Arginine methyltransferase inhibitors and uses thereof

Abstract

The present application provides a kind of arginine methyltransferase inhibitor and its use, specifically, the present application provides a kind of compound that can be used as type I PRMT inhibitor, its preparation method and application in the treatment of related diseases.The compound has the structure shown in formula I.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of pharmaceutical chemistry and medicine, in particular to a class of type I PRMT inhibitor compounds, a preparation method thereof and application in the field of disease treatment. BACKGROUND

[0002] Protein arginine methylation is a high-abundance post-translational modification mode widely existing in cytoplasm and nucleus, and the family of protein arginine methyltransferases (PRMTs) is a key enzyme involved in the process of protein arginine methylation. The enzyme mainly uses S-adenosyl methionine (SAM) as a methyl donor to methylate the nitrogen atom of the side chain of protein arginine, thereby generating S-adenosyl homocysteine and methylarginine. The PRMT family contains 9 PRMTs. According to the type of catalytic reaction, the PRMTs can be divided into type I (PRMT1, PRMT2, PRMT3, PRMT4, PRMT6 and PRMT8), type II (PRMT5 and PRMT9) and type III (PRMT7). Type I PRMT is responsible for asymmetric dimethylarginine (ADMA), type II PRMT is responsible for symmetric dimethylarginine (SDMA), and type III PRMT is responsible for monomethylarginine (MMA).

[0003] It has been confirmed in many literatures that abnormal expression of type I PRMT is closely related to the occurrence and development of various diseases. For example, PRMT1 is found to play a carcinogenic function in leukemia, lung cancer, liver cancer, gastric cancer, colon cancer, breast cancer, pancreatic cancer, head and neck tumor, prostate cancer, bladder cancer and the like. In malignant glioma, it is found that PRMT2 is highly expressed at the protein level and is closely related to poor prognosis. In 70% of patients with acute myeloid leukemia (AML), at least two-fold increase in the expression of PRMT4 can be observed. PRMT6 is found to be highly expressed in 52.6% of gastric cancer cells, and the expression amount thereof is significantly positively correlated with the modification level of the substrate. At the same time, since type I PRMT is mainly responsible for catalyzing asymmetric dimethylation of arginine, changes in the level of asymmetric dimethylation in vivo are closely related to cardiovascular diseases, diabetes, renal failure, asthma and chronic non-obstructive diseases. Therefore, it can be said that abnormal expression of type I PRMT is related to the occurrence and development of various diseases. In summary, it is of great significance to develop a new PRMT inhibitor molecule. SUMMARY

[0004] The purpose of the present application is to provide a new PRMT inhibitor molecule.

[0005] In a first aspect of the present application, a compound as shown in the following formula I, or a pharmaceutically acceptable salt or deuterated product thereof is provided:

[0006]

[0007] X 1 X 2 X 3 and X 4 Each is independently selected from the following group: CR, NR, or N; the dashed line indicates a chemical bond or none;

[0008] Ring A is selected from the following group: substituted or unsubstituted saturated or partially unsaturated (non-aromatic) 4-8 membered carbon rings, substituted or unsubstituted saturated or partially unsaturated (non-aromatic) 4-8 membered heterocycles.

[0009] The B ring is selected from the group consisting of: H, halogen, cyano, amino, nitro, hydroxyl, mercapto, aldehyde, carboxyl, sulfonyl, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C6-C6. 10 Aryl, substituted or unsubstituted 5-12 membered heteroaryl rings, substituted or unsubstituted 3-12 membered heterocycles containing 1-3 heteroatoms selected from oxygen, sulfur, and nitrogen, substituted or unsubstituted -C1-C6 alkyl-6-10 membered aryl, substituted or unsubstituted C3-C 12 Carbon rings, substituted or unsubstituted C2-C 10 Acyl, 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-;

[0010] m and n are each independently selected from the following groups: 0, 1, 2, 3, 4, 5 or 6;

[0011] L is selected from the following group: chemical bond, or -O-, -(CHR) 6 ) p -、-CHR 6 -O-、-CHR 6 -C(O)-, carbonyl, S, -NH-, -NHC(O)-, -NHS(O)2-, -NHC(O)NH-, -NHC(S)NH-, -COO-, -OS(O)2-, -COO-CH2-, -C(O)CH2-, -S(O)2-, or L is absent;

[0012] p is selected from the following group: 1, 2, or 3;

[0013] R 1 and R 2 Each is independently selected from the following group: H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C6 cycloalkyl;

[0014] R 3A group selected from the group consisting of: H, halogen, cyano, amino, nitro, hydroxyl, mercapto, aldehyde, carboxyl, sulfonyl, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C1-C6 alkylamine, substituted or unsubstituted C6-C 10 Aryl, substituted or unsubstituted 5-12 membered heteroaryl, substituted or unsubstituted 5-7 membered heterocycles containing 1-3 heteroatoms selected from oxygen, sulfur, and nitrogen, substituted or unsubstituted -C1-C6 alkyl-phenyl, substituted or unsubstituted C3-C 12 Carbon rings, substituted or unsubstituted C2-C 10 Acyl, 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-;

[0015] R is a group selected from the group consisting of: H, halogen, cyano, amino, nitro, hydroxyl, mercapto, aldehyde, carboxyl, sulfonyl, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C1-C6 alkylamine, substituted or unsubstituted C6-C6... 10 Aryl, substituted or unsubstituted 5-12-membered heteroaryl, substituted or unsubstituted 4-7-membered heterocycles containing 1-3 heteroatoms selected from oxygen, sulfur, and nitrogen, substituted or unsubstituted -C1-C6 alkyl-phenyl, substituted or unsubstituted C3-C 12 Carbon rings, substituted or unsubstituted C2-C 10 Acyl, 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-;

[0016] Alternatively, two R atoms located on adjacent ring atoms together with the ring atoms they are connected to form a substituted or unsubstituted 5-11 member carbon ring or heterocycle, wherein the ring is partially unsaturated or saturated; preferably, the carbon ring or heterocycle is a 5-9 member carbon ring or heterocycle, more preferably a 5-7 member carbon ring or heterocycle (the carbon ring or heterocycle is saturated, partially unsaturated or aromatic).

[0017] R 4A group selected from the group consisting of: H, halogen, cyano, amino, nitro, hydroxyl, mercapto, aldehyde, carboxyl, sulfonyl, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C1-C6 alkylamine, substituted or unsubstituted C6-C 10 Aryl, substituted or unsubstituted 5-12 membered heteroaryl, substituted or unsubstituted 5-7 membered heterocycles containing 1-3 heteroatoms selected from oxygen, sulfur, and nitrogen, substituted or unsubstituted -C1-C6 alkyl-phenyl, substituted or unsubstituted C3-C 12 Carbon rings, substituted or unsubstituted C2-C 10 Acyl, 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-;

[0018] Or two R atoms located on the same or adjacent ring atoms 4 The ring atoms attached to it together form substituted or unsubstituted 3-11 membered carbon rings or heterocycles, wherein the rings are partially unsaturated rings, saturated rings or aromatic rings;

[0019] R 6 The group is selected from the following group: H, halogen, cyano, amino, nitro, hydroxyl, mercapto, aldehyde, carboxyl, acylsulfonyl, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C1-C6 alkylamine.

[0020] Unless otherwise specified, in the above formulas, substitution refers to the replacement of the hydrogen atom on the corresponding group by one or more substituents selected from the group consisting of: deuterium, tritium, halogen, hydroxyl, carboxyl, mercapto, benzyl, oxygen (=O), C1-C. 12 Alkoxycarbonyl, C1-C6 aldehyde, amino, C1-C6 amide, nitro, cyano, unsubstituted or halogenated C1-C6 alkyl, C2-C 10 alkenyl, C1-C6 alkoxy, C1-C6 alkyl-amine, C1-C6 alkyl-sulfonamide, C1-C6 alkyl-urea, C1-C6 alkyl-S-, C6-C 10 Aryl, five- or six-membered heteroaryl, five- or six-membered non-aromatic heterocyclic group, five- or six-membered non-aromatic heterocyclic group -(CH2)-, -O-(C6-C 10 aryl), -O- (five- or six-membered heteroaryl), -NH- (C6-C 10 aryl), -NH- (five- or six-membered heteroaryl), C1-C 12Alkylaminocarbonyl, unsubstituted or halogenated C2-C 10 Acyl, sulfonyl (-SO2-OH), sulfonamide (-SO2-NH2), phosphoryl (-PO3-OH), unsubstituted or halogenated C1-C4 alkyl -S(O)2-, unsubstituted or halogenated C1-C4 alkyl -SO-, In each formula, the heterocycle or heteroaromatic ring has 1-3 heteroatoms selected from the group consisting of N, S or O; each aryl, heteroaromatic or heterocyclic group may be independently substituted by 1-3 substituents selected from the group consisting of deuterium, tritium, halogen, hydroxyl, carboxyl, mercapto, C1-C6 alkyl, C1-C6 alkoxy.

[0021] In another preferred embodiment, the aromatic ring, aromatic ring or aromatic system includes conventional tautomers of the aromatic ring, such as pyridone, benzimidazole, benzopyrazole, etc.

[0022] In another preferred example, X 1 X 2 X 3 and X 4 At least one of them is N.

[0023] In another preferred embodiment, the described The ring is an aromatic ring.

[0024] In another preferred embodiment, the two R atoms located on adjacent ring atoms together with the ring atoms they are connected to form a substituted or unsubstituted 5-11 membered carbon ring or heterocycle, and the rings and The rings together form an aromatic ring system.

[0025] In another preferred embodiment, when ring B is H, m is 2, 3, 4, 5, or 6; and R on at least two identical or adjacent ring atoms 4 The ring atoms attached to it together form substituted or unsubstituted 5-11 membered carbon rings or heterocycles (the rings are partially unsaturated, saturated, or aromatic rings).

[0026] In another preferred embodiment, L is selected from the group consisting of: chemical bonds, or -O-, -(CHR) 6 ) p -、-CHR 6 -O-、-CHR 6 -C(O)-, carbonyl, S, -NH-, -NHC(O)-, -COO-, -COO-CH2-, -C(O)CH2-, -S(O)2-, or L is not present.

