Crystal form of tricyclic derivative inhibitor and preparation method thereof

Abstract

The invention relates to a crystal form of a tricyclic derivative inhibitor and a preparation method thereof. Specifically, the invention relates to a crystal form of a compound with a general formula (I), a preparation method, a pharmaceutical composition containing a therapeutically effective amount of the crystal form, and an application of the crystal form in treatment of cancers and autoimmune diseases.

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceutical chemistry, and specifically relates to a crystal form of a tricyclic derivative inhibitor, a preparation method and an application thereof. Background Art

[0002] MALT1 (mucosa-associated lymphoid tissue lymphoma translocation protein 1) is a protease and scaffold protein, an intracellular signaling molecule, and plays an important role in immunity and inflammation. It is involved in the signal transduction of NF-kB downstream of B cell and T cell receptor (BCR, TCR). MALT1 forms a CBM complex with CARM1 and BCL10, and mutations in these genes can cause constitutive activation of the NF-kB signaling pathway.

[0003] The growth of ABC-DLBCL is strongly dependent on the continuous activation of the NF-kB signaling pathway. It accounts for 16% of the incidence of lymphoma in China and 40% of DLBCL in China. MALT lymphoma is caused by the translocation and rearrangement of the MALT1 and BCL10 genes, accounting for 9% of the incidence of lymphoma in China. In addition, MALT inhibitors are also expected to be used in CLL patients resistant to BTK inhibitors.

[0004] Currently, only Johnson & Johnson's compound JNJ-67856633 has entered clinical phase I in the world. The NCT03900598 trial in April 2019 was a phase I clinical trial, and the NCT04657224 trial in December 2020 was a phase I clinical trial, using a combination with a BTK inhibitor.

[0005] Published patent applications for MALT1 inhibitors include:

[0006] Johnson & Johnson's patented compounds (WO2018119036, WO2019243964, WO2019243965, WO2020208222); Novartis's MLT-985, etc. (WO2015181747, WO2017081641); Lupin's LND-700110, etc. (WO2018020474); Medvir's cmpd A et al. (WO2018226150); Takeda's patented compound (WO2020111087); Cornell University's patented compound (WO2014074815, WO2018165385, WO2018085247) and Toray's patented compound (WO2017057695, WO2018021520, WO2018159650).

[0007] MALT1 inhibitors have good application prospects as drugs in the pharmaceutical industry:

[0008] First, it is expected to become a targeted therapy for ABC-DLBCL. The current standard therapy is R-Chop, which has a poor prognosis.

[0009] Second: It is expected to become a follow-up treatment for CLL and MCL patients after BTK resistance.

[0010] The main problems of current inhibitors are: the in vitro activity decreases significantly from enzyme activity to cell activity, and the drugability of the compounds needs to be improved (short half-life, etc.).

[0011] The present invention discloses a series of structures of inhibitors containing tricyclic derivatives. In order to make the products easy to handle, filter, dry, store, have long-term stability and high bioavailability, the present invention conducts a comprehensive study on the crystal forms of the above substances and is committed to obtaining the most suitable crystal form. Summary of the invention

[0012] All contents involved in patent application PCT / CN2022 / 143665 are added to the present invention by citation.

[0013] The object of the present invention is to provide a crystalline form of a compound represented by general formula (I), the structure of which is as follows:

[0014]

[0015] Where: M 1 N or CH; M 2 N or CR 1b ;M 3 N or CR 1c ;

[0016] R 1a Selected from hydrogen, deuterium, halogen, hydroxyl, cyano, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclyl, phenyl or 5-8 membered heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclyl, phenyl or 5-8 membered heteroaryl, optionally further substituted by deuterium, halogen, hydroxyl, cyano or C 1-6The alkyl group is substituted by one or more substituents;

[0017] R 1b Selected from hydrogen, deuterium, halogen, hydroxyl, cyano, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclyl, phenyl or 5-8 membered heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclyl, phenyl or 5-8 membered heteroaryl, optionally further substituted by deuterium, halogen, hydroxyl, cyano or C 1-6 The alkyl group is substituted by one or more substituents;

[0018] R 1c Selected from hydrogen, deuterium, halogen, hydroxyl, cyano, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclyl, phenyl or 5-8 membered heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclyl, phenyl or 5-8 membered heteroaryl, optionally further substituted by deuterium, halogen, hydroxyl, cyano or C 1-6 The alkyl group is substituted by one or more substituents;

[0019] R 2a Selected from hydrogen, deuterium, halogen, hydroxyl, cyano, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl or C 3-8 Cycloalkyl;

[0020] R 2b Selected from hydrogen, deuterium, halogen, hydroxyl, cyano, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl or C 3-8 Cycloalkyl.

[0021] In a preferred embodiment of the present invention, the structure of the compound is shown in general formula (II):

[0022]

[0023] Where: M 1 N or CH; M 3 N or CR 1c ;

[0024] Ring A is a 5-membered N-containing heteroaryl group; preferably

[0025] R 1a Selected from hydrogen, deuterium, fluorine, chlorine, bromine, hydroxyl, cyano, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl, wherein the C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl, optionally further substituted by deuterium, halogen, hydroxyl, cyano or C 1-3 The alkyl group is substituted by one or more substituents; preferably fluorine, chlorine, bromine, difluoromethyl or trifluoromethyl;

[0026] R 1c Selected from hydrogen, deuterium, fluorine, chlorine, bromine, hydroxyl, cyano, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl, wherein the C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, C 3-6Cycloalkyl, 3-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl, optionally further substituted by deuterium, halogen, hydroxyl, cyano or C 1-3 The alkyl group is substituted by one or more substituents;

[0027] R 2a Selected from hydrogen, deuterium, fluorine, chlorine, bromine, hydroxyl, cyano, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Hydroxyalkyl or C 3-6 Cycloalkyl; preferably trifluoromethyl or cyclopropyl.

[0028] In a preferred embodiment of the present invention, the crystalline form of the compound is the crystalline form of the following compound:

[0029] 1-(2-Carbonyl-1,2-dihydropyrrolo[2,3,4-ij]isoquinolin-5-yl)-5-trifluoromethyl-N-(2-trifluoromethylpyridin-4-yl)-1H-pyrazole-4-carboxamide

[0030] 1-(2-Carbonyl-1,2-dihydropyrrolo[4,3,2-ij]isoquinolin-6-yl)-5-trifluoromethyl-N-(2-trifluoromethylpyridin-4-yl)-1H-pyrazole-4-carboxamide;

[0031] N-(6-(2H-1,2,3-triazol-2-yl)-5-chloropyridin-3-yl)-1-(2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)-5-trifluoromethyl-1H-pyrazole-4-carboxamide;

[0032] N-(6-(2H-1,2,3-triazol-2-yl)-5-trifluoromethylpyridin-3-yl)-1-(2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)-5-trifluoromethyl-1H-pyrazole-4-carboxamide;

[0033] N-(6-(oxazol-2-yl)-5-(trifluoromethyl)pyridin-3-yl)-1-(2-carbonyl-1,2-dihydrobenzo[cd]indol-6-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide;

[0034] N-(5-difluoromethyl-6-(2H-1,2,3-triazol-2-yl)-pyridin-3-yl)-1-(2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)-5-trifluoromethyl-1H-pyrazole-4-carboxamide;

[0035] N-(4-(2H-1,2,3-triazol-2-yl)-3-(trifluoromethyl)phenyl)-1-(2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide;

[0036] N-(3-chloro-4-(2H-1,2,3-triazol-2-yl)phenyl)-1-(2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide;

[0037] 5-cyclopropyl-1-(2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)-N-(2-(trifluoromethyl)pyridin-4-yl)-1H-pyrazole-4-carboxamide;

[0038] N-(6-(2H-1,2,3-triazol-2-yl)-5-(trifluoromethyl)pyridin-3-yl)-5-cyclopropyl-1-(2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)-1H-pyrazole-4-carboxamide;

[0039] N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)-pyridin-3-yl)-5-cyclopropyl-1-(2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)-1H-pyrazole-4-carboxamide;

[0040] N-(3-chloro-4-(2H-1,2,3-triazol-2-yl)phenyl)-5-cyclopropyl-1-(2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)-1H-pyrazole-4-carboxamide;

[0041] N-(6-(2H-1,2,3-triazol-2-yl)-5-(trifluoromethyl)pyridin-3-yl)-1-(2-carbonyl-1,2-dihydrobenzo[cd]indol-6-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide;

[0042] N-(3-chloro-4-(2H-1,2,3-triazol-2-yl)phenyl)-1-(2-carbonyl-1,2-dihydropyrrolo[4,3,2-ij]isoquinolin-6-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide;

[0043] N-(6-(2H-1,2,3-triazol-2-yl)-5-(trifluoromethyl)pyridin-3-yl)-5-cyclopropyl-1-(2-oxo-1,2-dihydropyrrolo[4,3,2-ij]isoquinolin-6-yl)-1H-pyrazole-4-carboxamide;

[0044] N-(4-(2H-1,2,3-triazol-2-yl)-3-(trifluoromethyl)phenyl)-5-cyclopropyl-1-(2-oxo-1,2-dihydropyrrolo[4,3,2-ij]isoquinolin-6-yl)-1H-pyrazole-4-carboxamide.

[0045] In a preferred embodiment of the present invention, the crystalline form is a crystalline form of the compound N-(3-chloro-4-(2H-1,2,3-triazol-2-yl)phenyl)-1-(2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide.

[0046] In a preferred embodiment of the present invention, a crystalline form I, II, III, IV, V, VI, VII, VIII, X1, X2, X3, X4, X5 or X6 of the compound N-(3-chloro-4-(2H-1,2,3-triazol-2-yl)phenyl)-1-(2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide is provided, wherein:

[0047] The X-ray powder diffraction spectrum of the crystalline form I has a diffraction peak at 2θ of 6.8±0.2°; or a diffraction peak at 16.0±0.2°; or a diffraction peak at 23.0±0.2°; or a diffraction peak at 20.9±0.2°; or a diffraction peak at 11.4±0.2°; or a diffraction peak at 13.7±0.2°; or a diffraction peak at 4.6±0.2°; or a diffraction peak at 24.2±0.2°; or a diffraction peak at 24.8±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, and more preferably including any 6, 7 or 8 thereof;

[0048] The X-ray powder diffraction spectrum of the crystalline form II has a diffraction peak at 2θ of 20.9±0.2°; or a diffraction peak at 16.1±0.2°; or a diffraction peak at 24.2±0.2°; or a diffraction peak at 17.4±0.2°; or a diffraction peak at 27.3±0.2°; or a diffraction peak at 26.8±0.2°; or a diffraction peak at 6.9±0.2°; or a diffraction peak at 17.8±0.2°; or a diffraction peak at 11.4±0.2°; or a diffraction peak at 19.0±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;

[0049] The X-ray powder diffraction spectrum of the crystalline form III has a diffraction peak at 2θ of 10.3±0.2°; or a diffraction peak at 20.7±0.2°; or a diffraction peak at 26.8±0.2°; or a diffraction peak at 11.3±0.2°; or a diffraction peak at 26.5±0.2°; or a diffraction peak at 14.3±0.2°; or a diffraction peak at 22.8±0.2°; or a diffraction peak at 16.1±0.2°; or a diffraction peak at 21.9±0.2°; or a diffraction peak at 12.2±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;

[0050] The X-ray powder diffraction spectrum of the crystalline form IV has a diffraction peak at 2θ of 25.2±0.2°; or a diffraction peak at 15.1±0.2°; or a diffraction peak at 14.2±0.2°; or a diffraction peak at 14.8±0.2°; or a diffraction peak at 21.6±0.2°; or a diffraction peak at 12.4±0.2°; or a diffraction peak at 24.9±0.2°; or a diffraction peak at 18.3±0.2°; or a diffraction peak at 23.7±0.2°; or a diffraction peak at 11.4±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;

[0051] The X-ray powder diffraction spectrum of the crystalline form V has a diffraction peak at 2θ of 25.4±0.2°; or a diffraction peak at 15.3±0.2°; or a diffraction peak at 15.0±0.2°; or a diffraction peak at 14.4±0.2°; or a diffraction peak at 21.8±0.2°; or a diffraction peak at 12.6±0.2°; or a diffraction peak at 24.6±0.2°; or a diffraction peak at 23.9±0.2°; or a diffraction peak at 18.5±0.2°; or a diffraction peak at 8.7±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, and more preferably including any 6, 7 or 8 thereof;

[0052] The X-ray powder diffraction spectrum of the crystalline form VI has a diffraction peak at 2θ of 11.3±0.2°; or a diffraction peak at 10.2±0.2°; or a diffraction peak at 22.6±0.2°; or a diffraction peak at 16.0±0.2°; or a diffraction peak at 25.8±0.2°; or a diffraction peak at 20.7±0.2°; or a diffraction peak at 7.0±0.2°; or a diffraction peak at 14.5±0.2°; or a diffraction peak at 22.2±0.2°; or a diffraction peak at 21.7±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;

[0053] The X-ray powder diffraction spectrum of the crystalline form VII has a diffraction peak at 2θ of 8.9±0.2°; or a diffraction peak at 10.4±0.2°; or a diffraction peak at 24.3±0.2°; or a diffraction peak at 25.6±0.2°; or a diffraction peak at 14.0±0.2°; or a diffraction peak at 18.0±0.2°; or a diffraction peak at 20.1±0.2°; or a diffraction peak at 22.5±0.2°; or a diffraction peak at 27.5±0.2°; or a diffraction peak at 27.2±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;

[0054] The X-ray powder diffraction spectrum of the crystalline form VIII has a diffraction peak at 2θ of 4.7±0.2°; or a diffraction peak at 7.1±0.2°; or a diffraction peak at 11.9±0.2°; or a diffraction peak at 16.8±0.2°; or a diffraction peak at 24.1±0.2°; or a diffraction peak at 14.4±0.2°; or a diffraction peak at 15.7±0.2°; preferably including any 2-5, or 3-5, or 3-6, or 3-7, or 5-7, or 6-7 of the above diffraction peaks, more preferably including any 6 or 7 thereof;

[0055] The X-ray powder diffraction spectrum of the crystal form X1 has a diffraction peak at 2θ of 16.7±0.2°; or a diffraction peak at 20.8±0.2°; or a diffraction peak at 21.7±0.2°; or a diffraction peak at 25.2±0.2°; or a diffraction peak at 17.0±0.2°; or a diffraction peak at 17.6±0.2°; or a diffraction peak at 12.9±0.2°; or a diffraction peak at 23.4±0.2°; or a diffraction peak at 14.8±0.2°; or a diffraction peak at 9.0±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, and more preferably including any 6, 7 or 8 thereof;

[0056] The X-ray powder diffraction spectrum of the crystal form X2 has a diffraction peak at 2θ of 9.5±0.2°; or a diffraction peak at 19.8±0.2°; or a diffraction peak at 15.2±0.2°; or a diffraction peak at 28.8±0.2°; or a diffraction peak at 10.8±0.2°; or a diffraction peak at 14.1±0.2°; or a diffraction peak at 24.5±0.2°; or a diffraction peak at 26.6±0.2°; or a diffraction peak at 38.8±0.2°; or a diffraction peak at 39.2±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, and more preferably including any 6, 7 or 8 thereof;

[0057] The X-ray powder diffraction spectrum of the crystal form X3 has a diffraction peak at 2θ of 12.0±0.2°; or a diffraction peak at 14.4±0.2°; or a diffraction peak at 7.2±0.2°; or a diffraction peak at 25.8±0.2°; or a diffraction peak at 13.5±0.2°; or a diffraction peak at 21.6±0.2°; or a diffraction peak at 4.9±0.2°; or a diffraction peak at 16.7±0.2°; or a diffraction peak at 17.8±0.2°; or a diffraction peak at 17.4±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, and more preferably including any 6, 7 or 8 thereof;

[0058] The X-ray powder diffraction spectrum of the crystal form X4 has a diffraction peak at 2θ of 11.3±0.2°; or a diffraction peak at 10.2±0.2°; or a diffraction peak at 22.6±0.2°; or a diffraction peak at 20.7±0.2°; or a diffraction peak at 14.2±0.2°; or a diffraction peak at 16.1±0.2°; or a diffraction peak at 7.1±0.2°; or a diffraction peak at 14.5±0.2°; or a diffraction peak at 25.8±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;

[0059] The X-ray powder diffraction spectrum of the crystal form X5 has a diffraction peak at 2θ of 11.4±0.2°; or a diffraction peak at 13.6±0.2°; or a diffraction peak at 17.5±0.2°; or a diffraction peak at 12.2±0.2°; or a diffraction peak at 24.8±0.2°; or a diffraction peak at 18.7±0.2°; or a diffraction peak at 23.4±0.2°; or a diffraction peak at 22.9±0.2°; or a diffraction peak at 21.8±0.2°; or a diffraction peak at 22.4±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;

[0060] The X-ray powder diffraction pattern of the crystal form X6 has a diffraction peak at 2θ of 11.4±0.2°; or a diffraction peak at 10.2±0.2°; or a diffraction peak at 20.7±0.2°; or a diffraction peak at 22.6±0.2°; or a diffraction peak at 25.9±0.2°; or a diffraction peak at 16.1±0.2°; or a diffraction peak at 7.1±0.2°; or a diffraction peak at 14.6±0.2°; or a diffraction peak at 12.2±0.2°; or a diffraction peak at 18.5±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.

