A crystalline form of a pentacyclic derivative inhibitor, a salt or a crystalline form thereof, and a preparation method and application thereof

Abstract

The present invention relates to a crystalline form, salt or crystalline form thereof of a pentacyclic derivative inhibitor, and methods of preparation and use thereof. In particular, the present invention relates to a free base crystalline form, salt or crystalline form thereof of a compound of general formula (I), methods of preparation and pharmaceutical compositions containing a therapeutically effective amount of the salt and / or crystalline form, and use thereof as an inhibitor in the treatment of autoimmune diseases.

Description

Technical Field

[0001] This invention belongs to the field of biomedicine, specifically relating to the crystal form, salt or crystal form of a pentacyclic derivative inhibitor, its preparation method and application. Background Technology

[0002] TNFα is a member of the tumor necrosis factor (TNF) superfamily of proteins. It is a pro-inflammatory cytokine produced by macrophages and monocytes, participating in normal inflammatory and immune responses and driving the expression of other cytokines such as interleukin-1 (IL-1) and interleukin-6 (IL-6). It possesses pro-inflammatory and immunomodulatory functions and is considered a pleiotropic cytokine. TNFα is expressed as a membrane-bound precursor (mTNF) and requires cleavage by TNFα convertase to release it as a soluble cytokine (sTNF). Both mTNFα and sTNFα are biologically active symmetrical trimeric proteins that signal through two separate tumor necrosis factor receptors, TNFR1 and TNFR2.

[0003] TNFR1 is widely expressed and primarily promotes TNF-induced inflammatory responses, while TNFR2 expression is limited to immune cells and maintains local immune homeostasis. The TNFR1 signaling pathway uses the typical nuclear factor-κB (NF-κB) and mitogen-activated protein kinase (MAP) pathways to transmit pro-inflammatory signals. Conversely, TNFR2 signals via the atypical NF-κB pathway. TNFR2 activation is crucial for Treg cell proliferation, survival, lineage stability, and thymic Treg cell development, and is involved in immune regulation. At physiological concentrations, sTNF activates TNFR1 but not TNFR2, while mTNF can activate both receptors.

[0004] TNFα is associated with the development of chronic inflammatory diseases such as rheumatoid arthritis (RA), inflammatory bowel disease (IBD), psoriasis, psoriatic arthritis (PsA), ankylosing spondylitis, and certain types of juvenile idiopathic arthritis (JIA). RA is a common chronic inflammatory disease with a global prevalence of 0.51%. It is a complex autoimmune disease involving multiple inflammatory mediators that contribute to driving chronic inflammation in the joints, such as TNF, IL-6, and IL-1, as well as immune cells (T cells, B cells, monocytes, and macrophages). Rheumatoid arthritis can lead to cumulative joint damage and irreversible disability, but it can also cause extra-articular manifestations such as rheumatoid nodules, lung involvement, or vasculitis, as well as other systemic comorbidities. Current drug treatment for RA involves symptomatic medications, such as nonsteroidal anti-inflammatory drugs (NSAIDs), and disease-modifying drugs, known as disease-modified antirheumatic drugs (DMARDs), which consist of small molecules and biologics. Disease-modifying antirheumatic drugs aim to improve patients' signs and symptoms of the disease and restore bodily function by inhibiting the progression of damage to cartilage and bone structures.

[0005] TNF-α inhibitors, such as infliximab, adalimumab, etanercept, golimumab, and pecelizumab, have ushered in a new era of rheumatic immunotherapy and have become one of the most powerful weapons in the treatment of rheumatic and immune diseases, receiving consistent recommendations from authoritative domestic and international guidelines. Anti-TNF-α biologics have been successfully used in the clinical treatment of RA, JIA, PsA, ankylosing spondylitis, psoriasis, and IBD, especially Crohn's disease (CD) and ulcerative colitis (UC). Anti-TNF-α biologics have revolutionized the treatment of RA; despite their significant success, the disease remission rate for RA remains quite low, with only 25% of patients achieving remission. Furthermore, there are reports that after 6 months of anti-TNF-α combined with methotrexate treatment, only 25% of patients achieved low disease activity (LDA). Other limitations of anti-TNF-α biologics include the occurrence of adverse reactions such as opportunistic infections, reactivation of latent tuberculosis, and an increased risk of certain malignancies (such as lymphoma), as well as the immunogenicity of the drug itself leading to the development of anti-drug antibodies (ADA), all of which may limit their efficacy. The high cost and intravenous administration of biologics pose significant obstacles to their widespread clinical use.

[0006] To date, there are no marketed small molecule inhibitors of TNFα, thus there is a high clinical demand for oral TNFα small molecule inhibitors. The aim of this project is to develop highly specific, safe, and effective oral TNFα small molecule inhibitors for the treatment of rheumatic immune diseases.

[0007] There are already patent reports on small molecule inhibitors of TNFα, such as WO2016050975A1, WO2018167176, WO2018197503, and WO2020084008 (Sanofi). Currently, the most advanced is SAR-441566, which is in Phase I clinical trials, while the others are in the preclinical development stage. This invention aims to develop an orally administered small molecule inhibitor of TNFα.

[0008] PCT / CN2024 / 098249 discloses a series of inhibitors containing thiazole derivatives. In subsequent research and development, in order to facilitate the handling, filtration and drying of the products, and to seek suitable crystals that are easy to store, have long-term product stability and high bioavailability, this invention has conducted a comprehensive study on the salts and crystal forms of the above-mentioned compounds. Summary of the Invention

[0009] All contents covered in PCT / CN2024 / 098249 are incorporated herein by reference.

[0010] The purpose of this invention is to provide free base crystal forms, acid salts, or crystal forms thereof of compounds of general formula (I) or their stereoisomers.

[0011] in, M 16 Selected from N or CR2; R and R' are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl, the amino, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10Aryl or 5-10 heteroaryl groups may optionally be further converted by hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 One or more substitutions of aryl and 5-10 heteroaryl groups; R1 is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl, the amino, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl groups may optionally be further converted by hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10One or more substitutions of aryl and 5-10 heteroaryl groups; R2 is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl, the amino, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl groups may optionally be further converted by hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 One or more substitutions of aryl and 5-10 heteroaryl groups; R4 is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 3-8Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl, wherein the amino group, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl groups may optionally be further converted by hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 One or more substitutions of aryl and 5-10 heteroaryl groups; x is 1, 2, 3, 4 or 5; The acid is an inorganic acid or an organic acid, wherein the inorganic acid is selected from hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, hydrofluoric acid, hydroiodic acid, or phosphoric acid; the organic acid is selected from 2,5-dihydroxybenzoic acid, 1-hydroxy-2-naphtholic acid, acetic acid, dichloroacetic acid, trichloroacetic acid, acetoxyxamic acid, adipic acid, 4-chlorobenzenesulfonic acid, benzoic acid, 4-acetaminobenzoic acid, 4-aminobenzoic acid, decanoic acid, hexanoic acid, caprylic acid, cinnamic acid, citric acid, cyclohexanesulfonic acid, camphorsulfonic acid, aspartic acid, camphoric acid, gluconic acid, glucuronic acid, glutamic acid, isoascorbic acid, lactic acid, malic acid, mandelic acid, pyroglutamic acid, tartaric acid, dodecyl sulfate, dibenzoyl tartaric acid, ethane-1, 2-Disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galactobionic acid, gentian acid, glutaric acid, 2-ketoglutaric acid, glycolic acid, hippuric acid, hydroxyethylsulfonic acid, lactobionic acid, ascorbic acid, aspartic acid, lauric acid, camphoric acid, maleic acid, malonic acid, methanesulfonic acid, 1,5-naphthalenedisulfonic acid, naphthalene-2-sulfonic acid, nicotinic acid, oleic acid, orotic acid, oxalic acid, palmitic acid, dihydroxynaphthalic acid, propionic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, thiocyanate, undecanoic acid, trifluoroacetic acid, benzenesulfonic acid, p-toluenesulfonic acid, or L-malic acid; preferably hydrochloric acid, sulfuric acid, hydrobromic acid, p-toluenesulfonic acid, fumaric acid, phosphoric acid, or oxalic acid; most preferably hydrochloric acid, sulfuric acid, hydrobromic acid, or fumaric acid.

[0012] In some embodiments of the present invention, R and R' are each independently selected from hydrogen, deuterium, halogen, and C. 1-3 Alkyl, C 1-3 Deuterated alkyl or C 1-3 Halogenated alkyl; preferably hydrogen or halogen; more preferably hydrogen or F; R1 is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, and C. 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 Hydroxyalkyl; preferably hydrogen, methyl, ethyl, NH2, OH, CN, CD3, F, Cl, CHF2, CH2F, CF3, OCF3, CH2OH, , , or ; R2 is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, and C. 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3Halogenated alkoxy groups, C 1-3 Hydroxyalkyl; preferably hydrogen or halogen, more preferably hydrogen or F; R4 is selected from hydrogen, methyl, ethyl, or deuterated methyl; Further preferred Selected from , , , , , or .

[0013] In some embodiments of the present invention, the compound is shown below: or .

[0014] In some embodiments of the present invention, the number of acids in the acid salt is 0.2-3; preferably 0.2, 0.5, 1, 1.5, 2, 2.5 or 3; more preferably 0.5, 1, 2 or 3, and even more preferably 1.

[0015] In some embodiments of the present invention, the free base crystal form or acid salt is a hydrate or anhydrous form; when the acid salt is a hydrate, the number of water molecules is 0.2-3; preferably 0.2, 0.5, 1, 1.5, 2, 2.5 or 3. The free base crystal form or acid salt crystal form is a solvate crystal form, a hydrate crystal form, or an anhydrous crystal form; when the crystal form is a hydrate or solvate, the number of water or solvent is 0.2-3; preferably 0.2, 0.5, 1, 1.5, 2, 2.5 or 3, and more preferably 2.

[0016] In some embodiments of the present invention, the acid salt or its crystal form is (1S,3s)-3-amino-3-(5-((8R,15R)-2,2-difluoro-7-(methyl-d3)-6-carbonyl-6,7,8,15-tetrahydro-8,15-methylene[1,3]dioxazolo[4',5':3,4]benzo[1,2-f]benzo[4,5]imidazo[1,2-a][1,4]diacoxin-12-yl)pyrimidin-2-yl)-1-methylcyclobutane-1-carboxynitrile hydrochloride crystal form A; The X-ray powder diffraction pattern of the hydrochloride crystal form A shows a diffraction peak at 2θ of 6.0 ± 0.2°; or at 6.3 ± 0.2°; or at 12.0 ± 0.2°; or at 16.1 ± 0.2°; or at 16.4 ± 0.2°; or at 16.9 ± 0.2°; or at 18.4 ± 0.2°. The diffraction peaks are present; or diffraction peaks are present at 19.9±0.2°; or diffraction peaks are present at 22.9±0.2°; or diffraction peaks are present at 25.9±0.2°; preferably, any 2-5, 3-5, 3-6, 3-8, 5-8, 6-8, or 8-10 of the above diffraction peaks are included; more preferably, any 6, 7, 8, 9, or 10 of the above diffraction peaks are included. Alternatively, the acid salt or its crystal form is (1S,3s)-3-amino-3-(5-((8R,15R)-2,2-difluoro-7-(methyl-d3)-6-carbonyl-6,7,8,15-tetrahydro-8,15-methylene[1,3]dioxazolo[4',5':3,4]benzo[1,2-f]benzo[4,5]imidazo[1,2-a][1,4]diacoxin-12-yl)pyrimidin-2-yl)-1-methylcyclobutane-1-carboxynitrile p-toluenesulfonate crystal form A; The X-ray powder diffraction pattern of the p-toluenesulfonate crystal form A shows a diffraction peak at 2θ of 4.6 ± 0.2°; or at 9.2 ± 0.2°; or at 10.1 ± 0.2°; or at 14.1 ± 0.2°; or at 15.8 ± 0.2°; or at 16.8 ± 0.2°; or at 17.9 ± 0.2°. It has diffraction peaks; or has diffraction peaks at 18.8±0.2°; or has diffraction peaks at 20.7±0.2°; or has diffraction peaks at 25.1±0.2°; preferably includes any 2-5, 3-5, 3-6, 3-8, 5-8, 6-8, or 8-10 of the above diffraction peaks; more preferably includes any 6, 7, 8, 9, or 10 of them; Alternatively, the acid salt or its crystal form is (1S,3s)-3-amino-3-(5-((8R,15R)-2,2-difluoro-7-(methyl-d3)-6-carbonyl-6,7,8,15-tetrahydro-8,15-methylene[1,3]dioxazolo[4',5':3,4]benzo[1,2-f]benzo[4,5]imidazo[1,2-a][1,4]diacoxin-12-yl)pyrimidin-2-yl)-1-methylcyclobutane-1-carboxynitrile fumarate crystal form A; The X-ray powder diffraction pattern of the fumarate crystal form A shows a diffraction peak at 2θ of 9.5 ± 0.2°; or at 12.7 ± 0.2°; or at 13.9 ± 0.2°; or at 17.2 ± 0.2°; or at 18.2 ± 0.2°; or at 19.1 ± 0.2°; or at 23.2 ± 0.2°. It has diffraction peaks; or has diffraction peaks at 23.9±0.2°; or has diffraction peaks at 27.9±0.2°; or has diffraction peaks at 30.4±0.2°; preferably includes any 2-5, 3-5, 3-6, 3-8, 5-8, 6-8, or 8-10 of the above diffraction peaks; more preferably includes any 6, 7, 8, 9, or 10 of them; Alternatively, the acid salt or its crystal form is (1S,3s)-3-amino-3-(5-((8R,15R)-2,2-difluoro-7-(methyl-d3)-6-carbonyl-6,7,8,15-tetrahydro-8,15-methylene[1,3]dioxazolo[4',5':3,4]benzo[1,2-f]benzo[4,5]imidazo[1,2-a][1,4]diacoxin-12-yl)pyrimidin-2-yl)-1-methylcyclobutane-1-carboxynitrile fumarate crystal form B; The X-ray powder diffraction pattern of the fumarate crystal form B shows a diffraction peak at 2θ of 6.9 ± 0.2°; or at 7.4 ± 0.2°; or at 10.5 ± 0.2°; or at 12.6 ± 0.2°; or at 13.1 ± 0.2°; or at 15.2 ± 0.2°; or at 18.7 ± 0.2°. It has diffraction peaks; or has diffraction peaks at 22.1±0.2°; or has diffraction peaks at 26.0±0.2°; or has diffraction peaks at 26.2±0.2°; preferably includes any 2-5, 3-5, 3-6, 3-8, 5-8, 6-8, or 8-10 of the above diffraction peaks; more preferably includes any 6, 7, 8, 9, or 10 of them; Alternatively, the acid salt or its crystal form is (1S,3s)-3-amino-3-(5-((8R,15R)-2,2-difluoro-7-(methyl-d3)-6-carbonyl-6,7,8,15-tetrahydro-8,15-methylene[1,3]dioxazolo[4',5':3,4]benzo[1,2-f]benzo[4,5]imidazo[1,2-a][1,4]diacoxin-12-yl)pyrimidin-2-yl)-1-methylcyclobutane-1-carboxynitrile phosphate crystal form A; The X-ray powder diffraction pattern of the phosphate crystal form A shows a diffraction peak at 2θ of 4.3 ± 0.2°; or at 6.7 ± 0.2°; or at 8.6 ± 0.2°; or at 10.4 ± 0.2°; or at 14.4 ± 0.2°; or at 16.3 ± 0.2°; or at 17.3 ± 0.2°. The diffraction peaks are present; or diffraction peaks are present at 20.6±0.2°; or diffraction peaks are present at 20.9±0.2°; or diffraction peaks are present at 26.4±0.2°; preferably, any 2-5, 3-5, 3-6, 3-8, 5-8, 6-8, or 8-10 of the above diffraction peaks are included; more preferably, any 6, 7, 8, 9, or 10 of the above diffraction peaks are included. Alternatively, the acid salt or its crystal form is (1S,3s)-3-amino-3-(5-((8R,15R)-2,2-difluoro-7-(methyl-d3)-6-carbonyl-6,7,8,15-tetrahydro-8,15-methylene[1,3]dioxazolo[4',5':3,4]benzo[1,2-f]benzo[4,5]imidazo[1,2-a][1,4]diacoxin-12-yl)pyrimidin-2-yl)-1-methylcyclobutane-1-carboxynitrile oxalate crystal form A; The X-ray powder diffraction pattern of the oxalate crystal form A has a diffraction peak at 2θ of 10.2 ± 0.2°; or at 11.8 ± 0.2°; or at 14.4 ± 0.2°; or at 20.1 ± 0.2°; or at 20.6 ± 0.2°; or at 24.6 ± 0.2°; preferably including any 2-5, 3-5, or 3-6 of the above diffraction peaks; more preferably including any 4, 5, or 6 of them.

[0017] In certain embodiments of the present invention, X-ray powder diffraction of the (1S,3s)-3-amino-3-(5-((8R,15R)-2,2-difluoro-7-(methyl-d3)-6-carbonyl-6,7,8,15-tetrahydro-8,15-methylene[1,3]dioxazolo[4',5':3,4]benzo[1,2-f]benzo[4,5]imidazo[1,2-a][1,4]diacoxin-12-yl)pyrimidin-2-yl)-1-methylcyclobutane-1-carboxynitrile hydrochloride crystal form A The spectrum contains at least one or more diffraction peaks located at 2θ of 12.0±0.2°, 16.9±0.2°, 19.9±0.2°, and 25.9±0.2°, preferably two, more preferably three or four; even more preferably, it may also contain at least one of 2θ of 6.0±0.2°, 6.3±0.2°, 16.1±0.2°, 16.4±0.2°, 18.4±0.2°, and 22.9±0.2°, preferably two, three, four, five, or six. More preferably, the X-ray powder diffraction pattern of the hydrochloride crystal form A includes one or more diffraction peaks located at 6.0±0.2°, 6.3±0.2°, 12.0±0.2°, 16.1±0.2°, 16.4±0.2°, 16.9±0.2°, 18.4±0.2°, 19.9±0.2°, 22.9±0.2°, and 25.9±0.2°; preferably, it includes diffraction peaks at any of the selected 4, 5, 6, 8, or 10 locations. More preferably, the X-ray powder diffraction pattern of the hydrochloride crystal form A may also include one or more diffraction peaks with 2θ values ​​of 17.8±0.2°, 20.4±0.2°, 22.1±0.2°, 22.3±0.2°, 22.5±0.2°, and 25.1±0.2°; preferably, it includes at least 2-3, 4-5, or 5-6 peaks; more preferably, it includes any 2, 3, 4, 5, or 6 peaks. For example, the X-ray powder diffraction pattern of the hydrochloride crystal form A has diffraction peaks at the following positions with a 2θ value: 6.0±0.2°, 12.0±0.2°, 16.4±0.2°, 16.9±0.2°, 18.4±0.2°, 22.9±0.2°; 6.0±0.2°, 12.0±0.2°, 16.4±0.2°, 16.9±0.2°, 18.4±0.2°, 19.9±0.2°, 25.9±0.2°; 6.0±0.2°, 12.0±0.2°, 16.4±0.2°, 16.9±0.2°, 18.4±0.2°, 19.9±0.2°, 22.9±0.2°; 6.0±0.2°, 12.0±0.2°, 16.4±0.2°, 16.9±0.2°, 18.4±0.2°, 22.9±0.2°, 25.1±0.2°; 6.0±0.2°, 6.3±0.2°, 12.0±0.2°, 16.4±0.2°, 16.9±0.2°, 18.4±0.2°, 19.9±0.2°, 25.9±0.2°; 6.0±0.2°, 12.0±0.2°, 16.4±0.2°, 16.9±0.2°, 18.4±0.2°, 19.9±0.2°, 22.9±0.2°, 25.9±0.2°; 6.0±0.2°, 6.3±0.2°, 12.0±0.2°, 16.1±0.2°, 16.4±0.2°, 16.9±0.2°, 18.4±0.2°, 22.9±0.2°; 6.0±0.2°, 6.3±0.2°, 12.0±0.2°, 16.1±0.2°, 16.4±0.2°, 16.9±0.2°, 18.4±0.2°, 19.9±0.2°, 22.9±0.2°; 6.0±0.2°, 6.3±0.2°, 12.0±0.2°, 16.1±0.2°, 16.4±0.2°, 16.9±0.2°, 18.4±0.2°, 22.9±0.2°, 25.9±0.2°.

[0018] In some embodiments of the present invention, the characteristic X-ray diffraction peaks of (1S,3s)-3-amino-3-(5-((8R,15R)-2,2-difluoro-7-(methyl-d3)-6-carbonyl-6,7,8,15-tetrahydro-8,15-methylene[1,3]dioxazolo[4',5':3,4]benzo[1,2-f]benzo[4,5]imidazo[1,2-a][1,4]diacoxin-12-yl)pyrimidin-2-yl)-1-methylcyclobutane-1-carboxynitrile hydrochloride crystal form A are shown in Table 1, expressed in terms of 2θ angle and interplanar spacing d, under Cu-Kα irradiation.

[0019] Table 1

[0020] In certain embodiments of the present invention, the X-ray powder diffraction pattern of the (1S,3s)-3-amino-3-(5-((8R,15R)-2,2-difluoro-7-(methyl-d3)-6-carbonyl-6,7,8,15-tetrahydro-8,15-methylene[1,3]dioxazolo[4',5':3,4]benzo[1,2-f]benzo[4,5]imidazo[1,2-a][1,4]diacoxine-12-yl)pyrimidin-2-yl)-1-methylcyclobutane-1-carboxynitrile hydrochloride crystal form A is substantially as follows Figure 1 As shown; its DSC spectrum is basically as follows Figure 2 As shown; its TGA spectrum is basically as follows. Figure 3 As shown.

[0021] In certain embodiments of the present invention, the X-ray powder of (1S,3s)-3-amino-3-(5-((8R,15R)-2,2-difluoro-7-(methyl-d3)-6-carbonyl-6,7,8,15-tetrahydro-8,15-methylene[1,3]dioxazolo[4',5':3,4]benzo[1,2-f]benzo[4,5]imidazo[1,2-a][1,4]diacoxin-12-yl)pyrimidin-2-yl)-1-methylcyclobutane-1-carboxynitrile p-toluenesulfonate crystal form A is described. The diffraction pattern contains at least one or more diffraction peaks located at 2θ of 4.6±0.2°, 10.1±0.2°, 17.9±0.2°, and 18.8±0.2°, preferably two, more preferably three or four; even more preferably, it may also contain at least one of 2θ of 9.2±0.2°, 14.1±0.2°, 15.8±0.2°, 16.8±0.2°, 20.7±0.2°, and 25.1±0.2°, preferably two, three, four, five, or six. More preferably, the X-ray powder diffraction pattern of the p-toluenesulfonate crystal form A includes one or more diffraction peaks located at 2θ of 4.6±0.2°, 9.2±0.2°, 10.1±0.2°, 14.1±0.2°, 15.8±0.2°, 16.8±0.2°, 17.9±0.2°, 18.8±0.2°, 20.7±0.2°, and 25.1±0.2°; preferably, it includes diffraction peaks at any of 4, 5, 6, 7, 8, or 10 locations. More preferably, the X-ray powder diffraction pattern of the p-toluenesulfonate crystal form A may also include one or more diffraction peaks with 2θ values ​​of 12.9±0.2°, 13.8±0.2°, 16.4±0.2°, 18.4±0.2°, 19.6±0.2°, and 22.2±0.2°; preferably, it includes at least 2-3, 4-5, or 5-6 peaks; more preferably, it includes any 2, 3, 4, 5, or 6 peaks. For example, the X-ray powder diffraction pattern of p-toluenesulfonate crystal form A shows diffraction peaks at the following positions with a 2θ value: 4.6±0.2°, 10.1±0.2°, 14.1±0.2°, 16.8±0.2°, 17.9±0.2°, 18.8±0.2°, 25.1±0.2°; 4.6±0.2°, 10.1±0.2°, 14.1±0.2°, 15.8±0.2°, 16.8±0.2°, 18.8±0.2°, 25.1±0.2°; 4.6±0.2°, 10.1±0.2°, 14.1±0.2°, 16.8±0.2°, 18.8±0.2°, 20.7±0.2°, 25.1±0.2°; 4.6±0.2°, 10.1±0.2°, 14.1±0.2°, 16.4±0.2°, 16.8±0.2°, 18.8±0.2°, 25.1±0.2°; 4.6±0.2°, 10.1±0.2°, 14.1±0.2°, 16.4±0.2°, 16.8±0.2°, 17.9±0.2°, 18.8±0.2°, 25.1±0.2°; 4.6±0.2°, 10.1±0.2°, 14.1±0.2°, 16.8±0.2°, 17.9±0.2°, 18.8±0.2°, 20.7±0.2°, 25.1±0.2°; 4.6±0.2°, 10.1±0.2°, 14.1±0.2°, 16.8±0.2°, 17.9±0.2°, 18.8±0.2°, 19.6±0.2°, 25.1±0.2°; 4.6±0.2°, 10.1±0.2°, 14.1±0.2°, 16.4±0.2°, 16.8±0.2°, 17.9±0.2°, 18.8±0.2°, 20.7±0.2°, 25.1±0.2°; 4.6±0.2°, 10.1±0.2°, 14.1±0.2°, 15.8±0.2°, 16.8±0.2°, 17.9±0.2°, 18.8±0.2°, 20.7±0.2°, 25.1±0.2°.

[0022] In some embodiments of the present invention, the characteristic X-ray diffraction peaks of (1S,3s)-3-amino-3-(5-((8R,15R)-2,2-difluoro-7-(methyl-d3)-6-carbonyl-6,7,8,15-tetrahydro-8,15-methylene[1,3]dioxazolo[4',5':3,4]benzo[1,2-f]benzo[4,5]imidazo[1,2-a][1,4]diacoxin-12-yl)pyrimidin-2-yl)-1-methylcyclobutane-1-carboxynitrile p-toluenesulfonate crystal form A are shown in Table 2, expressed in terms of 2θ angle and interplanar spacing d.

[0023] Table 2

[0024] In certain embodiments of the present invention, the X-ray powder diffraction pattern of (1S,3s)-3-amino-3-(5-((8R,15R)-2,2-difluoro-7-(methyl-d3)-6-carbonyl-6,7,8,15-tetrahydro-8,15-methylene[1,3]dioxazolo[4',5':3,4]benzo[1,2-f]benzo[4,5]imidazo[1,2-a][1,4]diacoxin-12-yl)pyrimidin-2-yl)-1-methylcyclobutane-1-carboxynitrile p-toluenesulfonate crystal form A is substantially as follows Figure 4 As shown; its DSC spectrum is basically as follows Figure 5 As shown; its TGA spectrum is basically as follows. Figure 6 As shown.

[0025] In certain embodiments of the present invention, X-ray powder diffraction of the (1S,3s)-3-amino-3-(5-((8R,15R)-2,2-difluoro-7-(methyl-d3)-6-carbonyl-6,7,8,15-tetrahydro-8,15-methylene[1,3]dioxazolo[4',5':3,4]benzo[1,2-f]benzo[4,5]imidazo[1,2-a][1,4]diacoxin-12-yl)pyrimidin-2-yl)-1-methylcyclobutane-1-carboxynitrile fumarate crystal form A was performed. The spectrum contains at least one or more diffraction peaks located at 2θ of 13.9±0.2°, 18.2±0.2°, 23.2±0.2°, and 23.9±0.2°, preferably two of them, more preferably three or four; even more preferably, it may also contain at least one of 2θ of 9.5±0.2°, 12.7±0.2°, 17.2±0.2°, 19.1±0.2°, 27.9±0.2°, and 30.4±0.2°, preferably two, three, four, five, or six of them; More preferably, the X-ray powder diffraction pattern of the fumarate crystal form A includes one or more diffraction peaks located at 2θ of 9.5±0.2°, 12.7±0.2°, 13.9±0.2°, 17.2±0.2°, 18.2±0.2°, 19.1±0.2°, 23.2±0.2°, 23.9±0.2°, 27.9±0.2°, and 30.4±0.2°; preferably, it includes diffraction peaks at any of 4, 5, 6, 7, 8, or 10 locations. More preferably, the X-ray powder diffraction pattern of the fumarate crystal form A may also include one or more diffraction peaks with 2θ values ​​of 16.7±0.2°, 20.4±0.2°, 21.4±0.2°, 23.4±0.2°, 24.2±0.2°, and 29.7±0.2°; preferably, it includes at least 2-3, 4-5, or 5-6 peaks; more preferably, it includes any 2, 3, 4, 5, or 6 peaks. For example, the X-ray powder diffraction pattern of fumarate crystal form A shows diffraction peaks at the following positions with a 2θ value: 9.5±0.2°, 12.7±0.2°, 13.9±0.2°, 18.2±0.2°, 19.1±0.2°, 23.2±0.2°, 23.9±0.2°; 9.5±0.2°, 12.7±0.2°, 13.9±0.2°, 18.2±0.2°, 23.2±0.2°, 23.9±0.2°, 27.9±0.2°; 9.5±0.2°, 12.7±0.2°, 13.9±0.2°, 18.2±0.2°, 23.2±0.2°, 23.9±0.2°, 27.9±0.2°, 30.4±0.2°; 9.5±0.2°, 12.7±0.2°, 13.9±0.2°, 18.2±0.2°, 19.1±0.2°, 23.2±0.2°, 23.9±0.2°, 30.4±0.2°; 9.5±0.2°, 17.2±0.2°, 12.7±0.2°, 13.9±0.2°, 18.2±0.2°, 19.1±0.2°, 23.2±0.2°, 23.9±0.2°; 9.5±0.2°, 12.7±0.2°, 13.9±0.2°, 16.7±0.2°, 18.2±0.2°, 19.1±0.2°, 23.2±0.2°, 23.9±0.2°; 9.5±0.2°, 12.7±0.2°, 13.9±0.2°, 16.7±0.2°, 18.2±0.2°, 19.1±0.2°, 23.2±0.2°, 23.9±0.2°, 27.9±0.2°.

[0026] In some embodiments of the present invention, the characteristic X-ray diffraction peaks of (1S,3s)-3-amino-3-(5-((8R,15R)-2,2-difluoro-7-(methyl-d3)-6-carbonyl-6,7,8,15-tetrahydro-8,15-methylene[1,3]dioxazolo[4',5':3,4]benzo[1,2-f]benzo[4,5]imidazo[1,2-a][1,4]diacoxin-12-yl)pyrimidin-2-yl)-1-methylcyclobutane-1-carboxynitrile fumarate crystal form A are shown in Table 3, expressed in terms of 2θ angle and interplanar spacing d, under Cu-Kα irradiation.

[0027] Table 3

[0028] In certain embodiments of the present invention, the X-ray powder diffraction pattern of the (1S,3s)-3-amino-3-(5-((8R,15R)-2,2-difluoro-7-(methyl-d3)-6-carbonyl-6,7,8,15-tetrahydro-8,15-methylene[1,3]dioxazolo[4',5':3,4]benzo[1,2-f]benzo[4,5]imidazo[1,2-a][1,4]diacoxin-12-yl)pyrimidin-2-yl)-1-methylcyclobutane-1-carboxynitrile fumarate crystal form A is substantially as follows Figure 7 As shown; its DSC spectrum is basically as follows Figure 8As shown; its TGA spectrum is basically as follows. Figure 9 As shown; In certain embodiments of the present invention, the X-ray powder diffraction of the (1S,3s)-3-amino-3-(5-((8R,15R)-2,2-difluoro-7-(methyl-d3)-6-carbonyl-6,7,8,15-tetrahydro-8,15-methylene[1,3]dioxazolo[4',5':3,4]benzo[1,2-f]benzo[4,5]imidazo[1,2-a][1,4]diacoxin-12-yl)pyrimidin-2-yl)-1-methylcyclobutane-1-carboxynitrile fumarate crystal form B is described. The diffraction pattern contains at least one or more diffraction peaks located at 2θ of 7.4±0.2°, 10.5±0.2°, 12.6±0.2°, and 18.7±0.2°, preferably two, more preferably three or four; even more preferably, it may also contain at least one of 2θ of 6.9±0.2°, 13.1±0.2°, 15.2±0.2°, 22.1±0.2°, 26.0±0.2°, and 26.2±0.2°, preferably two, three, four, five, or six. More preferably, the X-ray powder diffraction pattern of the fumarate crystal form B includes one or more locations located at 2θ of 6.9±0.2°, 7.4±0.2°, 10.5±0.2°, 12.6±0.2°, 13.1±0.2°, 15.2±0.2°, 18.7±0.2°, 22.1±0.2°, 26.0±0.2°, and 26.2±0.2°. Diffraction peaks; preferably, including any 4, 5, 6, 7, 8 or 10 diffraction peaks; more preferably, it may also include at least one of 2θ being 9.3±0.2°, 12.3±0.2°, 15.6±0.2°, 17.1±0.2°, 19.1±0.2°, 21.1±0.2°, preferably including 2, 3, 4, 5 or 6 of them; For example, the X-ray powder diffraction pattern of fumarate crystal form B shows diffraction peaks at the following positions with a 2θ value: 6.9±0.2°, 7.4±0.2°, 10.5±0.2°, 12.6±0.2°, 18.7±0.2°, 22.1±0.2°, 26.2±0.2°; 6.9±0.2°, 7.4±0.2°, 10.5±0.2°, 12.6±0.2°, 15.6±0.2°, 18.7±0.2°, 22.1±0.2°; 6.9±0.2°, 7.4±0.2°, 10.5±0.2°, 12.6±0.2°, 18.7±0.2°, 21.1±0.2°, 22.1±0.2°; 6.9±0.2°, 7.4±0.2°, 10.5±0.2°, 12.6±0.2°, 15.2±0.2°, 15.6±0.2°, 18.7±0.2°, 22.1±0.2°; 6.9±0.2°, 7.4±0.2°, 10.5±0.2°, 12.6±0.2°, 15.2±0.2°, 18.7±0.2°, 21.1±0.2°, 22.1±0.2°; 6.9±0.2°, 7.4±0.2°, 10.5±0.2°, 12.6±0.2°, 13.1±0.2°, 18.7±0.2°, 22.1±0.2°, 26.2±0.2°; 6.9±0.2°, 7.4±0.2°, 10.5±0.2°, 12.6±0.2°, 13.1±0.2°, 15.6±0.2°, 18.7±0.2°, 22.1±0.2°, 26.2±0.2°; 6.9±0.2°, 7.4±0.2°, 10.5±0.2°, 12.6±0.2°, 13.1±0.2°, 18.7±0.2°, 21.1±0.2°, 22.1±0.2°, 26.2±0.2°.

