Terpyridinedione compound crystal form as shown in formula (I) and preparation method and application thereof

Abstract

The invention belongs to the technical field of chemical medicines, and relates to a terpyridyl diketone compound crystal form shown in a formula (I), which is used as a p38 / MK2 inhibitor, can inhibit the generation of a cell factor TNF alpha, and is used for treating diseases such as arthritis and the like. # imgabs0 #

Description

A terpyridinedione compound crystal form represented by formula (I) and its preparation method and application Technical Field

[0001] The present invention belongs to the technical field of chemical drugs and relates to a terpyridinedione compound crystal form, and a preparation method and application thereof. Background Art

[0002] Mitogen-activated protein kinases (MAPKs) are a conserved family of enzymes that use phosphorylation cascades to transmit and mediate external stimuli to produce coordinated cellular responses to the environment. MAPKs are proline-directed, serine / threonine-specific protein kinases that regulate cellular activities such as gene expression, mitosis, differentiation, and cell survival / apoptosis. To date, four different classes of mammalian MAPKs have been identified: extracellular signaling kinases (ERK1 and ERK2), c-jun N-terminal kinase-1 (JNK1-3), p38 MAPK (p38α, p38β, p38γ, and p38δ), and ERK5.

[0003] Scientific exploration of this pathway from a biological, cellular, and in vivo perspective is primarily facilitated by the availability of well-characterized, selective small-molecule inhibitors of p38 MAPK, targeting the α and, to a lesser extent, the β isoforms. p38α MAPK is the primary isoform involved in immune and inflammatory responses. As such, its function is crucial for the production and activity of numerous proinflammatory cytokines, including TNFα, IL-1, IL-6, and IL-8, in cells such as macrophages, monocytes, synoviocytes, and endothelial cells. p38 MAPK is also responsible for inducing key inflammatory enzymes, such as COX2 and iNOS, which are the primary sources of eicosanoids and nitric oxide, respectively, at sites of inflammation. Furthermore, the p38 MAPK pathway regulates the expression of matrix metalloproteinases (MMPs), including MMP2, MMP9, and MMP13.

[0004] The use of selective and potent inhibitors has facilitated the discovery of several families of p38 MAPK substrates, including transcription factors, MAPKAP kinases, and other enzymes. While MAPKAP kinases (MK2, MK-3, and PRAK) are selectively phosphorylated by p38 MAPK, phosphorylation of MSK1 / 2, MNK1 / 2, and RSKb is catalyzed by both p38 MAPK and ERK. Although identification of substrates is difficult due to the lack of specific inhibitors, activation of RSKb is thought to play a role in cell survival.

[0005] Once phosphorylated and activated by p38 MAPK, MK-2, MK-3, and PRAK share similar substrate specificity. All of these kinases can phosphorylate the small heat shock protein Hsp27. Studies have shown that PRAK- and MK3-deficient mice do not show any tolerance to endotoxin shock or lipopolysaccharide (LPS)-induced reductions in cytokine production. In contrast, MK-2-deficient mice show tolerance to endotoxin shock and impaired inflammatory responses, as well as significant reductions in the production of cytokines such as TNFα, IFNγ, and IL-6. Therefore, the p38 / MK2 axis is particularly necessary and sufficient for regulating proinflammatory responses.

[0006] Exploiting the p38:MK2 interaction and using MK2 as a p38 substrate, new p38α inhibitors that exhibit interesting properties were discovered (Davidson et al.). This inhibitor exhibits substrate selectivity by preventing p38α-dependent phosphorylation of MK2 (Ki app 300nM) while retaining p38α-dependent phosphorylation of ATF2 (Ki app>20uM). Compared to conventional p38 ATP-competitive inhibitors that block p38-dependent phosphorylation of all p38 substrates, this new inhibitor is unique in function. A second independent study also described p38 inhibitors with unique mechanistic properties. This work shows a new mechanism for selectively inhibiting p38-dependent phosphorylation of MK2. Unlike previous studies by Davidson et al., these mechanistically unique compounds compete with ATP and stabilize the p38 / MK2 complex.

[0007] Taken together, these two studies clearly demonstrate proof of concept that selective blockade of the p38 / MK2 axis can be achieved using small-molecule inhibitors that should retain or enhance efficacy and exhibit an improved safety profile relative to conventional p38 MAPK inhibitors in animal models of disease or in human clinical settings.

[0008] In previous studies, the applicant obtained a terpyridinedione compound represented by formula (I), which has a good p38MAPK inhibitory effect. The present invention further studies and develops a physical form of the terpyridinedione compound suitable for pharmaceutical use.

[0009] Summary of the Invention

[0010] The terpyridinedione compound crystal form provided in the present application, as a p38 / MK2 inhibitor, can inhibit the production of the cytokine TNFα, thereby regulating inflammatory responses and other related diseases.

[0011] The present application provides a polymorphic form AO of a terpyridinedione compound represented by formula (I). Specifically, the present invention is achieved through the following technical solutions:

[0012] In a first aspect, the present application provides a terpyridinedione compound crystal form A represented by formula (I), wherein:

[0013] The X-ray diffraction pattern of the crystalline form A shows characteristic peaks at 5.00°, 7.70°, 12.82°, 14.08°, 15.44°, 16.72°, 17.17°, 19.70°, 20.41°, 20.88°, 23.08°, 23.78°, and 26.83° in terms of 2θ angle, with an error of ±0.2°.

[0014] Furthermore, the X-ray diffraction pattern of the crystalline form A is represented by 2θ angles at 9.24°, 11.40°, 11.63°, 12.23°, 13.85°, 14.80°, 15.71°, 15.96°, 17.75°, 17.93°, 18.20°, 18.67°, 18.94°, 21.15°, 21.48°, 22.51°, 22.71 There are characteristic peaks at 22.44°, 24.65°, 25.20°, 25.66°, 25.84°, 26.60°, 27.47°, 27.74°, 27.92°, 28.81°, 29.57°, 30.27°, 30.72°, 31.38°, 32.11°, 32.70°, 33.57°, and 36.70°, with an error of ±0.2°.

[0015] In a second aspect, the present application also provides a terpyridinedione compound crystal form B shown in formula (I), wherein the X-ray diffraction pattern of the crystal form B has characteristic peaks at 5.97°, 7.80°, 9.26°, 11.57°, 14.41°, 15.17°, 17.93°, 18.12°, 19.64°, 20.10°, 22.88°, and 23.50°, expressed in terms of 2θ angle, with an error of ±0.2°.

[0016] In a third aspect, the present application also provides a terpyridinedione compound crystal form C shown in formula (I), wherein the X-ray diffraction pattern of the crystal form C has characteristic peaks at 6.03°, 14.45°, 16.31°, 17.44°, 18.16°, 21.02°, 24.40°, 24.98°, 26.48°, and 27.84°, expressed in terms of 2θ angle, with an error of ±0.2°.

[0017] In a fourth aspect, the present application also provides a terpyridinedione compound crystal form D shown in formula (I), wherein the X-ray diffraction pattern of the crystal form D has characteristic peaks at 4.15° and 18.37° expressed in 2θ angles, with an error of ±0.2°.

[0018] In a fifth aspect, the present application also provides a terpyridinedione compound crystal form E shown in formula (I), wherein the X-ray diffraction pattern of the crystal form E has characteristic peaks at 9.22°, 10.72°, 12.58°, 14.72°, 16.14°, 16.78°, 17.40°, 18.45°, 19.73°, 20.16°, 20.73°, 21.33°, 23.21°, 24.98°, 25.25°, and 27.82°, expressed in terms of 2θ angle, with an error of ±0.2°.

[0019] In a sixth aspect, the present application also provides a terpyridinedione compound crystal form F shown in formula (I), wherein the X-ray diffraction pattern of the crystal form F has characteristic peaks at 12.75°, 15.13°, 15.37°, 16.01°, 16.21°, 17.35°, 18.44°, and 19.30° in terms of 2θ angle, with an error of ±0.2°.

[0020] Furthermore, the X-ray diffraction pattern of the crystal form F shows characteristic peaks at 5.03°, 5.34°, 6.85°, 10.05°, 10.86°, 12.95°, 13.52°, 14.26°, 18.20°, 20.17°, 22.01°, 22.73°, 23.61°, 24.82°, 25.55°, 26.05°, 26.32°, and 28.09°, with an error of ±0.2°.

[0021] Furthermore, the X-ray diffraction pattern of the crystal form F also has characteristic peaks at 3.80°, 10.64°, 13.72°, 16.95°, 21.29°, 22.30°, 27.21°, and 30.13°, expressed in 2θ angles, with an error of ±0.2°.

[0022] Furthermore, the differential thermal analysis spectrum of the crystal form F has a characteristic absorption peak at 129.4°C with an error of ±5°C, as shown in Figure 17.

[0023] In the seventh aspect, the present application also provides a terpyridinedione compound crystal form G of formula (I), wherein the X-ray diffraction pattern of the crystal form G has characteristic peaks at 5.06°, 6.46°, 9.24°, 10.07°, and 15.09° expressed in 2θ angles, with an error of ±0.2°.

[0024] In an eighth aspect, the present application also provides a terpyridinedione compound crystal form H shown in formula (I), wherein the X-ray diffraction pattern of the crystal form H has characteristic peaks at 4.69°, 6.52°, 10.13°, 14.97°, 15.91°, 16.94°, 18.41°, 19.17°, 19.99°, 21.27°, and 22.49°, expressed in terms of 2θ angle, with an error of ±0.2°.

[0025] In the ninth aspect, the present application also provides a terpyridinedione compound crystal form I shown in formula (I), wherein the X-ray diffraction pattern of the crystal form I has characteristic peaks at 9.47°, 13.46°, 15.07°, 17.91°, 19.19°, 21.33°, and 25.39° expressed in 2θ angles, with an error of ±0.2°.

