction angles (2θ values) in powder X-ray diffraction. [D4-4] The crystal according to [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) in powder X-ray diffraction. [D5] The crystal according to [D3], wherein the hydrate crystal is a 5A type crystal having peaks at diffraction angles (2θ values) of 7.4°, 8.8°, and 9.5° (±0.2°) 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 7.4°, 8.8°, 9.5°, 10.8°, 12.7°, 16.0°, 16.8°, 17.3°, 17.9°, and 19.2° (±0.2°) as a diffraction angle (2θ value) in 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 7.4°, 8.8°, 9.5°, 10.8°, 12.7°, 16.0°, 16.8°, 17.3°, 17.9°, and 19.2° (±0.2°) as a diffraction angle (2θ value) in 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 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) in 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 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) in powder X-ray diffraction. [D6-4] The crystal according to [D3], wherein the hydrate crystal is a 5A type crystal having 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) in powder X-ray diffraction. [D7] The crystal according to any of [D6] to [D6-4], wherein the diffraction angles (2θ values) are those of the hydrate crystal stored at 25°C and 10% relative humidity for 1 hour. [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 7.4°, 8.8°, 9.5°, 10.5°, 12.2°, 15.6°, 16.6°, 17.1°, 17.3°, and 17.5° (±0.2°) as a diffraction angle (2θ value) 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 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) in 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 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) in powder X-ray diffraction. [D8-3] The crystal according to [D3], wherein the hydrate crystal is a 5A type crystal containing at least seven peaks selected from the group consisting 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) in powder X-ray diffraction. [D8-4] The crystal according to [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) in powder X-ray diffraction. [D9] The crystal according to any one of [D8] to [D8-4], wherein the diffraction angle (2θ value) is that of a hydrate crystal stored at a temperature of 25°C and 20% relative humidity for 1 hour. [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 7.4°, 8.8°, 9.5°, 10.5°, 12.2°, 15.5°, 16.4°, 16.6°, 17.1°, and 17.6° (±0.2°) as a diffraction angle (2θ value) by powder X-ray diffraction. [D10-1] The crystal according to [D3], wherein the hydrate crystal is a 5A type crystal containing at least three peaks selected from the group consisting 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 diffraction angles (2θ values) in powder X-ray diffraction.[D10-2] The crystal according to [D3], wherein the hydrate crystal is a 5A type crystal containing at least five peaks selected from the group consisting 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 diffraction angles (2θ values) in powder X-ray diffraction. [D10-3] The crystal according to [D3], wherein the hydrate crystal is a 5A type crystal containing at least seven peaks selected from the group consisting 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 diffraction angles (2θ values) in powder X-ray diffraction. [D10-4] The crystal according to [D3], wherein the hydrate crystal is a 5A type crystal having 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) in powder X-ray diffraction. [D11] The crystal according to any of [D10] to [D10-4], wherein the diffraction angles (2θ values) are those of the hydrate crystal stored at 25°C and 30% relative humidity for 1 hour. [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 7.4°, 8.8°, 9.5°, 10.3°, 12.2°, 15.4°, 16.3°, 16.6°, 17.0°, and 17.6° (±0.2°) as a diffraction angle (2θ value) in 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 7.4°, 8.8°, 9.5°, 10.3°, 12.2°, 15.4°, 16.3°, 16.6°, 17.0°, and 17.6° (±0.2°) as a diffraction angle (2θ value) in powder X-ray diffraction. [D12-2] The crystal according to [D3], wherein the hydrate crystal is a 5A type crystal containing at least five peaks selected from the group consisting 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) in powder X-ray diffraction.[D12-3] The crystal according to [D3], wherein the hydrate crystal is a 5A type crystal containing at least seven peaks selected from the group consisting 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) in powder X-ray diffraction. [D12-4] The crystal according to [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) in powder X-ray diffraction. [D13] The crystal according to any one of [D12] to [D12-4], wherein the diffraction angle (2θ value) is that of a hydrate crystal stored at a temperature of 25°C and 60% relative humidity for 1 hour. [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 9.2°, 10.6°, 11.9°, 13.7°, 15.0°, 15.8°, 16.6°, 17.1°, 18.5°, and 19.2° (±0.2°) as a diffraction angle (2θ value) 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 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) in 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 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) in powder X-ray diffraction. [D14-3] The crystal according to [D3], wherein the hydrate crystal is a 5E-type crystal containing at least seven peaks selected from the group consisting 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 diffraction angles (2θ values) in powder X-ray diffraction.[D14-4] The crystal according to [D3], wherein the hydrate crystal is a 5E-type crystal having 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) in powder X-ray diffraction. [D15] The crystal according to [D3], wherein the hydrate crystal is a 5J-type crystal having 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) in 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 a diffraction angle (2θ value) in 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 7.3°, 9.0°, 9.6°, 10.9°, 12.3°, 15.9°, 16.6°, 17.1°, and 17.5° (±0.2°) as a diffraction angle (2θ value) in powder X-ray diffraction. [D16-2] The crystal according to [D3], wherein the hydrate crystal is a 5J type crystal containing at least five peaks 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) in powder X-ray diffraction. [D16-3] The crystal according to [D3], wherein the hydrate crystal is a 5J type crystal containing at least seven peaks 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) in powder X-ray diffraction. [D16-4] The crystal according to [D3], wherein the hydrate crystal is a 5J-type crystal containing peaks at 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°) by powder X-ray diffraction.[D17] The crystal according to any one of [D16] to [D16-4], wherein the diffraction angle (2θ value) is that of a hydrate crystal stored at a temperature of 25°C and 30% relative humidity for 1 hour. [D18] The crystal according to [D3], wherein the hydrate crystal is a 5J-type crystal containing 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 a diffraction angle (2θ value) by powder X-ray diffraction. [D18-1] The crystal according to [D3], wherein the hydrate crystal is a 5J type crystal containing at least three peaks 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) in powder X-ray diffraction. [D18-2] The crystal according to [D3], wherein the hydrate crystal is a 5J type crystal containing at least five peaks 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) in powder X-ray diffraction. [D18-3] The crystal according to [D3], wherein the hydrate crystal is a 5J type crystal containing at least seven peaks 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) in powder X-ray diffraction. [D18-4] The crystal according to [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) in 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 at a temperature of 25°C and a relative humidity of 40% for 1 hour.[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 7.3°, 8.9°, 9.6°, 10.7°, 12.1°, 15.6°, 16.2°, 16.6°, 16.9°, and 17.2° (±0.2°) as a diffraction angle (2θ value) 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 7.3°, 8.9°, 9.6°, 10.7°, 12.1°, 15.6°, 16.2°, 16.6°, 16.9°, and 17.2° (±0.2°) as a diffraction angle (2θ value) by powder X-ray diffraction. [D20-2] The crystal according to [D3], wherein the hydrate crystal is a 5J type crystal containing at least five peaks selected from the group consisting 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 diffraction angles (2θ values) in powder X-ray diffraction. [D20-3] The crystal according to [D3], wherein the hydrate crystal is a 5J type crystal containing at least seven peaks selected from the group consisting 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 diffraction angles (2θ values) in powder X-ray diffraction. [D20-4] The crystal according to [D3], wherein the hydrate crystal is a 5J-type crystal having 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) in powder X-ray diffraction. [D21] The crystal according to any of [D20] to [D20-4], wherein the diffraction angles (2θ values) are those of the hydrate crystal stored at 25°C and 50 to 60% relative humidity for 1 hour. [D22] The crystal described in [D3], wherein the hydrate crystal is a 5J-type crystal containing at least one peak selected from the group consisting of 7.2°, 8.9°, 9.5°, 10.6°, 12.0°, 15.5°, 16.1°, 16.6°, and 17.1° (±0.2°) as a diffraction angle (2θ value) 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 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) in 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 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) in powder X-ray diffraction. [D22-3] The crystal according to [D3], wherein the hydrate crystal is a 5J type crystal containing at least seven peaks selected from the group consisting of 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) in powder X-ray diffraction. [D22-4] The crystal according to [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) in powder X-ray diffraction. [D23] The crystal according to any one of [D22] to [D22-4], wherein the diffraction angle (2θ value) is that of a hydrate crystal stored at a temperature of 25°C and a relative humidity of 70% or more for 1 hour. [D24] The crystal according to [D1], wherein the crystal is a non-solvate crystal of a compound represented by formula (4). [D25] The crystal according to [D1] or [D24], wherein the crystal is a 5C type crystal comprising at least one peak selected from the group consisting of 7.3°, 9.7°, 12.1°, 14.8°, 15.2°, 15.7°, 16.6°, and 17.7° (±0.2°) as a diffraction angle (2θ value) by powder X-ray diffraction. [D25-1] The crystal according to [D1] or [D24], wherein the crystal is a 5C type crystal containing at least three peaks selected from the group consisting of 7.3°, 9.7°, 12.1°, 14.8°, 15.2°, 15.7°, 16.6°, and 17.7° (±0.2°) as diffraction angles (2θ values) in powder X-ray diffraction.[D25-2] The crystal according to [D1] or [D24], wherein the crystal is a 5C type crystal containing at least five peaks selected from the group consisting of 7.3°, 9.7°, 12.1°, 14.8°, 15.2°, 15.7°, 16.6°, and 17.7° (±0.2°) as diffraction angles (2θ values) in powder X-ray diffraction. [D25-3] The crystal according to [D1] or [D24], wherein the crystal is a 5C type crystal containing at least seven peaks selected from the group consisting of 7.3°, 9.7°, 12.1°, 14.8°, 15.2°, 15.7°, 16.6°, and 17.7° (±0.2°) as diffraction angles (2θ values) in powder X-ray diffraction. [D25-4] The crystal according to [D1] or [D24], wherein the crystal is a 5C type crystal containing peaks at diffraction angles (2θ values) of 7.3°, 9.7°, 12.1°, 14.8°, 15.2°, 15.7°, 16.6°, and 17.7° (±0.2°) in powder X-ray diffraction. [D26] The crystal according to [D1] or [D24], wherein the non-solvate crystal is a 5D type crystal containing 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°) in powder X-ray diffraction. [D26-1] The crystal according to [D1] or [D24], wherein the non-solvate crystal is a 5D type crystal containing at least three peaks 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) in powder X-ray diffraction. [D26-2] The crystal according to [D1] or [D24], wherein the non-solvate crystal is a 5D type crystal containing at least five peaks 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) in powder X-ray diffraction.[D26-3] The crystal according to [D1] or [D24], wherein the non-solvate crystal is a 5D type crystal comprising at least seven peaks 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) in powder X-ray diffraction. [D26-4] The crystal according to [D1] or [D24], wherein the non-solvate crystal is a 5D type crystal comprising 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) in powder X-ray diffraction. [D27] The crystal according to [D1] or [D2], wherein the crystal is a 5G-type crystal containing at least one peak selected from the group consisting 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 a diffraction angle (2θ value) by powder X-ray diffraction. [D27-1] The crystal according to [D1] or [D2], wherein the crystal is a 5G-type crystal containing at least three peaks selected from the group consisting 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 a diffraction angle (2θ value) by powder X-ray diffraction. [D27-2] The crystal according to [D1] or [D2], wherein the crystal is a 5G-type crystal containing at least five peaks selected from the group consisting 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 diffraction angles (2θ values) by powder X-ray diffraction. [D27-3] The crystal according to [D1] or [D2], wherein the crystal is a 5G-type crystal containing at least seven peaks selected from the group consisting 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 diffraction angles (2θ values) by powder X-ray diffraction.[D27-4] The crystal according to [D1] or [D2], which is a 5G-type crystal containing peaks at 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°) in powder X-ray diffraction. [E1] The crystal of the following formula (5): [E2] The crystal according to [E1], wherein the crystal is a solvate crystal of a 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 comprising at least one peak selected from the group consisting 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 a diffraction angle (2θ value) in 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 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) in 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 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) in powder X-ray diffraction. [E4-3] The crystal according to [E3], wherein the hydrate crystal is a 4B type crystal containing at least seven peaks selected from the group consisting 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 diffraction angles (2θ values) in powder X-ray diffraction. [E4-4] The crystal according to [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) in powder X-ray diffraction. [E5] The crystal according to [E1] or [E2], wherein the crystal is a 4A type crystal containing at least one peak selected from the group consisting 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 a diffraction angle (2θ value) by powder X-ray diffraction.[E5-1] The crystal according to [E1] or [E2], wherein the crystal is a 4A type crystal containing at least three peaks selected from the group consisting 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 diffraction angles (2θ values) in powder X-ray diffraction. [E5-2] The crystal according to [E1] or [E2], wherein the crystal is a 4A type crystal containing at least five peaks selected from the group consisting 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 diffraction angles (2θ values) in powder X-ray diffraction. [E5-3] The crystal according to [E1] or [E2], wherein the crystal is a 4A type crystal containing at least seven peaks selected from the group consisting 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 diffraction angles (2θ values) in powder X-ray diffraction. [E5-4] The crystal according to [E1] or [E2], wherein the crystal is a 4A type crystal containing peaks 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 diffraction angles (2θ values) in powder X-ray diffraction. [F1] The crystal according to the following formulas (1) to (5): [F2] The crystal according to [F1], which is a crystal of a compound according to any one of [A1] to [A13-4], [B1] to [B7-4], [C1] to [C6-4], [D1] to [D27-4], and [E1] to [E5-4], or a salt thereof, or a solvate thereof. [G1] A pharmaceutical composition comprising a crystal of a compound according to any one 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], or a salt thereof, or a solvate thereof. [G2] The pharmaceutical composition according to [G1], for the prevention and / or treatment of neurodegenerative diseases, pulmonary diseases, or renal diseases. [G3] A method for preventing and / or treating a neurodegenerative disease, a pulmonary disease, or a renal disease, comprising administering to a subject an effective amount of a compound according to any one 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], or a salt thereof, or a crystal of a solvate thereof. [G4] A compound according to any one 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], or a salt thereof, or a crystal of a solvate thereof, for use in the prevention and / or treatment of a neurodegenerative disease, a pulmonary disease, or a renal disease. [G5] Use of a compound described in any one 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], or a salt thereof, or a crystal of a solvate thereof, for the manufacture of a pharmaceutical composition for the prevention and / or treatment of neurodegenerative diseases, pulmonary diseases, or renal diseases. [G6] A pharmaceutical composition comprising a compound described in any one 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], or a salt thereof, or a crystal of a solvate thereof, mixed with a pharmaceutically acceptable carrier or vehicle.[G7] A pharmaceutical composition comprising a compound according to any one 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], or a salt thereof, or a crystal of a solvate thereof dissolved in a pharmaceutically acceptable carrier or medium. [H1] A pharmaceutical composition comprising a compound according to any one of the following formulas (1) to (5): A method for producing a pharmaceutical composition containing, as an active ingredient, a compound represented by any one of the following formulas: or a salt thereof, or a solvate thereof, the method comprising a step of mixing a crystal of a compound or a salt thereof, or a solvate thereof, according to any one 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 vehicle. [H2] The method according to [H1], wherein the crystal of the compound or a salt thereof, or a solvate thereof is a solvate crystal 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 crystal of the compound or a salt thereof, or a solvate thereof is a non-solvate crystal of the compound. [H5] The method according to any one of [H1] to [H4], wherein the step of mixing the crystal of the compound, or a salt thereof, or a solvate thereof with a pharmaceutically acceptable carrier or medium is a step of dissolving the crystal of the compound, or a salt thereof, or a solvate thereof in a pharmaceutically acceptable carrier or medium. [H6] A compound represented by the following formulas (1) to (5) [H7] The method of [H6], wherein the compound represented by any one of formulas (1) to (5), a salt thereof, or a solvate thereof is a solvate of a compound represented by any one of formulas (1) to (5). [H8] The method of [H7], wherein the solvate is a hydrate. [H9] The method of [H6], wherein the compound represented by any one of formulas (1) to (5), a salt thereof, or a solvate thereof is a non-solvate of a compound represented by any one of formulas (1) to (5). [H10] The method of any one of [H6] to [H9], wherein the step of mixing the compound represented by any one of formulas (1) to (5), a salt thereof, or a solvate thereof with a pharmaceutically acceptable carrier or vehicle is a step of dissolving the compound represented by any one of formulas (1) to (5). In the above numbering scheme, the numbers referred to in dependent claims include their sub-numbers unless otherwise specified. For example, [A4] referred to in a dependent claim includes not only [A4] but also its sub-numbers [A4-1], [A4-2], [A4-3], and [A4-4]. The same applies to other numbering schemes.