[0029] In some embodiments of the present invention, the (1S,3s)-3-amino-3-(5-((8R,15R)-2,2-difluoro-7-(methyl-d3)-6-carbonyl-6,7,8,15-tetrahydro-8,15-methylene[1,3]dioxazolo[4',5':3,4]benzo[1,2-f]benzo[4,5]imidazo[1,2-a][1,4]diacoxin-12-yl)pyrimidin-2-yl)-1-methylcyclobutane-1-carboxynitrile fumarate crystal form B was subjected to Cu-Kα radiation, and the characteristic X-ray diffraction peaks expressed in terms of 2θ angle and interplanar spacing d are shown in Table 4.

[0030] Table 4

[0031] In certain embodiments of the present invention, the X-ray powder diffraction pattern of the (1S,3s)-3-amino-3-(5-((8R,15R)-2,2-difluoro-7-(methyl-d3)-6-carbonyl-6,7,8,15-tetrahydro-8,15-methylene[1,3]dioxazolo[4',5':3,4]benzo[1,2-f]benzo[4,5]imidazo[1,2-a][1,4]diacoxin-12-yl)pyrimidin-2-yl)-1-methylcyclobutane-1-carboxynitrile fumarate crystal form B is substantially as follows Figure 10 As shown; its DSC spectrum is basically as follows Figure 11As shown; its TGA spectrum is basically as follows. Figure 12 As shown.

[0032] In certain embodiments of the present invention, the X-ray powder diffraction of the (1S,3s)-3-amino-3-(5-((8R,15R)-2,2-difluoro-7-(methyl-d3)-6-carbonyl-6,7,8,15-tetrahydro-8,15-methylene[1,3]dioxazolo[4',5':3,4]benzo[1,2-f]benzo[4,5]imidazo[1,2-a][1,4]diacoxin-12-yl)pyrimidin-2-yl)-1-methylcyclobutane-1-carboxynitrile phosphate crystal form A is described. The diffraction pattern contains at least one or more diffraction peaks located at 2θ of 4.3±0.2°, 6.7±0.2°, 8.6±0.2°, and 17.3±0.2°, preferably two, more preferably three or four; even more preferably, it may also contain at least one of 2θ of 10.4±0.2°, 14.4±0.2°, 16.3±0.2°, 20.6±0.2°, 20.9±0.2°, and 26.4±0.2°, preferably two, three, four, five, or six. More preferably, the X-ray powder diffraction pattern of the phosphate crystal form A includes one or more diffraction peaks located at 2θ of 4.3±0.2°, 6.7±0.2°, 8.6±0.2°, 10.4±0.2°, 14.4±0.2°, 16.3±0.2°, 17.3±0.2°, 20.6±0.2°, 20.9±0.2°, and 26.4±0.2°; For example, the X-ray powder diffraction pattern of phosphate crystal form A shows diffraction peaks at the following positions with a 2θ value: 4.3±0.2°, 6.7±0.2°, 8.6±0.2°, 14.4±0.2°, 17.3±0.2°, 20.6±0.2°, 20.9±0.2°; 4.3±0.2°, 6.7±0.2°, 8.6±0.2°, 10.4±0.2°, 14.4±0.2°, 20.6±0.2°, 20.9±0.2°; 4.3±0.2°, 6.7±0.2°, 8.6±0.2°, 14.4±0.2°, 14.4±0.2°, 17.3±0.2°, 20.6±0.2°; 4.3±0.2°, 6.7±0.2°, 8.6±0.2°, 14.4±0.2°, 14.4±0.2°, 17.3±0.2°, 20.6±0.2°, 20.9±0.2°; 4.3±0.2°, 6.7±0.2°, 8.6±0.2°, 14.4±0.2°, 17.3±0.2°, 20.6±0.2°, 20.9±0.2°, 26.4±0.2°; 4.3±0.2°, 6.7±0.2°, 8.6±0.2°, 10.4±0.2°, 14.4±0.2°, 20.6±0.2°, 20.9±0.2°, 26.4±0.2°.

[0033] In some embodiments of the present invention, the characteristic X-ray diffraction peaks of (1S,3s)-3-amino-3-(5-((8R,15R)-2,2-difluoro-7-(methyl-d3)-6-carbonyl-6,7,8,15-tetrahydro-8,15-methylene[1,3]dioxazolo[4',5':3,4]benzo[1,2-f]benzo[4,5]imidazo[1,2-a][1,4]diacoxin-12-yl)pyrimidin-2-yl)-1-methylcyclobutane-1-carboxynitrile phosphate crystal form A are shown in Table 5, expressed in terms of 2θ angle and interplanar spacing d, under Cu-Kα radiation.

[0034] Table 5

[0035] In certain embodiments of the present invention, the characteristic X-ray diffraction peaks of (1S,3s)-3-amino-3-(5-((8R,15R)-2,2-difluoro-7-(methyl-d3)-6-carbonyl-6,7,8,15-tetrahydro-8,15-methylene[1,3]dioxazolo[4',5':3,4]benzo[1,2-f]benzo[4,5]imidazo[1,2-a][1,4]diacoxo-12-yl)pyrimidin-2-yl)-1-methylcyclobutane-1-carboxynitrile oxalate crystal form A are shown in Table 6, expressed in terms of 2θ angle and interplanar spacing d, under Cu-Kα radiation.

[0036] Table 6

[0037] In certain embodiments of the present invention, the positions of the top ten diffraction peaks with relative intensities in the X-ray powder diffraction patterns of the (1S,3s)-3-amino-3-(5-((8R,15R)-2,2-difluoro-7-(methyl-d3)-6-carbonyl-6,7,8,15-tetrahydro-8,15-methylene[1,3]dioxazolo[4',5':3,4]benzo[1,2-f]benzo[4,5]imidazo[1,2-a][1,4]diacoxo-12-yl)pyrimidin-2-yl)-1-methylcyclobutane-1-carboxylonite hydrochloride crystal form A, p-toluenesulfonate crystal form A, fumarate crystal form A, and fumarate crystal form B are respectively... Figure 1 , Figure 4 , Figure 7 and Figure 10 The 2θ error of the diffraction peak at the corresponding position is ±0.2°~±0.5°; preferably ±0.2°~±0.3°, and most preferably ±0.2°.

[0038] In some embodiments of the present invention, the acid salt or its crystal form is (1 S ,3 S )-3-(5-((8 R 15 R )-2,2-difluoro-7-(methyl- d 3 )-6-carbonyl-6,7,8,15-tetrahydro-8,15-methylene[1,3]dioxazolo[4',5':3,4]benzo[1,2-f]benzo[4,5]imidazo[1,2-a][1,4]diacoxine-12-yl)pyrimidin-2-yl)-3-hydroxy-1-methylcyclobutane-1-carboxynitrile hydrochloride crystal form A; The X-ray powder diffraction pattern of the hydrochloride crystal form A shows a diffraction peak at 2θ of 4.2 ± 0.2°; or at 8.4 ± 0.2°; or at 12.4 ± 0.2°; or at 15.0 ± 0.2°; or at 16.8 ± 0.2°; or at 18.7 ± 0.2°; or at 21.4 ± 0.2°. The diffraction peaks are present; or diffraction peaks are present at 21.9±0.2°; or diffraction peaks are present at 23.1±0.2°; or diffraction peaks are present at 23.7±0.2°; preferably, any 2-5, 3-5, 3-6, 3-8, 5-8, 6-8, or 8-10 of the above diffraction peaks are included; more preferably, any 6, 7, 8, 9, or 10 of the above diffraction peaks are included. Alternatively, the acid salt or its crystal form is (1 S ,3 S )-3-(5-((8 R 15 R )-2,2-difluoro-7-(methyl- d 3 )-6-carbonyl-6,7,8,15-tetrahydro-8,15-methylene[1,3]dioxazolo[4',5':3,4]benzo[1,2-f]benzo[4,5]imidazo[1,2-a][1,4]diacoxine-12-yl)pyrimidin-2-yl)-3-hydroxy-1-methylcyclobutane-1-carboxynitrile sulfate crystal form A; The X-ray powder diffraction pattern of the sulfate crystal form A shows a diffraction peak at 2θ of 5.0 ± 0.2°; or at 6.4 ± 0.2°; or at 8.2 ± 0.2°; or at 13.2 ± 0.2°; or at 16.3 ± 0.2°; or at 17.1 ± 0.2°; or at 22.2 ± 0.2°. The diffraction peaks are present; or diffraction peaks are present at 22.7±0.2°; or diffraction peaks are present at 23.3±0.2°; or diffraction peaks are present at 25.0±0.2°; preferably, any 2-5, 3-5, 3-6, 3-8, 5-8, 6-8, or 8-10 of the above diffraction peaks are included; more preferably, any 6, 7, 8, 9, or 10 of the above diffraction peaks are included. Alternatively, the acid salt or its crystal form is (1 S ,3 S )-3-(5-((8 R 15 R )-2,2-difluoro-7-(methyl- d 3 )-6-carbonyl-6,7,8,15-tetrahydro-8,15-methylene[1,3]dioxazolo[4',5':3,4]benzo[1,2-f]benzo[4,5]imidazo[1,2-a][1,4]diacoxine-12-yl)pyrimidin-2-yl)-3-hydroxy-1-methylcyclobutane-1-carboxynitrile hydrobromide crystal form A; The X-ray powder diffraction pattern of the hydrobromide crystal form A shows a diffraction peak at 2θ of 4.3 ± 0.2°; or at 8.2 ± 0.2°; or at 12.4 ± 0.2°; or at 15.7 ± 0.2°; or at 16.7 ± 0.2°; or at 18.6 ± 0.2°; or at 21.8 ± 0.2°. It has a diffraction peak; or a diffraction peak at 23.0±0.2°; or a diffraction peak at 23.4±0.2°; or a diffraction peak at 24.2±0.2°; preferably, it includes any 2-5, 3-5, 3-6, 3-8, 5-8, 6-8, or 8-10 of the above diffraction peaks; more preferably, it includes any 6, 7, 8, 9, or 10 of them.

[0039] In some embodiments of the present invention, the (1) S ,3 S )-3-(5-((8 R 15 R )-2,2-difluoro-7-(methyl- d3 The X-ray powder diffraction pattern of 6-carbonyl-6,7,8,15-tetrahydro-8,15-methylene[1,3]dioxazolo[4',5':3,4]benzo[1,2-f]benzo[4,5]imidazo[1,2-a][1,4]diacoxine-12-yl)pyrimidin-2-yl)-3-hydroxy-1-methylcyclobutane-1-carboxynitrile hydrochloride crystal form A contains at least the following positions at 2θ = 8.4±0.2° and 21.4±0°. The diffraction peaks are selected from 0.2°, 18.7±0.2°, and 21.9±0.2°, preferably including 2, more preferably including 3 or 4; and even more preferably, the diffraction peaks are selected from 4.2±0.2°, 12.4±0.2°, 15.0±0.2°, 16.8±0.2°, 23.1±0.2°, and 23.7±0.2°, preferably including 2, 3, 4, 5 or 6. More preferably, the X-ray powder diffraction pattern of the hydrochloride crystal form A includes one or more diffraction peaks located at 4.2±0.2°, 8.4±0.2°, 12.4±0.2°, 15.0±0.2°, 16.8±0.2°, 18.7±0.2°, 21.4±0.2°, 21.9±0.2°, 23.1±0.2°, and 23.7±0.2°; preferably, it includes diffraction peaks at any of 4, 5, 6, 8, or 10 locations. More preferably, the X-ray powder diffraction pattern of the hydrochloride crystal form A may also include one or more diffraction peaks with 2θ values ​​of 12.0±0.2°, 15.7±0.2°, 20.9±0.2°, 24.2±0.2°, 24.5±0.2°, and 31.5±0.2°; preferably, it includes at least 2-3, 4-5, or 5-6 peaks; more preferably, it includes any 2, 3, 4, 5, or 6 peaks. For example, the X-ray powder diffraction pattern of the hydrochloride crystal form A has diffraction peaks at the following positions with a 2θ value: 8.4±0.2°, 12.4±0.2°, 16.8±0.2°, 18.7±0.2°, 21.4±0.2°, 21.9±0.2°; 8.4±0.2°, 12.4±0.2°, 16.8±0.2°, 18.7±0.2°, 21.4±0.2°, 21.9±0.2°, 23.1±0.2°; 8.4±0.2°, 12.4±0.2°, 16.8±0.2°, 18.7±0.2°, 21.4±0.2°, 21.9±0.2°, 23.7±0.2°; 8.4±0.2°, 12.4±0.2°, 15.7±0.2°, 16.8±0.2°, 18.7±0.2°, 21.4±0.2°, 21.9±0.2°; 4.2±0.2°, 8.4±0.2°, 15.0±0.2°, 16.8±0.2°, 18.7±0.2°, 21.4±0.2°, 21.9±0.2°, 23.1±0.2°; 8.4±0.2°, 15.0±0.2°, 16.8±0.2°, 18.7±0.2°, 21.4±0.2°, 21.9±0.2°, 23.1±0.2°, 23.7±0.2°; 8.4±0.2°, 15.0±0.2°, 15.7±0.2°, 16.8±0.2°, 18.7±0.2°, 21.4±0.2°, 21.9±0.2°, 23.1±0.2°, 23.7±0.2°; 8.4±0.2°, 15.0±0.2°, 15.7±0.2°, 16.8±0.2°, 18.7±0.2°, 21.4±0.2°, 21.9±0.2°, 23.1±0.2°, 23.7±0.2°.

[0040] In some embodiments of the present invention, the (1) S ,3 S )-3-(5-((8 R 15 R )-2,2-difluoro-7-(methyl- d 3 The characteristic X-ray diffraction peaks of 6-carbonyl-6,7,8,15-tetrahydro-8,15-methylene[1,3]dioxazolo[4',5':3,4]benzo[1,2-f]benzo[4,5]imidazo[1,2-a][1,4]diacoxine-12-yl)pyrimidin-2-yl)-3-hydroxy-1-methylcyclobutane-1-carboxynitrile hydrochloride crystal form A, expressed in terms of 2θ angle and interplanar spacing d, are shown in Table 7 under Cu-Kα radiation.

[0041] Table 7

[0042] In some embodiments of the present invention, the (1) S ,3 S )-3-(5-((8 R 15 R )-2,2-difluoro-7-(methyl- d 3The X-ray powder diffraction pattern of 6-carbonyl-6,7,8,15-tetrahydro-8,15-methylene[1,3]dioxazolo[4',5':3,4]benzo[1,2-f]benzo[4,5]imidazo[1,2-a][1,4]diacoxine-12-yl)pyrimidin-2-yl)-3-hydroxy-1-methylcyclobutane-1-carboxynitrile hydrochloride crystal form A is basically as follows Figure 13 As shown; its DSC spectrum is basically as follows Figure 14 As shown; its TGA spectrum is basically as follows. Figure 15 As shown.

[0043] In some embodiments of the present invention, the (1) S ,3 S )-3-(5-((8 R 15 R )-2,2-difluoro-7-(methyl- d 3 The X-ray powder diffraction pattern of 6-carbonyl-6,7,8,15-tetrahydro-8,15-methylene[1,3]dioxazolo[4',5':3,4]benzo[1,2-f]benzo[4,5]imidazo[1,2-a][1,4]diacoxin-12-yl)pyrimidin-2-yl)-3-hydroxy-1-methylcyclobutane-1-carboxynitrile sulfate crystal form A contains at least the following 2θ values ​​at 5.0±0.2° and 8.2±0. The diffraction peaks are selected from 2°, 23.3±0.2° and 25.0±0.2°, preferably including 2, more preferably including 3 or 4; and even more preferably, the diffraction peaks are selected from 2θ, 6.4±0.2°, 13.2±0.2°, 16.3±0.2°, 17.1±0.2°, 22.2±0.2° and 22.7±0.2°, preferably including 2, 3, 4, 5 or 6. More preferably, the X-ray powder diffraction pattern of the sulfate crystal form A includes one or more diffraction peaks located at 5.0±0.2°, 6.4±0.2°, 8.2±0.2°, 13.2±0.2°, 16.3±0.2°, 17.1±0.2°, 22.2±0.2°, 22.7±0.2°, 23.3±0.2°, and 25.0±0.2°; preferably, it includes diffraction peaks at any of 4, 5, 6, 8, or 10 selected locations. More preferably, the X-ray powder diffraction pattern of the sulfate crystal form A may also include one or more diffraction peaks with 2θ values ​​of 14.8±0.2°, 19.4±0.2°, 20.0±0.2°, 21.0±0.2°, 24.5±0.2°, and 29.9±0.2°; preferably, it includes at least 2-3, 4-5, or 5-6 peaks; more preferably, it includes any 2, 3, 4, 5, or 6 peaks. For example, the X-ray powder diffraction pattern of the sulfate crystal form A has diffraction peaks at the following positions with a 2θ value: 5.0±0.2°, 13.2±0.2°, 16.3±0.2°, 17.1±0.2°, 23.3±0.2°, 25.0±0.2°; 5.0±0.2°, 13.2±0.2°, 16.3±0.2°, 17.1±0.2°, 22.7±0.2°, 23.3±0.2°, 25.0±0.2°; 5.0±0.2°, 8.2±0.2°, 13.2±0.2°, 16.3±0.2°, 17.1±0.2°, 23.3±0.2°, 25.0±0.2°; 5.0±0.2°, 6.4±0.2°, 13.2±0.2°, 16.3±0.2°, 17.1±0.2°, 23.3±0.2°, 25.0±0.2°; 5.0±0.2°, 13.2±0.2°, 16.3±0.2°, 17.1±0.2°, 22.7±0.2°, 23.3±0.2°, 25.0±0.2°; 5.0±0.2°, 6.4±0.2°, 8.2±0.2°, 13.2±0.2°, 16.3±0.2°, 17.1±0.2°, 23.3±0.2°, 25.0±0.2°; 5.0±0.2°, 8.2±0.2°, 13.2±0.2°, 14.8±0.2°, 16.3±0.2°, 17.1±0.2°, 23.3±0.2°, 25.0±0.2°; 5.0±0.2°, 6.4±0.2°, 8.2±0.2°, 13.2±0.2°, 16.3±0.2°, 17.1±0.2°, 22.7±0.2°, 23.3±0.2°, 25.0±0.2°.

[0044] In some embodiments of the present invention, the (1) S ,3 S )-3-(5-((8 R 15 R)-2,2-difluoro-7-(methyl- d 3 The characteristic X-ray diffraction peaks of 6-carbonyl-6,7,8,15-tetrahydro-8,15-methylene[1,3]dioxazolo[4',5':3,4]benzo[1,2-f]benzo[4,5]imidazo[1,2-a][1,4]diacoxine-12-yl)pyrimidin-2-yl)-3-hydroxy-1-methylcyclobutane-1-carboxynitrile sulfate crystal form A, expressed in terms of 2θ angle and interplanar spacing d, are shown in Table 8 under Cu-Kα radiation.

[0045] Table 8

[0046] In some embodiments of the present invention, the (1) S ,3 S )-3-(5-((8 R 15 R )-2,2-difluoro-7-(methyl- d 3 The X-ray powder diffraction pattern of 6-carbonyl-6,7,8,15-tetrahydro-8,15-methylene[1,3]dioxazolo[4',5':3,4]benzo[1,2-f]benzo[4,5]imidazo[1,2-a][1,4]diacoxine-12-yl)pyrimidin-2-yl)-3-hydroxy-1-methylcyclobutane-1-carboxynitrile sulfate crystal form A is basically as follows Figure 16 As shown; its DSC spectrum is basically as follows Figure 17 As shown; its TGA spectrum is basically as follows. Figure 18 As shown.

[0047] In some embodiments of the present invention, the (1) S ,3 S )-3-(5-((8 R 15 R )-2,2-difluoro-7-(methyl- d 3The X-ray powder diffraction pattern of crystalline form A of 6-carbonyl-6,7,8,15-tetrahydro-8,15-methylene[1,3]dioxazolo[4',5':3,4]benzo[1,2-f]benzo[4,5]imidazo[1,2-a][1,4]diacoxin-12-yl)pyrimidin-2-yl)-3-hydroxy-1-methylcyclobutane-1-carboxynitrile hydrobromide contains at least the following 2θ values: 4.3±0.2° and 8.2±0. The diffraction peaks are selected from 2°, 21.8±0.2° and 23.0±0.2°, preferably including 2, more preferably including 3 or 4; and even more preferably, the diffraction peaks are selected from 12.4±0.2°, 15.7±0.2°, 16.7±0.2°, 18.6±0.2°, 23.4±0.2° and 24.2±0.2°, preferably including 2, 3, 4, 5 or 6. More preferably, the X-ray powder diffraction pattern of the hydrobromide crystal form A includes one or more diffraction peaks located at 4.3±0.2°, 8.2±0.2°, 12.4±0.2°, 15.7±0.2°, 16.7±0.2°, 18.6±0.2°, 21.8±0.2°, 23.0±0.2°, 23.4±0.2°, and 24.2±0.2°; preferably, it includes diffraction peaks at any of 4, 5, 6, 8, or 10 locations. More preferably, the (1) S ,3 S )-3-(5-((8 R 15 R )-2,2-difluoro-7-(methyl- d 3 The X-ray powder diffraction pattern of 6-carbonyl-6,7,8,15-tetrahydro-8,15-methylene[1,3]dioxazolo[4',5':3,4]benzo[1,2-f]benzo[4,5]imidazo[1,2-a][1,4]diacoxine-12-yl)pyrimidin-2-yl)-3-hydroxy-1-methylcyclobutane-1-carboxynitrile hydrobromide crystal form A may also contain one or more diffraction peaks with 2θ of 14.8±0.2°, 21.3±0.2°, 24.6±0.2° and 27.2±0.2°; preferably, it may contain at least 2-3 of them, or 3-4 of them; For example, the X-ray powder diffraction pattern of the hydrobromide crystal form A has diffraction peaks at the following positions with a 2θ value: 4.3±0.2°, 8.2±0.2°, 18.6±0.2°, 21.8±0.2°, 23.0±0.2°, 23.4±0.2°; 4.3±0.2°, 8.2±0.2°, 18.6±0.2°, 21.8±0.2°, 23.0±0.2°, 23.4±0.2°; 4.3±0.2°, 8.2±0.2°, 16.7±0.2°, 18.6±0.2°, 21.8±0.2°, 23.0±0.2°, 23.4±0.2°; 4.3±0.2°, 8.2±0.2°, 12.4±0.2°, 16.7±0.2°, 18.6±0.2°, 21.8±0.2°, 23.0±0.2°, 23.4±0.2°; 4.3±0.2°, 8.2±0.2°, 15.7±0.2°, 16.7±0.2°, 18.6±0.2°, 21.8±0.2°, 23.0±0.2°, 23.4±0.2°; 4.3±0.2°, 8.2±0.2°, 15.7±0.2°, 16.7±0.2°, 18.6±0.2°, 21.8±0.2°, 23.0±0.2°, 23.4±0.2°, 24.2±0.2°; 4.3±0.2°, 8.2±0.2°, 12.4±0.2°, 15.7±0.2°, 16.7±0.2°, 18.6±0.2°, 21.8±0.2°, 23.0±0.2°, 23.4±0.2°.

[0048] In some embodiments of the present invention, the (1) S ,3 S )-3-(5-((8 R 15 R )-2,2-difluoro-7-(methyl- d 3 The characteristic X-ray diffraction peaks of 6-carbonyl-6,7,8,15-tetrahydro-8,15-methylene[1,3]dioxazolo[4',5':3,4]benzo[1,2-f]benzo[4,5]imidazo[1,2-a][1,4]diacoxine-12-yl)pyrimidin-2-yl)-3-hydroxy-1-methylcyclobutane-1-carboxynitrile hydrobromide crystal form A, expressed in terms of 2θ angle and interplanar spacing d, are shown in Table 9.

[0049] Table 9

[0050] In some embodiments of the present invention, the (1) S ,3 S )-3-(5-((8 R 15 R)-2,2-difluoro-7-(methyl- d 3 The X-ray powder diffraction pattern of 6-carbonyl-6,7,8,15-tetrahydro-8,15-methylene[1,3]dioxazolo[4',5':3,4]benzo[1,2-f]benzo[4,5]imidazo[1,2-a][1,4]diacoxine-12-yl)pyrimidin-2-yl)-3-hydroxy-1-methylcyclobutane-1-carboxynitrile hydrobromide crystal form A is basically as follows Figure 19 As shown; its DSC spectrum is basically as follows Figure 20 As shown; its TGA spectrum is basically as follows. Figure 21 As shown.

[0051] In some embodiments of the present invention, the crystal form is (1S,3s)-3-amino-3-(5-((8R,15R)-2,2-difluoro-7-(methyl-d3)-6-carbonyl-6,7,8,15-tetrahydro-8,15-methylene[1,3]dioxazolo[4',5':3,4]benzo[1,2-f]benzo[4,5]imidazo[1,2-a][1,4]diacoxine-12-yl)pyrimidin-2-yl)-1-methylcyclobutane-1-formonitrile crystal form 1; The X-ray powder diffraction pattern of crystal form 1 has a diffraction peak at 2θ of 6.6±0.2°; or at 8.5±0.2°; or at 11.0±0.2°; or at 16.7±0.2°; or at 18.3±0.2°; or at 19.1±0.2°; or at 19.5±0.2°; preferably including any 2-5, 3-5, or 3-6 of the above diffraction peaks; more preferably including any 4, 5, or 6 of them.

[0052] In some embodiments of the present invention, the crystal form 1 is subjected to Cu-Kα radiation, and the characteristic X-ray diffraction peaks expressed in terms of 2θ angle and interplanar spacing d are shown in Table 10.

[0053] Table 10

[0054] In some embodiments of the present invention, the crystal form is (1S,3s)-3-amino-3-(5-((8R,15R)-2,2-difluoro-7-(methyl-d3)-6-carbonyl-6,7,8,15-tetrahydro-8,15-methylene[1,3]dioxazolo[4',5':3,4]benzo[1,2-f]benzo[4,5]imidazo[1,2-a][1,4]diacoxine-12-yl)pyrimidin-2-yl)-1-methylcyclobutane-1-formonitrile crystal form 2; The X-ray powder diffraction pattern of crystal form 2 shows a diffraction peak at 2θ of 6.0 ± 0.2°; or at 7.4 ± 0.2°; or at 11.9 ± 0.2°; or at 13.5 ± 0.2°; or at 14.0 ± 0.2°; or at 14.7 ± 0.2°; or at 19.9 ± 0.2°. The diffraction peak is present at 20.6±0.2°; or at 22.2±0.2°; or at 23.9±0.2°; preferably, any 2-5, 3-5, 3-6, 3-8, 5-8, 6-8, or 8-10 of the above diffraction peaks are included; more preferably, any 6, 7, 8, 9, or 10 of the above diffraction peaks are included.

[0055] In some embodiments of the present invention, the X-ray powder diffraction pattern of the crystal form 2 includes at least one or more diffraction peaks located at 2θ of 6.0±0.2°, 7.4±0.2°, 11.9±0.2°, and 19.9±0.2°, preferably including two such peaks, more preferably including three or four such peaks; even more preferably, it may also include at least one of 2θ of 13.5±0.2°, 14.0±0.2°, 14.7±0.2°, 20.6±0.2°, 22.2±0.2°, and 23.9±0.2°, preferably including two, three, four, five, or six such peaks; More preferably, the X-ray powder diffraction pattern of the crystal form 2 includes one or more diffraction peaks located at 6.0±0.2°, 7.4±0.2°, 11.9±0.2°, 13.5±0.2°, 14.0±0.2°, 14.7±0.2°, 19.9±0.2°, 20.6±0.2°, 22.2±0.2°, and 23.9±0.2°; preferably, it includes diffraction peaks at any of 4, 5, 6, 8, or 10 locations. More preferably, the X-ray powder diffraction pattern of the crystal form 2 may also include one or more diffraction peaks with 2θ values ​​of 11.3±0.2°, 17.4±0.2°, 18.5±0.2°, 21.6±0.2°, 25.9±0.2°, and 27.8±0.2°; preferably, it includes at least 2-3, 4-5, or 5-6 peaks; more preferably, it includes any 2, 3, 4, 5, or 6 peaks. For example, the X-ray powder diffraction pattern of crystal form 2 has diffraction peaks at the following positions with a 2θ value: 6.0±0.2°, 7.4±0.2°, 11.9±0.2°, 14.7±0.2°, 19.9±0.2°, 23.9±0.2°; 6.0±0.2°, 7.4±0.2°, 11.9±0.2°, 14.7±0.2°, 19.9±0.2°, 20.6±0.2°, 23.9±0.2°; 6.0±0.2°, 7.4±0.2°, 11.9±0.2°, 14.7±0.2°, 19.9±0.2°, 22.2±0.2°, 23.9±0.2°; 6.0±0.2°, 7.4±0.2°, 11.9±0.2°, 14.7±0.2°, 19.9±0.2°, 21.6±0.2°, 23.9±0.2°; 6.0±0.2°, 7.4±0.2°, 11.9±0.2°, 14.7±0.2°, 19.9±0.2°, 23.9±0.2°, 25.9±0.2°; 6.0±0.2°, 7.4±0.2°, 11.9±0.2°, 14.7±0.2°, 19.9±0.2°, 20.6±0.2°, 22.2±0.2°, 23.9±0.2°; 6.0±0.2°, 7.4±0.2°, 11.9±0.2°, 14.7±0.2°, 19.9±0.2°, 20.6±0.2°, 21.6±0.2°, 23.9±0.2°; 6.0±0.2°, 7.4±0.2°, 11.9±0.2°, 13.5±0.2°, 14.0±0.2°, 14.7±0.2°, 19.9±0.2°, 23.9±0.2°; 6.0±0.2°, 7.4±0.2°, 11.9±0.2°, 13.5±0.2°, 14.7±0.2°, 19.9±0.2°, 20.6±0.2°, 22.2±0.2°, 23.9±0.2°.

[0056] In some embodiments of the present invention, the crystal form 2 is subjected to Cu-Kα radiation, and the characteristic X-ray diffraction peaks expressed in terms of 2θ angle and interplanar spacing d are shown in Table 11.

[0057] Table 11

[0058] In some embodiments of the present invention, the X-ray powder diffraction pattern of crystal form 2 is substantially as follows: Figure 22 As shown; its DSC spectrum is basically as follows Figure 23 As shown; its TGA spectrum is basically as follows. Figure 24 As shown.

[0059] In some embodiments of the present invention, the crystal form is (1S,3s)-3-amino-3-(5-((8R,15R)-2,2-difluoro-7-(methyl-d3)-6-carbonyl-6,7,8,15-tetrahydro-8,15-methylene[1,3]dioxazolo[4',5':3,4]benzo[1,2-f]benzo[4,5]imidazo[1,2-a][1,4]diacoxo-12-yl)pyrimidin-2-yl)-1-methylcyclobutane-1-carboxynitrile crystal form 3; The X-ray powder diffraction pattern of the crystal form 3 has a diffraction peak at 2θ of 5.9±0.2°; or at 11.7±0.2°; or at 13.5±0.2°; or at 15.6±0.2°; or at 16.4±0.2°; or at 17.4±0.2°; or at 22.7±0.2°; or at 26.4±0.2°; preferably including any 2-5, 3-5, 3-6, 3-8, 5-8, or 6-8 of the above diffraction peaks; more preferably including any 6, 7, or 8 of them.

[0060] In some embodiments of the present invention, the crystal form 3 is subjected to Cu-Kα radiation, and the characteristic X-ray diffraction peaks expressed in terms of 2θ angle and interplanar spacing d are shown in Table 12.