[0026] In the tenth aspect, the present application also provides a terpyridinedione compound crystal form J shown in formula (I), wherein the X-ray diffraction pattern of the crystal form J has characteristic peaks at 5.18°, 10.25°, 12.93°, 13.51°, 14.53°, 15.24°, 16.55°, 17.52°, 18.45°, 19.38°, 24.83°, 25.72°, and 28.01°, expressed in 2θ angles, with an error of ±0.2°.

[0027] In the eleventh aspect, the present application also provides a terpyridinedione compound crystal form K shown in formula (I), wherein the X-ray diffraction pattern of the crystal form K has characteristic peaks at 15.28°, 17.75°, 19.54°, 19.93°, 20.80°, and 22.34° in terms of 2θ angle, with an error of ±0.2°.

[0028] Furthermore, in the X-ray diffraction pattern of the crystal form K, there are characteristic peaks at 5.00°, 7.49°, 11.40°, 12.80°, 14.02°, 15.56°, 16.43°, 16.84°, 17.07°, 18.10°, 18.70°, 18.90°, 21.29°, 22.65°, 23.70°, 23.87°, 24.36°, 24.59°, 25.04°, 25.76°, 26.48°, 27.29°, 27.84°, 28.27°, 29.47°, 30.05°, and 31.30°, with an error of ±0.2°.

[0029] Furthermore, in the X-ray diffraction pattern of the crystal form K, there are characteristic peaks at 9.12°, 9.86°, 12.15°, 13.20°, 14.72°, 18.47°, 22.90°, 30.52°, 30.89°, 32.66°, 33.53°, 34.18°, 35.55°, 35.92°, 36.14°, 36.51°, 37.38°, 38.12°, 38.49°, 38.94°, 40.18°, 42.49°, and 42.92°, expressed in terms of 2θ angle, with an error of ±0.2°.

[0030] In the twelfth aspect, the present application also provides a terpyridinedione compound crystal form L shown in formula (I), wherein the X-ray diffraction pattern of the crystal form L has characteristic peaks at 16.62°, 17.56°, and 21.60° expressed in 2θ angles, with an error of ±0.2°.

[0031] In a thirteenth aspect, the present application also provides a terpyridinedione compound crystal form M shown in formula (I), wherein the X-ray diffraction pattern of the crystal form M has characteristic peaks at 6.42°, 9.24°, 10.06°, 13.55°, 13.71°, 15.05°, 15.67°, 16.49°, 17.52°, 18.06°, 18.51°, 19.13°, 20.08°, 21.25°, 22.53°, 24.42°, 25.31°, and 25.58°, expressed in terms of 2θ angle, with an error of ±0.2°.

[0032] In the fourteenth aspect, the present application also provides a terpyridinedione compound crystal form N shown in formula (I), wherein the X-ray diffraction pattern of the crystal form N has characteristic peaks at 16.49° and 17.46° expressed in 2θ angles, with an error of ±0.2°.

[0033] Furthermore, the X-ray diffraction pattern of the crystal form N also has characteristic peaks at 7.88°, 8.71°, 13.13°, 18.63°, 19.58°, 19.93°, 21.48°, and 22.96°, expressed in 2θ angles, with an error of ±0.2°.

[0034] Furthermore, in the X-ray diffraction pattern of the crystal form N, there are characteristic peaks at 11.45°, 14.10°, 15.19°, 15.34°, 17.97°, 20.78°, 22.55°, 23.27°, 23.91°, 24.42°, 24.96°, 25.29°, 26.32°, 27.18°, 28.44°, 28.81°, 29.12°, 29.47°, 30.72°, and 34.27°, expressed in terms of 2θ angle, with an error of ±0.2°.

[0035] In the fifteenth aspect, the present application also provides a terpyridinedione compound crystal form O shown in formula (I), wherein the X-ray diffraction pattern of the crystal form O has characteristic peaks at 5.22°, 14.68°, 16.66°, 18.61°, 19.15°, 19.83°, and 23.41° as expressed in 2θ angles, with an error of ±0.2°.

[0036] The present application further provides a pharmaceutical composition comprising a therapeutically effective amount of any of the above-mentioned crystalline forms and one or more pharmaceutically acceptable carriers.

[0037] The present application further provides the use of the crystal form in the preparation of a drug for treating a disease, wherein the disease is a p38 / MK2-related disease, specifically selected from chronic inflammatory diseases and acute inflammatory diseases, wherein the chronic inflammatory disease is preferably rheumatoid arthritis.

[0038] The terpyridinedione compound crystal form represented by formula (I) of the present application has good stability and good purity and is suitable for pharmaceutical applications.

[0039] For the sake of clarity, general terms used in the description of the compounds are defined herein.

[0040] The term "pharmaceutically acceptable carrier" refers to any formulation carrier or medium that can deliver an effective amount of the active substance of the present invention, does not interfere with the biological activity of the active substance, and has no toxic side effects on the host or patient. Representative carriers include water, oils, vegetables and minerals, cream bases, lotion bases, ointment bases, etc. These bases include suspending agents, viscosity increasing agents, transdermal enhancers, etc. Their preparations are well known to those skilled in the art of cosmetics or topical medicine. For additional information about carriers, reference can be made to Remington: The Science and Practice of Pharmacy, 21st Ed., Lippincott, Williams & Wilkins (2005), the contents of which are incorporated herein by reference.

[0041] With respect to a drug or pharmacologically active agent, the term "effective amount" or "therapeutically effective amount" refers to a non-toxic amount of the drug or agent sufficient to achieve the intended effect. For the oral dosage forms of the present invention, an "effective amount" of an active substance in the composition means the amount required to achieve the intended effect when used in combination with another active substance in the composition. The determination of an effective amount varies from person to person, depending on the age and general condition of the recipient, as well as the specific active substance. The appropriate effective amount in each individual case can be determined by those skilled in the art through routine experimentation.

[0042] The compounds of the present application can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthesis methods, and equivalent replacement methods well known to those skilled in the art. Preferred embodiments include but are not limited to the examples of the present invention. BRIEF DESCRIPTION OF THE DRAWINGS

[0043] FIG1 is a schematic diagram of the crystal structure of a single molecule of compound 1A.

[0044] FIG2 is a crystal parameter diagram of the crystal structure of compound 1A.

[0045] FIG3 shows the atomic coordinates and isotropic displacement parameters of the crystal structure of compound 1A.

[0046] FIG4 is a diagram showing bond length parameters of the crystal structure of compound 1A.

[0047] FIG5 is a bond angle parameter diagram of the crystal structure of compound 1A.

[0048] FIG6 is a diagram showing dihedral parameters of the crystal structure of compound 1A.

[0049] FIG7 is the X-ray diffraction pattern of the first characterization of Form A.

[0050] FIG8 is an X-ray diffraction pattern of the second characterization of Form A.

[0051] FIG9 is an X-ray diffraction pattern of Form B.

[0052] FIG10 is an X-ray diffraction pattern of Form C.

[0053] FIG11 is the thermogravimetric analysis and differential thermal analysis spectra of Form C.

[0054] FIG12 is an X-ray diffraction pattern of Form D.

[0055] FIG13 is the thermogravimetric analysis and differential thermal analysis spectra of Form D.

[0056] FIG14 is an X-ray diffraction pattern of Form E.

[0057] FIG15 is the thermogravimetric analysis and differential thermal analysis spectra of Form E.

[0058] FIG16 is an X-ray diffraction pattern of Form F prepared in one embodiment.

[0059] FIG17 is the thermogravimetric analysis and differential thermal analysis spectra of Form F.

[0060] FIG18 is an X-ray diffraction pattern of Form F prepared in another example.

[0061] FIG19 is an X-ray diffraction pattern of Form G.

[0062] FIG20 is an X-ray diffraction pattern of Form H.

[0063] FIG21 is the thermogravimetric analysis and differential thermal analysis spectra of Form H.

[0064] FIG2 is an X-ray diffraction pattern of Form I.

[0065] Figure 23 is the thermogravimetric analysis and differential thermal analysis spectra of Form I.

[0066] FIG24 is an X-ray diffraction pattern of Form J.

[0067] FIG25 is an X-ray diffraction pattern of the first characterization of Form K.

[0068] FIG26 is an X-ray diffraction pattern of the second characterization of Form K.

[0069] FIG27 is an X-ray diffraction pattern of Form L.

[0070] FIG28 is an X-ray diffraction pattern of Form M.

[0071] FIG29 is the thermogravimetric analysis and differential thermal analysis spectra of Form M.

[0072] Figure 30 is the X-ray diffraction pattern of the first characterization of Form N. Figure 31 is the thermogravimetric analysis and differential thermal analysis patterns of Form N.

[0073] FIG32 is an X-ray diffraction pattern of the second characterization of Form N.

[0074] FIG33 is an X-ray diffraction pattern of Form O. DETAILED DESCRIPTION

[0075] The present application is further described in detail below with reference to examples, but the implementation methods of the present application are not limited thereto.

[0076] Example 1

[0077] The synthetic route of compound No. 1 is as follows:

[0078] Step A: Synthesis of 2-(bromomethyl)-3,5-difluoropyridine.

[0079] At 0°C, triphenylphosphine (PPh3, 813.5 mg, 3.11 mmol) and carbon tetrabromide (CBr4, 823.8 mg, 2.48 mmol) were added sequentially to tetrahydrofuran (THF, 5.0 ml) containing (3,5-difluoro-2-pyridine)methanol (300.0 mg, 2.07 mmol) and reacted at room temperature (rt) for 1 hour.

[0080] After the reaction was complete, the product was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 10 / 1). 372.4 mg of 2-(bromomethyl)-3,5-difluoropyridine was obtained as a colorless oil (yield: 86.5%). LC-MS: RT = 1.89 min, [M+H] + =208.01.

[0081] Step B: Synthesis of 3″-chloro-4″-((3,5-difluoropyridin-2-yl)methoxy)-3-(2-hydroxypropan-2-yl)-5′,6″-dimethyl-2H,2″H-[1,2′:4′,1″-terpyridine]-2,2″-dione.