[0027] In another preferred embodiment, the R 3H, halogen, cyano, amino, nitro, hydroxy, thiol, aldehyde, carboxyl, sulfonyl, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6alkoxy, substituted or unsubstituted C1-C6alkylamino, substituted or unsubstituted C6-C10aryl, substituted or unsubstituted 5-10 membered heteroaryl, substituted or unsubstituted 5-7 membered heterocycle containing 1-3 heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen, substituted or unsubstituted C3-C8carbocycle, substituted or unsubstituted C2-C6acyl, substituted or unsubstituted C2-C6ester, substituted or unsubstituted C6-C10aryl-C1-C6alkyl, substituted or unsubstituted C1-C4alkyl-S(O)2-, substituted or unsubstituted C1-C4alkyl-SO-; and / or 10 H, halogen, cyano, amino, nitro, hydroxy, thiol, aldehyde, carboxyl, sulfonyl, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6alkoxy, substituted or unsubstituted C1-C6alkylamino, substituted or unsubstituted C6-C10aryl, substituted or unsubstituted 5-10 membered heteroaryl, substituted or unsubstituted 5-7 membered heterocycle containing 1-3 heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen, substituted or unsubstituted C3-C8carbocycle, substituted or unsubstituted C2-C6acyl, substituted or unsubstituted C2-C6ester, substituted or unsubstituted C6-C10aryl-C1-C6alkyl, substituted or unsubstituted C1-C4alkyl-S(O)2-, substituted or unsubstituted C1-C4alkyl-SO-; and / or 10 H, halogen, cyano, amino, nitro, hydroxy, thiol, aldehyde, carboxyl, sulfonyl, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6alkoxy, substituted or unsubstituted C1-C6alkylamino, substituted or unsubstituted C6-C10aryl, substituted or unsubstituted 5-10 membered heteroaryl, substituted or unsubstituted 5-7 membered heterocycle containing 1-3 heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen, substituted or unsubstituted C3-C8carbocycle, substituted or unsubstituted C2-C6acyl, substituted or unsubstituted C2-C6ester, substituted or unsubstituted C6-C10aryl-C1-C6alkyl, substituted or unsubstituted C1-C4alkyl-S(O)2-, substituted or unsubstituted C1-C4alkyl-SO-; and / or

[0028] H, halogen, cyano, amino, nitro, hydroxy, thiol, aldehyde, carboxyl, sulfonyl, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6alkoxy, substituted or unsubstituted C1-C6alkylamino, substituted or unsubstituted C6-C10aryl, substituted or unsubstituted 5-10 membered heteroaryl, substituted or unsubstituted 5-7 membered heterocycle containing 1-3 heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen, substituted or unsubstituted C3-C8carbocycle, substituted or unsubstituted C2-C6acyl, substituted or unsubstituted C2-C6ester, substituted or unsubstituted C6-C10aryl-C1-C6alkyl, substituted or unsubstituted C1-C4alkyl-S(O)2-, substituted or unsubstituted C1-C4alkyl-SO-; and / or 10 H, halogen, cyano, amino, nitro, hydroxy, thiol, aldehyde, carboxyl, sulfonyl, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6alkoxy, substituted or unsubstituted C1-C6alkylamino, substituted or unsubstituted C6-C10aryl, substituted or unsubstituted 5-10 membered heteroaryl, substituted or unsubstituted 5-7 membered heterocycle containing 1-3 heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen, substituted or unsubstituted C3-C8carbocycle, substituted or unsubstituted C2-C6acyl, substituted or unsubstituted C2-C6ester, substituted or unsubstituted C6-C10aryl-C1-C6alkyl, substituted or unsubstituted C1-C4alkyl-S(O)2-, substituted or unsubstituted C1-C4alkyl-SO-; and / or 10 H, halogen, cyano, amino, nitro, hydroxy, thiol, aldehyde, carboxyl, sulfonyl, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6alkoxy, substituted or unsubstituted C1-C6alkylamino, substituted or unsubstituted C6-C10aryl, substituted or unsubstituted 5-10 membered heteroaryl, substituted or unsubstituted 5-7 membered heterocycle containing 1-3 heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen, substituted or unsubstituted C3-C8carbocycle, substituted or unsubstituted C2-C6acyl, substituted or unsubstituted C2-C6ester, substituted or unsubstituted C6-C10aryl-C1-C6alkyl, substituted or unsubstituted C1-C4alkyl-S(O)2-, substituted or unsubstituted C1-C4alkyl-SO-; and / or

[0029] In another preferred embodiment, R 4 H, halogen, cyano, amino, nitro, hydroxy, thiol, aldehyde, carboxyl, sulfonyl, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6alkoxy, substituted or unsubstituted C1-C6alkylamino, substituted or unsubstituted C6-C10aryl, substituted or unsubstituted 5-10 membered heteroaryl, substituted or unsubstituted 5-7 membered heterocycle containing 1-3 heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen, substituted or unsubstituted C3-C8carbocycle, substituted or unsubstituted C2-C6acyl, substituted or unsubstituted C2-C6ester, substituted or unsubstituted C6-C10aryl-C1-C6alkyl, substituted or unsubstituted C1-C4alkyl-S(O)2-, substituted or unsubstituted C1-C4alkyl-SO-; and / or 10substituted or unsubstituted C2-C6acyl, substituted or unsubstituted C2-C6ester, substituted or unsubstituted C1-C6amide, substituted or unsubstituted C1-C4alkyl-S(O)2-, substituted or unsubstituted C1-C4alkyl-SO-; and / or 10 substituted or unsubstituted C2-C6acyl, substituted or unsubstituted C2-C6ester, substituted or unsubstituted C1-C6amide, substituted or unsubstituted C1-C4alkyl-S(O)2-, substituted or unsubstituted C1-C4alkyl-SO-; and / or 10 substituted or unsubstituted C2-C6acyl, substituted or unsubstituted C2-C6ester, substituted or unsubstituted C1-C6amide, substituted or unsubstituted C1-C4alkyl-S(O)2-, substituted or unsubstituted C1-C4alkyl-SO-; and / or 4 substituted or unsubstituted C2-C6acyl, substituted or unsubstituted C2-C6ester, substituted or unsubstituted C1-C6amide, substituted or unsubstituted C1-C4alkyl-S(O)2-, substituted or unsubstituted C1-C4alkyl-SO-; and / or

[0030] In another preferred embodiment, said B ring is selected from the group consisting of H, or substituted or unsubstituted phenyl, substituted or unsubstituted 5-10 membered heteroaromatic ring, substituted or unsubstituted 3-12 membered heterocyclic ring containing 1-3 heteroatoms selected from oxygen, sulfur and nitrogen, substituted or unsubstituted C3-C 12 substituted or unsubstituted C2-C6acyl, substituted or unsubstituted C2-C6ester, substituted or unsubstituted C1-C6amide, substituted or unsubstituted C1-C4alkyl-S(O)2-, substituted or unsubstituted C1-C4alkyl-SO-; and / or

[0031] In another preferred embodiment, said R 3 substituted or unsubstituted C2-C6acyl, substituted or unsubstituted C2-C6ester, substituted or unsubstituted C1-C6amide, substituted or unsubstituted C1-C4alkyl-S(O)2-, substituted or unsubstituted C1-C4alkyl-SO-; and / or 10 substituted or unsubstituted C2-C6acyl, substituted or unsubstituted C2-C6ester, substituted or unsubstituted C1-C6amide, substituted or unsubstituted C1-C4alkyl-S(O)2-, substituted or unsubstituted C1-C4alkyl-SO-; and / or

[0032] substituted or unsubstituted C2-C6acyl, substituted or unsubstituted C2-C6ester, substituted or unsubstituted C1-C6amide, substituted or unsubstituted C1-C4alkyl-S(O)2-, substituted or unsubstituted C1-C4alkyl-SO-; and / or substituted or unsubstituted C2-C6acyl, substituted or unsubstituted C2-C6ester, substituted or unsubstituted C1-C6amide, substituted or unsubstituted C1-C4alkyl-S(O)2-, substituted or unsubstituted C1-C4alkyl-SO-; and / or

[0033] R 4 is selected from the group consisting of H, halogen, cyano, amino, nitro, hydroxyl, thiol, aldehyde, carboxyl, sulfonyl, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C8 carbocycle, substituted or unsubstituted C2-C6 acyl, substituted or unsubstituted C2-C 10 ester, substituted or unsubstituted C1-C6 amido, substituted or unsubstituted C1-C4 alkyl-S(O)2-, substituted or unsubstituted C1-C4 alkyl-SO-; or two R 4 atoms to which they are attached together form a substituted or unsubstituted 5-9 membered carbocyclic or heterocyclic ring, said ring being partially unsaturated or saturated.

[0034] In another preferred embodiment, said ring is

[0035] In another preferred embodiment, said ring is selected from the group consisting of:

[0036] In another preferred embodiment, said B ring is selected from the group consisting of: substituted or unsubstituted C6-C 10 aryl, substituted or unsubstituted 5-12 membered heteroaryl, substituted or unsubstituted 4-12 membered heterocycle containing 1-3 heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen, substituted or unsubstituted C3-C 12 carbocycle.

[0037] In another preferred embodiment, said A ring is selected from the group consisting of:

[0038] wherein Y 1 and Y 2 are each independently selected from the group consisting of CHR 6 or NR 6 ; 0-2 indicates that the number of carbon atoms can be 0, 1 or 2; and said L-B structure can be located on Y 1 , Y 2 or other ring atoms (preferably on Y 1 , Y 2 );

[0039] or said A ring together with 2 R 4 forms a group selected from the group consisting of:

[0040] wherein Y 1 and Y 2 are each independently selected from the group consisting of CHR 6 , O or NR 6 ; X5 , X 6 , X 7 , and X 8 are each independently selected from the group consisting of CR 6 or N.

[0041] In another preferred embodiment, the A ring is a substituted or unsubstituted group selected from the group consisting of:

[0042] (wherein, when the point of attachment to another structural fragment or substituent group is NH, the hydrogen atom on the NH is lost to form the point of attachment);

[0043] or the A ring is taken together with 2 R 4 to form a group selected from the group consisting of substituted or unsubstituted:

[0044] (wherein, when the point of attachment to another structural fragment or substituent group is NH, the hydrogen atom on the NH is lost to form the point of attachment).

[0045] In another preferred embodiment, the substituents on the A ring are selected from the group consisting of H, halogen, cyano, amino, nitro, carbonyl, hydroxyl, thiol, aldehyde, carboxyl, sulfonyl, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkylamino, substituted or unsubstituted C3-C8 carbocycle, substituted or unsubstituted C2-C6 acyl, substituted or unsubstituted C2-C 10 ester, substituted or unsubstituted C1-C6 amido, substituted or unsubstituted C1-C4 alkyl-S(O)2-.

[0046] In another preferred embodiment, the compound has the structure of Formula II:

[0047]

[0048] In another preferred embodiment, the compound has the structure of Formula III:

[0049]

[0050] wherein,

[0051] the A ring is selected from the group consisting of substituted or unsubstituted saturated or partially unsaturated (non-aromatic) 4-8 membered carbocyclic ring, substituted or unsubstituted saturated or partially unsaturated (non-aromatic) 4-8 membered heterocyclic ring;

[0052] the B ring is selected from the group consisting of substituted or unsubstituted C6-C 10aryl, substituted or unsubstituted 5-12 membered heteroaryl, substituted or unsubstituted 3-12 membered heterocycles containing 1-3 heteroatoms selected from oxygen, sulfur, and nitrogen, substituted or unsubstituted C3-C 12 Carbon rings;

[0053] Ideally, R 3 The group is selected from the group consisting of: H, halogen, cyano, amino, nitro, hydroxyl, mercapto, aldehyde, carboxyl, sulfonyl, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C1-C6 alkylamine, substituted or unsubstituted C2-C6 acyl, substituted or unsubstituted C2-C6 ester, substituted or unsubstituted C1-C4 alkyl-S(O)2-, substituted or unsubstituted C1-C4 alkyl-SO-;

[0054] Ideally, R 4 A group selected from the group consisting of: H, halogen, cyano, amino, nitro, hydroxyl, mercapto, aldehyde, carboxyl, sulfonyl, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C1-C6 alkylamine, substituted or unsubstituted C6-C6 10 Aryl, substituted or unsubstituted 5-7 membered heteroaryl, substituted or unsubstituted 5-7 membered heterocycle containing 1-3 heteroatoms selected from oxygen, sulfur and nitrogen, substituted or unsubstituted -C1-C6 alkyl-phenyl, substituted or unsubstituted C3-C8 carbocyclic ring, substituted or unsubstituted C2-C6 acyl, substituted or unsubstituted C2-C6 ester, substituted or unsubstituted C1-C4 alkyl-S(O)2-, substituted or unsubstituted C1-C4 alkyl-SO-.