[0061] Table 12

[0062] In some embodiments of the present invention, the DSC spectrum of crystal form 3 is substantially as follows: Figure 25 As shown, its TGA spectrum is basically as follows: Figure 26 As shown.

[0063] In some embodiments of the present invention, the crystal form is (1S,3s)-3-amino-3-(5-((8R,15R)-2,2-difluoro-7-(methyl-d3)-6-carbonyl-6,7,8,15-tetrahydro-8,15-methylene[1,3]dioxazolo[4',5':3,4]benzo[1,2-f]benzo[4,5]imidazo[1,2-a][1,4]diacoxine-12-yl)pyrimidin-2-yl)-1-methylcyclobutane-1-formonitrile crystal form 4; The X-ray powder diffraction pattern of crystal form 4 shows a diffraction peak at 2θ of 5.3 ± 0.2°; or at 5.6 ± 0.2°; or at 6.7 ± 0.2°; or at 7.5 ± 0.2°; or at 11.1 ± 0.2°; or at 12.2 ± 0.2°; or at 14.1 ± 0.2°. The peak; or a diffraction peak at 17.7±0.2°; or a diffraction peak at 19.5±0.2°; or a diffraction peak at 21.6±0.2°; preferably including any 2-5, 3-5, 3-6, 3-8, 5-8, 6-8, or 8-10 of the above diffraction peaks; more preferably including any 6, 7, 8, 9, or 10 of them.

[0064] In some embodiments of the present invention, the X-ray powder diffraction pattern of the crystal form 4 includes at least one or more diffraction peaks located at 2θ of 6.7±0.2°, 11.1±0.2°, 12.2±0.2°, and 21.6±0.2°, preferably including two such peaks, more preferably including three or four such peaks; even more preferably, it may also include at least one of 2θ of 5.3±0.2°, 5.6±0.2°, 7.5±0.2°, 14.1±0.2°, 17.7±0.2°, and 19.5±0.2°, preferably including two, three, four, five, or six such peaks; More preferably, the X-ray powder diffraction pattern of the crystal form 4 includes one or more diffraction peaks located at 2θ of 5.3±0.2°, 5.6±0.2°, 6.7±0.2°, 7.5±0.2°, 11.1±0.2°, 12.2±0.2°, 14.1±0.2°, 17.7±0.2°, 19.5±0.2°, and 21.6±0.2°; preferably, it includes diffraction peaks at any of 4, 5, 6, 7, 8, or 10 of these locations. More preferably, the X-ray powder diffraction pattern of the crystal form 4 may also include one or more diffraction peaks with 2θ values ​​of 10.0±0.2°, 13.3±0.2°, 16.7±0.2°, 18.9±0.2°, 20.4±0.2°, and 23.3±0.2°; preferably, it includes at least 2-3, 4-5, or 5-6 peaks; more preferably, it includes any 2, 3, 4, 5, or 6 peaks. For example, the X-ray powder diffraction pattern of crystal form 4 shows diffraction peaks at the following positions with a 2θ value: 6.7±0.2°, 7.5±0.2°, 11.1±0.2°, 12.2±0.2°, 14.1±0.2°, 19.5±0.2°; 6.7±0.2°, 7.5±0.2°, 11.1±0.2°, 12.2±0.2°, 14.1±0.2°, 19.5±0.2°, 21.6±0.2°; 5.6±0.2°, 6.7±0.2°, 7.5±0.2°, 11.1±0.2°, 12.2±0.2°, 14.1±0.2°, 19.5±0.2°; 5.3±0.2°, 6.7±0.2°, 7.5±0.2°, 11.1±0.2°, 12.2±0.2°, 19.5±0.2°, 21.6±0.2°; 6.7±0.2°, 7.5±0.2°, 11.1±0.2°, 12.2±0.2°, 14.1±0.2°, 19.5±0.2°, 21.6±0.2°, 23.3±0.2°; 5.3±0.2°, 6.7±0.2°, 7.5±0.2°, 11.1±0.2°, 12.2±0.2°, 14.1±0.2°, 19.5±0.2°, 21.6±0.2°; 5.6±0.2°, 6.7±0.2°, 7.5±0.2°, 11.1±0.2°, 12.2±0.2°, 14.1±0.2°, 19.5±0.2°, 21.6±0.2°; 5.3±0.2°, 5.6±0.2°, 6.7±0.2°, 7.5±0.2°, 11.1±0.2°, 12.2±0.2°, 14.1±0.2°, 19.5±0.2°, 21.6±0.2°; 5.6±0.2°, 6.7±0.2°, 7.5±0.2°, 11.1±0.2°, 12.2±0.2°, 14.1±0.2°, 19.5±0.2°, 21.6±0.2°, 23.3±0.2°.

[0065] In some embodiments of the present invention, the crystal form 4 uses Cu-Kα radiation, and the characteristic X-ray diffraction peaks expressed in terms of 2θ angle and interplanar spacing d are shown in Table 13.

[0066] Table 13

[0067] In some embodiments of the present invention, the X-ray powder diffraction pattern of crystal form 4 is substantially as follows: Figure 27 As shown; its DSC spectrum is basically as follows Figure 28 As shown; its TGA spectrum is basically as follows. Figure 29 As shown.

[0068] In some embodiments of the present invention, the crystal form is (1S,3s)-3-amino-3-(5-((8R,15R)-2,2-difluoro-7-(methyl-d3)-6-carbonyl-6,7,8,15-tetrahydro-8,15-methylene[1,3]dioxazolo[4',5':3,4]benzo[1,2-f]benzo[4,5]imidazo[1,2-a][1,4]diacoxo-12-yl)pyrimidin-2-yl)-1-methylcyclobutane-1-formonitrile crystal form 5; The X-ray powder diffraction pattern of crystal form 5 shows a diffraction peak at 2θ of 5.9 ± 0.2°; or at 11.2 ± 0.2°; or at 11.6 ± 0.2°; or at 13.3 ± 0.2°; or at 15.5 ± 0.2°; or at 17.0 ± 0.2°; or at 17.3 ± 0.2°. The diffraction peak is present at 19.3±0.2°; or at 19.6±0.2°; or at 25.9±0.2°; preferably, any 2-5, 3-5, 3-6, 3-8, 5-8, 6-8, or 8-10 of the above diffraction peaks are included; more preferably, any 6, 7, 8, 9, or 10 of the above diffraction peaks are included.

[0069] In some embodiments of the present invention, the X-ray powder diffraction pattern of the crystal form 5 includes at least one or more diffraction peaks located at 2θ of 5.9±0.2°, 11.6±0.2°, 17.3±0.2°, and 19.3±0.2°, preferably including two such peaks, more preferably including three or four such peaks; even more preferably, it may also include at least one of 2θ of 11.2±0.2°, 13.3±0.2°, 15.5±0.2°, 17.0±0.2°, 19.6±0.2°, and 25.9±0.2°, preferably including two, three, four, five, or six such peaks; More preferably, the X-ray powder diffraction pattern of the crystal form 5 includes one or more diffraction peaks located at 2θ of 5.9±0.2°, 11.2±0.2°, 11.6±0.2°, 13.3±0.2°, 15.5±0.2°, 17.0±0.2°, 17.3±0.2°, 19.3±0.2°, 19.6±0.2°, and 25.9±0.2°; preferably, it includes diffraction peaks at any of 4, 5, 6, 7, 8, or 10 locations. More preferably, the X-ray powder diffraction pattern of the crystal form 5 may also include one or more diffraction peaks with 2θ values ​​of 16.1±0.2°, 17.6±0.2°, 19.1±0.2°, 20.0±0.2°, 22.2±0.2°, and 22.9±0.2°; preferably, it includes at least 2-3, 4-5, or 5-6 peaks; more preferably, it includes any 2, 3, 4, 5, or 6 peaks. For example, the X-ray powder diffraction pattern of crystal form 5 shows diffraction peaks at the following positions with a 2θ value: 5.9±0.2°, 11.2±0.2°, 17.0±0.2°, 17.3±0.2°, 19.3±0.2°, 25.9±0.2°; 5.9±0.2°, 11.2±0.2°, 15.5±0.2°, 17.0±0.2°, 17.3±0.2°, 19.3±0.2°, 25.9±0.2°; 5.9±0.2°, 11.2±0.2°, 13.3±0.2°, 17.0±0.2°, 17.3±0.2°, 19.3±0.2°, 25.9±0.2°; 5.9±0.2°, 11.2±0.2°, 17.0±0.2°, 17.3±0.2°, 19.3±0.2°, 19.6±0.2°, 25.9±0.2°; 5.9±0.2°, 11.2±0.2°, 17.0±0.2°, 17.3±0.2°, 19.3±0.2°, 22.2±0.2°, 25.9±0.2°; 5.9±0.2°, 11.2±0.2°, 13.3±0.2°, 15.5±0.2°, 17.0±0.2°, 17.3±0.2°, 19.3±0.2°, 25.9±0.2°; 5.9±0.2°, 11.2±0.2°, 15.5±0.2°, 17.0±0.2°, 17.3±0.2°, 19.3±0.2°, 19.6±0.2°, 25.9±0.2°; 5.9±0.2°, 11.2±0.2°, 13.3±0.2°, 17.0±0.2°, 17.3±0.2°, 19.3±0.2°, 22.2±0.2°, 25.9±0.2°; 5.9±0.2°, 11.2±0.2°, 11.6±0.2°, 13.3±0.2°, 15.5±0.2°, 17.0±0.2°, 17.3±0.2°, 19.3±0.2°, 25.9±0.2°; 5.9±0.2°, 11.2±0.2°, 11.6±0.2°, 15.5±0.2°, 17.0±0.2°, 17.3±0.2°, 19.3±0.2°, 22.2±0.2°, 25.9±0.2°.

[0070] In some embodiments of the present invention, the crystal form 5 uses Cu-Kα radiation, and the characteristic X-ray diffraction peaks expressed in terms of 2θ angle and interplanar spacing d are shown in Table 14.

[0071] Table 14

[0072] In some embodiments of the present invention, the X-ray powder diffraction pattern of crystal form 5 is substantially as follows: Figure 30 As shown; its DSC spectrum is basically as follows Figure 31 As shown; its TGA spectrum is basically as follows. Figure 32 As shown.

[0073] In certain embodiments of the present invention, the positions of the top ten diffraction peaks with relative intensities in the X-ray powder diffraction patterns of crystal forms 2, 4, and 5 of (1S,3s)-3-amino-3-(5-((8R,15R)-2,2-difluoro-7-(methyl-d3)-6-carbonyl-6,7,8,15-tetrahydro-8,15-methylene[1,3]dioxazolo[4',5':3,4]benzo[1,2-f]benzo[4,5]imidazo[1,2-a][1,4]diacoxin-12-yl)pyrimidin-2-yl)-1-methylcyclobutane-1-carboxynitrile are respectively... Figure 1 , Figure 6 and Figure 9 The 2θ error of the diffraction peak at the corresponding position is ±0.2°~±0.5°; preferably ±0.2°~±0.3°, and most preferably ±0.2°.

[0074] The present invention also provides a method for preparing an acidic salt of the compound or its stereoisomer as described above, or its crystal form, comprising the following steps: Method 1: 1) Weigh an appropriate amount of free base and dissolve it in a good solvent; 2) Weigh an appropriate amount of the counterion acid, dissolve it in an organic solvent or water, or add it directly; the amount of the counterion acid is preferably 1-3 times the equivalent, more preferably 1.2 or 2.1 equivalents; 3) Combine 1) and 2), stir to precipitate, or add a poor solvent and stir to precipitate; 4) Rapid centrifugation or static evaporation to obtain the target product; Method 2: 1) Weigh an appropriate amount of free base and suspend it in a poor solvent; 2) Weigh an appropriate amount of the counterion acid, dissolve it in an organic solvent or water, or add it directly to the solid counterion acid; the amount of the counterion acid is preferably 1-3 times the equivalent, more preferably 1.2 or 2.1 equivalents; 3) Combine 1) and 2) and stir to dissolve, continue stirring to precipitate, or add a poor solvent and stir to precipitate; 4) Rapid centrifugation or static evaporation to obtain the target product; in: The beneficial solvent is selected from one or more of methanol, acetone, ethyl acetate, isopropyl acetate, acetonitrile, ethanol, 88% acetone, tetrahydrofuran, 2-methyltetrahydrofuran, dichloromethane, 1,4-dioxane, benzene, toluene, isopropanol, n-butanol, isobutanol, N,N-dimethylformamide, N,N-dimethylacetamide, n-propanol, tert-butanol, 2-butanone, 3-pentanone, N-methylpyrrolidone, and water; preferably one or more of tert-butanol, acetone, ethyl acetate, 2-butanone, and 2-methyltetrahydrofuran. The organic solvent is selected from methanol, ethanol, ethyl acetate, dichloromethane, acetone, n-hexane, petroleum ether, benzene, toluene, chloroform, acetonitrile, carbon tetrachloride, dichloroethane, tetrahydrofuran, 2-butanone, 3-pentanone, heptane, methyl tert-butyl ether, isopropyl ether, 1,4-dioxane, tert-butanol, or N,N-dimethylformamide; preferably methanol, ethanol, acetone, or acetonitrile; the above-mentioned benign solvents and organic solutions must be miscible when used. The unsuitable solvent is selected from one or more of n-heptane, cyclohexane, n-hexane, n-pentane, water, ethyl acetate, methyl tert-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, acetone, isopropyl acetate, methyl isobutyl ketone, tert-butanol, toluene, or isopropyl ether; preferably one or more of water, heptane, methyl tert-butyl ether, or isopropyl ether; the above unsuitable solvents and organic solutions must be miscible when used; The aforementioned counterionic acid is an inorganic acid or an organic acid, wherein the inorganic acid is selected from hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, hydrofluoric acid, hydroiodic acid, or phosphoric acid; and the organic acid is selected from 2,5-dihydroxybenzoic acid, 1-hydroxy-2-naphtholic acid, acetic acid, dichloroacetic acid, trichloroacetic acid, acetoxyxamic acid, adipic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, benzoic acid, 4-acetaminobenzoic acid, 4-aminobenzoic acid, decanoic acid, hexanoic acid, caprylic acid, cinnamic acid, citric acid, cyclohexanesulfonic acid, camphorsulfonic acid, aspartic acid, camphoric acid, gluconic acid, glucuronic acid, glutamic acid, isoascorbic acid, lactic acid, malic acid, mandelic acid, pyroglutamic acid, tartaric acid, dodecyl sulfate, dibenzoic acid, etc. Acyl tartaric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galactobionic acid, gentian acid, glutaric acid, 2-ketoglutaric acid, glycolic acid, hippuric acid, hydroxyethyl sulfonic acid, lactobionic acid, ascorbic acid, aspartic acid, lauric acid, camphoric acid, maleic acid, malonic acid, methanesulfonic acid, 1,5-naphthalenedisulfonic acid, naphthalene-2-sulfonic acid, nicotinic acid, oleic acid, orotic acid, oxalic acid, palmitic acid, dihydroxynaphthalic acid, propionic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, thiocyanate, undecanoic acid, trifluoroacetic acid, benzenesulfonic acid, p-toluenesulfonic acid, or L-malic acid; preferably hydrochloric acid, p-toluenesulfonic acid, fumaric acid, phosphoric acid, or oxalic acid; most preferably hydrochloric acid and fumaric acid.

[0075] The present invention also provides a method for preparing the free base crystal form of the compound or its stereoisomer as described above, characterized by comprising the following steps: Method 1: 1) Weigh an appropriate amount of the free base of the compound and dissolve it in a good solvent; 2) Stir the solution obtained in 1) until solid precipitates, preferably at a temperature of 0~25℃; 3) Filter or rapidly centrifuge the suspension from 2) to remove the liquid and obtain the target product; Method 2: 1) Weigh an appropriate amount of the free base of the compound and dissolve it in a good solvent; 2) Add the antisolvent to the solution obtained in 1), and stir until a solid precipitates. Preferably, the temperature is 15~25℃ or -10~-5℃. 3) Filter or rapidly centrifuge the suspension from 2) to remove the liquid and obtain the target product; Method 3: 1) Weigh an appropriate amount of the free base of the compound and suspend it in a poor solvent. The preferred suspension density is 50~200 mg / mL. 2) Stir the suspension in 1), preferably at a temperature of 0~50℃; 3) Filter or rapidly centrifuge the suspension from 2) to remove the liquid and obtain the target product; in: The beneficial solvent is selected from one or more of methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, acetone, ethyl acetate, n-propyl acetate, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, dichloromethane, 1,4-dioxane, benzene, toluene, N,N-dimethylformamide, N,N-dimethylacetamide, 2-butanone, and 3-pentanone; preferably isopropanol. The undesirable solvent is selected from one or more of methyl tert-butyl ether, isopropyl ether, diethyl ether, n-hexane, n-heptane, cyclohexane, n-pentane, and water; preferably water, methyl tert-butyl ether, isopropyl ether, or diethyl ether.

[0076] The present invention also provides a pharmaceutical composition comprising a therapeutically effective amount of the free base crystal form, acid salt or crystal form of the compound or its stereoisomer as described above, and one or more pharmaceutically acceptable carriers or excipients.

[0077] The present invention also provides the use of the free base crystal form, acid salt or crystal form of the compound or its stereoisomer as described above, or the pharmaceutical composition as described above in the preparation of a medicament for treating and / or preventing TNFα-related diseases.

[0078] The present invention also provides the use of the free base crystal form, acid salt or crystal form of the compound or its stereoisomer as described above, or the pharmaceutical composition as described above in the preparation of a medicament for treating and / or preventing autoimmune diseases; preferably, the autoimmune disease is selected from rheumatoid arthritis, psoriatic arthritis, inflammatory bowel disease, psoriasis, Crohn's disease, ulcerative colitis, psoriasis, spondyloarthritis, plaque psoriasis, septic shock, ankylosing spondylitis, juvenile idiopathic arthritis, hidradenitis suppurativa, uveitis, systemic lupus erythematosus (lupus), axial spondyloarthritis, polymyositis, pemphigus, multiple sclerosis, neuromyelitis optica, primary cholangitis, autoimmune hepatitis, lupus nephritis, pulmonary hemorrhage-nephritis syndrome, autoimmune oophoritis, or autoimmune orchitis.

[0079] The present invention also provides a method for treating and / or preventing autoimmune diseases, comprising administering to a desired subject the free base crystal form, acid salt or crystal form of the compound or its stereoisomer as described above, or the pharmaceutical composition as described above, preferably, the autoimmune disease being selected from rheumatoid arthritis, psoriatic arthritis, inflammatory bowel disease, psoriasis, Crohn's disease, ulcerative colitis, psoriasis, spondyloarthritis, plaque psoriasis, septic shock, ankylosing spondylitis, juvenile idiopathic arthritis, hidradenitis suppurativa, uveitis, systemic lupus erythematosus (lupus), axial spondyloarthritis, polymyositis, pemphigus, multiple sclerosis, neuromyelitis optica, primary cholangitis, autoimmune hepatitis, lupus nephritis, pulmonary hemorrhage-nephritis syndrome, autoimmune oophoritis, or autoimmune orchitis.

[0080] Detailed description of the invention

[0081] "Pharmaceutical composition" means a mixture containing one or more of the compounds described herein or their physiologically / pharmacologically acceptable salts or prodrugs, along with other chemical components, such as physiologically / pharmacologically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to a living organism, thereby promoting the absorption of the active ingredient and the exertion of its biological activity.

[0082] "Medicinal salts" refer to the salts of the compounds of this invention, which are safe and effective when used in mammals and have the appropriate biological activity.

[0083] The term "alkyl" refers to a straight-chain or branched saturated aliphatic hydrocarbon group, which may optionally be substituted with one or more substituents. In certain embodiments, alkyl refers to a group having a carbon density of 1 to 20 (C). 1-20 ), 1 to 15 (C 1-15 ), 1 to 12 (C 1-12 ), 1 to 10 (C 1-10 ), 1 to 8 (C 1-8 ), 1 to 6 (C 1-6 ) or 1 to 3 (C 1-3 A straight-chain saturated hydrocarbon group with 3 to 20 carbon atoms, or a group with 3 to 20 carbon atoms. 3-20 ), 3 to 15 (C 3-15 ), 3 to 12 (C 3-12 ), 3 to 10 (C 3-10 ), 3 to 8 (C 3-8 ) or 3 to 6 (C 3-6 A branched saturated hydrocarbon group with 1 carbon atom. The straight-chain C group used here... 1-6 Alkyl and branched C 3-6 Alkyl groups are also called "lower alkyl groups". For example, C 1-6Alkyl groups refer to linear saturated monovalent hydrocarbon groups having 1 to 6 carbon atoms or branched saturated monovalent hydrocarbon groups having 3 to 6 carbon atoms. In one embodiment, the C... 1-6 The alkyl group contains 1 to 6 carbon atoms (e.g., 1, 2, 3, 4, 5, 6). Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2, 3-Dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched isomers thereof. In one embodiment, the alkyl group is an optionally substituted alkyl group as described elsewhere herein.

[0084] The term "alkylene" refers to an alkyl group in which one hydrogen atom is further substituted, wherein "alkyl" is defined as described above. Non-limiting examples of "alkylene" include methylene (-CH2-), ethylene (-(CH2)2-), propylene (-(CH2)3-), or butylene (-(CH2)4-). In one embodiment, the alkylene is an optionally substituted alkyl group as described elsewhere herein.

[0085] The term "alkenyl" refers to a straight-chain or branched unsaturated aliphatic hydrocarbon group containing at least one carbon-carbon double bond, which can be located at any position within the alkenyl group, and the alkenyl group may optionally be substituted by one or more substituents. In a particular embodiment, the alkenyl group has a carbon content of 2 to 20 (C₂O₃). 2-20 ), 2 to 15 (C 2-15 ), 2 to 12 (C 2-12 ), 2 to 10 (C 2-10 ), 2 to 8 (C 2-8 ), 2 to 6 (C 2-6 ) or 2 to 4 (C2-4 A straight-chain unsaturated hydrocarbon group with 3 to 20 carbon atoms, or a hydrocarbon group with 3 to 20 carbon atoms. 3-20 ), 3 to 15 (C 3-15 ), 3 to 12 (C 3-12 ), 3 to 10 (C 3-10 ), 3 to 8 (C 3-8 ) or 3 to 6 (C 3-6 A branched unsaturated hydrocarbon group with 16 carbon atoms. Unless otherwise specified, the term "alkenyl" as used herein includes both straight-chain and branched alkenyl groups. For example, C 2-6 Alkenyl refers to a straight-chain unsaturated hydrocarbon group having 2 to 6 carbon atoms or a branched unsaturated hydrocarbon group having 3 to 6 carbon atoms. In one embodiment, the C 2-6 Alkenyl groups contain 2 to 6 (e.g., 2, 3, 4, 5, or 6) carbon atoms. Non-limiting examples of alkenyl groups include: , , , , or Those skilled in the art will understand that the term "alkenyl" may also include groups having "cis" and "trans" configurations, or alternatively, "E" and "Z" configurations. In one embodiment, the alkenyl is an optionally substituted alkenyl as described elsewhere herein.

[0086] The term "alkynyl" refers to a straight-chain or branched unsaturated aliphatic hydrocarbon group containing at least one carbon-carbon triple bond, which can be located at any position within the alkynyl group. The alkynyl group may optionally be substituted by one or more substituents. In a particular embodiment, the alkynyl group has a carbon content of 2 to 20 (C₂O₃). 2-20 ), 2 to 15 (C 2-15 ), 2 to 12 (C 2-12 ), 2 to 10 (C 2-10 ), 2 to 8 (C 2-8 ), 2 to 6 (C 2-6 ) or 2 to 4 (C 2-4 A straight-chain unsaturated hydrocarbon group with 3 to 20 carbon atoms, or a hydrocarbon group with 3 to 20 carbon atoms. 3-20 ), 3 to 15 (C 3-15 ), 3 to 12 (C 3-12 ), 3 to 10 (C 3-10 ), 3 to 8 (C 3-8 ) or 3 to 6 (C 3-6 A branched unsaturated hydrocarbon group with 12 carbon atoms. Unless otherwise specified, the term "alkynyl" as used herein includes both straight-chain and branched alkynyl groups. For example, C 2-6Alkyne refers to a straight-chain unsaturated hydrocarbon group having 2 to 6 carbon atoms or a branched unsaturated hydrocarbon group having 3 to 6 carbon atoms. In one embodiment, the C 2-6 The alkynyl group contains 2 to 6 (e.g., 2, 3, 4, 5, 6) carbon atoms. Non-limiting examples of the alkynyl group include: , , or In one embodiment, the alkynyl group is an optionally substituted alkynyl group as described elsewhere herein.

[0087] The term "cycloalkyl" refers to a monocyclic or polycyclic (two or more) cyclic group of a saturated or partially unsaturated aliphatic hydrocarbon, which may optionally be substituted with one or more substituents. In certain embodiments, the cycloalkyl ring comprises 3 to 20 (C 3-20 ), 3 to 12 (C 3-12 ), 3 to 8 (C 3-8 ) or 3 to 6 (C 3-6 ) carbon atoms; in one embodiment, the cycloalkyl ring comprises 6 to 14 (C 6-14 ) or 7 to 10 (C 7-10 It has 10 carbon atoms; it may contain one or more double bonds, but does not have a fully conjugated π-electron system. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cyclohepttrienyl, or cyclooctyl, etc.; polycyclic cycloalkyl groups include spirocyclic alkyl, fused cycloalkyl, and bridged cycloalkyl groups in one embodiment. In one embodiment, the cycloalkyl group is an optionally substituted cycloalkyl group or an optionally fused cycloalkyl group with a heterocyclic group, aryl group, or heteroaryl group as described elsewhere herein, and non-limiting examples include indanyl, tetrahydronaphthyl, benzocycloheptyl, etc.

[0088] The term "spirocycloalkyl" refers to an aliphatic hydrocarbon polycyclic group that shares a single carbon atom (called a spiro atom) between its monocyclic rings. It may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. In certain embodiments, the spirocycloalkyl group comprises 5 to 20 carbon atoms. 5-20 ), 6 to 14 (C 6-14 ) or 7 to 10 (C 7-10 (e.g., 7, 8, 9, 10) carbon atoms. Spirocycloalkyl groups are classified as monospirocycloalkyl, bispirocycloalkyl, or polyspirocycloalkyl groups based on the number of shared spiro atoms between rings, with one embodiment being monospirocycloalkyl and bispirocycloalkyl. In one embodiment, it is a 4-membered / 4-membered, 3-membered / 5-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 5-membered, or 5-membered / 6-membered monospirocycloalkyl. In one embodiment, the spirocycloalkyl group is an optionally substituted spirocycloalkyl group described elsewhere herein. Non-limiting examples of spirocycloalkyl groups include: .

[0089] The term "fused-cycle alkyl" refers to a fully carbon polycyclic group in which each ring in a system shares an adjacent pair of carbon atoms with the other rings in the system, wherein one or more rings may contain one or more double bonds, but no ring has a fully conjugated π-electron system. In a particular embodiment, the fused-cycle alkyl comprises 5 to 20 (C 5-20 ), 6 to 14 (C 6-14 ) or 7 to 10 (C 7-10 (e.g., 7, 8, 9, 10) carbon atoms. Depending on the number of rings, they can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic fused-ring alkyl groups. In one embodiment, they are bicyclic or tricyclic, and in another embodiment, they are 3-membered / 5-membered, 4-membered / 5-membered, 5-membered / 5-membered, or 5-membered / 6-membered bicyclic alkyl groups. In one embodiment, the fused-ring alkyl group is an optionally substituted fused-ring alkyl group described elsewhere herein or an fused-ring alkyl group optionally fused with a heterocyclic group, aryl group, or heteroaryl group. Non-limiting examples of fused-ring alkyl groups include: , , , , , or .

[0090] The term "bridged cycloalkyl" refers to a fully carbon polycyclic group in which any two rings share two non-directly bonded carbon atoms. It may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. In certain embodiments, the bridged cycloalkyl group comprises 5 to 20 (C...) 5-20 ), 6 to 14 (C 6-14 ) or 7 to 10 (C 7-10 (e.g., 7, 8, 9, 10) carbon atoms. Depending on the number of rings, they can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic bridged alkyl groups, preferably bicyclic or tricyclic. In one embodiment, the bridged alkyl group is an optionally substituted bridged alkyl group described elsewhere herein. Non-limiting examples of bridged alkyl groups include: .

[0091] The term "heterocyclic group" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon group, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen, boron, phosphorus, or sulfur, wherein the nitrogen, phosphorus, or sulfur atom may optionally be oxidized, the nitrogen atom may optionally be quaternized, the ring carbon atom may optionally be substituted with oxygen, excluding the -OO- or -OS- ring moiety, and the remaining ring atoms are carbon, which may contain one or more double bonds but does not have a fully conjugated π-electron system. In a particular embodiment, the heterocyclic group comprises 3 to 20, 3 to 12, 3 to 8, or 3 to 6 ring atoms, wherein 1 to 4 are heteroatoms; in one embodiment, the heterocyclic group comprises 3 to 6, 4 to 6, 3 to 8, 3 to 10, 6 to 10, or 7 to 11 ring atoms; in one embodiment, the heterocyclic group comprises 3 to 8 (e.g., 3, 4, 5, 6, 7, 8) ring atoms. Non-limiting examples of monocyclic heterocyclic groups include tetrahydropyrrole, azahexacyclic butyl, oxacyclobutyl, oxacyclohexyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiophenyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrole, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, and pyranyl. Polycyclic heterocyclic groups include spiroheterocyclic, fused heterocyclic, and bridged heterocyclic groups. In one embodiment, the heterocyclic group is optionally substituted as described elsewhere herein, or is a heterocyclic group further cyclically linked to other cycloalkyl, heterocyclic, aryl, and heteroaryl groups by any two or more atoms on the ring.

[0092] The term "spiroheterocyclic group" refers to a polycyclic heterocyclic group in which one or more ring atoms share a single atom (called a spiro atom), wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen, boron, phosphorus, or sulfur, and the remaining ring atoms are carbon. It may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. In certain embodiments, the spiroheterocyclic group comprises 5 to 20 or 6 to 14 ring atoms; in one embodiment, it comprises 7 to 11 (e.g., 7, 8, 9, 10, 11) ring atoms; spiroheterocyclic groups are classified as monospirocyclic, bispirocyclic, or multispirocyclic groups according to the number of spiro atoms shared between the rings; monospirocyclic and bispirocyclic groups are preferred; in one embodiment, the spiroheterocyclic group is a 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 5-membered, or 5-membered / 6-membered monospirocyclic group; in one embodiment, the spiroheterocyclic group is an optionally substituted spiroheterocyclic group described elsewhere herein; non-limiting examples of spiroheterocyclic groups include: , , , , , , , , , , , , or .

[0093] The term "fused heterocyclic group" refers to a polycyclic heterocyclic group in which each ring in a system shares an adjacent pair of atoms with other rings in the system. One or more rings may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. One or more ring atoms are heteroatoms selected from nitrogen, oxygen, boron, phosphorus, or sulfur, and the remaining ring atoms are carbon. In a particular embodiment, the fused heterocyclic group comprises 5 to 20 or 6 to 14 ring atoms, and in one embodiment comprises 7 to 10 (e.g., 7, 8, 9, 10) ring atoms; it can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic fused heterocyclic groups depending on the number of constituent rings; bicyclic or tricyclic is preferred; in one embodiment, it is a 5-membered / 5-membered or 5-membered / 6-membered bicyclic fused heterocyclic group; in one embodiment, the fused heterocyclic group is optionally substituted as described elsewhere herein, or a fused heterocyclic group that can be fused with cycloalkyl, heterocyclic, aryl, or heteroaryl groups; non-limiting examples of fused heterocyclic groups include: , , , , , , , , , , , , , , , , , , , , , or .

[0094] The term "bridged heterocyclic group" refers to a polycyclic heterocyclic group in which any two rings share two non-directly bonded atoms. It may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. One or more ring atoms are heteroatoms selected from nitrogen, oxygen, boron, phosphorus, or sulfur, and the remaining ring atoms are carbon. In certain embodiments, the bridged heterocyclic group comprises 5 to 20 or 6 to 14 ring atoms; in one embodiment, it comprises 7 to 10 (e.g., 7, 8, 9, 10) ring atoms; depending on the number of constituent rings, it can be classified as a bicyclic, tricyclic, tetracyclic, or polycyclic bridged heterocyclic group; preferably bicyclic, tricyclic, or tetracyclic; in one embodiment, it is bicyclic or tricyclic; in one embodiment, the bridged heterocyclic group is an optionally substituted bridged heterocyclic group described elsewhere herein; non-limiting examples of bridged heterocyclic groups include: , , , , , , , or .