[0082] At room temperature, 2-(bromomethyl)-3,5-difluoropyridine (37.4 mg, 0.18 mmol) and potassium carbonate (K2CO3, 33.12 mg, 0.24 mmol) were added to N,N-dimethylformamide (DMF, 2.0 ml) containing 3"-chloro-4"-hydroxy-3-(2-hydroxypropan-2-yl)-5',6"-dimethyl-2H,2"H-[1,2':4',1"-terpyridine]-2,2"-dione (50.0 mg, 0.12 mmol) and the reaction was carried out at room temperature for 2 hours.

[0083] After the reaction was complete, the mixture was quenched with water and extracted with ethyl acetate (20 ml x 3 times). The organic phases were combined, washed with saturated brine (20 ml x 2 times), dried over anhydrous sodium sulfate, and concentrated. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1 / 0). 28.0 mg of 3"-chloro-4"-((3,5-difluoropyridin-2-yl)methoxy)-3-(2-hydroxypropan-2-yl)-5',6"-dimethyl-2H,2"H-[1,2':4',1"-terpyridine]-2,2"-dione was obtained as a white solid (yield: 53.7%).

[0084] LC-MS: RT = 1.86 min, [M+H] + =529.22. 1H NMR (400MHz, DMSO) δ8.68(s,1H),8.60(d,J=2.3Hz,1H),8.13–8.05(m,1H),7.85(dd,J=6.9,2.1Hz,1H),7.78(s,1H),7.69(dd,J=7.0 ,2.1Hz,1H),6.79(s,1H),6.42(t,J=7.0Hz,1H),5.47(d,J=1.6Hz,2H),5.22(s,1H),2.07(s,3H),2.00(s,3H),1.47(s,3H),1.46(s, 3H).

[0085] The racemic Example 1 compound was separated using supercritical fluid chromatography (AS-H column) with a mobile phase of carbon dioxide and isopropanol, eluting the atropisomers Example 1A compound (amorphous) and 1B compound (amorphous) in sequence:

[0086] Compound of Example 1A: RT = 4.21 min (SFC, AS-H, 0.46 cm ID x 15 cm L column, 30% isopropanol isocratic method, flow rate 2.5 mL / min and cycle time 10 min); [a] D 25＝ –1.68° (MeOH, Rudolph Autopol I rotator); 1 H NMR (400MHz, DMSO) δ8.68(s,1H),8.59(d,J=2.3Hz,1H),8.11–8.05(m,1H),7.85(dd,J=6.9,2.0Hz,1H),7.79(s,1H),7.69(dd,J=7.0,2 .0Hz,1H),6.80(s,1H),6.42(t,J=6.9Hz,1H),5.48(d,J=1.2Hz,2H),5.23(s,1H),2.07(s,3H),2.00(s,3H),1.47(s,3H),1.46(s,3H).

[0087] Example 1B compound: RT = 4.68 min (SFC, AS-H, 0.46 cm ID x 15 cm L column, 30% isopropanol isocratic method, flow rate 2.5 mL / min and cycle time 10 min). [a] D 25 +1.64° (MeOH, Rudolph Autopol I rotator); 1H NMR (500MHz, DMSO) δ8.68(s,1H),8.59(d,J=2.3Hz,1H),8.11–8.06(m,1H),7.85(dd,J=6.9,2.1Hz,1H),7.78(s,1H),7.69(dd,J=7.0,2 .1Hz,1H),6.80(s,1H),6.42(t,J=6.9Hz,1H),5.47(d,J=1.3Hz,2H),5.24(s,1H),2.07(s,3H),2.00(s,3H),1.47(s,3H),1.46(s,3H).

[0088] Comparative Example 1

[0089] The structure of the compound 3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-2'-(2-(2-hydroxypropan-2-yl)pyrimidin-4-yl)-5',6-dimethyl-2H-[1,4'-bipyridyl]-2-one is:

[0090] The synthetic route of the compound of Ratio 1 is shown in the synthetic route of the compound No. 49 in the specification of Chinese Patent No. CN201480032278.5.

[0091] The racemic compound of Comparative Example 1 was separated using supercritical fluid chromatography (OD-H column) with a mobile phase of carbon dioxide and ethanol, and the atropisomers of Comparative Example 1A and 1B were eluted successively:

[0092] Comparative Example 1A compound: RT = 4.47 min (SFC, OD-H, 0.46 cm ID × 15 cm L column, 40% ethanol isocratic method, flow rate 2.5 mL / min and cycle time 10 min); [a] D 25 -0.66° (MeOH, Rudolph Autopol I rotator).

[0093] Compound of Comparative Example 1B: RT = 4.68 min (SFC, OD-H, 0.46 cm ID x 15 cm L column, 40% ethanol isocratic method, flow rate 2.5 mL / min and cycle time 10 min). [a] D 25 +0.68° (MeOH, Rudolph Autopol I rotator).

[0094] Example 2: LPS-induced TNFα release experiment in U937

[0095] Cytokine Regulation in Human Monocytes: The p38 pathway has been shown to be key to the biosynthesis of a variety of proinflammatory cytokines, including TNFα, IL-1β, and IL-6. Therefore, inhibition of the p38 MAPK pathway reduces the inflammatory response by reducing the biosynthesis of proinflammatory cytokines. This study showed that half the amount of the compound of the present invention was required to inhibit the biosynthesis of TNFα (a proinflammatory cytokine). This is a reflection of the effect of the compound of the present invention in helping to reduce inflammation, which is helpful in treating many diseases, including chronic inflammatory conditions, acute inflammatory conditions, and autoinflammatory conditions. The efficacy and effectiveness of p38 inhibitors in blocking cytokine production were evaluated using the human U937 cell line.

[0096] Reagents and instruments:

[0097] 1640 Medium, Catalog No. A10491-01, Gibco. Penicillin-Streptomycin, Catalog No. 15140-122, Gibco. Fetal Bovine Serum, Catalog No. 10099-141C, Gibco. PBS, Catalog No. 10010-031, Gibco. LPS, Catalog No. L2880, Sigma. PMA, Catalog No. P1585, Sigma. Dimethyl Sulfoxide, Catalog No. D8418-1L, Sigma. TNFα Kit, Catalog No. K151QWD-4, MSD.

[0098] 96-well plate, Catalog No. 3599, Corning. Plate shaker, Catalog No. QB-9002, Qilinbeier. Centrifuge, Catalog No. 5810R, Eppendorf. CO2 incubator, Catalog No. 371, Thermo. Counter, Catalog No. C10281, Gibco. Microscope, Catalog No. CKX41, Olympus. MSD plate reader, 1201MESO SECTOR 600, MSD.

[0099] Experimental cells:

[0100] U937, ATCC, catalog number CRL-1593.2.

[0101] Drug preparation:

[0102] Weigh approximately 2 mg of a drug and prepare a 10 mM (based on the free base) stock solution in DMSO. Dilute the stock solution 10-fold to 1 mM, then dilute it 4-fold to 250 μM, 62.5 μM, 15.6 μM, 3.9 μM, 0.97 μM, 0.24 μM, and 0.061 μM. Then, dilute the DMSO solution 20-fold in culture medium to prepare the working solution.

[0103] Experimental methods:

[0104] Day 0: 10,000 cells / well were seeded and stimulated with 20 ng / ml PMA for 48 h, incubated at 37°C in 5% CO2;

[0105] Day 2: 1. Remove the supernatant from the differentiated U937 cells, wash once with PBS, and add 96 μl of 1640 culture medium;

[0106] 2. Add 2 μl of compound containing (final concentration 0.1% DMSO) and incubate at 37°C, 5% CO2 for 30 min;

[0107] 3. Add 2 μl LPS (final concentration 100 ng / ml) to stimulate the cells and incubate at 37°C, 5% CO2 for 4 h;

[0108] 4. Centrifuge, take the supernatant, and determine the TNFα content in the supernatant by ELISA.

[0109] Statistical methods:

[0110] The TNFα content corresponding to each well was calculated using the standard curve in the kit;

[0111] Example: Calculating compound IC using GraphPad nonlinear fitting formula 50 , the experimental results are shown in Table 1.

[0112] Table 1 IC of the compounds of the present invention for inhibiting TNFα production 50 value

[0113] From the experimental results in Table 1 above, it can be seen that the compounds of the present invention have significant inhibitory activity on the production of TNFα and can regulate inflammatory reactions and other related diseases.

[0114] Example 3: Determination of solubility.

[0115] 1. Preparation of control solution

[0116] About 0.5 mg of the sample to be tested was weighed into a centrifuge tube, and an appropriate amount of DMSO was first added to completely dissolve the sample, and then methanol was added to make the volume to 1 ml. The samples to be tested were the compound No. 1 and the compound of Comparative Example 1.

[0117] 2. Preparation of test solution

[0118] Weigh approximately 1.0 mg of each of the compound of Comparative Example 1 and Compound No. 1 into two centrifuge tubes, and add 1 ml of PBS buffer solution (2.0 and 7.4, respectively) to each of the two aliquots. (If more pH values ​​need to be examined, the preparation method can be analogously applied).

[0119] 3. Place the prepared control solution and test solution in a 37°C water bath and heat for 1 hour. After 1 hour, take them out and cool to room temperature. Filter with a 0.22μm filter membrane before sampling.

[0120] 4. Calculate the concentration of the sample in the test solution according to C = (A*(ms / vs)) / AS; the experimental results are shown in Table 2.

[0121] Note: ms, vs, and AS are the weight, volume, and peak area of ​​the sample in the control solution, respectively;

[0122] A is the peak area of ​​the test solution.

[0123] Table 2 shows the solubility of the compounds of the present invention.

[0124] From the experimental results in Table 2, it can be seen that the compounds numbered 1, 2, 3 and 20 of the present application have good solubility, and are better than the solubility of the compound in Comparative Example 1.

