Crystal form of tricyclic derivative inhibitor and preparation method therefor

Abstract

Provided are a crystal form of a tricyclic derivative inhibitor and a preparation method therefor. The present invention specifically relates to a crystal form of a compound of general formula (I), a preparation method for the crystal form, a pharmaceutical composition containing a therapeutically effective amount of the crystal form, and a use of the crystal form in treating cancers and autoimmune diseases.

Description

A crystal form of a tricyclic derivative inhibitor and a preparation method thereof Technical Field

[0001] The present invention belongs to the technical field of medicinal chemistry, and particularly 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 that plays a crucial role in immunity and inflammation. It participates in NF-κB signaling downstream of the B and T cell receptors (BCRs, TCRs). MALT1 forms the CBM complex with CARM1 and BCL10. Mutations in these genes can lead to constitutive activation of the NF-κB signaling pathway.

[0003] The growth of ABC-DLBCL is strongly dependent on the sustained activation of the NF-κB signaling pathway. It accounts for 16% of lymphomas and 40% of DLBCL cases in China. MALT lymphoma, caused by a translocation rearrangement of the MALT1 and BCL10 genes, accounts for 9% of lymphomas in China. MALT inhibitors also hold promise for CLL patients resistant to BTK inhibitors.

[0004] Currently, only Johnson & Johnson's compound JNJ-67856633 has entered clinical phase I worldwide. 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 in the pharmaceutical industry as drugs.

[0008] First, it has the potential to become a targeted therapy for ABC-DLBCL. The current standard treatment 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 the structures of a series of tricyclic derivative inhibitors. In order to make the products easy to handle, filter, dry, store, and 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.

[0012] Summary of the Invention

[0013] All contents involved in patent application PCT / CN2022 / 143665 are added to the present invention by reference.

[0014] 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:

[0015] in:

[0016] M1 is N or CH; M2 is N or CR 1b ; M3 is N or CR 1c ;

[0017] R 1a Selected from hydrogen, deuterium, halogen, hydroxyl, cyano, C1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, phenyl or 5-8 membered heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, 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 1b Selected from hydrogen, deuterium, halogen, hydroxyl, cyano, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, phenyl or 5-8 membered heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, 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 1c Selected from hydrogen, deuterium, halogen, hydroxyl, cyano, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, phenyl or 5-8 membered heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 3-8Cycloalkyl, 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;

[0020] R 2a Selected from hydrogen, deuterium, halogen, hydroxyl, cyano, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl or C 3-8 Cycloalkyl;

[0021] R 2b Selected from hydrogen, deuterium, halogen, hydroxyl, cyano, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl or C 3-8 Cycloalkyl.

[0022] In a preferred embodiment of the present invention, the structure of the compound is shown in general formula (II):

[0023] Where: M1 is N or CH; M3 is 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 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, phenyl or 5-6 membered heteroaryl, wherein the C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, 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 1cSelected from hydrogen, deuterium, fluorine, chlorine, bromine, hydroxyl, cyano, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, phenyl or 5-6 membered heteroaryl, wherein the C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, 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;

[0027] R 2a Selected from hydrogen, deuterium, fluorine, chlorine, bromine, hydroxyl, cyano, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, 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; or

[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, there are provided crystalline forms A to H 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, wherein:

[0046] The X-ray powder diffraction pattern of the crystalline form A has a diffraction peak at 2θ of 16.0±0.2°; or a diffraction peak at 26.3±0.2°; or a diffraction peak at 16.4±0.2°; or a diffraction peak at 11.3±0.2°; or a diffraction peak at 23.6±0.2°; or a diffraction peak at 25.3±0.2°; or a diffraction peak at 21.2±0.2°; or a diffraction peak at 12.1±0.2°; or a diffraction peak at 24.1±0.2°; or a diffraction peak at 10.7±0.2°; preferably includes any 2-5, or 3-5, or 3-6, or 3-8, or 5-8, or 6-8 of the above diffraction peaks, more preferably includes any 6, 7 or 8 thereof;

[0047] The X-ray powder diffraction pattern of the crystalline form B has a diffraction peak at 2θ of 16.0±0.2°; or a diffraction peak at 23.7±0.2°; or a diffraction peak at 21.0±0.2°; or a diffraction peak at 15.6±0.2°; or a diffraction peak at 17.3±0.2°; or a diffraction peak at 11.3±0.2°; or a diffraction peak at 26.4±0.2°; or a diffraction peak at 25.4±0.2°; or a diffraction peak at 16.3±0.2°; or a diffraction peak at 24.1±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 diffraction peaks, more preferably includes any 6, 7 or 8 thereof;

[0048] The X-ray powder diffraction pattern of the crystalline form C has a diffraction peak at 2θ of 14.3±0.2°; or a diffraction peak at 26.8±0.2°; or a diffraction peak at 26.6±0.2°; or a diffraction peak at 22.0±0.2°; or a diffraction peak at 16.0±0.2°; or a diffraction peak at 24.4±0.2°; or a diffraction peak at 13.2±0.2°; or a diffraction peak at 19.9±0.2°; or a diffraction peak at 25.0±0.2°; or a diffraction peak at 25.5±0.2°; preferably includes any 2-5, or 3-5, or 3-6, or 3-8, or 5-8, or 6-8 of the above diffraction peaks, more preferably includes any 6, 7 or 8 thereof;

[0049] The X-ray powder diffraction pattern of the crystalline form D has a diffraction peak at 2θ of 21.1±0.2°; or a diffraction peak at 22.0±0.2°; or a diffraction peak at 16.9±0.2°; or a diffraction peak at 25.4±0.2°; or a diffraction peak at 17.2±0.2°; or a diffraction peak at 17.8±0.2°; or a diffraction peak at 23.6±0.2°; or a diffraction peak at 30.5±0.2°; or a diffraction peak at 13.1±0.2°; or a diffraction peak at 15.0±0.2°; preferably includes any 2-5, or 3-5, or 3-6, or 3-8, or 5-8, or 6-8 of the above diffraction peaks, and more preferably includes any 6, 7 or 8 thereof;

[0050] The X-ray powder diffraction pattern of the crystalline form E has a diffraction peak at 2θ of 15.6±0.2°; or a diffraction peak at 23.6±0.2°; or a diffraction peak at 26.8±0.2°; or a diffraction peak at 26.6±0.2°; or a diffraction peak at 14.2±0.2°; or a diffraction peak at 25.4±0.2°; or a diffraction peak at 25.7±0.2°; or a diffraction peak at 24.3±0.2°; or a diffraction peak at 17.1±0.2°; or a diffraction peak at 20.8±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 diffraction peaks, more preferably includes any 6, 7 or 8 thereof;

[0051] The X-ray powder diffraction pattern of the crystalline form F has a diffraction peak at 2θ of 24.3±0.2°; or a diffraction peak at 11.4±0.2°; or a diffraction peak at 24.0±0.2°; or a diffraction peak at 10.7±0.2°; or a diffraction peak at 26.0±0.2°; or a diffraction peak at 24.7±0.2°; or a diffraction peak at 21.4±0.2°; or a diffraction peak at 16.2±0.2°; or a diffraction peak at 17.1±0.2°; or a diffraction peak at 15.4±0.2°; preferably includes any 2-5, or 3-5, or 3-6, or 3-8, or 5-8, or 6-8 of the above diffraction peaks, more preferably includes any 6, 7 or 8 thereof;

[0052] The X-ray powder diffraction pattern of the crystalline form G has a diffraction peak at 7.0±0.2°2θ; or a diffraction peak at 11.9±0.2°; or a diffraction peak at 16.1±0.2°; or a diffraction peak at 14.3±0.2°; or a diffraction peak at 21.1±0.2°; or a diffraction peak at 7.2±0.2°; or a diffraction peak at 11.6±0.2°; or a diffraction peak at 4.6±0.2°; or a diffraction peak at 24.4±0.2°; or a diffraction peak at 21.6±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 diffraction peaks, more preferably includes any 6, 7 or 8 thereof;

[0053] The X-ray powder diffraction pattern of the crystalline form H has a diffraction peak at 2θ of 20.8±0.2°; or a diffraction peak at 7.0±0.2°; or a diffraction peak at 16.0±0.2°; or a diffraction peak at 23.2±0.2°; or a diffraction peak at 4.7±0.2°; or a diffraction peak at 24.3±0.2°; or a diffraction peak at 24.0±0.2°; or a diffraction peak at 21.2±0.2°; or a diffraction peak at 26.2±0.2°; or a diffraction peak at 11.6±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 diffraction peaks, and more preferably includes any 6, 7 or 8 thereof.

[0054] In a further preferred embodiment of the present invention,

[0055] The X-ray powder diffraction pattern of Form A comprises at least one or more diffraction peaks located at 2θ of 16.0±0.2°, 26.3±0.2°, and 16.4±0.2°, preferably two of them, more preferably three; optionally, it may further comprise at least one of 11.3±0.2°, 23.6±0.2°, 25.3±0.2°, 21.2±0.2°, and 12.1±0.2°, preferably two, three, four or five of them;

[0056] The X-ray powder diffraction pattern of the crystalline form B comprises at least one or more diffraction peaks located at 2θ of 16.0±0.2°, 23.7±0.2°, and 21.0±0.2°, preferably two of them, more preferably three; optionally, it may further comprise at least one of 15.6±0.2°, 17.3±0.2°, 11.3±0.2°, 26.4±0.2°, and 25.4±0.2°, preferably two, three, four or five of them;

[0057] The X-ray powder diffraction pattern of the crystalline form C contains at least one or more diffraction peaks located at 2θ of 14.3±0.2°, 26.8±0.2°, and 26.6±0.2°, preferably two of them, more preferably three; optionally, it may further contain at least one of 22.0±0.2°, 16.0±0.2°, 24.4±0.2°, 13.2±0.2°, and 19.9±0.2°, preferably two, three, four or five of them; for example,

[0058] 14.3±0.2°, 26.8±0.2°;

[0059] 14.3±0.2°, 26.6±0.2°;

[0060] 14.3±0.2°, 26.8±0.2°, 26.6±0.2°, 22.0±0.2°;

[0061] 14.3±0.2°, 26.8±0.2°, 22.0±0.2°, 16.0±0.2°;

[0062] 14.3±0.2°, 26.8±0.2°, 26.6±0.2°, 22.0±0.2°, 16.0±0.2°;

[0063] 14.3±0.2°, 26.8±0.2°, 26.6±0.2°, 16.0±0.2°, 13.2±0.2°;

[0064] 14.3±0.2°, 26.8±0.2°, 26.6±0.2°, 22.0±0.2°, 16.0±0.2°, 24.4±0.2°;

[0065] 14.3±0.2°, 26.8±0.2°, 26.6±0.2°, 22.0±0.2°, 16.0±0.2°, 13.2±0.2°;

[0066] 14.3±0.2°, 26.8±0.2°, 26.6±0.2°, 22.0±0.2°, 16.0±0.2°, 24.4±0.2°, 13.2±0.2°;

[0067] 14.3±0.2°, 26.8±0.2°, 26.6±0.2°, 22.0±0.2°, 16.0±0.2°, 13.2±0.2°, 19.9±0.2°;

[0068] 14.3±0.2°, 26.8±0.2°, 26.6±0.2°, 22.0±0.2°, 16.0±0.2°, 24.4±0.2°, 13.2±0.2°, 19.9±0.2°;

[0069] The X-ray powder diffraction pattern of the crystalline form D comprises at least one or more diffraction peaks located at 2θ of 21.1±0.2°, 22.0±0.2°, and 16.9±0.2°, preferably two of them, more preferably three; optionally, it may further comprise at least one of 25.4±0.2°, 17.2±0.2°, 17.8±0.2°, 23.6±0.2°, and 30.5±0.2°, preferably two, three, four or five of them;

[0070] The X-ray powder diffraction pattern of the crystalline form E comprises at least one or more diffraction peaks located at 2θ of 15.6±0.2°, 23.6±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 26.6±0.2°, 14.2±0.2°, 25.4±0.2°, 25.7±0.2°, and 24.3±0.2°, preferably two, three, four, or five of them;

[0071] The X-ray powder diffraction pattern of the crystalline form F comprises at least one or more diffraction peaks located at 2θ of 24.3±0.2°, 11.4±0.2°, and 24.0±0.2°, preferably two of them, more preferably three; optionally, it may further comprise at least one of 10.7±0.2°, 26.0±0.2°, 24.7±0.2°, 21.4±0.2°, and 16.2±0.2°, preferably two, three, four or five of them;

[0072] The X-ray powder diffraction pattern of the crystalline form G comprises at least one or more diffraction peaks located at 2θ of 7.0±0.2°, 11.9±0.2°, and 16.1±0.2°, preferably two of them, more preferably three; optionally, it may further comprise at least one of 14.3±0.2°, 21.1±0.2°, 7.2±0.2°, 11.6±0.2°, and 4.6±0.2°, preferably two, three, four or five of them;

[0073] The X-ray powder diffraction pattern of the crystalline form H comprises at least one or more diffraction peaks located at 2θ of 20.8±0.2°, 7.0±0.2°, and 16.0±0.2°, preferably two of them, more preferably three; optionally, it may further comprise at least one of 23.2±0.2°, 4.7±0.2°, 24.3±0.2°, 24.0±0.2°, and 21.2±0.2°, preferably 2, 3, 4 or 5 of them.