[0095] The term "aryl" refers to an all-carbon monocyclic or fused polycyclic (i.e., a ring sharing adjacent carbon atom pairs) group containing at least one conjugated π-electron system, which may optionally be substituted by one or more substituents. In certain embodiments, the aryl group comprises 6 to 20, 6 to 14, or 6 to 10 ring atoms; in one embodiment, the aryl group may further refer to a bicyclic, tricyclic, or tetracyclic ring system, wherein at least one ring is an aromatic ring, and the other rings may be saturated, partially unsaturated carbon rings, or rings containing one or more heteroatoms independently selected from O, S, and N; in one embodiment, the aryl group is selected from benzo5-10-membered heteroaryl, benzo3-10-membered cycloalkyl, or benzo3-10-membered heterocyclic groups. In one embodiment, the aryl group is selected from benzo5-6-membered heteroaryl, benzo3-6-membered cycloalkyl, or benzo3-6-membered heterocyclic groups, wherein the heterocyclic group is a heterocyclic group containing 1 to 3 nitrogen, oxygen, or sulfur atoms. Non-limiting examples include phenyl, naphthyl, fluorenyl, chamomilecycloyl, anthraceneyl, phenanthryl, pyrene, biphenyl, terphenyl, dihydronaphthyl, indene, tetrahydronaphthyl (naphthyl), , , , , , , , , , , , , and .

[0096] The term "arylene" refers to a divalent aryl group formed by further substitution of one hydrogen atom of an aryl group, wherein the arylene group may be optionally substituted or unsubstituted, as defined above for aryl groups.

[0097] The term "heteroaryl" refers to an optionally substituted monocyclic, polycyclic group or ring system comprising at least one aromatic ring having one or more heteroatoms independently selected from O, S, and N. In certain embodiments, the heteroaryl comprises 5 to 20, 5 to 15, or 5 to 10 ring atoms, of which 1 to 4 are heteroatoms; in one embodiment, the heteroaryl comprises 5 or 6 ring atoms; in certain embodiments, the heteroaryl may further refer to a bicyclic, tricyclic, or tetracyclic ring, wherein at least one ring is an aromatic ring having one or more heteroatoms independently selected from O, S, and N, and the other rings may be saturated, partially unsaturated carbocyclic rings, or rings comprising one or more heteroatoms independently selected from O, S, and N. In one embodiment, the heteroaryl group is selected from heteroaryl-6-10 aryl, heteroaryl-3-10 cycloalkyl, or heteroaryl-3-10 heterocyclic group; in a further embodiment, the heteroaryl group is selected from 5- or 6-membered heteroaryl-6-10 aryl, 5- or 6-membered heteroaryl-3-6 cycloalkyl, or 5- or 6-membered heteroaryl-3-6 heterocyclic group, wherein the heterocyclic group is a heterocyclic group containing 1-3 nitrogen atoms, oxygen atoms, or sulfur atoms. Non-limiting examples include: furanyl, imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrroloyl, thiadiazolyl, thiazolyl, thiophene, tetrazolyl, triazinyl, triazolyl, benzofuranyl, benzimidazolyl, benziisoxazolyl, benzopyranyl, benzothiadiazolyl, benzothiaphenyl, benzobenzenethio, benzothiaphenyl, benzotriazolyl, imidazopyridyl, imidazothiazolyl Indazinyl, indolyl, inzolyl, isobenzofuranyl, isobenzothiophenyl, isoindolyl, isoquinolinyl, naphridinyl, oxazolopyridyl, phthalazinyl, pteridinyl, purine, pyridopyridyl, pyrrolopyridyl, quinolinyl, quinoxolinyl, quinazolinyl, thiadiazopyrimidinyl, thienenopyridyl, acridineyl, benzoindolyl, carbazole, biphenylfuranyl, phenanthrololinyl, phenanthidyl, phenpyrazinyl, phenazinyl, phenthiazinyl, phenoxazinyl, xanthonyl, , , , , , , , , and .

[0098] The term "heteroaryl" refers to a divalent heteroaryl group formed by further substitution of one hydrogen atom of a cycloalkyl group, wherein the heteroaryl group may be optionally substituted or unsubstituted, as defined above.

[0099] The term "heteroalkyl" refers to a stable straight-chain or branched, or cyclic, hydrocarbon group, or a combination thereof, consisting of the indicated number of carbon atoms and one or more (one to three in one embodiment) heteroatoms selected from O, N, Si, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen heteroatom may optionally be quaternized. In one embodiment, the heteroatoms O, N, and S may be placed at any internal position within the heteroalkyl group. In one embodiment, the heteroatom Si may be placed at any position within the heteroalkyl group (e.g., internal or terminal positions), including positions where the alkyl group is attached to the remainder of the molecule. Non-limiting examples include: -CH2-CH2-O-CH3, -CH2-CH2-NH-CH3, -CH2-CH2-N(CH3)-CH3, -CH2-S-CH2-CH3, -CH2-CH2-S(O)-CH3, -CH2-CH2-S(O)2-CH3, -CH=CH-O-CH3, -Si(CH3)3, -CH2-CH=N-OCH3, and -CH=CH-N(CH3)-CH3. At most two heteroatoms can be consecutive, for example, -CH2-NH-O-CH3 and -CH2-O-Si(CH3)3. In certain embodiments, the heteroalkyl group is an optionally substituted heteroalkyl group described elsewhere herein.

[0100] The term "alkoxy" refers to -O- (alkyl) and -O- (unsubstituted cycloalkyl), wherein the definition of alkyl or cycloalkyl is as described above. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentoxy, or cyclohexyloxy. In one embodiment, the alkoxy group is an optionally substituted alkoxy group as described elsewhere herein.

[0101] The term "alkylacyl" refers to -C(O)-alkyl, where the definition of alkyl is as described above.

[0102] The term "haloalkyl" refers to an alkyl group substituted with one or more halogens, wherein the definition of alkyl is as described above. Non-limiting examples of said haloalkyl groups include: trifluoromethyl, -CH2CF3, or .

[0103] The term “haloalkoxy” refers to an alkoxy group that has been substituted with one or more halogens, where the definition of an alkoxy group is as described above.

[0104] The term "hydroxyalkyl" refers to an alkyl group that has been substituted with a hydroxyl group, where the definition of alkyl is as described above.

[0105] The term "alkathio" refers to -S- (alkyl) and -S- (unsubstituted cycloalkyl), wherein the definition of alkyl or cycloalkyl is as described above. Non-limiting examples of alkathio groups include: methylthio, ethylthio, propylthio, butylthio, cyclopropylthio, cyclobutylthio, cyclopentylthio, or cyclohexylthio. In one embodiment, the alkathio group is an optionally substituted alkathio group described elsewhere herein.

[0106] The term "haloalkylthio" refers to an alkylthio group substituted with one or more halogens, wherein the definition of alkylthio is as described above.

[0107] The term "alkenyl carbonyl" refers to -C(O)-(alkenyl), where alkenyl is defined as previously stated. Non-limiting examples of alkenyl carbonyl include vinyl carbonyl, propenyl carbonyl, or butenyl carbonyl. In one embodiment, the alkenyl carbonyl is an optionally substituted alkenyl carbonyl as described elsewhere herein.

[0108] The term "aminocarbonyl" refers to NH2-C(O)-.

[0109] The term "alkylaminocarbonyl" refers to an aminocarbonyl group (NH2-C(O)-) in which one or both hydrogen atoms are replaced by an alkyl group, as defined above.

[0110] The term "alkylamino" refers to an amino group in which one or both of the two hydrogen atoms are replaced by an alkyl group, as defined above.

[0111] The term "carbonyl" refers to the -C(O)-, -(CO)-, or -C(=O)- group. All designations are interchangeable in the specification.

[0112] The term "hydrogen" includes protons ( 1 H), deuterium ( 2 H), tritium ( 3 H) and / or mixtures thereof. In certain embodiments, one or more hydrogen-occupied sites in the compound may be enriched with deuterium and / or tritium. Such isotopically enriched analogs can be prepared from suitable isotopically labeled starting materials available from commercial sources or by known literature procedures.

[0113] The alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, arylene, heteroaryl, heteroarylene, heteroalkyl, alkoxy, alkylthio, hydroxyalkyl, alkenylcarbonyl, aminocarbonyl, alkylaminocarbonyl, alkylamino, and alkylacyl groups may be substituted or unsubstituted. In one embodiment, the substituent is selected from one or more of the following groups: alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, alkylacyl, halogen, mercapto, hydroxyl, nitro, cyano, azide, oxime, phosphate ester, oxo, thio, carboxyl, carboxylic acid ester, cycloalkyl, heterocyclic, aryl, heteroaryl, heterocycloalkoxy, cycloalkylthio, or heterocycloalkylthio.

[0114] The different terms such as "X is selected from A, B, or C", "X is selected from A, B, and C", "X is A, B, or C", and "X is A, B, and C" all express the same meaning, that is, X can be any one or more of A, B, and C.

[0115] "Optional" or "optionally" means that the event or environment described below may but does not have to occur, and the description includes the possibility or absence of such event or environment. For example, "optionally alkyl-substituted heterocyclic group" means that the alkyl group may but does not have to be present, and the description includes cases where the heterocyclic group is substituted with an alkyl group and cases where the heterocyclic group is not substituted with an alkyl group.

[0116] Linking substituents are described in various parts of this invention. When the structure clearly requires a linking group, the Markush variable listed for that group should be understood as the linking group. For example, if the structure requires a linking group and the Markush group definition for that variable lists "alkyl" or "aryl," it should be understood that "alkyl" or "aryl" represents a linked alkylene group or an arylene group, respectively.

[0117] "Substituted" means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, provided that the valence state of the particular atom is normal and the substituted compound is stable in one embodiment and in another. When the substituent is oxo (i.e., =O), it means that two hydrogen atoms are replaced. The term "optionally substituted" means that it may or may not be substituted, and unless otherwise specified, the type and number of substituents can be arbitrary on a chemically feasible basis. It goes without saying that substituents are only in their possible chemical positions, and those skilled in the art can determine (by experiment or theory) possible or impossible substitutions without much effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when combined with a carbon atom having an unsaturated bond (such as an alkene).

[0118] Unless otherwise stated, the indefinite articles “a” and “an” and the definite article “the” in this specification and claims include both plural and singular forms.

[0119] "Stereoisomers" encompass all enantiomers / non-corresponding isomers / stereoisomers of the present invention, as well as enantiomers / non-corresponding isomers / stereoisomers enriched in this invention.

[0120] "Stereoisopure" refers to a composition containing one stereoisomer of a compound but substantially lacking another stereoisomer of that compound. For example, a stereoisopure composition of a compound having one chiral center will substantially lack the opposing enantiomer of that compound. A stereoisopure composition of a compound having two chiral centers will substantially lack other diastereomers of that compound. A typical stereoisomeric pure compound comprises, by mass, more than about 80% of one stereoisomer of the compound and less than about 20% of another stereoisomer of the compound; more than about 90% of one stereoisomer of the compound and less than about 10% of another stereoisomer of the compound; more than about 95% of one stereoisomer of the compound and less than about 5% of another stereoisomer of the compound; more than about 97% of one stereoisomer of the compound and less than about 3% of another stereoisomer of the compound; or more than about 99% of one stereoisomer of the compound and less than about 1% of another stereoisomer of the compound.

[0121] "Stereoisomeric enrichment" refers to a composition containing a stereoisomer of a compound at a mass content greater than about 55%, about 60%, about 70%, or about 80%.

[0122] "Enantiomerically pure" refers to a stereoisomerically pure composition of a compound having a single chiral center. Similarly, the term "enantiomerically enriched" refers to a stereoisomerically enriched composition of a compound having a single chiral center.

[0123] "Optical activity" and "enantiomeric activity" refer to a molecular combination having an enantiomer excess of not less than about 50%, not less than about 70%, not less than about 80%, not less than about 90%, not less than about 91%, not less than about 92%, not less than about 93%, not less than about 94%, not less than about 95%, not less than about 96%, not less than about 97%, not less than about 98%, not less than about 99%, not less than about 99.5%, or not less than about 99.8%. In a particular embodiment, the compound comprises about 95% or more of the desired enantiomer or diastereomer by weight of the racemic compound and about 5% or less of the subpreferred enantiomer or diastereomer.

[0124] In describing optically active compounds, the prefixes R and S are used to indicate the absolute configuration of the molecule relative to its chiral center. (+) and (-) are used to indicate the optical rotation of the compound, i.e., the direction of the plane of polarized light rotated by the optically active compound. The prefix (-) indicates that the compound is levorotatory, i.e., the compound rotates the plane of polarized light to the left or counterclockwise. The prefix (+) indicates that the compound is dextrorotatory, i.e., the compound rotates the plane of polarized light to the right or clockwise. However, the signs (+) and (-) for optical rotation are independent of the absolute configuration R and S of the molecule. Attached Figure Description

[0125] Figure 1 This is the XRPD image of hydrochloride crystal form A in Example 6.

[0126] Figure 2 This is the DSC diagram of hydrochloride crystal form A in Example 6.

[0127] Figure 3 This is a TGA image of hydrochloride crystal form A in Example 6.

[0128] Figure 4 This is the XRPD image of toluenesulfonate crystal form A in Example 6.

[0129] Figure 5 This is the DSC diagram of p-toluenesulfonate crystal form A in Example 6.

[0130] Figure 6 This is a TGA image of toluenesulfonate crystal form A from Example 6.

[0131] Figure 7 This is the XRPD image of fumarate crystal form A in Example 6.

[0132] Figure 8 This is the DSC diagram of fumarate crystal form A in Example 6.

[0133] Figure 9 This is a TGA image of fumarate crystal form A in Example 6.

[0134] Figure 10 This is the XRPD image of fumarate crystal form B in Example 6.

[0135] Figure 11 This is the DSC diagram of fumarate crystal form B in Example 6.

[0136] Figure 12 This is a TGA image of fumarate crystal form B from Example 6.

[0137] Figure 13 This is the XRPD image of hydrochloride crystal form A in Example 2.

[0138] Figure 14This is the DSC diagram of hydrochloride crystal form A in Example 2.

[0139] Figure 15 This is a TGA image of hydrochloride crystal form A in Example 2.

[0140] Figure 16 This is the XRPD diagram of sulfate crystal form A in Example 2.

[0141] Figure 17 This is the DSC diagram of sulfate crystal form A in Example 2.

[0142] Figure 18 This is a TGA image of sulfate crystal form A in Example 2.

[0143] Figure 19 This is the XRPD image of hydrobromide crystal form A in Example 2.

[0144] Figure 20 This is the DSC diagram of hydrobromide crystal form A in Example 2.

[0145] Figure 21 This is a TGA image of hydrobromide crystal form A in Example 2.

[0146] Figure 22 This is an XRPD image of crystal form 2 of compound 6 in Example 6.

[0147] Figure 23 This is the DSC diagram of crystal form 2 of compound 6 in Example 6.

[0148] Figure 24 This is a TGA image of crystal form 2 of compound 6 in Example 6.

[0149] Figure 25 The image shows a DSC diagram of crystal form 3 of compound 6 in Example 6.

[0150] Figure 26 This is a TGA image of crystal form 3 of compound in Example 6.

[0151] Figure 27 This is an XRPD image of crystal form 4 of compound in Example 6.

[0152] Figure 28 This is the DSC diagram of crystal form 4 of compound in Example 6.

[0153] Figure 29 This is a TGA image of crystal form 4 of compound in Example 6.

[0154] Figure 30 This is an XRPD image of crystal form 5 of compound 6 in Example 6.

[0155] Figure 31 This is a DSC diagram of crystal form 5 of compound 6 in Example 6.

[0156] Figure 32 This is a TGA image of crystal form 5 of compound 6 in Example 6. Detailed Implementation

[0157] The present invention is further described below with reference to embodiments, but these embodiments are not intended to limit the scope of the present invention.

[0158] I. Preparation of Compounds

[0159] Example

[0160] The structures of the compounds of this invention were determined by nuclear magnetic resonance (NMR) and / or liquid chromatography-mass spectrometry (LC-MS). NMR chemical shifts ( The values ​​are given in parts per million (ppm). NMR measurements were performed using a Bruker AVANCE-400 NMR spectrometer, with deuterated dimethyl sulfoxide (DMSO) as the solvent. d 6 ), deuterated methanol (CD3OD) and deuterated chloroform (CDCl3), with tetramethylsilane (TMS) as the internal standard.

[0161] LC-M determination was performed using an Agilent 1200 Infinity Series mass spectrometer. HPLC determination was performed using an Agilent 1200DAD high-performance liquid chromatograph (Sunfire C18 150 × 4.6 mm column) and a Waters 2695-2996 high-performance liquid chromatograph (Gimini C). 18 150 × 4.6 mm chromatographic column).

[0162] Thin-layer chromatography (TLC) uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates. The standard size for TLC is 0.15 mm to 0.20 mm, while the standard size for separating and purifying products using TLC is 0.4 mm to 0.5 mm. Column chromatography generally uses Yantai Huanghai 200-300 mesh silica gel as the carrier.

[0163] The starting materials used in the embodiments of the present invention are known and commercially available, or can be synthesized using or in accordance with methods known in the art.

[0164] Unless otherwise specified, all reactions in this invention are carried out under continuous magnetic stirring, in a dry nitrogen or argon atmosphere, using a dry solvent, and the reaction temperature is expressed in degrees Celsius.

[0165] Example 1

[0166] (8 R 15 R)-12-(2-(1-aminocyclobutyl)pyrimidin-5-yl)-2,2-difluoro-7-methyl-7,8-dihydro-8,15-methylene[1,3]dioxazolo[4',5':3,4]benzo[1,2-f]benzo[4,5]imidazo[1,2-a][1,4]diacoxine-6(15H)-one

[0167] Step 1: Preparation of 5-bromo-2,2-difluorobenzo[d][1,3]dioxazole-4-carboxaldehyde

[0168] 5-Bromo-2,2-difluorobenzo[d][1,3]dioxazole (10 g, 42.2 mmol) was dissolved in dry THF (100 mL) under dry ice and acetone bath conditions. LDA (31.6 mL, 63.3 mmol) was added dropwise while stirring for 1 hour. Dry DMF (4.9 mL, 63.3 mmol) was added dropwise while stirring continued for another hour. The reaction was quenched with saturated ammonium chloride solution. The reaction mixture was extracted with EtOAc (150 mL x 3), washed with saturated sodium chloride solution (200 mL x 3), and the organic phase was collected. The solution was dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by silica gel column chromatography to give the title compound (9.2 g, 82.3%). MS m / z (ESI): 265.1 [M+H] + .

[0169] Step Two: ( S , E Preparation of 5-bromo-2,2-difluorobenzo[d][1,3]dioxazol-4-yl)methylene)-2-methylpropane-2-sulfinamide

[0170] 5-Bromo-2,2-difluorobenzo[d][1,3]dioxazole-4-carboxaldehyde (9.2 g, 34.7 mmol) and ( S 5-tert-butylsulfinamide (5.05 g, 41.7 mmol) was dissolved in THF (100 mL) solution, and tetraethyl titanate (11.88 g, 52.1 mmol) was added dropwise while stirring for 16 hours. After the reaction was complete, the reaction mixture was extracted with EtOAc (150 mL x 3), washed with saturated sodium chloride aqueous solution (200 mL x 3), and the organic phase was collected, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by silica gel column chromatography to give the title compound (12 g, 93.9%). m / z(ESI): 368.1 [M+H] + .

[0171] Step 3: N-(( R Preparation of 1-(5-bromo-2,2-difluorobenzo[d][1,3]dioxazol-4-yl)but-3-en-1-yl)-2-methylpropane-2-sulfinamide

[0172] Under an ice water bath, ( S , E )-N-((5-bromo-2,2-difluorobenzo[d][1,3]dioxazol-4-yl)methylene)-2-methylpropane-2-sulfinamide (10 g, 27.2 mmol) was dissolved in dry DCM (200 mL), and propenyl magnesium bromide (40.7 mL, 40.7 mmol, 1 mol / L in Et2O) was added dropwise while stirring for 1 hour. The reaction was quenched with saturated ammonium chloride aqueous solution, the reaction mixture was extracted with DCM (150 mL x 3), washed with saturated sodium chloride aqueous solution (200 mL x 3), the organic phase was collected, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by silica gel column chromatography to give the title compound (8.3 g, 74.5%). MS m / z (ESI): 410.1 [M+H] + .

[0173] Step 4: ( R Preparation of 1-(5-bromo-2,2-difluorobenzo[d][1,3]dioxazol-4-yl)but-3-en-1-amine

[0174] N-(( R 1-(5-bromo-2,2-difluorobenzo[d][1,3]dioxazol-4-yl)but-3-en-1-yl)-2-methylpropane-2-sulfinamide (8.3 g, 20.2 mmol) was dissolved in dioxane hydrochloride solution (50 mL, 4.0 N) and stirred for 1 hour. The reaction mixture was concentrated and extracted with EtOAc (150 mL x 3), washed with saturated sodium bicarbonate aqueous solution (200 mL x 3), washed with saturated sodium chloride aqueous solution (200 mL x 3), and the organic phase was collected, dried over anhydrous sodium sulfate, filtered, concentrated, and dried to give the title compound (5.5 g, 88.8%). MS m / z (ESI): 306.1 [M+H] + .

[0175] Step 5: (R Preparation of 5-N-(1-(5-bromo-2,2-difluorobenzo[d][1,3]dioxazol-4-yl)but-3-en-1-yl)-5-chloro-2-nitroaniline

[0176] Will( R 1-(5-bromo-2,2-difluorobenzo[d][1,3]dioxazol-4-yl)but-3-en-1-amine (5.5 g, 18 mmol), 4-chloro-2-fluoro-1-nitrobenzene (3.78 g, 21.6 mmol), and potassium carbonate (9.93 g, 71.9 mmol) were suspended in DMF (100 mL) solution and heated to 80 °C with stirring for 16 hours. The reaction mixture was allowed to return to room temperature, and the reaction solution was extracted with EtOAc (150 mL x 3), washed with saturated sodium chloride aqueous solution (200 mL x 3), and the organic phase was collected, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by silica gel column chromatography to give the title compound (5 g, 60.3%). m / z (ESI): 461.1 [M+H] + .

[0177] Step 6: ( R Preparation of 3-(5-bromo-2,2-difluorobenzo[d][1,3]dioxazol-4-yl)-3-((5-chloro-2-nitrophenyl)amino)propionaldehyde

[0178] Will( R 5 g (10.8 mmol) of 5-N-(1-(5-bromo-2,2-difluorobenzo[d][1,3]dioxazol-4-yl)but-3-en-1-yl)-5-chloro-2-nitroaniline was dissolved in a mixture of THF (150 mL) and water (150 mL). After adding potassium osmium tetroxide dihydrate (169 mg, 0.54 mmol), the mixture was stirred for 1 hour. Then, sodium periodate (7 g, 32.5 mmol) was added, and the mixture was stirred for another 16 hours. The reaction mixture was extracted with EtOAc (150 mL x 3), washed with saturated sodium chloride aqueous solution (200 mL x 3), and the organic phase was collected, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by silica gel column chromatography to obtain the title compound (4.5 g, 89.6%). m / z (ESI): 463.1 [M+H] + .

[0179] Step 7: (4) RPreparation of 4-(5-bromo-2,2-difluorobenzo[d][1,3]dioxazol-4-yl)-4-((5-chloro-2-nitrophenyl)amino)-2-((trimethylsilyl)oxo)butyronitrile

[0180] Under nitrogen protection, ( R 3-(5-bromo-2,2-difluorobenzo[d][1,3]dioxazol-4-yl)-3-((5-chloro-2-nitrophenyl)amino)propionaldehyde (4.5 g, 9.7 mmol), trimethylcyanosilane (1.93 g, 19.4 mmol), zinc iodide (310 mg, 0.97 mmol), and triethylamine (98 mg, 0.97 mmol) were dissolved in DCM (100 mL) solution and reacted with stirring at room temperature for 2 hours. After the reaction was completed, the reaction solution was extracted with EtOAc (150 mL x 3), washed with saturated sodium chloride aqueous solution (200 mL x 3), the organic phase was collected, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by silica gel column chromatography to give the title compound (5 g, 91.5%). MS m / z (ESI): 562.1 [M+H] + .

[0181] Step 8: (1) R ,3 S Preparation of 1-(5-bromo-2,2-difluorobenzo[d][1,3]dioxazol-4-yl)-7-chloro-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-3-ol

[0182] (4) R 5-Bromo-2,2-difluorobenzo[d][1,3]dioxazol-4-yl)-4-((5-chloro-2-nitrophenyl)amino)-2-((trimethylsilyl)oxo)butyronitrile (5 g, 8.9 mmol) and stannous chloride (8.4 g, 44.4 mmol) were dissolved in ethanol (100 mL) solution, and the mixture was heated to 80 °C and stirred for 16 hours. After returning to room temperature, the pH of the reaction solution was adjusted to 8 with potassium hydroxide aqueous solution (1 mol / L), the reaction solution was extracted with EtOAc (150 mL x 3), washed with saturated sodium chloride aqueous solution (200 mL x 3), the organic phase was collected, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated by chiral resolution column to give the title compound (650 mg, 16.5%). MS m / z (ESI): 443.1 [M+H] + .

[0183] Step 9: (1) R ,3 R Preparation of 1-(5-bromo-2,2-difluorobenzo[d][1,3]dioxazol-4-yl)-7-chloro-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-3-amine

[0184] (1) R ,3 S 1-(5-bromo-2,2-difluorobenzo[d][1,3]dioxazol-4-yl)-7-chloro-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-3-ol (650 mg, 1.47 mmol), diphenyl azidophosphate (463 mg, 1.9 mmol), and 1,8-diazabicyclo[5.4.0]undec-7-ene (312 mg, 2.05 mmol) were dissolved in toluene (10 mL) solution, and the mixture was heated to 60 °C and stirred for 16 hours. The reaction mixture was allowed to return to room temperature, and 15 mL x 3 EtOAc extracts were used to extract the reaction mixture. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and the residue and PPh3 (576 mg, 2.2 mmol) were dissolved in a mixture of THF (10 mL) and water (10 mL). The mixture was heated to 60 °C and stirred for 1 hour. The reaction solution was brought to room temperature, extracted with EtOAc (15 mL x 3), washed with saturated sodium chloride aqueous solution (20 mL x 3), and the organic phase was collected, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by silica gel column chromatography to give the title compound (477 mg, 74.2%). m / z (ESI): 442.1 [M+H] + .

[0185] Step 10: (8) R 15 R Preparation of 1,2-chloro-2,2-difluoro-7,8-dihydro-8,15-methylene[1,3]dioxazolo[4',5':3,4]benzo[1,2-f]benzo[4,5]imidazo[1,2-a][1,4]diacoxine-6(15H)-one

[0186] In a carbon monoxide atmosphere, (1) R ,3 R1-(5-bromo-2,2-difluorobenzo[d][1,3]dioxazol-4-yl)-7-chloro-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-3-amine (477 mg, 1.08 mmol), tris(dibenzylideneacetone)dipalladium (99 mg, 0.11 mmol), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (125 mg, 0.22 mmol) and potassium carbonate (447 mg, 3.24 mmol) were suspended in anhydrous DMF (10 mL) solution and the mixture was heated to 130°C and stirred for 16 hours. The reaction mixture was brought to room temperature, extracted with EtOAc (30 mL x 3), washed with saturated sodium chloride aqueous solution (20 mL x 3), and the organic phase was collected, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by silica gel column chromatography to give the title compound (200 mg, 47.6%). m / z (ESI): 390.1 [M+H] + .

[0187] Step 11: (8) R 15 R Preparation of 1,2-chloro-2,2-difluoro-7-methyl-7,8-dihydro-8,15-methylene[1,3]dioxazolo[4',5':3,4]benzo[1,2-f]benzo[4,5]imidazo[1,2-a][1,4]diacoxine-6(15H)-one

[0188] Under an ice water bath, (8) R 15 R 100 mg, 0.26 mmol) of 1,2-chloro-2,2-difluoro-7,8-dihydro-8,15-methylene[1,3]dioxazolo[4',5':3,4]benzo[1,2-f]benzo[4,5]imidazo[1,2-a][1,4]diacoxine-6(15H)-one (100 mg, 0.26 mmol) was dissolved in dry THF (10 mL), sodium hydride (21 mg, 0.52 mmol) was added, and the mixture was stirred for 1 hour. Iodomethane (55 mg, 0.38 mmol) was added, and the mixture was stirred for another 1 hour. The reaction mixture was extracted with EtOAc (15 mL x 3), washed with saturated sodium chloride aqueous solution (20 mL x 3), and the organic phase was collected, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by silica gel column chromatography to give the title compound (87 mg, 84%).

[0189] MS m / z (ESI): 404.1 [M+H] + .

[0190] Step 12: N-(1-(5-((8) R 15 R Preparation of 2,2-difluoro-7-methyl-6-carbonyl-6,7,8,15-tetrahydro-8,15-methylene[1,3]dioxazolo[4',5':3,4]benzo[1,2-f]benzo[4,5]imidazo[1,2-a][1,4]diacoxine-12-yl)pyrimidin-2-yl)cyclobutyl)-2-methylpropane-2-sulfinamide

[0191] (8) R 15 R 12-Chloro-2,2-difluoro-7-methyl-7,8-dihydro-8,15-methylene[1,3]dioxazolo[4',5':3,4]benzo[1,2-f]benzo[4,5]imidazo[1,2-a][1,4]diacoxine-6(15H)-one (87 mg, 0.22 mmol), (2-(1-((tert-butylsulfinylamino)cyclobutyl)pyrimidin-5-yl)boronic acid (70 mg, 0.24 mmol), (2-dicyclohexylphosphine-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-methylamino-1,1'-biphenyl-2-yl)palladium(II) (18.5 mg, 0.02 mmol) and potassium carbonate (60 mg, 0.44 mmol). The compound (100 mg, 74.8%) was suspended in a mixture of 1,4-dioxane (10 mL) and water (2 mL) and reacted in a microwave at 110°C for 1 hour. The reaction mixture was allowed to return to room temperature, extracted with EtOAc (30 mL x 3), washed with saturated sodium chloride aqueous solution (20 mL x 3), and the organic phase was collected, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by silica gel column chromatography to give the title compound (100 mg, 74.8%).

[0192] MS m / z (ESI): 621.1 [M+H] + .

[0193] Step 13: (8) R 15 R Preparation of 12-(2-(1-aminocyclobutyl)pyrimidin-5-yl)-2,2-difluoro-7-methyl-7,8-dihydro-8,15-methylene[1,3]dioxazolo[4',5':3,4]benzo[1,2-f]benzo[4,5]imidazo[1,2-a][1,4]diacoxine-6(15H)-one

[0194] N-(1-(5-((8) R 15 R 2,2-Difluoro-7-methyl-6-carbonyl-6,7,8,15-tetrahydro-8,15-methylene[1,3]dioxazolo[4',5':3,4]benzo[1,2-f]benzo[4,5]imidazo[1,2-a][1,4]diacoxine-12-yl)pyrimidin-2-yl)cyclobutyl)-2-methylpropane-2-sulfinamide (100 mg, 0.16 mmol) was dissolved in dioxane hydrochloride (5 mL, 4N) solution and stirred for 1 hour. The reaction mixture was concentrated and purified by prep-HPLC to obtain the title compound (59.5 mg, 71.5%). MS m / z (ESI): 517.2 [M+H] + .

[0195] 1 H NMR (400 MHz, DMSO- d 6 ) δ 9.09 (s, 2H), 8.32-8.24 (m, 2H), 7.82-7.71 (m, 2H), 7.64 (dd, J = 8.4, 1.6 Hz, 1H), 7.45 (d, J = 8.8 Hz, 1H), 6.14 (d, J = 6.4 Hz, 1H), 5.34 (d, J = 7.2 Hz, 1H), 3.53 (s, 2H), 3.38 (s, 3H), 2.96 (d, J = 13.6 Hz, 1H), 2.65 (ddd, J = 11.2, 9.0, 5.5 Hz, 2H), 2.21 (td, J = 10.4,7.6 Hz, 2H), 2.09-1.82 (m, 2H).

[0196] Example 2

[0197] (1 S ,3 S )-3-(5-((8 R 15 R )-2,2-difluoro-7-(methyl- d 3)-6-carbonyl-6,7,8,15-tetrahydro-8,15-methylene[1,3]dioxazolo[4',5':3,4]benzo[1,2-f]benzo[4,5]imidazo[1,2-a][1,4]diacoxine-12-yl)pyrimidin-2-yl)-3-hydroxy-1-methylcyclobutane-1-carboxynitrile

[0198] Step 1: (8) R 15 R )-12-chloro-2,2-difluoro-7-(methyl- d 3 Preparation of 7,8-dihydro-8,15-methylene[1,3]dioxazolo[4',5':3,4]benzo[1,2-f]benzo[4,5]imidazo[1,2-a][1,4]diacoxine-6(15H)-one

[0199] Under an ice water bath, (8) R 15 R 100 mg, 0.26 mmol) of 1,2-chloro-2,2-difluoro-7,8-dihydro-8,15-methylene[1,3]dioxazolo[4',5':3,4]benzo[1,2-f]benzo[4,5]imidazo[1,2-a][1,4]diacoxine-6(15H)-one (100 mg, 0.26 mmol) was dissolved in THF (10 mL), sodium hydride (21 mg, 0.52 mmol, 60% purity) was added, and the mixture was stirred for 1 hour. Iodomethane (55 mg, 0.38 mmol) was added, and the mixture was stirred for another 1 hour. The reaction mixture was extracted with EtOAc (15 mL x 3), washed with saturated sodium chloride aqueous solution (20 mL x 3), and the organic phase was collected, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by silica gel column chromatography to give the title compound (90 mg, 86%).

