Salt containing pyridine polycyclic derivative, crystal form, preparation method and application thereof

Abstract

The invention relates to a salt containing a pyridine polycyclic derivative, a crystal form, a preparation method and application thereof. In particular, the present invention relates to a salt containing a pyridine polycyclic derivative, a crystal form and a preparation method thereof, and a pharmaceutical composition containing a therapeutically effective amount of the crystal form, the invention also relates to application of the compound as a biological regulator in preparation of drugs for treating autoimmune diseases, chronic inflammatory diseases, acute inflammatory diseases, autoinflammatory diseases, atherosclerosis, diabetes, fibrotic diseases, metabolic diseases, cancers, tumors, leukemia and lymphoma.

Description

Technical Field

[0001] The present invention belongs to the field of biomedicine, and specifically relates to a salt, a crystal form, a preparation method and an application thereof containing a pyridine polycyclic derivative. Background Art

[0002] MK2 (MAPK activated protein kinase 2) is a protein kinase that is an important downstream molecule of the classic inflammatory signal transduction pathway MAPK and regulates the expression of inflammatory factors. After cells are stimulated by inflammatory factors, the activated p38 MAPK protein phosphorylates and activates MK2, leading to the phosphorylation of MK2 substrate TTP, promoting the stability of pro-inflammatory cytokine mRNA, thereby increasing the protein expression level of inflammatory cytokines.

[0003] In both mouse arthritis models and chondrocytes of osteoarthritis patients, MK2 is activated. Inhibition of the p38-MK2 pathway by genetic or pharmacological means can inhibit the expression of inflammatory factors, indicating that MK2 is involved in mediating the inflammatory regulation of arthritis. p38-MK2 inhibitors are expected to treat patients with relapsed, refractory rheumatoid arthritis who have poor response to existing therapies.

[0004] Currently, only Aclaris Therapeutics' p38-MK2 inhibitor ATI-450 has entered clinical stage IIb for rheumatoid arthritis. Preliminary clinical trial results show that ATI-450 is safe and tolerable in patients with rheumatoid arthritis, with outstanding and sustained efficacy. Other MK2 inhibitors in clinical trials include BMS's CC-99677 and Moerae Matrix's MMI-0100, both of which can directly inhibit the activity of MK2, with a different mechanism from ATI-450.

[0005] As drugs, p38-MK2 inhibitors have good application prospects in the pharmaceutical industry. p38-MK2 inhibitors provide a safer and more effective treatment for patients with rheumatoid arthritis who have relapsed, are refractory, and respond poorly to existing therapies; p38-MK2 inhibitors have a broad spectrum of anti-inflammatory effects (TNF / IL-6 / IL-1), and can theoretically be used to treat a variety of inflammatory diseases and autoimmune diseases; p38-MK2 inhibitors are small molecule inhibitors, which have advantages over large molecule drugs such as TNF monoclonal antibodies, such as oral convenience and good patient compliance. At the same time, p38-MK2 inhibitors have not been reported to have the toxic side effects of JAK inhibitors such as infection, tumors, thrombosis, and cardiac toxicity. Therefore, there is a huge clinical demand for the development of new p38-MK2 inhibitors.

[0006] The international application (application number: PCT / CN2023 / 072370) discloses the structures of a series of heterocyclic derivative inhibitors. In subsequent research and development, in order to make the products easy to handle, filter, dry, store, have long-term stability, and have high bioavailability, the present invention has conducted a comprehensive study on the crystal forms of the above-mentioned substances and is committed to obtaining the most suitable crystal form. Summary of the invention

[0007] All contents involved in patent application PCT / CN2023 / 072370 are added to the present invention by citation.

[0008] The object of the present invention is to provide a crystalline form of a compound represented by general formula (I) or a stereoisomer thereof

[0009]

[0010] in:

[0011] Ring A is selected from a 5-6 membered heteroaryl group containing 1 to 3 N atoms;

[0012] Ring B is selected from a 6-12 membered heterocyclic group containing 1 to 3 N atoms;

[0013] R 1 Selected from hydrogen, halogen or C 1-3 alkyl;

[0014] R 2 Selected from hydrogen, halogen, C 1-3 Alkyl, C 1-3 Hydroxyalkyl or -(CR aa R bb ) n NR cc C(O)R dd ;

[0015] R aa , R bb , R cc and R dd are each independently selected from hydrogen, deuterium or C 1-3 alkyl;

[0016] n is 0, 1, 2 or 3; and

[0017] a is 0, 1, 2 or 3.

[0018] In a preferred embodiment of the present invention,

[0019] Ring A is selected from pyrimidinyl or pyrazolyl;

[0020] Ring B is selected from

[0021] R 1is selected from hydrogen or F;

[0022] R 2 Selected from hydrogen, F, and

[0023] a is 1 or 2.

[0024] In a preferred embodiment of the invention, the compound is selected from the group consisting of

[0025] (S)-11-chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d 2 )-2-(2-(2-hydroxypropane-2-yl)pyrimidin-4-yl)-5,6,7,8-tetrahydro-12H-bipyrido[1,2-a:3',4'-g]azocine-12-one;

[0026] (S)-11-chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d 2 )-2-(3-(2-hydroxypropane-2-yl)-1H-pyrazol-1-yl)-5,6,7,8-tetrahydro-12H-bipyrido[1,2-a:3',4'-g]azocine-12-one;

[0027] (S)-N-(2-(1-(11-chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d 2 )-12-carbonyl-6,7,8,12-tetrahydro-5H-bipyrido[1,2-a:3',4'-g]azocin-2-yl)-4-fluoro-1H-pyrazol-3-yl)propan-2-yl)acetamide;

[0028] (S)-N-(2-(4-(11-chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d 2 )-12-carbonyl-6,7,8,12-tetrahydro-5H-bipyrido[1,2-a:3',4'-g]azocine-2-yl)pyrimidin-2-yl)propan-2-yl)acetamide;

[0029] (R)-N-(2-(1-(11-chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d 2 )-1-fluoro-12-carbonyl-6,7,8,12-tetrahydro-5H-bipyrido[1,2-a:3',4'-g]azocin-2-yl)-4-fluoro-1H-pyrazol-3-yl)propan-2-yl)acetamide;

[0030] (R)-N-(2-(4-(11-chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d 2)-1-fluoro-12-carbonyl-6,7,8,12-tetrahydro-5H-bipyrido[1,2-a:3',4'-g]azocine-2-yl)pyrimidin-2-yl)propan-2-yl)acetamide;

[0031] (R)-11-chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d 2 )-1-fluoro-2-(3-(2-hydroxypropane-2-yl)-1H-pyrazol-1-yl)-5,6,7,8-tetrahydro-12H-bipyrido[1,2-a:3',4'-g]azocine-12-one;

[0032] (R)-11-chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d 2 )-1-fluoro-2-(2-(2-hydroxypropane-2-yl)pyrimidin-4-yl)-5,6,7,8-tetrahydro-12H-bipyrido[1,2-a:3',4'-g]azocine-12-one;

[0033] (S,Z)-11-chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d 2 )-2-(2-(2-hydroxypropane-2-yl)pyrimidin-4-yl)-7,8-dihydro-12H-dipyrido[1,2-a:3',4'-g]azocine-12-one;

[0034] (S,Z)-11-chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d 2 )-2-(3-(2-hydroxypropane-2-yl)-1H-pyrazol-1-yl)-7,8-dihydro-12H-dipyrido[1,2-a:3',4'-g]azocine-12-one; or

[0035] (S,Z)-N-(2-(1-(11-chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d 2 )-12-carbonyl-8,12-dihydro-7H-bipyrido[1,2-a:3',4'-g]azocin-2-yl)-4-fluoro-1H-pyrazol-3-yl)propan-2-yl)acetamide.

[0036] In a preferred embodiment of the present invention, the compound (R)-11-chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d 2The crystalline form of )-1-fluoro-2-(2-(2-hydroxypropane-2-yl)pyrimidin-4-yl)-5,6,7,8-tetrahydro-12H-bipyrido[1,2-a:3',4'-g]azocine-12-one is crystalline form A, and the X-ray powder diffraction spectrum of the crystalline form A has a diffraction peak at 2θ of 4.8±0.2°; or a diffraction peak at 7.4±0.2°; or a diffraction peak at 9.5±0.2°; or a diffraction peak at 11.3±0.2°; or a diffraction peak at 14.6 ±0.2°; or has a diffraction peak at 16.6±0.2°; or has a diffraction peak at 19.2±0.2°; or has a diffraction peak at 20.3±0.2°; or has a diffraction peak at 23.8±0.2°; or has a diffraction peak at 27.0±0.2°; preferably includes any 2-5, or 3-5, or 3-6, or 3-8, or 5-8, or 6-8 of the above-mentioned diffraction peaks, and more preferably includes any 6, 7 or 8 of them.

[0037] In a preferred embodiment of the present invention, the X-ray powder diffraction pattern of the crystalline form A comprises at least one or more diffraction peaks located at 2θ of 4.8±0.2°, 14.6±0.2°, and 23.8±0.2°, preferably two of them, and more preferably three of them; optionally, it may further comprise at least one of 2θ of 7.4±0.2°, 11.3±0.2°, 16.6±0.2°, 19.2±0.2°, and 20.3±0.2°, preferably 2, 3, 4 or 5 of them; for example,

[0038] 4.8±0.2°, 14.6±0.2°;

[0039] 4.8±0.2°, 23.8±0.2°;

[0040] 14.6±0.2°, 23.8±0.2°;

[0041] 4.8±0.2°, 19.2±0.2°;

[0042] 4.8±0.2°, 14.6±0.2°, 23.8±0.2°;

[0043] 4.8±0.2°, 14.6±0.2°, 19.2±0.2°;

[0044] 4.8±0.2°, 19.2±0.2°, 23.8±0.2°;

[0045] 14.6±0.2°, 19.2±0.2°, 23.8±0.2°;

[0046] 4.8±0.2°、11.3±0.2°、14.6±0.2°；

[0047] 4.8±0.2°、11.3±0.2°、23.8±0.2°；

[0048] 11.3±0.2°、14.6±0.2°、19.2±0.2°、23.8±0.2°；

[0049] 4.8±0.2°、11.3±0.2°、19.2±0.2°、23.8±0.2°；

[0050] 4.8±0.2°、11.3±0.2°、14.6±0.2°、16.6±0.2°；

[0051] 4.8±0.2°、14.6±0.2°、16.6±0.2°、23.8±0.2°；

[0052] 4.8±0.2°、14.6±0.2°、19.2±0.2°、23.8±0.2°；

[0053] 4.8±0.2°、14.6±0.2°、20.3±0.2°、23.8±0.2°；

[0054] 14.6±0.2°、11.3±0.2°、16.6±0.2°、19.2±0.2°、23.8±0.2°；

[0055] 4.8±0.2°、11.3±0.2°、16.6±0.2°、19.2±0.2°、23.8±0.2°；

[0056] 4.8±0.2°、11.3±0.2°、14.6±0.2°、16.6±0.2°、19.2±0.2°；

[0057] 4.8±0.2°、11.3±0.2°、19.2±0.2°、20.3±0.2°、23.8±0.2°；

[0058] 4.8±0.2°、14.6±0.2°、16.6±0.2°、19.2±0.2°、23.8±0.2°；

[0059] 4.8±0.2°、11.3±0.2°、14.6±0.2°、19.2±0.2°、20.3±0.2°；

[0060] In a preferred embodiment of the present invention, the X-ray powder diffraction pattern of the crystalline form A optionally further comprises one or more diffraction peaks located at 2θ of 9.5±0.2°, 15.7±0.2°, 19.8±0.2°, 20.0±0.2°, 21.5±0.2°, 26.3±0.2°, and 27.0±0.2°; preferably, at least any 2-3, or 4-5, or 6-7 thereof; further preferably, any 2, 3, 4, 5, 6, or 7 thereof; for example,

[0061] 9.5±0.2°, 27.0±0.2°;

[0062] 15.7±0.2°, 27.0±0.2°;

[0063] 26.3±0.2°, 27.0±0.2°;

[0064] 9.5±0.2°, 15.7±0.2°, 27.0±0.2°;

[0065] 9.5±0.2°, 26.3±0.2°, 27.0±0.2°;

[0066] 15.7±0.2°, 26.3±0.2°, 27.0±0.2°;

[0067] 9.5±0.2°, 15.7±0.2°, 26.3±0.2°, 27.0±0.2°;

[0068] 9.5±0.2°, 15.7±0.2°, 20.0±0.2°, 27.0±0.2°;

[0069] 9.5±0.2°, 20.0±0.2°, 26.3±0.2°, 27.0±0.2°;

[0070] 15.7±0.2°, 20.0±0.2°, 26.3±0.2°, 27.0±0.2°;

[0071] 9.5±0.2°, 15.7±0.2°, 20.0±0.2°, 26.3±0.2°, 27.0±0.2°;

[0072] 9.5±0.2°, 15.7±0.2°, 19.8±0.2°, 26.3±0.2°, 27.0±0.2°;

[0073] 9.5±0.2°, 15.7±0.2°, 19.8±0.2°, 20.0±0.2°, 27.0±0.2°;

[0074] 9.5±0.2°, 19.8±0.2°, 20.0±0.2°, 26.3±0.2°, 27.0±0.2°;

[0075] 15.7±0.2°, 19.8±0.2°, 20.0±0.2°, 26.3±0.2°, 27.0±0.2°;

[0076] 9.5±0.2°, 15.7±0.2°, 19.8±0.2°, 20.0±0.2°, 26.3±0.2°, 27.0±0.2°;

[0077] 9.5±0.2°, 15.7±0.2°, 20.0±0.2°, 21.5±0.2°, 26.3±0.2°, 27.0±0.2°;

[0078] 9.5±0.2°, 15.7±0.2°, 19.8±0.2, 21.5±0.2°, 26.3±0.2°, 27.0±0.2°;

[0079] 9.5±0.2°, 15.7±0.2°, 19.8±0.2°, 20.0±0.2°, 21.5±0.2°, 27.0±0.2°;

[0080] 9.5±0.2°, 19.8±0.2°, 20.0±0.2°, 21.5±0.2°, 26.3±0.2°, 27.0±0.2°;

[0081] 15.7±0.2°, 19.8±0.2°, 20.0±0.2°, 21.5±0.2°, 26.3±0.2°, 27.0±0.2°.

[0082] In a preferred embodiment of the present invention, the X-ray powder diffraction pattern of the crystalline form A comprises one or more diffraction peaks located at 2θ of 4.8±0.2°, 7.4±0.2°, 9.5±0.2°, 11.3±0.2°, 14.6±0.2°, 15.7±0.2°, 16.6±0.2°, 19.2±0.2°, 20.3±0.2°, 23.8±0.2°, 26.3±0.2°, and 27.0±0.2°; preferably, it comprises 4, 5, 6, 8, 10, or 12 selected therefrom; for example, the X-ray powder diffraction pattern of the crystalline form A has diffraction peaks at the following positions at 2θ:

[0083] 11.3±0.2°, 14.6±0.2°, 19.2±0.2°, 23.8±0.2°;

[0084] 4.8±0.2°、14.6±0.2°、19.2±0.2°、23.8±0.2°；

[0085] 4.8±0.2°、11.3±0.2°、14.6±0.2°、23.8±0.2°；

[0086] 4.8±0.2°、11.3±0.2°、14.6±0.2°、19.2±0.2°；

[0087] 4.8±0.2°、11.3±0.2°、19.2±0.2°、23.8±0.2°；

[0088] 4.8±0.2°、11.3±0.2°、14.6±0.2°、19.2±0.2°、23.8±0.2°；

[0089] 11.3±0.2°、14.6±0.2°、16.6±0.2、19.2±0.2°、23.8±0.2°；

[0090] 4.8±0.2°、14.6±0.2°、16.6±0.2°、19.2±0.2°、23.8±0.2°；

[0091] 4.8±0.2°、11.3±0.2°、16.6±0.2°、19.2±0.2°、23.8±0.2°；

[0092] 4.8±0.2°、11.3±0.2°、14.6±0.2°、16.6±0.2°、23.8±0.2°；

[0093] 4.8±0.2°、11.3±0.2°、14.6±0.2°、16.6±0.2°、19.2±0.2°；

[0094] 4.8±0.2°、11.3±0.2°、14.6±0.2°、16.6±0.2°、19.2±0.2°、23.8±0.2°；

[0095] 11.3±0.2°、14.6±0.2°、16.6±0.2°、19.2±0.2°、20.3±0.2°、23.8±0.2°；

[0096] 4.8±0.2°、11.3±0.2°、16.6±0.2°、19.2±0.2°、20.3±0.2°、23.8±0.2°；

[0097] 4.8±0.2°、11.3±0.2°、14.6±0.2°、16.6±0.2°、19.2±0.2°、20.3±0.2°；

[0098] 4.8±0.2°、11.3±0.2°、14.6±0.2°、19.2±0.2°、20.3±0.2°、23.8±0.2°；

[0099] 4.8±0.2°、14.6±0.2°、16.6±0.2°、19.2±0.2°、20.3±0.2°、23.8±0.2°；

[0100] 4.8±0.2°、11.3±0.2°、14.6±0.2°、16.6±0.2°、20.3±0.2°、23.8±0.2°；

[0101] 7.4±0.2°、11.3±0.2°、14.6±0.2°、16.6±0.2°、19.2±0.2°、20.3±0.2°、23.8±0.2°、27.0±0.2°；

[0102] 4.8±0.2°、7.4±0.2°、11.3±0.2°、16.6±0.2°、19.2±0.2°、20.3±0.2°、23.8±0.2°、27.0±0.2°；

[0103] 4.8±0.2°、7.4±0.2°、11.3±0.2°、14.6±0.2°、16.6±0.2°、19.2±0.2°、20.3±0.2°、27.0±0.2°；

[0104] 4.8±0.2°、7.4±0.2°、11.3±0.2°、14.6±0.2°、16.6±0.2°、20.3±0.2°、23.8±0.2°、27.0±0.2°；

[0105] 4.8±0.2°、7.4±0.2°、14.6±0.2°、16.6±0.2°、19.2±0.2°、20.3±0.2°、23.8±0.2°、27.0±0.2°；

[0106] 4.8±0.2°、7.4±0.2°、11.3±0.2°、14.6±0.2°、16.6±0.2°、19.2±0.2°、20.3±0.2°、23.8±0.2°；

[0107] 4.8±0.2°、11.3±0.2°、14.6±0.2°、16.6±0.2°、19.2±0.2°、20.3±0.2°、23.8±0.2°、27.0±0.2°；

[0108] 4.8±0.2°、7.4±0.2°、11.3±0.2°、14.6±0.2°、16.6±0.2°、19.2±0.2°、23.8±0.2°、27.0±0.2°；

[0109] 4.8±0.2°、7.4±0.2°、11.3±0.2°、14.6±0.2°、19.2±0.2°、20.3±0.2°、23.8±0.2°、27.0±0.2°；

[0110] 4.8±0.2°、7.4±0.2°、9.5±0.2°、11.3±0.2°、14.6±0.2°、16.6±0.2°、19.2±0.2°、20.3±0.2°、23.8±0.2°、27.0±0.2°；

[0111] 4.8±0.2°、9.5±0.2°、11.3±0.2°、14.6±0.2°、15.7±0.2°、16.6±0.2°、19.2±0.2°、20.3±0.2°、23.8±0.2°、27.0±0.2°；

[0112] 7.4±0.2°、9.5±0.2°、11.3±0.2°、14.6±0.2°、15.7±0.2°、16.6±0.2°、19.2±0.2°、20.3±0.2°、23.8±0.2°、27.0±0.2°；

[0113] 4.8±0.2°、7.4±0.2°、9.5±0.2°、11.3±0.2°、15.7±0.2°、16.6±0.2°、19.2±0.2°、20.3±0.2°、23.8±0.2°、27.0±0.2°；

[0114] 4.8±0.2°、7.4±0.2°、9.5±0.2°、11.3±0.2°、14.6±0.2°、15.7±0.2°、16.6±0.2°、19.2±0.2°、20.3±0.2°、27.0±0.2°；

[0115] 4.8±0.2°、7.4±0.2°、9.5±0.2°、11.3±0.2°、14.6±0.2°、15.7±0.2°、16.6±0.2°、20.3±0.2°、23.8±0.2°、27.0±0.2°；

[0116] 4.8±0.2°、7.4±0.2°、9.5±0.2°、14.6±0.2°、15.7±0.2°、16.6±0.2°、19.2±0.2°、20.3±0.2°、23.8±0.2°、27.0±0.2°；

[0117] 4.8±0.2°、7.4±0.2°、9.5±0.2°、11.3±0.2°、14.6±0.2°、15.7±0.2°、19.2±0.2°、20.3±0.2°、23.8±0.2°、27.0±0.2°；

[0118] 4.8±0.2°、7.4±0.2°、9.5±0.2°、11.3±0.2°、14.6±0.2°、15.7±0.2°、16.6±0.2°、19.2±0.2°、23.8±0.2°、27.0±0.2°；

[0119] 4.8±0.2°、9.5±0.2°、11.3±0.2°、14.6±0.2°、15.7±0.2°、16.6±0.2°、19.2±0.2°、20.3±0.2°、23.8±0.2°、27.0±0.2°；

[0120] 4.8±0.2°、7.4±0.2°、11.3±0.2°、14.6±0.2°、15.7±0.2°、16.6±0.2°、19.2±0.2°、20.3±0.2°、23.8±0.2°、27.0±0.2°；

[0121] 4.8±0.2°、7.4±0.2°、9.5±0.2°、11.3±0.2°、14.6±0.2°、15.7±0.2°、16.6±0.2°、19.2±0.2°、20.3±0.2°、23.8±0.2°；

[0122] 4.8±0.2°、9.5±0.2°、11.3±0.2°、14.6±0.2°、15.7±0.2°、16.6±0.2°、19.2±0.2°、20.3±0.2°、23.8±0.2°、27.0±0.2°。

[0123] In a preferred embodiment of the present invention, the crystal form A uses Cu-Kα radiation, and the X-ray characteristic diffraction peaks represented by 2θ angles and interplanar spacing d values ​​are shown in Table 1.

[0124] Table 1

[0125]

[0126]

[0127] In a preferred embodiment of the present invention, the X-ray powder diffraction pattern of the crystalline form A is substantially as follows Figure 1 shown.

[0128] In a preferred embodiment of the present invention, the TGA spectrum of the crystalline form A is as follows Figure 2 shown.

[0129] In a preferred embodiment of the present invention, the DSC spectrum of the crystalline form A is as follows Figure 3 shown.

[0130] In a preferred embodiment of the present invention, the compound (R)-11-chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d 2 The crystalline form of )-1-fluoro-2-(2-(2-hydroxypropane-2-yl)pyrimidin-4-yl)-5,6,7,8-tetrahydro-12H-bipyrido[1,2-a:3',4'-g]azocine-12-one is crystalline form B, and the X-ray powder diffraction spectrum of the crystalline form B has a diffraction peak at 2θ of 5.9±0.2°; or a diffraction peak at 7.8±0.2°; or a diffraction peak at 8.5±0.2°; or a diffraction peak at 11.0±0.2°; or a diffraction peak at 11.8 ±0.2°; or has a diffraction peak at 15.2±0.2°; or has a diffraction peak at 18.8±0.2°; or has a diffraction peak at 20.3±0.2°; or has a diffraction peak at 23.4±0.2°; or has a diffraction peak at 25.5±0.2°; preferably includes any 2-5, or 3-5, or 3-6, or 3-8, or 5-8, or 6-8 of the above-mentioned diffraction peaks, and more preferably includes any 6, 7 or 8 of them.

[0131] In a preferred embodiment of the present invention, the X-ray powder diffraction pattern of the crystalline form B comprises at least one or more diffraction peaks located at 2θ of 7.8±0.2°, 8.5±0.2°, and 15.2±0.2°, preferably two of them, and more preferably three of them; optionally, it may further comprise at least one of 2θ of 5.9±0.2°, 11.0±0.2°, 20.3±0.2°, 23.4±0.2°, and 25.5±0.2°, preferably 2, 3, 4 or 5 of them; for example,

[0132] 7.8±0.2°, 8.5±0.2°;

[0133] 8.5±0.2°, 15.2±0.2°;

[0134] 7.8±0.2°, 15.2±0.2°;

[0135] 8.5±0.2°, 11.0±0.2°;

[0136] 7.8±0.2°, 8.5±0.2°, 15.2±0.2°;

[0137] 7.8±0.2°, 8.5±0.2°, 11.0±0.2°;

[0138] 8.5±0.2°, 11.0±0.2°, 15.2±0.2°;

[0139] 7.8±0.2°, 11.0±0.2°, 15.2±0.2°;

[0140] 8.5±0.2°, 11.0±0.2°, 20.3±0.2°;

[0141] 7.8±0.2°, 8.5±0.2°, 11.0±0.2°, 15.2±0.2°;

[0142] 7.8±0.2°, 8.5±0.2°, 11.0±0.2°, 20.3±0.2°;

[0143] 8.5±0.2°, 11.0±0.2°, 15.2±0.2°, 20.3±0.2°;

[0144] 7.8±0.2°, 11.0±0.2°, 15.2±0.2°, 20.3±0.2°;

[0145] 5.9±0.2°, 8.5±0.2°, 11.0±0.2°, 20.3±0.2°;

[0146] 7.8±0.2°, 8.5±0.2°, 11.0±0.2°, 15.2±0.2°, 20.3±0.2°;

[0147] 5.9±0.2°, 7.8±0.2°, 8.5±0.2°, 11.0±0.2°, 20.3±0.2°;

[0148] 5.9±0.2°, 8.5±0.2°, 11.0±0.2°, 15.2±0.2°, 20.3±0.2°;

[0149] 5.9±0.2°, 7.8±0.2°, 11.0±0.2°, 15.2±0.2°, 20.3±0.2°;

[0150] 5.9±0.2°, 8.5±0.2°, 11.0±0.2°, 20.3±0.2°, 25.5±0.2°.

[0151] In a preferred embodiment of the present invention, the X-ray powder diffraction pattern of the crystalline form B optionally further comprises one or more diffraction peaks located at 2θ of 11.8±0.2°, 12.3±0.2°, 16.1±0.2°, 18.8±0.2°, 20.6±0.2°, 24.8±0.2°, and 25.8±0.2°; preferably, at least any 2-3, or 4-5, or 6-7 thereof; further preferably, any 2, 3, 4, 5, 6, or 7 thereof; for example,

[0152] 11.8±0.2°, 18.8±0.2°;

[0153] 18.8±0.2°, 24.8±0.2°;

[0154] 11.8±0.2°, 24.8±0.2°;

[0155] 11.8±0.2°, 18.8±0.2°, 24.8±0.2°;

[0156] 11.8±0.2°, 12.3±0.2°, 18.8±0.2°;

[0157] 12.3±0.2°, 18.8±0.2°, 24.8±0.2°;

[0158] 11.8±0.2°, 12.3±0.2°, 18.8±0.2°, 24.8±0.2°;

[0159] 11.8±0.2°, 12.3±0.2°, 18.8±0.2°, 20.6±0.2°;

[0160] 12.3±0.2°, 18.8±0.2°, 20.6±0.2°, 24.8±0.2°;

[0161] 11.8±0.2°, 12.3±0.2°, 18.8±0.2°, 20.6±0.2°, 24.8±0.2°;

[0162] 11.8±0.2°, 12.3±0.2°, 16.1±0.2°, 18.8±0.2°, 24.8±0.2°;

[0163] 11.8±0.2°, 16.1±0.2°, 18.8±0.2°, 20.6±0.2°, 24.8±0.2°;

[0164] 11.8±0.2°, 12.3±0.2°, 16.1±0.2°, 18.8±0.2°, 20.6±0.2°, 24.8±0.2°;

[0165] 11.8±0.2°, 12.3±0.2°, 18.8±0.2°, 20.6±0.2°, 24.8±0.2°, 25.8±0.2°;

[0166] 11.8±0.2°, 12.3±0.2°, 16.1±0.2°, 18.8±0.2°, 24.8±0.2°, 25.8±0.2°.

[0167] In a preferred embodiment of the present invention, the X-ray powder diffraction pattern of the crystalline form B comprises one or more diffraction peaks located at 2θ of 5.9±0.2°, 7.8±0.2°, 8.5±0.2°, 11.0±0.2°, 11.8±0.2°, 12.3±0.2°, 15.2±0.2°, 18.8±0.2°, 20.3±0.2°, 23.4±0.2°, 24.8±0.2°, and 25.5±0.2°; preferably, it comprises 4, 5, 6, 8, 10 or 12 selected therefrom; for example, the X-ray powder diffraction pattern of the crystalline form B has diffraction peaks at the following positions at 2θ:

[0168] 7.8±0.2°, 8.5±0.2°, 11.0±0.2°, 15.2±0.2°;

[0169] 7.8±0.2°, 8.5±0.2°, 15.2±0.2°, 20.3±0.2°;

[0170] 7.8±0.2°, 8.5±0.2°, 11.0±0.2°, 15.2±0.2°, 20.3±0.2°;

[0171] 5.9±0.2°, 7.8±0.2°, 8.5±0.2°, 11.0±0.2°, 15.2±0.2°;

[0172] 5.9±0.2°, 7.8±0.2°, 8.5±0.2°, 11.0±0.2°, 15.2±0.2°, 20.3±0.2°;

[0173] 7.8±0.2°, 8.5±0.2°, 11.0±0.2°, 15.2±0.2°, 20.3±0.2°, 25.5±0.2°;

[0174] 5.9±0.2°, 7.8±0.2°, 8.5±0.2°, 11.0±0.2°, 15.2±0.2°, 20.3±0.2°, 23.4±0.2°, 25.5±0.2°;

[0175] 5.9±0.2°, 7.8±0.2°, 8.5±0.2°, 11.0±0.2°, 15.2±0.2°, 18.8±0.2°, 20.3±0.2°, 23.4±0.2°;

[0176] 5.9±0.2°, 7.8±0.2°, 8.5±0.2°, 11.0±0.2°, 11.8±0.2°, 15.2±0.2°, 18.8±0.2°, 20.3±0.2°, 23.4±0.2°, 25.5±0.2°;

[0177] 5.9±0.2°, 7.8±0.2°, 8.5±0.2°, 11.0±0.2°, 15.2±0.2°, 18.8±0.2°, 20.3±0.2°, 23.4±0.2°, 24.8±0.2°, 25.5±0.2°.

[0178] In a preferred embodiment of the present invention, the crystal form B uses Cu-Kα radiation, and the X-ray characteristic diffraction peaks represented by 2θ angles and interplanar spacing d values ​​are shown in Table 2.

[0179] Table 2

[0180]

[0181]

[0182] In a preferred embodiment of the present invention, the X-ray powder diffraction pattern of the crystalline form B is substantially as follows Figure 4 shown.

[0183] In a preferred embodiment of the present invention, the crystalline form B has Figure 5 TGA spectrum shown.

[0184] In a preferred embodiment of the present invention, the crystalline form B has Figure 6 DSC spectrum shown.