[0074] In a further preferred embodiment of the present invention,

[0075] The X-ray powder diffraction pattern of the crystalline form A optionally further comprises one or more diffraction peaks located at 2θ of 24.1±0.2°, 10.7±0.2°, 17.2±0.2°, 12.4±0.2°, 16.9±0.2°, 27.9±0.2° or 21.8±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;

[0076] The X-ray powder diffraction pattern of the crystalline form B optionally further comprises one or more diffraction peaks located at 2θ of 16.3±0.2°, 24.1±0.2°, 10.6±0.2°, 26.2±0.2°, 24.9±0.2°, 4.9±0.2° or 12.3±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;

[0077] The X-ray powder diffraction pattern of the crystalline form C optionally further comprises one or more diffraction peaks located at 2θ of 25.0±0.2°, 25.5±0.2°, 29.4±0.2°, 15.3±0.2°, 18.5±0.2°, 19.2±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; for example,

[0078] 25.0±0.2°, 25.5±0.2°;

[0079] 25.0±0.2°, 15.3±0.2°;

[0080] 25.0±0.2°, 25.5±0.2°, 29.4±0.2°;

[0081] 25.0±0.2°, 25.5±0.2°, 15.3±0.2°;

[0082] 25.0±0.2°, 25.5±0.2°, 29.4±0.2°, 15.3±0.2°;

[0083] 25.0±0.2°, 25.5±0.2°, 15.3±0.2°, 18.5±0.2°;

[0084] 25.0±0.2°, 25.5±0.2°, 29.4±0.2°, 15.3±0.2°, 18.5±0.2°;

[0085] 25.0±0.2°, 25.5±0.2°, 29.4±0.2°, 18.5±0.2°, 19.2±0.2°;

[0086] 25.0±0.2°, 25.5±0.2°, 29.4±0.2°, 15.3±0.2°, 18.5±0.2°, 19.2±0.2°;

[0087] 25.0±0.2°, 25.5±0.2°, 29.4±0.2°, 15.3±0.2°, 18.5±0.2°, 16.6±0.2°;

[0088] 25.0±0.2°, 25.5±0.2°, 29.4±0.2°, 15.3±0.2°, 18.5±0.2°, 19.2±0.2°, 16.6±0.2°;

[0089] The X-ray powder diffraction pattern of the crystalline form D optionally further comprises one or more diffraction peaks located at 2θ of 13.1±0.2°, 15.0±0.2°, 9.3±0.2°, 24.0±0.2°, 27.5±0.2°, 25.7±0.2° or 19.6±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;

[0090] The X-ray powder diffraction pattern of the crystalline form E optionally further comprises one or more diffraction peaks located at 2θ of 17.1±0.2°, 20.8±0.2°, 22.0±0.2°, 11.3±0.2°, 16.7±0.2°, 10.5±0.2° or 12.5±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;

[0091] The X-ray powder diffraction pattern of the crystalline form F optionally further comprises one or more diffraction peaks located at 2θ of 17.1±0.2°, 15.4±0.2°, 12.6±0.2°, 20.8±0.2°, 7.4±0.2°, 27.0±0.2° or 12.2±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;

[0092] The X-ray powder diffraction pattern of the crystalline form G optionally further comprises one or more diffraction peaks located at 2θ of 24.4±0.2°, 21.6±0.2°, or 23.2±0.2°; preferably, at least any 2-3 of them; more preferably, any 2 or 3 of them;

[0093] The X-ray powder diffraction pattern of the crystalline form H optionally further includes one or more diffraction peaks located at 2θ of 26.2±0.2°, 11.6±0.2°, 10.7±0.2°, 12.0±0.2°, 27.3±0.2°, 13.9±0.2° or 14.4±0.2°; preferably, it includes at least any 2-3, or 4-5, or 6-7 of them; further preferably, it includes any 2, 3, 4, 5, 6, or 7 of them.

[0094] In a preferred embodiment of the present invention, the X-ray powder diffraction pattern of the crystalline form A optionally includes one or more diffraction peaks located at 2θ of 10.7±0.2°, 11.3±0.2°, 12.1±0.2°, 12.4±0.2°, 16.0±0.2°, 16.4±0.2°, 16.9±0.2°, 17.2±0.2°, 21.2±0.2°, 21.8±0.2°, 23.6±0.2°, 24.1±0.2°, 25.3±0.2°, 26.3±0.2° or 27.9±0.2°; preferably, it includes diffraction peaks at 4, 5, 6, 8 or 10 of the diffraction peaks.

[0095] The X-ray powder diffraction pattern of the crystalline form B optionally includes one or more diffraction peaks located at 2θ of 4.9±0.2°, 10.6±0.2°, 11.3±0.2°, 12.3±0.2°, 15.6±0.2°, 16.0±0.2°, 16.3±0.2°, 17.3±0.2°, 21.0±0.2°, 23.7±0.2°, 24.1±0.2°, 24.9±0.2°, 25.4±0.2°, 26.2±0.2° or 26.4±0.2°; preferably, the X-ray powder diffraction pattern comprises diffraction peaks at 4, 5, 6, 8 or 10 of the diffraction peaks.

[0096] The X-ray powder diffraction pattern of the crystalline form C optionally includes one or more diffraction peaks located at 2θ of 13.2±0.2°, 14.3±0.2°, 15.3±0.2°, 16.0±0.2°, 16.6±0.2°, 18.5±0.2°, 19.2±0.2°, 19.9±0.2°, 22.0±0.2°, 24.4±0.2°, 25.0±0.2°, 25.5±0.2°, 26.6±0.2°, 26.8±0.2° or 29.4±0.2°; preferably, it includes diffraction peaks at 4, 5, 6, 8 or 10 of the diffraction peaks; for example, the X-ray powder diffraction pattern of C has diffraction peaks at the following positions at 2θ:

[0097] 14.3±0.2°、26.8±0.2°、22.0±0.2°、16.0±0.2°；

[0098] 14.3±0.2°、26.8±0.2°、16.0±0.2°、24.4±0.2°；

[0099] 14.3±0.2°、26.8±0.2°、22.0±0.2°、16.0±0.2°、24.4±0.2°；

[0100] 14.3±0.2°、26.8±0.2°、16.0±0.2°、24.4±0.2°、13.2±0.2°；

[0101] 14.3±0.2°、26.8±0.2°、26.6±0.2°、24.4±0.2°、13.2±0.2°、19.9±0.2°；

[0102] 14.3±0.2°、26.8±0.2°、22.0±0.2°、16.0±0.2°、24.4±0.2°、13.2±0.2°；

[0103] 14.3±0.2°、26.8±0.2°、26.6±0.2°、22.0±0.2°、16.0±0.2°、24.4±0.2°、25.0±0.2°、25.5±0.2°；

[0104] 14.3±0.2°、26.8±0.2°、26.6±0.2°、16.0±0.2°、13.2±0.2°、19.9±0.2°、25.0±0.2°、15.3±0.2°；

[0105] 14.3±0.2°、26.8±0.2°、26.6±0.2°、22.0±0.2°、16.0±0.2°、24.4±0.2°、13.2±0.2°、19.9±0.2°、25.0±0.2°、15.3±0.2°；

[0106] 14.3±0.2°、26.8±0.2°、26.6±0.2°、22.0±0.2°、16.0±0.2°、24.4±0.2°、13.2±0.2°、25.0±0.2°、15.3±0.2°、18.5±0.2°；

[0107] The X-ray powder diffraction pattern of the crystalline form D optionally includes one or more diffraction peaks located at 2θ of 9.3±0.2°, 13.1±0.2°, 15.0±0.2°, 16.9±0.2°, 17.2±0.2°, 17.8±0.2°, 19.6±0.2°, 21.1±0.2°, 22.0±0.2°, 23.6±0.2°, 24.0±0.2°, 25.4±0.2°, 25.7±0.2°, 27.5±0.2° or 30.5±0.2°; preferably, the X-ray powder diffraction pattern comprises diffraction peaks at 4, 5, 6, 8 or 10 of the diffraction peaks.

[0108] The X-ray powder diffraction pattern of the crystalline form E optionally includes one or more diffraction peaks located at 2θ of 10.5±0.2°, 11.3±0.2°, 12.5±0.2°, 14.2±0.2°, 15.6±0.2°, 16.7±0.2°, 17.1±0.2°, 20.8±0.2°, 22.0±0.2°, 23.6±0.2°, 24.3±0.2°, 25.4±0.2°, 25.7±0.2°, 26.6±0.2° or 26.8±0.2°; preferably, the X-ray powder diffraction pattern includes one or more diffraction peaks at 4, 5, 6, 8 or 10 of the diffraction peaks.

[0109] The X-ray powder diffraction pattern of the crystalline form F optionally includes one or more diffraction peaks located at 2θ of 7.4±0.2°, 10.7±0.2°, 11.4±0.2°, 12.2±0.2°, 12.6±0.2°, 15.4±0.2°, 16.2±0.2°, 17.1±0.2°, 20.8±0.2°, 21.4±0.2°, 24.0±0.2°, 24.3±0.2°, 24.7±0.2°, 26.0±0.2° or 27.0±0.2°; preferably, the X-ray powder diffraction pattern includes one or more diffraction peaks at 4, 5, 6, 8 or 10 of the diffraction peaks.

[0110] The X-ray powder diffraction pattern of the crystalline form G optionally includes one or more diffraction peaks located at 2θ of 4.6±0.2°, 7.2±0.2°, 7.0±0.2°, 11.6±0.2°, 11.9±0.2°, 14.3±0.2°, 16.1±0.2°, 21.1±0.2°, 21.6±0.2°, 23.2±0.2° or 24.4±0.2°; preferably, the X-ray powder diffraction pattern includes one or more diffraction peaks at 4, 5, 6, 8 or 10 of the diffraction peaks.

[0111] The X-ray powder diffraction pattern of the crystalline form H optionally includes one or more diffraction peaks located at 2θ of 4.7±0.2°, 7.0±0.2°, 10.7±0.2°, 11.6±0.2°, 12.0±0.2°, 13.9±0.2°, 14.4±0.2°, 16.0±0.2°, 20.8±0.2°, 21.2±0.2°, 23.2±0.2°, 24.0±0.2°, 24.3±0.2°, 26.2±0.2° or 27.3±0.2°; preferably, it includes diffraction peaks at 4, 5, 6, 8 or 10 of the diffraction peaks.