[0200] MS m / z (ESI): 407.1 [M+H] + .

[0201] Step 2: (8) R 15 R )-2,2-difluoro-7-(methyl- d 3Preparation of 12-(4,4,5,5-tetramethyl-1,3,2-dioxoboropentane-2-yl)-7,8-dihydro-8,15-methylene[1,3]dioxazolo[4',5':3,4]benzo[1,2-f]benzo[4,5]imidazo[1,2-a][1,4]diacoxine-6(15H)-one

[0202] (8) R 15 R )-12-chloro-2,2-difluoro-7-(methyl- d 3 7,8-dihydro-8,15-methylene[1,3]dioxazolo[4',5':3,4]benzo[1,2-f]benzo[4,5]imidazo[1,2-a][1,4]diazoxine-6(15H)-one (60 mg, 0.15 mmol), pinacol diboronate (56 mg, 0.22 mmol), methanesulfonic acid (2-dicyclohexylphosphine-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-methylamino-1,1'-biphenyl-2-yl)palladium(II) (13 mg, 0.015 mmol) and potassium acetate (44 mg, 0.45 mmol) were suspended in 1,4-dioxane (10 mL) solution and reacted in a microwave at 125°C for 2 hours. The reaction mixture was brought to room temperature, extracted with EtOAc (30 mL x 3), washed with saturated sodium chloride aqueous solution (20 mL x 3), and the organic phase was collected, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by silica gel column chromatography to give the title compound (72 mg, 98%). MS m / z (ESI): 499.1 [M+H] + .

[0203] Step 3 (1) S ,3 S )-3-(5-((8 R 15 R )-2,2-difluoro-7-(methyl- d 3 Preparation of 6-carbonyl-6,7,8,15-tetrahydro-8,15-methylene[1,3]dioxazolo[4',5':3,4]benzo[1,2-f]benzo[4,5]imidazo[1,2-a][1,4]diacoxine-12-yl)pyrimidin-2-yl)-3-hydroxy-1-methylcyclobutane-1-carboxylonitrile

[0204] (8) R 15 R)-2,2-difluoro-7-(methyl- d 3 )-12-(4,4,5,5-tetramethyl-1,3,2-dioxoboropentane-2-yl)-7,8-dihydro-8,15-methylene[1,3]dioxazolo[4',5':3,4]benzo[1,2-f]benzo[4,5]imidazo[1,2-a][1,4]diacoxine-6(15H)-one (35 mg, 0.07 mmol), (1 s ,3 s 3-(5-bromopyrimidin-2-yl)-3-hydroxy-1-methylcyclobutane-1-carboxynitrile (20.7 mg, 0.77 mmol, prepared according to WO2020084008), methanesulfonic acid (2-dicyclohexylphosphine-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-methylamino-1,1'-biphenyl-2-yl)palladium(II) (6 mg, 0.007 mmol) and potassium carbonate (19.4 mg, 0.14 mmol) were suspended in a mixed solution of 1,4-dioxane (10 mL) and water (2 mL) and reacted in a microwave at 110°C for 1 hour. The reaction mixture was brought to room temperature, extracted with EtOAc (30 mL x 3), washed with saturated sodium chloride aqueous solution (20 mL x 3), and the organic phase was collected, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated by prep-HPLC to give the title compound (12.9 mg, 32.7%). MS m / z (ESI): 560.2 [M+H] + .

[0205] 1 H NMR (400 MHz, DMSO- d 6 ) δ 9.11 (s, 2H), 8.29 (d, J = 8.8 Hz, 1H), 7.79 (d, J = 8.4 Hz, 1H), 7.74 (s, 1H), 7.65 (dd, J = 8.4, 1.6 Hz, 1H), 7.45(d, J = 8.8 Hz, 1H), 6.21-6.11 (m, 2H), 5.33 (d, J = 7.2 Hz, 1H), 3.51 (dt, J = 14.0, 7.2 Hz, 1H), 2.99-2.86 (m, 3H), 2.76 (d, J= 12.8 Hz, 2H), 1.43 (s, 3H).

[0206] Example 3

[0207] (8 R 15 R )-12-(2-((1s,3S)-1-amino-3-(fluoromethyl)cyclobutyl)pyrimidin-5-yl)-2,2-difluoro-7-methyl-7,8-dihydro-8,15-methylene[1,3]dioxazolo[4',5':3,4]benzo[1,2-f]benzo[4,5]imidazo[1,2-a][1,4]diacoxine-6(15H)-one

[0208] Step 1: (8) R 15 R Preparation of 2,2-difluoro-7-methyl-12-(4,4,5,5-tetramethyl-1,3,2-dioxoboropentane-2-yl)-7,8-dihydro-8,15-methylene[1,3]dioxazolo[4',5':3,4]benzo[1,2-f]benzo[4,5]imidazo[1,2-a][1,4]diacoxine-6(15H)-one

[0209] (8) R 15 R 1,4-Dichloro-2,2-difluoro-7-methyl-7,8-dihydro-8,15-methylene[1,3]dioxazolo[4',5':3,4]benzo[1,2-f]benzo[4,5]imidazo[1,2-a][1,4]diacoxine-6(15H)-one (1 g, 2.48 mmol), pinacol diboronate (1.26 g, 4.96 mmol), mesylate (2-dicyclohexylphosphine-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-methylamino-1,1'-biphenyl-2-yl)palladium(II) (213 mg, 0.24 mmol) and potassium acetate (486 mg, 4.96 mmol) were suspended in 1,4-dioxane (10 The reaction mixture was microwaved at 125°C for 2 hours in a solution of 1.5 mL. The reaction mixture was then cooled to room temperature, extracted with EtOAc (30 mL x 3), washed with saturated sodium chloride aqueous solution (20 mL x 3), and the organic phase was collected, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by silica gel column chromatography to give the title compound (1.1 g, 89.7%). m / z (ESI): 496.1 [M+H] + .

[0210] Step 2: N-((1) s ,3 S )-1-(5-((8 R 15 R Preparation of 2,2-difluoro-7-methyl-6-carbonyl-6,7,8,15-tetrahydro-8,15-methylene[1,3]dioxazolo[4',5':3,4]benzo[1,2-f]benzo[4,5]imidazo[1,2-a][1,4]diacoxine-12-yl)pyrimidin-2-yl)-3-(fluoromethyl)cyclobutyl)-2-methylpropane-2-sulfinamide

[0211] (8) R 15 R )-2,2-difluoro-7-methyl-12-(4,4,5,5-tetramethyl-1,3,2-dioxoboropentane-2-yl)-7,8-dihydro-8,15-methylene[1,3]dioxazolo[4',5':3,4]benzo[1,2-f]benzo[4,5]imidazo[1,2-a][1,4]diacoxine-6(15H)-one (200 mg, 0.4 mmol), N-((1 s ,3 s 1-(5-bromopyrimidin-2-yl)-3-(fluoromethyl)cyclobutyl)-2-methylpropane-2-sulfinamide (162 mg, 0.44 mmol), methanesulfonic acid (2-dicyclohexylphosphine-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-methylamino-1,1'-biphenyl-2-yl)palladium(II) (34.7 mg, 0.04 mmol), and potassium carbonate (112 mg, 0.81 mmol) were suspended in a mixed solution of 1,4-dioxane (10 mL) and water (2 mL) and reacted in a microwave at 110°C with stirring for 1 hour. The reaction mixture was brought to room temperature, extracted with EtOAc (30 mL x 3), washed with saturated sodium chloride aqueous solution (20 mL x 3), and the organic phase was collected, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by silica gel column chromatography to give the title compound (218 mg, 82.7%). m / z (ESI): 653.1 [M+H] + .

[0212] Step 3: (8) R 15 RPreparation of )-12-(2-((1s,3S)-1-amino-3-(fluoromethyl)cyclobutyl)pyrimidin-5-yl)-2,2-difluoro-7-methyl-7,8-dihydro-8,15-methylene[1,3]dioxazolo[4',5':3,4]benzo[1,2-f]benzo[4,5]imidazo[1,2-a][1,4]diacoxine-6(15H)-one

[0213] N-((1) s ,3 S )-1-(5-((8 R 15 R 2,2-Difluoro-7-methyl-6-carbonyl-6,7,8,15-tetrahydro-8,15-methylene[1,3]dioxazolo[4',5':3,4]benzo[1,2-f]benzo[4,5]imidazo[1,2-a][1,4]diacoxine-12-yl)pyrimidin-2-yl)-3-(fluoromethyl)cyclobutyl)-2-methylpropane-2-sulfinamide (218 mg, 0.33 mmol) was dissolved in dioxane hydrochloride (5 mL, 4N) solution and stirred for 1 hour. The reaction mixture was concentrated and separated by prep-HPLC to obtain the title compound (100 mg, 55%). MS m / z (ESI): 549.2 [M+H] + .

[0214] 1 H NMR (400 MHz, DMSO- d 6 ) δ 9.10 (s, 2H), 8.77 (s, 2H), 8.30 (d, J =8.8 Hz, 1H), 7.79 (d, J = 8.8 Hz, 1H), 7.74 (d, J = 1.6 Hz, 1H), 7.65 (dd, J = 8.4, 1.6 Hz, 1H), 7.45 (d, J = 8.4 Hz, 1H), 6.15 (d, J = 6.4 Hz, 1H), 5.34(d, J = 7.2 Hz, 1H), 4.60 (d, J = 6.0 Hz, 1H), 4.48 (d, J = 6.0 Hz, 1H), 3.52(d,J = 6.8 Hz, 1H), 3.38 (s, 3H), 2.96 (d, J = 13.6 Hz, 1H), 2.75-2.55 (m,3H), 2.12-2.03 (m, 2H).

[0215] Example 4

[0216] (8 R 15 R )-12-(2-((1 s ,3 S )-1-amino-3-methoxy-3-methylcyclobutyl)pyrimidin-5-yl)-2,2-difluoro-7-(methyl- d 3 )-7,8-dihydro-8,15-methylene[1,3]dioxazolo[4',5':3,4]benzo[1,2-f]benzo[4,5]imidazo[1,2-a][1,4]diacoxine-6(15H)-one

[0217] Step 1: Preparation of 3-(benzyloxy)-1-methylcyclobutane-1-ol

[0218] 3-(benzyloxy)cyclobutane-1-one (20 g, 113.5 mmol) was dissolved in THF (200 mL) under dry ice-acetone bath conditions. Methyl magnesium chloride (56.7 mL, 170.25 mmol, 3.0 mol / L in THF) was added dropwise, followed by stirring for 1 hour. The reaction was quenched with saturated ammonium chloride. The reaction mixture was extracted with ethyl acetate (150 mL x 3), washed with saturated sodium chloride aqueous solution (200 mL x 3), and the organic phase was collected, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by silica gel column chromatography to give the title compound (20.8 g, 95.3%). MS m / z (ESI): 193.1 [M+H] + .

[0219] Step 2: Preparation of ((3-methoxy-3-methylcyclobutoxy)methyl)benzene

[0220] 3-(benzyloxy)-1-methylcyclobutane-1-ol (20.8 g, 108.19 mmol) was dissolved in THF (200 mL) under ice-water bath conditions. Sodium hydride (8.66 g, 216.38 mmol, 60% purity) was slowly added, and the mixture was stirred for 1 hour. Iodomethane (23 g, 162.29 mmol) was added dropwise, and the mixture was stirred for 16 hours. The reaction was quenched with saturated ammonium chloride. The reaction mixture was extracted with ethyl acetate (150 mL x 3), washed with saturated sodium chloride aqueous solution (200 mL x 3), and the organic phase was collected. The solution was dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by silica gel column chromatography to give the title compound (17 g, 76.2%). MS m / z (ESI): 207.1 [M+H] + .

[0221] Step 3: Preparation of 3-methoxy-3-methylcyclobutane-1-ol

[0222] Under nitrogen protection, ((3-methoxy-3-methylcyclobutoxy)methyl)benzene (17 g, 82.41 mmol) was dissolved in a mixed solvent of THF (100 mL) and methanol (100 mL). After adding Pd(OH)₂ / C (1.16 g, 8.24 mmol) and Pd / C (1 g, 8.24 mmol), the reaction mixture was purged into a hydrogen atmosphere. The mixture was heated to 50 °C and stirred for 16 hours. The reaction solution was filtered and concentrated to give the title compound (9 g, 94%). MS m / z (ESI): 117.1 [M+H] + .

[0223] Step 4: Preparation of 3-methoxy-3-methylcyclobutane-1-one

[0224] 3-Methoxy-3-methylcyclobutane-1-ol (9 g, 77.48 mmol) was dissolved in DCM (200 mL) under ice-water bath conditions. Desmartin oxidant (39.44 g, 92.98 mmol) was slowly added, followed by heating to room temperature and stirring for 1 hour. The reaction was quenched using saturated sodium bicarbonate. The reaction mixture was extracted with DCM (150 mL x 3), washed with saturated sodium chloride aqueous solution (200 mL x 3), and the organic phase was collected, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by silica gel column chromatography to obtain the title compound (5.5 g, 62.2%). MS m / z (ESI): 115.1 [M+H]+ .

[0225] Step 5: ( S Preparation of 2-N-(3-methoxy-3-methylcyclobutylene)-2-methylpropane-2-sulfinamide

[0226] 3-Methoxy-3-methylcyclobutane-1-one (5.5 g, 48.19 mmol) and ( S 7 g tert-butylsulfinamide (7 g, 57.82 mmol) was dissolved in THF (200 mL), and tetraethyl titanate (16.49 g, 72.28 mmol) was slowly added. The mixture was then heated to room temperature and stirred for 16 hours. The reaction was quenched with water. The filtrate was extracted with ethyl acetate (150 mL x 3), washed with saturated sodium chloride aqueous solution (200 mL x 3), and the organic phase was collected, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by silica gel column chromatography to give the title compound (5.3 g, 50.5%). MS m / z (ESI): 218.1 [M+H] + .

[0227] Step 6: ( S )-N-((1 s ,3 R Preparation of 1-(5-bromopyrimidin-2-yl)-3-methoxy-3-methylcyclobutyl)-2-methylpropane-2-sulfinamide

[0228] Under dry ice-acetone bath conditions, 5-bromo-2-iodopyrimidine (2.36 g, 8.28 mmol) was dissolved in DCM (50 mL), and n-butyllithium (3.31 mL, 8.28 mmol, 2.5 mol / L in Hexanes) was added dropwise, followed by stirring for 1 hour. (The remaining text appears to be incomplete and requires further context.) S A solution of 1.5 g (6.90 mmol) of 1-N-(3-methoxy-3-methylcyclobutylene)-2-methylpropane-2-sulfinamide (DCM) was added and the reaction mixture was stirred for 1 hour. The reaction mixture was extracted with DCM (50 mL x 3), washed with saturated sodium chloride aqueous solution (30 mL x 3), the organic phase was collected, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by silica gel column chromatography and chiral resolution to give the title compound (138 mg, 5.3%). MS m / z (ESI): 376.1 [M+H] + .

[0229] Step 7: N-((1) s ,3 S )-1-(5-((8 R 15 R )-2,2-difluoro-7-(methyl- d 3 Preparation of 6-carbonyl-6,7,8,15-tetrahydro-8,15-methylene[1,3]dioxazolo[4',5':3,4]benzo[1,2-f]benzo[4,5]imidazo[1,2-a][1,4]diacoxine-12-yl)pyrimidin-2-yl)-3-methoxy-3-methylcyclobutyl)-2-methylpropane-2-sulfinamide

[0230] (8) R 15 R )-2,2-difluoro-7-(methyl- d 3 )-12-(4,4,5,5-tetramethyl-1,3,2-dioxoboropentane-2-yl)-7,8-dihydro-8,15-methylene[1,3]dioxazolo[4',5':3,4]benzo[1,2-f]benzo[4,5]imidazo[1,2-a][1,4]diacoxine-6(15H)-one (65 mg, 0.13 mmol), S )-N-((1 s ,3 R 1-(5-bromopyrimidin-2-yl)-3-methoxy-3-methylcyclobutyl)-2-methylpropane-2-sulfinamide (58.9 mg, 0.156 mmol), methanesulfonic acid (2-dicyclohexylphosphine-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-methylamino-1,1'-biphenyl-2-yl)palladium(II) (11.2 mg, 0.013 mmol) and potassium carbonate (36 mg, 0.26 mmol) were suspended in a mixed solution of 1,4-dioxane (5 mL) and water (1 mL) and reacted in a microwave at 110 °C for 1 hour. The reaction mixture was brought to room temperature and extracted with ethyl acetate (10 mL x 3). The extract was washed with saturated sodium chloride aqueous solution (10 mL x 3), and the organic phase was collected, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by silica gel column chromatography to give the title compound (75 mg, 86.1%). MS m / z (ESI): 668.1 [M+H] + .

[0231] Step 8: (8) R 15 R )-12-(2-((1s ,3 S )-1-amino-3-methoxy-3-methylcyclobutyl)pyrimidin-5-yl)-2,2-difluoro-7-(methyl- d 3 Preparation of 7,8-dihydro-8,15-methylene[1,3]dioxazolo[4',5':3,4]benzo[1,2-f]benzo[4,5]imidazo[1,2-a][1,4]diacoxine-6(15H)-one

[0232] Under nitrogen protection, N-((1) s ,3 S )-1-(5-((8 R 15 R )-2,2-difluoro-7-(methyl- d 3 6-carbonyl-6,7,8,15-tetrahydro-8,15-methylene[1,3]dioxazolo[4',5':3,4]benzo[1,2-f]benzo[4,5]imidazo[1,2-a][1,4]diacoxine-12-yl)pyrimidin-2-yl)-3-methoxy-3-methylcyclobutyl)-2-methylpropane-2-sulfinamide (75 mg, 0.112 mmol) was dissolved in dioxane hydrochloride (2 mL, 4N) solution and reacted with stirring at room temperature for 1 hour. After concentrating the reaction solution, the title compound (50.4 mg, 78.9%) was obtained by prep-HPLC. MS m / z (ESI): 564.2 [M+H] + .

[0233] 1 H NMR (400 MHz, DMSO- d 6 ) δ 9.06 (s, 2H), 8.29 (d, J = 8.8 Hz, 1H), 7.79 (d, J = 8.4 Hz, 1H), 7.72 (d, J = 1.6 Hz, 1H), 7.63 (dd, J = 8.4, 1.6Hz, 1H), 7.45 (d, J = 8.8 Hz, 1H), 6.14 (d, J = 6.4 Hz, 1H), 5.33 (d, J= 7.2Hz, 1H), 3.53-3.48 (m, 3H), 3.07 (s, 3H), 2.95 (d, J = 13.6 Hz, 1H), 2.82-2.76 (m, 2H), 2.08-2.01 (m, 2H), 1.56 (s, 3H).

[0234] Example 5

[0235] (1 R ,3 r )-3-amino-3-(5-((8) R 15 R )-2,2-difluoro-7-(methyl- d 3 )-6-carbonyl-6,7,8,15-tetrahydro-8,15-methylene[1,3]dioxazolo[4',5':3,4]benzo[1,2- f ]Benzo[4,5]imidazo[1,2- a [1,4]Diacoxin-12-yl)pyrimidin-2-yl)-1-(fluoromethyl)cyclobutane-1-carboxynitrile

[0236] Step 1: (1) s ,3 s Preparation of 3-(5-bromopyrimidin-2-yl)-1-(fluoromethyl)-3-hydroxycyclobutanenitrile

[0237] At -78°C, n BuLi (2.5 M, 18.9 mL) was added dropwise to a DCM solution of 5-bromo-2-iodopyrimidine (13.45 g, 47.20 mmol) and 1-(fluoromethyl)-3-carbonylcyclobutanenitrile (5 g, 39.33 mmol) in 200 mL, and the mixture was slowly heated to -10°C (over 0.5 h). The reaction mixture was quenched with saturated ammonium chloride solution (50 mL), separated, the organic layer was washed with water (50 mL), concentrated under reduced pressure, and the residue was purified by silica gel column chromatography, followed by resolution by chiral column chromatography to give the title compound (1.40 g, 12.4%). MS m / z (ESI): 286.0 [M+H] + .

[0238] Step 2: (1) s ,3 s Preparation of 1-(5-bromopyrimidin-2-yl)-3-cyano-3-(fluoromethyl)cyclobutyl 4-methylbenzenesulfonate

[0239] Under ice bath conditions, NaH (157 mg, 3.93 mmol, 60%) was added in portions to (1 s ,3 s 3-(5-bromopyrimidin-2-yl)-1-(fluoromethyl)-3-hydroxycyclobutanenitrile (0.75 g, 2.62 mmol) was added to a THF solution (14 mL), stirred for 10 minutes, and then p-toluenesulfonyl chloride (750 mg, 3.93 mmol) was added. The mixture was heated to room temperature and stirred for 1 hour. The reaction solution was poured into ice water (10 mL), concentrated under reduced pressure, and the residue was diluted with ethyl acetate (20 mL). The residue was washed with water (10 mL) and saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to give the title compound (1.01 g, 87.5%). MS m / z (ESI): 440.1 [M+H] + .

[0240] Step 3: (1) r ,3 r Preparation of 3-azido-3-(5-bromopyrimidin-2-yl)-1-(fluoromethyl)cyclobutanenitrile

[0241] Add NaN3 (80 mg, 1.23 mmol) to (1 s ,3 s The reaction mixture was microwaved at 80°C for 30 minutes in a DMF solution of 1-(5-bromopyrimidin-2-yl)-3-cyano-3-(fluoromethyl)cyclobutyl 4-methylbenzenesulfonate (31 mg, 0.42 mmol) for 30 minutes. The reaction mixture was diluted with water (20 mL), extracted with ethyl acetate (30 mL), and the organic layer was washed with water (10 mL × 2) and used directly in the next step. m / z (ESI): 311.1 [M+H] + .

[0242] Step 4: (1) r ,3 r Preparation of 3-amino-3-(5-bromopyrimidin-2-yl)-1-(fluoromethyl)cyclobutanenitrile

[0243] (1) r ,3 rA mixture of ethyl acetate solution (approximately 0.42 mmol) of crude ethyl acetate of 3-azido-3-(5-bromopyrimidin-2-yl)-1-(fluoromethyl)cyclobutanenitrile, triphenylphosphine (165 mg, 0.63 mmol), and water (1 mL) was refluxed and stirred for 16 hours. After cooling, 0.5 M HCl (5 mL) was added, and the mixture was stirred and separated. The aqueous layer was adjusted to alkalinity with saturated sodium bicarbonate solution and extracted with ethyl acetate (20 mL × 2). The combined organic layers were concentrated under reduced pressure, and the residue was separated by preparative HPLC to give the title compound (75 mg, two-step yield 62.5%). MS m / z (ESI): 285.1 [M+H] + .

[0244] Step 5: (1) R ,3 r )-3-amino-3-(5-((8) R 15 R )-2,2-difluoro-7-(methyl- d 3 Preparation of 6-carbonyl-6,7,8,15-tetrahydro-8,15-methylene[1,3]dioxazolo[4',5':3,4]benzo[1,2-f]benzo[4,5]imidazo[1,2-a][1,4]diacoxine-12-yl)pyrimidin-2-yl)-1-(fluoromethyl)cyclobutane-1-carboxylon

[0245] (1) r ,3 r 3-Amino-3-(5-bromopyrimidin-2-yl)-1-(fluoromethyl)cyclobutyronitrile (38 mg, 0.13 mmol) was added to (8 R 15 R )-2,2-difluoro-7-(methyl- d 3 )-12-(4,4,5,5-tetramethyl-1,3,2-dioxoboropentane-2-yl)-7,8-dihydro-8,15-methylene[1,3]dioxazolo[4',5':3,4]benzo[1,2- f ]Benzo[4,5]imidazo[1,2- a [1,4]ErAxin-6(15 HA mixture of dioxane (2 mL) and water (74 mg) of dioxane (74 mg, 0.53 mmol) containing ketone (66 mg, 0.133 mmol), XPhosPdG4 (11.5 mg, 0.013 mmol), and potassium carbonate (74 mg, 0.53 mmol) was purged with nitrogen three times, and then microwaved to 100°C with stirring for 1 hour. The reaction mixture was poured into water (10 mL) and DCM (10 mL), separated, and the organic layer was concentrated under reduced pressure. The residue was purified by prep-HPLC to give the title compound (32 mg, 40.8%). m / z (ESI): 577.2 [M+H] + .

[0246] 1 H NMR (400 MHz, CDCl3) δ 8.92 (s, 2H), 8.48 (d, J = 8.8 Hz, 1H), 7.87(d, J = 8.5 Hz, 1H), 7.66-7.61 (m, 1H), 7.50-7.43 (m, 1H), 7.11 (d, J = 8.8Hz, 1H), 5.97 (d, J = 6.8 Hz, 1H), 5.07 (d, J = 7.2 Hz, 1H), 4.69 (d, J =46.7 Hz, 2H), 3.58-3.47 (m, 1H), 3.19-3.11 (m, 2H), 2.99 (d, J = 13.5 Hz,1H), 2.76-2.69 (m, 2H).

[0247] Example 6

[0248] (1 S ,3 s )-3-amino-3-(5-((8) R 15 R )-2,2-difluoro-7-(methyl- d 3 )-6-carbonyl-6,7,8,15-tetrahydro-8,15-methylene[1,3]dioxazolo[4',5':3,4]benzo[1,2-f]benzo[4,5]imidazo[1,2-a][1,4]diacoxine-12-yl)pyrimidin-2-yl)-1-methylcyclobutane-1-carboxynitrile

[0249] first step:( S Preparation of 2-N-(3-cyano-3-methylcyclobutylene)-2-methylpropane-2-sulfinamide

[0250] Under ice-water bath conditions, 1-methyl-3-carbonylcyclobutane-1-carboxynitrile (10.5 g, 96.38 mmol) and ( S 14 g of tert-butylsulfinamide (14 g, 115.64 mmol) was dissolved in THF (400 mL), and tetraethyl titanate (32.98 g, 144.56 mmol) was slowly added. The mixture was then heated to room temperature and stirred for 16 hours. The reaction was quenched with water, and the filtrate was extracted with ethyl acetate (150 mL x 3), washed with saturated sodium chloride aqueous solution (200 mL x 3), and the organic phase was collected, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by silica gel column chromatography to give the title compound (18.50 g, 90.6%). m / z (ESI): 213.1 [M+H] + .

[0251] Step Two: ( S )-N-((1 s ,3 R Preparation of 1-(5-bromopyrimidin-2-yl)-3-cyano-3-methylcyclobutyl)-2-methylpropane-2-sulfinamide

[0252] Under dry ice-acetone bath conditions, 5-bromo-2-iodopyrimidine (4.72 g, 16.56 mmol) was dissolved in DCM (100 mL), and n-butyllithium (6.62 mL, 16.56 mmol, 2.5 mol / L in Hexanes) was added dropwise, followed by stirring for 1 hour. (The remaining text appears to be incomplete and requires further context.) S A solution of 2.93 g (13.80 mmol) of 2-N-(3-cyano-3-methylcyclobutylene)-2-methylpropane-2-sulfinamide (DCM) was added and the reaction mixture was stirred for 1 hour. The reaction mixture was extracted with DCM (50 mL x 3). The solution was washed with saturated sodium chloride aqueous solution (30 mL x 3), the organic phase was collected, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by silica gel column chromatography and chiral column resolution to give the title compound (700 mg, 13.7%). MS m / z (ESI): 371.0 [M+H] + .

[0253] Step 3: N-((1) s ,3 S )-3-cyano-1-(5-((8) R 15 R )-2,2-difluoro-7-(methyl- d 3 Preparation of 6-carbonyl-6,7,8,15-tetrahydro-8,15-methylene[1,3]dioxazolo[4',5':3,4]benzo[1,2-f]benzo[4,5]imidazo[1,2-a][1,4]diacoxine-12-yl)pyrimidin-2-yl)-3-methylcyclobutyl)-2-methylpropane-2-sulfinamide

[0254] (8) R 15 R )-2,2-difluoro-7-(methyl- d 3 )-12-(4,4,5,5-tetramethyl-1,3,2-dioxoboropentane-2-yl)-7,8-dihydro-8,15-methylene[1,3]dioxazolo[4',5':3,4]benzo[1,2-f]benzo[4,5]imidazo[1,2-a][1,4]diacoxine-6(15H)-one (1.0 g, 2.00 mmol), S )-N-((1 s ,3 R 1-(5-bromopyrimidin-2-yl)-3-cyano-3-methylcyclobutyl)-2-methylpropane-2-sulfinamide (816.2 mg, 2.20 mmol), methanesulfonic acid (2-dicyclohexylphosphine-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-methylamino-1,1'-biphenyl-2-yl)palladium(II) (171.5 mg, 0.20 mmol) and potassium carbonate (828.0 mg, 6.00 mmol) were suspended in a mixture of 1,4-dioxane (20 mL) and water (4 mL) and reacted in a microwave at 110 °C for 1 hour. The reaction mixture was brought to room temperature and extracted with EtOAc (30 mL x 3). The extract was washed with saturated sodium chloride aqueous solution (20 mL x 3), and the organic phase was collected, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by silica gel column chromatography to give the title compound (1.10 g, 83.3%). MS m / z (ESI): 663.2 [M+H] + .

[0255] Step 4: (1) S ,3 s )-3-amino-3-(5-((8)R 15 R )-2,2-difluoro-7-(methyl- d 3 Preparation of 6-carbonyl-6,7,8,15-tetrahydro-8,15-methylene[1,3]dioxazolo[4',5':3,4]benzo[1,2-f]benzo[4,5]imidazo[1,2-a][1,4]diacoxine-12-yl)pyrimidin-2-yl)-1-methylcyclobutane-1-carboxylon

[0256] N-((1) s ,3 S )-3-cyano-1-(5-((8) R 15 R )-2,2-difluoro-7-(methyl- d 3 1.10 g (1.66 mmol) of 6-carbonyl-6,7,8,15-tetrahydro-8,15-methylene[1,3]dioxazolo[4',5':3,4]benzo[1,2-f]benzo[4,5]imidazo[1,2-a][1,4]diacoxine-12-yl)pyrimidin-2-yl)-3-methylcyclobutyl)-2-methylpropane-2-sulfinamide (1.10 g, 1.66 mmol) was dissolved in dioxane hydrochloride (10 mL, 4N) solution and stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was concentrated and separated by prep-HPLC to obtain the title compound (433.5 mg, 46.7%). MS m / z (ESI): 559.2 [M+H] + .

[0257] 1 H NMR (400 MHz, DMSO- d 6 ) δ 9.09 (s, 2H), 8.29 (d, J = 8.9 Hz, 1H), 7.79 (d, J = 8.4 Hz, 1H), 7.73 (dd, J = 1.7, 0.7 Hz, 1H), 7.63 (dd, J = 8.5, 1.8 Hz, 1H), 7.45 (d, J = 8.9 Hz, 1H), 6.14 (d, J = 6.6 Hz, 1H), 5.33 (d, J=7.2 Hz, 1H), 3.51 (dt, J = 13.9, 7.0 Hz, 1H), 2.95 (d, J = 13.8 Hz, 1H), 2.85-2.77 (m, 2H), 2.68-2.59 (m, 2H), 1.46 (s, 3H).

[0258] Example 7

[0259] The preparation process of Example 7 is the same as that of Example 1.

[0260] 1 H NMR (400 MHz, DMSO- d 6) δ 8.69–8.64 (m, 1H), 8.29 (d, J = 8.9 Hz, 1H), 7.96 (dd, J = 12.0, 1.9 Hz, 1H), 7.76 (d, J = 8.5 Hz, 1H), 7.71 (d, J =1.7 Hz, 1H), 7.62 (dd, J = 8.5, 1.8 Hz, 1H), 7.45 (d, J = 8.9 Hz, 1H), 6.20(s, 1H), 6.13 (d, J = 6.6 Hz, 1H), 5.33 (d, J = 7.2 Hz, 1H), 3.50 (dt, J =13.9, 7.0 Hz, 1H), 2.96 (dd, J = 13.0, 5.7 Hz, 3H), 2.85-2.77 (m, 2H), 1.32(s, 3H).

[0261] Biological testing evaluation

[0262] The present invention will be further described and explained below with reference to test examples, but these embodiments are not intended to limit the scope of the present invention.

[0263] I. Combining experiments

[0264] The compounds in the embodiments of the present invention showed strong binding activity to TNFα protein in experiments on the thermal shift effect on the thermostability of TNFα protein and in experiments on the effect of TNFα protein on the binding of TNFR1 receptor.

[0265] II. Cell Function Experiments

[0266] Test Example 1: Determination of the effect of the compound of the present invention on TNF-induced NF-κB phosphorylation in HEK293 cells.