[0185] In a preferred embodiment of the present invention, the compound (R)-11-chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d 2 The crystalline form of )-1-fluoro-2-(2-(2-hydroxypropane-2-yl)pyrimidin-4-yl)-5,6,7,8-tetrahydro-12H-bipyrido[1,2-a:3',4'-g]azocine-12-one is crystalline form C, and the X-ray powder diffraction spectrum of the crystalline form C has a diffraction peak at 2θ of 8.2±0.2°; or a diffraction peak at 9.9±0.2°; or a diffraction peak at 12.9±0.2°; or a diffraction peak at 15.1±0.2°; or a diffraction peak at 18.0 ±0.2°; or has a diffraction peak at 19.9±0.2°; or has a diffraction peak at 22.2±0.2°; or has a diffraction peak at 23.7±0.2°; or has a diffraction peak at 24.6±0.2°; or has a diffraction peak at 26.2±0.2°; preferably includes any 2-5, or 3-5, or 3-6, or 3-8, or 5-8, or 6-8 of the above-mentioned diffraction peaks, and more preferably includes any 6, 7 or 8 of them.

[0186] In a preferred embodiment of the present invention, the X-ray powder diffraction pattern of the crystalline form C comprises at least one or more diffraction peaks located at 2θ of 9.9±0.2°, 19.9±0.2°, and 22.2±0.2°, preferably two of them, and more preferably three of them; optionally, it may further comprise at least one of 2θ of 8.2±0.2°, 15.1±0.2°, 23.7±0.2°, 24.6±0.2°, and 26.2±0.2°, preferably 2, 3, 4 or 5 of them; for example,

[0187] 9.9±0.2°, 22.2±0.2°;

[0188] 9.9±0.2°, 19.9±0.2°;

[0189] 19.9±0.2°, 22.2±0.2°;

[0190] 9.9±0.2°, 19.9±0.2°, 22.2±0.2°;

[0191] 9.9±0.2°, 22.2±0.2°, 23.7±0.2°;

[0192] 9.9±0.2°, 19.9±0.2°, 23.7±0.2°;

[0193] 19.9±0.2°, 22.2±0.2°, 23.7±0.2°;

[0194] 9.9±0.2°, 19.9±0.2°, 22.2±0.2°, 23.7±0.2°;

[0195] 9.9±0.2°, 22.2±0.2°, 23.7±0.2°, 26.2±0.2°;

[0196] 9.9±0.2°, 19.9±0.2°, 23.7±0.2°, 26.2±0.2°;

[0197] 19.9±0.2°, 22.2±0.2°, 23.7±0.2°, 26.2±0.2°;

[0198] 9.9±0.2°, 19.9±0.2°, 22.2±0.2°, 23.7±0.2°, 26.2±0.2°;

[0199] 9.9±0.2°, 15.1±0.2°, 22.2±0.2°, 23.7±0.2°, 26.2±0.2°;

[0200] 9.9±0.2°, 15.1±0.2°, 19.9±0.2°, 23.7±0.2°, 26.2±0.2°;

[0201] 15.1±0.2°, 19.9±0.2°, 22.2±0.2°, 23.7±0.2°, 26.2±0.2°.

[0202] In a preferred embodiment of the present invention, the X-ray powder diffraction pattern of the crystalline form C optionally further comprises one or more diffraction peaks located at 2θ of 6.5±0.2°, 12.9±0.2°, 16.0±0.2°, 18.0±0.2°, 20.7±0.2°, 24.7±0.2°, and 25.6±0.2°; preferably, at least any 2-3, or 4-5, or 6-7 thereof; further preferably, any 2, 3, 4, 5, 6, or 7 thereof; for example,

[0203] 12.9±0.2°, 18.0±0.2°;

[0204] 12.9±0.2°, 24.7±0.2°;

[0205] 18.0±0.2°、24.7±0.2°；

[0206] 12.9±0.2°、18.0±0.2°、24.7±0.2°；

[0207] 12.9±0.2°、18.0±0.2°、20.7±0.2°；

[0208] 12.9±0.2°、20.7±0.2°、24.7±0.2°；

[0209] 12.9±0.2°、18.0±0.2°、20.7±0.2°、24.7±0.2°；

[0210] 6.5±0.2°、12.9±0.2°、18.0±0.2°、24.7±0.2°；

[0211] 6.5±0.2°、12.9±0.2°、18.0±0.2°、20.7±0.2°；

[0212] 6.5±0.2°、12.9±0.2°、18.0±0.2°、20.7±0.2°、24.7±0.2°；

[0213] 12.9±0.2°、16.0±0.2°、18.0±0.2°、20.7±0.2°、24.7±0.2°；

[0214] 6.5±0.2°、12.9±0.2°、16.0±0.2°、18.0±0.2°、24.7±0.2°；

[0215] 6.5±0.2°、12.9±0.2°、16.0±0.2°、18.0±0.2°、20.7±0.2°、24.7±0.2°；

[0216] 6.5±0.2°、12.9±0.2°、18.0±0.2°、20.7±0.2°、24.7±0.2°、25.6±0.2°；

[0217] 12.9±0.2°、16.0±0.2°、18.0±0.2°、20.7±0.2°、24.7±0.2°、25.6±0.2°。

[0218] In a preferred embodiment of the present invention, the X-ray powder diffraction pattern of the crystalline form C comprises one or more diffraction peaks located at 2θ of 8.2±0.2°, 9.9±0.2°, 12.9±0.2°, 15.1±0.2°, 18.0±0.2°, 18.1±0.2°, 19.9±0.2°, 22.2±0.2°, 23.7±0.2°, 24.6±0.2°, 24.7±0.2°, and 26.2±0.2°; preferably, it comprises 4, 5, 6, 8, 10 or 12 selected therefrom; for example, the X-ray powder diffraction pattern of the crystalline form C has diffraction peaks at the following positions at 2θ:

[0219] 9.9±0.2°, 19.9±0.2°, 22.2±0.2°, 23.7±0.2°;

[0220] 9.9±0.2°, 19.9±0.2°, 22.2±0.2°, 26.2±0.2°;

[0221] 9.9±0.2°, 19.9±0.2°, 22.2±0.2°, 23.7±0.2°, 26.2±0.2°;

[0222] 9.9±0.2°, 15.1±0.2°, 19.9±0.2°, 22.2±0.2°, 23.7±0.2°;

[0223] 9.9±0.2°, 15.1±0.2°, 19.9±0.2°, 22.2±0.2°, 23.7±0.2°, 26.2±0.2°;

[0224] 8.2±0.2°, 9.9±0.2°, 19.9±0.2°, 22.2±0.2°, 23.7±0.2°, 26.2±0.2°;

[0225] 8.2±0.2°, 9.9±0.2°, 15.1±0.2°, 19.9±0.2°, 22.2±0.2°, 23.7±0.2°, 24.6±0.2°, 26.2±0.2°;

[0226] 8.2±0.2°, 9.9±0.2°, 12.9±0.2°, 15.1±0.2°, 19.9±0.2°, 22.2±0.2°, 23.7±0.2°, 26.2±0.2°;

[0227] 8.2±0.2°, 9.9±0.2°, 12.9±0.2°, 15.1±0.2°, 18.0±0.2°, 19.9±0.2°, 22.2±0.2°, 23.7±0.2°, 24.6±0.2°, 26.2±0.2°;

[0228] 8.2±0.2°, 9.9±0.2°, 12.9±0.2°, 15.1±0.2°, 19.9±0.2°, 22.2±0.2°, 23.7±0.2°, 24.6±0.2°, 24.7±0.2°, 26.2±0.2°.

[0229] In a preferred embodiment of the present invention, the crystal form C uses Cu-Kα radiation, and the X-ray characteristic diffraction peaks represented by 2θ angles and interplanar spacing d values ​​are shown in Table 3.

[0230] Table 3

[0231]

[0232]

[0233] In a preferred embodiment of the present invention, the X-ray powder diffraction pattern of the crystalline form C is substantially as follows Figure 7 shown.

[0234] In a preferred embodiment of the present invention, the crystalline form C has Figure 8 TGA spectrum shown.

[0235] In a preferred embodiment of the present invention, the crystalline form C has Fig. 9 DSC spectrum shown.

[0236] In a preferred embodiment of the present invention, the compound (R)-11-chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d 2The crystalline form of )-1-fluoro-2-(2-(2-hydroxypropane-2-yl)pyrimidin-4-yl)-5,6,7,8-tetrahydro-12H-bipyrido[1,2-a:3',4'-g]azocine-12-one is crystalline form D, and the X-ray powder diffraction spectrum of the crystalline form D has a diffraction peak at 2θ of 6.1±0.2°; or a diffraction peak at 6.7±0.2°; or a diffraction peak at 9.1±0.2°; or a diffraction peak at 10.5±0.2°; or a diffraction peak at 11.6 ±0.2°; or has a diffraction peak at 14.9±0.2°; or has a diffraction peak at 20.2±0.2°; or has a diffraction peak at 21.0±0.2°; or has a diffraction peak at 21.3±0.2°; or has a diffraction peak at 23.7±0.2°; preferably includes any 2-5, or 3-5, or 3-6, or 3-8, or 5-8, or 6-8 of the above-mentioned diffraction peaks, and more preferably includes any 6, 7 or 8 of them.

[0237] In a preferred embodiment of the present invention, the X-ray powder diffraction pattern of the crystalline form D comprises at least one or more diffraction peaks located at 2θ of 6.1±0.2°, 6.7±0.2°, and 10.5±0.2°, preferably two of them, and more preferably three of them; optionally, it may further comprise at least one of 2θ of 9.1±0.2°, 11.6±0.2°, 14.9±0.2°, 21.3±0.2°, and 23.7±0.2°, preferably 2, 3, 4 or 5 of them; for example,

[0238] 6.7±0.2°, 10.5±0.2°;

[0239] 6.1±0.2°, 6.7±0.2°;

[0240] 6.7±0.2°, 10.5±0.2°;

[0241] 6.1±0.2°, 6.7±0.2°, 10.5±0.2°;

[0242] 6.7±0.2°, 10.5±0.2°, 23.7±0.2°;

[0243] 6.1±0.2°, 6.7±0.2°, 23.7±0.2°;

[0244] 6.7±0.2°, 10.5±0.2°, 23.7±0.2°;

[0245] 6.1±0.2°, 6.7±0.2°, 10.5±0.2°, 23.7±0.2°;

[0246] 6.7±0.2°, 10.5±0.2°, 14.9±0.2°, 23.7±0.2°;

[0247] 6.1±0.2°, 6.7±0.2°, 14.9±0.2°, 23.7±0.2°;

[0248] 6.7±0.2°, 10.5±0.2°, 14.9±0.2°, 23.7±0.2°;

[0249] 6.1±0.2°, 6.7±0.2°, 10.5±0.2°, 14.9±0.2°, 23.7±0.2°;

[0250] 6.7±0.2°, 10.5±0.2°, 11.6±0.2°, 14.9±0.2°, 23.7±0.2°;

[0251] 6.1±0.2°, 6.7±0.2°, 11.6±0.2°, 14.9±0.2°, 23.7±0.2°;

[0252] 6.7±0.2°, 10.5±0.2°, 11.6±0.2°, 14.9±0.2°, 23.7±0.2°.

[0253] In a preferred embodiment of the present invention, the X-ray powder diffraction pattern of the crystalline form D optionally further comprises one or more diffraction peaks located at 2θ of 5.4±0.2°, 15.3±0.2°, 18.0±0.2°, 20.2±0.2°, 21.0±0.2°, 24.6±0.2°, and 26.1±0.2°; preferably, at least any 2-3, or 4-5, or 6-7 thereof; further preferably, any 2, 3, 4, 5, 6, or 7 thereof; for example,

[0254] 20.2±0.2°, 21.0±0.2°;

[0255] 5.4±0.2°, 21.0±0.2°;

[0256] 5.4±0.2°, 20.2±0.2°;

[0257] 5.4±0.2°, 20.2±0.2°, 21.0±0.2°;

[0258] 18.0±0.2°, 20.2±0.2°, 21.0±0.2°;

[0259] 5.4±0.2°, 18.0±0.2°, 21.0±0.2°;

[0260] 5.4±0.2°, 18.0±0.2°, 20.2±0.2°, 21.0±0.2°;

[0261] 5.4±0.2°, 15.3±0.2°, 20.2±0.2°, 21.0±0.2°;

[0262] 15.3±0.2°, 18.0±0.2°, 20.2±0.2°, 21.0±0.2°;

[0263] 5.4±0.2°, 15.3±0.2°, 18.0±0.2°, 20.2±0.2°, 21.0±0.2°;

[0264] 5.4±0.2°, 18.0±0.2°, 20.2±0.2°, 21.0±0.2°, 26.1±0.2°;

[0265] 5.4±0.2°, 15.3±0.2°, 20.2±0.2°, 21.0±0.2°, 26.1±0.2°;

[0266] 5.4±0.2°, 15.3±0.2°, 18.0±0.2°, 20.2±0.2°, 21.0±0.2°, 26.1±0.2°;

[0267] 5.4±0.2°, 15.3±0.2°, 18.0±0.2°, 20.2±0.2°, 21.0±0.2°, 24.6±0.2°;

[0268] 5.4±0.2°, 18.0±0.2°, 20.2±0.2°, 21.0±0.2°, 24.6±0.2°, 26.1±0.2°.

[0269] In a preferred embodiment of the present invention, the X-ray powder diffraction pattern of the crystalline form D comprises one or more diffraction peaks located at 2θ of 5.4±0.2°, 6.1±0.2°, 6.7±0.2°, 9.1±0.2°, 10.5±0.2°, 11.6±0.2°, 14.9±0.2°, 18.0±0.2°, 20.2±0.2°, 21.0±0.2°, 21.3±0.2°, and 23.7±0.2°; preferably, it comprises 4, 5, 6, 8, 10, or 12 selected therefrom; for example, the X-ray powder diffraction pattern of the crystalline form D has diffraction peaks at the following positions at 2θ:

[0270] 6.1±0.2°, 6.7±0.2°, 10.5±0.2°, 23.7±0.2°;

[0271] 6.1±0.2°, 6.7±0.2°, 10.5±0.2°, 14.9±0.2°;

[0272] 6.1±0.2°, 6.7±0.2°, 10.5±0.2°, 14.9±0.2°, 23.7±0.2°;

[0273] 6.1±0.2°, 6.7±0.2°, 10.5±0.2°, 11.6±0.2°, 14.9±0.2°;

[0274] 6.1±0.2°, 6.7±0.2°, 10.5±0.2°, 11.6±0.2°, 14.9±0.2°, 23.7±0.2°;

[0275] 6.1±0.2°, 6.7±0.2°, 10.5±0.2°, 14.9±0.2°, 21.3±0.2°, 23.7±0.2°;

[0276] 6.1±0.2°, 6.7±0.2°, 9.1±0.2°, 10.5±0.2°, 11.6±0.2°, 14.9±0.2°, 21.3±0.2°, 23.7±0.2°;

[0277] 6.1±0.2°, 6.7±0.2°, 10.5±0.2°, 11.6±0.2°, 14.9±0.2°, 21.0±0.2°, 21.3±0.2°, 23.7±0.2°;

[0278] 6.1±0.2°, 6.7±0.2°, 9.1±0.2°, 10.5±0.2°, 11.6±0.2°, 14.9±0.2°, 20.2±0.2°, 21.0±0.2°, 21.3±0.2°, 23.7±0.2°;

[0279] 5.4±0.2°, 6.1±0.2°, 6.7±0.2°, 9.1±0.2°, 10.5±0.2°, 11.6±0.2°, 14.9±0.2°, 21.0±0.2°, 21.3±0.2°, 23.7±0.2°.

[0280] In a preferred embodiment of the present invention, the crystal form D uses Cu-Kα radiation, and the X-ray characteristic diffraction peaks represented by 2θ angles and interplanar spacing d values ​​are shown in Table 4.

[0281] Table 4

[0282]

[0283]

[0284] In a preferred embodiment of the present invention, the X-ray powder diffraction pattern of the crystalline form D is substantially as follows Fig.10 shown.

[0285] In a preferred embodiment of the present invention, the compound (R)-11-chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d 2 The crystalline form of )-1-fluoro-2-(2-(2-hydroxypropane-2-yl)pyrimidin-4-yl)-5,6,7,8-tetrahydro-12H-bipyrido[1,2-a:3',4'-g]azocine-12-one is crystalline form E, and the X-ray powder diffraction spectrum of the crystalline form E has a diffraction peak at 2θ of 6.9±0.2°; or a diffraction peak at 11.9±0.2°; or a diffraction peak at 12.4±0.2°; or a diffraction peak at 13.7±0.2°; or a diffraction peak at 15. The invention relates to a 3D optical spectrum having a diffraction peak at 7±0.2°; or having a diffraction peak at 16.9±0.2°; or having a diffraction peak at 18.0±0.2°; or having a diffraction peak at 19.1±0.2°; or having a diffraction peak at 23.9±0.2°; or having a diffraction peak at 24.7±0.2°; preferably including any 2-5, or 3-5, or 3-6, or 3-8, or 5-8, or 6-8 of the above-mentioned diffraction peaks, and more preferably including any 6, 7 or 8 thereof.

[0286] In a preferred embodiment of the present invention, the X-ray powder diffraction pattern of the crystalline form E comprises at least one or more diffraction peaks located at 2θ of 11.9±0.2°, 15.7±0.2°, and 19.1±0.2°, preferably two of them, and more preferably three of them; optionally, it may further comprise at least one of 2θ of 12.4±0.2°, 13.7±0.2°, 18.0±0.2°, 23.9±0.2°, and 24.7±0.2°, preferably 2, 3, 4 or 5 of them; for example,

[0287] 11.9±0.2°, 15.7±0.2°;

[0288] 11.9±0.2°, 15.7±0.2°;

[0289] 15.7±0.2°, 19.1±0.2°;

[0290] 11.9±0.2°, 15.7±0.2°, 19.1±0.2°;

[0291] 11.9±0.2°, 15.7±0.2°, 18.0±0.2°;

[0292] 11.9±0.2°, 15.7±0.2°, 18.0±0.2°;

[0293] 15.7±0.2°, 18.0±0.2°, 19.1±0.2°;

[0294] 11.9±0.2°, 15.7±0.2°, 18.0±0.2°, 19.1±0.2°;

[0295] 11.9±0.2°, 15.7±0.2°, 18.0±0.2°, 24.7±0.2°;

[0296] 15.7±0.2°, 18.0±0.2°, 19.1±0.2°, 24.7±0.2°;

[0297] 11.9±0.2°, 15.7±0.2°, 18.0±0.2°, 19.1±0.2°, 24.7±0.2°;

[0298] 11.9±0.2°, 12.4±0.2°, 15.7±0.2°, 18.0±0.2°, 24.7±0.2°;

[0299] 12.4±0.2°, 15.7±0.2°, 18.0±0.2°, 19.1±0.2°, 24.7±0.2°.

[0300] In a preferred embodiment of the present invention, the X-ray powder diffraction pattern of the crystalline form E optionally further comprises one or more diffraction peaks located at 2θ of 6.9±0.2°, 14.8±0.2°, 16.5±0.2°, 16.9±0.2°, 18.2±0.2°, 20.6±0.2°, and 27.5±0.2°; preferably, at least any 2-3, or 4-5, or 6-7 thereof; further preferably, any 2, 3, 4, 5, 6, or 7 thereof; for example,

[0301] 6.9±0.2°, 16.9±0.2°;

[0302] 16.5±0.2°, 16.9±0.2°;

[0303] 6.9±0.2°, 16.5±0.2°;

[0304] 6.9±0.2°, 16.5±0.2°, 16.9±0.2°;

[0305] 6.9±0.2°, 16.9±0.2°, 18.2±0.2°;

[0306] 16.5±0.2°, 16.9±0.2°, 18.2±0.2°;

[0307] 6.9±0.2°, 16.5±0.2°, 16.9±0.2°, 18.2±0.2°;

[0308] 6.9±0.2°, 14.8±0.2°, 16.5±0.2°, 16.9±0.2°;

[0309] 6.9±0.2°, 14.8±0.2°, 16.5±0.2°, 16.9±0.2°;

[0310] 6.9±0.2°, 14.8±0.2°, 16.5±0.2°, 16.9±0.2°, 18.2±0.2°;

[0311] 6.9±0.2°, 16.5±0.2°, 16.9±0.2°, 18.2±0.2°, 20.6±0.2°;

[0312] 6.9±0.2°, 14.8±0.2°, 16.5±0.2°, 16.9±0.2°, 20.6±0.2°;

[0313] 6.9±0.2°, 14.8±0.2°, 16.5±0.2°, 16.9±0.2°, 18.2±0.2°, 20.6±0.2°;

[0314] 6.9±0.2°, 14.8±0.2°, 16.5±0.2°, 16.9±0.2°, 18.2±0.2°, 27.5±0.2°;

[0315] 6.9±0.2°, 16.5±0.2°, 16.9±0.2°, 18.2±0.2°, 20.6±0.2°, 27.5±0.2°.

[0316] In a preferred embodiment of the present invention, the X-ray powder diffraction pattern of the crystalline form E comprises one or more diffraction peaks located at 2θ of 6.9±0.2°, 11.9±0.2°, 12.4±0.2°, 13.7±0.2°, 15.7±0.2°, 16.5±0.2°, 16.9±0.2°, 18.0±0.2°, 18.2±0.2°, 19.1±0.2°, 23.9±0.2°, and 24.7±0.2°; preferably, it comprises 4, 5, 6, 8, 10, or 12 selected therefrom; for example, the X-ray powder diffraction pattern of the crystalline form E has diffraction peaks at the following positions at 2θ:

[0317] 11.9±0.2°, 15.7±0.2°, 18.0±0.2°, 19.1±0.2°;

[0318] 11.9±0.2°, 15.7±0.2°, 19.1±0.2°, 24.7±0.2°;

[0319] 11.9±0.2°, 15.7±0.2°, 18.0±0.2°, 19.1±0.2°, 24.7±0.2°;

[0320] 11.9±0.2°, 12.4±0.2°, 15.7±0.2°, 18.0±0.2°, 19.1±0.2°;

[0321] 11.9±0.2°, 12.4±0.2°, 15.7±0.2°, 18.0±0.2°, 19.1±0.2°, 24.7±0.2°;

[0322] 11.9±0.2°, 15.7±0.2°, 18.0±0.2°, 19.1±0.2°, 23.9±0.2°, 24.7±0.2°;

[0323] 11.9±0.2°, 12.4±0.2°, 13.7±0.2°, 15.7±0.2°, 18.0±0.2°, 19.1±0.2°, 23.9±0.2°, 24.7±0.2°;

[0324] 11.9±0.2°, 12.4±0.2°, 13.7±0.2°, 15.7±0.2°, 16.9±0.2°, 18.0±0.2°, 19.1±0.2°, 24.7±0.2°;

[0325] 6.9±0.2°, 11.9±0.2°, 12.4±0.2°, 13.7±0.2°, 15.7±0.2°, 16.9±0.2°, 18.0±0.2°, 19.1±0.2°, 23.9±0.2°, 24.7±0.2°;

[0326] 6.9±0.2°, 11.9±0.2°, 12.4±0.2°, 13.7±0.2°, 15.7±0.2°, 16.5±0.2°, 18.0±0.2°, 19.1±0.2°, 23.9±0.2°, 24.7±0.2°.

[0327] In a preferred embodiment of the present invention, the crystal form E uses Cu-Kα radiation, and the X-ray characteristic diffraction peaks represented by 2θ angles and interplanar spacing d values ​​are shown in Table 5.

[0328] Table 5

[0329]

[0330]

[0331] In a preferred embodiment of the present invention, the X-ray powder diffraction pattern of the crystalline form E is substantially as follows Fig.11 shown.

[0332] In a preferred embodiment of the present invention, the compound (R)-11-chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d 2 The crystalline form of )-1-fluoro-2-(2-(2-hydroxypropane-2-yl)pyrimidin-4-yl)-5,6,7,8-tetrahydro-12H-bipyrido[1,2-a:3',4'-g]azocine-12-one is crystalline form F, and the X-ray powder diffraction spectrum of the crystalline form F has a diffraction peak at 2θ of 14.0±0.2°; or a diffraction peak at 15.6±0.2°; or a diffraction peak at 15.8±0.2°; or a diffraction peak at 16.1±0.2°; or a diffraction peak at 18. The present invention has a diffraction peak at 7±0.2°; or has a diffraction peak at 18.9±0.2°; or has a diffraction peak at 20.0±0.2°; or has a diffraction peak at 23.6±0.2°; or has a diffraction peak at 25.0±0.2°; or has a diffraction peak at 26.9±0.2°; preferably includes any 2-5, or 3-5, or 3-6, or 3-8, or 5-8, or 6-8 of the above-mentioned diffraction peaks, and more preferably includes any 6, 7 or 8 thereof.

[0333] In a preferred embodiment of the present invention, the X-ray powder diffraction pattern of the crystalline form F comprises at least one or more diffraction peaks located at 2θ of 14.0±0.2°, 18.9±0.2°, and 20.0±0.2°, preferably two of them, and more preferably three of them; optionally, it may further comprise at least one of 2θ of 15.6±0.2°, 15.8±0.2°, 16.1±0.2°, 18.7±0.2°, and 25.0±0.2°, preferably 2, 3, 4 or 5 of them; for example,

[0334] 14.0±0.2°, 20.0±0.2°;

[0335] 14.0±0.2°, 18.9±0.2°;

[0336] 18.9±0.2°, 20.0±0.2°;

[0337] 14.0±0.2°, 18.9±0.2°, 20.0±0.2°;

[0338] 14.0±0.2°, 15.6±0.2°, 20.0±0.2°;

[0339] 14.0±0.2°, 15.6±0.2°, 18.9±0.2°;

[0340] 15.6±0.2°, 18.9±0.2°, 20.0±0.2°;

[0341] 14.0±0.2°, 15.6±0.2°, 18.9±0.2°, 20.0±0.2°;

[0342] 14.0±0.2°, 15.6±0.2°, 16.1±0.2°, 20.0±0.2°;

[0343] 14.0±0.2°, 15.6±0.2°, 16.1±0.2°, 18.9±0.2°;

[0344] 15.6±0.2°, 16.1±0.2°, 18.9±0.2°, 20.0±0.2°;

[0345] 14.0±0.2°, 15.6±0.2°, 16.1±0.2°, 18.9±0.2°, 20.0±0.2°;

[0346] 14.0±0.2°, 15.6±0.2°, 16.1±0.2°, 18.7±0.2°, 20.0±0.2°;

[0347] 14.0±0.2°, 15.6±0.2°, 16.1±0.2°, 18.7±0.2°, 18.9±0.2°;

[0348] 15.6±0.2°, 16.1±0.2°, 18.7±0.2°, 18.9±0.2°, 20.0±0.2°.

[0349] In a preferred embodiment of the present invention, the X-ray powder diffraction pattern of the crystalline form F optionally further comprises one or more diffraction peaks located at 2θ of 14.3±0.2°, 20.3±0.2°, 23.6±0.2°, 25.9±0.2°, and 26.9±0.2°; preferably, at least any 2-3, or 4-5 of them; further preferably, any 2, 3, 4, or 5 of them; for example,

[0350] 23.6±0.2°, 26.9±0.2°;

[0351] 20.3±0.2°, 26.9±0.2°;

[0352] 20.3±0.2°, 23.6±0.2°;

[0353] 20.3±0.2°, 23.6±0.2°, 26.9±0.2°;

[0354] 14.3±0.2°, 23.6±0.2°, 26.9±0.2°;

[0355] 14.3±0.2°, 20.3±0.2°, 26.9±0.2°;

[0356] 14.3±0.2°, 20.3±0.2°, 23.6±0.2°, 26.9±0.2°;

[0357] 20.3±0.2°, 23.6±0.2°, 25.9±0.2°, 26.9±0.2°;

[0358] 14.3±0.2°, 23.6±0.2°, 25.9±0.2°, 26.9±0.2°.

[0359] In a preferred embodiment of the present invention, the X-ray powder diffraction pattern of the crystalline form F comprises one or more diffraction peaks located at 2θ of 14.0±0.2°, 14.3±0.2°, 15.6±0.2°, 15.8±0.2°, 16.1±0.2°, 18.7±0.2°, 18.9±0.2°, 20.0±0.2°, 20.3±0.2°, 23.6±0.2°, 25.0±0.2°, and 26.9±0.2°; preferably, it comprises 4, 5, 6, 8, 10 or 12 selected therefrom; for example, the X-ray powder diffraction pattern of the crystalline form F has diffraction peaks at the following positions at 2θ:

[0360] 14.0±0.2°, 15.6±0.2°, 18.9±0.2°, 20.0±0.2°;

[0361] 14.0±0.2°, 16.1±0.2°, 18.9±0.2°, 20.0±0.2°;

[0362] 14.0±0.2°, 15.6±0.2°, 16.1±0.2°, 18.9±0.2°, 20.0±0.2°;

[0363] 14.0±0.2°, 15.6±0.2°, 18.7±0.2°, 18.9±0.2°, 20.0±0.2°;

[0364] 14.0±0.2°, 15.6±0.2°, 16.1±0.2°, 18.7±0.2°, 18.9±0.2°, 20.0±0.2°;

[0365] 14.0±0.2°, 15.6±0.2°, 15.8±0.2°, 16.1±0.2°, 18.9±0.2°, 20.0±0.2°;

[0366] 14.0±0.2°, 15.6±0.2°, 15.8±0.2°, 16.1±0.2°, 18.7±0.2°, 18.9±0.2°, 20.0±0.2°, 25.0±0.2°;

[0367] 14.0±0.2°, 15.6±0.2°, 15.8±0.2°, 16.1±0.2°, 18.7±0.2°, 18.9±0.2°, 20.0±0.2°, 26.9±0.2°;

[0368] 14.0±0.2°, 15.6±0.2°, 15.8±0.2°, 16.1±0.2°, 18.7±0.2°, 18.9±0.2°, 20.0±0.2°, 23.6±0.2°, 25.0±0.2°, 26.9±0.2°;

[0369] 14.0±0.2°, 15.6±0.2°, 15.8±0.2°, 16.1±0.2°, 18.7±0.2°, 18.9±0.2°, 20.0±0.2°, 20.3±0.2°, 25.0±0.2°, 26.9±0.2°.

[0370] In a preferred embodiment of the present invention, the crystal form F uses Cu-Kα radiation, and the X-ray characteristic diffraction peaks represented by 2θ angles and interplanar spacing d values ​​are shown in Table 6.

[0371] Table 6

[0372]

[0373] In a preferred embodiment of the present invention, the X-ray powder diffraction pattern of the crystalline form F is substantially as follows Fig.12 shown.

[0374] The position of the diffraction peaks with the top ten relative peak intensities in the X-ray powder diffraction pattern of the crystal form A, crystal form B, crystal form C, crystal form D, crystal form E or crystal form F is Figure 1 , Figure 4 , Figure 7 , Fig.10 , Fig.11 and Fig.12 The 2θ error of the diffraction peak at the corresponding position is ±0.2° to ±0.5°, preferably ±0.2° to ±0.3°, and most preferably ±0.2°.

[0375] In a preferred embodiment of the present invention, the crystal form is a 1,2-propylene glycol solvate, a hydrate or an anhydrous form, and the number of 1,2-propylene glycol or water is 0.2 to 3, preferably 0.2, 0.5, 1, 1.5, 2, 2.5 or 3; wherein the water in the hydrate is selected from pipeline water, crystal water or a combination of the two; the preferred crystal form is an anhydrous form.

