Malt1 inhibitor, and preparation method therefor and use thereof

Abstract

The present disclosure relates to an MALT1 inhibitor, and a preparation method therefor and the use thereof. Specifically, disclosed are a compound as represented by formula (I), a preparation method therefor, a pharmaceutical composition containing same, and the use thereof as an MALT1 inhibitor for preventing and / or treating autoimmune diseases, inflammatory diseases, cancers and tumors, wherein each group in formula (I) is as defined in the description.

Description

A MALT1 inhibitor and preparation method and use thereof

[0001] The present disclosure claims priority to Chinese Patent Application No. 202410971140.7, filed on July 19, 2024, and Chinese Patent Application No. 202510780640.7, filed on June 12, 2025, and incorporates the entire text of the above-mentioned Chinese patent applications. TECHNICAL FIELD

[0002] The present disclosure belongs to the field of medicine, and relates to a MALT1 inhibitor, a preparation method thereof, a pharmaceutical composition containing the same, and use thereof for preventing and / or treating autoimmune diseases, inflammatory diseases, cancers, and tumors. BACKGROUND

[0003] Mucosa-associated-lymphoid-tissue lymphoma-translocation 1 (MALT1) is an important protein molecule upstream of the NF-κB signaling pathway, and forms a complex CBM with B-cell chronic lymphocytic leukemia / lymphoma 10 (BCL10) and caspase-recruitment domain (CARD) containing membrane-associated guanylate kinase protein 1 (CARMA1), which transmits the signal of proximal antigen receptor protein to IκB kinase (IKK), and then activates the NF-κB signaling pathway. Overactivation of the MALT1-NF-κB signaling pathway is closely related to inflammation and tumor occurrence.

[0004] Disclosed MALT1 inhibitor patent applications include WO2015181747A, WO2017081641A, WO2018119036A, and WO2022106857A. SUMMARY

[0005] The present disclosure provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof,

[0006] wherein,

[0007] X1 is selected from CH, N;

[0008] X2 is selected from CH, N, S;

[0009] X3, X4are each independently selected from C, N;

[0010] G is selected from O, NH, C(R C )(R C’ ), R C , R C’ are each independently selected from hydrogen, deuterium, halogen (e.g. fluorine, chlorine, bromine, iodine), hydroxyl, cyano;

[0011] when G is selected from O or NH, ring A is selected from 4-9 membered cycloalkyl (e.g. 4 membered cycloalkyl, 5 membered cycloalkyl, 6 membered cycloalkyl, 7 membered cycloalkyl, 8 membered cycloalkyl, 9 membered cycloalkyl), 4-9 membered heterocycloalkyl (e.g. 4 membered heterocycloalkyl, 5 membered heterocycloalkyl, 6 membered heterocycloalkyl, 7 membered heterocycloalkyl, 8 membered heterocycloalkyl, 9 membered heterocycloalkyl);

[0012] when G is selected from C(R C )(R C’ ), ring A is selected from provided that when ring A is selected from n is not 0;

[0013] R 1 are each independently selected from deuterium, oxo (=0), hydroxyl, cyano, halogen (e.g. fluorine, chlorine, bromine, iodine), C 1-3 alkoxy (e.g. C1 alkoxy, C2 alkoxy, C3 alkoxy), C 1-3 alkyl (e.g. methyl, ethyl, isopropyl, n-propyl), 3-5 membered cycloalkyl (e.g. cyclopropane, cyclobutane, cyclopentane), 4-6 membered heterocycloalkyl (e.g. 4 membered heterocycloalkyl, 5 membered heterocycloalkyl, 6 membered heterocycloalkyl, heteroatoms can be N, O, S), -S(=0)2-R 7 , -S(=0)(=NH)-R 7 , said C 1-3 alkoxy, C 1-3 alkyl, 3-5 membered cycloalkyl, 4-6 membered heterocycloalkyl is optionally substituted with one or more substituents independently selected from R A , said R A is selected from deuterium, oxo (=0), halogen (e.g. fluorine, chlorine, bromine, iodine), C 1-3 alkoxy (e.g. C1, C2, C3), deuterated C 1-3 alkoxy, C 1-3 alkyl (e.g. methyl, ethyl, isopropyl, n-propyl), hydroxyl, cyano, -S(=0)2-R 7 , -S(=0)(=NH)-R 7 ;

[0014] R 2 are each independently selected from halogen (e.g. fluorine, chlorine, bromine, iodine), cyano, C1-3 Alkyl groups (e.g., methyl, ethyl, isopropyl, n-propyl), C 1-3 Alkoxy groups (e.g., C1 alkoxy, C2 alkoxy, C3 alkoxy), 3-5 membered cycloalkyl groups (e.g., cyclopropane, cyclobutane, cyclopentane), 4-6 membered heterocyclic alkyl groups (e.g., 4-membered heterocyclic alkyl, 5-membered heterocyclic alkyl, 6-membered heterocyclic alkyl, where the heteroatom can be N, O, or S), wherein the C 1-3 Alkyl, C 1-3 Alkoxy, 3-5 membered cycloalkyl, and 4-6 membered heterocycloalkyl may be optionally substituted with one or more deuterium atoms;

[0015] R 3 Selected from hydrogen, C 1-3 Alkyl groups (e.g., methyl, ethyl, isopropyl, n-propyl), deuterated C 1-3 alkyl;

[0016] R 4 Selected from hydrogen, C 1-3 Alkyl groups (e.g., methyl, ethyl, isopropyl, n-propyl), C 1-3 Alkoxy groups (e.g., C1 alkoxy, C2 alkoxy, C3 alkoxy), wherein the C 1-3 Alkyl, C 1-3 The alkoxy group is optionally selected from halogens (e.g., fluorine, chlorine, bromine, iodine), oxo (=O), deuterated, hydroxyl, cyano, C. 1-3 Alkoxy groups (e.g., C1 alkoxy, C2 alkoxy, C3 alkoxy), deuterated C 1-3 Alkoxy, C 1-3 Alkyl groups (e.g., methyl, ethyl, isopropyl, n-propyl) are substituted with one or more substituents;

[0017] Or R 3 and R 4 Together with the atoms they are attached to, they form 4-8 membered rings (e.g., 4-membered, 5-membered, 6-membered, 7-membered, 8-membered rings), wherein the 4-8 membered rings are optionally selected by one or more independently chosen from R. B The substituents replaced by R B Selected from deuterium, halogens (e.g., fluorine, chlorine, bromine, iodine), C 1-3 Alkyl groups (e.g., methyl, ethyl, isopropyl, n-propyl), C 1-3 Alkoxy groups (e.g., C1 alkoxy, C2 alkoxy, C3 alkoxy), 3-5 membered cycloalkyl groups (e.g., cyclopropane, cyclobutane, cyclopentane), 4-6 membered heterocyclic alkyl groups (e.g., 4-membered heterocyclic alkyl, 5-membered heterocyclic alkyl, 6-membered heterocyclic alkyl, where the heteroatom can be N, O, or S), wherein the C 1-3 Alkyl, C 1-3 Alkoxy, 3-5 membered cycloalkyl, and 4-6 membered heterocycloalkyl may be optionally substituted with one or more halogens (e.g., fluorine, chlorine, bromine, iodine);

[0018] R 5 selected from halogen (e.g., fluorine, chlorine, bromine, iodine), deuterium, C 1-3 alkyl (e.g., methyl, ethyl, isopropyl, n-propyl), C 1-3 alkoxy (e.g., C1alkoxy, C2alkoxy, C3alkoxy), the C 1-3 alkyl, C 1-3 alkoxy is optionally substituted with one or more substituents selected from deuterium and halogen (e.g., fluorine, chlorine, bromine, iodine);

[0019] R 6 selected from C 1-3 alkyl (e.g., methyl, ethyl, isopropyl, n-propyl), deuterated C 1-3 alkyl;

[0020] R 7 selected from C 1-3 alkyl (e.g., methyl, ethyl, isopropyl, n-propyl), 3-5 membered cycloalkyl (e.g., cyclopropane, cyclobutane, cyclopentane), the C 1-3 alkyl, C 3-5 cycloalkyl is optionally substituted with one or more substituents selected from halogen (e.g., fluorine, chlorine, bromine, iodine), C 1-3 alkoxy (e.g., C1alkoxy, C2alkoxy, C3alkoxy);

[0021] m is selected from 0, 1, or 2;

[0022] n is selected from 0, 1, or 2.

[0023] In some embodiments, the 4-8 membered ring is selected from 4-8 membered heterocycloalkyl, 4-8 membered heteroaryl.

[0024] In some embodiments, the compound of Formula (I) or pharmaceutically acceptable salt thereof is selected from Formula (I-1), Formula (I-2):

[0025] wherein X1, X2, X3, X4, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , n, m, ring A are as defined in Formula (I).

[0026] In some embodiments, the compound of Formula (I) or pharmaceutically acceptable salt thereof is selected from Formula (I-3):

[0027] wherein X1, X2, X3, X4, R 1 , R2 R 3 R 4 R 5 R 6 R C R C’ , n, m, and ring A are defined as in equation (I).

[0028] In some implementations, X1 is N; in other implementations, X1 is CH.

[0029] In some implementations, X2 is CH, X3 is C, and X4 is N.

[0030] In some implementations, X2 is CH, X3 is N, and X4 is C.

[0031] In some implementation schemes, R 3 Selected from hydrogen, methyl, and deuterated methyl.

