A class of PRMT5 inhibitors and uses thereof

Abstract

The present invention provides a class of compounds having methyltransferase inhibitory activity, specifically, the present invention provides a class of compounds having PRMT5 inhibitory activity. The compounds can be used to prepare a pharmaceutical composition for treating diseases related to PRMT5 activity.

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical compounds. Specifically, the present invention provides a class of compounds for inhibiting PRMT5, and use thereof in pharmaceutical compositions. Background Art

[0002] Epigenetic regulation of gene expression is an important biological determinant of protein production and cellular differentiation and plays a major pathogenic role in many human diseases.

[0003] Epigenetic regulation involves heritable modifications of genetic material without changing its nucleotide sequence. Typically, epigenetic regulation is mediated by selective and reversible modifications (e.g., methylation) of DNA and proteins (e.g., histones) that control conformational transitions between transcriptionally active and inactive states of chromatin. These covalent modifications can be controlled by enzymes such as methyltransferases (e.g., PRMT5), many of which are associated with specific genetic alterations that may cause human disease. PRMT5 plays a role in diseases such as proliferative, metabolic, and hematological disorders.

[0004] PRMT5 is a known cellular essential gene, and conditional PRMT5 knockout and siRNA knockdown studies have shown that PRMT5 inhibition in normal tissues is associated with a range of diseases (e.g., pancytopenia, infertility, skeletal muscle loss, cardiac hypertrophy). Therefore, new strategies are needed to exploit this metabolic vulnerability and preferentially target PRMT5 in MTAP-null tumors while sparing PRMT5 in normal tissues (MTAPWT). Targeting PRMT5 with MTA-synergistic small molecule inhibitors can preferentially target the MTA-bound state of PRMT5, which is enriched in MTAP-null tumor cells, while providing a therapeutic index superior to normal cells with MTAP intact and low MTA levels.

[0005] Therefore, there is a need in the art to provide new small molecule compounds that target PRMT5 in MTAP-null tumors. Summary of the invention

[0006] The purpose of the present invention is to provide a new class of small molecule compounds targeting PRMT5 in MTAP-null tumors.

[0007] The first aspect of the present invention provides a compound as shown in the following formula I, or a pharmaceutically acceptable stereoisomer, salt or deuterated product thereof:

[0008]

[0009] in,

[0010] Ra is selected from the group consisting of:

[0011] W is O or S;

[0012] X1 and X2 are each independently selected from the following group: CR, N; X3 is N;

[0013] The L1 is selected from the following group: chemical bond, -O-, -CHR-, -C(R)R-;

[0014] Ring A is selected from the following group: substituted or unsubstituted 8-12 membered fused bicyclic heterocyclic group (including carbocyclic or heterocyclic ring, preferably pentahedral and hexacyclic ring), substituted or unsubstituted 7-10 membered fused bicyclic heteroaryl group (preferably pentahedral and hexacyclic ring);

[0015] R8 is selected from the group consisting of H, halogen, cyano, amino, nitro, hydroxyl, thiol, aldehyde, carboxyl, C2-C6 alkynyl, SF5, substituted or unsubstituted or halogenated C1-C6 alkyl, or R8 is

[0016] The L3 is selected from the following group: chemical bond, -O-, -CHR-, -C(R)R-, carbonyl, S, -NH-;

[0017] Ring B is selected from the following group: substituted or unsubstituted benzene ring, substituted or unsubstituted 5-6 membered heteroaromatic ring, substituted or unsubstituted C3-C6 carbon ring (including saturated or partially unsaturated), substituted or unsubstituted 3-7 membered heterocyclic ring (including saturated or partially unsaturated);

[0018] R2 is selected from the following group: R7, -L2R7; wherein, L2 is selected from the following group: -O-, -CHR-, -C(R)R-, carbonyl; wherein R7 is selected from the following group: hydrogen or none, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C 6-10 aromatic ring, substituted or unsubstituted 5-12 membered heteroaromatic ring, substituted or unsubstituted C3-C 10 Carbocyclic ring (including saturated or partially unsaturated, including monocyclic, condensed, spirocyclic or bridged ring), substituted or unsubstituted 3-10 membered heterocyclic ring (including saturated or partially unsaturated, including monocyclic, condensed, spirocyclic or bridged ring);

[0019] R3 is selected from the group consisting of H, halogen, cyano, substituted or unsubstituted C1-C6 alkyl;

[0020] R4 and R5 are each independently selected from the following group: H, halogen, cyano, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C3-C6 carbocycle (including saturated or partially unsaturated), substituted or unsubstituted 3-6 membered heterocycle; or R4 and R5 together with the connected ring atoms form a 5-12 membered saturated or unsaturated ring, and the ring may be substituted or unsubstituted;

[0021] R is H, halogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 alkoxy, substituted or unsubstituted C3-C6 cycloalkyl;

[0022] Unless otherwise specified, in the above formulae, the substitution refers to the substitution of hydrogen atoms on the corresponding groups by one or more substituents selected from the group consisting of deuterium, tritium, halogen, hydroxyl, carboxyl, mercapto, benzyl, C1-C 12 Alkoxycarbonyl, C1-C6 aldehyde, amino, C1-C6 amide, nitro, cyano, unsubstituted or halogenated C1-C6 alkyl, unsubstituted or halogenated C3-C8 cycloalkyl, C2-C 10 Alkenyl, C1-C6 alkoxy, C1-C6 alkyl-amino, C6-C 10 aryl, five-membered or six-membered heteroaryl, five-membered or six-membered non-aromatic heterocyclic group, -O-(C6-C 10 aryl), -O-(five-membered or six-membered heteroaryl), C1-C 12 Alkylaminocarbonyl, unsubstituted or halogenated C2-C 10 Acyl, sulfonyl (-SO2-OH), phosphoryl (-PO3-OH), unsubstituted or halogenated C1-C4 alkyl-S(O)2-, unsubstituted or halogenated C1-C4 alkyl-SO-.

[0023] Another aspect of the present invention provides a compound as shown in the following formula I, or a pharmaceutically acceptable stereoisomer salt or deuterated product thereof:

[0024]

[0025] in,

[0026] Ra is selected from the group consisting of:

[0027] W is O or S;

[0028] X1 and X2 are each independently selected from the following group: CR, N;

[0029] The L1 is selected from the following group: chemical bond, -O-, -CHR-, -C(R)R-;

[0030] Ring A is selected from the following group: substituted or unsubstituted 8-12 membered fused bicyclic heterocyclic group (including carbocyclic or heterocyclic ring, preferably pentahedral and hexacyclic ring), substituted or unsubstituted 7-10 membered fused bicyclic heteroaryl group (preferably pentahedral and hexacyclic ring);

[0031] R8 is selected from the group consisting of H, deuterium, halogen, cyano, amino, nitro, hydroxyl, thiol, aldehyde, carboxyl, C2-C6 alkynyl, SF5, substituted or unsubstituted or halogenated C1-C6 alkyl, unsubstituted or halogenated C1-C6 alkoxy, or R8 is

[0032] The L3 is selected from the following group: chemical bond, -O-, -CHR-, -C(R)R-, carbonyl, S, -NH-;

[0033] Ring B is selected from the following group: substituted or unsubstituted benzene ring, substituted or unsubstituted 5-6 membered heteroaromatic ring, substituted or unsubstituted C3-C6 carbon ring (including saturated or partially unsaturated), substituted or unsubstituted 3-7 membered heterocyclic ring (including saturated or partially unsaturated);

[0034] R is H, halogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 alkoxy, substituted or unsubstituted C3-C6 cycloalkyl;

[0035] R2 is selected from the following group: R7, -L2R7; wherein, L2 is selected from the following group: -O-, -CHR-, -C(R)R-, carbonyl; wherein R7 is selected from the following group: hydrogen or none, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C 6- C 10 aromatic ring, substituted or unsubstituted 5-12 membered (preferably 5-6 membered or 8-10 membered) heteroaromatic ring, substituted or unsubstituted C3-C 10 Carbocyclic ring (including saturated or partially unsaturated, including monocyclic, condensed, spirocyclic or bridged ring), substituted or unsubstituted 3-10 membered heterocyclic ring (including saturated or partially unsaturated, including monocyclic, condensed, spirocyclic or bridged ring);

[0036] R9 is selected from the following group: deuterium, tritium, halogen, hydroxyl, carboxyl, substituted or unsubstituted or halogenated C1-C6 alkyl, substituted or unsubstituted or halogenated C1-C6 alkoxy, substituted or unsubstituted C1-C6 alkyl-OH, -NH(substituted or unsubstituted or halogenated C1-C6 alkyl), -N(substituted or unsubstituted or halogenated C1-C6 alkyl)2.