[0376] The present invention also provides a method for preparing the above-mentioned compound or a crystalline form of its stereoisomer:

[0377] Method 1 comprises the following steps: the compound is slurried with a poor solvent at a certain temperature to obtain a crystalline form, preferably, the temperature is 0 to 50° C.; more preferably, the temperature is 20 to 30° C.;

[0378] The poor solvent is selected from one or more of water, 1,2-propylene glycol, methanol, ethanol, isopropyl acetate, acetone, ethyl acetate, acetonitrile, ethanol, 88% acetone, tetrahydrofuran, 2-methyltetrahydrofuran, dichloromethane, 1,4-dioxane, benzene, toluene, isopropanol, n-butanol, isobutanol n-propanol, tert-butanol, 2-butanone, 3-pentanone and N-methylpyrrolidone; preferably one or more of water, 1,2-propylene glycol or acetone;

[0379] Method 2 comprises the following steps: dissolving the compound in a good solvent, adding a poor solvent and stirring until a solid is precipitated to obtain a crystalline form;

[0380] Method three comprises the following steps: dissolving the compound in a good solvent, placing the compound in a vacuum oven without a lid and rapidly evaporating the compound until the solvent evaporates to obtain a crystalline form;

[0381] In method 2 and method 3:

[0382] The good solvent is selected from one or more of methanol, ethanol, isopropanol, ethyl acetate, acetonitrile, acetone, tetrahydrofuran, dichloromethane, 1,4-dioxane and 2-butanone; preferably one or more of isopropanol, ethanol, ethyl acetate or tetrahydrofuran; further preferably, the good solvent in method 2 is selected from one or more of ethanol, ethyl acetate or tetrahydrofuran; the good solvent in method 3 is selected from isopropanol;

[0383] The poor solvent is selected from one or more of n-heptane, cyclohexane, n-hexane, n-pentane, water, ethyl acetate, methyl tert-butyl ether, toluene or isopropyl ether; preferably n-hexane;

[0384] Method 4 comprises the following steps: the compound is heated to a certain temperature using TGA to obtain a crystalline form, preferably, the temperature is 130-140°C.

[0385] Another object of the present invention is to provide an acid salt of the compound represented by general formula (I) and a crystalline form of the acid salt thereof.

[0386]

[0387] The substituents are defined as above,

[0388] The acid in the acid salt 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-naphthoic acid, acetic acid, dichloroacetic acid, trichloroacetic acid, acetohydroxamic acid, adipic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, 4-aminobenzoic acid, capric acid, caproic acid, caprylic acid, cinnamic acid, citric acid, cyclohexanesulfamic 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 sulfuric acid, dibenzoyltartaric acid, ethane- 1,2-disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galactonic acid, gentisic acid, glutaric acid, 2-ketoglutaric acid, glycolic acid, hippuric acid, isethionic 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, pamoic acid, propionic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, thiocyanic acid, undecylenic acid, trifluoroacetic acid, benzenesulfonic acid, p-toluenesulfonic acid or L-malic acid; preferably p-toluenesulfonic acid, hydrochloric acid, hydrobromic acid or methanesulfonic acid; more preferably hydrochloric acid, hydrobromic acid or methanesulfonic acid; most preferably hydrochloric acid.

[0389] In a preferred embodiment of the invention, the compound is selected from the group consisting of

[0390] (S)-11-chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d 2 )-2-(2-(2-hydroxypropane-2-yl)pyrimidin-4-yl)-5,6,7,8-tetrahydro-12H-bipyrido[1,2-a:3',4'-g]azocine-12-one;

[0391] (S)-11-chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d 2)-2-(3-(2-hydroxypropane-2-yl)-1H-pyrazol-1-yl)-5,6,7,8-tetrahydro-12H-bipyrido[1,2-a:3',4'-g]azocine-12-one;

[0392] (S)-N-(2-(1-(11-chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d 2 )-12-carbonyl-6,7,8,12-tetrahydro-5H-bipyrido[1,2-a:3',4'-g]azocin-2-yl)-4-fluoro-1H-pyrazol-3-yl)propan-2-yl)acetamide;

[0393] (S)-N-(2-(4-(11-chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d 2 )-12-carbonyl-6,7,8,12-tetrahydro-5H-bipyrido[1,2-a:3',4'-g]azocine-2-yl)pyrimidin-2-yl)propan-2-yl)acetamide;

[0394] (R)-N-(2-(1-(11-chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d 2 )-1-fluoro-12-carbonyl-6,7,8,12-tetrahydro-5H-bipyrido[1,2-a:3',4'-g]azocin-2-yl)-4-fluoro-1H-pyrazol-3-yl)propan-2-yl)acetamide;

[0395] (R)-N-(2-(4-(11-chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d 2 )-1-fluoro-12-carbonyl-6,7,8,12-tetrahydro-5H-bipyrido[1,2-a:3',4'-g]azocine-2-yl)pyrimidin-2-yl)propan-2-yl)acetamide;

[0396] (R)-11-chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d 2 )-1-fluoro-2-(3-(2-hydroxypropane-2-yl)-1H-pyrazol-1-yl)-5,6,7,8-tetrahydro-12H-bipyrido[1,2-a:3',4'-g]azocine-12-one;

[0397] (R)-11-chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d 2 )-1-fluoro-2-(2-(2-hydroxypropane-2-yl)pyrimidin-4-yl)-5,6,7,8-tetrahydro-12H-bipyrido[1,2-a:3',4'-g]azocine-12-one;

[0398] (S,Z)-11-chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d 2 )-2-(2-(2-hydroxypropane-2-yl)pyrimidin-4-yl)-7,8-dihydro-12H-dipyrido[1,2-a:3',4'-g]azocine-12-one;

[0399] (S,Z)-11-chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d 2 )-2-(3-(2-hydroxypropane-2-yl)-1H-pyrazol-1-yl)-7,8-dihydro-12H-dipyrido[1,2-a:3',4'-g]azocine-12-one; or

[0400] (S,Z)-N-(2-(1-(11-chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d 2 )-12-carbonyl-8,12-dihydro-7H-bipyrido[1,2-a:3',4'-g]azocin-2-yl)-4-fluoro-1H-pyrazol-3-yl)propan-2-yl)acetamide.

[0401] In a preferred embodiment of the present invention, the number of acids 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, further preferably 1.

[0402] In a preferred embodiment of the present invention, the acid salt is a hydrate or an anhydrate; when the acid salt is a hydrate, the number of water 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.

[0403] In a preferred embodiment of the present invention, the crystalline form of the acid salt is a hydrate or an anhydrate; when the crystalline form of the acid salt is a hydrate, the number of water 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.

[0404] In a preferred embodiment of the present invention, the compound (R)-11-chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d 2 The acid salt crystalline form of )-1-fluoro-2-(2-(2-hydroxypropane-2-yl)pyrimidin-4-yl)-5,6,7,8-tetrahydro-12H-bipyrido[1,2-a:3',4'-g]azocine-12-one is:

[0405] The hydrochloride salt form A has an X-ray powder diffraction pattern having a diffraction peak at 2θ of 7.5±0.2°; or a diffraction peak at 9.8±0.2°; or a diffraction peak at 12.4±0.2°; or a diffraction peak at 14.1±0.2°; or a diffraction peak at 14.4±0.2°; or a diffraction peak at 15.2±0.2°; or a diffraction peak at 16.3±0.2°; or a diffraction peak at 18.4±0.2°; or a diffraction peak at 19.6±0.2°; or a diffraction peak at 21.0±0.2°; preferably comprising any 2-5, or 3-5, or 3-6, or 3-8, or 5-8, or 6-8 of the above-mentioned diffraction peaks, and more preferably comprising any 6, 7 or 8 thereof.

[0406] In a preferred embodiment of the present invention, the X-ray powder diffraction pattern of the hydrochloride crystal form A comprises at least one or more diffraction peaks located at 2θ of 12.4±0.2°, 15.2±0.2°, and 16.3±0.2°, preferably two of them, and more preferably three of them; optionally, it may further comprise at least one of 2θ of 9.8±0.2°, 14.1±0.2°, 14.4±0.2°, 18.4±0.2°, and 19.6±0.2°, preferably 2, 3, 4 or 5 of them; for example,

[0407] 15.2±0.2°, 16.3±0.2°;

[0408] 12.4±0.2°, 15.2±0.2°;

[0409] 12.4±0.2°, 15.2±0.2°, 16.3±0.2°;

[0410] 15.2±0.2°, 16.3±0.2°, 18.4±0.2°;

[0411] 12.4±0.2°, 15.2±0.2°, 16.3±0.2°, 18.4±0.2°;

[0412] 14.1±0.2°, 15.2±0.2°, 16.3±0.2°, 18.4±0.2°;

[0413] 14.1±0.2°, 12.4±0.2°, 15.2±0.2°, 16.3±0.2°, 18.4±0.2°;

[0414] 14.1±0.2°, 14.4±0.2°, 15.2±0.2°, 16.3±0.2°, 18.4±0.2°.

[0415] In a preferred embodiment of the present invention, the X-ray powder diffraction pattern of the hydrochloride crystal form A optionally further comprises one or more diffraction peaks located at 2θ of 6.4±0.2°, 7.5±0.2°, 17.4±0.2°, 21.0±0.2°, and 22.4±0.2°; preferably, at least any 2-3 or 4-5 of them; further preferably, any 2, 3, 4, or 5 of them; for example,

[0416] 7.5±0.2°, 21.0±0.2°;

[0417] 6.4±0.2°, 21.0±0.2°;

[0418] 6.4±0.2°, 7.5±0.2°, 21.0±0.2°;

[0419] 6.4±0.2°, 21.0±0.2°, 22.4±0.2°;

[0420] 6.4±0.2°, 7.5±0.2°, 21.0±0.2°, 22.4±0.2°;

[0421] 6.4±0.2°, 17.4±0.2°, 21.0±0.2°, 22.4±0.2°.

[0422] In a preferred embodiment of the present invention, the X-ray powder diffraction pattern of the hydrochloride crystal form A comprises one or more diffraction peaks located at 2θ of 6.4±0.2°, 7.5±0.2°, 9.8±0.2°, 12.4±0.2°, 14.1±0.2°, 14.4±0.2°, 15.2±0.2°, 16.3±0.2°, 18.4±0.2°, 19.6±0.2°, 21.0±0.2°, and 22.4±0.2°; preferably, it comprises 4, 5, 6, 8, 10, or 12 of them; for example, the X-ray powder diffraction pattern of the hydrochloride crystal form A has diffraction peaks at the following positions at 2θ:

[0423] 12.4±0.2°, 15.2±0.2°, 16.3±0.2°, 18.4±0.2°;

[0424] 14.1±0.2°, 14.4±0.2°, 15.2±0.2°, 16.3±0.2°;

[0425] 14.1±0.2°, 12.4±0.2°, 15.2±0.2°, 16.3±0.2°, 18.4±0.2°;

[0426] 9.8±0.2°, 14.1±0.2°, 14.4±0.2°, 15.2±0.2°, 16.3±0.2°;

[0427] 9.8±0.2°, 14.1±0.2°, 12.4±0.2°, 15.2±0.2°, 16.3±0.2°, 18.4±0.2°;

[0428] 9.8±0.2°, 14.1±0.2°, 14.4±0.2°, 15.2±0.2°, 16.3±0.2°, 19.6±0.2°;

[0429] 9.8±0.2°, 14.1±0.2°, 12.4±0.2°, 15.2±0.2°, 16.3±0.2°, 18.4±0.2°, 19.6±0.2°, 21.0±0.2°;

[0430] 7.5±0.2°, 9.8±0.2°, 14.1±0.2°, 14.4±0.2°, 15.2±0.2°, 16.3±0.2°, 19.6±0.2°, 21.0±0.2°;

[0431] 6.4±0.2°, 7.5±0.2°, 9.8±0.2°, 14.1±0.2°, 12.4±0.2°, 15.2±0.2°, 16.3±0.2°, 18.4±0.2°, 19.6±0.2°, 21.0±0.2°;

[0432] 6.4±0.2°, 7.5±0.2°, 9.8±0.2°, 14.1±0.2°, 14.4±0.2°, 15.2±0.2°, 16.3±0.2°, 19.6±0.2°, 21.0±0.2°, 22.4±0.2°.

[0433] In a preferred embodiment of the present invention, the hydrochloride crystal form A uses Cu-Kα radiation, and the X-ray characteristic diffraction peaks represented by 2θ angles and interplanar spacing d values ​​are shown in Table 7.

[0434] Table 7

[0435]

[0436] In a preferred embodiment of the present invention, the X-ray powder diffraction pattern of the hydrochloride crystal form A is substantially as follows Fig.14 shown.

[0437] In a preferred embodiment of the present invention, the DSC spectrum of the hydrochloride crystal form A is as follows Fig.15 shown.

[0438] In a preferred embodiment of the present invention, the compound (R)-11-chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d 2 The acid salt crystalline form of )-1-fluoro-2-(2-(2-hydroxypropane-2-yl)pyrimidin-4-yl)-5,6,7,8-tetrahydro-12H-bipyrido[1,2-a:3',4'-g]azocine-12-one is:

[0439] The hydrochloride salt form B has an X-ray powder diffraction pattern having a diffraction peak at 2θ of 11.8±0.2°; or a diffraction peak at 12.2±0.2°; or a diffraction peak at 13.3±0.2°; or a diffraction peak at 13.7±0.2°; or a diffraction peak at 14.2±0.2°; or a diffraction peak at 15.6±0.2°; or a diffraction peak at 16.3±0.2°; or a diffraction peak at 18.3±0.2°; or a diffraction peak at 20.9±0.2°; or a diffraction peak at 25.6±0.2°; preferably comprising any 2-5, or 3-5, or 3-6, or 3-8, or 5-8, or 6-8 of the above-mentioned diffraction peaks, and more preferably comprising any 6, 7 or 8 thereof.

[0440] In a preferred embodiment of the present invention, the X-ray powder diffraction pattern of the hydrochloride crystal form B comprises at least one or more diffraction peaks located at 2θ of 12.2±0.2°, 14.2±0.2°, and 15.6±0.2°, preferably two of them, and more preferably three of them; optionally, it may further comprise at least one of 2θ of 11.8±0.2°, 13.7±0.2°, 16.3±0.2°, 18.3±0.2°, and 20.9±0.2°, preferably 2, 3, 4 or 5 of them; for example,

[0441] 14.2±0.2°, 15.6±0.2°;

[0442] 12.2±0.2°, 15.6±0.2°;

[0443] 12.2±0.2°, 14.2±0.2°, 15.6±0.2°;

[0444] 12.2±0.2°, 13.7±0.2°, 15.6±0.2°;

[0445] 12.2±0.2°, 13.7±0.2°, 14.2±0.2°, 15.6±0.2°;

[0446] 12.2±0.2°, 13.7±0.2°, 15.6±0.2°, 16.3±0.2°;

[0447] 12.2±0.2°, 13.7±0.2°, 14.2±0.2°, 15.6±0.2°, 16.3±0.2°;

[0448] 12.2±0.2°, 13.7±0.2°, 15.6±0.2°, 16.3±0.2°, 18.3±0.2°.

[0449] In a preferred embodiment of the present invention, the X-ray powder diffraction pattern of the hydrochloride salt form B optionally further comprises one or more diffraction peaks located at 2θ of 6.9±0.2°, 10.3±0.2°, 13.3±0.2°, 15.0±0.2°, 16.7±0.2°, 18.8±0.2°, and 25.6±0.2°; preferably, at least any 2-3, or 4-5, or 6-7 thereof; further preferably, any 2, 3, 4, 5, 6, or 7 thereof; for example,

[0450] 13.3±0.2°, 25.6±0.2°;

[0451] 6.9±0.2°, 13.3±0.2°;

[0452] 6.9±0.2°, 13.3±0.2°, 25.6±0.2°;

[0453] 6.9±0.2°, 10.3±0.2°, 13.3±0.2°;

[0454] 6.9±0.2°, 10.3±0.2°, 13.3±0.2°, 25.6±0.2°;

[0455] 6.9±0.2°, 10.3±0.2°, 13.3±0.2°, 18.8±0.2°;

[0456] 6.9±0.2°, 10.3±0.2°, 13.3±0.2°, 15.0±0.2°, 25.6±0.2°;

[0457] 6.9±0.2°, 10.3±0.2°, 13.3±0.2°, 15.0±0.2°, 18.8±0.2°;

[0458] 6.9±0.2°, 10.3±0.2°, 13.3±0.2°, 15.0±0.2°, 16.7±0.2°, 25.6±0.2°;

[0459] 6.9±0.2°, 10.3±0.2°, 13.3±0.2°, 15.0±0.2°, 16.7±0.2°, 18.8±0.2°.

[0460] In a preferred embodiment of the present invention, the X-ray powder diffraction pattern of the hydrochloride form B comprises one or more diffraction peaks located at 2θ of 6.9±0.2°, 10.3±0.2°, 11.8±0.2°, 12.2±0.2°, 13.3±0.2°, 13.7±0.2°, 14.2±0.2°, 15.6±0.2°, 16.3±0.2°, 18.3±0.2°, 20.9±0.2°, and 25.6±0.2°; preferably, it comprises 4, 5, 6, 8, 10, or 12 of them; for example, the X-ray powder diffraction pattern of the hydrochloride form B has diffraction peaks at the following positions at 2θ:

[0461] 12.2±0.2°, 13.7±0.2°, 14.2±0.2°, 15.6±0.2°;

[0462] 12.2±0.2°, 14.2±0.2°, 15.6±0.2°, 16.3±0.2°;

[0463] 12.2±0.2°, 13.7±0.2°, 14.2±0.2°, 15.6±0.2°, 16.3±0.2°;

[0464] 12.2±0.2°, 14.2±0.2°, 15.6±0.2°, 16.3±0.2°, 18.3±0.2°;

[0465] 12.2±0.2°, 13.7±0.2°, 14.2±0.2°, 15.6±0.2°, 16.3±0.2°, 18.3±0.2°;

[0466] 11.8±0.2°, 12.2±0.2°, 14.2±0.2°, 15.6±0.2°, 16.3±0.2°, 18.3±0.2°;

[0467] 11.8±0.2°, 12.2±0.2°, 13.7±0.2°, 14.2±0.2°, 15.6±0.2°, 16.3±0.2°, 18.3±0.2°, 20.9±0.2°;

[0468] 11.8±0.2°, 12.2±0.2°, 13.3±0.2°, 14.2±0.2°, 15.6±0.2°, 16.3±0.2°, 18.3±0.2°, 20.9±0.2°;

[0469] 6.9±0.2°, 11.8±0.2°, 12.2±0.2°, 13.7±0.2°, 14.2±0.2°, 15.6±0.2°, 16.3±0.2°, 18.3±0.2°, 20.9±0.2°, 25.6±0.2°;

[0470] 6.9±0.2°, 11.8±0.2°, 12.2±0.2°, 13.3±0.2°, 14.2±0.2°, 15.6±0.2°, 16.3±0.2°, 18.3±0.2°, 20.9±0.2°, 25.6±0.2°.

[0471] In a preferred embodiment of the present invention, the hydrochloride crystal form B uses Cu-Kα radiation, and the X-ray characteristic diffraction peaks represented by 2θ angles and interplanar spacing d values ​​are shown in Table 8.

[0472] Table 8

[0473]

[0474] In a preferred embodiment of the present invention, the X-ray powder diffraction pattern of the hydrochloride crystal form B is substantially as follows Fig.16 shown.

[0475] In a preferred embodiment of the present invention, the hydrochloride crystal form B has Fig.17 DSC spectrum shown.

[0476] In a preferred embodiment of the present invention, the compound (R)-11-chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d 2 The acid salt crystalline form of )-1-fluoro-2-(2-(2-hydroxypropane-2-yl)pyrimidin-4-yl)-5,6,7,8-tetrahydro-12H-bipyrido[1,2-a:3',4'-g]azocine-12-one is:

[0477] Hydrobromide type A, whose X-ray powder diffraction pattern has a diffraction peak at 2θ of 12.1±0.2°; or a diffraction peak at 12.3±0.2°; or a diffraction peak at 13.6±0.2°; or a diffraction peak at 14.1±0.2°; or a diffraction peak at 15.5±0.2°; or a diffraction peak at 16.2±0.2°; or a diffraction peak at 18.1±0.2°; or a diffraction peak at 20.9±0.2°; or a diffraction peak at 25.5±0.2°; or a diffraction peak at 26.7±0.2°; preferably contains any 2-5, or 3-5, or 3-6, or 3-8, or 5-8, or 6-8 of the above-mentioned diffraction peaks, and more preferably contains any 6, 7 or 8 of them.

[0478] In a preferred embodiment of the present invention, the X-ray powder diffraction pattern of the hydrobromide salt form A comprises at least one or more diffraction peaks located at 2θ of 12.1±0.2°, 13.6±0.2°, and 25.5±0.2°, preferably two of them, and more preferably three of them; optionally, it may further comprise at least one of 2θ of 14.1±0.2°, 15.5±0.2°, 18.1±0.2°, 20.9±0.2°, and 26.7±0.2°, preferably 2, 3, 4 or 5 of them; for example,

[0479] 12.1±0.2°, 13.6±0.2°;

[0480] 13.6±0.2°, 25.5±0.2°;

[0481] 12.1±0.2°, 13.6±0.2°, 25.5±0.2°;

[0482] 12.1±0.2°, 13.6±0.2°, 14.1±0.2°;

[0483] 12.1±0.2°, 13.6±0.2°, 14.1±0.2°, 25.5±0.2°;

[0484] 12.1±0.2°, 13.6±0.2°, 14.1±0.2°, 15.5±0.2°;

[0485] 12.1±0.2°, 13.6±0.2°, 14.1±0.2°, 15.5±0.2°, 25.5±0.2°;

[0486] 12.1±0.2°, 13.6±0.2°, 14.1±0.2°, 15.5±0.2°, 20.9±0.2°.

[0487] In a preferred embodiment of the present invention, the X-ray powder diffraction pattern of the hydrobromide salt form A optionally further comprises one or more diffraction peaks located at 2θ of 10.4±0.2°, 12.3±0.2°, 16.2±0.2°, 17.3±0.2°, 21.5±0.2°, 27.5±0.2°, 29.1±0.2°; preferably at least any 2-3, or 4-5, or 6-7 thereof; further preferably, any 2, 3, 4, 5, 6, or 7 thereof; for example,

[0488] 12.3±0.2°, 16.2±0.2°;

[0489] 12.3±0.2°, 17.3±0.2°;

[0490] 12.3±0.2°, 16.2±0.2°, 17.3±0.2°;

[0491] 12.3±0.2°, 17.3±0.2°, 27.5±0.2°;

[0492] 12.3±0.2°, 16.2±0.2°, 17.3±0.2°, 27.5±0.2;

[0493] 12.3±0.2°, 17.3±0.2°, 21.5±0.2°, 27.5±0.2°;

[0494] 12.3±0.2°, 16.2±0.2°, 17.3±0.2°, 21.5±0.2°, 27.5±0.2;

[0495] 12.3±0.2°, 17.3±0.2°, 21.5±0.2°, 27.5±0.2°, 29.1±0.2°;

[0496] 12.3±0.2°, 16.2±0.2°, 17.3±0.2°, 21.5±0.2°, 27.5±0.2, 29.1±0.2°;

[0497] 10.4±0.2°, 12.3±0.2°, 17.3±0.2°, 21.5±0.2°, 27.5±0.2°, 29.1±0.2°.

[0498] In a preferred embodiment of the present invention, the X-ray powder diffraction pattern of the hydrobromide salt form A comprises one or more diffraction peaks located at 2θ of 12.1±0.2°, 12.3±0.2°, 13.6±0.2°, 14.1±0.2°, 15.5±0.2°, 16.2±0.2°, 17.3±0.2°, 18.1±0.2°, 20.9±0.2°, 25.5±0.2°, 26.7±0.2°, 27.5±0.2°; preferably, it comprises 4, 5, 6, 8, 10 or 12 of them; for example, the X-ray powder diffraction pattern of the hydrobromide salt form A has diffraction peaks at the following positions at 2θ:

[0499] 12.1±0.2°, 13.6±0.2°, 14.1±0.2°, 25.5±0.2°;

[0500] 12.1±0.2°, 13.6±0.2°, 14.1±0.2°, 15.5±0.2°;

[0501] 12.1±0.2°, 13.6±0.2°, 14.1±0.2°, 15.5±0.2°, 25.5±0.2°;

[0502] 12.1±0.2°, 13.6±0.2°, 14.1±0.2°, 15.5±0.2°, 20.9±0.2°;

[0503] 12.1±0.2°, 13.6±0.2°, 14.1±0.2°, 15.5±0.2°, 20.9±0.2°, 25.5±0.2°;

[0504] 12.1±0.2°, 13.6±0.2°, 14.1±0.2°, 15.5±0.2°, 18.1±0.2°, 20.9±0.2°;

[0505] 12.1±0.2°, 13.6±0.2°, 14.1±0.2°, 15.5±0.2°, 18.1±0.2°, 20.9±0.2°, 25.5±0.2°, 26.7±0.2°;

[0506] 12.1±0.2°, 12.3±0.2°, 13.6±0.2°, 14.1±0.2°, 15.5±0.2°, 18.1±0.2°, 20.9±0.2°, 26.7±0.2°;

[0507] 12.1±0.2°, 12.3±0.2°, 13.6±0.2°, 14.1±0.2°, 15.5±0.2°, 16.2±0.2°, 18.1±0.2°, 20.9±0.2°, 25.5±0.2°, 26.7±0.2°;

[0508] 12.1±0.2°, 12.3±0.2°, 13.6±0.2°, 14.1±0.2°, 15.5±0.2°, 16.2±0.2°, 17.3±0.2°, 18.1±0.2°, 20.9±0.2°, 26.7±0.2°.

[0509] In a preferred embodiment of the present invention, the hydrobromide salt form A uses Cu-Kα radiation, and the X-ray characteristic diffraction peaks represented by 2θ angles and interplanar spacing d values ​​are shown in Table 9.

[0510] Table 9

[0511]

[0512]

[0513] In a preferred embodiment of the present invention, the X-ray powder diffraction pattern of the hydrobromide salt form A is substantially as follows Fig.18 shown.

[0514] In a preferred embodiment of the present invention, the hydrobromide salt form A has the following Fig.19 DSC spectrum shown.

[0515] In a preferred embodiment of the present invention, the compound (R)-11-chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d 2 The acid salt crystalline form of )-1-fluoro-2-(2-(2-hydroxypropane-2-yl)pyrimidin-4-yl)-5,6,7,8-tetrahydro-12H-bipyrido[1,2-a:3',4'-g]azocine-12-one is:

[0516] Hydrobromide type B, whose X-ray powder diffraction pattern has a diffraction peak at 2θ of 11.9±0.2°; or a diffraction peak at 13.1±0.2°; or a diffraction peak at 15.0±0.2°; or a diffraction peak at 15.4±0.2°; or a diffraction peak at 16.1±0.2°; or a diffraction peak at 16.7±0.2°; or a diffraction peak at 18.0±0.2°; or a diffraction peak at 19.3±0.2°; or a diffraction peak at 20.4±0.2°; or a diffraction peak at 21.4±0.2°; preferably includes any 2-5, or 3-5, or 3-6, or 3-8, or 5-8, or 6-8 of the above-mentioned diffraction peaks, and more preferably includes any 6, 7 or 8 thereof.

[0517] In a preferred embodiment of the present invention, the X-ray powder diffraction pattern of the hydrobromide salt form B comprises at least one or more diffraction peaks located at 2θ of 11.9±0.2°, 13.1±0.2°, and 21.4±0.2°, preferably two of them, and more preferably three of them; optionally, it may further comprise at least one of 2θ of 15.0±0.2°, 15.4±0.2°, 16.1±0.2°, 16.7±0.2°, 18.0±0.2°, 19.3±0.2°, and 20.4±0.2°, preferably 2, 3, 4 or 5 of them; for example,

[0518] 11.9±0.2°, 13.1±0.2°;

[0519] 13.1±0.2°, 21.4±0.2°;

[0520] 11.9±0.2°, 13.1±0.2°, 21.4±0.2°;

[0521] 13.1±0.2°, 16.7±0.2°, 21.4±0.2°;

[0522] 11.9±0.2°, 13.1±0.2°, 16.7±0.2°, 21.4±0.2°;

[0523] 13.1±0.2°, 16.1±0.2°, 16.7±0.2°, 21.4±0.2°;

[0524] 11.9±0.2°, 13.1±0.2°, 16.1±0.2°, 16.7±0.2°, 21.4±0.2°;

[0525] 13.1±0.2°, 16.1±0.2°, 16.7±0.2°, 18.0±0.2°, 21.4±0.2°;

[0526] 13.1±0.2°, 15.4±0.2°, 16.1±0.2°, 16.7±0.2°, 18.0±0.2°, 21.4±0.2°;

[0527] 13.1±0.2°, 16.1±0.2°, 16.7±0.2°, 18.0±0.2°, 19.3±0.2°, 21.4±0.2°.

[0528] In a preferred embodiment of the present invention, the hydrobromide salt form B uses Cu-Kα radiation, and the X-ray characteristic diffraction peaks represented by 2θ angles and interplanar spacing d values ​​are shown in Table 10.

[0529] Table 10

[0530]

[0531] In a preferred embodiment of the present invention, the X-ray powder diffraction pattern of the hydrobromide salt form B is substantially as follows Fig. 20 shown.

[0532] In a preferred embodiment of the present invention, the hydrobromide salt form B has Fig.21 DSC spectrum shown.

[0533] In a preferred embodiment of the present invention, the compound (R)-11-chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d 2 The acid salt crystalline form of )-1-fluoro-2-(2-(2-hydroxypropane-2-yl)pyrimidin-4-yl)-5,6,7,8-tetrahydro-12H-bipyrido[1,2-a:3',4'-g]azocine-12-one is:

[0534] Methanesulfonate type A, whose X-ray powder diffraction pattern has a diffraction peak at 2θ of 6.5±0.2°; or a diffraction peak at 9.4±0.2°; or a diffraction peak at 9.9±0.2°; or a diffraction peak at 11.5±0.2°; or a diffraction peak at 12.0±0.2°; or a diffraction peak at 12.5±0.2°; or a diffraction peak at 15.2±0.2°; or a diffraction peak at 19.0±0.2°; or a diffraction peak at 19.9±0.2°; or a diffraction peak at 20.2±0.2°; preferably contains any 2-5, or 3-5, or 3-6, or 3-8, or 5-8, or 6-8 of the above-mentioned diffraction peaks, and more preferably contains any 6, 7 or 8 of them.

