Tricyclic compounds as MALT1 inhibitors and pharmaceutical compositions and uses thereof

Abstract

The present invention relates to a tricyclic compound as a MALT1 inhibitor and its pharmaceutical composition and application. The compound is a compound shown in formula I, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a tautomer thereof, or a hydrate thereof, or a solvate thereof, or a metabolite thereof, or a prodrug thereof, wherein the R1 to R7 and the Z, L, X1, Y1, Y2 and A groups are as defined in the specification. The compound of the present invention and the pharmaceutical composition containing the compound have good MALT1 enzyme inhibitory activity, and thus can be used as a MALT1 inhibitor and used to prepare a drug for treating and / or preventing diseases related to MALT1 such as cancer and immune diseases.

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical chemistry, and specifically relates to a class of tricyclic compounds as MALT1 inhibitors, and pharmaceutical compositions and applications thereof. Background Art

[0002] MALT1 (Mucosa-associated lymphoid tissue lymphoma translocation protein 1) was discovered in mucosa-associated lymphoid tissue lymphoma and is a key regulator of the NF-κB signaling pathway. NF-κB is a transcription factor that plays a key regulatory role in lymphocyte activation, survival, and proliferation. This pathway is activated through different receptors, including T cell antigen receptor (TCR), B cell antigen receptor (BCR), tumor necrosis factor receptor (TNFR), and B cell activating factor receptor (BAFF). Depending on the receptor, the NF-κB signaling pathway can be divided into classical pathways and non-classical pathways.

[0003] MALT1 is the only caspase in the human body, which transmits signals from B cell receptors and T cell receptors. MALT1 exerts its enzymatic activity through the CBM protein complex, which is composed of multiple subunits of three proteins: CARD11 (Caspase recruitment domain family member 11, also known as CARMA1), BCL10 (B-Cell CLL / lymphoma 10) and MALT1. The CBM complex is considered to be a driver of ABC-type diffuse large B-cell lymphoma (ABC-DLBCL). MALT1 has both scaffold protein function and protease function, and regulates the NF-κB signaling pathway through two mechanisms of action. The first mechanism is the scaffold protein function, which activates the signaling pathway by recruiting NF-κB signaling pathway related proteins such as TRAF6 and TAB-TAK1. In addition, as a cysteine ​​enzyme, it inactivates the negative regulators of the NF-κB signaling pathway by cutting negative regulators of the NF-κB signaling pathway such as RelB, A20, etc., thereby activating the NF-κB signaling pathway. Activation of the NF-κB signaling pathway leads to excessive proliferation of T and B lymphocytes and secretion of cytokines such as IL-2, which in turn leads to related cancers or autoimmune diseases. Therefore, targeting the MALT1 protein to inhibit excessive activation of the NF-κB signaling pathway can provide a new treatment for cancer or autoimmune diseases. In addition, ibrutinib resistance in chronic lymphocytic leukemia (CLL) is an urgent problem to be solved. The mechanism of resistance is the presence of gene mutations in BTK or BTK downstream gene PLCG2. Studies have found that inhibiting MALT1 activity can work in ibrutinib-resistant CLL cells.

[0004] In another MCL study at the MD Anderson Cancer Center in the United States, it was found that 28.8% of 110 MCL patients had gene mutations in the NF-κB pathway, and NF-κB signaling was activated in ibrutinib-resistant MCL cells. In MCL cell lines, ibrutinib-resistant cells had higher MALT1 expression, indicating that targeting MALT1 may solve the problem of drug resistance.

[0005] In general, the development of MALT1 inhibitors has great clinical application prospects for cancer, especially various blood tumors, immune disease treatment, and overcoming drug resistance. Summary of the invention

[0006] The purpose of the present invention is to overcome the problems existing in the prior art and provide a class of tricyclic compounds as MALT1 inhibitors and their pharmaceutical compositions and uses, which exhibit good inhibitory activity on tumor cells and good drugability and have broad prospects for drug development.

[0007] In order to achieve the above object, the present invention adopts the following technical solutions:

[0008] In a first aspect, the present invention provides a compound as shown in Formula I or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, metabolite or prodrug thereof, wherein

[0009]

[0010] in,

[0011] L is independently selected from -(CH 2 ) m -or-(CH 2 ) m -O-(CH 2 ) p -O-(CH 2 ) o -, wherein each of m, o and p is independently any integer from 0 to 3;

[0012] Y 1 and Y 2 Independently selected from O, NR 8 or CR 8 ;

[0013] X 1 Independently selected from CR 8 or N;

[0014] Z is independently selected from C or N;

[0015] Ring A is independently selected from a five-membered or six-membered aromatic heterocyclic ring, the aromatic heterocyclic ring contains 1 to 3 heteroatoms, the heteroatoms are independently selected from one or more of N, O and S, and the aromatic heterocyclic ring is optionally substituted by n R 5 Substitution, wherein n is selected from any integer between 0 and 5;

[0016] R 1 Selected from hydrogen, deuterium, halogen, cyano, amino, hydroxyl, C 1 -C 6 Alkyl, C 1 -C 6 Heteroalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 8 Cycloalkyl, C 3 -C 8 Heterocycloalkyl, C 1 -C 3 Alkoxy, C 1 -C 3 Haloalkoxy or C 1 -C 6 wherein the alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, alkoxy, haloalkoxy and haloalkyl are each optionally substituted with at least one R 9 replace;

[0017] R 2 and R 3 independently selected from hydrogen, deuterium, halogen, cyano, amino, hydroxyl, H, C 3 -C 8 Cycloalkyl, C 3 -C 8 Heterocycloalkyl, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, -NR a R b OR c , and wherein the alkyl, cycloalkyl, heterocycloalkyl and alkoxy groups are each optionally substituted with at least one R 9 Replace, or, R 2 and R 3 Together with the connected C, it forms a 3-7 membered cycloalkyl or heterocycloalkyl, wherein the heteroatom in the heterocycloalkyl is selected from one or more of N, O and S, and the number of the heteroatoms is 1-3;

[0018] R 4 are independently selected from hydrogen, deuterium, hydroxyl, amino or C 1 -C 6Alkyl, and wherein the alkyl is C 1 -C 6 Alkoxy substituted;