[0037] Another aspect of the present invention provides a compound as shown in the following formula I, or a pharmaceutically acceptable stereoisomer, salt or deuterated product thereof:

[0038]

[0039] Wherein, the Ra has a structure as shown in the following formula:

[0040]

[0041] W is O or S;

[0042] The L1 is selected from the following group: -CHR-, -C(R)R-;

[0043] Ring A is selected from the following group: substituted or unsubstituted 8-12 membered fused bicyclic heterocyclic group (including carbocyclic or heterocyclic ring, preferably pentahedral and hexacyclic ring), substituted or unsubstituted 7-10 membered fused bicyclic heteroaryl group (preferably pentahedral and hexacyclic ring);

[0044] R8 is selected from the group consisting of H, deuterium, halogen, cyano, amino, nitro, hydroxyl, thiol, aldehyde, carboxyl, C2-C6 alkynyl, SF5, substituted or unsubstituted or halogenated C1-C6 alkyl, unsubstituted or halogenated C1-C6 alkoxy;

[0045] R2 is selected from the following group: R7, -L2R7; wherein, L2 is selected from the following group: -O-, -CHR-, -C(R)R-, carbonyl; wherein R7 is selected from the following group: hydrogen or none, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C 6- C 10 aromatic ring, substituted or unsubstituted 5-12 membered (preferably 5-6 membered or 8-10 membered) heteroaromatic ring, substituted or unsubstituted C3-C 10 Carbocyclic ring (including saturated or partially unsaturated, including monocyclic, condensed, spirocyclic or bridged ring), substituted or unsubstituted 3-10 membered heterocyclic ring (including saturated or partially unsaturated, including monocyclic, condensed, spirocyclic or bridged ring);

[0046] R9 is selected from the group consisting of deuterium, tritium, halogen, hydroxy, carboxyl, substituted or unsubstituted or halogenated C1-C6 alkyl, substituted or unsubstituted or halogenated C1-C6 alkoxy, substituted or unsubstituted C1-C6 alkyl-OH, -NH(substituted or unsubstituted or halogenated C1-C6 alkyl), -N(substituted or unsubstituted or halogenated C1-C6 alkyl)2;

[0047] R is H, deuterium, halogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 alkoxy, substituted or unsubstituted C3-C6 cycloalkyl;

[0048] Unless otherwise specified, in the above formulae, the substitution refers to the substitution of hydrogen atoms on the corresponding groups by one or more substituents selected from the group consisting of deuterium, tritium, halogen, hydroxyl, carboxyl, mercapto, benzyl, C1-C 12 Alkoxycarbonyl, C1-C6 aldehyde, amino, C1-C6 amide, nitro, cyano, unsubstituted or halogenated C1-C6 alkyl, unsubstituted or halogenated C3-C8 cycloalkyl, C2-C 10 Alkenyl, C1-C6 alkoxy, C1-C6 alkyl-amino, C6-C10 aryl, five-membered or six-membered heteroaryl, five-membered or six-membered non-aromatic heterocyclic group, -O-(C6-C 10 aryl), -O-(five-membered or six-membered heteroaryl), C1-C 12 Alkylaminocarbonyl, unsubstituted or halogenated C2-C 10 Acyl, sulfonyl (-SO2-OH), phosphoryl (-PO3-OH), unsubstituted or halogenated C1-C4 alkyl-S(O)2-, unsubstituted or halogenated C1-C4 alkyl-SO-, -SF5.

[0049] In another preferred embodiment, ring A has a structure selected from the following group:

[0050]

[0051] Wherein, the C ring is selected from the following groups: a substituted or unsubstituted benzene ring, a substituted or unsubstituted 5-6-membered heteroaromatic ring, a substituted or unsubstituted C3-C6 carbon ring (including saturated or partially unsaturated), and a substituted or unsubstituted 3-6-membered heterocyclic ring (including saturated or partially unsaturated).

[0052] In another preferred embodiment, the R2 is a substituted or unsubstituted benzene ring, a substituted or unsubstituted 5-6 membered heteroaromatic ring, preferably, R2 is selected from a substituted or unsubstituted group selected from the following group:

[0053]

[0054] The A ring is selected from the following group: a substituted or unsubstituted 8-12-membered fused bicyclic heterocyclic group (including a carbocyclic ring or a heterocyclic ring, preferably a pentahedral hexacyclic ring), a substituted or unsubstituted 7-10-membered fused bicyclic heteroaryl group (preferably a pentahedral hexacyclic ring); preferably, the A ring is selected from the following group:

[0055]

[0056] Wherein, the C ring is selected from the following group: a substituted or unsubstituted benzene ring, a substituted or unsubstituted 5-6 membered heteroaromatic ring; and R8 is CF3.

[0057] In another preferred embodiment, the R2 is selected from the following group: R7, -L2R7; wherein the L2 is selected from the following group: -O-, -CHR-, carbonyl, S, -NH-; wherein R7 is selected from the following group: substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C 6- C 10 Preferably, R7 is selected from the following groups: substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted benzene ring, substituted or unsubstituted 5-7 membered heteroaromatic ring.

[0058] In another preferred embodiment, R2 is selected from the following group: R7, -(CHR)R7; wherein R7 is selected from the following group: substituted or unsubstituted C 6- C 10 Preferably, the R2 is a substituted or unsubstituted 5-7 membered heteroaromatic ring; and the A ring is selected from the following group: a substituted or unsubstituted 7-10 membered fused bicyclic heteroaryl; and the R8 is CF3.

[0059] In another preferred embodiment, it has a structure as shown in the following formula:

[0060]

[0061] The L1 is -CH2-, -CD2-;

[0062] The R9 is selected from substituted or unsubstituted methyl, more preferably methyl, deuterated methyl, halogenated methyl;

[0063] The R2 is selected from the following group: a substituted or unsubstituted benzene ring, a substituted or unsubstituted 5-6 membered heteroaromatic ring, more preferably, R2 is selected from a substituted or unsubstituted group selected from the following group:

[0064]

[0065] The A ring is selected from the following group: a substituted or unsubstituted 8-12-membered fused bicyclic heterocyclic group (including a carbocyclic ring or a heterocyclic ring, preferably a pentahedral hexacyclic ring), a substituted or unsubstituted 7-10-membered fused bicyclic heteroaryl group (preferably a pentahedral hexacyclic ring); preferably, the A ring is selected from the following group:

[0066]

[0067] Wherein, the C ring is selected from the following group: substituted or unsubstituted benzene ring, substituted or unsubstituted 5-6 membered heteroaromatic ring; said R8 is CF3. In another preferred embodiment, it has the structure shown in the following formula:

[0068]

[0069] The L1 is -CH2-, -CD2-;

[0070] Ring A is selected from the group consisting of:

[0071] Wherein, the C ring is selected from the following group: a substituted or unsubstituted 5-6 membered heteroaromatic ring; said R8 is CF3;

[0072] The R9 is selected from substituted or unsubstituted methyl, more preferably methyl, deuterated methyl, halogenated methyl; preferably, the R2 is selected from the following group: substituted or unsubstituted 5-6 membered heteroaromatic ring, more preferably, R2 is selected from substituted or unsubstituted groups selected from the following group:

[0073]

[0074] In another preferred embodiment, the compound has a structure selected from the following table:

[0075] Table 1

[0076]

[0077]

[0078]

[0079] The absolute stereochemistry of the compounds of Table 1 is arbitrarily assigned (e.g., 2 & 3 are randomly assigned based on the order of chiral SFC separation). Compounds with stereogenic centers (where the configuration is not indicated in the depicted structure) and not assigned in the stereochemistry column of Table 1 are mixtures of enantiomers at that center.

[0080] The second aspect of the present invention provides a pharmaceutical composition, which contains a therapeutically effective amount of the compound as described in the first aspect of the present invention, its pharmaceutically acceptable salts, racemates, optical isomers, stereoisomers or tautomers, and one or more pharmaceutically acceptable carriers, excipients, adjuvants, auxiliary materials and / or diluents.

[0081] The third aspect of the present invention provides the use of the compound or composition as described in the first aspect of the present invention, its racemate, stereoisomer or pharmaceutically acceptable salt in the preparation of a drug for treating or preventing a disease associated with abnormal gene level or abnormal expression of PRMT5 (such as corresponding nucleic acid mutation, deletion, or abnormal MTAP gene level, or ectopic or fused or overexpressed methyltransferase); preferably, the disease is a malignant tumor or cancer, which can be selected from the following group: ovarian cancer, lung cancer, lymphoma, glioblastoma, colon cancer, melanoma, Malignant peripheral nerve sheath tumor (MPNST), esophageal cancer (e.g., esophageal squamous cell carcinoma or esophageal adenocarcinoma), bladder cancer (e.g., bladder cancer, urothelial carcinoma), mesothelioma, non-small cell lung cancer (NSCLC; e.g., lung squamous cell carcinoma or lung adenocarcinoma), astrocytoma, undifferentiated pleomorphic sarcoma, diffuse large B-cell lymphoma (DLBCL), leukemia, head and neck cancer, gastric adenocarcinoma, myxofibrosarcoma, cholangiosarcoma, and brain cancer, gastric cancer, kidney cancer, breast cancer, endometrial cancer, urinary tract cancer, liver cancer, soft tissue cancer, pleural cancer, and colorectal cancer or sarcoma.