[0535] In a preferred embodiment of the present invention, the X-ray powder diffraction pattern of the mesylate salt form A comprises at least one or more diffraction peaks located at 2θ of 6.5±0.2°, 9.9±0.2°, and 12.5±0.2°, preferably two of them, and more preferably three of them; optionally, it may further comprise at least one of 2θ of 9.4±0.2°, 11.5±0.2°, 12.0±0.2°, 19.9±0.2°, and 20.2±0.2°, preferably 2, 3, 4 or 5 of them; for example,

[0536] 9.9±0.2°, 12.5±0.2°;

[0537] 6.5±0.2°, 9.9±0.2°;

[0538] 6.5±0.2°, 9.9±0.2°, 12.5±0.2°;

[0539] 6.5±0.2°, 9.9±0.2°, 19.9±0.2°;

[0540] 6.5±0.2°, 9.9±0.2°, 12.5±0.2°, 19.9±0.2°;

[0541] 6.5±0.2°, 9.9±0.2°, 11.5±0.2°, 19.9±0.2°;

[0542] 6.5±0.2°, 9.9±0.2°, 11.5±0.2°, 12.5±0.2°, 19.9±0.2°;

[0543] 6.5±0.2°, 9.4±0.2°, 9.9±0.2°, 11.5±0.2°, 19.9±0.2°.

[0544] In a preferred embodiment of the present invention, the X-ray powder diffraction pattern of the mesylate salt form A optionally further comprises one or more diffraction peaks located at 2θ of 10.6±0.2°, 15.2±0.2°, 16.9±0.2°, 17.6±0.2°, 19.0±0.2°, 22.0±0.2°, 23.1±0.2°; preferably at least any 2-3, or 4-5, or 6-7 thereof; further preferably, any 2, 3, 4, 5, 6, or 7 thereof; for example,

[0545] 15.2±0.2°, 19.0±0.2°;

[0546] 15.2±0.2°, 22.0±0.2°;

[0547] 15.2±0.2°, 19.0±0.2°, 22.0±0.2°;

[0548] 15.2±0.2°, 17.6±0.2°, 22.0±0.2°;

[0549] 15.2±0.2°, 17.6±0.2°, 19.0±0.2°, 22.0±0.2°;

[0550] 15.2±0.2°, 16.9±0.2°, 17.6±0.2°, 22.0±0.2°;

[0551] 15.2±0.2°, 16.9±0.2°, 17.6±0.2°, 19.0±0.2°, 22.0±0.2°;

[0552] 10.6±0.2°, 15.2±0.2°, 16.9±0.2°, 17.6±0.2°, 22.0±0.2°;

[0553] 10.6±0.2°, 15.2±0.2°, 16.9±0.2°, 17.6±0.2°, 19.0±0.2°, 22.0±0.2°;

[0554] 10.6±0.2°, 15.2±0.2°, 16.9±0.2°, 17.6±0.2°, 22.0±0.2°, 23.1±0.2°.

[0555] In a preferred embodiment of the present invention, the X-ray powder diffraction pattern of the mesylate salt form A comprises one or more diffraction peaks located at 2θ of 6.5±0.2°, 9.4±0.2°, 9.9±0.2°, 11.5±0.2°, 12.0±0.2°, 12.5±0.2°, 15.2±0.2°, 17.6±0.2°, 19.0±0.2°, 19.9±0.2°, 20.2±0.2°, 22.0±0.2°; preferably, it comprises 4, 5, 6, 8, 10 or 12 of them; for example, the X-ray powder diffraction pattern of the mesylate salt form A has diffraction peaks at the following positions at 2θ:

[0556] 6.5±0.2°, 9.9±0.2°, 12.5±0.2°, 19.9±0.2°;

[0557] 11.5±0.2°, 9.9±0.2°, 12.5±0.2°, 19.9±0.2°;

[0558] 6.5±0.2°, 9.9±0.2°, 11.5±0.2°, 12.5±0.2°, 19.9±0.2°;

[0559] 9.4±0.2°, 11.5±0.2°, 9.9±0.2°, 12.5±0.2°, 19.9±0.2°;

[0560] 6.5±0.2°, 9.4±0.2°, 9.9±0.2°, 11.5±0.2°, 12.5±0.2°, 19.9±0.2°;

[0561] 9.4±0.2°, 11.5±0.2°, 9.9±0.2°, 12.0±0.2°, 12.5±0.2°, 19.9±0.2°;

[0562] 6.5±0.2°, 9.4±0.2°, 9.9±0.2°, 11.5±0.2°, 12.0±0.2°, 12.5±0.2°, 19.9±0.2°, 20.2±0.2°;

[0563] 9.4±0.2°, 11.5±0.2°, 9.9±0.2°, 12.0±0.2°, 12.5±0.2°, 15.2±0.2°, 19.9±0.2°, 20.2±0.2°;

[0564] 6.5±0.2°, 9.4±0.2°, 9.9±0.2°, 11.5±0.2°, 12.0±0.2°, 12.5±0.2°, 15.2±0.2°, 19.0±0.2°, 19.9±0.2°, 20.2±0.2°;

[0565] 9.4±0.2°, 11.5±0.2°, 9.9±0.2°, 12.0±0.2°, 12.5±0.2°, 15.2±0.2°, 19.0±0.2°, 19.9±0.2°, 20.2±0.2°, 22.0±0.2°.

[0566] In a preferred embodiment of the present invention, the mesylate salt form A uses Cu-Kα radiation, and the X-ray characteristic diffraction peaks represented by 2θ angles and interplanar spacing d values ​​are shown in Table 11.

[0567] Table 11

[0568]

[0569] In a preferred embodiment of the present invention, the X-ray powder diffraction pattern of the mesylate salt form A is substantially as follows: Fig. 22 shown.

[0570] In a preferred embodiment of the present invention, the X-ray powder diffraction pattern of the hydrochloride crystal form A, the hydrochloride crystal form B, the hydrobromide crystal form A, the hydrobromide crystal form B or the methanesulfonate crystal form A has the top ten diffraction peak positions with the same relative peak intensity as Fig.14 , Fig.16 , Fig.18 , Fig. 20 or Fig. 22 The 2θ error of the diffraction peak at the corresponding position is ±0.2° to ±0.5°, preferably ±0.2° to ±0.3°, and most preferably ±0.2°.

[0571] In a preferred embodiment of the present invention, the compound (R)-N-(2-(1-(11-chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d 2 The acid salt crystalline form of )-1-fluoro-12-carbonyl-6,7,8,12-tetrahydro-5H-bipyrido[1,2-a:3',4'-g]azocine-2-yl)-4-fluoro-1H-pyrazol-3-yl)propane-2-yl)acetamide is:

[0572] p-Toluenesulfonate salt type A, whose X-ray powder diffraction spectrum has a diffraction peak at 2θ of 6.2±0.2°; or a diffraction peak at 10.7±0.2°; or a diffraction peak at 12.0±0.2°; or a diffraction peak at 12.5±0.2°; or a diffraction peak at 17.0±0.2°; or a diffraction peak at 17.7±0.2°; or a diffraction peak at 18.6±0.2°; or a diffraction peak at 19.2±0.2°; preferably contains any 2-5, or 3-5, or 3-6, or 3-8, or 5-8, or 6-8 of the above-mentioned diffraction peaks, and more preferably contains any 6, 7 or 8 of them.

[0573] In a preferred embodiment of the present invention, the X-ray powder diffraction pattern of p-toluenesulfonate salt form A comprises at least one or more diffraction peaks located at 2θ of 12.0±0.2°, 17.7±0.2°, and 19.2±0.2°, preferably two of them, and more preferably three of them; optionally, it may further comprise at least one of 2θ of 6.2±0.2°, 10.7±0.2°, 12.5±0.2°, 17.0±0.2°, and 18.6±0.2°, preferably 2, 3, 4 or 5 of them;

[0574] In a preferred embodiment of the present invention, the X-ray powder diffraction pattern of p-toluenesulfonate salt form A comprises one or more diffraction peaks located at 2θ of 6.2±0.2°, 10.7±0.2°, 12.0±0.2°, 12.5±0.2°, 17.0±0.2°, 17.7±0.2°, 18.6±0.2°, and 19.2±0.2°; preferably, it comprises 4, 5, 6 or 8 selected therefrom.

[0575] In a preferred embodiment of the present invention, the p-toluenesulfonate salt type A uses Cu-Kα radiation, and the X-ray characteristic diffraction peaks represented by 2θ angle and crystal plane spacing d value are shown in Table 12.

[0576] Table 12

[0577]

[0578] In a preferred embodiment of the present invention, the X-ray powder diffraction pattern of the p-toluenesulfonate salt form A is substantially as follows Fig.23 shown.

[0579] In a preferred embodiment of the present invention, the X-ray powder diffraction pattern of the p-toluenesulfonate salt form A has the top ten diffraction peak positions with the relative peak intensity being Fig.23The 2θ error of the diffraction peak at the corresponding position is ±0.2° to ±0.5°, preferably ±0.2° to ±0.3°, and most preferably ±0.2°.

[0580] The present invention also provides a method for preparing the acid salt of the compound of formula (I).

[0581] Method 1 includes the following steps:

[0582] 1) Weigh an appropriate amount of free base and dissolve it in a benign solvent;

[0583] 2) Weigh an appropriate amount of counter ion acid and dissolve it in an organic solvent; the amount of the counter ion acid is preferably 1.2 equivalents;

[0584] 3) combining the above two solutions, stirring to precipitate or adding a poor solvent dropwise and stirring to precipitate, and the acid salt of the compound is obtained by precipitation;

[0585] 4) Rapid centrifugation or vacuum filtration to obtain the target product;

[0586] in:

[0587] The benign solvent is selected from one or more of acetone, acetonitrile, ethanol, ethyl acetate, dichloromethane or tetrahydrofuran; preferably one or more of acetone, acetonitrile or ethyl acetate;

[0588] The organic solvent is selected from one or more of methanol, ethanol, ethyl acetate, dichloromethane, acetone, n-hexane, petroleum ether, benzene, toluene, chloroform, acetonitrile, carbon tetrachloride, ethylene dichloride, tetrahydrofuran, 2-butanone, 3-pentanone, heptane, methyl tert-butyl ether, isopropyl ether, 1,4-dioxane, tert-butanol or N,N-dimethylformamide; preferably ethanol; the above-mentioned benign solvent and organic solution need to be miscible when used;

[0589] The poor solvent is selected from one or more of heptane, water, methyl tert-butyl ether, cyclohexane, toluene, isopropyl ether or ethyl acetate; preferably isopropyl ether or n-heptane;

[0590] The counter ion acid is selected from hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, hydrofluoric acid, hydroiodic acid, phosphoric acid, 2,5-dihydroxybenzoic acid, 1-hydroxy-2-naphthoic acid, acetic acid, dichloroacetic acid, trichloroacetic acid, acetohydroxamic acid, adipic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, benzoic acid, 4-acetylaminobenzoic acid, 4-aminobenzoic acid, capric acid, caproic acid, caprylic acid, cinnamic acid, citric acid, cyclohexanesulfamic 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 sulfuric acid, dibenzoyltartaric acid, acetic acid Preferably, the acid is 1,2-disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galactonic acid, gentisic acid, glutaric acid, 2-ketoglutaric acid, glycolic acid, hippuric acid, isethionic acid, lactobionic acid, ascorbic acid, aspartic acid, lauric acid, camphoric acid, maleic acid, malonic acid, methanesulfonic acid, 1,5-naphthalene disulfonic acid, naphthalene-2-sulfonic acid, nicotinic acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, propionic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, thiocyanic acid, undecylenic acid, trifluoroacetic acid, benzenesulfonic acid, p-toluenesulfonic acid or L-malic acid; preferably, hydrochloric acid, hydrobromic acid or methanesulfonic acid; most preferably, hydrochloric acid.

[0591] Method 2 includes the following steps:

[0592] 1) Weigh an appropriate amount of free base and suspend it with a poor solvent;

[0593] 2) Weigh an appropriate amount of counter ion acid and dissolve it in an organic solvent or not; the amount of the counter ion acid is preferably 1.2 equivalents;

[0594] 3) Combine the above two solutions and stir to dissolve, continue stirring to react, and after stirring for a suitable time, the acid salt of the compound is obtained;

[0595] 4) Rapid centrifugation or vacuum filtration to obtain the target product;

[0596] in:

[0597] The organic solvent is selected from methanol, ethanol, ethyl acetate, dichloromethane, acetone, n-hexane, petroleum ether, benzene, toluene, chloroform, acetonitrile, carbon tetrachloride, ethylene dichloride, tetrahydrofuran, 2-butanone, 3-pentanone, heptane, methyl tert-butyl ether, isopropyl ether, 1,4-dioxane, tert-butanol or N,N-dimethylformamide; preferably methanol;

[0598] The poor solvent is selected from acetone, ethyl acetate, methanol, 2-methyl-tetrahydrofuran or acetonitrile; preferably acetone;

[0599] The counter ion acid is selected from hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, hydrofluoric acid, hydroiodic acid, phosphoric acid, 2,5-dihydroxybenzoic acid, 1-hydroxy-2-naphthoic acid, acetic acid, dichloroacetic acid, trichloroacetic acid, acetohydroxamic acid, adipic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, benzoic acid, 4-acetylaminobenzoic acid, 4-aminobenzoic acid, capric acid, caproic acid, caprylic acid, cinnamic acid, citric acid, cyclohexanesulfamic 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 sulfuric acid, dibenzoyltartaric acid, acetic acid The present invention can be selected from the group consisting of 1,2-disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galactosonic acid, gentisic acid, glutaric acid, 2-ketoglutaric acid, glycolic acid, hippuric acid, isethionic 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, pamoic acid, propionic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, thiocyanic acid, undecylenic acid, trifluoroacetic acid, benzenesulfonic acid, p-toluenesulfonic acid or L-malic acid; preferably p-toluenesulfonic acid, hydrochloric acid, hydrobromic acid or methanesulfonic acid.

[0600] The present invention also provides a method for preparing the acid salt crystalline form of the compound of formula (I).

[0601] Method 1 includes the following steps:

[0602] 1) Weigh an appropriate amount of free base and dissolve it in a benign solvent;

[0603] 2) Weigh an appropriate amount of counter ion acid and dissolve it in an organic solvent; the amount of the counter ion acid is preferably 1.2 equivalents;

[0604] 3) combining the above two solutions, stirring to precipitate or adding a poor solvent dropwise and stirring to precipitate;

[0605] 4) Rapid centrifugation or vacuum filtration to obtain the target product;

[0606] in:

[0607] The benign solvent is selected from one or more of acetone, acetonitrile, ethanol, ethyl acetate, dichloromethane or tetrahydrofuran; preferably one or more of acetone, acetonitrile or ethyl acetate;

[0608] The organic solvent is selected from one or more of methanol, ethanol, ethyl acetate, dichloromethane, acetone, n-hexane, petroleum ether, benzene, toluene, chloroform, acetonitrile, carbon tetrachloride, ethylene dichloride, tetrahydrofuran, 2-butanone, 3-pentanone, heptane, methyl tert-butyl ether, isopropyl ether, 1,4-dioxane, tert-butanol or N,N-dimethylformamide; preferably ethanol; the above-mentioned benign solvent and organic solution need to be miscible when used;

[0609] The poor solvent is selected from one or more of heptane, water, methyl tert-butyl ether, cyclohexane, toluene, isopropyl ether or ethyl acetate; preferably isopropyl ether or n-heptane;

[0610] The counter ion acid is selected from hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, hydrofluoric acid, hydroiodic acid, phosphoric acid, 2,5-dihydroxybenzoic acid, 1-hydroxy-2-naphthoic acid, acetic acid, dichloroacetic acid, trichloroacetic acid, acetohydroxamic acid, adipic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, benzoic acid, 4-acetylaminobenzoic acid, 4-aminobenzoic acid, capric acid, caproic acid, caprylic acid, cinnamic acid, citric acid, cyclohexanesulfamic 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 sulfuric acid, dibenzoyltartaric acid, acetic acid Preferably, the acid is 1,2-disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galactonic acid, gentisic acid, glutaric acid, 2-ketoglutaric acid, glycolic acid, hippuric acid, isethionic acid, lactobionic acid, ascorbic acid, aspartic acid, lauric acid, camphoric acid, maleic acid, malonic acid, methanesulfonic acid, 1,5-naphthalene disulfonic acid, naphthalene-2-sulfonic acid, nicotinic acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, propionic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, thiocyanic acid, undecylenic acid, trifluoroacetic acid, benzenesulfonic acid, p-toluenesulfonic acid or L-malic acid; preferably, hydrochloric acid, hydrobromic acid or methanesulfonic acid; most preferably, hydrochloric acid.

[0611] Method 2 includes the following steps:

[0612] 1) Weigh an appropriate amount of free base and suspend it with a poor solvent;

[0613] 2) Weigh an appropriate amount of counter ion acid and dissolve it in an organic solvent or not; the amount of the counter ion acid is preferably 1.2 equivalents;

[0614] 3) Combine the above two solutions and stir to dissolve, and continue stirring to react;

[0615] 4) Rapid centrifugation or vacuum filtration to obtain the target product;

[0616] in:

[0617] The organic solvent is selected from methanol, ethanol, ethyl acetate, dichloromethane, acetone, n-hexane, petroleum ether, benzene, toluene, chloroform, acetonitrile, carbon tetrachloride, ethylene dichloride, tetrahydrofuran, 2-butanone, 3-pentanone, heptane, methyl tert-butyl ether, isopropyl ether, 1,4-dioxane, tert-butanol or N,N-dimethylformamide; preferably methanol;

[0618] The poor solvent is selected from acetone, ethyl acetate, methanol, 2-methyl-tetrahydrofuran or acetonitrile; preferably acetone;

[0619] The counter ion acid is selected from hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, hydrofluoric acid, hydroiodic acid, phosphoric acid, 2,5-dihydroxybenzoic acid, 1-hydroxy-2-naphthoic acid, acetic acid, dichloroacetic acid, trichloroacetic acid, acetohydroxamic acid, adipic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, benzoic acid, 4-acetylaminobenzoic acid, 4-aminobenzoic acid, capric acid, caproic acid, caprylic acid, cinnamic acid, citric acid, cyclohexanesulfamic 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 sulfuric acid, dibenzoyltartaric acid, acetic acid Alkane-1,2-disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galactonic acid, gentisic acid, glutaric acid, 2-ketoglutaric acid, glycolic acid, hippuric acid, isethionic acid, lactobionic acid, ascorbic acid, aspartic acid, lauric acid, camphoric acid, maleic acid, malonic acid, methanesulfonic acid, 1,5-naphthalene disulfonic acid, naphthalene-2-sulfonic acid, nicotinic acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, propionic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, thiocyanic acid, undecylenic acid, trifluoroacetic acid, benzenesulfonic acid, p-toluenesulfonic acid or L-malic acid; preferably p-toluenesulfonic acid, hydrochloric acid, hydrobromic acid or methanesulfonic acid. The present invention also provides a pharmaceutical composition, which contains a therapeutically effective amount of an acid salt, a crystalline form or an acid salt crystalline form of the above-mentioned compound and one or more pharmaceutically acceptable carriers, diluents or excipients.

[0620] The pharmaceutical composition of the invention includes suitable administration routes such as oral administration and injection, preferably oral administration route. The dosage form includes tablets, capsules, dispersions and suspensions, preferably tablets.

[0621] The present invention further relates to a pharmaceutical composition, which contains a therapeutically effective amount of an acid salt, a crystal form or an acid salt crystal form of the above-mentioned compound; further, the acid salt, a crystal form or an acid salt crystal form of the compound accounts for 0.1% to 95% by weight in the composition, preferably 0.5% to 85%, more preferably 1% to 60%, further preferably 10% to 50%, further preferably 15-40%, further preferably 20-30%, further preferably 20-25% (based on the total weight of the pharmaceutical composition).

[0622] The present invention further relates to the use of the acid salt, crystal form or acid salt crystal form of the compound, or the pharmaceutical composition in the preparation of drugs for treating diseases mediated by p38 kinase.

[0623] The present invention further relates to the use of the acid salt, crystal form or acid salt crystal form of the compound, or its pharmaceutical composition in the preparation of drugs for treating autoimmune diseases, metabolic diseases and tumors, etc. The autoimmune diseases are selected from chronic inflammatory diseases, acute inflammatory diseases, autoinflammatory diseases and atherosclerosis, etc.; the metabolic diseases are selected from diabetes and fibrotic diseases, etc.; the tumors are selected from leukemia and lymphoma, etc.

[0624] The present invention also relates to a method for treating, preventing and / or treating autoimmune diseases, metabolic diseases and tumors, which comprises administering to a patient a therapeutically effective dose of an acid salt, a crystal form or an acid salt crystal form of the compound of the present invention, or a pharmaceutical composition thereof; wherein the autoimmune disease is selected from chronic inflammatory diseases, acute inflammatory diseases, autoinflammatory diseases and atherosclerosis, etc.; the metabolic disease is selected from diabetes and fibrotic diseases, etc.; and the tumor is selected from leukemia and lymphoma, etc.

[0625] The present invention also provides methods of using the acid salts, crystalline forms, crystalline forms of acid salts or pharmaceutical compositions of the present invention to treat disease conditions, including but not limited to conditions associated with p38 kinase-mediated diseases. BRIEF DESCRIPTION OF THE DRAWINGS

[0626] Figure 1 This is an XRPD diagram of free base Form A.

[0627] Figure 2 This is a TGA diagram of free base form A.

[0628] Figure 3 This is a DSC diagram of free base form A.

[0629] Figure 4 This is the XRPD diagram of free base Form B.

[0630] Figure 5 This is the TGA diagram of free base form B.

[0631] Figure 6 This is the DSC diagram of free base form B.

[0632] Figure 7 This is an XRPD diagram of free base Form C.

[0633] Figure 8 This is the TGA diagram of free base form C.

[0634] Fig. 9 This is the DSC diagram of free base form C.

[0635] Fig.10 This is the XRPD diagram of free base Form D.

[0636] Fig.11This is an XRPD diagram of free base Form E.

[0637] Fig.12 This is the XRPD diagram of free base Form F.

[0638] Fig.13 This is the NMR image of free base form B.

[0639] Fig.14 This is an XRPD diagram of hydrochloride form A.

[0640] Fig.15 This is a DSC diagram of hydrochloride form A.

[0641] Fig.16 This is an XRPD diagram of hydrochloride form B.

[0642] Fig.17 This is a DSC diagram of hydrochloride form B.

[0643] Fig.18 This is an XRPD diagram of hydrobromide salt form A.

[0644] Fig.19 This is a DSC diagram of hydrobromide form A.

[0645] Fig. 20 This is an XRPD diagram of hydrobromide salt form B.

[0646] Fig.21 This is a DSC diagram of hydrobromide form B.

[0647] Fig. 22 This is an XRPD diagram of mesylate Form A.

[0648] Fig.23 This is an XRPD diagram of p-toluenesulfonate Form A.

[0649] Detailed description of the invention

[0650] Unless stated otherwise, the terms used in the specification and claims have the following meanings.

[0651] The term "alkyl" refers to a saturated aliphatic hydrocarbon group, which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 12 carbon atoms, more preferably an alkyl group containing 1 to 8 carbon atoms, further preferably an alkyl group containing 1 to 6 carbon atoms, and most preferably an alkyl group containing 1 to 3 carbon atoms. 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, 4-heptyl, 1-propylbutyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2-Methyl-2-ethyl-pentyl, 2-methyl-3-ethyl-pentyl, n-nonyl, 2-methyl-2-ethyl-hexyl, 2-methyl-3-ethyl-hexyl, 2,2-diethyl-pentyl, n-decyl, 3,3-diethyl-hexyl, 2,2-diethyl-hexyl, and various branched-chain isomers thereof. More preferred are lower alkyl groups containing 1 to 6 carbon atoms, non-limiting examples of which 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, n-heptyl, 4-heptyl, 1-propylbutyl, 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, and the like.The alkyl group may be substituted or unsubstituted. When substituted, the substituent may be substituted at any available attachment point. The substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl or carboxylate groups. Methyl, ethyl, isopropyl, tert-butyl, haloalkyl, deuterated alkyl, alkoxy-substituted alkyl and hydroxy-substituted alkyl are preferred in the present invention.

[0652] The term "alkylene" refers to a divalent alkyl group formed by further replacing one hydrogen atom of an alkyl group, wherein alkyl is as defined above. For example, "methylene" refers to -CH 2 -, "ethylene" means -(CH 2 ) 2 -, "propylene" refers to -(CH 2 ) 3 -, "butylene" refers to -(CH 2 ) 4 - etc. The connection point of the alkylene chain to the rest of the molecule and to the group can be through one carbon or any two carbons in the chain. The alkylene group can be substituted or unsubstituted. When substituted, the substituent can be substituted at any available connection point, and the substituent is preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, sulfhydryl, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl or carboxylate groups, and the present invention preferably has methyl, ethyl, isopropyl, tert-butyl, haloalkyl, deuterated alkyl, alkoxy-substituted alkyl and hydroxy-substituted alkyl.

[0653] The term "alkenyl" refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond, which is a straight or branched group comprising 2 to 20 carbon atoms, preferably an alkenyl group containing 2 to 12 carbon atoms, more preferably an alkenyl group containing 2 to 8 carbon atoms, further preferably an alkenyl group containing 2 to 6 carbon atoms, and most preferably an alkenyl group containing 2 to 4 carbon atoms. For example, vinyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl or 3-butenyl, etc. Alkenyl can be substituted or unsubstituted, and when substituted, substituents are preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, sulfhydryl, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio.

[0654] The term "alkenylene" refers to a divalent alkenyl group formed by further replacing one hydrogen atom of an alkenyl group, wherein the alkenyl group is as defined above, for example, vinylene, propenylene, butenylene, etc. The alkenylene group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio.

[0655] The term "alkynyl" refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon triple bond, which is a straight or branched group containing 2 to 20 carbon atoms, preferably an alkynyl group containing 2 to 12 carbon atoms, more preferably an alkynyl group containing 2 to 8 carbon atoms, further preferably an alkynyl group containing 2 to 6 carbon atoms, and most preferably an alkynyl group containing 2 to 4 carbon atoms. For example, ethynyl, propynyl, 1-butynyl, 2-butynyl or 3-butynyl, etc. Alkynyl can be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, sulfhydryl, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio.

[0656] The term "alkynylene" refers to a divalent alkynyl group formed by further replacing one of the hydrogen atoms of an alkynyl group, wherein the alkynyl group is as defined above. For example, ethynylene, propynylene, butynylene, etc. Alkynylidene can be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, sulfhydryl, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio.

[0657] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, wherein the cycloalkyl ring contains 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, more preferably 3 to 8 carbon atoms, and further preferably 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, etc.; polycyclic cycloalkyls include cycloalkyls of spirocyclic, condensed and bridged rings, preferably cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl and cycloheptyl.

[0658] The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent containing 3 to 20 ring atoms, wherein one or more ring atoms are selected from nitrogen, oxygen, C(O) or S(O). m(wherein m is an integer from 0 to 2) heteroatoms, but excluding the ring part of -OO-, -OS- or -SS-, the remaining ring atoms are carbon. Preferably, it contains 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; more preferably, it contains 3 to 8 ring atoms, of which 1 to 3 N atoms, preferably 1, 2 or 3 N atoms, are optionally substituted by 1-2 oxygen atoms, sulfur atoms, oxo groups.

[0659] The term "heteroaryl" refers to a heteroaromatic system containing 1 to 4 heteroatoms, 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen. The heteroaryl is preferably a 5-6 membered heteroaryl, wherein 1 to 3 are heteroatoms, preferably 1, 2 or 3 N atoms, such as imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazinyl, etc., preferably pyrimidinyl and pyrazolyl.

[0660] "Haloalkyl" refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined above. Non-limiting examples of haloalkyl groups include trifluoromethyl, -CH 2 CF 3 ,

[0661] "Haloalkoxy" refers to an alkoxy group substituted with one or more halogens, wherein alkoxy is as defined above.

[0662] "Hydroxyalkyl" refers to an alkyl group substituted with a hydroxy group, wherein alkyl is as defined above, preferably

[0663] The term "alkenylcarbonyl" refers to -C(O)-(alkenyl), wherein the definition of alkenyl is as described above. Non-limiting examples of alkenylcarbonyl include: vinylcarbonyl, propenylcarbonyl, butenylcarbonyl. Alkenylcarbonyl can be optionally substituted or unsubstituted, and when substituted, substituents are preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, sulfhydryl, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.

[0664] "Aminocarbonyl" refers to NH 2 -C(O)-.

[0665] "Alkylaminocarbonyl" refers to an aminocarbonyl (NH 2 One or both of the two hydrogen atoms on -C(O)-) are replaced by alkyl groups, wherein alkyl groups are as defined above.

[0666] "Alkylamino" refers to an amino group in which one or both of the two hydrogen atoms are replaced by an alkyl group, wherein the alkyl group is as defined above.

[0667] "Alkylcarbonyl" or "acyl" refers to (alkyl)-C(O)- wherein alkyl is as previously described.

[0668] Different expressions such as “X is selected from A, B, or C”, “X is selected from A, B and C”, “X is A, B or C”, “X is A, B and C” all express the same meaning, that is, X can be any one or more of A, B, C.

[0669] The hydrogen atoms described in the present invention can be replaced by their isotope deuterium, and any hydrogen atom in the example compounds of the present invention can also be replaced by a deuterium atom.

[0670] "Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and the description includes instances where the event or circumstance occurs or does not occur. For example, "a heterocyclic group optionally substituted with an alkyl group" means that an alkyl group may but need not be present, and the description includes instances where the heterocyclic group is substituted with an alkyl group and instances where the heterocyclic group is not substituted with an alkyl group.

[0671] "Substituted" means that one or more hydrogen atoms, preferably up to 5, more preferably 1 to 3 hydrogen atoms in the group are replaced independently of each other by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and the skilled person can determine (by experiment or theory) possible or impossible substitutions without undue effort. For example, amino or hydroxy groups with free hydrogens may be unstable when combined with carbon atoms with unsaturated (e.g. olefinic) bonds.

[0672] "Pharmaceutical composition" means a mixture containing one or more compounds described herein or their physiologically / pharmaceutically acceptable salts or prodrugs and other chemical components, as well as other components such as physiologically / pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to an organism, facilitate the absorption of the active ingredient, and thus exert biological activity.

[0673] "Pharmaceutically acceptable salts" refer to salts of the compounds of the present invention, which are safe and effective when used in mammals and have the desired biological activity.

[0674] X-ray powder diffraction pattern (XRPD) refers to the experimentally observed diffraction pattern or the parameters derived therefrom, and the X-ray powder diffraction pattern is characterized by the peak position (abscissa) and the peak intensity (ordinate). It will be understood by those skilled in the art that the experimental error depends on the conditions of the instrument, the preparation of the sample and the purity of the sample. In particular, it is well known to those skilled in the art that the X-ray diffraction pattern will usually change with the conditions of the instrument, and those skilled in the art should understand that the appropriate error tolerance of XRPD can be: 2θ±0.5°; 2θ±0.4°; 2θ±0.3°; 2θ±0.2°. It should be particularly noted that the relative intensity of the X-ray diffraction pattern may also change with changes in experimental conditions, so the order of peak intensity cannot be used as the only or decisive factor. In addition, due to the influence of experimental factors such as sample height, the overall deviation of the peak angle will be caused, and a certain deviation is usually allowed. Therefore, it will be understood by those skilled in the art that any crystal form having the same or similar characteristic peaks as the spectrum of the present invention belongs to the scope of the present invention.