[0032] In some specific implementations, the R 3 It is hydrogen.

[0033] In some implementations, the R 4 Selected from methyl and ethyl, wherein the methyl and ethyl groups are optionally selected from C. 1-3 Alkoxy, deuterated C 1-3 Alkoxy, C 1-3 It is substituted by one or more substituents of the alkyl group.

[0034] In some implementations, the R 4 The group is selected from methyl and ethyl, wherein the methyl or ethyl group is optionally substituted with one or more substituents selected from methyl or methoxy.

[0035] In some implementations, the R 4 Selected from

[0036] In some specific implementations, the R 4 Selected from

[0037] In some implementations, the R 3 and R 4 Together with the atoms it is attached to, they form a 4-8 membered ring, which is optionally composed of one or more independently selected from R. B The substituents replaced by R B Selected from deuterium and methyl, wherein the methyl group is optionally substituted with one or more halogens.

[0038] In some implementations, the R 3 and R 4with the atom to which it is attached, form a 5- or 6-membered ring, which is optionally substituted with one or more substituents independently selected from R B B selected from deuterium, methyl, which is optionally substituted with one or more halogen.

[0039] In some embodiments, the R 3 and R 4 with the atom to which it is attached, form a 5- or 6-membered ring, which is optionally substituted with one or more substituents independently selected from R B B selected from methyl, trifluoromethyl.

[0040] In some embodiments, the compound of Formula (I) or pharmaceutically acceptable salt thereof is: selected from wherein R 5 is as defined in Formula (I).

[0041] In some embodiments, the compound of Formula (I) or pharmaceutically acceptable salt thereof is: selected from wherein R 5 is as defined in Formula (I).

[0042] In some embodiments, the compound of Formula (I) or pharmaceutically acceptable salt thereof is: selected from

[0043] In some embodiments, the R 2 is selected from fluorine, chlorine, bromine, methyl, methoxy, -OCD3.

[0044] In some embodiments, the R 2 is selected from fluorine, chlorine, methyl.

[0045] In some embodiments, the R 2 is selected from fluorine or chlorine.

[0046] In some embodiments, the m is selected from 0 or 1.

[0047] In some particular embodiments, the m is 0.

[0048] In some embodiments, the R 6 is selected from methyl, deuterated methyl.

[0049] In some particular embodiments, the R 6 is selected from methyl. ​​

[0050] In some embodiments, the R 5 is selected from halogen, methyl, deuterated methyl.

[0051] In some specific embodiments, the R 5 is selected from F, CI, methyl.

[0052] In some embodiments, the compound of Formula (I) or pharmaceutically acceptable salt thereof, wherein Formula (I) is selected from Formula (I-4), Formula (I-5), Formula (I-7), Formula (I-8):

[0053] wherein R 1 , n, ring A are as defined in Formula (I).

[0054] In some embodiments, the compound of Formula (I) or pharmaceutically acceptable salt thereof, wherein Formula (I) is selected from Formula (I-6), Formula (I-9), Formula (I-10):

[0055] wherein R C , R C’ , R 1 , n, ring A are as defined in Formula (I).

[0056] In some embodiments, the R 1 is each independently selected from cyclopropyl, hydroxyl, oxo (=0), -S(=0)2-R 7 , -S(=0)(=NH)-R 7 wherein R 7 is as defined in Formula (I).

[0057] In some embodiments, the R 7 is selected from methyl, ethyl, cyclopropyl.

[0058] In some embodiments, the n is selected from 0, 1 or 2.

[0059] In some embodiments, the R C , R C’ is each independently selected from hydrogen.

[0060] In some embodiments, the ring A is selected from

[0061] In some embodiments, the compound of Formula (I) or pharmaceutically acceptable salt thereof, wherein, is selected from

[0062] In some embodiments, the compound of Formula (I) or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:

[0063] The present disclosure provides an isotopically substituted compound of Formula (I) or a pharmaceutically acceptable salt thereof.

[0064] In some embodiments, the isotopic substitution is deuterium atom substitution.

[0065] The present disclosure also provides a pharmaceutical composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof, as described above, and one or more pharmaceutically acceptable carriers, diluents, or excipients.

[0066] In some embodiments, the unit dose of the pharmaceutical composition is 0.001 mg to 1000 mg.

[0067] In certain embodiments, the pharmaceutical composition contains 0.01-99.99% of the compound of Formula (I) or a pharmaceutically acceptable salt thereof, as described above, based on the total weight of the composition. In certain embodiments, the pharmaceutical composition contains 0.1-99.9% of the compound of Formula (I) or a pharmaceutically acceptable salt thereof, as described above. In certain embodiments, the pharmaceutical composition contains 0.5-99.5% of the compound of Formula (I) or a pharmaceutically acceptable salt thereof, as described above. In certain embodiments, the pharmaceutical composition contains 1-99% of the compound of Formula (I) or a pharmaceutically acceptable salt thereof, as described above. In certain embodiments, the pharmaceutical composition contains 2-98% of the compound of Formula (I) or a pharmaceutically acceptable salt thereof, as described above.

[0068] In certain embodiments, the pharmaceutical composition contains 0.01-99.99% of a pharmaceutically acceptable excipient, based on the total weight of the composition. In certain embodiments, the pharmaceutical composition contains 0.1-99.9% of a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition contains 0.5-99.5% of a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition contains 1-99% of a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition contains 2-98% of a pharmaceutically acceptable excipient.

[0069] The present disclosure provides the use of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, or an isotopically substituted compound of Formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, in the manufacture of a medicament for the treatment and / or prevention of a disease or disorder associated with MALT1.

[0070] The present disclosure provides use of a compound represented by Formula (I) or a pharmaceutically acceptable salt thereof, or an isotopically-substituted compound represented by Formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, in the manufacture of a medicament for treating and / or preventing an autoimmune disease, an inflammatory disease, a cancer, a tumor.

[0071] The present disclosure provides a method of treating and / or preventing a disease or disorder associated with MALT1, comprising administering to a subject in need thereof a therapeutically effective amount of a compound represented by Formula (I) or a pharmaceutically acceptable salt thereof, or an isotopically-substituted compound represented by Formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.

[0072] The present disclosure provides a method of treating and / or preventing an autoimmune disease, an inflammatory disease, a cancer, a tumor, comprising administering to a subject in need thereof a therapeutically effective amount of a compound represented by Formula (I) or a pharmaceutically acceptable salt thereof, or an isotopically-substituted compound represented by Formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.

[0073] The present disclosure provides a compound represented by Formula (I) or a pharmaceutically acceptable salt thereof, or an isotopically-substituted compound represented by Formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use as a medicament.

[0074] The present disclosure provides a compound represented by Formula (I) or a pharmaceutically acceptable salt thereof, or an isotopically-substituted compound represented by Formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use in treating and / or preventing a disease or disorder associated with MALT1.

[0075] The present disclosure provides a compound represented by Formula (I) or a pharmaceutically acceptable salt thereof, or an isotopically-substituted compound represented by Formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use in treating and / or preventing an autoimmune disease, an inflammatory disease, a cancer, a tumor.

[0076] In some embodiments, the autoimmune disease and inflammatory disease is selected from rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, or a vasculitic disease.

[0077] In some embodiments, the cancer or tumor is selected from a hematopoietic primary cancer or a solid tumor.

[0078] In some embodiments, the cancer or tumor is selected from chronic myelogenous leukemia, myeloid leukemia, non-Hodgkin lymphoma and other B-cell lymphomas.

[0079] In some embodiments, the cancer or tumor is non-Hodgkin lymphoma.

[0080] In some specific embodiments, the non-Hodgkin lymphoma is diffuse large B-cell lymphoma.

[0081] The present disclosure also provides a method for preparing a compound of Formula (I-3) or a pharmaceutically acceptable salt thereof or an isotopically-substituted compound of Formula (I-3) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, comprising the step of: reacting a compound of Formula (B) or a pharmaceutically acceptable salt thereof and a compound of Formula (B-1) or a pharmaceutically acceptable salt thereof in a solvent (dichloromethane (DCM), N,N-dimethylformamide (DMF)) in the presence of a base (triethylamine (TEA), N,N-diisopropylethylamine (DIEA), potassium carbonate, cesium carbonate) and a condensing agent (propylphosphonic anhydride (T3P)) to give a compound of Formula (I-3) or a pharmaceutically acceptable salt thereof,

[0082] wherein Q is selected from H or halogen (e.g., bromo or chloro),

[0083] R C , R C’ , X1, X2, X3, X4, ring A, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , m, n are as defined in Formula (I).

[0084] In some embodiments, the Q is H.

[0085] In some embodiments, the Q is chloro.

[0086] The present disclosure also provides a method for preparing a compound of Formula (I-1) or a pharmaceutically acceptable salt thereof or an isotopically-substituted compound of Formula (I-1) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, comprising the step of: reacting a compound of Formula (B’) or a pharmaceutically acceptable salt thereof and a compound of Formula (B-2) or a pharmaceutically acceptable salt thereof in a solvent (dichloromethane (DCM), N,N-dimethylformamide (DMF)) in the presence of a base (triethylamine (TEA), N,N-diisopropylethylamine (DIEA), potassium carbonate, cesium carbonate) to give a compound of Formula (I-1) or a pharmaceutically acceptable salt thereof,

[0087] wherein X1, X2, X3, X4, ring A, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , m, n are as defined in Formula (I).