[0019] R 5 are independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, -NR a -C(=O)-N(R b )(R c )、-C(=O)-N(R b )(R c )、-C(=O)-R b 、-C(=O)-OR b , C 1 -C 6 Alkyl, C 3 -C 6 Cycloalkyl, 3- to 8-membered heterocycloalkyl, 5- to 10-membered aryl or heteroaryl, C 1 -C 3 Alkoxy or C 1 -C 6 A haloalkyl group, or R 7 and R 8 Together with the nitrogen atom to which it is attached, it forms a 5- to 6-membered heterocycloalkyl group, wherein the alkyl, cycloalkyl, heterocycloalkyl, alkoxy, haloalkyl, aryl and heteroaryl groups are each optionally substituted by at least one R 9 replace;

[0020] R 6 and R 7 are each independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, C 1 -C 6 Alkyl, C 1 -C 6 Heteroalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 8 Cycloalkyl, C 3 -C 8 Heterocycloalkyl, C 1 -C 8 Alkoxy, C 3 -C 8 Cycloalkoxy, C 3 -C 8 Heterocycloalkoxy, C 1 -C 3 Haloalkoxy or C 1 -C 6wherein the alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, alkoxy, cycloalkyloxy, heterocycloalkyloxy, haloalkoxy and haloalkyl are each optionally substituted with at least one R 9 replace;

[0021] R a , R b and R c are each independently selected from hydrogen, deuterium, C 1 -C 8 Alkyl, C 1 -C 8 Heteroalkyl, C 3 -C 6 Cycloalkyl or C 3 -C 8 wherein the alkyl, heteroalkyl, cycloalkyl and heterocycloalkyl are each optionally substituted by at least one R 9 replace;

[0022] R 1 To R 8 The heteroatoms or heteroatoms contained in the heteroalkyl, heterocycloalkyl, heterocycloalkoxy and heteroaryl are independently selected from -C(=O)N(R a )-、-N(R a )-, -NH-, -N=, -O-, -S-, -C(=O)O-, -C(=O)-, -C(=S)-, -S(=O)-, -S(=O) 2 -or-N(R a )C(=O)N(R a )-, and the number of the heteroatoms or heteroatom groups is independently selected from 1, 2 or 3;

[0023] R 9 Each is independently selected from hydrogen, chlorine, fluorine, cyano, hydroxy, amino, isopropyl, cyclopropyl, methyl, ethyl, difluoromethyl, trifluoromethyl, methoxy, trifluoromethoxy, ethoxy, 2,2-difluoroethoxy, 2,2,2-trifluoroethoxy or phenyl.

[0024] Preferably, it is a compound as shown in any one of formula I-1 or I-2,

[0025]

[0026] Among them, R 1 ~R 8 and Y 2 As defined in the first aspect of the specification, n is independently any integer from 0 to 5; Z 1 and Z 2 are each independently selected from C or N.

[0027] Further preferably, it is a compound as shown in any one of Formula I-1-1, Formula I-1-2, Formula I-1-3, Formula I-1-4, Formula I-1-5, Formula I-2-1, Formula I-2-2, Formula I-2-3, Formula I-2-4 and Formula I-2-5,

[0028]

[0029] Further preferably, the present invention provides a specific compound as shown in any one of Formula 1 to Formula 4, whose structural formula is:

[0030]

[0031] In a second aspect, the present invention provides a pharmaceutical composition comprising an effective dose of one or more of the compounds as described above, or pharmaceutically acceptable salts thereof, or carriers thereof, or stereoisomers thereof, or tautomers thereof, or hydrates thereof, or solvates thereof, or metabolites thereof, or prodrugs thereof.

[0032] Preferably, the pharmaceutical composition further comprises at least one pharmaceutically acceptable excipient.

[0033] In a third aspect, the present invention provides the use of one or more of the compounds described above, or pharmaceutically acceptable salts thereof, or carriers thereof, or stereoisomers thereof, or tautomers thereof, or hydrates thereof, or solvates thereof, or metabolites thereof, or prodrugs thereof, or pharmaceutical compositions thereof in the preparation of drugs for preventing and / or treating diseases or conditions caused by overexpression of MALT1.

[0034] In a fourth aspect, the present invention provides the use of one or more of the compounds described above, or pharmaceutically acceptable salts thereof, or carriers thereof, or stereoisomers thereof, or tautomers thereof, or hydrates thereof, or solvates thereof, or metabolites thereof, or prodrugs thereof, or pharmaceutical compositions thereof in the preparation of MALT1 inhibitor drugs.

[0035] Preferably, the disease or condition comprises an autoimmune disorder, an inflammatory disease or cancer, wherein the disease or condition is treated after inhibiting MALT1 activity.

[0036] Preferably, the autoimmune disorder, inflammatory disease or cancer is any one or more of diffuse large B-cell lymphoma, mantle cell lymphoma (MCL), follicular lymphoma (FL), chronic lymphocytic leukemia (CML), myeloid leukemia, non-Hodgkin's lymphoma (NHL), lung adenocarcinoma, breast cancer, pancreatic cancer, liver cancer, gastric cancer, colorectal cancer, rheumatoid arthritis (RA), psoriatic arthritis (PsA), ulcerative colitis (UC), multiple sclerosis (MS), psoriasis, Crohn's disease, systemic lupus erythematosus (SLE), Sjögren's syndrome, Hashimoto's thyroiditis, ulcerative colitis, asthma or chronic obstructive pulmonary disease (COPD).

[0037] In a fifth aspect, the present invention provides a method for preventing and / or treating a disease or condition caused by overexpression of MALT1, comprising administering a preventively and / or therapeutically effective amount of a compound as described above or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, metabolite or prodrug thereof, or a pharmaceutical composition comprising the same, to an individual in need thereof.

[0038] Compared with the prior art, the present invention has the following beneficial effects:

[0039] The present invention provides a series of tricyclic compounds with novel structures. It is proved by relevant enzyme and cell activity tests that the compounds of the present invention and pharmaceutical compositions containing the compounds have excellent MALT1 enzyme inhibitory activity and cell proliferation inhibitory activity, and are therefore suitable for preparing MALT1 inhibitors, and for preparing drugs for preventing and / or treating diseases or disorders associated with MALT1 activation, such as autoimmune disorders, inflammatory diseases or cancers. DETAILED DESCRIPTION

[0040] General Terms and Definitions

[0041] Unless otherwise stated, the terms used in the present invention have the following meanings.