[0055] In another preferred embodiment, the compound has the structure shown in Formula IV:

[0056]

[0057] in,

[0058] A 1 The ring is selected from the following group: substituted or unsubstituted saturated or partially unsaturated (non-aromatic) 5-8 membered carbon rings, substituted or unsubstituted saturated or partially unsaturated (non-aromatic) 5-8 membered heterocycles.

[0059] A 2 Cycles selected from the group below: substituted or unsubstituted C6-C 10 aryl, substituted or unsubstituted 5-12 membered heteroaryl, substituted or unsubstituted 5-7 membered heterocycles containing 1-3 heteroatoms selected from oxygen, sulfur, and nitrogen, substituted or unsubstituted C3-C 12 Carbon ring; and A 2 Ring and A 1 Ring fusion;

[0060] A 3 Ring and A 4 each ring is independently selected from the group consisting of substituted or unsubstituted saturated or partially unsaturated (non-aromatic) 5-8 membered carbocyclic ring, substituted or unsubstituted saturated or partially unsaturated (non-aromatic) 3-8 membered heterocyclic ring;

[0061] m is 0, 1, 2, 3 or 4; R 5 selected from the group consisting of H, halogen, cyano, amino, nitro, hydroxy, mercapto, aldehyde, carboxyl, sulfonyl, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C1-C6 alkylamino, substituted or unsubstituted C2-C6 acyl, substituted or unsubstituted C2-C6 ester, substituted or unsubstituted C6-C 10 substituted or unsubstituted C6-C 10 substituted or unsubstituted C1-C6 acylamino, substituted or unsubstituted C1-C6 alkyl-phenyl, substituted or unsubstituted C1-C4 alkyl-S(O)2-, substituted or unsubstituted C1-C4 alkyl-SO-; and R 5 may be located on A 1 Ring, A 2 Ring, A 3 Ring or A 4 Ring.

[0062] In another preferred embodiment, the compound has the structure shown in Formula V or Formula VI:

[0063]

[0064] wherein C ring is substituted or unsubstituted phenyl, substituted or unsubstituted 5-7 membered heterocyclyl, or substituted or unsubstituted 5-6 membered heteroaryl;

[0065] A ring is selected from the group consisting of substituted or unsubstituted saturated or partially unsaturated (non-aromatic) 5-6 membered carbocyclic ring, substituted or unsubstituted saturated or partially unsaturated (non-aromatic) 4-8 membered heterocyclic ring;

[0066] B ring is selected from the group consisting of substituted or unsubstituted C6-C 10 aryl, substituted or unsubstituted 5-12 membered heteroaryl, substituted or unsubstituted 4-12 membered heterocyclic ring containing 1-3 heteroatoms selected from oxygen, sulfur and nitrogen, substituted or unsubstituted C3-C 12 carbocyclic ring;

[0067] R 3H, halogen, cyano, amino, nitro, hydroxy, thiol, aldehyde, carboxyl, sulfonyl, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6alkoxy, substituted or unsubstituted C1-C6alkylamino, substituted or unsubstituted C2-C6acyl, substituted or unsubstituted C2-C6ester, substituted or unsubstituted C1-C4alkyl-S(O)2-, substituted or unsubstituted C1-C4alkyl-SO-;

[0068] R is preferably selected from the group consisting of H, halogen, cyano, amino, nitro, hydroxy, thiol, aldehyde, carboxyl, sulfonyl, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6alkoxy, substituted or unsubstituted C1-C6alkylamino, substituted or unsubstituted C6-C 4 H, halogen, cyano, amino, nitro, hydroxy, thiol, aldehyde, carboxyl, sulfonyl, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6alkoxy, substituted or unsubstituted C1-C6alkylamino, substituted or unsubstituted C6-C 10 substituted or unsubstituted C1-C6alkyl-S(O)2-, substituted or unsubstituted C1-C4alkyl-SO-.

[0069] In another preferred embodiment, the C ring is selected from the group consisting of a phenyl ring, a 5-7 membered heteroaromatic ring, a 5-7 membered saturated or partially unsaturated heterocyclic ring.

[0070] In another preferred embodiment, the A ring is selected from the group consisting of a substituted or unsubstituted saturated or partially unsaturated (non-aromatic) 5-6 membered carbocyclic ring, a substituted or unsubstituted saturated or partially unsaturated (non-aromatic) 5-7 membered heterocyclic ring.

[0071] In another preferred embodiment, the B ring is selected from the group consisting of a substituted or unsubstituted C6-C 10 substituted or unsubstituted C1-C6alkyl-S(O)2-, substituted or unsubstituted C1-C4alkyl-SO-. 12 substituted or unsubstituted C1-C6alkyl-S(O)2-, substituted or unsubstituted C1-C4alkyl-SO-.

[0072] In another preferred embodiment, the compound of formula I has the structure shown in the following formula:

[0073]

[0074] X 5 , X 6 , X 7 , and X 8 each independently is selected from the group consisting of C(R)2, NR, CR, or N; the dotted line is a bond or null.

[0075] In a second aspect of the present application, there is provided a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, as described in the first aspect of the present application, and one or more pharmaceutically acceptable carriers, excipients, adjuvants, auxiliaries and / or diluents.

[0076] In a third aspect of the present application, there is provided a use of a compound of Formula I, or a pharmaceutically acceptable salt thereof, as described in the first aspect of the present application, in the manufacture of a pharmaceutical composition for the treatment or prevention of a disease associated with PRMT; preferably, the PRMT is Type I PRMT.

[0077] In another preferred embodiment, the disease is selected from the group consisting of a tumor, a cardiovascular disease, a neurodegenerative disease, malaria, AIDS, gout, diabetes, renal failure, chronic pulmonary disease, oculopharyngeal muscular dystrophy, cocaine addiction, pulmonary hypertension disease, amyotrophic lateral sclerosis, alcoholic cirrhosis.

[0078] In another preferred embodiment, the tumor is selected from any one of brain cancer, glioblastoma, leukemia, lymphoma, Bannayan-Zonana syndrome, Cowden disease, Lhermitte-Duclos disease, breast cancer, Wilm's tumor, Ewing's sarcoma, rhabdomyosarcoma, ependymoma, medulloblastoma, colon cancer, gastric cancer, bladder cancer, head and neck cancer, renal cancer, lung cancer, liver cancer, melanoma, ovarian cancer, pancreatic cancer, prostate cancer, sarcoma, osteosarcoma, giant cell tumor of bone, and thyroid cancer.

[0079] It should be understood that, within the scope of the present application, the above technical features of the present application and the technical features specifically described hereinafter (e.g. in the examples) can be combined with each other to form new or preferred technical solutions. Due to the limited space, they are not listed one by one here. DETAILED DESCRIPTION

[0080] The present inventors, through extensive and in-depth research, have for the first time accidentally discovered a class of compounds having PRMT inhibitory effect. On this basis, the present application is completed.

[0081] Terminology

[0082] In the present application, the halogen is F, Cl, Br or I.

[0083] In the present application, unless specifically indicated, the terms used have the general meanings known to those skilled in the art. In the present application, if not specifically indicated, all chemical formulas are intended to encompass any possible optical or geometric isomers (e.g. R form, S form or racemate, or cis-trans isomers of olefins, etc.).

[0084] In the present application, the term "C1-C6 alkyl" means a straight or branched chain alkyl group having 1 to 6 carbon atoms, including, without limitation, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl, and hexyl groups, and the like; preferably ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, and t-butyl groups.

[0085] In the present application, the term "C1-C6 alkoxy" means a straight or branched chain alkoxy group having 1 to 6 carbon atoms, including, without limitation, methoxy, ethoxy, propoxy, isopropoxy, and butoxy groups, and the like.

[0086] In the present application, the term "C2-C6 alkenyl" means a straight or branched chain alkenyl group having 2 to 6 carbon atoms containing one double bond, including, without limitation, ethenyl, propenyl, butenyl, isobutenyl, pentenyl, and hexenyl groups, and the like.

[0087] In the present application, the term "C2-C6 alkynyl" means a straight or branched chain alkynyl group having 2 to 6 carbon atoms containing one triple bond, including, without limitation, ethynyl, propynyl, butynyl, isobutynyl, pentynyl, and hexynyl groups, and the like.

[0088] In the present application, the term "C3-C10 cycloalkyl" means a cyclic alkyl group having 3 to 10 carbon atoms in the ring, including, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and cyclodecyl groups, and the like. The terms "C3-C8 cycloalkyl", "C3-C7 cycloalkyl", and "C3-C6 cycloalkyl" have similar meanings.

[0089] In the present application, the term "C3-C10 cycloalkenyl" means a cyclic alkenyl group having 3 to 10 carbon atoms in the ring, including, without limitation, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, and cyclodecylalkenyl groups, and the like. The term "C3-C7 cycloalkenyl" has a similar meaning.

[0090] In the present application, the term "C1-C12 alkoxycarbonyl" means an alkoxycarbonyl group having 1 to 12 carbon atoms in the alkyl chain, including, without limitation, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, t-butoxycarbonyl, benzyloxycarbonyl, and the like.

[0091] In the present application, the term "C1-C12 alkylaminocarbonyl" means an alkylaminocarbonyl group having 1 to 12 carbon atoms in the alkyl chain, including, without limitation, methylaminocarbonyl, ethylaminocarbonyl, propylaminocarbonyl, isopropylaminocarbonyl, t-butylaminocarbonyl, benzylaminocarbonyl, dimethylaminocarbonyl, and the like.

[0092] In the present application, the term "C5-C9 furanosyl" refers to a furanosyl group having 5 to 9 carbon atoms, wherein the 1 position of the sugar group is attached to the backbone, including, without limitation, furanoribosyl, furanodeoxyribosyl, furanogalactosyl, and the like.

[0093] In the present application, the term "C5-C9 pyranosyl" refers to a pyranosyl group having 5 to 9 carbon atoms, wherein the 1 position of the sugar group is attached to the backbone, including, without limitation, pyranoglucosyl, pyranoglucuronosyl, pyranoramirnosyl, pyranogalactosyl, pyranomannosyl, pyranoxylsosyl, and the like.

[0094] In the present application, the terms "aromatic ring" or "aryl" have the same meaning, and preferably "aryl" is "C6-C12 aryl" or "C6-C10 aryl". The term "C6-C12 aryl" refers to an aromatic ring group having 6 to 12 carbon atoms in the ring, which does not contain heteroatoms, such as phenyl, naphthyl, and the like. The term "C6-C10 aryl" has a similar meaning.

[0095] In the present application, the terms "aromatic heterocycle" or "heteroaryl" have the same meaning, and refer to a heteroaromatic group containing one to several heteroatoms. The heteroatoms referred to herein include oxygen, sulfur, and nitrogen. Examples include furanyl, thienyl, pyridyl, pyrazolyl, pyrrolyl, N-alkyl pyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl, and the like. The heteroaryl ring can be fused to an aryl, heterocyclyl, or cycloalkyl ring, wherein the ring attached to the parent structure is the heteroaryl ring. The heteroaryl group can be optionally substituted or unsubstituted.

[0096] In the present application, the term "3-12 membered heterocyclyl" refers to a saturated or unsaturated 3-12 membered ring group containing 1 to 3 heteroatoms selected from oxygen, sulfur, and nitrogen in the ring, such as dioxolanyl, and the like. The term "3-7 membered heterocyclyl" has a similar meaning.