[0088] The present disclosure also provides a preparation method of a compound represented by formula (I-2) or a pharmaceutically acceptable salt thereof or an isotopically substituted compound of the compound represented by formula (I-2) or the pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, comprising the following steps: reacting a compound represented by formula (B') or a pharmaceutically acceptable salt thereof and a compound represented by formula (B-3) or a pharmaceutically acceptable salt thereof in a solvent (dichloromethane (DCM), N,N-dimethylformamide (DMF)) in the presence of a base (triethylamine (TEA), N,N-diisopropylethylamine (DIEA), potassium carbonate, cesium carbonate) to obtain a compound represented by formula (I-2) or a pharmaceutically acceptable salt thereof,

[0089] wherein X1, X2, X3, X4, ring A, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , m and n are as defined in formula (I).

[0090] In some embodiments, the compound represented by formula (B') or a pharmaceutically acceptable salt thereof described above can be obtained by the following steps: reacting a compound represented by formula (B) or a pharmaceutically acceptable salt thereof and triphosgene (BTC) in a solvent (dichloromethane (DCM), N,N-dimethylformamide (DMF)) in the presence of a base (triethylamine (TEA), N,N-diisopropylethylamine (DIEA), potassium carbonate, cesium carbonate) to obtain a compound represented by formula (B') or a pharmaceutically acceptable salt thereof,

[0091] wherein X1, X2, X3, X4, R 2 , R 3 , R 4 , R 5 , R 6 , and m are as defined in formula (I).

[0092] The present disclosure also provides a compound represented by formula (B') or a pharmaceutically acceptable salt thereof, wherein X1, X2, X3, X4, R 2 , R 3 , R 4 , R 5 , R 6 , and m are as defined in formula (I).

[0093] The pharmaceutically acceptable salt of the compound described in the present disclosure is selected from inorganic salts or organic salts, and the compound described in the present disclosure can react with acidic or basic substances to form the corresponding salt.

[0094] The compounds disclosed herein can exist in specific geometric or stereoisomeric forms. This disclosure envisions all such compounds, including cis and trans isomers, (-)- and (+)- enantiomers, (R)- and (S)- enantiomers, diastereomers, (D)- isomers, (L)- isomers, and racemic mixtures thereof, as well as other mixtures, such as mixtures enriched with enantiomers or diastereomers, all of which are within the scope of this disclosure. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers and mixtures thereof are included within the scope of this disclosure. The compounds containing asymmetric carbon atoms of this disclosure can be isolated in optically active pure form or in racemic form. Optically active pure forms can be resolved from racemic mixtures or synthesized using chiral starting materials or chiral reagents.

[0095] Optically active (R)- and (S)- isomers, as well as D- and L- isomers, can be prepared by chiral synthesis, chiral reagents, or other conventional techniques. To obtain an enantiomer of a compound disclosed herein, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide the desired enantiomer in pure form. Alternatively, when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), a salt of the diastereomeric isomer is formed with a suitable optically active acid or base, followed by diastereomeric resolution using conventional methods known in the art, and then the pure enantiomer is recovered. Furthermore, the separation of enantiomers and diastereomeric isomers is typically accomplished by using chromatography employing a chiral stationary phase and optionally combined with chemical derivatization (e.g., from amines to carbamates).

[0096] In the chemical structure of the compounds described in this disclosure, the bonds... This indicates that the configuration is not specified; that is, if chiral isomers exist in the chemical structure, the bond... It can be Or simultaneously include Two configurations.

[0097] This disclosure covers the compounds described herein, their pharmaceutically acceptable salts, or any isotopically labeled derivatives of their isomers. Atoms capable of being isotopically labeled include, but are not limited to, hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, and iodine. They can be labeled with isotopes. 2 H(D), 3 H, 11 C 13 C 14 C 15 N、 18 F, 31 P, 32 P,35 S, 36 Cl and 125 I, etc., are used instead.

[0098] Unless otherwise specified, when a position is specifically designated as deuterium (D), that position should be understood as having a deuterium abundance of at least 1000 times greater than the natural abundance of deuterium (which is 0.015%) (i.e., at least 10% deuterium incorporation). The natural abundance of deuterium in the example compounds can be at least 1000 times, at least 2000 times, at least 3000 times, at least 4000 times, at least 5000 times, at least 6000 times, or even higher. This disclosure also includes various deuterated forms of compounds of formula (I). Each available hydrogen atom bonded to a carbon atom can be independently replaced by a deuterium atom. Those skilled in the art can synthesize the deuterated forms of compounds of formula (I) with reference to relevant literature. Commercially available deuterated starting materials can be used to prepare the deuterated form of the compound of formula (I), or they can be synthesized using conventional techniques with deuterated reagents, including but not limited to deuterated boranes, trideuterated borane tetrahydrofuran solutions, deuterated lithium aluminum hydride, deuterated iodoethane, and deuterated iodomethane.

[0099] Terminology Explanation

[0100] To facilitate understanding of this disclosure, certain technical and scientific terms are specifically defined below. Unless otherwise expressly defined in this disclosure, all other technical and scientific terms used in this disclosure shall have the meaning commonly understood by one of ordinary skill in the art to which this disclosure pertains.

[0101] The prefix "Cu-v" indicates that the following group has from u to v carbon atoms. For example, "C1-3 alkyl" means that the alkyl group has 1 to 3 carbon atoms, specifically alkyl groups with 1, 2 or 3 carbon atoms.

[0102] The term "alkyl" refers to a saturated aliphatic hydrocarbon group, including straight-chain and branched groups with 1 to 20 carbon atoms. For example, alkyl groups containing 1 to 6 carbon atoms include, non-limiting examples, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, and their various branched isomers; or, alkyl groups containing 1 to 3 carbon atoms include, non-limiting examples, methyl, ethyl, n-propyl, and isopropyl. Alkyl groups can be substituted or unsubstituted. When substituted, the substituent can be substituted at any usable connection point, preferably one or more of the following groups, independently selected from halogens, hydroxyl groups, oxo groups, cyano groups, amino groups, C6 groups, etc. 1-6 Alkyl, C 1-6Alkoxy, 3- to 6-membered cycloalkyl, or 3- to 6-membered heterocycloalkyl, wherein the alkyl, alkoxy, cycloalkyl, or heterocycloalkyl may optionally be substituted with halogen, hydroxyl, nitro, cyano, or amino.

[0103] The term "alkoxy" refers to -O- (alkyl), where alkyl is defined as described above. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy, and isopropoxy. Alkoxy groups can be optionally substituted or unsubstituted; when substituted, the substituent is preferably one or more of the following groups, independently selected from deuterium, halogen, hydroxyl, oxo, cyano, amino, C... 1-6 Alkyl, C 1-6 Alkoxy, 3- to 7-membered cycloalkyl, or 3- to 7-membered heterocycloalkyl, wherein the alkyl, alkoxy, cycloalkyl, or heterocycloalkyl may optionally be substituted with halogen, hydroxyl, nitro, cyano, or amino.

[0104] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent containing 3 to 20 carbon atoms, preferably 4 to 12 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, etc.; polycyclic cycloalkyl groups include spirocyclic, fused-ring, and bridged-ring cycloalkyl groups. Cycloalkyl groups can be substituted or unsubstituted; when substituted, the substituent can be replaced at any usable connection point, preferably one or more of the following groups, independently selected from halogens, hydroxyl, oxo, cyano, amino, C... 1-6 Alkyl, C 1-6 Alkoxy, 3- to 6-membered cycloalkyl, or 3- to 6-membered heterocycloalkyl, wherein the alkyl, alkoxy, cycloalkyl, or heterocycloalkyl may optionally be substituted with halogen, hydroxyl, nitro, cyano, or amino.

[0105] The term "heterocyclic alkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent containing 3 to 20 ring atoms, one or more of which are selected from nitrogen, oxygen, or S(O). m (where m is an integer from 0 to 2) heteroatoms, but excluding the -OO-, -OS-, or -SS- ring portions, with the remaining ring atoms being carbon. Preferably, it contains 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; more preferably, it contains 8 to 9 ring atoms. Non-limiting examples of "heterocyclic alkyl" include: wait.

[0106] The heterocyclic alkyl ring may be fused to an aryl or heteroaryl ring, wherein the ring attached to the parent structure is a heterocyclic alkyl ring, and non-limiting examples include:

[0107] wait.

[0108] Heterocycloalkyl can be optionally substituted or unsubstituted, when substituted, the substituents are preferably one or more groups independently selected from halogen, hydroxy, oxo, cyano, amino, C 1-3 alkyl, C 1-3 alkoxy, 3- to 6-membered cycloalkyl, or 3- to 6-membered heterocycloalkyl, said alkyl, alkoxy, cycloalkyl, or heterocycloalkyl being optionally substituted with halogen, hydroxy, nitro, cyano, or amino.

[0109] The term "aryl" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (that is, rings which share adjacent pairs of carbon atoms) ring systems having a conjugated pi-electron system, preferably 6- to 12-membered, such as phenyl and naphthyl. The aryl ring can be fused to a heteroaryl, heterocyclyl, or cycloalkyl ring, wherein the ring that is attached to the parent structure is the aryl ring, non-limiting examples of which include:

[0110] The aryl group can be substituted or unsubstituted, when substituted, the substituents are preferably one or more groups independently selected from halogen, hydroxy, oxo, nitro, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, 3- to 6-membered cycloalkyl, 3- to 6-membered heterocycloalkyl, C 3-8 cycloalkenyl, 5- to 6-membered aryl, or heteroaryl, said C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, 3- to 6-membered cycloalkyl, 3- to 6-membered heterocycloalkyl, 3- to 8-membered cycloalkenyl, 5- to 6-membered aryl, or heteroaryl, optionally substituted with one or more groups selected from halogen, hydroxy, cyano, amino, C 1-6 alkyl, or C 1-6 alkoxy.