[0042] "Alkyl" refers to a saturated aliphatic hydrocarbon group, including straight and branched groups of 1 to 20 carbon atoms, for example, straight and branched groups of 1 to 18 carbon atoms, 1 to 12 carbon atoms, 1 to 8 carbon atoms, 1 to 6 carbon atoms or 1 to 4 carbon atoms. In the present invention, "alkyl" can be a monovalent, divalent or trivalent group. Non-limiting examples include, but are not limited to, 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 and various branched chain isomers thereof, etc. Non-limiting examples also include, but are not limited to, methylene, methine, ethylene, ethylene, propylene, propylene, butylene, butylene and various branched chain isomers thereof. In addition, in the present invention, "alkyl" may be optionally substituted or unsubstituted.

[0043] "Alkoxy" refers to an "-O-alkyl" group wherein "alkyl" is as defined above.

[0044] "Alkenyl" refers to an unsaturated aliphatic hydrocarbon group, including straight and branched chain groups of 1 to 20 carbon atoms and at least one carbon-carbon double bond, for example, straight and branched chain groups of 1 to 18 carbon atoms, 1 to 12 carbon atoms, 1 to 8 carbon atoms, 1 to 6 carbon atoms, or 1 to 4 carbon atoms. In the present invention, "alkenyl" can be a monovalent, divalent, or trivalent group. Non-limiting examples include, but are not limited to, vinyl (-CH=CH 2 ), propen-1-yl (-CH=CH-CH 3 ), propene-2-yl (-C(CH 3 )=CH 2 ), buten-1-yl (-CH=CH-CH 2 -CH 3 ), butene-2-yl (-C (C 2 H 5 )=CH 2 ), 1-methylpropen-1-yl (-C(CH 3 )=CH-CH 3 ) and its various branched isomers, etc. Non-limiting examples also include, but are not limited to, 1,1-vinylene (=C=CH 2 ), 1,2-vinylene (-CH=CH-), 1,1-propenylene (=C=CH-CH 3 ), 1,2-propenyl (-CH=C(CH 3)-), 1,3-propenylene (-CH=CH-CH 2 -) and its various branched isomers. In addition, in the present invention, "alkenyl" may be optionally substituted or unsubstituted.

[0045] "Alkynyl" refers to an unsaturated aliphatic hydrocarbon group, including straight and branched groups of 1 to 20 carbon atoms and at least one carbon-carbon triple bond, for example, straight and branched groups of 1 to 18 carbon atoms, 1 to 12 carbon atoms, 1 to 8 carbon atoms, 1 to 6 carbon atoms, or 1 to 4 carbon atoms. In the present invention, "alkynyl" can be a monovalent, divalent, or trivalent group. Non-limiting examples include, but are not limited to, ethynyl (-C≡CH), propynyl (-C≡C-CH 3 ), butynyl Pentynyl and its various branched chain isomers, etc. Non-limiting examples also include, but are not limited to, ethynyl (-C≡C-), propynyl Butynylene and various branched isomers thereof. In addition, in the present invention, "alkynyl" may be optionally substituted or unsubstituted.

[0046] "Heteroalkyl" refers to a saturated aliphatic hydrocarbon group, including straight and branched chain groups of 2 to 20 atoms, for example, straight and branched chain groups of 2 to 18 atoms, 2 to 12 atoms, 2 to 8 atoms, 2 to 6 atoms or 2 to 4 atoms, wherein one or more atoms is selected from nitrogen, oxygen or S(O) m (wherein m is 0, 1 or 2) heteroatoms, and the rest are carbon. In the present invention, "heteroalkyl" can be a monovalent, divalent or trivalent group. Non-limiting examples include, but are not limited to, methoxymethyl (2-oxapropyl), methylthiomethyl (2-thiapropyl), methylaminomethyl (2-aziridine propyl) and various branched chain isomers thereof. In addition, in the present invention, "heteroalkyl" can be optionally substituted or unsubstituted.

[0047] "Cycloalkyl" refers to a saturated or partially unsaturated, monocyclic or polycyclic aliphatic hydrocarbon group, including 3 to 12 ring atoms, for example, 3 to 12, 3 to 10 or 3 to 6 ring atoms (i.e., 3 to 6 rings). Non-limiting examples of monocyclic cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, etc. In the present invention, "cycloalkyl" can be optionally substituted or unsubstituted.

[0048] "Heterocycloalkyl" refers to a saturated or partially unsaturated, monocyclic or polycyclic aliphatic hydrocarbon group comprising 3 to 20 ring atoms, for example 3 to 16, 3 to 12, 3 to 10 or 3 to 6 ring atoms, wherein one or more of the ring atoms is selected from nitrogen, oxygen or S(O)m (wherein m is 0,1 or 2) heteroatoms, and the remaining ring atoms are carbon.Preferably, heterocycloalkyl includes 3 to 12 ring atoms, wherein 1 to 4 ring atoms are heteroatoms, more preferably includes 3 to 10 ring atoms, most preferably includes 5 or 6 ring atoms, wherein 1 to 4, preferably 1 to 3, more preferably 1 to 2 are heteroatoms.The limiting examples of monocyclic heterocycloalkyl include but are not limited to pyrrolidinyl, piperidyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl etc.The limiting examples of polycyclic heterocycloalkyl include but are not limited to the heterocycloalkyl of ring, spirocycle or bridged ring.

[0049] "Halogen" refers to fluorine, chlorine, bromine and iodine, with fluorine, chlorine and bromine being preferred.

[0050] "Haloalkyl" or "haloalkoxy" refers to an alkyl or alkoxy group substituted by one or more halogen atoms which are the same or different. Preferred examples of alkyl or alkoxy include, but are not limited to, trifluoromethyl, trifluoroethyl, and trifluoromethoxy.

[0051] "Cyano" refers to a "-CN" group.

[0052] "Hydroxy" refers to a "-OH" group.

[0053] "Amino" refers to "-NH 2 ” group.

[0054] "Carbamoyl" refers to "-(C=O)-NH 2 ” group.