[0112] In a further preferred embodiment of the present invention, the crystalline form A 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 in 2θ angles and interplanar spacing d values ​​are shown in Table 1.

[0113] Table 1 XRPD diffraction data of compound free base form A

[0114] The X-ray powder diffraction pattern of Form A 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, is substantially as shown in FIG1 .

[0115] In a further preferred embodiment of the present invention, Form B 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 in 2θ angles and interplanar spacing d values ​​are shown in Table 2.

[0116] Table 2 XRPD diffraction data of compound free base form B

[0117] The X-ray powder diffraction pattern of Form B 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, is substantially as shown in FIG2 .

[0118] In a further preferred embodiment of the present invention, the crystalline form C 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 in 2θ angles and interplanar spacing d values ​​are shown in Table 3.

[0119] Table 3 XRPD diffraction data of compound free base form C

[0120] The crystalline form C 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 shown in FIG3 ; its DSC pattern is shown in FIG4 ; and its TGA pattern is shown in FIG5 .

[0121] In a further preferred embodiment of the present invention, Form D 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 in 2θ angles and interplanar spacing d values ​​are shown in Table 4.

[0122] Table 4 XRPD diffraction data of compound free base form D

[0123] The crystalline form D 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 shown in FIG6 ; its DSC pattern is shown in FIG7 ; and its TGA pattern is shown in FIG8 .

[0124] In a further preferred embodiment of the present invention, the crystalline form E 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 in 2θ angles and interplanar spacing d values ​​are shown in Table 5.

[0125] Table 5 XRPD diffraction data of compound free base form E

[0126] The X-ray powder diffraction pattern of Form E 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, is substantially as shown in FIG9 .

[0127] In a further preferred embodiment of the present invention, the crystalline form F 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 in 2θ angles and interplanar spacing d values ​​are shown in Table 6.

[0128] Table 6 XRPD diffraction data of compound free base form F

[0129] The X-ray powder diffraction pattern of Form F 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, is substantially as shown in FIG10 .

[0130] In a further preferred embodiment of the present invention, the crystalline form G 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 in 2θ angles and interplanar spacing d values ​​are shown in Table 7.

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

[0132] The X-ray powder diffraction pattern of Form G 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, is substantially as shown in Figure 11.

[0133] In a further preferred embodiment of the present invention, the crystalline form H 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 in 2θ angles and interplanar spacing d values ​​are shown in Table 8.

[0134] Table 8 XRPD diffraction data of compound free base form H

[0135] The X-ray powder diffraction pattern of Form H 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, is substantially as shown in Figure 12.

[0136] In a further preferred embodiment of the present invention, the 2θ error of the diffraction peak positions with the top ten relative peak intensities in the X-ray powder diffraction patterns of Form A, Form B, Form C, Form D, Form E, Form F, Form G and Form H of the compound N-(3-chloro-4-(2H-1,2,3-triazol-2-yl)phenyl)-1-(2-oxo-1,2-dihydrobenz[cd]indol-6-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide and the diffraction peaks at the corresponding positions in Figures 1, 2, 3, 4, 6, 9, 10, 11 and 12 is ±0.2° to ±0.5°; preferably ±0.2° to ±0.3°; and most preferably ±0.2°.

[0137] The error described in the present invention refers to a certain degree of overall drift in the diffraction peak positions in the X-ray powder diffraction patterns of different batches of samples due to experimental error factors such as differences in sample preparation technology levels, operational standardization, sample thickness, and the use of different sample holders during the experiment. For those skilled in the art, the overall drift in the diffraction peak positions due to experimental error is predictable.

[0138] In a further preferred embodiment of the present invention, the crystalline form is an anhydrate.

[0139] 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.

[0140] In a further preferred embodiment of the present invention, the method for preparing the above-mentioned crystalline form of the compound specifically comprises the following steps:

[0141] 1) Weigh an appropriate amount of free base or its crystal form and dissolve it in a mixed solvent;

[0142] 2) Optionally, add an anti-solvent to the above solution and stir until a solid precipitates;

[0143] 3) Optionally, stirring, cooling and crystallizing to obtain the target product;

[0144] Wherein: the mixed solvent is selected from two or more of methanol, acetone, ethyl acetate, acetonitrile, ethanol, tetrahydrofuran, 2-methyltetrahydrofuran, dichloromethane, 1,4-dioxane, benzene, toluene, isopropyl alcohol, n-butanol, isobutyl alcohol, N,N-dimethylformamide, N,N-dimethylacetamide, n-propanol, tert-butanol, 2-butanone, 3-pentanone and N-methylpyrrolidone; preferably two or more of methanol, acetone, dichloromethane, ethyl acetate, tetrahydrofuran or 2-methyl-tetrahydrofuran;

[0145] 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;

[0146] In a further preferred embodiment of the present invention, the method for preparing the above-mentioned crystalline form of the compound specifically comprises the following steps:

[0147] Weigh an appropriate amount of free base or its crystal form, and beat with a poor solvent at a certain temperature, preferably 0-50°C;

[0148] Wherein: the poor solvent is selected from one or more of methanol, ethanol, acetonitrile, ethyl acetate, acetone, tetrahydrofuran, 2-methyltetrahydrofuran, dichloromethane, isopropyl alcohol, 2-butanone, isopropyl acetate, ethyl formate, 1,4-dioxane, benzene, toluene, n-butanol, isobutyl alcohol, N,N-dimethylformamide, N,N-dimethylacetamide, n-propanol, tert-butanol, 3-pentanone, methyl tert-butyl ether or water; preferably one or more of methanol, isopropyl alcohol, acetonitrile, ethyl acetate, methyl tert-butyl ether, acetone, dichloromethane, isopropyl acetate, tetrahydrofuran, 2-methyl-tetrahydrofuran, 2-butanone or water; more preferably methanol, isopropyl alcohol, methyl tert-butyl ether, acetone or 2-butanone;

[0149] In a further preferred embodiment of the present invention, the preparation method of the above-mentioned compound crystal form C specifically comprises the following steps:

[0150] 1) Weigh an appropriate amount of free base or its crystal form, add a mixed solvent and water, and cool to a temperature preferably between 0 and 10°C;

[0151] 2) adding sodium hydroxide solution to adjust the pH to 9-10; the concentration of the sodium hydroxide solution is selected from 1-5N, preferably 4N;

[0152] 3) extracting, separating the liquids, concentrating and drying the organic phase to obtain the target product;

[0153] Wherein: the mixed solvent is selected from two 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 two or more of dichloromethane, ethyl acetate, tetrahydrofuran or 2-methyl-tetrahydrofuran; more preferably ethyl acetate and tetrahydrofuran.

[0154] The present invention also aims to provide a pharmaceutical composition comprising a therapeutically effective amount of a crystalline form of any of the above compounds, and one or more pharmaceutically acceptable carriers, diluents or excipients.

[0155] 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.

[0156] The present invention also aims to provide the 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 autoimmune diseases; 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.

[0157] 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. BRIEF DESCRIPTION OF THE DRAWINGS

[0158] FIG1 is an XRPD diagram of free base Form A.

[0159] FIG2 is an XRPD diagram of free base Form B.

[0160] FIG3 is an XRPD diagram of free base Form C.

[0161] FIG4 is a DSC diagram of free base Form C.

[0162] FIG5 is a TGA diagram of free base Form C.

[0163] FIG6 is an XRPD diagram of free base Form D.

[0164] FIG7 is a DSC diagram of free base Form D.

[0165] FIG8 is a TGA diagram of free base Form D.

[0166] FIG9 is an XRPD diagram of free base Form E.

[0167] FIG10 is an XRPD diagram of free base Form F.

[0168] FIG11 is an XRPD diagram of free base Form G.

[0169] FIG12 is an XRPD diagram of free base Form H.

[0170] Detailed Description of the Invention

[0171] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0172] 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 containing 1 to 6 carbon atoms, non-limiting examples of which include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 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 point of attachment. 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, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl or carboxylate groups. Methyl, ethyl, isopropyl, tert-butyl, haloalkyl, deuterated alkyl, alkoxy-substituted alkyl and hydroxy-substituted alkyl are preferred.

[0173] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent, wherein the cycloalkyl ring contains 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, and more preferably 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like; polycyclic cycloalkyls include spirocyclic, fused, and bridged cycloalkyls, preferably cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, and cycloheptyl.

[0174] 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, excluding the ring portion of -OO-, -OS- or -SS-, and 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 with 1-2 oxygen atoms, sulfur atoms, or 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.

[0175] Non-limiting examples of monocyclic heterocyclic groups include pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, 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, fused and bridged heterocyclic groups; wherein the spirocyclic, fused and bridged heterocyclic groups are optionally connected to other groups by single bonds, or further connected to other cycloalkyl, heterocyclic, aryl and heteroaryl groups through any two or more atoms on the ring.

[0176] The heterocyclyl group may be optionally substituted or unsubstituted. 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, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl or carboxylate.

[0177] The term "aryl" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (i.e., rings 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- to 10-membered heteroaryl, benzo 3- to 8-membered cycloalkyl, and benzo 3- to 8-membered heteroalkyl, preferably benzo 5- to 6-membered heteroaryl, benzo 3- to 6-membered cycloalkyl, and benzo 3- to 6-membered heteroalkyl, wherein the heterocyclic group is a heterocyclic group containing 1-3 nitrogen atoms, oxygen atoms, or sulfur atoms; or further comprises a three-membered nitrogen-containing fused ring containing a benzene ring.

[0178] Wherein the ring connecting to the parent structure is an aryl ring, non-limiting examples of which include:

[0179] wait.

[0180] The aryl group may be substituted or unsubstituted. 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, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.

[0181] 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 group is preferably 5 to 12-membered, more preferably 5 to 8-membered, further preferably 5 to 7-membered, and further preferably 5-membered or 6-membered, such as imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, thiadiazole, pyrazinyl, etc., preferably triazolyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, pyrimidinyl or thiazolyl; more preferably pyrazolyl, pyrrolyl, imidazolyl, triazolyl, oxazolyl or pyridinyl. The heteroaryl ring can be fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring, non-limiting examples of which include:

[0182] wait.

[0183] 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, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.

[0184] The term "alkoxy" refers to-O-(alkyl) and-O-(unsubstituted cycloalkyl), wherein the definition of alkyl is as described above. The 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 following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, sulfydryl, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.

[0185] "Haloalkyl" refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined above.

[0186] "Haloalkoxy" refers to an alkoxy group substituted with one or more halogens, wherein alkoxy is as defined above.

[0187] "Hydroxyalkyl" refers to an alkyl group substituted with a hydroxy group, wherein alkyl is as defined above.

[0188] 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”, and “X is A, B and C” all express the same meaning, that is, X can be any one or more of A, B, and C.

[0189] The hydrogen atoms described in the present invention can all 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.

[0190] "Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not. For example, "a heterocyclic group optionally substituted with an alkyl group" means that the alkyl group may but need not be present, and that 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.

[0191] "Substituted" means that one or more hydrogen atoms, preferably up to 5, more preferably 1 to 3 hydrogen atoms, in a group are replaced independently of one another by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and a person skilled in the art can determine (by experiment or theory) which substitutions are possible or impossible without undue effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when combined with a carbon atom with an unsaturated (e.g., olefinic) bond. DETAILED DESCRIPTION

[0192] The present invention is further described below with reference to the following examples, but these examples are not intended to limit the scope of the present invention.

[0193] Example

[0194] The structures of the compounds of the present invention are determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). -6 The unit of ppm is given. NMR measurements were performed using a Bruker AVANCE-400 NMR spectrometer. The solvents used were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD), with tetramethylsilane (TMS) as the internal standard.

[0195] MS was measured using a FINNIGAN LCQAd (ESI) mass spectrometer (manufacturer: Thermo, model: Finnigan LCQ advantage MAX).