[0111] The term "heteroaryl" refers to a heteroaromatic system comprising 1 to 4 heteroatoms, 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur, and nitrogen. The heteroaryl is preferably 6- to 12-membered, more preferably 5- or 6-membered. For example. Non-limiting examples include: imidazolyl, furanyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, isoxazolyl, pyrrolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazinyl, triazolyl, indazolyl, benzimidazolyl, and the like.

[0112] The heteroaryl ring can be fused to an aryl, heterocyclyl, or cycloalkyl ring, wherein the ring that is attached to the parent structure is the heteroaryl ring, non-limiting examples of which include:

[0113] The above cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups include residues derived from removal of one hydrogen atom from a parent ring atom, or two hydrogen atoms from the same ring atom or two different ring atoms of the parent, i.e., "cycloalkylene", "heterocyclylene", "arylene", "heteroarylene". Non-limiting examples include: etc. Those skilled in the art will recognize from the context the number of valences that can be utilized.

[0114] The term "heterocycle" refers to a ring composed of atoms other than carbon, including heterocycloalkyl and heteroaryl groups.

[0115] The term "halogen" means fluorine, chlorine, bromine or iodine.

[0116] The term "oxo" means a =0 substituent.

[0117] "Substituted" means that one or more hydrogen atoms, preferably up to 5, more preferably 1 to 3, of a group are independently of each other replaced with a corresponding number of substituents. When the substituents are ketones or oxo (i.e., =0), then two (2) hydrogens on the atom are replaced.

[0118] "Pharmaceutical composition" means a mixture that comprises one or more active ingredients described herein, or physiologically / pharmaceutically acceptable salts or prodrugs thereof, with other chemical components, such as carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration of the active ingredient to an organism.

[0119] "Pharmaceutically acceptable carrier, diluent or excipient" includes any material other than the active ingredient that is used in the formulation of a pharmaceutical composition. Examples include but are not limited to any of the standard pharmaceutical carriers such as phosphate buffered saline solution, water, emulsions such as an oil / water emulsion, and various types of wetting agents. In some embodiments, the diluent used for aerosol or parenteral administration is phosphate buffered saline (PBS) or normal (0.9%) saline. Compositions containing such carriers are formulated by well known conventional methodology (see, for example, Remington's Pharmaceutical Sciences, 18th Ed., A. Gennaro, editor, Mack Publishing Co., Easton, PA, 1990; and R Remington, The Science and Practice of Pharmacy 20th Ed. Mack Publishing, 2000).

[0120] "Treat" means to administer a therapeutic agent to a subject. Typically, a therapeutic agent is administered in an amount effective to alleviate one or more symptoms of a disease in a treated subject or population, to any clinically measurable extent, by preventing or delaying the onset of symptoms or complications, lessening symptoms or complications, or eliminating the disease, condition, or disorder. The amount of a therapeutic agent effective to alleviate any particular symptom of a disease (also referred to as a "therapeutically effective amount") can vary according to factors such as the disease state, age, and weight of the subject, and the ability of the drug to elicit a desired effect in the subject. Whether a disease symptom has been alleviated can be assessed by any clinical detection method typically used by a physician or other health care professional to assess the severity or progression of the symptom. While an embodiment of the disclosure (e.g., a therapeutic method or article of manufacture) can not be effective in alleviating a target disease symptom in a certain subject, it should alleviate the target disease symptom in a statistically significant number of subjects, as determined according to any statistical test known in the art, such as the Student t-test, the chi-square test, the U test according to Mann and Whitney, the Kruskal-Wallis test (H test), the Jonckheere-Terpstra test, and the Wilcoxon test. The patient to be treated is a mammal, and preferably a human.

[0121] "Prevent" or "prevention" means to reduce the risk or incidence of, or to eliminate or slow the progression of, one or more conditions, symptoms, complications, or disorders.

[0122] "Subject" or "patient" means a mammal, especially a primate, and especially a human.

[0123] "Optionally" or "optional" means that the subsequently described event or circumstance can or can not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not. For example, "an optionally substituted C 1-3 "Alkyl" means that halogen can or can not be present, and that the description includes instances where the alkyl group is substituted with halogen and instances where the alkyl group is not substituted with halogen.

[0124] Unless the context clearly requires otherwise, throughout the description and the claims, the words "comprise," "comprising," "include," "including," and the like are to be construed in an inclusive sense as opposed to an exclusive or exhaustive sense; that is to say, in the sense of "including, but not limited to.". DETAILED DESCRIPTION

[0125] The present disclosure is further described in the following Examples, which do not limit the scope of the disclosure.

[0126] The experimental methods in the embodiments or test examples of the present disclosure not specified with specific conditions are generally according to the conventional conditions, or according to the conditions suggested by the manufacturers of raw materials or commodities. The reagents not specified with specific sources are the conventional reagents purchased in the market.

[0127] The structure of the compound is determined by nuclear magnetic resonance (NMR) or / and mass spectrometry (MS). The NMR shift (δ) is given in units of 10 -6 (ppm). The determination of NMR is determined by Bruker AVANCE-400 nuclear magnetic instrument with deuterated dimethyl sulfoxide (DMSO-d6) as solvent.

[0128] The determination of MS is determined by Agilent 1200 / 1290 DAD-6110 / 6120 Quadrupole MS liquid chromatography-mass spectrometer (manufacturer: Agilent, MS model: 6110 / 6120 Quadrupole MS), waters ACQuity UPLC-QD / SQD (manufacturer: waters, MS model: waters ACQuity Qda Detector / waters SQ Detector), THERMO Ultimate 3000-Q Exactive (manufacturer: THERMO, MS model: THERMO Q Exactive).

[0129] The high performance liquid chromatography (HPLC) analysis uses Agilent HPLC 1200DAD, Agilent HPLC 1200VWD and Waters HPLC e2695-2489 high performance liquid chromatograph.

[0130] The preparation and analysis of chiral compounds use Waters UPC2 analytical SFC (SFC-H) high performance liquid chromatograph.

[0131] The high performance liquid preparation chromatography uses Waters 2545-2767, Waters 2767-SQ Detecor2, Shimadzu LC-20AP and Gilson GX-281 preparative chromatograph.

[0132] The CombiFlash rapid preparation instrument uses Combiflash Rf200 (TELEDYNE ISCO).

[0133] The silica gel column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier.

[0134] The known starting materials of the present disclosure can be synthesized using or according to methods known in the art, or purchased from ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, J & K, Accela ChemBio Inc, Shanghai Bide Pharmaceutical, Dary Chemicals, etc.

[0135] Unless otherwise specified in the examples, the reactions can be carried out under an argon or nitrogen atmosphere.

[0136] An argon or nitrogen atmosphere means that a reaction flask is connected to an argon or nitrogen balloon with a volume of about 1 L.

[0137] A hydrogen atmosphere means that a reaction flask is connected to a hydrogen balloon with a volume of about 1 L.

[0138] A pressurized hydrogenation reaction uses a Parr 3916EKX hydrogenation instrument and a Qinglan QL-500 hydrogen generator or an HC2-SS hydrogenation instrument.

[0139] A hydrogenation reaction is usually vacuumed, filled with hydrogen, and the operation is repeated 3 times.

[0140] Unless otherwise specified in the examples, the solution refers to an aqueous solution.

[0141] Unless otherwise specified in the examples, the reaction temperature is room temperature, which is 20-30°C.

[0142] The reaction progress in the examples uses liquid chromatography-mass spectrometry (HPLC-MS).

[0143] Examples 1-1 and 1-2

[0144] N-((S)-1-(4-(2-chloro-8,9-dihydropyrazolo[1,5-a]pyrido[2,3-e]pyrimidin-6(7H)-yl)phenyl)-2,2,2-trifluoroethyl)-N-methyl-2-((R)-5-oxopyrrolidin-3-yl)acetamide and N-((S)-1-(4-(2-chloro-8,9-dihydropyrazolo[1,5-a]pyrido[2,3-e]pyrimidin-6(7H)-yl)phenyl)-2,2,2-trifluoroethyl)-N-methyl-2-((S)-5-oxopyrrolidin-3-yl)acetamide

[0145] First step

[0146] N-((S)-1-(4-(2-chloro-8,9-dihydropyrazolo[1,5-a]pyrido[2,3-e]pyrimidin-6(7H)-yl)phenyl)-2,2,2-trifluoroethyl)-N-methyl-2-(5-oxopyrrolidin-3-yl)acetamide (Compound 1)

[0147] Compound 1a (118.0 mg, 0.30 mmol) (prepared according to (WO2022106857A1)), compound 1b (43.0 mg, 0.11 mmol) were dissolved into dichloromethane (10.0 mL), followed by the addition of triethylamine (91.0 mg, 0.90 mmol), stirring at room temperature for 10 minutes. Then T3P (307.0 mg, 0.90 mmol) was added, stirring at room temperature for 3 hours. Concentration under reduced pressure gave a crude product, which was purified by HPLC to give compound 1 (75.0 mg, 0.14 mmol, yield 48.1%).