[0055] "Aryl" refers to monocyclic, bicyclic and tricyclic carbon ring systems containing 6-14 ring atoms, wherein at least one ring system is aromatic, wherein each ring system contains a ring consisting of 3-7 atoms and has one or more points of attachment to the rest of the molecule. Examples include, but are not limited to, phenyl, naphthyl, anthracene, etc. Preferably, the aryl group is a carbon ring system of 6-10 or 6-7 ring atoms.

[0056] "Heteroaryl" refers to monocyclic, bicyclic and tricyclic ring systems containing 5-14 ring atoms, wherein at least one ring system is aromatic and at least one ring system contains one or more heteroatoms selected from nitrogen, oxygen and sulfur, wherein each ring system contains a ring consisting of 5-7 atoms and has one or more points of attachment to the rest of the molecule. The term "heteroaryl" can be used interchangeably with the terms "heteroaromatic ring" or "heteroaromatic compound". Examples include, but are not limited to: furanyl, imidazolyl, 2-pyridyl, 3-pyridyl, thiazolyl, purinyl, quinolyl. Preferably, the heteroaryl is a ring system of 5-10 ring atoms.

[0057] "Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and the description includes instances where the event or circumstance occurs or does not occur. For example, "a heterocyclic group optionally substituted with an alkyl group" means that the alkyl group may but need not be present, and the description includes instances where the heterocyclic group is substituted with an alkyl group and instances where the heterocyclic group is not substituted with an alkyl group.

[0058] "Substituted" means that one or more hydrogen atoms, preferably up to 5, more preferably 1 to 3 hydrogen atoms in the group are replaced independently of one another by a corresponding number of substituents.

[0059] "Pharmaceutically acceptable salt" refers to a salt prepared from a compound of the present invention and a relatively non-toxic acid or base. When the compound of the present invention contains a relatively acidic functional group (e.g., a carboxyl group or a sulfonic acid group), a base addition salt can be obtained by contacting its free form with a sufficient amount of a base in a pure solution or a suitable inert solvent. Non-limiting examples of pharmaceutically acceptable base addition salts include, but are not limited to, sodium salts, potassium salts, ammonium salts, calcium salts, magnesium salts, organic amine salts, or similar salts. When the compound of the present invention contains a relatively alkaline functional group (e.g., an amino group or a guanidine group), an acid addition salt can be obtained by contacting its free form with a sufficient amount of an acid in a pure solution or a suitable inert solvent. Non-limiting examples of pharmaceutically acceptable acid addition salts include, but are not limited to, inorganic acid salts (e.g., hydrochlorides, hydrobromides, hydroiodides, nitrates, carbonates, bicarbonates, phosphates, monohydrogen phosphates, dihydrogen phosphates, phosphites, sulfates, hydrogen sulfates, etc.), organic acid salts (e.g., acetates, propionates, isobutyrates, malonates, succinates, suberates, maleates, fumarates, citrates, tartrates, lactates, mandelates, benzoates, phthalates, methanesulfonates, benzenesulfonates, p-toluenesulfonates, glucuronic acid, etc.), and amino acid salts (e.g., arginine salts, etc.). Specific forms of pharmaceutically acceptable salts can also be found in Berge et al., "Pharmaceutical Salts", Journal of Pharmaceutical Science, 1977, 66: 1-19). Certain specific compounds of the present invention contain basic and acidic functional groups and can be converted into either base addition salts or acid addition salts. Preferably, the salt is contacted with an alkali or acid in a conventional manner, and the parent compound is separated, thereby regenerating the neutral form of the compound. The parent form of the compound differs from its various salt forms in certain physical properties, such as different solubility in polar solvents. According to embodiments of the present invention, the pharmaceutically acceptable salt of the compound preferably as shown in Formula I is an acid addition salt, preferably hydrochloride, hydrobromide, phosphate or sulfate, more preferably hydrochloride.

[0060] A "pharmaceutical composition" refers to a composition for pharmaceutical use, which comprises one or more compounds as shown in Formula I or a pharmaceutically acceptable form thereof (e.g., salts, hydrates, solvates, stereoisomers, tautomers, metabolites, prodrugs, etc.), and other components (e.g., pharmaceutically acceptable excipients).

[0061] In the present invention, "pharmaceutically acceptable excipients" refer to auxiliary materials widely used in the field of drug production. The main purpose of using excipients is to provide a pharmaceutical composition that is safe to use, stable in nature and / or has specific functionality, and also to provide a method so that after the drug is administered to the subject, the active ingredient can be dissolved at a desired rate, or to promote the effective absorption of the active ingredient in the subject receiving the drug. Pharmaceutically acceptable excipients can be inert fillers, or they can be functional ingredients that provide a certain function for the pharmaceutical composition (for example, stabilizing the overall pH value of the composition or preventing the degradation of the active ingredient in the composition). Non-limiting examples of pharmaceutically acceptable excipients include, but are not limited to, adhesives, suspending agents, emulsifiers, diluents (or fillers), granulating agents, adhesives, disintegrants, lubricants, anti-adhesive agents, glidants, wetting agents, gelling agents, absorption delay agents, dissolution inhibitors, enhancers, adsorbents, buffers, chelating agents, preservatives, colorants, flavoring agents, sweeteners, etc.

[0062] The pharmaceutical compositions of the present invention can be prepared by any method known to those skilled in the art, for example, conventional mixing, dissolving, granulating, emulsifying, grinding, encapsulating, embedding and / or lyophilizing processes.

[0063] In the present invention, the purpose of using the pharmaceutical composition is to promote the administration of the organism, which is conducive to the absorption of the active ingredient and then exerts biological activity. The pharmaceutical composition of the present invention can be administered in any form, including injection (intra-arterial, intravenous, intramuscular, intraperitoneal, subcutaneous), mucosal, oral (oral solid preparations, oral liquid preparations), rectal, inhalation, implantation, local (e.g., eye) administration, etc. Non-limiting examples of oral solid preparations include, but are not limited to, powders, capsules, lozenges, granules, tablets, etc. Non-limiting examples of liquid preparations for oral or mucosal administration include, but are not limited to, suspensions, tinctures, elixirs, solutions, etc. Non-limiting examples of topical preparations include, but are not limited to, emulsions, gels, ointments, creams, patches, pastes, foams, lotions, drops or serum preparations. Non-limiting examples of parenteral preparations include, but are not limited to, solutions for injection, dry powders for injection, suspensions for injection, emulsions for injection, etc. The pharmaceutical composition of the present invention can also be made into controlled release or delayed release dosage forms (e.g., liposomes or microspheres).

