Arginine methyltransferase inhibitors and their applications

Abstract

The present invention provides an arginine methyltransferase inhibitor and its use, specifically, the present invention provides a compound that can be used as a type I PRMT inhibitor, its preparation method, and its application in the treatment of related diseases. The compound has the structure shown in formula I. [Formula 1] JPEG2024521741000090.jpg5555

Description

[Technical Field]

[0001] This invention relates to the fields of medical chemistry and medicine, and more specifically to type I PRMT inhibitor compounds, methods for preparing the same, and their applications in the field of disease treatment. [Background technology]

[0002] Protein arginine methylation is a highly abundant post-translational modification method widely present in the cytoplasm and cell nucleus. The protein arginine methyltransferase (PRMT) family are key enzymes involved in the protein arginine methylation process, primarily using S-adenosylmethionine (SAM) as a methyl group donor to methylate the nitrogen atom of the protein arginine side chain to produce S-adenosylhomocysteine ​​and methylarginine. The PRMT family includes nine types of PRMTs. Depending on the type of catalytic reaction, PRMTs can be classified into Type I (PRMT1, PRMT2, PRMT3, PRMT4, PRMT6, PRMT8), Type II (PRMT5, PRMT9), and Type III (PRMT7). Type I PRMTs are responsible for asymmetric dimethylated arginine (ADMA), Type II PRMTs are responsible for symmetric dimethylated arginine (SDMA), and Type III PRMTs are responsible for monomethylated arginine (MMA).

[0003] Numerous studies have confirmed that abnormal expression of type I PRMT is closely related to the development and progression of various diseases. For example, PRMT1 is known to play an oncogenic role in cancers such as leukemia, lung cancer, liver cancer, gastric cancer, colon cancer, breast cancer, pancreatic cancer, head and neck tumors, prostate cancer, and bladder cancer. In malignant gliomas, PRMT2 is highly expressed at the protein level and has been found to be closely associated with poor prognosis. At least a twofold increase in PRMT4 expression is observed in 70% of acute myeloid leukemia (AML) patients. PRMT6 has been found to be highly expressed in 52.6% of gastric cancer cells, and its expression level is significantly positively correlated with the level of modification of its substrate. At the same time, since type I PRMT is mainly responsible for catalyzing the asymmetric dimethylation of arginine, alterations in asymmetric dimethylation levels in vivo are closely related to cardiovascular disease, diabetes, renal failure, asthma, and chronic non-obstructive diseases. Therefore, it can be said that the abnormal expression of type I PRMT is involved in the development and progression of various diseases. In summary, developing novel PRMT inhibitor molecules is of great importance. [Overview of the Initiative] [Problems that the invention aims to solve]

[0004] The object of the present invention is to provide a novel PRMT inhibitor molecule. [Means for solving the problem]

[0005] A first aspect of the present invention provides a compound represented by the following formula I, or a pharmaceutically acceptable salt or deuterated product thereof, [ka] X 1 , X 2 , X 3 and X 4 Each element is independently selected from the group consisting of CR, NR, or N, and the dashed line indicates a chemical bond or no bond. Ring A is selected from the group consisting of a substituted or unsubstituted saturated or partially unsaturated (non-aromatic) 4- to 8-member carbon ring, a substituted or unsubstituted saturated or partially unsaturated (non-aromatic) 4- to 8-member heterocyclic ring. Ring B is selected from the group consisting of H, halogen, cyano group, amino group, nitro group, hydroxy group, mercapto group, aldehyde group, carboxy group, sulfonyl group, substituted or unsubstituted C1-C6 alkyl group, substituted or unsubstituted C1-C6 alkoxy group, substituted or unsubstituted C6-C 10 aryl group, substituted or unsubstituted 5- to 12-member heteroaryl ring, substituted or unsubstituted 3- to 12-member heterocyclic ring containing 1 to 3 heteroatoms selected from oxygen, sulfur and nitrogen, substituted or unsubstituted -C1-C6 alkyl-6- to 10-member aryl group, substituted or unsubstituted C3-C 12 carbon ring, substituted or unsubstituted C2-C 10 acyl group, substituted or unsubstituted C2-C 10 ester group, substituted or unsubstituted C6-C 10 aryloxy group, substituted or unsubstituted C1-C6 amide group, substituted or unsubstituted C1-C4 alkyl-S(O)2-, substituted or unsubstituted C1-C4 alkyl-SO-, and is selected from the group consisting of m and n are each independently selected from the group consisting of 0, 1, 2, 3, 4, 5 or 6. L is a chemical bond, or -O-, -(CHR 6 ) p- , -CHR 6 -O-, -CHR 6 -C(O)-, carbonyl group, S, -NH-, -NHC(O)-, -NHS(O)2-, -NHC(O)NH-, -NHC(S)NH-, -COO-, -O-S(O)2-, -COO-CH2-, -C(O)CH2-, -S(O)2-, and is selected from the group consisting of, or L is absent. p is selected from the group consisting of 1, 2 or 3. R 1 and R 2 are each independently selected from the group consisting of H, substituted or unsubstituted C1-C6 alkyl group, substituted or unsubstituted C3-C6 cycloalkyl group. R 3This includes H, halogens, cyano groups, amino groups, nitro groups, hydroxyl groups, mercapto groups, aldehyde groups, carboxyl groups, sulfonyl groups, substituted or unsubstituted C1-C6 alkyl groups, substituted or unsubstituted C2-C6 alkenyl groups, substituted or unsubstituted C1-C6 alkoxy groups, substituted or unsubstituted C1-C6 alkylamine groups, and substituted or unsubstituted C6-C 10 aryl groups, substituted or unsubstituted 5-12 membered heteroaryl groups, substituted or unsubstituted 5-7 membered heterocycles containing 1-3 heteroatoms selected from oxygen, sulfur, and nitrogen, substituted or unsubstituted -C1-C6 alkylphenyl groups, substituted or unsubstituted C3-C 12 Carbon rings, substituted or unsubstituted C2-C 10 Acyl group, substituted or unsubstituted C2-C 10 Ester group, substituted or unsubstituted C6-C 10 A group selected from the group consisting of aryloxy groups, substituted or unsubstituted C1-C6 amide groups, substituted or unsubstituted C1-C4 alkyl-S(O)2-, and substituted or unsubstituted C1-C4 alkyl-SO-. R is H, halogen, cyano group, amino group, nitro group, hydroxyl group, mercapto group, aldehyde group, carboxyl group, sulfonyl group, substituted or unsubstituted C1-C6 alkyl group, substituted or unsubstituted C1-C6 alkoxy group, substituted or unsubstituted C1-C6 alkylamine group, substituted or unsubstituted C6-C 10 aryl groups, substituted or unsubstituted 5-12 membered heteroaryl groups, substituted or unsubstituted 4-7 membered heterocycles containing 1-3 heteroatoms selected from oxygen, sulfur, and nitrogen, substituted or unsubstituted -C1-C6 alkylphenyl groups, substituted or unsubstituted C3-C 12 Carbon rings, substituted or unsubstituted C2-C 10 Acyl group, substituted or unsubstituted C2-C 10 Ester group, substituted or unsubstituted C6-C 10 A group selected from the group consisting of an aryloxy group, a substituted or unsubstituted C1-C6 amide group, a substituted or unsubstituted C1-C4 alkyl-S(O)2-, or a substituted or unsubstituted C1-C4 alkyl-SO-, Alternatively, two R atoms located on adjacent ring atoms, together with the ring atom to which they are bonded, form a substituted or unsubstituted 5-11 membered carbon ring or heterocycle, wherein the ring is partially unsaturated or saturated, preferably a 5-9 membered carbon ring or heterocycle, more preferably a 5-7 membered carbon ring or heterocycle (where the carbon ring or heterocycle is saturated, partially unsaturated, or aromatic). R 4 This includes H, halogens, cyano groups, amino groups, nitro groups, hydroxyl groups, mercapto groups, aldehyde groups, carboxyl groups, sulfonyl groups, substituted or unsubstituted C1-C6 alkyl groups, substituted or unsubstituted C2-C6 alkenyl groups, substituted or unsubstituted C1-C6 alkoxy groups, substituted or unsubstituted C1-C6 alkylamine groups, and substituted or unsubstituted C6-C 10 aryl groups, substituted or unsubstituted 5-12 membered heteroaryl groups, substituted or unsubstituted 5-7 membered heterocycles containing 1-3 heteroatoms selected from oxygen, sulfur, and nitrogen, substituted or unsubstituted -C1-C6 alkylphenyl groups, substituted or unsubstituted C3-C 12 Carbon rings, substituted or unsubstituted C2-C 10 Acyl group, substituted or unsubstituted C2-C 10 Ester group, substituted or unsubstituted C6-C 10 A group selected from the group consisting of an aryloxy group, a substituted or unsubstituted C1-C6 amide group, a substituted or unsubstituted C1-C4 alkyl-S(O)2-, or a substituted or unsubstituted C1-C4 alkyl-SO-, Or two R atoms located on the same or adjacent ring atoms. 4 These, together with the ring atoms to which they are bonded, form a substituted or unsubstituted 3- to 11-membered carbon ring or heterocycle, wherein the ring is a partially unsaturated ring, a saturated ring, or an aromatic ring. R 6 This group is selected from the group consisting of H, halogen, cyano group, amino group, nitro group, hydroxyl group, mercapto group, aldehyde group, carboxyl group, acylsulfonyl group, substituted or unsubstituted C1-C6 alkyl group, substituted or unsubstituted C1-C6 alkoxy group, and substituted or unsubstituted C1-C6 alkylamine group. Unless otherwise specified, in the above formulas, the substitution means that the hydrogen atom on the corresponding group is deuterium, tritium, halogen, hydroxyl group, carboxyl group, mercapto group, benzyl group, oxygen (=O), C1-C 12 Alkoxycarbonyl group, C1-C6 aldehyde group, amino group, C1-C6 amide group, nitro group, cyano group, unsubstituted or halogenated C1-C6 alkyl group, C2-C 10 Alkenyl group, C1-C6 alkoxy group, C1-C6 alkylamine group, C1-C6 alkylsulfonamide group, C1-C6 alkylureido group, C1-C6 alkyl-S-, C6-C 10 Aryl group, 5-membered or 6-membered heteroaryl group, 5-membered or 6-membered non-aromatic heterocyclic group, 5-membered or 6-membered non-aromatic heterocyclic group -(CH2)-, -O-(C6-C 10 aryl), -O- (5-membered or 6-membered heteroaryl), -NH- (C6-C 10 aryl), -NH- (5-membered or 6-membered heteroaryl), C1-C 12 Alkylaminocarbonyl group, unsubstituted or halogenated C2-C 10 Acyl group, sulfonyl (-SO2-OH), sulfonamide group (-SO2-NH2), phosphoryl group (-PO3-OH), unsubstituted or halogenated C1-C4 alkyl-S(O)2-, unsubstituted or halogenated C1-C4 alkyl-SO-, [ka] This refers to substitution by one or more substituents selected from the group consisting of the following: in each formula, the heterocyclic or heteroaryl ring has 1 to 3 heteroatoms selected from the group consisting of N, S, or O, and each aryl group, heteroaryl group, and heterocyclic group can be independently substituted by 1 to 3 substituents selected from the group consisting of deuterium, tritium, halogen, hydroxyl group, carboxyl group, mercapto group, C1-C6 alkyl group, and C1-C6 alkoxy group.

[0006] In another preferred example, the aromatic ring, aromatic ring, or aromatic system includes conventional tautomers of aromatic rings such as pyridone, benzimidazole, and benzopyrazole.

[0007] In another preferred example, X 1 , X 2 , X 3 and X 4 At least one of them is N.

[0008] In another preferred example, the above [ka] The ring is an aromatic ring.

[0009] In another preferred example, the two R atoms located on the adjacent ring atom, together with the ring atom to which they are bonded, form a substituted or unsubstituted 5- to 11-membered carbon ring or heterocycle, and the ring is [ka] They combine with other rings to form an aromatic ring system.

[0010] In another preferred example, if the B ring is H, then m is 2, 3, 4, 5 or 6, and there are at least two R on the same or adjacent ring atoms. 4 These, together with the ring atoms to which they are bonded, form substituted or unsubstituted 5- to 11-membered carbon rings or heterocycles (the rings are partially unsaturated, saturated, or aromatic rings).

[0011] In another preferred example, L is a chemical bond, or -O-, -(CHR 6 ) p- ,-CHR 6 -O-, -CHR 6 L is selected from the group consisting of -C(O)-, carbonyl group, S, -NH-, -NHC(O)-, -COO-, -COO-CH2-, -C(O)CH2-, and -S(O)2-, or L is absent.

[0012] In another preferred example, R 3 This includes H, halogens, cyano groups, amino groups, nitro groups, hydroxyl groups, mercapto groups, aldehyde groups, carboxyl groups, sulfonyl groups, substituted or unsubstituted C1-C6 alkyl groups, substituted or unsubstituted C1-C6 alkoxy groups, substituted or unsubstituted C1-C6 alkylamine groups, and substituted or unsubstituted C6-C 10 aryl group, substituted or unsubstituted 5-10 membered heteroaryl group, substituted or unsubstituted 5-7 membered heterocycle containing 1-3 heteroatoms selected from oxygen, sulfur and nitrogen, substituted or unsubstituted C3-C8 carbon ring, substituted or unsubstituted C2-C6 acyl group, substituted or unsubstituted C2-C6 ester group, substituted or unsubstituted C6-C 10 A group selected from the group consisting of an aryloxy group, a substituted or unsubstituted C1-C6 amide group, a substituted or unsubstituted -C1-C6 alkyl-phenyl group, a substituted or unsubstituted C1-C4 alkyl-S(O)2-, and / or a substituted or unsubstituted C1-C4 alkyl-SO-. R is H, halogen, cyano group, amino group, nitro group, hydroxyl group, mercapto group, aldehyde group, carboxyl group, sulfonyl group, substituted or unsubstituted C1-C6 alkyl group, substituted or unsubstituted C1-C6 alkoxy group, substituted or unsubstituted C1-C6 alkylamine group, substituted or unsubstituted C6-C 10 aryl group, substituted or unsubstituted 5-10 membered heteroaryl group, substituted or unsubstituted 5-7 membered heterocycle containing 1-3 heteroatoms selected from oxygen, sulfur and nitrogen, substituted or unsubstituted -C1-C6 alkylphenyl group, substituted or unsubstituted C3-C8 carbon ring, substituted or unsubstituted C2-C6 acyl group, substituted or unsubstituted C2-C6 ester group, substituted or unsubstituted C6-C 10A group selected from the group consisting of an aryloxy group, a substituted or unsubstituted C1-C6 amide group, a substituted or unsubstituted -C1-C6 alkyl-phenyl group, a substituted or unsubstituted C1-C4 alkyl-S(O)2-, or a substituted or unsubstituted C1-C4 alkyl-SO-, or two R groups located on adjacent ring atoms, together with the carbon atoms to which they are bonded, form a substituted or unsubstituted 5- to 9-membered carbon ring or heterocycle, wherein the ring is partially unsaturated, saturated or aromatic, and / or In another preferred example, R 4 This includes H, halogens, cyano groups, amino groups, nitro groups, hydroxyl groups, mercapto groups, aldehyde groups, carboxyl groups, sulfonyl groups, substituted or unsubstituted C1-C6 alkyl groups, substituted or unsubstituted C1-C6 alkoxy groups, substituted or unsubstituted C1-C6 alkylamine groups, and substituted or unsubstituted C6-C 10 aryl group, substituted or unsubstituted 5-7 membered heteroaryl group, substituted or unsubstituted 5-7 membered heterocycle containing 1-3 heteroatoms selected from oxygen, sulfur and nitrogen, substituted or unsubstituted -C1-C6 alkylphenyl group, substituted or unsubstituted C3-C8 carbon ring, substituted or unsubstituted C2-C6 acyl group, substituted or unsubstituted C2-C 10 Ester group, substituted or unsubstituted C6-C 10 A group selected from the group consisting of an aryloxy group, a substituted or unsubstituted C1-C6 amide group, a substituted or unsubstituted -C1-C6 alkyl-phenyl group, a substituted or unsubstituted C1-C4 alkyl-S(O)2-, or a substituted or unsubstituted C1-C4 alkyl-SO-, or two R groups located on adjacent ring atoms. 4 These, together with the carbon atoms to which they are bonded, form a substituted or unsubstituted 5- to 9-membered carbon ring or heterocycle, the ring being partially unsaturated or saturated.

[0013] In another preferred example, the B ring is H, or a substituted or unsubstituted phenyl group, a substituted or unsubstituted 5-10 membered heteroaryl ring, a substituted or unsubstituted 3-12 membered heterocycle containing 1-3 heteroatoms selected from oxygen, sulfur, and nitrogen, or a substituted or unsubstituted C3-C 12Selected from the group consisting of carbocyclic rings.

[0014] In another preferred example, R 3 This includes H, halogens, cyano groups, amino groups, nitro groups, hydroxyl groups, mercapto groups, aldehyde groups, carboxyl groups, sulfonyl groups, substituted or unsubstituted C1-C6 alkyl groups, substituted or unsubstituted C1-C6 alkoxy groups, substituted or unsubstituted C1-C6 alkylamine groups, and substituted or unsubstituted C6-C 10 A group selected from the group consisting of an aryl group, a substituted or unsubstituted 5-10 membered heteroaryl group, a substituted or unsubstituted 5-7 membered heterocycle containing 1-3 heteroatoms selected from oxygen, sulfur, and nitrogen, a substituted or unsubstituted C2-C6 acyl group, a substituted or unsubstituted C2-C6 ester group, a substituted or unsubstituted C1-C6 amide group, a substituted or unsubstituted C1-C4 alkyl-S(O)2-, and / or a substituted or unsubstituted C1-C4 alkyl-SO- R is a group selected from the group consisting of H, halogen, cyano group, amino group, nitro group, hydroxyl group, mercapto group, aldehyde group, carboxyl group, sulfonyl group, substituted or unsubstituted C1-C6 alkyl group, substituted or unsubstituted C1-C6 alkoxy group, substituted or unsubstituted C1-C6 alkylamine group, substituted or unsubstituted C2-C6 acyl group, substituted or unsubstituted C2-C6 ester group, substituted or unsubstituted C1-C6 amide group, substituted or unsubstituted C1-C4 alkyl-S(O)2-, substituted or unsubstituted C1-C4 alkyl-SO-, or two Rs located on adjacent ring atoms, together with the ring atom to which they are bonded, form a substituted or unsubstituted 5- to 7-membered carbon ring or heterocycle, and / or R 4 This includes H, halogens, cyano groups, amino groups, nitro groups, hydroxyl groups, mercapto groups, aldehyde groups, carboxyl groups, sulfonyl groups, substituted or unsubstituted C1-C6 alkyl groups, substituted or unsubstituted C3-C8 carbon rings, substituted or unsubstituted C2-C6 acyl groups, and substituted or unsubstituted C2-C 10A group selected from the group consisting of an ester group, a substituted or unsubstituted C1-C6 amide group, a substituted or unsubstituted C1-C4 alkyl-S(O)2-, or a substituted or unsubstituted C1-C4 alkyl-SO-, or two R groups located on adjacent ring atoms. 4 These, together with the carbon atoms to which they are bonded, form a substituted or unsubstituted 5- to 9-membered carbon ring or heterocycle, the ring being partially unsaturated or saturated.

[0015] In another preferred example, the above [ka] The ring is, [ka] That is the case.

[0016] In another preferred example, the above [ka] The ring is, [ka] It is selected from the group consisting of the following.

[0017] In another preferred example, the B ring is a substituted or unsubstituted C6-C 10 An aryl group, a substituted or unsubstituted 5-12 membered heteroaryl group, a substituted or unsubstituted 4-12 membered heterocycle containing 1-3 heteroatoms selected from oxygen, sulfur, and nitrogen, or a substituted or unsubstituted C3-C 12 Selected from the group consisting of carbocyclic rings.

[0018] In another preferred example, ring A is, [ka] A group consisting of Y is selected, where Y 1 and Y 2 Each of them is independent of CHR 6 or NR6 Selected from the group consisting of, 0-2 means that the number of carbon atoms can be 0, 1 or 2, and the LB structure is Y 1 , Y 2 or can be located on other ring atoms (preferably Y 1 , Y 2 (located above), Alternatively, the A ring consists of two R 4 Together, [ka] A group is formed by selecting from the group consisting of Y, where Y 1 and Y 2 Each of them is independent of CHR 6 , O or NR 6 Selected from the group consisting of X 5 , X 6 , X 7 and X 8 Each of them operates independently, CR 6 Alternatively, it is selected from the group consisting of N.

[0019] In another preferred example, ring A is, [ka] A substituted or unsubstituted group selected from the group consisting of (where, if the linking site that connects to other structural fragments or substituents is NH, a hydrogen atom on the NH is lost, thereby forming the linking site), Alternatively, the A ring consists of two R 4 Together with, [ka] A substituted or unsubstituted group is formed from the selected group (where, if the linking site to other structural fragments or substituents is NH, a hydrogen atom on the NH is lost, thereby forming the linking site).

[0020] In another preferred example, the substituent on the A ring is H, halogen, cyano group, amino group, nitro group, carbonyl group, hydroxy group, mercapto group, aldehyde group, carboxy group, sulfonyl group, substituted or unsubstituted C1-C6 alkyl group, substituted or unsubstituted C1-C6 alkylamine group, substituted or unsubstituted C3-C8 carbocyclic ring, substituted or unsubstituted C2-C6 acyl group, substituted or unsubstituted C2-C 10 ester group, substituted or unsubstituted C1-C6 amide group, substituted or unsubstituted C1-C4 alkyl-S(O)2-, and is selected from the group consisting of groups.

[0021] In another preferred example, the compound has a structure as shown in the following formula II.

Chemical formula

[0022] In another preferred example, the compound has a structure as shown in the following formula III,

Chemical formula

[0023] In another preferred example, the compound has a structure as shown in the following formula IV or formula IVA: [ka] Here, A 1 The ring is selected from the group consisting of substituted or unsubstituted saturated or partially unsaturated (non-aromatic) 5- to 8-membered carbon rings, and substituted or unsubstituted saturated or partially unsaturated (non-aromatic) 5- to 8-membered heterocycles. A 2 The ring is C6-C, either substituted or unsubstituted. 10An aryl group, a substituted or unsubstituted 5- to 12-member heteroaryl group, a substituted or unsubstituted 5- to 7-member heterocyclic ring containing 1 to 3 heteroatoms selected from oxygen, sulfur and nitrogen, a substituted or unsubstituted C3-C 12 selected from the group consisting of carbocyclic rings, and A 2 ring and A 1 rings are fused, A 3 ring and A 4 rings are each independently selected from the group consisting of a substituted or unsubstituted saturated or partially unsaturated (non-aromatic) 5- to 8-member carbocyclic ring, a substituted or unsubstituted saturated or partially unsaturated (non-aromatic) 3- to 8-member heterocyclic ring, m is 0, 1, 2, 3 or 4, and R 5 is H, halogen, cyano group, amino group, nitro group, hydroxy group, mercapto group, aldehyde group, carboxy group, sulfonyl group, a substituted or unsubstituted C1-C6 alkyl group, a substituted or unsubstituted C1-C6 alkoxy group, a substituted or unsubstituted C1-C6 alkylamine group, a substituted or unsubstituted C2-C6 acyl group, a substituted or unsubstituted C2-C6 ester group, a substituted or unsubstituted C6-C 10 aryloxy group or heteroaryloxy group, a substituted or unsubstituted C6-C 10 arylamine group or heteroarylamine group, a substituted or unsubstituted C1-C6 amide group, a substituted or unsubstituted -C1-C6 alkyl-phenyl group, a substituted or unsubstituted C1-C4 alkyl-S(O)2-, a substituted or unsubstituted C1-C4 alkyl-SO- selected from the group consisting of, and R 5 is A 1 ring, A 2 ring, A 3 ring or A 4 can be located on the ring.

[0024] In another preferred example, the compound has a structure as shown in the following formula V or formula VI,

Chemical formula

[0025] In another preferred example, the C ring is selected from the group consisting of a benzene ring, a 5- to 7-membered heteroaryl ring, and a 5- to 7-membered saturated or partially unsaturated heterocycle.

[0026] In another preferred example, the A ring is selected from the group consisting of substituted or unsubstituted saturated or partially unsaturated (non-aromatic) 5-6 membered carbon rings and substituted or unsubstituted saturated or partially unsaturated (non-aromatic) 5-7 membered hetero rings.