[0267] 1. Experimental objective: To detect the effect of the compound on TNF-induced pNF-κB levels in HEK293 cells.

[0268] 2. Experimental instruments and reagents: 2.1 Instruments: Envision (PE-Cisbio: 2105-0020); Centrifuge (Eppendorf: 5810R); Pure Water System (THERMO: Pacific T II+Micropure); Ice Maker (Xueke Electric, IMS-150); Incubator (Boxun, BC-J80S) 2.2 Reagents: Cell culture plates (Corning: 3599); PBS (Gibco, 10010023); DMSO (Sigma: D2650); TNFα (MCE: HY-P7085); PMSF (100mM) (Beyotime, ST506); Pierce BCA Protein Assay Kit (Thermo Fisher, 23227); Protease phosphatase inhibitor mixture (universal, 50X) (Beyotime, P1045); NF kappaB p65 (pS536) ELISA kit (Abcam, ab176647); Hek293 cell line (ATCC); DMEM (Gibco, 11995-065); FBS serum (Gibco, 30067-334); Pen strep antibiotics (Gibco, 15140-122); trypsin (Gibco, 25200-056).

[0269] 3. Experimental Methods: 1) HepG2 cell line was cultured in complete medium at 37°C with 5% CO2 until 70%~90% confluence.

[0270] 2) Digest and resuspend the cells in experimental culture medium, and seed 40,000 cells / well / 100 μL into a 96-well cell culture plate and incubate overnight at 37°C with 5% CO2.

[0271] 3) Prepare a 5x final concentration mixture of the compound and TNF protein in the culture medium and incubate it in a 37°C incubator for 1 hour.

[0272] 4) Add the incubated compound and TNF protein mixture to the corresponding cell wells, 25 μL per well, and incubate at 37°C for 10 min. At this time, the final concentration of TNF is 25 ng / mL and the concentration of DMSO is 0.1%.

[0273] 5) Centrifuge at 2000 rpm for 5 min, discard the supernatant, and wash the cells twice with 100 uL PBS.

[0274] 6) Pre-cool the centrifuge to 4°C, prepare the cell lysis buffer (the reagent components are included in the ELISA kit), add an appropriate amount of protease inhibitor, add 70 μL of lysis buffer to each well, and incubate on ice for 10 min for lysis.

[0275] 7) Take 5 μL of the lysed sample for BCA protein concentration detection, and use the remaining sample for ELISA assay.

[0276] 8) Dilute the lysed sample with ELISA buffer at appropriate concentrations and prepare a standard curve. The highest concentration point of the standard curve is the 25% control lysate concentration. The remaining gradients are diluted 2-fold, for a total of 8 concentration points.

[0277] 9) Add the sample and standard curve to each well, 50 μL per well.

[0278] 10) Calculate the total volume required for the experiment, mix Capture Antibody and Detector Antibody in a 1:1 ratio, add 50 uL to each well, seal the plate, and incubate at 25°C on a shaker at 400 rpm for 1 h.

[0279] 11) Remove the liquid, dilute 10x wash buffer 10 times with deionized water, add 350 uL to each well, and wash three times, draining the liquid from the plate each time.

[0280] 12) Add 100 μL of TMB Substrate to each well, protect from light, and incubate on a shaker at 400 rpm for 15 min for color development.

[0281] 13) Add 100 μL of Stop solution to each well, shake at 400 rpm for 1 min to mix, and read the Envision value as OD 450 nm.

[0282] 4. Experimental data processing methods: IC was calculated by fitting the compound concentration, corresponding inhibition rate, and retrograde nonlinearity using a graph pad four-parameter log(inhibitor) vs. response -- variable slope (four parameters) to the data. 50 .

[0283] 5. Experimental Results and Conclusions: Experimental conclusion: The compounds in the embodiments of this invention showed a strong inhibitory effect on TNF-induced pNF-κB levels in HEK293 cells in the experiment.

[0284] Test Example 2: Detection of the inhibitory effect of the compound of the present invention on the release of IL-8 from TNF-stimulated hPBMCs.

[0285] 1. Experimental objective: The inhibitory effect of the compound on TNF-induced release of IL-8 from hPBMCs was investigated.

[0286] 2. Experimental instruments and reagents: 2.1 Instruments: Envision (PE-Cisbio: 2105-0020); Biosafety cabinet (Su Jing An Tai, BSC-1604ⅡA2); Cell counter (Invitrogen, Countess II) 2.2 Reagents and Consumables: hPBMCs (Saili, XFB-HP010B), PBS (Gibco, 10010023), DMSO (Sigma: D2650), TNFα (MCE: HY-P7085), RPMI 1640 medium (Gibco, 22400-105), FBS serum (Gibco, 30067-334), Penstrep antibody (Gibco, 15140-122), cell culture plates (Corning: 3599), Human IL-8 / CXCL8 DuoSet ELISA (RD, DY208-05), DuoSet ELISA Ancillary Reagent Kit 2 (RD, DY008B), 1200uL 12-lane electric pipette (Eppendorf, J51515K) 3. Experimental Methods: 1) Thaw the hPBMC cryopreservation solution in a 37°C water bath; 2) Add the thawed cells dropwise to 10 mL of preheated 1640 medium (+10% FBS+1% PS), centrifuge at 2000 rpm for 10 min; 3) After centrifugation, remove the supernatant from the cells, add 10 mL of fresh culture medium to resuspend them, mix well by pipetting, and count them; 4) Adjust the cell density to 1 10 6 Add cells / mL, 100 uL / well to a 96-well plate; 5) Incubate the well plate in a 37°C incubator for 4 hours; 6) Prepare working solutions of 6x final concentration compound (final concentration 1 uM Top, 3-Fold, 8Dose) and TNF protein (final concentration 3 ng / mL) using serum-free 1640 medium. Then mix the compound with TNFα 1:1 and incubate at 37°C for 1 h. 7) Add the incubated mixture to the corresponding well plate, 50 μL per well, and incubate at 37°C for 18 h. At the same time, prepare the ELISA capture antibody with coating buffer, add 100 μL to each well of the high-binding plate, with a final concentration of 4 ug / mL, and incubate overnight at 4°C. 8) ELISA sample preparation: Centrifuge the incubated cell plate at 1500 rpm for 10 min, collect the supernatant, and dilute the supernatant 15 times with dilution buffer (6.7 uL supernatant + 93.3 uL dilution buffer). 9) Preparation of standard curve: The standard curve IL-8 concentration is 250 ng / mL, 2-fold, 8-dose, 2-fold dilution to 125 uL + 125 uL dilution buffer; 10) Prepare 1x wash buffer, add 300 uL to each well of the plate and wash three times. After each wash, let it stand for 30 seconds to ensure it is clean. 11) Add the diluted sample and standard curve to each well of the plate, 100 μL, and incubate at room temperature for 2 h. 12) Repeat step 10, washing the plate three times. 13) Prepare the detection antibody to a final concentration of 10 ng / mL, add 100 μL to each well of the plate, and incubate at room temperature for 2 h; 14) Same as step 10, wash the plate three times; 15) Prepare SA-HRP to a final concentration of 1x, add 100 μL to each well of the plate, and incubate at room temperature for 30 min; 16) Repeat step 10, washing the plate three times; 17) Add 100 μL of TMB solution and incubate at room temperature in the dark for 20 min to develop color; 18) Add 50 uL of stop solution, shake well, and after the solution turns completely yellow, read the OD value as 450-570.

[0287] 4. Experimental data processing methods: The IC was calculated using XLfit's four-parameter log(inhibitor) vs. response -- variable slope (four parameters) to fit the compound concentration, corresponding inhibition rate, and nonlinearity. 50 .

[0288] 5. Experimental conclusion: The compound of this invention has a good inhibitory effect on the release of IL-8 from hPBMCs stimulated by TNF.

[0289] III. Pharmacokinetic Determination in Balb / C Mice

[0290] 1. Research objective: Using Balb / C mice as test animals, this study investigates the pharmacokinetic behavior of the compounds of this invention in mouse plasma after oral administration at a dose of 30 mg / kg.

[0291] 2. Test Plan

[0292] 2.1 Test reagents: The compounds of this invention, prepared in-house.

[0293] 2.2 Test animals: Balb / C Mouse (3 mice per example), male, Shanghai Bikai Laboratory Animal Co., Ltd., Animal Production License Number (SCXK (Shanghai) 2013-0006 N0.311620400001794).

[0294] 2.3 Drug administration: Balb / C mice, male; after fasting overnight, administered p.o. respectively, with a dose of 30 mg / kg and a dosing volume of 10 mL / kg.

[0295] 2.4 Sample collection: Before and after drug administration to mice, at 0, 0.5, 1, 2, 4, 6, 8, and 24 hours, 0.04 mL of blood was collected from the orbital cavity, placed in an EDTA-K2 test tube, centrifuged at 6000 rpm for 6 min at 4 °C to separate plasma, and stored at -80 °C.

[0296] 2.5 Sample treatment: 1) Add 20 μL of plasma sample to 100 μL of acetonitrile for precipitation, mix and centrifuge at 5000 × g for 15 - 20 minutes.

[0297] 2) Take the supernatant solution after treatment for LC / MS / MS analysis to determine the concentration of the test compound. LC / MS / MS analysis instrument: AB Sciex API 4000

[0298] 2.6 Liquid phase analysis

[0299] Liquid phase conditions: Shimadzu LC-20AD pump

[0300] Mass spectrometry conditions: AB Sciex API 4000 mass spectrometer

[0301] Chromatographic column: Waters Xbridge C18 5μm, 4.6 X 50 mm

[0302] Mobile phase: Solution A is 0.1% formic acid aqueous solution, Solution B is methanol. Flow rate: 1 mL / min

[0303] Elution time: 0 - 4.0 minutes, eluent is as follows: 3. Test results and analysis The main pharmacokinetic parameters were calculated using WinNonlin 6.1. The results of the mouse pharmacokinetic experiment are as follows: 4. Experimental conclusion: The compound of the present invention shows good pharmacokinetic properties.

[0304] IV. Caco-2 cell permeability test of the compound

[0305] 1. Experimental objective: The purpose of this experiment was to test the bidirectional permeability of the compound through the Caco-2 cell model and to assess whether it was transported by efflux transporters.

[0306] 2. Compounds and test materials

[0307] 2.1 Prepare a 10 mM stock solution of the test compound using DMSO (or other suitable solution) and store it at -20 °C for later use.

[0308] 2.2 Control compounds: Cimetidine, Metoprolol, and Erythromycin were prepared as 10 mM stock solutions for later use.

[0309] 2.3 Caco-2 cells were purchased from the American Type Culture Collection (ATTC). PBS (Gibco, pH 7.4), HBSS (Thermo Fisher Scientific), DMEM medium (Gibco), Sigma-Aldrich (Sigma), and HEPES (Solarbio) were also used.

[0310] 3. Experiment Introduction

[0311] Caco-2 cells are a type of human colon cancer cell. Under specific in vitro culture conditions, they can form tightly connected cell layers that differentiate into cell layers with morphology and function similar to human small intestinal cells. Because they express various types of transporters, they can be used to construct an in vitro model for studying drug absorption by small intestinal epithelial cells. Using the Caco-2 cell permeability model, drugs were added to both the basal and apical sides of the cell monolayer, and the bidirectional permeability of the compounds was measured. Simultaneously, because efflux transporters are expressed on the basal side of the cells, the efflux ratio can be used to preliminarily assess whether a compound is an efflux substrate.

[0312] 4. Experimental Procedure

[0313] 4.1 Preparation of transport buffer: Take 1 mL of 1M HEPES and 99 mL of HBSS to prepare a 10 mM HBSS transport buffer.

[0314] 4.2 Preparation of fluorescein solution: Take 100 mL of transporter buffer and 100 μL (20 mM) of fluorescein solution to prepare 20 μM of fluorescein-containing working solution.

[0315] 4.3 Preparation of working solutions for compounds: To prepare the working solution for a compound, add 1 µL of the compound stock solution to 999 µL of working solution containing fluorescein, bringing the final concentration to 10 µM. The ratio and final concentration can be adjusted as needed based on the properties of the compound. Preparation of working solutions for control compounds: Follow the same procedure as for the control compounds.

[0316] 4.4 Preparation of reaction termination solution: Dilute the internal standard with acetonitrile (or other suitable solution) to prepare the termination solution and store it in a refrigerator at 2-8°C.

[0317] 4.5 Testing Process

[0318] a. Construction of a Caco-2 cell permeability model

[0319] Remove the Caco-2 plate from the incubator. Wash the monolayer twice with preheated HBSS (25 mM HEPES, pH 7.4). Then incubate at 37°C.

[0320] b. Compound permeability test

[0321] 1) Determine the transport rate of the compound from the top to the base. Take 8 μL of sample and add 72 μL of HBSS to 240 μL of acetonitrile containing internal standard as a sample administered to the top of the Transwell culture at 0 minutes for detection.

[0322] 2) To determine the transport rate of the compound from the base to the top, 8 μL of sample was added to 72 μL of HBSS and then to 240 μL of acetonitrile containing the internal standard. This was used as a sample administered via Transwell at the base side for 0 minutes for analysis.

[0323] 3) After merging the upper and lower devices, incubate them in a 37°C incubator for 120 min.

[0324] 4) Take 8 μL of sample from the drug delivery end (D end), dilute it 10 times with 72 μL of transport buffer, and add 240 μL of acetonitrile containing internal standard to terminate the process. This solution is used as the working solution for the drug delivery end (D end) at T120.

[0325] 5) Take 80 μL of A to B acceptor (R end) sample and add 240 μL of acetonitrile containing internal standard to terminate; take 100 μL of B to A acceptor (R end) sample and add 240 μL of acetonitrile containing internal standard to terminate.

[0326] 6) Take 20 μL of the base-side sample and add 100 μL of transport buffer; take 120 μL of the base-side sample and detect the fluorescence intensity at excitation / emission spectra of 480 / 530 nm.

[0327] 7) Centrifuge the sample at 3500 rpm for 10 min, and take the supernatant for LC-MS / MS analysis.

[0328] 4.6 Chromatographic Analysis

[0329] 1) Chromatographic conditions

[0330] Instrument: Shimadzu LC-30 AD; Column: HALO® 90Å, Biphemyl 2.7μm, 2.1×50mm; Mobile phase: A: 0.1% formic acid in water; B: 0.1% formic acid in acetonitrile Rinse gradient: 0~0.7 min 5%A to 95%A, 1.2~1.5 min 95%A to 5%A; Flow rate: 0.7 ml / min; run time: 1.5 min; injection volume: 5 µL.

[0331] 2) Mass spectrometry conditions

[0332] Instrument: API5500 Qtrap liquid chromatography-mass spectrometry system, AB Sciex; Ion source: Electrospray ionization source (ESI); Dry gas: N2, temperature 420°C; Electrospray voltage: 5500V; Detection method: positive ion detection; Scanning method: reaction monitoring (MRM) method; 5. Experimental Results: The bidirectional permeability of the compounds in the embodiments of the present invention through the Caco-2 cell model is shown in the table below. 6. Experimental conclusion: The compounds in the embodiments of the present invention have high permeability.

[0333] V. In vivo pharmacodynamic studies of the compounds in a collagen antibody-induced mouse model of arthritis

[0334] 1.1 Experimental Objective

[0335] To evaluate the in vivo efficacy of the compound in a collagen antibody-induced mouse model of arthritis.

[0336] 1.2 Reagents

[0337] 1. Mouse arthritis induction 5-clonal compound (53100, Chondrex)

[0338] 2. Tween 80 (30189828, Sinopharm Reagent)

[0339] 3. Sodium carboxymethyl cellulose (30036365, Sinopharm Reagent)

[0340] 1.3 Experimental Procedures and Data Processing

[0341] 1.3.1 Animal Procurement

[0342] BALB / c nude mice, 8-10 weeks old, female, purchased from Shanghai Bikeyi Biotechnology Co., Ltd.

[0343] 1.3.2 CAIA Model Establishment

[0344] a. After the animals have adapted for 2-3 days, they are tagged with disposable ear tags, weighed, and then randomly grouped according to their weight. b. On the day of the experiment (D0), administer 1.0 mg of a 5-clonal antibody mixture via the tail vein or intraperitoneal injection to the animals; c. One day later (D1), inject the animals intraperitoneally with 10 μg of E. coli lipopolysaccharide (LPS) (both 5-clone compound and LPS were thawed and placed on wet ice); 1.3.3 Drug administration and weighing score a. Six hours after injection of LPS on day 1, the test drug was administered (administration route: oral; administration volume: 10 mL / kg; administration frequency: QD / BID; administration period: 7 days; solvent: 0.5% CMC-Na / 1% Tween). b. Starting from day 2 of the experiment, mice were weighed daily, and their paw CAIA arthritis scores were recorded (from D2 to D7). CAIA Clinical Scoring Criteria (total score is the sum of 4 claws, total score 0-16) 0 is normal; 1. Redness and swelling in any part of the ankle / tarsal / toe joint; 2. Redness and swelling in any two of the following areas: ankle / tarsal / toe joints; 3. There is obvious redness and swelling in all three areas: ankle, tarsal, and toe joints; 4. Maximum inflammation and swelling of the ankle / tarsal / toe joints.

[0345] c. Euthanize the animals after the experiment.

[0346] d. Process the data using software such as Excel. Calculation of the percentage (%) of the compound inhibiting CAIA arthritis: TGI(%) = [1 - (mean arthritis score at the end of the treatment group of a certain compound / mean arthritis score at the end of the treatment group of the solvent)] × 100%.

[0347] 1.4 Experimental Results and Conclusions: In an antibody-collagen-induced mouse model of arthritis, the compounds of the present invention effectively improved arthritis symptoms and were well tolerated by animals at therapeutic doses. Oral administration of the compounds of the present invention (30 mg / kg, BID) showed a relative therapeutic rate of 55% to 95% based on the D7 score, with some compounds showing a relative therapeutic rate of 70% to 90%.

[0348] VI. In vitro metabolic stability study of the compounds of this invention in liver microsomes of mice, rats and dogs

[0349] 1. Experimental objective: The objective of this experiment is to evaluate the metabolic stability of the compound in phase I and part of phase II of the liver microsomes in mice, rats and dogs.

[0350] 2. Experimental Design

[0351] 2.1 Test reagents: The compounds of this invention, prepared in-house, Alamethicin (Abcam), 7-Hydroxycoumarin (Sigma), liver microsomes (XenoTech, Shanghai Quanyang Biotechnology Co., Ltd.), phosphate buffer (Gibco, Lot#SLBS7904 and Lot#SLBR3106V, pH 7.4), NADPH (reduced nicotinamide adenine dinucleotide phosphate, Shanghai Bid Pharmaceutical Technology Co., Ltd.), UDPGA (Sigma), Alamethicin (Abcam), methanol (Merck), and acetonitrile (Merck).

[0352] 2.2 Drug preparation: The compounds of the present invention are prepared into 10 mM stock solutions using DMSO (or other suitable solutions) and stored at -20 °C for later use.

[0353] The control compound, 7-Hydroxycoumarin, was prepared as a 10 mM stock solution for later use.

[0354] 2.3 Experimental Procedure

[0355] 1) Prepare buffer solution: Take 4.01 mL of 1M K2HPO4·3H2O (AR grade) and 0.99 mL of 1M KH2PO4 (AR grade), dissolve them in ultrapure water and bring the volume to 50 mL to prepare a phosphate buffer solution with a final concentration of 100 mM.

[0356] 2) Preparation of compound working solution

[0357] Preparation of the working solution for the compound: Add 2 µL of the compound stock solution to 998 µL of phosphate buffer to a final concentration of 20 µM. The ratio of the solutions can be adjusted to adjust the final concentration according to the properties of the compound.

[0358] Preparation of working solution for control compound: The preparation process should be consistent with that of control compound.

[0359] 3) Prepare liver microsome working solution: 156.3 µL of 20 mg / mL microsomes, diluted with 100 mM phosphate buffer to 5 mL, mixed well, with a final concentration of 0.625 mg / mL.

[0360] 4) Prepare NADPH and UDPGA: Weigh 33.3 mg of NADPH and 25.8 mg of UDPGA, add 2 mL of 100 mM phosphate buffer, and the final concentration of both is 20 mM.

[0361] 5) Prepare the pore-drilling agent (Alamethicin): Weigh 1 mg of Alamethicin and add it to 200 µL of methanol to prepare a 5 mg / mL solution. Then take 10 µL of this solution and add it to 990 µL of phosphate buffer (pH 7.4) to obtain a final concentration of 50 µg / mL.

[0362] 6) Prepare the reaction termination solution: Dilute the internal standard with acetonitrile (or other suitable solution) to prepare the termination solution and store it in a refrigerator at 2-8°C.

[0363] 7) Incubation Procedure: Add 400 µL of prepared liver microsomes, 25 µL of the compound working solution (10 µM), and 25 µL of Alamethicin (50 µg / mL) sequentially to a 96-well plate, and pre-incubate at 37 °C for 10 min. Then add 50 µL of prepared NADPH / UDPGA to initiate the reaction, and incubate at 37 °C. The total volume of the reaction system is 500 µL. The final concentrations of each component are as follows: At time points of 0, 5, 15, 30, 60 and 120 min, 50 µL of each sample was taken and 200 µL of cold stop solution containing internal standard was added to terminate the reaction. The sample was centrifuged at 3500 rpm for 10 min and the supernatant was taken for LC-MS / MS analysis.

[0364] 2.4 Chromatographic Analysis

[0365] 1) Chromatographic conditions

[0366] Instrument: Shimadzu LC-30 AD; Column: XBridge® C18 (50) 4.6 mm, 5 µm particle size); Mobile phase: A: 0.1% formic acid aqueous solution, B: methanol; Flushing gradient: 0.2~1.6 min 10%A to 95%A, 3.0~3.1 min 95%A to 10%A; Flow rate: 1.0 ml / min; Run time: 4.0 min; Injection volume: 5 µL.

[0367] 2) Mass spectrometry conditions

[0368] Instrument: API5500 Qtrap liquid chromatography-mass spectrometry system, AB Sciex; Ion source: Electrospray ionization source (ESI); Dry gas: N2, temperature 500°C; Electrospray voltage: 5000V; Detection method: positive ion detection; Scanning method: Measurand Reaction Monitoring (MRM) method; 3. Experimental Results and Data Processing The original data is calculated using the following formula: Residual rate % = (Peak area ratio of compound to internal standard at any time point) / (Peak area ratio of compound to internal standard at 0 minutes) × 100 T 1 / 2 =0.693 / Ke, where Ke represents the elimination rate constant.

[0369] In vitro intrinsic clearance rate of liver microsomes (CL) was calculated using Ke. int ) and hepatic intrinsic clearance (CL) int, liver )

[0370] CL int = 0.693 / T 1 / 2 / Microsomal protein content (microsomal concentration during incubation, mg / mL)

[0371] CL int,liver =CL int × Liver microsomal protein content (mg / g) × Liver weight to body weight ratio

[0372] Based on the well-stirred model, the in vivo liver clearance rate (CL) was estimated. int, liver )

[0373] CL = (CL) int,liver × fu × Qh) / (CL int,liver × fu + Qh), where fu represents the free fraction in the blood, which is 1 by default.

[0374] The parameters in the formula are shown in the table below.

[0375] The test results are as follows: Experimental conclusion: The compounds of this invention have good metabolic stability.

[0376] Research on Salts and Their Crystal Forms

[0377] 1. Experimental Apparatus

[0378] 1.1 Some parameters of physicochemical testing instruments 2. Preparation of different salt forms of the compounds in Examples 2 and 6

[0379] 2.1 The salt formation of the compound in Example 2 with different acid counterions was investigated and screened.

[0380] The experiments were conducted using six solvents: ethanol, acetone, ethyl acetate, acetonitrile, tetrahydrofuran, and dichloromethane, as well as hydrochloric acid, hydrobromic acid, sulfuric acid, methanesulfonic acid, and p-toluenesulfonic acid. Acids were dissolved in organic solvents or water, or added directly.

[0381] Weigh approximately 10 mg of the free base of compound Example 2, add 45 μl of solvent, sonicate to completely dissolve, stir at room temperature, add acid (molar reaction ratio of free base to acid = 1:1.2) to carry out the reaction, and the precipitated solid is dried under vacuum at 40°C and then characterized by XRPD to obtain the salt of the corresponding acid and the crystal form A of hydrochloride, sulfate and hydrobromide.

[0382] 2.2 The compounds in Example 6 were investigated and screened for salt formation with different acid counterions.

[0383] 2.2.1 The experiments were conducted using methanol, acetone, and ethyl acetate as solvents, and hydrochloric acid, hydrobromic acid, sulfuric acid, methanesulfonic acid, p-toluenesulfonic acid, and benzenesulfonic acid as solvents. Acids were dissolved in organic solvents or water, or added directly.

[0384] Weigh approximately 20 mg of the free base from Example 6, add 45 μl of solvent, sonicate until completely dissolved, stir at room temperature, add an acid solution (free base: acid = 1:1.2 molar reaction ratio) to react, precipitate a solid, dry under vacuum at 40°C, and perform XRPD characterization to obtain the corresponding acid salt and hydrochloride crystal form A and p-toluenesulfonate crystal form A.

[0385] 2.2.2 Acetonitrile, acetone, and ethyl acetate were used as solvents for experiments, along with phosphoric acid, acetic acid, maleic acid, fumaric acid, tartaric acid, malonic acid, malic acid, citric acid, and oxalic acid. Acids were dissolved in organic solvents or water, or added directly.

[0386] Weigh approximately 20 mg of the free base of the compound from Example 6, add 45 μl of solvent, sonicate until completely dissolved, stir at room temperature, suspend, add acid (free base: acid = 1:1.2 molar reaction ratio) to carry out the reaction, and the precipitated solid was dried under vacuum at 40°C and characterized by XRPD to obtain the salts of the corresponding acids and fumarate crystal form A, oxalate crystal form A and phosphate crystal form A.

[0387] 2.3 Preparation of the crystal form of the salt in Example 2

[0388] Add 200 μL of ethyl acetate to the acidic salt sample from section 2.1, and after stirring at room temperature for one week, centrifuge and dry the sample to test XRPD.

[0389] Through the above experiments, sulfate crystal form A, hydrochloride crystal form A and hydrobromide crystal form A were obtained.

[0390] 2.4 Example 2 Preparation of hydrochloride and hydrobromide

[0391] Weigh approximately 50 mg of the free base of the compound from Example 2, add 500 μL of reaction solvent to dissolve the sample, add different counterion solutions at a molar ratio of 1:1.2, stir overnight at room temperature, and if solid precipitates, dry the sample and test for XRPD.

[0392]

[0393] 3. Example 6: Screening of Hydrochloride Crystal Forms

[0394] 3.1 Weigh about 10 mg of the hydrochloride crystal form A obtained in Example 6 above, add 200 μl of solvent, suspend at room temperature for 1 week (1 w), then centrifuge and dry or dissolve, and detect the crystal form by XRPD.

[0395] 3.2 Weigh approximately 10 mg of the free base of the compound from Example 6, add 200 μl of different solvents, add hydrochloric acid (1.2 equivalents) and methanol solution, stir magnetically for 3 days (3d), centrifuge and dry the precipitated solid, volatilize the unprecipitated solid, and detect the crystal form by XRPD.

[0396] 4. Example 6: Screening of Fumarate Crystal Forms

[0397] 4.1 Weigh approximately 25 mg of the free base of the compound from Example 6 and approximately 5.3 mg of fumaric acid solid, add 500 μL of reaction solvent, stir overnight at room temperature, centrifuge and dry the sample to test XRPD.

[0398] 4.2 Weigh about 15 mg of the fumarate crystal form A of the compound in Example 6, add 150 / 300 μL of reaction solvent, stir at room temperature for 7 days, then centrifuge and dry the sample to test XRPD.

[0399] Through the above experiments, fumarate crystal form A and fumarate crystal form B were obtained.

[0400] 5. Study on crystal form stability

[0401] 5.1 Chromatographic conditions

[0402] 5.2 Crystal form stability investigation

[0403] 0.5 mg of each of the following crystal forms were weighed: Example 6 Hydrochloride Crystal Form A, Example 6 p-Toluenesulfonate Crystal Form A, Example 6 Fumarate Crystal Form A, Example 2 Hydrochloride Crystal Form A, Example 2 Sulfate Crystal Form A, and Example 2 Hydrobromide Crystal Form A. Each was placed in a 2 mL glass bottle and subjected to light (5000±500 lx), high temperature (60°C), high humidity (92.5% RH), and high temperature and high humidity (50°C, 75%) conditions, respectively. Samples were taken and tested after 7 and 14 days. The test results are as follows: 5.2.1 Stability results of hydrochloride crystal form A in Example 6

[0404] 5.2.2 Stability results of p-Toluenesulfonate crystal form A in Example 6

[0405] 5.2.3 The stability results of fumarate crystal form A in Example 6 are as follows:

[0406] 5.2.4 The stability results of hydrochloride crystal form A in Example 2 are as follows:

[0407] 5.2.5 The stability results of sulfate crystal form A in Example 2 are as follows:

[0408] 5.2.6 The stability results of hydrobromide crystal form A in Example 2 are as follows:

[0409] 5.3 Experimental Results

[0410] Based on stability data, the crystal form of this invention is relatively stable under conditions such as high temperature, high humidity, high temperature and high humidity, and light exposure, with no significant increase in impurities observed, which can well meet the requirements of later drug development.

[0411] Free base crystal form study

[0412] 1. Preparation of different crystal forms of the compound in Example 6

[0413] 1.1 Preparation of Crystal Form 1

[0414] Weigh 50 mg of the amorphous compound from Example 6 and place it in a liquid chromatography vial. Add 0.5 mL of methanol, sonicate to dissolve, and allow to evaporate overnight at room temperature to precipitate a white solid. XRPD analysis showed that it was a free base crystal form 1.

[0415] Weigh 5g of the amorphous compound from Example 6 into a reaction vessel, add 50mL of methanol, stir and dissolve at 30-35℃, and filter. Cool the filtrate to -5-0℃, add 100mg of free base crystal form 1 seed crystals under stirring, and a white solid precipitates. Stir and crystallize for 2-3 hours, filter, and vacuum dry at 40℃ for 8-10 hours. XRPD analysis shows it to be free base crystal form 1.

[0416] 1.2 Preparation of Crystal Form 2

[0417] Weigh 50 mg of the amorphous compound from Example 6 and place it in a liquid chromatography vial. Add 0.5 mL of ethanol, sonicate to dissolve, and stir overnight at room temperature. A white solid precipitates out. After centrifugation, dry under vacuum at 40°C for 8-10 hours. XRPD analysis shows that it is free base crystal form 2.

[0418] Weigh 50 mg of the amorphous compound from Example 6 into a liquid chromatography vial, add 0.5 mL of isopropanol, sonicate to dissolve, and stir overnight at room temperature. A white solid precipitates out. After centrifugation, dry under vacuum at 40°C for 8-10 hours. XRPD analysis shows it to be free base crystal form 2.

[0419] Weigh 50 mg of the amorphous compound from Example 6 into a liquid chromatography vial, add 0.5 mL of MTBE, suspend and stir overnight at room temperature, centrifuge, and then vacuum dry at 40°C for 8-10 hours. XRPD analysis showed that it was free base crystal form 2.

[0420] Weigh 50 mg of the amorphous compound from Example 6 into a liquid chromatography vial, add 0.5 mL of isopropyl ether, suspend and stir overnight at room temperature, centrifuge, and then vacuum dry at 40°C for 8-10 hours. XRPD analysis showed that it was free base crystal form 2.

[0421] Weigh 2g of the amorphous compound from Example 6 into a reaction vessel, add 20mL of ethanol, and stir to dissolve at 30-35℃. Cool to 20-25℃, stir for 30min, and a white solid precipitates. Continue stirring for 3-4h, then filter, and vacuum dry at 40℃ for 8-10h. XRPD analysis shows it to be free base crystal form 2.

[0422] 1.3 Preparation of Crystal Form 3

[0423] Weigh 50 mg of the amorphous form of compound 6 in a liquid chromatography vial, add 0.5 mL of ethyl acetate, suspend and stir overnight at room temperature, centrifuge, and then vacuum dry at 40 °C for 8-10 hours. XRPD analysis showed that it was free base crystal form 3.

[0424] Weigh 50 mg of the amorphous form of compound 6 in a liquid chromatography vial, add 0.5 mL of acetone, sonicate to dissolve, and stir overnight at room temperature. A white solid precipitates out. After centrifugation, dry under vacuum at 40°C for 8-10 hours. XRPD analysis shows that it is free base crystal form 3.

[0425] Weigh 50 mg of the amorphous form of compound 6 in a liquid chromatography vial, add 0.5 mL of acetonitrile, sonicate to dissolve, and stir overnight at room temperature. A white solid precipitates out. After centrifugation, dry under vacuum at 40°C for 8-10 hours. XRPD analysis shows that it is free base crystal form 3.