[0010] Provided are crystals of a compound having Nrf2 activating activity, a salt thereof, or a solvate thereof, which can be used as a preventive or therapeutic agent for various diseases such as neurodegenerative diseases, pulmonary diseases, and renal diseases.

[0011]

[0033] Figure 1 shows the results of powder X-ray diffraction measurement of the crystals obtained in Example 2-1-1. The vertical axis is diffraction intensity, and the horizontal axis is diffraction angle 2θ (°).

[0034] Figure 1 shows the results of TG-DTA measurement of the crystals obtained in Example 2-1-1. The vertical axis of (A) is weight change, and the horizontal axis is temperature. The vertical axis of (B) is heat flow, and the horizontal axis is temperature. The + symbols and temperatures on the graph in (B) indicate melting points or other transition points.

[0035] Figure 1 shows the results of powder X-ray diffraction measurement of the crystals obtained in Example 2-1-3. The vertical axis is diffraction intensity, and the horizontal axis is diffraction angle 2θ (°).

[0036] Figure 1 shows the results of TG-DTA measurement of the crystals obtained in Example 2-1-3. The vertical axis of (A) is weight change, and the horizontal axis is temperature. The vertical axis of (B) is heat flow, and the horizontal axis is temperature. The + symbols and temperatures on the graph in (B) indicate melting points or other transition points.

[0046] Figure 1 shows the results of powder X-ray diffraction measurement under humidity-controlled conditions obtained in Example 2-1-4. The vertical axis represents diffraction intensity, and the horizontal axis represents diffraction angle 2θ (°). The relative humidity (RH) of each pattern is shown in the figure. The broad peak near 6.4° is due to the measurement equipment.

[0047] Figure 1 shows the results of powder X-ray diffraction measurement of the crystals obtained in Example 2-1-5. The vertical axis represents diffraction intensity, and the horizontal axis represents diffraction angle 2θ (°).

[0048] Figure 1 shows the crystal structure of the 1G-type crystal described in Example 2-1-6.

[0049] Figure 1 shows the results of powder X-ray diffraction measurement of the crystals obtained in Example 2-2-2. The vertical axis represents diffraction intensity, and the horizontal axis represents diffraction angle 2θ (°).

[0050] Figure 1 shows the results of powder X-ray diffraction measurement of the crystals obtained in Example 2-2-4. The vertical axis represents diffraction intensity, and the horizontal axis represents diffraction angle 2θ (°).

[0051] Figure 1 shows the results of TG-DTA measurement of the crystals obtained in Example 2-2-4. The vertical axis of (A) represents weight change, and the horizontal axis represents temperature. The vertical axis of (B) is heat flow, and the horizontal axis is temperature. The + symbols and temperatures on the graph of (B) indicate melting points or other transition points. The results of powder X-ray diffraction measurement of the crystals obtained in Example 2-2-5 are shown. The vertical axis is diffraction intensity, and the horizontal axis is diffraction angle 2θ (°). The results of TG-DTA measurement of the crystals obtained in Example 2-2-5 are shown. The vertical axis of (A) is weight change, and the horizontal axis is temperature. The vertical axis of (B) is heat flow, and the horizontal axis is temperature. The + symbols and temperatures on the graph of (B) indicate melting points or other transition points. The results of powder X-ray diffraction measurement of the crystals obtained in Example 2-2-6 are shown. The vertical axis is diffraction intensity, and the horizontal axis is diffraction angle 2θ (°).The results of TG-DTA measurement of the crystals obtained in Example 2-2-6 are shown. The vertical axis of (A) is weight change, and the horizontal axis is temperature. The vertical axis of (B) is heat flow, and the horizontal axis is temperature. The + symbols and temperatures on the graph in (B) indicate melting points or other transition points. The results of powder X-ray diffraction measurement of the crystals before vacuum drying obtained in Example 2-3-1 are shown. The vertical axis is diffraction intensity, and the horizontal axis is diffraction angle 2θ (°). The results of powder X-ray diffraction measurement of the crystals after vacuum drying obtained in Example 2-3-1 are shown. The vertical axis is diffraction intensity, and the horizontal axis is diffraction angle 2θ (°). The results of TG-DTA measurement of the crystals obtained in Example 2-3-1 are shown. The vertical axis of (A) is weight change, and the horizontal axis is temperature. The vertical axis of (B) is heat flow, and the horizontal axis is temperature. The + symbols and temperatures on the graph in (B) indicate melting points or other transition points. The results of powder X-ray diffraction measurement of the crystals obtained in Example 2-3-2 are shown. The vertical axis is diffraction intensity, and the horizontal axis is diffraction angle 2θ (°). The results of powder X-ray diffraction measurement of the crystals obtained in Example 2-3-3 are shown. The vertical axis is diffraction intensity, and the horizontal axis is diffraction angle 2θ (°). The results of TG-DTA measurement of the crystals obtained in Example 2-3-3 are shown. The vertical axis of (A) is weight change, and the horizontal axis is temperature. The vertical axis of (B) is heat flow, and the horizontal axis is temperature. The + marks and temperatures on the graph of (B) indicate melting points or other transition points. The results of powder X-ray diffraction measurement of the crystals obtained in Example 2-4-1 are shown. The vertical axis is diffraction intensity, and the horizontal axis is diffraction angle 2θ (°). The crystal structure of the type 4B crystal described in Example 2-4-2 is shown. The results of powder X-ray diffraction measurement of the crystals obtained in Example 2-4-3 are shown. The vertical axis is the diffraction intensity, and the horizontal axis is the diffraction angle 2θ (°). The results of TG-DTA measurement of the crystals obtained in Example 2-4-3 are shown. The vertical axis of (A) is the weight change, and the horizontal axis is the temperature. The vertical axis of (B) is the heat flow, and the horizontal axis is the temperature. The + marks and temperatures on the graph of (B) indicate the melting point or other transition point. The results of powder X-ray diffraction measurement of the crystals obtained in Example 2-5-2 are shown. The vertical axis is the diffraction intensity, and the horizontal axis is the diffraction angle 2θ (°). The results of TG-DTA measurement of the crystals obtained in Example 2-5-2 are shown. The vertical axis of (A) is the weight change, and the horizontal axis is the temperature. The vertical axis of (B) is the heat flow, and the horizontal axis is the temperature.The + marks and temperatures on graph (B) indicate melting points or other transition points. 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 is diffraction intensity, and the horizontal axis is diffraction angle 2θ (°). The results of TG-DTA measurements of the crystals obtained in Example 2-5-3 before vacuum drying are shown. The vertical axis of (A) is weight change, and the horizontal axis is temperature. The vertical axis of (B) is heat flow, and the horizontal axis is temperature. The + marks and temperatures on graph (B) indicate melting points or other transition points. The results of powder X-ray diffraction measurements of the crystals obtained in Example 2-5-3 after vacuum drying are shown. The vertical axis is diffraction intensity, and the horizontal axis is diffraction angle 2θ (°). The results of powder X-ray diffraction measurements under various humidity conditions obtained in Example 2-5-4 are shown. The vertical axis is diffraction intensity, and the horizontal axis is diffraction angle 2θ (°). The relative humidity (RH) of each pattern is indicated in the figure.

[0046] Figure 1 shows the results of powder X-ray diffraction measurement (first and second runs) under a relative humidity (RH) condition of 60% obtained in Example 2-5-4. The vertical axis represents the 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 near 6.4° is due to the measurement equipment.

[0047] Figure 1 shows the results of powder X-ray diffraction measurement of the crystals obtained in Example 2-5-5. The vertical axis represents the diffraction intensity, and the horizontal axis represents the diffraction angle 2θ (°).

[0048] Figure 1 shows the results of powder X-ray diffraction measurement of the crystals obtained in Example 2-5-6. The vertical axis represents the diffraction intensity, and the horizontal axis represents the diffraction angle 2θ (°).

[0049] Figure 2 shows the crystal structure of the type 5A crystal described in Example 2-5-6.