[0061] In a further preferred embodiment of the present invention,

[0062] The X-ray powder diffraction pattern of Form I comprises at least one or more diffraction peaks located at 2θ of 6.8±0.2°, 16.0±0.2°, and 23.0±0.2°, preferably two of them, and more preferably three of them; optionally, it may further comprise at least one of 20.9±0.2°, 11.4±0.2°, 13.7±0.2°, 4.6±0.2°, and 24.2±0.2°, preferably 2, 3, 4 or 5 of them;

[0063] The X-ray powder diffraction pattern of Form II contains at least one or more diffraction peaks located at 2θ of 20.9±0.2°, 16.1±0.2°, and 24.2±0.2°, preferably two of them, and more preferably three of them; optionally, it may further contain at least one of 17.4±0.2°, 27.3±0.2°, 26.8±0.2°, 6.9±0.2°, and 17.8±0.2°, preferably 2, 3, 4 or 5 of them;

[0064] The X-ray powder diffraction pattern of Form III comprises at least one or more diffraction peaks located at 2θ of 10.3±0.2°, 20.7±0.2°, and 26.8±0.2°, preferably two of them, and more preferably three of them; optionally, it may further comprise at least one of 11.3±0.2°, 26.5±0.2°, 14.3±0.2°, 22.8±0.2°, and 16.1±0.2°, preferably 2, 3, 4 or 5 of them;

[0065] The X-ray powder diffraction pattern of Form IV comprises at least one or more diffraction peaks located at 2θ of 25.2±0.2°, 15.1±0.2°, and 14.2±0.2°, preferably two of them, and more preferably three of them; optionally, it may further comprise at least one of 14.8±0.2°, 21.6±0.2°, 12.4±0.2°, 24.9±0.2°, and 18.3±0.2°, preferably 2, 3, 4 or 5 of them;

[0066] The X-ray powder diffraction pattern of Form V contains at least one or more diffraction peaks located at 2θ of 25.4±0.2°, 15.3±0.2°, and 15.0±0.2°, preferably two of them, and more preferably three of them; optionally, it may further contain at least one of 14.4±0.2°, 21.8±0.2°, 12.6±0.2°, 24.6±0.2°, and 23.9±0.2°, preferably 2, 3, 4 or 5 of them;

[0067] The X-ray powder diffraction pattern of Form VI comprises at least one or more diffraction peaks located at 2θ of 11.3±0.2°, 10.2±0.2°, and 22.6±0.2°, preferably two of them, and more preferably three of them; optionally, it may further comprise at least one of 16.0±0.2°, 25.8±0.2°, 20.7±0.2°, 7.0±0.2°, and 14.5±0.2°, preferably 2, 3, 4 or 5 of them;

[0068] The X-ray powder diffraction pattern of Form VII comprises at least one or more diffraction peaks located at 2θ of 8.9±0.2°, 10.4±0.2°, and 24.3±0.2°, preferably two of them, and more preferably three of them; optionally, it may further comprise at least one of 25.6±0.2°, 14.0±0.2°, 18.0±0.2°, 20.1±0.2°, and 22.5±0.2°, preferably 2, 3, 4 or 5 of them;

[0069] The X-ray powder diffraction pattern of Form VIII comprises at least one or more diffraction peaks located at 2θ of 4.7±0.2°, 7.1±0.2°, and 11.9±0.2°, preferably two of them, and more preferably three of them; optionally, it may further comprise at least one of 16.8±0.2°, 24.1±0.2°, 14.4±0.2°, and 15.7±0.2°, preferably 2, 3, 4 or 5 of them;

[0070] The X-ray powder diffraction pattern of Form X1 contains at least one or more diffraction peaks located at 2θ of 16.7±0.2°, 20.8±0.2°, and 21.7±0.2°, preferably two of them, and more preferably three of them; optionally, it may further contain at least one of 25.2±0.2°, 17.0±0.2°, 17.6±0.2°, 12.9±0.2°, and 23.4±0.2°, preferably 2, 3, 4 or 5 of them;

[0071] The X-ray powder diffraction pattern of Form X2 contains at least one or more diffraction peaks located at 2θ of 9.5±0.2°, 19.8±0.2°, and 15.2±0.2°, preferably two of them, and more preferably three of them; optionally, it may further contain at least one of 28.8±0.2°, 10.8±0.2°, 14.1±0.2°, 24.5±0.2°, and 26.6±0.2°, preferably 2, 3, 4 or 5 of them;

[0072] The X-ray powder diffraction pattern of Form X3 comprises at least one or more diffraction peaks located at 2θ of 12.0±0.2°, 14.4±0.2°, and 7.2±0.2°, preferably two of them, and more preferably three of them; optionally, it may further comprise at least one of 25.8±0.2°, 13.5±0.2°, 21.6±0.2°, 4.9±0.2°, and 16.7±0.2°, preferably 2, 3, 4 or 5 of them;

[0073] The X-ray powder diffraction pattern of Form X4 comprises at least one or more diffraction peaks located at 2θ of 11.3±0.2°, 10.2±0.2°, and 22.6±0.2°, preferably two of them, and more preferably three of them; optionally, it may further comprise at least one of 20.7±0.2°, 14.2±0.2°, 16.1±0.2°, 7.1±0.2°, and 14.5±0.2°, and preferably 2, 3, 4 or 5 of them;

[0074] The X-ray powder diffraction pattern of Form X5 comprises at least one or more diffraction peaks located at 2θ of 11.4±0.2°, 13.6±0.2°, and 17.5±0.2°, preferably two of them, and more preferably three of them; optionally, it may further comprise at least one of 12.2±0.2°, 24.8±0.2°, 18.7±0.2°, 23.4±0.2°, and 22.9±0.2°, and preferably 2, 3, 4 or 5 of them;

[0075] The X-ray powder diffraction pattern of Form X6 contains at least one or more diffraction peaks located at 2θ of 11.4±0.2°, 10.2±0.2°, and 20.7±0.2°, preferably two of them, and more preferably three; optionally, it may further contain at least one of 22.6±0.2°, 25.9±0.2°, 16.1±0.2°, 7.1±0.2°, and 14.6±0.2°, preferably 2, 3, 4 or 5 of them.

[0076] In a further preferred embodiment of the present invention,

[0077] The X-ray powder diffraction pattern of the crystalline form I optionally further comprises one or more diffraction peaks located at 2θ of 24.8±0.2°, 26.2±0.2°, 22.6±0.2°, 17.2±0.2°, 19.1±0.2°, 17.7±0.2° or 20.3±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;

[0078] The X-ray powder diffraction pattern of the crystalline form II optionally further comprises one or more diffraction peaks located at 2θ of 11.4±0.2°, 19.0±0.2°, 32.1±0.2° or 10.5±0.2°; preferably, at least any 2-4 of them; more preferably, any 2, 3 or 4 of them;

[0079] The X-ray powder diffraction pattern of the crystalline form III optionally further comprises one or more diffraction peaks located at 2θ of 21.9±0.2°, 12.2±0.2°, 13.2±0.2°, 25.8±0.2°, 24.3±0.2°, 18.5±0.2° or 7.1±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;

[0080] The X-ray powder diffraction pattern of the crystalline form IV optionally further comprises one or more diffraction peaks located at 2θ of 23.7±0.2°, 11.4±0.2°, 26.8±0.2°, 8.5±0.2°, 17.5±0.2°, 20.6±0.2° or 16.3±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;

[0081] The X-ray powder diffraction pattern of the crystalline form V optionally further comprises one or more diffraction peaks located at 2θ of 18.5±0.2°, 8.7±0.2°, 11.6±0.2°, 17.7±0.2°, 23.3±0.2°, 25.7±0.2° or 20.8±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;

[0082] The X-ray powder diffraction pattern of the crystalline form VI optionally further comprises one or more diffraction peaks located at 2θ of 22.2±0.2°, 21.7±0.2°, 21.3±0.2°, 27.6±0.2°, 23.1±0.2°, 23.8±0.2° or 29.6±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;

[0083] The X-ray powder diffraction pattern of the crystalline form VII optionally further comprises one or more diffraction peaks located at 2θ of 27.5±0.2°, 27.2±0.2°, 29.4±0.2°, 31.8±0.2°, 21.1±0.2°, 20.5±0.2° or 16.6±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;

[0084] The X-ray powder diffraction pattern of the crystal form X1 optionally further comprises one or more diffraction peaks located at 2θ of 14.8±0.2°, 9.0±0.2°, 14.4±0.2°, 18.6±0.2° or 19.4±0.2°; preferably, at least any 2-3, or 4-5 of them; further preferably, any 2, 3, 4 or 5 of them;

[0085] The X-ray powder diffraction pattern of the crystal form X2 optionally further comprises one or more diffraction peaks located at 2θ of 38.8±0.2°, 39.2±0.2° or 49.4±0.2°; preferably, at least any 2-3 of them; more preferably, any 2 or 3 of them;

[0086] The X-ray powder diffraction pattern of the crystal form X3 optionally further comprises one or more diffraction peaks located at 2θ of 17.8±0.2°, 17.4±0.2°, 12.9±0.2°, 23.0±0.2°, 24.0±0.2°, 25.3±0.2° or 15.8±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;

[0087] The X-ray powder diffraction pattern of the crystal form X4 optionally further comprises one or more diffraction peaks located at 2θ of 25.8±0.2°, 21.4±0.2°, 26.5±0.2°, 26.8±0.2°, 13.2±0.2°, 18.5±0.2° or 22.2±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;

[0088] The X-ray powder diffraction pattern of the crystal form X5 optionally further comprises one or more diffraction peaks located at 2θ of 21.8±0.2°, 22.4±0.2°, 14.4±0.2°, 27.3±0.2°, 25.3±0.2°, 15.5±0.2° or 16.5±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;

[0089] The X-ray powder diffraction pattern of the crystal form X6 optionally further comprises one or more diffraction peaks located at 2θ of 12.2±0.2°, 18.5±0.2°, 19.5±0.2°, 21.4±0.2°, 21.8±0.2°, 22.3±0.2° or 26.5±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;

[0090] In a preferred embodiment of the present invention, the X-ray powder diffraction pattern of the crystalline form I optionally includes one or more diffraction peaks located at 2θ of 6.8±0.2°, 16.0±0.2°, 23.0±0.2°, 20.9±0.2°, 11.4±0.2°, 13.7±0.2°, 4.6±0.2°, 24.2±0.2°, 24.8±0.2°, 26.2±0.2°, 22.6±0.2°, 17.2±0.2°, 19.1±0.2°, 17.7±0.2° or 20.3±0.2°; preferably, it includes diffraction peaks at 4, 5, 6, 8 or 10 of them;

[0091] The X-ray powder diffraction pattern of Form II optionally includes one or more diffraction peaks located at 2θ of 20.9±0.2°, 16.1±0.2°, 24.2±0.2°, 17.4±0.2°, 27.3±0.2°, 26.8±0.2°, 6.9±0.2°, 17.8±0.2°, 11.4±0.2°, 19.0±0.2°, 32.1±0.2° or 10.5±0.2°; preferably, it includes diffraction peaks at 4, 5, 6, 8 or 10 positions selected therefrom;

[0092] The X-ray powder diffraction pattern of Form III optionally includes one or more diffraction peaks located at 2θ of 10.3±0.2°, 20.7±0.2°, 26.8±0.2°, 11.3±0.2°, 26.5±0.2°, 14.3±0.2°, 22.8±0.2°, 16.1±0.2°, 21.9±0.2°, 12.2±0.2°, 13.2±0.2°, 25.8±0.2°, 24.3±0.2°, 18.5±0.2° or 7.1±0.2°; preferably, it includes diffraction peaks at 4, 5, 6, 8 or 10 of them;

[0093] The X-ray powder diffraction pattern of Form IV optionally includes one or more diffraction peaks located at 2θ of 25.2±0.2°, 15.1±0.2°, 14.2±0.2°, 14.8±0.2°, 21.6±0.2°, 12.4±0.2°, 24.9±0.2°, 18.3±0.2°, 23.7±0.2°, 11.4±0.2°, 26.8±0.2°, 8.5±0.2°, 17.5±0.2°, 20.6±0.2° or 16.3±0.2°; preferably, it includes diffraction peaks at 4, 5, 6, 8 or 10 of them;

[0094] The X-ray powder diffraction pattern of Form V optionally includes one or more diffraction peaks located at 2θ of 25.4±0.2°, 15.3±0.2°, 15.0±0.2°, 14.4±0.2°, 21.8±0.2°, 12.6±0.2°, 24.6±0.2°, 23.9±0.2°, 18.5±0.2°, 8.7±0.2°, 11.6±0.2°, 17.7±0.2°, 23.3±0.2°, 25.7±0.2° or 20.8±0.2°; preferably, it includes diffraction peaks at 4, 5, 6, 8 or 10 of them;

[0095] The X-ray powder diffraction pattern of Form VI optionally includes one or more diffraction peaks located at 2θ of 11.3±0.2°, 10.2±0.2°, 22.6±0.2°, 16.0±0.2°, 25.8±0.2°, 20.7±0.2°, 7.0±0.2°, 14.5±0.2°, 22.2±0.2°, 21.7±0.2°, 21.3±0.2°, 27.6±0.2°, 23.1±0.2°, 23.8±0.2° or 29.6±0.2°; preferably, it includes diffraction peaks at 4, 5, 6, 8 or 10 of them;

[0096] The X-ray powder diffraction pattern of Form VII optionally comprises one or more diffraction peaks located at 2θ of 8.9±0.2°, 10.4±0.2°, 24.3±0.2°, 25.6±0.2°, 14.0±0.2°, 18.0±0.2°, 20.1±0.2°, 22.5±0.2°, 27.5±0.2°, 27.2±0.2°, 29.4±0.2°, 31.8±0.2°, 21.1±0.2°, 20.5±0.2° or 16.6±0.2°; preferably, it comprises diffraction peaks at 4, 5, 6, 8 or 10 of them;

[0097] The X-ray powder diffraction pattern of Form X1 optionally comprises one or more diffraction peaks located at 2θ of 16.7±0.2°, 20.8±0.2°, 21.7±0.2°, 25.2±0.2°, 17.0±0.2°, 17.6±0.2°, 12.9±0.2°, 23.4±0.2°, 14.8±0.2°, 9.0±0.2°, 14.4±0.2°, 18.6±0.2° or 19.4±0.2°; preferably,

[0098] Including 4, 5, 6, 8 or 10 diffraction peaks selected therefrom;

[0099] The X-ray powder diffraction pattern of Form X2 optionally includes one or more diffraction peaks located at 2θ of 9.5±0.2°, 19.8±0.2°, 15.2±0.2°, 28.8±0.2°, 10.8±0.2°, 14.1±0.2°, 24.5±0.2°, 26.6±0.2°, 38.8±0.2°, 39.2±0.2° or 49.4±0.2°; preferably, it includes diffraction peaks at 4, 5, 6, 8 or 10 of them;

[0100] The X-ray powder diffraction pattern of Form X3 optionally includes one or more diffraction peaks located at 2θ of 12.0±0.2°, 14.4±0.2°, 7.2±0.2°, 25.8±0.2°, 13.5±0.2°, 21.6±0.2°, 4.9±0.2°, 16.7±0.2°, 17.8±0.2°, 17.4±0.2°, 12.9±0.2°, 23.0±0.2°, 24.0±0.2°, 25.3±0.2° or 15.8±0.2°; preferably, it includes diffraction peaks at 4, 5, 6, 8 or 10 of them;

[0101] The X-ray powder diffraction pattern of Form X4 optionally includes one or more diffraction peaks located at 2θ of 11.3±0.2°, 10.2±0.2°, 22.6±0.2°, 20.7±0.2°, 14.2±0.2°, 16.1±0.2°, 7.1±0.2°, 14.5±0.2°, 25.8±0.2°, 21.4±0.2°, 26.5±0.2°, 26.8±0.2°, 13.2±0.2°, 18.5±0.2° or 22.2±0.2°; preferably, it includes diffraction peaks at 4, 5, 6, 8 or 10 of them;

[0102] The X-ray powder diffraction pattern of Form X5 optionally includes one or more diffraction peaks located at 2θ of 11.4±0.2°, 13.6±0.2°, 17.5±0.2°, 12.2±0.2°, 24.8±0.2°, 18.7±0.2°, 23.4±0.2°, 22.9±0.2°, 21.8±0.2°, 22.4±0.2°, 14.4±0.2°, 27.3±0.2°, 25.3±0.2°, 15.5±0.2° or 16.5±0.2°; preferably, it includes diffraction peaks at 4, 5, 6, 8 or 10 of them;

[0103] The X-ray powder diffraction pattern of Form X6 optionally includes one or more diffraction peaks located at 2θ of 11.4±0.2°, 10.2±0.2°, 20.7±0.2°, 22.6±0.2°, 25.9±0.2°, 16.1±0.2°, 7.1±0.2°, 14.6±0.2°, 12.2±0.2°, 18.5±0.2°, 19.5±0.2°, 21.4±0.2°, 21.8±0.2°, 22.3±0.2° or 26.5±0.2°; preferably, it includes diffraction peaks at 4, 5, 6, 8 or 10 of them.

[0104] In a further preferred embodiment of the present invention, the crystalline form I of the compound N-(3-chloro-4-(2H-1,2,3-triazol-2-yl)phenyl)-1-(2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide, using Cu-Kα radiation, the X-ray characteristic diffraction peaks represented by 2θ angles and interplanar spacing d values ​​are shown in Table 1.

[0105] Table 1 XRPD diffraction data of compound free base form I

[0106]

[0107] The crystalline form I of the compound N-(3-chloro-4-(2H-1,2,3-triazol-2-yl)phenyl)-1-(2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide of the present invention has an X-ray powder diffraction pattern substantially as follows Figure 1 shown.

[0108] In a further preferred embodiment of the present invention, the crystalline form II of the compound N-(3-chloro-4-(2H-1,2,3-triazol-2-yl)phenyl)-1-(2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide, using Cu-Kα radiation, the X-ray characteristic diffraction peaks represented by 2θ angles and interplanar spacing d values ​​are shown in Table 2.

[0109] Table 2 XRPD diffraction data of free base form II of the compound

[0110]

[0111] The crystalline form II of the compound N-(3-chloro-4-(2H-1,2,3-triazol-2-yl)phenyl)-1-(2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide of the present invention has an X-ray powder diffraction pattern substantially as follows Figure 2 shown.

[0112] In a further preferred embodiment of the present invention, the crystalline form III of the compound N-(3-chloro-4-(2H-1,2,3-triazol-2-yl)phenyl)-1-(2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide, using Cu-Kα radiation, the X-ray characteristic diffraction peaks represented by 2θ angles and interplanar spacing d values ​​are shown in Table 3.

[0113] Table 3 XRPD diffraction data of compound free base form III

[0114]

[0115] The crystalline form III of the compound N-(3-chloro-4-(2H-1,2,3-triazol-2-yl)phenyl)-1-(2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide of the present invention has an X-ray powder diffraction pattern substantially as follows Figure 3 shown.

[0116] In a further preferred embodiment of the present invention, the crystalline form IV of the compound N-(3-chloro-4-(2H-1,2,3-triazol-2-yl)phenyl)-1-(2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide, using Cu-Kα radiation, the X-ray characteristic diffraction peaks represented by 2θ angles and interplanar spacing d values ​​are shown in Table 4.

[0117] Table 4 XRPD diffraction data of compound free base form IV

[0118]

[0119]

[0120] The crystalline form IV of the compound N-(3-chloro-4-(2H-1,2,3-triazol-2-yl)phenyl)-1-(2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide of the present invention has an X-ray powder diffraction pattern substantially as follows Figure 4 shown.

[0121] In a further preferred embodiment of the present invention, the crystalline form V of the compound N-(3-chloro-4-(2H-1,2,3-triazol-2-yl)phenyl)-1-(2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide, using Cu-Kα radiation, the X-ray characteristic diffraction peaks represented by 2θ angles and interplanar spacing d values ​​are shown in Table 5.

[0122] Table 5 XRPD diffraction data of compound free base form V

[0123]

[0124] The crystalline form V of the compound N-(3-chloro-4-(2H-1,2,3-triazol-2-yl)phenyl)-1-(2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide of the present invention has an X-ray powder diffraction pattern substantially as follows Figure 5 shown.

[0125] In a further preferred embodiment of the present invention, the crystalline form VI of the compound N-(3-chloro-4-(2H-1,2,3-triazol-2-yl)phenyl)-1-(2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide, using Cu-Kα radiation, the X-ray characteristic diffraction peaks represented by 2θ angles and interplanar spacing d values ​​are shown in Table 6.

[0126] Table 6 XRPD diffraction data of compound free base form VI

[0127]

[0128]

[0129] The crystalline form VI of the compound N-(3-chloro-4-(2H-1,2,3-triazol-2-yl)phenyl)-1-(2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide of the present invention has an X-ray powder diffraction pattern substantially as follows Figure 6 shown.

[0130] In a further preferred embodiment of the present invention, the crystalline form VII of the compound N-(3-chloro-4-(2H-1,2,3-triazol-2-yl)phenyl)-1-(2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide, using Cu-Kα radiation, the X-ray characteristic diffraction peaks expressed by 2θ angles and interplanar spacing d values ​​are shown in Table 7.

[0131] Table 7 XRPD diffraction data of compound free base form VII

[0132]

[0133] The crystalline form VII of the compound of the present invention N-(3-chloro-4-(2H-1,2,3-triazol-2-yl)phenyl)-1-(2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide has an X-ray powder diffraction pattern substantially as follows Figure 7 shown.