[0027] In another preferred example, the B ring is a substituted or unsubstituted C6-C 10 An aryl group, a substituted or unsubstituted 5-7 membered heteroaryl group, a substituted or unsubstituted 4-12 membered heterocycle containing 1-3 heteroatoms selected from oxygen, sulfur, and nitrogen, or a substituted or unsubstituted C3-C 12 Selected from the group consisting of carbocyclic rings.

[0028] In another preferred example, the compound of formula I has a structure as shown in the following formula, [ka] X 5 , X 6 , X 7 and X 8 Each element is independently selected from the group consisting of C(R)2, NR, CR, or N, and the dashed lines indicate chemical bonding or absence.

[0029] A second aspect of the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I described in the first aspect of the present invention, or a pharmaceutically acceptable salt thereof, as well as one or more pharmaceutically acceptable carriers, excipients, adjuvants, auxiliaries and / or diluents.

[0030] A third aspect of the present invention provides the use of a compound of formula I described in the first aspect of the present invention, or a pharmaceutically acceptable salt thereof, in the preparation of a pharmaceutical composition for treating or preventing a disease associated with PRMT, preferably type I PRMT.

[0031] In another preferred example, the disease is selected from the group consisting of tumors, cardiovascular diseases, neurodegenerative diseases, malaria, AIDS, gout, diabetes, renal failure, chronic lung disease, oculopharyngeal muscular dystrophy, cocaine addiction, pulmonary hypertension, amyotrophic lateral sclerosis, and alcoholic cirrhosis.

[0032] In another preferred example, the tumor is selected from one of the following: brain tumor, glioblastoma, leukemia, lymphoma, Bannayan-Zonana syndrome, Cowden disease, Lhermitte-Duclos disease, breast cancer, Wilms' tumor, Ewing's sarcoma, rhabdomyosarcoma, ependymoma, medulloblastoma, colon cancer, stomach cancer, bladder cancer, head and neck cancer, kidney cancer, lung cancer, liver cancer, melanoma, ovarian cancer, pancreatic cancer, prostate cancer, sarcoma, osteosarcoma, giant cell tumor of bone, and thyroid cancer. [Effects of the Invention]

[0033] It should be understood that, within the scope of the present invention, new or preferred technical solutions can be constructed by combining the above-described technical features of the present invention with the technical features specifically described below (e.g., in the examples). Due to space limitations, this will not be repeated here. [Modes for carrying out the invention]

[0034] Through extensive and detailed research, the inventors unexpectedly discovered a compound with PRMT inhibitory effects for the first time. Based on this, the present invention was completed.

[0035] term In the present invention, the halogen is F, Cl, Br, or I. In this invention, unless otherwise specified, terms used have the ordinary meanings known to those skilled in the art. In this invention, unless otherwise specified, all chemical formulas encompass all conceivable optical or geometric isomers (e.g., R-type, S-type, or racemic mixtures, or cis-trans isomers of alkenes, etc.).

[0036] In the present invention, the term "C1-C6 alkyl group" refers to a linear or branched alkyl group having 1 to 6 carbon atoms, and is not limited to methyl, ethyl, propyl, isotropylic, butyl, isobutyl, s-butyl, t-butyl, pentyl, and hexyl groups, and preferably includes ethyl, propyl, isotropylic, butyl, isobutyl, s-butyl, and t-butyl groups.

[0037] In the present invention, the term "C1-C6 alkoxy group" refers to a linear or branched alkoxy group having 1 to 6 carbon atoms, and is not limited to methoxy groups, ethoxy groups, propoxy groups, isopropoxy groups, and butoxy groups.

[0038] In the present invention, the term "C2-C6 alkenyl group" refers to a linear or branched alkenyl group having 2 to 6 carbon atoms including a double bond, and non-limitedly includes vinyl groups, propenyl groups, butenyl groups, isobutenyl groups, pentenyl groups, and hexenyl groups.

[0039] In the present invention, the term "C2-C6 alkynyl group" refers to a linear or branched alkynyl group having 2 to 6 carbon atoms including a triple bond, and non-limited to ethynyl, propynyl, butynyl, isobutynyl, pentynyl, and hexynyl groups.

[0040] In this invention, "C3-C 10The term "cycloalkyl group" refers to a cyclic alkyl group having 3 to 10 carbon atoms in its ring, and non-limitingly includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and cyclodecyl groups. The terms "C3-C8 cycloalkyl group," "C3-C7 cycloalkyl group," and "C3-C6 cycloalkyl group" have similar meanings.

[0041] In this invention, "C3-C 10 The term "cycloalkenyl group" refers to a cyclic alkenyl group having 3 to 10 carbon atoms in the ring, and non-limitingly includes cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, and cyclodecenyl groups. The term "C3-C7 cycloalkenyl group" has a similar meaning.

[0042] In this invention, "C1-C 12 The term "alkoxycarbonyl group" refers to an alkoxycarbonyl group having 1 to 12 carbon atoms in an alkyl chain, and non-limiting examples include methoxycarbonyl group, ethoxycarbonyl group, propoxycarbonyl group, isopropoxycarbonyl group, t-butoxycarbonyl group, benzyloxycarbonyl group, etc.

[0043] In this invention, "C1-C 12 The term "alkylaminocarbonyl group" refers to an alkylaminocarbonyl group having 1 to 12 carbon atoms in the alkyl chain, and non-limiting examples include methylaminocarbonyl group, ethylaminocarbonyl group, propylaminocarbonyl group, isopropylaminocarbonyl group, t-butylaminocarbonyl group, benzylaminocarbonyl group, dimethylaminocarbonyl group, etc.

[0044] In the present invention, the term "C5-C9 furanosyl group" refers to a furanosyl group having 5 to 9 carbon atoms bonded to the main chain at position 1 of the sugar group, and non-limiting examples include ribofuranosyl, furanodeoxyribosyl, galactofuranosyl, and the like.

[0045] In the present invention, the term "C5-C9 pyranosyl group" refers to a pyranosyl group having 5 to 9 carbon atoms bonded to the main chain at position 1 of the sugar group, and non-limiting examples include glucopyranuronosyl group, glucopyranuronosyl group, rhamnopyranosyl group, galactopyranosyl group, mannopyranosyl group, xylopyranosyl group, etc.

[0046] In the present invention, the terms "aromatic ring" and "aryl group" have the same meaning, and preferably, "aryl group" is "C6-C 12 "Aryl group" or "C6-C 10 It is an aryl group. 12 The term "aryl group" refers to aromatic ring groups such as phenyl groups and naphthyl groups, which have 6 to 12 carbon atoms in the ring and do not contain heteroatoms. 10 The term "aryl group" has a similar meaning.

[0047] In the present invention, the terms "aromatic heterocycle" and "heteroaryl group" have the same meaning and refer to a heteroaromatic group containing one or more heteroatoms. Heteroatoms referred to herein include oxygen, sulfur, and nitrogen. Examples include furyl, thienyl, pyridyl, pyrazolyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, and tetrazolyl groups. The heteroaryl group ring can be condensed with an aryl group, a heterocyclic group, or a cycloalkyl group, where the ring bonded to the parent structure is the heteroaryl group ring. The heteroaryl group may be optionally substituted or unsubstituted.

[0048] In this invention, the term "3-12 membered heterocyclic group" refers to a saturated or unsaturated 3-12 membered cyclic group, such as a dioxolyl group, which contains 1 to 3 heteroatoms selected from oxygen, sulfur, and nitrogen in its ring. The term "3-7 membered heterocyclic group" has a similar meaning.

[0049] In the present invention, the term “substitution” refers to the substitution of one or more hydrogen atoms of a particular group with a particular substituent. The particular substituent is the corresponding substituent described above, or the substituent appearing in each example. Unless otherwise specified, a substituent may have substituents selected from a particular group at any substituted position of the group, and such substituents may be the same or different at each position. Cyclic substituents, such as heterocycloalkyl groups, can bond to another ring, such as a cycloalkyl group, to form a spirocyclic system, for example, two rings having a common carbon atom. Those skilled in the art will understand that the substituent combinations envisioned by the present invention are stable or chemically feasible. The substituents include, but are not limited to, C1-8 alkyl groups, C2-8 alkenyl groups, C2-8 alkynyl groups, C3-8 cycloalkyl groups, 3-12 membered heterocyclic groups, aryl groups, heteroaryl groups, halogens, hydroxyl groups, carboxyl groups (-COOH), C1-8 aldehyde groups, C2-10 acyl groups, C2-10 ester groups, C1-C12 alkoxycarbonyl groups, amino groups, alkoxy groups, C1-10 sulfonyl groups, etc.

[0050] PRMT inhibitor compounds The present invention provides compounds having PRMT inhibitory activity, or pharmaceutically acceptable salts or deuterated products thereof. [ka] Here, the definitions of each group are as described above. In the present invention, preferred compounds have a structure such as that shown in any of the compounds P001 to P448 of the examples.

[0051] Pharmaceutical composition and method of administration Because the compounds of the present invention possess excellent type I PRMT inhibitory activity, the compounds of the present invention and their various crystalline forms, pharmaceutically acceptable inorganic or organic salts, hydrates or solvates, and pharmaceutical compositions containing the compounds of the present invention as a major active ingredient can be used to treat, prevent and alleviate related diseases caused by abnormal activity or expression levels of PRMT.

[0052] The pharmaceutical composition of the present invention comprises the compound of the present invention or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient or carrier in a safe and effective amount. Here, “safe and effective amount” means an amount of the compound sufficient to significantly improve the condition without causing serious side effects. Typically, the pharmaceutical composition contains 1 to 2000 mg of the compound / agent of the present invention, more preferably 5 to 500 mg of the compound / agent of the present invention. Preferably, “one agent” is one capsule or tablet.

[0053] "Pharmacochemically acceptable carrier" means one or more compatible solid or liquid fillers or gels that are suitable for human use and must have sufficient purity and sufficiently low toxicity. "Compatibility" means that each component of the composition can be blended with each other in relation to the compounds of the present invention and among them without significantly reducing the potency of the compounds. Some examples of pharmaceutically acceptable carriers include cellulose and its derivatives (e.g., sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (e.g., stearic acid, magnesium stearate), calcium sulfate, vegetable oils (e.g., soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (e.g., propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (e.g., Tween®), wetting agents (e.g., sodium lauryl sulfate), colorants, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0054] The method of administration of the compound or pharmaceutical composition of the present invention is not particularly limited, and typical methods of administration include (but are not limited to) oral, intratumoral, rectal, parenteral (intravenous, intramuscular, or subcutaneous), and topical administration.

[0055] 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 inactive excipient (or carrier), such as sodium citrate or dicalcium phosphate, or (a) fillers or compatibilizers such as starch, lactose, sucrose, glucose, mannitol, and silicic acid; (b) binders such as hydroxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and gum arabic; (c) humectants such as glycerin; (d) agar, calcium carbonate, potato starch. It is mixed with components such as (e) potato starch or tapioca starch, tapioca starch, alginic acid, certain complex silicates, and disintegrants such as sodium carbonate, (e) retarders such as paraffin, (f) absorption enhancers such as quaternary amine compounds, (g) wetting agents such as cetyl alcohol and glyceryl monostearate, (h) adsorbents such as kaolin, and (i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, or mixtures thereof. In capsules, tablets, and pills, the dosage form may also include a buffer.

[0056] Solid dosage forms such as tablets, sugar pills, capsules, pills, and granules can be prepared using coating 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 compound from such compositions can be delayed in specific parts of the digestive tract. Examples of usable embedding components are polymers and waxes. If necessary, the active compound can form microcapsules with one or more of the above excipients.

[0057] 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 inert diluents conventionally used in the art, such as water or other solvents, and solubilizers and emulsifiers such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butanediol, dimethylformamide, and oils, particularly cottonseed oil, peanut oil, corn germ oil, olive oil, sesame oil, and sesame oil, or mixtures thereof.

[0058] In addition to these inert diluents, the composition may also include auxiliary agents such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents and fragrances.

[0059] In addition to the active compound, the suspension may include suspending agents such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan, microcrystalline cellulose, aluminum methoxide and agar, or mixtures thereof.

[0060] Compositions for parenteral injection may include physiologically acceptable sterile aqueous or aqueous 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.

[0061] Dosage forms of the compounds of the present invention used for topical administration 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 as needed.

[0062] 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 by forming a PROTAC with other small molecule compounds or by forming an ADC with other large molecule compounds such as monoclonal antibodies.

[0063] When the pharmaceutical composition is used, the compound of the present invention is applied to mammals (e.g., humans) in need of treatment, where the dose at the time of administration is the effective dose to be considered, and for a person weighing 60 kg, the daily dose is usually 1 to 2000 mg, preferably 5 to 500 mg. Of course, the specific dose must also take into account factors such as the route of administration and the patient's health condition, all of which are within the scope of the skills of a skilled physician.

[0064] The present invention will be further described below in conjunction with specific embodiments. It should be understood that these embodiments are used solely for illustrative purposes and do not limit the scope of the invention. In the following embodiments, experimental methods that do not specify conditions generally follow conventional conditions or conditions proposed by the manufacturer. Unless otherwise specified, percentages and parts are calculated by weight.

[0065] Common synthesis methods: Intermediate Synthesis 1: Synthesis of 2-(2,3-difluoro-6,9-dihydro-5H-benzo[7]cyclopenten-7-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane (Intermediate A): [ka]

[0066] Stage 1:Dissolve 1,2-dibromo-4,5-difluorobenzene (A-1) (2.0 g, 7.36 mmol) and methyl acrylate (1.90 g, 22.1 mmol, 1.99 mL) in dimethylformamide (10 mL), add tetrabutylammonium bromide (2.37 g, 7.36 mmol) and potassium carbonate (2.54 g, 18.4 mmol), purge the reaction mixture with nitrogen gas for 1 minute, and add palladium acetate (33.03 mg, 147 μmol). Stir the reaction mixture at 80 °C for 16 hours. Filter the reaction mixture by suction, wash the filter cake three times with ethyl acetate (50 mL), wash the organic layer with water (100 mL), dry with magnesium sulfate, filter by suction, and concentrate the filtrate under reduced pressure until dry. Purification by column chromatography (silica, 15% ethyl acetate in petroleum ether) yielded the white solid compound (2E,2'E)-dimethyl 3,3'-(4,5-difluoro-1,2-phenylene) diacrylate (A-2) (6.0 g, 21.26 mmol, 96.3% yield). 1 H NMR (400MHz, CDCl3) δ (ppm) 7.93 (d, 2H), 7.39 (t, 2H), 6.31 (d, 2H), 3.85 (s, 6H).

[0067] Stage 2: (2E,2'E)-dimethyl 3,3'-(4,5-difluoro-1,2-phenylene) diacrylate (A-2) (6.0 g, 21.3 mmol) is dissolved in methanol (150 mL), palladium / carbon (1.0 g, 10%) is added, and the reaction mixture is degassed under reduced pressure and purged several times with hydrogen gas. The reaction mixture is stirred under a hydrogen balloon atmosphere and allowed to react for 16 hours. The reaction mixture is filtered by suction through diatomaceous earth, and the filter cake is washed three times with ethyl acetate (50 mL). The filtrate is concentrated under reduced pressure until dry. The filtrate is purified by column chromatography (silica, 15% ethyl acetate in petroleum ether) to obtain the colorless oily compound dimethyl 3,3'-(4,5-difluoro-1,2-phenylene)dipropionate (A-3) (5.8 g, 20.26 mmol, 95.31% yield). 1H NMR (400MHz, CDCl3) δ (ppm) 6.98 (t, 2H), 3.71 (s, 6H), 2.94 (t, 4H), 2.61 (t, 4H).

[0068] Stage 3: At 95°C, a solution of dimethyl 3,3'-(4,5-difluoro-1,2-phenylene)dipropionate (A-3) (1.0 g, 3.49 mmol) in xylene (5 mL) is slowly added dropwise to a suspension of xylene (5 mL) in NaH (209.59 mg, 5.24 mmol, 60% purity) under stirring conditions. Then, one drop of anhydrous ethanol is added dropwise to 1 mL of the dimethyl 3,3'-(4,5-difluoro-1,2-phenylene)dipropionate (A-3) xylene solution. After the addition is complete, the reaction temperature is raised to 115°C and the reaction is continued at this temperature for 1.5 hours. The six reactions are set up in parallel. The completion of the reactions and the formation of the target product are detected by LC-MS. The six reactions are combined and quenched with ice water (30 mL) and 1 M hydrochloric acid aqueous solution (30 mL), and extracted three times with ethyl acetate (40 mL). The organic layer was dried over magnesium sulfate, filtered by suction, and the filtrate was concentrated under reduced pressure until dry to obtain the yellow oily crude product 2,3-difluoro-7-oxo-6,7,8,9-tetrahydro-5H-benzo[7]cyclopentene-6-carboxylate methyl ester (A-4) (5.3g), which was used directly in the next step of the reaction without the need for purification. LCMS: (ESI) m / z = 254.7 [M + H] + ,268.8[M+14] + .

[0069] Stage 4:2,3-Difluoro-7-oxo-6,7,8,9-tetrahydro-5H-benzo[7]cyclopenten-6-carboxylate methyl ester (A-4) (5.3 g, 20.85 mmol) is dissolved in ethanol (60 mL), sodium hydroxide (1 M aqueous solution, 62.5 mL) is added, and the reaction mixture is reacted at 90 °C for 2 hours. The completion of the reaction and the formation of the target product are detected by LC-MS. The reaction mixture is concentrated under reduced pressure until dry, diluted with ethyl acetate (30 mL), washed with water (30 mL), the organic layer is dried over anhydrous magnesium sulfate, filtered by suction, and the filtrate is concentrated under reduced pressure until dry. The filtrate is purified by column chromatography (silica, 12% ethyl acetate in petroleum ether) to obtain the yellow solid compound 2,3-difluoro-8,9-dihydro-5H-benzo[7]cyclopenten-7(6H)-one (A-5) (2.6 g, 13.2 mmol, 2-step yield 78.9%). 1 H NMR (400MHz, CDCl3) δ (ppm) 7.06 (t, 2H), 2.78-2.95 (m, 4H), 2.53-2.69 (m, 4H).

[0070] Stage 5:Dissolve 2,3-difluoro-8,9-dihydro-5H-benzo[7]cyclopenten-7(6H)-one (A-5) (1.0 g, 5.10 mmol) in tetrahydrofuran (10 mL), add lithium bis(trimethylsilyl)amide (1 M tetrahydrofuran solution, 5.61 mL) at -70 °C, and react at -70 °C for 1 hour under nitrogen gas protection. Add N-phenylbis(trifluoromethanesulfonyl)imide (2.00 g, 5.61 mmol) at -70 °C, and slowly raise the reaction mixture to room temperature over 15 hours. Detect the end of the reaction by TLC (petroleum ether:ethyl acetate = 8:1, Rf = 0.8). Quench the reaction mixture with water (25 mL) and extract three times with ethyl acetate (15 mL). Dry the organic layer over magnesium sulfate, filter by suction, and concentrate the filtrate under reduced pressure until dry. The compound was purified by column chromatography (silica, 5% ethyl acetate in petroleum ether) to obtain the colorless oily compound 2,3-difluoro-6,9-dihydro-5H-benzo[7]cyclopenten-7-yltriflate (A-6) (1.27 g, 3.87 mmol, 75.91% yield). 1 H NMR (400MHz, CDCl3) δ (ppm) 6.87-7.09 (m, 2H), 5.89-5.97 (m, 1H), 3.35-3.49 (m, 2H), 2.89-3.02 (m, 2H), 2.55-2.75 (m, 2H).

[0071] Stage 6:2,3-Difluoro-6,9-Dihydro-5H-benzo[7]cyclopenten-7-yltriflate (A-6) (1.27 g, 3.87 mmol) and bis(pinacolate)diborone (1.08 g, 4.26 mmol) are dissolved in dioxane (20 mL). Potassium acetate (1.14 g, 11.61 mmol) and 1,1-bis(diphenylphosphonium)ferrocenepalladium chloride (283.09 mg, 386.89 μmol) are added, and the reaction mixture is purged with nitrogen gas for 1 minute. The reaction mixture is stirred at 100 °C for 16 hours under nitrogen gas protection. Complete depletion of the starting materials and the formation of new spots are detected by TLC (petroleum ether:ethyl acetate = 8:1, Rf = 0.8). The reaction mixture is cooled to room temperature, diluted with water (20 mL), and extracted three times with ethyl acetate (20 mL). The organic layer is dried over magnesium sulfate, filtered by suction, and the filtrate is concentrated under reduced pressure until dry. The filtrate is purified by column chromatography (silica, 3% ethyl acetate in petroleum ether) to obtain the yellow solid compound 2-(2,3-difluoro-6,9-dihydro-5H-benzo[7]cyclopenten-7-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane (intermediate A) (880 mg, 2.87 mmol, 74.3% yield). 1 H NMR:(400MHz,CDCl3)δ(ppm)6.95(m,1H),6.86(m,1H),6.54-6.69(m,1H),3.45-3.58(m,2H),2.87-3.01(m,2H),2.29-2.54(m,2H),1.25(s,12H)

[0072] Intermediate Synthesis 2: Synthesis of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)-1-(m-tolyl)-1,2,3,6-tetrahydropyridine (Intermediate B): [ka]

[0073] Stage 1:Dissolve 1-benzylpiperidine-4-one (B-1) (100 g, 528 mmol, 1.0 equivalent) in acetone (700 mL), add iodomethane (90.0 g, 634 mmol, 39.5 mL, 1.2 equivalents), and stir the reaction mixture at 20°C for 16 hours. A white solid precipitates. Filter the reaction mixture by suction filtration, wash the filter cake twice with dry acetone (200 mL), collect the filter cake, and concentrate it under reduced pressure until dry to obtain an off-white solid 1-benzyl-1-methyl-4-oxopiperidine-1-iodide (B-2) (297 g, 897 mmol, 84.86% yield), which can be used directly in the next step of the reaction without purification.

[0074] Stage 2: A turbid solution of 1-benzyl-1-methyl-4-oxopiperidine-1-iodide (B-2) (162 g, 489 mmol, 1.3 equivalents) in ethanol (400 mL) and water (200 mL) is added in batches to ethanol (500 mL) containing 3-methylaniline (40 g, 373 mmol, 1.0 equivalent) and potassium carbonate (7.74 g, 56.0 mmol, 0.15 equivalents) under reflux (90 °C). The reaction mixture is stirred further at 90 °C for 40 minutes. The reaction is terminated by TLC (petroleum ether:ethyl acetate = 4:1, Rf = 0.5), and the formation of new spots is detected. The reaction mixture is diluted with water (300 mL) and extracted three times with dichloromethane (200 mL). The organic layer is dried over magnesium sulfate, filtered by suction, and the filtrate is concentrated under reduced pressure until dry. The compound was purified by column chromatography (silica, 12% ethyl acetate in petroleum ether) to obtain the yellow syrup-like compound 1-(m-tolyl)piperidine-4-one (B-3) (59 g, 312 mmol, 83.5% yield). 1 H NMR (400MHz, CDCl3) δ (ppm) 7.21 (t, 1H), 6.79-6.89 (m, 2H), 6.75 (d, 1H), 3.61 (t, 4H), 2.59 (t, 4H), 2.35 (s, 3H).

[0075] Stage 3:Dissolve 1-(m-tolyl)piperidine-4-one (B-3) (90 g, 475 mmol, 1 equivalent) and 1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonyl fluoride (216 g, 715 mmol, 1.5 equivalents) in tetrahydrofuran (1200 mL), and add DBU (217 g, 1.43 mol, 215 mL, 3 equivalents) dropwise at 0°C. Stir the reaction mixture at 25°C for 3 hours. Detect completion of the reaction by LC-MS. Dilute the reaction mixture with water (1 L), adjust the pH to 3-4 with 10% phosphoric acid, and extract three times with methyl t-butyl ether (1 L). The organic layer is dried over magnesium sulfate, filtered by suction, and the filtrate is concentrated under reduced pressure until dry to obtain the crude product. The crude product is dispersed in petroleum ether (1.5 L), stirred at 20°C for 1 hour, filtered by suction, and the filtrate is concentrated under reduced pressure until dry to obtain the yellow oily crude product 1-(m-tolyl)-1,2,3,6-tetrahydropyridine-4-yl 1,1,2,2,3,3,4,4,4,4-nonafluorobutane-1-sulfonic acid ester (B-4) (175 g), which can be used directly in the next step of the reaction without purification. LCMS: (ESI) m / z = 472.1 [M + H] + .