[0097] In the present application, the term "substituted" means that one or more hydrogen atoms on a specified group are replaced with a specified substituent. The specified substituents are those described in the foregoing or those appearing in each embodiment. Unless otherwise specified, a substituted group can have at each substitutable position one substituent selected from a specified group, which can be the same or different at each position. A cyclic substituent, such as a heterocycloalkyl group, can be attached to another ring, such as a cycloalkyl group, to form a spiro bicyclic ring system, for example, two rings sharing a common carbon atom. Those skilled in the art will appreciate that combinations of substituents contemplated by the present application are those combinations that result in stable or chemically feasible compounds. The substituents include, but are not limited to, C1-8alkyl, C2-8alkenyl, C2-8alkynyl, C3-8cycloalkyl, 3- to 12-membered heterocyclyl, aryl, heteroaryl, halogen, hydroxyl, carboxyl (-COOH), C1-8aldehyde, C2-10acyl, C2-10ester, C1-C12alkoxycarbonyl, amino, alkoxy, C1-10sulfonyl, and the like.

[0098] PRMT inhibitor compounds

[0099] Provided in the present application are compounds having PRMT inhibitory activity, or a pharmaceutically acceptable salt or deuterated product thereof:

[0100]

[0101] wherein each group is as described above. Preferred compounds in the present application have a structure as shown in any one of the example compounds P001-P448.

[0102] Pharmaceutical compositions and methods of administration

[0103] Since the compounds of the present application have excellent activity in inhibiting type I PRMT, the compounds of the present application and various crystal forms thereof, pharmaceutically acceptable inorganic or organic salts, hydrates or solvates thereof, and pharmaceutical compositions containing the compounds of the present application as the main active ingredient can be used for treating, preventing, and alleviating diseases related to abnormal activity or expression of PRMT.

[0104] The pharmaceutical composition of the present application contains a safe and effective amount of the compound of the present application or a pharmacologically acceptable salt thereof and a pharmacologically acceptable excipient or carrier. The "safe and effective amount" means an amount of the compound sufficient to significantly improve the condition without causing serious side effects. Generally, the pharmaceutical composition contains 1-2000 mg of the compound of the present application per dose, more preferably 5-500 mg of the compound of the present application per dose. Preferably, the "one dose" is one capsule or tablet.

[0105] "Pharmaceutically acceptable carrier" means one or more compatible solid or liquid filler substances or gel materials, which are suitable for use in humans and which are of sufficient purity and sufficiently low toxicity to be used in humans. By "compatible" is meant that the carrier is not chemically reactive with the compound of the application in a deleterious manner and does not adversely affect the therapeutic efficacy of the compound of the application. Examples of pharmaceutically acceptable carriers suitable for use in the compositions of the application include, but are not limited to, one or more of the following: celluloses and their derivatives, such as sodium carboxymethylcellulose, ethyl cellulose, cellulose acetate, and the like; gelatin; talc, solid lubricants such as stearic acid, magnesium or calcium stearate; calcium sulfate; vegetable oils such as peanut oil, sesame oil, safflower oil, olive oil, and the like; polyols such as propylene glycol, glycerine, mannitol, sorbitol, and the like; emulsifiers such as ), wetting agents such as sodium lauryl sulfate, coloring agents, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, and the like.

[0106] The mode of administration of the compounds or pharmaceutical compositions of the present application is not narrowly critical and representative modes of administration include, but are not limited to, oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration.

[0107] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is admixed with at least one inert excipient (or carrier) such as sodium citrate or dicalcium phosphate, or with such solid or liquid fillers, diluents, or binders as carboxymethylcellulose, alginic acid, gelatin, polyvinylpyrrolidone, sucrose, and acacia; or with granulating agents, such as dicalcium phosphate; or with lubricants, such as magnesium stearate, stearic acid, and the like; or with binders, such as carboxymethylcellulose, polyvinylpyrrolidone, sucrose, acacia, and the like; or with disintegrating agents, such as starch, pronios, methyl cellulose, and the like; or with absorbents, such as kaolin and the like. In the case of capsules, tablets, and pills, the dosage forms can also comprise buffering agents.

[0108] Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other materials well known in the art. They can contain opacifying agents, and can also be of such composition that they release the active compound or compounds in a certain part of the intestinal tract in a delayed manner. Examples of embedding compositions that can be used are polymeric substances and waxes. The active compounds can also be in micro-encapsulated form, if appropriate, with one or more of the above-mentioned excipients.

[0109] Liquid dosage forms for oral administration include pharmaceutically-acceptable emulsions, solutions, suspensions, syrups, or elixirs. In addition to the active compounds, the liquid dosage forms can include inert diluents commonly used in the art such as water or other solvents, solubilizing agents and emulsifiers, as for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3- butylene glycol, dimethylformamide, and the like, or mixtures thereof.

[0110] Besides such inert diluents, compositions can also include adjuvants, such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[0111] Suspensions, in addition to the active compounds, can contain suspending agents as for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, and agar-agar, or mixtures thereof, and the like.

[0112] Compositions for parenteral injection can contain physiologically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyol, and suitable mixtures thereof.

[0113] Dosage forms of the compounds of the present application for topical administration include ointments, powders, sprays, and inhalers. The active compound is admixed under sterile conditions with physiologically acceptable carriers and any preservatives, buffers, or propellants as can be required.

[0114] The compounds of the present application can be administered alone, or in combination with other pharmaceutically acceptable compounds. In some preferred embodiments, the compounds of the present application can be formed into a PROTAC with other small molecule compounds, or an ADC with other large molecule compounds such as mAbs.

[0115] Pharmaceutical compositions are used in a safe and effective amount, which is an amount of the compound of the present application that, when administered to a mammal, such as a human in need of treatment, is sufficient to provide treatment. The amount of the compound of the present application administered will generally be in the range of 1-2000 mg, preferably 5-500 mg, per day for a 60 kg body weight adult, in a single dose or in divided doses. The specific dose used will vary depending on a number of factors, including the route of administration, the patient's health, the type of use, and the particular use. These factors are within the skill of a skilled medical practitioner.

[0116] The application will be further described in conjunction with specific examples. It should be understood that these examples are only used to illustrate the application but not to limit the scope of the application. The experimental methods in the following examples, if not otherwise specified, are usually carried out under conventional conditions or under the conditions recommended by the manufacturers. Unless otherwise specified, percentages and parts are by weight.

[0117] General synthetic procedure:

[0118] Intermediate synthesis 1 : Synthesis of 2-(2,3-difluoro-6,9-dihydro-5H- benzo[7]annulen-7-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (Intermediate A): Synthesis of 2-(2,3-difluoro-6,9-dihydro-5H- benzo[7]annulen-7-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (Intermediate A):

[0119]

[0120] Step 1 : To a solution of 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) was added tetrabutylammonium bromide (2.37 g, 7.36 mmol), potassium carbonate (2.54 g, 18.4 mmol), and the reaction was purged with nitrogen for 1 min. Palladium acetate (33.03 mg, 147 μmol) was added and the reaction was stirred at 80 °C for 16 h. The reaction was filtered and the filter cake was washed with ethyl acetate (50 mL) three times. The organic layer was washed with water (100 mL), dried over magnesium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. Purification by column chromatography (silica, 15% ethyl acetate in petroleum ether) gave (2E,2'E)-dimethyl 3,3'-(4,5-difluoro-1,2-phenylene)diacrylate (A-2) as a white solid (6.0 g, 21.26 mmol, 96.3% yield). 1 H NMR (400 MHz, CDC13) δ (ppm) 7.93 (d, 2H), 7.39 (t, 2H), 6.31 (d, 2H), 3.85 (s, 6H)

[0121] Step 2: To a solution of (2E,2'E)-dimethyl 3,3'-(4,5-difluoro-1,2-phenylene)diacrylate (A-2) (6.0 g, 21.3 mmol) in methanol (150 mL) was added palladium on carbon (1.0 g, 10%) and the reaction was purged with hydrogen several times under reduced pressure. The reaction was stirred under an atmosphere of hydrogen for 16 h. The reaction was filtered through celite and the filter cake was washed with ethyl acetate (50 mL) three times. The filtrate was concentrated to dryness under reduced pressure. Purification by column chromatography (silica, 15% ethyl acetate in petroleum ether) gave 3,3'-(4,5-difluoro-1,2-phenylene)dipropionic acid dimethyl ester (A-3) as a colorless oil (5.8 g, 20.26 mmol, 95.31% yield). 1H NMR (400 MHz, CDC13) δ (ppm) 6.98 (t, 2H), 3.71 (s, 6H), 2.94 (t, 4H), 2.61 (t, 4H);

[0122] Step 3: 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) was added slowly to a suspension of NaH (209.59 mg, 5.24 mmol, 60% purity) in xylene (5 mL) at 95 °C with stirring. One drop of absolute ethanol was added after each 1 mL of dimethyl 3,3'-(4,5-difluoro- 1,2-phenylene)dipropionate (A-3) in xylene was added. The temperature of the reaction rose to 115 °C after the addition was complete and the reaction was continued at this temperature for 1.5 h. Six reactions were run in parallel. LC-MS indicated that the reaction was complete and the desired product was formed. The six reactions were combined and quenched with ice water (30 mL) and 1 M aqueous HC1 (30 mL) and extracted with ethyl acetate (40 mL) three times. The organic layer was dried over magnesium sulfate, filtered, and concentrated under reduced pressure to dryness to give crude methyl 2,3-difluoro-7-oxo-6,7,8,9-tetrahydro-5H- benzo[7]annulene-6-carboxylate (A-4) (5.3 g) as a yellow oil which was used in the next step without purification. LCMS: (ESI) m / z = 254.7 [M+H] + ,268.8 [M+14] + ;

[0123] Step 4: Methyl 2,3-difluoro-7-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-6-carboxylate (A-4) (5.3 g, 20.85 mmol) was dissolved in ethanol (60 mL) and sodium hydroxide (1 M aqueous solution, 62.5 mL) was added. The reaction was stirred at 90 °C for 2 h. LC-MS indicated that the reaction was complete and the desired product was formed. The reaction was concentrated under reduced pressure to dryness, diluted with ethyl acetate (30 mL), washed with water (30 mL), and the organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to dryness. Purification by column chromatography (silica, 12% ethyl acetate in petroleum ether) gave compound 2,3-difluoro-8,9-dihydro-5H-benzo[7]annulene-7(6H)-one (A-5) (2.6 g, 13.2 mmol, 78.9% over two steps) as a yellow solid. 1 H NMR (400 MHz, CDC13) δ (ppm) 7.06 (t, 2H), 2.78-2.95 (m, 4H), 2.53-2.69 (m, 4H),

[0124] Step 5:To a solution of 2,3-difluoro-8,9-dihydro-5H-benzo[7]annulene-7(6H)-one (A-5) (1.0 g, 5.10 mmol) in tetrahydrofuran (10 mL) was added lithium bis(trimethylsilyl)amide (1 M in tetrahydrofuran, 5.61 mL) at -70 °C under nitrogen. The reaction mixture was stirred at -70 °C for 1 h, and N-phenylbis(trifluoromethanesulfonyl)imide (2.00 g, 5.61 mmol) was added at -70 °C. The reaction mixture was allowed to warm to room temperature slowly over 15 h. The reaction was monitored by TLC (petroleum ether: ethyl acetate = 8:1, Rf= 0.8). The reaction mixture was quenched with water (25 mL) and extracted with ethyl acetate (15 mL) three times. The organic layer was dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (silica, 5% ethyl acetate in petroleum ether) to give compound 2,3-difluoro-6,9-dihydro-5H-benzo[7]annulen-7-yl trifluoromethanesulfonate (A-6) (1.27 g, 3.87 mmol, 75.91% yield) as a colorless oil. 1 H NMR (400 MHz, CDC13) 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);