[0134] In a further preferred embodiment of the present invention, the crystalline form VIII of the compound N-(3-chloro-4-(2H-1,2,3-triazol-2-yl)phenyl)-1-(2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide, using Cu-Kα radiation, the X-ray characteristic diffraction peaks represented by 2θ angles and interplanar spacing d values ​​are shown in Table 8.

[0135] Table 8 XRPD diffraction data of compound free base form VIII

[0136]

[0137] The crystalline form VIII of the compound of the present invention, N-(3-chloro-4-(2H-1,2,3-triazol-2-yl)phenyl)-1-(2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide, has an X-ray powder diffraction pattern substantially as follows Figure 8 shown.

[0138] In a further preferred embodiment of the present invention, the crystalline form X1 of the compound N-(3-chloro-4-(2H-1,2,3-triazol-2-yl)phenyl)-1-(2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide, using Cu-Kα radiation, the X-ray characteristic diffraction peaks expressed by 2θ angles and crystal plane spacing d values ​​are shown in Table 9.

[0139] Table 9 XRPD diffraction data of compound free base crystal form X1

[0140]

[0141] The crystalline form X1 of the compound of the present invention, N-(3-chloro-4-(2H-1,2,3-triazol-2-yl)phenyl)-1-(2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide, has an X-ray powder diffraction pattern substantially as follows: Fig. 9 shown.

[0142] In a further preferred embodiment of the present invention, the crystalline form X2 of the compound N-(3-chloro-4-(2H-1,2,3-triazol-2-yl)phenyl)-1-(2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide, using Cu-Kα radiation, the X-ray characteristic diffraction peaks expressed by 2θ angles and crystal plane spacing d values ​​are shown in Table 10.

[0143] Table 10 XRPD diffraction data of compound free base crystal form X2

[0144]

[0145]

[0146] The crystalline form X2 of the compound of the present invention, N-(3-chloro-4-(2H-1,2,3-triazol-2-yl)phenyl)-1-(2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide, has an X-ray powder diffraction pattern substantially as follows Fig.10 shown.

[0147] In a further preferred embodiment of the present invention, the crystalline form X3 of the compound N-(3-chloro-4-(2H-1,2,3-triazol-2-yl)phenyl)-1-(2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide, using Cu-Kα radiation, the X-ray characteristic diffraction peaks expressed by 2θ angles and crystal plane spacing d values ​​are shown in Table 11.

[0148] Table 11 XRPD diffraction data of compound free base crystal form X3

[0149]

[0150] The crystalline form X3 of the compound N-(3-chloro-4-(2H-1,2,3-triazol-2-yl)phenyl)-1-(2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide of the present invention has an X-ray powder diffraction pattern substantially as follows Fig.11 shown.

[0151] In a further preferred embodiment of the present invention, the crystalline form X4 of the compound N-(3-chloro-4-(2H-1,2,3-triazol-2-yl)phenyl)-1-(2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide, using Cu-Kα radiation, the X-ray characteristic diffraction peaks expressed by 2θ angles and crystal plane spacing d values ​​are shown in Table 12.

[0152] Table 12 XRPD diffraction data of compound free base crystal form X4

[0153]

[0154]

[0155] The crystalline form X4 of the compound N-(3-chloro-4-(2H-1,2,3-triazol-2-yl)phenyl)-1-(2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide of the present invention has an X-ray powder diffraction pattern substantially as follows Fig.12 shown.

[0156] In a further preferred embodiment of the present invention, the crystalline form X5 of the compound N-(3-chloro-4-(2H-1,2,3-triazol-2-yl)phenyl)-1-(2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide, using Cu-Kα radiation, the X-ray characteristic diffraction peaks expressed by 2θ angles and crystal plane spacing d values ​​are shown in Table 13.

[0157] Table 13 XRPD diffraction data of compound free base crystal form X5

[0158]

[0159] The crystalline form X5 of the compound of the present invention, N-(3-chloro-4-(2H-1,2,3-triazol-2-yl)phenyl)-1-(2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide, has an X-ray powder diffraction pattern substantially as follows: Fig.13 shown.

[0160] In a further preferred embodiment of the present invention, the crystalline form X6 of the compound N-(3-chloro-4-(2H-1,2,3-triazol-2-yl)phenyl)-1-(2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide, using Cu-Kα radiation, the X-ray characteristic diffraction peaks expressed by 2θ angles and crystal plane spacing d values ​​are shown in Table 14.

[0161] Table 14 XRPD diffraction data of compound free base crystal form X6

[0162]

[0163] The crystalline form X6 of the compound of the present invention, N-(3-chloro-4-(2H-1,2,3-triazol-2-yl)phenyl)-1-(2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide, has an X-ray powder diffraction pattern substantially as follows: Fig.14 shown.

[0164] The positions of the top ten diffraction peaks with the highest relative peak intensity in the X-ray powder diffraction patterns of Form I, Form II, Form III, Form IV, Form V, Form VI, Form VII, Form VIII, Form X1, Form X2, Form X3, Form X4, Form X5 and Form X6 are the same as those in the above table. Figure 1 , Figure 2 , Figure 3 , Figure 4 , Figure 5 , Figure 6 , Figure 7 , Figure 8 , Fig. 9 , Fig.10 , Fig.11 , Fig.12 , Fig.13 and Fig.14The 2θ error of the diffraction peak at the corresponding position is ±0.2° to ±0.5°; preferably ±0.2° to ±0.3°; most preferably ±0.2°.

[0165] The error described in the present invention refers to a certain degree of overall drift in the diffraction peak position in the X-ray powder diffraction patterns of different batches of samples caused by experimental error factors such as differences in sample preparation technology levels, standardization of operations, sample preparation thickness, and use of different sample holders during the experiment. For those skilled in the art, the overall drift of the diffraction peak position due to experimental errors is predictable.

[0166] In a further preferred embodiment of the present invention, the crystalline form is an anhydrate.

[0167] In a further preferred embodiment of the present invention, the crystal form is a hydrate, and the number of water is 0.2-3, preferably 0.2, 0.5, 1, 1.5, 2, 2.5 or 3, and more preferably 0.5, 1, 2 or 3.

[0168] In a further preferred embodiment of the present invention, the method for preparing the above-mentioned compound crystal form specifically comprises the following steps:

[0169] 1) Weigh an appropriate amount of free base or its crystal form and dissolve it in an organic solvent;

[0170] 2) Optionally, add an anti-solvent to the above solution and stir until a solid precipitates;

[0171] 3) Optionally, stirring, cooling and crystallizing to obtain the target product;

[0172] in:

[0173] The organic solvent is selected from one or more of methanol, acetone, ethyl acetate, acetonitrile, ethanol, tetrahydrofuran, 2-methyltetrahydrofuran, dichloromethane, 1,4-dioxane, benzene, toluene, isopropanol, n-butanol, isobutanol, N,N-dimethylformamide, N,N-dimethylacetamide, n-propanol, tert-butanol, 2-butanone, 3-pentanone and N-methylpyrrolidone; preferably one or more of methanol, acetone, 2-butanone, ethyl acetate, tetrahydrofuran or acetonitrile; more preferably acetone or 2-butanone;

[0174] The anti-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 one or more of n-heptane, methyl tert-butyl ether or isopropyl ether;

[0175] In a further preferred embodiment of the present invention, the method for preparing the above-mentioned compound crystal form specifically comprises the following steps: weighing an appropriate amount of free base or its crystal form, and beating the mixture with a poor solvent at a certain temperature, preferably 0 to 65°C;

[0176] Wherein: the poor solvent is selected from one or more of methanol, ethanol, acetonitrile, ethyl acetate, acetone, tetrahydrofuran, 2-methyltetrahydrofuran, dichloromethane, isopropanol, 2-butanone, isopropyl acetate, ethyl formate, 1,4-dioxane, benzene, toluene, n-butanol, isobutanol, N,N-dimethylformamide, N,N-dimethylacetamide, n-propanol, tert-butanol, 3-pentanone, methyl tert-butyl ether or water; preferably methanol, isopropanol, acetonitrile, ethyl acetate, methyl tert-butyl ether, acetone, dichloromethane, isopropyl acetate, tetrahydrofuran, 2-methyl-tetrahydrofuran, 2-butanone or water; more preferably methanol, isopropanol, methyl tert-butyl ether, acetone or 2-butanone;

[0177] In a further preferred embodiment of the present invention, the method for preparing the above-mentioned compound crystal form specifically comprises the following steps:

[0178] 1) Weigh an appropriate amount of free base or its crystal form and add an organic solvent;

[0179] 2) heating and filtering, preferably at a temperature of 50 to 85°C;

[0180] 3) cooling the filtrate and crystallizing to obtain the target product;

[0181] Wherein: the organic solvent is selected from one or more of methanol, acetone, ethyl acetate, acetonitrile, ethanol, tetrahydrofuran, 2-methyltetrahydrofuran, dichloromethane, 1,4-dioxane, benzene, toluene, isopropanol, n-butanol, isobutanol, N,N-dimethylformamide, N,N-dimethylacetamide, n-propanol, tert-butanol, 2-butanone, 3-pentanone and N-methylpyrrolidone; preferably one or more of methanol, isopropanol, 2-butanone, acetonitrile or ethanol;

[0182] In a further preferred embodiment of the present invention, the method for preparing the above-mentioned compound crystal form specifically comprises the following steps: weighing an appropriate amount of free base or its crystal form, heating and drying to obtain the target product, and the temperature is preferably 50-85°C.

[0183] The present invention also aims to provide a pharmaceutical composition, which contains a therapeutically effective amount of a crystalline form of any of the above compounds, and one or more pharmaceutically acceptable carriers, diluents or excipients.

[0184] The present invention also aims to provide the use of any of the above-mentioned compounds in a crystalline form or the above-mentioned pharmaceutical composition in the preparation of MALT1 inhibitor drugs.

[0185] The present invention also aims to provide a use of a crystalline form of any of the above compounds or the above pharmaceutical composition in the preparation of a method for treating cancer or an autoimmune disease; wherein the cancer or autoimmune disease is selected from B-cell lymphoma, non-Hodgkin's lymphoma, mantle cell lymphoma, follicular lymphoma, mucosa-associated lymphoid tissue lymphoma, chronic lymphocytic leukemia, rheumatoid arthritis, psoriatic arthritis, psoriasis, ulcerative colitis, Crohn's disease, systemic lupus erythematosus, asthma or chronic obstructive pulmonary disease.

[0186] In certain embodiments of the present invention, the cancer or autoimmune disease is a cancer or autoimmune disease caused by mutation or overexpression of the MALT1 gene.

[0187] Detailed description of the invention

[0188] Unless stated otherwise, the terms used in the specification and claims have the following meanings.

[0189] 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 8 carbon atoms, more 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, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2, 3-Dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched chain isomers thereof. More preferred are lower alkyl groups having 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, 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.

[0190] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, the cycloalkyl ring containing 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, more 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 spiro rings, fused rings and bridged rings, preferably cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl and cycloheptyl.

[0191] The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent containing 3 to 20 ring atoms, one or more of which is selected from nitrogen, oxygen 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; further preferably, it contains 3-8 membered heterocyclic groups containing 1-3 nitrogen atoms, optionally substituted by 1-2 oxygen atoms, sulfur atoms, oxo groups, including nitrogen-containing monocyclic heterocyclic groups, nitrogen-containing spiro heterocyclic groups or nitrogen-containing fused heterocyclic groups; further preferably, it contains 3 to 7 ring atoms, of which 1 to 4 are heteroatoms; in one embodiment, the heterocyclic group contains 3, 4, 5, 6, 7 or 8 ring atoms.

[0192] Non-limiting examples of monocyclic heterocyclic groups include pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, azepanyl, 1,4-diazepanyl, pyranyl, etc., preferably pyrrolidinyl, morpholinyl, piperidinyl, azepanyl, 1,4-diazepanyl and piperazinyl. Polycyclic heterocyclic groups include spirocyclic, condensed and bridged heterocyclic groups; wherein the spirocyclic, condensed and bridged heterocyclic groups are optionally connected to other groups by single bonds, or further connected to other cycloalkyl, heterocyclic, aryl and heteroaryl groups by any two or more atoms on the ring.

[0193] The heterocyclyl group may be optionally substituted or unsubstituted, and when substituted, the substituents are 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.

[0194] The term "aryl" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (i.e., a ring sharing adjacent pairs of carbon atoms) group having a conjugated π electron system, preferably 6- to 12-membered, such as phenyl and naphthyl. More preferably phenyl. The aryl ring may be fused to a heteroaryl, heterocyclic or cycloalkyl ring, including benzo 5-10-membered heteroaryl, benzo 3-8-membered cycloalkyl and benzo 3-8-membered heteroalkyl, preferably benzo 5-6-membered heteroaryl, benzo 3-6-membered cycloalkyl and benzo 3-6-membered heteroalkyl, wherein the heterocyclic group is a heterocyclic group containing 1-3 nitrogen atoms, oxygen atoms, and sulfur atoms; or further comprising a three-membered nitrogen-containing fused ring containing a benzene ring.

[0195] Wherein the ring attached to the parent structure is an aryl ring, non-limiting examples of which include:

[0196]

[0197] wait.

[0198] The aryl 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, carboxyl or carboxylate.

[0199] The term "heteroaryl" refers to a heteroaromatic system containing 1 to 4 heteroatoms and 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen. The heteroaryl is preferably 5 to 12 yuan, more preferably 5 to 8 yuan, further preferably 5 to 7 yuan, and further preferably 5 yuan or 6 yuan, such as imidazolyl, furanyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, triazolyl, tetrazolyl, pyridyl, pyrimidyl, thiadiazole, pyrazinyl, etc., preferably triazolyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, pyrimidyl or thiazolyl; more preferably pyrazolyl, pyrrolyl, imidazolyl, triazolyl, oxazolyl or pyridyl. The heteroaryl ring can be fused to an aryl, heterocyclic or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring, and its non-limiting examples include:

[0200]

[0201] wait.

[0202] The heteroaryl group may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.

[0203] The term "alkoxy" refers to-O-(alkyl) and-O-(unsubstituted cycloalkyl), wherein the definition of alkyl is as described above. The non-limiting examples of alkoxy include: methoxy, ethoxy, propoxy, butoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy. Alkoxy 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.

[0204] "Haloalkyl" refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined above.

[0205] "Haloalkoxy" refers to an alkoxy group substituted with one or more halogens, wherein alkoxy is as defined above.

[0206] "Hydroxyalkyl" refers to an alkyl group substituted with a hydroxy group, wherein alkyl is as defined above.

[0207] 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.

[0208] 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.

[0209] "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.

[0210] "Substituted" means that one or more hydrogen atoms, preferably 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 those skilled in the art can determine (by experiment or theory) possible or impossible substitutions without undue effort. For example, amino or hydroxy groups with free hydrogen may be unstable when combined with carbon atoms with unsaturated (such as olefinic) bonds. BRIEF DESCRIPTION OF THE DRAWINGS

[0211] Figure 1 This is an XRPD diagram of free base Form I.

[0212] Figure 2 This is an XRPD diagram of the free base form II.

[0213] Figure 3 This is an XRPD diagram of the free base form III.

[0214] Figure 4 This is an XRPD diagram of free base Form IV.

[0215] Figure 5 This is an XRPD diagram of the free base form V.

[0216] Figure 6 This is an XRPD diagram of the free base form VI.

[0217] Figure 7 This is the XRPD diagram of free base form VII.

[0218] Figure 8 This is an XRPD diagram of the free base form VIII.

[0219] Fig. 9 This is an XRPD diagram of the free base form X1.

[0220] Fig.10 This is an XRPD diagram of the free base form X2.

[0221] Fig.11 This is an XRPD diagram of the free base form X3.

[0222] Fig.12 This is an XRPD diagram of the free base form X4.

[0223] Fig.13 This is an XRPD diagram of the free base form X5.

[0224] Fig.14 This is an XRPD diagram of the free base form X6. DETAILED DESCRIPTION

[0225] 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.

[0226] Example

[0227] The structures of the compounds of the present invention are determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). -6 The NMR measurements were performed using a Bruker AVANCE-400 NMR spectrometer, and the solvent used was deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDCl 3 ), deuterated methanol (CD 3 OD), and the internal standard was tetramethylsilane (TMS).

[0228] MS was measured using a FINNIGAN LCQAd (ESI) mass spectrometer (manufacturer: Thermo, model: Finnigan LCQadvantage MAX).

[0229] HPLC analysis 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).

[0230] Average kinase inhibition rate and IC 50 The values ​​were determined using NovoStar microplate reader (BMG, Germany).

[0231] The thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate. The silica gel plate used in thin layer chromatography (TLC) adopts a specification of 0.15mm-0.2mm, and the specification used for thin layer chromatography separation and purification products is 0.4mm-0.5mm.

[0232] Column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier.

[0233] The known starting materials of the present invention can be synthesized by methods known in the art, or can be purchased from ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, AccelaChemBio Inc, Darui Chemicals and other companies.

[0234] Unless otherwise specified in the examples, the reactions can be carried out under an argon atmosphere or a nitrogen atmosphere.

[0235] Argon atmosphere or nitrogen atmosphere means that the reaction bottle is connected to an argon or nitrogen balloon with a capacity of about 1L.

[0236] Hydrogen atmosphere means that the reaction bottle is connected to a hydrogen balloon with a capacity of about 1L.

[0237] The pressurized hydrogenation reaction uses a Parr 3916EKX hydrogenator and a Qinglan QL-500 hydrogen generator or a HC2-SS hydrogenator.

[0238] The hydrogenation reaction is usually carried out by evacuating the vacuum, filling with hydrogen, and repeating the operation three times.

[0239] The microwave reaction was carried out using a CEM Discover-S 908860 microwave reactor.

[0240] Unless otherwise specified in the examples, the solution refers to an aqueous solution, and the reaction temperature is room temperature, 20°C to 30°C.

[0241] The reaction progress in the embodiment is monitored by thin layer chromatography (TLC), and the developing solvent system used in the reaction includes: A: dichloromethane and methanol system, B: n-hexane and ethyl acetate system, C: petroleum ether and ethyl acetate system, D: acetone, and the volume ratio of the solvent is adjusted according to the polarity of the compound. The eluent system of column chromatography and the developing solvent system of thin layer chromatography used for purifying the compound include: A: n-hexane and ethyl acetate system, B: n-hexane and tetrahydrofuran system, and 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.

[0242] Intermediate 1

[0243] 1-(2-Carbonyl-1,2-dihydrobenzo[cd]indol-6-yl)-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid

[0244] Step 1: 6-Bromobenz[cd]indol-2(1H)-one

[0245] Dissolve benzo[cd]indol-2(1H)-one (20 g, 118.2 mmol) in 150 mL of glacial acetic acid, add liquid bromine (37.8 g, 236.5 mmol) dropwise to the reaction solution under ice bath, and stir at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure to obtain the title product 6-bromobenzo[cd]indol-2(1H)-one (18.7 g), yield: 63.8%. MS m / z (ESI): 248 [M+1].

[0246] Step 2: 6-Bromo-1-(4-methoxybenzyl)benzo[cd]indol-2(1H)-one

[0247] 6-Bromobenz[cd]indol-2(1H)-one (10 g, 40.3 mmol) was dissolved in 200 mL dimethylformamide, 4-methoxybenzyl bromide (12.2 g, 61.5 mmol) and potassium carbonate (11.3 g, 82 mmol) were added, and the mixture was stirred at room temperature for 16 hours. The reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system A to obtain the title product 6-bromo-1-(4-methoxybenzyl)benzo[cd]indol-2(1H)-one (10.7 g), yield: 72.1%. MS m / z (ESI): 368 [M+1].