[0196] 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).

[0197] Average kinase inhibition rate and IC 50 The values ​​were determined using a NovoStar microplate reader (BMG, Germany).

[0198] The thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate. The specification of the silica gel plate used in thin layer chromatography (TLC) is 0.15mm~0.2mm, and the specification used for thin layer chromatography separation and purification products is 0.4mm~0.5mm.

[0199] Column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier.

[0200] 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, Accela ChemBio Inc, Darui Chemicals, and other companies.

[0201] Unless otherwise specified in the examples, all reactions can be carried out under an argon atmosphere or a nitrogen atmosphere.

[0202] Argon atmosphere or nitrogen atmosphere means that the reaction bottle is connected to an argon or nitrogen balloon with a capacity of about 1 L.

[0203] Hydrogen atmosphere means that the reaction bottle is connected to a hydrogen balloon with a capacity of about 1L.

[0204] The pressurized hydrogenation reaction uses a Parr 3916EKX hydrogenator and a Qinglan QL-500 hydrogen generator or an HC2-SS hydrogenator.

[0205] The hydrogenation reaction is usually carried out by evacuating the chamber and filling it with hydrogen, and the operation is repeated three times.

[0206] A CEM Discover-S 908860 microwave reactor was used for the microwave reaction.

[0207] Unless otherwise specified in the examples, the solution refers to an aqueous solution.

[0208] Unless otherwise specified in the examples, the reaction temperature is room temperature, 20°C to 30°C.

[0209] The reaction progress in the examples was monitored using thin-layer chromatography (TLC). The developing solvent systems used in the reactions included: A: dichloromethane and methanol, B: n-hexane and ethyl acetate, C: petroleum ether and ethyl acetate, and D: acetone. The volume ratio of the solvents was adjusted according to the polarity of the compounds. The eluent systems for column chromatography and the developing solvent systems for thin-layer chromatography used to purify the compounds included: A: n-hexane and ethyl acetate, and B: n-hexane and tetrahydrofuran. The volume ratio of the solvents was adjusted according to the polarity of the compounds. Small amounts of alkaline or acidic reagents such as triethylamine and acetic acid could also be added for adjustment.

[0210] Intermediate 1

[0211] 1-(2-Carbonyl-1,2-dihydrobenzo[cd]indol-6-yl)-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid

[0212] Step 1: 6-Bromobenz[cd]indol-2(1H)-one

[0213] Benzo[cd]indol-2(1H)-one (20 g, 118.2 mmol) was dissolved in 150 mL of glacial acetic acid. Liquid bromine (37.8 g, 236.5 mmol) was added dropwise to the reaction mixture under ice-cooling. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure to yield the title product, 6-bromobenz[cd]indol-2(1H)-one (18.7 g), in a 63.8% yield. MS m / z (ESI): 248 [M+1].

[0214] Step 2: 6-Bromo-1-(4-methoxybenzyl)benzo[cd]indol-2(1H)-one

[0215] 6-Bromobenz[cd]indol-2(1H)-one (10 g, 40.3 mmol) was dissolved in 200 mL of dimethylformamide. 4-Methoxybenzyl bromide (12.2 g, 61.5 mmol) and potassium carbonate (11.3 g, 82 mmol) were added and stirred at room temperature for 16 hours. The reaction mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent System A to yield the title product, 6-bromo-1-(4-methoxybenzyl)benz[cd]indol-2(1H)-one (10.7 g), in a yield of 72.1%. MS m / z (ESI): 368 [M+1].

[0216] Step 3: 6-Hydrazino-1-(4-methoxybenzyl)benzo[cd]indol-2(1H)-one

[0217] Palladium chloride (π-cinnamyl) dimer (229.4 mg, 0.44 mmol) and N-[2-bis(1-adamantyl)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)benz[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 mixture. The mixture was stirred at room temperature for 5 minutes. Hydrazine hydrate (897.3 mg, 17.92 mmol) was added to the reaction mixture and stirred at 50°C for 2 hours. The reaction mixture was filtered, and the residue was washed with 20 mL of ethyl acetate. The filtrate was concentrated under reduced pressure to give the title product, 6-hydrazino-1-(4-methoxybenzyl)benzo[cd]indol-2(1H)-one (2.66 g), in a 93.0% yield. MS m / z (ESI): 319 [M+1].

[0218] Step 4: 1-(1-(4-methoxybenzyl)-2-carbonyl-1,2-dihydrobenzo[cd]indol-6-yl)-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid ethyl ester

[0219] 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-methylenetrifluoroacetoacetate (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 resulting 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) in a yield of 21.3%. MS m / z (ESI): 496 [M+1].

[0220] Step 5: 1-(1-(4-methoxybenzyl)-2-carbonyl-1,2-dihydrobenzo[cd]indol-6-yl)-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid

[0221] Ethyl 1-(1-(4-methoxybenzyl)-2-carbonyl-1,2-dihydrobenzo[cd]indol-6-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate (880 mg, 1.78 mmol) and sodium hydroxide (350 mg, 8.9 mmol) were dissolved in 2 mL of tetrahydrofuran and 1 mL of 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 the mixture was extracted with ethyl acetate (50 mL × 3). The organic phases were combined, washed sequentially with water (50 mL × 1) and saturated sodium chloride solution (50 mL × 1), 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), in a 93% yield. MS m / z(ESI):468[M+1]

[0222] Step 6: 1-(2-Carbonyl-1,2-dihydrobenzo[cd]indol-6-yl)-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid

[0223] 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 mixture was filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent System A to provide 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].

[0224] 1 H NMR (400MHz, DMSO-d6) 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).

[0225] Example 1

[0226] 1-(2-Carbonyl-1,2-dihydropyrrolo[2,3,4-ij]isoquinolin-5-yl)-5-trifluoromethyl-N-(2-trifluoromethylpyridin-4-yl)-1H-pyrazole-4-carboxamide

[0227] Step 1: 8-Bromo-4-chloroisoquinolin-1(2H)-one

[0228] 8-Bromoisoquinolin-1(2H)-one 1a (5.00 g, 22.32 mmol) was dissolved in 50 mL of N,N-dimethylformamide. N-chlorosuccinimide (3.15 g, 23.59 mmol) was added to the reaction mixture under ice-cooling, and the reaction was stirred at room temperature for 12 hours. The mixture was extracted with ethyl acetate (50 mL x 3). The combined organic phases were washed sequentially with water (50 mL x 1) and saturated sodium chloride solution (50 mL x 1), 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 afford 8-bromo-4-chloroisoquinolin-1(2H)-one 1b (4.70 g) in an 81.5% yield. MS m / z (ESI): 258 [M+1].

[0229] Step 2: 8-Bromo-1,4-dichloroisoquinoline

[0230] 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 mixture was filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography using eluent System A to obtain the title product, 8-bromo-1,4-dichloroisoquinoline 1c (4.50 g), in an 89.3% yield. MS m / z (ESI): 276 [M+1]

[0231] Step 3: 8-Bromo-4-chloro-1-iodoisoquinoline

[0232] 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 mixture. The mixture was stirred at room temperature for 5 minutes. Trimethylsilyl chloride (3.30 mg, 30.37 mmol) was added to the reaction mixture, and the mixture was stirred at 80°C for 12 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent System A to obtain the title product, 8-bromo-4-chloro-1-iodoisoquinoline 1d (3.50 g), in a yield of 58.6%. MS m / z (ESI): 368 [M+1].

[0233] Step 4: 8-Bromo-4-chloro-1-cyanoisoquinoline

[0234] 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 x 3). The combined organic phases were washed sequentially with water (50 mL x 1) and saturated sodium chloride solution (50 mL x 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using eluent System A to afford the title product, 8-bromo-4-chloro-1-cyanoisoquinoline 1e (2.00 g), in a yield of 79.1%. MS m / z (ESI): 267 [M+1].

[0235] Step 5: 4-chloro-8-(4-methoxybenzyl)amino-1-cyanoisoquinoline

[0236] 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 the mixture was stirred at 90°C for 16 hours. The mixture was extracted with ethyl acetate (50 mL x 3). The combined organic phases were washed sequentially with water (50 mL x 1) and saturated sodium chloride solution (50 mL x 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using eluent System A to yield the title product, 4-chloro-8-(4-methoxybenzyl)amino-1-cyanoisoquinoline 1f (2.10 g), in an 86.2% yield. MS m / z (ESI): 324 [M+1].

[0237] Step 6: 5-chloro-1-(4-methoxybenzyl)pyrrolo[2,3,4-ij]isoquinolin-2(1H)-one

[0238] 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 to ice water and filter to obtain the title product, 5-chloro-1-(4-methoxybenzyl)pyrrolo[2,3,4-ij]isoquinolin-2(1H)-one, 1 g (450 mg), in a 21.3% yield. MS m / z (ESI): 325 [M+1].

[0239] Step 7: 5-Hydrazino-1-(4-methoxybenzyl)pyrrolo[2,3,4-ij]isoquinolin-2(1H)-one

[0240] Palladium chloride (π-cinnamyl) dimer (35 mg, 0.068 mmol) and N-[2-bis(1-adamantyl)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 mixture. The mixture was stirred at room temperature for 5 minutes. Hydrazine hydrate (897 mg, 17.92 mmol) was added to the reaction mixture and stirred at 50°C for 2 hours. The reaction mixture 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]

[0241] 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

[0242] 5-Hydrazino-1-(4-methoxybenzyl)pyrrolo[2,3,4-ij]isoquinolin-2(1H)-one 1h (500 mg, 1.56 mmol) and ethyl ethoxy-2-methylenetrifluoroacetoacetate (750 mg, 3.12 mmol) were dissolved in 10 mL of ethanol and stirred at 80°C for 3 hours. The reaction mixture was concentrated under reduced pressure, and the resulting 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) in a yield of 25.9%. MS m / z (ESI): 496 [M+1]

[0243] 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

[0244] 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, 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. The reaction mixture was adjusted to a pH below 7 by adding 2M hydrochloric acid. The mixture was extracted with ethyl acetate (50 mL × 3). The organic phases were combined, washed sequentially with water (50 mL × 1) and saturated sodium chloride solution (50 mL × 1), dried over anhydrous sodium sulfate, filtered, and the filtrate 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), in a yield of 53.0%. MS m / z (ESI): 468 [M+1].

[0245] Step 10: 1-(2-oxo-1,2-dihydropyrrolo[2,3,4-ij]isoquinolin-5-yl)-2-trifluoromethyl-1H-pyrrole-3-carboxylic acid

[0246] 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 resulting residue was purified by silica gel column chromatography using eluent System C to afford 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 65.7% yield. MS m / z (ESI): 348 [M+1]

[0247] 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

[0248] 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 mixture, and the mixture was washed sequentially with water (50 mL × 1) and saturated sodium chloride solution (50 mL × 1), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure. The resulting 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), in a yield of 81.24%. MS m / z (ESI): 492 [M+1].

[0249] Example 2

[0250] 1-(2-Carbonyl-1,2-dihydropyrrolo[4,3,2-ij]isoquinolin-6-yl)-5-trifluoromethyl-N-(2-trifluoromethylpyridin-4-yl)-1H-pyrazole-4-carboxamide

[0251] Step 1: 8-Bromo-4-chloro-N-(4-methoxybenzyl)isoquinolin-1-amine

[0252] 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 mixture. The mixture was stirred at 80°C for 12 hours. The mixture was extracted with ethyl acetate (50 mL x 3). The combined organic phases were washed sequentially with water (50 mL x 1) and saturated sodium chloride solution (50 mL x 1), 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 afford 8-bromo-4-chloro-N-(4-methoxybenzyl)isoquinolin-1-amine 2b (4.7 g) in a 68.9% yield. MS m / z (ESI): 377 [M+1].

[0253] Referring to the synthesis methods of steps 4, 6, and 11 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].

[0254] 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).