[0125] Step 6: To a solution of 2,3-difluoro-6,9-dihydro-5H-benzo[7]annulene-7-yl trifluoromethanesulfonate (A-6) (1.27 g, 3.87 mmol) and bis(pinacolato)diboron (1.08 g, 4.26 mmol) in dioxane (20 mL) was added potassium acetate (1.14 g, 11.61 mmol), 1,1'-bis(diphenylphosphino)ferrocene palladium chloride (283.09 mg, 386.89 μmol). The reaction mixture was purged with nitrogen for 1 min. The reaction mixture was stirred at 100 °C under nitrogen for 16 h. The reaction was monitored by TLC (petroleum ether: ethyl acetate = 8:1, Rf= 0.8). The reaction mixture was cooled to room temperature, diluted with water (20 mL), and extracted with ethyl acetate (20 mL) three times. The organic layer was dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (silica, 3% ethyl acetate in petroleum ether) to give compound 2-(2,3-difluoro-6,9-dihydro-5H-benzo[7]annulen-7-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (Intermediate A) (880 mg, 2.87 mmol, 74.3% yield) as a yellow solid. 1H 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)

[0126] Intermediate synthesis 2: Synthesis of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)- 1 -(m-tolyl)-1,2,3,6-tetrahydropyridine (Intermediate B): Synthesis of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1 -(m-tolyl)-1,2,3,6- tetrahydropyridine (Intermediate B):

[0127]

[0128] Step 1 : 1-Benzylpiperidin-4-one (B-1) (100 g, 528 mmol, 1.0 equivalent) was dissolved in acetone (700 mL), and iodomethane (90.0 g, 634 mmol, 39.5 mL, 1.2 equivalent) was added. The reaction mixture was stirred at 20 °C for 16 hours. A white solid precipitated. The reaction mixture was filtered, and the filter cake was washed twice with dry acetone (200 mL). The filter cake was collected and concentrated under reduced pressure to dryness to obtain a white solid, 1-benzyl-1-methyl-4-oxopiperidin-1-iodide (B-2) (297 g, 897 mmol, 84.86% yield), which could be used directly in the next reaction without purification.

[0129] Step 2: 1-Benzyl-1-methyl-4-oxoperidin-1-iodide (B-2) (162 g, 489 mmol, 1.3 equivalences) in a turbid mixture of ethanol (400 mL) and water (200 mL) was added in portions to reflux (90 °C) of 3-methylaniline (40 g, 373 mmol, 1.0 equivalences) and potassium carbonate (7.74 g, 56.0 mmol, 0.15 equivalences) in ethanol (500 mL). The reaction mixture was stirred at 90 °C for another 40 minutes. TLC (petroleum ether:ethyl acetate = 4:1, R f =0.5) The reaction was detected as complete, and a new spot was formed. The reaction solution was diluted with water (300 mL) and extracted three times with dichloromethane (200 mL). The organic layer was dried over magnesium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. Purified by column chromatography (silica, 12% ethyl acetate in petroleum ether) to give a yellow syrupy compound 1-(m-tolyl)piperidin-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)

[0130] Step 3:To a solution of 1-(m-tolyl)piperidin-4-one (B-3) (90 g, 475 mmol, 1.0 eq.) and 1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonyl fluoride (216 g, 715 mmol, 1.5 eq.) in tetrahydrofuran (1200 mL) was added DBU (217 g, 1.43 mol, 215 mL, 3.0 eq.) dropwise at 0 °C. The reaction was stirred at 25 °C for 3 h. LCMS indicated the reaction was completed. The reaction was diluted with water (1 L), adjusted to pH 3-4 with 10% phosphoric acid, and extracted with methyl tert-butyl ether (1 L) three times. The organic layer was dried over magnesium sulfate, filtered, and concentrated to dryness under reduced pressure to give the crude product. The crude product was dispersed in petroleum ether (1.5 L) at 20 °C for 1 h, filtered, and concentrated to dryness under reduced pressure to give the crude product 1-(m-tolyl)-1,2,3,6-tetrahydropyridin-4-yl 1,1,2,2,3,3,4,4,4,4-nonafluorobutane-1-sulfonate (B-4) (175 g) as a yellow oil. The product was used directly in the next step without further purification. LCMS: (ESI) m / z = 472.1 [M+H] + ;

[0131] Step 4: Two reactions were set up in parallel. To a solution of 1-(m-tolyl)-1,2,3,6-tetrahydropyridin-4-yl 1,1,2,2,3,3,4,4,4,4-nonafluorobutane-1-sulfonate (B-4) (70 g, 148 mmol, 1.0 eq.), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (42.0 g, 165 mmol, 1.11 eq.) in 1,4-dioxane (1000 mL) was added potassium acetate (44 g, 448 mmol), the reaction was degassed under reduced pressure and replaced with nitrogen several times, 2-dicyclohexylphospho-2,4,6-triisopropylbiphenyl (4.3 g, 9.02 mmol, 0.06 eq.) and tris(dibenzylideneacetone)dipalladium (4.10 g, 4.47 mmol, 0.03 eq.) were added. The reaction was stirred at 90 °C under nitrogen for 16 h. LCMS indicated the reaction was completed. The reaction was cooled to room temperature, filtered, the filter cake was rinsed with petroleum ether (500 mL) three times, and the filtrate was concentrated to dryness under reduced pressure. The crude product was purified by column chromatography (silica, 5% ethyl acetate in petroleum ether) to give the crude product, which was slurry in n-pentane (150 mL) at 20 °C for 1 h, filtered, and the crude product 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(m-tolyl)-1,2,3,6-tetrahydropyridine (Intermediate B) (32 g, 101.60 mmol, 34.21% yield, 95% purity) as a yellow solid. LCMS: (ESI) m / z = 300.2 [M+H] + ; 1H NMR (400 MHz, CDC13) 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)

[0132] Intermediate synthesis 3: Synthesis of 2,3,4,5-tetrahydro-1 H-benzo[d]azepine (Intermediate C):

[0133]

[0134] Step 1 : Hydrogen bromide (196.23 g, 800.34 mmol, 131.70 mL, 33% hydrogen bromide in acetic acid) was added drop wise slowly over a period of 1 h at 25 °C to a solution of 2,2'-(l,2-phenylene)diacetonitrile (C-l) (50 g, 320.14 mmol) in acetic acid (60 mL). The reaction was stirred for 1 h. TLC indicated completion of the reaction. The reaction was filtered off, washed with isopropyl ether to get the solid compound which was dried under reduced pressure to get 4-bromo-lH-benzo[d]azepine -2-amine (C-2) as a bright yellow solid. The crude product was used as such without purification for the next step.

[0135] Step 2: 4-bromo-lH-benzo[d]azepine -2-amine (C-2) (88 g, 276.72 mmol, hydrogen bromide hydrochloride) was dissolved in water (600 mL) and heated to 85 °C. Sodium acetate (29.51 g, 359.74 mmol) was added portion wise. The reaction was heated to 95 °C and stirred for 6 h. TLC indicated completion of the reaction. It was cooled to room temperature and filtered to get the solid compound which was washed with water to get 1H-benzo[d]azepine -2,4(3H, 5H)-dione (C-3) as a bright yellow solid. The crude product was used as such without purification for the next step.

[0136] Step 3: 1H-benzo[d]azepine - 2,4(3H,5H)-dione (C-3) (47 g, 268.29 mmol) was dissolved in toluene (50 mL) and borane dimethyl sulfide complex (10 M, 80.49 mL) was added slowly dropwise under nitrogen atmosphere. The pink reaction solution was heated to 110 °C and stirred for 6 h. TLC (Rf = 0.40) indicated that the starting material was consumed completely. The reaction solution was cooled to room temperature and methanol (115 mL) was added slowly dropwise to the reaction solution. After the addition was completed, the reaction solution was heated to 100 °C and stirred for 1 h. It was cooled to 20 °C and 4 M hydrochloric acid-dioxane was added to adjust the pH of the reaction solution to 4-5. The reaction was stirred at 20 °C for 2 h. The reaction suspension was filtered to give 2,3,4,5-tetrahydro-1 H-benzo[d]azepine-2,4(3H,5H)-dione (C-4) as a pink solid (46 g, 97.6% yield).1H NMR (400 MHz, DMSO-d6) δ (ppm) 7.14-7.24 (m, 4H), 3.10-3.20 (m, 8H). (Intermediate C) (26 g, 141 mmol, 52.7% yield, hydrochloride salt). 1 H NMR (400 MHz, DMSO-d6) δ (ppm) 9.50 (br, 2H), 7.14-7.24 (m, 4H), 3.10-3.20 (m, 8H);

[0137] Intermediate synthesis 4: Synthesis of 7-(trifluoromethyl)-2,3,4,5-tetrahydro-1 H- benzo[d]azepine (Intermediate D): Step 1 : Step 2:

[0138]

[0139] Step 3: 2,3,4,5-tetrahydro-1 H-benzo[d]azepine-2,4(3H,5H)-dione (C-4) (46 g, 268.29 mmol) was dissolved in toluene (50 mL) and borane dimethyl sulfide complex (10 M, 80.49 mL) was added slowly dropwise under nitrogen atmosphere. The pink reaction solution was heated to 110 °C and stirred for 6 h. TLC (Rf = 0.40) indicated that the starting material was consumed completely. The reaction solution was cooled to room temperature and methanol (115 mL) was added slowly dropwise to the reaction solution. After the addition was completed, the reaction solution was heated to 100 °C and stirred for 1 h. It was cooled to 20 °C and 4 M hydrochloric acid-dioxane was added to adjust the pH of the reaction solution to 4-5. The reaction was stirred at 20 °C for 2 h. The reaction suspension was filtered to give 2,3,4,5-tetrahydro-1 H-benzo[d]azepine-2,4(3H,5H)-dione (C-4) as a pink solid (46 g, 97.6% yield).1H NMR (400 MHz, DMSO-d6) δ (ppm) 7.14-7.24 (m, 4H), 3.10-3.20 (m, 8H). (Intermediate C) (11 g of free base, 74.72 mmol) was dissolved in dichloromethane (220 mL) and triethylamine (9.07 g, 89.7 mmol) was added under nitrogen atmosphere at 25 °C. Trifluoromethanesulfonic anhydride (18.8 g, 89.7 mmol) was added dropwise at 0 °C and the reaction solution was stirred at 0 °C for 1 h. LCMS indicated that the reaction was complete. The reaction solution was washed with saturated aqueous sodium bicarbonate solution (200 mL) once, 1 M aqueous hydrochloric acid solution (200 mL) twice and saturated aqueous sodium chloride solution (200 mL) once. The organic phase was dried over magnesium sulfate and filtered. The filtrate was concentrated to dryness under reduced pressure and purified by column chromatography (silica, 13% ethyl acetate in petroleum ether) to give 1-(4,5-dihydro-1 H-benzo[d]azepin-3(2H)-yl)-2,2,2-trifluoroethanone (D-1) as a white solid (16 g, 65.8 mmol, 88.0% yield). LCMS: (ESI) m / z = 244.1 [M+H] -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] + ; 1H 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);