[0064] Preferably, the compound of the present invention or the pharmaceutical composition comprising the same is administered orally or intravenously to an individual in need thereof. Depending on the specific circumstances of the subject to be administered, other routes of administration may also be applicable or even preferred. For example, for patients who are forgetful or irritable to oral medications, transdermal administration will be a very important route of administration. In the present invention, the route of administration can be changed or adjusted in any suitable manner to meet the needs of the nature of the drug, the convenience of the patient and medical staff, and other relevant factors.

[0065] The compound of the present invention or its pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, metabolite or prodrug or pharmaceutical composition comprising the same has excellent PLK1 enzyme inhibitory activity and cell proliferation inhibitory activity, can be used as a PLK inhibitor for preventing and / or treating diseases or conditions caused by overexpression of PLK, and has good clinical application and medical use. Preferably, a non-limiting example of a disease or condition caused by overexpression of PLK1 is cancer, including but not limited to blood tumors, pancreatic cancer, colorectal cancer and lung cancer.

[0066] The technical scheme of the present invention will be described below in conjunction with specific embodiments. The following embodiments are provided to further illustrate the present invention, but are not intended to limit the scope of the present invention. It will be apparent to those skilled in the art that various changes and improvements can be made to the specific embodiments of the present invention without departing from the spirit and scope of the present invention.

[0067] The preparation of the compounds of the present invention can be achieved by synthetic methods well known to those skilled in the art, including but not limited to the specific embodiments listed below, embodiments formed by combining them with other chemical synthesis methods, and equivalent substitution methods well known to those skilled in the art, and preferred embodiments include but are not limited to the embodiments of the present invention. The known starting materials used in the present invention can be synthesized by methods known in the art, or purchased by conventional commercial means (for example, purchased from Shaoyuan Chemical Technology, Beijing Coupling Technology, etc.). Unless otherwise specified, the reactions are carried out under an argon atmosphere or a nitrogen atmosphere. The hydrogenation reaction is usually evacuated, filled with hydrogen, and the operation is repeated 3 times. The reaction temperature is room temperature, and the temperature range is 20°C-30°C. Monitoring of the reaction progress can be achieved by synthetic methods well known to those skilled in the art, including but not limited to thin layer chromatography (TLC). The thin layer chromatography silica gel plate uses Qingdao Ocean GF254 silica gel plate, and the developing solvent system includes but is not limited to A: dichloromethane and methanol system; B: petroleum ether and ethyl acetate system, and the volume ratio of the solvent can be adjusted according to the polarity of the compound.

[0068] The separation and purification of the compounds of the present invention can be achieved by synthetic methods well known to those skilled in the art, including but not limited to column chromatography (CC), high performance liquid chromatography (HPLC), ultra-high performance liquid chromatography (UPLC), etc. Column chromatography generally uses Qingdao Ocean 200-300 mesh silica gel as a carrier, and the eluent system includes but is not limited to A: dichloromethane and methanol system; B: petroleum ether and ethyl acetate system. The volume ratio of the solvent can be adjusted according to the polarity of the compound, and a small amount of acidic or alkaline anti-tailing reagent can also be added for adjustment. The HPLC spectrum is measured using an Agilent 1200 DAD HPLC chromatograph (chromatographic column: Sunfire C18, 150×4.6mm, 5μm) or a Waters 2695-2996 HPLC chromatograph (chromatographic column: Gimini C18, 150×4.6mm, 5μm).

[0069] The structural identification of the compounds of the present invention can be achieved by methods well known to those skilled in the art, including but not limited to nuclear magnetic resonance (NMR), mass spectrometry (MS), etc. The NMR spectrum is measured using a Bruker AVANCE-400 or Varian Oxford-300 NMR spectrometer, and the measurement solvent is deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDC1 3 ) or deuterated methanol (CD 3 OD), the internal standard was tetramethylsilane (TMS), and the chemical shift was 10 -6 The MS spectra were measured using an Agilent SQD (ESI) mass spectrometer (model: 6110) or a Shimadzu SQD (ESI) mass spectrometer (model: 2020).

[0070] Preparation of intermediates

[0071] Preparation of intermediate INT-1

[0072]

[0073] Step 1: Synthesis of compound INT-1C

[0074] Compound INT-1A (1.32 g, 5.93 mmol) was dissolved in anhydrous tetrahydrofuran (20 mL) solution, and compound INT-1B (1.0 g, 5.43 mmol) was added, followed by triphenylphosphine (2.14 g, 8.17 mmol), and then the reaction apparatus was replaced with nitrogen, and DIAD (1.65 g, 8.17 mmol) was added dropwise under an ice bath. After the addition was complete, the ice bath was removed, and the reaction solution was heated to 50°C and reacted for 2 h. After TLC showed that the reaction was complete, the reaction solution was dried, and the residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 5:1 (volume ratio)) to obtain compound INT-1C (1.18 g, light yellow oil, yield 51%)

[0075] MS (ESI): m / z 388.0 [M+H] +

[0076] Step 2: Synthesis of compound INT-1D

[0077] Compound INT-1C (1 g) was dissolved in methanol (3 mL) and ethyl acetate (2 mL), and then 8% HCl-EA (10 mL) was added, and then the reaction solution was reacted at 50°C for 2 h. After TLC showed that the reaction was completed, the reaction solution was adjusted to a weak base with a saturated sodium bicarbonate solution, and then extracted with ethyl acetate (20 mL×3), and then the organic phase was dried with anhydrous sodium sulfate, and the organic phase was spin-dried, and the residue was purified by silica gel column chromatography (eluent: PE: EA = 1: 1 (volume ratio)) to obtain compound INT-1D (720 mg, white solid, yield 97%).

[0078] MS (ESI): m / z 288 [M+H] +

[0079] Step 3: Synthesis of compound INT-1E

[0080] Compound INT-1D (700 mg, 2.43 mmol) was added to DMSO (10 mL) solution, cesium fluoride (737 mg, 7.32 mmol) was added to the reaction solution, and then the reaction solution was taken to 80°C for overnight reaction. After TLC showed that the reaction was completed, the reaction solution was extracted with ethyl acetate (20 mL) and water (50 mL), extracted three times, and then the organic phase was dried with anhydrous sodium sulfate, the organic phase was spin-dried, and the residue was purified by silica gel column chromatography (eluent: PE: EA = 5: 1 (volume ratio)) to obtain compound INT-1E (160 mg, yellow solid, yield 26%).