[0248] Step 3: 6-Hydrazino-1-(4-methoxybenzyl)benzo[cd]indol-2(1H)-one

[0249] Palladium chloride (π-cinnamyl) dimer (229.4 mg, 0.44 mmol) and N-[2-di(1-adamantane)phosphinophenyl]morpholine (415.5 mg, 0.89 mmol) were dissolved in 5 mL of dioxane and stirred at room temperature for 15 minutes. 6-Bromo-1-(4-methoxybenzyl)benzo[cd]indol-2(1H)-one (3.3 g, 8.96 mmol) and sodium tert-butoxide (1.72 g, 17.90 mmol) were dissolved in 50 mL of dioxane and added to the reaction solution, and stirred at room temperature for 5 minutes. Hydrazine hydrate (897.3 mg, 17.92 mmol) was added to the reaction solution, and stirred at 50°C for 2 hours. The reaction solution was filtered, and the residue was washed with 20 mL of ethyl acetate. The filtrate was concentrated under reduced pressure to obtain the title product 6-hydrazino-1-(4-methoxybenzyl)benzo[cd]indol-2(1H)-one (2.66 g), with a yield of 93.0%. MS m / z (ESI): 319 [M+1].

[0250] Step 4: 1-(1-(4-methoxybenzyl)-2-carbonyl-1,2-dihydrobenzo[cd]indol-6-yl)-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid ethyl ester

[0251] 6-Hydrazino-1-[(4-methoxybenzyl]benzo[cd]indol-2(1H)-one (2.66 g, 8.33 mmol), potassium carbonate (2.3 g, 16.7 mmol) and ethyl ethoxy-2-methylene trifluoroacetoacetate (4 g, 16.7 mmol) were dissolved in 50 mL of ethanol and stirred at 80°C for 3 hours. The reaction solution was concentrated under reduced pressure and the residue was purified by silica gel column chromatography using eluent system A to obtain the title product, ethyl 1-(1-(4-methoxybenzyl)-2-carbonyl-1,2-dihydrobenzo[cd]indol-6-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate (880 mg), yield: 21.3%. MS m / z (ESI): 496 [M+1].

[0252] Step 5: 1-(1-(4-methoxybenzyl)-2-carbonyl-1,2-dihydrobenzo[cd]indol-6-yl)-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid

[0253] 1-(1-(4-methoxybenzyl)-2-carbonyl-1,2-dihydrobenzo[cd]indol-6-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid ethyl ester (880 mg, 1.78 mmol) and sodium hydroxide (350 mg, 8.9 mmol) were dissolved in 2 mL tetrahydrofuran and 1 mL water, and stirred at 60°C for 16 hours. 2M hydrochloric acid was added to the reaction solution to adjust the pH to less than 7, and extracted with ethyl acetate (50 mL×3), and the organic phases were combined, washed with water (50 mL×1) and saturated sodium chloride solution (50 mL×1) in turn, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the title product 1-(1-(4-methoxybenzyl)-2-carbonyl-1,2-dihydrobenzo[cd]indol-6-yl)-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid (770 mg), with a yield of 93%. MS m / z(ESI):468[M+1]

[0254] Step 6: 1-(2-Carbonyl-1,2-dihydrobenzo[cd]indol-6-yl)-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid

[0255] 1-(1-(4-methoxybenzyl)-2-carbonyl-1,2-dihydrobenzo[cd]indol-6-yl)-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid (770 mg, 1.65 mmol) was dissolved in 20 mL of trifluoroacetic acid and stirred at 90°C for 16 hours. The reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system A to give the title intermediate 1-(2-carbonyl-1,2-dihydrobenzo[cd]indol-6-yl)-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid (450 mg) in a yield of 78.5%. MS m / z(ESI):348[M+1]

[0256] 1 H NMR (400 MHz, DMSO-d 6 )δ11.09(s,1H),8.33(s,1H),8.12(d,1H),7.86(dd,1H),7.69(d,1H),7.61(d,1H),7.08(d,1H).

[0257] Example 1

[0258] 1-(2-Carbonyl-1,2-dihydropyrrolo[2,3,4-ij]isoquinolin-5-yl)-5-trifluoromethyl-N-(2-trifluoromethylpyridin-4-yl)-1H-pyrazole-4-carboxamide

[0259]

[0260] Step 1: 8-Bromo-4-chloroisoquinolin-1(2H)-one

[0261] 8-Bromoisoquinolin-1(2H)-one 1a (5.00 g, 22.32 mmol) was dissolved in 50 mL of N,N-dimethylformamide, and N-chlorosuccinimide (3.15 g, 23.59 mmol) was added to the reaction solution under ice bath, and the reaction was stirred at room temperature for 12 hours. The mixture was extracted with ethyl acetate (50 mL × 3), and the organic phases were combined, washed with water (50 mL × 1) and saturated sodium chloride solution (50 mL × 1) in sequence, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system A to obtain 8-bromo-4-chloroisoquinolin-1(2H)-one 1b (4.70 g), with a yield of 81.5%. MS m / z (ESI): 258 [M+1]

[0262] Step 2: 8-Bromo-1,4-dichloroisoquinoline

[0263] 8-Bromo-4-chloroisoquinolin-1(2H)-one 1b (4.70 g, 18.18 mmol) was dissolved in 50 mL of phosphorus oxychloride and stirred at 100°C for 16 hours. The reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system A to obtain the title product 8-bromo-1,4-dichloroisoquinoline 1c (4.50 g), with a yield of 89.3%. MS m / z (ESI): 276 [M+1]

[0264] Step 3: 8-Bromo-4-chloro-1-iodoisoquinoline

[0265] 8-Bromo-1,4-dichloroisoquinoline 1c (4.50 g, 16.25 mmol) and sodium iodide (4.90 g, 32.69 mmol) were dissolved in 50 mL of acetonitrile and added to the reaction solution. The mixture was stirred at room temperature for 5 minutes. Trimethylsilyl chloride (3.30 mg, 30.37 mmol) was added to the reaction solution and stirred at 80°C for 12 hours. The reaction solution was concentrated under reduced pressure and the residue was purified by silica gel column chromatography with eluent system A to obtain the title product 8-bromo-4-chloro-1-iodoisoquinoline 1d (3.50 g) with a yield of 58.6%. MS m / z (ESI): 368 [M+1]

[0266] Step 4: 8-Bromo-4-chloro-1-cyanoisoquinoline

[0267] 8-Bromo-4-chloro-1-iodoisoquinoline 1d (3.50 g, 9.50 mmol), zinc cyanide (700 mg, 5.96 mmol) and tetrakis(triphenylphosphine)palladium (550 mg, 0.48 mmol) were dissolved in 50 mL of dimethylformamide and stirred at 80°C for 13 hours. The mixture was extracted with ethyl acetate (50 mL × 3), and the organic phases were combined and washed with water (50 mL × 1) and saturated sodium chloride solution (50 mL × 1) in sequence, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system A to obtain the title product 8-bromo-4-chloro-1-cyanoisoquinoline 1e (2.00 g), with a yield of 79.1%. MS m / z (ESI): 267 [M+1]

[0268] Step 5: 4-Chloro-8-(4-methoxybenzyl)amino-1-cyanoisoquinoline

[0269] 8-Bromo-4-chloro-1-cyanoisoquinoline 1e (2.00 g, 7.48 mmol) and 4-methoxybenzylamine (1.10 g, 8.02 mmol) were dissolved in 10 mL of dioxane, cesium carbonate (4.9 g, 15.04 mmol) and bis(dibenzylideneacetone)palladium (430 mg, 0.76 mmol) were added, and then stirred at 90°C for 16 hours. The mixture was extracted with ethyl acetate (50 mL × 3), and the organic phases were combined, washed with water (50 mL × 1) and saturated sodium chloride solution (50 mL × 1) in sequence, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system A to obtain the title product 4-chloro-8-(4-methoxybenzyl)amino-1-cyanoisoquinoline 1f (2.10 g), with a yield of 86.2%. MS m / z (ESI): 324 [M+1]

[0270] Step 6: 5-Chloro-1-(4-methoxybenzyl)pyrrolo[2,3,4-ij]isoquinolin-2(1H)-one

[0271] Dissolve 4-chloro-8-((4-methoxybenzyl)amino)isoquinoline-1-carbonitrile 1f (2.10 g, 6.48 mmol) in 20 mL of concentrated sulfuric acid and stir at 100°C for 16 hours. Add the reaction solution into ice water and filter to obtain the title product 5-chloro-1-(4-methoxybenzyl)pyrrolo[2,3,4-ij]isoquinolin-2(1H)-one 1g (450 mg), yield: 21.3%. MS m / z (ESI): 325 [M+1]

[0272] Step 7: 5-Hydrazino-1-(4-methoxybenzyl)pyrrolo[2,3,4-ij]isoquinolin-2(1H)-one

[0273] Palladium chloride (π-cinnamyl) dimer (35 mg, 0.068 mmol) and N-[2-di(1-adamantane)phosphinophenyl]morpholine (64 mg, 0.14 mmol) were dissolved in 5 mL of dioxane and stirred at room temperature for 15 minutes. 5-Chloro-1-(4-methoxybenzyl)pyrrolo[2,3,4-ij]isoquinolin-2(1H)-one 1 g (450 mg, 1.38 mmol) and sodium tert-butoxide (265 mg, 2.76 mmol) were dissolved in 50 mL of dioxane and added to the reaction solution, and stirred at room temperature for 5 minutes. Hydrazine hydrate (897 mg, 17.92 mmol) was added to the reaction solution, and stirred at 50°C for 2 hours. The reaction solution was filtered and the residue was washed with ethyl acetate (20 mL). The filtrate was concentrated under reduced pressure to obtain the title product 5-hydrazino-1-(4-methoxybenzyl)pyrrolo[2,3,4-ij]isoquinolin-2(1H)-one 1h (500 mg) as a crude product. MS m / z (ESI): 320 [M+1]

[0274] Step 8: 1-(1-(4-methoxybenzyl)-2-carbonyl-1,2-dihydropyrrolo[2,3,4-ij]isoquinolin-5-yl)-2-trifluoromethyl-1H-pyrrole-3-carboxylic acid ethyl ester

[0275] 5-Hydrazino-1-(4-methoxybenzyl)pyrrolo[2,3,4-ij]isoquinolin-2(1H)-one 1h (500 mg, 1.56 mmol) and ethyl ethoxy-2-methylene trifluoroacetoacetate (750 mg, 3.12 mmol) were dissolved in 10 mL of ethanol and stirred at 80°C for 3 hours. The reaction solution was concentrated under reduced pressure and the residue was purified by silica gel column chromatography using eluent system A to obtain the title product, ethyl 1-(1-(4-methoxybenzyl)-2-carbonyl-1,2-dihydropyrrolo[2,3,4-ij]isoquinolin-5-yl)-2-trifluoromethyl-1H-pyrrole-3-carboxylate 1i (200 mg), yield: 25.9%. MS m / z(ESI):496[M+1]

[0276] Step 9: 1-(1-(4-methoxybenzyl)-2-carbonyl-1,2-dihydropyrrolo[2,3,4-ij]isoquinolin-5-yl)-2-trifluoromethyl-1H-pyrrole-3-carboxylic acid

[0277] 1-(1-(4-methoxybenzyl)-2-carbonyl-1,2-dihydropyrrolo[2,3,4-ij]isoquinolin-5-yl)-2-trifluoromethyl-1H-pyrrole-3-carboxylic acid ethyl ester 1i (200 mg, 0.40 mmol) and sodium hydroxide (350 mg, 8.75 mmol) were dissolved in 4 mL of tetrahydrofuran and 2 mL of water, and the mixture was stirred at 30°C for 16 hours. 2M hydrochloric acid was added to the reaction solution to adjust the pH to less than 7, and the mixture was extracted with ethyl acetate (50 mL×3). The organic phases were combined, washed with water (50 mL×1) and saturated sodium chloride solution (50 mL×1) in sequence, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the title product 1-(1-(4-methoxybenzyl)-2-carbonyl-1,2-dihydropyrrolo[2,3,4-ij]isoquinolin-5-yl)-2-trifluoromethyl-1H-pyrrole-3-carboxylic acid 1j (100 mg), with a yield of 53.0%. MS m / z(ESI):468[M+1]

[0278] Step 10: 1-(2-oxo-1,2-dihydropyrrolo[2,3,4-ij]isoquinolin-5-yl)-2-trifluoromethyl-1H-pyrrole-3-carboxylic acid

[0279] 1-(1-(4-methoxybenzyl)-2-carbonyl-1,2-dihydropyrrolo[2,3,4-ij]isoquinolin-5-yl)-2-trifluoromethyl-1H-pyrrole-3-carboxylic acid 1j (100 mg, 0.21 mmol) was dissolved in 10 mL of trifluoroacetic acid and stirred at 90°C for 16 hours. The reaction solution was concentrated under reduced pressure and the residue was purified by silica gel column chromatography using eluent system C to give the title compound 1-(2-oxo-1,2-dihydropyrrolo[2,3,4-ij]isoquinolin-5-yl)-2-trifluoromethyl-1H-pyrrole-3-carboxylic acid 1k (75 mg) in a yield of 65.7%. MS m / z(ESI):348[M+1]

[0280] Step 11: 1-(2-Carbonyl-1,2-dihydropyrrolo[2,3,4-ij]isoquinolin-5-yl)-2-trifluoromethyl-N-(2-trifluoromethylpyridin-4-yl)-1H-pyrrole-3-carboxamide

[0281] 1-(2-Oxo-1,2-dihydropyrrolo[2,3,4-ij]isoquinolin-5-yl)-2-trifluoromethyl-1H-pyrrole-3-carboxylic acid 1k (70 mg, 0.20 mmol), 2-trifluoromethyl-4-aminopyridine (31 mg, 0.19 mmol), pyridine (76 mg, 0.96 mmol) and phosphorus oxychloride (73 mg, 0.48 mmol) were dissolved in 5 mL of dichloromethane and stirred at room temperature for 2 hours. Dichloromethane (50 mL) was added to the reaction solution, and the mixture was washed with water (50 mL × 1) and saturated sodium chloride solution (50 mL × 1) in sequence, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system A to obtain the title product 1-(1-(4-methoxybenzyl)-2-carbonyl-1,2-dihydropyrrolo[2,3,4-ij]isoquinolin-5-yl)-2-trifluoromethyl-N-(2-trifluoromethylpyridin-4-yl)-1H-pyrrole-3-carboxamide 1 (80 mg), yield: 81.24%. MS m / z (ESI): 492 [M+1].

[0282] Example 2

[0283] 1-(2-Carbonyl-1,2-dihydropyrrolo[4,3,2-ij]isoquinolin-6-yl)-5-trifluoromethyl-N-(2-trifluoromethylpyridin-4-yl)-1H-pyrazole-4-carboxamide

[0284]

[0285] Step 1: 8-Bromo-4-chloro-N-(4-methoxybenzyl)isoquinolin-1-amine

[0286] 8-Bromo-1,4-dichloroisoquinoline 2a (5.00 g, 18.05 mmol) was dissolved in 50 mL of acetonitrile, and 4-methoxybenzylamine (4.90 g, 35.72 mol) was added to the reaction solution, and the mixture was stirred at 80°C for 12 hours. The mixture was extracted with ethyl acetate (50 mL × 3), and the organic phases were combined, washed with water (50 mL × 1) and saturated sodium chloride solution (50 mL × 1) in sequence, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system A to obtain 8-bromo-4-chloro-N-(4-methoxybenzyl)isoquinolin-1-amine 2b (4.7 g), with a yield of 68.9%. MS m / z (ESI): 377 [M+1]

[0287] Referring to the synthesis methods of the fourth step, the sixth step to the eleventh step of Example 1, 1-(2-carbonyl-1,2-dihydropyrrolo[4,3,2-ij]isoquinolin-6-yl)-5-trifluoromethyl-N-(2-trifluoromethylpyridin-4-yl)-1H-pyrazole-4-carboxamide 2 (10 mg) was obtained from 8-bromo-4-chloro-N-(4-methoxybenzyl)isoquinolin-1-amine 2b (4.70 g, 12.44 mmol), yield: 0.2%. MS m / z (ESI): 492 [M+1].

[0288] 1 H NMR(400MHz,MeOD)δ8.63(d,J=5.6Hz,1H),8.37(s,1H),8.30(s,1H),8.23(d,J=2.0Hz,1H),8.16 (d,J=7.0Hz,1H),8.05(dd,J=8.2,7.0Hz,1H),7.97(dd,J=5.6,2.1Hz,1H),7.71(d,J=8.2Hz,1H).

[0289] Example 3

[0290] N-(6-(2H-1,2,3-triazol-2-yl)-5-chloropyridin-3-yl)-1-(2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)-5-trifluoromethyl-1H-pyrazole-4-carboxamide

[0291]

[0292] Referring to the synthesis method of the eleventh step of Example 1, intermediate 1 (18 mg, 0.052 mmol) and 6-(2H-1,2,3-triazol-2-yl)-3-amino-5-chloropyridine 3a (10 mg, 0.052 mmol, synthesized by the known method "Patent US20180170909A1") were used to obtain the title product N-(6-(2H-1,2,3-triazol-2-yl)-5-chloropyridin-3-yl)-1-(2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)-5-trifluoromethyl-1H-pyrazole-4-carboxamide 3 (16 mg) with a yield of 58.6%. MS m / z(ESI):525,527[M+1]

[0293] 1 H NMR (400 MHz, DMSO-d 6 )δ11.3(broad s,1H),11.0(s,1H),9.11(d,1H),8.93(d,1H),8.59(s,1H),8.22(s,2H),8.10(d,1H),7.84(dd,1H),7.77(d,1H),7.62(d,1H),7.13(d,1H).

[0294] Example 4

[0295] N-(6-(2H-1,2,3-triazol-2-yl)-5-trifluoromethylpyridin-3-yl)-1-(2-oxo-1,2-dihydrobenz[cd]indole

[0296] -6-yl)-5-trifluoromethyl-1H-pyrazole-4-carboxamide

[0297]

[0298] Referring to the synthesis method of the eleventh step of Example 1, intermediate 1 (18 mg, 0.052 mmol) and 6-(2H-1,2,3-triazol-2-yl)-3-amino-5-trifluoromethylpyridine 4a (12 mg, 0.052 mmol, synthesized by the known method "Patent US20180170909A1") were used to obtain the title product N-(6-(2H-1,2,3-triazol-2-yl)-5-trifluoromethylpyridin-3-yl)-1-(2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)-5-trifluoromethyl-1H-pyrazole-4-carboxamide 4 (16 mg) with a yield of 55.1%. MS m / z(ESI):559[M+1]

[0299] 1 H NMR (400 MHz, DMSO-d 6)δ11.4(broad s,1H),11.1(s,1H),9.18(d,1H),8.90(d,1H),8.57(s,1H),8.21(s,2H),8.15(d,1H),7.91(dd,1H),7.74(d,1H),7.61(d,1H),7.12(d,1H).