[0050] Figure 3 shows the results of powder X-ray diffraction measurement under a relative humidity condition of 5% obtained in Example 2-5-8. The vertical axis represents the diffraction intensity, and the horizontal axis represents the diffraction angle 2θ (°). The broad peak near 6.4° is due to the measurement equipment. Representative powder X-ray diffraction measurement results obtained in Examples 2-5-9 under various humidity conditions are shown below. The vertical axis represents the diffraction intensity, and the horizontal axis represents the diffraction angle 2θ (°). The relative humidity (RH) of each pattern is also shown in the figure. The broad peak near 6.4° is due to the measurement equipment.

[0012] The present invention will be described in detail below by showing definitions of symbols, terms, etc. used in this specification, and embodiments of the present invention.

[0013] In one embodiment, the present invention relates to a crystal of a compound represented by any one of formulas (1) to (5), a salt thereof, or a solvate thereof. Specific examples of the crystal of this compound include a nonsolvate crystal or a solvate crystal of this compound, or a nonsolvate crystal or a solvate crystal of a salt of this compound. Specific examples of the solvate crystal include a hydrate crystal, an acetone solvate crystal, a dimethyl sulfoxide (DMSO) solvate crystal, a dimethylformamide (DMF) solvate crystal, an acetonitrile solvate crystal, a tetrahydrofuran solvate crystal, a methyl ethyl ketone solvate crystal, a methyl isobutyl ketone solvate crystal, an ethyl acetate solvate crystal, a heptane solvate crystal, a polyethylene glycol (PEG) solvate crystal, a 2-propanol solvate crystal, a methanol solvate crystal, and an ethanol solvate crystal, and preferred are hydrate crystals.

[0014] The compounds described herein may be salts or solvates thereof. Furthermore, as used herein, the term "compound or a salt thereof, or a solvate thereof" includes compounds, salts of compounds, solvates of compounds, and solvates of salts of compounds. Examples of salts of compounds include hydrochlorides; hydrobromides; hydroiodides; phosphates; phosphonates; sulfates; sulfonates such as methanesulfonate and p-toluenesulfonate; carboxylates such as acetate, citrate, malate, tartrate, succinate, and salicylate; alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as magnesium salt and calcium salt; and ammonium salts such as ammonium salt, alkylammonium salt, dialkylammonium salt, trialkylammonium salt, and tetraalkylammonium salt. These salts are produced, for example, by contacting a compound with an acid or a base. As used herein, the term "solvate" refers to a compound that forms a molecular group together with a solvent, and is not particularly limited as long as the solvate is formed with a solvent that is acceptable for ingestion accompanying pharmaceutical administration. Examples of solvates include hydrates, alcoholates (ethanol solvates, methanol solvates, 1-propanol solvates, 2-propanol solvates, etc.), and solvates with a single solvent such as dimethyl sulfoxide, as well as solvates formed with multiple solvents per molecule of the compound, or solvates formed with multiple types of solvents per molecule of the compound. A solvate formed when the solvent is water is called a hydrate. As the solvate of the compound of the present invention, hydrates are preferred, and specific examples of such hydrates include mono- to decahydrates, preferably mono- to pentahydrates, and more preferably mono- to trihydrates.

[0015] The diffraction angle 2θ in powder X-ray diffraction is a diffraction peak measured using CuKα or CuKα1 radiation. These solvate crystals further specified by the diffraction angle 2θ in powder X-ray diffraction are sometimes referred to as, for example, the "form 1A crystal" of the hydrate shown below, or simply as "form 1A."

[0016] In the notation of the diffraction angle 2θ, when the listed diffraction angle 2θ is followed by "(±0.2°)", this means that for all listed diffraction angles 2θ, a range of ±0.2° is allowed for each listed value.

[0017] In one embodiment, the hydrate crystal of the compound of formula (1) is a type 1A crystal that contains at least one of the following peaks in powder X-ray diffraction at diffraction angles 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 contains at least three of the following peaks in powder X-ray diffraction at diffraction angles 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 contains at least five of the following peaks in powder X-ray diffraction at diffraction angles 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 Form 1A crystal that contains at least seven of the following peaks in powder X-ray diffraction at diffraction angles 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 having the following peaks in powder X-ray diffraction as a diffraction angle 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 contains at least one of the following peaks in powder X-ray diffraction at diffraction angles 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 contains at least three of the following peaks in powder X-ray diffraction at diffraction angles 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 contains at least five of the following peaks in powder X-ray diffraction at diffraction angles 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 contains at least seven of the following peaks in powder X-ray diffraction at diffraction angles 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 having the following peaks in powder X-ray diffraction at diffraction angles 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 contains at least one of the following peaks as diffraction angles 2θ in powder X-ray diffraction. The following diffraction angles (2θ values) are preferably those of the hydrate crystal stored at a temperature of 34°C and a relative humidity of 60% 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 contains at least three of the following peaks as diffraction angles 2θ in powder X-ray diffraction. The following diffraction angles (2θ values) 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 contains at least five of the following peaks as diffraction angles 2θ in powder X-ray diffraction. The following diffraction angles (2θ values) are preferably those of the hydrate crystal stored at a temperature of 34°C and a relative humidity of 60% 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 contains at least seven of the following peaks as diffraction angles 2θ in powder X-ray diffraction. The following diffraction angles (2θ values) are preferably those of the hydrate crystal stored at a temperature of 34°C and a relative humidity of 60% 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 having the following peaks as diffraction angles 2θ in powder X-ray diffraction. The following diffraction angles (2θ values) are preferably those of the hydrate crystal stored at a temperature of 34°C and a relative humidity of 60% 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 contains at least one of the following peaks as a diffraction angle 2θ in powder X-ray diffraction. The following diffraction angles (2θ values) may be those of the hydrate crystal stored at a temperature of 34°C and a relative humidity of 30% 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 contains at least three of the following peaks as diffraction angles 2θ in powder X-ray diffraction. The following diffraction angles (2θ values) may be those of the hydrate crystal stored at a temperature of 34°C and a relative humidity of 30% 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 contains at least five of the following peaks as diffraction angles 2θ in powder X-ray diffraction. The following diffraction angles (2θ values) 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 contains at least seven of the following peaks as diffraction angles 2θ in powder X-ray diffraction. The following diffraction angles (2θ values) may be those of the hydrate crystal stored at a temperature of 34°C and a relative humidity of 30% 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 having the following peaks as diffraction angles 2θ in powder X-ray diffraction. The following diffraction angles (2θ values) may be those of the hydrate crystal stored at a temperature of 34°C and a relative humidity of 30% 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 containing at least one of the following peaks as a diffraction angle 2θ in powder X-ray diffraction. The following diffraction angles (2θ values) may be those 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 contains at least three of the following peaks as diffraction angles 2θ in powder X-ray diffraction. The following diffraction angles (2θ values) may be those 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°).

[0039] In one embodiment, the nonsolvate crystal of the compound of formula (1) is a 1H-type crystal that contains at least five of the following peaks as diffraction angles 2θ in powder X-ray diffraction. The following diffraction angles (2θ values) may be those 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°).

[0040] In one embodiment, the nonsolvate crystal of the compound of formula (1) is a 1H-type crystal that contains at least seven of the following peaks as diffraction angles 2θ in powder X-ray diffraction. The following diffraction angles (2θ values) may be those 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°).

[0041] In one embodiment, the nonsolvate crystal of the compound of formula (1) is a 1H-type crystal having the following peaks as diffraction angles 2θ in powder X-ray diffraction. Note that the following diffraction angles (2θ values) may be those 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 contains at least one of the following peaks in powder X-ray diffraction at diffraction angles 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 contains at least three of the following peaks in powder X-ray diffraction at diffraction angles 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 contains at least five of the following peaks in powder X-ray diffraction at diffraction angles 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 contains at least seven of the following peaks in powder X-ray diffraction at diffraction angles 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 having the following peaks in powder X-ray diffraction as a diffraction angle 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 non-solvated crystal of the compound of formula (2) is a 3A-type crystal that contains at least one of the following peaks in powder X-ray diffraction at diffraction angles 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 non-solvated crystal of the compound of formula (2) is a 3A type crystal that contains at least three of the following peaks in powder X-ray diffraction at diffraction angles 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 non-solvated crystal of the compound of formula (2) is a 3A type crystal that contains at least five of the following peaks in powder X-ray diffraction at diffraction angles 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 non-solvated crystal of the compound of formula (2) is a 3A type crystal that contains at least seven of the following peaks in powder X-ray diffraction at diffraction angles 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 non-solvated crystal of the compound of formula (2) is a 3A-type crystal having the following peaks in powder X-ray diffraction as a diffraction angle 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 non-solvated crystal of the compound of formula (2) is a 3C type crystal that contains at least one of the following peaks in powder X-ray diffraction at diffraction angles 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 non-solvated crystal of the compound of formula (2) is a 3C type crystal containing at least three of the following peaks in powder X-ray diffraction at diffraction angles 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 non-solvated crystal of the compound of formula (2) is a 3C type crystal that contains at least five of the following peaks in powder X-ray diffraction as a diffraction angle 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 non-solvated crystal of the compound of formula (2) is a 3C type crystal that contains at least seven of the following peaks in powder X-ray diffraction at diffraction angles 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 non-solvated crystal of the compound of formula (2) is a 3C type crystal that contains the following peaks in powder X-ray diffraction at diffraction angles 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 crystal containing at least one of the following peaks at diffraction angles 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°).

[0058] In one embodiment, the crystal of the compound of formula (2) is a 3D crystal containing at least three of the following peaks in powder X-ray diffraction at diffraction angles 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 crystal containing at least five of the following peaks in powder X-ray diffraction as a 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°).

[0060] In one embodiment, the crystal of the compound of formula (2) is a 3D crystal that contains at least seven of the following peaks in powder X-ray diffraction at diffraction angles 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 crystal having the following peaks at diffraction angles 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 type 3B crystal that contains at least one of the following peaks in powder X-ray diffraction at diffraction angles 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 type 3B crystal that contains at least three of the following peaks in powder X-ray diffraction at diffraction angles 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 type 3B crystal that contains at least five of the following peaks in powder X-ray diffraction at diffraction angles 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 type 3B crystal that contains at least seven of the following peaks in powder X-ray diffraction at diffraction angles 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 type 3B crystal that contains the following peaks in powder X-ray diffraction as a diffraction angle 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 non-solvated crystal of the compound of formula (3) is a type 2B crystal that contains at least one of the following peaks in powder X-ray diffraction at diffraction angles 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 non-solvated crystal of the compound of formula (3) is a type 2B crystal that contains at least three of the following peaks in powder X-ray diffraction at diffraction angles 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 non-solvated crystal of the compound of formula (3) is a type 2B crystal that contains at least five of the following peaks in powder X-ray diffraction at diffraction angles 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 non-solvated crystal of the compound of formula (3) is a type 2B crystal that contains at least seven of the following peaks in powder X-ray diffraction as a diffraction angle 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 non-solvated crystal of the compound of formula (3) is a type 2B crystal that contains the following peaks in powder X-ray diffraction at diffraction angles 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 non-solvated crystal of the compound of formula (3) is a type 2A crystal that contains, in powder X-ray diffraction, at least one of the following peaks at diffraction angles 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 non-solvated crystal of the compound of formula (3) is a type 2A crystal that contains at least three of the following peaks in powder X-ray diffraction at diffraction angles 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 non-solvated crystal of the compound of formula (3) is a type 2A crystal that contains at least five of the following peaks in powder X-ray diffraction at diffraction angles 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 non-solvated crystal of the compound of formula (3) is a type 2A crystal that contains at least seven of the following peaks in powder X-ray diffraction at diffraction angles 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 non-solvated crystal of the compound of formula (3) is a type 2A crystal that contains the following peaks in powder X-ray diffraction at diffraction angles 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 non-solvated crystal of the compound of formula (3) is a 2C-type crystal containing at least one of the following peaks in powder X-ray diffraction at diffraction angles 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 non-solvated crystal of the compound of formula (3) is a 2C-type crystal containing at least three of the following peaks in powder X-ray diffraction at diffraction angles 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 non-solvated crystal of the compound of formula (3) is a 2C-type crystal containing at least five of the following peaks in powder X-ray diffraction at diffraction angles 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 non-solvated crystal of the compound of formula (3) is a 2C-type crystal that contains at least seven of the following peaks in powder X-ray diffraction as a diffraction angle 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 non-solvated crystal of the compound of formula (3) is a 2C-type crystal containing the following peaks in powder X-ray diffraction at diffraction angles 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 non-solvated crystal of the compound of formula (3) is a 2F type crystal that contains at least one of the following peaks in powder X-ray diffraction at diffraction angles 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 non-solvated crystal of the compound of formula (3) is a 2F type crystal containing at least three of the following peaks in powder X-ray diffraction at diffraction angles 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 non-solvated crystal of the compound of formula (3) is a 2F type crystal that contains at least five of the following peaks in powder X-ray diffraction as a diffraction angle 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 non-solvated crystal of the compound of formula (3) is a 2F type crystal that contains at least seven of the following peaks in powder X-ray diffraction as a diffraction angle 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 non-solvated crystal of the compound of formula (3) is a 2F type crystal having the following peaks in powder X-ray diffraction at diffraction angles 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 contains at least one of the following peaks in powder X-ray diffraction at diffraction angles 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 contains at least three of the following peaks in powder X-ray diffraction at diffraction angles 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 contains at least five of the following peaks in powder X-ray diffraction at diffraction angles 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 contains at least seven of the following peaks in powder X-ray diffraction at diffraction angles 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 having the following peaks in powder X-ray diffraction as a diffraction angle 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 having the following peaks in powder X-ray diffraction at diffraction angles 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 type 5A crystal that contains at least one of the following peaks as a diffraction angle 2θ in powder X-ray diffraction. The following diffraction angles (2θ values) may be those 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 type 5A crystal that contains at least three of the following peaks as diffraction angles 2θ in powder X-ray diffraction. The following diffraction angles (2θ values) may be those 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°).