[0675] "TGA" refers to a thermogravimetric analysis (TGA) experiment.

[0676] "DSC" refers to a differential scanning calorimetry (DSC) experiment. DETAILED DESCRIPTION

[0677] The present invention is further described below with reference to examples, but these examples are not intended to limit the scope of the present invention.

[0678] Example

[0679] The structures of the compounds of the present invention are determined by nuclear magnetic resonance (NMR) and / or liquid chromatography-mass spectrometry (LC-MS). The NMR chemical shift (δ) is given in parts per million (ppm). The NMR measurement is performed using a Bruker AVANCE-400 nuclear magnetic spectrometer with a detection frequency of 400 MHz and a measurement solvent of deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated methanol (CD 3 OD), deuterated chloroform (CDCl 3 ) or deuterated water (D 2 O), and the internal standard was tetramethylsilane (TMS).

[0680] Liquid chromatography-mass spectrometry (LC-MS) was performed using an Agilent 1200 Infinity Series mass spectrometer, and HPLC was performed using an Agilent 1200DAD high pressure liquid chromatograph (Sunfire C18 150×4.6 mm column) and a Waters 2695-2996 high pressure liquid chromatograph (Gimini C18 150×4.6 mm column).

[0681] Thin layer chromatography silica gel plates use Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates. The specifications used for TLC are 0.15mm-0.20mm, and the specifications used for thin layer chromatography separation and purification products are 0.4mm-0.5mm. Column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier.

[0682] The starting materials in the examples of the present invention are known and can be purchased on the market, or can be synthesized by or according to methods known in the art.

[0683] Unless otherwise specified, all reactions of the present invention are carried out under continuous magnetic stirring in a dry nitrogen or argon atmosphere, the solvent is a dry solvent, and the reaction temperature is in degrees Celsius.

[0684] The eluent system of silica gel column chromatography and the developing solvent system of thin layer chromatography used for the intermediates and purified compounds in the examples include: A: dichloromethane and methanol system, B: n-hexane and ethyl acetate system, C: dichloromethane and acetone system. The volume ratio of the solvent is adjusted according to the polarity of the compound, and a small amount of alkaline or acidic reagents such as triethylamine and acetic acid can also be added for adjustment.

[0685] Unless otherwise specified, in the embodiments of the present invention, the ratios in the mobile phases in the HPLC chiral separation conditions and HPLC chiral analysis conditions are volume ratios.

[0686] Intermediate 1

[0687] 2-(Chloromethyl-d2)-3,5-difluoropyridine

[0688]

[0689] first step

[0690] Lithium aluminum deuteride (388 mg, 9.24 mmol) was added in batches to a solution of methyl 3,5-difluoropyridine-2-carboxylate (1.00 g, 5.78 mmol) in tetrahydrofuran (20 mL) under an ice bath. The reaction was stirred at room temperature for 2 hours. The reaction was quenched with ice cubes and the reaction solution was filtered. The filtrate was concentrated and the residue was separated by silica gel column chromatography (eluent system B) to obtain the product (3,5-difluoropyridin-2-yl)methane-d2-ol 1A (345 mg) with a yield of 40.6%.

[0691] MS m / z(ESI):148.0[M+H] + .

[0692] Step 2

[0693] Thionyl chloride (839 mg, 7.06 mmol) was added dropwise to a solution of (3,5-difluoropyridin-2-yl)methane-d2-ol 1A (346 mg, 2.35 mmol) in dichloromethane (5 mL) and N,N-dimethylformamide (0.1 mL) under stirring. The reaction was stirred at room temperature for 3 hours. The reaction solution was diluted with ethyl acetate (160 mL), and the organic phase was washed with saturated sodium bicarbonate and water. The organic phase was concentrated, and the residue was separated by silica gel column chromatography (eluent system B) to obtain the product 2-(chloromethyl-d2)-3,5-difluoropyridine intermediate 1 (150 mg), with a yield of 38.5%.

[0694] MS m / z(ESI):166.0[M+H] + .

[0695] Intermediate 2

[0696] 2-(1H-Pyrazol-3-yl)propan-2-ol

[0697]

[0698] first step

[0699] 1H-pyrazole-3-carboxylic acid methyl ester (2 g, 15.9 mmol) was dissolved in tetrahydrofuran (50 mL) and cooled to 0°C. Methylmagnesium chloride (1 M, 47.58 mL) was added dropwise to the reaction solution under stirring. After the addition was completed, the reaction was warmed to room temperature and stirred for 2 hours. Ethyl acetate (100 mL) was added to the reaction solution, and the organic phase was washed with water and saturated ammonium chloride, dried, and concentrated to obtain the product 2-(1H-pyrazol-3-yl)propan-2-ol intermediate 2 (840 mg), with a yield of 42%.

[0700] MS m / z(ESI):127.1[M+H] + .

[0701] 1 H NMR (400 MHz, CDCl 3 )δ7.51(d,1H),6.64(s,2H),6.18(d,1H),1.62(s,6H).

[0702] Intermediate 3

[0703] N-(2-(4-Fluoro-1H-pyrazol-3-yl)propan-2-yl)acetamide

[0704]

[0705] first step

[0706] Under ice bath, methyl 4-fluoro-1H-pyrazole-3-carboxylate (600 mg, 4.16 mmol) was dissolved in anhydrous tetrahydrofuran (20 mL), and a tetrahydrofuran solution of methyl magnesium bromide (3 M, 6.9 mL, 20.7 mmol) was added dropwise to the reaction solution under stirring, and the reaction was stirred at room temperature for 3 hours. The reaction solution was poured into a saturated ammonium chloride solution (50 mL), and the aqueous phase was extracted with ethyl acetate (50 mL×3). The organic phases were combined, washed with water (50 mL) and a saturated sodium chloride solution (50 mL) in sequence, dried, and concentrated to obtain 2-(4-fluoro-1H-pyrazol-3-yl)propane-2-ol 3A (600 mg), which was used directly in the next step without purification.

[0707] MS m / z(ESI):145.1[M+H] + .

[0708] Step 2

[0709] 3A (600 mg, 4.17 mmol) was dissolved in acetonitrile (15 mL) and stirred. Concentrated sulfuric acid (5 mL) was added dropwise to the reaction solution at 0°C. The reaction was heated to room temperature and stirred for 3 hours. The reaction solution was poured into a saturated sodium bicarbonate solution (100 mL), and the aqueous phase was extracted with ethyl acetate (50 mL × 3). The organic phases were combined, washed with water (50 mL) and saturated sodium chloride solution (50 mL) in sequence, dried, concentrated, and the residue was purified by silica gel column chromatography (elution system B) to obtain N-(2-(4-fluoro-1H-pyrazol-3-yl)propane-2-yl)acetamide intermediate 3 (510 mg), with a yield of 86.8%.

[0710] MS m / z(ESI):186.1[M+H] + .

[0711] Example 1

[0712] 11-Chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d2)-2-(2-(2-hydroxypropane-2-yl)pyrimidin-4-yl)-

[0713] 5,6,7,8-Tetrahydro-12H-bipyrido[1,2-a:3',4'-g]azocine-12-one

[0714]

[0715] first step

[0716] At -50 ° C, lithium bis(trimethylsilyl)amide (66.1 mL, 1M tetrahydrofuran solution) was added dropwise to a tetrahydrofuran (20 mL) solution of 2,2,6-trimethyl-4H-1,3-dioxo-4-one 1a (9.50 g, 66.8 mmol) under stirring. After the reaction was stirred at -50 ° C for 1 hour, 4-ene valeryl chloride (4.40 g, 37.11 mmol) was added dropwise to the reaction solution and continued to stir for 1 hour. The reaction solution was quenched with formic acid, filtered, and the filtrate was concentrated. The residue was separated by silica gel column chromatography (eluent system A) to obtain the title product 2,2-dimethyl-6-(2-oxohex-5-en-1-yl)-4H-1,3-dioxo-4-one 1b (3.60 g), with a yield of 43.3%.

[0717] MS m / z(ESI):225.1[M+H] + .

[0718] Step 2

[0719] Under nitrogen protection, 1j (1.50 g, 5.89 mmol), tributyl vinyl tin (2.43 g, 7.66 mmol) and 1,1-bis(diphenylphosphine)diphenylferropalladium dichloride (431 mg, 0.59 mmol) were dissolved in 1,4-dioxane (15 mL), sealed in a microwave tube, and heated to 100°C with microwave for 2 hours. The reaction solution was concentrated, and the residue was separated by silica gel column chromatography (eluent system A) to obtain the title product 2-chloro-4-amino-5-vinylpyridine 1k (460 mg), with a yield of 50.5%.

[0720] MS m / z(ESI):155.0[M+H] + .

[0721] Step 3

[0722] 1b (6.70 g, 29.88 mmol) and 1k (3.08 g, 19.92 mmol) were dissolved in 1,4-dioxane (80 mL) and heated to 100°C and stirred for 1.5 hours. Concentrated sulfuric acid (4.88 g, 49.80 mmol) was slowly added dropwise to the reaction solution, and the reaction was continued to stir at 100°C for 2 hours. The reaction solution was concentrated, methanol and water were added to the residue, filtered, and the filtrate was concentrated. The title product 6-(but-3-ene-1-yl)-2'-chloro-4-hydroxy-5'-vinyl-2H-[1,4'-bipyridine]-2-one 1c (3.80 g) was separated using reverse phase HPLC preparative separation (formic acid system), with a yield of 63.0%.

[0723] MS m / z(ESI):303.1[M+H] + .

[0724] Step 4

[0725] Under nitrogen protection, 1c (334 mg, 1.11 mmol) and Grubbs second generation catalyst (93 mg, 0.11 mmol) were dissolved in 1,2-dichloroethane (300 mL), and the reaction was heated to 60°C and stirred for 2 hours. Methanol (10 mL) was added to the reaction solution, concentrated, and the residue was separated by silica gel column chromatography (eluent system A) to obtain the title product (Z)-2-chloro-10-hydroxy-7,8-dihydro-12H-bipyrido[1,2-a:3',4'-g]azocine-12-one 1d (110 mg), yield: 36.0%.

[0726] MS m / z(ESI):275.0[M+H] + .

[0727] Step 5

[0728] Under hydrogen atmosphere, 1d (300 mg, 0.19 mmol) and platinum dioxide (25 mg, 0.19 mmol) were dissolved in tetrahydrofuran (20 mL), and the reaction was stirred at 25°C for 3 hours. The reaction solution was filtered, the filtrate was concentrated, and the residue was separated by silica gel column chromatography (eluent system A) to obtain the title product 2-chloro-10-hydroxy-5,6,7,8-tetrahydro-12H-bipyrido[1,2-a:3',4'-g]azocine-12-one 1e (200 mg), with a yield of 66.2%.

[0729] MS m / z(ESI):277.1[M+H] + .

[0730] Step 6

[0731] 1e (480 mg, 1.76 mmol) and N-chlorosuccinimide (347 mg, 2.61 mmol) were dissolved in isopropanol (20 mL), and the reaction was heated to 35°C and stirred for 1 hour. The reaction solution was concentrated, and the residue was separated by silica gel column chromatography (eluent system A) to obtain the title product 2,11-dichloro-10-hydroxy-5,6,7,8-tetrahydro-12H-bipyrido[1,2-a:3',4'-g]azocine-12-one 1f (200 mg), with a yield of 64.3%.

[0732] MS m / z(ESI):311.0[M+H] + .

[0733] Step 7

[0734] 1f (168 mg, 0.54 mmol), potassium carbonate (149 mg, 1.08 mmol) and intermediate 1 (119 mg, 0.81 mmol) were dissolved in N,N-dimethylformamide (5 mL), and the reaction was heated to 70°C and stirred for 16 hours. The reaction solution was concentrated, and the residue was separated by reverse phase HPLC preparative separation (formic acid system) to obtain the title product 2,11-dichloro-10-((3,5-difluoropyridin-2-yl)methoxy-d2)-5,6,7,8-tetrahydro-12H-dipyrido[1,2-a:3',4'-g]azocine-12-one 1g (172 mg), yield: 72.4%.

[0735] MS m / z(ESI):40.1[M+H] + .

[0736] Step 8

[0737] Under nitrogen protection, 1g (150mg, 0.34mmol), tributyl (1-ethoxyvinyl) stannane (185mg, 0.51mmol) and bis (triphenylphosphine) palladium dichloride (24mg, 0.03mmol) were dissolved in 1,4-dioxane (5mL) solution, and the reaction was heated to 123°C by microwave and stirred for 2 hours. The reaction solution was quenched with dilute hydrochloric acid (0.6M, 0.5mL), stirred at room temperature for 30 minutes, concentrated, and the residue was separated by reverse phase HPLC preparative separation (formic acid system) to obtain the title product 2-acetyl-11-chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d2)-5,6,7,8-tetrahydro-12H-bipyrido [1,2-a: 3', 4'-g] azin-12-one 1h (132mg), yield: 86.5%.

[0738] MS m / z(ESI):448.1[M+H] + .

[0739] Step 9

[0740] A solution of 1h (160 mg, 0.36 mmol) in N,N-dimethylformamide (2 mL) and 1,1-dimethoxy-N,N-dimethylmethylamine (2 mL) was heated to 70°C and stirred for 16 hours. The reaction solution was concentrated, and the residue was separated by reverse phase HPLC preparative separation (formic acid system) to obtain the title product (Z)-11-chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d2)-2-(3-(dimethylamino)acryloyl)-5,6,7,8-tetrahydro-12H-dipyrido[1,2-a:3',4'-g]azocine-12-one 1i (85 mg), yield: 47.3%.

[0741] MS m / z(ESI):503.2[M+H] + .

[0742] Step 10

[0743] 1i (85 mg, 0.17 mmol), 2-hydroxy-2-methylpropionamidine hydrochloride (70 mg, 0.51 mmol) and potassium carbonate (70 mg, 0.51 mmol) were dissolved in N,N-dimethylformamide (3 mL), and the reaction was heated to 75°C and stirred for 16 hours. The reaction solution was cooled to room temperature, filtered, and the filtrate was separated by reverse phase HPLC (formic acid system) to obtain the title product 11-chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d2)-2-(2-(2-hydroxypropane-2-yl)pyrimidin-4-yl)-5,6,7,8-tetrahydro-12H-bipyrido[1,2-a:3',4'-g]azocine-12-one 1 (50 mg), yield: 54.6%.

[0744] MS m / z(ESI):542.2[M+H]+.

[0745] 1 H NMR (400MHz, CD 3 OD)δ8.90(d,1H),8.86(s,1H),8.54(s,1H),8.46(d,1H),8.29(d,1H),7.7 3(m,1H),6.84(s,1H),2.90(m,2H),2.26(m,3H),2.04(m,1H),1.62(m,8H).

[0746] Example 1 Resolution of (S)-11-chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d2)-2-(2-(2-hydroxypropane-2-yl)pyrimidin-4-yl)-5,6,7,8-tetrahydro-12H-bipyrido[1,2-a:3',4'-g]azocin-12-one and (R)-11-chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d2)-2-(2-(2-hydroxypropane-2-yl)pyrimidin-4-yl)-5,6,7,8-tetrahydro-12H-bipyrido[1,2-a:3',4'-g]azocin-12-one

[0747]

[0748] Example 1 (50 mg, 0.091 mmol) was subjected to chiral separation (OD column) to give 1-1 (20 mg, RT = 3.807 min), yield: 40.0%; 1-2 (20 mg, RT = 7.060 min), yield: 40.0%.

[0749] Example 1-1: MS m / z (ESI): 542.2 [M+H] + ;

[0750] 1 H NMR (400MHz, CD 3 OD)δ8.90(d,1H),8.86(s,1H),8.54(s,1H),8.46(d,1H),8.29(d,1H),7.7 3(m,1H),6.84(s,1H),2.90(m,2H),2.26(m,3H),2.04(m,1H),1.62(m,8H).

[0751] Example 1-2: MS m / z (ESI): 542.2 [M+H] + ;

[0752] 1 H NMR (400MHz, CD 3 OD)δ8.90(d,1H),8.86(s,1H),8.54(s,1H),8.46(d,1H),8.29(d,1H),7.7 3(m,1H),6.84(s,1H),2.90(m,2H),2.26(m,3H),2.04(m,1H),1.62(m,8H).

[0753] HPLC chiral separation conditions:

[0754]

[0755] HPLC chiral analysis conditions:

[0756] instrument HPLC (Waters) Column Type DAICEL CHIRALCEL OD-H 4.6mm ID×150mmL 5.0μm Column pressure 45psi Mobile phase Hexane:MeOH(+0.1%DEA)=70:30 Flow rate 1mL / min Detection wavelength UV 214nm Column temperature 35℃

[0757] Example 2

[0758] 11-Chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d2)-2-(3-(2-hydroxypropane-2-yl)-1H-pyrazol-1-yl)-5,6,7,8-tetrahydro-12H-dipyrido[1,2-a:3',4'-g]azocine-12-one

[0759]

[0760] first step

[0761] Under nitrogen protection, 2-bromo-11-chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d2)-5,6,7,8-tetrahydro-12H-bipyrido[1,2-a:3',4'-g]azocine-12-one 2a (50 mg, 0.10 mmol, its synthesis method refers to the synthesis of 1 g in Example 1), intermediate 2 (20 mg, 0.15 mmol), cesium carbonate (50 mg, 0.15 mmol), and cuprous iodide (10 mg, 0.05 mmol) were dissolved in 1,4-dioxane (3 mL), and the reaction was heated to 100 ° C and stirred for 2 hours. The reaction solution was concentrated and the residue was separated by silica gel column chromatography (eluent system A) to give 11-chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d2)-2-(3-(2-hydroxypropane-2-yl)-1H-pyrazol-1-yl)-5,6,7,8-tetrahydro-12H-dipyrido[1,2-a:3',4'-g]azocine-12-one 2 (41 mg), yield: 75.0%.

[0762] MS m / z(ESI):530.2[M+H] + .

[0763] 1 H NMR (400 MHz, DMSO-d 6 )δ8.60(m,2H),8.52(d,1H),8.10(m,1H),7.70(s,1H),6.80(s,1H),6.56 (d,1H),5.13(s,1H),2.85(m,2H),2.09(m,3H),1.90(m,1H),1.47(m,8H).

[0764] Decomposition of Example 2

[0765] (S)-11-chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d2)-2-(3-(2-hydroxypropane-2-yl)-1H-pyrazol-1-yl)-5,6,7,8-tetrahydro-12H-dipyrido[1,2-a:3',4'-g]azocin-12-one and (R)-11-chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d2)-2-(3-(2-hydroxypropane-2-yl)-1H-pyrazol-1-yl)-

[0766] 5,6,7,8-Tetrahydro-12H-bipyrido[1,2-a:3',4'-g]azocine-12-one

[0767]

[0768] Example 2 (80 mg, 0.151 mmol) was subjected to chiral separation (IB column) to give 2-1 (35 mg, RT = 3.677 min), yield: 43.7%; 2-2 (30 mg, RT = 6.300 min), yield: 37.5%.

[0769] Example 2-1: MS m / z (ESI): 530.2 [M+H] + ;

[0770] 1 H NMR (400 MHz, DMSO-d 6 )δ8.60(m,2H),8.52(d,1H),8.10(m,1H),7.70(s,1H),6.80(s,1H),6.56 (d,1H),5.13(s,1H),2.85(m,2H),2.09(m,3H),1.90(m,1H),1.47(m,8H).

[0771] Example 2-2: MS m / z (ESI): 530.2 [M+H] + ;

[0772] 1 H NMR (400 MHz, DMSO-d 6 )δ8.60(m,2H),8.52(d,1H),8.10(m,1H),7.70(s,1H),6.80(s,1H),6.56 (d,1H),5.13(s,1H),2.85(m,2H),2.09(m,3H),1.90(m,1H),1.47(m,8H).

[0773] HPLC chiral separation conditions:

[0774]

[0775]

[0776] HPLC chiral analysis conditions:

[0777] instrument HPLC (Waters) Column Type DAICEL CHIRALCEL IB-H 4.6mm ID×150mmL 5.0μm Column pressure 45psi Mobile phase Hexane:EtOH:MeOH(+0.1%DEA)=70:15:15 Flow rate 1mL / min Detection wavelength UV 214nm Column temperature 35℃

[0778] Example 3

[0779] N-(2-(1-(11-chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d2)-12-carbonyl-6,7,8,12-tetrahydro-5H-dipyrido[1,2-a:3',4'-g]azocin-2-yl)-4-fluoro-1H-pyrazol-3-yl)propan-2-yl)acetamide

[0780]

[0781] first step

[0782] Under nitrogen protection, 2a (100 mg, 0.206 mmol), intermediate 3 (52 mg, 0.280 mmol), cuprous iodide (19.64 mg, 0.103 mmol), (1R, 2R)-N1, N2-dimethylcyclohexane-1,2-diamine (23.48 mg, 0.165 mmol) and cesium carbonate (100.58 mg, 0.309 mmol) were dissolved in 1,4-dioxane (2 mL), and the reaction solution was heated to 100 ° C and stirred for 0.5 hours. The reaction solution was filtered and concentrated. The residue was purified by silica gel column chromatography (elution system C) to give N-(2-(1-(11-chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d2)-12-carbonyl-6,7,8,12-tetrahydro-5H-dipyrido[1,2-a:3',4'-g]azocin-2-yl)-4-fluoro-1H-pyrazol-3-yl)propan-2-yl)acetamide 3 (90 mg) with a yield of 74.1%.

[0783] MS m / z(ESI):589.2[M+H] + .

[0784] Decomposition of Example 3

[0785] (S)-N-(2-(1-(11-chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d2)-12-carbonyl-6,7,8,12-tetrahydro-5H-bipyrido[1,2-a:3',4'-g]azocin-2-yl)-4-fluoro-1H-pyrazol-3-yl)propan-2-yl)acetamide and (R)-N-(2-(1-(11-chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d2)-12-carbonyl-6,7,8,12-tetrahydro-5H-bipyrido[1,2-a:3',4'-g]azocin-2-yl)-4-fluoro-1H-pyrazol-3-yl)propan-2-yl)acetamide

[0786]

[0787] Example 3 (90 mg, 0.152 mmol) was subjected to chiral separation (OD column) to give 3-1 (20.4 mg, RT = 3.403 min), yield: 22.35%; 3-2 (21.9 mg, RT = 4.447 min), yield: 23.56%.

[0788] Example 3-1: MS m / z (ESI): 589.2 [M+H]+ ;

[0789] 1 H NMR (400 MHz, DMSO-d 6 )δ8.64–8.51(m,3H),8.15–8.04(m,2H),7.68(s,1H),6.79(s,1H),2.93–2. 76(m,2H),2.15–1.89(m,4H),1.79(s,3H),1.57(d,6H),1.53–1.29(m,2H).

[0790] Example 3-2: MS m / z (ESI): 589.2 [M+H] + ;

[0791] 1 H NMR (400 MHz, DMSO-d 6 )δ8.64–8.54(m,3H),8.15–8.06(m,2H),7.68(s,1H),6.79(s,1H),2.93–2. 76(m,2H),2.16–1.89(m,4H),1.79(s,3H),1.57(d,6H),1.50–1.29(m,2H).

[0792] HPLC chiral separation conditions:

[0793]

[0794] HPLC chiral analysis method:

[0795]

[0796] Example 4

[0797] N-(2-(4-(11-chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d2)-12-carbonyl-6,7,8,12-tetrahydro-

[0798] 5H-Bipyrido[1,2-a:3',4'-g]azocine-2-yl)pyrimidin-2-yl)propan-2-yl)acetamide

[0799]

[0800] Referring to the synthesis method of Example 1, the target product N-(2-(4-(11-chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d2)-12-carbonyl-6,7,8,12-tetrahydro-5H-dipyrido[1,2-a:3',4'-g]azocine-2-yl)pyrimidin-2-yl)propan-2-yl)acetamide 4 was synthesized.

[0801] MS m / z(ESI):583.2[M+H] + ;

[0802] Decomposition of Example 4

[0803] (S)-N-(2-(4-(11-chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d2)-12-carbonyl-6,7,8,12-tetrahydro-5H-bipyrido[1,2-a:3',4'-g]azocin-2-yl)pyrimidin-2-yl)propan-2-yl)acetamide and (R)-N-(2-(4-(11-chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d2)-12-carbonyl-6,7,8,12-tetrahydro-5H-bipyrido[1,2-a:3',4'-g]azocin-2-yl)pyrimidin-2-yl)propan-2-yl)acetamide

[0804]

[0805] Example 4 (26 mg, 0.047 mmol) was subjected to chiral separation (IB column) to give 4-1 (5 mg, RT = 4.387 min), yield: 19.23%; 4-2 (5 mg, RT = 5.183 min), yield: 19.23%.

[0806] Example 4-1: MS m / z (ESI): 583.2 [M+H] + ;

[0807] Example 4-2: MS m / z (ESI): 583.2 [M+H] + ;

[0808] 1 H NMR (400 MHz, DMSO-d 6)δ8.94–8.83(m,2H),8.61(d,1H),8.24(d,2H),8.16(d,1H),8.10(ddd,1H),6.81(s,1H),2.98(dd,1 H),2.80(dd,1H),2.21–2.05(m,3H),1.95–1.82(m,1H),1.77(s,3H),1.60(d,6H),1.48–1.29(m,2H).

[0809] HPLC chiral separation conditions:

[0810]

[0811] HPLC chiral analysis conditions:

[0812] instrument HPLC (Waters) Column Type DAICEL CHIRALCEL IB-H 4.6mm ID×150mmL 5.0μm Column pressure 45psi Mobile phase Hexane:EtOH:MeOH(+0.1%DEA)=70:15:15 Flow rate 1mL / min Detection wavelength UV 214nm Column temperature 35℃

[0813] Example 5

[0814] N-(2-(1-(11-chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d 2 )-1-fluoro-12-carbonyl-6,7,8,12-tetrahydro-5H-bipyrido[1,2-a:3',4'-g]azocine-2-yl)-4-fluoro-1H-pyrazol-3-yl)propan-2-yl)acetamide

[0815] first step

[0816] Under nitrogen protection, 5a (4 g, 27.3 mmol) was dissolved in anhydrous acetonitrile (60 mL), N-iodosuccinimide (7.37 g, 32.8 mmol) and p-toluenesulfonic acid (235 mg, 1.36 mmol) were added, and the reaction was heated to 80 ° C and stirred for 16 hours. The reaction solution was cooled to room temperature, diluted with ethyl acetate (100 mL), and then washed with saturated sodium sulfite solution (80 mL), water (80 mL) and saturated sodium chloride solution (80 mL) in sequence, dried, concentrated, and the residue was purified by silica gel column chromatography (elution system A) to obtain 2-chloro-3-fluoro-5-iodo-pyridin-4-amine 5b (6.5 g), yield: 87.4%.

[0817] MS m / z(ESI):272.9[M+H] + ;

[0818] 1 H NMR (400 MHz, DMSO-d 6 )δ8.10(s,1H),6.69(s,2H).

[0819] Step 2

[0820] Under nitrogen protection, 5b (4 g, 14.7 mmol) was dissolved in 1,4-dioxane (60 mL) and water (12 mL), and potassium ethylene trifluoroborate (2.36 g, 17.6 mmol), 1,1-bis(diphenylphosphino)ferrocene palladium dichloride (533 mg, 0.734 mmol) and sodium carbonate (3.89 g, 36.7 mmol) were added, and the reaction was heated to 80°C and stirred for 4 hours. The reaction solution was cooled to room temperature, diluted with ethyl acetate (100 mL), washed with water (60 mL) and saturated sodium chloride solution (60 mL) in sequence, dried, filtered, concentrated, and the residue was purified by silica gel column chromatography (elution system B) to obtain 2-chloro-3-fluoro-5-vinyl-pyridin-4-amine 5c (2.1 g) with a yield of 82.9%.

[0821] MS m / z(ESI):173.0[M+H] + ;

[0822] 1 H NMR (400 MHz, DMSO-d 6 )δ7.98(s,1H),6.82(dd,1H),6.62(s,2H),5.78(dd,1H),5.33(dd,1H).

[0823] Step 3

[0824] 5c (1 g, 5.79 mmol) was dissolved in 1,4-dioxane (15 mL), 1b (1.30 g, 5.79 mmol) was added, and the reaction was heated to 100°C and stirred for 2 hours. Concentrated sulfuric acid (1.42 g, 0.772 mL) was added to the reaction solution, and the reaction was continued to stir at 100°C for 0.5 hours. The reaction solution was cooled to room temperature, diluted with ethyl acetate (50 mL), washed with water (50 mL) and saturated sodium chloride solution (50 mL) in sequence, dried, concentrated, and the residue was purified by silica gel column chromatography (elution system B) to obtain 6-(but-3-en-1-yl)-2'-chloro-3'-fluoro-4-hydroxy-5'-vinyl-2H-[1,4'-bipyridyl]-2-one 5d (1.1 g), yield: 59.2%.

[0825] MS m / z(ESI):321.0[M+H] + ;

[0826] 1 H NMR (400 MHz, DMSO-d 6)δ11.13(s,1H),8.80(s,1H),6.29–6.22(m,1H),6.08-6.00(m,2H),5.6 7-5.58(m,3H),4.95-4.89(m,2H),2.19-2.16(m,2H),2.13-2.09(m,2H).

[0827] Step 4

[0828] 5d (100 mg, 0.312 mmol) was dissolved in N,N-dimethylformamide (3 mL), and intermediate 1 (77 mg, 0.468 mmol), 18-crown-6 (124 mg, 0.468 mmol) and potassium carbonate (129 mg, 0.935 mmol) were added, and the reaction was heated to 75°C and stirred for 2 hours. The reaction solution was cooled to room temperature and extracted with ethyl acetate (50 mL). The organic phase was washed with water (30 mL×2) and saturated sodium chloride solution (30 mL) in turn, dried, and concentrated. The residue was purified by silica gel column chromatography (elution system B) to obtain 6-(but-3-en-1-yl)-2'-chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d2)-3'-fluoro-5'-vinyl-2H-[1,4'-bipyridyl]-2-one 5e (110 mg) with a yield of 78.4%.

[0829] MS m / z(ESI):450.1[M+H] + ;

[0830] Step 5

[0831] 5e (110 mg, 0.245 mmol) and Grubbs second generation catalyst (21 mg, 0.0245 mmol) were dissolved in 1,2-dichloroethane (80 mL), and the reaction was heated to 40°C and stirred for 1 hour under nitrogen protection. The reaction solution was cooled to room temperature and concentrated, and the residue was purified by silica gel column chromatography (elution system B) to obtain (Z)-2-chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d2)-1-fluoro-7,8-dihydro-12H-bipyrido[1,2-a:3',4'-g]azocine-12-one 5f (95 mg), yield: 92.1%.

[0832] MS m / z(ESI):422.1[M+H] + ;

[0833] 1 H NMR (400 MHz, DMSO-d 6)δ8.59(d,1H),8.32(s,1H),8.10-8.05(m,1H),6.43(d,1H),6.19(d,1H),6.04(d ,1H),6.03–5.98(m,1H),2.72-2.64(m,2H),2.59–2.52(m,1H),2.47-2.41(m,1H).