[0140] Step 4: The two reactions were set up in parallel, with 1-(4,5-dihydro-1H-benzo[d]aza)a at 0 degrees Celsius. -3(2H)-yl)-2,2,2-trifluoroethyl ketone (D-1) (8.0 g, 32.9 mmol) was added to concentrated sulfuric acid (32 mL) and stirred for 10 minutes to obtain a grayish-yellow solution. Potassium nitrate (2.66 g, 26.3 mmol) was added in portions over 20 minutes at 0°C. The reaction mixture was stirred at 0°C for 30 minutes. TLC was used to determine complete consumption of the starting material. The reaction mixture was slowly poured into stirred ice water (50 mL) and extracted three times with ethyl acetate (50 mL). The organic layer was washed once with saturated brine (50 mL), dried over magnesium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. The filtrate was purified by column chromatography (silica, 15% ethyl acetate in petroleum ether) to give a white solid 2,2,2-trifluoro-1-(7-nitro-4,5-dihydro-1H-benzo[d]aza) -3(2H)-yl)acetone (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)

[0141] Step 5: 2,2,2-trifluoro-1-(7-nitro-4,5-dihydro-1H-benzo[d]aza) -3(2H)-yl)ethyl ketone (D-2) (4.3 g, 14.9 mmol) was dissolved in methanol (130 mL), and 10% wet palladium on carbon (794 mg, 746 μmol) was added under nitrogen protection. The suspension was replaced three times with hydrogen balloons, and the reaction was stirred at 25 °C for 16 h under a hydrogen atmosphere. The reaction was confirmed by LCMS. The reaction solution was filtered, and the filtrate was concentrated to dryness under reduced pressure and purified by column chromatography (silica, 30% ethyl acetate in petroleum ether) to give a bright yellow solid 1-(7-amino-4,5-dihydro-1H-benzo[d]aza)a -3(2H)-yl)-2,2,2-trifluoroacetone (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)

[0142] Step 6: 1-(7-amino-4,5-dihydro-1H-benzo[d]aza) at 0 degrees Celsius -3(2H)-yl)-2,2,2-trifluoroethyl ketone (D-3) (4.5 g, 17.4 mmol) was dissolved in a mixture of water (58 mL) and sulfuric acid (9.57 g, 97.6 mmol), and an aqueous solution of NaNO2 (1.56 g, 22.6 mmol) (29 mL) was added dropwise. After the addition was complete, the mixture was stirred for 10 minutes. An aqueous solution of NaI (3.92 g, 26.1 mmol) in sulfuric acid (1 mol / L, 5.8 mL) was added to the above solution. The reaction mixture was allowed to heat naturally to 25°C and stirred for 16 hours. TLC was used to confirm complete consumption of the starting materials. The reaction mixture was extracted 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, and the filtrate was concentrated to dryness under reduced pressure. The filtrate was then purified by column chromatography (silica, 4.3% ethyl acetate in petroleum ether) to give a white solid 2,2,2-trifluoro-1-(7-iodo-4,5-dihydro-1H-benzo[d]aza) -3(2H)-yl)ethyl ketone (D-4) (4.7 g, 12.7 mmol, 73.1% yield). 1 H NMR (400MHz, CDCl3) δ (ppm) 7.46-7.57 (m, 2H), 6.86-6.94 (m, 1H), 3.72-3.83 (m, 2H), 3.62-3.72 (m, 2H), 2.93 (m, 4H); 19 F NMR(376MHz,CDCl3)δ(ppm)-68.07

[0143] Intermediate synthesis 5: Synthesis of 7,8-difluoro-2,3,4,5-tetrahydro-1 H-benzo[d]azepine 2,2,2-trifluoro-1-(7-iodo-4,5-dihydro-1H-benzo[d]aza) -3(2H)-yl)ethyl ketone (D-4) (250 mg, 677 μmol) was dissolved in dimethylformamide (2 mL). Under a nitrogen atmosphere at 25°C, methyl fluorosulfonyl difluoroacetate (651 mg, 3.39 mmol), cuprous iodide (26 mg, 135 μmol), and N-methylpyrrolidone (806 mg, 8.13 mmol) were added sequentially. The reaction mixture was heated to 80°C and stirred for 12 hours. The reaction was confirmed by LCMS. The reaction mixture was diluted with water (10 mL) and filtered. The filtrate was extracted twice with ethyl acetate (10 mL). The organic layer was dried over magnesium sulfate, filtered, concentrated to dryness under reduced pressure, and purified by column chromatography (silica, 4% ethyl acetate in petroleum ether) to give a yellow solid 2,2,2-trifluoro-1-(7-(trifluoromethyl)-4,5-dihydro-1H-benzo[d]aza) -3(2H)-yl)ethyl ketone (D-5) (180 mg, 578 μmol, 85.4% yield).

[0144] (Intermediate E): 2,2,2-trifluoro-1-(7-(trifluoromethyl)-4,5-dihydro-1H-benzo[d]aza 3(2H)-yl)ethyl ketone (D-5) (120 mg, 386 μmol) was dissolved in methanol (3 mL), and potassium carbonate (160 mg, 1.16 mmol) was added in one batch. The reaction mixture was heated to 50 °C and stirred for 12 hours. LCMS analysis showed complete consumption of the starting material and formation of the target product. The reaction mixture was concentrated to dryness. Water (5 mL) was added, and the mixture was extracted three times with ethyl acetate (5 mL). The organic layer was dried over magnesium sulfate, filtered, and concentrated to dryness under reduced pressure to give a yellow syrupy crude product 7-(trifluoromethyl)-2,3,4,5-tetrahydro-1H-benzo[d]aza Intermediate D (80 mg) can be used directly in the next reaction without further purification. LCMS: (ESI) m / z = 215.9 [M+H] + ;

[0145] Step 1 : Step 2:

[0146]

[0147] Step 3:To a solution of 2-(2-bromoethoxy)tetrahydro-2H-pyran (E-1) (18 g, 86.09 mmol) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(l,3,2-dioxaborolane) (26.2 g, 103 mmol) in dimethylformamide (350 mL) was added lithium methoxide (6.54 g, 172.18 mmol, 2.0 eq), copper iodide (1.64 g, 8.61 mmol) and triphenylphosphine resin (2.25 g, ~3 mmol / g, 8.61 mmol). The reaction was stirred at 25 °C for 12 h. After the reaction was complete, the reaction was diluted with dichloromethane (200 mL) and filtered through celite. The filter cake was washed with dichloromethane (100 mL) twice and the filtrates were combined and concentrated to dryness under reduced pressure. The residue was poured into saturated ammonium chloride solution and extracted with tert-butyl methyl ether (200 mL) three times. The organic phase was washed with water (300 mL) and saturated brine (300 mL), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated to dryness under reduced pressure. The crude product, 4,4,5,5-tetramethyl-2-(2-(((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-l,3,2-dioxaborolane (E-2) (19.0 g) was used in the next step without further purification. 1 H NMR (400 MHz, CDC13) 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)

[0148] Step 4: To a solution of 4,4,5,5-tetramethyl-2-(2-(((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-l,3,2-dioxaborolane (E-2) (19 g, 74.18 mmol) in tetrahydrofuran (540 mL) was added potassium hydrogen fluoride (17.38 g, 222.53 mmol, 7.33 mL) in water (60 mL) and stirred at 25 °C for 2 h. The reaction was concentrated to dryness under reduced pressure and lyophilized to give a white solid. The solid was washed with dry acetone (50 mL) four times, filtered and the filtrate was concentrated to dryness under reduced pressure. The resulting solid was slurried with tert-butyl methyl ether (100 mL), filtered and dried to give white solid, potassium (2-(((tetrahydro-2H-pyran-2-yl)oxy)ethyl)trifluoroborate (E-3) (13.5 g, 57.18 mmol, 77.09% yield). 1H NMR (400 MHz, DMSO-d6) d (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)

[0149] Step 5: To a solution of 1,2-dibromo-4,5-difluorobenzene (E-4) (2.0 g, 7.36 mmol) and potassium (2-(((tetrahydro-2H-pyran-2-yl)oxy)ethyl)trifluoroborate (E-3) (3.99 g, 16.92 mmol) in water (10 mL) and dioxane (50 mL) was added bis(1-adamantyl)-butyl-phosphine (527.49 mg, 1.47 mmol), cesium carbonate (14.38 g, 44.14 mmol) and palladium acetate (495.45 mg, 2.21 mmol) respectively, the reaction was purged with nitrogen for 5 minutes. Stirring at 100 °C for 16 hours. TLC (petroleum ether: ethyl acetate = 8: 1) showed the starting material was consumed completely and a new spot was generated. The reaction was filtered through celite, then diluted with water (30 mL), extracted with ethyl acetate (50 mL) for 3 times, the combined organic phase was washed with brine (100 mL), dried over anhydrous magnesium sulfate, filtered and the filtrate was concentrated to dryness under reduced pressure. Purification by column chromatography (silica, 10% ethyl acetate in petroleum ether) gave 2,2'-((((4,5-difluoro-1,2-phenylene)bis(ethane-2,1-diyl))bis(oxy))bis(tetrahydro-2H-pyran) (E-5) as yellow oil (1.25 g, 3.37 mmol, 45.87% yield). 1 H NMR (400 MHz, CDCl3) d (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)

[0150] Step 6: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), add p-toluenesulfonic acid monohydrate (801.08 mg, 4.21 mmol, 1.2 eq). Stir the reaction solution at 25 °C for 16 hours. TLC (petroleum ether: ethyl acetate = 10:1) test shows the starting material is consumed completely and a new spot is generated. Concentrate the solution under reduced pressure to remove the solvent, then add dichloromethane (20 mL) and saturated sodium bicarbonate solution (20 mL), extract the aqueous phase with dichloromethane (20 mL) for 5 times. Wash the organic layer with saturated brine (50 mL), dry over anhydrous magnesium sulfate, filter, and concentrate the filtrate under reduced pressure to dryness. Obtain 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 without further purification. 1 H NMR (400 MHz, CDC13) δ (ppm) 7.03 (t, 2H), 3.86 (t, 4H), 2.88 (t, 4H), 1.97 (br, 2H)

[0151] Step 7: 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), add methanesulfonic anhydride (1.51 g, 8.65 mmol) at 0 °C. Stir the reaction solution at 0-25 °C for 1 hour. TLC (petroleum ether: ethyl acetate = 10:1) test shows the starting material is consumed completely and a new spot is generated. Quench with saturated sodium bicarbonate (20 mL), extract with dichloromethane (20 mL) for 3 times, dry the combined organic phase, filter, and concentrate the filtrate under reduced pressure to dryness. Obtain yellow solid (4,5-difluoro-1,2-phenylene)bis(ethane-2,1-diyl)dimethanesulfonate (E-7) (1.32 g) crude, which can be used directly in the next step without further purification. 1 H NMR (400 MHz, CDC13) δ (ppm) 7.07 (t, 2H), 4.39 (t, 4H), 3.08 (t, 4H), 2.98 (s, 6H)