[0148] Compound 1 was resolved by a chiral column (chromatographic column ChiralPak OJ (100 x 4.6 mm I.D., 3 μm), mobile phase: A: supercritical CO2 fluid, B: methanol (0.1% diethanolamine); column temperature: 40 °C; flow rate: 3.0 mL / min) to give a compound with a retention time of 2.801 minutes (this compound is defined as compound 1-1) and a compound with a retention time of 3.027 minutes (this compound is defined as compound 1-2).

[0149] Compound 1-1:

[0150] MS m / z (ESI): 521.8 [M+H] + ;

[0151] 1 H NMR (400 MHz, DMSO-d6) δ 8.30 (s, 1H), 7.49 (s, 1H), 7.36 - 7.23 (m, 4H), 6.82 (s, 1H), 6.51 (q, J = 9.3 Hz, 1H), 3.76 - 3.67 (m, 2H), 3.43 (dd, J = 9.6, 7.4 Hz, 1H), 3.10 (t, J = 6.7 Hz, 2H), 2.91 - 2.87 (m, 4H), 2.78 - 2.70 (m, 1H), 2.67 (dd, J = 7.0, 2.3 Hz, 2H), 2.30 (dd, J = 16.6, 8.4 Hz, 1H), 2.01 - 1.83 (m, 3H).

[0152] Compound 1-2:

[0153] MS m / z (ESI): 521.8 [M+H] + ;

[0154] 1H NMR (400 MHz, DMSO-d6) δ 8.30 (s, 1H), 7.49 (s, 1H), 7.36 - 7.22 (m, 4H), 6.82 (s, 1H), 6.51 (q, J = 9.3 Hz, 1H), 3.76 - 3.68 (m, 2H), 3.46 - 3.38 (m, 1H), 3.10 (t, J = 6.7 Hz, 2H), 2.93 - 2.89 (m, 4H), 2.80 - 2.70 (m, 1H), 2.70 - 2.63 (m, 2H), 2.31 (dd, J = 16.5, 8.4 Hz, 1H), 2.01 - 1.90 (m, 2H), 1.87 (dd, J = 16.6, 7.3 Hz, 1H).

[0155] Example 2-1 and 2-2

[0156] 1-((S)-1-(4-(2-chloro-8,9-dihydropyrazolo[1,5-a]pyrido[2,3-e]pyrimidin-6(7H)-yl)phenyl)-2,2,2- trifluoroethyl)-1-methyl-3-((R)-5-oxopyrrolidin-3-yl)urea and 1-((S)-1-(4-(2-chloro-8,9- dihydropyrazolo[1,5-a]pyrido[2,3-e]pyrimidin-6(7H)-yl)phenyl)-2,2,2-trifluoroethyl)-1-methyl-3- ((S)-5-oxopyrrolidin-3-yl)urea

[0157] First step (S)-(1-(4-(2-chloro-8,9-dihydropyrazolo[1,5-a]pyrido[2,3-e]pyrimidin-6(7H)-yl)phenyl)- 2,2,2-trifluoroethyl)(methyl)carbamoyl chloride (Compound 2a)

[0158] Compound 1a (790.0 mg, 2.00 mmol) was dissolved in super dry dichloromethane (10 mL), triethylamine (606.0 mg, 6.00 mmol) was added, and triphosgene (593.4 mg, 2.00 mmol) was added portionwise, and the reaction was carried out at 0 °C for 15 minutes. The reaction was poured into anhydrous ethanol (10 mL), and concentrated under reduced pressure to obtain crude compound 2a (810.0 mg, 1.77 mmol) with a yield of 88.6%.

[0159] MS m / z (ESI): 458.4 [M+H] + .

[0160] Second step

[0161] 1 -((S)-1 -(4-(2-chloro-8,9-dihydropyrazolo[1,5-a]pyrimido[2,3- e]pyrimidin-6(7H)-yl)phenyl)-2,2,2-trifluoroethyl)-1 -methyl-3-(5- oxopyrrolidin-3-yl)urea (Compound 2)

[0162] Compound 2a (58.0 mg, 0.126 mmol), Compound 2b (12.6 mg, 0.126 mmol) were dissolved in anhydrous DMF (3 mL), potassium carbonate (52.2 mg, 0.38 mmol) was added, and the reaction was heated at 70 °C for 1 h. The crude product was concentrated under reduced pressure, and the crude product was purified by HPLC to obtain Compound 2 (26.0 mg, 0.05 mmol) with a yield of 39.7%.

[0163] Compound 2 was resolved by a chiral column (Chromolith® column ChiralPak OJ (100 x 4.6 mm I.D., 3 μm), mobile phase: A: supercritical CO2 fluid, B: isopropanol (0.1% diethanolamine); column temperature: 40 °C; flow rate: 3.0 mL / min) to obtain a compound with a retention time of 3.039 min (this compound is defined as Compound 2-1) and a compound with a retention time of 3.300 min (this compound is defined as Compound 2-2).

[0164] Compound 2-1:

[0165] MS m / z (ESI): 522.7 [M+H] + ;

[0166] 1 H NMR (400 MHz, DMSO-d6) δ 8.30 (s, 1H), 7.57 (s, 1H), 7.40 - 7.18 (m, 4H), 6.97 (d, J = 6.5 Hz, 1H), 6.82 (s, 1H), 6.29 (q, J = 9.4 Hz, 1H), 4.36 (dq, J = 13.4, 6.5 Hz, 1H), 3.75 - 3.66 (m, 2H), 3.52 (dd, J = 9.9, 7.3 Hz, 1H), 3.18 - 3.01 (m, 3H), 2.70 (s, 3H), 2.43 (dd, J = 16.8, 8.6 Hz, 1H), 2.18 (dd, J = 16.8, 5.8 Hz, 1H), 2.01 - 1.84 (m, 2H).

[0167] Compound 2-2:

[0168] MS m / z (ESI): 522.7 [M+H] + ;

[0169] 1H NMR (400 MHz, DMSO-d6) δ 8.30 (s, 1H), 7.56 (s, 1H), 7.41 - 7.18 (m, 4H), 6.95 (d, J = 6.4 Hz, 1H), 6.82 (s, 1H), 6.28 (q, J = 9.4 Hz, 1H), 4.35 (p, J = 6.6 Hz, 1H), 3.78 - 3.65 (m, 2H), 3.50 (dd, J = 9.9, 7.3 Hz, 1H), 3.16 - 2.96 (m, 3H), 2.70 (s, 3H), 2.48 - 2.37 (m, 1H), 2.20 (dd, J = 16.8, 5.7 Hz, 1H), 1.96 (t, J = 5.4 Hz, 2H).

[0170] Example 3

[0171] N-[(1S)-1-[4-(2-chloro-6,7,8,9-tetrahydropyrido[2,3-e]pyrazolo[1,5-a]pyrimidin-6- yl)phenyl]-2,2,2-trifluoroethyl]-1-{[(3R)-tetrahydrofuran-3-yl]amino}-N-methylmethanamide (3)

[0172] Compound 2a (30.0 mg, 0.065 mmol), compound 3b (5.7 mg, 0.065 mmol) were dissolved in N,N-dimethylformamide (2.0 mL) at room temperature, N,N- diisopropylethylamine (0.032 mL, 0.196 mmol) was added to the mixed solution, stirred at room temperature for 2 h. The reaction solution was directly prepared by high performance liquid chromatography to obtain compound 3 (1.0 mg, yield 3.0%).

[0173] MS m / z (ESI): 509.1 [M+H] + .

[0174] 1 H NMR (400 MHz, DMSO-d6) δ 8.30 (s, 1H), 7.56 (s, 1H), 7.41 - 7.18 (m, 4H), 6.95 (d, J = 6.4 Hz, 1H), 6.82 (s, 1H), 6.28 (q, J = 9.4 Hz, 1H), 4.35 (p, J = 6.6 Hz, 1H), 3.78 - 3.65 (m, 2H), 3.50 (dd, J = 9.9, 7.3 Hz, 1H), 3.16 - 2.96 (m, 3H), 2.70 (s, 3H), 2.48 - 2.37 (m, 1H), 2.20 (dd, J = 16.8, 5.7 Hz, 1H), 1.96 (t, J = 5.4 Hz, 2H).

[0175] Example 4

[0176] N-[(1S)-1-[4-(2-chloro-6,7,8,9-tetrahydropyrido[2,3-e]pyrazolo[1,5-a]pyrimidin-6-yl)phenyl]-2,2,2-trifluoroethyl]-1-{[(3S)-tetrahydrofuran-3-yl]amino}-N-methylmethanamide (4)

[0177] Compound 2a (40.0 mg, 0.087 mmol), compound 4b (7.6 mg, 0.087 mmol) were dissolved in N,N-dimethylformamide (2.0 mL) at room temperature, N,N-diisopropyl ethylamine (0.04 mL, 0.26 mmol) was added to the mixed solution, stirred at room temperature for 2 h. The reaction solution was directly prepared by high performance liquid chromatography to obtain compound 4 (2.7 mg, yield 6.06%).

[0178] MS m / z (ESI): 509.1 [M+H] + .