[0834] Step 6

[0835] 5f (95 mg, 0.225 mmol) and platinum dioxide (5 mg, 0.0225 mmol) were dissolved in tetrahydrofuran (3 mL), the reaction was replaced with hydrogen three times, and then stirred at room temperature for 2 hours under a hydrogen atmosphere. The reaction solution was filtered and concentrated, and the residue was purified by silica gel column chromatography (elution system B) to obtain 2-chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d2)-1-fluoro-5,6,7,8-tetrahydro-12H-bipyrido[1,2-a:3',4'-g]azocine-12-one 5g (90 mg), yield: 94.3%.

[0836] MS m / z(ESI):424.1[M+H] + ;

[0837] Step 7

[0838] 5g (90mg, 0.212mmol) and N-chlorosuccinimide (34mg, 0.255mmol) were dissolved in 1,2-dichloroethane (9mL) and isopropanol (3mL), and the reaction was heated to 60°C for 2 hours. The reaction solution was cooled to room temperature, washed with water (20mL) and saturated sodium chloride solution (20mL) in sequence, dried, and concentrated. The residue was purified by silica gel column chromatography (elution system B) to obtain 2,11-dichloro-10-((3,5-difluoropyridin-2-yl)methoxy-d2)-1-fluoro-5,6,7,8-tetrahydro-12H-dipyrido[1,2-a:3',4'-g]azocine-12-one 5h (90mg), yield: 92.5%.

[0839] MS m / z(ESI):458.0[M+H] + ;

[0840] 1 H NMR (400 MHz, CDCl 3)δ8.39(d,1H),8.26(s,1H),7.35-7.30(m,1H),6.43(s,1H),2.93–2.88(m,1H ),2.80-2.75(m,1H),2.28-2.17(m,3H),2.05-1.95(m,1H),1.62-1.45(m,2H).

[0841] Step 8

[0842] Under nitrogen protection, 5h (100 mg, 0.218 mmol), intermediate 3 (81 mg, 0.436 mmol), cesium carbonate (213 mg, 0.655 mmol), cuprous iodide (62 mg, 0.327 mmol) and trans-N,N-dimethyl-1,2-cyclohexanediamine (31 mg, 0.218 mmol) were dissolved in 1,4-dioxane (2 mL), and the reaction was heated to 100 ° C and stirred for 16 hours. The reaction solution was cooled to room temperature and filtered. The filtrate was diluted with ethyl acetate (50 mL), washed with water (30 mL) and saturated sodium chloride solution (30 mL) in turn, dried, concentrated, and the residue was purified by reverse phase column chromatography (eluent system C) to obtain N-(2-(1-(11-chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d 2 )-1-fluoro-12-carbonyl-6,7,8,12-tetrahydro-5H-bipyrido[1,2-a:3',4'-g]azocine-2-yl)-4-fluoro-1H-pyrazol-3-yl)propan-2-yl)acetamide 5 (40 mg), yield: 30.2%.

[0843] MS m / z(ESI):607.2[M+H] + ;

[0844] Decomposition of Example 5

[0845] (R)-N-(2-(1-(11-chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d 2 )-1-fluoro-12-carbonyl-6,7,8,12-tetrahydro-5H-bipyrido[1,2-a:3',4'-g]azocin-2-yl)-4-fluoro-1H-pyrazol-3-yl)propan-2-yl)acetamide and (S)-N-(2-(1-(11-chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d 2 )-1-fluoro-12-carbonyl-6,7,8,12-tetrahydro-5H-bipyrido[1,2-a:3',4'-g]azocine-2-yl)-4-fluoro-1H-pyrazol-3-yl)propan-2-yl)acetamide

[0846]

[0847] Example 5 (40 mg, 0.066 mmol) was subjected to chiral separation (IB column) to give 5-1 (13.2 mg, RT = 4.940 min), yield: 33.0%; 5-2 (15.8 mg, RT = 7.710 min), yield: 21.3%.

[0848] Example 5-1: MS m / z (ESI): 607.2 [M+H] + ;

[0849] 1 H NMR (400 MHz, DMSO-d 6 )δ8.60(d,1H),8.50(s,1H),8.45(d,1H),8.13-8.07(m,2H),6.86(s,1H),3.03-2.98(m,1H ),2.86-2.80(m,1H),2.18-1.99(m,4H),1.79(s,3H),1.61-1.50(m,7H),1.40-1.34(m,1H).

[0850] Example 5-2: MS m / z (ESI): 607.2 [M+H] + ;

[0851] 1 H NMR (400 MHz, DMSO-d 6 )δ8.60(d,1H),8.50(s,1H),8.45(d,1H),8.13-8.07(m,2H),6.86(s,1H),3.03-2.98(m,1H ),2.86-2.80(m,1H),2.18-1.99(m,4H),1.79(s,3H),1.61-1.50(m,7H),1.40-1.34(m,1H).

[0852] HPLC chiral separation conditions:

[0853]

[0854] HPLC chiral analysis method:

[0855]

[0856] Example 6

[0857] N-(2-(4-(11-chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d 2)-1-fluoro-12-carbonyl-6,7,8,12-tetrahydro-5H-bipyrido[1,2-a:3',4'-g]azocine-2-yl)pyrimidin-2-yl)propan-2-yl)acetamide

[0858] first step

[0859] Under nitrogen protection, 5h (90 mg, 0.196 mmol) was dissolved in 1,4-dioxane (2 mL), tributyl (1-ethoxyethylene) tin (75 mg, 0.206 mmol) and bistriphenylphosphine palladium dichloride (14 mg, 0.019 mmol) were added, and the mixture was reacted at 125 ° C in a microwave reactor for 2 hours. The reaction solution was cooled to room temperature, and dilute hydrochloric acid (0.2M, 1 mL) was added and stirred for 1 hour. After the reaction solution was diluted with ethyl acetate (50 mL), it was washed with saturated sodium bicarbonate solution (30 mL) and saturated sodium chloride solution (30 mL) in sequence, the organic phase was dried and concentrated, and the residue was purified by silica gel column chromatography (elution system B) to obtain 2-acetyl-11-chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d 2 )-1-fluoro-5,6,7,8-tetrahydro-12H-bipyrido[1,2-a:3′,4′-g]azocine-12-one 6a (90 mg), yield: 98.4%.

[0860] MS m / z(ESI):466.1[M+H] + .

[0861] Step 2

[0862] Under nitrogen protection, 6a (90 mg, 0.193 mmol) was dissolved in N,N-dimethylformamide (2 mL), and N,N-dimethylformamide dimethyl acetal (115 mg, 0.966 mmol) was added. The reaction was heated to 55 °C and stirred for 6 hours. The reaction solution was cooled to room temperature, diluted with ethyl acetate (50 mL), washed with water (30 mL × 2) and saturated sodium chloride solution (30 mL), dried, and concentrated to obtain 11-chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d 2 )-2-(3-(dimethylamino)acryloyl)-1-fluoro-5,6,7,8-tetrahydro-12H-bipyrido[1,2-a:3',4'-g]azocine-12-one 6b (110 mg) was used directly in the next step without purification.

[0863] MS m / z(ESI):521.2[M+H] + .

[0864] Step 3

[0865] Under nitrogen protection, 6b (110 mg, 0.211 mmol) was dissolved in N,N-dimethylformamide (3 mL), and N-(1-amino-1-imino-2-methylpropane-2-yl)acetamide acetate (90 mg, 0.443 mmol, its preparation method is referenced in Chemistry of Heterocyclic Compounds 2020, 56 (10), 1329–1334.) and potassium carbonate (146 mg, 1.06 mmol) were added. The reaction was heated to 75 °C and stirred for 16 hours. The reaction was cooled to room temperature, diluted with ethyl acetate (50 mL), washed with water (30 mL × 2) and saturated sodium chloride solution (30 mL) in turn, dried, concentrated, and the residue was separated by preparative HPLC (formic acid system) to obtain N-(2-(4-(11-chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d 2 )-1-fluoro-12-carbonyl-6,7,8,12-tetrahydro-5H-bipyrido[1,2-a:3',4'-g]azocine-2-yl)pyrimidin-2-yl)propan-2-yl)acetamide 6 (35 mg), yield: 27.6%.

[0866] MS m / z(ESI):601.2[M+H] + ;

[0867] Decomposition of Example 6

[0868] (R)-N-(2-(4-(11-chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d 2 )-1-fluoro-12-carbonyl-6,7,8,12-tetrahydro-5H-bipyrido[1,2-a:3',4'-g]azocin-2-yl)pyrimidin-2-yl)propan-2-yl)acetamide and (S)-N-(2-(4-(11-chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d 2 )-1-fluoro-12-carbonyl-6,7,8,12-tetrahydro-

[0869] 5H-Bipyrido[1,2-a:3',4'-g]azocine-2-yl)pyrimidin-2-yl)propan-2-yl)acetamide

[0870]

[0871] Example 6 (35 mg, 0.058 mmol) was subjected to chiral separation (IB column) to give 6-1 (10.7 mg, RT = 4.640 min), yield: 30.45%; 6-2 (10.4 mg, RT = 5.473 min), yield: 29.54%.

[0872] Example 6-1: MS m / z (ESI): 601.2 [M+H] + ;

[0873] 1 H NMR (400 MHz, DMSO-d 6 )δ8.92(d,1H),8.77(s,1H),8.60(d,1H),8.22(s,1H),8.10(ddd,1H),7.93(d,1H),6.86(s,1H),3.05 (dd,1H),2.84(dd,1H),2.16(q,3H),2.07–1.94(m,1H),1.76(s,3H),1.59(d,7H),1.49–1.35(m,1H).

[0874] Example 6-2: MS m / z (ESI): 601.2 [M+H] + ;

[0875] 1 H NMR (400 MHz, DMSO-d 6 )δ8.92(d,1H),8.77(s,1H),8.60(d,1H),8.22(s,1H),8.10(ddd,1H),7.93(d,1H),6.86(s,1H),3.05 (dd,1H),2.84(dd,1H),2.16(q,3H),2.07–1.94(m,1H),1.76(s,3H),1.59(d,7H),1.49–1.35(m,1H).

[0876] HPLC chiral separation conditions:

[0877]

[0878] HPLC chiral analysis method:

[0879]

[0880] Example 7

[0881] 11-Chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d 2 )-1-fluoro-2-(3-(2-hydroxypropane-2-yl)-1H-pyrazol-1-yl)-5,6,7,8-tetrahydro-12H-bipyrido[1,2-a:3',4'-g]azocine-12-one

[0882]

[0883] Referring to the synthesis method of Example 5, the target product 11-chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d 2 )-1-fluoro-2-(3-(2-hydroxypropan-2-yl)-1H-pyrazol-1-yl)-5,6,7,8-tetrahydro-12H-bipyrido[1,2-a:3',4'-g]azocine-12-one 7 (20 mg), yield: 32.1%.

[0884] MS m / z(ESI):548.2[M+H] + ;

[0885] Decomposition of Example 7

[0886] (R)-11-chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d 2 )-1-fluoro-2-(3-(2-hydroxypropane-2-yl)-1H-pyrazol-1-yl)-5,6,7,8-tetrahydro-12H-dipyrido[1,2-a:3',4'-g]azocine-12-one and (S)-11-chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d 2 )-1-fluoro-2-(3-(2-hydroxypropane-2-yl)-1H-pyrazol-1-yl)-5,6,7,8-tetrahydro-12H-bipyrido[1,2-a:3',4'-g]azocine-12-one

[0887]

[0888] Example 7 (20 mg, 0.036 mmol) was subjected to chiral separation (IB column) to give 7-1 (10 mg, RT = 4.923 min), yield: 50.0%; 7-2 (3 mg, RT = 9.473 min), yield: 15%.

[0889] Example 7-1: MS m / z (ESI): 548.2 [M+H] + ;

[0890] 1 H NMR (400 MHz, DMSO-d 6 )δ8.60(d,1H),8.50(s,1H),8.33(d,1H),8.10(ddd,1H),6.86(s,1H),6.57(d,1H),5.11(s,1H ),3.01(dd,1H),2.83(dd,1H),2.20–1.97(m,4H),1.55(d,1H),1.46(d,6H),1.41–1.31(m,1H).

[0891] Example 7-2: MS m / z (ESI): 548.2 [M+H] + ;

[0892] 1 H NMR (400 MHz, DMSO-d 6 )δ8.60(d,1H),8.50(s,1H),8.33(d,1H),8.10(ddd,1H),6.86(s,1H),6.57(d,1H),5.11(s,1H ),3.01(dd,1H),2.83(dd,1H),2.20–1.97(m,4H),1.55(d,1H),1.46(d,6H),1.41–1.31(m,1H).

[0893] HPLC chiral separation conditions:

[0894]

[0895]

[0896] HPLC chiral analysis method:

[0897]

[0898] Example 8

[0899] 11-Chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d 2 )-1-Fluoro-2-(2-(2-hydroxypropane-2-yl)pyrimidin-4-yl)-5,6,7,8-tetrahydro-12H-bipyrido[1,2-a:3',4'-g]azocine-12-one

[0900]

[0901] first step

[0902] Under nitrogen protection, 6b (100 mg, 0.192 mmol) was dissolved in N,N-dimethylformamide (2 mL), 2-hydroxy-2-methylpropionamidine hydrochloride (80 mg, 0.576 mmol) and potassium carbonate (133 mg, 0.960 mmol) were added, and the reaction was heated to 75 ° C and stirred for 16 hours. The reaction was cooled to room temperature, diluted with ethyl acetate (50 mL), and washed with water (30 mL × 2) and saturated sodium chloride solution (30 mL) in sequence. The organic phase was dried and concentrated, and the residue was purified by silica gel column chromatography (elution system B) to obtain 11-chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d 2)-1-fluoro-2-(2-(2-hydroxypropane-2-yl)pyrimidin-4-yl)-5,6,7,8-tetrahydro-12H-bipyrido[1,2-a:3',4'-g]azocine-12-one 8 (50 mg), yield: 46.5%.

[0903] MS m / z(ESI):560.2[M+H] + .

[0904] Decomposition of Example 8

[0905] (R)-11-chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d 2 )-1-fluoro-2-(2-(2-hydroxypropane-2-yl)pyrimidin-4-yl)-5,6,7,8-tetrahydro-12H-dipyrido[1,2-a:3',4'-g]azocin-12-one and (S)-11-chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d 2 )-1-Fluoro-2-(2-(2-hydroxypropane-2-yl)pyrimidin-4-yl)-5,6,7,8-tetrahydro-12H-bipyrido[1,2-a:3',4'-g]azocine-12-one

[0906]

[0907] Example 8 (50 mg, 0.089 mmol) was subjected to chiral separation (IB column) to give 8-1 (15.4 mg, RT = 4.973 min), yield: 30.8%; 8-2 (15.8 mg, RT = 8.337 min), yield: 31.6%.

[0908] Example 8-1: MS m / z (ESI): 560.2 [M+H] + ;

[0909] 1 H NMR (400 MHz, DMSO-d 6 )δ9.02(d,1H),8.79(s,1H),8.61(d,1H),8.13-8.08(m,1H),8.03(d,1H),6.87(s,1H),5.09(s,1H),3.09–3.04(m ,1H),2.88–2.82(m,1H),2.22–2.11(m,3H),2.06–1.99(m,1H),1.62–1.53(m,1H),1.52(s,6H),1.46-1.39(m,1H).

[0910] Example 8-2: MS m / z (ESI): 560.2 [M+H]+ ;

[0911] 1 H NMR (400 MHz, DMSO-d 6 )δ9.02(d,1H),8.79(s,1H),8.61(d,1H),8.13-8.08(m,1H),8.03(d,1H),6.87(s,1H),5.09(s,1H),3.09–3.04(m ,1H),2.88–2.82(m,1H),2.22–2.13(m,3H),2.06–1.99(m,1H),1.62–1.53(m,1H),1.52(s,6H),1.46-1.39(m,1H).

[0912] HPLC chiral separation conditions:

[0913]

[0914] HPLC chiral analysis method:

[0915]

[0916] Example 9

[0917] (Z)-11-chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d2)-2-(2-(2-hydroxypropane-2-yl)pyrimidin-4-yl)-7,8-dihydro-12H-dipyrido[1,2-a:3',4'-g]azocine-12-one

[0918]

[0919] Referring to the synthesis method of Example 1, the target product (Z)-11-chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d2)-2-(2-(2-hydroxypropane-2-yl)pyrimidin-4-yl)-7,8-dihydro-12H-dipyrido[1,2-a:3',4'-g]azocine-12-one 9 was synthesized.

[0920] MS m / z(ESI):540.2[M+H] + .

[0921] 1 H NMR (400 MHz, DMSO-d 6)δ8.99(d,1H),8.80(s,1H),8.66–8.57(m,2H),8.26(d,1H),8.11(ddd,1H),6.81(s,1H),6. 53(dd,1H),6.03(d,1H),5.29(s,1H),2.76(d,2H),2.57(dd,1H),2.00(q,1H),1.53(d,6H).

[0922] Decomposition of Example 9

[0923] (S,Z)-11-chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d2)-2-(2-(2-hydroxypropan-2-yl)pyrimidin-4-yl)-7,8-dihydro-12H-bipyrido[1,2-a:3',4'-g]azocin-12-one and (R,Z)-11-chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d2)-2-(2-(2-hydroxypropan-2-yl)pyrimidin-4-yl)-7,8-dihydro-12H-bipyrido[1,2-a:3',4'-g]azocin-12-one

[0924]

[0925] Example 9 (20 mg, 0.037 mmol) was subjected to chiral separation (OD column) to give the title product 9-1 (8 mg, RT = 3.623 min), yield: 40%; 9-2 (6 mg, RT = 7.39 min), yield: 30%.

[0926] Example 9-1, MS m / z (ESI): 540.2 [M+H] + ;

[0927] Example 9-2, MS m / z (ESI): 540.2 [M+H] + ;

[0928] 1 H NMR (400 MHz, DMSO-d 6 )δ8.99(d,1H),8.80(s,1H),8.66–8.57(m,2H),8.26(d,1H),8.11(ddd,1H),6.81(s,1H),6. 53(dd,1H),6.03(d,1H),5.29(s,1H),2.76(d,2H),2.57(dd,1H),2.00(q,1H),1.53(d,6H).

[0929] HPLC chiral separation conditions:

[0930]

[0931]

[0932] HPLC chiral analysis method:

[0933]

[0934] Example 10

[0935] (Z)-11-chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d2)-2-(3-(2-hydroxypropane-2-yl)-1H-pyrazol-1-yl)-7,8-dihydro-12H-dipyrido[1,2-a:3',4'-g]azocine-12-one

[0936]

[0937] Referring to the synthesis method of Example 2, the target product (Z)-11-chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d2)-2-(3-(2-hydroxypropane-2-yl)-1H-pyrazol-1-yl)-7,8-dihydro-12H-dipyrido[1,2-a:3',4'-g]azocine-12-one 10 was synthesized.

[0938] MS m / z(ESI):528.2[M+H] + .

[0939] Decomposition of Example 10

[0940] (S,Z)-11-chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d2)-2-(3-(2-hydroxypropan-2-yl)-1H-pyrazol-1-yl)-7,8-dihydro-12H-bipyrido[1,2-a:3',4'-g]azocin-12-one and (R,Z)-11-chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d2)-2-(3-(2-hydroxypropan-2-yl)-1H-pyrazol-1-yl)-7,8-dihydro-12H-bipyrido[1,2-a:3',4'-g]azocin-12-one

[0941]

[0942] Example 10 (80 mg, 0.152 mmol) was subjected to chiral separation (OD column) to give the title product 10-1 (36 mg, RT = 3.553 min), yield: 45%; 10-2 (38 mg, RT = 5.693 min), yield: 47.5%.

[0943] Example 10-1, MS m / z (ESI): 528.2 [M+H] + ;

[0944] Example 10-2, MS m / z (ESI): 528.2 [M+H] + ;

[0945] 1 H NMR (400 MHz, DMSO-d 6 )δ8.60(d,1H),8.53(d,1H),8.49(s,1H),8.10(td,1H),7.72(s,1H),6.79(s,1H),6.57(d,1H),6.4 7–6.39(m,1H),5.99–5.88(m,1H),5.14(s,1H),2.80–2.67(m,2H),2.67–2.52(m,2H),1.47(d,6H).

[0946] HPLC chiral separation conditions:

[0947]

[0948] HPLC chiral analysis method:

[0949]

[0950] Embodiment 11

[0951] (Z)-N-(2-(1-(11-chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d2)-12-carbonyl-8,12-dihydro-

[0952] 7H-dipyrido[1,2-a:3',4'-g]azocine-2-yl)-4-fluoro-1H-pyrazol-3-yl)propan-2-yl)acetamide

[0953]

[0954] Referring to the synthesis method of Example 3, the target product (Z)-N-(2-(1-(11-chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d2)-12-carbonyl-8,12-dihydro-7H-dipyrido[1,2-a:3',4'-g]azocine-2-yl)-4-fluoro-1H-pyrazol-3-yl)propan-2-yl)acetamide 11 was synthesized.

[0955] MS m / z(ESI):587.2[M+H] + .

[0956] Decomposition of Example 11

[0957] (S,Z)-N-(2-(1-(11-chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d2)-12-carbonyl-8,12-dihydro-7H-bipyrido[1,2-a:3',4'-g]azocin-2-yl)-4-fluoro-1H-pyrazol-3-yl)propan-2-yl)acetamide and (R,Z)-N-(2-(1-(11-chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d2)-12-carbonyl-8,12-dihydro-7H-bipyrido[1,2-a:3',4'-g]azocin-2-yl)-4-fluoro-1H-pyrazol-3-yl)propan-2-yl)acetamide

[0958]

[0959] Example 11 (86 mg, 0.147 mmol) was subjected to chiral separation (OD column) to give the title product 11-1 (32 mg, RT = 3.280 min), yield: 37.2%; 11-2 (32 mg, RT = 4.387 min), yield: 37.2%.

[0960] Example 11-1, MS m / z (ESI): 587.2 [M+H] + ;

[0961] Example 11-2, MS m / z (ESI): 587.2 [M+H] + ;

[0962] 1 H NMR (400 MHz, DMSO-d 6 )δ8.59(dd,2H),8.48(s,1H),8.18–8.02(m,2H),7.71(s,1H),6.78(s,1H),6.44(d, 1H),5.99–5.91(m,1H),2.78–2.65(m,2H),2.57(dd,2H),1.79(s,3H),1.58(d,6H).

[0963] HPLC chiral separation conditions:

[0964]

[0965] HPLC chiral analysis method:

[0966]

[0967] Example Test Evaluation

[0968] The present invention is further described and explained below in conjunction with test examples, but these embodiments are not intended to limit the scope of the present invention.

[0969] Test Example 1: Determination of the inhibitory effect of the compounds of the present invention on p38α / MK2 enzyme activity

[0970] 1. Experimental purpose: The purpose of this test case is to measure the inhibitory ability of the compound on p38α / MK2 enzyme activity.

[0971] 2. Experimental instruments and reagents:

[0972] 2.1 Instruments:

[0973] Instrument Name factory Specifications EnVision PerkinElmer ENVISION 2015

[0974] 2.2 Reagents:

[0975] Reagents and Materials factory Part Number Active p38 alpha Protein R&D systems 5477-KS-010 Inactive MK2 Thermo PV3316 ULight-CREBtide Perkinelmer TRF0107 ATP Solution Invitrogen PV3227 DMSO Sigma D2650 HEPES(1M) Gibco 15630-080 <![CDATA[MgCl 2 (1M)]]> Invitrogen AM9530G Tween 20 Sigma P9416 EGTA Alfa Aesar J60767 DTT(1M) Sigma 43816 Europium-anti-phospho-CREB PerkinElmer TRF0200 EDTA(0.5M) Invitrogen AM9260G 10X LANCE detection buffer PerkinElmer CR97-100 384-well plate Perkinelmer 6007299 96V base plate (PS) Axygen WIPP02280

[0976] 3. Experimental methods:

[0977] p38 / MK2 enzyme activity assay method: in 1× enzyme reaction buffer (50mM HEPES pH 7.5, 1mM EGTA, 10mM MgCl 2 ,2mM DTT,0.01% Tween-20), incubate 0.06nM p38α(Active p38 alpha Protein), 1.2nM MK2(Inactive MK2) and gradient dilutions of compounds for 1 hour. Add 50nM ULight-CREBtide and 25μM ATP(ATP Solution) and react at room temperature for 1.5 hours. Add an equal volume of detection and termination mixture (1×LANCE detection buffer containing 20mMEDTA and 2nM Europium-anti-phospho-CREB), mix and centrifuge, apply sealing film, and react at room temperature for 1 hour. Read the plate using the TR-FRET program of the EnVision instrument and detect the fluorescence value of each well at 665nm / 615nm.

[0978] p38 enzyme activity assay method: in 1× enzyme reaction buffer (50mM HEPES pH 7.5, 1mM EGTA, 10mM MgCl 2, 2mM DTT, 0.01% Tween-20), incubate 3nM p38α (Active p38 alpha Protein) and gradient dilutions of compounds for 1 hour. Add 50nM ULight-MBP and 50μM ATP (ATP 10mM Solution) and react at room temperature for 1.5 hours. Add an equal volume of detection and termination mixture (1×LANCE detection buffer containing 20mM EDTA and 2nM Europium-anti-P-MBP), mix and centrifuge, apply sealing film, and react at room temperature for 1 hour. Read the plate using the TR-FRET program of the EnVision instrument and detect the fluorescence value of each well at 665nm / 615nm.

[0979] 4. Experimental data processing method:

[0980] The raw data (665nm / 615nm reading ratio) was calculated according to the following formula to obtain the inhibition rate: Inhibition rate % = [(average value of positive control wells - sample wells) / (average value of positive control wells - average value of negative control wells)] × 100, where the positive control wells are reaction wells without compound enzymes, and the negative control wells are reaction wells without enzymes.

[0981] Use log(inhibitor) vs.response--Variable slope(four parameters) in GraphPad Prism 6 to fit the compound concentration and the corresponding inhibition rate, fit the curve and obtain the compound IC 50 value.

[0982] The fitting calculation equation is Y = Bottom + (Top-Bottom) / (1 + 10^((LogIC 50 -X)*HillSlope))

[0983] 5. Experimental results:

[0984] Example <![CDATA[p38 / MK2 IC 50 (nM)]]> Example <![CDATA[p38 / MK2 IC 50 (nM)]]> 1-1 0.71 7-1 0.25 2-1 0.42 8-1 0.14 3-1 0.18 9-1 0.49 5-1 0.10 10-1 0.27 6-1 0.34 11-1 0.12

[0985] 6. Experimental conclusion:

[0986] The above data show that the compounds of the present invention have strong inhibitory ability on p38α / MK2 enzyme activity and good selectivity.

[0987] Test Example 2: Determination of the inhibitory effect of the compounds of the present invention on p-Hsp27 in U937 cells

[0988] 1. Experimental purpose: The purpose of this test example is to test the inhibitory ability of the compounds of the present invention on p-Hsp27 of U937 cells.

[0989] 2. Experimental instruments and reagents:

[0990] 2.1 Instruments:

[0991] Instrument Name factory Specifications EnVision PerkinElmer ENVISION 2015

[0992] 2.2 Reagents:

[0993] Reagents and Materials factory Part Number U937 ATCC CRL-1593.2 Phospho-HSP27(S78 / S82)DuoSet IC ELISA R&D systems DYC2314-5 DuoSet ELISAAncillary Reagent Kit 2 R&D systems DY008 Phorbol 12-myristate 13-acetate(PMA) Abcam Ab120297 Lipopolysaccharides from Escherichia coli O111:B4 Sigma-Aldrich L4391

[0994] 3. Experimental methods:

[0995] Treat U937 with 20ng / ml PMA for differentiation overnight, change to fresh culture medium, and let U937 rest overnight. After differentiation, digest and count U937 cells, and seed 25,000 cells per well in a 96-well plate until the cells adhere to the wall. Prepare compound concentration gradient, pre-treat cells with compounds for 1 hour (the highest final concentration of the compound is 1μM, 3-fold concentration gradient dilution), and add 10ng / ml LPS (Lipopolysaccharides from Escherichia coli O111:B4) to stimulate for 0.5 hours. After washing the cells with PBS, the cells were lysed with lysis buffer. Use Phospho-HSP27 (S78 / S82) DuoSet IC ELISA kit to detect p-Hsp27 in cell lysate. For specific steps, refer to the standard steps provided by the kit manufacturer.

[0996] 4. Experimental data processing method:

[0997] Calculate the p-Hsp27 inhibition rate: inhibition rate percentage = [(average p-Hsp27 in positive control wells - average p-Hsp27 in sample wells) / (average p-Hsp27 in positive control wells - average p-Hsp27 in negative control wells)] × 100%, where the positive control wells are wells without compound (DMSO-treated wells) and the negative control wells are wells without LPS stimulation.

[0998] Dose response curve fitting: Use log(inhibitor) vs.response--Variable slope(four parameters) in GraphPad Prism 6 to fit the compound concentration and the corresponding inhibition rate, fit the curve and obtain the compound IC 50 value.

[0999] The fitting calculation equation is Y = Bottom + (Top-Bottom) / (1 + 10^((LogIC50 -X)*HillSlope))

[1000] 5. Experimental results:

[1001]

[1002] 6. Experimental conclusion:

[1003] The above data show that the compounds of the present invention have a strong inhibitory ability on p-Hsp27 of U937 cells.

[1004] Test Example 3: Determination of the inhibitory effect of the compounds of the present invention on the expression level of TNF-α in U937 cells

[1005] 1. Experimental purpose: The purpose of this test example is to measure the inhibitory ability of the compounds of the present invention on the expression level of TNF-α in U937 cells.

[1006] 2. Experimental instruments and reagents:

[1007] 2.1 Instruments:

[1008] Instrument Name factory Specifications EnVision PerkinElmer 2105-0020

[1009] 2.2 Reagents:

[1010]

[1011]

[1012] 3. Experimental methods:

[1013] U937 cells were treated with 20ng / ml PMA for differentiation overnight, and then fresh culture medium was replaced. U937 cells were rested overnight. U937 cells were digested and counted after differentiation, and 50,000 cells were seeded in 96-well plates per well until the cells adhered to the wall. Compound concentration gradients were prepared, and cells were pretreated with compounds for 1 hour (the highest final concentration of the compound was 1μM, and the concentration gradient was diluted 3 times). After adding 10ng / ml LPS (Lipopolysaccharides from Escherichia coli O111:B4) for stimulation for 4 hours, the culture supernatant was collected by centrifugation for subsequent ELISA detection of TNF-α concentration in the supernatant. TNF-α concentration detection was performed according to the standard steps provided by the ELISA kit manufacturer.

[1014] 4. Experimental data processing method:

[1015] The standard curve of TNF-α standard was drawn by linear regression method, and the TNF-α concentration of the sample was converted according to the standard curve.

[1016] Calculate the inhibition rate: inhibition rate percentage = [(average TNF-α concentration in positive control wells - average TNF-α concentration in sample wells) / (average TNF-α concentration in positive control wells - average TNF-α concentration in negative control wells)] × 100%, where the positive control wells are compound-free wells (DMSO-treated wells) and the negative control wells are culture medium wells.