[0082] It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features specifically described below (such as embodiments) can be combined with each other to form a new or preferred technical solution. Due to space limitations, they will not be described one by one here. DETAILED DESCRIPTION

[0083] The present inventors, through extensive and in-depth research, unexpectedly discovered for the first time a class of compounds with PRMT5 regulatory effects, and completed the present invention on this basis.

[0084] the term

[0085] In the present invention, the halogen is F, Cl, Br or I.

[0086] In the present invention, unless otherwise specified, the terms used have the general meanings known to those skilled in the art. In the present invention, if not otherwise specified, all chemical formulae are intended to cover any possible optical or geometric isomers (e.g., R-type, S-type or racemate, or cis-trans isomers of olefins, etc.).

[0087] In the present invention, the term "C1-C6 alkyl" refers to a straight or branched alkyl group having 1 to 6 carbon atoms, including but not limited to methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl and hexyl, etc.; preferably ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl.

[0088] In the present invention, the term "C1-C6 alkoxy" refers to a straight or branched alkoxy group having 1 to 6 carbon atoms, including but not limited to methoxy, ethoxy, propoxy, isopropoxy, butoxy and the like.

[0089] In the present invention, the term "C2-C6 alkenyl" refers to a straight or branched alkenyl group having 2 to 6 carbon atoms and containing one double bond, including but not limited to ethenyl, propenyl, butenyl, isobutenyl, pentenyl and hexenyl.

[0090] In the present invention, the term "C2-C6 alkynyl" refers to a straight or branched alkynyl group having 2 to 6 carbon atoms and containing one triple bond, including but not limited to ethynyl, propynyl, butynyl, isobutynyl, pentynyl and hexynyl.

[0091] In the present invention, the term "C3-C 10 "Cycloalkyl" refers to a cyclic alkyl group having 3 to 10 carbon atoms in the ring, including but not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and cyclodecyl. The terms "C3-C8 cycloalkyl", "C3-C7 cycloalkyl", and "C3-C6 cycloalkyl" have similar meanings.

[0092] In the present invention, the term "C3-C 10 The term "cycloalkenyl" refers to a cyclic alkenyl group having 3 to 10 carbon atoms in the ring, including but not limited to cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl and cyclodecenyl. The term "C3-C7 cycloalkenyl" has a similar meaning.

[0093] In the present invention, the term "C1-C 12 The term "alkoxycarbonyl" refers to an alkoxycarbonyl group having 1 to 12 carbon atoms in the alkyl chain, including but not limited to methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, tert-butoxycarbonyl, benzyloxycarbonyl and the like.

[0094] In the present invention, the term "C1-C 12 The term "alkylaminocarbonyl" refers to an alkylaminocarbonyl group having 1 to 12 carbon atoms in the alkyl chain, including but not limited to methylaminocarbonyl, ethylaminocarbonyl, propylaminocarbonyl, isopropylaminocarbonyl, tert-butylaminocarbonyl, benzylaminocarbonyl, dimethylaminocarbonyl and the like.

[0095] In the present invention, the term "aromatic ring" or "aryl group" has the same meaning, preferably "aryl group" is "C6-C 12 Aryl" or "C6-C 10 The term "C6-C 12 "Aryl" refers to an aromatic ring group having 6 to 12 carbon atoms without heteroatoms in the ring, such as phenyl, naphthyl, etc. The term "C6-C 10 "Aryl" has a similar meaning.

[0096] In the present invention, the term "aromatic heterocycle" or "heteroaryl" has the same meaning and refers to a heteroaromatic group containing one to multiple heteroatoms. The heteroatoms referred to here include oxygen, sulfur and nitrogen. For example, furanyl, thienyl, pyridyl, pyrazolyl, pyrrolyl, N-alkylpyrrolyl, pyrimidyl, pyrazinyl, imidazolyl, tetrazolyl, etc. The heteroaryl ring can be fused to an aryl, heterocyclic or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring. The heteroaryl group can be optionally substituted or unsubstituted.

[0097] In the present invention, the term "3-12 membered heterocyclic group" refers to a saturated or unsaturated 3-12 membered ring group containing 1 to 3 heteroatoms selected from oxygen, sulfur and nitrogen in the ring, such as dioxolanyl, etc. The term "3-7 membered heterocyclic group" has a similar meaning.

[0098] In the present invention, the term "substituted" means that one or more hydrogen atoms on a specific group are replaced by a specific substituent. The specific substituent is the substituent described above or the substituent appearing in the embodiments. Unless otherwise specified, a substituted group may have a substituent selected from a specific group at any substitutable position of the group, and the substituent may be the same or different at each position. A cyclic substituent, such as a heterocycloalkyl, may be connected to another ring, such as a cycloalkyl, to form a spirobicyclic system, for example, the two rings have a common carbon atom. It should be understood by those skilled in the art that the combinations of substituents contemplated by the present invention are those that are stable or chemically feasible. The substituents include, but are not limited to: C1-C8 alkyl, C 2- C8 alkenyl, C2-C8 alkynyl, C 3- C8 cycloalkyl, 3- to 12-membered heterocyclic group, aryl, heteroaryl, halogen, hydroxyl, carboxyl (-COOH), C1-C8 aldehyde, C2-C 10 Acyl, C2-C 10 Ester group, C1-C 12 Alkoxycarbonyl, amino, alkoxy, C1-C 10 Sulfonyl, etc.

[0099] When, for example, "C1-C8" or similar expressions are used, it means that the group can have 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms.

[0100] When, for example, "3-12 membered" or similar expressions are used, it means that the group may have 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 carbon atoms or heteroatoms as ring atoms.

[0101] PRMT5 modulator compounds

[0102] A compound shown in the following formula I, or a pharmaceutically acceptable stereoisomer, salt or deuterated product thereof:

[0103]

[0104] Wherein, the Ra has a structure as shown in the following formula:

[0105]

[0106] W is O or S;

[0107] The L1 is selected from the following group: -CHR-, -C(R)R-;

[0108] Ring A is selected from the following group: substituted or unsubstituted 8-12 membered fused bicyclic heterocyclic group (including carbocyclic or heterocyclic ring, preferably pentahedral and hexacyclic ring), substituted or unsubstituted 7-10 membered fused bicyclic heteroaryl group (preferably pentahedral and hexacyclic ring);

[0109] R8 is selected from the group consisting of H, deuterium, halogen, cyano, amino, nitro, hydroxyl, thiol, aldehyde, carboxyl, C2-C6 alkynyl, SF5, substituted or unsubstituted or halogenated C1-C6 alkyl, unsubstituted or halogenated C1-C6 alkoxy;

[0110] R2 is selected from the following group: R7, -L2R7; wherein, L2 is selected from the following group: -O-, -CHR-, -C(R)R-, carbonyl; wherein R7 is selected from the following group: hydrogen or none, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C 6- C 10 aromatic ring, substituted or unsubstituted 5-12 membered (preferably 5-6 membered or 8-10 membered) heteroaromatic ring, substituted or unsubstituted C3-C 10 Carbocyclic ring (including saturated or partially unsaturated, including monocyclic, condensed, spirocyclic or bridged ring), substituted or unsubstituted 3-10 membered heterocyclic ring (including saturated or partially unsaturated, including monocyclic, condensed, spirocyclic or bridged ring);

[0111] R9 is selected from the group consisting of deuterium, tritium, halogen, hydroxy, carboxyl, substituted or unsubstituted or halogenated C1-C6 alkyl, substituted or unsubstituted or halogenated C1-C6 alkoxy, substituted or unsubstituted C1-C6 alkyl-OH, -NH(substituted or unsubstituted or halogenated C1-C6 alkyl), -N(substituted or unsubstituted or halogenated C1-C6 alkyl)2;

[0112] R is H, deuterium, halogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 alkoxy, substituted or unsubstituted C3-C6 cycloalkyl;

[0113] Unless otherwise specified, in the above formulae, the substitution refers to the substitution of hydrogen atoms on the corresponding groups by one or more substituents selected from the group consisting of deuterium, tritium, halogen, hydroxyl, carboxyl, mercapto, benzyl, C1-C 12 Alkoxycarbonyl, C1-C6 aldehyde, amino, C1-C6 amide, nitro, cyano, unsubstituted or halogenated C1-C6 alkyl, unsubstituted or halogenated C3-C8 cycloalkyl, C2-C 10 Alkenyl, C1-C6 alkoxy, C1-C6 alkyl-amino, C6-C 10 aryl, five-membered or six-membered heteroaryl, five-membered or six-membered non-aromatic heterocyclic group, -O-(C6-C 10 aryl), -O-(five-membered or six-membered heteroaryl), C1-C 12Alkylaminocarbonyl, unsubstituted or halogenated C2-C 10 Acyl, sulfonyl (-SO2-OH), phosphoryl (-PO3-OH), unsubstituted or halogenated C1-C4 alkyl-S(O)2-, unsubstituted or halogenated C1-C4 alkyl-SO-, -SF5.