[0179] 1 H NMR (400 MHz, DMSO-d6) d 8.30 (s, 1H), 7.38 - 7.18 (m, 4H), 6.82 (s, 1H), 6.69 (d, J = 6.0 Hz, 1H), 6.30 (q, J = 9.4 Hz, 1H), 4.22 (dtd, J = 12.2, 6.1, 3.1 Hz, 1H), 3.85 - 3.75 (m, 2H), 3.74 - 3.62 (m, 3H), 3.48 (dd, J = 8.8, 4.6 Hz, 1H), 3.10 (t, J = 6.7 Hz, 2H), 2.70 (s, 3H), 2.09 (dtd, J = 12.5, 7.9, 6.6 Hz, 1H), 1.95 (dp, J = 10.1, 3.9 Hz, 2H), 1.90 - 1.78 (m, 1H).

[0180] Example 5

[0181] 1-((S)-1-(4-(2-chloro-8,9-dihydropyrazolo[1,5-a]pyrido[2,3-e]pyrimidin-6(7H)-yl)phenyl)-2,2,2-trifluoroethyl)-1-methyl-3-(4-oxo-5-azaspiro[2.4]heptan-7-yl)urea (5)

[0182] Compound 2a (40.0 mg, 0.087 mmol), compound 5b (12.1 mg, 0.096 mmol) were dissolved in N,N-dimethylformamide (4.0 mL), followed by the addition of potassium carbonate (36.2 mg, 0.26 mmol). Stirring at 70 °C for half an hour. Concentration under reduced pressure to obtain a crude product, which was purified by HPLC to obtain compound (11.1 mg, 0.020 mmol), with a yield of 23.21%.

[0183] MS m / z (ESI): 548.2 [M+H] + .

[0184] Examples 6-1 and 6-2

[0185] N-(((S)-1-(4-((2-chloro-7-((S)-1-methoxyethyl)pyrazolo[1,5-a]pyrimidin-6-yl)amino)phenyl)-2,2,2-trifluoroethyl)-N-methyl-2-((S)-5-oxopyrrolidin-3-yl)acetamide 6-1 and N-((S)-1-(4-((2-chloro-7-(S)-1-methoxyethyl)pyrazolo[1,5-a]pyrimidin-6-yl)amino)phenyl)-2,2,2-trifluoroethyl)-N-methyl-2-(R)-5-oxopyrrolidin-3-yl)acetamide 6-2

[0186] First step

[0187] (S)-N-(1-(4-bromophenyl)-2,2,2-trifluoroethyl)formamide (compound 6f)

[0188] (1S)-1-(4-bromophenyl)-2,2,2-trifluoroethylamine hydrochloride 6e (10.0 g, 34.42 mmol, commercially available) was dissolved in toluene (30 mL), and formic acid (15.7 g, 0.34 mol) was added. The reaction was heated to 120 °C and refluxed overnight. The reaction was concentrated under reduced pressure to obtain a crude compound 6f (9.0 g, 31.91 mmol).

[0189] MS m / z (ESI): 281.9 [M+H] + .

[0190] Second step

[0191] (S)-1-(4-bromophenyl)-2,2,2-trifluoro-N-methyl ethanol-1-amine (compound 6g)

[0192] Compound 6f (9.0 g, 31.91 mmol) was dissolved in tetrahydrofuran (30 mL), and borane dimethyl sulfide (140 mL, 3088.81 mmol) was added dropwise at room temperature, and the reaction was allowed to proceed overnight at room temperature. The reaction was quenched by slowly adding methanol (30 mL) dropwise, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (PE:EtOAc = 20:1) to obtain compound 6g (8.2 g, 30.71 mmol) with a yield of 96.2%.

[0193] MS m / z (ESI): 269.7 [M+H] + .

[0194] Third step

[0195] (S)-(1-(4-bromophenyl)-2,2,2-trifluoroethyl)(methyl)carbamate (compound 6b)

[0196] Compound 6g (8.2 g, 30.71 mmol) was dissolved in dichloromethane (40 mL), and di-tert-butyl dicarbonate (10.0 g, 45.71 mmol), dimethylamine pyridine (370.0 mg, 3.1 mmol), triethylamine (9.3 g, 92.14 mmol) were added, and the reaction was allowed to proceed overnight at 30°C. The reaction was concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (PE:EtOAc = 40:1) to obtain compound 6b (9.2 g, 25.07 mmol) with a yield of 81.6%.

[0197] MS m / z (ESI): 312.0 [M+H-56] + .

[0198] Fourth step (S)-1-(4-((2-chloro-7-((S)-1-methoxyethyl)pyrazolo[1,5-a]pyrimidin-6-yl)amino)phenyl)-2,2,2-trifluoroethyl)(methyl)carbamate (compound 6c)

[0199] Compound 6a (660.0 mg, 2.91 mmol) (prepared by referring to WO2018226150A1) was dissolved in 1,4-dioxane (40 mL), and then compound 6b (1608.1 mg, 4.37 mmol), K2CO3 (1608.1 mg, 4.37 mmol), and methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (243.4 mg, 0.29 mmol) were sequentially added, and the reaction was allowed to proceed overnight at 100°C with stirring. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (PE:EA = 97:3) to obtain compound 6c (1.07 g, 2.08 mmol) with a yield of 71.3%.

[0200] MS m / z (ESI): 514.3 [M+H] + .

[0201] Fifth step

[0202] 2-chloro-7-(((S)-1-methoxyethyl)-N-(4-(((S)-2,2-trifluoro-1-(methylamino)ethyl)phenyl)pyrazolo[1,5-a]

[0203] Pyrimidin-6-amine (Compound 6d)

[0204] Compound 6c (1.07 mg, 2.08 mmol) was dissolved in dichloromethane (6 mL), trifluoroacetic acid (3 mL) was added, and the reaction was allowed to proceed at room temperature for 3 hours. Saturated aqueous sodium bicarbonate solution (100 mL) was added, and after stirring at room temperature for 10 minutes, dichloromethane (60 mL) was added to extract the organic phase, which was then concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (PE:EtOAc = 90:10) to obtain compound 6d (630.0 mg, 1.53 mmol) with a yield of 73.4%. MS m / z (ESI): 414.3 [M+H] + .

[0205] Sixth step

[0206] N-((S)-1-(4-((2-chloro-7-((S)-1-methoxyethyl)pyrazolo[1,5-a]pyrimidin-6-yl)amino)phenyl)-2,2,2- trifluoroethyl)-N-methyl-2-((S)-5-oxopyrrolidin-3-yl)acetamide 6-1 and N-((S)-1-(4-((2-chloro-7-(S)-1- methoxyethyl)pyrazolo[1,5-a]pyrimidin-6-yl)amino)phenyl)-2,2,2-trifluoroethyl)-N-methyl-2-(R)-5- oxopyrrolidin-3-yl)acetamide 6-2

[0207] Compound 6d (41.0 mg, 0.10 mmol), compound 1b (15.7 mg, 0.11 mmol) were dissolved in dichloromethane (4.0 mL), followed by the addition of triethylamine (30.68 mg, 0.30 mmol). The mixture was stirred at room temperature for 10 minutes. Then T3P (101.5 mg, 0.30 mmol) was added, and the reaction was allowed to proceed at room temperature for 2 hours. The crude product was obtained by concentration under reduced pressure, and compound 6 (21.0 mg, 0.04 mmol) was obtained by purification by HPLC with a yield of 40.31%.

[0208] MS m / z (ESI): 539.4 [M+H] + .

[0209] Compound 6 was resolved by chiral column (chromatographic column ChiralPak AS-3 (100 x 4.6 mm I.D., 3 μm), mobile phase: A: supercritical CO2 fluid, B: methanol (0.1% diethanolamine); column temperature: 40 °C; flow rate: 3.0 mL / min) to give the compound with retention time of 2.876 min (as compound 6-1) and the compound with retention time of 3.101 min (as compound 6-2).

[0210] Compound 6-1:

[0211] MS m / z (ESI): 539.4 [M+H] + .

[0212] 1 H NMR (400 MHz, DMSO-d6) δ 8.54 (s, 1H), 7.79 (s, 1H), 7.49 (s, 1H), 7.19 (d, J = 8.2 Hz, 2H), 6.92 - 6.90 (m, 3H), 6.43 (q, J = 9.4 Hz, 1H), 5.27 (q, J = 6.7 Hz, 1H), 3.43 (dd, J = 9.4, 7.7 Hz, 1H), 3.16 (s, 3H), 2.88 (dd, J = 9.7, 6.1 Hz, 1H), 2.82 (s, 3H), 2.78 - 2.68 (m, 1H), 2.67 - 2.61 (m, 2H), 2.35 - 2.25 (m, 1H), 1.88 (dd, J = 16.5, 7.4 Hz, 1H), 1.59 (d, J = 6.7 Hz, 3H).

[0213] Compound 6-2:

[0214] MS m / z (ESI): 539.4 [M+H] + .

[0215] 1H NMR (400 MHz, DMSO-d6) δ 8.54 (s, 1H), 7.80 (s, 1H), 7.49 (s, 1H), 7.19 (d, J = 8.2 Hz, 2H), 6.92 - 6.90 (m, 3H), 6.42 (q, J = 9.3 Hz, 1H), 5.27 (q, J = 6.7 Hz, 1H), 3.46 - 3.37 (m, 1H), 3.16 (s, 3H), 2.90 (dd, J = 9.7, 6.1 Hz, 1H), 2.83 (s, 3H), 2.78 - 2.68 (m, 1H), 2.68 - 2.62 (m, 2H), 2.30 (dd, J = 16.5, 8.4 Hz, 1H), 1.86 (dd, J = 16.6, 7.4 Hz, 1H), 1.59 (d, J = 6.6 Hz, 3H).