[0426] Weigh 50 mg of the amorphous form of compound 6 in a liquid chromatography vial, add 0.5 mL of toluene, sonicate to dissolve, and stir overnight at room temperature. A white solid precipitates, which is then centrifuged and dried under vacuum at 40 °C for 8-10 hours. XRPD analysis shows that it is free base crystal form 3.

[0427] 1.4 Preparation of Crystal Form 4

[0428] Weigh 50 mg of the amorphous form of compound 6 in a liquid chromatography vial, add 0.5 mL of tetrahydrofuran, sonicate to dissolve, and stir overnight at room temperature. A white solid precipitates, which is then centrifuged and dried under vacuum at 40°C for 8-10 hours. XRPD analysis shows that it is free base crystal form 4.

[0429] Weigh 50 mg of the amorphous form of compound 6 in a liquid chromatography vial, add 0.5 mL of 2-methyltetrahydrofuran, sonicate to dissolve, and stir overnight at room temperature. A white solid precipitates, which is then centrifuged and dried under vacuum at 40°C for 8-10 hours. XRPD analysis shows that it is free base crystal form 4.

[0430] 1.5 Preparation of crystal form 5

[0431] Weigh 50 mg of the amorphous form of compound 6 in a liquid chromatography vial, add 0.5 mL of n-hexane, suspend and stir at room temperature overnight, centrifuge, and then vacuum dry at 40 °C for 8-10 hours. XRPD analysis showed that it was free base crystal form 5.

[0432] Weigh 50 mg of the amorphous form of compound 6 in a liquid chromatography vial, add 0.5 mL of n-heptane, suspend and stir overnight at room temperature, centrifuge, and then vacuum dry at 40 °C for 8-10 hours. XRPD analysis showed that it was free base crystal form 5.

[0433] Weigh 50 mg of the amorphous form of compound 6 in a liquid chromatography vial, add 0.5 mL of water, suspend and stir at room temperature overnight, centrifuge, and then vacuum dry at 40 °C for 8-10 hours. XRPD analysis showed that it was free base crystal form 5.

[0434] 2. Stability assessment of crystal form 2

[0435] Weigh 0.5 mg of crystal form 2 and place it in a 2 mL glass bottle. Expose it to light (5000±500 lx), high temperature (60℃), high humidity (92.5% RH), and high temperature and high humidity (50℃, 75%) conditions. Samples were taken and tested after 7 and 14 days. The test results are as follows: Crystal form 2 stability data

[0436] in conclusion: Based on stability data, the crystal form of this invention is relatively stable under high temperature, high humidity, and high temperature and high humidity conditions, with no significant increase in impurities observed, which can well meet the requirements of later drug development.

Claims

1. A free base crystal form, acid salt, or crystal form thereof of a compound of general formula (I) or its stereoisomers, ； in, M 16 Selected from N or CR2; R and R' are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl, the amino, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl groups may optionally be further converted by hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 One or more substitutions of aryl and 5-10 heteroaryl groups; R1 is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl, the amino, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl groups may optionally be further converted by hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 One or more substitutions of aryl and 5-10 heteroaryl groups; R2 is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl, the amino, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl groups may optionally be further converted by hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 One or more substitutions of aryl and 5-10 heteroaryl groups; R4 is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl, wherein the amino group, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl groups may optionally be further converted by hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 6-10 One or more substitutions of aryl and 5-10 heteroaryl groups; x is 1, 2, 3, 4 or 5; The acid is an inorganic acid or an organic acid, wherein the inorganic acid is selected from hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, hydrofluoric acid, hydroiodic acid, or phosphoric acid; the organic acid is selected from 2,5-dihydroxybenzoic acid, 1-hydroxy-2-naphtholic acid, acetic acid, dichloroacetic acid, trichloroacetic acid, acetoxyxamic acid, adipic acid, 4-chlorobenzenesulfonic acid, benzoic acid, 4-acetaminobenzoic acid, 4-aminobenzoic acid, decanoic acid, hexanoic acid, caprylic acid, cinnamic acid, citric acid, cyclohexanesulfonic acid, camphorsulfonic acid, aspartic acid, camphoric acid, gluconic acid, glucuronic acid, glutamic acid, isoascorbic acid, lactic acid, malic acid, mandelic acid, pyroglutamic acid, tartaric acid, dodecyl sulfate, dibenzoyl tartaric acid, ethane-1, 2-Disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galactobionic acid, gentian acid, glutaric acid, 2-ketoglutaric acid, glycolic acid, hippuric acid, hydroxyethylsulfonic acid, lactobionic acid, ascorbic acid, aspartic acid, lauric acid, camphoric acid, maleic acid, malonic acid, methanesulfonic acid, 1,5-naphthalenedisulfonic acid, naphthalene-2-sulfonic acid, nicotinic acid, oleic acid, orotic acid, oxalic acid, palmitic acid, dihydroxynaphthalic acid, propionic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, thiocyanate, undecanoic acid, trifluoroacetic acid, benzenesulfonic acid, p-toluenesulfonic acid, or L-malic acid; preferably hydrochloric acid, sulfuric acid, hydrobromic acid, p-toluenesulfonic acid, fumaric acid, phosphoric acid, or oxalic acid; most preferably hydrochloric acid, sulfuric acid, hydrobromic acid, or fumaric acid.

2. The acid salt of the compound or its stereoisomer according to claim 1, or its crystal form, characterized in that, R and R' are each independently selected from hydrogen, deuterium, halogen, and C. 1-3 Alkyl, C 1-3 Deuterated alkyl or C 1-3 Halogenated alkyl; preferably hydrogen or halogen; more preferably hydrogen or F; R1 is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, and C. 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 Hydroxyalkyl; preferably hydrogen, methyl, ethyl, NH2, OH, CN, CD3, F, Cl, CHF2, CH2F, CF3, OCF3, CH2OH, , , or ; R2 is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, and C. 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 Hydroxyalkyl; preferably hydrogen or halogen, more preferably hydrogen or F; R4 is selected from hydrogen, methyl, ethyl, or deuterated methyl; Further preferred Selected from , , , , , or .

3. The acid salt of the compound or its stereoisomer according to claim 1 or 2, or its crystal form, characterized in that, The compound is shown below: or .

4. The free base crystal form, acid salt, or crystal form of the compound or its stereoisomer according to any one of claims 1 to 3, characterized in that, The free base crystal form or acid salt is a hydrate or anhydrous form; when the acid salt is a hydrate, the number of water molecules is 0.2-3; preferably 0.2, 0.5, 1, 1.5, 2, 2.5 or 3. The free base crystal form or acid salt crystal form is a solvate crystal form, a hydrate crystal form, or an anhydrous crystal form; when the crystal form is a hydrate or solvate, the number of water or solvent is 0.2-3; preferably 0.2, 0.5, 1, 1.5, 2, 2.5 or 3, and more preferably 2.

5. The free base crystal form, acid salt, or crystal form of the compound or its stereoisomer according to any one of claims 1 to 4, characterized in that, The number of acids in the acid salt is 0.2-3; preferably 0.2, 0.5, 1, 1.5, 2, 2.5 or 3; more preferably 0.5, 1, 2 or 3, and even more preferably 1.

6. The free base crystal form, acid salt, or crystal form of the compound or its stereoisomer according to any one of claims 1 to 5, characterized in that, It is (1S,3s)-3-amino-3-(5-((8R,15R)-2,2-difluoro-7-(methyl-d3)-6-carbonyl-6,7,8,15-tetrahydro-8,15-methylene[1,3]dioxazolo[4',5':3,4]benzo[1,2-f]benzo[4,5]imidazo[1,2-a][1,4]diacoxin-12-yl)pyrimidin-2-yl)-1-methylcyclobutane-1-carboxynitrile hydrochloride crystal form A; The X-ray powder diffraction pattern of the hydrochloride crystal form A shows a diffraction peak at 2θ of 6.0 ± 0.2°; or at 6.3 ± 0.2°; or at 12.0 ± 0.2°; or at 16.1 ± 0.2°; or at 16.4 ± 0.2°; or at 16.9 ± 0.2°; or at 18.4 ± 0.2°. The diffraction peaks are present; or diffraction peaks are present at 19.9±0.2°; or diffraction peaks are present at 22.9±0.2°; or diffraction peaks are present at 25.9±0.2°; preferably, any 2-5, 3-5, 3-6, 3-8, 5-8, 6-8, or 8-10 of the above diffraction peaks are included; more preferably, any 6, 7, 8, 9, or 10 of the above diffraction peaks are included. Alternatively, it is (1S,3s)-3-amino-3-(5-((8R,15R)-2,2-difluoro-7-(methyl-d3)-6-carbonyl-6,7,8,15-tetrahydro-8,15-methylene[1,3]dioxazolo[4',5':3,4]benzo[1,2-f]benzo[4,5]imidazo[1,2-a][1,4]diacoxin-12-yl)pyrimidin-2-yl)-1-methylcyclobutane-1-carboxynitrile p-toluenesulfonate crystal form A; The X-ray powder diffraction pattern of the p-toluenesulfonate crystal form A shows a diffraction peak at 2θ of 4.6 ± 0.2°; or at 9.2 ± 0.2°; or at 10.1 ± 0.2°; or at 14.1 ± 0.2°; or at 15.8 ± 0.2°; or at 16.8 ± 0.2°; or at 17.9 ± 0.2°. It has diffraction peaks; or has diffraction peaks at 18.8±0.2°; or has diffraction peaks at 20.7±0.2°; or has diffraction peaks at 25.1±0.2°; preferably includes any 2-5, 3-5, 3-6, 3-8, 5-8, 6-8, or 8-10 of the above diffraction peaks; more preferably includes any 6, 7, 8, 9, or 10 of them; Alternatively, it is (1S,3s)-3-amino-3-(5-((8R,15R)-2,2-difluoro-7-(methyl-d3)-6-carbonyl-6,7,8,15-tetrahydro-8,15-methylene[1,3]dioxazolo[4',5':3,4]benzo[1,2-f]benzo[4,5]imidazo[1,2-a][1,4]diacoxin-12-yl)pyrimidin-2-yl)-1-methylcyclobutane-1-carboxynitrile fumarate crystal form A; The X-ray powder diffraction pattern of the fumarate crystal form A shows a diffraction peak at 2θ of 9.5 ± 0.2°; or at 12.7 ± 0.2°; or at 13.9 ± 0.2°; or at 17.2 ± 0.2°; or at 18.2 ± 0.2°; or at 19.1 ± 0.2°; or at 23.2 ± 0.2°. It has diffraction peaks; or has diffraction peaks at 23.9±0.2°; or has diffraction peaks at 27.9±0.2°; or has diffraction peaks at 30.4±0.2°; preferably includes any 2-5, 3-5, 3-6, 3-8, 5-8, 6-8, or 8-10 of the above diffraction peaks; more preferably includes any 6, 7, 8, 9, or 10 of them; Alternatively, it is (1S,3s)-3-amino-3-(5-((8R,15R)-2,2-difluoro-7-(methyl-d3)-6-carbonyl-6,7,8,15-tetrahydro-8,15-methylene[1,3]dioxazolo[4',5':3,4]benzo[1,2-f]benzo[4,5]imidazo[1,2-a][1,4]diacoxin-12-yl)pyrimidin-2-yl)-1-methylcyclobutane-1-carboxynitrile fumarate crystal form B; The X-ray powder diffraction pattern of the fumarate crystal form B shows a diffraction peak at 2θ of 6.9 ± 0.2°; or at 7.4 ± 0.2°; or at 10.5 ± 0.2°; or at 12.6 ± 0.2°; or at 13.1 ± 0.2°; or at 15.2 ± 0.2°; or at 18.7 ± 0.2°. It has diffraction peaks; or has diffraction peaks at 22.1±0.2°; or has diffraction peaks at 26.0±0.2°; or has diffraction peaks at 26.2±0.2°; preferably includes any 2-5, 3-5, 3-6, 3-8, 5-8, 6-8, or 8-10 of the above diffraction peaks; more preferably includes any 6, 7, 8, 9, or 10 of them; Alternatively, it is (1S,3s)-3-amino-3-(5-((8R,15R)-2,2-difluoro-7-(methyl-d3)-6-carbonyl-6,7,8,15-tetrahydro-8,15-methylene[1,3]dioxazolo[4',5':3,4]benzo[1,2-f]benzo[4,5]imidazo[1,2-a][1,4]diacoxine-12-yl)pyrimidin-2-yl)-1-methylcyclobutane-1-carboxynitrile phosphate crystal form A; The X-ray powder diffraction pattern of the phosphate crystal form A shows a diffraction peak at 2θ of 4.3 ± 0.2°; or at 6.7 ± 0.2°; or at 8.6 ± 0.2°; or at 10.4 ± 0.2°; or at 14.4 ± 0.2°; or at 16.3 ± 0.2°; or at 17.3 ± 0.2°. The diffraction peaks are present; or diffraction peaks are present at 20.6±0.2°; or diffraction peaks are present at 20.9±0.2°; or diffraction peaks are present at 26.4±0.2°; preferably, any 2-5, 3-5, 3-6, 3-8, 5-8, 6-8, or 8-10 of the above diffraction peaks are included; more preferably, any 6, 7, 8, 9, or 10 of the above diffraction peaks are included. Alternatively, it is (1S,3s)-3-amino-3-(5-((8R,15R)-2,2-difluoro-7-(methyl-d3)-6-carbonyl-6,7,8,15-tetrahydro-8,15-methylene[1,3]dioxazolo[4',5':3,4]benzo[1,2-f]benzo[4,5]imidazo[1,2-a][1,4]diacoxin-12-yl)pyrimidin-2-yl)-1-methylcyclobutane-1-carboxynitrile oxalate crystal form A; The X-ray powder diffraction pattern of the oxalate crystal form A has a diffraction peak at 2θ of 10.2 ± 0.2°; or at 11.8 ± 0.2°; or at 14.4 ± 0.2°; or at 20.1 ± 0.2°; or at 20.6 ± 0.2°; or at 24.6 ± 0.2°; preferably including any 2-5, 3-5, or 3-6 of the above diffraction peaks; more preferably including any 4, 5, or 6 of them.

7. The free base crystal form, acid salt, or crystal form of the compound or its stereoisomer according to claim 6, characterized in that, The X-ray powder diffraction pattern of the hydrochloride crystal form A includes at least one or more diffraction peaks located at 2θ of 12.0±0.2°, 16.9±0.2°, 19.9±0.2°, and 25.9±0.2°, preferably two, more preferably three or four; even more preferably, it may also include at least one of 2θ of 6.0±0.2°, 6.3±0.2°, 16.1±0.2°, 16.4±0.2°, 18.4±0.2°, and 22.9±0.2°, preferably two, three, four, five, or six. More preferably, the X-ray powder diffraction pattern of the hydrochloride crystal form A includes one or more diffraction peaks located at 6.0±0.2°, 6.3±0.2°, 12.0±0.2°, 16.1±0.2°, 16.4±0.2°, 16.9±0.2°, 18.4±0.2°, 19.9±0.2°, 22.9±0.2°, and 25.9±0.2°; preferably, it includes diffraction peaks at any of the selected 4, 5, 6, 8, or 10 locations. More preferably, the X-ray powder diffraction pattern of the hydrochloride crystal form A may also include one or more diffraction peaks with 2θ values ​​of 17.8±0.2°, 20.4±0.2°, 22.1±0.2°, 22.3±0.2°, 22.5±0.2°, and 25.1±0.2°; preferably, it includes at least 2-3, 4-5, or 5-6 peaks; more preferably, it includes any 2, 3, 4, 5, or 6 peaks. For example, the X-ray powder diffraction pattern of the hydrochloride crystal form A has diffraction peaks at the following positions with a 2θ value: 6.0±0.2°、12.0±0.2°、16.4±0.2°、16.9±0.2°、18.4±0.2°、22.9±0.2°； 6.0±0.2°、12.0±0.2°、16.4±0.2°、16.9±0.2°、18.4±0.2°、19.9±0.2°、25.9±0.2°； 6.0±0.2°、12.0±0.2°、16.4±0.2°、16.9±0.2°、18.4±0.2°、19.9±0.2°、22.9±0.2°； 6.0±0.2°、12.0±0.2°、16.4±0.2°、16.9±0.2°、18.4±0.2°、22.9±0.2°、25.1±0.2°； 6.0±0.2°、6.3±0.2°、12.0±0.2°、16.4±0.2°、16.9±0.2°、18.4±0.2°、19.9±0.2°、25.9±0.2°； 6.0±0.2°、12.0±0.2°、16.4±0.2°、16.9±0.2°、18.4±0.2°、19.9±0.2°、22.9±0.2°、25.9±0.2°； 6.0±0.2°、6.3±0.2°、12.0±0.2°、16.1±0.2°、16.4±0.2°、16.9±0.2°、18.4±0.2°、22.9±0.2°； 6.0±0.2°、6.3±0.2°、12.0±0.2°、16.1±0.2°、16.4±0.2°、16.9±0.2°、18.4±0.2°、19.9±0.2°、22.9±0.2°； 6.0±0.2°、6.3±0.2°、12.0±0.2°、16.1±0.2°、16.4±0.2°、16.9±0.2°、18.4±0.2°、22.9±0.2°、25.9±0.2°； Most preferably, the X-ray powder diffraction pattern of the hydrochloride crystal form A is basically as shown in Figure 1; its DSC pattern is basically as shown in Figure 2; and its TGA pattern is basically as shown in Figure 3. The X-ray powder diffraction pattern of the p-toluenesulfonate crystal form A includes at least one or more diffraction peaks located at 2θ of 4.6±0.2°, 10.1±0.2°, 17.9±0.2°, and 18.8±0.2°, preferably two, more preferably three or four; even more preferably, it may also include at least one of 2θ of 9.2±0.2°, 14.1±0.2°, 15.8±0.2°, 16.8±0.2°, 20.7±0.2°, and 25.1±0.2°, preferably two, three, four, five, or six. More preferably, the X-ray powder diffraction pattern of the p-toluenesulfonate crystal form A includes one or more diffraction peaks located at 2θ of 4.6±0.2°, 9.2±0.2°, 10.1±0.2°, 14.1±0.2°, 15.8±0.2°, 16.8±0.2°, 17.9±0.2°, 18.8±0.2°, 20.7±0.2°, and 25.1±0.2°; preferably, it includes diffraction peaks at any of 4, 5, 6, 7, 8, or 10 locations. More preferably, the X-ray powder diffraction pattern of the p-toluenesulfonate crystal form A may also include one or more diffraction peaks with 2θ values ​​of 12.9±0.2°, 13.8±0.2°, 16.4±0.2°, 18.4±0.2°, 19.6±0.2°, and 22.2±0.2°; preferably, it includes at least 2-3, 4-5, or 5-6 peaks; more preferably, it includes any 2, 3, 4, 5, or 6 peaks. For example, the X-ray powder diffraction pattern of p-toluenesulfonate crystal form A shows diffraction peaks at the following positions with a 2θ value: 4.6±0.2°、10.1±0.2°、14.1±0.2°、16.8±0.2°、17.9±0.2°、18.8±0.2°、25.1±0.2°； 4.6±0.2°、10.1±0.2°、14.1±0.2°、15.8±0.2°、16.8±0.2°、18.8±0.2°、25.1±0.2°； 4.6±0.2°、10.1±0.2°、14.1±0.2°、16.8±0.2°、18.8±0.2°、20.7±0.2°、25.1±0.2°； 4.6±0.2°、10.1±0.2°、14.1±0.2°、16.4±0.2°、16.8±0.2°、18.8±0.2°、25.1±0.2°； 4.6±0.2°、10.1±0.2°、14.1±0.2°、16.4±0.2°、16.8±0.2°、17.9±0.2°、18.8±0.2°、25.1±0.2°； 4.6±0.2°、10.1±0.2°、14.1±0.2°、16.8±0.2°、17.9±0.2°、18.8±0.2°、20.7±0.2°、25.1±0.2°； 4.6±0.2°、10.1±0.2°、14.1±0.2°、16.8±0.2°、17.9±0.2°、18.8±0.2°、19.6±0.2°、25.1±0.2°； 4.6±0.2°、10.1±0.2°、14.1±0.2°、16.4±0.2°、16.8±0.2°、17.9±0.2°、18.8±0.2°、20.7±0.2°、25.1±0.2°； 4.6±0.2°、10.1±0.2°、14.1±0.2°、15.8±0.2°、16.8±0.2°、17.9±0.2°、18.8±0.2°、20.7±0.2°、25.1±0.2°； Most preferably, the X-ray powder diffraction pattern of the p-toluenesulfonate crystal form A is basically as shown in Figure 4; its DSC pattern is basically as shown in Figure 5; and its TGA pattern is basically as shown in Figure 6. The X-ray powder diffraction pattern of the fumarate crystal form A includes at least one or more diffraction peaks located at 2θ of 13.9±0.2°, 18.2±0.2°, 23.2±0.2°, and 23.9±0.2°, preferably two of these peaks, more preferably three or four; even more preferably, it may also include at least one of 2θ of 9.5±0.2°, 12.7±0.2°, 17.2±0.2°, 19.1±0.2°, 27.9±0.2°, and 30.4±0.2°, preferably two, three, four, five, or six of these peaks. More preferably, the X-ray powder diffraction pattern of the fumarate crystal form A includes one or more diffraction peaks located at 2θ of 9.5±0.2°, 12.7±0.2°, 13.9±0.2°, 17.2±0.2°, 18.2±0.2°, 19.1±0.2°, 23.2±0.2°, 23.9±0.2°, 27.9±0.2°, and 30.4±0.2°; preferably, it includes diffraction peaks at any of 4, 5, 6, 7, 8, or 10 locations. More preferably, the X-ray powder diffraction pattern of the fumarate crystal form A may also include one or more diffraction peaks with 2θ values ​​of 16.7±0.2°, 20.4±0.2°, 21.4±0.2°, 23.4±0.2°, 24.2±0.2°, and 29.7±0.2°; preferably, it includes at least 2-3, 4-5, or 5-6 peaks; more preferably, it includes any 2, 3, 4, 5, or 6 peaks. For example, the X-ray powder diffraction pattern of fumarate crystal form A shows diffraction peaks at the following positions with a 2θ value: 9.5±0.2°、12.7±0.2°、13.9±0.2°、18.2±0.2°、19.1±0.2°、23.2±0.2°、23.9±0.2°； 9.5±0.2°、12.7±0.2°、13.9±0.2°、18.2±0.2°、23.2±0.2°、23.9±0.2°、27.9±0.2°； 9.5±0.2°、12.7±0.2°、13.9±0.2°、18.2±0.2°、23.2±0.2°、23.9±0.2°、27.9±0.2°、30.4±0.2°； 9.5±0.2°、12.7±0.2°、13.9±0.2°、18.2±0.2°、19.1±0.2°、23.2±0.2°、23.9±0.2°、30.4±0.2°； 9.5±0.2°、17.2±0.2°、12.7±0.2°、13.9±0.2°、18.2±0.2°、19.1±0.2°、23.2±0.2°、23.9±0.2°； 9.5±0.2°、12.7±0.2°、13.9±0.2°、16.7±0.2°、18.2±0.2°、19.1±0.2°、23.2±0.2°、23.9±0.2°； 9.5±0.2°、12.7±0.2°、13.9±0.2°、16.7±0.2°、18.2±0.2°、19.1±0.2°、23.2±0.2°、23.9±0.2°、27.9±0.2°； Most preferably, the X-ray powder diffraction pattern of the fumarate crystal form A is basically as shown in Figure 7; its DSC pattern is basically as shown in Figure 8; and its TGA pattern is basically as shown in Figure 9. The X-ray powder diffraction pattern of fumarate crystal form B includes at least one or more diffraction peaks located at 2θ of 7.4±0.2°, 10.5±0.2°, 12.6±0.2°, and 18.7±0.2°, preferably two, more preferably three or four; even more preferably, it may also include at least one of 2θ of 6.9±0.2°, 13.1±0.2°, 15.2±0.2°, 22.1±0.2°, 26.0±0.2°, and 26.2±0.2°, preferably two, three, four, five, or six. More preferably, the X-ray powder diffraction pattern of the fumarate crystal form B includes one or more locations located at 2θ of 6.9±0.2°, 7.4±0.2°, 10.5±0.2°, 12.6±0.2°, 13.1±0.2°, 15.2±0.2°, 18.7±0.2°, 22.1±0.2°, 26.0±0.2°, and 26.2±0.2°. Diffraction peaks; preferably, including any 4, 5, 6, 7, 8 or 10 diffraction peaks; more preferably, it may also include at least one of 2θ being 9.3±0.2°, 12.3±0.2°, 15.6±0.2°, 17.1±0.2°, 19.1±0.2°, 21.1±0.2°, preferably including 2, 3, 4, 5 or 6 of them; For example, the X-ray powder diffraction pattern of fumarate crystal form B shows diffraction peaks at the following positions with a 2θ value: 6.9±0.2°、7.4±0.2°、10.5±0.2°、12.6±0.2°、18.7±0.2°、22.1±0.2°、26.2±0.2°； 6.9±0.2°、7.4±0.2°、10.5±0.2°、12.6±0.2°、15.6±0.2°、18.7±0.2°、22.1±0.2°； 6.9±0.2°、7.4±0.2°、10.5±0.2°、12.6±0.2°、18.7±0.2°、21.1±0.2°、22.1±0.2°； 6.9±0.2°、7.4±0.2°、10.5±0.2°、12.6±0.2°、15.2±0.2°、15.6±0.2°、18.7±0.2°、22.1±0.2°； 6.9±0.2°、7.4±0.2°、10.5±0.2°、12.6±0.2°、15.2±0.2°、18.7±0.2°、21.1±0.2°、22.1±0.2°； 6.9±0.2°、7.4±0.2°、10.5±0.2°、12.6±0.2°、13.1±0.2°、18.7±0.2°、22.1±0.2°、26.2±0.2°； 6.9±0.2°、7.4±0.2°、10.5±0.2°、12.6±0.2°、13.1±0.2°、15.6±0.2°、18.7±0.2°、22.1±0.2°、26.2±0.2°； 6.9±0.2°、7.4±0.2°、10.5±0.2°、12.6±0.2°、13.1±0.2°、18.7±0.2°、21.1±0.2°、22.1±0.2°、26.2±0.2°； Most preferably, the X-ray powder diffraction pattern of the fumarate crystal form B is basically as shown in Figure 10; its DSC pattern is basically as shown in Figure 11; and its TGA pattern is basically as shown in Figure 12. The X-ray powder diffraction pattern of the phosphate crystal form A includes at least one or more diffraction peaks located at 2θ of 4.3±0.2°, 6.7±0.2°, 8.6±0.2°, and 17.3±0.2°, preferably two, more preferably three or four; even more preferably, it may also include at least one of 2θ of 10.4±0.2°, 14.4±0.2°, 16.3±0.2°, 20.6±0.2°, 20.9±0.2°, and 26.4±0.2°, preferably two, three, four, five, or six. More preferably, the X-ray powder diffraction pattern of the phosphate crystal form A includes one or more diffraction peaks located at 2θ of 4.3±0.2°, 6.7±0.2°, 8.6±0.2°, 10.4±0.2°, 14.4±0.2°, 16.3±0.2°, 17.3±0.2°, 20.6±0.2°, 20.9±0.2°, and 26.4±0.2°; For example, the X-ray powder diffraction pattern of phosphate crystal form A shows diffraction peaks at the following positions with a 2θ value: 4.3±0.2°、6.7±0.2°、8.6±0.2°、14.4±0.2°、17.3±0.2°、20.6±0.2°、20.9±0.2°； 4.3±0.2°、6.7±0.2°、8.6±0.2°、10.4±0.2°、14.4±0.2°、20.6±0.2°、20.9±0.2°； 4.3±0.2°、6.7±0.2°、8.6±0.2°、14.4±0.2°、14.4±0.2°、17.3±0.2°、20.6±0.2°； 4.3±0.2°、6.7±0.2°、8.6±0.2°、14.4±0.2°、14.4±0.2°、17.3±0.2°、20.6±0.2°、20.9±0.2°； 4.3±0.2°、6.7±0.2°、8.6±0.2°、14.4±0.2°、17.3±0.2°、20.6±0.2°、20.9±0.2°、26.4±0.2°； 4.3±0.2°、6.7±0.2°、8.6±0.2°、10.4±0.2°、14.4±0.2°、20.6±0.2°、20.9±0.2°、26.4±0.2°。 8. The free base crystal form, acid salt, or crystal form of the compound or its stereoisomer according to any one of claims 6 or 7, characterized in that, (1S,3s)-3-amino-3-(5-((8R,15R)-2,2-difluoro-7-(methyl-d3)-6-carbonyl-6,7,8,15-tetrahydro-8,15-methylene[1,3]dioxazolo[4',5':3,4]benzo[1,2-f]benzo[4,5]imidazo[1,2-a][1,4]diacoxine-12-yl)pyrimidin-2-yl The positions of the top ten diffraction peaks with the highest relative intensities in the X-ray powder diffraction patterns of the hydrochloride crystal form A, p-toluenesulfonate crystal form A, fumarate crystal form A, and fumarate crystal form B of 1-methylcyclobutane-1-carboxynitrile have a 2θ error of ±0.2° to ±0.5° compared with the diffraction peaks at the corresponding positions in Figures 1, 4, 7, and 10, respectively; preferably ±0.2° to ±0.3°, and most preferably ±0.2°.

9. The acid salt of the compound or its stereoisomer according to any one of claims 1 to 5, or its crystal form, characterized in that, It is (1S,3S)-3-(5-((8R,15R)-2,2-difluoro-7-(methyl-d3)-6-carbonyl-6,7,8,15-tetrahydro-8,15-methylene[1,3]dioxazolo[4',5':3,4]benzo[1,2-f]benzo[4,5]imidazo[1,2-a][1,4]diacoxin-12-yl)pyrimidin-2-yl)-3-hydroxy-1-methylcyclobutane-1-carboxynitrile hydrochloride crystal form A; The X-ray powder diffraction pattern of the hydrochloride crystal form A shows a diffraction peak at 2θ of 4.2 ± 0.2°; or at 8.4 ± 0.2°; or at 12.4 ± 0.2°; or at 15.0 ± 0.2°; or at 16.8 ± 0.2°; or at 18.7 ± 0.2°; or at 21.4 ± 0.2°. The diffraction peaks are present; or diffraction peaks are present at 21.9±0.2°; or diffraction peaks are present at 23.1±0.2°; or diffraction peaks are present at 23.7±0.2°; preferably, any 2-5, 3-5, 3-6, 3-8, 5-8, 6-8, or 8-10 of the above diffraction peaks are included; more preferably, any 6, 7, 8, 9, or 10 of the above diffraction peaks are included. Alternatively, it is (1S,3S)-3-(5-((8R,15R)-2,2-difluoro-7-(methyl-d3)-6-carbonyl-6,7,8,15-tetrahydro-8,15-methylene[1,3]dioxazolo[4',5':3,4]benzo[1,2-f]benzo[4,5]imidazo[1,2-a][1,4]diacoxine-12-yl)pyrimidin-2-yl)-3-hydroxy-1-methylcyclobutane-1-carboxynitrile sulfate crystal form A; The X-ray powder diffraction pattern of the sulfate crystal form A shows a diffraction peak at 2θ of 5.0 ± 0.2°; or at 6.4 ± 0.2°; or at 8.2 ± 0.2°; or at 13.2 ± 0.2°; or at 16.3 ± 0.2°; or at 17.1 ± 0.2°; or at 22.2 ± 0.2°. The diffraction peaks are present; or diffraction peaks are present at 22.7±0.2°; or diffraction peaks are present at 23.3±0.2°; or diffraction peaks are present at 25.0±0.2°; preferably, any 2-5, 3-5, 3-6, 3-8, 5-8, 6-8, or 8-10 of the above diffraction peaks are included; more preferably, any 6, 7, 8, 9, or 10 of the above diffraction peaks are included. Alternatively, it is (1S,3S)-3-(5-((8R,15R)-2,2-difluoro-7-(methyl-d3)-6-carbonyl-6,7,8,15-tetrahydro-8,15-methylene[1,3]dioxazolo[4',5':3,4]benzo[1,2-f]benzo[4,5]imidazo[1,2-a][1,4]diacoxin-12-yl)pyrimidin-2-yl)-3-hydroxy-1-methylcyclobutane-1-carboxynitrile hydrobromide crystal form A; The X-ray powder diffraction pattern of the hydrobromide crystal form A shows a diffraction peak at 2θ of 4.3 ± 0.2°; or at 8.2 ± 0.2°; or at 12.4 ± 0.2°; or at 15.7 ± 0.2°; or at 16.7 ± 0.2°; or at 18.6 ± 0.2°; or at 21.8 ± 0.2°. It has a diffraction peak; or a diffraction peak at 23.0±0.2°; or a diffraction peak at 23.4±0.2°; or a diffraction peak at 24.2±0.2°; preferably, it includes any 2-5, 3-5, 3-6, 3-8, 5-8, 6-8, or 8-10 of the above diffraction peaks; more preferably, it includes any 6, 7, 8, 9, or 10 of them.