[0300] Example 5

[0301] N-(6-(oxazol-2-yl)-5-(trifluoromethyl)pyridin-3-yl)-1-(2-carbonyl-1,2-dihydrobenzo[cd]indol-6-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide

[0302]

[0303] Step 1: 2-(5-nitro-3-(trifluoromethyl)pyridin-2-yl)oxazole

[0304] 2-Bromo-5-nitro-3-(trifluoromethyl)pyridine 5a (302 mg, 1.12 mmol) was dissolved in 10 mL of toluene, tributyl(oxazol-2-yl)stannane (0.20 g, 0.56 mmol, 0.1 mL) and tetrakistriphenylphosphine palladium (64 mg, 0.056 mmol) were added, nitrogen was replaced three times, and the reaction was heated to 110 °C for 15 hours. The reaction was cooled to room temperature and concentrated. 10 mL of water was added to the residue, extracted with ethyl acetate (30 mL×3), the organic phases were combined, washed with saturated sodium chloride aqueous solution (30 mL×1), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography with eluent system C to obtain the title product 2-(5-nitro-3-(trifluoromethyl)pyridin-2-yl)oxazole 5b (20 mg), with a yield of 13.8%. MS m / z (ESI): 260 [M+1]

[0305] Step 2: 6-(Oxazol-2-yl)-5-(trifluoromethyl)pyridin-3-amine

[0306] 2-(5-nitro-3-(trifluoromethyl)pyridin-2-yl)oxazole 5b (0.20 g, 0.77 mmol) was dissolved in (5 mL) ethanol and (2 mL) water, and iron powder (215 mg, 3.85 mmol) and ammonium chloride (199 mg, 3.85 mmol) were added. The nitrogen was replaced three times, and the reaction was heated to 70 ° C for 2 hours. The reaction solution was cooled to room temperature, filtered, the filter cake was washed with ethanol (10 mL × 3), and the filtrate was concentrated. The residue was dissolved in (DCM / MeOH = 10 / 1, 30 mL), stirred for 1 hour, filtered, and concentrated to give the title product 6-(oxazol-2-yl)-5-(trifluoromethyl)pyridin-3-amine 5c (50 mg), yield: 28.3%. MS m / z (ESI): 230 [M+1]

[0307] Step 3: N-(6-(oxazol-2-yl)-5-(trifluoromethyl)pyridin-3-yl)-1-(2-carbonyl-1,2-dihydrobenzo[cd]indol-6-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide

[0308] 1-(2-Carbonyl-1,2-dihydrobenzo[cd]indol-6-yl)-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid (20 mg, 0.058 mmol), 6-(oxazol-2-yl)-5-(trifluoromethyl)pyridin-3-amine 5c (16 mg, 0.069 mmol) and DMAP (3 mg, 0.024 mmol) were dissolved in 5 mL of dichloromethane, nitrogen was replaced three times, cooled to 0°C, pyridine (14 mg, 0.17 mmol) and phosphorus oxychloride (26 mg, 0.17 mmol) were added, and the reaction temperature was raised to 25°C for 2 hours. The reaction was quenched by adding water and concentrated. The resulting residue was purified by silica gel column chromatography using eluent System A to give the title product, N-(6-(oxazol-2-yl)-5-(trifluoromethyl)pyridin-3-yl)-1-(2-carbonyl-1,2-dihydrobenzo[cd]indol-6-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide 5 (1.8 mg), yield: 5.2%. MS m / z (ESI): 559 [M+1]

[0309] 1H NMR (400MHz, DMSO): δ11.34(s,1H),11.13(s,1H),9.27(d,J=2.3Hz,1H),8.81(d,J=2.3Hz,1H),8.56(s,1H),8.39(s,1H),8.15 (d,J=7.0Hz,1H),7.92(dd,J=8.3,7.0Hz,1H),7.73(d,J=7.5Hz,1H),7.61(d,J=8.2Hz,1H),7.53(s,1H),7.12(d,J=7.5Hz,1H).

[0310] Example 6

[0311] N-(5-Difluoromethyl-6-(2H-1,2,3-triazol-2-yl)-pyridin-3-yl)-1-(2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)-5-trifluoromethyl-1H-pyrazole-4-carboxamide

[0312]

[0313] Referring to the synthesis method of the eleventh step of Example 1, 5-difluoromethyl-6-(2H-1,2,3-triazol-2-yl)pyridin-3-amine (21 mg, 0.10 mmol, prepared by the known method "WO2018020474") and intermediate 1 (34 mg, 0.10 mmol) were used to obtain the title product N-(5-difluoromethyl-6-(2H-1,2,3-triazol-2-yl)-pyridin-3-yl)-1-(2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)-5-trifluoromethyl-1H-pyrazole-4-carboxamide (21 mg), yield: 38.8%. MS m / z(ESI):541[M+1]

[0314] 1 H NMR (400 MHz, DMSO-d 6 )δ11.13(bs,2H),9.07(d,1H),8.78(d,1H),8.56(s,1H),8.25(s,2H),8.16 (d,1H),7.92(dd,1H),7.74(d,1H),7.62(d,1H),7.40(t,1H),7.13(t,1H).

[0315] Example 7

[0316] N-(4-(2H-1,2,3-triazol-2-yl)-3-(trifluoromethyl)phenyl)-1-(2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide

[0317]

[0318] The synthesis method of the eleventh step of reference example 1 was obtained by intermediate 1 (70 mg, 0.222 mmol) and 4-(2H-1,2,3-triazol-2-yl)-3-(trifluoromethyl)aniline 7a (100 mg, 0.44 mmol, synthesized by the known method "patent WO2018020474 A1") to obtain the title product N-(4-(2H-1,2,3-triazol-2-yl)-3-(trifluoromethyl)phenyl)-1-(2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide 7 (35 mg), yield: 28.5%. MS m / z(ESI):558[M+1]

[0319] 1 H NMR (400 MHz, DMSO-d 6 )δ11.12(d,J=4.4Hz,2H),8.54(s,1H),8.41(d,J=2.2Hz,1H),8.23(dd,J=8.7,2.2Hz,1H),8.17–8.12(m,3H),7.92 (dd,J=8.2,7.1Hz,1H),7.82(d,J=8.8Hz,1H),7.72(d,J=7.5Hz,1H),7.61(d,J=8.3Hz,1H),7.12(d,J=7.5Hz,1H).

[0320] Example 8

[0321] N-(3-chloro-4-(2H-1,2,3-triazol-2-yl)phenyl)-1-(2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)-5-

[0322] (Trifluoromethyl)-1H-pyrazole-4-carboxamide

[0323]

[0324] The intermediate 1 (70 mg, 0.22 mmol), 3-chloro-4-(2H-1,2,3-triazol-2-yl)aniline 8a (85 mg, 0.44 mmol, synthesized by the known method "Patent WO2018020474 A1"), pyridine (76 mg, 0.96 mmol) and phosphorus oxychloride (73 mg, 0.48 mmol) were dissolved in 5 mL of dichloromethane and stirred at room temperature for 2 hours. Dichloromethane (50 mL) was added to the reaction solution, and the mixture was washed with water (50 mL × 1) and saturated sodium chloride solution (50 mL × 1) in sequence, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system A to obtain the title product N-(3-chloro-4-(2H-1,2,3-triazol-2-yl)phenyl)-1-(2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide 8 (36 mg), yield: 31.2%. MS m / z (ESI): 524 [M+1]

[0325] 1 H NMR (400 MHz, DMSO-d 6 )δ11.12(s,1H),11.00(s,1H),8.52(s,1H),8.19–8.13(m,4H),7.95–7.8 4(m,2H),7.77–7.69(m,2H),7.61(d,J=8.3Hz,1H),7.12(d,J=7.5Hz,1H).

[0326] Example 9

[0327] 5-cyclopropyl-1-(2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)-N-(2-(trifluoromethyl)pyridin-4-yl)-1H-

[0328] Pyrazole-4-carboxamide

[0329]

[0330] Step 1: 5-cyclopropyl-1-(1-(4-methoxybenzyl)-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)-1H-pyrazole-4-carboxylic acid ethyl ester

[0331] 6-Hydrazino-1-[(4-methoxybenzyl]benzo[cd]indol-2(1H)-one (5.10 g, 15.99 mmol), potassium carbonate (4.14 g, 30 mmol) and ethyl 2-(cyclopropylcarbonyl)-3-(dimethylamino)acrylate (6.33 g, 30 mmol) were dissolved in 50 mL of ethanol and stirred at 80°C for 3 hours. The reaction solution was concentrated under reduced pressure and the residue was purified by silica gel column chromatography using eluent system A to obtain the title product 5-cyclopropyl-1-(1-(4-methoxybenzyl)-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)-1H-pyrazole-4-carboxylate 9a (1.60 g) in a yield of 21.4%. MS m / z (ESI): 468 [M+1].

[0332] Step 2: 5-cyclopropyl-1-(1-(4-methoxybenzyl)-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)-1H-pyrazole-4-carboxylic acid

[0333] Ethyl 5-cyclopropyl-1-(1-(4-methoxybenzyl)-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)-1H-pyrazole-4-carboxylate 9a (1.6 g, 3.42 mmol) and sodium hydroxide (673 mg, 17.11 mmol) were dissolved in 10 mL of tetrahydrofuran and 5 mL of water, and the mixture was stirred at 60 °C for 16 hours. 2M hydrochloric acid was added to the reaction solution to adjust the pH to less than 7, and the mixture was extracted with ethyl acetate (50 mL × 3). The organic phases were combined, washed with water (50 mL × 1) and saturated sodium chloride solution (50 mL × 1) in sequence, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the title product 5-cyclopropyl-1-(1-(4-methoxybenzyl)-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)-1H-pyrazole-4-carboxylic acid 9b (1.45 g), with a yield of 96.5%. MS m / z (ESI): 440 [M+1]

[0334] Step 3: 5-cyclopropyl-1-(2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)-1H-pyrazole-4-carboxylic acid

[0335] 5-Cyclopropyl-1-(1-(4-methoxybenzyl)-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)-1H-pyrazole-4-carboxylic acid 9b (1.45 g, 3.30 mmol) was dissolved in 20 mL of trifluoroacetic acid and stirred at 90°C for 16 hours. The reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system A to give the title product 5-cyclopropyl-1-(2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)-1H-pyrazole-4-carboxylic acid 9c (794 mg) in a yield of 75.2%. MS m / z(ESI):320[M+1]

[0336] Step 4: 5-cyclopropyl-1-(2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)-N-(2-trifluoromethylpyridin-4-yl)-1H-pyrazole-4-carboxamide

[0337] 5-Cyclopropyl-1-(2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)-1H-pyrazole-4-carboxylic acid 9c (64 mg, 0.20 mmol), 2-trifluoromethyl-4-aminopyridine (31 mg, 0.19 mmol), pyridine (76 mg, 0.96 mmol) and phosphorus oxychloride (73 mg, 0.48 mmol) were dissolved in 5 mL of dichloromethane and stirred at room temperature for 2 hours. Dichloromethane (50 mL) was added to the reaction solution, and the mixture was washed with water (50 mL × 1) and saturated sodium chloride solution (50 mL × 1) in sequence, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system A to obtain the title product 5-cyclopropyl-1-(2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)-N-(2-trifluoromethylpyridin-4-yl)-1H-pyrazole-4-carboxamide 9 (32 mg), yield: 34.4%. MS m / z (ESI): 464 [M+1].

[0338] 1 H NMR (400 MHz, DMSO-d 6 )δ11.05(s,1H),10.63(s,1H),8.67(d,J=5.5Hz,1H),8.32(s,1H),8.29(d,J=1.8Hz,1H),8.13(d,J=6.9Hz,1H),8.01(dd,J=5.6,1 .7Hz,1H),7.91–7.84(m,1H),7.70(dd,J=24.2,7.9Hz,2H),7.11(d,J=7.5Hz,1H),2.01(td,J=8.6,4.3Hz,1H),0.75–0.50(m,4H).

[0339] Example 10

[0340] N-(6-(2H-1,2,3-triazol-2-yl)-5-(trifluoromethyl)pyridin-3-yl)-5-cyclopropyl-1-(2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)-1H-pyrazole-4-carboxamide

[0341]

[0342] Referring to the synthesis method of the eleventh step of Example 1, 9c (70 mg, 0.22 mmol) and 6-(2H-1,2,3-triazol-2-yl)-3-amino-5-trifluoromethylpyridine 10a (100 mg, 0.44 mmol, synthesized by the known method "Patent US20180170909A1") were used to obtain the title product N-(6-(2H-1,2,3-triazol-2-yl)-5-(trifluoromethyl)pyridin-3-yl)-5-cyclopropyl-1-(2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)-1H-pyrazole-4-carboxamide 10 (31 mg) with a yield of 26.6%. MS m / z(ESI):531[M+1]

[0343] 1 H NMR (400 MHz, DMSO-d 6 )δ11.05(s,1H),10.74(s,1H),9.21(d,J=2.4Hz,1H),8.93(d,J=2.4Hz,1H),8.36(s,1H),8.21(s,2H),8.13(d,J=6.9Hz,1H),7 .92–7.86(m,1H),7.72(dd,J=20.8,7.9Hz,2H),7.12(d,J=7.5Hz,1H),2.10–1.98(m,1H),0.77–0.67(m,2H),0.66–0.54(m,2H).

[0344] Embodiment 11

[0345] N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)-pyridin-3-yl)-5-cyclopropyl-1-(2-oxo-1,2-dihydrobenzo[cd]

[0346] Indol-6-yl)-1H-pyrazole-4-carboxamide

[0347]

[0348] Referring to the synthesis method of the eleventh step of Example 1, 9c (35 mg, 0.10 mmol) and 6-(2H-1,2,3-triazol-2-yl)-3-amino-5-chloropyridine 11a (20 mg, 0.10 mmol, synthesized by the known method "Patent US20180170909A1") were used to obtain the title product N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)-pyridin-3-yl)-5-cyclopropyl-1-(2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)-1H-pyrazole-4-carboxamide 11 (25 mg) with a yield of 50.3%. MS m / z(ESI):497[M+1]

[0349] 1 H NMR (400 MHz, DMSO-d 6 )δ11.04(s,1H),10.61(s,1H),8.88(d,1H),8.70(d,1H),8.33(s,1H),8.18(s,2H),8.13(d,1H),7.88 (dd,1H),7.74(d,1H),7.68(d,1H),7.11(d,1H),2.02(ddd,1H),0.77-0.68(m,2H),0.64-0.55(m,2H).

[0350] Example 12

[0351] N-(3-chloro-4-(2H-1,2,3-triazol-2-yl)phenyl)-5-cyclopropyl-1-(2-oxo-1,2-dihydrobenzo[cd]indole-6-yl)-

[0352] 1H-pyrazole-4-carboxamide

[0353]

[0354] Referring to the synthesis method of the eleventh step of Example 1, 9c (35 mg, 0.10 mmol) and 3-chloro-4-(2H-1,2,3-triazol-2-yl)aniline 12a (19 mg, 0.10 mmol, synthesized by the known method "Patent WO2018020474A1") were used to obtain the title product N-(3-chloro-4-(2H-1,2,3-triazol-2-yl)phenyl)-5-cyclopropyl-1-(2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)-1H-pyrazole-4-carboxamide 12 (19 mg) with a yield of 38.3%. MS m / z(ESI):496[M+1]

[0355] 1 H NMR (400 MHz, DMSO-d6 )δ11.03(s,1H),10.35(s,1H),8.28(s,1H),8.20(d,1H),8.14(s,2H),8.12(d,1H),7.92-7.84(m,2H ),7.75(d,1H),7.67(dd,2H),7.11(d,1H),2.06-1.95(m,1H),0.75-0.66(m,2H),0.65-0.54(m,2H).

[0356] Embodiment 13

[0357] N-(6-(2H-1,2,3-triazol-2-yl)-5-(trifluoromethyl)pyridin-3-yl)-1-(2-carbonyl-1,2-dihydrobenzo[cd]indol-6-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide

[0358]

[0359] The synthesis method of the eleventh and twelfth steps of reference example 3 was used to obtain N-(6-(2H-1,2,3-triazol-2-yl)-5-(trifluoromethyl)pyridin-3-amine 13a (50 mg, 0.22 mmol) in a yield of 16.4% by using 6-(2H-1,2,3-triazol-2-yl)-5-(trifluoromethyl)pyridin-3-yl)-1-(2-carbonyl-1,2-dihydrobenzo[cd]indol-6-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide 13 (20 mg). MS m / z (ESI): 560 [M+1].

[0360] 1H NMR (400MHz, CD 3 OD)δ8.30(s,1H),8.23(d,J=2.1Hz,1H),8.15(d,J=7.0Hz,1H),8.06(dd,J=8.4,2.2Hz,1H),7.87 (dd,J=8.3,7.0Hz,1H),7.66(dd,J=9.2,7.9Hz,2H),7.50(d,J=8.3Hz,1H),7.13(d,J=7.5Hz,1H).

[0361] Embodiment 14

[0362] N-(3-chloro-4-(2H-1,2,3-triazol-2-yl)phenyl)-1-(2-carbonyl-1,2-dihydropyrrolo[4,3,2-ij]isoquinoline-6-yl)-

[0363] 1H-pyrazole-4-carboxamide

[0364]

[0365] The synthesis method of the eleventh and twelfth steps of reference example 3 was used to obtain N-(3-chloro-4-(2H-1,2,3-triazol-2-yl)phenyl)-1-(2-carbonyl-1,2-dihydropyrrolo[4,3,2-ij]isoquinolin-6-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide 14 (12 mg) from 3-chloro-4-(2H-1,2,3-triazol-2-yl)aniline 14a (50 mg, 0.26 mmol). Yield: 8.9%. MS m / z (ESI): 525 [M+1].

[0366] 1H NMR (400MHz, CD 3 OD)δ8.33(d,J=12.5Hz,2H),8.23–8.12(m,2H),8.06(dd,J=8.2,7.0Hz,1H),7.99 (s,2H),7.81(dd,J=8.7,2.3Hz,1H),7.72(d,J=8.2Hz,1H),7.62(d,J=8.7Hz,1H).

[0367] Embodiment 15

[0368] N-(6-(2H-1,2,3-triazol-2-yl)-5-(trifluoromethyl)pyridin-3-yl)-5-cyclopropyl-1-(2-oxo-1,2-dihydropyrrolo[4,3,2-ij]isoquinolin-6-yl)-1H-pyrazole-4-carboxamide

[0369]

[0370] The synthetic method of the eleventh step of reference Example 1 was carried out by using 2-cyclopropyl-1-(2-oxo-1,2-dihydropyrrolo[4,3,2-ij]isoquinolin-6-yl)-1H-pyrrole-3-carboxylic acid (70 mg, 0.22 mmol) and 6-(2H-1,2,3-triazol-2-yl)-3-amino-5-trifluoromethylpyridine 15a (100 mg, 0.44 mmol, using known The title product N-(6-(2H-1,2,3-triazol-2-yl)-5-(trifluoromethyl)pyridin-3-yl)-5-cyclopropyl-1-(2-oxo-1,2-dihydropyrrolo[4,3,2-ij]isoquinolin-6-yl)-1H-pyrazole-4-carboxamide 15 (41 mg) was obtained with a yield of 35.2%. MS m / z (ESI): 531 [M+1]

[0371] 1H NMR (400MHz, DMSO) δ11.64(s,1H),10.76(s,1H),9.21(d,J=2.3Hz,1H),8.92(d,J=2.3Hz,1H),8.40(d,J=8.4Hz,2H), 8.21–8.15(m,3H),8.08–8.02(m,1H),7.82(d,J=8.2Hz,1H),2.15–2.04(m,1H),0.85–0.72(m,2H),0.66–0.55(m,2H).