[0095] In one embodiment, the hydrate crystal of the compound of formula (4) is a type 5A crystal that contains at least five of the following peaks as diffraction angles 2θ in powder X-ray diffraction. The following diffraction angles (2θ values) may be those 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°).

[0096] In one embodiment, the hydrate crystal of the compound of formula (4) is a type 5A crystal that contains at least seven of the following peaks as diffraction angles 2θ in powder X-ray diffraction. The following diffraction angles (2θ values) may be those 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°).

[0097] In one embodiment, the hydrate crystal of the compound of formula (4) is a type 5A crystal having the following peaks as diffraction angles 2θ in powder X-ray diffraction. Note that the following diffraction angles (2θ values) may be those 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 type 5A crystal that contains at least one of the following peaks as a diffraction angle 2θ in powder X-ray diffraction. The following diffraction angles (2θ values) may be those of the hydrate crystal stored at a temperature of 25°C and 20% relative humidity for 1 hour: 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 type 5A crystal that contains at least three of the following peaks as diffraction angles 2θ in powder X-ray diffraction. The following diffraction angles (2θ values) may be those of the hydrate crystal stored at a temperature of 25°C and 20% relative humidity for 1 hour: 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 type 5A crystal that contains at least five of the following peaks as diffraction angles 2θ in powder X-ray diffraction. The following diffraction angles (2θ values) may be those of the hydrate crystal stored at a temperature of 25°C and 20% relative humidity for 1 hour: 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 type 5A crystal that contains at least seven of the following peaks as diffraction angles 2θ in powder X-ray diffraction. The following diffraction angles (2θ values) may be those of the hydrate crystal stored at a temperature of 25°C and 20% relative humidity for 1 hour: 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 having the following peaks at diffraction angles 2θ in powder X-ray diffraction. The following diffraction angles (2θ values) may be those of the hydrate crystal stored at a temperature of 25°C and 20% relative humidity for 1 hour: 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 type 5A crystal that contains at least one of the following peaks as a diffraction angle 2θ in powder X-ray diffraction. The following diffraction angles (2θ values) may be those of the hydrate crystal stored at a temperature of 25°C and a relative humidity of 30% for 1 hour: 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 type 5A crystal that contains at least three of the following peaks as diffraction angles 2θ in powder X-ray diffraction. The following diffraction angles (2θ values) may be those of the hydrate crystal stored at a temperature of 25°C and 30% relative humidity for 1 hour: 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 type 5A crystal that contains at least five of the following peaks as diffraction angles 2θ in powder X-ray diffraction. The following diffraction angles (2θ values) may be those of the hydrate crystal stored at a temperature of 25°C and 30% relative humidity for 1 hour: 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 type 5A crystal that contains at least seven of the following peaks as diffraction angles 2θ in powder X-ray diffraction. The following diffraction angles (2θ values) may be those of the hydrate crystal stored at a temperature of 25°C and a relative humidity of 30% for 1 hour: 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 type 5A crystal having the following peaks at diffraction angles 2θ in powder X-ray diffraction. The following diffraction angles (2θ values) may be those of the hydrate crystal stored at a temperature of 25°C and a relative humidity of 30% for 1 hour: 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 contains at least one of the following peaks as a diffraction angle 2θ in powder X-ray diffraction. The following diffraction angles (2θ values) may be those of the hydrate crystal stored at a temperature of 25°C and a relative humidity of 60% for 1 hour: 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 type 5A crystal that contains at least three of the following peaks as diffraction angles 2θ in powder X-ray diffraction. The following diffraction angles (2θ values) may be those of the hydrate crystal stored at a temperature of 25°C and 60% relative humidity for 1 hour: 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 type 5A crystal that contains at least five of the following peaks as diffraction angles 2θ in powder X-ray diffraction. The following diffraction angles (2θ values) may be those of the hydrate crystal stored at a temperature of 25°C and 60% relative humidity for 1 hour: 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 type 5A crystal that contains at least seven of the following peaks as diffraction angles 2θ in powder X-ray diffraction. The following diffraction angles (2θ values) may be those of the hydrate crystal stored at a temperature of 25°C and a relative humidity of 60% for 1 hour: 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 having the following peaks at diffraction angles 2θ in powder X-ray diffraction. Note that the following diffraction angles (2θ values) may be those of the hydrate crystal stored at a temperature of 25°C and 60% relative humidity for 1 hour: 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 contains at least one of the following peaks in powder X-ray diffraction at diffraction angles 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 contains at least three of the following peaks in powder X-ray diffraction at diffraction angles 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 contains at least five of the following peaks in powder X-ray diffraction at diffraction angles 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 contains at least seven of the following peaks in powder X-ray diffraction at diffraction angles 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 having the following peaks in powder X-ray diffraction as a diffraction angle 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 contains at least one of the following peaks in powder X-ray diffraction at diffraction angles 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 contains at least one of the following peaks as a diffraction angle 2θ in powder X-ray diffraction. The following diffraction angles (2θ values) may be those of the hydrate crystal stored at a temperature of 25°C and a relative humidity of 30% for 1 hour: 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 contains at least three of the following peaks as diffraction angles 2θ in powder X-ray diffraction. The following diffraction angles (2θ values) may be those of the hydrate crystal stored at a temperature of 25°C and a relative humidity of 30% for 1 hour: 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 contains at least five of the following peaks as diffraction angles 2θ in powder X-ray diffraction. The following diffraction angles (2θ values) may be those of the hydrate crystal stored at a temperature of 25°C and a relative humidity of 30% for 1 hour: 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 contains at least seven of the following peaks as diffraction angles 2θ in powder X-ray diffraction. The following diffraction angles (2θ values) may be those of the hydrate crystal stored at a temperature of 25°C and a relative humidity of 30% for 1 hour: 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 having the following peaks as diffraction angles 2θ in powder X-ray diffraction. Note that the following diffraction angles (2θ values) may be those of the hydrate crystal stored at a temperature of 25°C and 30% relative humidity for 1 hour: 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 contains at least one of the following peaks as a diffraction angle 2θ in powder X-ray diffraction. The following diffraction angles (2θ values) may be those of the hydrate crystal stored at a temperature of 25°C and a relative humidity of 40% for 1 hour: 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 contains at least three of the following peaks as diffraction angles 2θ in powder X-ray diffraction. The following diffraction angles (2θ values) are preferably those of the hydrate crystal stored at a temperature of 25°C and 40% relative humidity for 1 hour: 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 contains at least five of the following peaks as diffraction angles 2θ in powder X-ray diffraction. The following diffraction angles (2θ values) are preferably those of the hydrate crystal stored at a temperature of 25°C and 40% relative humidity for 1 hour: 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 contains at least seven of the following peaks as diffraction angles 2θ in powder X-ray diffraction. The following diffraction angles (2θ values) are preferably those of the hydrate crystal stored at a temperature of 25°C and 40% relative humidity for 1 hour: 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 having the following peaks as diffraction angles 2θ in powder X-ray diffraction. The following diffraction angles (2θ values) are preferably those of the hydrate crystal stored at a temperature of 25°C and a relative humidity of 40% for 1 hour: 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 embodiment, the hydrate crystal of the compound of formula (4) is a 5J-type crystal that contains at least one of the following peaks as a diffraction angle 2θ in powder X-ray diffraction. The following diffraction angles (2θ values) may be those 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 embodiment, the hydrate crystal of the compound of formula (4) is a 5J-type crystal that contains at least three of the following peaks as diffraction angles 2θ in powder X-ray diffraction. The following diffraction angles (2θ values) may be those 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 embodiment, the hydrate crystal of the compound of formula (4) is a 5J-type crystal that contains at least five of the following peaks as diffraction angles 2θ in powder X-ray diffraction. The following diffraction angles (2θ values) may be those 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 embodiment, the hydrate crystal of the compound of formula (4) is a 5J-type crystal that contains at least seven of the following peaks as diffraction angles 2θ in powder X-ray diffraction. The following diffraction angles (2θ values) may be those 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 having the following peaks as diffraction angles 2θ in powder X-ray diffraction. The following diffraction angles (2θ values) may be those 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°).

[0134] In one embodiment, the hydrate crystal of the compound of formula (4) is a 5J-type crystal that contains at least one of the following peaks as a diffraction angle 2θ in powder X-ray diffraction. The following diffraction angles (2θ values) may be those of the hydrate crystal stored at a temperature of 25°C and a relative humidity of 70% or higher for 1 hour: 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 contains at least three of the following peaks as diffraction angles 2θ in powder X-ray diffraction. The following diffraction angles (2θ values) may be those of the hydrate crystal stored at a temperature of 25°C and a relative humidity of 70% or higher for 1 hour: 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 contains at least five of the following peaks as diffraction angles 2θ in powder X-ray diffraction. The following diffraction angles (2θ values) may be those of the hydrate crystal stored at a temperature of 25°C and a relative humidity of 70% or higher for 1 hour: 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 contains at least seven of the following peaks as diffraction angles 2θ in powder X-ray diffraction. The following diffraction angles (2θ values) may be those of the hydrate crystal stored at a temperature of 25°C and a relative humidity of 70% or higher for 1 hour: 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 having the following peaks as diffraction angles 2θ in powder X-ray diffraction. Note that the following diffraction angles (2θ values) may be those of the hydrate crystal stored at a temperature of 25°C and a relative humidity of 70% or higher for 1 hour: 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 contains at least one of the following peaks in powder X-ray diffraction at diffraction angles 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 contains at least three of the following peaks in powder X-ray diffraction at diffraction angles 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 contains at least five of the following peaks in powder X-ray diffraction at diffraction angles 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 contains at least seven of the following peaks in powder X-ray diffraction at diffraction angles 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 contains the following peaks in powder X-ray diffraction as a diffraction angle 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 non-solvated crystal of the compound of formula (4) is a 5D-type crystal that contains at least one of the following peaks in powder X-ray diffraction at diffraction angles 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 non-solvated crystal of the compound of formula (4) is a 5D-type crystal that contains at least three of the following peaks in powder X-ray diffraction at diffraction angles 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 non-solvated crystal of the compound of formula (4) is a 5D-type crystal that contains at least five of the following peaks in powder X-ray diffraction as a diffraction angle 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 one embodiment, the non-solvated crystal of the compound of formula (4) is a 5D-type crystal that contains at least seven of the following peaks in powder X-ray diffraction as a diffraction angle 2θ: 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 one embodiment, the non-solvated crystal of the compound of formula (4) is a 5D-type crystal that contains the following peaks in powder X-ray diffraction at diffraction angles 2θ: 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 one embodiment, the crystal of the compound of formula (4) is a 5G-type crystal that contains at least one of the following peaks in powder X-ray diffraction at diffraction angles 2θ: 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 one embodiment, the crystal of the compound of formula (4) is a 5G-type crystal that contains at least three of the following peaks in powder X-ray diffraction at diffraction angles 2θ: 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 one embodiment, the crystal of the compound of formula (4) is a 5G-type crystal that contains at least five of the following peaks in powder X-ray diffraction as a diffraction angle 2θ: 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 contains at least seven of the following peaks in powder X-ray diffraction at diffraction angles 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 contains the following peaks in powder X-ray diffraction at diffraction angles 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 contains at least one of the following peaks in powder X-ray diffraction at diffraction angles 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 contains at least three of the following peaks in powder X-ray diffraction at diffraction angles 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 contains at least five of the following peaks in powder X-ray diffraction at diffraction angles 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 contains at least seven of the following peaks in powder X-ray diffraction at diffraction angles 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 having the following peaks in powder X-ray diffraction as a diffraction angle 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 contains at least one of the following peaks in powder X-ray diffraction at diffraction angles 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 contains at least three of the following peaks in powder X-ray diffraction at diffraction angles 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 contains at least five of the following peaks in powder X-ray diffraction at diffraction angles 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 contains at least seven of the following peaks in powder X-ray diffraction at diffraction angles 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 having the following peaks in powder X-ray diffraction as a diffraction angle 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 term "to" indicating a numerical range includes both ends of the range. For example, "A to B" means a numerical range that is equal to or greater than A and equal to or less than B.