[0125] Example 4: p38α / MK2 complex kinase screening experiment

[0126] Table 3 Reagents:

[0127] Table 4 Instruments:

[0128] Drug preparation:

[0129] Weigh a specific amount of drug and prepare a 10 mM stock solution in DMSO. Dilute the stock solution to 100 μM (100X working solution) in two steps. Then dilute the solution three-fold to 33.33 μM, 11.11 μM, 3.70 μM, 1.23 μM, 0.41 μM, 0.14 μM, 0.046 μM, 0.015 μM, and 0.005 μM. A DMSO control was also established.

[0130] The above series of DMSO diluted drugs were then diluted 25 times with 1X IMAP Reaction Buffer to prepare 4X drug working solutions.

[0131] Experimental methods:

[0132] a) Prepare enzymes (MEK6 (active), p38α (inactive), MK2 (inactive), substrate (HSP27), and ATP in 1X IMAP Reaction Buffer.

[0133] b) To a black 384-well plate, add 10 μL of 2X enzyme & substrate working solution and 5 μL of 4X drug working solution, sequentially. After rapid centrifugation, add 5 μL of ATP working solution to initiate the enzyme reaction. Set up a 10-well gradient for each compound, with duplicate wells. Also include a DMSO control group and a negative control group (DMSO, no ATP). The final concentrations of each component are shown in Table 5 below:

[0134] Table 5

[0135] c) After incubation at room temperature for 1 hour, 1X Progressive Binding Solution was added to terminate the enzyme reaction. After incubation for 30 minutes, the fluorescence polarization (FP) signal [FP (Ex485 / Em520 / Em520 nm)] was detected using a BMG PHERASTER FSX multifunctional microplate reader.

[0136] Statistical methods:

[0137] Compound IC was calculated using the nonlinear fitting formula in GraphPad Prism 7. 50 , the results are shown in Table 6.

[0138] Table 6: IC inhibition of the compounds of the present invention on p38α / MK2 complex 50 value

[0139] From the experimental results in Table 6 above, it can be seen that the compounds of the present invention have significant inhibitory activity against the p38α / MK2 complex and can regulate inflammatory responses and other related diseases.

[0140] Example 5: p38α kinase screening experiment

[0141] Table 7 Reagents:

[0142] Table 8 Instruments:

[0143] Drug preparation:

[0144] Weigh a certain compound, prepare it into a 10 / 50 mM stock solution with DMSO, dilute it 3 times with DMSO, and dilute it to 10 concentration points as the compound working solution.

[0145] Experimental methods:

[0146] Using an Echo 655, 50 nL of the diluted compound working solution was transferred to each well of a reaction plate (784075, Greiner). Then, 2.5 μL (4 ng / μL) of p38α kinase solution was added. After incubation at room temperature for 10 minutes, 2.5 μL of a mixture of kinase substrate (0.2 mg / mL) and ATP (150 μM) was added. After incubation at room temperature for 60 minutes, 4 μL of ADP Glo reagent was added and incubated at room temperature for 40 minutes. 8 μL of kinase detection reagent was added and incubated at room temperature for 40 minutes. Finally, the luminescence signal was read on an Envision 2104.

[0147] Data Analysis

[0148] Compound IC was calculated using the nonlinear fitting formula in GraphPad Prism 8. 50 , the test results are shown in Table 9.

[0149] Table 9: IC inhibition of p38α by the compounds of the present invention 50 value

[0150] It can be seen from the experimental results in Table 9 above that, compared with the prior art, the compound of the present invention has a higher activity multiple relative to p38α / (p38α / MK2 complex) and has better selectivity.

[0151] Note: The data of p38α / MK2 complex kinase are from Example 4.

[0152] Instruments used for crystal characterization analysis

[0153] The XRD patterns and data of Form F were obtained by X-ray diffraction (XRD) spectra using a PANalytical Empyrean X-ray diffractometer. The detection conditions were Cu-Kα radiation, wavelength The divergence slit was 1 / 4°, the X-ray tube voltage was 45 kV, the X-ray tube current was 40 mA, the scanning range was 3-40° (2θ), the step size was 0.0262606°, and the dwell time per step was 33.915 s.

[0154] The spectra and data for other crystal forms were obtained using a Bruker D8 Advance X-ray powder diffractometer (Bruker, Germany). Scan angles ranged from 3° to 45°, with a scan step size of 0.02° and an exposure time of 0.12 seconds. The tube voltage and current for the samples were 40 kV and 40 mA, respectively, and the sample pan was a zero-background sample pan.

[0155] Thermogravimetric Analyzer (TGA): Model TA Discovery 550 (TA, US). 2-5 mg of sample was placed in an aluminum sample pan, and 2-5 mg of sample was placed in a equilibrated open aluminum sample pan and automatically weighed in the TGA furnace. The sample was heated to the final temperature at a rate of 10°C / min. Nitrogen purge rates were 60 mL / min at the sample and 40 mL / min at the balance.

[0156] Differential Scanning Calorimetry (DSC): Model: TA Discovery 250 (TA, US). 1-2 mg of sample was accurately weighed and placed in a perforated DSC Tzero sample pan and heated to the final temperature at a rate of 10°C / min. The nitrogen purge rate in the furnace was 50 mL / min.

[0157] High performance liquid chromatography (HPLC): model: ACQUITY ARC-2489 (Waters, US).

[0158] Unless otherwise specified, the error of Pos.[°2θ] of the crystal form of the present invention is ±0.2°.

[0159] Example 6 Preparation and Characterization of Form A

[0160] 6.1 Preparation of Form A Take 1.0036 g of compound 1A, add 20.0 mL of ethanol / n-heptane (1 / 9, v / v) to form a suspension, suspend and stir at 50°C for 1 day, and vacuum dry the obtained solid at 40°C overnight to obtain 0.9405 g of Form A (yield: 93.7%). The schematic diagram of the crystal structure of a single molecule is shown in Figure 1, the crystal parameter diagram of the crystal structure is shown in Figure 2, the atomic coordinates and isotropic displacement parameter diagram of the crystal structure is shown in Figure 3, the bond length parameter diagram of the crystal structure is shown in Figure 4, the bond angle parameter diagram of the crystal structure is shown in Figure 5, and the dihedral angle parameter diagram of the crystal structure is shown in Figure 6. 6.2 Characterization of Form A

[0161] The crystal form A prepared in 6.1 above was used for XRD characterization, and the specific characterization results are shown in Figure 7. Among them, the main characteristic absorption peaks of crystal form A are shown in Table 10:

[0162] Table 10 is the XRD data of Form A

[0163] Form A was prepared using the method of Preparation Example 1 in 6.1, and Form A was again subjected to XRD characterization. The specific characterization results are shown in Figure 8. The comparison of the XRD characterization results of Form A from the two times is shown in Table 11, with an error of ±0.2°.

[0164] Table 11 is the XRD data of Form A characterized twice

[0165] Wherein, No. = serial number, Rel.Int = Relative Intensity only indicates the approximate intensity of the characteristic peak intensity and should not be used as a limitation of the specific crystal form A.

[0166] As shown in Table 10 and Figure 7, expressed in terms of 2θ angle, Form A has the strongest characteristic absorption peak at 20.41°, with a relative absorption intensity of 100%.

[0167] Furthermore, Form A also has characteristic peaks at 5.00°, 7.70°, 12.82°, 14.08°, 15.44°, 16.72°, 17.17°, 19.70°, 20.88°, 23.08°, 23.78°, and 26.83°, with relative absorption intensity greater than 50%.

[0168] Furthermore, Form A also has the following peaks: 9.24°, 11.40°, 11.63°, 12.23°, 13.85°, 14.80°, 15.71°, 15.96°, 17.75°, 17.93°, 18.20°, 18.67°, 18.94°, 21.15°, 21.48°, 22.51°, 22.71°, 22.44°, There are characteristic peaks at 24.65°, 25.20°, 25.66°, 25.84°, 26.60°, 27.47°, 27.74°, 27.92°, 28.81°, 29.57°, 30.27°, 30.72°, 31.38°, 32.11°, 32.70°, 33.57°, and 36.70°, and the relative absorption intensity is greater than 20%.

[0169] Furthermore, Form A also has characteristic peaks at 9.88° and 13.30°, with relative absorption intensities greater than 10%. This allows for more detailed identification of other substances as representing this crystal form. Other weak absorption peaks may vary significantly due to experimental errors, and those skilled in the art consider these peaks unnecessary for characterizing this crystal form.

[0170] Example 7: Preparation and Characterization of Form B

[0171] 7.1 Preparation of Form B

[0172] 19.1 mg of compound 1A was weighed, 0.9 mL of ethyl acetate / n-heptane (1 / 2, v / v) was added, and the mixture was suspended and stirred at low temperature (-20°C) for a certain period of time. The suspension was centrifuged and dried in vacuo at 40°C to obtain Form B.

[0173] 7.2 Characterization of Form B

[0174] The crystal form B prepared in 7.1 above was subjected to XRD characterization, and the relevant characterization results are shown in Figure 9. Among them, the main characteristic absorption peaks of crystal form B are shown in Table 12:

[0175] Table 12 is the XRD data of Form B

[0176] Wherein, No. = serial number, Rel.Int = Relative Intensity only indicates the approximate intensity of the characteristic peak intensity and should not be used as a limitation of the specific crystal form B.

[0177] As shown in Table 12 and Figure 9, expressed in terms of 2θ angle, Form B has the strongest characteristic absorption peak at 5.97°, with a relative absorption intensity of 100%.

[0178] Furthermore, Form B also has characteristic peaks at 7.80°, 9.26°, 11.57°, 14.41°, 15.17°, 17.93°, 18.12°, 19.64°, 20.10°, 22.88°, and 23.50°, with relative absorption intensity greater than 50%.