[0114] Pharmaceutical compositions and methods of administration

[0115] Since the compounds of the present invention have excellent methyltransferase inhibitory activity, the compounds of the present invention and their various crystal forms, pharmaceutically acceptable inorganic or organic salts, hydrates or solvates, and pharmaceutical compositions containing the compounds of the present invention as the main active ingredient can be used to treat, prevent and alleviate related diseases caused by abnormal activity or expression of methyltransferases (such as PRMT5).

[0116] The pharmaceutical composition of the present invention comprises a safe and effective amount of the compound of the present invention or a pharmacologically acceptable salt thereof and a pharmacologically acceptable excipient or carrier. Wherein "safe and effective amount" means: the amount of the compound is sufficient to significantly improve the condition without causing serious side effects. Usually, the pharmaceutical composition contains 1-2000 mg of the compound of the present invention per dose, and more preferably, contains 5-200 mg of the compound of the present invention per dose. Preferably, the "one dose" is a capsule or tablet.

[0117] "Pharmaceutically acceptable carrier" refers to: one or more compatible solid or liquid fillers or gel substances, which are suitable for human use and must have sufficient purity and sufficiently low toxicity. "Compatibility" here means that the components in the composition can be mixed with the compounds of the present invention and with each other without significantly reducing the efficacy of the compounds. Some examples of pharmaceutically acceptable carriers include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers (such as ), wetting agents (such as sodium lauryl sulfate), colorants, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0118] There is no particular limitation on the administration of the compound or pharmaceutical composition of the present invention. Representative administrations include, but are not limited to, oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration.

[0119] Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) fillers or extenders, for example, starches, lactose, sucrose, glucose, mannitol, and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose, and acacia; (c) humectants, for example, glycerol; (d) disintegrants, for example, agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) solubilizers, for example, paraffin; (f) absorption accelerators, for example, quaternary ammonium compounds; (g) wetting agents, for example, cetyl alcohol and glyceryl monostearate; (h) adsorbents, for example, kaolin; and (i) lubricants, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents.

[0120] Solid dosage forms such as tablets, pills, capsules, pills and granules can be prepared using coatings and shell materials, such as enteric coatings and other materials known in the art. They may contain opacifiers, and the release of the active compound or compounds in such compositions can be delayed in a certain part of the digestive tract. Examples of embedding components that can be used are polymeric substances and waxes. If necessary, the active compound can also be formed into microencapsulated form with one or more of the above-mentioned excipients.

[0121] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compound, the liquid dosage form may contain an inert diluent conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butylene glycol, dimethylformamide and oils, in particular cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances.

[0122] Besides such inert diluents, the composition may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[0123] Suspensions, in addition to the active compounds, may contain suspending agents such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methanol and agar, or mixtures of these substances, and the like.

[0124] Compositions for parenteral injection may include physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.

[0125] Dosage forms for topical administration of the compounds of the invention include ointments, powders, patches, sprays and inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be required.

[0126] The compounds of the present invention can be administered alone or in combination with other pharmaceutically acceptable compounds. In some preferred embodiments, the compounds of the present invention can be administered together with other small molecule compounds to form PROTAC, or together with other macromolecular compounds such as monoclonal antibodies to form ADC.

[0127] When using the pharmaceutical composition, a safe and effective amount of the compound of the present invention is applied to a mammal (such as a human) in need of treatment, wherein the dosage during administration is a pharmaceutically effective dosage, and for a person weighing 60 kg, the daily dosage is usually 1 to 2000 mg, preferably 5 to 500 mg. Of course, the specific dosage should also take into account factors such as the route of administration and the health status of the patient, which are all within the skill range of a skilled physician.

[0128] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are only used to illustrate the present invention and are not intended to limit the scope of the present invention. The experimental methods in the following examples without specifying specific conditions are usually based on conventional conditions or the conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are calculated by weight.

[0129] The definitions of each abbreviation are as follows:

[0130]

[0131] The raw materials can be obtained from commercial sources or prepared by methods known or disclosed in the art.

[0132] The purification of intermediates and compounds is carried out by normal phase or reverse phase chromatography or conventional chemical experimental operations such as recrystallization. Normal phase chromatography is pre-filled with silica gel chromatographic columns or preparative thin layer chromatography. Silica gel chromatographic columns are mainly glass columns or rapid preparative chromatographs. The mobile phase of normal phase chromatography is selected and proportioned from petroleum ether / ethyl acetate, dichloromethane / methanol or other suitable solvents for elution. Reverse phase preparative liquid chromatography uses a C18 column, and is carried out using a preparative liquid chromatograph or a rapid preparative chromatograph, 214nm and 254nm or preparative liquid chromatography-mass spectrometry instrument detection, and uses water / acetonitrile containing 0.1% hydrochloric acid, water / acetonitrile, water / acetonitrile containing 0.1% ammonium bicarbonate, water / acetonitrile containing 0.1% formic acid, 0.1% ammonia water / acetonitrile, 0.1% trifluoroacetic acid water / acetonitrile or other suitable solvent systems as mobile phases for gradient elution.

[0133] The structures of intermediates and compounds were characterized by nuclear magnetic resonance (NMR) and mass spectrometry (LCMS). The NMR spectrometer used for NMR was Bruker Ascend 400 or Varian 400 or ZKNJ BIXI-1 300MHz or Bruker Avance III 400MHz or Bruker AVANCE Neo 400MHz. The solvents used were deuterated dimethyl sulfoxide, deuterated chloroform, deuterated methanol or other deuterated solvents as noted. Spectral data were reported in the mode: chemical shift δ (peak splitting number, coupling constant J (Hz), number of hydrogens). Tetramethylsilane was used as an internal standard for chemical shift, and its chemical shift was set to zero (δ, 0ppm). The meanings of some abbreviations are: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), br (broad peak).

[0134] Representative methods for liquid chromatography-mass spectrometry (LCMS) in the structural characterization of intermediates and compounds are as follows:

[0135] Method 1: Agilent LC1260 system coupled to a 6120 single quadrupole mass spectrometer

[0136] Column: Waters CORTECS C-18, 2.7 μm, 4.6*30 mm. Solvent A: 0.05% formic acid in water, solvent 20B: 0.05% formic acid in acetonitrile, 5% acetonitrile to 95% acetonitrile in one minute, hold for one minute, 2.5 minutes in total; flow rate: 1.8 mL / min; column temperature 40°C.

[0137] Column: XSelect CSH C18, 3.5μm, 4.6*50mm. Solvent A: 0.05% ammonia solution, solvent B: 0.05% ammonia in acetonitrile solution, 5% acetonitrile to 95% acetonitrile within one minute, hold for one minute, a total of 2.5 minutes; flow rate: 1.8mL / min; column temperature 40℃.

[0138] Method 2: performed on an Agilent LC / MSD 1200 system coupled to a quadrupole mass spectrometer.

[0139] Column: ODS2000 (50×4.6 mm, 5 μm) (ES (+) or (-) ionization mode), temperature 30°C; flow rate 1.5 mL / min.

[0140] Representative SFC (supercritical fluid chromatography) chiral separation and chiral compound characterization equipment and methods:

[0141] Method 3:

[0142] Chromatographic column: DAICEL CHIRALPAK IC (250mm*30mm, 10um

[0143] Mobile phase: A:CO2 B:[MeOH(0.1%IPAM)]

[0144] Elution gradient: 40%

[0145] Method 4:

[0146] Chromatographic column: DAICEL CHIRALPAK AD (250mm*30mm, 10um);

[0147] Mobile phase: [ACN / EtOH (0.1% NH3H2O]; B%: 69%, 20 min, isocratic elution)

[0148] Method 5:

[0149] Chromatographic column: DAICEL CHIRALPAK AD (250mm*50mm, 10um);

[0150] Mobile phase: [CO2-EtOH (0.1% NH3H2O)]; B%: 55%, isocratic elution mode)

[0151] Representative preparative HPLC (high performance liquid chromatography) method:

[0152] Method 6:

[0153] Chromatographic column: Waters Xbridge BEH C18 100*30mm*10um; mobile phase: [H2O(10mM NH4HCO3)-ACN]; B%: 25%-55%, 8.0 minutes, UV 220&254nm.

[0154] Method 7:

[0155] Chromatographic column: Waters Xbridge BEH C18 250*50mm*10μm; mobile phase: [water (NH4HCO3 10mM)-ACN]; B%: 20%-45%, 10 minutes, UV 220&254nm.

[0156] Method 8:

[0157] Chromatographic column: Welch Xtimate C18 250*70mm#10μm; mobile phase: [water (NH4HCO3)-ACN]; B%: 20%-50%, 20 minutes, UV 220&254nm.