[0076] Stage 4:Set up the two reactions in parallel. 1-(m-tolyl)-1,2,3,6-tetrahydropyridine-4-yl 1,1,2,2,3,3,4,4,4,4-nonafluorobutane-1-sulfonic acid ester (B-4) (70g, 148 mmol, 1.0 equivalent) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis(1,3,2-dioxaborane) (42.0g, 165 mmol, 1.11 equivalents) are mixed in 1,4 - Dissolve in dioxane (1000 mL), add potassium acetate (44 g, 448 mmol), degas the reaction mixture under reduced pressure, purge several times with nitrogen gas, and add 2-dicyclohexylphosphone-2,4,6-triisopropylbiphenyl (4.3 g, 9.02 mmol, 0.06 equivalents) and tris(dibenzylideneacetone)dipalladium (4.10 g, 4.47 mmol, 0.03 equivalents). Stir the reaction mixture at 90°C for 16 hours under nitrogen gas protection. Detect completion of the reaction by LC-MS. Cool the reaction mixture to room temperature, filter the reaction mixture by suction, wash the filter cake three times with petroleum ether (500 mL), and concentrate the filtrate under reduced pressure until dry. The crude product was purified by column chromatography (silica, 5% ethyl acetate in petroleum ether) to obtain a crude product. The crude product was slurryed with n-pentane (150 mL) to obtain the yellow solid 4-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)-1-(m-tolyl)-1,2,3,6-tetrahydropyridine (intermediate B) (32 g, 101.60 mmol, 34.21% yield, 95% purity). LCMS: (ESI) m / z = 300.2 [M + H] + , 1 H NMR(400MHz,CDCl3)δ(ppm)7.10-7.22(m,1H),6.70-6.81(m,2H),6.56-6.69(m,2H),3.76- 3.83(m,2H),3.33(t,2H),2.38-2.45(m,2H),2.38-2.46(m,1H),2.34(s,3H),1.30(s,12H).

[0077] Intermediate Synthesis 3: Synthesis of 2,3,4,5-tetrahydro-1H-benzo[d]azepine (intermediate C): [ka]

[0078] Stage 1: Hydrogen bromide (196.23 g, 800.34 mmol, 131.70 mL, 33% hydrogen bromide in acetic acid solution) is slowly added dropwise to a solution of 2,2'-(1,2-phenylene)diacetonitrile (C-1) (50 g, 320.14 mmol) in acetic acid (60 mL) at 25°C for 1 hour. The reaction mixture is then stirred for another hour. The end of the reaction is detected by TLC. The suspension is filtered, the isopropyl ether is washed off, and the solid compound is obtained. It is dried under reduced pressure to obtain a bright yellow solid 4-bromo-1H-benzo[d]azepine-2-amine (C-2). The bright yellow crude solid is used directly in the next step of the reaction without purification.

[0079] Stage 2: Dissolve 4-bromo-1H-benzo[d]azepine-2-amine(C-2) (88 g, 276.72 mmol, hydrochloride hydrobromide) in water (600 mL) and heat to 85°C. Gradually add sodium acetate (29.51 g, 359.74 mmol). Heat the reaction mixture to 95°C and stir for 6 hours. Detect the end of the reaction by TLC. Cool to room temperature, filter to obtain a solid compound, wash the solid compound with water to obtain the pink solid crude product 1H-benzo[d]azepine-2,4(3H,5H)-dione(C-3) (47 g). Use this crude product directly in the next step of the reaction without purification.

[0080] Stage 3:Dissolve 1H-benzo[d]azepine-2,4(3H,5H)-dione(C-3) (47g, 268.29 mmol) in toluene solution (50 mL), and slowly add boranedimethyl sulfide solution (10M, 80.49 mL) dropwise under a nitrogen gas atmosphere. Heat the pink reaction solution to 110°C and stir for 6 hours. Detect the completion of the reaction of the starting materials by TLC (Rf=0.40). Cool the reaction solution to room temperature, slowly add methanol (115 mL) dropwise, and after the addition is complete, heat the reaction solution to 100°C and stir for 1 hour. Cool to 20°C, add 4M hydrochloric acid-dioxane to adjust the pH of the reaction solution to 4-5, and stir the reaction mixture at 20°C for 2 hours. The reaction suspension was filtered to obtain a pink solid 2,3,4,5-tetrahydro-1H-benzo[d]azepine (intermediate C) (26 g, 141 mmol, 52.7% yield, hydrochloride). 1 H NMR (400MHz, DMSO-d6) δ (ppm) 9.50 (br, 2H), 7.14-7.24 (m, 4H), 3.10-3.20 (m, 8H).

[0081] Intermediate Synthesis 4: Synthesis of 7-(trifluoromethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (intermediate D): [ka]

[0082] Stage 1:Dissolve 2,3,4,5-tetrahydro-1H-benzo[d]azepine (intermediate C) (11 g free base, 74.72 mmol) in dichloromethane (220 mL), and add triethylamine (9.07 g, 89.7 mmol) at 25°C under nitrogen gas protection. Add trifluoromethanesulfonic anhydride (18.8 g, 89.7 mmol) dropwise at 0°C and stir the reaction mixture at 0°C for 1 hour. Detect the end of the reaction by LC-MS. Wash the reaction mixture sequentially once with saturated sodium bicarbonate aqueous solution (200 mL), twice with 1 M hydrochloric acid aqueous solution (200 mL), and once with saturated saline solution (200 mL). Dry the organic phase over magnesium sulfate and filter by suction. The filtrate was concentrated under reduced pressure until dry and purified by column chromatography (silica, 3% ethyl acetate in 1 petroleum ether) to obtain the white solid 1-(4,5-dihydro-1H-benzo[d]azepine-3(2H)-yl)-2,2,2-trifluoroethanone(D-1) (16 g, 65.8 mmol, 88.0% yield). LCMS: (ESI) m / z = 244.1 [M + H] + , 1 H NMR (400MHz, CDCl3) δ (ppm) 7.15-7.24 (m, 4H), 3.77-3.83 (m, 2H), 3.70-3.75 (m, 2H), 2.98-3.04 (m, 4H).

[0083] Stage 2:Two reactions are set up in parallel. At 0°C, 1-(4,5-dihydro-1H-benzo[d]azepine-3(2H)-yl)-2,2,2-trifluoroethanone (D-1) (8.0 g, 32.9 mmol) is added to concentrated sulfuric acid (32 mL) and stirred for 10 minutes to obtain a grayish-yellow solution. At 0°C, potassium nitrate (2.66 g, 26.3 mmol) is added in batches over 20 minutes. The reaction mixture is stirred at 0°C for 30 minutes. Complete depletion of the starting materials is detected by TLC. The reaction mixture is slowly poured into ice water (50 mL) while stirring and extracted three times with ethyl acetate (50 mL). The organic layer was washed once with saturated saline (50 mL), dried over magnesium sulfate, filtered by suction, and the filtrate was concentrated under reduced pressure until dry. Purification by column chromatography (silica, 5% ethyl acetate in 1 petroleum ether) yielded the white solid 2,2,2-trifluoro-1-(7-nitro-4,5-dihydro-1H-benzo[d]azepine-3(2H)-yl)ethanone (D-2) (8.6 g, 29.8 mmol, 45.2% yield, 99.7% purity). LCMS: (ESI) m / z = 288.9 [M + H] + , 1 H NMR (400MHz, CDCl3) δ (ppm) 8.05-8.10 (m, 2H), 7.32-7.39 (m, 1H), 3.80-3.87 (m, 2H), 3.77 (m, 2H), 3.09-3.17 (m, 4H).

[0084] Stage 3:Dissolve 2,2,2-trifluoro-1-(7-nitro-4,5-dihydro-1H-benzo[d]azepine-3(2H)-yl)ethanone (D-2) (4.3 g, 14.9 mmol) in methanol (130 mL), and add 10% wet palladium carbon (794 mg, 746 μmol) under nitrogen gas protection. The suspension is purged three times with a hydrogen balloon, and the reaction mixture is stirred at 25°C for 16 hours under a hydrogen gas atmosphere. The end of the reaction is detected by LC-MS. The reaction mixture was filtered by suction, and the filtrate was concentrated under reduced pressure until dry. Purification by column chromatography (silica, 30% ethyl acetate in petroleum ether) yielded a bright yellow solid, 1-(7-amino-4,5-dihydro-1H-benzo[d]azepine-3(2H)-yl)-2,2,2-trifluoroethanone(D-3) (6.6 g, 25.5 mmol, 85.4% yield, 99.7% purity). LCMS: (ESI) m / z = 259.0 [M + H] + , 1 H NMR (400MHz, CDCl3) δ (ppm) 6.94 (dd, 1H), 6.47-6.55 (m, 2H), 3.71-3.78 (m, 2H), 3.57-3.70 (m, 4H), 2.83-2.94 (m, 4H).

[0085] Stage 4:Dissolve 1-(7-amino-4,5-dihydro-1H-benzo[d]azepine-3(2H)-yl)-2,2,2-trifluoroethanone(D-3) (4.5 g, 17.4 mmol) in a mixed solution of water (58 mL) and sulfuric acid (9.57 g, 97.6 mmol) at 0°C, and add an aqueous solution of NaNO2 (1.56 g, 22.6 mmol) (29 mL) dropwise. After the addition is complete, stir for 10 minutes. Add an aqueous solution of NaI (3.92 g, 26.1 mmol) in sulfuric acid (1 mol / L, 5.8 mL) to the above solution. Allow the reaction mixture to rise naturally to 25°C and stir for 16 hours. Detect complete depletion of the starting materials by TLC. Extract the reaction mixture three times with dichloromethane (100 mL). The organic layer was washed twice with a semi-saturated sodium thiosulfate aqueous solution (100 mL), dried over magnesium sulfate, filtered by suction, and the filtrate was concentrated under reduced pressure until dry. The filtrate was then purified by column chromatography (silica, 4.3% ethyl acetate in petroleum ether) to obtain the white solid 2,2,2-trifluoro-1-(7-iodo-4,5-dihydro-1H-benzo[d]azepine-3(2H)-yl)ethanone (D-4) (4.7 g, 12.7 mmol, 73.1% yield). 1 19F NMR(376MHz, CDCl3)δ(ppm)-68.07.

[0086] Stage 5:2,2,2-trifluoro-1-(7-iodo-4,5-dihydro-1H-benzo[d]azepine-3(2H)-yl)ethanone (D-4) (250 mg, 677 μmol) is dissolved in dimethylformamide (2 mL), and fluorosulfonyl difluoroacetate methyl (651 mg, 3.39 mmol), cuprous iodide (26 mg, 135 μmol), and azomethylpyrrolidone (806 mg, 8.13 mmol) are added sequentially at 25°C under a nitrogen atmosphere. The reaction mixture is heated to 80°C and stirred for 12 hours. The end of the reaction is detected by LC-MS. The reaction mixture is diluted with water (10 mL) and filtered by suction. The filtrate is extracted twice with ethyl acetate (10 mL). The organic layer was dried over magnesium sulfate, filtered by suction, concentrated under reduced pressure until dry, and purified by column chromatography (silica, 4% ethyl acetate in petroleum ether) to obtain the yellow solid 2,2,2-trifluoro-1-(7-(trifluoromethyl)-4,5-dihydro-1H-benzo[d]azepine-3(2H)-yl)ethanone (D-5) (180 mg, 578 μmol, 85.4% yield).

[0087] Stage 6: Dissolve 2,2,2-trifluoro-1-(7-(trifluoromethyl)-4,5-dihydro-1H-benzo[d]azepine-3(2H)-yl)ethanone (D-5) (120 mg, 386 μmol) in methanol (3 mL), and add potassium carbonate (160 mg, 1.16 mmol) all at once. Heat the reaction mixture to 50°C and stir for 12 hours. Detect complete depletion of the starting materials and the formation of the target product by LC-MS. Concentrate the reaction mixture to dryness. Add water (5 mL) and extract three times with ethyl acetate (5 mL). Dry the organic layer over magnesium sulfate, filter by suction, and concentrate under reduced pressure to dryness to obtain a yellow syrup-like crude product, 7-(trifluoromethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (intermediate D) (80 mg), which does not require further purification and can be used directly in the next step of the reaction. LCMS:(ESI)m / z=215.9[M+H] + ,

[0088] Intermediate Synthesis 5: Synthesis of 7,8-difluoro-2,3,4,5-tetrahydro-1H-benzo[d]azepine (intermediate E): [ka]

[0089] Stage 1: Dissolve 2-(2-bromoethoxy)tetrahydro-2H-pyran(E-1) (18g, 86.09 mmol) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis(1,3,2-dioxaborane) (26.2g, 103 mmol) in dimethylformamide (350 mL), and add lithium methoxide (6.54 g, 172.18 mmol, 2.0 equivalents), cuprous iodide (1.64 g, 8.61 mmol), and triphenylphosphine resin (2.25 g, ~3 mmol / g, 8.61 mmol). Stir the reaction mixture at 25°C for 12 hours. After detecting the end of the reaction, dichloromethane (200 mL) is added to dilute the mixture, diatomaceous earth is added, and the mixture is filtered. The filter cake is washed twice with dichloromethane (100 mL), the filtrates are combined, and the mixture is concentrated under reduced pressure until dry. The mixture is poured into a saturated ammonium chloride solution and extracted three times with t-butyl methyl ether (200 mL). The resulting organic phases are washed with water (300 mL) and saturated brine (300 mL), respectively, dried over anhydrous sodium sulfate, filtered by suction, and the filtrate is concentrated under reduced pressure until dry to obtain a colorless oily crude product, 4,4,5,5-tetramethyl-2-(2-(((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1,3,2-dioxaborane(E-2) (19.0 g). The crude product does not need to be further purified and can be used directly in the next step of the reaction. 1 H NMR(400MHz,CDCl3)δ(ppm)4.62(t,1H),3.83-3.94(m,2H),3.46-3.59(m,2H),1. 77-1.91(m,1H),1.65-1.74(m,1H),1.45-1.61(m,4H),1.25(s,12H),1.19(t,2H).

[0090] Stage 2:Dissolve 4,4,5,5-tetramethyl-2-(2-(((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1,3,2-dioxaborane(E-2) (19 g, 74.18 mmol) in tetrahydrofuran (540 mL), dissolve potassium hydrogen fluoride (17.38 g, 222.53 mmol, 7.33 mL) in water (60 mL), add to the above solution, and stir at 25°C for 2 hours. Concentrate the reaction mixture under reduced pressure until dry, and freeze. The mixture is dried to obtain a white solid. It is washed four times with dry acetone (50 mL), filtered by suction, and the filtrate is concentrated under reduced pressure until dry. The obtained solid is slurryed and purified with t-butyl methyl ether (100 mL), filtered and collected, and dried to obtain a white solid (2-(((tetrahydro-2H-pyran-2-yl)oxy)ethyl) trifluoroborate potassium (E-3) (13.5 g, 57.18 mmol, 77.09% yield). 1 H NMR(400MHz,DMSO-d6)δ(ppm)4.44(dd,1H),3.72(ddd,1H),3.58(ddd,1H),3.33-3.39(m,1H) ,3.23(ddd,1H),1.64-1.77(m,1H),1.50-1.60(m,1H),1.29-1.49(m,4H),0.20-0.45(m,2H).

[0091] Stage 3:Dissolve 1,2-dibromo-4,5-difluorobenzene (E-4) (2.0 g, 7.36 mmol) and (2-(((tetrahydro-2H-pyran-2-yl)oxy)ethyl)trifluoroborate potassium (E-3) (3.99 g, 16.92 mmol) in water (10 mL) and dioxane (50 mL), respectively. Add bis(1-adamantyl)-butylphosphine (527.49 mg, 1.47 mmol), cesium carbonate (14.38 g, 44.14 mmol), and palladium acetate (495.45 mg, 2.21 mmol), respectively, and replace the reaction mixture with nitrogen gas for 5 minutes. Stir at 100°C for 16 hours. TLC (petroleum ether:ethyl acetate = 8: 1) Complete depletion of the raw materials and the formation of new spots are detected. The reaction mixture is filtered through diatomaceous earth, then diluted with water (30 mL), extracted three times with ethyl acetate (50 mL), the organic phases are combined, washed with brine (100 mL), dried over anhydrous magnesium sulfate, filtered by suction, and the filtrate is concentrated under reduced pressure until dry. Purified by column chromatography (silica, 10% ethyl acetate in petroleum ether) to obtain yellow oily 2,2'-((((4,5-difluoro-1,2-phenylene)bis(ethane-2,1-diyl))bis(oxy))bis(tetrahydro-2H-pyran)(E-5) (1.25 g, 3.37 mmol, 45.87% yield). 1 H NMR(400MHz,CDCl3)δ(ppm)7.03(t,1H),6.97-7.09(m,1H),4.56-4.60(m,2H),3.91(td,2H),3.68-3.77(m, 2H), 3.57 (td, 2H), 3.42-3.52 (m, 2H), 2.91 (t, 4H), 1.75-1.87 (m, 2H), 1.65-1.74 (m, 2H), 1.45-1.63 (m, 8H).

[0092] Stage 4:Dissolve 2,2'-((((4,5-difluoro-1,2-phenylene)bis(ethane-2,1-diyl))bis(oxy))bis(tetrahydro-2H-pyran)(E-5) (1.25 g, 3.37 mmol) in methanol (15 mL), and add p-toluenesulfonic acid monohydrate (801.08 mg, 4.21 mmol, 1.2 equivalents). Stir the reaction mixture at 25 °C for 16 hours. Detect complete depletion of the starting material and the formation of new spots by TLC (petroleum ether:ethyl acetate = 10:1). Concentrate under reduced pressure. The solvent is removed, then dichloromethane (20 mL) and saturated sodium bicarbonate solution (20 mL) are added, and the aqueous phase is extracted five times with dichloromethane (20 mL). The organic layer is washed with saturated brine (50 mL), dried over anhydrous magnesium sulfate, filtered by suction, and the filtrate is concentrated under reduced pressure until dry to obtain the yellow solid 2,2'-(4,5-difluoro-1,2-phenylene)diethanol (E-6) (700 mg, 3.46 mmol, 98.65% yield), which can be used directly in the next step of the reaction without the need to purify the crude product. 1 H NMR (400MHz, CDCl3) δ (ppm) 7.03 (t, 2H), 3.86 (t, 4H), 2.88 (t, 4H), 1.97 (br, 2H).

[0093] Stage 5: Dissolve 2,2'-(4,5-difluoro-1,2-phenylene)diethanol (E-6) (700 mg, 3.46 mmol) and triethylamine (1.75 g, 17.31 mmol) in dichloromethane (15 mL), and add methanesulfonic anhydride (1.51 g, 8.65 mmol) at 0°C. Stir the reaction mixture at 0-25°C for 1 hour. Detect complete depletion of the starting materials and the formation of new spots by TLC (petroleum ether:ethyl acetate = 10:1). The mixture is quenched by adding saturated sodium bicarbonate (20 mL) dropwise, extracted three times with dichloromethane (20 mL), the organic phases are combined, dried, filtered by suction, and the filtrate is concentrated under reduced pressure until dry to obtain the crude product (4,5-difluoro-1,2-phenylene)bis(ethane-2,1-diyl)methanesulfonate (E-7) (1.32 g), which does not require further purification and can be used directly in the next step of the reaction. 1H NMR (400MHz, CDCl3) δ (ppm) 7.07 (t, 2H), 4.39 (t, 4H), 3.08 (t, 4H), 2.98 (s, 6H).

[0094] Stage 6: (4,5-difluoro-1,2-phenylene)bis(ethane-2,1-diyl)methanesulfonate (E-7) (1.22 g, 3.40 mmol) is dissolved in 1,2-dichloroethane (20 mL), benzylamine (3.65 g, 34.04 mmol) is added, and the reaction mixture is stirred at 50°C for 16 hours. LC-MS indicates the completion of the reaction. Saturated sodium bicarbonate (15 mL) is added, and the mixture is extracted twice with dichloromethane (15 mL). The organic phases are combined, dried over anhydrous magnesium sulfate, filtered by suction, and the filtrate is concentrated under reduced pressure until dry. Purification by column chromatography (silica, 5% ethyl acetate in petroleum ether) yielded a pale yellow liquid N-benzyl-7,8-difluoro-2,3,4,5-tetrahydro-1H-benzo[d]azepine (E-8) (600 mg, 1.98 mmol, 58.04% yield, 90% purity). LCMS: (ESI) m / z = 273.8 [M + H] + .

[0095] Stage 7: N-benzyl-7,8-difluoro-2,3,4,5-tetrahydro-1H-benzo[d]azepine (E-8) (600 mg, 2.20 mmol) is dissolved in methanol (15 mL) in hydrochloric acid / methanol (1 mL), and 10% palladium / carbon (233.62 mg, 219.52 μmol) is added. The reactants are purged several times with hydrogen gas under vacuum. The reactants are stirred at 50°C for 16 hours under a hydrogen balloon (15 Psi). The reaction is completed by LC-MS. The solvent is removed by concentration under reduced pressure to obtain a white solid 7,8-difluoro-2,3,4,5-tetrahydro-1H-benzo[d]azepine (intermediate E) (400 mg crude hydrochloride), which does not require further purification and is used directly in the next step of the reaction. LC-MS: (ESI) m / z = 184.0 [M + H] + , 1H NMR (400MHz, DMSO-d6) δ (ppm) 8.83 (br s, 1H), 7.31 (t, 2H), 2.98-3.16 (m, 8H).

[0096] Intermediate Synthesis 6: Synthesis of 2-(6,9-dihydro-5H-benzo[7]cyclopenten-7-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane (intermediate F): [ka] The synthesis of intermediate F can be traced back to the synthesis of intermediate A. 1 HNMR(400MHz,CHCl3)δ(ppm)7.15-7.18(m,2H),7.04-7.09(m,2H),6.62-6.73(m, 1H), 3.55-3.62(m, 2H), 3.01-3.07(m, 2H), 2.46-2.53(m, 2H), 1.21-1.27(m, 12H).

[0097] Example 1: (N 1 -((2-(4,5-dihydro-1H-benzo[d]azepine-3(2H)-yl)-6-methylpyridine-3-yl)methyl)-N 1 ,N 2 Synthesis of -dimethylethane-1,2-diamine) (compound P110): [ka]

[0098] Stage 1:Under nitrogen gas protection, 2-chloro-6-methylnicotinaldehyde (1-1) (100 mg, 643 μmol) and 2,3,4,5-tetrahydro-1H-benzo[d]azepine (intermediate C) (104 mg, 707 μmol) were dissolved in DMF (2 mL), DIPEA (166 mg, 1.29 mmol) was added, and the reaction was carried out at 100°C for 16 hours with stirring. The reaction was completed by LC-MS. After concentrating the reaction mixture, it was separated and purified by column chromatography (silica gel column, 0-7% ethyl acetate / petroleum ether gradient elution) to obtain the yellow solid compound 2-(4,5-dihydro-1H-benzo[d]azepine-3(2H)-yl)-6-methylnicotinaldehyde (1-2) (90 mg, 314.26 μmol, 48.89% yield, 93% purity). LCMS:(ESI)m / z=267.1[M+H] + .

[0099] Stage 2: Compounds 2-(4,5-dihydro-1H-benzo[d]azepine-3(2H)-yl)-6-methylnicotinaldehyde (1-2) (110 mg, 413 μmol) and methyl(2-(methylamino)ethyl)carbamate t-butyl ester (78 mg, 413 μmol) were dissolved in 10 ml of dichloromethane, and AcOH (25 mg, 413 μmol) was added dropwise. The yellow reaction mixture was stirred at 20°C for 2 hours. NaBH(OAc)3 (263 mg, 1.24 mmol) was added in batches, and the yellow reaction mixture was stirred at 20°C for 14 hours. The reaction was completed by LC-MS. The reaction was quenched by adding saturated NaHCO3 (20 mL) aqueous solution dropwise, and the mixture was extracted with dichloromethane (20 mL x 3). The organic phase is washed with saturated brine, dried over magnesium sulfate, filtered, and concentrated to obtain a yellow mucilage crude product (2-((2-(4,5-dihydro-1H-benzo[d]azepine-3(2H)-yl)-6-methylpyridine-3-yl)methyl)(methyl)amino)ethyl)(methyl)carbamate t-butyl ester (1-3) (150 mg, crude), which does not require purification and can be used directly in the next step of the reaction. LCMS: (ESI) m / z = 439.3 [M + H] + .