[0179] Further, Form B also has characteristic peaks at 6.73 °, 10.07 °, 11.12 °, 12.64 °, 13.44 °, 14.21 °, 15.63 °, 15.96 °, 16.74 °, 17.19 °, 17.42 °, 18.55 °, 19.29 °, 20.69 °, 21.52 °, 22.59 °, 24.59 °, 25.27 °, 25.66 °, 26.07 °, 27.22 °, 28.64 °, 29.41 °, and 31.26 °, and relative absorption intensity is greater than 20%. Other substances can be distinguished in more detail to represent this crystal form. And other weak absorption peaks may vary significantly due to experimental operation error, and for those skilled in the art, other absorption peaks are all absorption peaks that can be considered unnecessary when characterizing this crystal form.

[0180] Example 8: Preparation and Characterization of Form C

[0181] 8.1 Preparation of Form C

[0182] 100 mg of compound 1A was weighed, 1 mL of isopropyl ether was added, and the mixture was suspended and stirred at room temperature for a certain period of time. The suspension was centrifuged and dried in vacuo at 40° C. to obtain Form C.

[0183] 8.2 Characterization of Form C

[0184] The crystal form C prepared in 8.1 was subjected to XRD, TGA and DSC characterization, and the relevant characterization results are shown in Figures 10 and 11. Among them, the main characteristic absorption peaks of crystal form C are shown in Table 13:

[0185] Table 13 is the XRD data of Form C

[0186] Wherein, No. = serial number, Rel.Int = Relative Intensity only indicates the approximate intensity of the characteristic peak intensity and should not be used as a limitation of the specific crystal form C.

[0187] As shown in Table 13 and Figure 10, expressed in 2θ angle, Form C has the strongest characteristic absorption peak at 17.44°, with a relative absorption intensity of 100%.

[0188] Furthermore, Form C also has characteristic peaks at 6.03°, 14.45°, 16.31°, 18.16°, 21.02°, 24.40°, 24.98°, 26.48°, and 27.84°, with relative absorption intensity greater than 50%.

[0189] Further, Form C also has characteristic peaks at 9.28 °, 10.46 °, 12.37 °, 12.95 °, 13.61 °, 15.32 °, 18.86 °, 22.01 °, 22.77 °, 23.41 °, 25.60 °, 26.98 °, 29.08 °, 30.58 °, 31.71 °, and 32.72 °, with a relative absorption intensity greater than 20%. Other substances can be distinguished in more detail to represent this crystal form. Other weak absorption peaks may vary significantly due to experimental operation errors, and for those skilled in the art, other absorption peaks are all absorption peaks that can be considered unnecessary when characterizing this crystal form.

[0190] Example 9: Preparation and Characterization of Form D

[0191] 9.1 Preparation of Form D

[0192] 100 mg of compound 1A was weighed, 1 mL of methyl tert-butyl ether was added, and the mixture was suspended and stirred at room temperature for a certain period of time. The suspension was centrifuged and dried in vacuo at 40° C. to obtain Form D.

[0193] 9.2 Characterization of Form D

[0194] The crystal form D prepared in 9.1 above was subjected to XRD, TGA and DSC characterization, and the relevant characterization results are shown in Figures 12 and 13. Among them, the main characteristic absorption peaks of crystal form D are shown in Table 14:

[0195] Table 14 XRD data of Form D

[0196] Wherein, No. = serial number, Rel.Int = Relative Intensity only indicates the approximate intensity of the characteristic peak intensity and should not be used as a limitation of the specific crystal form D.

[0197] As shown in Table 14 and Figure 12, expressed in 2θ angle, Form D has the strongest characteristic absorption peak at 18.37°, with a relative absorption intensity of 100%.

[0198] Furthermore, Form D also has a characteristic peak at 4.15°, and the relative absorption intensity is greater than 50%.

[0199] Furthermore, Form D also has characteristic peaks at 7.12°, 9.18°, 10.46°, 12.31°, 12.62°, 13.05°, 14.31°, 15.17°, 15.52°, 15.89°, 16.86°, 19.68°, 20.74°, 21.09°, 22.14°, 24.46°, 24.90°, and 25.58°, and the relative absorption intensity is greater than 20%.

[0200] Further, Form D also has characteristic peaks at 13.51°, 14.70°, 16.53°, 17.29°, 26.69°, 27.45°, 28.19°, 28.91°, 30.05°, 30.58°, 30.81°, 32.43°, and 33.55°, with a relative absorption intensity greater than 10%. Other substances can be distinguished in more detail to represent this crystal form. Other weak absorption peaks may vary significantly due to experimental operation errors, and for those skilled in the art, other absorption peaks are all absorption peaks that can be considered unnecessary when characterizing this crystal form.

[0201] Example 10: Preparation and Characterization of Form E

[0202] 10.1 Preparation of Form E

[0203] 100 mg of compound 1A was weighed, 1 mL of isopropyl acetate was added, and the mixture was suspended and stirred at room temperature for a certain period of time. The suspension was centrifuged and dried in vacuo at 40° C. to obtain Form E.

[0204] 10.2 Characterization of Form E

[0205] The crystal form E prepared in 10.1 above was subjected to XRD, TGA, and DSC characterization. The relevant characterization results are shown in Figures 14 and 15. Among them, the main characteristic absorption peaks of crystal form E are shown in Table 15:

[0206] Table 15 is the XRD data of Form E

[0207] Wherein, No. = serial number, Rel.Int = Relative Intensity only indicates the approximate intensity of the characteristic peak intensity and should not be used as a limitation of the specific crystal form E.

[0208] As shown in Table 15 and Figure 14, expressed in 2θ angle, Form E has the strongest characteristic absorption peak at 17.40°, with a relative absorption intensity of 100%.

[0209] Furthermore, Form E also has characteristic peaks at 9.22°, 10.72°, 12.58°, 14.72°, 16.14°, 16.78°, 18.45°, 19.73°, 20.16°, 20.73°, 21.33°, 23.21°, 24.98°, 25.25°, and 27.82°, with a relative absorption intensity greater than 20%.

[0210] Further, Form E also has characteristic peaks at 8.44°, 13.24°, 15.21°, 18.00°, 19.02°, 22.36°, 23.58°, 24.22°, 26.19°, 26.60°, 27.29°, 29.34°, 30.05°, 31.90°, 32.41°, 34.12°, and 40.18°, with a relative absorption intensity greater than 10%. Other substances can be distinguished in more detail to represent this crystal form. Other weak absorption peaks may vary significantly due to experimental operation errors, and for those skilled in the art, other absorption peaks are all absorption peaks that can be considered unnecessary when characterizing this crystal form.

[0211] Example 11: Preparation and Characterization of Form F

[0212] 11.1 Preparation Example 1 of Form F

[0213] Weigh 100 mg of compound 1A, add 1 mL of dichloromethane, and suspend and stir at room temperature for a period of time to dissolve. Add 4 mL of n-heptane and stir to precipitate a solid. The suspension is centrifuged and dried in vacuo at 40°C to obtain Form F.

[0214] The X-ray diffraction pattern of the obtained Form F is shown in FIG16 , and the specific characteristic absorption peaks are: 3.80°, 5.03°, 5.34°, 6.85°, 10.05°, 10.64°, 10.86°, 12.75°, 12.95°, 13.52°, 13.72°, 14.26°, 15.13°, 15.37°, 16.01°, 16.21°, 1 There are characteristic peaks at 6.95°, 17.35°, 18.20°, 18.44°, 19.30°, 20.17°, 21.29°, 22.01°, 22.30°, 22.73°, 23.61°, 24.82°, 25.55°, 26.05°, 26.32°, 27.21°, 28.09°, and 30.13°, with an error of ±0.2°.

[0215] The TGA and DSC characterizations of the obtained crystal form F are shown in FIG17 , wherein DSC has a characteristic absorption peak at 129.4° C. with an error of ±5° C.

[0216] 11.2 Preparation Example 2 of Form F

[0217] Weigh the crude product of compound 1A (X kg), start stirring, add activated carbon (0.1X kg), protect from light, heat to 50-60°C, stir and decolorize for about 30 minutes, filter while hot, and rinse with ethyl acetate. The mother liquor is concentrated under reduced pressure at 40-50°C until no obvious effluent is observed. Protect from light, add ethanol (3.2X kg), stir and dissolve, cool to 20-30°C, and stir until a large amount of solid precipitates (if no precipitation occurs after more than 4 hours, add a small amount of seed crystals). Slowly add n-heptane (8.2X kg). After addition, stir and grow the crystals for 2-3 hours, centrifuge, and rinse with n-heptane. The wet product is dried in vacuum at 45-55°C in water to obtain Form F as a white solid.

[0218] The X-ray diffraction pattern of the obtained Form F is shown in FIG18 , and the specific characteristic absorption peaks are: 3.79°, 5.01°, 5.32°, 6.83°, 10.02°, 10.64°, 10.84°, 12.73°, 12.95°, 13.51°, 13.73°, 14.21°, 15.11°, 15.35°, 15.97°, 16.19°, 1 There are characteristic peaks at 6.94°, 17.34°, 18.12°, 18.41°, 19.27°, 20.13°, 21.27°, 21.96°, 22.25°, 22.70°, 23.60°, 24.81°, 25.51°, 26.04°, 26.28°, 27.17°, 28.00°, and 30.07°, with an error of ±0.2°.

[0219] Among them, the comparison of the main absorption peaks in Figures 16 and 18 is shown in Table 16 below, with an error of ±0.2°.

[0220] Table 16 is the XRD data of Form F

[0221] Wherein, No. = serial number, Rel.Int. = Relative Intensity, and the error is ±0.2°. Rel.Int. = Relative Intensity only indicates the approximate intensity of the characteristic peak and should not be used as a limitation on the specific crystal form F.

[0222] Summary: According to the XRD spectra in Figures 16 and 18 and the XRD characteristic peak data in Table 15, the strongest characteristic absorption peak is expressed in 2θ angle at 17.35°, with an error of ±0.2° and a relative absorption intensity of 100%.