[0158] Embodiment Synthesis general method:

[0159]

[0160] General Method: Synthesis of Intermediate A5a and Intermediate A5b

[0161]

[0162] Intermediate A5 is a known compound. Intermediate A5 was separated by SFC (conditions: chromatographic column: DAICEL CHIRALPAKIC (250mm*30mm, 10um); mobile phase: [MeOH (0.1% IPAM)]; B%: 42%-42%, 15min) to obtain the first peak (peak 1) as a white solid intermediate A5a (600mg, 2.46mmol, 40.0% yield), and the second peak (peak 2) as a white solid intermediate A5b (600mg, 2.46mmol, 40.0% yield). Note: According to SFC separation, the first peak (peak 1) is A5a, and the second peak (peak 2) is A5b. The absolute configuration of the chiral center of the two compounds is randomly assigned.

[0163] Intermediate A5a: 1H NMR(400MHz,DMSO-d6)δppm:8.07(d,J=1.9Hz,1H),7.98(dd,J=1.9,8.8Hz,1H),7.54(d,J=8.8 Hz,1H),6.74(s,2H),5.47-5.35(m,2H),5.34-5.25(m,1H),1.41(d,J=6.0Hz,3H).LC-MS,[MH] + 245.0.SFC:RT=3.971min.

[0164] Intermediate A5b: 1 H NMR (400MHz, DMSO-d6) δppm: 8.05 (d, J = 1.8Hz, 1H), 7.98 (dd, J = 1.9, 8.8Hz, 1H), 7.52 (d, J = 8. 8Hz,1H),6.68(s,2H),5.46-5.35(m,2H),5.33-5.26(m,1H),1.41(d,J=6.1Hz,3H)LC-MS,[MH] + 245.0.SFC:RT=5.913min.

[0165] General Method: Synthesis of Intermediate B2

[0166] Synthesis route:

[0167]

[0168] Step 1: 2-Dichloromethyl-6-trifluoromethylimidazo[1,2-a]pyridine (3)

[0169] A mixture of 5-(trifluoromethyl)pyridin-2-amine (1) (30 g, 185 mmol, 1.0 eq), chlorobenzene (450 mL) and 1,1,3-trichloro-2-propanone (45 g, 277 mmol, 1.5 eq) was reacted at 135°C for 4 hours. The target product was detected by LCMS. The reaction solution was adjusted to pH 8 with sodium carbonate, extracted with ethyl acetate (500 mL*3), the organic phases were combined and dried over magnesium sulfate, the filtrate was filtered and concentrated to dryness under reduced pressure, and purified by column chromatography (silica, 15% ethyl acetate in petroleum ether) to obtain a yellow solid 2-dichloromethyl-6-trifluoromethylimidazo[1,2-a]pyridine (3) (30 g, 111 mmol, 60% yield). 1 H NMR (400MHz, DMSO-d6) δppm: 9.24 (s, 1H), 8.27 (s, 1H), 7.79 (d, J = 9.68Hz, 1H), 7.65 (s, 1H), 7.56 (dd, J = 1.65, 9.57Hz, 1H).

[0170] Step 2: 6-(Trifluoromethyl)imidazo[1,2-a]pyridine-2-carbaldehyde (4)

[0171] 2-Dichloromethyl-6-trifluoromethylimidazo[1,2-a]pyridine (3) (30 g, 111 mmol, 1.0 eq), water (600 mL), calcium carbonate (33 g, 334 mmol, 3.0 eq) were heated to 100 °C and reacted for 2 hours. LCMS detected the formation of the target product. Celite and ethyl acetate (600 mL) were added to the reaction solution, stirred at room temperature for 30 minutes, filtered, and extracted with ethyl acetate (600 mL*2). The combined organic phases were dried over magnesium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain a brown solid 6-(trifluoromethyl)imidazo[1,2-a]pyridine-2-carboxaldehyde (4) (35 g). The crude product was used directly in the next step without further purification. 1 HNMR (400MHz, CDCl3) δppm: 10.09-10.29 (m, 1H), 8.59 (s, 1H), 8.27 (s, 1H), 7.82 (br d, J = 9.46Hz, 1H), 7.44 (brd, J = 9.02Hz, 1H).

[0172] Step 3: 1-Methyl-N-((6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazol-4-amine (Intermediate B2)

[0173] To a solution of 6-(trifluoromethyl)imidazo[1,2-a]pyridine-2-carbaldehyde (4) (100 mg, 467 μmol, 1.0 eq) in DCM (2.00 mL) was added KOAc (91.7 mg, 934 μmol, 2.0 eq) and 1-methyl-1H-pyrazol-4-amine (45.4 mg, 467 μmol, 1.0 eq) at -5°C and the reaction mixture was stirred at -5°C for 1 hour. Then NaBH(OAc)3 (198 mg, 934 μmol, 2.0 eq) was added and stirred at -5°C for another 3 hours. LCMS showed complete consumption of the starting material and several new peaks were shown on LCMS. The reaction mixture was diluted with saturated Na2CO3 aqueous solution (3.00 mL) and extracted with dichloromethane (2.00 mL×4). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (ethyl acetate / methanol=8 / 1) to give 1-methyl-N-((6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazol-4-amine (Intermediate B2) (80.0 mg, 271 μmol, 58.0% yield) as a yellow solid. 1H NMR (400MHz, CDCl3) δppm: 8.47 (s, 1H), 7.69 (d, J = 9.5Hz, 1H), 7.64 (s, 1H), 7.35 (d, J=1.5,9.5Hz,1H),7.30(s,2H),6.97(s,1H),4.39(s,2H),3.81(s,3H); LC-MS,[MH] + 217.0.

[0174] General Method: Synthesis of Intermediate B3

[0175] Synthesis route:

[0176]

[0177] Step 1: 1,3-Dimethyl-N-((6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazol-4-amine (Intermediate B3)

[0178] 6-(Trifluoromethyl)imidazo[1,2-a]pyridine-2-carboxaldehyde (4) (10 g, 46 mmol, 1.0 eq) and 1,3-dimethylpyrazol-4-amine (6 g, 56 mmol, 1.2 eq) were dissolved in dichloromethane (150 mL), acetic acid (3 g, 56 mmol, 3 mL, 1.2 eq) was added, the reaction solution was reacted at 25°C for 1 hour, sodium triacetoxyborohydride (25 g, 117 mmol, 2.5 eq) was added, the reaction solution was reacted at 25°C for 3 hours, and the target product was detected by LCMS. The reaction solution was quenched with 200 mL of sodium bicarbonate and extracted with ethyl acetate (150 mL*2). The combined organic phases were washed with 400 mL of saturated brine, dried over magnesium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. Purification by column chromatography (silica, 35% ethyl acetate:ethanol (3:1) in petroleum ether) gave 1,3-dimethyl-N-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazol-4-amine (Intermediate B3) (14 g, 45 mmol, 97% yield) as a brown solid. 1 HNMR(400MHz,DMSO-d6)δppm:9.19(s,1H),7.92(s,1H),7.67(d,J=9.46Hz,1H),7.41(dd,J=1.76,9.46Hz,1H),6.93(s,1H),4.56(br s,1H),4.17(br d,J=3.96Hz,2H),3.52-3.61(m,3H),2.04(s,3H).LCMS:[MH] + 310.3,RT=0.64min.

[0179] General Method: Synthesis of Intermediate B4

[0180] Synthesis route:

[0181]

[0182] Step 1: 2-(Dichloromethyl)-5-(trifluoromethyl)imidazo[1,2-a]pyridine (3)

[0183] 1,1,3-trichloro-2-acetone (74.7 g, 278 mmol, 1.5 eq) was added to a solution of 6- (trifluoromethyl) pyridine-2-amine (30.0 g, 185 mmol, 1.0 eq) in PhCl (300 mL). The mixture was stirred at 125 ° C for 16 hours. LC-MS showed that 6- (trifluoromethyl) pyridine-2-amine was retained and the desired compound was detected. The reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether / ethyl acetate=30 / 1 to 10 / 1, Rf=0.21) to obtain 2- (dichloromethyl) -5- (trifluoromethyl) imidazo [1,2-a] pyridine (3) (25.0 g, 92.9 mmol, 50.2% yield) as a yellow solid. 1 H NMR (400MHz, CDCl3) δppm: 8.00 (d, J = 0.8Hz, 1H), 7.87-7.81 (m, 1H), 7.37-7.33 (m, 1H), 7.33 (s, 1H), 6.96 (s, 1H). LC-MS, [MH] + 270.9.