10. The free base crystal form, acid salt, or crystal form of the compound or its stereoisomer according to claim 9, characterized in that, The X-ray powder diffraction pattern of the hydrochloride crystal form A includes at least one or more diffraction peaks located at 2θ of 8.4±0.2°, 18.7±0.2°, 21.4±0.2°, and 21.9±0.2°, preferably two of these peaks, more preferably three or four; even more preferably, it may also include at least one of 2θ of 4.2±0.2°, 12.4±0.2°, 15.0±0.2°, 16.8±0.2°, 23.1±0.2°, and 23.7±0.2°, preferably two, three, four, five, or six of these peaks. More preferably, the X-ray powder diffraction pattern of the hydrochloride crystal form A includes one or more diffraction peaks located at 4.2±0.2°, 8.4±0.2°, 12.4±0.2°, 15.0±0.2°, 16.8±0.2°, 18.7±0.2°, 21.4±0.2°, 21.9±0.2°, 23.1±0.2°, and 23.7±0.2°; preferably, it includes diffraction peaks at any of 4, 5, 6, 8, or 10 locations. More preferably, the X-ray powder diffraction pattern of the hydrochloride crystal form A may also include one or more diffraction peaks with 2θ values ​​of 12.0±0.2°, 15.7±0.2°, 20.9±0.2°, 24.2±0.2°, 24.5±0.2°, and 31.5±0.2°; preferably, it includes at least 2-3, 4-5, or 5-6 peaks; more preferably, it includes any 2, 3, 4, 5, or 6 peaks. For example, the X-ray powder diffraction pattern of the hydrochloride crystal form A has diffraction peaks at the following positions with a 2θ value: 8.4±0.2°、12.4±0.2°、16.8±0.2°、18.7±0.2°、21.4±0.2°、21.9±0.2°； 8.4±0.2°、12.4±0.2°、16.8±0.2°、18.7±0.2°、21.4±0.2°、21.9±0.2°、23.1±0.2°； 8.4±0.2°、12.4±0.2°、16.8±0.2°、18.7±0.2°、21.4±0.2°、21.9±0.2°、23.7±0.2°； 8.4±0.2°、12.4±0.2°、15.7±0.2°、16.8±0.2°、18.7±0.2°、21.4±0.2°、21.9±0.2°； 8.2±0.2°、8.4±0.2°、15.0±0.2°、16.8±0.2°、18.7±0.2°、21.4±0.2°、21.9±0.2°、23.1±0.2°； 8.4±0.2°、15.0±0.2°、16.8±0.2°、18.7±0.2°、21.4±0.2°、21.9±0.2°、23.1±0.2°、23.7±0.2°； 8.4±0.2°、15.0±0.2°、15.7±0.2°、16.8±0.2°、18.7±0.2°、21.4±0.2°、21.9±0.2°、23.1±0.2°、23.7±0.2°； 8.4±0.2°、15.0±0.2°、15.7±0.2°、16.8±0.2°、18.7±0.2°、21.4±0.2°、21.9±0.2°、23.1±0.2°、23.7±0.2°； Most preferably, the X-ray powder diffraction pattern of the hydrochloride crystal form A is basically as shown in Figure 13; its DSC pattern is basically as shown in Figure 14; and its TGA pattern is basically as shown in Figure 15. The X-ray powder diffraction pattern of the sulfate crystal form A includes at least one or more diffraction peaks located at 2θ of 5.0±0.2°, 8.2±0.2°, 23.3±0.2°, and 25.0±0.2°, preferably two of these peaks, more preferably three or four; even more preferably, it may also include at least one of 2θ of 6.4±0.2°, 13.2±0.2°, 16.3±0.2°, 17.1±0.2°, 22.2±0.2°, and 22.7±0.2°, preferably two, three, four, five, or six of these peaks. More preferably, the X-ray powder diffraction pattern of the sulfate crystal form A includes one or more diffraction peaks located at 5.0±0.2°, 6.4±0.2°, 8.2±0.2°, 13.2±0.2°, 16.3±0.2°, 17.1±0.2°, 22.2±0.2°, 22.7±0.2°, 23.3±0.2°, and 25.0±0.2°; preferably, it includes diffraction peaks at any of 4, 5, 6, 8, or 10 selected locations. More preferably, the X-ray powder diffraction pattern of the sulfate crystal form A may also include one or more diffraction peaks with 2θ values ​​of 14.8±0.2°, 19.4±0.2°, 20.0±0.2°, 21.0±0.2°, 24.5±0.2°, and 29.9±0.2°; preferably, it includes at least 2-3, 4-5, or 5-6 peaks; more preferably, it includes any 2, 3, 4, 5, or 6 peaks. For example, the X-ray powder diffraction pattern of the sulfate crystal form A has diffraction peaks at the following positions with a 2θ value: 5.0±0.2°、13.2±0.2°、16.3±0.2°、17.1±0.2°、23.3±0.2°、25.0±0.2°； 5.0±0.2°、13.2±0.2°、16.3±0.2°、17.1±0.2°、22.7±0.2°、23.3±0.2°、25.0±0.2°； 5.0±0.2°、8.2±0.2°、13.2±0.2°、16.3±0.2°、17.1±0.2°、23.3±0.2°、25.0±0.2°； 5.0±0.2°、6.4±0.2°、13.2±0.2°、16.3±0.2°、17.1±0.2°、23.3±0.2°、25.0±0.2°； 5.0±0.2°、13.2±0.2°、16.3±0.2°、17.1±0.2°、22.7±0.2°、23.3±0.2°、25.0±0.2°； 5.0±0.2°、6.4±0.2°、8.2±0.2°、13.2±0.2°、16.3±0.2°、17.1±0.2°、23.3±0.2°、25.0±0.2°； 5.0±0.2°、8.2±0.2°、13.2±0.2°、14.8±0.2°、16.3±0.2°、17.1±0.2°、23.3±0.2°、25.0±0.2°； 5.0±0.2°、6.4±0.2°、8.2±0.2°、13.2±0.2°、16.3±0.2°、17.1±0.2°、22.7±0.2°、23.3±0.2°、25.0±0.2°； Most preferably, the X-ray powder diffraction pattern of the sulfate crystal form A is basically as shown in Figure 16; its DSC pattern is basically as shown in Figure 17; and its TGA pattern is basically as shown in Figure 18. The X-ray powder diffraction pattern of the hydrobromide crystal form A includes at least one or more diffraction peaks located at 2θ of 4.3±0.2°, 8.2±0.2°, 21.8±0.2°, and 23.0±0.2°, preferably including two such peaks, more preferably including three or four such peaks; even more preferably, it may also include at least one of 2θ of 12.4±0.2°, 15.7±0.2°, 16.7±0.2°, 18.6±0.2°, 23.4±0.2°, and 24.2±0.2°, preferably including two, three, four, five, or six such peaks; More preferably, the X-ray powder diffraction pattern of the hydrobromide crystal form A includes one or more diffraction peaks located at 4.3±0.2°, 8.2±0.2°, 12.4±0.2°, 15.7±0.2°, 16.7±0.2°, 18.6±0.2°, 21.8±0.2°, 23.0±0.2°, 23.4±0.2°, and 24.2±0.2°; preferably, it includes diffraction peaks at any of 4, 5, 6, 8, or 10 locations. More preferably, the X-ray powder diffraction pattern of the hydrobromide crystal form A may also include one or more diffraction peaks with 2θ values ​​of 14.8±0.2°, 21.3±0.2°, 24.6±0.2°, and 27.2±0.2°; preferably, it may include at least 2-3 of these peaks, or 3-4 of them. For example, the X-ray powder diffraction pattern of the hydrobromide crystal form A has diffraction peaks at the following positions with a 2θ value: 4.3±0.2°、8.2±0.2°、18.6±0.2°、21.8±0.2°、23.0±0.2°、23.4±0.2°； 4.3±0.2°、8.2±0.2°、18.6±0.2°、21.8±0.2°、23.0±0.2°、23.4±0.2°； 4.3±0.2°、8.2±0.2°、16.7±0.2°、18.6±0.2°、21.8±0.2°、23.0±0.2°、23.4±0.2°； 4.3±0.2°、8.2±0.2°、12.4±0.2°、16.7±0.2°、18.6±0.2°、21.8±0.2°、23.0±0.2°、23.4±0.2°； 4.3±0.2°、8.2±0.2°、15.7±0.2°、16.7±0.2°、18.6±0.2°、21.8±0.2°、23.0±0.2°、23.4±0.2°； 4.3±0.2°、8.2±0.2°、15.7±0.2°、16.7±0.2°、18.6±0.2°、21.8±0.2°、23.0±0.2°、23.4±0.2°、24.2±0.2°； 4.3±0.2°、8.2±0.2°、12.4±0.2°、15.7±0.2°、16.7±0.2°、18.6±0.2°、21.8±0.2°、23.0±0.2°、23.4±0.2°； Most preferably, the X-ray powder diffraction pattern of the hydrobromide crystal form A is basically as shown in Figure 19; its DSC pattern is basically as shown in Figure 20; and its TGA pattern is basically as shown in Figure 21.

11. The free base crystal form, acid salt, or crystal form of the compound or its stereoisomer according to any one of claims 1 to 4, characterized in that, It is (1S,3s)-3-amino-3-(5-((8R,15R)-2,2-difluoro-7-(methyl-d3)-6-carbonyl-6,7,8,15-tetrahydro-8,15-methylene[1,3]dioxazolo[4',5':3,4]benzo[1,2-f]benzo[4,5]imidazo[1,2-a][1,4]diacoxin-12-yl)pyrimidin-2-yl)-1-methylcyclobutane-1-formonitrile crystal form 1; The X-ray powder diffraction pattern of crystal form 1 has a diffraction peak at 2θ of 6.6±0.2°; or at 8.5±0.2°; or at 11.0±0.2°; or at 16.7±0.2°; or at 18.3±0.2°; or at 19.1±0.2°; or at 19.5±0.2°; preferably, it includes any 2-5, 3-5, or 3-6 of the above diffraction peaks; more preferably, it includes any 4, 5, or 6 of them. Alternatively, it is (1S,3s)-3-amino-3-(5-((8R,15R)-2,2-difluoro-7-(methyl-d3)-6-carbonyl-6,7,8,15-tetrahydro-8,15-methylene[1,3]dioxazolo[4',5':3,4]benzo[1,2-f]benzo[4,5]imidazo[1,2-a][1,4]diacoxine-12-yl)pyrimidin-2-yl)-1-methylcyclobutane-1-formonitrile crystal form 2; The X-ray powder diffraction pattern of crystal form 2 shows a diffraction peak at 2θ of 6.0 ± 0.2°; or at 7.4 ± 0.2°; or at 11.9 ± 0.2°; or at 13.5 ± 0.2°; or at 14.0 ± 0.2°; or at 14.7 ± 0.2°; or at 19.9 ± 0.2°. The diffraction peak is present at 20.6±0.2°; or at 22.2±0.2°; or at 23.9±0.2°; preferably, any 2-5, 3-5, 3-6, 3-8, 5-8, 6-8, or 8-10 of the above diffraction peaks are included; more preferably, any 6, 7, 8, 9, or 10 of the above diffraction peaks are included. Alternatively, it is (1S,3s)-3-amino-3-(5-((8R,15R)-2,2-difluoro-7-(methyl-d3)-6-carbonyl-6,7,8,15-tetrahydro-8,15-methylene[1,3]dioxazolo[4',5':3,4]benzo[1,2-f]benzo[4,5]imidazo[1,2-a][1,4]diacoxine-12-yl)pyrimidin-2-yl)-1-methylcyclobutane-1-formonitrile crystal form 3; The X-ray powder diffraction pattern of crystal form 3 has a diffraction peak at 2θ of 5.9±0.2°; or at 11.7±0.2°; or at 13.5±0.2°; or at 15.6±0.2°; or at 16.4±0.2°; or at 17.4±0.2°; or at 22.7±0.2°; or at 26.4±0.2°; preferably including any 2-5, 3-5, 3-6, 3-8, 5-8, or 6-8 of the above diffraction peaks; more preferably including any 6, 7, or 8 of them; Alternatively, it is (1S,3s)-3-amino-3-(5-((8R,15R)-2,2-difluoro-7-(methyl-d3)-6-carbonyl-6,7,8,15-tetrahydro-8,15-methylene[1,3]dioxazolo[4',5':3,4]benzo[1,2-f]benzo[4,5]imidazo[1,2-a][1,4]diacoxine-12-yl)pyrimidin-2-yl)-1-methylcyclobutane-1-formonitrile crystal form 4; The X-ray powder diffraction pattern of crystal form 4 shows a diffraction peak at 2θ of 5.3 ± 0.2°; or at 5.6 ± 0.2°; or at 6.7 ± 0.2°; or at 7.5 ± 0.2°; or at 11.1 ± 0.2°; or at 12.2 ± 0.2°; or at 14.1 ± 0.2°. The peak; or a diffraction peak at 17.7±0.2°; or a diffraction peak at 19.5±0.2°; or a diffraction peak at 21.6±0.2°; preferably including any 2-5, 3-5, 3-6, 3-8, 5-8, 6-8, or 8-10 of the above diffraction peaks; more preferably including any 6, 7, 8, 9, or 10 of them; Alternatively, it is (1S,3s)-3-amino-3-(5-((8R,15R)-2,2-difluoro-7-(methyl-d3)-6-carbonyl-6,7,8,15-tetrahydro-8,15-methylene[1,3]dioxazolo[4',5':3,4]benzo[1,2-f]benzo[4,5]imidazo[1,2-a][1,4]diacoxine-12-yl)pyrimidin-2-yl)-1-methylcyclobutane-1-formonitrile crystal form 5; The X-ray powder diffraction pattern of crystal form 5 shows a diffraction peak at 2θ of 5.9 ± 0.2°; or at 11.2 ± 0.2°; or at 11.6 ± 0.2°; or at 13.3 ± 0.2°; or at 15.5 ± 0.2°; or at 17.0 ± 0.2°; or at 17.3 ± 0.2°. The diffraction peak is present at 19.3±0.2°; or at 19.6±0.2°; or at 25.9±0.2°; preferably, any 2-5, 3-5, 3-6, 3-8, 5-8, 6-8, or 8-10 of the above diffraction peaks are included; more preferably, any 6, 7, 8, 9, or 10 of the above diffraction peaks are included.

12. The free base crystal form, acid salt, or crystal form of the compound or its stereoisomer according to claim 11, characterized in that, The X-ray powder diffraction pattern of the crystal form 2 includes at least one or more diffraction peaks located at 2θ of 6.0±0.2°, 7.4±0.2°, 11.9±0.2°, and 19.9±0.2°, preferably two of them, more preferably three or four; even more preferably, it may also include at least one of 2θ of 13.5±0.2°, 14.0±0.2°, 14.7±0.2°, 20.6±0.2°, 22.2±0.2°, and 23.9±0.2°, preferably two, three, four, five, or six of them; More preferably, the X-ray powder diffraction pattern of the crystal form 2 includes one or more diffraction peaks located at 6.0±0.2°, 7.4±0.2°, 11.9±0.2°, 13.5±0.2°, 14.0±0.2°, 14.7±0.2°, 19.9±0.2°, 20.6±0.2°, 22.2±0.2°, and 23.9±0.2°; preferably, it includes diffraction peaks at any of 4, 5, 6, 8, or 10 locations. More preferably, the X-ray powder diffraction pattern of the crystal form 2 may also include one or more diffraction peaks with 2θ values ​​of 11.3±0.2°, 17.4±0.2°, 18.5±0.2°, 21.6±0.2°, 25.9±0.2°, and 27.8±0.2°; preferably, it includes at least 2-3, 4-5, or 5-6 peaks; more preferably, it includes any 2, 3, 4, 5, or 6 peaks. For example, the X-ray powder diffraction pattern of crystal form 2 has diffraction peaks at the following positions with a 2θ value: 6.0±0.2°、7.4±0.2°、11.9±0.2°、14.7±0.2°、19.9±0.2°、23.9±0.2°； 6.0±0.2°、7.4±0.2°、11.9±0.2°、14.7±0.2°、19.9±0.2°、20.6±0.2°、23.9±0.2°； 6.0±0.2°、7.4±0.2°、11.9±0.2°、14.7±0.2°、19.9±0.2°、22.2±0.2°、23.9±0.2°； 6.0±0.2°、7.4±0.2°、11.9±0.2°、14.7±0.2°、19.9±0.2°、21.6±0.2°、23.9±0.2°； 6.0±0.2°、7.4±0.2°、11.9±0.2°、14.7±0.2°、19.9±0.2°、23.9±0.2°、25.9±0.2°； 6.0±0.2°、7.4±0.2°、11.9±0.2°、14.7±0.2°、19.9±0.2°、20.6±0.2°、22.2±0.2°、23.9±0.2°； 6.0±0.2°、7.4±0.2°、11.9±0.2°、14.7±0.2°、19.9±0.2°、20.6±0.2°、21.6±0.2°、23.9±0.2°； 6.0±0.2°、7.4±0.2°、11.9±0.2°、13.5±0.2°、14.0±0.2°、14.7±0.2°、19.9±0.2°、23.9±0.2°； 6.0±0.2°、7.4±0.2°、11.9±0.2°、13.5±0.2°、14.7±0.2°、19.9±0.2°、20.6±0.2°、22.2±0.2°、23.9±0.2°； Most preferably, the X-ray powder diffraction pattern of crystal form 2 is basically as shown in Figure 22; its DSC pattern is basically as shown in Figure 23; and its TGA pattern is basically as shown in Figure 24. The X-ray powder diffraction pattern of the crystal form 4 includes at least one or more diffraction peaks located at 2θ of 6.7±0.2°, 11.1±0.2°, 12.2±0.2°, and 21.6±0.2°, preferably two of them, more preferably three or four; even more preferably, it may also include at least one of 2θ of 5.3±0.2°, 5.6±0.2°, 7.5±0.2°, 14.1±0.2°, 17.7±0.2°, and 19.5±0.2°, preferably two, three, four, five, or six of them; More preferably, the X-ray powder diffraction pattern of the crystal form 4 includes one or more diffraction peaks located at 2θ of 5.3±0.2°, 5.6±0.2°, 6.7±0.2°, 7.5±0.2°, 11.1±0.2°, 12.2±0.2°, 14.1±0.2°, 17.7±0.2°, 19.5±0.2°, and 21.6±0.2°; preferably, it includes diffraction peaks at any of 4, 5, 6, 7, 8, or 10 of these locations. More preferably, the X-ray powder diffraction pattern of the crystal form 4 may also include one or more diffraction peaks with 2θ values ​​of 10.0±0.2°, 13.3±0.2°, 16.7±0.2°, 18.9±0.2°, 20.4±0.2°, and 23.3±0.2°; preferably, it includes at least 2-3, 4-5, or 5-6 peaks; more preferably, it includes any 2, 3, 4, 5, or 6 peaks. For example, the X-ray powder diffraction pattern of crystal form 4 shows diffraction peaks at the following positions with a 2θ value: 6.7±0.2°、7.5±0.2°、11.1±0.2°、12.2±0.2°、14.1±0.2°、19.5±0.2°； 6.7±0.2°、7.5±0.2°、11.1±0.2°、12.2±0.2°、14.1±0.2°、19.5±0.2°、21.6±0.2°； 5.6±0.2°、6.7±0.2°、7.5±0.2°、11.1±0.2°、12.2±0.2°、14.1±0.2°、19.5±0.2°； 5.3±0.2°、6.7±0.2°、7.5±0.2°、11.1±0.2°、12.2±0.2°、19.5±0.2°、21.6±0.2°； 6.7±0.2°、7.5±0.2°、11.1±0.2°、12.2±0.2°、14.1±0.2°、19.5±0.2°、21.6±0.2°、23.3±0.2°； 5.3±0.2°、6.7±0.2°、7.5±0.2°、11.1±0.2°、12.2±0.2°、14.1±0.2°、19.5±0.2°、21.6±0.2°； 5.6±0.2°、6.7±0.2°、7.5±0.2°、11.1±0.2°、12.2±0.2°、14.1±0.2°、19.5±0.2°、21.6±0.2°； 5.3±0.2°、5.6±0.2°、6.7±0.2°、7.5±0.2°、11.1±0.2°、12.2±0.2°、14.1±0.2°、19.5±0.2°、21.6±0.2°； 5.6±0.2°、6.7±0.2°、7.5±0.2°、11.1±0.2°、12.2±0.2°、14.1±0.2°、19.5±0.2°、21.6±0.2°、23.3±0.2°； Most preferably, the X-ray powder diffraction pattern of crystal form 4 is basically as shown in Figure 27; its DSC pattern is basically as shown in Figure 28; and its TGA pattern is basically as shown in Figure 29. The X-ray powder diffraction pattern of the crystal form 5 includes at least one or more diffraction peaks located at 2θ of 5.9±0.2°, 11.6±0.2°, 17.3±0.2°, and 19.3±0.2°, preferably including two such peaks, more preferably including three or four such peaks; even more preferably, it may also include at least one of 2θ of 11.2±0.2°, 13.3±0.2°, 15.5±0.2°, 17.0±0.2°, 19.6±0.2°, and 25.9±0.2°, preferably including two, three, four, five, or six such peaks; More preferably, the X-ray powder diffraction pattern of the crystal form 5 includes one or more diffraction peaks located at 2θ of 5.9±0.2°, 11.2±0.2°, 11.6±0.2°, 13.3±0.2°, 15.5±0.2°, 17.0±0.2°, 17.3±0.2°, 19.3±0.2°, 19.6±0.2°, and 25.9±0.2°; preferably, it includes diffraction peaks at any of 4, 5, 6, 7, 8, or 10 locations. More preferably, the X-ray powder diffraction pattern of the crystal form 5 may also include one or more diffraction peaks with 2θ values ​​of 16.1±0.2°, 17.6±0.2°, 19.1±0.2°, 20.0±0.2°, 22.2±0.2°, and 22.9±0.2°; preferably, it includes at least 2-3, 4-5, or 5-6 peaks; more preferably, it includes any 2, 3, 4, 5, or 6 peaks. For example, the X-ray powder diffraction pattern of crystal form 5 shows diffraction peaks at the following positions with a 2θ value: 5.9±0.2°、11.2±0.2°、17.0±0.2°、17.3±0.2°、19.3±0.2°、25.9±0.2°； 5.9±0.2°、11.2±0.2°、15.5±0.2°、17.0±0.2°、17.3±0.2°、19.3±0.2°、25.9±0.2°； 5.9±0.2°、11.2±0.2°、13.3±0.2°、17.0±0.2°、17.3±0.2°、19.3±0.2°、25.9±0.2°； 5.9±0.2°、11.2±0.2°、17.0±0.2°、17.3±0.2°、19.3±0.2°、19.6±0.2°、25.9±0.2°； 5.9±0.2°、11.2±0.2°、17.0±0.2°、17.3±0.2°、19.3±0.2°、22.2±0.2°、25.9±0.2°； 5.9±0.2°、11.2±0.2°、13.3±0.2°、15.5±0.2°、17.0±0.2°、17.3±0.2°、19.3±0.2°、25.9±0.2°； 5.9±0.2°、11.2±0.2°、15.5±0.2°、17.0±0.2°、17.3±0.2°、19.3±0.2°、19.6±0.2°、25.9±0.2°； 5.9±0.2°、11.2±0.2°、13.3±0.2°、17.0±0.2°、17.3±0.2°、19.3±0.2°、22.2±0.2°、25.9±0.2°； 5.9±0.2°、11.2±0.2°、11.6±0.2°、13.3±0.2°、15.5±0.2°、17.0±0.2°、17.3±0.2°、19.3±0.2°、25.9±0.2°； 5.9±0.2°、11.2±0.2°、11.6±0.2°、15.5±0.2°、17.0±0.2°、17.3±0.2°、19.3±0.2°、22.2±0.2°、25.9±0.2°； Most preferably, the X-ray powder diffraction pattern of the crystal form 5 is basically as shown in Figure 30; its DSC pattern is basically as shown in Figure 31; and its TGA pattern is basically as shown in Figure 32.

13. The free base crystal form, acid salt, or crystal form of the compound or its stereoisomer according to any one of claims 9-10, characterized in that, The positions of the top ten diffraction peaks with the highest relative intensities in the X-ray powder diffraction patterns of (1S,3S)-3-(5-((8R,15R)-2,2-difluoro-7-(methyl-d3)-6-carbonyl-6,7,8,15-tetrahydro-8,15-methylene[1,3]dioxazolo[4',5':3,4]benzo[1,2-f]benzo[4,5]imidazo[1,2-a][1,4]diacoxo-12-yl)pyrimidin-2-yl)-3-hydroxy-1-methylcyclobutane-1-carboxynitrile hydrochloride crystal form A, sulfate crystal form A and hydrobromide crystal form A are 2θ errors of ±0.2° to ±0.5° with respect to the diffraction peaks at the corresponding positions in Figures 13, 16 and 19, respectively; preferably ±0.2° to ±0.3°, most preferably ±0.2°.

14. The free base crystal form, acid salt, or crystal form of the compound or its stereoisomer according to any one of claims 11 or 12, characterized in that, The positions of the top ten diffraction peaks with the highest relative intensities in the X-ray powder diffraction patterns of (1S,3s)-3-amino-3-(5-((8R,15R)-2,2-difluoro-7-(methyl-d3)-6-carbonyl-6,7,8,15-tetrahydro-8,15-methylene[1,3]dioxazolo[4',5':3,4]benzo[1,2-f]benzo[4,5]imidazo[1,2-a][1,4]diacoxo-12-yl)pyrimidin-2-yl)-1-methylcyclobutane-1-carboxynitrile crystal forms 2, 4 and 5 have a 2θ error of ±0.2° to ±0.5° compared with the corresponding positions of the diffraction peaks in Figures 22, 27 and 30, respectively; preferably ±0.2° to ±0.3°, and most preferably ±0.2°.

15. A method for preparing a free base crystal form, acid salt, or crystal form of the compound or its stereoisomer as described in any one of claims 1-11, characterized in that, Includes the following steps: Method 1: 1) Weigh an appropriate amount of free base and dissolve it in a good solvent; 2) Weigh an appropriate amount of the counterion acid, dissolve it in an organic solvent or water, or add it directly; the amount of the counterion acid is preferably 1-3 times the equivalent, more preferably 1.2 or 2.1 equivalents; 3) Combine 1) and 2), stir to precipitate, or add a poor solvent and stir to precipitate; 4) Rapid centrifugation or static evaporation to obtain the target product; Method 2: 1) Weigh an appropriate amount of free base and suspend it in a poor solvent; 2) Weigh an appropriate amount of the counterion acid, dissolve it in an organic solvent or water, or add it directly; the amount of the counterion acid is preferably 1-3 times the equivalent, more preferably 1.2 or 2.1 equivalents; 3) Combine 1) and 2) and stir to dissolve, continue stirring to precipitate, or add a poor solvent and stir to precipitate; 4) Rapid centrifugation or static evaporation to obtain the target product; in: The beneficial solvent is selected from one or more of methanol, ethanol, acetone, ethyl acetate, isopropyl acetate, acetonitrile, 88% acetone, tetrahydrofuran, 2-methyltetrahydrofuran, dichloromethane, 1,4-dioxane, benzene, toluene, isopropanol, n-butanol, isobutanol, N,N-dimethylformamide, N,N-dimethylacetamide, n-propanol, tert-butanol, 2-butanone, 3-pentanone, N-methylpyrrolidone, and water; preferably one or more of tert-butanol, acetone, ethyl acetate, 2-butanone, and 2-methyltetrahydrofuran. The organic solvent is selected from methanol, ethanol, ethyl acetate, dichloromethane, acetone, n-hexane, petroleum ether, benzene, toluene, chloroform, acetonitrile, carbon tetrachloride, dichloroethane, tetrahydrofuran, 2-butanone, 3-pentanone, heptane, methyl tert-butyl ether, isopropyl ether, 1,4-dioxane, tert-butanol, or N,N-dimethylformamide; preferably methanol, ethanol, acetone, or acetonitrile; the above-mentioned benign solvents and organic solutions must be miscible when used. The unsuitable solvent is selected from one or more of n-heptane, cyclohexane, n-hexane, n-pentane, water, ethyl acetate, methyl tert-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, acetone, isopropyl acetate, methyl isobutyl ketone, tert-butanol, toluene, or isopropyl ether; preferably one or more of water, heptane, methyl tert-butyl ether, or isopropyl ether; the above unsuitable solvents and organic solutions must be miscible when used; The aforementioned counterionic acid is an inorganic acid or an organic acid, wherein the inorganic acid is selected from hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, hydrofluoric acid, hydroiodic acid, or phosphoric acid; and the organic acid is selected from 2,5-dihydroxybenzoic acid, 1-hydroxy-2-naphtholic acid, acetic acid, dichloroacetic acid, trichloroacetic acid, acetoxyxamic acid, adipic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, benzoic acid, 4-acetaminobenzoic acid, 4-aminobenzoic acid, decanoic acid, hexanoic acid, octanoic acid, cinnamic acid, citric acid, cyclohexanesulfonic acid, camphorsulfonic acid, aspartic acid, camphoric acid, gluconic acid, glucuronic acid, glutamic acid, isoascorbic acid, lactic acid, malic acid, mandelic acid, pyroglutamic acid, tartaric acid, dodecyl sulfate, dibenzoyl tartaric acid, ethane. -1,2-Disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galactobionic acid, gentian acid, glutaric acid, 2-ketoglutaric acid, glycolic acid, hippuric acid, hydroxyethylsulfonic acid, lactobionic acid, ascorbic acid, aspartic acid, lauric acid, camphoric acid, maleic acid, malonic acid, methanesulfonic acid, 1,5-naphthalenedisulfonic acid, naphthalene-2-sulfonic acid, nicotinic acid, oleic acid, orotic acid, oxalic acid, palmitic acid, dihydroxynaphthalic acid, propionic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, thiocyanate, undecanoic acid, trifluoroacetic acid, benzenesulfonic acid, p-toluenesulfonic acid, or L-malic acid; preferably hydrochloric acid, sulfuric acid, hydrobromic acid, p-toluenesulfonic acid, fumaric acid, phosphoric acid, or oxalic acid; most preferably hydrochloric acid, sulfuric acid, hydrobromic acid, or fumaric acid.

16. A method for preparing a free base crystal form, acid salt, or crystal form of the compound or its stereoisomer as described in any one of claims 11-12 or 14, characterized in that, Includes the following steps: Method 1: 1) Weigh an appropriate amount of the free base of the compound and dissolve it in a good solvent; 2) Stir the solution obtained in 1) until solid precipitates, preferably at a temperature of 0~25℃; 3) Filter or rapidly centrifuge the suspension from 2) to remove the contaminant and obtain the target product; Method 2: 1) Weigh an appropriate amount of the free base of the compound and dissolve it in a good solvent; 2) Add the antisolvent to the solution obtained in 1), and stir until a solid precipitates. Preferably, the temperature is 15~25℃ or -10~-5℃. 3) Filter or rapidly centrifuge the suspension from 2) to remove the liquid and obtain the target product; Method 3: 1) Weigh an appropriate amount of the free base of the compound and suspend it in a poor solvent. The preferred suspension density is 50~200 mg / mL. 2) Stir the suspension in 1), preferably at a temperature of 0~50℃; 3) Filter or rapidly centrifuge the suspension from 2) to remove the liquid and obtain the target product; in: The beneficial solvent is selected from one or more of methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, acetone, ethyl acetate, n-propyl acetate, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, dichloromethane, 1,4-dioxane, benzene, toluene, N,N-dimethylformamide, N,N-dimethylacetamide, 2-butanone, and 3-pentanone; preferably isopropanol. The undesirable solvent is selected from one or more of methyl tert-butyl ether, isopropyl ether, diethyl ether, n-hexane, n-heptane, cyclohexane, n-pentane, and water; preferably water, methyl tert-butyl ether, isopropyl ether, or diethyl ether.

17. A pharmaceutical composition comprising a therapeutically effective amount of a free base crystal form, an acid salt or crystal form thereof of any one of claims 1 to 14, and one or more pharmaceutically acceptable carriers or excipients.

18. Use of the free base crystal form, acid salt or crystal form of the compound or stereoisomer thereof according to any one of claims 1 to 14, or the pharmaceutical composition according to claim 17 in the preparation of a medicament for treating and / or preventing TNFα-related diseases.

19. The use of the free base crystal form, acid salt or crystal form of the compound or stereoisomer of any one of claims 1 to 14, or the pharmaceutical composition of claim 17, in the preparation of a medicament for treating and / or preventing autoimmune diseases; preferably, the autoimmune disease is selected from rheumatoid arthritis, psoriatic arthritis, inflammatory bowel disease, psoriasis, Crohn's disease, ulcerative colitis, psoriasis, spondyloarthritis, plaque psoriasis, septic shock, ankylosing spondylitis, juvenile idiopathic arthritis, hidradenitis suppurativa, uveitis, systemic lupus erythematosus (lupus), axial spondyloarthritis, polymyositis, pemphigus, multiple sclerosis, neuromyelitis optica, primary cholangitis, autoimmune hepatitis, lupus nephritis, pulmonary hemorrhage-nephritis syndrome, autoimmune oophoritis, or autoimmune orchitis.

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