[0165] As used herein, the term "about" when used in conjunction with a numerical value means a range of values ​​of plus and minus 10% of that numerical value.

[0166] As used herein, the term "and / or" includes any combination of "and" and "or." 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, and (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. The compounds represented by formulas (1) to (5) can be synthesized, for example, by the method described in Example 1 below.

[0168] <Production Method> Crystals of the compound of the present invention, or a salt thereof, or a solvate thereof can be produced, for example, by the method shown below. Crystals of the compound, or a salt thereof, or a solvate thereof 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 that allows the compound to form crystals; however, a solvent that allows an operation to be performed on a solution in which the compound is dissolved, is preferred. For example, when crystallization is possible by reducing the solubility of the compound by adding a poor solvent or cooling the solution, a solvent that allows such an operation is exemplified. Furthermore, when crystals of the compound can be obtained by maintaining crude crystals of the compound in a suspension state for a desired period of time, a solvent that allows such an operation 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, ethanol, and mixed solvents thereof.

[0169] <Pharmaceutical Compositions> The present invention provides pharmaceutical compositions containing the compound of the present invention, or a crystalline salt thereof, or a solvate thereof. The pharmaceutical compositions of the present invention can be formulated by known methods by incorporating a pharmaceutically acceptable carrier in addition to the compound of the present invention, or a crystalline salt thereof, or a solvate thereof. For formulation, commonly used excipients, binders, lubricants, colorants, flavorings, and, if necessary, stabilizers, emulsifiers, absorption enhancers, surfactants, pH adjusters, preservatives, antioxidants, etc. may be used. The compositions are formulated by conventional methods by blending ingredients commonly used as raw materials for pharmaceutical formulations. For formulation, known methods can be used to process the active ingredients used in pharmaceuticals into optimal shapes or properties, i.e., dosage forms, suited to the intended use and intended purpose. Examples of commonly used dosage forms include liquid pharmaceutical preparations (liquids) such as injections, suspensions, emulsions, and eye drops, and solid pharmaceutical preparations (solid preparations) such as tablets, powders, fine granules, granules, coated tablets, capsules, dry syrups, lozenges, and suppositories, but are not limited thereto.

[0170] For example, to prepare a liquid formulation, a pharmaceutically acceptable carrier or vehicle, specifically, pharmaceutically acceptable additives commonly used in the field of pharmaceutical formulations, such as sterile water, physiological saline, vegetable oil, emulsifier, suspending agent, surfactant, stabilizer, flavoring agent, excipient, vehicle, preservative, binder, etc., are added in appropriate combination to the crystals of the compound of the present invention, or its salt, or solvate thereof, and then mixed together to form a unit dose required for generally accepted pharmaceutical practice. Alternatively, a solid formulation prepared for liquid formulation can be dissolved as needed by adding an appropriate solvent, such as sterile water or physiological saline, before administration, and then used for administration.

[0171] Such liquid preparations can also be used parenterally, for example, in the form of a sterile solution or suspension injection in water or other pharmaceutically acceptable liquid. For example, they can be formulated by appropriately combining them with pharmaceutically acceptable carriers or vehicles, specifically, sterile water, physiological saline, vegetable oils, emulsifiers, suspending agents, surfactants, stabilizers, flavoring agents, excipients, vehicles, preservatives, binders, etc., and blending them in a unit dosage form required for generally accepted pharmaceutical practice. Specific 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 fatty acid triglycerides, polyoxyethylene hydrogenated castor oil 60, sucrose, carboxymethylcellulose, cornstarch, inorganic salts, etc. The amount of active ingredient in these preparations is such that an appropriate dose within the indicated range can be obtained. Sterile compositions for injection can be formulated according to conventional pharmaceutical practice using a vehicle such as distilled water for injection.

[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, and may be used in combination with an appropriate solubilizing agent, such as alcohol, specifically ethanol, polyalcohols such as propylene glycol and polyethylene glycol, or nonionic surfactants such as Polysorbate 80 (registered trademark) and HCO-50.

[0173] Examples of oily liquids include sesame oil and soybean oil, and they may be used in combination with solubilizing agents such as benzyl benzoate and benzyl alcohol. They may also contain buffers such as phosphate buffer and sodium acetate buffer, soothing agents such as procaine hydrochloride, stabilizers such as benzyl alcohol, phenol, and antioxidants. The prepared injection solution is usually filled into suitable ampoules.

[0174] For example, to produce a solid preparation, an excipient and, if necessary, pharmaceutically acceptable additives commonly used in the field of pharmaceutical preparations such as binders, disintegrants, lubricants, colorants, and flavoring agents are added in appropriate combination to crystals of the compound of the present invention, or a salt thereof, or a solvate thereof, and then the mixture is formed into tablets, powders, fine granules, granules, coated tablets, capsules, dry syrups, troches, suppositories, etc. by conventional methods.

[0175] Examples of pharmaceutically acceptable additives used in such solid preparations 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 hydroxyethyl cellulose, polyacrylic acid, carboxyvinyl polymers, 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 hydrate, fructose, and sucrose; inorganic powders such as silicic anhydride, aluminum magnesium silicate, and aluminum silicate; and purified water.

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

[0177] Examples of binders include polyvinyl alcohol, polyvinyl ether, methyl cellulose, ethyl cellulose, gum arabic, tragacanth, gelatin, shellac, hydroxypropylmethyl cellulose, hydroxypropyl cellulose, polyvinylpyrrolidone, polypropylene glycol-polyoxyethylene block polymers, and the like.

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

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

[0180] Coloring agents that are permitted to be added to pharmaceuticals are used, and flavoring agents include cocoa powder, peppermint, aromatic powder, peppermint oil, borneol, cinnamon powder, etc.

[0181] Of course, these tablets and granules may be coated with sugar or other suitable coatings as necessary. When producing liquid preparations such as syrups and injection preparations, a pH adjuster, a solubilizer, an isotonicity agent, and the like, and if necessary, a solubilizing agent, a stabilizer, and the like, are added to crystals of the compound of the present invention, or a salt thereof, or a solvate thereof, and the preparation is prepared in a conventional manner.

[0182] The administration is preferably parenteral, but the administration method is not limited to parenteral administration. Specific examples of parenteral administration include injections, intranasal administrations, pulmonary administrations, transdermal administrations, etc. Examples of injections include intravenous injections, intramuscular injections, intraperitoneal injections, subcutaneous injections, etc., which can be used for systemic or local administration.

[0183] In addition, the administration method can be selected appropriately depending on the patient's age and symptoms. The dosage of a pharmaceutical composition containing the compound of the present invention, or a salt thereof, or a crystal of a solvate thereof produced by the method of the present invention can be selected, for example, from the range of 0.0001 mg to 1000 mg per kg of body weight per administration. Alternatively, the dosage can be selected, for example, from the range of 0.001 to 100,000 mg / body weight per patient, but is not necessarily limited to these values. The dosage and administration method vary depending on the patient's weight, age, symptoms, etc., but can be appropriately selected by those skilled in the art.

[0184] In certain embodiments, the compound of the present invention, or a salt thereof, or a crystal of a solvate thereof can be used for activating Nrf2, or for inhibiting Keap1 and activating Nrf2.

[0185] In one aspect, the pharmaceutical composition of the present invention is used to treat diseases in a subject, for example, those described in Nature Reviews DrugDiscovery, 2019, 18, pp. 295-317, more specifically, neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease, Friedreich's ataxia, and amyotrophic lateral sclerosis, pulmonary 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, ophthalmological diseases such as uveitis, glaucoma, and age-related macular degeneration, liver diseases such as non-alcoholic steatohepatitis, immune / inflammatory diseases such as multiple sclerosis, rheumatoid arthritis, and ulcerative colitis, head and neck cancer (pharyngeal cancer, laryngeal cancer, tongue cancer, etc.), esophageal cancer, gastric cancer, and colon cancer ( The present invention can be used to treat or prevent cell proliferative disorders exemplified by solid cancers such as appendicitis, 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 / ureter cancer, malignant melanoma, and skin cancer, as well as cancers of the blood and lymphatics such as leukemia (acute myeloid leukemia, acute lymphocytic leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia, etc.), malignant lymphoma (Hodgkin's disease, non-Hodgkin's lymphoma, etc.), multiple myeloma, and myelodysplastic syndrome.

[0186] As used herein, the term "subject" includes mammals, preferably humans.

[0187] The present invention provides a pharmaceutical composition comprising a crystalline compound of the present invention, or a salt thereof, or a solvate thereof, mixed with a pharmaceutically acceptable carrier or vehicle. The present invention also provides a method for producing a pharmaceutical composition comprising a crystalline compound of the present invention, or a salt thereof, or a solvate thereof, as an active ingredient, the method comprising mixing the crystalline compound with a pharmaceutically acceptable carrier or vehicle.

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

[0189] As used herein, "mixing a crystal of a compound or a salt thereof, or a solvate thereof with a pharmaceutically acceptable carrier or vehicle" includes both of the following: (a) adding another component sequentially to either (1) a crystal of a compound or a salt thereof, or a solvate thereof, and (2) a pharmaceutically acceptable carrier or vehicle; and (b) adding (1) and (2) simultaneously. Furthermore, as used herein, "mixing a compound or a salt thereof, or a solvate thereof with a pharmaceutically acceptable carrier or vehicle" includes both of the following: (a') adding another component sequentially to either (1') a compound or a salt thereof, or a solvate thereof, and (2') a pharmaceutically acceptable carrier or vehicle; and (b') adding (1') and (2') simultaneously. Here, "mixing" does not necessarily require that a homogeneous mixture be obtained when mixing (1) and (2), or (1') and (2'). For example, "mixing" includes "dissolving," "suspending," and "emulsifying."

[0190] The present invention is further illustrated 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 compounds was performed using an AutoPurification HPLC / MS System (Waters) or Trilution (Gilson). １H-NMR spectra were measured with or without Me4Si as an internal standard using an MR400 OneNMR probe (400 MHz, Agilent technology), an AVANCE III HD 400 SMART-BBFO probe (400 MHz, Bruker), an ECP400 (400 MHz, JEOL), an AVANCE III HD 400 SMART-BBFO probe (400 MHz, Bruker), an MR400 OneNMR probe (400 MHz, Agilent technology), or an AVANCE NEO 400 iProbe (400 MHz). NMR was measured using a 300 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 ultra-high performance liquid chromatograph (Nexera UC or Nexera) equipped with a single quadrupole mass spectrometer (LCMS-2020) or a Waters Corporation Acquity ultra-high performance liquid chromatograph (UPLC or UPLC I-Class) equipped with a single quadrupole mass spectrometer (SQD or SQD2). When two retention times are given, they represent the retention times of rotamers. Microwave irradiation was performed using Initiator™ (manufactured by Biotage).