[0081] MS (ESI): m / z 252 [M+H] +

[0082] Step 4: Synthesis of compound INT-1G

[0083] Compound INT-1E (150 mg, 0.60 mmol) was added to a dioxane (3 mL) solution, followed by cesium carbonate (692 mg, 1.2 mmol), xantphos (69 mg, 0.12 mmol), and Pd 2 (dba) 3 (54 mg, 0.06 mmol), and finally compound INT-1F (130.5 mg, 0.71 mmol) was added to the reaction solution, and then the reaction solution was replaced with nitrogen for three times, and then the reaction solution was taken to 100°C for overnight reaction. After TLC showed that the reaction was completed, the reaction solution was spin-dried, and the residue was purified by silica gel column chromatography (eluent: PE: EA = 3: 1 (volume ratio)) to obtain compound INT-1G (60 mg, yellow oil, yield 29%).

[0084] MS(ESI):m / z 353[M+H] +

[0085] Step 5: Synthesis of compound INT-1

[0086] Compound INT-1G (60 mg, 0.17 mmol) was added to 8% HCl-EA (234 mg, 551.35 mmol) solution, and the reaction solution was reacted at room temperature for 2 h. After TLC showed that the reaction was completed, the reaction solution was adjusted to a weak base with a saturated sodium bicarbonate aqueous solution, and then extracted with ethyl acetate for three times, and then the organic phase was dried with anhydrous sodium sulfate, and the organic phase was spin-dried, and the residue was purified by silica gel column chromatography (eluent: EA (volume ratio)) to obtain compound INT-1 (29 mg, yellow oil, yield 91%).

[0087] MS (ESI): m / z 189 [M+H] +

[0088] Preparation of intermediate INT-2

[0089]

[0090] Step 1: Synthesis of compound INT-2B

[0091] Compound INT-2A (9 g, 48.86 mmol) was added to a DMF (90 mL) solution, potassium carbonate (10.14 g, 73.29 mmol) was added, and then compound A (9.18 g, 48.86 mmol) was added, and then the reaction solution was reacted at 60°C for 3 h. After TLC showed that the reaction was completed, the reaction solution was poured into water (100 mL), and then ethyl acetate (100 mL) was added for extraction, and the extraction was repeated three times. The organic phase was then dried over anhydrous sodium sulfate, and the organic phase was spin-dried. The residue was purified by silica gel column chromatography (eluent: PE: EA = 3: 1 (volume ratio)) to obtain compound INT-2B (7.4 g, white oil, yield: 52.02%).

[0092] MS (ESI): m / z 291 [M+H] +

[0093] 1 H NMR (300 MHz, DMSO-d 6 )δ7.84(d,J=2.9Hz,1H),5.91(d,J=2.9Hz,1H),4.62(t,J=5.9Hz,2H),3.67(t,J=5.9Hz,2H),1.61(s,9H).

[0094] Step 2: Synthesis of compound INT-2D

[0095] Compound INT-2B (6 g, 20.61 mmol) was added to a DMF (60 mL) solution, followed by compound INT-2C (3.96 g, 20.61 mmol), and then potassium carbonate (4.283 g, 30.915 mmol), and then the reaction solution was reacted at 60°C for 16 h. After TLC showed that the reaction was complete, the reaction solution was poured into water, and then ethyl acetate was added for extraction, and the extraction was repeated three times. The organic phase was then dried over anhydrous sodium sulfate, and the organic phase was spin-dried. The residue was purified by silica gel column chromatography (eluent: PE:EA=3:1 (volume ratio)) to obtain compound INT-2D (2.8 g, white powder, yield: 34%).

[0096] MS (ESI): m / z 402 [M+H] +

[0097] Step 3: Synthesis of compound INT-2E

[0098] Compound INT-2D (2.9 g, 7.21 mmol) was added to ethyl acetate (6 mL) solution, and then methanol (6 mL) solution was added, and then 8% HCl-EA (29 mL) was added under ice bath, and then the reaction solution was taken to 50°C for reaction for 3 h. After TLC showed that the reaction was completed, the reaction solution was spin-dried, and the residue was extracted with saturated sodium bicarbonate solution and ethyl acetate solution for three times, and then the organic phase was dried with anhydrous sodium sulfate, and then the organic phase was spin-dried, and the residue was purified by silica gel column chromatography (eluent: PE: EA = 3: 1 (volume ratio)) to obtain compound INT-2E (1.6 g, white solid, yield: 73%).

[0099] MS (ESI): m / z 302 [M+H] +

[0100] 1 H NMR (300 MHz, CDCl 3 )δ7.85-7.80(m,1H),7.53-7.44(m,1H),7.38(dd,J=2.5,0.9Hz,1H),5.77(dd,J=2.5,1.0Hz,1H),4.58-4.55(m,2H),4.43-4.38(m,2H).

[0101] Step 4: Synthesis of compound INT-2F

[0102] Compound INT-2E (1 g, 3.31 mmol) was added to DMSO (150 mL) solution, and then cesium carbonate (3.25 g, 9.93 mmol) was added, and then the reaction solution was taken to 50°C for 6 h. After TLC showed that the reaction was completed, the reaction solution was added to water (300 mL), and then the mixed solution was filtered, and the mother liquor was extracted with ethyl acetate (100 mL) and brine (100 mL) for three times, and then the organic phase was dried over anhydrous sodium sulfate, and then the organic phase was spin-dried, and the residue was purified by silica gel column chromatography (eluent: PE: EA = 3: 1 (volume ratio)) to obtain compound INT-2F (80 mg, white solid, yield: 8.57%)

[0103] MS (ESI): m / z 282 [M+H] +

[0104] Step 5: Synthesis of compound INT-2G

[0105] Compound INT-2F (60 mg, 0.21 mmol) was added to a dioxane (3 mL) solution, followed by cesium carbonate (140 mg, 0.52 mmol), xantphos (12 mg, 0.02 mmol), and Pd 2(dba) 3 (10 mg, 0.01 mmol), and finally compound INT-1F (58 mg, 0.32 mmol) was added to the reaction solution, and then the reaction solution was replaced with nitrogen for three times, and then the reaction solution was taken to 90°C for 4 hours. After TLC showed that the reaction was completed, the reaction solution was spin-dried, and the residue was purified by prep-TLC (PE: EA = 2: 1) to obtain compound INT-2G (70 mg, light yellow oil, yield 86%).