[1017] Dose response curve fitting: Use log(inhibitor) vs.response--Variable slope(four parameters) in GraphPad Prism 6 to fit the compound concentration and the corresponding inhibition rate, fit the curve and obtain the compound IC 50 The fitting calculation equation is Y = Bottom + (Top-Bottom) / (1 + 10^((LogIC 50 -X)*HillSlope)).

[1018] 5. Experimental results:

[1019]

[1020] 6. Experimental conclusion:

[1021] The above data show that the example compounds of the present invention have a strong inhibitory ability on the expression level of TNF-α in U937 cells.

[1022] Test Example 4: Pharmacokinetics in SD rats

[1023] 1. Experimental purpose:

[1024] SD rats were used as test animals to study the pharmacokinetic behavior of the compound of the present invention in rats (plasma) at a dose of 5 mg / kg or 2 mg / kg orally and a dose of 1 mg / kg intravenously.

[1025] 2. Experimental Plan

[1026] 2.1 Trial Drugs:

[1027] The compound of the present invention is homemade.

[1028] 2.2 Experimental Animals:

[1029] There were 3 male SD rats in each group, from Shanghai Jiesijie Experimental Animal Co., Ltd., with animal production license number (SCXK (Shanghai) 2013-0006N0.311620400001794).

[1030] 2.3 Drug preparation:

[1031] PO, 10% solutol HS15, dissolve by ultrasound, prepare as a clear solution or homogeneous suspension.

[1032] IV, 5% DMSO + 10% Solutol HS15 + 85% PBS, sonicated to prepare a clear solution.

[1033] 2.4 Dosage regimen:

[1034] 3 male SD rats were administered in each group after overnight fasting, with a dose of 5 mg / kg or 2 mg / kg or 10 mL / kg, respectively; and an iv dose of 1 mg / kg or 5 mL / kg, respectively.

[1035] 2.5 Sample collection:

[1036] After oral administration to rats, blood samples were collected at 0.25, 0.5, 1, 2, 4, 6, 8 and 24 hours; after intravenous administration to rats, blood samples were collected at 0.083, 0.25, 0.5, 1, 2, 4, 6, 8 and 24 hours; 0.2 mL of blood was collected from the jugular vein and placed in EDTA-K 2 The plasma was separated by centrifugation at 6000 rpm for 6 min at 4°C in the test tube and stored at -80°C.

[1037] 2.6 Sample processing:

[1038] 1) Add 100uL acetonitrile to 20uL of plasma sample for precipitation, mix and centrifuge at 3500×g for 5 to 20 minutes.

[1039] 2) The supernatant solution after treatment is subjected to LC / MS / MS analysis to determine the concentration of the test compound. The LC / MS / MS analysis instrument is AB Sciex API 4000Qtrap.

[1040] 2.7 Liquid phase analysis:

[1041] Liquid phase conditions: Shimadzu LC-20AD pump

[1042] ·Chromatographic column: Waters Xbridge C18 5μm, 4.6X 50mm Mobile phase: Liquid A is 0.1% formic acid in water, Liquid B is methanol

[1043] Flow rate: 1.0mL / min

[1044] Elution time: 0-4.0 minutes, eluent is as follows:

[1045]

[1046] 3. Test results and data processing:

[1047] The main pharmacokinetic parameters were calculated using WinNonlin 6.1.

[1048]

[1049]

[1050] 4. Experimental conclusion

[1051] The results of pharmacokinetic assay in SD rats showed that the compound of the present invention exhibited good PK properties.

[1052] Crystalline Form Study of Examples

[1053] It is well known to those skilled in the art that the above-mentioned example compounds have been shown to have a good inhibitory effect on the expression level of TNF-α and p-HSP27 in U937 cells, and their crystal forms and pharmaceutically acceptable salts often have the same pharmacological and pharmacodynamic activity. On this basis, the inventors further studied the crystal forms and salt forms of the corresponding compounds and the physical and chemical properties of the crystal forms, but the preparation and characterization of the following specific crystal forms do not represent a limitation on the scope of protection of the present invention. Those skilled in the art can obtain more crystals of the compounds of the present invention by conventional crystallization methods based on the present invention, and these crystals, salt forms and crystals are all solutions protected by the present invention. Specifically as follows:

[1054] 1.1 Experimental Instruments

[1055] 1.1.1 Some parameters of physical and chemical testing instruments

[1056]

[1057] 1.2 Instruments and liquid phase analysis conditions

[1058] 1.2.1 Instruments and equipment

[1059] Instrument Name model Analytical Balance Sartorius BSA224S-CW Water Purifier Milli-Q Plus, Millipore High performance liquid chromatography Agilent1260 Pump Agilent G1311B Injector G1329B Column oven G1316A Detector G1315D

[1060] 1.2.2 Chromatographic conditions

[1061] Chromatographic column: ZOBAX SB C8 (4.6*75mm, 3.5μm)

[1062] Flow rate: 1.0mL / min

[1063] Column temperature: 35°C

[1064] Detection wavelength: 254nm

[1065] Injection volume: 3 μL

[1066] Run time: 10 minutes

[1067] Diluent: DMSO

[1068] Mobile phase: A: water (0.05% trifluoroacetic acid); B: acetonitrile (0.05% trifluoroacetic acid)

[1069] T(min) A(％) B(％) 0.00 90.0 10.0 4.00 20.0 80.0 7.00 20.0 80.0 7.01 90.0 10.0 10.00 90.0 10.0

[1070] 1. Preparation of different crystalline forms of the compound of Example 8

[1071] 1.1 Preparation of Form A

[1072] Weigh 10 mg of the free base amorphous form, add 100 μL of water, slurry at room temperature for 2 weeks, centrifuge, remove the supernatant, and dry the obtained solid in vacuum at 40°C. Figure 1 The XRPD pattern shown in Figure 2 The TGA diagram shown in Figure 3 The DSC graph shown is Form A.

[1073] 1.2 Preparation of Form A

[1074] Weigh 10 mg of the free base amorphous form, add 50 μL of ethanol, sonicate to dissolve it, add 100 μL of n-hexane, stir overnight to solidify, centrifuge, remove the supernatant, and dry the obtained solid in vacuum at 40°C. XRPD detection shows that it is Form A.

[1075] 1.3 Preparation of Form A

[1076] Weigh 10 mg of the free base amorphous form, add 50 μL of tetrahydrofuran, sonicate to dissolve it, add 100 μL of n-hexane, stir overnight to solidify, centrifuge, remove the supernatant, and dry the obtained solid in vacuum at 40°C. XRPD detection shows that it is Form A.

[1077] 1.4 Preparation of Form B

[1078] Weigh 10 mg of free base amorphous, add 100 μL of 1,2-propylene glycol, and slurry at room temperature. After the sample is dissolved and precipitated, add 200 μL of methyl tert-butyl ether, slurry for 2 hours, centrifuge, remove the supernatant, and dry the obtained solid at 40°C in vacuum. Figure 4 The XRPD pattern shown in Figure 5 The TGA diagram shown in Figure 6 The DSC graph shown is Form B.

[1079] Further NMR characterization of Form B was performed, and the NMR results are as follows Fig.13 As shown, the results show that Form B is a 1,2-propylene glycol solvate, and the stoichiometric ratio of the compound to 1,2-propylene glycol is 1:1.

[1080] 1.5 Preparation of Form C

[1081] Weigh 200 mg of the free base amorphous form, add 4 mL of a mixed solvent of acetone: water (1:9), slurry at room temperature for 3 days, vacuum filter, and dry the filter cake at 40°C to obtain a solid. Figure 7 The XRPD pattern shown is Fig. 9 The DSC graph shown is Form C.

[1082] 1.6 Preparation of Form D

[1083] Weigh 10 mg of the amorphous free base, add 500 μL of isopropanol, sonicate to dissolve it, then place it in a vacuum drying oven without a lid, and dry it under vacuum at 40°C to obtain a solid. Fig.10 The XRPD pattern shown is Form D.

[1084] 1.7 Preparation of Form E

[1085] Weigh 10 mg of the free base amorphous form, add 50 μL of ethyl acetate, sonicate to dissolve it, add 100 μL of the anti-solvent n-hexane, and solid precipitates out, sticks to the wall and forms a gel. After stirring overnight, it solidifies, centrifuges, removes the supernatant, and the obtained solid is vacuum dried at 40°C. After detection and analysis, it is as follows Fig.11 The XRPD pattern shown is Form E.

[1086] 1.8 Preparation of Form F

[1087] Weigh an appropriate amount of free base crystal form E and heat it to 130°C using TGA to obtain a solid. Fig.12 The XRPD pattern shown is Form F.

[1088] 2. Solid stability test

[1089] 2.1 Experimental Purpose:

[1090] The physicochemical stabilities of the compounds with different crystalline forms were investigated at high temperature of 60°C, room temperature and high humidity of RH=92.5% and 50°C and RH=75% for 7 days, 14 days and 30 days.

[1091] 2.2 Experimental plan:

[1092] About 1 mg of the above-mentioned crystal form was taken and placed in an oven at 60°C, room temperature and high humidity RH=92.5% and 50°C RH=75% for 7 days, 14 days and 30 days to examine the physicochemical stability of the compound. The changes in related substances were calculated using the HPLC peak area normalization method.

[1093] 2.3 Experimental results:

[1094] The results of the physicochemical stability of the crystal form under different conditions:

[1095]

[1096] From the stability data, it can be seen that the free base crystal form A has good stability under high temperature, high humidity, and high temperature and high humidity conditions.

[1097] 3. Hygroscopicity test

[1098] 3.1 Experimental Purpose

[1099] The hygroscopicity of different crystalline forms of the compound under different relative humidity conditions was investigated.

[1100] 3.2 Experimental plan:

[1101] The above-mentioned crystal form of the compound is placed in saturated water vapor with different relative humidity to make the crystal form and the water vapor reach dynamic equilibrium, and the percentage of moisture absorption and weight gain of the crystal form after equilibrium is calculated.

[1102] 3.3 Experimental results:

[1103] Crystalline Form A absorbs moisture at RH80% and gains weight by about 1.282%, and is slightly hygroscopic. After 2 cycles of moisture absorption and desorption at 0-95% relative humidity, the XRPD spectrum of Crystalline Form A does not change, that is, the crystal form does not change.

[1104] Crystalline Form B absorbs moisture at RH80% and gains weight by about 0.283%, which is slightly hygroscopic. After two cycles of moisture absorption and desorption at 0-95% relative humidity, the XRPD spectrum of Crystalline Form B does not change, that is, the crystal form does not change.

[1105] 4 Solubility experiments in different media

[1106] 4.1 Experimental Purpose

[1107] The solubility of the above-mentioned crystalline forms in different pH buffers, water, artificial simulated gastric fluid (FaSSGF), fasting artificial simulated intestinal fluid (FaSSIF) and non-fasting artificial simulated intestinal fluid (FeSSIF) media was compared.

[1108] 4.2 Experimental plan:

[1109] About 1 mg of the above crystal form was weighed and suspended in different pH buffers, SGF, FaSSIF, FeSSIF and water, respectively, shaken at 37°C for 4 hours, filtered, and the thermodynamic solubility of the above crystal form at 37°C was determined by the external standard method.

[1110] 4.3 Experimental results:

[1111]

[1112]

[1113] Both Form A and Form B have good solubility and are pH dependent to a certain extent.

[1114] 5 PK study of different crystal forms in rats

[1115] 5.1 Experimental Purpose

[1116] SD rats were used as test animals to study the pharmacokinetic behavior of different crystal forms in rats (plasma) after oral administration.

[1117] 5.2 Experimental plan

[1118] The above-mentioned crystal forms were uniformly suspended in an aqueous solution containing 0.5% HPMC K4M, and then gavaged and administered to rats. Three rats were administered in parallel, and the dosages were crystal form A (30 mg / kg as suspension, administration volume 10 mL / kg) and crystal form B (30 mg / kg as suspension, administration volume 10 mL / kg).

[1119] 5.3 Experimental results and conclusions:

[1120] The crystal form of the present invention has good PK data and high oral bioavailability.

[1121] Compound salt and crystal form screening

[1122] 2.1 Screening of compound salt forms and salt crystal forms

[1123] 2.1.1 Experimental Purpose:

[1124] Select different counter-ion acids and detect which counter-ion acids can form compound salts through appropriate crystallization methods.

[1125] 2.1.2 Experimental procedures

[1126] 1) Using ethanol natural evaporation method

[1127] Weigh about 75 mg of the amorphous compound of Example 8, add 3.75 mL of ethanol, ultrasonically dissolve it, and filter it as a stock solution. Take 500 μL of the stock solution, add 21.4 μL of ethanol solutions of different counter-ion acids at a molar ratio of 1:1.2, evaporate to dryness at room temperature, and characterize the obtained solid if there is solid; if no solid is precipitated, add 100 μL of ethyl acetate and continue to slurry, and characterize the solid after precipitation. The salt or salt crystal form of the compound of the present invention can be obtained by the natural evaporation method of ethanol.

[1128] 2) Salt formation by reaction dissolution crystallization

[1129] Weigh 10 mg of the amorphous compound of Example 8, add 100 μL of solvent, stir at room temperature, add 21.4 μL of ethanol solution of the counter-ion acid at a molar ratio of 1:1.2, add IPE (isopropyl ether) or HEP (n-heptane) to clarify overnight without precipitating solid, centrifuge vacuum dry the precipitated solid and characterize it. The characterization results are shown in the following table.

[1130] Solvents acid result Acetonitrile 1M hydrobromic acid in ethanol Hydrobromide Form A Acetonitrile 1M hydrochloric acid in ethanol Hydrochloride Form A Acetonitrile 1M benzenesulfonic acid in ethanol Benzenesulfonate Form A acetone 1M methanesulfonic acid in ethanol Methanesulfonate Form A Ethyl acetate 1M hydrobromic acid in ethanol Hydrobromide Form B

[1131] Through salt screening by reaction crystallization method, the compound formed salts with hydrochloric acid, hydrobromic acid, methanesulfonic acid and benzenesulfonic acid respectively, among which the salt with hydrobromic acid had two crystal forms and a total of 5 salts.

[1132] 3) Preparation of hydrochloride crystal form B

[1133] Weigh 201.39 mg of the amorphous compound of Example 8, add 2 mL of acetonitrile, stir at room temperature, add 428 μL of ethanol solution of hydrochloric acid at a molar ratio of 1:1.2, stir for a while after dissolving, add 3 mL of isopropyl ether, precipitate a yellow solid, vacuum filter, put it in a 40°C oven under vacuum and characterize it. XRPD results show that it is hydrochloride form B.

[1134] 4) Using acetone suspension beating method

[1135] About 20 mg of the amorphous compound of Example 5 was weighed, 200 μL of acetone was added, and the mixture was suspended and dispersed evenly by ultrasound. The mixture was stirred at room temperature, and 39.5 μL of methanol solutions of different counter-ion acids were added at a molar ratio of 1:1.2, to which the sample of the methanol solution of p-toluenesulfonate was added. After stirring at room temperature for three days, p-toluenesulfonate was obtained. The solid was centrifuged and vacuum dried and characterized. The XRPD results showed that it was p-toluenesulfonate crystalline form A.

[1136] Study on the stability of compound salt crystals

[1137] About 10 mg of Example 8 compound hydrochloride crystal form B was weighed, 100 μL of solvent was added, and the sample was centrifuged after being slurried at room temperature for 5 days. The obtained solid was vacuum dried at 40° C. overnight and characterized by XRPD. The phenomenon and characterization results are as follows:

[1138] Solvents Phenomenon after adding pulping solvent result n-Hexane Suspension Crystalline Form B n-Heptane Suspension Crystalline Form B Methyl tert-butyl ether Suspension Crystalline Form B

[1139] The above results show that hydrochloride crystal form B has high stability.

Claims

1. A compound represented by general formula (I) or an acid salt of its stereoisomer, in: Ring A is selected from a 5-6 membered heteroaryl group containing 1 to 3 N atoms; Ring B is selected from a 6-12 membered heterocyclic group containing 1 to 3 N atoms; R 1 Selected from hydrogen, halogen or C 1-3 alkyl; R 2 Selected from hydrogen, halogen, C 1-3 Alkyl, C 1-3 Hydroxyalkyl or -(CR aa R bb ) n NR cc C(O)R dd ; R aa , R bb , R cc and R dd are each independently selected from hydrogen, deuterium or C 1-3 alkyl; n is 0, 1, 2 or 3; a is 0, 1, 2 or 3; and The acid in the acid salt 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-naphthoic acid, acetic acid, dichloroacetic acid, trichloroacetic acid, acetohydroxamic acid, adipic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, 4-aminobenzoic acid, capric acid, caproic acid, caprylic acid, cinnamic acid, citric acid, cyclohexanesulfamic 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 sulfuric acid, dibenzoyltartaric acid, ethane- 1,2-disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galactonic acid, gentisic acid, glutaric acid, 2-ketoglutaric acid, glycolic acid, hippuric acid, isethionic 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, pamoic acid, propionic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, thiocyanic acid, undecylenic acid, trifluoroacetic acid, benzenesulfonic acid, p-toluenesulfonic acid or L-malic acid; preferably p-toluenesulfonic acid, hydrochloric acid, hydrobromic acid or methanesulfonic acid; more preferably hydrochloric acid, hydrobromic acid or methanesulfonic acid; most preferably hydrochloric acid; Preferably, Ring A is selected from pyrimidinyl or pyrazolyl; Ring B is selected from R 1 is selected from hydrogen or F; R 2 Selected from hydrogen, F, and a is 1 or 2.

2. A compound represented by general formula (I) or a crystalline form of its stereoisomer or a crystalline form of its acid salt, in: Ring A is selected from a 5-6 membered heteroaryl group containing 1 to 3 N atoms; Ring B is selected from a 6-12 membered heterocyclic group containing 1 to 3 N atoms; R 1 Selected from hydrogen, halogen or C 1-3 alkyl; R 2 Selected from hydrogen, halogen, C 1-3 Alkyl, C 1-3 Hydroxyalkyl or -(CR aa R bb ) n NR cc C(O)R dd ; R aa , R bb , R cc and R dd are each independently selected from hydrogen, deuterium or C 1-3 alkyl; n is 0, 1, 2 or 3; a is 0, 1, 2 or 3; and The acid in the acid salt 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-naphthoic acid, acetic acid, dichloroacetic acid, trichloroacetic acid, acetohydroxamic acid, adipic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, 4-aminobenzoic acid, capric acid, caproic acid, caprylic acid, cinnamic acid, citric acid, cyclohexanesulfamic 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 sulfuric acid, dibenzoyltartaric acid, ethane- 1,2-disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galactonic acid, gentisic acid, glutaric acid, 2-ketoglutaric acid, glycolic acid, hippuric acid, isethionic 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, pamoic acid, propionic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, thiocyanic acid, undecylenic acid, trifluoroacetic acid, benzenesulfonic acid, p-toluenesulfonic acid or L-malic acid; preferably p-toluenesulfonic acid, hydrochloric acid, hydrobromic acid or methanesulfonic acid; more preferably hydrochloric acid, hydrobromic acid or methanesulfonic acid; most preferably hydrochloric acid; Preferably, Ring A is selected from pyrimidinyl or pyrazolyl; Ring B is selected from R 1 is selected from hydrogen or F; R 2 Selected from hydrogen, F, and a is 1 or 2.

3. The compound of formula (I) or the crystalline form of its stereoisomer, acid salt and the crystalline form of its acid salt according to any one of claims 1 or 2, characterized in that: The compound is selected from: (S)-11-chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d2)-2-(2-(2-hydroxypropane-2-yl)pyrimidin-4-yl)-5,6,7,8-tetrahydro-12H-dipyrido[1,2-a:3',4'-g]azocine-12-one; (S)-11-chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d2)-2-(3-(2-hydroxypropane-2-yl)-1H-pyrazol-1-yl)-5,6,7,8-tetrahydro-12H-dipyrido[1,2-a:3',4'-g]azocine-12-one; (S)-N-(2-(1-(11-chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d2)-12-carbonyl-6,7,8,12-tetrahydro-5H-dipyrido[1,2-a:3',4'-g]azocin-2-yl)-4-fluoro-1H-pyrazol-3-yl)propan-2-yl)acetamide; (S)-N-(2-(4-(11-chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d2)-12-carbonyl-6,7,8,12-tetrahydro-5H-dipyrido[1,2-a:3',4'-g]azocin-2-yl)pyrimidin-2-yl)propan-2-yl)acetamide; (R)-N-(2-(1-(11-chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d2)-1-fluoro-12-carbonyl-6,7,8,12-tetrahydro-5H-dipyrido[1,2-a:3',4'-g]azocin-2-yl)-4-fluoro-1H-pyrazol-3-yl)propan-2-yl)acetamide; (R)-N-(2-(4-(11-chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d2)-1-fluoro-12-carbonyl-6,7,8,12-tetrahydro-5H-dipyrido[1,2-a:3',4'-g]azocin-2-yl)pyrimidin-2-yl)propan-2-yl)acetamide; (R)-11-chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d2)-1-fluoro-2-(3-(2-hydroxypropane-2-yl)-1H-pyrazol-1-yl)-5,6,7,8-tetrahydro-12H-dipyrido[1,2-a:3',4'-g]azocine-12-one; (R)-11-chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d2)-1-fluoro-2-(2-(2-hydroxypropan-2-yl)pyrimidin-4-yl)-5,6,7,8-tetrahydro-12H-dipyrido[1,2-a:3',4'-g]azocine-12-one; (S,Z)-11-chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d2)-2-(2-(2-hydroxypropan-2-yl)pyrimidin-4-yl)-7,8-dihydro-12H-dipyrido[1,2-a:3',4'-g]azocine-12-one; (S,Z)-11-chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d2)-2-(3-(2-hydroxypropan-2-yl)-1H-pyrazol-1-yl)-7,8-dihydro-12H-dipyrido[1,2-a:3',4'-g]azocine-12-one; or (S,Z)-N-(2-(1-(11-chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d2)-12-carbonyl-8,12-dihydro-7H-dipyrido[1,2-a:3',4'-g]azocine-2-yl)-4-fluoro-1H-pyrazol-3-yl)propan-2-yl)acetamide.

4. The compound of formula (I) or the acid salt or the crystalline form of the acid salt thereof according to any one of claims 1 to 3, characterized in that: The number of acids 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, further preferably 1.

5. The compound of formula (I) or the crystalline form of its stereoisomer or the crystalline form of its acid salt according to any one of claims 2 to 4, characterized in that: The crystal form is a 1,2-propylene glycol solvate, a hydrate or an anhydrous form, the number of 1,2-propylene glycol or water is 0.2 to 3, preferably 0.2, 0.5, 1, 1.5, 2, 2.5 or 3; wherein the water in the hydrate is selected from pipeline water, crystal water or a combination of the two; the preferred crystal form is an anhydrous form; The acid salt is in the form of a hydrate or an anhydrate; when the acid salt or its acid salt is in the form of a hydrate, the number of water 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.

6. The compound according to claim 3 or the crystal form of its stereoisomer or the crystal form of its acid salt, characterized in that: The crystalline form of the compound (R)-11-chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d2)-1-fluoro-2-(2-(2-hydroxypropane-2-yl)pyrimidin-4-yl)-5,6,7,8-tetrahydro-12H-dipyrido[1,2-a:3',4'-g]azocine-12-one is crystalline form A, crystalline form B, crystalline form C, crystalline form D, crystalline form E or crystalline form F; in: The X-ray powder diffraction spectrum of the crystalline form A has a diffraction peak at 2θ of 4.8±0.2°; or a diffraction peak at 7.4±0.2°; or a diffraction peak at 9.5±0.2°; or a diffraction peak at 11.3±0.2°; or a diffraction peak at 14.6±0.2°; or a diffraction peak at 16.6±0.2°; or a diffraction peak at 19.2±0.2°; or a diffraction peak at 20.3±0.2°; or a diffraction peak at 23.8±0.2°; or a diffraction peak at 27.0±0.2°; preferably including any 2-5, or 3-5, or 3-6, or 3-8, or 5-8, or 6-8 of the above diffraction peaks, more preferably including any 6, 7 or 8 thereof; The X-ray powder diffraction spectrum of the crystalline form B has a diffraction peak at 2θ of 5.9±0.2°; or a diffraction peak at 7.8±0.2°; or a diffraction peak at 8.5±0.2°; or a diffraction peak at 11.0±0.2°; or a diffraction peak at 11.8±0.2°; or a diffraction peak at 15.2±0.2°; or a diffraction peak at 18.8±0.2°; or a diffraction peak at 20.3±0.2°; or a diffraction peak at 23.4±0.2°; or a diffraction peak at 25.5±0.2°; preferably including any 2-5, or 3-5, or 3-6, or 3-8, or 5-8, or 6-8 of the above diffraction peaks, more preferably including any 6, 7 or 8 thereof; The X-ray powder diffraction spectrum of the crystalline form C has a diffraction peak at 2θ of 8.2±0.2°; or a diffraction peak at 9.9±0.2°; or a diffraction peak at 12.9±0.2°; or a diffraction peak at 15.1±0.2°; or a diffraction peak at 18.0±0.2°; or a diffraction peak at 19.9±0.2°; or a diffraction peak at 22.2±0.2°; or a diffraction peak at 23.7±0.2°; or a diffraction peak at 24.6±0.2°; or a diffraction peak at 26.2±0.2°; preferably including any 2-5, or 3-5, or 3-6, or 3-8, or 5-8, or 6-8 of the above diffraction peaks, more preferably including any 6, 7 or 8 thereof; The X-ray powder diffraction spectrum of the crystalline form D has a diffraction peak at 2θ of 6.1±0.2°; or a diffraction peak at 6.7±0.2°; or a diffraction peak at 9.1±0.2°; or a diffraction peak at 10.5±0.2°; or a diffraction peak at 11.6±0.2°; or a diffraction peak at 14.9±0.2°; or a diffraction peak at 20.2±0.2°; or a diffraction peak at 21.0±0.2°; or a diffraction peak at 21.3±0.2°; or a diffraction peak at 23.7±0.2°; preferably including any 2-5, or 3-5, or 3-6, or 3-8, or 5-8, or 6-8 of the above diffraction peaks, more preferably including any 6, 7 or 8 thereof; The X-ray powder diffraction spectrum of the crystalline form E has a diffraction peak at 2θ of 6.9±0.2°; or a diffraction peak at 11.9±0.2°; or a diffraction peak at 12.4±0.2°; or a diffraction peak at 13.7±0.2°; or a diffraction peak at 15.7±0.2°; or a diffraction peak at 16.9±0.2°; or a diffraction peak at 18.0±0.2°; or a diffraction peak at 19.1±0.2°; or a diffraction peak at 23.9±0.2°; or a diffraction peak at 24.7±0.2°; preferably including any 2-5, or 3-5, or 3-6, or 3-8, or 5-8, or 6-8 of the above diffraction peaks, more preferably including any 6, 7 or 8 thereof; The X-ray powder diffraction spectrum of the crystalline form F has a diffraction peak at 2θ of 14.0±0.2°; or a diffraction peak at 15.6±0.2°; or a diffraction peak at 15.8±0.2°; or a diffraction peak at 16.1±0.2°; or a diffraction peak at 18.7±0.2°; or a diffraction peak at 18.9±0.2°; or a diffraction peak at 20.0±0.2°; or a diffraction peak at 23.6±0.2°; or a diffraction peak at 25.0±0.2°; or a diffraction peak at 26.9±0.2°; preferably including any 2-5, or 3-5, or 3-6, or 3-8, or 5-8, or 6-8 of the above diffraction peaks, more preferably including any 6, 7 or 8 thereof; The acid salt crystalline form of the compound (R)-11-chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d2)-1-fluoro-2-(2-(2-hydroxypropane-2-yl)pyrimidin-4-yl)-5,6,7,8-tetrahydro-12H-dipyrido[1,2-a:3',4'-g]azocine-12-one is: Hydrochloride form A, whose X-ray powder diffraction spectrum has a diffraction peak at 2θ of 7.5±0.2°; or a diffraction peak at 9.8±0.2°; or a diffraction peak at 12.4±0.2°; or a diffraction peak at 14.1±0.2°; or a diffraction peak at 14.4±0.2°; or a diffraction peak at 15.2±0.2°; or a diffraction peak at 16.3±0.2°; or a diffraction peak at 18.4±0.2°; or a diffraction peak at 19.6±0.2°; or a diffraction peak at 21.0±0.2°; preferably comprising any 2-5, or 3-5, or 3-6, or 3-8, or 5-8, or 6-8 of the above diffraction peaks, more preferably comprising any 6, 7 or 8 thereof; Hydrochloride form B, whose X-ray powder diffraction spectrum has a diffraction peak at 2θ of 11.8±0.2°; or a diffraction peak at 12.2±0.2°; or a diffraction peak at 13.3±0.2°; or a diffraction peak at 13.7±0.2°; or a diffraction peak at 14.2±0.2°; or a diffraction peak at 15.6±0.2°; or a diffraction peak at 16.3±0.2°; or a diffraction peak at 18.3±0.2°; or a diffraction peak at 20.9±0.2°; or a diffraction peak at 25.6±0.2°; preferably including any 2-5, or 3-5, or 3-6, or 3-8, or 5-8, or 6-8 of the above diffraction peaks, more preferably including any 6, 7 or 8 thereof; Hydrobromide type A, whose X-ray powder diffraction spectrum has a diffraction peak at 2θ of 12.1±0.2°; or a diffraction peak at 12.3±0.2°; or a diffraction peak at 13.6±0.2°; or a diffraction peak at 14.1±0.2°; or a diffraction peak at 15.5±0.2°; or a diffraction peak at 16.2±0.2°; or a diffraction peak at 18.1±0.2°; or a diffraction peak at 20.9±0.2°; or a diffraction peak at 25.5±0.2°; or a diffraction peak at 26.7±0.2°; preferably including any 2-5, or 3-5, or 3-6, or 3-8, or 5-8, or 6-8 of the above diffraction peaks, more preferably including any 6, 7 or 8 thereof; Hydrobromide type B, whose X-ray powder diffraction spectrum has a diffraction peak at 2θ of 11.9±0.2°; or a diffraction peak at 13.1±0.2°; or a diffraction peak at 15.0±0.2°; or a diffraction peak at 15.4±0.2°; or a diffraction peak at 16.1±0.2°; or a diffraction peak at 16.7±0.2°; or a diffraction peak at 18.0±0.2°; or a diffraction peak at 19.3±0.2°; or a diffraction peak at 20.4±0.2°; or a diffraction peak at 21.4±0.2°; preferably including any 2-5, or 3-5, or 3-6, or 3-8, or 5-8, or 6-8 of the above diffraction peaks, more preferably including any 6, 7 or 8 thereof; Methanesulfonate type A, whose X-ray powder diffraction spectrum has a diffraction peak at 2θ of 6.5±0.2°; or a diffraction peak at 9.4±0.2°; or a diffraction peak at 9.9±0.2°; or a diffraction peak at 11.5±0.2°; or a diffraction peak at 12.0±0.2°; or a diffraction peak at 12.5±0.2°; or a diffraction peak at 15.2±0.2°; or a diffraction peak at 19.0±0.2°; or a diffraction peak at 19.9±0.2°; or a diffraction peak at 20.2±0.2°; preferably comprising any 2-5, or 3-5, or 3-6, or 3-8, or 5-8, or 6-8 of the above-mentioned diffraction peaks, more preferably comprising any 6, 7 or 8 thereof; The acid salt crystalline form of the compound (R)-N-(2-(1-(11-chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d2)-1-fluoro-12-carbonyl-6,7,8,12-tetrahydro-5H-dipyrido[1,2-a:3',4'-g]azocine-2-yl)-4-fluoro-1H-pyrazol-3-yl)propan-2-yl)acetamide is: p-Toluenesulfonate salt type A, whose X-ray powder diffraction spectrum has a diffraction peak at 2θ of 6.2±0.2°; or a diffraction peak at 10.7±0.2°; or a diffraction peak at 12.0±0.2°; or a diffraction peak at 12.5±0.2°; or a diffraction peak at 17.0±0.2°; or a diffraction peak at 17.7±0.2°; or a diffraction peak at 18.6±0.2°; or a diffraction peak at 19.2±0.2°; preferably contains any 2-5, or 3-5, or 3-6, or 3-8, or 5-8, or 6-8 of the above-mentioned diffraction peaks, and more preferably contains any 6, 7 or 8 of them.