[0191]

[0192] [Example 1] Synthesis of Compounds <Example 1-1> Compound A methyl 4-[3-(4-bromo-2,6-dichlorobenzoyl)-2,4-dihydro-1,3-benzoxazin-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 A solution of 3-bromo-2-hydroxybenzaldehyde (5.00 g, 24.9 mmol) and tert-butyl carbamate (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 and 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. Further water was added and the mixture was stirred for 30 minutes. The reaction mixture was filtered and washed with acetonitrile / water (1 / 2). The mixture was further washed with heptane and dried under reduced pressure to obtain the title compound (88%, 6.60 g). LCMS: m / z 300 [M-H] － HPLC retention time: 1.16 minutes (Analysis conditions F)

[0193] Second Step: Compound A2 tert-butyl 8-bromo-2,4-dihydro-1,3-benzoxazine-3-carboxylate 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% aqueous formaldehyde 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 30 minutes. The reaction mixture was filtered and washed with acetonitrile / water (1 / 2). The mixture was dried under reduced pressure to give the title compound (81%, 4.20 g). LCMS: m / z 214 [M-Boc+H] ＋ HPLC retention time: 1.31 minutes (Analysis conditions F)

[0194] Third Step Compound A3 4-bromo-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid To a suspension of 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) in tetrahydrofuran (6.00 mL) was added a 1 M solution of lithium(bistrimethylsilyl)amide in tetrahydrofuran (50.6 mL, 50.6 mmol) at room temperature over 12 minutes. 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, followed by extraction with ethyl acetate. The aqueous layer was extracted again with ethyl acetate, and the two organic layers were combined and washed with 20% aqueous ammonium chloride and 15% aqueous sodium chloride. The washed organic layer was concentrated to give the title compound as a crude product. LCMS: m / z 330 [M+H] ＋ HPLC retention time: 0.61 minutes (Analysis conditions D)

[0195] Fourth step Compound A4 methyl 4-bromo-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoate Potassium carbonate (2.10 g, 15.2 mmol) and iodomethane (1.58 mL, 25.3 mmol) were added 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), and the mixture was stirred at room temperature for 30 minutes. 20% aqueous ammonium chloride solution and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with 20% aqueous ammonium chloride solution and concentrated. Methanol was added to the resulting crude product, and the mixture was heated to 60°C, cooled to room temperature, and stirred for 30 minutes. Water was added and the mixture was stirred for 1 hour, after which more water was added and the mixture was stirred for 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 conditions 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 A solution of methyl 4-bromo-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoate (1.21 g, 3.50 mmol) in tetrahydrofuran (5.30 mL) was cooled to -10°C. 2M isopropylmagnesium chloride in tetrahydrofuran (1.91 mL, 3.82 mmol) was added and stirred for 1 hour. 2M zinc(II) chloride in 2-methyltetrahydrofuran (0.955 mL, 1.91 mmol) was added to the reaction mixture. 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, and the mixture was heated to 45°C and stirred for 90 minutes. After cooling to room temperature, ethyl acetate and aqueous ammonium chloride were added, and the mixture was extracted with ethyl acetate. The organic layer was washed with aqueous N-acetylcysteine ​​and aqueous sodium chloride, and then concentrated to obtain a crude product. Ethanol was added to the resulting crude product, and the mixture was heated to 80°C to dissolve the product. The mixture was cooled to room temperature. Heptane was added, and the mixture was cooled to 0°C. The solid obtained after 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 conditions F)

[0197] Sixth Step Compound A6 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 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 (10.0 g, 20.1 mmol) in acetonitrile (100 mL) was added a 4M solution of hydrochloric acid in ethyl acetate (25.1 mL, 100 mmol), and the mixture was stirred at room temperature for 2 hours. Filtration afforded the title compound (76%, 7.16 g) as crystals. LCMS: m / z 399 [M+H] ＋ HPLC retention time: 0.75 minutes (Analysis conditions F)

[0198] Seventh step: Compound A7 4-bromo-2,6-dichlorobenzoyl chloride Thionyl chloride (24.5 mL, 337 mmol) and N,N-dimethylformamide (0.261 mL, 3.37 mmol) were added to a solution of 4-bromo-2,6-dichlorobenzoic acid (45.5 g, 169 mmol) in toluene (241 mL), 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 purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (99%, 48.0 g). HPLC retention time: 1.48 minutes (analysis condition F). １ H NMR (400 MHz, CDCl ３ ) δ 7.56 (s, 2H)

[0199] Eighth step: Compound A methyl 4-[3-(4-bromo-2,6-dichlorobenzoyl)-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoate To 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)benzoato dihydrochloride (9.22 g, 19.6 mmol) in toluene (92.0 mL), 4-bromo-2,6-dichlorobenzoyl chloride (7.33 g, 25.4 mmol) and pyridine (11.1 mL, 137 mmol) were added and the mixture was stirred at 70°C for 12 hours. The reaction mixture was extracted with ethyl acetate and 1M hydrochloric acid, and the organic layer was washed with 50% saturated aqueous sodium bicarbonate and 50% saturated aqueous sodium chloride, and then dried over anhydrous magnesium sulfate. After concentration, the resulting residue was triturated with hexane to give 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-benzoxazin-8-yl]-5-fluoro-2-morpholin-4-ylbenzoate First Step: Compound B1: 4-bromo-5-fluoro-2-morpholin-4-ylbenzoic acid 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 mixture, followed by extraction and washing with saturated brine. The organic layer was concentrated to give 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-morpholin-4-ylbenzoate To a solution of 4-bromo-5-fluoro-2-morpholin-4-ylbenzoic acid (400 mg, 1.32 mmol) in dichloromethane (5.00 mL) and methanol (1.00 mL) was added 2M trimethylsilyldiazomethane-hexane solution (1.32 mL, 2.63 mmol), and the mixture was stirred at room temperature for 30 minutes. Acetic acid was added to the reaction mixture, and the reaction mixture was concentrated. The reaction mixture was then 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-morpholin-4-ylphenyl)-2,4-dihydro-1,3-benzoxazine-3-carboxylate A solution of methyl 4-bromo-5-fluoro-2-morpholin-4-ylbenzoate (2.95 g, 9.28 mmol), bis(pinacolato)diboron (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(diphenylphosphino)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, followed by stirring at 90°C for 3 hours. The reaction mixture was cooled to room temperature, and water and ethyl acetate were added. The mixture was filtered through Celite. The organic layer was washed with brine, dried, and concentrated. The resulting residue was purified by silica gel chromatography (hexane / ethyl acetate) to give the title compound (91%, 3.63 g). LCMS: m / z 473 [M+H] ＋ HPLC retention time: 1.34 minutes (Analysis conditions F)

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

[0204] Fifth step: Compound B methyl 4-[3-(4-bromo-2,6-dichlorobenzoyl)-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-morpholin-4-ylbenzoate A solution of methyl 4-(3,4-dihydro-2H-1,3-benzoxazin-8-yl)-5-fluoro-2-morpholin-4-ylbenzoate 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 give the title compound (56%, 110 mg). LCMS: m / z 623 [M+H] ＋ HPLC retention time: 1.37 minutes (Analysis conditions F)

[0205] Example 1-3 Compound 1, 4-[3-[2,6-dichloro-4-[(2R)-2,4-dimethylpiperazin-1-yl]benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid Step 1 Compound 1-1, methyl 4-[3-[2,6-dichloro-4-[(2R)-2,4-dimethylpiperazin-1-yl]benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoate 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, and the organic layer was concentrated. The resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate / methanol) to give the title compound (75%, 15.9 g). LCMS: m / z 683 [M+H] ＋ HPLC retention time: 0.89 minutes (Analysis conditions F)

[0206] Second step: Compound 14-[3-[2,6-dichloro-4-[(2R)-2,4-dimethylpiperazin-1-yl]benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid To a solution of methyl 4-[3-[2,6-dichloro-4-[(2R)-2,4-dimethylpiperazin-1-yl]benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoato (18.6 g, 27.2 mmol) in 1-methylpyrrolidin-2-one (186 mL), 8M aqueous potassium hydroxide solution (11.9 mL, 95.0 mmol) was added and stirred at 60 °C for 2 hours. Aqueous formic acid was added to the reaction mixture, and the mixture was purified by reverse phase column chromatography (acetonitrile / water, 0.1% formic acid) to give 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] Example 1-4 Compound 24-[3-[2,6-dichloro-4-[4-(2-methoxyethyl)piperazin-1-yl]benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-morpholin-4-ylbenzoic acid A solution of 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) in toluene (15.0 mL) was heated 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 aqueous sodium hydroxide 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, and formic acid was added. The reaction mixture was purified by reverse phase column chromatography (acetonitrile / water, 0.1% formic acid) to give 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] <Example 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-benzoxazin-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 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 and washed with 5% aqueous sodium bicarbonate and 15% aqueous sodium chloride. The organic layer was then dried over magnesium sulfate and concentrated. The resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (84%, 17.9 g). LCMS: m / z 292 [M+H] ＋ HPLC retention time: 1.15 minutes (Analysis conditions F)

[0209] Second step: Compound 3-27,7-dimethyl-5,9-dioxa-2-azaspiro[3.5]nonane 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 on activated carbon (wet) (306 mg, 0.436 mmol) was added, and the mixture was stirred under a hydrogen atmosphere for 14 hours. The reaction solution was filtered through Celite, washed with 1,4-dioxane, and concentrated to obtain the title compound as a crude product in 1,4-dioxane.

[0210] Third step: Compound 3-3 methyl 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-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoate A mixture of 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 (30.8 mL) of rac-BINAP Pd G4 (204 mg, 0.203 mmol) was 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 15% aqueous sodium chloride solution and then extracted. The organic layer was dried over sodium sulfate and concentrated. Ethyl acetate and hexane were added to the resulting residue, and the mixture was triturated to quantitatively obtain the title compound (4.96 g). LCMS: m / z 726 [M+H] ＋ HPLC retention time: 1.48 minutes (Analysis conditions F)

[0211] Fourth Step: Compound 34-[3-[2,6-dichloro-4-(7,7-dimethyl-5,9-dioxa-2-azaspiro[3.5]nonan-2-yl)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid To a solution of methyl 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-benzoxazin-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) was added 8 M aqueous potassium hydroxide solution (6.61 mL, 52.8 mmol), and the mixture was stirred at 50°C for 3 hours. The reaction mixture was cooled to room temperature, and 1 M hydrochloric acid was added. Water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with 3% aqueous N-acetylcysteine ​​and 15% aqueous sodium chloride, dried over sodium sulfate, and concentrated. Ethanol was added to the residue, and the mixture was heated at 60°C. Water was added and the mixture was cooled to room temperature. Water was further added, and the resulting solid was collected by filtration and washed with ethanol / water (1 / 6) to give 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] Example 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-benzoxazin-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 To a solution of 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), allylpalladium(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) in 1,3-dimethyl-2-imidazolidinone (23.7 mL) was added 1 M sodium bis(trimethylsilyl)amide tetrahydrofuran solution (19.0 mL, 19.0 mmol) dropwise. The reaction mixture was stirred at room temperature for 17 hours, and then aqueous formic acid and dimethyl sulfoxide were added. The mixture was purified by reverse phase column chromatography (acetonitrile / water, 0.1% formic acid) to give the title compound (84%, 1.26 g). LCMS: m / z 316 [M+H] ＋ HPLC retention time: 1.01 minutes (Analysis conditions F)

[0213] Second 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-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoate To a solution of 2,6-dichloro-4-(6-methoxy-2-azaspiro[3.3]heptan-2-yl)benzoic acid (698 mg, 2.21 mmol) in ethyl acetate (14.0 mL) was added Ghosez reagent (0.350 mL, 2.65 mmol). 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)benzoate dihydrochloride (944 mg, 2.01 mmol) were added. The reaction mixture was stirred at 50°C overnight, after which 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 aqueous sodium bicarbonate and concentrated to give the crude 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-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid 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-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoato (196 mg, 0.281 mmol) and 8M aqueous potassium hydroxide (0.352 mL, 2.81 mmol) in tetrahydrofuran (0.471 mL) and ethanol (1.57 mL) was stirred at 60°C for 1 hour. After cooling the reaction mixture 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 give 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] Example 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-benzoxazin-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-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoate 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-methylpyrrolidin-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, and ethyl acetate and water were added for extraction. The organic layer was washed with an aqueous N-acetylcysteine ​​solution and an aqueous sodium chloride solution, dried over magnesium sulfate, and then concentrated. The resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give 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 step: Compound 4, 4-[3-[2,6-dichloro-4-(6-methoxy-2-azaspiro[3.3]heptan-2-yl)benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid 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-benzoxazin-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) was added 8 M aqueous potassium hydroxide solution (11.0 mL, 88.0 mmol), and the mixture was stirred at 60°C for 2.5 hours. The reaction mixture was cooled to room temperature, and 0.5 M hydrochloric acid and water were added, followed by stirring. The resulting solid was collected by filtration, washed with water, and then dried under reduced pressure. An ethanol / water (1 / 9) solution was added to the resulting solid, and the solution was frozen in a −80° C. freezer and then lyophilized to give 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] <Example 1-8> Compound 5: 4-[3-[2-chloro-4-[(2R,5R)-2,4,5-trimethylpiperazin-1-yl]benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid Step 1: Compound 5-1: (2R,5R)-1,2,5-trimethylpiperazine To a solution of (2R,5R)-1,2,5-trimethylpiperazine dihydrochloride (10.3 g, 51.0 mmol) in tetrahydrofuran (49.6 mL) was added 50% aqueous potassium hydroxide solution (11.4 g, 102 mmol), the mixture was stirred at room temperature, filtered, and washed with tetrahydrofuran. The filtrate was concentrated to give a solution of the title compound in tetrahydrofuran. 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 step: Compound 5-22-chloro-4-[(2R,5R)-2,4,5-trimethylpiperazin-1-yl]benzoic acid 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 vessel, allylpalladium(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 above prepared solution was added, and the mixture was stirred at 90°C for 2 hours. After cooling the reaction mixture to room temperature, an aqueous N-acetylcysteine ​​solution 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 by adding an 8M aqueous sodium hydroxide solution. Ammonium sulfate was added to the obtained aqueous layer, and the mixture 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 obtained solid was collected by filtration, 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-benzoxazin-8-yl)-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoate methanesulfonate Methanesulfonic acid (4.58 mL, 70.6 mmol) was added 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 the mixture was stirred at room temperature for 2 hours to obtain a solution of the title compound in acetonitrile.