[0106] MS (ESI): m / z 383 [M+H] +

[0107] Step 6: Synthesis of compound INT-2

[0108] Compound INT-2G (60 mg, 0.18 mmol) was dissolved in methanol (2 mL), added to 8% HCl-EA (0.2 mL) solution, and the reaction solution was reacted at room temperature for 1 h. After TLC showed that the reaction was completed, the reaction solution was adjusted to a weak base with a saturated sodium bicarbonate aqueous solution, and then extracted with ethyl acetate for three times, and then the organic phase was dried with anhydrous sodium sulfate, and the organic phase was spin-dried, and the residue was purified by silica gel column chromatography (eluent: EA (volume ratio)) to obtain compound INT-2 (29 mg, yellow solid, yield 75%).

[0109] MS (ESI): m / z 219 [M+H] +

[0110] 1 H NMR (300 MHz, CDCl 3 )δ8.48(d,J=2.0Hz,1H),7.76(d,J=2.0Hz,1H),7.68(d,J=1.8Hz,1H),5.94(d,J=1.8Hz,1H),4.38-4.29(m,4H).

[0111] Preparation and functional verification of target compounds

[0112] Example 1: Preparation of Compound 1

[0113] The structural formula of compound 1 is:

[0114]

[0115] The synthetic route of compound 1 is:

[0116]

[0117] The specific preparation method of compound 1 includes:

[0118] Step 1: Synthesis of Compound 1C

[0119] Dissolve compound 1B (5.77 g, 36 mmol) in anhydrous tetrahydrofuran (50 mL), add isopropyl magnesium chloride tetrahydrofuran solution (2M, 42 mL, 84 mmol) dropwise in a nitrogen atmosphere in an ice bath, and stir at room temperature for 3 hours. Dissolve compound 1A (2.5 g, 24 mmol) in anhydrous tetrahydrofuran (25 mL), add N,N-carbonyl diimidazole (4.3 g, 26.1 mmol) in batches in an ice bath, and stir at room temperature for 3 hours. Then, add the reaction solution of compound 1A dropwise into the reaction solution of compound 1B in an ice bath, and stir at room temperature for 16 hours. After TLC showed that the reaction was complete, the reaction solution was poured into a saturated aqueous ammonium chloride solution, extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate and spin-dried. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 10:1 (volume ratio)) to obtain compound 1C (4.4 g, light yellow oil, yield 90%).

[0120] 1 H NMR (300 MHz, CDCl 3 )δ3.82(q,J=6.8Hz,1H),3.47(d,J=6.1Hz,2H),3.38(s,3H),1.47(s,9H),1.31(d,J=6.9Hz,3H).

[0121] Step 2: Synthesis of Compound 1D

[0122] Compound 1C (1.5 g, 7.4 mmol) was added to DMF (15 mL), and N,N-dimethylformamide dimethyl acetal (1.76 g, 14.8 mmol) was added under ice bath, and the temperature was raised to 110°C for reaction for 0.5 h. After TLC showed that the reaction was complete, the crude reaction liquid was dried to obtain compound 1D, which was directly used for the next step.

[0123] Step 3: Synthesis of Compound 1F

[0124] The crude compound 1D (1.9 g, 7.4 mmol) was added to ethanol (20 mL), and 1E (600 mg, 5.2 mmol) was added in batches, and the temperature was raised to 80°C for 16 h. After TLC showed that the reaction was completed, part of the ethanol was dried by spin drying, the residue was slurried with ethanol, the solid obtained was filtered, and the compound 1F (1.4 g, white solid, yield 61%) was obtained by spin drying.

[0125] MS (ESI): m / z 312 [M+H] + .

[0126] 1H NMR (300 MHz, CDCl 3 )δ8.54(s,1H),6.69(s,1H),5.35(t,J=6.7Hz,1H),3.31(s,3H),1.74(d,J=6.7Hz,3H),1.61(s,9H).

[0127] Step 4: Synthesis of Compound 1G

[0128] Compound 1F (1.4 g, 4.5 mmol) was added to DCM (10 mL), TFA (5 mL) was added dropwise under ice bath, and the mixture was heated to room temperature and stirred for 4 h. After TLC showed that the reaction was complete, the mixture was spin-dried and the residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 1:1 (volume ratio)) to obtain compound 1G (1 g, light yellow solid, yield 87%).

[0129] MS (ESI): m / z 256 [M+H] + .

[0130] Step 5: Synthesis of Compound 1

[0131] Compound INT-1 (15 mg, 0.08 mmol) was dissolved in dioxane (1 mL), DPPA (44 mg, 0.16 mmol) and triethylamine (40 mg, 0.40 mmol) were added dropwise under ice bath, and the mixture was heated to room temperature and stirred for 0.5 h. Compound 1G (30 mg, 0.12 mmol) was added to the reaction solution, and the reaction mixture was heated to 100 °C and stirred for 12 h. After TLC showed that the reaction was complete, the mixture was added to water, extracted with ethyl acetate, and the organic phase was dried with anhydrous sodium sulfate and dried by spin drying. The residue was subjected to prep-TLC (EtOAc: MeOH = 10:1) and prep-HPLC (FA) to obtain compound 1 (8 mg, light yellow solid, yield 23%)

[0132] MS (ESI): m / z 441 [M+H] + .

[0133] 1 H NMR (300 MHz, DMSO-d 6 )δ9.94(s,1H),8.94(s,1H),8.43(s,1H),8.39(d,J=2.3Hz,1H),8.09(d,J=2.2Hz,1H),7.58(d,J=1. 9Hz,1H),6.91(s,1H),5.81(d,J=1.9Hz,1H),5.47-5.36(m,3H),3.31(s,3H),1.56(d,J=6.7Hz,3H).

[0134] Example 2: Preparation of Compound 2

[0135] The structural formula of compound 2 is:

[0136]

[0137] The synthesis of compound 2 was carried out according to the synthesis steps of compound 1 in Example 1, wherein (R)-2-methoxypropionic acid was used instead of compound 1A in the first step to synthesize compound 2.