[0100] Stage 3: 2-((2-(4,5-dihydro-1H-benzo[d]azepine-3(2H)-yl)-6-methylpyridine-3-yl)methyl)(methyl)amino)ethyl)(methyl)carbamate t-butyl ester (1-3) (150 mg, 342 μmol) was carefully mixed with HCl / 1,4-dioxane (5 mL) solution and reacted at room temperature with stirring for 16 hours. The reaction was monitored by LC-MS to confirm completion, and the reaction mixture was concentrated to obtain the crude product. The crude product was purified by preparative HPLC (column: Boston Green ODS 150 × 30 mm × 5 μm, liquid phase: [water (0.05% HCl)-ACN], B%: 0%~38%, 9 minutes), collected, and freeze-dried at low temperature to obtain a yellow solid product N 1 -((2-(4,5-dihydro-1H-benzo[d]azepine-3(2H)-yl)-6-methylpyridine-3-yl)methyl)-N 1 ,N 2 Dimethylethane-1,2-diamine (P110, Example 1) (110 mg, 318 μmol, 93.1% yield, 98% purity) was obtained. LC-MS: (ESI) m / z = 339.3 [M + H] + , 1 H NMR(400MHz,D2O)δ(ppm)8.29(d,1H),7.32(d,1H),7.27(s,4H),4.35(s,2H),3 .53(t,4H),3.39(s,4H),3.16(t,,4H),2.72(s,3H),2.60(s,3H),2.46(s,3H).

[0101] Example 2: Compound N 1 ,N 2 -dimethyl-N 1 Synthesis of -((6-methyl-2-(1-(m-tolyl)piperidine-4-yl)pyridine-3-yl)methyl)ethane-1,2-diamine (P081) [ka]

[0102] Stage 1:Compound 2-chloro-6-methylnicotinaldehyde (2-1) (10.0 g, 64.3 mmol), methyl (2-(methylamino)ethyl)carbamate t-butyl ester (13.3 g, 70.7 mmol), and AcOH (4.25 g, 70.7 mmol) were dissolved in dichloromethane (150 mL) and reacted for 2 hours with stirring at 25°C. NaBH(OAc)3 (40.9 g, 1923 mmol) was carefully added in batches and the mixture was continued to stir at room temperature for 16 hours. After the starting materials disappeared by LC-MS, the reaction was quenched by carefully adding NaHCO3 (300 mL) and extracted with dichloromethane (200 mL x 3). The organic phases were combined, dried over anhydrous magnesium sulfate, filtered, concentrated, and then separated and purified by column chromatography (silica gel column, 0-10% ethyl acetate / petroleum ether gradient elution). The mixture was then concentrated again to obtain a yellow, viscous product: (2-((2-chloro-6-methylpyridine-3-yl)methyl)(methyl)amino)ethyl)(methyl)carbamate t-butyl ester (2-2) (13.0 g, 38.4 mmol, 59.8% yield). LCMS: (ESI) m / z = 328.0 [M + H] + , 1 H NMR(400MHz,CDCl3)δ(ppm)7.65-7.78(m,1H),7.09(d,1H),3.60(s,2H),3.25-3.50( m,2H),2.86(s,3H),2.52-2.65(m,2H),2.52(s,3H),2.30(s,3H),1.35-1.49(m,9H).

[0103] Stage 2:To 70 mL of tetrahydrofuran, (2-((2-chloro-6-methylpyridine-3-yl)methyl)(methyl)amino)ethyl)(methyl)carbamate t-butyl ester (2-2) (7.02 g, 21.4 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)-1-(m-tolyl)-1,2,3,6-tetrahydropyridine (intermediate B) (7.05 g, 23.6 mmol), and an aqueous solution of tripotassium phosphate (9.10 g, 42.9 mmol) (14 mL) were added sequentially. After the reaction system was subjected to several rounds of reduced pressure and nitrogen gas purging, XPhos-Pd-G2 (510 mg, 648 μmol) was added, and the reaction mixture was heated to 85°C in an oil bath under nitrogen gas protection and reacted for 30 hours, while monitoring the disappearance of the starting materials by LCMS. After cooling to room temperature, the reaction mixture is diluted with saturated saline (50 mL) and ethyl acetate (100 mL). The organic phase is separated, the aqueous phase is extracted with ethyl acetate, the organic phases are combined, dried over anhydrous magnesium sulfate, filtered, concentrated, and then separated by column chromatography (silica gel column, 0-10-30% ethyl acetate / dichloromethane gradient elution). Concentrated to obtain the yellow mucilage methyl(2-(methyl((6-methyl-1'-(m-tolyl)-1',2',3',6'-tetrahydro-[2,4'-bipyridine]-3-yl)methyl)amino)ethyl)carbamate t-butyl ester (2-3) (10.9 g, 19.9 mmol, 93.1% yield, 85% purity). LCMS: (ESI) m / z = 465.2 [M + H] + , 1 H NMR(400MHz,CDCl3)δ(ppm)7.70(d,1H),7.18(t,1H),6.99-7.08(m,1H),6.81 (s,1H),6.78-6.81(m,1H),6.66(d,1H),5.84-5.93(m,1H),3.86-3.93(m,2H) ,3.56(t,2H),3.51(s,2H),3.21-3.41(m,2H),2.82(s,3H),2.62-2.71(m,2H) ,2.54(s,3H),2.39-2.52(m,2H),2.35(s,3H),2.20(s,3H),1.34-1.54(m,9H).

[0104] Stage 3:Dissolve methyl(2-(methyl((6-methyl-1'-(m-tolyl)-1',2',3',6'-tetrahydro-[2,4'-bipyridine]-3-yl)methyl)amino)ethyl)carbamate t-butyl ester (2-3) (7.84 g, 16.9 mmol) in 250 mL of ethyl acetate, and add 10% wet Pd(OH)2 / C (3.16 g) under nitrogen gas protection. After purging the system several times with a hydrogen balloon, react at room temperature with stirring under hydrogen gas protection for 36 hours. Monitor the completion of the reaction by LC-MS. The reaction mixture was filtered through diatomaceous earth, washed with ethyl acetate, and then combined with the organic phase and concentrated. Separation and purification were performed by column chromatography (silica gel column, 0-25% ethyl acetate / dichloromethane gradient elution) to obtain the yellow mucilage methyl(2-(methyl((6-methyl-2-(1-(m-tolyl)piperidine-4-yl)pyridine-3-yl)methyl)amino)ethyl)carbamate t-butyl ester (2-4) (8.86 g, 18.0 mmol, 76.9% yield). LCMS: (ESI) m / z = 467.4 [M + H] + , 1 H NMR(400MHz,CDCl3)δ(ppm)7.45(d,1H),7.17(t,1H),6.92(d,1H),6.82(s,1H) ,6.78-6.81(m,1H),6.67(d,1H),3.76-3.86(m,2H),3.50(s,2H),3.23-3.43(m, 2H),3.03-3.17(m,1H),2.84(s,3H),2.73-2.83(m,2H),2.49-2.63(m,1H),2.4 9(s,3H),2.33(s,3H),2.14-2.29(m,5H),1.75-1.84(m,2H),1.33-1.51(m,9H).

[0105] Stage 4:Methyl (2-(methyl((6-methyl-2-(1-(m-tolyl)piperidine-4-yl)pyridine-3-yl)methyl)amino)ethyl)carbamate t-butyl ester (2-4) (11.7 g, 25.1 mmol) is dissolved in methanol (70 mL), and HCl / 1,4-dioxane (4 M, 75 mL) is added dropwise while stirring. The reaction mixture is stirred at room temperature under nitrogen gas protection for 16 hours, and the completion of the reaction is monitored by LC-MS. After concentrating the reaction mixture, about 200 mL of methanol is added, and the mixture is spin-dried under reduced pressure. This process is repeated to remove hydrochloric acid. The concentrate is diluted with methanol, decolorized by heating on activated carbon, cooled to room temperature, filtered, washed with methanol, concentrated to about 100 mL, isopropanol is added to replace the methanol, and concentrated to 250 mL. The reaction emulsion is heated at 85 °C for 30 minutes, stirred at 30 °C for 10 hours, and cooled to room temperature. The mixture is filtered, and the solid is collected after sequentially washing with isopropanol (100 mL) and n-pentane (200 mL x 2), and dried under vacuum. The solid product is dissolved in 150 mL of water, filtered, and the filtrate is freeze-dried to obtain a white solid product N. 1 ,N 2 -dimethyl-N 1 -((6-methyl-2-(1-(m-tolyl)piperidine-4-yl)pyridine-3-yl)methyl)ethane-1,2-diamine (P081, Example 2) (hydrochloride, 9.8 g, 19.1 mmol, 76.2% yield, 99.9% purity) was obtained. LCMS: (ESI) m / z = 367.3 [M + H] + , 1 H NMR(400MHz,D2O)δ(ppm)8.52(d,1H),7.83(d,1H),7.52(s,1H),7.43-7.51(m,2H),7.36-7.42(m,1H),4.72(s,2H),3.93-4.07(m,3H),3.82- 3.91(m,2H),3.67-3.76(m,2H),3.55-3.63(m,2H),2.85(s,3H),2.81( s,3H),2.80(s,3H),2.46-2.60(m,2H),2.39(s,3H),2.31-2.39(m,2H).

[0106] Example 3: N 1 -((6-amino-2-(1-(m-tolyl)piperidine-4-yl)pyridine-3-yl)methyl)-N 1 ,N 2 Synthesis of -dimethylethane-1,2-diamine (P226) [ka]

[0107] Stage 1: Add triethylamine (17.2 g, 170 mmol, 23.7 mL) to a solution of 2,6-dichloronicotinic acid (3-1) (25 g, 142 mmol) and bis(4-methoxybenzyl)amine (40.2 g, 156 mmol) in DMF (200 mL). Stir the reaction mixture at 50 °C for 16 hours and monitor for the completion of the reaction by LC-MS. Pour the mixture into 200 mL of ice water and extract with ethyl acetate (400 mL x 1, 200 mL x 2). The organic phase was combined, washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, concentrated, and separated and purified by column chromatography (silica gel column, 0-20% ethyl acetate / (petroleum ether:dichloromethane = 5:1) gradient elution) to obtain the white solid compound 6-(bis(4-methoxybenzyl)amino)-2-chloronicotinic acid (3-2) (50 g, 124.83 mmol, 87.88% yield, 99.08% purity). LCMS: (ESI) m / z = 397.1 [M + H] + , 1 H NMR (400MHz, DMSO-d6), δ (ppm) 10.02 (s, 1H), 7.86 (d, 1H), 7.27- 7.12 (m, 4H), 6.90 (d, 4H), 6.73 (d, 1H), 4.78 (br, 4H), 3.73 (s, 6H).

[0108] Stage 2:6-(bis(4-methoxybenzyl)amino)-2-chloronicotinic acid (3-2) (800 mg, 2.02 mmol), 1-(m-tolyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)-3,6-dihydro-2H-pyridine (intermediate B) (1.02 g, 2.40 mmol, 70% purity), tetrahydrofuran (6 mL), and aqueous potassium phosphate solution (856 mg of potassium phosphate dissolved in 1 mL of water) were added sequentially to the reaction bottle. The reaction system was then purged several times with nitrogen gas under reduced pressure, and XPhos-Pd-G3 (37 mg, 43.71 μmol) was added under nitrogen gas protection. The mixture was heated to 70°C in an oil bath under nitrogen gas protection and reacted for 2.5 hours with stirring, while monitoring product formation by LC-MS. After cooling to room temperature, saturated saline solution was added to the reaction mixture, and it was extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous magnesium sulfate, filtered, concentrated, and then separated and purified by column chromatography (silica gel column, 0-10-15% ethyl acetate / petroleum ether gradient elution) to obtain the yellow viscous product 6-(bis(4-methoxybenzyl)amino)-1'-(m-tolyl)-1',2',3',6'-tetrahydro-[2,4'-bipyridine]-3-formaldehyde(3-3) (1.01 g, 1.50 mmol, 74.2% yield, 79% purity), LCMS: (ESI) m / z = 534.3 [M+H]. + .

[0109] Stage 3:Add 6-(bis(4-methoxybenzyl)amino)-1'-(m-tolyl)-1',2',3',6'-tetrahydro-[2,4'-bipyridine]-3-formaldehyde (3-3) (801 mg, 1.50 mmol) and ethyl acetate (50 mL) to the reaction bottle, and add Pd(OH)2 / C (450 mg, 10% Pd(OH)2 / C) under nitrogen gas protection. After purging the reaction system with hydrogen gas, the reaction is carried out at room temperature with stirring under a hydrogen gas atmosphere (hydrogen balloon) for 18 hours. The reaction mixture was filtered and concentrated, then separated and purified by column chromatography (silica gel column, 0-25% ethyl acetate / petroleum ether gradient elution) to obtain the yellow viscous product (6-(bis(4-methoxybenzyl)amino)-2-(1-(m-tolyl)piperidine-4-yl)pyridine-3-yl)methanol(3-4) (695 mg, 1.23 mmol, 64.9% yield, 95% purity). LCMS: (ESI) m / z = 538.3 [M+H] + , 1 H NMR(400MHz,CDCl3)δ(ppm)7.34(d,1H),7.09-7.24(m,5H),6.77-6.92(m,6H),6.68(br d,1H),6.29(d,1H),4.73(s,4H),4.65(d,2H),3.81(s,6H),3.72-3.81(m,1H),2.99-3.13( m,1H),2.75-2.88(m,2H),2.33(s,3H),2.15-2.30(m,2H),1.80-1.92(m,2H),1.40(t,1H).

[0110] Stage 4:The compound (6-(bis(4-methoxybenzyl)amino)-2-(1-(m-tolyl)piperidine-4-yl)pyridine-3-yl)methanol (3-4) (440 mg, 818 μmol) is added to 10 ml of dichloromethane, and Dess-Martin periodinane (347 mg, 818 μmol) is added while cooling in an ice bath. The reaction mixture is stirred at room temperature for 16 hours. The reaction is quenched by adding 20 ml of 10% sodium thiosulfate aqueous solution. After stirring for 30 minutes, 50 ml of saturated sodium bicarbonate aqueous solution is added, and the mixture is extracted three times with dichloromethane. The organic phases were combined, washed sequentially with saturated saline solution and saturated sodium bicarbonate aqueous solution, dried over anhydrous magnesium sulfate, filtered, concentrated, and then separated and purified by column chromatography (silica gel column, 0-16.8% ethyl acetate / petroleum ether gradient elution) to obtain a yellow, viscous liquid product, 6-(bis(4-methoxybenzyl)amino)-2-(1-(m-tolyl)piperidine-4-yl)nicotinic acid (3-5) (250 mg, 373 μmol, 45.6% yield). LCMS: (ESI) m / z = 536.2 [M + H] + .

[0111] Stage 5:Add 5 ml of dichloromethane to the reaction bottle, then sequentially add 6-(bis(4-methoxybenzyl)amino)-2-(1-(m-tolyl)piperidine-4-yl)nicotinic acid (3-5) (250 mg, 466.70 μmol) and methyl(2-(methylamino)ethyl)carbamate t-butyl ester (88 mg, 466 μmol), then add AcOH (28.03 mg, 466.70 μmol), and stir at room temperature for 2 hours. Add NaBH(OAc)3 (297 mg, 1.40 mmol) in batches, and continue stirring for 14 hours. Carefully add 20 ml of saturated sodium bicarbonate aqueous solution dropwise to quench the reaction, stir, extract three times with dichloromethane, combine the organic phases, wash with saturated brine, and dry over anhydrous magnesium sulfate. After filtration and concentration, the compound was separated and purified by column chromatography (silica gel column, 0-17% tetrahydrofuran / petroleum ether gradient elution) to obtain a yellow, viscous liquid compound (2-((6-(bis(4-methoxybenzyl)amino)-2-(1-(m-tolyl)piperidine-4-yl)pyridine-3-yl)m-ethyl)(methyl)amino)ethyl)(methyl)carbamate t-butyl ester (3-6) (60 mg, 83.1 μmol, 17.80% yield, 98% purity). LCMS: (ESI) m / z = 708.4 [M + H] + , 1 H NMR(400MHz,CDCl3)δ(ppm)7.24(d,1H),7.10-7.19(m,5H),6.74-6.88(m,6H),6 .65(d,1H),6.25(d,1H),4.69(s,4H),3.79(s,6H),3.70-3.79(m,2H),3.41(s,2H) ),3.21-3.41(m,2H),2.98-3.09(m,1H),2.84(s,3H),2.72-2.84(m,2H),2.44-2. 59(m,2H),2.31(s,3H),2.09-2.27(m,5H),1.78-1.87(m,2H),1.36-1.49(m,9H).

[0112] Stage 6:tert-Butyl (2-((6-(Bis(4-methoxybenzyl)amino)-2-(1-(m-tolyl)piperidin-4-yl)pyridin-3-yl)m-ethyl)(methyl)amino)ethyl)(methyl)carbamate (3-6) (60 mg, 84.7 μmol) is added with 1 mL of trifluoroacetic acid, and then trifluoromethanesulfonic acid (29 mg, 194 μmol) is added. The reactants are stirred at room temperature for 16 hours under nitrogen gas protection. After the reaction mixture is concentrated, it is separated and purified by preparative HPLC (column: Boston Green ODS 150×30 mm×5 um, mobile phase: [water(0.05%HCl)-ACN], B%: 0% - 25%, for 9 minutes). The target product is lyophilized to obtain the yellow solid product N 1 -((6-Amino-2-(1-(m-tolyl)piperidin-4-yl)pyridin-3-yl)methyl)-N 1 ,N 2 -Dimethylethane-1,2-diamine (P226, Example 3) (22 mg, 58.7 μmol, 69.2% yield) is obtained. LCMS: (ESI) m / z = 368.3 [M+H] + , 1 H NMR (400 MHz, D2O) δ (ppm) 7.91 (d, 1H), 7.43 - 7.51 (m, 2H), 7.36 - 7.43 (m, 2H), 6.98 (d, 1H), 4.40 (s, 2H), 3.78 - 3.89 (m, 4H), 3.63 - 3.72 (m, 1H), 3.49 - 3.62 (m, 4H), 2.78 (s, 6H), 2.39 (s, 3H), 2.31 - 2.44 (m, 2H), 2.18 - 2.30 (m, 2H).

[0113] Example 4: N 1 ,N 2 -dimethyl-N 1 Synthesis of -((4-(1-(m-tolyl)piperidine-4-yl)-1H-indazole-5-yl)methyl)ethane-1,2-diamine (P190):

Chemical Structure

[0114] Stage 1:2-Bromo-4-fluorobenzoic acid (4-1) (23 g, 105 mmol) is dissolved in t-butanol (200 mL). Under room temperature conditions, 4-dimethylaminopyridine (12.8 g, 105 mmol) and di-t-butyl dicarbonate (68.8 g, 315 mmol, 3.0 equivalents) (releasing gas) are added, and the reaction mixture is reacted at 90°C for 2 hours under nitrogen gas protection. Complete depletion of the starting materials and the formation of new spots are detected by TLC. The reaction mixture is diluted with water (100 mL) and extracted twice with ethyl acetate (150 mL). The organic layer was washed once with saturated saline solution (80 mL), dried over magnesium sulfate, filtered by suction, and the filtrate was concentrated under reduced pressure until dry. The filtrate was then purified by column chromatography (silica, petroleum ether:ethyl acetate = 10:1) to obtain a colorless liquid 2-bromo-4-fluorobenzoate t-butyl ester (4-2) (26.8 g, 95.0 mmol, 90.4% yield, 97.5% purity). 1 H NMR (400MHz, CDCl3) δ (ppm) 7.77 (dd, 1H), 7.37 (dd, 1H), 7.02-7.10 (m, 1H), 1.61 (s, 9H).

[0115] Stage 2:Synthesis of lithium diisopropylamide: Diisopropylamine (5.15 g, 50.9 mmol, 7.19 mL) is dissolved in tetrahydrofuran (100 mL), and n-butyllithium (2.5 M, 17.45 mL) is added dropwise at -70°C. After the addition is complete, the reaction mixture is raised to room temperature and stirred for 30 minutes to obtain a yellow lithium diisopropylamide solution. 2-bromo-4-fluorobenzoate t-butyl ester (4-2) (10 g, 36.35 mmol) is dissolved in tetrahydrofuran (20 mL), and this is added dropwise to the freshly prepared lithium diisopropylamide at -75°C, and the reaction mixture is allowed to react at -75°C for 1.5 hours. Dimethylformamide (10.6 g, 145 mmol) is added to the reaction mixture at -75°C and the reaction is allowed to continue for 0.5 hours. Complete consumption of the starting materials and the formation of new spots are detected by TLC. Quenched dropwise with acetic acid (20 mL) at -70°C, diluted with water (150 mL), and extracted twice with ethyl acetate (200 mL). The organic layer was washed with saturated brine (100 mL), dried over magnesium sulfate, filtered by suction, and the filtrate was concentrated under reduced pressure until dry. The filtrate was purified by column chromatography (silica, 3% ethyl acetate in petroleum ether) to obtain off-white solid 2-bromo-4-fluoro-3-formylbenzoate t-butyl ester (4-3) (8.7 g, 27.7 mmol, 76.2% yield). 1 H NMR(400MHz,CDCl3)δ(ppm)10.39(s,1H),7.80(dd,1H),7.19(t,1H),1.63(s,9H),

[0116] Stage 3:2-Bromo-4-fluoro-3-formylbenzoate t-butyl ester (4-3) (8.7 g, 28.7 mmol) is dissolved in ethylene glycol dimethyl ether (100 mL), and hydrazine hydrate (31.6 g, 537 mmol, 85%, 18.7 equivalents) is added. The reaction mixture is stirred at 90°C for 1 hour. Complete depletion of the starting materials and formation of the target product are detected by LC-MS. After cooling the reaction mixture, it is diluted with water (100 mL) and extracted twice with ethyl acetate (150 mL). The organic layer is washed with saturated brine (100 mL), dried over magnesium sulfate, filtered by suction, and the filtrate is concentrated under reduced pressure until dry. The filtrate is purified by column chromatography (silica, 3% ethyl acetate in petroleum ether) to obtain the yellow solid 4-bromo-1H-indazole-5-carboxylic acid t-butyl ester (4-4) (4.5 g, 15.1 mmol, 52.7% yield). LCMS:(ESI)m / z=296.9 / 298.9[M+H] + .

[0117] Stage 4: Dissolve 4-bromo-1H-indazole-5-carboxylate t-butyl ester (4-4) (4.5 g, 15.14 mmol) and 3,4-dihydro-2H-pyran (3.82 g, 45.43 mmol, 4.15 mL) in dichloromethane (60 mL), and add p-toluenesulfonic acid monohydrate (288 mg, 1.51 mmol). Stir the reaction mixture at 15°C for 1 hour. Detect complete depletion of the starting materials and formation of the target product by LC-MS. Dilute the reaction mixture with water (50 mL) and extract twice with ethyl acetate (100 mL). The organic layer was washed with saturated saline (80 mL), dried over magnesium sulfate, filtered by suction, and the filtrate was concentrated under reduced pressure until dry. Purification by column chromatography (silica, 3% ethyl acetate in petroleum ether) yielded a yellow syrup of 4-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-5-carboxylate t-butyl ester (4-5) (4.5 g, 11.6 mmol, 76.7% yield). LCMS: (ESI) m / z = 240.9 / 242.9 [M + H-THP-tBu] + , 1H NMR(400MHz,CDCl3)δ(ppm)8.16(s,1H),7.81(d,1H),7.55(d,1H),5.72(dd,1H),3.93-4.03(m,1H),3.6 7-3.80(m,1H),2.43-2.59(m,1H),2.12-2.21(m,1H),2.02-2.12(m,1H),1.66-1.85(m,3H),1.64(s,9H).

[0118] Stage 5: 4-Bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-5-carboxylate t-butyl ester (4-5) (1.0 g, 2.62 mmol, 1.0 equivalent) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)-1-(m-tolyl)-1,2,3,6-tetrahydropyridine (intermediate B) (863 mg, 2.89 mmol) are dissolved in tetrahydrofuran (8 mL), and an aqueous solution of potassium phosphate (1.67 g, 7.87 mmol) (2 mL) is added. The reaction mixture is degassed under reduced pressure and replaced several times with nitrogen gas. Add (2-dicyclohexylphosphine-2,4,6-triisopropyl-1,1-biphenyl)[2-(2-amino-1,1-biphenyl)]palladium(II) methanesulfonate (XPhos-Pd-g3) (67 mg, 78.7 μmol). Stir the reaction mixture at 80°C for 16 hours under nitrogen gas protection. Detect complete depletion of the starting materials and formation of the target product by LC-MS. Dilute the reaction mixture with water (30 mL) and extract three times with ethyl acetate (20 mL). The organic layer was washed with saturated saline (20 mL), dried over magnesium sulfate, filtered by suction, and the filtrate was concentrated under reduced pressure until dry. Purification by column chromatography (silica, 3% ethyl acetate in petroleum ether) yielded a yellow syrup of 1-(tetrahydro-2H-pyran-2-yl)-4-(1-(m-tolyl)-1,2,3,6-tetrahydropyridine-4-yl)-1H-indazole-5-carboxylate t-butyl ester (4-6) (800 mg, 1.55 mmol, 59.0% yield). LCMS: (ESI) m / z = 474.4 [M + H] + .