[0255] Example 3

[0256] 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

[0257] Referring to the synthesis method of step 11 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 using 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) in a yield of 58.6%. MS m / z (ESI): 525,527 [M+1].

[0258] 1 H NMR(400MHz,DMSO-d6)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).

[0259] Example 4

[0260] 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

[0261] Referring to the synthesis method of step 11 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 using 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) in a yield of 55.1%. MS m / z (ESI): 559 [M+1]

[0262] 1H NMR(400MHz,DMSO-d6)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).

[0263] Example 5

[0264] 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

[0265] Step 1: 2-(5-nitro-3-(trifluoromethyl)pyridin-2-yl)oxazole

[0266] 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. The nitrogen atmosphere was purged three times and the reaction was heated to 110°C for 15 hours. The reaction mixture was cooled to room temperature and concentrated. The residue was added with 10 mL of water and extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed with saturated sodium chloride solution (30 mL x 1), dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was purified by silica gel column chromatography using eluent System C to afford the title product, 2-(5-nitro-3-(trifluoromethyl)pyridin-2-yl)oxazole 5b (20 mg) in a yield of 13.8%. MS m / z (ESI): 260 [M+1].

[0267] Step 2: 6-(oxazol-2-yl)-5-(trifluoromethyl)pyridin-3-amine

[0268] 2-(5-nitro-3-(trifluoromethyl)pyridin-2-yl)oxazole 5b (0.20 g, 0.77 mmol) was dissolved in 5 mL of ethanol and 2 mL of water. Iron powder (215 mg, 3.85 mmol) and ammonium chloride (199 mg, 3.85 mmol) were added. The nitrogen atmosphere was purged three times and the reaction was heated to 70°C for 2 hours. The reaction mixture was cooled to room temperature and filtered. The filter cake was washed with ethanol (10 mL x 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), in a yield of 28.3%. MS m / z (ESI): 230 [M+1].

[0269] 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

[0270] 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. The atmosphere was purged with nitrogen three times and cooled to 0°C. Pyridine (14 mg, 0.17 mmol) and phosphorus oxychloride (26 mg, 0.17 mmol) were added and the reaction mixture was warmed 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 afford 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) in a 5.2% yield. MS m / z (ESI): 559 [M+1].

[0271] 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).

[0272] Example 6

[0273] 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

[0274] Referring to the synthesis method of step 11 of Example 1, 5-difluoromethyl-6-(2H-1,2,3-triazol-2-yl)pyridin-3-amine (21 mg, 0.10 mmol, prepared using the known method of WO2018020474) and Intermediate 1 (34 mg, 0.10 mmol) were reacted to give 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), in a yield of 38.8%. MS m / z (ESI): 541 [M+1].

[0275] 1 H NMR(400MHz,DMSO-d6)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).

[0276] Example 7

[0277] 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

[0278] The synthesis method of the eleventh step of Reference Example 1 was carried out by reacting intermediate 1 (70 mg, 0.22 mmol) and 4-(2H-1,2,3-triazol-2-yl)-3-(trifluoromethyl)aniline 7a (100 mg, 0.44 mmol, synthesized using 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) in a yield of 28.5%. MS m / z (ESI): 558 [M+1]

[0279] 1 H NMR (400MHz, DMSO-d6) 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).

[0280] Example 8

[0281] 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

[0282] 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 mixture, and the mixture was washed sequentially with water (50 mL × 1) and saturated sodium chloride solution (50 mL × 1), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure. The resulting 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) in a yield of 31.2%. MS m / z (ESI): 524 [M+1].

[0283] 1 H NMR(400MHz,DMSO-d6)δ11.12(s,1H),11.00(s,1H),8.52(s,1H),8.19–8.13(m,4H) ,7.95–7.84(m,2H),7.77–7.69(m,2H),7.61(d,J=8.3Hz,1H),7.12(d,J=7.5Hz,1H).

[0284] Example 9

[0285] 5-Cyclopropyl-1-(2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)-N-(2-(trifluoromethyl)pyridin-4-yl)-1H-pyrazole-4-carboxamide

[0286] Step 1: 5-cyclopropyl-1-(1-(4-methoxybenzyl)-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)-1H-pyrazole-4-carboxylic acid ethyl ester

[0287] 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 resulting residue was purified by silica gel column chromatography using eluent System A to obtain the title product, ethyl 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].

[0288] Step 2: 5-cyclopropyl-1-(1-(4-methoxybenzyl)-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)-1H-pyrazole-4-carboxylic acid

[0289] 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. The reaction mixture was adjusted to a pH below 7 by adding 2M hydrochloric acid. The mixture was extracted with ethyl acetate (50 mL × 3). The organic phases were combined and washed sequentially with water (50 mL × 1) and saturated sodium chloride solution (50 mL × 1). The mixture was 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). Yield: 96.5%. MS m / z (ESI): 440 [M+1].

[0290] Step 3: 5-cyclopropyl-1-(2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)-1H-pyrazole-4-carboxylic acid

[0291] 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 mixture was filtered, the filtrate was concentrated under reduced pressure, and the resulting 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 75.2% yield. MS m / z (ESI): 320 [M+1].

[0292] Step 4: 5-cyclopropyl-1-(2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)-N-(2-trifluoromethylpyridin-4-yl)-1H-pyrazole-4-carboxamide

[0293] 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 mixture, and the mixture was washed sequentially with water (50 mL × 1) and saturated sodium chloride solution (50 mL × 1), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography with 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), in a yield of 34.4%. MS m / z (ESI): 464 [M+1].

[0294] 1 H NMR (400MHz, DMSO-d6) 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(d d,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).

[0295] Example 10

[0296] 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

[0297] Referring to the synthesis method of step 11 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 using 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) in a yield of 26.6%. MS m / z (ESI): 531 [M+1]

[0298] 1 H NMR (400MHz, DMSO-d6) 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).

[0299] Example 11

[0300] 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

[0301] Referring to the synthesis method of step 11 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 using 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) in a yield of 50.3%. MS m / z (ESI): 497 [M+1]

[0302] 1 H NMR(400MHz,DMSO-d6)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).

[0303] Example 12

[0304] 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

[0305] Referring to the synthesis method of step 11 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 using 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), in a yield of 38.3%. MS m / z (ESI): 496 [M+1].

[0306] 1H NMR(400MHz,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).

[0307] Example 13

[0308] 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

[0309] The synthesis method of steps 11 and 12 of Reference Example 3 was followed by the preparation of N-(6-(2H-1,2,3-triazol-2-yl)-5-(trifluoromethyl)pyridin-3-amine 13a (50 mg, 0.22 mmol) to afford 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 13 (20 mg) in a 16.4% yield. MS m / z (ESI): 560 [M+1].

[0310] 1H NMR (400MHz, CD3OD) 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,1 H),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).

[0311] Example 14

[0312] 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

[0313] The synthesis method of steps 11 and 12 of Reference Example 3 was followed by the preparation of 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].

[0314] 1H NMR(400MHz,CD3OD)δ8.33(d,J=12.5Hz,2H),8.23–8.12(m,2H),8.06(dd,J=8.2,7.0Hz,1 H),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).

[0315] Example 15

[0316] 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

[0317] The synthesis 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 in a 35.2% yield. MS m / z (ESI): 531 [M+1]

[0318] 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).

[0319] Example 16

[0320] 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

[0321] With reference 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") to obtain 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) with a yield of 31.7%. MS m / z(ESI):531[M+1]

[0322] 1 H 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).

[0323] Biological test evaluation

[0324] The present invention is further described and explained below in conjunction with test examples, but these examples are not intended to limit the scope of the present invention.

[0325] Test Example 1: Determination of the inhibitory effect of the compounds of the present invention on MALT1 enzyme activity

[0326] 1.1 Experimental purpose: Using Ac-LRSR-AMC as substrate, test the IC of the compound for inhibition of MALT1 enzyme activity at its Km concentration 50 .

[0327] 1.2 Experimental instruments and reagents:

[0328] 1.3 Experimental methods:

[0329] Using Ac-LRSR-AMC as a substrate, the product of MALT1 cleavage produces fluorescence, detectable at 460 nm. The highest concentration tested was 1000 nM, with three-fold dilutions, resulting in a total of 11 concentrations (1000 nM to 0.017 nM). The reaction system consisted of 10 nM FL MALT1 protein, 200 mM Ac-LRSR-AMC, 50 mM Tris pH 7.5, 0.6 M Citrate, 1 mM DTT, 1 mM EDTA, 0.05% BSA, and 1.5% DMSO. Compounds and enzyme were preincubated at room temperature for 50 minutes, followed by the addition of substrate and the reaction was allowed to proceed for 4 hours.

[0330] 1.4 Experimental data processing method:

[0331] 1. Inhibition rate (%):

[0332] The original data (460 nm reading) was calculated according to the following formula to obtain the inhibition rate.

[0333] 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 reaction wells without compound enzyme, and the negative control wells are reaction wells without enzyme.

[0334] 2. Curve fitting:

[0335] Use GraphPad Prism 6's log(inhibitor) vs.response--Variable slope (four parameters) to perform fitting equation analysis on the compound concentration and the corresponding inhibition rate, fit the curve, and derive the compound IC 50 value.

[0336] The fitting calculation equation is Y=Bottom+(Top-Bottom) / (1+10^((LogIC 50 -X)*HillSlope))

[0337] 1.5 Experimental Conclusions:

[0338] Table 9: IC values ​​of compounds for MALT1 enzyme inhibition 50 value

[0339] 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.

[0340] Test Example 2: Determination of the Proliferation Inhibitory Effect of the Compounds of the Invention on TMD8 and OCI-Ly3 Cells

[0341] 2.1 Experimental purpose: To evaluate the inhibitory effect of the compound on TMD8 and OCI-Ly3 cell proliferation by cell proliferation inhibition assay.

[0342] 2.2 Experimental instruments and reagents:

[0343] 2.3 Experimental Methods: The inhibitory effects of compounds on TMD8 and OCI-Ly3 cell proliferation were assessed using the CellTiter-Glo assay. The highest concentration tested was 1000 nM, with three-fold dilutions for a total of nine concentrations (1000 nM to 0.15 nM). Cells were plated at appropriate density and compounds were added the following day. After incubation for 96 hours, the cells were assayed using the CellTiter-Glo Luminescence Detection Kit.

[0344] 2.4 Experimental data processing method:

[0345] 1. Inhibition rate (%):

[0346] 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.

[0347] 2. Curve fitting:

[0348] Use GraphPad Prism 6's log(inhibitor) vs.response--Variable slope (four parameters) to perform fitting equation analysis on the compound concentration and the corresponding inhibition rate, fit the curve, and derive the compound IC50 The fitting calculation equation is Y=Bottom+(Top-Bottom) / (1+10^((LogIC 50 -X)*HillSlope))

[0349] 2.5 Experimental Conclusions:

[0350] Table 10: IC values ​​of compounds for inhibition of proliferation of OCI-Ly3 cells 50 value

[0351] 2.6 Experimental Conclusion: The data in the table show that the example compounds of the present invention have good proliferation inhibitory activity on TMD8 and OCI-Ly3 cells.

[0352] Test Example 3: Intracellular MALT1 protease activity detection experiment

[0353] 3.1 Study Objective: To investigate the inhibitory effect of compounds on MALT1 protease activity in TMD8 cells by detecting the cleavage level of MALT1 on the substrate BCL-10.

[0354] 3.2 Experimental instruments and reagents:

[0355] 3.3 Experimental Methods: The level of uncleaved BCL-10 protein in cells was determined by sandwich ELISA to assess the inhibitory effect of compounds on MALT1 protease activity. The highest concentration of the compound tested was 10,000 nM, and the compound was diluted three-fold to a total of nine concentrations (10,000 nM–1.5 nM). Cells were plated at an appropriate density and treated with the corresponding concentration of compound for 30 minutes. After stimulation with eBioscience cell stimulation cocktail for 2 hours, the cells were harvested and lysed. The cell lysate was added to a plate pre-coated with a recombinant BCL-10 antibody (Abcam, #Ab33905) and incubated overnight at 4°C. The next day, a BCL-10 detection antibody (Santacruz, #Sc-5273 HRP) was added and incubated for 2 hours. Color development was performed using TMB substrate for approximately 30 minutes, followed by detection using a microplate reader.