[0138] MS (ESI): m / z 441 [M+H] + .

[0139] 1 H NMR (300 MHz, DMSO-d 6 )δ9.94(s,1H),8.94(s,1H),8.43(s,1H),8.39(d,J=2.3Hz,1H),8.09(d,J=2.2Hz,1H),7.58(d,J=1. 9Hz,1H),6.91(s,1H),5.81(d,J=1.9Hz,1H),5.47-5.36(m,3H),3.31(s,3H),1.56(d,J=6.7Hz,3H).

[0140] Example 3: Preparation of Compound 3

[0141] The structural formula of compound 3 is:

[0142]

[0143] The synthesis of compound 3 was carried out according to the synthesis steps of compound 1 in Example 1, wherein (S)-2-methoxypropionic acid was used instead of compound 1A in the first step to synthesize compound 3.

[0144] MS (ESI): m / z 441 [M+H] + .

[0145] 1 H NMR (300 MHz, DMSO-d 6 )δ9.94(s,1H),8.94(s,1H),8.43(s,1H),8.39(d,J=2.3Hz,1H),8.09(d,J=2.2Hz,1H),7.58(d,J=1. 9Hz,1H),6.91(s,1H),5.81(d,J=1.9Hz,1H),5.47-5.36(m,3H),3.31(s,3H),1.56(d,J=6.7Hz,3H).

[0146] Example 4: Preparation of Compound 4

[0147] The structural formula of compound 4 is:

[0148]

[0149] The synthesis of compound 4 followed the synthesis steps of compound 1 in Example 1, wherein INT-2 was used instead of compound INT-1 in the fifth step to obtain compound 4.

[0150] MS (ESI): m / z 471 [M+H] + .

[0151] Experimental Example 1: Activity test of the compound of the present invention against MALT1 enzymatic activity

[0152] Experimental Materials:

[0153] Fluorogenic MALT1 assay kit was purchased from BPS biosciences. Nivo multi-label analyzer (PerkinElmer).

[0154] Experimental methods:

[0155] The compound to be tested was diluted 5 times to the 8th concentration using a shot gun, i.e., from 100 μM to 1.28 nM, with a final DMSO concentration of 10%, and a double-well experiment was set up. 2.5 μL of inhibitor concentration gradients and 10 μl MALT1 enzyme (150 ng) were added to the microplate, and pre-incubated at 25 degrees for 50 minutes. After the incubation was completed, 12.5 μl of substrate was added, and the final compound concentration gradient was diluted from 10 μM to 0.128 nM. The reaction system was placed at 25 degrees for 30 minutes. After the reaction was completed, the fluorescence excitation wavelength was read using a PerkinElmer Nivo multi-label analyzer at 360 nM and the emission wavelength was 460 nM.

[0156] Data Analysis:

[0157] The raw data were converted into inhibition rate, IC using the equation (Sample-Min) / (Max-Min)*100%. 50 The value can be obtained by curve fitting with four parameters (obtained by log(inhibitor) vs. response--Variable slope mode in GraphPad Prism). Table 1 provides the inhibitory activity of the compounds of the present invention on MALT1 enzyme.

[0158] Table 1. The inhibitory activity of the compounds of the present invention on MALT1 enzyme (IC 50 )

[0159]

[0160] It can be seen from the experimental results in Table 1 that some compounds in the present invention have very good inhibitory activity on MALT1 enzyme and have good clinical application prospects.

[0161] Although the embodiments of the present invention have been shown and described above, it is understood that the above embodiments are exemplary and cannot be understood as limiting the present invention. Without departing from the principles and purpose of the present invention, those skilled in the art may change, modify, replace and modify the above embodiments within the scope of the present invention, and these changes, modifications, replacements and modifications are all included in the scope of the present invention.

Claims

1. A tricyclic compound as a MALT1 inhibitor, characterized in that The tricyclic compound is a compound as shown in Formula I or a pharmaceutically acceptable salt or stereoisomer thereof, I in, Y1 is absent, and L is selected from -CH2-; or Y1 is selected from O, and L is selected from -(CH2)2-; R1 is selected from halogen; R2 and R3 are independently selected from hydrogen, C1-C6 alkyl or C1-C6 alkoxy; R4 is selected from hydrogen or C1-C6 alkyl.

2. The compound according to claim 1, characterized in that It is a compound as shown in any one of Formula 1 to Formula 4, 。 3. A pharmaceutical composition comprising an effective dose of one or more of the compound according to any one of claims 1 to 2, its pharmaceutically acceptable salt, or its stereoisomer.

4. The pharmaceutical composition according to claim 3, characterized in that The pharmaceutical composition further comprises at least one pharmaceutically acceptable excipient.

5. Use of one or more of the compound according to any one of claims 1 to 2, its pharmaceutically acceptable salt, its stereoisomer and the pharmaceutical composition according to claim 3 in the preparation of a medicament for preventing and / or treating a disease or condition caused by overexpression of MALT1.

6. Use of one or more of the compound according to any one of claims 1 to 2, its pharmaceutically acceptable salt, its stereoisomer and the pharmaceutical composition according to claim 3 in the preparation of a MALT1 inhibitor drug.

7. Use of one or more of the compound according to any one of claims 1 to 2, its pharmaceutically acceptable salt, its stereoisomer and the pharmaceutical composition according to claim 3 in the preparation of a medicament for preventing and / or treating a disease or condition caused by overexpression of MALT1.

8. The use according to claim 7, characterized in that The disease or disorder includes an autoimmune disorder, an inflammatory disease or cancer.

9. The use according to claim 7, characterized in that: The disease or condition is any one or more of diffuse large B-cell lymphoma, mantle cell lymphoma, follicular lymphoma, chronic lymphocytic leukemia, myeloid leukemia, non-Hodgkin's lymphoma, lung adenocarcinoma, breast cancer, pancreatic cancer, liver cancer, gastric cancer, colorectal cancer, rheumatoid arthritis, psoriatic arthritis, ulcerative colitis, multiple sclerosis, psoriasis, Crohn's disease, systemic lupus erythematosus, Sjögren's syndrome, Hashimoto's thyroiditis, asthma or chronic obstructive pulmonary disease.

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