[0223] Furthermore, the crystalline form F also has characteristic peaks at 12.75°, 15.13°, 15.37°, 16.01°, 16.21°, 18.44°, and 19.30°, with an error of ±0.2° and a relative absorption intensity greater than 50%;

[0224] Further, the crystal form F has characteristic peaks at 5.03°, 5.34°, 6.85°, 10.05°, 10.86°, 12.95°, 13.52°, 14.26°, 18.20°, 20.17°, 22.01°, 22.73°, 23.61°, 24.82°, 25.55°, 26.05°, 26.32°, and 28.09°, with an error of ±0.2° and a relative absorption intensity greater than 20%;

[0225] Furthermore, the crystal form F also has characteristic peaks at 3.80°, 10.64°, 13.72°, 16.95°, 21.29°, 22.30°, 27.21°, and 30.13°, with an error of ±0.2° and a relative absorption intensity greater than 10%, which can more accurately distinguish other substances as representing this crystal form. Other weak absorption peaks may vary significantly due to experimental operation errors. For those skilled in the art, these other absorption peaks are considered unnecessary absorption peaks when characterizing this crystal form.

[0226] Example 12: Preparation and Characterization of Form G

[0227] 12.1 Preparation of Form G

[0228] Weigh 100 mg of compound 1A, add 1 mL of ethyl acetate, and suspend and stir at room temperature for a period of time to dissolve. Add 4 mL of n-heptane and stir to precipitate a solid. The suspension is centrifuged and dried in vacuo at 40°C to obtain Form G.

[0229] 12.2 Characterization of Form G

[0230] The crystal form G prepared in 12.2 was subjected to XRD characterization, and the relevant characterization results are shown in Figure 19. Among them, the main characteristic absorption peaks of crystal form G are shown in Table 17:

[0231] Table 17 is the XRD data of Form G

[0232] Wherein, No. = serial number, Rel.Int. = Relative Intensity only indicates the approximate intensity of the characteristic peak intensity and should not be used as a limitation of the specific crystal form G.

[0233] As shown in FIG19 and Table 17, expressed in terms of 2θ angle, Form G has the strongest characteristic absorption peak at 10.07°, with a relative absorption intensity of 100%.

[0234] Furthermore, the crystalline form G also has characteristic peaks at 5.06°, 6.46°, 9.24°, and 15.09°, with relative absorption intensity greater than 50%;

[0235] Furthermore, the crystalline form G also has characteristic peaks at 8.25°, 10.29°, 11.32°, 12.39°, 17.69°, 18.02°, 18.51°, 19.33°, 20.14°, 21.08°, 21.33°, 22.53°, 22.88°, 25.80°, and 29.34°, with a relative absorption intensity greater than 20%;

[0236] Further, the crystalline form G also has characteristic peaks at 12.82°, 13.61°, 14.20°, 14.62°, 15.79°, 16.29°, 16.57°, 20.59°, 21.78°, 23.21°, 23.66°, 24.24°, 24.85°, 27.70°, 30.37°, and 31.51°, with a relative absorption intensity greater than 10%, which can distinguish other substances from representing the present crystalline form in more detail. Other weak absorption peaks may vary significantly due to experimental operation errors. For those skilled in the art, other absorption peaks are all absorption peaks that can be considered unnecessary when characterizing the present crystalline form.

[0237] Example 13: Preparation and Characterization of Form H

[0238] 13.1 Characterization of Form H

[0239] 50 mg of Form G was placed in a vacuum drying oven and vacuum dried at 50°C for 1 day to obtain Form H.

[0240] 13.2 Characterization of Form H

[0241] The crystal form H prepared in 13.1 above was subjected to XRD, TGA, and DSC characterization. The relevant characterization results are shown in Figures 20 and 21. Among them, the main characteristic absorption peak data of crystal form H are shown in Table 18:

[0242] Table 18 is the XRD data of Form H

[0243] Wherein, No. = serial number, Rel.Int. = Relative Intensity only indicates the approximate intensity of the characteristic peak intensity and should not be used as a limitation on the specific crystal form H.

[0244] As shown in FIG20 and Table 18, expressed in terms of 2θ angle, Form H has the strongest characteristic absorption peak at 4.69°, with a relative absorption intensity of 100%.

[0245] Furthermore, the crystalline form H also has characteristic peaks at 6.52°, 10.13°, 14.97°, 15.91°, 16.94°, 18.41°, 19.17°, 19.99°, 21.27°, and 22.49°, with a relative absorption intensity greater than 50%;

[0246] Furthermore, Form H exhibits characteristic peaks at 9.24°, 10.50°, 12.39°, 13.59°, and 25.66°, with relative absorption intensities greater than 20%, enabling more detailed identification of other substances as representing this crystal form. Other weak absorption peaks may vary significantly due to experimental errors and, for those skilled in the art, are considered unnecessary for characterizing this crystal form.

[0247] Example 14: Preparation and Characterization of Form I

[0248] 14.1 Preparation of Form I

[0249] 100 mg of compound 1A was weighed, 0.5 mL of cyclohexanone was added, and the mixture was suspended and stirred at room temperature for a certain period of time. The suspension was centrifuged and vacuum-dried at 40° C. to obtain Form I.

[0250] 14.2 Characterization of Form I

[0251] The crystal form I prepared in 14.1 was subjected to XRD, TGA, and DSC characterization. The relevant characterization results are shown in Figures 22 and 23. Among them, the main characteristic absorption peak data of crystal form I are shown in Table 19:

[0252] Table 19 is the XRD data of Form I

[0253] Wherein, No. = serial number, Rel.Int. = Relative Intensity only indicates the approximate intensity of the characteristic peak intensity and should not be used as a limitation of the specific crystal form I.

[0254] As shown in FIG22 and Table 19, expressed in 2θ angle, Form I has the strongest characteristic absorption peak at 17.91°, and the relative absorption intensity is 100%.

[0255] Furthermore, the crystalline form I also has characteristic peaks at 9.47°, 13.46°, 15.07°, 19.19°, 21.33°, and 25.39°, with relative absorption intensity greater than 50%;

[0256] Furthermore, the crystalline form I also has characteristic peaks at 5.93°, 8.79°, 11.36°, 12.02°, 12.60°, 13.98°, 14.35°, 15.52°, 16.31°, 16.80°, 17.29°, 19.97°, 21.87°, 22.38°, 22.82°, 23.93°, 24.22°, 25.12°, 26.65°, 27.16°, 28.31°, 28.77°, 29.08°, 29.67°, 30.52°, and 31.42°, with a relative absorption intensity greater than 20%; other substances can be distinguished in more detail to represent this crystalline form. Other weak absorption peaks may vary significantly due to experimental operation errors. For those skilled in the art, other absorption peaks are all absorption peaks that can be considered unnecessary when characterizing this crystalline form.

[0257] Example 15: Preparation and Characterization of Form J

[0258] 15.1 Preparation of Form J

[0259] Weigh 200 mg of compound 1A, add 0.5 mL of dichloromethane, and suspend and stir at room temperature for a period of time to dissolve. Add 2 mL of n-heptane and stir to precipitate a solid. The suspension is centrifuged and dried in vacuo at 40°C to obtain Form J.

[0260] 15.2 Characterization of Form J

[0261] The crystal form J prepared in 15.1 above was subjected to XRD characterization, and the relevant characterization results are shown in Figure 24. Among them, the main characteristic absorption peaks of crystal form J are shown in Table 20:

[0262] Table 20 is the XRD data of Form J

[0263] Wherein, No. = serial number, Rel.Int. = Relative Intensity only indicates the approximate intensity of the characteristic peak intensity and should not be used as a limitation on the specific crystal form J.

[0264] As shown in Figure 24 and Table 20, expressed in terms of 2θ angle, Form J has the strongest characteristic absorption peak at 5.18°, with a relative absorption intensity of 100%.

[0265] Furthermore, the crystal form J also has characteristic peaks at 10.25°, 12.93°, 13.51°, 14.53°, 15.24°, 16.55°, 17.52°, 18.45°, 19.38°, 24.83°, 25.72°, and 28.01°, with relative absorption intensities greater than 50%, which can more accurately distinguish other substances as representing this crystal form. Other weak absorption peaks may vary significantly due to experimental operation errors. For those skilled in the art, these other absorption peaks are considered unnecessary absorption peaks when characterizing this crystal form.

[0266] Example 16: Preparation and Characterization of Form K

[0267] 16.1 Preparation of Form K

[0268] 400 mg of compound 1A was weighed, 2 mL of anisole was added, and the mixture was suspended and stirred at room temperature for a certain period of time. The suspension was centrifuged and dried in vacuo at 40° C. to obtain Form K.

[0269] 16.2 Characterization of Form K

[0270] The crystal form K prepared in 16.1 was characterized by XRD, TGA, and DSC. The relevant characterization results are shown in FIG25 . Among them, the main characteristic absorption peaks of crystal form K are shown in Table 21:

[0271] Table 21 is the XRD data of Form K

[0272] Form K was prepared using the preparation method described in 16.1 and subjected to XRD characterization. The specific characterization results are shown in Figure 26. A comparison of the XRD characterization results of Form K from the two runs is shown in Table 22, with an error of ±0.2°.

[0273] Table 22 is the XRD data of Form K characterized twice

[0274] Wherein, No. = serial number, Rel.Int. = Relative Intensity only indicates the approximate intensity of the characteristic peak intensity and should not be used as a limitation on the specific crystal form K.

[0275] As shown in Figure 25 and Table 21, expressed in terms of 2θ angle, Form K has the strongest characteristic absorption peak at 19.93°, with a relative absorption intensity of 100%.