[0372] Example 16

[0373] N-(4-(2H-1,2,3-triazol-2-yl)-3-(trifluoromethyl)phenyl)-5-cyclopropyl-1-(2-oxo-1,2-dihydropyrrole

[0374] [4,3,2-ij]isoquinolin-6-yl)-1H-pyrazole-4-carboxamide

[0375]

[0376] Referring to the synthesis method of the eleventh step of Example 1, 2-cyclopropyl-1-(2-oxo-1,2-dihydropyrrole [4,3,2-ij] isoquinolin-6-yl)-1H-pyrrole-3-carboxylic acid (70 mg, 0.22 mmol) and 4-(2H-1,2,3-triazol-2-yl)-3-(trifluoromethyl)aniline 16a (100 mg, 0.44 mmol, synthesized by the known method "Patent WO2018020474A1"), the title product N-(4-(2H-1,2,3-triazol-2-yl)-3-(trifluoromethyl)phenyl)-5-cyclopropyl-1-(2-oxo-1,2-dihydropyrrole [4,3,2-ij] isoquinolin-6-yl)-1H-pyrazole-4-carboxamide 16 (37 mg) was obtained with a yield of 31.7%. MS m / z(ESI):531[M+1]

[0377] 1H NMR (400MHz, DMSO) δ11.04(s,1H),10.50(s,1H),8.44(d,J=2.3Hz,1H),8.32(s,1H),8.25(dd,J=8.8,2.4Hz,1H),8.14(d,J=13.5Hz,3H),7.88(dd,J= 8.3,6.9Hz,1H),7.76(dd,J=10.3,8.6Hz,1H),7.68(d,J=7.5Hz,1H),7.11 (d,J=7.5Hz,1H),2.09–1.97(m,1H),0.76–0.68(m,2H),0.63–0.55(m,2H).

[0378] Biological test evaluation

[0379] 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.

[0380] Test Example 1: Determination of the inhibitory effect of the compounds of the present invention on MALT1 enzyme activity 1.1 Experimental purpose: Using Ac-LRSR-AMC as substrate, test the IC of the compound for MALT1 enzyme activity inhibition at its Km concentration 50 .

[0381] 1.2 Experimental instruments and reagents:

[0382]

[0383] 1.3 Experimental method: Ac-LRSR-AMC was used as substrate, and the product after being cleaved by MALT1 produced fluorescence, which could be detected at 460nm. The highest concentration of the compound tested was 1000nM, and it was diluted 3 times, with a total of 11 concentrations (1000nM-0.017nM). The reaction system was 10nM FL MALT1 protein, 200mM Ac-LRSR-AMC, 50mM Tris pH 7.5, 0.6M Citrate, 1mM DTT, 1mM EDTA, 0.05% BSA and 1.5% DMSO. The compound and enzyme were pre-incubated at room temperature for 50 minutes, and then the substrate was added to react for 4 hours.

[0384] 1.4 Experimental data processing method:

[0385] 1. Inhibition rate (%): The original data (460 nm reading) 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.

[0386] 2. 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))

[0387] 1.5 Experimental results:

[0388] Table 15: IC values ​​of compounds for MALT1 enzyme inhibition 50 value

[0389] Example No. <![CDATA[MALT1 IC 50 (μM)]]> Example No. <![CDATA[MALT1 IC 50 (μM)]]> Example 2 0.105 Example 10 0.031 Example 3 0.015 Embodiment 11 0.016 Example 4 0.024 Example 12 0.028 Example 5 0.032 Embodiment 13 0.051 Example 6 0.028 Embodiment 14 0.024 Example 7 0.039 Embodiment 15 0.035 Example 8 0.025 Example 16 0.050 Example 9 0.171 JNJ-67856633 0.531

[0390] 1.6 Experimental conclusion: The data in the table show that the example compounds of the present invention have good MALT1 enzyme activity inhibition activity.

[0391] Test Example 2: Determination of the Proliferation Inhibitory Effect of the Compounds of the Invention on TMD8 and OCI-Ly3 Cells

[0392] 2.1 Experimental purpose: To evaluate the inhibitory effect of the compounds on TMD8 and OCI-Ly3 cell proliferation by cell proliferation inhibition experiment.

[0393] 2.2 Experimental instruments and reagents:

[0394]

[0395]

[0396] 2.3 Experimental method: The CellTiter-Glo method was used to detect the inhibitory effect of the compounds on the proliferation of TMD8 and OCI-Ly3 cells. The highest concentration of the compound tested was 1000nM, and it was diluted 3 times, with a total of 9 concentrations (1000nM-0.15nM). After the cells were plated at an appropriate density, the compounds were added on the second day, and the cells were incubated for 96 hours before detection using the CellTiter-Glo Luminescebt detection kit.

[0397] 2.4 Experimental data processing method:

[0398] 1. Inhibition rate (%): Inhibition rate % = [(average value of positive control wells - value of sample wells) / (average value of positive control wells - average value of negative control wells)] × 100, where the positive control wells are wells without compound, and the negative control wells are wells with PBS.

[0399] 2. 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))

[0400] 2.5 Experimental results:

[0401] Table 16: IC values ​​of compounds for inhibition of proliferation of OCI-Ly3 cells 50 value

[0402]

[0403] 2.6 Experimental conclusion: The data in the table show that the example compounds of the present invention have good proliferation inhibition activity on TMD8 and OCI-Ly3 cells.

[0404] Test Example 3: Intracellular MALT1 protease activity detection experiment

[0405] 3.1 Study purpose: To detect the cleavage level of MALT1 on substrate BCL-10 in TMD8 cells and test the inhibitory effect of compounds on MALT1 protease activity in the cell environment

[0406] 3.2 Experimental instruments and reagents:

[0407]

[0408]

[0409] 3.3 Experimental methods: The ELISA sandwich method was used to detect the content of uncut BCL-10 protein in cells to determine the inhibitory effect of the compounds on the activity of MALT1 protease in cells. The highest concentration of the compound detection was 10000nM, and it was diluted 3 times, with a total of 9 concentrations (10000nM–1.5nM). The cells were plated at an appropriate density, and the corresponding concentration of the compound was added for 30 minutes. After the cells were stimulated with eBioscience cell stimulation cocktail for 2 hours, the cells were collected and lysed. The cell lysate was added to the detection plate pre-coated with recombinant BCL-10 antibody (Abcam, #Ab33905) and incubated overnight at 4°C. The next day, BCL-10 detection antibody (Santacruz, #Sc-5273HRP) was added for incubation for 2 hours. The color development was terminated after about 30 minutes using TMB substrate, and the detection was performed by microplate reader.

[0410] 3.4 Experimental data processing method:

[0411] 1) Inhibition rate (%): Inhibition rate % = [(sample well value - negative control well average value) / (positive control well average value - negative control well average value)] × 100, where the positive control well is the high concentration reference compound well, and the negative control well is the DMSO well.

[0412] 2) 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))

[0413] 3.5 Experimental results:

[0414] Table 17: IC values ​​of compounds for inhibition of MALT1 protease activity in cells 50 value

[0415] Example No. <![CDATA[Bcl10 TMD8 IC 50 (μM)]]> Example No. <![CDATA[Bcl10 TMD8 IC 50 (μM)]]> Example 2 0.083 Example 10 0.093 Example 3 0.036 Embodiment 11 0.057 Example 4 0.061 Example 12 0.058 Example 6 0.073 Embodiment 13 0.072 Example 8 0.056 Embodiment 14 0.083 Example 9 0.050 Embodiment 15 0.067

[0416] 3.6 Experimental conclusion: The data in the table show that the example compounds of the present invention have good MALT1 protease activity.

[0417] Test Example 4: Oral administration pharmacokinetic determination in Balb / C mice

[0418] 4.1 Study purpose: Balb / C mice were used as test animals to study the pharmacokinetic behavior of the compound in the plasma of mice at a dose of 30 mg / kg after oral administration.

[0419] 4.2 Experimental plan

[0420] 4.2.1 Test drugs: Compounds of the examples of the present invention, homemade.

[0421] 4.2.2 Experimental animals: 3 Balb / C mice (3 / example), male, Shanghai JXJ Experimental Animal Co., Ltd., Animal Production License No. (SCXK(Shanghai)2013-0006N0.311620400001794).

[0422] 4.2.3 Administration: 3 male Balb / C mice were fasted overnight and administered orally at a dose of 30 mg / kg in a volume of 10 mL / kg.

[0423] 4.2.4 Sample collection: Before and after administration, 0.1 mL of blood was collected from the eye sockets of mice at 0, 0.5, 1, 2, 4, 6, 8 and 24 hours and placed in EDTA-K 2 The plasma was separated by centrifugation at 6000 rpm for 6 min at 4°C in a test tube and stored at -80°C.

[0424] 4.2.5 Sample processing:

[0425] 1) Add 160uL acetonitrile to 40uL of plasma sample for precipitation, mix and centrifuge at 3500×g for 5-20 minutes.

[0426] 2) Take 100uL of the supernatant solution after treatment and perform LC / MS / MS analysis to determine the concentration of the test compound.

[0427] 4.2.6 Liquid phase analysis:

[0428] Liquid phase conditions: Shimadzu LC-20AD pump Mass spectrometry conditions: AB Sciex API 4000 mass spectrometer

[0429] Chromatographic column: phenomenex Gemiu 5um C18 50×4.6mm

[0430] Mobile phase: Liquid A is 0.1% formic acid in water, Liquid B is acetonitrile Flow rate: 0.8 mL / min

[0431] Elution time: 0-4.0 minutes, eluent is as follows:

[0432]

[0433]

[0434] 4.3 Experimental results and analysis: The main pharmacokinetic parameters were calculated using WinNonlin 8.2. The results of the mouse pharmacokinetic experiment are shown in the following table:

[0435] Table 18: Pharmacokinetic parameters of the compounds of the present invention in mice after oral administration

[0436]

[0437] 5.4 Experimental conclusion: The data in the table show that the example compounds of the present invention have good oral pharmacokinetic parameters in mice.

[0438] Test Example 6: Permeability Test of the Compounds of the Invention

[0439] 6.1 Experimental Purpose: The purpose of this study is to test the bidirectional permeability of compounds across the Caco-2 cell model and to assess whether they are transported by efflux transporters.

[0440] 6.2 Experimental instruments and materials: liquid chromatography-mass spectrometry instrument, centrifuge, vortexer, pipette, 96-well test plate (HTS Transwell Plate), acetonitrile solution with internal standard, Caco-2 cells (ATCC), Hanks' balanced solution (HBSS), fluorescent yellow (LY), and dimethyl sulfoxide (DMSO).

[0441] 6.3 Experimental steps:

[0442] 1) Cultivation of Caco-2 monolayer cells: Select Caco-2 cells in good condition for plating, replace the culture medium every 2 to 3 days, and culture for 21 to 28 days to form a dense cell monolayer for testing.

[0443] 2) Test the permeability of the example compounds:

[0444] aAdd 108 μL of transport buffer (HBSS containing 10 μM of the example compound) to the dosing end of A to B.

[0445] Add 300 μL of transport buffer (HBSS containing DMSO) from A to the receiving end of B.

[0446] cB Add 300 μL of transport buffer (HBSS containing 10 μM of the example compound) to the administration end of A

[0447] Add 108 μL of transport buffer (HBSS containing DMSO) to the receiving end of dBA.

[0448] e. Incubate for 90 min. d. Take samples for processing and detect by mass spectrometry.

[0449] 6.4 Chromatographic conditions:

[0450] Instrument: liquid chromatography; Column: Waters XSelect HSS T3 2.5 μm (2.1 × 50 mm);

[0451] Mobile phase: Phase A: 0.1% formic acid in pure water; Phase B: 0.1% formic acid in acetonitrile.

[0452] 6.5 Mass spectrometry conditions:

[0453] Instrument: API6500+ liquid chromatography-mass spectrometer; ion source: electrospray ionization source (ESI);

[0454] The detection method was positive ion detection; the scanning method was selected reaction monitoring (MRM) method.

[0455] 6.6 Experimental Results

[0456] Table 19: Permeability test of example compounds

[0457]

[0458] 6.7 Experimental conclusion: The data in the table show that the compounds of the examples of the present invention have good permeability and significantly improved efflux properties.

[0459] Test Example 7: Tumor inhibition experiment of the compound of the present invention in the NOG mouse model of subcutaneous xenograft tumor of human diffuse large B-cell lymphoma OCI-LY3 cells

[0460] 7.1 Experimental purpose: To evaluate the efficacy of the test drug in the human diffuse large B-cell lymphoma OCI-LY3 mouse subcutaneous tumor model

[0461] 7.2 Experimental instruments and reagents:

[0462] 7.2.1 Instruments:

[0463] 1. Precision balance (SECURA225D-1CN, Sartorius)

[0464] 2. Electronic balance (HZ2002A, Changzhou Keyuan Electronics Co., Ltd.)

[0465] 3. Biological safety cabinet (BSC1300L-II-A2, SHINVA)

[0466] 4. Vernier caliper (CD-6" ASX (0-150) mm, Mitutoyo)

[0467] 5. Biological safety cabinet (BSC-1604IIA2, AIRTECH)

[0468] 6. Centrifuge (5910R, eppendorf) 7. CO 2 Incubator (HERAceII-240i, Thermo) 7.2.2 Reagents:

[0469] 1. Sodium carboxymethyl cellulose (CMC-Na) (C5678, SIGMA)

[0470] 2. Kolliphor HS15 (Polyethylene glycol 12-hydrogen stearate) (42966, SIGMA)

[0471] 3. RPMI1640 (22400-089, Gibco)

[0472] 4. FBS (35-081-CV, Corning) 5. DPBS (21-031-CVC, Corning)

[0473] 6. Matrigel Matrix (354234, Corning) 7. OCI-LY3 cells (ACC-761, DSMZ) 7.3 Experimental operation and data processing:

[0474] 1. Animals: NOG mice, female, 6-8 weeks old, weighing 18-22 grams, 65 mice in total, purchased from Beijing Weitonglihua Laboratory Animal Technology Co., Ltd. or other qualified suppliers.

[0475] 2. Cells: Human diffuse large B-cell lymphoma OCI-LY3 cells were cultured in monolayer in vitro and routinely digested and passaged with trypsin-EDTA twice a week. When the cell saturation reached 80%-90% and the number reached the required level, the cells were collected, counted, and inoculated.

[0476] 3. Inoculation grouping: Inoculate cells (5×10^6 cells + Matrigel / 0.2 ml) subcutaneously into each mouse, and regularly observe the growth of the animals and transplanted tumors. When the tumor volume grows to 150-200 mm 3 The tumor volume of each mouse was calculated and randomly divided into groups according to the tumor volume and body weight. The calculation formula of tumor volume is: V = 0.5a × b 2 , a and b represent the long and short diameters of the tumor, respectively.

[0477] 4. Administration: According to the grouping results, the test drug was administered (administration method: oral administration; administration volume: 10 mL / kg; administration frequency: 2 times / day; administration cycle: 28 days; solvent: 10% solutol HS15-0.25% CMC-Na). Tumors were measured and weighed twice a week after the administration of the test drug.

[0478] 5. Euthanize the animals after the experiment

[0479] 6. Data processing: The anti-tumor efficacy of the compound is evaluated by TGI (%) or relative tumor proliferation rate T / C (%). TGI (%) reflects the tumor growth inhibition rate. Calculation of TGI (%): TGI (%) = [(1-(average tumor volume at the end of drug administration in a certain treatment group - average tumor volume at the beginning of drug administration in the treatment group)) / (average tumor volume at the end of treatment in the solvent control group - average tumor volume at the beginning of treatment in the solvent control group)] × 100%.

[0480] Relative tumor proliferation rate T / C (%): The calculation formula is as follows: T / C% = TRTV / CRTV × 100% (TRTV: RTV of the treatment group; CRTV: RTV of the negative control group). The relative tumor volume (RTV) is calculated based on the results of tumor measurement. The calculation formula is RTV = V t / V 0 , where V 0 When the drug is administered in groups (i.e., d 0 ) The average tumor volume measured, V t It is the average tumor volume at a certain measurement. TRTV and CRTV are obtained from the same day.

[0481] After the experiment, the tumor weight was measured and the T / Cweight percentage was calculated. Tweight and Cweight represent the tumor weights of the drug-treated group and the vehicle control group, respectively.

[0482] 7.4 Experimental results:

[0483] Table 20 Tumor inhibition experiment of the compounds in the examples

[0484]

[0485] Note: The data in brackets indicate the tumor volume of the Vehicle group (i.e., control group) at the corresponding time in this example 7.5 Experimental conclusion: The experimental results in the table show that the compounds of the examples of the present invention have good tumor inhibition effects, low toxicity, and no significant changes in the body weight of animals in each group.

[0486] Crystalline study of compounds

[0487] It is well known to those skilled in the art that the above-mentioned example compounds have been shown to have good inhibitory activity on OCI-Ly3 cell proliferation, and their crystal forms often have the same pharmacological and pharmacodynamic activity. On this basis, the inventors further studied the physicochemical properties of the corresponding compound 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 based on the present invention by conventional crystallization methods, and these crystals are all the solutions protected by the present invention. Specifically as follows:

[0488] 1. Experimental instruments

[0489] 1.1 Some parameters of physical and chemical testing instruments

[0490]

[0491] 1.2 Instruments and liquid phase analysis conditions

[0492] 1.2.1 Instruments and equipment

[0493] Instrument Name model Instrument Name model Analytical Balance Sartorius BSA224S-CW Injector G1329B Water Purifier Milli-Q Plus, Millipore Column oven G1316A High performance liquid chromatography Agilent1260 Detector G1315D Pump Agilent G1311B

[0494] 1.2.2 Chromatographic conditions

[0495] Chromatographic column: ZOBAX Bonus RP (4.6*150mm, 3.5μm) Flow rate: 1.0mL / min

[0496] Column temperature: 35°C Detection wavelength: 220nm Injection volume: 5μL

[0497] Run time: 15 min Diluent: DMSO

[0498] Mobile phase: A: water (0.1% phosphoric acid); B: acetonitrile

[0499]

[0500]

[0501] 2. Preparation of free base crystal forms I to X6 of the compound of Example 8

[0502] 2.1 Preparation of Form I: Weigh 0.1 g of the compound of Example 8, add 5 ml of methanol, and heat to 50° C. to dissolve. Place the clear solution directly in a -5° C. to -10° C. environment and stir for 15 min, and filter to obtain Form I.

[0503] 2.2 Preparation of Form II: Weigh 0.24 g of the compound of Example 8, add 2 ml of methanol, slurry at room temperature for 72 h, and filter to obtain Form II.

[0504] 2.3 Preparation of Form III: Weigh 0.2 g of the compound of Example 8, add 2 ml of isopropanol, slurry at room temperature for 24 h, and filter to obtain Form III.

[0505] 2.4 Preparation of Form IV: Weigh 0.24 g of the compound of Example 8, add 2 ml of methanol, slurry at 50° C. for 48 h, and filter to obtain Form IV.

[0506] 2.5 Preparation of Form V: Weigh 0.2 g of the compound of Example 8, add 3 ml of methanol, stir at 65° C. for 24 h, and filter to obtain Form V.

[0507] 2.6 Preparation of Form VI: Weigh 0.1 g of the compound of Example 8, add 7 ml of isopropanol, heat to 50°C and filter, place the filtrate directly in a -5°C to -10°C environment and stir for 0.5 h, and filter to obtain Form VI.

[0508] 2.7 Preparation of Form VII: Weigh 0.1 g of the compound of Example 8, add 1.5 ml of 2-butanone, heat to 50° C. and filter. Stir the filtrate at -5° C. to -10° C. for 0.5 h, and filter to obtain Form VII.

[0509] 2.8 Preparation of Form VIII: Weigh 0.1 g of the compound of Example 8, add 5.5 ml of acetonitrile, heat to 50° C. and filter. Stir the filtrate at -5° C. to -10° C. for 0.5 h, and filter to obtain Form VIII.