[0356] 3.4 Experimental data processing method:

[0357] 1) Inhibition rate (%):

[0358] Inhibition rate % = [(sample well value - negative control well average) / (positive control well average - negative control well average)] × 100, where the positive control wells are high-concentration reference compound wells and the negative control wells are DMSO wells.

[0359] 2) Curve fitting: Use the log(inhibitor) vs. response--Variable slope (four parameters) function in GraphPad Prism 6 to perform fitting equation analysis on 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))

[0360] 3.5 Experimental Conclusions:

[0361] Table 11: IC values ​​of compounds for inhibition of MALT1 protease activity in cells 50 value

[0362] 3.6 Experimental conclusion: The data in the table show that the example compounds of the present invention have good MALT1 protease activity.

[0363] Test Example 4: Oral Pharmacokinetics in Balb / C Mice

[0364] 4.1 Study Objective: Balb / C mice were used as test animals to study the pharmacokinetic behavior of the compound in the plasma of mice after oral administration at a dose of 30 mg / kg.

[0365] 4.2 Experimental plan

[0366] 4.2.1 Test drugs: Compounds of the present invention, homemade.

[0367] 4.2.2 Experimental animals: 3 male Balb / C mice (3 mice / example), Shanghai Jiesijie Experimental Animal Co., Ltd., Animal Production License No. (SCXK (Shanghai) 2013-0006N0.311620400001794).

[0368] 4.2.3 Administration: Three male Balb / C mice were fasted overnight and administered orally at a dose of 30 mg / kg in a volume of 10 mL / kg.

[0369] 4.2.4 Sample collection: Before and after administration of the drug, 0.1 mL of blood was collected from the mouse orbital cavity at 0, 0.5, 1, 2, 4, 6, 8, and 24 hours. The blood was placed in an EDTA-K2 tube and centrifuged at 6000 rpm for 6 min at 4°C to separate the plasma, which was then stored at -80°C.

[0370] 4.2.5 Sample processing:

[0371] 1) Add 160uL of acetonitrile to 40uL of plasma sample for precipitation, mix and centrifuge at 3500×g for 5-20 minutes.

[0372] 2) Take 100 μL of the supernatant solution after treatment and perform LC / MS / MS analysis to determine the concentration of the test compound.

[0373] 4.2.6 Liquid phase analysis:

[0374] Liquid phase conditions: Shimadzu LC-20AD pump Mass spectrometry conditions: AB Sciex API 4000 mass spectrometer

[0375] ●Chromatographic column: phenomenex Gemiu 5um C18 50×4.6mm

[0376] ●Mobile phase: Liquid A is 0.1% formic acid in water, Liquid B is acetonitrile Flow rate: 0.8mL / min

[0377] Elution time: 0-4.0 minutes, eluent is as follows:

[0378] 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 table below.

[0379] Table 12: Pharmacokinetic parameters of the compounds of the present invention after oral administration to mice

[0380] 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.

[0381] Test Example 6: Permeability Test of the Compounds of the Invention

[0382] 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.

[0383] 6.2 Experimental instruments and materials: liquid chromatography-mass spectrometry, centrifuge, vortexer, pipette, 96-well test plate (HTS Transwell Plate), acetonitrile solution with internal standard, Caco-2 cells (ATCC), Hanks' balanced solution (HBSS), Lucifer Yellow (LY), and dimethyl sulfoxide (DMSO).

[0384] 6.3 Experimental steps:

[0385] 1) Cultivation of Caco-2 cell monolayers: Select Caco-2 cells in good condition for plating, replace the culture medium every 2-3 days, and culture for 21-28 days to form a dense cell monolayer for testing.

[0386] 2) Testing the permeability of the example compounds:

[0387] Add 108 μL of transport buffer (HBSS containing 10 μM of the example compound) to the dosing end of aA to B.

[0388] Add 300 μL of transport buffer (HBSS containing DMSO) to the receiving end of bA to B.

[0389] Add 300 μL of transport buffer (HBSS containing 10 μM of the example compound) to the administration end of cB A.

[0390] Add 108 μL of transport buffer (HBSS containing DMSO) to the receiving end of dBA

[0391] e. Incubate for 90 min, d. Take samples for processing and detect by mass spectrometry.

[0392] 6.4 Chromatographic conditions:

[0393] Instrument: Liquid chromatography; Column: Waters XSelect HSS T3 2.5 μm (2.1 × 50 mm);

[0394] Mobile phase: Phase A: 0.1% formic acid in pure water; Phase B: 0.1% formic acid in acetonitrile.

[0395] 6.5 Mass spectrometry conditions:

[0396] Instrument: API6500+ liquid chromatography-mass spectrometer; ion source: electrospray ionization (ESI);

[0397] The detection mode was positive ion detection, and the scanning mode was selected reaction monitoring (MRM).

[0398] 6.6 Experimental Results

[0399] Table 13: Permeability test of example compounds

[0400] 6.7 Experimental Conclusion: The data in the table show that the compounds of the present invention have good permeability and significantly improved efflux properties.

[0401] 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

[0402] 7.1 Experimental Objective: To evaluate the efficacy of the test drug in the human diffuse large B-cell lymphoma OCI-LY3 mouse subcutaneous tumor model

[0403] 7.2 Experimental instruments and reagents:

[0404] 7.2.1 Instruments:

[0405] 1. Precision balance (SECURA225D-1CN, Sartorius)

[0406] 2. Electronic balance (HZ2002A, Changzhou Keyuan Electronics Co., Ltd.)

[0407] 3. Biological safety cabinet (BSC1300L-II-A2, SHINVA)

[0408] 4. Vernier caliper (CD-6" ASX (0-150) mm, Mitutoyo)

[0409] 5. Biological Safety Cabinet (BSC-1604IIA2, AIRTECH)

[0410] 6. Centrifuge (5910R, Eppendorf)

[0411] 7. CO2 incubator (HERAceII-240i, Thermo)

[0412] 7.2.2 Reagents:

[0413] 1. Sodium carboxymethyl cellulose (CMC-Na) (C5678, SIGMA)

[0414] 2. Kolliphor HS15 (Polyethylene glycol 12-hydrogen stearate) (42966, SIGMA)

[0415] 3. RPMI1640 (22400-089, Gibco) 4. FBS (35-081-CV, Corning)

[0416] 5. DPBS (21-031-CVC, Corning) 6. Matrigel Matrix (354234, Corning)

[0417] 7. OCI-LY3 cells (ACC-761, DSMZ)

[0418] 7.3 Experimental operation and data processing:

[0419] 1. Animals: 65 female NOG mice, 6-8 weeks old, weighing 18-22 g. Purchase from Beijing Weitonglihua Laboratory Animal Technology Co., Ltd. or other qualified suppliers.

[0420] 2. Cells: Human diffuse large B-cell lymphoma OCI-LY3 cells were cultured as monolayers in vitro and routinely digested and passaged twice weekly using trypsin-EDTA. When cell saturation reached 80%-90% and the required number of cells was reached, the cells were harvested, counted, and plated.

[0421] 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 diameter and short diameter of the tumor, respectively.

[0422] 4. Administration: Based on the grouping results, the test drug was administered orally (administration route: oral administration; administration volume: 10 mL / kg; administration frequency: twice daily; administration cycle: 28 days; solvent: 10% solutol HS15-0.25% CMC-Na). Tumors were measured and weighed twice weekly after the start of administration of the test drug.

[0423] 5. Euthanize the animals after the experiment

[0424] 6. Data Processing: The tumor inhibition efficacy of a compound was evaluated using TGI (%) or relative tumor growth rate (T / C) (%). TGI (%) reflects the rate of tumor growth inhibition. TGI (%) is calculated as follows: TGI (%) = [(1 - (mean tumor volume of a treatment group at the end of dosing - mean tumor volume of that treatment group at the start of dosing)) / (mean tumor volume of the solvent control group at the end of treatment - mean tumor volume of the solvent control group at the start of treatment)] × 100%.

[0425] Relative tumor growth 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) was calculated based on the tumor measurement results using the formula RTV = V t / V0, where V0 is the average tumor volume measured at the time of group administration (i.e., d0), V t It is the average tumor volume at a certain measurement. TRTV and CRTV data are taken on the same day.

[0426] 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.

[0427] 7.4 Experimental Results

[0428] Table 14 Tumor inhibition experiment of the compounds in the examples

[0429] Note: The data in brackets indicate the tumor volume at the corresponding time in the Vehicle group (i.e., control group) in this example.

[0430] 7.5 Experimental Conclusion: The experimental results in the table show that the compounds of the present invention have good tumor inhibition effects and low toxicity, and there is no significant change in the body weight of the animals in each group.

[0431] Crystal form study of compounds

[0432] It is well known to those skilled in the art that the compounds of the above examples have been shown to have good inhibitory activity against 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 crystal forms of the compounds. However, the preparation and characterization of the specific crystal forms described below do not limit the scope of protection of the present invention. Based on this invention, those skilled in the art can obtain more crystals of the compounds of the present invention through conventional crystallization methods, and these crystals are all protected by the present invention. Specifically, they are as follows:

[0433] 1. Experimental instruments

[0434] 1.1 Some parameters of physical and chemical testing instruments

[0435] 1.2 Instruments and liquid analysis conditions

[0436] 1.2.1 Instruments and Equipment

[0437] 1.2.2 Chromatographic conditions

[0438] Chromatographic column: ZOBAX Bonus RP (4.6*150mm, 3.5μm) Flow rate: 1.0mL / min

[0439] Column temperature: 35°C Detection wavelength: 220 nm

[0440] Injection volume: 5 μL Run time: 15 min Diluent: DMSO

[0441] Mobile phase: A: water (0.1% phosphoric acid); B: acetonitrile

[0442] 2. Preparation of Free Base Forms A to H of Compound Example 8

[0443] 2.1 Preparation of Form A: The compound of Example 8 was passed through a column, allowed to stand, and recrystallized from ethyl acetate-petroleum ether (1:1) to obtain a solid. XRPD analysis of the resulting solid indicated Form A. Analysis revealed the XRPD pattern shown in Figure 1.

[0444] 2.2 Preparation of Form B: Weigh 20 mg of free base Form A, add 100 μL of methanol, slurry at room temperature for 2 weeks, centrifuge, and vacuum dry at 40°C to obtain a solid. XRPD analysis of the obtained solid confirmed Form B. Analysis revealed the XRPD pattern shown in Figure 2.

[0445] 2.3 Preparation of Form C: Weigh 20 mg of free base Form A, add 100 μL of methyl tert-butyl ether, slurry at room temperature for 2 weeks, centrifuge, and vacuum dry at 40°C to obtain a solid. XRPD analysis of the obtained solid confirmed Form C. Analysis showed the XRPD pattern shown in Figure 3, the DSC pattern shown in Figure 4, and the TGA pattern shown in Figure 5.

[0446] Alternatively, EA / THF solution (130 mL, 1:1) and water (60 mL) were added to the concentrate of Example 8, cooled to 0-10°C, and 4N NaOH solution was added dropwise to adjust the pH to 9-10. Extraction and separation were performed, and the organic phase was washed sequentially with 5% aqueous NaOH (60 mL) and saturated sodium chloride solution (60 mL), dried over anhydrous sodium sulfate, concentrated to dryness under reduced pressure, and purified by column chromatography to obtain an off-white solid. XRPD analysis of the obtained solid showed Form C.