[0276] Furthermore, the crystal form K also has characteristic peaks at 15.28°, 17.75°, 19.54°, 20.80°, and 22.34°, with relative absorption intensity greater than 50%;

[0277] Furthermore, the crystalline form K also has characteristic peaks at 5.00°, 7.49°, 11.40°, 12.80°, 14.02°, 15.56°, 16.43°, 16.84°, 17.07°, 18.10°, 18.70°, 18.90°, 21.29°, 22.65°, 23.70°, 23.87°, 24.36°, 24.59°, 25.04°, 25.76°, 26.48°, 27.29°, 27.84°, 28.27°, 29.47°, 30.05°, and 31.30°, and the relative absorption intensity is greater than 20%;

[0278] Furthermore, the crystal form K also has characteristic peaks at 9.12°, 9.86°, 12.15°, 13.20°, 14.72°, 18.47°, 22.90°, 30.52°, 30.89°, 32.66°, 33.53°, 34.18°, 35.55°, 35.92°, 36.14°, 36.51°, 37.38°, 38.12°, 38.49°, 38.94°, 40.18°, 42.49°, and 42.92°, with a relative absorption intensity greater than 10%; this allows for more detailed distinction of other substances representing this crystal form. Other weak absorption peaks may vary significantly due to experimental operation errors, and for those skilled in the art, other absorption peaks are considered unnecessary absorption peaks when characterizing this crystal form.

[0279] Example 17: Preparation and Characterization of Form L

[0280] 17.1 Preparation of Form L

[0281] 400 mg of compound 1A was weighed, 2 mL of cyclopentanone was added, and the mixture was suspended and stirred at room temperature for a certain period of time. Then, 8 ml of tert-methyl ether was added. The suspension was centrifuged and dried in vacuo at 40°C to obtain Form L.

[0282] 17.2 Characterization of Form L

[0283] The crystal form L prepared in 17.1 above was subjected to XRD, TGA and DSC characterization, and the relevant characterization results are shown in Figure 27. Among them, the main characteristic absorption peak data of crystal form L are shown in Table 23:

[0284] Table 23 is the XRD data of Form L

[0285] Wherein, No. = serial number, Rel.Int. = Relative Intensity only indicates the approximate intensity of the characteristic peak intensity and should not be used as a limitation of the specific crystal form L.

[0286] As shown in Figure 27 and Table 23, expressed in terms of 2θ angle, Form L has the strongest characteristic absorption peak at 16.62°, with a relative absorption intensity of 100%.

[0287] Furthermore, the crystal form L also has characteristic peaks at 17.56° and 21.60°, with a relative absorption intensity greater than 50%;

[0288] Furthermore, the crystalline form L also has characteristic peaks at 6.87°, 7.98°, 8.81°, 12.37°, 13.22°, 14.20°, 14.64°, 15.24°, 15.73°, 18.16°, 18.63°, 19.70°, 20.10°, 20.41°, 20.76°, 22.24°, 23.08°, 23.74°, 24.53°, 25.00°, 25.35°, 26.38°, 26.71°, 27.49°, 27.84°, 28.46°, 29.86°, and 30.83°, and the relative absorption intensity is greater than 20%;

[0289] Furthermore, Form L exhibits characteristic peaks at 9.34°, 10.06°, 13.59°, 13.85°, 31.63°, 32.23°, and 33.49°, with relative absorption intensities greater than 10%, enabling more detailed identification of other substances as representing this crystal form. Other weak absorption peaks may vary significantly due to experimental errors and, for those skilled in the art, are considered unnecessary for characterizing this crystal form.

[0290] Example 18: Preparation and Characterization of Form M

[0291] 18.1 Preparation of Form M

[0292] 400 mg of compound 1A was weighed, 1 mL of ethyl acetate was added, and the mixture was suspended and stirred at room temperature for a certain period of time. The suspension was centrifuged and dried in vacuo at 40°C to obtain Form M.

[0293] 18.2 Characterization of Form M

[0294] The crystal form M prepared in 18.1 was subjected to XRD, TGA, and DSC characterization. The relevant characterization results are shown in Figures 28 and 29. Among them, the main characteristic absorption peaks of the crystal form M are shown in Table 22:

[0295] Table 24 is the XRD data of Form M

[0296] Wherein, No. = serial number, Rel.Int. = Relative Intensity only indicates the approximate intensity of the characteristic peak intensity and should not be used as a limitation on the specific crystal form M.

[0297] As shown in Figure 28 and Table 24, expressed in terms of 2θ angle, Form M has the strongest characteristic absorption peak at 20.08°, with a relative absorption intensity of 100%.

[0298] Furthermore, the crystalline form M also has characteristic peaks at 6.42°, 9.24°, 10.06°, 13.55°, 13.71°, 15.05°, 15.67°, 16.49°, 17.52°, 18.06°, 18.51°, 19.13°, 21.25°, 22.53°, 24.42°, 25.31°, and 25.58°, with a relative absorption intensity greater than 50%;

[0299] Furthermore, the crystal form M also has characteristic peaks at 8.19°, 11.26°, 12.19°, 12.93°, 14.47°, 17.07°, 20.88°, 21.85°, 23.43°, 24.05°, 24.75°, 26.05°, 26.48°, 27.24°, 27.94°, 29.04°, 29.80°, 30.23°, 30.99°, 31.32°, 32.06°, and 33.32°, with a relative absorption intensity greater than 20%; other substances can be distinguished in more detail to represent this crystal form. Other weak absorption peaks may vary significantly due to experimental operation errors. For those skilled in the art, other absorption peaks are all absorption peaks that can be considered unnecessary when characterizing this crystal form.

[0300] Example 19: Preparation and Characterization of Form N

[0301] 19.1 Preparation of Form N

[0302] 400 mg of compound 1A was weighed, 1 mL of cyclic ketone was added, and the mixture was suspended and stirred at room temperature for a certain period of time. Then, 4 mL of tert-methyl ether was added. The suspension was centrifuged and dried in vacuo at 40° C. to obtain Form N.

[0303] 19.2 Characterization of Form N

[0304] The crystal form N prepared in 19.1 was subjected to XRD, TGA, and DSC characterization. The relevant characterization results are shown in Figures 30 and 31. Among them, the main characteristic absorption peaks of crystal form N are shown in Table 25:

[0305] Table 25 is the XRD data of Form N

[0306] Form N was prepared using the preparation method described in 19.1 and subjected to XRD characterization. The specific characterization results are shown in Figure 32. A comparison of the XRD characterization results of Form N from the two runs is shown in Table 26, with an error of ±0.2°.

[0307] Table 26 is the XRD data of Form N characterized twice

[0308] Wherein, No. = serial number, Rel.Int. = Relative Intensity only indicates the approximate intensity of the characteristic peak intensity and should not be used as a limitation on the specific crystal form N.

[0309] As shown in Figure 30 and Table 25, expressed in terms of 2θ angle, Form N has the strongest characteristic absorption peak at 16.49°, with a relative absorption intensity of 100%.

[0310] Furthermore, the crystal form N also has a characteristic peak at 17.46°, with a relative absorption intensity greater than 50%;

[0311] Furthermore, the crystal form N also has characteristic peaks at 7.88°, 8.71°, 13.13°, 18.63°, 19.58°, 19.93°, 21.48°, and 22.96°, with a relative absorption intensity greater than 20%;

[0312] Furthermore, the crystal form N also has characteristic peaks at 11.45°, 14.10°, 15.19°, 15.34°, 17.97°, 20.78°, 22.55°, 23.27°, 23.91°, 24.42°, 24.96°, 25.29°, 26.32°, 27.18°, 28.44°, 28.81°, 29.12°, 29.47°, 30.72°, and 34.27°, with a relative absorption intensity greater than 10%; this can more accurately distinguish other substances as representing this crystal form. Other weak absorption peaks may vary significantly due to experimental operation errors. For those skilled in the art, other absorption peaks are all considered unnecessary absorption peaks when characterizing this crystal form.

[0313] Example 20: Preparation and Characterization of Form O

[0314] 20.1 Preparation of Form O

[0315] Form O can be obtained by suspending a high concentration of amorphous starting material in ethanol at room temperature.

[0316] 100 mg of compound 1A was weighed, 1 mL of ethanol was added, and the mixture was suspended and stirred at room temperature for a certain period of time. The suspension was then centrifuged to obtain Form O.

[0317] 20.2 Characterization of Form O

[0318] The crystal form O prepared in 20.1 above was subjected to XRD characterization. The relevant characterization results are shown in FIG33 . Among them, the main characteristic absorption peak data of the crystal form O are shown in Table 27:

[0319] Table 27 is the XRD data of Form O

[0320] Wherein, No. = serial number, Rel.Int. = Relative Intensity only indicates the approximate intensity of the characteristic peak intensity and should not be used as a limitation of the specific crystal form O.

[0321] As shown in Figure 33 and Table 27, expressed in terms of 2θ angle, Form O has the strongest characteristic absorption peak at 14.68°, with a relative absorption intensity of 100%.

[0322] Furthermore, the crystal form O also has characteristic peaks at 5.22°, 16.66°, 18.61°, 19.15°, 19.83°, and 23.41°, and the relative absorption intensity is greater than 50%.

[0323] Furthermore, the crystalline form O also has characteristic peaks at 6.54°, 8.31°, 9.32°, 9.59°, 10.37°, 13.03°, 15.26°, 15.54°, 17.64°, 18.02°, 18.74°, 19.58°, 20.51°, 21.23°, 21.85°, 23.74°, 24.28°, 24.57°, 25.04°, 26.11°, 27.08°, 28.11°, 28.40°, 28.83°, 29.53°, and 31.28°, and the relative absorption intensity is greater than 20%;

[0324] Furthermore, Form O exhibits characteristic peaks at 33.13° and 33.63°, with relative absorption intensities exceeding 10%, enabling more detailed identification of other substances as representing this crystal form. Other weak absorption peaks may vary significantly due to experimental errors, and those skilled in the art consider these peaks unnecessary for characterizing this crystal form.

[0325] Example 21: Stability Study

[0326] The stability of Form A, Form F, Form K, Form N, and amorphous samples under illumination (25°C / 4500 Lux) was studied. Sampling was performed on day 0 and day 26, and the HPLC purity of the samples was evaluated. The results are shown in Table 28.