[0119] Stage 6: Dissolve 1-(tetrahydro-2H-pyran-2-yl)-4-(1-(m-tolyl)-1,2,3,6-tetrahydropyridine-4-yl)-1H-indazole-5-carboxylate t-butyl ester (4-6) (800 mg, 1.69 mmol) in methanol (160 mL) and add 10% Pd / C (150 mg). Degas the reaction mixture under reduced pressure and purge several times with hydrogen gas. Stir the reaction mixture at 50°C for 32 hours under a hydrogen balloon atmosphere. Detect the formation of the target product by LC-MS. The reaction mixture was filtered by suction, and the filtrate was concentrated under reduced pressure until dry. Purification by column chromatography (silica, 30% ethyl acetate in petroleum ether) yielded a yellow syrup-like 1-(tetrahydro-2H-pyran-2-yl)-4-(1-(m-tolyl)piperidine-4-yl)-1H-indazole-5-carboxylate t-butyl ester (4-7) (630 mg, 1.24 mmol, 73.2% yield). LCMS: (ESI) m / z = 476.3 [M + H] + RT=0.857min. 1 H NMR(400MHz,CDCl3)δ(ppm)8.31(s,1H),7.64(d,1H),7.45(d,1H),7.19(t,1H),6.80-6.9 1(m,2H),6.71(d1H),5.71(dd,1H),3.99-4.07(m,1H),3.86-3.94(m,2H),3.65-3.79(m,2H ),2.82-3.93(m,2H),2.51-2.65(m,1H),2.37-2.49(m,2H),2.35(s,3H),2.11-2.22(m,1H) ,2.04-2.10(m,1H),1.93-2.02(m,2H),1.71-1.85(m,2H),1.64-1.71(m,1H),1.63(s,9H).

[0120] Stage 7:Dissolve 1-(tetrahydro-2H-pyran-2-yl)-4-(1-(m-tolyl)piperidine-4-yl)-1H-indazole-5-carboxylate t-butyl ester (4-7) (630 mg, 1.32 mmol) in tetrahydrofuran (6 mL), and add lithium aluminum tetrahydrogen (THF in 1 M, 5.5 mL) dropwise at -5°C. Stir the reaction mixture at 20°C for 3 hours. Detect complete depletion of the starting material and the formation of new spots by TLC (petroleum ether / ethyl acetate = 1:1). Quench the reaction mixture dropwise by adding water (10 mL) at -5°C, dilute with water (5 mL), and extract twice with ethyl acetate (30 mL). The organic layer was washed with saturated brine (20 mL), dried over magnesium sulfate, filtered by suction, and the filtrate was concentrated under reduced pressure until dry. Purification by column chromatography (silica, 50% ethyl acetate in petroleum ether) yielded a white solid (1-(tetrahydro-2H-pyran-2-yl)-4-(1-(m-tolyl)piperidine-4-yl)-1H-indazole-5-yl)methanol (4-8) (500 mg, 849 μmol, 64.1% yield). LCMS: (ESI) m / z = 406.3 [M + H] + .

[0121] Stage 8:(1-(tetrahydro-2H-pyran-2-yl)-4-(1-(m-tolyl)piperidine-4-yl)-1H-indazole-5-yl)methanol (4-8) (200 mg, 493.18 μmol) is dissolved in dichloromethane (10 mL), and Dess-Martin reagent (220 mg, 518 μmol) is added. The reaction mixture is allowed to react at 25 °C for 6 hours. Complete depletion of the starting materials and formation of the target product are detected by LC-MS. The reaction mixture is quenched with 10% sodium thiosulfate solution (20 mL), stirred at room temperature for 30 minutes, saturated sodium bicarbonate (50 mL) is added to the reaction mixture, and the mixture is extracted three times with dichloromethane (50 mL). The organic layer was washed with saturated saline (50 mL), dried over magnesium sulfate, filtered by suction, and the filtrate was concentrated under reduced pressure until dry. Purification by column chromatography (silica, 30% ethyl acetate in petroleum ether) yielded a yellow syrup of 1-(tetrahydro-2H-pyran-2-yl)-4-(1-(m-tolyl)piperidine-4-yl)-1H-indazole-5-formaldehyde (4-9) (140 mg, 293 μmol, 59.4% yield). LCMS: (ESI) m / z = 404.3 [M + H] + .

[0122] Stage 9:Dissolve 1-(tetrahydro-2H-pyran-2-yl)-4-(1-(m-tolyl)piperidine-4-yl)-1H-indazole-5-formaldehyde (4-9) (200 mg, 496 μmol) and methyl (2-(methylamino)ethyl)carbamate t-butyl ester (112 mg, 595 μmol) in dichloromethane (5 mL), and add acetic acid (36 mg, 595 μmol). Stir the reaction mixture at 20 °C for 2 hours. Add sodium triacetoxyborohydride (315 mg, 1.49 mmol, 3 equivalents). Stir the reaction mixture at 20 °C for 14 hours. Detect complete depletion of the starting materials and the formation of the target product by LC-MS. The reaction mixture was quenched with saturated sodium bicarbonate solution (10 mL), diluted with water (5 mL), extracted twice with dichloromethane (20 mL), dried over magnesium sulfate, filtered by suction, concentrated the filtrate under reduced pressure until dry, and purified by column chromatography (silica, 50% ethyl acetate in dichloromethane) to obtain yellow syrup-like methyl(2-(methyl((1-(tetrahydro-2H-pyran-2-yl)-4-(1-(m-tolyl)piperidine-4-yl)-1H-indazole-5-yl)methyl)amino)ethyl)carbamate t-butyl ester (4-10) (210 mg, 365 μmol, 73.6% yield). LCMS: (ESI) m / z = 576.5 [M + H] + .

[0123] Stage 10:Methyl (2-(methyl((1-(tetrahydro-2H-pyran-2-yl)-4-(1-(m-tolyl)piperidine-4-yl)-1H-indazole-5-yl)methyl)amino)ethyl)carbamate t-butyl ester (4-10) (210 mg, 365 μmol) is dissolved in methanol (2 mL), and hydrogen chloride / 1,4-dioxane (4 M, 2.10 mL) is added. The reaction mixture is stirred at 25 °C for 16 hours. Complete depletion of the starting materials and formation of the target product are detected by LC-MS. The reaction mixture is concentrated under reduced pressure until dry, and purified by preparative liquid chromatography (Boston Green ODS column, 5 μm silica, 30 mm diameter, 150 mm length, using a mixture of water (containing 0.05% hydrochloric acid) and acetonitrile to reduce polarity as the eluent) to obtain a white solid N 1 ,N 2 -dimethyl-N 1 -(((4-(1-(m-tolyl)piperidine-4-yl)-1H-indazole-5-yl)methyl)ethane-1,2-diamine (P190, Example 4) (hydrochloride, 105 mg, 245 μmol, 67.3% yield) was obtained. LCMS: (ESI) m / z = 392.2 [M + H] + , 1 H NMR(400MHz,D2O)δ(ppm)8.63(s,1H),7.61(d,1H),7.54(s,1H),7.42-7.51(m,3H),7.36(d,1H),4.74(s,2H),3.86-4.02( m,2H),3.65-3.84(m,5H),3.52-3.64(m,2H),2.87(s,3H),2.70-2.94(m,2H),2.78(s,3H),2.37(s,3H),2.09-2.19(m,2H).

[0124] Example 5: N 1 -((4-(2,3-difluoro-6,7,8,9-tetrahydro-5H-benzo[7]cyclopenten-7-yl)-3-methyl-1H-indazole-5-yl)methyl)-N 1 ,N 2 Synthesis of -dimethylethane-1,2-diamine (P146): [ka]

[0125] Stage 1: Dissolve 4-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-5-carboxylate t-butyl ester (4-5) (1.95 g, 5.11 mmol), (2,3-difluoro-6,9-dihydro-5H-benzo[7]cyclopenta-7-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane (intermediate A) (1.80 g, 5.88 mmol, 1.15 equivalents), toluene (45 mL), and potassium phosphate (2.18 g, 10.3 mmol) in water (6.5 mL), add to a reaction bottle, purge several times with nitrogen gas, and then add chloro(2-dicyclohexylphosphino-2,4,6-triisopropyl-1,1-biphenyl)[2-(2-amino-1,1-biphenyl)]palladium(II) (0.03 equivalents). The reaction mixture is stirred at 60°C for 24 hours under nitrogen gas protection. The formation of the target product is detected by LC-MS. The reaction mixture is cooled to 25°C, dissolved in water (50 mL) and ethyl acetate (50 mL), the organic phase is separated, and then extracted three times with ethyl acetate (50 mL). The organic phases are combined, dried over magnesium sulfate, filtered by suction, and the filtrate is concentrated under reduced pressure until dry. Purification by column chromatography (silica, 15% ethyl acetate in petroleum ether) yields the yellow oily crude product 4-(2,3-difluoro-6,9-dihydro-5H-benzo[7]cyclopenten-7-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-5-carboxylic acid t-butyl ester (5-1). LC-MS: (ESI) m / z = 481.2 [M + H] + .

[0126] Stage 2:The crude product of the previous step, 4-(2,3-difluoro-6,9-dihydro-5H-benzo[7]cyclopenten-7-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-5-carboxylic acid t-butyl ester (5-1), is dissolved in ethyl acetate (50 mL), and palladium hydroxide / carbon (520 mg, 10%) is added under a nitrogen gas atmosphere. The reaction solution is replaced with hydrogen gas several times and stirred at 30 °C for 12 hours. The consumption of the raw material and the formation of the target product are detected by LCMS. The reaction solution is filtered to obtain the white solid 4-(2,3-difluoro-6,7,8,9-tetrahydro-5H-benzo[7]cyclopenten-7-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-5-carboxylic acid t-butyl ester (5-2), which is directly used in the next step of the reaction without further purification. LCMS: (ESI) m / z = 399.3 [M+H-THP] + , 1 H NMR (400 MHz, CDCl3) δ (ppm) 7.98 (s, 1H), 7.64 (d, 1H), 7.43 (d, 1H), 6.94 - 7.05 (m, 2H), 5.70 (dd, 1H), 3.98 - 4.07 (m, 1H), 3.89 - 3.98 (m, 1H), 3.69 - 3.80 (m, 1H), 2.91 - 3.06 (m, 2H), 2.76 - 2.91 (m, 2H), 2.46 - 2.59 (m, 1H), 2.11 - 2.23 (m, 3H), 1.95 - 2.10 (m, 3H), 1.66 - 1.84 (m, 4H), 1.65 (s, 9H).

[0127] <0OO0972> Stage 3:Dissolve 4-(2,3-difluoro-6,7,8,9-tetrahydro-5H-benzo[7]cyclopenten-7-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-5-carboxylic acid t-butyl ester (5-2) (1.9 g, 3.94 mmol) in methanol (30 mL) and tetrahydrofuran (30 mL), and add p-toluenesulfonic acid monohydrate (297 mg, 1.56 mmol). Stir the reaction mixture at 30°C for 3.5 minutes. Detect the formation of the target product and the residue of the starting materials by LC-MS. Quench the reaction mixture with saturated sodium bicarbonate solution (20 mL) and remove methanol by concentration under reduced pressure. Add ethyl acetate (100 mL) and water (50 mL), separate the organic phase, and extract twice with ethyl acetate (50 mL). The organic phases were combined, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure until dry. Purification was performed by thin-layer chromatography (silica, 5% ethyl acetate in petroleum ether). The solution was concentrated under reduced pressure until dry to obtain the white solid 4-(2,3-difluoro-6,7,8,9-tetrahydro-5H-benzo[7]cyclopenten-7-yl)-1H-indazole-5-carboxylate t-butyl ester (5-3) (827 mg, 2.08 mmol, 52.7% yield). LCMS: (ESI) m / z = 399.2 [M + H] + , 1 H NMR(400MHz,CDCl3)δ(ppm)8.06(s,1H),7.65(d,1H),7.34(d,1H),7.00(t,2H),3.90-4.02(m, 1H), 2.92-3.06 (m, 2H), 2.76-2.90 (m, 2H), 2.14-2.27 (m, 2H), 1.98-2.11 (m, 2H), 1.64 (s, 9H).

[0128] Stage 4:Dissolve 4-(2,3-difluoro-6,7,8,9-tetrahydro-5H-benzo[7]cyclopenten-7-yl)-1H-indazole-5-carboxylate t-butyl ester (5-3) (424 mg, 1.06 mmol) in dimethylformamide (10 mL), add potassium carbonate (458 mg, 3.31 mmol), and add elemental iodine (459 mg, 1.81 mmol). Stir the reaction mixture at 15-20°C for 16 hours. LC-MS detects 69% formation of the target product and 30% residue of the starting material. Add another elemental iodine (135 mg, 532 μmol) and potassium carbonate (180 mg, 1.30 mmol) to the reaction mixture and continue stirring at 15-30°C for 3 hours. LC-MS detects 10% residue of the starting material and formation of the target product. Combine with the previous 50 mg of crude product. Add ethyl acetate (50 mL) and 10% sodium thiosulfate solution (50 mL) to the reaction mixture, separate the organic phase, and extract the aqueous phase three times with ethyl acetate (50 mL). Combine the organic phases, wash once with 10% sodium thiosulfate solution, wash three times with 10% lithium chloride (25 mL), wash once with saturated brine (50 mL), dry, filter, and concentrate under reduced pressure to obtain a pale yellow foamy solid crude product, 4-(2,3-difluoro-6,7,8,9-tetrahydro-5H-benzo[7]cyclopenten-7-yl)-3-iodo-1H-indazole-5-carboxylic acid t-butyl ester (5-4), which does not require further purification and can be used directly in the next step of the reaction. LCMS: (ESI) m / z = 525.0 [M + H] + .

[0129] Stage 5:4-(2,3-difluoro-6,7,8,9-tetrahydro-5H-benzo[7]cyclopenten-7-yl)-3-iodo-1H-indazole-5-carboxylate t-butyl ester (5-4) (589 mg, 1.12 mmol) and 3,4-dihydropyran (420 mg, 4.99 mmol) are dissolved in dichloromethane (15 mL), and p-toluenesulfonic acid (50 mg, 263 μmol, 0.23 equivalents) is added in an ice bath at 0-5°C. The reaction mixture is stirred at 15-20°C for 3 hours. Complete consumption of the starting materials and formation of the target product are detected by LCMS. The reaction mixture is separated into layers with 5% sodium bicarbonate solution (50 mL) and dichloromethane (50 mL). The organic phase is separated, and the aqueous phase is extracted twice with dichloromethane (50 mL). The organic phases are combined, dried over magnesium sulfate, filtered, and concentrated under reduced pressure until dry. Purification by column chromatography (silica, 12% ethyl acetate in petroleum ether) yields the white solid 4-(2,3-difluoro-6,7,8,9-tetrahydro-5H-benzo[7]cyclopenten-7-yl)-3-iodo-1-(tetrahydro-2H-pyran-2--1)-indazole-5-carboxylate t-butyl ester (5-5) (564 mg, 742 μmol, 66.0% yield, 80% purity). LCMS: (ESI) m / z = 525.1 [M + H-THP] + , 1 H NMR(400MHz,CDCl3)δ(ppm)7.46(d,1H),7.40(d,1H),6.97(t,2H),5.67(dd,1H),4.52-4.67(m,1H),3.95-4.03(m,1H),3.67 -3.80(m,1H),3.05-3.16(m,2H),2.80(dd,2H),2.42-2.62(m,1H),2.04-2.27(m,6H),1.68-1.79(m,3H),1.27-1.44(m,9H).

[0130] Stage 6:Parallel execution of two reactions: Dissolve t-butyl 4-(2,3-difluoro-6,7,8,9-tetrahydro-5H-benzo[7]cyclopenten-7-yl)-3-iodo-1-(tetrahydro-2H-pyran-2--1)-indazole-5-carboxylic acid t-butyl ester (5-5) (225 mg, 370 μmol, 1.0 equivalent), 1,4-dioxane (5 mL), and potassium phosphate (236 mg, 1.11 mmol) in water (1 mL). After replacing the reaction mixture with nitrogen gas, 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (292 mg, 1.16 mmol, 50% in THF) and [1,1-bis(di-t-butylphosphine)diferrocene]palladium dichloride (17 mg, 26.1 μmol, 0.07 equivalents) are added, and the reaction mixture is stirred at 80°C for 2 hours under nitrogen gas protection. Complete depletion of the starting materials and formation of the target product are detected by LCMS. The mixture is cooled to 20°C, and the reaction mixture is separated into layers with saturated brine (50 mL) and ethyl acetate (50 mL). The organic phase is separated, and the aqueous phase is extracted twice with ethyl acetate (50 mL). The organic phases are combined, dried over magnesium sulfate, filtered, and concentrated under reduced pressure until dry. Purification by column chromatography (0.5% to 7% ethyl acetate in silica and petroleum ether) yields a bright yellow oily deiodination byproduct 4-(2,3-difluoro-6,9-dihydro-5H-benzo[7]cyclopenten-7-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-5-carboxylate t-butyl ester (5-1) (124 mg, 257 μmol, 34.7% yield) and a bright yellow oily target product t-butyl 4-(2,3-difluoro-6,7,8,9-tetrahydro-5H-benzo[7]cyclopenten-7-yl)-3-methyl-1-(tetrahydro-2H-pyran-2--1)-indazole-5-carboxylate t-butyl ester (5-6) (244 mg, 442 μmol, 59.8% yield). LCMS:(ESI)m / z=497.2[M+H] + , 1H NMR(400MHz,CDCl3)δ(ppm)7.38(d,1H),7.33(d,1H),6.97(t,2H),5.60(dd,1H ),4.02-4.09(m,1H),3.81-3.92(m,1H),3.68-3.78(m,1H),2.87-2.99(m,2H),2 .80-2.87(m,2H),2.80(s,3H),2.48-2.61(m,1H),2.19-2.33(m,2H),2.06-2.1 8(m,3H),1.95-2.04(m,1H),1.70-1.84(m,2H),1.62-1.70(m,2H),1.58(s,9H).

[0131] Stage 7: Add t-butyl 4-(2,3-difluoro-6,7,8,9-tetrahydro-5H-benzo[7]cyclopenten-7-yl)-3-methyl-1-(tetrahydro-2H-pyran-2--1)-indazole-5-carboxylic acid t-butyl ester (5-6) (239 mg, 481 μmol) and tetrahydrofuran (8 mL) to the reaction bottle. Add lithium aluminum tetrahydride (1 M tetrahydrofuran solution, 0.9 mL) at 15-2°C and continue stirring the reaction mixture for 2 hours. Detect residual starting materials and the formation of new spots by TLC. Subsequently add lithium aluminum tetrahydride (1 M tetrahydrofuran, 300 μL) and stir at 15-20°C for 1 hour. Detect the consumption of most of the starting materials and the formation of new spots by TLC (petroleum ether:ethyl acetate = 3:1). Quench the reaction mixture with water (50 mL) and 15% sodium hydroxide solution. The reaction mixture is dissolved in ethyl acetate (50 mL), dried over magnesium sulfate, and stirred for 10 minutes. The mixture is filtered and concentrated and dried under reduced pressure to obtain a yellow solid crude product, (4-(2,3-difluoro-6,7,8,9-tetrahydro-5H-benzo[7]cyclopenten-7-yl)-3-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-5-yl)methanol(5-7) (221 mg, 518 μmol). This crude product does not require further purification and can be used directly in the next step of the reaction. LCMS: (ESI) m / z = 427.3 [M + H] + .

[0132] Stage 8: (4-(2,3-difluoro-6,7,8,9-tetrahydro-5H-benzo[7]cyclopenten-7-yl)-3-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-5-yl)methanol (5-7) (210 mg, 492 μmol) is dissolved in dichloromethane (15 mL), and manganese dioxide (530 mg, 6.10 mmol) is added. The reaction mixture is stirred at 40 °C for 3.5 hours. The mixture is filtered and concentrated under reduced pressure to obtain the off-white solid crude product 4-(2,3-difluoro-6,7,8,9-tetrahydro-5H-benzo[7]cyclopenten-7-yl)-3-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-5-formaldehyde (5-8) (210 mg, 495 μmol). This crude product does not require further purification and can be used directly in the next step of the reaction. LC-MS: (ESI) m / z = 425.1 [M + H] + .

[0133] Stage 9:Dissolve 4-(2,3-difluoro-6,7,8,9-tetrahydro-5H-benzo[7]cyclopenten-7-yl)-3-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-5-formaldehyde (5-8) (204 mg, 480 μmol), methyl (2-(methylamino)ethyl)carbamate t-butyl ester (186 mg, 987 μmol), and acetic acid (62 mg, 1.03 mmol, 2.15 equivalents) in dichloromethane (3 mL), stir at 25°C for 2 hours, then add sodium triethoxycarbonylborohydride (340 mg, 1.60 mmol). Stir the reaction mixture at 25°C for 14 hours. Detect the consumption of starting materials and the formation of the target product by LCMS. The reaction mixture was separated into layers in a 5% sodium bicarbonate (15 mL) solution and dichloromethane, and the organic phase was separated. The aqueous phase was extracted three times with ethyl acetate (10 mL). The organic phases were combined, dried over magnesium sulfate, filtered, concentrated under reduced pressure until dry, and purified by column chromatography (silica, dichloromethane, 30% ethyl acetate) to obtain a bright yellow oily substance (2-((4-(2,3-difluoro-6,7,8,9-tetrahydro-5H-benzo[7]cyclopenten-7-yl)-3-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-5-yl)methyl)(methyl)amino)ethyl)(methyl)carbamate t-butyl ester (5-9) (204 mg, 325 μmol, 67.6% yield). LCMS: (ESI) m / z = 597.4 [M + H] + .

[0134] Stage 10:Add 1,4-dioxane hydrochloride (4M, 5 mL) to a methanol solution of (2-((4-(2,3-difluoro-6,7,8,9-tetrahydro-5H-benzo[7]cyclopenten-7-yl)-3-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-5-yl)methyl)(methyl)amino)ethyl)(methyl)carbamate t-butyl ester (5-9) (202 mg, 338 μmol). Stir the reaction mixture at 10-15°C for 12 hours. Detect complete depletion of the starting materials and the formation of the target product by LC-MS. Concentrate the reaction mixture under reduced pressure until dry. Purify by reverse-phase preparative liquid chromatography (YMC-ActusTriartC18 column, 5 μm silica, 30 mm diameter, 150 mm length, using a mixture of water (0.05% aqueous ammonia) and acetonitrile to reduce polarity as the eluent) to obtain a white solid N2. 1 -((4-(2,3-difluoro-6,7,8,9-tetrahydro-5H-benzo[7]cyclopenten-7-yl)-3-methyl-1H-indazole-5-yl)methyl-N 1 ,N 2 Dimethylethane-1,2-diamine (P146, Example 5) (hydrochloride, 105 mg, 214 μmol, 63.3% yield, 99% purity) was obtained. LC-MS: (ESI) m / z = 413.4 [M + H] + , 1H NMR(400MHz,CD3OD)tautomer mixture δ(ppm)7.84(d,0.5H),7.71(d,0.5H),7.49-7.55(m,1H),7.08-7.17(m,2H),4.74-4.84(m,1 H),4.36-4.74(m,1H),4.08-4.20(m,0.5H),3.74-3.87(m,1.5H),3.63-3.72(m,1H),3.43-3 .63(m,2H),3.29-3.37(m,1H)2.99-3.05(m,2H),2.96(s,1.5H),2.83-2.87(m,1H),2.83(s, 1.5H),2.81(s,3H),2.74(s,1.5H),2.26(s,1.5H),2.09-2.26(m,2H),1.84-2.08(m,2H);19F NMR(376MHz,CD3OD)tautomer mixture δ(ppm)-144.96,-145.32.