[0510] 2.9 Preparation of Form X1: Weigh 0.2 g of the compound of Example 8, add 4 ml of 2-butanone, add 4 ml of n-heptane after dissolving, and filter to obtain Form X1.

[0511] 2.10 Preparation of Form X2: Weigh 0.08 g of the compound of Example 8, add 2 ml of acetone, dissolve, add 3.2 ml of n-heptane, filter, and obtain Form X2.

[0512] 2.11 Preparation of Form X3: Weigh 10 mg of Form I sample, place it in a vacuum drying oven at 50°C and dry it for 24 h to convert it into Form X3.

[0513] 2.12 Preparation of Form X4: Weigh 10 mg of Form VI sample, place it in a vacuum drying oven at 50°C and dry it for 24 hours to convert it into Form X4.

[0514] 2.13 Preparation of Form X5: Weigh 0.15 g of the compound of Example 8, add 7.5 ml of ethanol, heat to reflux, cool to room temperature, add seed crystals (compound of Example 8), stir for 1 h, cool to 20°C, stir for 24 h, filter, and obtain Form X5.

[0515] 2.14 Preparation of Form X6: Weigh 0.15 g of the compound of Example 8, add 9 ml of isopropanol, heat to reflux, move to room temperature, add seed crystals (compound of Example 8), stir for 0.5 h, and filter to obtain Form X6.

[0516] 3. Solid stability test

[0517] 3.1 Experimental purpose: To investigate the physicochemical stability of the compounds of Forms I to X6 under the conditions of 5000 lx light, 60°C high temperature, RH = 92.5% at room temperature and RH = 75% at 50°C for 10 days, 20 days and 30 days.

[0518] 3.2 Experimental plan: Take about 1 mg of crystal form I~X6 and observe it for 10 days, 20 days and 30 days under light 5000lx, high temperature 60℃, room temperature and high humidity RH=92.5% and 50℃RH=75%. Use HPLC and external standard method to determine the content, and use the chromatographic peak area normalization method to calculate the changes of related substances.

[0519] 3.3 Experimental conclusion: The crystal form has good stability.

[0520] 4. Hygroscopicity test

[0521] 4.1 Experimental purpose: To investigate the hygroscopicity of compound crystalline forms I to X6 under different relative humidity conditions.

[0522] 4.2 Experimental plan: Compound crystal forms I to X6 are placed in saturated water vapor at different relative humidity to allow the crystal form and the water vapor to reach dynamic equilibrium, and the percentage of moisture absorption and weight gain of the crystal form after equilibrium is calculated.

[0523] 4.3 Experimental conclusion: The crystal form did not undergo transformation.

[0524] 5. Solubility experiments in different media

[0525] 5.1 Experimental purpose: To investigate the solubility of Forms I to X6 in different pH buffers, water, artificial simulated gastric fluid (SGF), fasting artificial simulated intestinal fluid (FaSSIF) and non-fasting artificial simulated intestinal fluid (FeSSIF).

[0526] 5.2 Experimental plan: About 1 mg of Forms I to X6 was suspended in different pH buffers, SGF, FaSSIF, FeSSIF and water, respectively, shaken at 37°C for 2 hours, filtered, and the thermodynamic solubility of Form C at 37°C was determined by the external standard method.

[0527] 5.3 Experimental conclusion: The crystal form has good solubility in different media.

Claims

1. The crystal form of the compound represented by general formula (I), the compound structure is as follows: in: M1 is N or CH; M2 is N or CR 1b ; M3 is N or CR 1c ; R 1a Selected from hydrogen, deuterium, halogen, hydroxyl, cyano, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclyl, phenyl or 5-8 membered heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclyl, phenyl or 5-8 membered heteroaryl, optionally further substituted by deuterium, halogen, hydroxyl, cyano or C 1-6 The alkyl group is substituted by one or more substituents; R 1b Selected from hydrogen, deuterium, halogen, hydroxyl, cyano, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclyl, phenyl or 5-8 membered heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclyl, phenyl or 5-8 membered heteroaryl, optionally further substituted by deuterium, halogen, hydroxyl, cyano or C 1-6 The alkyl group is substituted by one or more substituents; R 1c Selected from hydrogen, deuterium, halogen, hydroxyl, cyano, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclyl, phenyl or 5-8 membered heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclyl, phenyl or 5-8 membered heteroaryl, optionally further substituted by deuterium, halogen, hydroxyl, cyano or C 1-6 The alkyl group is substituted by one or more substituents; R 2a Selected from hydrogen, deuterium, halogen, hydroxyl, cyano, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl or C 3-8 Cycloalkyl; R 2b Selected from hydrogen, deuterium, halogen, hydroxyl, cyano, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl or C 3-8 Cycloalkyl; Preferably, the structure of the compound is as shown in general formula (II): in: M1 is N or CH; M3 is N or CR 1c ; Ring A is a 5-membered N-containing heteroaryl group; preferably R 1a Selected from hydrogen, deuterium, fluorine, chlorine, bromine, hydroxyl, cyano, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl, wherein the C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl, optionally further substituted by deuterium, halogen, hydroxyl, cyano or C 1-3 The alkyl group is substituted by one or more substituents; preferably fluorine, chlorine, bromine, difluoromethyl or trifluoromethyl; R 1c Selected from hydrogen, deuterium, fluorine, chlorine, bromine, hydroxyl, cyano, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl, wherein the C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl, optionally further substituted by deuterium, halogen, hydroxyl, cyano or C 1-3 The alkyl group is substituted by one or more substituents; R 2a Selected from hydrogen, deuterium, fluorine, chlorine, bromine, hydroxyl, cyano, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Hydroxyalkyl or C 3-6 Cycloalkyl; preferably trifluoromethyl or cyclopropyl.

2. The crystalline form of the compound according to claim 1, wherein the compound is: 1-(2-Carbonyl-1,2-dihydropyrrolo[2,3,4-ij]isoquinolin-5-yl)-5-trifluoromethyl-N-(2-trifluoromethylpyridin-4-yl)-1H-pyrazole-4-carboxamide; 1-(2-Carbonyl-1,2-dihydropyrrolo[4,3,2-ij]isoquinolin-6-yl)-5-trifluoromethyl-N-(2-trifluoromethylpyridin-4-yl)-1H-pyrazole-4-carboxamide; N-(6-(2H-1,2,3-triazol-2-yl)-5-chloropyridin-3-yl)-1-(2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)-5-trifluoromethyl-1H-pyrazole-4-carboxamide; N-(6-(2H-1,2,3-triazol-2-yl)-5-trifluoromethylpyridin-3-yl)-1-(2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)-5-trifluoromethyl-1H-pyrazole-4-carboxamide; N-(6-(oxazol-2-yl)-5-(trifluoromethyl)pyridin-3-yl)-1-(2-carbonyl-1,2-dihydrobenzo[cd]indol-6-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide; N-(5-difluoromethyl-6-(2H-1,2,3-triazol-2-yl)-pyridin-3-yl)-1-(2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)-5-trifluoromethyl-1H-pyrazole-4-carboxamide; N-(4-(2H-1,2,3-triazol-2-yl)-3-(trifluoromethyl)phenyl)-1-(2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide; N-(3-chloro-4-(2H-1,2,3-triazol-2-yl)phenyl)-1-(2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide; 5-cyclopropyl-1-(2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)-N-(2-(trifluoromethyl)pyridin-4-yl)-1H-pyrazole-4-carboxamide; N-(6-(2H-1,2,3-triazol-2-yl)-5-(trifluoromethyl)pyridin-3-yl)-5-cyclopropyl-1-(2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)-1H-pyrazole-4-carboxamide; N-(5-chloro-6-(2H-1,2,3-triazol-2-yl)-pyridin-3-yl)-5-cyclopropyl-1-(2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)-1H-pyrazole-4-carboxamide; N-(3-chloro-4-(2H-1,2,3-triazol-2-yl)phenyl)-5-cyclopropyl-1-(2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)-1H-pyrazole-4-carboxamide; N-(6-(2H-1,2,3-triazol-2-yl)-5-(trifluoromethyl)pyridin-3-yl)-1-(2-carbonyl-1,2-dihydrobenzo[cd]indol-6-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide; N-(3-chloro-4-(2H-1,2,3-triazol-2-yl)phenyl)-1-(2-carbonyl-1,2-dihydropyrrolo[4,3,2-ij]isoquinolin-6-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide; N-(6-(2H-1,2,3-triazol-2-yl)-5-(trifluoromethyl)pyridin-3-yl)-5-cyclopropyl-1-(2-oxo-1,2-dihydropyrrolo[4,3,2-ij]isoquinolin-6-yl)-1H-pyrazole-4-carboxamide; N-(4-(2H-1,2,3-triazol-2-yl)-3-(trifluoromethyl)phenyl)-5-cyclopropyl-1-(2-oxo-1,2-dihydropyrrolo[4,3,2-ij]isoquinolin-6-yl)-1H-pyrazole-4-carboxamide; Preferably, the crystalline form is Form I, II, III, IV, V, VI, VII, VIII, X1, X2, X3, X4, X5 or X6 of N-(3-chloro-4-(2H-1,2,3-triazol-2-yl)phenyl)-1-(2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide; The X-ray powder diffraction spectrum of the crystalline form I has a diffraction peak at 2θ of 6.8±0.2°; or a diffraction peak at 16.0±0.2°; or a diffraction peak at 23.0±0.2°; or a diffraction peak at 20.9±0.2°; or a diffraction peak at 11.4±0.2°; or a diffraction peak at 13.7±0.2°; or a diffraction peak at 4.6±0.2°; or a diffraction peak at 24.2±0.2°; or a diffraction peak at 24.8±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, and more preferably including any 6, 7 or 8 thereof; The X-ray powder diffraction spectrum of the crystalline form II has a diffraction peak at 2θ of 20.9±0.2°; or a diffraction peak at 16.1±0.2°; or a diffraction peak at 24.2±0.2°; or a diffraction peak at 17.4±0.2°; or a diffraction peak at 27.3±0.2°; or a diffraction peak at 26.8±0.2°; or a diffraction peak at 6.9±0.2°; or a diffraction peak at 17.8±0.2°; or a diffraction peak at 11.4±0.2°; or a diffraction peak at 19.0±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 III has a diffraction peak at 2θ of 10.3±0.2°; or a diffraction peak at 20.7±0.2°; or a diffraction peak at 26.8±0.2°; or a diffraction peak at 11.3±0.2°; or a diffraction peak at 26.5±0.2°; or a diffraction peak at 14.3±0.2°; or a diffraction peak at 22.8±0.2°; or a diffraction peak at 16.1±0.2°; or a diffraction peak at 21.9±0.2°; or a diffraction peak at 12.2±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 IV has a diffraction peak at 2θ of 25.2±0.2°; or a diffraction peak at 15.1±0.2°; or a diffraction peak at 14.2±0.2°; or a diffraction peak at 14.8±0.2°; or a diffraction peak at 21.6±0.2°; or a diffraction peak at 12.4±0.2°; or a diffraction peak at 24.9±0.2°; or a diffraction peak at 18.3±0.2°; or a diffraction peak at 23.7±0.2°; or a diffraction peak at 11.4±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; The X-ray powder diffraction spectrum of the crystalline form V has a diffraction peak at 2θ of 25.4±0.2°; or a diffraction peak at 15.3±0.2°; or a diffraction peak at 15.0±0.2°; or a diffraction peak at 14.4±0.2°; or a diffraction peak at 21.8±0.2°; or a diffraction peak at 12.6±0.2°; or a diffraction peak at 24.6±0.2°; or a diffraction peak at 23.9±0.2°; or a diffraction peak at 18.5±0.2°; or a diffraction peak at 8.7±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, and more preferably including any 6, 7 or 8 thereof; The X-ray powder diffraction spectrum of the crystalline form VI has a diffraction peak at 2θ of 11.3±0.2°; or a diffraction peak at 10.2±0.2°; or a diffraction peak at 22.6±0.2°; or a diffraction peak at 16.0±0.2°; or a diffraction peak at 25.8±0.2°; or a diffraction peak at 20.7±0.2°; or a diffraction peak at 7.0±0.2°; or a diffraction peak at 14.5±0.2°; or a diffraction peak at 22.2±0.2°; or a diffraction peak at 21.7±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 VII has a diffraction peak at 2θ of 8.9±0.2°; or a diffraction peak at 10.4±0.2°; or a diffraction peak at 24.3±0.2°; or a diffraction peak at 25.6±0.2°; or a diffraction peak at 14.0±0.2°; or a diffraction peak at 18.0±0.2°; or a diffraction peak at 20.1±0.2°; or a diffraction peak at 22.5±0.2°; or a diffraction peak at 27.5±0.2°; or a diffraction peak at 27.2±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 VIII has a diffraction peak at 2θ of 4.7±0.2°; or a diffraction peak at 7.1±0.2°; or a diffraction peak at 11.9±0.2°; or a diffraction peak at 16.8±0.2°; or a diffraction peak at 24.1±0.2°; or a diffraction peak at 14.4±0.2°; or a diffraction peak at 15.7±0.2°; preferably including any 2-5, or 3-5, or 3-6, or 3-7, or 5-7, or 6-7 of the above diffraction peaks, more preferably including any 6 or 7 thereof; The X-ray powder diffraction spectrum of the crystal form X1 has a diffraction peak at 2θ of 16.7±0.2°; or a diffraction peak at 20.8±0.2°; or a diffraction peak at 21.7±0.2°; or a diffraction peak at 25.2±0.2°; or a diffraction peak at 17.0±0.2°; or a diffraction peak at 17.6±0.2°; or a diffraction peak at 12.9±0.2°; or a diffraction peak at 23.4±0.2°; or a diffraction peak at 14.8±0.2°; or a diffraction peak at 9.0±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, and more preferably including any 6, 7 or 8 thereof; The X-ray powder diffraction spectrum of the crystal form X2 has a diffraction peak at 2θ of 9.5±0.2°; or a diffraction peak at 19.8±0.2°; or a diffraction peak at 15.2±0.2°; or a diffraction peak at 28.8±0.2°; or a diffraction peak at 10.8±0.2°; or a diffraction peak at 14.1±0.2°; or a diffraction peak at 24.5±0.2°; or a diffraction peak at 26.6±0.2°; or a diffraction peak at 38.8±0.2°; or a diffraction peak at 39.2±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, and more preferably including any 6, 7 or 8 thereof; The X-ray powder diffraction spectrum of the crystal form X3 has a diffraction peak at 2θ of 12.0±0.2°; or a diffraction peak at 14.4±0.2°; or a diffraction peak at 7.2±0.2°; or a diffraction peak at 25.8±0.2°; or a diffraction peak at 13.5±0.2°; or a diffraction peak at 21.6±0.2°; or a diffraction peak at 4.9±0.2°; or a diffraction peak at 16.7±0.2°; or a diffraction peak at 17.8±0.2°; or a diffraction peak at 17.4±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, and more preferably including any 6, 7 or 8 thereof; The X-ray powder diffraction spectrum of the crystal form X4 has a diffraction peak at 2θ of 11.3±0.2°; or a diffraction peak at 10.2±0.2°; or a diffraction peak at 22.6±0.2°; or a diffraction peak at 20.7±0.2°; or a diffraction peak at 14.2±0.2°; or a diffraction peak at 16.1±0.2°; or a diffraction peak at 7.1±0.2°; or a diffraction peak at 14.5±0.2°; or a diffraction peak at 25.8±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; The X-ray powder diffraction spectrum of the crystal form X5 has a diffraction peak at 2θ of 11.4±0.2°; or a diffraction peak at 13.6±0.2°; or a diffraction peak at 17.5±0.2°; or a diffraction peak at 12.2±0.2°; or a diffraction peak at 24.8±0.2°; or a diffraction peak at 18.7±0.2°; or a diffraction peak at 23.4±0.2°; or a diffraction peak at 22.9±0.2°; or a diffraction peak at 21.8±0.2°; or a diffraction peak at 22.4±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; The X-ray powder diffraction pattern of the crystal form X6 has a diffraction peak at 2θ of 11.4±0.2°; or a diffraction peak at 10.2±0.2°; or a diffraction peak at 20.7±0.2°; or a diffraction peak at 22.6±0.2°; or a diffraction peak at 25.9±0.2°; or a diffraction peak at 16.1±0.2°; or a diffraction peak at 7.1±0.2°; or a diffraction peak at 14.6±0.2°; or a diffraction peak at 12.2±0.2°; or a diffraction peak at 18.5±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.

3. The crystalline form of the compound according to any one of claims 1 or 2, characterized in that: The X-ray powder diffraction pattern of Form I comprises at least one or more diffraction peaks located at 2θ of 6.8±0.2°, 16.0±0.2°, and 23.0±0.2°, preferably two of them, and more preferably three of them; optionally, it may further comprise at least one of 20.9±0.2°, 11.4±0.2°, 13.7±0.2°, 4.6±0.2°, and 24.2±0.2°, preferably 2, 3, 4 or 5 of them; The X-ray powder diffraction pattern of Form II contains at least one or more diffraction peaks located at 2θ of 20.9±0.2°, 16.1±0.2°, and 24.2±0.2°, preferably two of them, and more preferably three of them; optionally, it may further contain at least one of 17.4±0.2°, 27.3±0.2°, 26.8±0.2°, 6.9±0.2°, and 17.8±0.2°, preferably 2, 3, 4 or 5 of them; The X-ray powder diffraction pattern of Form III comprises at least one or more diffraction peaks located at 2θ of 10.3±0.2°, 20.7±0.2°, and 26.8±0.2°, preferably two of them, and more preferably three of them; optionally, it may further comprise at least one of 11.3±0.2°, 26.5±0.2°, 14.3±0.2°, 22.8±0.2°, and 16.1±0.2°, preferably 2, 3, 4 or 5 of them; The X-ray powder diffraction pattern of Form IV comprises at least one or more diffraction peaks located at 2θ of 25.2±0.2°, 15.1±0.2°, and 14.2±0.2°, preferably two of them, and more preferably three of them; optionally, it may further comprise at least one of 14.8±0.2°, 21.6±0.2°, 12.4±0.2°, 24.9±0.2°, and 18.3±0.2°, preferably 2, 3, 4 or 5 of them; The X-ray powder diffraction pattern of Form V contains at least one or more diffraction peaks located at 2θ of 25.4±0.2°, 15.3±0.2°, and 15.0±0.2°, preferably two of them, and more preferably three of them; optionally, it may further contain at least one of 14.4±0.2°, 21.8±0.2°, 12.6±0.2°, 24.6±0.2°, and 23.9±0.2°, preferably 2, 3, 4 or 5 of them; The X-ray powder diffraction pattern of Form VI comprises at least one or more diffraction peaks located at 2θ of 11.3±0.2°, 10.2±0.2°, and 22.6±0.2°, preferably two of them, and more preferably three of them; optionally, it may further comprise at least one of 16.0±0.2°, 25.8±0.2°, 20.7±0.2°, 7.0±0.2°, and 14.5±0.2°, preferably 2, 3, 4 or 5 of them; The X-ray powder diffraction pattern of Form VII comprises at least one or more diffraction peaks located at 2θ of 8.9±0.2°, 10.4±0.2°, and 24.3±0.2°, preferably two of them, and more preferably three of them; optionally, it may further comprise at least one of 25.6±0.2°, 14.0±0.2°, 18.0±0.2°, 20.1±0.2°, and 22.5±0.2°, preferably 2, 3, 4 or 5 of them; The X-ray powder diffraction pattern of Form VIII comprises at least one or more diffraction peaks located at 2θ of 4.7±0.2°, 7.1±0.2°, and 11.9±0.2°, preferably two of them, and more preferably three of them; optionally, it may further comprise at least one of 16.8±0.2°, 24.1±0.2°, 14.4±0.2°, and 15.7±0.2°, preferably 2, 3, 4 or 5 of them; The X-ray powder diffraction pattern of Form X1 contains at least one or more diffraction peaks located at 2θ of 16.7±0.2°, 20.8±0.2°, and 21.7±0.2°, preferably two of them, and more preferably three of them; optionally, it may further contain at least one of 25.2±0.2°, 17.0±0.2°, 17.6±0.2°, 12.9±0.2°, and 23.4±0.2°, preferably 2, 3, 4 or 5 of them; The X-ray powder diffraction pattern of Form X2 contains at least one or more diffraction peaks located at 2θ of 9.5±0.2°, 19.8±0.2°, and 15.2±0.2°, preferably two of them, and more preferably three of them; optionally, it may further contain at least one of 28.8±0.2°, 10.8±0.2°, 14.1±0.2°, 24.5±0.2°, and 26.6±0.2°, preferably 2, 3, 4 or 5 of them; The X-ray powder diffraction pattern of Form X3 comprises at least one or more diffraction peaks located at 2θ of 12.0±0.2°, 14.4±0.2°, and 7.2±0.2°, preferably two of them, and more preferably three of them; optionally, it may further comprise at least one of 25.8±0.2°, 13.5±0.2°, 21.6±0.2°, 4.9±0.2°, and 16.7±0.2°, preferably 2, 3, 4 or 5 of them; The X-ray powder diffraction pattern of Form X4 comprises at least one or more diffraction peaks located at 2θ of 11.3±0.2°, 10.2±0.2°, and 22.6±0.2°, preferably two of them, and more preferably three of them; optionally, it may further comprise at least one of 20.7±0.2°, 14.2±0.2°, 16.1±0.2°, 7.1±0.2°, and 14.5±0.2°, and preferably 2, 3, 4 or 5 of them; The X-ray powder diffraction pattern of Form X5 comprises at least one or more diffraction peaks located at 2θ of 11.4±0.2°, 13.6±0.2°, and 17.5±0.2°, preferably two of them, and more preferably three of them; optionally, it may further comprise at least one of 12.2±0.2°, 24.8±0.2°, 18.7±0.2°, 23.4±0.2°, and 22.9±0.2°, and preferably 2, 3, 4 or 5 of them; The X-ray powder diffraction pattern of Form X6 contains at least one or more diffraction peaks located at 2θ of 11.4±0.2°, 10.2±0.2°, and 20.7±0.2°, preferably two of them, and more preferably three; optionally, it may further contain at least one of 22.6±0.2°, 25.9±0.2°, 16.1±0.2°, 7.1±0.2°, and 14.6±0.2°, preferably 2, 3, 4 or 5 of them.