[0184] Step 2: 5-(Trifluoromethyl)imidazo[1,2-a]pyridine-2-carbaldehyde (4)

[0185] To a solution of 2-(dichloromethyl)-5-(trifluoromethyl)imidazo[1,2-a]pyridine (3) (25.0 g, 92.9 mmol, 1.0 eq) in H2O (800 mL) was added CaCO3 (27.9 g, 279 mmol, 3.0 eq). The mixture was stirred at 100 °C for 16 h. LC-MS showed that 2-(dichloromethyl)5-(trifluoromethyl)imidazo[1,2-a]pyridine (3) was completely consumed and one major peak was detected. The reaction mixture was diluted with H2O (50.0 mL) and extracted with ethyl acetate (800 mL×3). The combined organic layers were washed with brine (300 mL), dried over MgSO4, filtered and concentrated under reduced pressure to give compound 5-(trifluoromethyl)imidazo[1,2-a]pyridine-2-carbaldehyde (4) (17.0 g, 79.4 mmol, 85.4% yield) as a yellow oil. 1H NMR (400MHz, CDCl3) δppm: 10.20 (s, 1H), 8.36 (s, 1H), 7.95-7.88 (m, 1H), 7.39 (d, J = 5.3Hz, 2H). LC-MS, [MH] + 215.1.

[0186] Step 3: 1-methyl-N-((5-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazol-4-amine (Intermediate B4)

[0187] To a solution of 1-methyl-1H-pyrazol-4-amine (7.71 g, 79.4 mmol, 1.0 eq) and 5-(trifluoromethyl)imidazo[1,2-a]pyridine-2-carbaldehyde (4) (17.0 g, 79.4 mmol, 1.0 eq) in DCM (600 mL) was added KOAc (15.58 g, 158.77 mmol, 2.0 eq) at -5 °C, and the reaction mixture was stirred at -5 °C for 1 hour. Then NaBH(OAc)3 (33.7 g, 159 mmol, 2.0 eq) was added at -5 °C. The mixture was stirred at 25 °C for 1.5 hours. LC-MS showed that 5-(trifluoromethyl)imidazo[1,2-a]pyridine-2-carbaldehyde (4) was completely consumed, and one major peak was detected. The reaction mixture was diluted with H2O (500 mL) and extracted with DCM (600 mL×3). The aqueous layer was washed with Na -2 The mixture was alkalized with CO3 to pH = 9, then extracted with DCM (600 mL × 3), dried over MgSO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (ethyl acetate / methanol = 50 / 1 to 10 / 1) to give 1-methyl-N-((5-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-amine (Intermediate B4) (15.0 g, 50.8 mmol, 64.0% yield) as a yellow solid. 1 H NMR(400MHz, CDCl3)δppm:7.81-7.76(m,1H),7.75(s,1H),7.27-7.23(m,2H),7.19(s,1H),6.98(s,1H),4.37(s,2H),3.80(s,3H).LC-MS,[MH]+296.1.

[0188] Example 1: Synthesis of Compounds 1, 2, and 3

[0189] Method 1:

[0190]

[0191] Step 1: 4-amino-3-methyl-N-(1-methyl-1H-pyrazol-4-yl)-N-((6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1,3-dihydrofuro[3,4-c]quinoline-8-carboxamide (Compound 1)

[0192] To a solution of intermediate B2 (3.50 g, 11.9 mmol, 1.0 eq) and intermediate A5 (3.04 g, 12.5 mmol, 1.05 eq) in DMF (35.0 mL) was added TCFH (4.99 g, 17.8 mmol, 1.5 eq) and NMI (4.87 g, 59.3 mmol, 4.72 mL, 5.0 eq). The mixture was stirred at 25 ° C for 16 hours. LC-MS showed that the intermediate was completely consumed and a major peak with the desired mass was detected. The reaction mixture was diluted with H2O (90.0 mL) and extracted with DCM (50.0 mL×3). The combined organic layers were washed with brine (100 mL), dried over MgSO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (petroleum ether / ethyl acetate=100 / 1 to DCM / MeOH=1 / 1) and then by preparative HPLC (column: Welch XtimateC18 250*70mm#10μm; mobile phase: [water(NH4HCO3)-ACN]; B%: 20%-50%, 20 minutes, UV 220&254nm) to give 4-amino-3-methyl-N-(1-methyl-1H-pyrazol-4-yl)-N-((6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1,3-dihydrofuran[3,4-c]quinoline-8-carboxamide (Compound 1) (3.00 g, 5.75 mmol, 48.5% yield) as a white solid. 1 H NMR (400MHz, DMSO-d6) δppm: 9.19 (s, 1H), 8.04 (s, 1H), 7.74 (d, J = 9.5Hz, 1H), 7.72-7.51 (m, 2H), 7.47 (dd, J = 1.4, 9.4H z,2H),7.43-6.97(m,2H),6.61(s,2H),5.45-5.35(m,1H),5.28-5.20(m,1H),5.18-5.11(m,1H),5.05(s,2H),3.67(br s,3H),1.39(d,J=6.1Hz,3H); LC-MS,[MH] + 522.1.

[0193] Step 2: (R)-4-amino-N-(1,3-dimethylpyrazol-4-yl)-3-methyl-N-(6-trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1,3-dihydrofuro[3,4-c]quinoline-8-carboxamide (Compound 2) and (S)-4-amino-N-(1,3-dimethylpyrazol-4-yl)-3-methyl-N-(6-trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1,3-dihydrofuro[3,4-c]quinoline-8-carboxamide (Compound 3)

[0194] 4-Amino-3-methyl-N-(1-methyl-1H-pyrazol-4-yl)-N-((6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1,3-dihydrofuro[3,4-c]quinoline-8-carboxamide (Compound 1) (3.00 g, 5.75 mmol, 1.0 eq) was separated by SFC (chromatographic column: DAICEL CHIRALPAK AD (250 mm*30 mm, 10 μm); mobile phase: [ACN / EtOH (0.1% NH3H2O)]; B%: 69%-69%, 20 minutes, UV 220 and 254 nm), to give the first eluting peak (peak 1) of (R)-4-amino-N-(1,3-dimethylpyrazol-4-yl)-3-methyl-N-(6-trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1,3-dihydrofuro[3,4-c]quinoline-8-carboxamide (compound 2) (1.18 g, 2.27 mmol, 100% purity) as a white solid, and the later eluting peak (peak 2) of (S)-4-amino-N-(1,3-dimethylpyrazol-4-yl)-3-methyl-N-(6-trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1,3-dihydrofuro[3,4-c]quinoline-8-carboxamide (compound 3) (1.24 g, 2.37 mmol, 99.3% purity) as a white solid. Note: According to SFC separation, the first peak (peak 1) is compound 2, and the second peak (peak 2) is compound 3. The absolute configurations of the chiral centers of the two compounds are randomly assigned.

[0195] Compound 2

[0196] 1H NMR (400MHz, DMSO-d6) δppm: 9.18 (s, 1H), 8.03 (s, 1H), 7.73 (d, J = 9.5Hz, 1H), 7.58 (br s,2H),7.46(dd,J=1.5,9.5Hz,2H),7.42-7.07(m,2H),6.59(s,2H),5.44 -5.34(m,1H),5.27-5.18(m,1H),5.17-5.08(m,1H),5.05(s,2H),3.66(br s,3H),1.39(d,J=6.3Hz,3H); LC-MS: Rt=1.739min, (ESI)m / z.[M+H] + 522.2;C 26 H 22 F3N7O2. SFC: RT = 2.149 min

[0197] Compound 3

[0198] 1 H NMR (400MHz, DMSO-d6) δppm: 9.18 (s, 1H), 8.03 (s, 1H), 7.73 (d, J = 9.4Hz, 1H), 7.58 (br s, 2H), 7.46 (br dd,J=1.4,9.5Hz,2H),7.42-7.00(m,2H),6.59(s,2H),5.43-5.34(m,1H),5.28-5.19(m,1H),5.17-5.11(m,1H),5.05(s,2H),3.66(br s,3H),1.39(d,J=6.1Hz,3H); LC-MS: Rt=1.738min, (ESI)m / z.[M+H] + 522.0;C 26 H 22 F3N7O2.SFC:RT=2.642min

[0199] Method 2:

[0200] Synthesis of compound 2

[0201]

[0202] Step: (R)-4-amino-3-methyl-N-(1-methyl-1H-pyrazol-4-yl)-N-((6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl))methyl)-1,3-dihydrofuro[3,4-c]quinoline-8-carboxamide (Compound 2)

[0203] To a DMF (5.00 mL) solution of intermediate B2 (500 mg, 1.69 mmol, 1.0 eq) and intermediate A5a (434 mg, 1.78 mmol, 1.05 eq) was added TCFH (713 mg, 2.54 mmol, 1.5 eq) and NMI (695 mg, 8.47 mmol, 5.0 eq). The mixture was stirred at 25 ° C for 16 hours. LC-MS showed that intermediate B2 was retained and the desired product mass was detected. The solution was purified by preparative HPLC (column: Waters Xbridge BEH C18

[0204] 250*50mm*10μm; mobile phase: [water (NH4HCO3, 10mM)-ACN]; B%: 20%-40%, 10 minutes, UV220&254nm) to obtain (R)-4-amino-3-methyl-N-(1-methyl-1H-pyrazol-4-yl)-N-((6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl))methyl)-1,3-dihydrofuran[3,4-c]quinoline-8-carboxamide (Compound 2) (571mg, 1.05mmol, 61.9% yield, 95.7% purity) as a white solid. 1 H NMR (400MHz, DMSO-d6) δppm: 9.18 (s, 1H), 8.03 (s, 1H), 7.73 (d, J = 9.5Hz, 1H), 7.69-7.49 (m, 2H), 7.49-7.42 (m, 2H), 7.42 -6.85(m,2H),6.60(s,2H),5.39(ddd,J=1.6,4.0,6.0Hz,1H),5.26-5.19(m,1H),5.18-5.10(m,1H),5.05(s,2H),3.66(br s,3H),1.38(d,J=6.3Hz,3H); LC-MS,[MH] + 522.2.SFC:RT=2.149min.