[0327] Table 28 shows the stability study results of Forms A, F, K, N and amorphous

[0328] As can be seen from Table 28, Form A, Form F, Form K and Form N have good stability under light conditions, and Form A, Form F, Form K and Form N have higher purity and better stability than the amorphous sample.

[0329] The above embodiments are preferred implementation modes of the present invention, but the implementation modes of the present invention are not limited to the above embodiments. Any other changes, modifications, substitutions, combinations, and simplifications that do not deviate from the spirit and principles of the present invention should be considered as equivalent replacement methods and are included in the scope of protection of the present invention.

Claims

1. A terpyridinedione compound crystalline form A represented by formula (I), characterized in that: The X-ray diffraction pattern of the crystalline form A shows characteristic peaks at 5.00°, 7.70°, 12.82°, 14.08°, 15.44°, 16.72°, 17.17°, 19.70°, 20.41°, 20.88°, 23.08°, 23.78°, and 26.83° in terms of 2θ angle, with an error of ±0.2°.

2. The terpyridinedione compound crystalline form A of formula (I) according to claim 1, characterized in that: The X-ray diffraction pattern of the crystalline form A is expressed in 2θ angles at 9.24°, 11.40°, 11.63°, 12.23°, 13.85°, 14.80°, 15.71°, 15.96°, 17.75°, 17.93°, 18.20°, 18.67°, 18.94°, 21.15°, 21.48°, 22.51°, 22.71°, There are characteristic peaks at 22.44°, 24.65°, 25.20°, 25.66°, 25.84°, 26.60°, 27.47°, 27.74°, 27.92°, 28.81°, 29.57°, 30.27°, 30.72°, 31.38°, 32.11°, 32.70°, 33.57°, and 36.70°, with an error of ±0.2°.

3. A terpyridinedione compound crystalline form B represented by formula (I), characterized in that: The X-ray diffraction pattern of the crystalline form B shows characteristic peaks at 5.97°, 7.80°, 9.26°, 11.57°, 14.41°, 15.17°, 17.93°, 18.12°, 19.64°, 20.10°, 22.88°, and 23.50° in terms of 2θ angle, with an error of ±0.2°.

4. A terpyridinedione compound crystalline form C represented by formula (I), characterized in that: The X-ray diffraction pattern of the crystalline form C shows characteristic peaks at 6.03°, 14.45°, 16.31°, 17.44°, 18.16°, 21.02°, 24.40°, 24.98°, 26.48°, and 27.84° in terms of 2θ angle, with an error of ±0.2°.

5. A terpyridinedione compound crystalline form D represented by formula (I), characterized in that: The X-ray diffraction pattern of the crystal form D shows characteristic peaks at 4.15° and 18.37° in terms of 2θ angle.

6. A terpyridinedione compound crystalline form E represented by formula (I), characterized in that: The X-ray diffraction pattern of the crystalline form E shows characteristic peaks at 9.22°, 10.72°, 12.58°, 14.72°, 16.14°, 16.78°, 17.40°, 18.45°, 19.73°, 20.16°, 20.73°, 21.33°, 23.21°, 24.98°, 25.25°, and 27.82°, as indicated by the 2θ angle.

7. A terpyridinedione compound crystalline form F represented by formula (I), characterized in that: The X-ray diffraction pattern of the crystal form F shows characteristic peaks at 12.75°, 15.13°, 15.37°, 16.01°, 16.21°, 17.35°, 18.44°, and 19.30° in terms of 2θ angle, with an error of ±0.2°.

8. The terpyridinedione compound crystal form F represented by formula (I) according to claim 7, characterized in that: The X-ray diffraction pattern of the crystalline form F is represented by a 2θ angle, and characteristic peaks are also present at 5.03°, 5.34°, 6.85°, 10.05°, 10.86°, 12.95°, 13.52°, 14.26°, 18.20°, 20.17°, 22.01°, 22.73°, 23.61°, 24.82°, 25.55°, 26.05°, 26.32°, and 28.09°, with an error of ±0.2°.

9. The terpyridinedione compound crystalline form F of formula (I) according to claim 7, characterized in that: The X-ray diffraction pattern of the crystal form F shows characteristic peaks at 3.80°, 10.64°, 13.72°, 16.95°, 21.29°, 22.30°, 27.21°, and 30.13°, expressed in terms of 2θ angle, with an error of ±0.2°.

10. The terpyridinedione compound crystal form F of formula (I) according to any one of claims 7 to 9, characterized in that: The differential thermal analysis spectrum of the crystal form F has a characteristic absorption peak at 129.4°C with an error of ±5°C.

11. A terpyridinedione compound crystalline form G represented by formula (I), characterized in that: The X-ray diffraction pattern of the crystal form G shows characteristic peaks at 5.06°, 6.46°, 9.24°, 10.07°, and 15.09° in terms of 2θ angle, with an error of ±0.2°.

12. A terpyridinedione compound of formula (I) in form H, characterized in that: The X-ray diffraction pattern of the crystalline form H shows characteristic peaks at 4.69°, 6.52°, 10.13°, 14.97°, 15.91°, 16.94°, 18.41°, 19.17°, 19.99°, 21.27°, and 22.49° in terms of 2θ angle, with an error of ±0.2°.

13. A terpyridinedione compound crystalline form I represented by formula (I), characterized in that: The X-ray diffraction pattern of the crystalline form I shows characteristic peaks at 9.47°, 13.46°, 15.07°, 17.91°, 19.19°, 21.33°, and 25.39° in terms of 2θ angle, with an error of ±0.2°.

14. A terpyridinedione compound of formula (I) in form J, characterized in that: The X-ray diffraction pattern of the crystal form J shows characteristic peaks at 5.18°, 10.25°, 12.93°, 13.51°, 14.53°, 15.24°, 16.55°, 17.52°, 18.45°, 19.38°, 24.83°, 25.72°, and 28.01° in terms of 2θ angle, with an error of ±0.2°.

15. A terpyridinedione compound of formula (I), crystalline form K, characterized in that: The X-ray diffraction pattern of the crystal form K shows characteristic peaks at 15.28°, 17.75°, 19.54°, 19.93°, 20.80°, and 22.34° in terms of 2θ angle, with an error of ±0.2°.

16. A terpyridinedione compound of formula (I) in form K according to claim 15, characterized in that: In the X-ray diffraction pattern of the form K, characteristic peaks are expressed in terms of 2θ angles at 5.00°, 7.49°, 11.40°, 12.80°, 14.02°, 15.56°, 16.43°, 16.84°, 17.07°, 18.10°, 18.70°, 18.90°, 21.29°, 22.65°, 23.70°, 23.87°, 24.36°, 24.59°, 25.04°, 25.76°, 26.48°, 27.29°, 27.84°, 28.27°, 29.47°, 30.05°, and 31.30°, with an error of ±0.2°.

17. A terpyridinedione compound of formula (I) in form K according to claim 15 or 16, characterized in that: In the X-ray diffraction pattern of the crystal form K, characteristic peaks are expressed in terms of 2θ angle at 9.12°, 9.86°, 12.15°, 13.20°, 14.72°, 18.47°, 22.90°, 30.52°, 30.89°, 32.66°, 33.53°, 34.18°, 35.55°, 35.92°, 36.14°, 36.51°, 37.38°, 38.12°, 38.49°, 38.94°, 40.18°, 42.49°, and 42.92°, with an error of ±0.2°.

18. A terpyridinedione compound crystalline form L represented by formula (I), characterized in that: The X-ray diffraction pattern of the crystal form L shows characteristic peaks at 16.62°, 17.56°, and 21.60° in terms of 2θ angle, with an error of ±0.2°.

19. A terpyridinedione compound of formula (I) in form M, characterized in that: The X-ray diffraction pattern of the crystalline form M shows characteristic peaks at 6.42°, 9.24°, 10.06°, 13.55°, 13.71°, 15.05°, 15.67°, 16.49°, 17.52°, 18.06°, 18.51°, 19.13°, 20.08°, 21.25°, 22.53°, 24.42°, 25.31°, and 25.58°, with an error of ±0.2°.

20. A terpyridinedione compound crystal form N represented by formula (I), characterized in that: The X-ray diffraction pattern of the crystal form N shows characteristic peaks at 16.49° and 17.46° in terms of 2θ angle, with an error of ±0.2°.

21. The terpyridinedione compound of formula (I) Form N according to claim 20, characterized in that: The X-ray diffraction pattern of the crystal form N also has characteristic peaks at 7.88°, 8.71°, 13.13°, 18.63°, 19.58°, 19.93°, 21.48°, and 22.96°, as expressed by the 2θ angle.

22. A terpyridinedione compound crystalline form N of formula (I) according to claim 20 or 21, characterized in that: In the X-ray diffraction pattern of the crystal form N, there are characteristic peaks at 11.45°, 14.10°, 15.19°, 15.34°, 17.97°, 20.78°, 22.55°, 23.27°, 23.91°, 24.42°, 24.96°, 25.29°, 26.32°, 27.18°, 28.44°, 28.81°, 29.12°, 29.47°, 30.72°, and 34.27°, with an error of ±0.2°.

23. A terpyridinedione compound of formula (I) in form O, characterized in that: The X-ray diffraction pattern of the crystal form O shows characteristic peaks at 5.22°, 14.68°, 16.66°, 18.61°, 19.15°, 19.83°, and 23.41° in terms of 2θ angle, with an error of ±0.2°.

24. A pharmaceutical composition, characterized in that Comprising a therapeutically effective amount of the crystal form according to any one of claims 1 to 23 and a pharmaceutically acceptable carrier.

25. Use of the crystal form according to any one of claims 1 to 23 in the preparation of a medicament for treating a disease, wherein the disease is a p38 / MK2-related disease selected from a chronic inflammatory disease and an acute inflammatory disease, wherein: The chronic inflammatory disorder is preferably rheumatoid arthritis.

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