[0216] Biological evaluation

[0217] The present disclosure is further described in the following test examples, which do not imply a limitation of the scope of the present disclosure.

[0218] Test Example 1, Test of inhibitory activity of the compounds of the present disclosure on diffuse large B-cell lymphoma (OCI-Ly3 and TMD8)

[0219] Human diffuse large B-cell lymphoma cell line OCI-Ly3 (Lot: CBP60265) was purchased from Nanjing Keye Biotechnology Co., Ltd., and TMD8 cells were purchased from ATCC.

[0220] 1.1, Experimental materials and instruments

[0221] Table 1, Experimental materials and instruments

[0222] 1.2, Experimental steps

[0223] OCI-Ly3 medium is IMDM + 20% FBS + 1% P.S. + 0.05mM β-mercaptoethanol, TMD8 medium is RPMI 1640 + 10% FBS + 1% P.S.. The above cells are cultured in a cell incubator at 37°C, 5% CO2. In 384-well plates, OCI-Ly3 cells are plated at a density of 2000 cells per well, and TMD8 cells are plated at a density of 3000 cells per well, and incubated in the incubator overnight. The next day, compound treatment is performed, with a maximum concentration of 30μM, 3-fold dilution, 9 concentrations, two replicates for each concentration, and a final concentration of DMSO of up to 0.3%. The cells are incubated in the incubator, and the OCI-Ly3 cells are treated with drugs for 3 days, and the TMD8 cells are treated with drugs for 4 days. The CTG Cell Viability Detection Reagent (MCE) is used to test cell viability, and the test method is consistent with the operation method provided in the kit. Readings are taken using the multifunctional microplate enzyme label instrument Envision. XLfit is used to process the data and calculate IC 50 .

[0224] Calculation formula: Y = Bottom + (Top-Bottom) / (1 + 10^((LogIC 50 -X)*HillSlope)). Where Y represents the cell proliferation inhibition rate (%); X represents the compound concentration; Bottom represents the minimum inhibition rate; Top represents the maximum inhibition rate; HillSlope represents the curve slope.

[0225] Table 2-1, IC 50 (nM)

[0226] Table 2-2, IC 50 (nM)

[0227] Test Example 2, Inhibitory activity of the compounds of the present disclosure on OCI-Ly3 cells

[0228] The inhibitory activity of the compounds of the present disclosure on OCI-Ly3 cells is tested according to the experimental method described in Test Example 1.

[0229] Compounds A1 and A2 are compound A The two isomers obtained after resolution are as follows: (compound 291 in patent WO2022106857A1), (compound 290 in patent WO2022106857A1).

[0230] Compound A was resolved by chiral column (chromatographic column ChiralPak AD (100 x 4.6 mm I.D., 3 pm), mobile phase: A: supercritical CO2 fluid, B: ethanol (0.1% diethanolamine); column temperature: 40 °C; flow rate: 3.0 mL / min), the compound with retention time of 3.183 min was defined as A1, and the compound with retention time of 3.302 min was defined as A2.

[0231] Compound B is compound 3.8 in patent WO2022081967A1, the structure of which is:

[0232] IC of compound A1 on OCI-Ly3 cells 50 is 1.43 times the IC of compound 6-2 on OCI-Ly3 cells 50 IC of compound A2 on OCI-Ly3 cells 50 is 1.59 times the IC of compound 6-2 on OCI-Ly3 cells 50 IC of compound B on OCI-Ly3 cells 50 is 18.2 times the IC of compound 6-2 on OCI-Ly3 cells 50 .

[0233] The experimental results show that the inhibitory activity of compound 6-2 of the present disclosure on OCI-Ly3 cells is better than that of compounds A1, A2 and B.

[0234] Test Example 3, inhibitory effect of compounds of the present disclosure on MALT1 enzyme activity

[0235] 3.1, reagents and consumables

[0236] Table 3, reagents and consumables

[0237] 3.2, experimental steps

[0238] Final test concentration of compound:

[0239] The final test concentration of the test compound is from 10 pM to 0.169 nM, with a 3-fold gradient dilution, 11 concentrations.

[0240] Dilute the 10 mM compound solution to 1 mM. Use ECHO to transfer the compound to the assay plate in increments of 2.5 nL, and spot the compound into the wells of the assay plate in a total volume of 100 nL DMSO. The final concentration of DMSO is 1% v / v.

[0241] Kinase detection:

[0242] Buffer preparation, buffer includes: 20mM Hepes, 1.5mM MgCl2, 10mM KCl, 10mM DTT, 0.01 Triton X-100 (v / v%), 1mM 2NA (EDTA . 2Na), 1M Trisodium Citrate.

[0243] MALT1 reaction:

[0244] Table 4, experimental conditions

[0245] 10ul of 2x MALT1 solution was added to the experimental plate using an Eppendorf 12 channel pipette, except for column 24, in which buffer was added. 10ul of 2x Ac-LRSR-MCA was added to each assay well of the experimental plate using an Eppendorf 12 channel pipette. Centrifugation at 1000rpm for 1 minute, followed by incubation at 23°C for 16 hours, then Evnvision detection, data acquisition.

[0246] Data analysis:

[0247] Data analysis and graphing was performed using XLfit 5 software mode 205, according to % inhibition vs. log [compound concentration].

[0248] Y = (A + ((B-A) / (1+((C / x)^D)))), where Y represents the inhibition rate; X represents the compound concentration; A represents the minimum inhibition rate; B represents the maximum inhibition rate; C represents the IC 50 value; D represents the slope of the fitted curve

[0249] Table 5, IC 50 (nM) of the compounds of the present disclosure on MALT1 enzyme inhibition

[0250] The data shows that the compounds of the present application have significant MALT1 enzyme activity inhibition activity.

[0251] Test Example 4, time-dependent inhibition (TDI) of the compounds of the present disclosure on each P450 enzyme in human liver microsomes

[0252] 4.1, preparation of test compound stock solution and human liver microsomes (HLM) information

[0253] The concentration of the test compound DMSO stock solution was 10mM, which was then diluted to 1mM using DMSO. The final concentration of the test compound was 10μM.

[0254] Human liver microsomes information:

[0255] 4.2. Preparation of positive inhibitor

[0256] Table 6. Concentration of positive inhibitor

[0257] 4.3. Preparation of substrate stock solution

[0258] Table 7. Preparation of substrate stock solution

[0259] 4.4. Preparation of phosphate buffer (100 mM, pH 7.4)

[0260] A solution preparation: weigh 7.098 g of disodium hydrogen phosphate into 500 mL of pure water, and sonicate to dissolve. B solution preparation: weigh 3.400 g of potassium dihydrogen phosphate into 250 mL of pure water, and sonicate to dissolve. Place solution A on a stirrer, and slowly add solution B into solution A until the pH value reaches 7.4.

[0261] 4.5. Preparation of 10 mM NADPH solution

[0262] Dissolve 8.334 mg / mL NADPH in phosphate buffer, and use freshly prepared NADPH solution for the test.

[0263] 4.6. Preparation of HLM mixed solution and substrate mixed solution

[0264] Table 8-1. Preparation method of HLM mixed solution

[0265] Table 8-2. Preparation method of substrate mixed solution

[0266] 4.7. Experimental procedure

[0267] 1) Pre-incubation

[0268] Add 89 μL of microsomal mixed solution, 1.0 μL of test substance solution or standard inhibitor solution into a new pre-incubation plate. Add 10 μL of 10 mM NADPH solution into the left half of the pre-incubation plate, and add an equal amount of phosphate buffer into the right half, and start the reaction. Pre-incubate at 37°C for 30 minutes.

[0269] 2) Second incubation

[0270] Take 10 μL pre-incubation solution into pre-heated 80 μL substrate mixture, then add 10 μL NADPH in the second incubation plate. Incubate at 37°C for 15 minutes. Add 150 μL quenching solution, 3% formic acid, 200 nM alprazolam (purchased from Sigma), 200 nM labetalol (purchased from China Institute for Drug Control) and 200 nM tolbutamide (purchased from Sigma) in cold acetonitrile to stop the reaction. Centrifuge at 4°C, 3220g for 50 minutes. Transfer 150 μL supernatant to a new plate. Dilute the supernatant with 150 μL pure water, mix well and analyze by UPLC-MS / MS.

[0271] Data processing:

[0272] Calculate the peak area of all samples and internal standard peak area automatically and import into Excel software.

[0273] Evaluate the degree of inhibition of human liver microsomal cytochrome P450 enzymes by comparing the reduction of specific probe substrate metabolites in sample groups with the solvent control group (100% activity). Compare the average of enzyme activity at each concentration (as a percentage of the uninhibited control group) with the inhibitor concentration.

[0274] Calculate the percentage of residual activity using the following formula:

[0275] Peak area ratio = Peak area 受试物 / Peak area 内标

[0276] Percentage of residual activity (%) = Peak area ratio 受试物 / Peak area ratio 空白 x 100

[0277] Percentage of inhibition (%) = 100 - Percentage of residual activity (%)

[0278] Calculate the time-dependent inhibition of each P450 enzyme in human liver microsomes as follows:

[0279] Percentage of activity (%) = Peak area ratio test substance + NADPH pre-incubation / Peak area ratio average 加NADPH预孵育 空白加 NADPH预孵育

[0280] Percentage of activity (%) without NADPH pre-incubation = Peak area ratio test substance without NADPH pre-incubation / Peak area ratio average 空白不 加NADPH预孵育

[0281] Predict irreversible IC using the following formula: 50 ​​

[0282] Predictable irreversible IC 50 = [I] x 10(50-%TDI) x 0.025

[0283] I in the formula is the concentration of the inhibitor in pre-incubation.