4. The crystalline form of the compound according to claim 3, characterized in that: The X-ray powder diffraction pattern of the crystalline form I optionally further comprises one or more diffraction peaks located at 2θ of 24.8±0.2°, 26.2±0.2°, 22.6±0.2°, 17.2±0.2°, 19.1±0.2°, 17.7±0.2° or 20.3±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; The X-ray powder diffraction pattern of the crystalline form II optionally further comprises one or more diffraction peaks located at 2θ of 11.4±0.2°, 19.0±0.2°, 32.1±0.2° or 10.5±0.2°; preferably, at least any 2-4 of them; more preferably, any 2, 3 or 4 of them; The X-ray powder diffraction pattern of the crystalline form III optionally further comprises one or more diffraction peaks located at 2θ of 21.9±0.2°, 12.2±0.2°, 13.2±0.2°, 25.8±0.2°, 24.3±0.2°, 18.5±0.2° or 7.1±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; The X-ray powder diffraction pattern of the crystalline form IV optionally further comprises one or more diffraction peaks located at 2θ of 23.7±0.2°, 11.4±0.2°, 26.8±0.2°, 8.5±0.2°, 17.5±0.2°, 20.6±0.2° or 16.3±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; The X-ray powder diffraction pattern of the crystalline form V optionally further comprises one or more diffraction peaks located at 2θ of 18.5±0.2°, 8.7±0.2°, 11.6±0.2°, 17.7±0.2°, 23.3±0.2°, 25.7±0.2° or 20.8±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; The X-ray powder diffraction pattern of the crystalline form VI optionally further comprises one or more diffraction peaks located at 2θ of 22.2±0.2°, 21.7±0.2°, 21.3±0.2°, 27.6±0.2°, 23.1±0.2°, 23.8±0.2° or 29.6±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; The X-ray powder diffraction pattern of the crystalline form VII optionally further comprises one or more diffraction peaks located at 2θ of 27.5±0.2°, 27.2±0.2°, 29.4±0.2°, 31.8±0.2°, 21.1±0.2°, 20.5±0.2° or 16.6±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; The X-ray powder diffraction pattern of the crystal form X1 optionally further comprises one or more diffraction peaks located at 2θ of 14.8±0.2°, 9.0±0.2°, 14.4±0.2°, 18.6±0.2° or 19.4±0.2°; preferably, at least any 2-3, or 4-5 of them; further preferably, any 2, 3, 4 or 5 of them; The X-ray powder diffraction pattern of the crystal form X2 optionally further comprises one or more diffraction peaks located at 2θ of 38.8±0.2°, 39.2±0.2° or 49.4±0.2°; preferably, at least any 2-3 of them; more preferably, any 2 or 3 of them; The X-ray powder diffraction pattern of the crystal form X3 optionally further comprises one or more diffraction peaks located at 2θ of 17.8±0.2°, 17.4±0.2°, 12.9±0.2°, 23.0±0.2°, 24.0±0.2°, 25.3±0.2° or 15.8±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; 17.8±0.2°、17.4±0.2°、12.9±0.2°、23.0±0.2°、24.0±0.2°、25.3±0.2°、15.8±0.2°； The X-ray powder diffraction pattern of the crystal form X4 optionally further comprises one or more diffraction peaks located at 2θ of 25.8±0.2°, 21.4±0.2°, 26.5±0.2°, 26.8±0.2°, 13.2±0.2°, 18.5±0.2° or 22.2±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; 25.8±0.2°、21.4±0.2°、26.5±0.2°、26.8±0.2°、13.2±0.2°、18.5±0.2°、22.2±0.2°； The X-ray powder diffraction pattern of the crystal form X5 optionally further comprises one or more diffraction peaks located at 2θ of 21.8±0.2°, 22.4±0.2°, 14.4±0.2°, 27.3±0.2°, 25.3±0.2°, 15.5±0.2° or 16.5±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; The X-ray powder diffraction pattern of the crystal form X6 optionally further includes one or more diffraction peaks located at 2θ of 12.2±0.2°, 18.5±0.2°, 19.5±0.2°, 21.4±0.2°, 21.8±0.2°, 22.3±0.2° or 26.5±0.2°; preferably, it includes at least any 2-3, or 4-5, or 6-7 thereof; further preferably, it includes any 2, 3, 4, 5, 6, or 7 thereof.

5. The crystalline form of the compound according to claim 1 or 2, characterized in that: The X-ray powder diffraction pattern of Form I optionally includes one or more diffraction peaks located at 2θ of 6.8±0.2°, 16.0±0.2°, 23.0±0.2°, 20.9±0.2°, 11.4±0.2°, 13.7±0.2°, 4.6±0.2°, 24.2±0.2°, 24.8±0.2°, 26.2±0.2°, 22.6±0.2°, 17.2±0.2°, 19.1±0.2°, 17.7±0.2° or 20.3±0.2°; preferably, it includes diffraction peaks at 4, 5, 6, 8 or 10 of them; The X-ray powder diffraction pattern of Form II optionally includes one or more diffraction peaks located at 2θ of 20.9±0.2°, 16.1±0.2°, 24.2±0.2°, 17.4±0.2°, 27.3±0.2°, 26.8±0.2°, 6.9±0.2°, 17.8±0.2°, 11.4±0.2°, 19.0±0.2°, 32.1±0.2° or 10.5±0.2°; preferably, it includes diffraction peaks at 4, 5, 6, 8 or 10 positions selected therefrom; The X-ray powder diffraction pattern of Form III optionally includes one or more diffraction peaks located at 2θ of 10.3±0.2°, 20.7±0.2°, 26.8±0.2°, 11.3±0.2°, 26.5±0.2°, 14.3±0.2°, 22.8±0.2°, 16.1±0.2°, 21.9±0.2°, 12.2±0.2°, 13.2±0.2°, 25.8±0.2°, 24.3±0.2°, 18.5±0.2° or 7.1±0.2°; preferably, it includes diffraction peaks at 4, 5, 6, 8 or 10 of them; The X-ray powder diffraction pattern of Form IV optionally includes one or more diffraction peaks located at 2θ of 25.2±0.2°, 15.1±0.2°, 14.2±0.2°, 14.8±0.2°, 21.6±0.2°, 12.4±0.2°, 24.9±0.2°, 18.3±0.2°, 23.7±0.2°, 11.4±0.2°, 26.8±0.2°, 8.5±0.2°, 17.5±0.2°, 20.6±0.2° or 16.3±0.2°; preferably, it includes diffraction peaks at 4, 5, 6, 8 or 10 of them; The X-ray powder diffraction pattern of Form V optionally includes one or more diffraction peaks located at 2θ of 25.4±0.2°, 15.3±0.2°, 15.0±0.2°, 14.4±0.2°, 21.8±0.2°, 12.6±0.2°, 24.6±0.2°, 23.9±0.2°, 18.5±0.2°, 8.7±0.2°, 11.6±0.2°, 17.7±0.2°, 23.3±0.2°, 25.7±0.2° or 20.8±0.2°; preferably, it includes diffraction peaks at 4, 5, 6, 8 or 10 of them; The X-ray powder diffraction pattern of Form VI optionally includes one or more diffraction peaks located at 2θ of 11.3±0.2°, 10.2±0.2°, 22.6±0.2°, 16.0±0.2°, 25.8±0.2°, 20.7±0.2°, 7.0±0.2°, 14.5±0.2°, 22.2±0.2°, 21.7±0.2°, 21.3±0.2°, 27.6±0.2°, 23.1±0.2°, 23.8±0.2° or 29.6±0.2°; preferably, it includes diffraction peaks at 4, 5, 6, 8 or 10 of them; The X-ray powder diffraction pattern of Form VII optionally comprises one or more diffraction peaks located at 2θ of 8.9±0.2°, 10.4±0.2°, 24.3±0.2°, 25.6±0.2°, 14.0±0.2°, 18.0±0.2°, 20.1±0.2°, 22.5±0.2°, 27.5±0.2°, 27.2±0.2°, 29.4±0.2°, 31.8±0.2°, 21.1±0.2°, 20.5±0.2° or 16.6±0.2°; preferably, it comprises diffraction peaks at 4, 5, 6, 8 or 10 of them; The X-ray powder diffraction pattern of Form X1 optionally includes one or more diffraction peaks located at 2θ of 16.7±0.2°, 20.8±0.2°, 21.7±0.2°, 25.2±0.2°, 17.0±0.2°, 17.6±0.2°, 12.9±0.2°, 23.4±0.2°, 14.8±0.2°, 9.0±0.2°, 14.4±0.2°, 18.6±0.2° or 19.4±0.2°; preferably, it includes diffraction peaks at 4, 5, 6, 8 or 10 of them; The X-ray powder diffraction pattern of Form X2 optionally includes one or more diffraction peaks located at 2θ of 9.5±0.2°, 19.8±0.2°, 15.2±0.2°, 28.8±0.2°, 10.8±0.2°, 14.1±0.2°, 24.5±0.2°, 26.6±0.2°, 38.8±0.2°, 39.2±0.2° or 49.4±0.2°; preferably, it includes diffraction peaks at 4, 5, 6, 8 or 10 of them; The X-ray powder diffraction pattern of Form X3 optionally includes one or more diffraction peaks located at 2θ of 12.0±0.2°, 14.4±0.2°, 7.2±0.2°, 25.8±0.2°, 13.5±0.2°, 21.6±0.2°, 4.9±0.2°, 16.7±0.2°, 17.8±0.2°, 17.4±0.2°, 12.9±0.2°, 23.0±0.2°, 24.0±0.2°, 25.3±0.2° or 15.8±0.2°; preferably, it includes diffraction peaks at 4, 5, 6, 8 or 10 of them; The X-ray powder diffraction pattern of Form X4 optionally includes one or more diffraction peaks located at 2θ of 11.3±0.2°, 10.2±0.2°, 22.6±0.2°, 20.7±0.2°, 14.2±0.2°, 16.1±0.2°, 7.1±0.2°, 14.5±0.2°, 25.8±0.2°, 21.4±0.2°, 26.5±0.2°, 26.8±0.2°, 13.2±0.2°, 18.5±0.2° or 22.2±0.2°; preferably, it includes diffraction peaks at 4, 5, 6, 8 or 10 of them; The X-ray powder diffraction pattern of Form X5 optionally includes one or more diffraction peaks located at 2θ of 11.4±0.2°, 13.6±0.2°, 17.5±0.2°, 12.2±0.2°, 24.8±0.2°, 18.7±0.2°, 23.4±0.2°, 22.9±0.2°, 21.8±0.2°, 22.4±0.2°, 14.4±0.2°, 27.3±0.2°, 25.3±0.2°, 15.5±0.2° or 16.5±0.2°; preferably, it includes diffraction peaks at 4, 5, 6, 8 or 10 of them; The X-ray powder diffraction pattern of Form X6 optionally includes one or more diffraction peaks located at 2θ of 11.4±0.2°, 10.2±0.2°, 20.7±0.2°, 22.6±0.2°, 25.9±0.2°, 16.1±0.2°, 7.1±0.2°, 14.6±0.2°, 12.2±0.2°, 18.5±0.2°, 19.5±0.2°, 21.4±0.2°, 21.8±0.2°, 22.3±0.2° or 26.5±0.2°; preferably, it includes diffraction peaks at 4, 5, 6, 8 or 10 of them.

6. The crystalline form of the compound according to any one of claims 2 to 5, characterized in that: Form I has an X-ray powder diffraction pattern as shown in Figure 1; Form II has an X-ray powder diffraction pattern as shown in Figure 2; Form III has an X-ray powder diffraction pattern as shown in Figure 3; Form IV has an X-ray powder diffraction pattern as shown in Figure 4; Form V has an X-ray powder diffraction pattern as shown in Figure 5; Form VI has an X-ray powder diffraction pattern as shown in Figure 6; Form VII has an X-ray powder diffraction pattern as shown in Figure 7; Form VIII has an X-ray powder diffraction pattern as shown in Figure 8; Form X1 has an X-ray powder diffraction pattern as shown in Figure 9; Form X2 has an X-ray powder diffraction pattern as shown in Figure 10; Form X3 has an X-ray powder diffraction pattern as shown in Figure 11; Form X4 has an X-ray powder diffraction pattern as shown in Figure 12; Form X5 has an X-ray powder diffraction pattern as shown in Figure 13; Form X6 has an X-ray powder diffraction pattern as shown in Figure 14.

7. The crystalline form of the compound according to any one of claims 2 to 6, characterized in that: The 2θ error between the diffraction peak positions with the top ten relative peak intensities in the X-ray powder diffraction patterns of Form I, Form II, Form III, Form IV, Form V, Form VI, Form VII, Form VIII, Form X1, Form X2, Form X3, Form X4, Form X5 and Form X6 and the diffraction peaks at the corresponding positions in Figures 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 and 14 is ±0.2° to ±0.5°; preferably ±0.2° to ±0.3°; and most preferably ±0.2°.

8. The crystalline form of the compound according to any one of claims 1 to 7, characterized in that: The crystal form is anhydrous; Alternatively, the crystalline form is a hydrate, and 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.

9. A method for preparing a crystalline form of the compound according to any one of claims 1 to 8, comprising the following steps: 1) Weigh an appropriate amount of free base or its crystal form and dissolve it in an organic solvent; 2) Optionally, add an anti-solvent to the above solution and stir until a solid precipitates; 3) Optionally, stirring, cooling and crystallizing to obtain the target product; in: The organic solvent is selected from one or more of methanol, acetone, ethyl acetate, acetonitrile, ethanol, tetrahydrofuran, 2-methyltetrahydrofuran, dichloromethane, 1,4-dioxane, benzene, toluene, isopropanol, n-butanol, isobutanol, N,N-dimethylformamide, N,N-dimethylacetamide, n-propanol, tert-butanol, 2-butanone, 3-pentanone and N-methylpyrrolidone; preferably one or more of methanol, acetone, 2-butanone, ethyl acetate, tetrahydrofuran or acetonitrile; more preferably acetone or 2-butanone; The anti-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 one or more of n-heptane, methyl tert-butyl ether or isopropyl ether; Alternatively, weigh an appropriate amount of the free base or its crystal form, and slurry it with a poor solvent at a certain temperature, preferably 0 to 65°C; Wherein: the poor solvent is selected from one or more of methanol, ethanol, acetonitrile, ethyl acetate, acetone, tetrahydrofuran, 2-methyltetrahydrofuran, dichloromethane, isopropanol, 2-butanone, isopropyl acetate, ethyl formate, 1,4-dioxane, benzene, toluene, n-butanol, isobutanol, N,N-dimethylformamide, N,N-dimethylacetamide, n-propanol, tert-butanol, 3-pentanone, methyl tert-butyl ether or water; preferably methanol, isopropanol, acetonitrile, ethyl acetate, methyl tert-butyl ether, acetone, dichloromethane, isopropyl acetate, tetrahydrofuran, 2-methyl-tetrahydrofuran, 2-butanone or water; more preferably methanol, isopropanol, methyl tert-butyl ether, acetone or 2-butanone; or, 1) Weigh an appropriate amount of free base or its crystal form and add an organic solvent; 2) heating and filtering, preferably at a temperature of 50 to 85°C; 3) cooling the filtrate and crystallizing to obtain the target product; in: The organic solvent is selected from one or more of methanol, acetone, ethyl acetate, acetonitrile, ethanol, tetrahydrofuran, 2-methyltetrahydrofuran, dichloromethane, 1,4-dioxane, benzene, toluene, isopropanol, n-butanol, isobutanol, N,N-dimethylformamide, N,N-dimethylacetamide, n-propanol, tert-butanol, 2-butanone, 3-pentanone and N-methylpyrrolidone; preferably one or more of methanol, isopropanol, 2-butanone, acetonitrile or ethanol; Alternatively, weigh an appropriate amount of the free base or its crystal form, heat and dry to obtain the target product, the temperature is preferably 50-85°C.

10. A pharmaceutical composition comprising a therapeutically effective amount of a crystalline form of the compound according to any one of claims 1 to 8, and one or more pharmaceutically acceptable carriers, diluents or excipients.

11. Use of the crystalline form of the compound according to any one of claims 1 to 8 or the pharmaceutical composition according to claim 10 in the preparation of a MALT1 inhibitor drug.

12. Use of the crystalline form of the compound according to any one of claims 1 to 8 or the pharmaceutical composition according to claim 10 in the preparation of a method for treating cancer or an autoimmune disease; wherein the cancer or the autoimmune disease is selected from B-cell lymphoma, non-Hodgkin's lymphoma, mantle cell lymphoma, follicular lymphoma, mucosa-associated lymphoid tissue lymphoma, chronic lymphocytic leukemia, rheumatoid arthritis, psoriatic arthritis, psoriasis, ulcerative colitis, Crohn's disease, systemic lupus erythematosus, asthma or chronic obstructive pulmonary disease.

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