[0447] 2.4 Preparation of Form D: 20 mg of free base Form A was weighed, 100 μL of 2-butanone was added, and the mixture was slurried at room temperature for 2 weeks, centrifuged, and dried under vacuum at 40°C to obtain a solid. XRPD analysis of the obtained solid confirmed Form D. Analysis showed the XRPD pattern shown in Figure 6, the DSC pattern shown in Figure 7, and the TGA pattern shown in Figure 8.

[0448] 2.5 Preparation of Form E: Weigh 20 mg of free base Form A, add 100 μL of acetone, slurry at room temperature for 2 weeks, centrifuge, and vacuum dry at 40°C to obtain a solid. XRPD analysis of the obtained solid confirmed Form E. Analysis revealed the XRPD pattern shown in Figure 9.

[0449] 2.6 Preparation of Form F: 20 mg of free base Form C was weighed and added to 0.5 mL of methanol-tetrahydrofuran (1:1). After sonication, the mixture was dissolved and filtered. 5 mL of the antisolvent, isopropyl ether, was added to precipitate a solid. The solid was immediately centrifuged and dried under vacuum at 40°C to obtain a solid. XRPD analysis of the resulting solid confirmed Form F. Analysis revealed the XRPD pattern shown in Figure 10.

[0450] 2.7 Preparation of Form G: 20 mg of free base Form A was weighed and added to 0.5 mL of methanol-ethyl acetate (1:1). After sonication, the mixture was filtered and cooled to -20°C. After 5 days, solid precipitated. The mixture was immediately centrifuged and dried under vacuum at 40°C to obtain a solid. XRPD analysis of the resulting solid confirmed Form G. Analysis revealed the XRPD pattern shown in Figure 11.

[0451] 2.8 Preparation of Form H: Weigh 20 mg of free base Form A, add 0.5 mL of methanol-tetrahydrofuran (1:1), sonicate to dissolve, filter, and vacuum dry at 40°C to obtain a solid. XRPD analysis of the resulting solid confirmed Form H. Analysis revealed the XRPD pattern shown in Figure 12.

[0452] 3. Polymorph screening

[0453] 3.1 Beating method - room temperature: Weigh 20 mg of free base Form A, add 100 μL of different solvents, and beat at room temperature for 2 weeks as follows:

[0454] 3.2 Beating method -50℃: Weigh 20 mg of free base form A, add 100 μL of different solvents, and beat at 50℃ for 1 week as follows:

[0455] 3.3 Polycrystalline Screening - Antisolvent Method: Weigh 20 mg of free base Form C, add a good solvent, and sonicate to dissolve. Filter, add antisolvent, and immediately centrifuge after solid precipitation. Dry under vacuum at 40°C and characterize. The specific steps are as follows:

[0456] 3.4 Polycrystalline Screening - Cooling Method: Weigh 20 mg of free base Form C, add a good solvent, and sonicate to dissolve. Filter, cool in the freezer, and after solid precipitation, centrifuge, dry in a vacuum at 40°C, and characterize. The specific steps are as follows:

[0457] 2.5 Polycrystalline Screening - Rapid Evaporation Method: Weigh 20 mg of free base Form C, add a good solvent, and sonicate to dissolve. Filter, dry under vacuum at 40°C, and characterize the solid. Specific steps are as follows:

[0458] 4. Solid Stability Test

[0459] 4.1 Experimental purpose: To investigate the physicochemical stability of Form C under conditions of 5000 lx illumination, 60°C, RH = 92.5% at room temperature and RH = 75% at 50°C for 10, 20, and 30 days.

[0460] 4.2 Experimental Plan: Approximately 1 mg of Form C was tested at 5000 lx illumination, 60°C, 92.5% RH at room temperature, and 75% RH at 50°C for 10, 20, and 30 days. The content was determined by HPLC using the external standard method, and the changes in related substances were calculated using the chromatographic peak area normalization method.

[0461] 4.3 Experimental Results

[0462] Table 15 Physicochemical stability results of Form C under different conditions

[0463] Experimental conclusion: From the stability data, it can be seen that Form C is relatively stable under high temperature, high humidity, high temperature and high humidity, and light conditions, with no significant increase in impurities, and can well meet the requirements of later long-term storage and formulation process.

[0464] 5. Hygroscopicity test

[0465] 5.1 Experimental purpose: To investigate the hygroscopicity of compound Form C under different relative humidity conditions.

[0466] 5.2 Experimental plan: Place the compound crystal form C in saturated water vapor at different relative humidity to allow the crystal form to reach dynamic equilibrium with the water vapor, and calculate the percentage of weight gain of the crystal form due to moisture absorption after equilibrium.

[0467] 5.3 Experimental Results: Form C absorbed moisture at 80% relative humidity and gained approximately 2.608% weight, indicating slight hygroscopicity. After two cycles of moisture absorption and desorption at 0-95% relative humidity, the XRPD pattern of Form C remained unchanged, indicating no crystal form transformation.

[0468] 6. Solubility experiments in different media

[0469] 6.1 Experimental purpose: To investigate the solubility of Form C in different pH buffers, water, artificial simulated gastric fluid (SGF), fasting artificial simulated intestinal fluid (FaSSIF) and non-fasting artificial simulated intestinal fluid (FeSSIF) media.

[0470] 6.2 Experimental Plan: Approximately 1 mg of Form C was suspended in different pH buffers, SGF, FaSSIF, FeSSIF, and water, shaken at 37°C for 2 hours, filtered, and the thermodynamic solubility of Form C at 37°C was determined using the external standard method.

[0471] 6.3 Experimental results: as shown in the table below

[0472] Table 16 Solubility test results of Form C in different media

[0473] Experimental conclusion: The solubility of free base form C has no significant dependence on pH.

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.

2. According to the crystalline form of the compound of claim 1, the structure of the compound is 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.

3. The crystalline form of the compound according to claim 1 or 2, 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; or 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.

4. The crystalline form of the compound according to any one of claims 1 to 3, characterized in that: The crystal form is crystal form A to H 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 A has a diffraction peak at 2θ of 16.0±0.2°; or a diffraction peak at 26.3±0.2°; or a diffraction peak at 16.4±0.2°; or a diffraction peak at 11.3±0.2°; or a diffraction peak at 23.6±0.2°; or a diffraction peak at 25.3±0.2°; or a diffraction peak at 21.2±0.2°; or a diffraction peak at 12.1±0.2°; or a diffraction peak at 24.1±0.2°; or a diffraction peak at 10.7±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 B has a diffraction peak at 2θ of 16.0±0.2°; or a diffraction peak at 23.7±0.2°; or a diffraction peak at 21.0±0.2°; or a diffraction peak at 15.6±0.2°. Having a diffraction peak; or having a diffraction peak at 17.3±0.2°; or having a diffraction peak at 11.3±0.2°; or having a diffraction peak at 26.4±0.2°; or having a diffraction peak at 25.4±0.2°; or having a diffraction peak at 16.3±0.2°; or having a diffraction peak at 24.1±0.2°; preferably including any 2-5, or 3-5, or 3-6, or 3-8, or 5-8, or 6-8 of the above diffraction peaks, more preferably including any 6, 7 or 8 thereof; The X-ray powder diffraction spectrum of the crystalline form C has a diffraction peak at 2θ of 14.3±0.2°; or a diffraction peak at 26.8±0.2°; or a diffraction peak at 26.6±0.2°; or a diffraction peak at 22.0±0.2°; or a diffraction peak at 16.0±0.2°; or a diffraction peak at 24.4±0.2°; or a diffraction peak at 13.2±0.2°; or a diffraction peak at 19.9±0.2°; or a diffraction peak at 25.0±0.2°; or a diffraction peak at 25.5±0.2°; preferably including any 2-5, or 3-5, or 3-6, or 3-8, or 5-8, or 6-8 of the above diffraction peaks, and more preferably including any 6, 7 or 8 thereof; The X-ray powder diffraction spectrum of the crystalline form D has a diffraction peak at 2θ of 21.1±0.2°; or a diffraction peak at 22.0±0.2°; or a diffraction peak at 16.9±0.2°; or a diffraction peak at 25.4±0.2°; or a diffraction peak at 17.2±0.2°; or a diffraction peak at 17.8±0.2°; or a diffraction peak at 23.6±0.2°; or a diffraction peak at 30.5±0.2°; or a diffraction peak at 13.1±0.2°; or a diffraction peak at 15.0±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 crystalline form E has a diffraction peak at 2θ of 15.6±0.2°; or a diffraction peak at 23.6±0.2°; or a diffraction peak at 26.8±0.2°; or a diffraction peak at 26.6±0.2°; or a diffraction peak at 14.2±0.2°; or a diffraction peak at 25.4±0.2°; or a diffraction peak at 25.7±0.2°; or a diffraction peak at 24.3±0.2°; or a diffraction peak at 17.1±0.2°; or a diffraction peak at 20.8±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 F has a diffraction peak at 2θ of 24.3±0.2°; or a diffraction peak at 11.4±0.2°; or a diffraction peak at 24.0±0.2°; or a diffraction peak at 10.7±0.2°; or a diffraction peak at 26.0±0.2°; or a diffraction peak at 24.7±0.2°; or a diffraction peak at 21.4±0.2°; or a diffraction peak at 16.2±0.2°; or a diffraction peak at 17.1±0.2°; or a diffraction peak at 15.4±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 crystalline form G has a diffraction peak at 2θ of 7.0±0.2°; or a diffraction peak at 11.9±0.2°; or a diffraction peak at 16.1±0.2°; or a diffraction peak at 14.3±0.2°; or a diffraction peak at 21.1±0.2°; or a diffraction peak at 7.2±0.2°; or A diffraction peak at 11.6±0.2°; or a diffraction peak at 4.6±0.2°; or a diffraction peak at 24.4±0.2°; or a diffraction peak at 21.6±0.2°; preferably including any 2-5, or 3-5, or 3-6, or 3-8, or 5-8, or 6-8 of the above diffraction peaks, more preferably including any 6, 7 or 8 thereof; The X-ray powder diffraction pattern of the crystalline form H has a diffraction peak at 2θ of 20.8±0.2°; or a diffraction peak at 7.0±0.2°; or a diffraction peak at 16.0±0.2°; or a diffraction peak at 23.2±0.2°; or a diffraction peak at 4.7±0.2°; or a diffraction peak at 24.3±0.2°; or a diffraction peak at 24.0±0.2°; or a diffraction peak at 21.2±0.2°; or a diffraction peak at 26.2±0.2°; or a diffraction peak at 11.6±0.2°; preferably includes any 2-5, or 3-5, or 3-6, or 3-8, or 5-8, or 6-8 of the above-mentioned diffraction peaks, and more preferably includes any 6, 7 or 8 thereof.