[0284] Table 9, TDI% of the compounds of the disclosure on CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A-M at a concentration of 10 μM

[0285] The structure of compound C is After resolution, 4 isomers are obtained (compound 280 in patent WO2022106857A1), (compound 279 in patent WO2022106857A1);

[0286] Compound C is resolved by chiral column (chromatographic column ChiralPak AD (100 x 4.6 mm I.D., 3 μm), mobile phase: A: supercritical CO2 fluid, B: ethanol (0.1% diethanolamine); column temperature: 40 °C; flow rate: 3.0 mL / min), the compound with retention time of 2.747 min is defined as C1, the compound with retention time of 2.940 min is defined as C2, the compound with retention time of 3.022 min is defined as C3, and the compound with retention time of 3.394 min is defined as C4.

[0287] The experimental results show that:

[0288] Compound 6, 6-1 and 6-2 have no inhibition on CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A-M (TDI (%) <20).

[0289] The compounds of the disclosure show better safety compared to patent compounds A and C, and isomers A1, A2 of A and isomers C1, C2, C3, C4 of C, suggesting that no CYP enzyme-based metabolic drug interactions will occur.

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein, X1is selected from CH, N; X2is selected from CH, N, S; X3, X4are each independently selected from C, N; G is selected from O, NH, C(R C )(R C’ ), R C and R C’ are each independently selected from hydrogen, deuterium, halogen, hydroxyl, cyano; when G is selected from O or NH, ring A is selected from 4-9 membered cycloalkyl, 4-9 membered heterocycloalkyl; when G is selected from C(R C )(R C’ ), ring A is selected from provided that when ring A is selected from n is not 0; R 1 are each independently selected from the group consisting of deuterium, oxo, hydroxyl, cyano, halogen, C 1-3 alkyl, 3-5 membered cycloalkyl, 4-6 membered heterocycloalkyl, -S(=O)2-R 1-3 , -S(=O)(=NH)-R 7 , -C(=O)-R 7 , -C(=O)N(R 1-3 )-R 1-3 alkyl, 3-5 membered cycloalkyl, 4-6 membered heterocycloalkyl optionally substituted with one or more substituents independently selected from the group consisting of R A ; and R A is selected from the group consisting of deuterium, oxo (=O), halogen, C 1-3 alkyl, deuterated C 1-3 alkyl, C 1-3 alkyl, hydroxyl, cyano, -S(=O)2-R 7 , -S(=O)(=NH)-R 7 ; R 2 each independently is selected from halogen, cyano, C 1-3 alkyl, C 1-3 alkoxy, 3- to 5-membered cycloalkyl, 4- to 6-membered heterocycloalkyl, said C 1-3 alkyl, C 1-3 alkoxy, 3- to 5-membered cycloalkyl, 4- to 6-membered heterocycloalkyl optionally substituted with one or more deuterium atoms; R 3 selected from hydrogen, C 1-3 alkyl, deuterated C 1-3 alkyl; R 4 selected from hydrogen, C 1-3 alkyl, C 1-3 alkoxy, the C 1-3 alkyl, C 1-3 alkoxy is optionally substituted with one or more substituents selected from halogen, oxo (=0), deuterium, hydroxyl, cyano, C 1-3 alkoxy, deuterated C 1-3 alkoxy, C 1-3 alkyl; Or R 3 and R 4 Together with the atoms it is attached to, they form a 4-8 membered ring, which is optionally composed of one or more independently selected from R. B The substituents replaced by R B Selected from deuterium, halogens, C 1-3 Alkyl, C 1-3 Alkoxy, 3-5 membered cycloalkyl, 4-6 membered heterocycloalkyl, wherein C 1-3 Alkyl, C 1-3 The alkoxy group, 3-5 membered cycloalkyl group, and 4-6 membered heterocycloalkyl group may be optionally substituted with one or more halogens; preferably, the 4-8 membered ring is selected from 4-8 membered heterocycloalkyl group and 4-8 membered heteroaryl group. R 5 selected from halogen, deuterium, C 1-3 alkyl, C 1-3 alkoxy, said C 1-3 alkyl, C 1-3 alkoxy is optionally substituted with one or more substituents selected from deuterium and halogen; R 6 selected from C 1-3 alkyl, deuterated C 1-3 alkyl; R 7 selected from C 1-3 alkyl, 3- to 5-membered cycloalkyl, said C 1-3 alkyl, 3- to 5-membered cycloalkyl, optionally substituted with one or more substituents selected from halogen and C 1-3 alkoxy; m is selected from 0, 1 or 2; n is selected from 0, 1 or 2.

2. The compound of formula (I) according to claim 1, wherein, or a pharmaceutically acceptable salt thereof. Formula (I) is selected from Formula (I-1), Formula (I-2): wherein X1, X2, X3, X4, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , n, m, ring A are as defined in claim 1.

3. The compound of formula (I) according to claim 1, wherein, ###0001### or a pharmaceutically acceptable salt thereof. Formula (I) is selected from Formula (I-3): wherein X1, X2, X3, X4, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R C , R C’ , n, m, ring A are as defined in claim 1.

4. The compound of Formula (I) according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein, X2is CH, X3is C, X4is N; or, X2is CH, X3is N, X4is C.

5. The compound of Formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, wherein, R 3 selected from hydrogen, methyl, deuterated methyl.

6. The compound of Formula (I) according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein, R 4 is selected from methyl, ethyl, said methyl, ethyl being optionally substituted with one or more substituents selected from C 1-3 alkoxy, deuterated C 1-3 alkoxy, C 1-3 alkyl; preferably, R 4 is selected from methyl, ethyl, said methyl, ethyl being optionally substituted with one or more substituents selected from methyl, methoxy; more preferably, R 4 is selected from more preferably, R 4 is selected from 7. The compound of Formula (I) according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein, R 3 and R 4 together with the atom to which they are attached form a 4-8 membered ring, which is optionally substituted with one or more substituents independently selected from R B , said R B is selected from deuterium, methyl, said methyl being optionally substituted with one or more halogen; Preferably, R 3 and R 4 Together with the atoms attached thereto, they form a 5-membered ring or a 6-membered ring, wherein the 5-membered ring or the 6-membered ring is optionally selected independently from R. B The substituents replaced by R B Selected from deuterium and methyl, wherein the methyl group is optionally substituted with one or more halogens; More preferably, R 3 and R 4 form, together with the atom to which they are attached, a 5- or 6-membered ring, which is optionally substituted with one or more substituents independently selected from R B , said R B is selected from methyl, trifluoromethyl.

8. The compound of Formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, wherein, selected from R 5 as defined in claim 1.

9. The compound of Formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 8, wherein, R 2 selected from fluorine, chlorine, bromine, methyl, methoxy, -OCD3; Preferably, R 2 selected from fluoro, chloro, methyl; Most preferably, R 2 is selected from fluoro or chloro.

10. The compound of Formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 9, wherein, m is selected from 0 or 1; preferably, m is 0.

11. The compound of Formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 10, wherein, R 6 is selected from methyl, deuterated methyl; preferably, R 6 is selected from methyl.

12. The compound of Formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 11, wherein, R 5 selected from halogen, methyl, deuterated methyl; preferably, R 5 is selected from F, CI, methyl.

13. The compound of Formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 12, wherein, Formula (I) is selected from Formula (I-4), Formula (I-5), Formula (I-7), Formula (I-8): wherein R 1 , n, ring A are as defined in claim 1.

14. The compound of Formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 12, wherein, Formula (I) is selected from Formula (I-6), Formula (I-9), Formula (I-10): wherein R C , R C’ , R 1 , n, ring A are as defined in claim 1.

15. The compound of Formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 14, wherein, Ring A is selected from 16. The compound of Formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 15, wherein, R 1 each independently selected from cyclopropyl, hydroxy, oxo, -S(=0)2-R 7 , -S(=0)(=NH)-R 7 wherein R 7 is as defined in claim 1 ; n is selected from 0, 1 or 2.

17. The compound of Formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 16, wherein, R 7 selected from methyl, ethyl, cyclopropyl.

18. The compound of Formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 17, wherein, R C , R C’ are each independently selected from hydrogen.

19. The compound of Formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 18, wherein, selected from 20. The compound of Formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 19, wherein the compound is selected from:

21. An isotopically-substituted compound of Formula (I) according to any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof; preferably, the isotope is deuterium.

22. A pharmaceutical composition comprising a compound of Formula (I) according to any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, or an isotopically-substituted compound according to claim 21, and one or more pharmaceutically acceptable carriers, diluents or excipients.

23. Use of a compound of Formula (I) according to any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, or an isotopically-substituted compound according to claim 21, or a pharmaceutical composition according to claim 22, for the manufacture of a medicament for the treatment and / or prevention of a disease or disorder associated with MALT1.

24. Use of a compound of Formula (I) according to any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, or an isotopically-substituted compound according to claim 21, or a pharmaceutical composition according to claim 22, for the manufacture of a medicament for the treatment and / or prevention of an autoimmune disease, an inflammatory disease, a cancer, a tumor; preferably, the cancer or tumor is a non-Hodgkin lymphoma; more preferably, the non-Hodgkin lymphoma is a diffuse large B-cell lymphoma.

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