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

[0221] Fifth step: Compound 5-5 methyl 4-[3-[2-chloro-4-[(2R,5R)-2,4,5-trimethylpiperazin-1-yl]benzoyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoate To the acetonitrile solution of 2-chloro-4-[(2R,5R)-2,4,5-trimethylpiperazin-1-yl]benzoyl chloride obtained in the fourth step was added 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)benzoat methanesulfonate obtained in the third step. 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, followed by extraction with water, 15% aqueous sodium chloride, 8M aqueous sodium hydroxide, and 1M hydrochloric acid. The organic layer obtained was concentrated. 1M hydrochloric acid and ethyl acetate were added to the resulting residue, and back-extraction was performed. 8M aqueous sodium hydroxide and 2M hydrochloric acid were added to the resulting aqueous layer, and the mixture was extracted with 4-methyltetrahydropyran. The organic layer was washed with 15% aqueous sodium chloride, concentrated and dried under reduced pressure to give the title compound (69%, 8.99 g). LCMS: m / z 663 [M+H] ＋ HPLC retention time: 0.86 minutes (Analysis conditions F)

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

[0223] <Example 1-9> Compound 6: 4-[3-[4-chloro-6-(7,7-dimethyl-5,9-dioxa-2-azaspiro[3.5]nonan-2-yl)-2-methylpyridine-3-carbonyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid Step 1: Compound 6-1: 4,6-dichloro-2-methylpyridine-3-carbonyl chloride 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. 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 a crude product.

[0224] Second step Compound 6-2 Methyl 4-[3-(4,6-dichloro-2-methylpyridine-3-carbonyl)-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoate The title compound was obtained using 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 and 4,6-dichloro-2-methylpyridine-3-carbonyl chloride in the same manner as in Compound B, Step 5, except that 4-methylmorpholine was used in place 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-azaspiro[3.5]nonan-2-yl)-2-methylpyridine-3-carbonyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoate A suspension of methyl 4-[3-(4,6-dichloro-2-methylpyridine-3-carbonyl)-2,4-dihydro-1,3-benzoxazin-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 1,4-dioxane (52.9 mL) was stirred at 60° C. overnight. The reaction mixture was cooled to room temperature, and XantPhos Pd G3 (0.376 g, 0.396 mmol) was added, followed by stirring 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 aqueous sodium chloride, dried over magnesium sulfate, and filtered. The resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (36%, 2.01 g). LCMS: m / z 707 [M+H] ＋ HPLC retention time: 1.39 minutes (Analysis conditions F)

[0226] Fourth Step: Compound 6: 4-[3-[4-chloro-6-(7,7-dimethyl-5,9-dioxa-2-azaspiro[3.5]nonan-2-yl)-2-methylpyridine-3-carbonyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoic acid Methyl 4-[3-[4-chloro-6-(7,7-dimethyl-5,9-dioxa-2-azaspiro[3.5]nonan-2-yl)-2-methylpyridine-3-carbonyl]-2,4-dihydro-1,3-benzoxazin-8-yl]-5-fluoro-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)benzoato (5.97 g, 8.44 mmol) in tetrahydrofuran (16.9 mL) and methanol (16.9 mL) was added to a solution of 8M aqueous potassium hydroxide (3.17 mL, 25.3 mmol) and stirred at 50 ° C. for 1.5 hours. After adding aqueous formic acid to the reaction mixture, the mixture was purified by reverse phase column chromatography (acetonitrile / water, 0.1% formic acid) to give 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] Example 1-10 Compound 7 (2S,3R)-3-[2-[2,6-dichloro-4-(2-methoxyethoxy)benzoyl]-3,4-dihydro-1H-isoquinolin-5-yl]-2-methylbutanoic acid First step Compound 7-1 Ethyl (E)-3-(3,4-dihydroisoquinolin-5-yl)but-2-enoate A solution of 5-bromo-3,4-dihydroisoquinoline (500 mg, 2.38 mmol), ethyl (E)-but-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 give a residue, which was purified by reverse-phase column chromatography (acetonitrile / water, 0.1% formic acid) to give the title compound (35%, 200 mg). LCMS: m / z 244 [M+H] ＋ HPLC retention time: 1.22 minutes (Analysis conditions L)

[0228] Second step Compound 7-2 Ethyl 3-(1,2,3,4-tetrahydroisoquinolin-5-yl)butanoate A solution of ethyl (E)-3-(3,4-dihydroisoquinolin-5-yl)but-2-enoate (100 mg, 0.410 mmol) and 10% palladium on carbon (20.0 mg) in ethanol (10.0 mL) was stirred under a hydrogen atmosphere for 10 days. After filtration, the filtrate was concentrated to give the title compound as a 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-tetrahydroisoquinolin-5-yl)butanoate hydrochloride Hydrochloric acid gas was bubbled through a solution of ethyl 3-(1,2,3,4-tetrahydroisoquinolin-5-yl)butanoate (500 mg, 2.02 mmol) in ethyl acetate (20.0 mL) at room temperature for 30 minutes. The resulting solid was collected by filtration to give the title compound as a crude product. LCMS: m / z 248 [M+H] ＋ HPLC retention time: 1.34 minutes (Analysis conditions K)

[0230] Fourth step: Compound 7-4 ethyl (3R)-3-(1,2,3,4-tetrahydroisoquinolin-5-yl)butanoate Ethyl 3-(1,2,3,4-tetrahydroisoquinolin-5-yl)butanoate hydrochloride (300 mg) was separated into two stereoisomers by SFC (Chiralpak IBZ x 25 cm, 0.005 mm chiral-PCIB, hexane (0.2% isopropanol) / ethanol (0.2% isopropanol)) to give the title compound (47.9 mg) and an isomer (121.2 mg). LCMS: 248 [M+H] ＋ HPLC retention time: 1.36 minutes (analysis condition K) SFC retention time: 3.19 minutes (isomer retention time: 4.90 minutes) (analysis conditions: CHIRALPAK IB-3, 0.46 x 15 cm, 3 μm, hexane (0.2% isopropanol):ethanol = 70:30, 9.0 minutes), 25°C, 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 Ethyl (3R)-3-(1,2,3,4-tetrahydroisoquinolin-5-yl)butanoate (29.0 mg, 0.117 mmol), di-tert-butyl dicarbonate (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 1M hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate, passed through a phase separator, and then concentrated. The resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (74%, 30.2 mg). LCMS: m / z 248 [M+H-tBu] ＋ HPLC retention time: 1.40 minutes (Analysis conditions I)

[0232] Sixth Step: Compound 7-6 (R)-3-(2-(tert-butoxycarbonyl)-1,2,3,4-tetrahydroisoquinolin-5-yl)butanoic acid 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) was added 5M aqueous sodium hydroxide solution (0.718 mL, 1.13 mmol), and the mixture was stirred at room temperature for 2 hours. Aqueous hydrochloric acid was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydroxide, passed through a phase separator, and concentrated to give the title compound as a crude product. LCMS: m / z 342 [M+Na] ＋ HPLC retention time: 1.17 minutes (Analysis conditions I)

[0233] Seventh step: Compound 7-7: tert-butyl 5-((R)-4-((S)-4-isopropyl-2-oxooxazolidin-3-yl)-4-oxobutan-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate A solution of the crude product of (R)-3-(2-(tert-butoxycarbonyl)-1,2,3,4-tetrahydroisoquinolin-5-yl)butanoic acid and triethylamine (0.499 mL, 3.59 mmol) in tetrahydrofuran (4.79 mL) was cooled to 0°C, and pivaloyl chloride (0.162 mL, 1.32 mmol) was added, followed by stirring 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 warming to room temperature. 1M hydrochloric acid and methanol were added to the reaction solution at 0°C, and the mixture was concentrated. The mixture was 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 conditions I)

[0234] Eighth step: Compound 7-8: tert-butyl 5-((2R,3S)-4-((S)-4-isopropyl-2-oxooxazolidin-3-yl)-3-methyl-4-oxobutan-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate A solution of tert-butyl 5-((R)-4-((S)-4-isopropyl-2-oxooxazolidin-3-yl)-4-oxobutan-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (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 stirred for 1 hour. Iodomethane (0.158 mL, 2.54 mmol) was added, and the mixture was stirred for 1 hour, followed by further stirring at -40°C for 2 hours. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium bicarbonate and saturated brine, concentrated through a phase separator, and purified by reverse-phase column chromatography (acetonitrile / water, 0.1% formic acid) to give 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-tetrahydroisoquinolin-5-yl)butanoyl]-4-propan-2-yl-1,3-oxazolidin-2-one hydrochloride 4M hydrochloric acid-1,4-dioxane (5.00 ml, 20.0 mmol) solution was added to tert-butyl 5-[(2R)-4-ethoxy-4-oxobutan-2-yl]-3,4-dihydro-1H-isoquinoline-2-carboxylate (228 mg, 0.513 mmol), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated to give the title compound as a crude product. LCMS: m / z 345 [M+H] ＋ HPLC retention time: 0.73 minutes (Analysis conditions G)

[0236] Tenth step: Compound 7-10 (4S)-3-[(2S,3R)-3-[2-[2,6-dichloro-4-(2-methoxyethoxy)benzoyl]-3,4-dihydro-1H-isoquinolin-5-yl]-2-methylbutanoyl]-4-propan-2-yl-1,3-oxazolidin-2-one 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 azeotroped with toluene to give 2,6-dichloro-4-(2-methoxyethoxy)benzoyl chloride as a crude product. A solution of (4S)-3-[(2S,3R)-2-methyl-3-(1,2,3,4-tetrahydroisoquinolin-5-yl)butanoyl]-4-propan-2-yl-1,3-oxazolidin-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 1M hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate, passed through a phase separator, and concentrated to give the title compound as a 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-isoquinolin-5-yl]-2-methylbutanoic acid A solution of (4S)-3-[(2S,3R)-3-[2-[2,6-dichloro-4-(2-methoxyethoxy)benzoyl]-3,4-dihydro-1H-isoquinolin-5-yl]-2-methylbutanoyl]-4-propan-2-yl-1,3-oxazolidin-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 (0.281 ml, 2.85 mmol) and lithium hydroxide monohydrate (51.2 mg, 1.22 mmol) were added and 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 give the title compound (96%, 187 mg). LCMS: m / z 480 [M+H] ＋ HPLC retention time: 1.07, 1.09 minutes (Analysis conditions C)

[0238] [Example 2] Method for producing crystals (Example 2-1-1) 120 μL of tetrahydrofuran was added to Compound 1 (28.9 mg) and dissolved at room temperature. 480 μL of a 9 / 1 (v / v) methanol / water mixed solution was added and stirred for 20 minutes. 600 μL of a 9 / 1 (v / v) methanol / water mixed solution was added and 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 1A crystal powder. The results of powder X-ray diffraction measurement of this powder are shown in FIG. 1, and representative peaks are shown in Table 2 below. The results of TG-DTA measurement are shown in FIG. 2.