7. The compound according to claim 6 or the crystalline form of its stereoisomer or the crystalline form of its acid salt, characterized in that: The X-ray powder diffraction pattern of the crystalline form A comprises at least one or more diffraction peaks located at 2θ of 4.8±0.2°, 14.6±0.2°, and 23.8±0.2°, preferably two of them, and more preferably three of them; optionally, it may further comprise at least one of 2θ of 7.4±0.2°, 11.3±0.2°, 16.6±0.2°, 19.2±0.2°, and 20.3±0.2°, preferably comprising 2, 3, 4 or 5; optionally further comprising one or more diffraction peaks located at 2θ of 9.5±0.2°, 15.7±0.2°, 19.8±0.2°, 20.0±0.2°, 21.5±0.2°, 26.3±0.2°, 27.0±0.2°; preferably comprising at least any 2-3, or 4-5, or 6-7 thereof; further preferably, comprising any 2, 3, 4, 5, 6, 7 thereof; The X-ray powder diffraction pattern of the crystalline form B at least comprises one or more diffraction peaks located at 2θ of 7.8±0.2°, 8.5±0.2°, and 15.2±0.2°, preferably two of them, and more preferably three of them; optionally, it may further comprise at least one of 2θ of 5.9±0.2°, 11.0±0.2°, 20.3±0.2°, 23.4±0.2°, and 25.5±0.2°, preferably 2 of them. , 3, 4 or 5; optionally further comprising one or more diffraction peaks located at 2θ of 11.8±0.2°, 12.3±0.2°, 16.1±0.2°, 18.8±0.2°, 20.6±0.2°, 24.8±0.2°, 25.8±0.2°; preferably comprising at least any 2-3, or 4-5, or 6-7 thereof; further preferably, comprising any 2, 3, 4, 5, 6, 7 thereof; The X-ray powder diffraction pattern of the crystalline form C at least comprises one or more diffraction peaks located at 2θ of 9.9±0.2°, 19.9±0.2°, and 22.2±0.2°, preferably two of them, and more preferably three of them; optionally, it may further comprise at least one of 2θ of 8.2±0.2°, 15.1±0.2°, 23.7±0.2°, 24.6±0.2°, and 26.2±0.2°, preferably comprising 2, 3, 4 or 5; optionally further comprising one or more diffraction peaks located at 2θ of 6.5±0.2°, 12.9±0.2°, 16.0±0.2°, 18.0±0.2°, 20.7±0.2°, 24.7±0.2°, 25.6±0.2°; preferably comprising at least any 2-3, or 4-5, or 6-7 thereof; further preferably, comprising any 2, 3, 4, 5, 6, 7 thereof; The X-ray powder diffraction pattern of the crystalline form D comprises at least one or more diffraction peaks located at 2θ of 6.1±0.2°, 6.7±0.2°, and 10.5±0.2°, preferably two of them, and more preferably three of them; optionally, it may further comprise at least one of 2θ of 9.1±0.2°, 11.6±0.2°, 14.9±0.2°, 21.3±0.2°, and 23.7±0.2°, preferably comprising 2, 3, 4 or 5; optionally further comprising one or more diffraction peaks located at 2θ of 5.4±0.2°, 15.3±0.2°, 18.0±0.2°, 20.2±0.2°, 21.0±0.2°, 24.6±0.2°, 26.1±0.2°; preferably comprising at least any 2-3, or 4-5, or 6-7 thereof; further preferably, comprising any 2, 3, 4, 5, 6, or 7 thereof; The X-ray powder diffraction pattern of the crystalline form E at least comprises one or more diffraction peaks located at 2θ of 11.9±0.2°, 15.7±0.2°, and 19.1±0.2°, preferably two of them, more preferably three; optionally, it may further comprise at least one of 2θ of 12.4±0.2°, 13.7±0.2°, 18.0±0.2°, 23.9±0.2°, and 24.7±0.2°, preferably comprising the following: 2, 3, 4 or 5 of them; optionally further comprising one or more diffraction peaks located at 2θ of 6.9±0.2°, 14.8±0.2°, 16.5±0.2°, 16.9±0.2°, 18.2±0.2°, 20.6±0.2°, 27.5±0.2°; preferably comprising at least any 2-3 of them, or 4-5 of them, or 6-7 of them; further preferably, comprising any 2, 3, 4, 5, 6, 7 of them; The X-ray powder diffraction pattern of the crystalline form F at least comprises one or more diffraction peaks located at 2θ of 14.0±0.2°, 18.9±0.2°, and 20.0±0.2°, preferably comprises two of them, and more preferably comprises three of them; optionally, it may further comprise at least one of 2θ of 15.6±0.2°, 15.8±0.2°, 16.1±0.2°, 18.7±0.2°, and 25.0±0.2°, preferably comprises 2, 3, 4 or 5 of them; optionally, it may further comprise one or more diffraction peaks located at 2θ of 14.3±0.2°, 20.3±0.2°, 23.6±0.2°, 25.9±0.2°, and 26.9±0.2°; preferably comprises at least any 2-3 of them, or 4-5 of them; further preferably, comprises any 2, 3, 4 or 5 of them; The X-ray powder diffraction spectrum of the hydrochloride salt form A at least comprises one or more diffraction peaks located at 2θ of 12.4±0.2°, 15.2±0.2°, and 16.3±0.2°, preferably two of them, and more preferably three of them; optionally, it may further comprise at least one of 2θ of 9.8±0.2°, 14.1±0.2°, 14.4±0.2°, 18.4±0.2°, and 19.6±0.2°, preferably 2, 3, 4 or 5 of them; optionally, it may further comprise one or more diffraction peaks located at 2θ of 6.4±0.2°, 7.5±0.2°, 17.4±0.2°, 21.0±0.2°, and 22.4±0.2°; preferably at least any 2-3 of them, or 4-5 of them; further preferably, any 2, 3, 4 or 5 of them are included; The X-ray powder diffraction pattern of the hydrochloride crystal form B comprises at least one or more diffraction peaks located at 2θ of 12.2±0.2°, 14.2±0.2°, and 15.6±0.2°, preferably two of them, more preferably three; optionally, it may further comprise at least one of 2θ of 11.8±0.2°, 13.7±0.2°, 16.3±0.2°, 18.3±0.2°, and 20.9±0.2°, preferably comprising Containing 2, 3, 4 or 5 of them; optionally further comprising one or more diffraction peaks located at 2θ of 6.9±0.2°, 10.3±0.2°, 13.3±0.2°, 15.0±0.2°, 16.7±0.2°, 18.8±0.2°, 25.6±0.2°; preferably comprising at least any 2-3, or 4-5, or 6-7 of them; further preferably, comprising any 2, 3, 4, 5, 6, 7 of them; The X-ray powder diffraction pattern of the hydrobromide salt form A comprises at least one or more diffraction peaks located at 2θ of 12.1±0.2°, 13.6±0.2°, and 25.5±0.2°, preferably two of them, and more preferably three of them; optionally, it may further comprise at least one of 2θ of 14.1±0.2°, 15.5±0.2°, 18.1±0.2°, 20.9±0.2°, and 26.7±0.2°, preferably comprising 2, 3, 4 or 5 of them; optionally further comprising one or more diffraction peaks located at 2θ of 10.4±0.2°, 12.3±0.2°, 16.2±0.2°, 17.3±0.2°, 21.5±0.2°, 27.5±0.2°, 29.1±0.2°; preferably comprising at least any 2-3, or 4-5, or 6-7 of them; further preferably, comprising any 2, 3, 4, 5, 6, 7 of them; The X-ray powder diffraction pattern of the hydrobromide salt form B comprises at least one or more diffraction peaks located at 2θ of 11.9±0.2°, 13.1±0.2°, and 21.4±0.2°, preferably two of them, and more preferably three of them; optionally, it may further comprise at least one of 2θ of 15.0±0.2°, 15.4±0.2°, 16.1±0.2°, 16.7±0.2°, 18.0±0.2°, 19.3±0.2°, and 20.4±0.2°, preferably 2, 3, 4 or 5 of them; The X-ray powder diffraction pattern of the mesylate salt type A comprises at least one or more diffraction peaks located at 2θ of 6.5±0.2°, 9.9±0.2°, and 12.5±0.2°, preferably two of them, more preferably three; optionally, it may further comprise at least one of 2θ of 9.4±0.2°, 11.5±0.2°, 12.0±0.2°, 19.9±0.2°, and 20.2±0.2°, preferably comprising the following: 2, 3, 4 or 5 of them; optionally further comprising one or more diffraction peaks located at 2θ of 10.6±0.2°, 15.2±0.2°, 16.9±0.2°, 17.6±0.2°, 19.0±0.2°, 22.0±0.2°, 23.1±0.2°; preferably comprising at least any 2-3 of them, or 4-5 of them, or 6-7 of them; further preferably, comprising any 2, 3, 4, 5, 6, 7 of them; The X-ray powder diffraction pattern of the p-toluenesulfonate salt type A comprises at least one or more diffraction peaks located at 2θ of 12.0±0.2°, 17.7±0.2°, and 19.2±0.2°, preferably two of them, and more preferably three of them; optionally, it may further comprise at least one of 2θ of 6.2±0.2°, 10.7±0.2°, 12.5±0.2°, 17.0±0.2°, and 18.6±0.2°, preferably 2, 3, 4 or 5 of them.

8. The compound according to claim 6 or the crystalline form of its stereoisomer or the crystalline form of its acid salt, characterized in that: The X-ray powder diffraction pattern of the crystalline form A comprises one or more diffraction peaks at 2θ of 4.8±0.2°, 7.4±0.2°, 9.5±0.2°, 11.3±0.2°, 14.6±0.2°, 15.7±0.2°, 16.6±0.2°, 19.2±0.2°, 20.3±0.2°, 23.8±0.2°, 26.3±0.2°, and 27.0±0.2°; preferably, it comprises 4, 5, 6, 8, 10, or 12 of them; The X-ray powder diffraction pattern of the crystalline form B comprises one or more diffraction peaks located at 2θ of 5.9±0.2°, 7.8±0.2°, 8.5±0.2°, 11.0±0.2°, 11.8±0.2°, 12.3±0.2°, 15.2±0.2°, 18.8±0.2°, 20.3±0.2°, 23.4±0.2°, 24.8±0.2°, and 25.5±0.2°; preferably, it comprises 4, 5, 6, 8, 10 or 12 of them; The X-ray powder diffraction pattern of the crystalline form C comprises one or more diffraction peaks located at 2θ of 8.2±0.2°, 9.9±0.2°, 12.9±0.2°, 15.1±0.2°, 18.0±0.2°, 18.1±0.2°, 19.9±0.2°, 22.2±0.2°, 23.7±0.2°, 24.6±0.2°, 24.7±0.2°, and 26.2±0.2°; preferably, it comprises 4, 5, 6, 8, 10 or 12 of them; The X-ray powder diffraction pattern of the crystalline form D comprises one or more diffraction peaks at 2θ of 5.4±0.2°, 6.1±0.2°, 6.7±0.2°, 9.1±0.2°, 10.5±0.2°, 11.6±0.2°, 14.9±0.2°, 18.0±0.2°, 20.2±0.2°, 21.0±0.2°, 21.3±0.2°, and 23.7±0.2°; preferably, it comprises 4, 5, 6, 8, 10, or 12 of them; The X-ray powder diffraction pattern of the crystalline form E comprises one or more diffraction peaks located at 2θ of 6.9±0.2°, 11.9±0.2°, 12.4±0.2°, 13.7±0.2°, 15.7±0.2°, 16.5±0.2°, 16.9±0.2°, 18.0±0.2°, 18.2±0.2°, 19.1±0.2°, 23.9±0.2°, and 24.7±0.2°; preferably, it comprises 4, 5, 6, 8, 10, or 12 of them; The X-ray powder diffraction pattern of the crystalline form F comprises one or more diffraction peaks located at 2θ of 14.0±0.2°, 14.3±0.2°, 15.6±0.2°, 15.8±0.2°, 16.1±0.2°, 18.7±0.2°, 18.9±0.2°, 20.0±0.2°, 20.3±0.2°, 23.6±0.2°, 25.0±0.2°, and 26.9±0.2°; preferably, it comprises 4, 5, 6, 8, 10 or 12 of them; The X-ray powder diffraction pattern of the hydrochloride crystal form A comprises one or more diffraction peaks located at 2θ of 6.4±0.2°, 7.5±0.2°, 9.8±0.2°, 12.4±0.2°, 14.1±0.2°, 14.4±0.2°, 15.2±0.2°, 16.3±0.2°, 18.4±0.2°, 19.6±0.2°, 21.0±0.2°, and 22.4±0.2°; preferably, it comprises 4, 5, 6, 8, 10 or 12 selected therefrom; The X-ray powder diffraction pattern of the hydrochloride crystal form B comprises one or more diffraction peaks located at 2θ of 6.9±0.2°, 10.3±0.2°, 11.8±0.2°, 12.2±0.2°, 13.3±0.2°, 13.7±0.2°, 14.2±0.2°, 15.6±0.2°, 16.3±0.2°, 18.3±0.2°, 20.9±0.2°, and 25.6±0.2°; preferably, it comprises 4, 5, 6, 8, 10, or 12 of them; The X-ray powder diffraction pattern of the hydrobromide salt form A comprises one or more diffraction peaks located at 2θ of 12.1±0.2°, 12.3±0.2°, 13.6±0.2°, 14.1±0.2°, 15.5±0.2°, 16.2±0.2°, 17.3±0.2°, 18.1±0.2°, 20.9±0.2°, 25.5±0.2°, 26.7±0.2°, 27.5±0.2°; preferably, it comprises 4, 5, 6, 8, 10 or 12 of them; The X-ray powder diffraction pattern of the mesylate salt form A comprises one or more diffraction peaks located at 2θ of 6.5±0.2°, 9.4±0.2°, 9.9±0.2°, 11.5±0.2°, 12.0±0.2°, 12.5±0.2°, 15.2±0.2°, 17.6±0.2°, 19.0±0.2°, 19.9±0.2°, 20.2±0.2°, 22.0±0.2°; preferably, it comprises 4, 5, 6, 8, 10 or 12 of them; The X-ray powder diffraction pattern of the toluenesulfonate salt type A comprises one or more diffraction peaks located at 2θ of 6.2±0.2°, 10.7±0.2°, 12.0±0.2°, 12.5±0.2°, 17.0±0.2°, 17.7±0.2°, 18.6±0.2°, and 19.2±0.2°; preferably, it comprises 4, 5, 6 or 8 selected therefrom.

9. The compound according to any one of claims 6 to 8 or the crystalline form of its stereoisomer or the crystalline form of its acid salt, characterized in that: The 2θ error between the top ten diffraction peak positions with relative peak intensity in the X-ray powder diffraction pattern of the crystalline form A, crystalline form B, crystalline form C, crystalline form D, crystalline form E or crystalline form F and the diffraction peaks at the corresponding positions in Figures 1, 4, 7, 10, 11 and 12 is ±0.2° to ±0.5°, preferably ±0.2° to ±0.3°, and most preferably ±0.2°; The 2θ error between the top ten diffraction peak positions with relative peak intensity in the X-ray powder diffraction pattern of the hydrochloride form A, hydrochloride form B, hydrobromide form A, hydrobromide form B, methanesulfonate form A or p-toluenesulfonate form A and the diffraction peaks at the corresponding positions in Figures 14, 16, 18, 20, 22 or 23 is ±0.2° to ±0.5°, preferably ±0.2° to ±0.3°, and most preferably ±0.2°.

10. The compound according to any one of claims 6 to 9 or the crystalline form of its stereoisomer or the crystalline form of its acid salt, characterized in that: The X-ray powder diffraction spectrum of the crystalline form A is shown in FIG1 ; and / or, the crystalline form A has a TGA spectrum as shown in FIG2 ; and / or, the crystalline form A has a DSC spectrum as shown in FIG3 ; The X-ray powder diffraction pattern of the crystalline form B is shown in FIG4 ; and / or, the crystalline form B has a TGA pattern as shown in FIG5 ; and / or, the crystalline form B has a DSC pattern as shown in FIG6 ; The X-ray powder diffraction pattern of the crystalline form C is shown in FIG7 ; and / or, the crystalline form C has a TGA pattern as shown in FIG8 ; and / or, the crystalline form C has a DSC pattern as shown in FIG9 ; The X-ray powder diffraction pattern of the crystalline form D is shown in FIG10 ; The X-ray powder diffraction pattern of the crystalline form E is shown in FIG11 ; The X-ray powder diffraction pattern of the crystalline form F is shown in FIG12 ; The X-ray powder diffraction spectrum of the hydrochloride crystal form A is shown in FIG14 ; and / or, the hydrochloride crystal form A has a DSC spectrum as shown in FIG15 ; The X-ray powder diffraction pattern of the hydrochloride crystal form B is shown in FIG16 ; and / or, the hydrochloride crystal form B has a DSC pattern as shown in FIG17 ; The X-ray powder diffraction pattern of the hydrobromide salt form A is shown in FIG18 ; and / or, the hydrobromide salt form A has a DSC pattern as shown in FIG19 ; The X-ray powder diffraction pattern of the hydrobromide salt form B is shown in FIG20 ; and / or, the hydrobromide salt form B has a DSC pattern as shown in FIG21 ; The X-ray powder diffraction pattern of the mesylate salt form A is shown in FIG22 ; The X-ray powder diffraction pattern of the p-toluenesulfonate salt type A is shown in Figure 23.

11. A method for preparing the compound according to any one of claims 1 or 4 or the acid salt of its stereoisomer: Method 1 includes the following steps: 1) Weigh an appropriate amount of free base and dissolve it in a benign solvent; 2) Weigh an appropriate amount of counter ion acid and dissolve it in an organic solvent; the amount of the counter ion acid is preferably 1.2 equivalents; 3) combining the above two solutions, stirring to precipitate or adding a poor solvent dropwise and stirring to precipitate, and the acid salt of the compound is obtained by precipitation; 4) Rapid centrifugation or vacuum filtration to obtain the target product; in: The benign solvent is selected from one or more of acetone, acetonitrile, ethanol, ethyl acetate, dichloromethane or tetrahydrofuran; preferably one or more of acetone, acetonitrile or ethyl acetate; The organic solvent is selected from one or more of methanol, ethanol, ethyl acetate, dichloromethane, acetone, n-hexane, petroleum ether, benzene, toluene, chloroform, acetonitrile, carbon tetrachloride, ethylene dichloride, tetrahydrofuran, 2-butanone, 3-pentanone, heptane, methyl tert-butyl ether, isopropyl ether, 1,4-dioxane, tert-butanol or N,N-dimethylformamide; preferably ethanol; the above-mentioned benign solvent and organic solution need to be miscible when used; The poor solvent is selected from one or more of heptane, water, methyl tert-butyl ether, cyclohexane, toluene, isopropyl ether or ethyl acetate; preferably isopropyl ether or n-heptane; The counter ion acid is selected from hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, hydrofluoric acid, hydroiodic acid, phosphoric acid, 2,5-dihydroxybenzoic acid, 1-hydroxy-2-naphthoic acid, acetic acid, dichloroacetic acid, trichloroacetic acid, acetohydroxamic acid, adipic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, benzoic acid, 4-acetylaminobenzoic acid, 4-aminobenzoic acid, capric acid, caproic acid, caprylic acid, cinnamic acid, citric acid, cyclohexanesulfamic 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 sulfuric acid, dibenzoyltartaric acid, acetic acid Preferably, the acid is 1,2-disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galactonic acid, gentisic acid, glutaric acid, 2-ketoglutaric acid, glycolic acid, hippuric acid, isethionic acid, lactobionic acid, ascorbic acid, aspartic acid, lauric acid, camphoric acid, maleic acid, malonic acid, methanesulfonic acid, 1,5-naphthalene disulfonic acid, naphthalene-2-sulfonic acid, nicotinic acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, propionic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, thiocyanic acid, undecylenic acid, trifluoroacetic acid, benzenesulfonic acid, p-toluenesulfonic acid or L-malic acid; preferably, hydrochloric acid, hydrobromic acid or methanesulfonic acid; most preferably, hydrochloric acid. Method 2 includes the following steps: 1) Weigh an appropriate amount of free base and suspend it with a poor solvent; 2) Weigh an appropriate amount of counter ion acid and dissolve it in an organic solvent or not; the amount of the counter ion acid is preferably 1.2 equivalents; 3) Combine the above two solutions and stir to dissolve, continue stirring to react, and after stirring for a suitable time, the acid salt of the compound is obtained; 4) Rapid centrifugation or vacuum filtration to obtain the target product; in: The organic solvent is selected from methanol, ethanol, ethyl acetate, dichloromethane, acetone, n-hexane, petroleum ether, benzene, toluene, chloroform, acetonitrile, carbon tetrachloride, ethylene dichloride, tetrahydrofuran, 2-butanone, 3-pentanone, heptane, methyl tert-butyl ether, isopropyl ether, 1,4-dioxane, tert-butanol or N,N-dimethylformamide; preferably methanol; The poor solvent is selected from acetone, ethyl acetate, methanol, 2-methyl-tetrahydrofuran or acetonitrile; preferably acetone; The counter ion acid is selected from hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, hydrofluoric acid, hydroiodic acid, phosphoric acid, 2,5-dihydroxybenzoic acid, 1-hydroxy-2-naphthoic acid, acetic acid, dichloroacetic acid, trichloroacetic acid, acetohydroxamic acid, adipic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, benzoic acid, 4-acetylaminobenzoic acid, 4-aminobenzoic acid, capric acid, caproic acid, caprylic acid, cinnamic acid, citric acid, cyclohexanesulfamic 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 sulfuric acid, dibenzoyltartaric acid, acetic acid The present invention can be selected from the group consisting of 1,2-disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galactosonic acid, gentisic acid, glutaric acid, 2-ketoglutaric acid, glycolic acid, hippuric acid, isethionic 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, pamoic acid, propionic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, thiocyanic acid, undecylenic acid, trifluoroacetic acid, benzenesulfonic acid, p-toluenesulfonic acid or L-malic acid; preferably p-toluenesulfonic acid, hydrochloric acid, hydrobromic acid or methanesulfonic acid.

12. A method for preparing a compound according to any one of claims 2 to 10 or a crystalline form of a stereoisomer thereof or a crystalline form of an acid salt thereof: The first method for preparing the crystal form comprises the following steps: the compound is slurried with a poor solvent at a certain temperature to obtain a crystal form, preferably, the temperature is 0 to 50° C.; more preferably, the temperature is 20 to 30° C.; The poor solvent is selected from one or more of water, 1,2-propylene glycol, methanol, ethanol, isopropyl acetate, acetone, ethyl acetate, acetonitrile, ethanol, 88% acetone, tetrahydrofuran, 2-methyltetrahydrofuran, dichloromethane, 1,4-dioxane, benzene, toluene, isopropanol, n-butanol, isobutanol n-propanol, tert-butanol, 2-butanone, 3-pentanone and N-methylpyrrolidone; preferably one or more of water, 1,2-propylene glycol or acetone; The second method for preparing the crystal form comprises the following steps: dissolving the compound in a good solvent, adding a poor solvent and stirring until a solid precipitates to obtain a crystal form; The third method for preparing the crystal form comprises the following steps: dissolving the compound in a good solvent, placing the compound in a vacuum oven without a lid and rapidly evaporating the compound until the solvent evaporates to obtain a crystal form; In the second and third methods for preparing the crystal form: The good solvent is selected from one or more of methanol, ethanol, isopropanol, ethyl acetate, acetonitrile, acetone, tetrahydrofuran, dichloromethane, 1,4-dioxane and 2-butanone; preferably one or more of isopropanol, ethanol, ethyl acetate or tetrahydrofuran; further preferably, the good solvent in method 2 is selected from one or more of ethanol, ethyl acetate or tetrahydrofuran; the good solvent in method 3 is selected from isopropanol; The poor solvent is selected from one or more of n-heptane, cyclohexane, n-hexane, n-pentane, water, ethyl acetate, methyl tert-butyl ether, toluene or isopropyl ether; preferably n-hexane; Method 4 comprises the following steps: the compound is heated to a certain temperature using TGA to obtain a crystalline form, preferably, the temperature is 130-140°C; A method for preparing a crystalline form of an acid salt of a compound, Method 1 includes the following steps: 1) Weigh an appropriate amount of free base and dissolve it in a benign solvent; 2) Weigh an appropriate amount of counter ion acid and dissolve it in an organic solvent; the amount of the counter ion acid is preferably 1.2 equivalents; 3) combining the above two solutions, stirring to precipitate or adding a poor solvent dropwise and stirring to precipitate; 4) Rapid centrifugation or vacuum filtration to obtain the target product; in: The benign solvent is selected from one or more of acetone, acetonitrile, ethanol, ethyl acetate, dichloromethane or tetrahydrofuran; preferably one or more of acetone, acetonitrile or ethyl acetate; The organic solvent is selected from one or more of methanol, ethanol, ethyl acetate, dichloromethane, acetone, n-hexane, petroleum ether, benzene, toluene, chloroform, acetonitrile, carbon tetrachloride, ethylene dichloride, tetrahydrofuran, 2-butanone, 3-pentanone, heptane, methyl tert-butyl ether, isopropyl ether, 1,4-dioxane, tert-butanol or N,N-dimethylformamide; preferably ethanol; the above-mentioned benign solvent and organic solution need to be miscible when used; The poor solvent is selected from one or more of heptane, water, methyl tert-butyl ether, cyclohexane, toluene, isopropyl ether or ethyl acetate; preferably isopropyl ether or n-heptane; The counter ion acid is selected from hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, hydrofluoric acid, hydroiodic acid, phosphoric acid, 2,5-dihydroxybenzoic acid, 1-hydroxy-2-naphthoic acid, acetic acid, dichloroacetic acid, trichloroacetic acid, acetohydroxamic acid, adipic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, benzoic acid, 4-acetylaminobenzoic acid, 4-aminobenzoic acid, capric acid, caproic acid, caprylic acid, cinnamic acid, citric acid, cyclohexanesulfamic 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 sulfuric acid, dibenzoyltartaric acid, acetic acid Preferably, the acid is 1,2-disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galactonic acid, gentisic acid, glutaric acid, 2-ketoglutaric acid, glycolic acid, hippuric acid, isethionic acid, lactobionic acid, ascorbic acid, aspartic acid, lauric acid, camphoric acid, maleic acid, malonic acid, methanesulfonic acid, 1,5-naphthalene disulfonic acid, naphthalene-2-sulfonic acid, nicotinic acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, propionic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, thiocyanic acid, undecylenic acid, trifluoroacetic acid, benzenesulfonic acid, p-toluenesulfonic acid or L-malic acid; preferably, hydrochloric acid, hydrobromic acid or methanesulfonic acid; most preferably, hydrochloric acid. Method 2 includes the following steps: 1) Weigh an appropriate amount of free base and suspend it with a poor solvent; 2) Weigh an appropriate amount of counter ion acid and dissolve it in an organic solvent or not; the amount of the counter ion acid is preferably 1.2 equivalents; 3) Combine the above two solutions and stir to dissolve, and continue stirring to react; 4) Rapid centrifugation or vacuum filtration to obtain the target product; in: The organic solvent is selected from methanol, ethanol, ethyl acetate, dichloromethane, acetone, n-hexane, petroleum ether, benzene, toluene, chloroform, acetonitrile, carbon tetrachloride, ethylene dichloride, tetrahydrofuran, 2-butanone, 3-pentanone, heptane, methyl tert-butyl ether, isopropyl ether, 1,4-dioxane, tert-butanol or N,N-dimethylformamide; preferably methanol; The poor solvent is selected from acetone, ethyl acetate, methanol, 2-methyl-tetrahydrofuran or acetonitrile; preferably acetone; The counter ion acid is selected from hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, hydrofluoric acid, hydroiodic acid, phosphoric acid, 2,5-dihydroxybenzoic acid, 1-hydroxy-2-naphthoic acid, acetic acid, dichloroacetic acid, trichloroacetic acid, acetohydroxamic acid, adipic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, benzoic acid, 4-acetylaminobenzoic acid, 4-aminobenzoic acid, capric acid, caproic acid, caprylic acid, cinnamic acid, citric acid, cyclohexanesulfamic 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 sulfuric acid, dibenzoyltartaric acid, acetic acid The present invention can be selected from the group consisting of 1,2-disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galactosonic acid, gentisic acid, glutaric acid, 2-ketoglutaric acid, glycolic acid, hippuric acid, isethionic 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, pamoic acid, propionic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, thiocyanic acid, undecylenic acid, trifluoroacetic acid, benzenesulfonic acid, p-toluenesulfonic acid or L-malic acid; preferably p-toluenesulfonic acid, hydrochloric acid, hydrobromic acid or methanesulfonic acid.

13. A pharmaceutical composition comprising a therapeutically effective dose of the compound according to any one of claims 1 to 10 or an acid salt, a crystalline form or an acid salt crystalline form thereof or a stereoisomer thereof and one or more pharmaceutically acceptable carriers, diluents or excipients.

14. The pharmaceutical composition according to claim 13, wherein The weight percentage of the acid salt, crystal form or acid salt crystal form of the compound or its stereoisomer is 0.1% to 95%, preferably 0.5% to 85%, more preferably 1% to 60%, further preferably 10% to 50%, further preferably 15-40%, further preferably 20-30%, further preferably 20-25%.

15. Use of the compound according to any one of claims 1 to 10 or the acid salt, crystal form or acid salt crystal form of its stereoisomer, or the pharmaceutical composition according to claim 13 in the preparation of a drug for treating p38 kinase-mediated diseases.

16. Use of the compound according to any one of claims 1 to 10 or the acid salt, crystal form or acid salt crystal form of its stereoisomer, or the pharmaceutical composition according to claim 13 in the preparation of a medicament for treating autoimmune diseases, chronic inflammatory diseases, acute inflammatory conditions, autoinflammatory diseases, atherosclerosis, diabetes, fibrotic diseases, metabolic diseases, cancer, tumors, leukemia or lymphoma.

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