[0205] Synthesis of compound 3

[0206]

[0207] Step: (S)-4-amino-3-methyl-N-(1-methyl-1H-pyrazol-4-yl)-N-((6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl))methyl)-1,3-dihydrofuro[3,4-c]quinoline-8-carboxamide (Compound 3)

[0208] To a solution of 1-methyl-N-((6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazol-4-amine (Intermediate B2) (500 mg, 1.69 mmol, 1.0 eq) and (S)-4-amino-3-methyl-1,3-dihydrofuro[3,4-c]quinoline-8-carboxylic acid (Intermediate A5b) (434 mg, 1.78 mmol, 1.05 eq) in DMF (5.00 mL) was added TCFH (713 mg, 2.54 mmol, 1.5 eq) and NMI (695 mg, 8.47 mmol, 675 mL, 5.0 eq). The mixture was stirred at 25 °C for 16 hours. LC-MS showed that Intermediate B2 was retained and the desired mass was detected. The solution was purified by preparative HPLC (chromatographic column: Waters Xbridge BEH C18 250*50mm*10μm; mobile phase: [water (NH4HCO3 10mM)-ACN]; B%: 20%-45%, 10 minutes, UV 220&254nm) to give (S)-4-amino-3-methyl-N-(1-methyl-1H-pyrazol-4-yl)-N-((6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl))methyl)-1,3-dihydrofuro[3,4-c]quinoline-8-carboxamide (Compound 3) (285 mg, 535μmol, 31.6% yield, 97.9% purity) as a white solid. 1 H NMR (400MHz, DMSO-d6) δppm:9.18(s,1H),8.03(s,1H),7.73(d,J=9.5Hz,1H),7.69-7.49(m,2H),7.46(dd,J=1.3,9.4H z,2H),7.42-6.94(m,2H),6.61(s,2H),5.43-5.35(m,1H),5.27-5.19(m,1H),5.18-5.10(m,1H),5.05(s,2H),3.66(br s,3H),1.38(d,J=6.3Hz,3H); LC-MS,[MH] + 522.2.SFC:RT=2.642min

[0209] Example 2: Synthesis of Compound 4

[0210]

[0211] Step: 4-amino-3-methyl-N-(1-methyl-1H-pyrazol-4-yl)-N-((5-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1,3-dihydrofuro[3,4-c]quinoline-8-carboxamide (Compound 4)

[0212] To a DMF (2 mL) solution of intermediate A5 (50.0 mg, 205 μmol, 1.0 eq) and intermediate B4 (60.4 mg, 205 μmol, 1 eq) was added TCFH (68.9 mg, 246 μmol, 1.2 eq) and NMI (84.0 mg, 1.02 mmol, 81.6 μL, 5.0 eq). The mixture was stirred at 25 ° C for 16 hours. LCMS showed that the starting material was completely consumed and the desired mass was detected. The residue was purified by preparative HPLC (column: Waters Xbridge BEH C18 100*30mm*10um; mobile phase: [H2O(10mMNH4HCO3)-ACN]; gradient: 25%-55% B, over 8.0 minutes, 220&254nm) to give 4-amino-3-methyl-N-(1-methyl-1H-pyrazol-4-yl)-N-((5-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-1,3-dihydrofuro[3,4-c] as a white solid.

[0213] Quinoline-8-carboxamide (Compound 4) (99.79 mg, 179 μmol, 87.4% yield, 93.5% purity). 1 H NMR (400MHz, DMSO-d6) δppm:8.04-7.81(m,3H),7.69-7.31(m,6H),6.62(s,2H),5.43-5.35(m,1H),5.26-5.11(m,2H),5.08(s,2H),3.66(br s,3H),1.38(d,J=6.1Hz,3H); LC-MS,[MH] + 522.2.

[0214] Example 3: Synthesis of Compounds 7, 8, and 9

[0215]

[0216] Step 1: 4-amino-N-(1,3-dimethylpyrazol-4-yl)-3-methyl-N-[[6-(trifluoromethyl)imidazo[1,2-a]

[0217] [pyridin-2-yl]methyl]-1,3-dihydrofuro[3,4-c]quinoline-8-carboxamide (Compound 7)

[0218] To a solution of 4-amino-3-methyl-1,3-dihydrofurano[3,4-c]quinoline-8-carboxylic acid (Intermediate A5) (2.0 g, 8.19 mmol, 1.0 eq) and 1,3-dimethyl-N-[[6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl]methyl]pyrazol-4-amine (Intermediate B3) (2.66 g, 8.60 mmol, 1.05 eq) in NMP (12 mL), NMI (2.02 g, 24.57 mmol, 1.96 mL, 3.0 eq) was added. The reaction mixture was stirred at 30 ° C for 1 hour. TCFH (3.45 g, 12.28 mmol, 1.5 eq) was added in batches, and the reaction mixture was then stirred at 40 ° C for 16 hours. LCMS showed that the reaction was complete and the desired product was detected. The reactants were purified directly after centrifugation. The reactants were purified by preparative HPLC (column: C18 250×80 mm; mobile phase: [water (NH3H2O+NH4HCO3)-ACN]; gradient: B% 20%-60%, over 20 minutes, 220 & 254 nm). The desired product fractions were combined and lyophilized to give 4-amino-N-(1,3-dimethylpyrazol-4-yl)-3-methyl-N-[[6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl]methyl]-1,3-dihydrofurano[3,4-c]quinoline-8-carboxamide (Compound 7) (3.4 g, 6.29 mmol, yield 76.76%, purity 99%) as a white solid. 1 H NMR(400MHz,DMSO-d6)δppm:9.21(s,1H),8.06(br s,1H),7.72(br d,J=9.38Hz,1H),7.59(s,1H),7.27-7.55(m,4H),6.61(s,2H),5.33-5.50(m,1H),5.08-5.28(m,2H),4.99(br s,2H),3.60(s,3H),1.68(br s,3H),1.39(d,J=6.13Hz,3H). 19 F NMR(376MHz,DMSO-d6)δ-60.40(s,3F).LC-MS,(ESI)m / z=536.3[M+1] + ,RT=0.71min.

[0219] Step 2: (3R)-4-amino-N-(1,3-dimethylpyrazol-4-yl)-3-methyl-N-[[6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl]methyl]-1,3-dihydrofuro[3,4-c]quinoline-8-carboxamide (Compound 8) and (3S)-4-amino-N-(1,3-dimethylpyrazol-4-yl)-3-methyl-N-[[6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl]methyl]-1,3-dihydrofuro[3,4-c]quinoline-8-carboxamide (Compound 9)

[0220] 4-Amino-N-(1,3-dimethylpyrazol-4-yl)-3-methyl-N-[[6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl]methyl]-1,3-dihydrofuro[3,4-c]quinoline-8-carboxamide (Compound 7) (3.4 g, 6.35 mmol, 1.0 eq) was separated by SFC (column: DAICEL CHIRALPAK AD (250 mm*50 mm, 10 um); mobile phase: [CO2-EtOH (0.1% NH3H2O)]; B%: 55%, isocratic elution mode). The components of the desired product were combined and concentrated to give the first eluting peak (peak 1) as a white solid (3R)-4-amino-N-(1,3-dimethylpyrazol-4-yl)-3-methyl-N-[[6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl]methyl]-1,3-dihydrofuro[3,4-c]quinoline-8-carboxamide (Compound 8) (1.3 g, 2.42 mmol, 38.2% yield, 99.3 7% purity), the latter peak (peak 2) is a white solid (3S)-4-amino-N-(1,3-dimethylpyrazol-4-yl)-3-methyl-N-[[6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl]methyl]-1,3-dihydrofuro[3,4-c]quinoline-8-carboxamide (Compound 9) (1.4 g, 2.46 mmol, 41.2% yield, 99.37% purity) as a white solid. Note: According to SFC separation, the first peak (peak 1) is compound 8, and the latter peak (peak 2) is compound 9. The absolute configuration of the chiral center of the two compounds is randomly assigned.