5. The crystalline form of the compound according to any one of claims 1 to 4, characterized in that: The X-ray powder diffraction spectrum of the crystalline form A at least comprises one or more diffraction peaks located at 2θ of 16.0±0.2°, 26.3±0.2°, and 16.4±0.2°, preferably comprises two of them, and more preferably comprises three of them; optionally, further comprises at least one of 11.3±0.2°, 23.6±0.2°, 25.3±0.2°, 21.2±0.2°, and 12.1±0.2°, preferably comprises 2, 3, 4 or 5 of them; The X-ray powder diffraction pattern of the crystalline form B at least comprises one or more diffraction peaks located at 2θ of 16.0±0.2°, 23.7±0.2°, and 21.0±0.2°, preferably comprises two of them, and more preferably comprises three of them; optionally, further comprises at least one of 15.6±0.2°, 17.3±0.2°, 11.3±0.2°, 26.4±0.2°, and 25.4±0.2°, preferably comprises 2, 3, 4 or 5 of them; The X-ray powder diffraction pattern of the crystalline form C at least comprises one or more diffraction peaks located at 2θ of 14.3±0.2°, 26.8±0.2°, and 26.6±0.2°, preferably two of them, and more preferably three of them; optionally, it may further comprise at least one of 22.0±0.2°, 16.0±0.2°, 24.4±0.2°, 13.2±0.2°, and 19.9±0.2°, and preferably 2, 3, 4 or 5 of them; The X-ray powder diffraction pattern of the crystalline form D comprises at least one or more diffraction peaks located at 2θ of 21.1±0.2°, 22.0±0.2°, and 16.9±0.2°, preferably two of them, and more preferably three of them; optionally, it may further comprise at least one of 25.4±0.2°, 17.2±0.2°, 17.8±0.2°, 23.6±0.2°, and 30.5±0.2°, and preferably 2, 3, 4 or 5 of them; The X-ray powder diffraction pattern of the crystalline form E at least comprises one or more diffraction peaks located at 2θ of 15.6±0.2°, 23.6±0.2°, and 26.8±0.2°, preferably comprises two of them, and more preferably comprises three of them; optionally, it may further comprise at least one of 26.6±0.2°, 14.2±0.2°, 25.4±0.2°, 25.7±0.2°, and 24.3±0.2°, and preferably comprises 2, 3, 4 or 5 of them; The X-ray powder diffraction spectrum of the crystalline form F at least comprises one or more diffraction peaks located at 2θ of 24.3±0.2°, 11.4±0.2°, and 24.0±0.2°, preferably comprises two of them, and more preferably comprises three of them; optionally, further comprises at least one of 10.7±0.2°, 26.0±0.2°, 24.7±0.2°, 21.4±0.2°, and 16.2±0.2°. At least one, preferably 2, 3, 4 or 5; The X-ray powder diffraction pattern of the crystalline form G at least comprises one or more diffraction peaks located at 2θ of 7.0±0.2°, 11.9±0.2°, and 16.1±0.2°, preferably comprises two of them, and more preferably comprises three of them; optionally, it may further comprise at least one of 14.3±0.2°, 21.1±0.2°, 7.2±0.2°, 11.6±0.2°, and 4.6±0.2°, and preferably comprises 2, 3, 4 or 5 of them; The X-ray powder diffraction pattern of the crystalline form H at least comprises one or more diffraction peaks located at 2θ of 20.8±0.2°, 7.0±0.2°, and 16.0±0.2°, preferably comprises two of them, and more preferably comprises three of them; optionally, it may further comprise at least one of 23.2±0.2°, 4.7±0.2°, 24.3±0.2°, 24.0±0.2°, and 21.2±0.2°, preferably comprises 2, 3, 4 or 5 of them.

6. The crystalline form of the compound according to claim 5, characterized in that: The X-ray powder diffraction pattern of the crystalline form A optionally further comprises one or more diffraction peaks located at 2θ of 24.1±0.2°, 10.7±0.2°, 17.2±0.2°, 12.4±0.2°, 16.9±0.2°, 27.9±0.2° or 21.8±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 B optionally further comprises one or more diffraction peaks located at 2θ of 16.3±0.2°, 24.1±0.2°, 10.6±0.2°, 26.2±0.2°, 24.9±0.2°, 4.9±0.2° or 12.3±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 C optionally further comprises one or more diffraction peaks located at 2θ of 25.0±0.2°, 25.5±0.2°, 29.4±0.2°, 15.3±0.2°, 18.5±0.2°, 19.2±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 crystalline form D optionally further comprises one or more diffraction peaks located at 2θ of 13.1±0.2°, 15.0±0.2°, 9.3±0.2°, 24.0±0.2°, 27.5±0.2°, 25.7±0.2° or 19.6±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 E optionally further comprises one or more diffraction peaks located at 2θ of 17.1±0.2°, 20.8±0.2°, 22.0±0.2°, 11.3±0.2°, 16.7±0.2°, 10.5±0.2° or 12.5±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 crystalline form F optionally further comprises one or more diffraction peaks located at 2θ of 17.1±0.2°, 15.4±0.2°, 12.6±0.2°, 20.8±0.2°, 7.4±0.2°, 27.0±0.2° or 12.2±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; The X-ray powder diffraction pattern of the crystalline form G optionally further comprises 2θ at 24.4±0.2°, 21.6±0.2° or one or more diffraction peaks at 23.2±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 crystalline form H optionally further includes one or more diffraction peaks located at 2θ of 26.2±0.2°, 11.6±0.2°, 10.7±0.2°, 12.0±0.2°, 27.3±0.2°, 13.9±0.2° or 14.4±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 are included.

7. The crystalline form of the compound according to any one of claims 1 to 4, characterized in that: The X-ray powder diffraction pattern of the crystalline form A optionally includes one or more diffraction peaks located at 2θ of 10.7±0.2°, 11.3±0.2°, 12.1±0.2°, 12.4±0.2°, 16.0±0.2°, 16.4±0.2°, 16.9±0.2°, 17.2±0.2°, 21.2±0.2°, 21.8±0.2°, 23.6±0.2°, 24.1±0.2°, 25.3±0.2°, 26.3±0.2° or 27.9±0.2°; preferably, it includes diffraction peaks at 4, 5, 6, 8 or 10 of them; The X-ray powder diffraction pattern of the crystalline form B optionally includes one or more diffraction peaks located at 2θ of 4.9±0.2°, 10.6±0.2°, 11.3±0.2°, 12.3±0.2°, 15.6±0.2°, 16.0±0.2°, 16.3±0.2°, 17.3±0.2°, 21.0±0.2°, 23.7±0.2°, 24.1±0.2°, 24.9±0.2°, 25.4±0.2°, 26.2±0.2° or 26.4±0.2°; preferably, it includes diffraction peaks at 4, 5, 6, 8 or 10 of them; The X-ray powder diffraction pattern of the crystalline form C optionally includes one or more diffraction peaks located at 2θ of 13.2±0.2°, 14.3±0.2°, 15.3±0.2°, 16.0±0.2°, 16.6±0.2°, 18.5±0.2°, 19.2±0.2°, 19.9±0.2°, 22.0±0.2°, 24.4±0.2°, 25.0±0.2°, 25.5±0.2°, 26.6±0.2°, 26.8±0.2° or 29.4±0.2°; preferably, it includes diffraction peaks at 4, 5, 6, 8 or 10 of them; The X-ray powder diffraction pattern of the crystalline form D optionally includes one or more diffraction peaks located at 2θ of 9.3±0.2°, 13.1±0.2°, 15.0±0.2°, 16.9±0.2°, 17.2±0.2°, 17.8±0.2°, 19.6±0.2°, 21.1±0.2°, 22.0±0.2°, 23.6±0.2°, 24.0±0.2°, 25.4±0.2°, 25.7±0.2°, 27.5±0.2° or 30.5±0.2°; preferably, it includes diffraction peaks at 4, 5, 6, 8 or 10 of them; The X-ray powder diffraction pattern of the crystalline form E optionally includes one or more diffraction peaks located at 2θ of 10.5±0.2°, 11.3±0.2°, 12.5±0.2°, 14.2±0.2°, 15.6±0.2°, 16.7±0.2°, 17.1±0.2°, 20.8±0.2°, 22.0±0.2°, 23.6±0.2°, 24.3±0.2°, 25.4±0.2°, 25.7±0.2°, 26.6±0.2° or 26.8±0.2°; preferably, it includes diffraction peaks at 4, 5, 6, 8 or 10 of them; The X-ray powder diffraction pattern of the crystalline form F optionally includes one or more diffraction peaks located at 2θ of 7.4±0.2°, 10.7±0.2°, 11.4±0.2°, 12.2±0.2°, 12.6±0.2°, 15.4±0.2°, 16.2±0.2°, 17.1±0.2°, 20.8±0.2°, 21.4±0.2°, 24.0±0.2°, 24.3±0.2°, 24.7±0.2°, 26.0±0.2° or 27.0±0.2°; preferably, it includes diffraction peaks at 4, 5, 6, 8 or 10 of them; The X-ray powder diffraction pattern of the crystalline form G optionally includes one or more diffraction peaks located at 2θ of 4.6±0.2°, 7.2±0.2°, 7.0±0.2°, 11.6±0.2°, 11.9±0.2°, 14.3±0.2°, 16.1±0.2°, 21.1±0.2°, 21.6±0.2°, 23.2±0.2° or 24.4±0.2°; preferably, it includes diffraction peaks at 4, 5, 6, 8 or 10 of them; The X-ray powder diffraction pattern of the crystalline form H optionally includes one or more diffraction peaks located at 2θ of 4.7±0.2°, 7.0±0.2°, 10.7±0.2°, 11.6±0.2°, 12.0±0.2°, 13.9±0.2°, 14.4±0.2°, 16.0±0.2°, 20.8±0.2°, 21.2±0.2°, 23.2±0.2°, 24.0±0.2°, 24.3±0.2°, 26.2±0.2° or 27.3±0.2°; preferably, it includes diffraction peaks at 4, 5, 6, 8 or 10 of them.

8. The crystalline form of the compound according to any one of claims 4 to 7, characterized in that: Form A has an X-ray powder diffraction pattern as shown in Figure 1; Form B has an X-ray powder diffraction pattern as shown in Figure 2; Form C has an X-ray powder diffraction pattern as shown in Figure 3, a DSC pattern as shown in Figure 4, or a TGA pattern as shown in Figure 5; Form D has an X-ray powder diffraction pattern as shown in Figure 6, a DSC pattern as shown in Figure 7, or a TGA pattern as shown in Figure 8; Form E has an X-ray powder diffraction pattern as shown in Figure 9; Form F has an X-ray powder diffraction pattern as shown in Figure 10; Form G has an X-ray powder diffraction pattern as shown in Figure 11; Form H has an X-ray powder diffraction pattern as shown in Figure 12.

9. The crystalline form of the compound according to any one of claims 4 to 8, 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 A, Form B, Form C, Form D, Form E, Form F, Form G and Form H and the diffraction peaks at the corresponding positions in Figures 1, 2, 3, 4, 6, 9, 10, 11 and 12 is ±0.2° to ±0.5°; preferably ±0.2° to ±0.3°; and most preferably ±0.2°.

10. The crystalline form of the compound according to any one of claims 1 to 9, characterized in that: The crystal form is anhydrous.

11. The crystalline form of the compound according to any one of claims 1 to 9, characterized in that: 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.

12. A method for preparing a crystalline form of the compound according to any one of claims 1 to 11, comprising the following steps: 1) Weigh an appropriate amount of free base or its crystal form and dissolve it in a mixed 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 mixed solvent is selected from 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 Two or more of N-methylpyrrolidone; preferably two or more of methanol, acetone, dichloromethane, ethyl acetate, tetrahydrofuran or 2-methyl-tetrahydrofuran; 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 50°C; in: 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 one or more of 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.

13. A method for preparing the crystalline form C of the compound according to any one of claims 1 to 11, comprising the following steps: 1) Weigh an appropriate amount of free base or its crystal form, add a mixed solvent and water, and cool to a temperature preferably between 0 and 10°C; 2) adding sodium hydroxide solution to adjust the pH to 9-10; the concentration of the sodium hydroxide solution is selected from 1-5N; preferably 4N; 3) extracting, separating the liquids, concentrating and drying the organic phase to obtain the target product; in: The mixed solvent is selected from two 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 two or more of dichloromethane, ethyl acetate, tetrahydrofuran or 2-methyl-tetrahydrofuran; more preferably ethyl acetate and tetrahydrofuran.

14. A pharmaceutical composition comprising a therapeutically effective amount of a crystalline form of the compound according to any one of claims 1 to 11, and one or more pharmaceutically acceptable carriers, diluents or excipients.

15. Use of the crystalline form of the compound according to any one of claims 1 to 11 or the pharmaceutical composition according to claim 14 in the preparation of a MALT1 inhibitor drug.

16. Use of the crystalline form of the compound according to any one of claims 1 to 11 or the pharmaceutical composition according to claim 14 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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