[0135] Example 6: N 1 ,N 2 -dimethyl-N 1 Synthesis of -((3-(7-(trifluoromethyl)-4,5-dihydro-1H-benzo[d]azepine-3(2H)-yl)pyridine-2-yl)methyl)ethane-1,2-diamine (P088) [ka] The synthesis of compound P088 is carried out as described in Example 1, via 3-fluoropyridinecarboxaldehyde and intermediate D. LCMS: (ESI)m / z=393.4[M+H] + , 1 H NMR(400MHz,D2O)δ(ppm)8.25(d,1H),7.91(d,1H),7.61(dd,1H),7.50(s,1H),7.47(d,1H),7.32(d, 1H),4.24(s,2H),3.28-3.36(m,2H),3.15-3.20(m,2H),3.06-3.13(m,8H),2.71(s,3H),2.43(s,3H)

[0136] Example 7: N 1 -((4-(4,4-bis(ethoxymethyl)cyclohexyl)-1H-indazole-5-yl)methyl)-N 1 ,N 2 Synthesis of -dimethylethane-1,2-diamine (P266) [ka] The synthesis of compound P266 is carried out as described in Example 4, via intermediate 4-4 and 2-(4,4-bis(ethoxymethyl)cyclohexy-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane. LCMS:(ESI)m / z=417.4[M+H] + , 1 H NMR(400MHz,D2O)δ(ppm)8.30(s,1H),7.52(d,1H),7.39(d,1H),4.60(s,2H),3 .65(s,2H),3.62(q,2H),3.58-3.65(m,2H),3.55(q,2H),3.48-3.57(m,2H),3. 30(s,2H),2.92-3.05(m,1H),2.82(s,3H),2.75(s,3H),1.97-2.14(m,2H),1.6 3-1.75(m,2H),1.48-1.58(m,2H),1.33-1.46(m,2H),1.20(t,3H),1.16(t,3H)

[0137] Example 8: N 1 -((4-(2,3-difluoro-6,7,8,9-tetrahydro-5H-benzo[7]cyclopenten-7-yl)-1H-indazole-5-yl)methyl)-N 1 ,N 2 Synthesis of -dimethylethane-1,2-diamine (P167) [ka] The synthesis of compound P167 is carried out as described in Example 4, via intermediates 4-5 and intermediate A. LCMS: (ESI) m / z = 399.2 [M + H] + , 1 H NMR(400MHz,D2O)δ(ppm)8.05(s,1H),7.56(d,1H),7.45(d,1H),7.05(t,2H),4.71(s,2H),3.65-3.78(m,2H),3.54 -3.63(m,2H),3.39-3.52(m,1H),2.95-3.08(m,2H),2.90(s,3H),2.75-2.85(m,2H),2.80(s,3H)1.88-2.12(m,4H)

[0138] Example 9: N 1 -((6-amino-2-(4,4-bis(ethoxymethyl)cyclohexyl)pyridine-3-yl)methyl)-N 1 ,N 2 Synthesis of -dimethylethane-1,2-diamine (P293) [ka] Compound P293 is synthesized by referring to the synthesis method in Example 3, via intermediates 3-2 and 2-(4,4-bis(ethoxymethyl)cyclohexy-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane. LCMS:(ESI)m / z=393.3[M+H] + , 1 H NMR(400MHz,CD3OD)δ(ppm)8.41(s,2H),7.61(d,1H),6.57(d,1H),3.56(s,2H) ,3.54(q,2H),3.49(s,2H),3.48(q,2H),3.24(s,2H),3.10-3.16(m,2H),2.87-2 .98(m,1H),2.67-2.71(m,2H),2.67(s,3H),2.24(s,3H),1.81-1.91(m,2H),1. 74-1.81(m,2H),1.50-1.62(m,2H),1.33-1.44(m,2H),1.20(t,2H),1.18(t,2H)

[0139] Example 10: N 1 -((2-(2,3-difluoro-6,7,8,9-tetrahydro-5H-benzo[7]cyclopenten-7-yl-6-methylpyridine-3-yl)methyl)-N 1 ,N 2 Synthesis of -dimethylethane-1,2-diamine (P038) [ka] Compound P038 is synthesized using the synthesis method of Example 2, via intermediates 2-2 and A. LCMS: (ESI) m / z = 374.2 [M + H] + , 1H NMR(400MHz,D2O)δ(ppm)8.49(d,1H),7.73(d,1H),7.07(t,2H),4.61(s,2H),3.57-3.70(m,3H),3.48-3.56(m,2H) ,2.92-3.06(m,2H),2.81-2.89(m,2H),2.78(s,3H),2.77(s,3H),2.70(s,3H),2.01-2.13(m,2H),1.74-1.91(m,2H)

[0140] Example 11: Synthesis of compound N,N'-dimethyl-N'-[[2-morpholine-4-[1-(m-tolyl)-4-piperidinyl]-1H-benzo[d]imidazole-5-yl]methyl]ethane-1,2-diamine (P406): [ka]

[0141] Step 1: A mixture of 2-nitro-3-bromoaniline (11-1) (150 g, 691.18 mmol), N-iodosuccinimide (171 g, 760.05 mmol), and acetic acid (1500 mL) is heated under reflux for approximately 2 hours. After reaction product 11-1 has changed, the mixture is cooled, the reaction solution is poured into 3600 mL of water, filtered, precipitated, dried under vacuum, and then dissolved in ethyl acetate. The mixture is then washed sequentially with water and saturated brine, extracted with ethyl acetate, the organic phases are combined, dried over anhydrous magnesium sulfate, filtered and concentrated, and separated by silica gel column chromatography to obtain 178 g of the brown solid 2-nitro-3-bromo-4-iodoaniline (11-2). 1 H NMR (400MHz, DMSO-d6) δ (ppm) 7.66 (d, 1H), 6.70 (d, 1H), 6.23 (s, 2H).

[0142] Step 2: Dissolve compound 2-nitro-3-bromo-4-iodoaniline (11-2) (80.0 g, 233.29 mmol) in a mixture of tetrahydrofuran (640 mL) / ethanol (640 mL) / water (320 mL), and add NH4Cl (187 g, 3.50 mol). Heat the mixture to 90°C, then slowly add iron powder (52.1 g, 933.17 mmol) in batches. Continue heating for 2 hours until the reaction is complete. The reaction mixture was cooled to 60°C, diatomaceous earth was added and stirred for 10 minutes, then cooled to room temperature and filtered. The filtrate was extracted with ethyl acetate, and after removing most of the water-soluble solvent by concentration, it was dissolved in a large amount of ethyl acetate, washed with saturated brine, and after extraction, the organic phase was dried, filtered and concentrated to obtain the brown solid crude product 3-bromo-4-iodo-o-phenylenediamine (11-3) (73.8 g, 224.04 mmol, 96.03% yield, 95% purity), which does not require further purification and can be used directly in the next step of the reaction. LCMS: (ESI) m / z = 314.8 [M + H] + , 1 H NMR (400MHz, DMSO-d6) δ (ppm) 6.92 (d, 1H), 6.35 (d, 1H), 4.99 (s, 2H), 4.90 (s, 2H).

[0143] Step 3: Dissolve compound 3-bromo-4-iodo-o-phenylenediamine (11-3) (35.0 g, 111.85 mmol) in tetrahydrofuran (350 mL), cool in an ice bath, and add carbonyldiimidazole (27.2 g, 167.77 mmol). Gradually return to room temperature and stir the reaction mixture for about 2 hours until the reaction is complete. After concentrating the reaction mixture, add water (500 mL) and slurry for 30 minutes. Filter and freeze-dry to obtain the brown solid crude product 4-bromo-5-iodo-1,3-dihydro-2H-benzo[d]imidazole-2-one (11-4) (37.8 g, 111.53 mmol, 99.72% yield), which does not require further purification and can be used directly in the next step of the reaction. 1 H NMR (400MHz, DMSO-d6) δ (ppm) 11.12 (s, 1H), 11.02 (s, 1H), 7.47 (d, 1H), 6.75 (d, 1H).

[0144] Step 4: Carefully add compound 4-bromo-5-iodo-1,3-dihydro-2H-benzo[d]imidazole-2-one (11-4) (28.0 g, 82.61 mmol) to phosphorus oxychloride (130 mL). Heat the mixture to 100°C and react for 3 hours, then heat to 120°C and continue reacting for 16 hours until the reaction is almost complete. After cooling to room temperature, distill under pressure to half the volume. Carefully pour in batches into 2 L of ice water, then carefully adjust the pH to 8 with potassium carbonate while stirring. Filter the precipitated brown solid and dry to obtain the crude product 2-chloro-4-bromo-5-iodo-1H-benzo[d]imidazole (11-5) (30.0 g, crude), which does not require further purification and is used directly in the next step of the reaction. LCMS: (ESI) m / z = 358.9 [M + H] + , 1 H NMR (400MHz, DMSO-d6) δ (ppm) 13.77 (br s, 1H), 7.72 (d, 1H), 7.32 (br d, 1H).

[0145] Step 5: Add morpholine (37.0 g, 424.70 mmol, 37.37 mL) to a suspension of the compound 2-chloro-4-bromo-5-iodo-1H-benzo[d]imidazole (11-5) (30.0 g, 83.95 mmol, 2.05 mL) to isopropanol (150 mL) and tetrahydrofuran (150 mL). The mixture was heated to 90°C and reacted for 4 days. After the starting materials were completely converted, it was cooled to room temperature, the organic solvent was removed by distillation, and the mixture was slurryed in water (300 mL). The solid was filtered and purified by silica gel column chromatography to obtain a brown viscous liquid. This was slurryed with ethanol to obtain 30.1 g of a yellow solid crude product. Further recrystallization with ethanol yielded a white solid 2-(4-morpholine)-4-bromo-5-iodo-1H-benzo[d]imidazole (11-6) (15.5 g, 37.99 mmol, 45.25% yield). LCMS: (ESI) m / z = 407.9, 409.9 [M + H] + , 1H NMR(400MHz,DMSO-d6)δ(ppm)11.82(s,0.85H),11.40(s,0.15H),7.48(d,0.1 5H),7.40(d,0.85H),6.97-7.05(m,1H),3.65-3.81(m,4H),3.44-3.59(m,4H).

[0146] Step 6: Add 2-(4-morpholine)-4-bromo-5-iodo-1H-benzo[d]imidazole (11-6) (15.5 g, 37.99 mmol) to a 20% purity ethanol solution of sodium ethoxide (180 mL). Deoxygenate the reaction mixture, purge it three times through a CO (balloon), add Pd(dppf)Cl2 (1.11 g, 1.52 mmol), deoxygenate again, and purge it three times with CO. Heat the system to 45°C and react for 16 hours. After cooling in an ice bath, carefully add acetic acid (8 mL, pH=6~7) to quench the reaction. After concentration, the solution was diluted with ethyl acetate, washed and extracted with saturated sodium bicarbonate and saline solution, the organic phase was dried over anhydrous magnesium sulfate, filtered, and after concentration, purified by silica gel column chromatography to obtain a pale yellow amorphous solid 4-bromo-2-(4-morpholine)-1H-benzo[d]imidazole-5-carboxylate ethyl ester (11-7) (16.5 g, 46.58 mmol, 77.12% yield). LCMS: (ESI) m / z = 356.0 [M + H] + .

[0147] Step 7: Compound 4-bromo-2-(4-morpholine)-1H-benzo[d]imidazole-5-carboxylate ethyl ester (11-7) (16.5 g, 46.58 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)-1-(m-tolyl)-1,2,3,6-tetrahydropyridine (intermediate B) (15.3 g, 51.24 mmol), and potassium phosphate (19.8 g, 93.17 mmol) are added to tetrahydrofuran (165 mL) and water (33 mL). The reactants are purged with nitrogen gas, XPhos-PD-G2 (1.10 g, 1.40 mmol) is added, and the mixture is then heated to 65 °C under nitrogen gas protection and reacted for 5 hours. The reaction mixture is cooled to 40°C, sodium diethylaminomethionyl thiolate (997.25 mg, 5.82 mmol) is added, and the mixture is stirred for 1 hour. The mixture is diluted with water (200 mL), extracted with ethyl acetate, and the organic phase is dried over anhydrous magnesium sulfate. The mixture is then filtered, concentrated, and the crude product is purified by silica gel column chromatography to obtain the yellow solid product 2-(4-morpholine)-4-(1-m-methylphenyl-1,2,3,6-tetrahydropyridine-4-yl)-1H-benzo[d]imidazole-5-carboxylate ethyl ester (11-8) (18.5 g, 41.43 mmol, 88.94% yield). LCMS: (ESI) m / z = 447.3 [M + H] + , 1 H NMR(400MHz,CDCl3)δ(ppm)9.59(br s,1H),7.89(d,1H),7.35(d,1H),7.23(t,1H),6.86-6.98(m,2H),6.81(br d,1H),5.75(br s,1H),4.33(q,2H),3.76-3.87(m,6H),3.50-3.64(m,6H),2.88(br d,2H),2.65(br s,2H),2.37(s,3H),1.39(t,3H).

[0148] Step 8: Add Pd(OH)2 / C (7.0g, 41.43 mmol, 10% purity) to a suspension of compound 2-(4-morpholine)-4-(1-m-methylphenyl-1,2,3,6-tetrahydropyridine-4-yl)-1H-benzo[d]imidazole-5-carboxylate ethyl ester (11-8) (18.5g, 41.43 mmol) in tetrahydrofuran (600 mL), purge with hydrogen gas, and then immerse in a hydrogen gas atmosphere (barrel). The reaction was carried out at 30°C for 16 hours until the reaction was almost complete. The mixture was filtered, the filter cake was washed with tetrahydrofuran (200 mL x 2), the filtrates were combined, concentrated, and dried to obtain the crude product 2-(4-morpholine)-4-(1-m-methylphenyl-4-piperidinyl)-3H-benzo[d]imidazole-5-carboxylate ethyl ester (11-9) (19 g). This product does not require further purification and can be used directly in the next step of the reaction. LCMS: (ESI) m / z = 449.3 [M + H] + .

[0149] Step 9: Dissolve compound 2-(4-morpholine)-4-(1-m-methylphenyl-4-piperidinyl)-3H-benzo[d]imidazole-5-carboxylate ethyl ester (11-9) (19 g, 42.36 mmol) in CH3CN (550 mL), add cesium carbonate (69.0 g, 211.79 mmol), then add SEM-Cl (19 g, 113.96 mmol, 20.17 mL) dropwise while stirring. Allow the reaction mixture to react at 30°C for 24 hours. The reaction is almost complete. The mixture was filtered, washed with ethyl acetate, combined with the organic phase, concentrated, and purified by silica gel column chromatography to obtain the colorless oily compound 2-(4-morpholine)-4-(1-m-methylphenyl-4-piperidinyl)-1-(2-trimethylsilylethoxymethylene)benzo[d]imidazole-5-carboxylate ethyl ester (11-10) (22.3 g, 38.53 mmol, 90.96% yield). LCMS: (ESI) m / z = 580.2 [M + H] + , 1H NMR(400MHz,CDCl3)δ(ppm)7.59(d,1H),7.08-7.21(m,2H),6.82-6.89(m,2H),6.65(d,1H),5.29(s,2H),4.40(q,2H),3.91(br d,2H),3.81-3.87(m,4H),3.64-3.76(m,4H),3.38-3.47(m,4H),2.98-3.12(m,2H),2.85-2.96(m,2H),2.35(s,3H),1.79(br d,2H),1.44(t,3H),0.05(s,2H),0.02(s,8H).

[0150] Step 10: While cooling in an ice bath, add dropwise to a tetrahydrofuran (300 mL) solution of 2-(4-morpholine)-4-(1-m-methylphenyl-4-piperidinyl)-1-(2-trimethylsilylethoxymethylene)benzo[d]imidazole-5-carboxylate ethyl ester (11-10) (22.0 g, 38.01 mmol) of compound The reaction is almost complete. While cooling in an ice bath, the reaction is quenched by carefully adding 3 mL of water, 3 mL of 15% sodium hydroxide aqueous solution, and 6 mL of water dropwise in sequence. Then, the mixture is stirred with anhydrous magnesium sulfate at room temperature for 15 minutes, dried, filtered, and the organic phase is concentrated to obtain a colorless viscous crude product, 2-(4-morpholine)-4-(1-m-methylphenyl-4-piperidinyl)-1-(2-trimethylsilylethoxymethylene)benzo[d]imidazole-5-methanol (11-11) (19.3 g, 35.96 mmol, 94.60% yield), which does not require further purification and can be used directly in the next step of the reaction. LCMS: (ESI) m / z = 537.3 [M + H] + , 1H NMR(400MHz,CDCl3)δ(ppm)7.28(s,1H),7.10-7.22(m,3H),6.83-6.92(m,2H),6.68(d,1H),5.23-5.34(m,2H),4.85(s,2H),3.90(br d,2H),3.80-3.86(m,4H),3.75-3.80(m,1H),3.67-3.75(m,2H),3.39-3.47(m,4H),3.27-3.38(m ,1H),3.06(m,2H),2.88-2.99(m,2H),2.35(s,3H),0.95-1.01(m,2H),0.05(s,2H),0.02(s,8H).

[0151] Step 11: Add DMP (9.01 g, 21.24 mmol, 6.58 mL) to a solution of compound 2-(4-morpholine)-4-(1-m-methylphenyl-4-piperidinyl)-1-(2-trimethylsilylethoxymethylene)benzo[d]imidazole-5-methanol (11-11) (9.5 g, 17.70 mmol) in dichloromethane (200 mL), then stir the reaction mixture at 30°C for 30 minutes until the reaction is almost complete. Add 100 mL of saturated sodium bicarbonate and 100 mL of sodium thiosulfate, stir for 30 minutes, extract with dichloromethane, then dry the organic phase over anhydrous magnesium sulfate, filter, concentrate, and purify by silica gel column to obtain the Woolwhite amorphous solid compound 2-(4-morpholine)-4-(1-m-methylphenyl-4-piperidinyl)-1-(2-trimethylsilylethoxymethylene)benzo[d]imidazole-5-formaldehyde (11-12) (11.7 g, 21.88 mmol, 61.81% yield). LCMS: (ESI) m / z = 535.3 [M + H] + , 1H NMR(400MHz,CDCl3)δ(ppm)10.50(s,1H),7.75(d,1H),7.25(d,1H),7.19(t, 1H),6.81-6.90(m,2H),6.67(d,1H),5.31(s,2H),4.10-4.16(m,1H),3.92(br d,2H),3.80-3.88(m,4H),3.69-3.77(m,2H),3.39-3.49(m,4H),2.90-3.08(m,4H),2.36(s,3H),1.82(br d,2H),0.94-1.04(m,2H),0.00-0.07(m,9H).

[0152] Step 12: Dissolve compound 2-(4-morpholine)-4-(1-m-methylphenyl-4-piperidinyl)-1-(2-trimethylsilylethoxymethylene)benzo[d]imidazole-5-formaldehyde (11-12) (10.7 g, 20.01 mmol) and N-methyl-N-[2-(methylamino)ethyl]carbamate t-butyl ester (4.52 g, 24.01 mmol) in 150 mL of dichloromethane, add acetic acid (1.44 g, 24.01 mmol, 1.37 mL), stir the reaction mixture at 30°C for 1 hour, add sodium borohydride acetate (12.7 g, 60.03 mmol) in batches, and stir at 30°C for 15 hours. The reaction is almost complete, so carefully add 100 mL of saturated sodium bicarbonate aqueous solution to quench the reaction and stir for 1 hour. Extraction with dichloromethane, organic phases were combined, dried over anhydrous magnesium sulfate, filtered, concentrated, and purified by silica gel column chromatography to obtain the product Nt-butoxycarbonyl-N,N'-dimethyl-N'-[[2-morpholine-4-[1-(m-tolyl)-4-piperidinyl]-1H-benzo[d]imidazole-5-yl]methyl]ethane-1,2-diamine (11-13) (10.6 g, 14.99 mmol, 68.12% yield) and the by-product 2-(4-morpholine)-4-(1-m-methylphenyl-4-piperidinyl)-1-(2-trimethylsilylethoxymethylene)benzo[d]imidazole-5-methanol (11-11) (1.9 g, 3.54 mmol, 17.69% yield). LCMS:(ESI)m / z=535.3[M+H] + ,1 H NMR(400MHz,CDCl3)δ(ppm)7.17(t,1H),7.04(s,2H),6.83-6.89(m,2H),6.65(d,1H),5.25(s,2H),3.89(br d,2H),3.78-3.85(m,4H),3.68-3.76(m,2H),3.61(s,2H),3.37-3.44(m,5H),3.30(br s,2H),3.02(m,2H),2.80-2.91(m,5H),2.46-2.64(m,2H),2.34(s,3H),2.22(br s,3H),1.69(br d,2H),1.36-1.45(m,9H),0.92-1.00(m,2H),-0.02-0.03(m,9H).

[0153] Step 13: Dissolve the compound Nt-butoxycarbonyl-N,N'-dimethyl-N'-[[2-morpholine-4-[1-(m-tolyl)-4-piperidinyl]-1H-benzo[d]imidazole-5-yl]methyl]ethane-1,2-diamine (11-13) (10.6 g, 14.99 mmol) in 50 mL of 1,4-dioxane, add HCl / dioxane (50 mL) solution, and stir at 70°C for 2 hours until a white solid precipitate forms. After cooling to room temperature, 10 mL of methanol is added, and after concentration, 50 mL of methanol is added. 500 mL of isopropyl ether is added dropwise while stirring, and a white precipitate forms. The mixture is then stirred and slurryed at room temperature for 16 hours, filtered, and freeze-dried to obtain a white solid N,N'-dimethyl-N'-[[2-morpholine-4-[1-(m-tolyl)-4-piperidinyl]-1H-benzo[d]imidazole-5-yl]methyl]ethane-1,2-diamine hydrochloride (quantitative measurement of hydrochloride coefficient is 4). LCMS: (ESI) m / z = 477.3 [M + H] + , 1 H NMR(400MHz,D2O)δ(ppm)7.33-7.55(m,6H),3.89-4.02(m,6H),3.69-3.87(m,9H),3 .54-3.66(m,2H),2.87(s,3H),2.80(s,3H),2.60-2.77(m,2H),2.39(s,3H),2.21(br d,2H). 400 mg of N,N'-dimethyl-N'-[[2-morpholine-4-[1-(m-tolyl)-4-piperidinyl]-1H-benzo[d]imidazole-5-yl]methyl]ethane-1,2-diamine hydrochloride was added to 5 mL of water, then saturated sodium carbonate aqueous solution was carefully added dropwise to adjust the pH to 8-10, and then extracted with ethyl acetate. The organic phase was washed with saturated saline solution, dried over anhydrous magnesium sulfate, filtered, concentrated, and the crude product was freeze-dried to obtain the pale yellow free compound N,N'-dimethyl-N'-[[2-morpholine-4-[1-(m-tolyl)-4-piperidinyl]-1H-benzo[d]imidazole-5-yl]methyl]ethane-1,2-diamine (P406, Example 11) (270 mg, 0.566 mmol, 88.15% yield). LCMS:(ESI)m / z=477.3[M+H] + , 1 H NMR(400MHz,DMSO-d6)δ(ppm)11.28(br s,1H),7.08(t,1H),6.94(br d,1H),6.80(s,1H),6.75(br t,2H),6.55(br d,1H),3.84(br d,2H),3.68(br s,4H),3.48(s,2H),3.05-3.29(m,6H),2.92(m,2H),2.69-2.80(m,2H), 2.55-2.63(m,2H),2.41-2.48(m,2H),2.26(d,6H),2.03(s,3H),1.50(br d,2H).

[0154] Example 12: Synthesis of compound 5-((methyl(2-(methylamino)ethyl)amino)methyl)-4-(1-m-methylphenyl)piperidine-4-yl)indorin-2-one (P180): [ka]

[0155] Step 1: Add compound 4-bromoindorin-2-one (12-1) (2.00 g, 9.43 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate t-butyl ester (2.92 g, 9.43 mmol), and potassium phosphate (6.01 g, 28.30 mmol) to a mixture of 100 mL of tetrahydrofuran and 20 mL of water, purge with nitrogen gas, and then add Xphos Pd G3 (239 mg, 0.28 mmol). Purge again with nitrogen gas and heat to 65°C under nitrogen gas protection, stirring and allowing to react for 2 hours. The reaction mixture was diluted with saturated saline solution, extracted with ethyl acetate, combined with the organic phase, dried over anhydrous magnesium sulfate, filtered, concentrated, and the crude product was purified by silica gel column chromatography to obtain the brown solid compound 4-(1-t-butoxycarbonyl-1,2,3,6-tetrahydropyridine-4-yl)-indorin-2-one(12-2) (2.8 g, 8.91 mmol, 94.43% yield). LCMS: (ESI) m / z = 214.9 [M + H] + , 1 H NMR(400MHz,DMSO-d6)δ(ppm)10.40(s,1H),7.16(t,1H),6.88(d,1H),6.73(d,1H),5.96(br s,1H),3.98(br s, 2H), 3.54 (s, 2H), 3.46-3.53 (m, 2H), 2.41 (br d, 2H), 1.44 (s, 9H).