[0239]

[0240] Example 2-1-2 To Compound 1 (10.8 mg) was added 50 μL of a mixed solution 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 type 1G crystals by powder X-ray diffraction.

[0241] Example 2-1-3: 120 μL of tetrahydrofuran was added to Compound 1 (30.3 mg) and dissolved 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 seed crystals. After an additional 30 minutes, 60 μL of water was added. After an additional 130 minutes, 60 μL of water was added. After an additional 50 minutes, 120 μL of water was added. After an additional 150 minutes, 120 μL of water was added. After an additional 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 type 1G crystal powder. The results of powder X-ray diffraction measurement of this powder are shown in FIG. 3, and representative peaks are shown in Table 3 below. The results of TG-DTA measurement are shown in FIG. 4.

[0242]

[0243] (Example 2-1-4) The 1G-type crystal was stored at 34°C and a relative humidity of 60% for approximately 5 minutes, and powder X-ray diffraction measurement was performed. Thereafter, the relative humidity was changed to 0%, and the crystal was stored for approximately 60 minutes, and powder X-ray diffraction measurement was performed. From these results, it was confirmed that when the relative humidity was changed from 60% to 0%, the 1G-type crystal transitioned to the 1H-type crystal, which is a non-solvate. The relative humidity was further changed to 30%, and the crystal was stored for approximately 15 minutes, and powder X-ray diffraction measurement was performed. From these results, it was confirmed that when the relative humidity was changed from 0% to 30%, the 1H-type crystal further transitioned to the hydrated 1J-type crystal. The results of these powder X-ray diffraction measurements are shown in Figure 5, and representative peaks at each humidity are shown in Table 4 below.

[0244]

[0245] (Example 2-1-5) Acetone (15 μL) was added to Compound 1 (5.6 mg) 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 FIG. 6, and representative peaks are shown in Table 5 below.

[0246]

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

[0248]

[0249] (Example 2-2-1) 2-Propanol (15 μL) was added to compound 4 (3 mg) and the mixture was shaken for 6 days to obtain crystals. The obtained crystals were confirmed to be non-solvated type 2A crystals by powder X-ray diffraction.

[0250] (Example 2-2-2) Ethanol (15 μL) was added to compound 4 (3 mg) and the mixture was shaken for 6 days to obtain non-solvated type 2B crystals. The results of powder X-ray diffraction are shown in FIG. 8, and representative peaks are shown in Table 7 below.

[0251]

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

[0253] Example 2-2-4: Compound 4 (146.8 mg) was added to DMSO (1 mL) and dissolved at 120°C. After cooling to room temperature, 2-propanol (5 mL) was added, followed by the crystals obtained in Example 2-2-1 (approximately 0.1 mg) as seed crystals. 2-propanol (10 mL) was then added, and the mixture was stirred for 18 hours and then filtered. The resulting solid was washed with 2-propanol (2 mL). After vacuum drying for one day, 125.3 mg of non-solvated type 2A crystals was 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]

[0255] Example 2-2-5: Acetonitrile (5 mL) was added to compound 4 (105.8 mg), dissolved under heating 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 non-solvated 2C-type crystals. The results of powder X-ray diffraction measurement are shown in Figure 11, and representative peaks are shown in Table 9 below. The results of TG-DTA measurement are shown in Figure 12.

[0256]

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

[0258]

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

[0260]

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

[0262]

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

[0264]

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

[0266]

[0267] (Example 2-4-2) Water / acetonitrile = 3 / 1 (v / v) (15 μL) was added to compound 6 (3 mg) and the mixture was shaken for 8 days to obtain 4B-type crystals, which are hydrates. The results of single-crystal X-ray crystal structure analysis are shown in Figure 22. In addition, the parameters characterizing this crystal are shown in Table 15 below.

[0268]

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

[0270]

[0271] Example 2-5-1 PEG 400 (15 μL) was added to compound 5 (5.4 mg) and heated to 80°C. The mixture was stirred overnight, and water (5 μL) was added. After a further 7 hours, the mixture 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 the crystals obtained in Example 2-5-1 (approximately 0.1 mg) were added as seed crystals, followed by stirring for 55 minutes. Water (120 μL) was added, and the mixture was stirred for 210 minutes. Water (120 μL) was then added, followed by stirring for 70 minutes, and water (240 μL) was then added. After stirring for an additional 15 hours, the suspension was filtered and dried at room temperature under normal pressure for 7 hours to obtain type 5A crystals (26.7 mg). The results of powder X-ray diffraction analysis are shown in Figure 25, and representative peaks are shown in Table 17 below. The results of TG-DTA analysis are shown in Figure 26.

[0273]

[0274] Example 2-5-3: Compound 5 (approximately 25 mg) was heated at 110°C for 1 hour. The mixture was cooled to room temperature and further stored under a condition of 100% relative humidity for 2 hours to obtain hydrate type 5E 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. The obtained type 5E crystals were then vacuum-dried to obtain non-solvate type 5D 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]

[0276] Example 2-5-4 Type 5A crystal, a hydrate, was stored at 25°C and a relative humidity of 95% for 1 hour. It was then stored at a relative humidity of 60% for 1 hour, and powder X-ray diffraction measurement was performed (first measurement). It was further stored at a relative humidity of 30% for 1 hour, and powder X-ray diffraction measurement was performed. It was further stored at a relative humidity of 20% for 1 hour, and powder X-ray diffraction measurement was performed. It was further stored at a relative humidity of 10% for 1 hour, and powder X-ray diffraction measurement was performed. The results of these powder X-ray diffraction measurements are shown in FIG. 30, and representative peaks at each humidity are shown in Table 19 below. It was then stored at a relative humidity of 5% for 1 hour, and then at a relative humidity of 60% for 1 hour, and powder X-ray diffraction measurement was performed (second measurement). As shown in FIG. 31, the pattern matched the pattern initially measured at a relative humidity of 60%. This demonstrated that Type 5A crystal is a crystalline form in which the peak positions change in response to humidity.

[0277]

[0278] (Example 2-5-5) Acetone (25 μL) was added to Type 5A crystal (5.0 mg), glass beads were added, and the mixture was shaken at room temperature at 2000 rpm for 7 days to obtain Type 5G crystal. The results of powder X-ray diffraction measurement are shown in Figure 32, and representative peaks are shown in Table 20 below.

[0279]

[0280] (Example 2-5-6) A mixed solution of methyl ethyl ketone / acetone = 2 / 1 (v / v) was prepared. This mixed solution was then mixed with water at a ratio of 65 / 35 (v / v). This solution (30 μL) was mixed with approximately 3 mg each of type 5A crystals and type 5G crystals, and 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. The solid obtained by this measurement was confirmed to be type 5A crystal. In addition, single crystal X-ray structural analysis was performed under conditions of 25°C and 30% relative humidity. The obtained crystal structure is shown in Figure 34. In addition, parameters characterizing this crystal are shown in Table 21 below.

[0281]

[0282] Example 2-5-7: Acetone (1.3 v / w, 1.1 mL) was added to a methyl ethyl ketone solution (1.4 v / w) of compound 5 (850 mg), and then methyl ethyl ketone (1.2 v / w, 1.0 mL) was added. Water (1.6 mL) was added, and type 5A crystals (8.5 mg) were added as seed crystals. Water (1.6 mL) was then added over 30 minutes and stirred for 1 hour. Water (3.2 mL) was then added and stirred for 21 hours. Water (3.2 mL) was then added over 1 hour and stirred for 3 hours, and water (3.2 mL) was then added over 1 hour and stirred for 17 hours and 30 minutes. Water (3.2 mL) was then added over 1 hour and 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 the wet crystals were dried under a nitrogen stream for about 5 hours to give dry crystals (269.4 mg). 206.2 mg of the dried crystals were further dried under a nitrogen stream for 5 hours and 30 minutes to give dry crystals (203.5 mg). 110.4 mg of these were further dried under a nitrogen stream for 28 hours to give type 5A crystals (110.3 mg).

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

[0284]

[0285] (Example 2-5-9) The 5C type crystals prepared by the method described in Example 2-5-8 were stored at 25°C and a relative humidity of about 30% or higher for 1 hour, and powder X-ray diffraction measurements were performed at each relative humidity. These results confirmed that when the relative humidity was changed to about 30% or higher, the 5C type crystals were transformed into the 5J type crystals, which are hydrates. It was also confirmed that the peak positions 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]

[0287] [Evaluation of Crystals] Powder X-ray diffraction measurements in Example 2 were carried out under any of the following conditions: (Measurement Method 1) Measurement device: 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 device: D8 Discover, 2D VÅNTEC-500 solid state detector (manufactured by Bruker) Radiation source: CuKα Tube voltage / tube current: 40 kV / 40 mA or 50 kV / 1000 μA Measurement range: 5 to 31° Exposure time: 40 to 600 seconds

[0288] Powder X-ray diffraction measurements under temperature and humidity control were performed under any 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° / sec Sampling width: 0.026° Number of accumulations: 3 (measurement was repeated 3 times under the above scanning conditions) (Measurement Method 2) Measurement device: SmartLab System, D / Tex Ultra detector, water vapor generator HUM-SL (manufactured by Rigaku) ​​Radiation source: CuKα1 Tube voltage: 45 kV Tube current: 200 mA Scanning speed: 2.0° / min Sampling width: 0.02°

[0289] Single crystal X-ray structural analysis was carried out under the following conditions: Measurement equipment: XtaLAB Synergy Custom with a VariMax Cu diffractometer or Rigaku R-AXIS RAPID-II with a VariMax Cu diffractometer (Rigaku Corporation) Radiation source: CuKα Tube voltage / current: 40 kV / 30 mA Temperature: -180°C or room temperature When either equipment was used, measurements were carried out using a strategy and exposure time that were thought to be sufficient to obtain diffraction spots for structural analysis. In addition, for structural analysis, initial structure determination was performed using a direct method (SHELXT2014 / 5 or SHELXT2018 / 2), and structural refinement was performed using the full-matrix least-squares method (SHELXL2017 / 1).

[0290] The simultaneous differential thermal and thermogravimetric analysis (TG-DTA) in Example 2 was carried out under the following conditions. The onset temperature was determined from the endothermic peak and used as the melting point. Apparatus: STA7200RV (Hitachi High-Tech Science Corporation) 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 transcription activity by ARE-dependent reporter assay in HepG2 cells. The pGL4.37 vector (pARE-Luc, Promega) was transfected into the human hepatoma-derived cell line HepG2, and the cells were incubated at 5% CO ２ The cells were incubated overnight at 37°C in a humidified atmosphere containing PEG-100. The cells were detached by trypsinization, seeded onto a 384-well plate containing a test compound, and incubated at 37°C for 4 hours. Bright-Glo Reagent (Promega) was then added, and luciferase activity was measured using an Envision plate reader. The luciferase activity in each well was converted to a response rate (%), with the luciferase activity measured when Compound 2 or Compound 7 was applied at a concentration of 3.75 μM being defined as 100%. A dose-response curve was prepared for each example compound, and the 50% effective concentration (EC ５０ ) was calculated. The results are shown in Table 24. These results demonstrate that the compounds of the present invention have an Nrf2 activating effect in vitro.

[0292]

[0293] The present invention provides a crystal of a low molecular weight compound having Nrf2 activation activity, a salt thereof, or a solvate thereof, and a pharmaceutical agent for preventing and / or treating various diseases, such as neurodegenerative diseases, pulmonary diseases, and renal 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 having peaks of 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 one peak 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 a diffraction angle (2θ value) by powder X-ray diffraction, and the diffraction angle (2θ value) is the diffraction angle (2θ value) of the 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 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.

12. 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.

13. 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.

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°, 10.8°, 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.

15. 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.

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°, 10.5°, 12.2°, 15.5°, 16.4°, 16.6°, 17.1°, and 17.6° (±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 30% relative humidity.

17. 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) 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.

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

19. 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 17.

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

21. 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 17, or a salt thereof, or a crystal of a solvate thereof, with a pharmaceutically acceptable carrier or medium.

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