[0221] Compound 8

[0222] 1H NMR (400MHz, DMSO-d6) δppm: 9.22 (s, 1H), 8.06 (br s, 1H), 7.72 (br d, J = 9.24Hz, 1H), 7.60 (s, 1H), 7.13-7.55 (m, 4H), 6.63 (s, 2H), 5.39 (br d,J=4.84Hz,1H),5.07-5.31(m,2H),5.00(br s,2H),3.60(s,3H),1.67(br s,3H),1.39(d,J=6.16Hz,3H). 19 F NMR (376MHz, DMSO-d6)δ-60.41 (br s, 1F).LC-MS: Rt=0.802min, (ESI)m / z.[M+H] + 536.3; SFC:

[0223] RT=2.052min

[0224] Compound 9

[0225] 1 H NMR(400MHz,DMSO-d6)δppm:9.21(s,1H),8.06(br s,1H),7.72(br d,J=9.38Hz,1H),7.59(s,1H),7.27-7.55(m,4H),6.61(s,2H),5.33-5.50(m,1H),5.08-5.28(m,2H),4.99(br s,2H),3.60(s,3H),1.68(br s,3H),1.39(d,J=6.13Hz,3H). 19 F NMR (376MHz, DMSO-d6)δ-60.40 (s, 3F).LC-MS: Rt=0.71min, (ESI)m / z.[M+H] + 536.3.SFC:RT=3.570min

[0226] Unless otherwise indicated, the absolute stereochemistry of all chiral atoms is as described. The absolute stereochemistry of Table 1 and the Examples is arbitrarily specified (e.g., based on the chiral SFC elutions described in the Examples section). Compounds with stereogenic centers (where the configuration is not indicated in the depicted structure) and not specified in the stereochemistry column of Table 1 are mixtures of enantiomers at that center.

[0227] Those skilled in the art can separate the racemic compound into its individual enantiomers using methods known in the art, such as chiral chromatography, chiral recrystallization, and the like.

[0228] The following compounds were synthesized based on the general method. The corresponding structures of the products are shown in Table 1 and the characterizations are shown in Table 2:

[0229] Table 2

[0230]

[0231]

[0232]

[0233]

[0234] Biological test example 1 HCT116, HCT116-MTAP-KO cell proliferation inhibition experiment in vitro

[0235] Experimental Materials

[0236] The HCT116 cell line was purchased from the Cell Bank of the Chinese Academy of Sciences. The MTAP gene was knocked out using CRISPR / Cas9 technology to obtain the HCT116-MTAP-KO cell line.

[0237] McCoy'5A medium (Gibco, catalog number 16600082), fetal bovine serum (Gibco, catalog number 10099141C), penicillin-streptomycin double antibody (Gibco, catalog number 15140122), trypsin (Gibco, catalog number 25200056), CellTiter-Glo detection kit (Promega, catalog number G7572), 384-well clear flat-bottom black-walled cell culture plates (Corning, catalog number 3764), ultra-micropipette instrument (Tecan, catalog number D300e), multi-function microplate reader (Biotek, catalog number SynergyHTX)

[0238] Experimental methods

[0239] 1. Cell culture: HCT116 and HCT116-MTAP-KO cells were cultured in McCoy'5A medium + 10% fetal bovine serum + 1% penicillin-streptomycin double antibody; they were always in the logarithmic growth phase and the cell viability was greater than 95%.

[0240] 2. Preparation of compound concentration gradient: The test compound was added to a 384-well plate using an ultra-micropipette, starting from 30 μM (HCT116 cells) or 3 μM (HCT116-MTAP-KO cells), and diluted 3-fold with DMSO, for a total of 9 concentrations, with triplicate wells.

[0241] 3. Compound treatment of cells: Add the trypsin-digested HCT116 or HCT116-MTAP-KO cell suspension to the 384-well plate with the test compound, 40 μL per well, i.e., 100 cells per well, and the final DMSO concentration is 0.4%. The cell culture plate is placed in a 37°C, 5% carbon dioxide incubator for 6 days.

[0242] 4. Detection: Add 20 μL of CellTiter-Glo reagent to each well of the cell culture plate and incubate at room temperature for 30 minutes with shaking. Use a multifunctional microplate reader to detect the luminescent signal at 578 nm.

[0243] 5. Data Analysis:

[0244] GraphPad Prism 8.0 software was used to fit the data using a four-parameter inhibitor-response model to obtain the IC values ​​of the test compounds. 50 value (half inhibitory concentration).

[0245] The biological activity of some compounds was measured by experimental methods, and "A" represents IC 50 (nm)<100, "B" means 100 <IC 50 (nm)<1000, “C” means 1000 <IC 50 (nm) <10000, see Table 4, where the first column is the cell proliferation inhibition rate HCT116MTAP WT IC 50 (nm), the second column is the cell proliferation inhibition rate HCT116-MTAP null IC 50 (nm):

[0246] Table 4

[0247]

[0248]

[0249] All documents mentioned in the present invention are cited as references in this application, just as each document is cited as reference individually. In addition, it should be understood that after reading the above teachings of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the claims attached to this application.

Claims

1. A compound as shown in the following formula I, or a pharmaceutically acceptable stereoisomer, salt or deuterated product thereof: in, The L1 is selected from the following group: -CHR-, -C(R)R-; R8 is CF3; R2 is selected from the following group: a substituted or unsubstituted C6 aromatic ring, a substituted or unsubstituted 5-6 membered heteroaromatic ring; R is H, deuterium, or halogen; The C ring is selected from the group consisting of a substituted or unsubstituted 6-membered heteroaromatic ring; R9 is selected from the group consisting of: substituted or unsubstituted C1-C6 alkyl; Unless otherwise specified, in the formulae, the substitution refers to the substitution of hydrogen atoms on the corresponding groups by one or more substituents selected from the group consisting of deuterium, tritium, halogen, hydroxyl, carboxyl, thiol, C1-C 12 Alkoxycarbonyl, C1-C6 aldehyde, amino, C1-C6 amide, nitro, cyano, unsubstituted or halogenated C1-C6 alkyl, unsubstituted or halogenated C3-C8 cycloalkyl, C2-C 10 alkenyl, C1-C6 alkoxy, C1-C6 alkyl-amino, unsubstituted or halogenated C2-C 10 Acyl, sulfonyl, phosphoryl, unsubstituted or halogenated C1-C4 alkyl-S(O)2-, unsubstituted or halogenated C1-C4 alkyl-SO-, -SF5.

2. The compound according to claim 1, or a pharmaceutically acceptable stereoisomer, salt or deuterated product thereof, characterized in that: The R2 is a substituted or unsubstituted benzene ring.

3. The compound according to claim 1, or a pharmaceutically acceptable stereoisomer, salt or deuterated product thereof, characterized in that: The R2 is a substituted or unsubstituted 5-6 membered heteroaromatic ring.

4. The compound according to claim 1, or a pharmaceutically acceptable stereoisomer, salt or deuterated product thereof, characterized in that: The L1 is -CH2-, -CD2-; The R9 is selected from substituted or unsubstituted methyl; The R2 is selected from the following group: a substituted or unsubstituted benzene ring, a substituted or unsubstituted 5-6 membered heteroaromatic ring.

5. The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable stereoisomer, salt or deuterated product thereof, characterized in that: The R9 is selected from the following group: methyl, deuterated methyl, and halogenated methyl.

6. The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable stereoisomer, salt or deuterated product thereof, characterized in that: The R2 is selected from a substituted or unsubstituted group selected from the following group: .

7. The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable stereoisomer, salt or deuterated product thereof, characterized in that: The compound has a structure selected from the following table: 。 8. A pharmaceutical composition, characterized in that The pharmaceutical composition contains a therapeutically effective amount of a compound as described in any one of claims 1 to 7, or one or more of its pharmaceutically acceptable stereoisomers, salts or deuterated products, and one or more pharmaceutically acceptable carriers, excipients, adjuvants, auxiliary materials and / or diluents.

9. Use of the compound according to any one of claims 1 to 7 or a pharmaceutically acceptable stereoisomer, salt or deuterated product thereof in the preparation of a medicament for treating or preventing a disease associated with abnormal gene level or abnormal expression of PRMT5.

10. The use according to claim 9, characterized in that The abnormal gene level or expression of PRMT5 is selected from the following group: nucleic acid mutation, deletion, or abnormal MTAP gene level, or ectopic or fused or overexpressed methyltransferase.

11. The use according to claim 9, characterized in that The disease is selected from the following group: lung cancer, lymphoma, glioblastoma, colon cancer, malignant peripheral nerve sheath tumor, esophageal cancer, bladder cancer, mesothelioma, non-small cell lung cancer, head and neck cancer, gastric adenocarcinoma, cholangiosarcoma, as well as brain cancer, gastric cancer, urinary tract cancer, liver cancer, and pleural cancer.

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