[0156] Step 2: Add compound 4-(1-t-butoxycarbonyl-1,2,3,6-tetrahydropyridine-4-)indorin-2-one(12-2) (2.30 g, 7.32 mmol) to 50 mL of methanol, purge with nitrogen gas, then add 10% palladium-carbon (460 mg, 0.43 mmol), purge with hydrogen gas, and stir at room temperature for 16 hours under a hydrogen gas atmosphere (balloon). The reaction is almost complete. Filter and wash with methanol, then concentrate the filtrate to obtain the yellow crude product 4-(1-t-butoxycarbonyl-piperidine-4-yl)indorin-2-one(12-3) (2.2 g, 6.95 mmol, 95.04% yield), which does not require further purification and can be used directly in the next step of the reaction. LCMS: (ESI) m / z = 216.9 [M + H] + , 1 H NMR(400MHz,CDCl3)δ(ppm)8.55(br s,1H),7.22(t,1H),6.89(d,1H),6.78(d,1H),4.28(br s,2H),3.52(s,2H),2.83(br t, 2H), 2.63 (tt, 1H), 1.75-1.82 (m, 2H), 1.61-1.73 (m, 2H), 1.51 (s, 9H).

[0157] Step 3: Dissolve the crude product 4-(1-t-butoxycarbonyl-piperidine-4-yl)-indorin-2-one (12-3) (3.70 g, 11.69 mmol) in 100 mL of dichloromethane, add N-bromosuccinimide (2.29 g, 12.86 mmol, 1.1 eq) in batches, and stir at room temperature for 16 hours until the reaction is almost complete. Carefully add 50 mL of 15% aqueous potassium carbonate solution to the reaction mixture while stirring, extract with dichloromethane, wash the organic phase with saturated brine, dry over anhydrous magnesium sulfate, filter, concentrate, and then slurry with ethyl acetate at room temperature to obtain the white solid crude product 4-(1-t-butoxycarbonyl-piperidine-4-yl)-5-bromo-indorin-2-one (12-4) (3.60 g, 9.11 mmol, 77.88% yield), which does not require further purification and can be used directly in the next step of the reaction. 1H NMR(400MHz,CDCl3)δ(ppm)δ 8.90(br s,1H),7.47(d,1H),6.67(d,1H),4.28(br d,2H),3.65(s,2H),3.37(br s,1H),2.83(br t,2H),1.78(br d,4H),1.51(s,9H).

[0158] Step 4: Dissolve the crude product 4-(1-t-butoxycarbonyl-piperidine-4-yl)-5-bromo-indorin-2-one(12-4) (3.60 g, 9.11 mmol) in 20 mL of 1,4-dioxane, then add 20 mL of 4 M hydrochloric acid-1,4-dioxane solution. Stir at room temperature for 16 hours until the reaction is almost complete. After filtration, wash the filter cake with methyl t-butyl ether. Concentrate and dry to obtain the white crude product 5-bromo-4-(piperidine-4-yl)indorin-2-one(12-5) hydrochloride (3.00 g, 9.05 mmol, 99.33% yield), which does not require further purification and can be used directly in the next step of the reaction. LCMS: (ESI) m / z = 295.0 [M + H] + , 1 H NMR(400MHz,D2O)δ(ppm)7.42(d,1H),6.66(d,1H),3.57-3.65(m,2H),3.46(br d,2H),3.36(br s,1H),3.07(m,2H),1.64-2.30(m,4H).

[0159] Step 5: While stirring, add N,N-diisopropylethylamine (1.55 g, 12.03 mmol, 2.10 mL) to a suspension of compound 5-bromo-4-(piperidine-4-yl)indole-2-one (12-5) hydrochloride (1.90 g, 5.73 mmol) in acetonitrile (20 mL), then add (4-nitrophenyl)2-trimethylsilylethylethyl carbonate (1.79 g, 6.30 mmol) dropwise. Stir the reaction mixture at room temperature for 15 hours, then filter, wash the filter cake with acetonitrile, combine the mother liquors, concentrate, and purify by silica gel column chromatography to obtain the yellow solid 5-bromo-4-(1-trimethylsilylethoxycarbonyl-piperidine-4-yl)indolin-2-one (12-6) (2.50 g, 5.40 mmol, 94.34% yield, 95% purity). LCMS:(ESI)m / z=413.1[M-2Me+H] + .

[0160] Step 6: Add 40 mL of tetrahydrofuran and 4 mL of water to a mixture of compound 5-bromo-4-(1-trimethylsilylethoxycarbonylpiperidine-4-yl)-indole-2-one (12-6) (2.00 g, 4.55 mmol), anhydrous potassium borotrifluoride [2-(t-butoxycarbonylmethylamineethyl)(methyl)amino]methyl trifluoride (4.21 g, 13.65 mmol), potassium phosphate (2.90 g, 13.65 mmol), and Ruphos Pd G2 (353 mg, 0.455 mmol). Purge with nitrogen gas and heat to 80°C under nitrogen gas protection for 16 hours until the reaction is almost complete. After cooling to room temperature, 30 mL of saturated saline solution was added, and the mixture was extracted with ethyl acetate. The organic phase was then dried over anhydrous magnesium sulfate, filtered, concentrated, and purified by silica gel column chromatography to obtain the yellow, viscous liquid compound 2-trimethylsilylethyl-4-(5-(((2-((t-butoxycarbonyl)(methyl)amino)ethyl)(methyl)amino)methyl-2-oxoindolin-4-yl)piperidine-1-carboxylic acid ester (12-7) (2.8 g, 4.49 mmol, 98.73% yield, 90% purity). LCMS: (ESI) m / z = 561.5 [M + H] + .

[0161] Step 7: Add 20 mL of acetonitrile to a mixture of compound 2-trimethylsilylethyl-4-(5-(((2-((t-butoxycarbonyl)(methyl)amino)ethyl)(methyl)amino)methyl-2-oxoindolin-4-yl)piperidine-1-carboxylic acid ester (12-7) (1.50 g, 2.41 mmol, 90% purity) and cesium carbonate (5.00 g, 15.35 mmol), and stir for 3 hours. Then add 4-methoxybenzyl chloride (565 mg, 3.61 mmol, 0.49 mL) dropwise and stir at room temperature for 1 hour. After this, the reaction is almost complete. After filtering and concentrating the filtrate, it is purified by silica gel column chromatography to obtain the yellow solid compound 2-trimethylsilylethyl-4-(5-(((2-((t-butoxycarbonyl)(methyl)amino)ethyl)(methyl)amino)methyl-1-(4-methoxybenzyl)-2,3-dioxoindorin-4-yl)piperidine-1-carboxylic acid ester (12-8) (1.32 g, 1.46 mmol, 60.76% yield, 77% purity). LCMS: (ESI) m / z = 695.6 [M + H] + .

[0162] Step 8: Dissolve compound 2-trimethylsilylethyl-4-(5-(((2-((t-butoxycarbonyl)(methyl)amino)ethyl)(methyl)amino)methyl-1-(4-methoxybenzyl)-2,3-dioxoindorin-4-yl)piperidine-1-carboxylic acid ester (12-8) (2.10 g, 2.33 mmol, 77% purity) in 30 mL of N,N-dimethylformamide, add cesium fluoride (1.77 g, 11.63 mmol, 0.43 mL), then heat to 65°C and react with stirring for 5 hours until the reaction is almost complete. Cool to room temperature, dilute with water, adjust pH to 3-4 with 10% phosphoric acid aqueous solution, and After extraction and washing with t-butyl ether, the pH of the aqueous phase was adjusted to 12 with 10M aqueous sodium hydroxide solution, extracted with ethyl acetate, dried the organic phase over anhydrous magnesium sulfate, filtered, concentrated, and then vacuum-dried to obtain the yellow solid crude product t-butyl(2-(((1-(4-methoxybenzyl)-2,3-dioxo-4-(piperidine-4-yl)indolin-5-yl)methyl)(methyl)amino)ethyl)(methyl)carbamate(12-9) (1.40 g, 2.16 mmol, 92.87% yield, 85% purity), which does not require further purification and can be used directly in the next step of the reaction. LCMS:(ESI)m / z=551.4[M+H] + .

[0163] Step 9: Add 20 mL of toluene to a mixture of compound t-butyl(2-(((1-(4-methoxybenzyl)-2,3-dioxo-4-(piperidine-4-yl)indolin-5-yl)methyl)(methyl)amino)ethyl)(methyl)carbamate (12-9) (1.30 g, 2.36 mmol), m-bromotoluene (605 mg, 3.54 mmol, 0.43 mL), and cesium carbonate (1.54 g, 4.72 mmol), purge with nitrogen gas, then add RuPhos Pd G3 (200 mg, 0.24 mmol), purge with nitrogen gas again, heat to 100°C, and react with stirring for 16 hours until the reaction is almost complete. The mixture was filtered, concentrated, and then purified by silica gel column chromatography to obtain the orange solid compound t-butyl(2-(((1-(4-methoxybenzyl)-2,3-dioxo-4-(1-m-methylphenylpiperidine-4-yl)indoline-5-yl)methyl)(methyl)amino)ethyl)(methyl)carbamate(12-10) (900 mg, 1.40 mmol, 59.49% yield, 100% purity). LCMS: (ESI) m / z = 641.4 [M+H] + . 1 H NMR(400MHz,CD3OD)δ(ppm)7.45(br s,1H),7.33(br d,2H),7.13(t,1H),6.72-6.94(m,5H),6.67(d,1H),3.68-3.91(m,5H),3.52(s,2H), 3.25-3.40(m,5H),2.67-2.91(m,4H),2.37-2.67(m,4H),2.09-2.36(m,7H),1.60(br d,2H),1.17-1.41(m,9H).

[0164] Step 10: Dissolve compound t-butyl(2-(((1-(4-methoxybenzyl)-2,3-dioxo-4-(1-m-methylphenylpiperidine-4-yl)indolin-5-yl)methyl)(methyl)amino)ethyl)(methyl)carbamate (12-10) (190 mg, 0.30 mmol) in 5 mL of ethanol, and add hydrazine hydrate (5.15 g, 87.44 mmol, 5.00 mL, 85% purity) and potassium hydroxide (332 mg, 5.93 mmol). Heat the mixture to 80°C and react with stirring for 3 hours until the reaction is almost complete. After removing most of the ethanol by concentration, the aqueous phase is extracted with ethyl acetate, combined with the organic phase, dried over anhydrous magnesium sulfate, filtered, and concentrated to obtain a yellow, viscous liquid crude product, t-butyl(2-(((1-(4-methoxybenzyl)-2-oxo-4-(1-m-methylphenylpiperidine-4-yl)indolin-5-yl)methyl)(methyl)amino)ethyl)(methyl)carbamate (12-11) (220 mg), which does not require further purification and can be used directly in the next step of the reaction. LCMS: (ESI) m / z = 627.5 [M + H] + .

[0165] Step 11: Dissolve compound t-butyl(2-(((1-(4-methoxybenzyl)-2-oxo-4-(1-m-methylphenylpiperidine-4-yl)indolin-5-yl)methyl)(methyl)amino)ethyl)(methyl)carbamate (12-11) (220 mg, 0.32 mmol, 92% purity) in 5 mL of trifluoroacetic acid, then add trifluoromethanesulfonic acid (200 mg, 1.33 mmol, 0.12 mL) dropwise while stirring, stir at room temperature for 5 hours, then heat to 40°C and react for 30 hours until the reaction is almost complete. After concentrating the reaction solution, dilute with 5 mL of dichloromethane and extract with 0.5 M dilute hydrochloric acid aqueous solution. Combine the aqueous phases, adjust the pH to 12 with 1 M sodium hydroxide aqueous solution, and then extract with dichloromethane. The organic phases were combined, dried over anhydrous magnesium sulfate, filtered, and concentrated to obtain the free base product 5-((methyl(2-(methylamino)ethyl)amino)methyl)-4-(1-m-methylphenyl)piperidine-4-yl)indorin-2-one (P180). This product was dissolved in 2 mL of 1,4-dioxane, and then 2 mL of 4 M hydrochloric acid-1,4-dioxane solution was added dropwise while stirring. The mixture was concentrated and freeze-dried to obtain the white solid 5-((methyl(2-(methylamino)ethyl)amino)methyl)-4-(1-m-methylphenyl)piperidine-4-yl)indorin-2-one (P180, Example 12) hydrochloride (80 mg, 48.12% yield, quantitative hydrochloride coefficient is 3). LCMS: (ESI) m / z = 407.3 [M + H] + . 1 H NMR(400MHz,D2O)δ(ppm)7.46(s,1H),7.39-7.44(m,2H),7.37(d,1H),7.31-7.36(m,1H),6.97(d,1H) ),4.55(s,2H),3.78-3.92(m,4H),3.70-3.77(m,2H),3.59-3.70(m,2H),3.48-3.57(m,2H),3.41(br t,1H),2.83(s,3H),2.73(s,3H),2.41-2.59(m,2H),2.34(s,3H),2.07(br d,2H).

[0166] Example 13: Synthesis of compound N-((5-amino-3-(1-(m-methylphenyl)piperidine-4-yl)pyrazine-2-yl)methyl)-N,N'-dimethyl-1,2-ethylenediamine (P292): [ka]

[0167] Step 1: Dissolve compound 2-cyano-3,5-dichloropyrazine (13-1) (145 g, 833.39 mmol) in 1000 mL of N,N-dimethylformamide, then add diisopropylethylamine (109 g, 843.37 mmol, 146.90 mL) dropwise at room temperature. After cooling to 5-10°C, dissolve bis(4-methoxybenzyl)amine (217.50 g, 845.23 mmol) in 500 mL of N,N-dimethylformamide solution and add dropwise while stirring. Slowly raise the temperature to room temperature and continue stirring for 3 hours until the reaction is almost complete. Pour the reaction mixture into a 5000 mL ice water mixture and stir for 5 minutes until a solid precipitate forms. After filtration, the solid is dissolved in 4000 mL of ethyl acetate, then washed with saturated brine, the organic phase is dried over anhydrous magnesium sulfate, filtered, concentrated, and the crude product is slurryed in 700 mL of methyl t-butyl ether at 20°C for 16 hours, filtered, and dried to obtain the yellow solid compound 2-cyano-3-chloro-5-(bis(4-methoxybenzyl)amino)pyrazine (13-2), which does not require further purification and can be used directly in the next step of the reaction. 1 H NMR (400MHz, CDCl3) δ (ppm) 7.87 (s, 1H), 7.14 (br d, 4H), 6.85-6.92 (m, 4H), 4.75 (br s, 4H), 3.81 (s, 6H).

[0168] Step 2: Dissolve compound 2-cyano-3-chloro-5-(bis(4-methoxybenzyl)amino)pyrazine (13-2) in 600 mL of tetrahydrofuran, cool to -78°C under nitrogen gas protection, add DIBALH (1 mol / L, 548 mL) dropwise while stirring, and continue stirring for 2 hours until the reaction is almost complete. The reaction is quenched by carefully adding 500 mL of 10% aqueous acetic acid solution while stirring at -78°C, slowly returning to room temperature, filtering through diatomaceous earth, washing with ethyl acetate, extracting the filtrate with ethyl acetate, combining the organic phases, adjusting the pH to 8-9 with saturated aqueous sodium bicarbonate solution, separating the organic phases, washing with saturated brine, drying over anhydrous magnesium sulfate, filtering, and after concentration, the product is slurryed with methyl t-butyl ether / petroleum ether (volume ratio 1:2) for 3 hours to obtain the yellow solid crude product 5-(bis(4-methoxybenzyl)amino)-3-chloropyrazine-2-formaldehyde (13-3) (100 g, 252.35 mmol, 92.69% yield), which is used directly in the next step of the reaction. 1 H NMR (400MHz, CDCl3) δ (ppm) 10.15 (s, 1H), 8.03 (s, 1H), 7.12-7.20 (m, 4H), 6.86-6.91 (m, 4H), 4.71-4.87 (m, 4H), 3.81 (s, 6H).

[0169] Step 3: Dissolve compound 5-(bis(4-methoxybenzyl)amino)-3-chloropyrazine-2-formaldehyde (13-3) (53.0 g, 133.21 mmol) and Nt-butoxycarbonyl-N,N'-dimethylethylenediamine (30.0 g, 159.35 mmol) in 1000 mL of dichloromethane, add acetic acid (9.60 g, 159.86 mmol, 9.14 mL), then add sodium borohydride acetate (71.0 g, 335.00 mmol) in batches at room temperature, continue to react with stirring for 2 hours, then carefully add 1000 mL of saturated sodium carbonate aqueous solution to quench the reaction. After extraction with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, concentrated, and purified by silica gel column chromatography to obtain a yellow, viscous liquid compound (2-((((5-(bis(4-methoxybenzyl)amino)-3-chloropyrazine-2-yl)(methyl)amino)ethyl)(methyl)carbamate t-butyl ester (13-4) (112 g, 196.45 mmol, 73.73% yield), which was used directly in the next step of the reaction without further purification of the crude product. 1 H NMR(400MHz,CDCl3)δ(ppm)7.83(s,1H),7.15(d,4H),6.83-6.89(m,4H),4.62-4.73(m,4H),3.80(s,6H),3.69(br s,2H),3.36(br s, 2H), 2.85 (s, 3H), 2.63 (br s, 2H), 2.34 (s, 3H), 1.44 (s, 9H).

[0170] Step 4: Add tetrahydrofuran (250 mL) and water (50 mL) to a mixture of compound (2-((((5-(bis(4-methoxybenzyl)amino)-3-chloropyrazine-2-yl)(methyl)amino)ethyl)(methyl)carbamate t-butyl ester (13-4) (37 g, 64.90 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)-1-(m-tolyl)-1,2,3,6-tetrahydropyridine (intermediate B) (25 g, 83.55 mmol) and potassium phosphate (35 g, 164.89 mmol), purge with nitrogen gas, add XPhos-Pd-G2 (1.65 g, 1.95 mmol), heat to 65°C under nitrogen gas protection and stir for 16 hours until the reaction is almost complete. After adding 500 mL of saturated saline solution to the substance, it is extracted with ethyl acetate, the organic phase is dried over anhydrous magnesium sulfate, filtered, concentrated, dissolved in 500 mL of methyl t-butyl ether, washed with 10% phosphoric acid aqueous solution (150 mL x 3), and the pH of the aqueous phase is adjusted to 13-14 with 10-15% sodium hydroxide aqueous solution. After extraction with ethyl acetate, the organic phase is dried over anhydrous magnesium sulfate, filtered and concentrated to obtain 101 g of a brownish, viscous crude product t-butyl(2-(((5-(bis(4-methoxybenzyl)amino)-3-(1-(m-methylphenyl)-1,2,3,6-tetrahydropyridine-4-yl)pyrazine-2-yl)methyl)(methyl)amino)ethyl)(methyl)carbamate (13-5), which is used directly in the next step of the reaction. 1 H NMR(400MHz,CDCl3)δ(ppm)7.84(s,1H),7.13-7.19(m,4H),6.85(br d,4H),6.77-6.82(m,2H),6.67(br d,1H),6.57(br s,1H),4.72(s,4H),4.13(q,1H),3.93(br s,2H),3.80(s,6H),3.54-3.64(m,2H),3.49(br t,2H),3.20-3.39(m,1H),2.69-2.85(m,5H),2.48-2.66(m,2H),2.35(s,3H),2.28(br s,2H),2.05(s,1H),1.47(br s,1H), 1.43(br s,9H).

[0171] Step 5: Dissolve compound t-butyl(2-(((5-(bis(4-methoxybenzyl)amino)-3-(1-(m-methylphenyl)-1,2,3,6-tetrahydropyridine-4-yl)pyrazine-2-yl)methyl)(methyl)amino)ethyl)(methyl)carbamate (13-5) (46.5 g, 65.78 mmol) in 600 mL of tetrahydrofuran, add palladium hydroxide / carbon (15 g, 21.36 mmol, 20% purity) under nitrogen gas protection, purge with hydrogen gas, and stir at room temperature for 4 days under a hydrogen gas atmosphere (balloon). After filtration, the mixture was concentrated, and the crude product was purified by silica gel column chromatography to obtain the yellow, viscous liquid compound t-butyl(2-(((5-(bis(4-methoxybenzyl)amino)-3-(1-(m-methylphenyl)piperidine-4-yl)pyrazine-2-yl)methyl)(methyl)amino)ethyl)(methyl)carbamate (13-6) (83.5 g, 117.78 mmol, 89.53% yield). 1 H NMR(400MHz,CDCl3)δ(ppm)7.75(s,1H),7.10-7.19(m,5H),6.77-6.90(m,6H),6.67(d,1H),4.69(s,4H),3.79(s,7H),3.60(br s,2H),3.25-3.42(m,2H),3.09(br s,1H),2.74-2.85(m,5H),2.48-2.65(m,2H),2.32(s,3H),2.27(br s, 3H), 2.14 (dq, 2H), 2.05 (s, 1H), 1.86 (br d, 2H), 1.41 (br s, 9H).

[0172] Step 6: Add 300 mL of trifluoroacetic acid to compound t-butyl(2-(((5-(bis(4-methoxybenzyl)amino)-3-(1-(m-methylphenyl)piperidine-4-yl)pyrazine-2-yl)methyl)(methyl)amino)ethyl)(methyl)carbamate (13-6) (56 g, 78.99 mmol), then add trifluoromethanesulfonic acid (30.0 g, 199.90 mmol, 17.65 mL), and stir the reaction mixture at room temperature for 16 hours until the reaction is almost complete. Concentrate the reaction mixture under reduced pressure, add 1 L of water and 2 L of ethyl acetate, and stir until the solid is dissolved. After separation and extraction, extract the organic phase with 1 M hydrochloric acid solution, and neutralize the pH of the aqueous phase to 9 with 30% aqueous sodium hydroxide solution. Next, the organic phase was extracted with ethyl acetate, dried, concentrated, and purified by silica gel column chromatography to obtain the white solid compound N-((5-amino-3-(1-(m-methylphenyl)piperidine-4-yl)pyrazine-2-yl)methyl)-N,N'-dimethyl-1,2-ethylenediamine (P292, Example 13). LCMS: (ESI)m / z=369.3[M+H] + , 1 H NMR(400MHz,methanol-d4)δ(ppm)7.90(s,1H),7.62(s,1H),7.56(br d,1H),7.46(t,1H),7.33(d,1H),6.02(s,3H),5.01(br s,25H),4.50(s,2H),3.88-3.99(m,2H),3.74(br d,2H),3.42-3.63(m,5H),2.90(s,3H),2.81(s,3H),2.41-2.56(m,5H),2.19-2.32(m,20H),2.13(br d,3H).

[0173] Using the same method as described above, compounds P001 to P448 were synthesized, and their characterization data is shown in the example on the right. [Table 1-1] [Table 1-2] [Table 1-3] Table 1-4 Table 1-5 Table 1-6 Table 1-7 Table 1-8 Table 1-9 Table 1-10 Table 1-11 Table 1-12 Table 1-13 Table 1-14 Table 1-15 Table 1-16 Table 1-17 Table 1-18 Table 1-19 Table 1-20 [Table 1-21] [Table 1-22] [Table 1-23] [Table 1-24] [Table 1-25] [Table 1-26] [Table 1-27] [Table 1-28] [Table 1-29] [Table 1-30]

[0174] Examples of biological tests Test Example 1. PRMT1 Enzyme Activity Test Method The PRMT1 enzyme activity test experiment is performed using a buffer prepared on the day, which consists of 10 mM Tirs-HCl (pH=8.0), 0.01% Tween-20, and 1 mM DTT. Using 100% DMSO, the compound is prepared to 100X, the highest inhibitor concentration ultimately required for the reaction, and then transferred to one well of a 384-well Echo plate (384-well polypropylene microplate 2.0, clear, flat-bottom, Echo-qualified), and subsequently diluted in the next well with a 3-fold dilution of 100% DMSO, and so on, until a total concentration of 10 is reached based on Precision. 100% DMSO is added to two empty wells in the same 384-well Echo plate as a control well without the compound and a control well without the enzyme. 250 nL of the compound is transferred from each well of the 384-well Echo plate to a 384-well measurement plate (384-well polypropylene storage microplate) via an Echo550 liquid handler. For control wells containing the compound and control wells without the compound, add a mixture containing the PRMT1 enzyme (15 μL) to the 384-well measurement plate. For control wells without the enzyme, add a mixture containing the test buffer (15 μL) instead. Incubate the compound with PRMT1 at room temperature for 15 minutes, then add a mixture containing 3H-SAM and peptide (10 μL) to initiate the reaction (final volume = 25 μL). The final concentrations of the components are as follows: PRMT1 0.5 nM, 3H-SAM 0.25 μM, peptide 0.1 μM, and DMSO concentration 1%. After incubation for 120 minutes, the measurement is terminated by adding non-radioactive labeled SAM (5 μL) to a final concentration of 125 μM, thereby diluting the 3H-SAM to a level where engagement with the peptide substrate is no longer detectable. Next, 25 μL of the reaction mixture from the 384-well measurement plate is transferred to a 384-well detection plate (Streptavidin FlashPlate HTS PLUS, large capacity, 384 wells). The biotinylated peptide is allowed to bind to the streptavidin surface at room temperature for at least 60 minutes. The Flashplate is then washed three times with 0.1% Tween-20 using a BioTek plate washer.The plate is read using a microwell plate counter (MicroBeta2), and the amount of 3H-labeled peptide bound to the surface of the detection plate is measured in counts / minute (cpm).

[0175] Curve fitting: Copy the original data from Reader and calculate the inhibition rate value in Excel via equation (1): Equation (1): Inh%=(CPMmax-CPMcmpd) / (CPMmax-CPMmin)×100, where the Max signal is obtained through the interaction between the enzyme and the substrate, and the Min signal is obtained through the substrate. Fit the data via equation (2) using the XLFit plugin version 45.4.0.8 in Excel. 50 Obtain the value. Equation (2): Y = Bottom + (Top - Bottom) / (1 + ((IC 50 / X) × HillSlope)), where Y represents the inhibition percentage and X represents the concentration of the compound.

[0176] Test Example 2: Toledo cell proliferation inhibition experimental method A. Objective: To confirm the effect of the compound on Toledo cells through a 6-day cell proliferation experiment.

[0177] B. Reagents and materials: 1. Cell medium: RPMI 1640 + 10% FBS 2.384-well cell culture plate (CORNING, catalog number 3764) 3.0.4% trypan blue staining solution (THERMO FISHER, catalog number T10282) 4. Cell counting plate (THERMO FISHER, catalog number C) 10 228) 5.50 ml reagent reservoir (CORNING, catalog number 4870) 6.50ml conical sterile polypropylene centrifuge tube (THERMO FISHER, catalog number 339653) 7. Automatic cell counter (THERMO FISHER, catalog number AMQAX) 1 000) 8. CellTiter-Glo Luminescent Cell Viability Detection Reagent (PROMEGA, Catalog No. G7572) 9. SpectraMax i3x Multimode Microplate Reader (MOLECULAR DEVICES, Catalog No. 5024062)

[0178] C. Experimental Method 1. Resuspend the cells using a pipette. Mix 2.0.4% trypan blue stain and Toledo cells in equal proportions, and count the cells using an automated cell counter. 3. Dilute the Toledo cells to a final concentration of 2000 cells per well and transfer them to a 50 ml reagent reservoir. 4. Add 40 µl per well of diluted Toledo cells to a 384-well cell culture plate. 5. Centrifuge briefly to pellet the cells. 6. Culture the cells in a cell incubator at 37°C and 5% CO2. 7. Mix the substrate in the CellTiter-Glo luminescent cell viability detection reagent uniformly with the solution. 8.6 days later, remove the 384-well cell culture plate from the incubator and add 20 µl of the prepared CellTiter-Glo reagent to each well. Place the 9.384-well cell culture plate in an orbital shaker and mix uniformly for 30 minutes. 10. Detect the emitted signal using the SpectraMax i3x multimode microplate reader.

[0179] Experimental method for inhibiting MV-4-11 cell proliferation Similar to the Toledo cell proliferation inhibition experiment method, the difference is that MV-4-11 cells are used, IMDM + 10% FBS is used as the cell medium, and the experiment method involves 250 cells per well in stage 3.

[0180] The results are shown in the table below. The results of the PRMT1 enzyme activity experiment are as follows: A is IC 50 Represents <50nM, B is 50nM≦IC 50 Represents <500nM, C is IC 50 Represents ≥ 500 nM, The results of the Toledo and MV-4-11 cell proliferation inhibition experiments are as follows: A is IC 50 Represents <1uM, B is 1uM ≤ IC 50 Represents <5uM, C is IC 50 This represents ≥ 5 μM.

[0181] The results of the PRMT1 enzyme activity test and the Toledo, MV-4-11 cell proliferation inhibition test are shown in the table below. [Table 2-1] [Table 2-2] [Table 2-3] [Table 2-4] [Table 2-5] [Table 2-6]

[0182] Test Example 3. PRMT Panel Selectivity Test The PRMT1 test method is the same as in Test Example 1, and the PRMT5, PRMT7 tests and curve fitting are performed using the PRMT1 test data processing method with minimal and optimized parameters. The PRMT3 test method is as follows: PRMT3 experimental method: This experiment is measured using a buffer prepared on the day, which consists of 10 mM Tirs-HCl (pH=8.0), 0.01% Tween-20, and 1 mM DTT. Using 100% DMSO, the compound is prepared to 100X the highest inhibitor concentration ultimately required for the reaction, then transferred to one well of a 384-well Echo plate (384-well polypropylene microplate 2.0, clear, flat-bottom, Echo-qualified), and subsequently diluted in the next well with a 3-fold dilution of 100% DMSO, and so on, until a total concentration of 10 is reached based on Precision. 100% DMSO is added to two empty wells in the same 384-well Echo plate as a control well without the compound and a control well without the enzyme. 100 nL of the compound is transferred from each well of the 384-well Echo plate to a 384-well measurement plate (OptiPlate (384-well, white)) via an Echo550 liquid handler. For control wells containing the compound and control wells without the compound, add a mixture containing the PRMT1 enzyme (5 μL) to the 384-well measurement plate. For control wells without the enzyme, add a mixture containing the test buffer (5 μL) instead. Incubate the compound with PRMT3 at room temperature for 15 minutes, then add a mixture containing cold SAM and peptide (5 μL) to start the reaction (final volume = 10 μL). The final concentrations of the components are as follows: PRMT3 0.1 nM, SAM 15 μM, peptide 0.05 μM, and DMSO concentration 1%. After incubation at room temperature for 60 minutes, terminate the reaction by adding donor beads and acceptor beads (15 μL) diluted to a final concentration of 10 μg / mL with AlphaLISA epigenetic buffer. Incubate the 384-well measurement plate at room temperature for 60 minutes, then measure the relative fluorescence units (RFU) using an Alpha mode (Ex680 / Em615) multimode plate reader.

[0183] Curve fitting: Copy the original data from Reader and calculate the inhibition rate values ​​in Excel via equation (1). Equation (1): Inh% = (RFUmax - RFUcmpd) / (RFUmax - RFU mins) × 100, where the Max signal is obtained through the interaction between enzyme and substrate, and the Min signal is obtained through the substrate. Use XLFit plugin version 45.4.0.8 in Excel and fit the data via equation (2) to obtain IC 50 Obtain the value. Equation (2): Y = Bottom + (Top - Bottom) / (1 + ((IC 50 / X) × HillSlope)), where Y represents the inhibition percentage and X represents the concentration of the compound.

[0184] The PRMT4, PRMT6, and PRMT8 tests and curve fittings are performed using optimized parameters, referring to the PRMT3 test and data processing methods.

[0185] The table below shows the results of the PRMT panel selectivity test, where A is IC. 50 Represents <50nM, B is 50nM≦IC 50 Represents <500nM, C is IC 50 This represents ≥10 μM. [Table 3]

[0186] Test Example 4. RKO in Cell Western Method Seed 2,000 cells per well and 100 μL of medium in a 96-well plate (Corning #3599) coated with polylysine, at a concentration of 20,000 cells / ml. Add 500 nL of the compound to the 96-well plate. 3) Incubate the 96-well plate in a 37°C, 5% carbon dioxide incubator for 72 hours. After 3 days, remove the 96-well plate from the incubator, add 100 μL of 8% paraformaldehyde solution to each well, and leave at room temperature for 15 minutes. After 15 minutes, shake off the liquid from the plate and wash three times with phosphate buffer (1 × PBS). Shake off the liquid from the plate, add 200 μL of membrane rupture buffer (PBS with 0.1% (v / v) Tween-20 added), and incubate in a shaker for 30 minutes. After 30 minutes, shake off the liquid from the plate, add blocking buffer, and incubate at room temperature with shaking for 2 hours. Next, shake off the liquid from the plate, add blocking solution containing the primary antibody (MMA primary antibody, CST#8711S, 1:1000v / v) to the 96-well plate, and incubate overnight at 4°C with shaking. The next day, wash three times with washing solution (PBS with 0.05% (v / v) Tween-20 added), add blocking solution containing the secondary antibody (goat anti-rabbit IgG(H+L) Invitrogen#31460, 1:10000v / v), and incubate at room temperature for 2 hours. Next, wash the 96-well plate four times with washing solution. Add the TMB mixture to the 96-well plate and incubate at room temperature with shaking for 15 minutes. Next, add the stop solution and read the OD450nm on a microplate reader. Wash three times with washing solution, add 50 μL of Janus green, and incubate at room temperature with shaking for 15 minutes. Wash 10 times with water until the color disappears, add 200 μL of 0.5 M hydrochloric acid solution to each well, and incubate at room temperature for 10 minutes. Read the values ​​at OD595 nm using a Flexstation.

[0187] Calculation: First, calculate the OD450 / OD595 ratio for each well. Each plate contains six DMSO-negative control groups (ZPEs) and six 10 μM positive control groups (HPEs). The average control group ratio is used to determine the activation percentage for each test well. The compound to be tested is diluted with DMSO three times at a total of eight concentration points, with a starting concentration of 5 μM. The formula for calculating the activation percentage for each test well is as follows: Activation percentage = 100 - [(HPE ratio - specific well ratio) / (HPE ratio - ZPE ratio)] × 100

[0188] Table 4. RKOICW experimental results A represents EC30 < 250 nM, B represents 250nM ≤ EC30 < 2500nM, C represents EC30 > 2500 nM. [Table 4-1] [Table 4-2]

[0189] All documents referenced in this invention are cited as references in this application, as if each document were cited individually. Furthermore, after reading the above teachings of this invention, persons skilled in the art can make various changes or modifications to the invention, and these equivalent forms are also included within the scope defined by the claims appended to this application.

Claims

1. A compound as shown in the following formula I, or a pharmaceutically acceptable salt or deuterated product thereof, 【Chemistry 1】 X １ and X ２ Each is independently selected from the group consisting of CR, NR, and N, and X ３ and X ４ Each is independently selected from the group consisting of CR' and N, and the dashed line indicates a chemical bond or no bond. Ring A is, 【Chemistry 2】 A selection is made from the group consisting of the following, where, if the connection site that connects to other structural fragments or substituents is NH, a hydrogen atom on NH is lost, thereby forming the connection site. Ring B is a substituted or unsubstituted C ６ Selected from the group consisting of aryl groups, substituted or unsubstituted 5- to 12-membered heteroaryl rings, and substituted or unsubstituted 4- to 12-membered heterocycles containing 1 to 3 heteroatoms selected from oxygen, sulfur, and nitrogen, m and n are each independently selected from the group consisting of 0, 1, 2, 3, 4, 5, and 6. L represents a chemical bond, or -O-, -(CHR). ６ ) ｐ－ ----CHR ６ Selected from the group consisting of -O-, S, and -NH-, p is selected from the group consisting of 1, 2, and 3. R １ is a substituted or unsubstituted C １ -C ６ alkyl group, R ２ H, substituted or unsubstituted C １ -C ６ It is an alkyl group, R ３ H, halogen, cyano group, amino group, nitro group, hydroxyl group, mercapto group, aldehyde group, carboxyl group, -SO ２ -OH group, substituted or unsubstituted C １ -C ６ Alkyl, substituted or unsubstituted C ２ -C ６ Alkenyl group, substituted or unsubstituted C １ -C ６ Alkoxy groups, substituted or unsubstituted C １ -C ６ Alkylamine group, substituted or unsubstituted C ６ -C １０ An aryl group, a substituted or unsubstituted 5- to 12-membered heteroaryl group, a substituted or unsubstituted 5- to 7-membered heterocycle containing 1 to 3 heteroatoms selected from oxygen, sulfur, and nitrogen, or a substituted or unsubstituted carbon. ３ -C １２ Carbon rings, substituted or unsubstituted C ２ -C １０ Acyl group, substituted or unsubstituted C ２ -C １０ Ester group, substituted or unsubstituted C １ -C ６ Amide group, substituted or unsubstituted C １ -C ４ Alkyl-S(O) ２ - and substituted or unsubstituted C １ -C ４ A group selected from the group consisting of alkyl-SO-, R is H, halogen, amino group, substituted or unsubstituted C １ -C ６ Alkyl, substituted or unsubstituted C １ -C ６ Alkoxy groups, substituted or unsubstituted C １ -C ６ Alkylamine group, substituted or unsubstituted C ６ -C １０ Aryl groups, substituted or unsubstituted 5- to 12-membered heteroaryl groups, substituted or unsubstituted C ２ -C １０ Acyl group, substituted or unsubstituted C １ -C ６ It is a group selected from the group consisting of amide groups, R' represents H, halogen, amino group, substituted or unsubstituted C １ -C ６ Alkyl, substituted or unsubstituted C １ -C ６ Alkoxy groups, substituted or unsubstituted C １ -C ６ Alkylamine groups, and substituted or unsubstituted C １ -C ６ Is it a group selected from the group consisting of amide groups? Alternatively, two R or R' atoms located on adjacent ring atoms, together with the ring atom to which they are bonded, form a substituted or unsubstituted 5- to 11-membered carbon ring or heterocycle, wherein the ring is partially unsaturated or saturated, or the carbon ring or heterocycle is a 5- to 9-membered carbon ring or heterocycle, which is aromatic. R ４ H, halogen, substituted or unsubstituted C １ -C ６ Is it an alkyl group? Or two R atoms located on the same or adjacent ring atoms. ４ These, together with the ring atoms to which they are bonded, form a substituted or unsubstituted 3- to 11-membered carbon ring or heterocycle, wherein the ring is a partially unsaturated ring, a saturated ring, or an aromatic ring. R ６ These are H, halogen, cyano group, and C １ -C ６ A group selected from the group consisting of alkyl groups, Unless otherwise specified, in the above formulas, the substitution means that the hydrogen atom on the corresponding group is deuterium, tritium, halogen, hydroxy group, carboxy group, mercapto group, benzyl group, oxygen (=O), C １ -C １２ alkoxycarbonyl group, C １ -C ６ aldehyde group, amino group, C １ -C ６ amide group, nitro group, cyano group, unsubstituted or halogenated C １ -C ６ alkyl group, C ２ -C １０ alkenyl group, C １ -C ６ alkoxy group, C １ -C ６ alkyl-amine group, C １ -C ６ alkyl-sulfonamide group, C １ -C ６ alkyl-ureido group, C １ -C ６ alkyl-S-, C ６ -C １０ aryl group, 5- or 6-membered heteroaryl group, 5- or 6-membered non-aromatic heterocyclic group, C １ -C １２ alkylaminocarbonyl group, unsubstituted or halogenated C ２ -C １０ acyl group, -SO ２ -OH, -SO ２ -NH ２ , -PO ３ -OH, unsubstituted or halogenated C １ -C ４ alkyl-S(O) ２ -, unsubstituted or halogenated C １ -C ４ alkyl-SO-, 【Transformation 3】 This refers to substitution by one or more substituents selected from the group consisting of , where in each formula, the heterocycle or heteroaryl ring has 1 to 3 heteroatoms selected from the group consisting of N, S, or O, and each aryl group, heteroaryl group, and heterocyclic group can independently be deuterium, tritium, halogen, hydroxyl group, carboxyl group, mercapto group, or C １ -C ６ alkyl group, C １ -C ６ It is characterized by being substituted with one to three substituents selected from the group consisting of alkoxy groups. A compound as shown in formula I, or a pharmaceutically acceptable salt or deuterated product thereof.

2. The aforementioned compound is as follows: 【Chemistry 4】 Having a structure selected from the group consisting of, Here, the C ring is characterized by being a substituted or unsubstituted phenyl group, a substituted or unsubstituted 5- to 7-membered heterocyclic group, or a substituted or unsubstituted 5- to 6-membered heteroaryl group. The compound according to claim 1, or a pharmaceutically acceptable salt or deuterated product thereof.

3. The aforementioned R ３ H, halogen, cyano group, amino group, nitro group, hydroxyl group, mercapto group, aldehyde group, carboxyl group, -SO ２ -OH group, substituted or unsubstituted C １ -C ６ Alkyl, substituted or unsubstituted C １ -C ６ Alkoxy groups, substituted or unsubstituted C １ -C ６ Alkylamine groups, substituted or unsubstituted 5- to 10-membered heteroaryl groups, substituted or unsubstituted 5- to 7-membered heterocycles containing 1 to 3 heteroatoms selected from oxygen, sulfur, and nitrogen, substituted or unsubstituted C ３ -C ８ Carbon rings, substituted or unsubstituted C ２ -C ６ Acyl group, substituted or unsubstituted C ２ -C ６ Ester group, substituted or unsubstituted C １ -C ６ Amide group, substituted or unsubstituted C １ -C ４ Alkyl-S(O) ２ -, Substitute or non-substitute C １ -C ４ A group selected from the group consisting of alkyl-SO-, and / or R is H, halogen, amino group, substituted or unsubstituted C １ -C ６ Alkyl, substituted or unsubstituted C １ -C ６ Alkoxy groups, substituted or unsubstituted C １ -C ６ Alkylamino group, substituted or unsubstituted 5- to 10-membered heteroaryl group, substituted or unsubstituted C ２ -C ６ Acyl group, substituted or unsubstituted C １ -C ６ It is a group selected from the group consisting of amide groups, R' represents H, halogen, amino group, substituted or unsubstituted C １ -C ６ Alkyl, substituted or unsubstituted C １ -C ６ Alkoxy groups, and substituted or unsubstituted C １ -C ６ A group selected from the group consisting of alkylamine groups, Alternatively, two R or R' atoms located on adjacent ring atoms, together with the carbon atom to which they are bonded, form a substituted or unsubstituted 5- to 9-membered carbon ring or heterocycle, wherein the ring is partially unsaturated, saturated, or aromatic. The compound according to claim 1, or a pharmaceutically acceptable salt or deuterated product thereof.

4. The B ring is characterized by being selected from the group consisting of substituted or unsubstituted phenyl groups and substituted or unsubstituted 5- to 10-membered heteroaryl rings. The compound according to claim 1, or a pharmaceutically acceptable salt or deuterated product thereof.

5. The aforementioned R is H, halogen, amino group, substituted or unsubstituted C １ -C ６ Alkyl, substituted or unsubstituted C １ -C ６ Alkoxy groups, substituted or unsubstituted C １ -C ６ Alkylamine group, substituted or unsubstituted C ２ -C ６ Acyl group, substituted or unsubstituted C １ -C ６ It is a group selected from the group consisting of amide groups, R' represents H, halogen, cyano group, amino group, nitro group, hydroxy group, mercapto group, aldehyde group, carboxyl group, and -SO ２ -OH group, substituted or unsubstituted C １ -C ６ Alkyl, substituted or unsubstituted C １ -C ６ Alkoxy groups, and substituted or unsubstituted C １ -C ６ It is characterized by being a group selected from the group consisting of alkylamine groups. The compound according to claim 1, or a pharmaceutically acceptable salt or deuterated product thereof.

6. The aforementioned R ４ These are H, halogens, and substituted or unsubstituted C １ -C ６ It is characterized by being a group selected from the group consisting of alkyl groups. The compound according to claim 1, or a pharmaceutically acceptable salt or deuterated product thereof.

7. The aforementioned 【Transformation 5】 The ring is, 【Transformation 6】 Characterized by being selected from the group consisting of, The compound according to claim 1, or a pharmaceutically acceptable salt or deuterated product thereof.

8. The aforementioned ring B is substituted or unsubstituted C ６ The material is characterized by being selected from the group consisting of an aryl group, a substituted or unsubstituted 5- to 12-membered heteroaryl group, and a substituted or unsubstituted 4- to 12-membered heterocycle containing 1 to 3 heteroatoms selected from oxygen, sulfur, and nitrogen. The compound according to claim 1, or a pharmaceutically acceptable salt or deuterated product thereof.

9. The aforementioned ring A is substituted or unsubstituted 【Transformation 7】 Characterized by, The compound according to claim 1, or a pharmaceutically acceptable salt or deuterated product thereof.

10. The compound has a structure as shown in the following formula III, 【Transformation 8】 Here, Ring A is, 【Chemistry 9】 A selection from the group consisting of the following, wherein, when the connection site that connects to other structural fragments or substituents is NH, a hydrogen atom on NH is lost, thereby forming the connection site. The compound according to claim 1, or a pharmaceutically acceptable salt or deuterated product thereof.

11. R ３ H, halogen, cyano group, amino group, nitro group, hydroxyl group, mercapto group, aldehyde group, carboxyl group, -SO ２ -OH group, substituted or unsubstituted C １ -C ６ Alkyl, substituted or unsubstituted C １ -C ６ Alkoxy groups, substituted or unsubstituted C １ -C ６ Alkylamine group, substituted or unsubstituted C ２ -C ６ Acyl group, substituted or unsubstituted C ２ -C ６ Ester group, substituted or unsubstituted C １ -C ４ Alkyl-S(O) ２ -, Substitute or non-substitute C １ -C ４ Characterized by being a group selected from the group consisting of alkyl-SO-, The compound according to claim 10, or a pharmaceutically acceptable salt or deuterated product thereof.

12. R ４ H, halogen, substituted or unsubstituted C １ -C ６ Characterized by being a group selected from alkyl groups, The compound according to claim 10, or a pharmaceutically acceptable salt or deuterated product thereof.

13. The compound is characterized by having a structure as shown in the following formula V. 【Chemistry 10】 The compound according to claim 1, or a pharmaceutically acceptable salt or deuterated product thereof.

14. R ３ H, halogen, cyano group, amino group, nitro group, hydroxyl group, mercapto group, aldehyde group, carboxyl group, -SO ２ -OH group, substituted or unsubstituted C １ -C ６ Alkyl, substituted or unsubstituted C １ -C ６ Alkoxy groups, substituted or unsubstituted C １ -C ６ Alkylamine group, substituted or unsubstituted C ２ -C ６ Acyl group, substituted or unsubstituted C ２ -C ６ Ester group, substituted or unsubstituted C １ -C ４ Alkyl-S(O) ２ -, Substitute or non-substitute C １ -C ４ Characterized by being a group selected from the group consisting of alkyl-SO-, The compound according to claim 13, or a pharmaceutically acceptable salt or deuterated product thereof.

15. R ４ These are H, halogens, and substituted or unsubstituted C １ -C ６ It is characterized by being a group selected from the group consisting of alkyl groups. The compound according to claim 13, or a pharmaceutically acceptable salt or deuterated product thereof.

16. The aforementioned compound is as follows: Table 1-1 Table 1-2 Table 1-3 Table 1-4 Table 1-5 Table 1-6 Table 1-7 Table 1-8 Table 1-9 Table 1-10 Table 1-11 Table 1-12 Table 1-13 Table 1-14 Table 1-15 Table 1-16 Table 1-17 Table 1-18 Table 1-19 Table 1-20 It is characterized by being one compound selected from the group consisting of the following, A compound, or a pharmaceutically acceptable salt or deuterated product thereof.

17. A pharmaceutical composition, The pharmaceutical composition is characterized by comprising a therapeutically effective amount of a compound of formula I according to any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, excipients, adjuvants and / or diluents.

18. The pharmaceutical composition according to claim 17, for use in the treatment or prevention of diseases related to PRMT.

19. The pharmaceutical composition according to claim 18, characterized in that the disease is selected from the group consisting of tumors, cardiovascular diseases, neurodegenerative diseases, malaria, AIDS, gout, diabetes, renal failure, chronic lung diseases, oculopharyngeal muscular dystrophy, cocaine addiction, pulmonary hypertension, amyotrophic lateral sclerosis, alcoholic cirrhosis, and viral infections.

20. The pharmaceutical composition according to claim 19, characterized in that the tumor is selected from one of the following: brain tumor, glioblastoma, leukemia, lymphoma, Banayan-Zonana syndrome, Cowden disease, Lhermitte-Duclos disease, breast cancer, Wilms' tumor, Ewing's sarcoma, rhabdomyosarcoma, ependymoma, medulloblastoma, colon cancer, stomach cancer, bladder cancer, head and neck cancer, kidney cancer, lung cancer, liver cancer, melanoma, ovarian cancer, pancreatic cancer, prostate cancer, sarcoma, osteosarcoma, giant cell tumor of bone, and thyroid cancer.

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