[0152] Example 1 : Synthesis of N1-((2-(4,5-dihydro-1 H-benzo[d]azepin-3(2H)-yl)-6- methylpyridin-3-yl)methyl)-N1,N2-dimethylethan-1,2-diamine (Compound P110):(4,5-difluoro-1,2-phenylene)bis(ethane-2,1-diyl)dimethanesulfonate (E-7) (1.22 g, 3.40 mmol) was dissolved in 1,2-dichloroethane (20 mL), and benzylamine (3.65 g, 34.04 mmol) was added. The reaction mixture was stirred at 50 °C for 16 hours. LC-MS showed that the reaction was complete. Saturated sodium bicarbonate (15 mL) was added, and the mixture was extracted twice with dichloromethane (15 mL). The organic phases were combined, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. The solution was purified by column chromatography (silica, 5% ethyl acetate in petroleum ether) to give a pale yellow liquid, N-benzyl-7,8-difluoro-2,3,4,5-tetrahydro-1H-benzo[d]aza (E-8) (600 mg, 1.98 mmol, 58.04% yield, 90% purity). LCMS: (ESI) m / z = 273.8 [M+H] + ,

[0153] Synthesis of N1-((2-(4,5-dihydro-1 H-benzo[d]azepin-3(2H)-yl)-6-methylpyridin-3- yl)methyl)-N1,N2-dimethylethan-1,2-diamine (Compound P110): N-benzyl-7,8-difluoro-2,3,4,5-tetrahydro-1H-benzo[d]aza (E-8) (600 mg, 2.20 mmol) was dissolved in 15 mL of methanol in hydrochloric acid / 1 mL of methanol, and 10% palladium / carbon (233.62 mg, 219.52 μmol) was added. The reaction was purged with hydrogen several times under vacuum. The reaction was stirred at 50 °C for 16 h under a hydrogen balloon (15 Psi). LC-MS showed that the reaction was complete. The solvent was removed by concentration under reduced pressure to give a white solid 7,8-difluoro-2,3,4,5-tetrahydro-1H-benzo[d]aza (Intermediate E) (400 mg crude hydrochloride product), this crude product can be used directly in the next reaction without further purification. LCMS: (ESI) m / z = 184.0 [M+H] + , 1 H NMR(400MHz,DMSO-d6)δ(ppm)8.83(br s,1H),7.31(t,2H),2.98-3.16(m,8H)

[0154] 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):

[0155]

[0156] The synthesis of intermediate F can be referenced from the synthesis of intermediate A. 1HNMR(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)

[0157] Step 1 : Step 2: Step 3:

[0158]

[0159] Step 1: Under nitrogen protection, 2-chloro-6-methylnicotinaldehyde (1-1) (100 mg, 643 μmol), 2,3,4,5-tetrahydro-1H-benzo[d]aza Intermediate C (104 mg, 707 μmol) was dissolved in DMF (2 mL), and DIPEA (166 mg, 1.29 mmol) was added. The reaction mixture was then stirred at 100 °C for 16 h. LC-MS showed that the reaction was complete. The reaction mixture was concentrated and purified by column chromatography (silica gel column, 0-7% ethyl acetate / petroleum ether gradient elution) to give a yellow solid compound 2-(4,5-dihydro-1H-benzo[d]aza) -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] + ;

[0160] Step 2: Compound 2-(4,5-dihydro-1H-benzo[d]aza) -3(2H)-yl)-6-methylnicotinaldehyde (1-2) (110 mg, 413 μmol) and methyl (2-(methylamino)ethyl)carbamate tert-butyl ester (78 mg, 413 μmol) were dissolved in 10 mL of dichloromethane. AcOH (25 mg, 413 μmol) was added dropwise, and the yellow reaction solution was stirred at 20 °C for 2 hours. NaBH(OAc)3 (263 mg, 1.24 mmol) was added in portions, and the yellow reaction solution was stirred at 20 °C for 14 hours. LCMS showed the reaction was complete. The reaction was quenched dropwise with saturated NaHCO3 (20 mL) aqueous solution, and extracted with dichloromethane (20 mL × 3). The organic phase was washed with saturated brine, dried over magnesium sulfate, filtered, and concentrated to obtain (2-((2-(4,5-dihydro-1H-benzo[d]aza) -3(2H)-yl)-6-methylpyridin-3-yl)methyl)(methyl)amino)ethyl)(methyl)carbamate tert-butyl ester (1-3) (150 mg, crude): Yellow viscous crude product, no purification required, directly used in the next reaction. LCMS: (ESI) m / z = 439.3 [M+H] + ;

[0161] Step 3: To 2-((2-(4,5-dihydro-1H-benzo[d]aza) -3(2H)-yl)-6-methylpyridin-3-yl)methyl)(methyl)amino)ethyl)(methyl)carbamate tert-butyl ester (1-3) (150 mg, 342 μmol) was carefully added to HCl / 1,4-dioxane (5 mL) solution; the reaction was stirred at room temperature for 16 hours, and the reaction was monitored by LCMS until complete. The reaction solution was concentrated to obtain crude product, which was purified by preparative HPLC (column: Boston Green ODS 150×30 mm×5 μm; mobile phase: [water (0.05% HCl)-ACN]; B%: 0%-38%, 9 min) and collected and lyophilized at low temperature to obtain yellow solid product N1-((2-(4,5-dihydro-1H-benzo[d]aza) -3(2H)-yl)-6-methylpyridin-3-yl)methyl)-N1,N2-dimethylethane-1,2-diamine (P110, Example 1) (110 mg, 318 μmol, 93.1% yield, 98% purity). LCMS: (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)

[0162] Example 2: Compound N 1 , N 2 - dimethyl-N1-((6-methyl-2-(1-(m-tolyl)piperidin-4-yl)pyridin- Step 4:

[0163]

[0164] Synthesis of N1-((2-(4,5-dihydro-1 H-benzo[d]azepin-3(2H)-yl)-6-methylpyridin-3- yl)methyl)-N1,N2-dimethylethan-1,2-diamine (Compound P110):Compound 2-chloro-6-methylnicotinaldehyde (2-1) (10.0 g, 64.3 mmol), methyl (2-(methylamino)ethyl)carbamic acid tert-butyl ester (13.3 g, 70.7 mmol) and AcOH (4.25 g, 70.7 mmol) were dissolved in dichloromethane (150 mL) and stirred at 25 °C for 2 h. NaBH(OAc)3 (40.9 g, 1923 mmol) was added carefully in portions and stirring was continued at room temperature for 16 h. LCMS showed the disappearance of starting material, NaHCO3 (300 mL) was added carefully to quench the reaction and extracted with dichloromethane (200 mL x 3). The combined organic phase was dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by column chromatography (silica gel, 0-10% ethyl acetate / petroleum ether gradient elution) to give the yellow sticky product (2-((2-chloro-6-methylpyridin-3-yl)methyl)(methyl)amino)ethyl)(methyl)carbamic acid tert-butyl ester (2-2) (13.0 g, 38.4 mmol, 59.8% yield). LCMS: (ESI) m / z = 328.0 [M+H] + ; 1 H NMR (400 MHz, 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)

[0165] Step 1 :70 mL of tetrahydrofuran was added tert-butyl (2-((2-chloro-6-methylpyridin-3- yl)methyl)(methyl)amino)ethyl)(methyl)carbamate (2-2) (7.02 g, 21.4 mmol), 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l-(m-tolyl)-l,2,3,6-tetrahydropyridine (Intermediate B) (7.05 g, 23.6 mmol), and aqueous potassium phosphate tribasic (9.10 g, 42.9 mmol) (14 mL). After the reaction system was purged with nitrogen several times, XPhos-Pd-G2 (510 mg, 648 μmol) was added, and the reaction was heated in an oil bath at 85 °C for 30 h under nitrogen protection. After the reaction was cooled to room temperature, the reaction solution was diluted with saturated brine (50 mL) and ethyl acetate (100 mL). The organic phase was separated, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over anhydrous magnesium sulfate, filtered, and concentrated. Column chromatography (silica gel column, 0-10-30% ethyl acetate / dichloromethane gradient elution) was used to separate the product. Concentration gave tert-butyl methyl(2-(methyl((6-methyl-l'-(m-tolyl)-l',2',3',6'-tetrahydro-[2,4'- bipyridinyl]-3-yl)methyl)amino)ethyl)carbamate (2-3) (10.9 g, 19.9 mmol, 93.1% yield, 85% purity) as a yellow sticky liquid. LCMS: (ESI) m / z = 465.2 [M+H] + ; 1 HNMR (400 MHz, CDC13) 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)

[0166] Step 2:Methyl (2-(methyl((6-methyl-l'-(m-tolyl)-l',2',3',6'-tetrahydro-[2,4'- bipyridine]-3-yl)methyl)amino)ethyl)carbamic acid tert-butyl ester (2-3) (7.84 g, 16.9 mmol) was dissolved in 250 mL of ethyl acetate and 10% wet Pd(OH)2 / C (3.16 g) was added under nitrogen. The system was purged with hydrogen balloon several times and stirred at room temperature for 36 hours under hydrogen protection. The reaction was monitored by LCMS and was complete. The reaction was filtered through celite and washed with ethyl acetate. The organic phases were combined and concentrated. The product was purified by column chromatography (silica gel column, 0-25% ethyl acetate / dichloromethane gradient elution) to give methyl (2-(methyl((6-methyl-2-(l-(m-tolyl)piperidin-4-yl)pyridin-3- yl)methyl)amino)ethyl)carbamic acid tert-butyl ester (2-4) (8.86 g, 18.0 mmol, 76.9% yield) as yellow sticky liquid. LCMS: (ESI) m / z = 467.4 [M+H] + ; 1 H NMR (400 MHz, CDC13) 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), 2.49 (s, 3H), 2.33 (s, 3H), 2.14-2.29 (m, 5H), 1.75-1.84 (m, 2H), 1.33-1.51 (m, 9H)

[0167] Step 3:Tert-butyl methyl(2-(methyl((6-methyl-2-(l-(m-tolyl)piperidin-4-yl)pyridin-3- yl)methyl)amino)ethyl)carbamate (2-4) (11.7 g, 25.1 mmol) was dissolved in methanol (70 mL) and HCl / 1,4-dioxane (4 M, 75 mL) was added dropwise with stirring. The reaction was stirred at room temperature under nitrogen for 16 hours and the reaction was monitored by LCMS to be complete. The reaction was concentrated and about 200 mL of methanol was added and the reaction was concentrated under reduced pressure and repeated twice to remove the hydrochloric acid. The concentrate was diluted with methanol and heated with activated carbon to decolorize, cooled to room temperature, filtered and washed with methanol, concentrated to about 100 mL and isopropanol was added to replace the methanol and concentrated to about 250 mL. The reaction emulsion was heated at 85 °C for 30 minutes, stirred at 30 °C for 10 hours and cooled to room temperature. The solid was filtered, washed with isopropanol (100 mL) and n-pentane (200 mL x 2) and collected and dried under vacuum. The solid product was dissolved in 150 mL of water, filtered and the filtrate was lyophilized to give the white solid product N 1 , N 2 - dimethyl-N 1 - ((6-methyl-2-(l-(m-tolyl)piperidin-4-yl)pyridin-3-yl)methyl)ethane- 1,2-diamine (P081, Example 2) (hydrochloride salt, 9.8 g, 19.1 mmol, 76.2% yield, 99.9% purity). LCMS: (ESI) m / z = 367.3 [M+H] + ; 1 H NMR (400 MHz, D20) 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)

[0168] Example 3: N 1 -((6-amino-2-(1-(m-tolyl)piperidin-4-yl)pyridin-3-yl)methyl)-N 1 , N 2 -di Step 4:

[0169]

[0170] Step 5:To a solution of 2,6-dichlorobenzaldehyde (3-1) (25 g, 142 mmol) and bis(4-methoxybenzyl)amine (40.2 g, 156 mmol) in DMF (200 mL) was added triethylamine (17.2 g, 170 mmol, 23.7 mL). The reaction was stirred at 50 °C for 16 h. The reaction was monitored by LCMS. The mixture was poured into 200 mL of ice water and extracted with ethyl acetate (400 mL x 1, 200 mL x 2). The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated and purified by column chromatography (silica gel, 0-20% ethyl acetate / petroleum ether: dichloromethane = 5:1 gradient elution) to give compound 6-(bis(4-methoxybenzyl)amino)-2-chlorobenzaldehyde (3-2) (50 g, 124.83 mmol, 87.88% yield, 99.08% purity) as a white solid. LCMS: (ESI) m / z = 397.1 [M+H] + ; 1 H NMR (400 MHz, 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)

[0171] Step 6: To a solution of 6-(bis(4-methoxybenzyl)amino)-2-chlorobenzaldehyde (3-2) (800 mg, 2.02 mmol), 1-(m-tolyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine (Intermediate B) (1.02 g, 2.40 mmol, 70% purity), tetrahydrofuran (6 mL) and potassium phosphate aqueous solution (856 mg potassium phosphate dissolved in 1 mL water) in a reaction flask, XPhos-Pd-G3 (37 mg, 43.71 μmol) was added after the reaction system was replaced by nitrogen for several times under reduced pressure. The reaction was stirred at 70 °C for 2.5 h under nitrogen. The reaction was monitored by LCMS. After cooling to room temperature, saturated brine was added to the reaction and extracted with ethyl acetate for 3 times. The combined organic phase was dried over anhydrous sodium sulfate, filtered, concentrated and purified by column chromatography (silica gel, 0-10-15% ethyl acetate / petroleum ether gradient elution) to give 6-(bis(4-methoxybenzyl)amino)-1'-(m-tolyl)-1',2',3',6'-tetrahydro-[2,4'-bipyridine]-3-carbaldehyde (3-3) (1.01 g, 1.50 mmol, 74.2% yield, 79% purity) as a yellow sticky liquid. LCMS: (ESI) m / z = 534.3 [M+H] + ;

[0172] Synthesis of N1-((2-(4,5-dihydro-1 H-benzo[d]azepin-3(2H)-yl)-6-methylpyridin-3- yl)methyl)-N1,N2-dimethylethan-1,2-diamine (Compound P110):Into a reaction flask was placed 6-(bis(4-methoxybenzyl)amino)-1 '-(m-tolyl)-1 ',2',3',6'- tetrahydro-[2,4'-bipyridine]-3-carbaldehyde (3-3) (801 mg, 1.50 mmol) and ethyl acetate (50 mL) under nitrogen protection. Pd(OH)2 / C (450 mg, 10% Pd(OH)2 / C) was added. After the reaction system was replaced with hydrogen, the reaction was stirred at room temperature for 18 hours under hydrogen atmosphere (hydrogen balloon). The reaction solution was filtered and concentrated, and then purified by column chromatography (silica gel column, 0-25% ethyl acetate / petroleum ether gradient elution) to give the yellow viscous liquid product (6-(bis(4-methoxybenzyl)amino)-2-(1 -(m-tolyl)piperidin-4-yl)pyridin-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 (400 MHz, CDC13) 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).

[0173] Step 1 : Compound (6-(bis(4-methoxybenzyl)amino)-2-(1 -(m-tolyl)piperidin-4-yl)pyridin-3-yl)methanol (3-4) (440 mg, 818 μmol) was added to 10 mL dichloromethane, and Dess-Martin periodinane (347 mg, 818 μmol) was added under ice bath cooling. The reaction solution was stirred at room temperature for 16 hours. 20 mL 10% aqueous sodium thiosulfate solution was added to quench the reaction. After stirring for half an hour, 50 mL saturated aqueous sodium bicarbonate solution was added, and extracted with dichloromethane three times. The combined organic phase was washed with saturated brine, saturated aqueous sodium bicarbonate solution, and dried over anhydrous magnesium sulfate. After filtration, concentration, and purification by column chromatography (silica gel column, 0-16.8% ethyl acetate / petroleum ether gradient elution), the yellow viscous liquid product 6-(bis(4-methoxybenzyl)amino)-2-(1 -(m-tolyl)piperidin-4-yl)nicotinaldehyde (3-5) (250 mg, 373 μmol, 45.6% yield) was obtained. LCMS: (ESI) m / z = 536.2 [M+H] + ;

[0174] Step 2: To a reaction flask was added 5 mL of dichloromethane, followed by 6-(bis(4- methoxybenzyl)amino)-2-(1-(m-tolyl)piperidin-4-yl)nicotinaldehyde (3-5) (250 mg, 466.70 μmol) and methyl (2-(methylamino)ethyl)carbamic acid tert-butyl ester (88 mg, 466 μmol) sequentially, followed by AcOH (28.03 mg, 466.70 μmol) and stirred at room temperature for 2 h. NaBH(OAc)3 (297 mg, 1.40 mmol) was added in portions and stirring was continued for 14 h. The reaction was quenched by careful dropwise addition of 20 mL of saturated aqueous sodium bicarbonate solution and after stirring, the organic phase was extracted with dichloromethane three times and the combined organic phase was washed with saturated brine and dried over anhydrous magnesium sulfate. After filtration and concentration, column chromatography (silica gel, 0-17% tetrahydrofuran / petroleum ether gradient elution) gave compound (2-((6-(bis(4-methoxybenzyl)amino)-2-(1-(m-tolyl)piperidin-4-yl)pyridin-3-yl)methyl)(methyl)amino)ethyl)(methyl)carbamic acid tert-butyl ester (3-6) (60 mg, 83.1 μmol, 17.80% yield, 98% purity) as a yellow viscous liquid. LCMS: (ESI) m / z = 708.4 [M+H] + ; 1 H NMR (400 MHz, CDC13) 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)

[0175] Step 3:tert-Butyl (2-((6-(bis(4-methoxybenzyl)amino)-2-(1-(m-tolyl)piperidin-4- yl)pyridin-3-yl)methoxy)(methyl)amino)ethyl)(methyl)carbamate (3-6) (60 mg, 84.7 μιηοΐ). 1 mL of trifluoroacetic acid was added, followed by trifluoromethanesulfonic acid (29 mg, 194 μιηοΐ). The reaction was stirred at room temperature for 16 hours under nitrogen. The reaction mixture was concentrated and purified by preparative HPLC (column: Boston Green ODS 150 x 30 mm x 5 um; mobile phase: [water (0.05% HC1) - ACN]; B%: 0% - 25%, 9 min). The target product was lyophilized to yield a 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 μιηοΐ, 69.2% yield). LCMS: (ESI) m / z = 368.3 [M+H] + ; 1 HNMR (400 MHz, D20) δ (ppm) 7.91 (d, 1 H), 7.43 - 7.51 (m, 2H), 7.36 - 7.43 (m, 2H), 6.98 (d, 1 H), 4.40 (s, 2H), 3.78 - 3.89 (m, 4H), 3.63 - 3.72 (m, 1 H), 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)

[0176] Example 4: N 1 , N 2 - dimethyl-N 1 - ((4-(1-(m-tolyl)piperidin-4-yl)-1H-indazol-5-yl)methyl) Step 4: :

[0177]

[0178] Step 5:: 2-Bromo-4-fluorobenzoic acid (4-1) (23 g, 105 mmol) was dissolved in t-butanol (200 mL) and 4-dimethylaminopyridine (12.8 g, 105 mmol) and di-tert-butyl dicarbonate (68.8 g, 315 mmol, 3.0 eq.) (gas evolution) were added at room temperature. The reaction was heated to 90 °C under nitrogen and stirred for 2 h. TLC indicated complete consumption of starting material and the formation of a new spot. The reaction was diluted with water (100 mL) and extracted with ethyl acetate (2 x 150 mL). The organic layer was washed with saturated brine (80 mL), dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (silica, petroleum ether: ethyl acetate = 10: 1) to give 2-bromo-4-fluorobenzotrt-butyl ester (4-2) as a colorless liquid (26.8 g, 95.0 mmol, 90.4% yield, 97.5% purity). 1 H NMR (400 MHz, CDC13) δ (ppm) 7.77 (dd, 1H), 7.37 (dd, 1H), 7.02-7.10 (m, 1H), 1.61 (s, 9H)

[0179] Step 6: Synthesis of lithium diisopropylamide: Diisopropylamine (5.15 g, 50.9 mmol, 7.19 mL) was dissolved in tetrahydrofuran (100 mL) and n-butyllithium (2.5 M, 17.45 mL) was added dropwise at -70 °C. After the addition was complete, the reaction was allowed to warm to room temperature and stirred for half an hour to give a yellow solution of lithium diisopropylamide. 2-Bromo-4-fluorobenzotrt-butyl ester (4-2) (10 g, 36.35 mmol) was dissolved in tetrahydrofuran (20 mL) and added dropwise to the freshly prepared lithium diisopropylamide at -75 °C. The reaction was stirred at -75 °C for 1.5 h. Dimethylformamide (10.6 g, 145 mmol) was added to the reaction at -75 °C and the reaction was continued for 0.5 h. TLC indicated complete consumption of starting material and the formation of a new spot. The reaction was quenched by the dropwise addition of acetic acid (20 mL) at -70 °C. The reaction was diluted with water (150 mL) and extracted with ethyl acetate (2 x 200 mL). The organic layer was washed with saturated brine (100 mL), dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (silica, 3% ethyl acetate in petroleum ether) to give 2-bromo-4-fluoro-3-formylbenzoic acid tert-butyl ester (4-3) as a white solid (8.7 g, 27.7 mmol, 76.2% yield). 1 H NMR (400 MHz, CDC13) δ (ppm) 10.39 (s, 1H), 7.80 (dd, 1H), 7.19 (t, 1H), 1.63 (s, 9H)

[0180] Step 7:Dissolve 2-bromo-4-fluoro-3-formylbenzoic acid tert-butyl ester (4-3) (8.7 g, 28.7 mmol) in ethylene glycol dimethyl ether (100 mL), add hydrazine hydrate (31.6 g, 537 mmol, 85%, 18.7 eq.). Stir the reaction at 90 °C for 1 h. LCMS check shows complete consumption of starting material and formation of desired product. Cool the reaction and dilute with water (100 mL), extract with ethyl acetate (2x 150 mL). Wash the organic layer with saturated brine (100 mL), dry over magnesium sulfate, filter and concentrate under reduced pressure. Purify the residue by column chromatography (silica, 3% ethyl acetate in petroleum ether) to give 4-bromo-lH-indazole-5-carboxylic acid tert-butyl ester (4-4) as a yellow solid (4.5 g, 15.1 mmol, 52.7% yield). LCMS: (ESI) m / z = 296.9 / 298.9 [M+H] + ;

[0181] Step 8: Dissolve 4-bromo-lH-indazole-5-carboxylic acid tert-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), add p-toluenesulfonic acid monohydrate (288 mg, 1.51 mmol). Stir the reaction at 15 °C for 1 h. LC-MS check shows complete consumption of starting material and formation of desired product. Dilute the reaction with water (50 mL), extract with ethyl acetate (2x 100 mL). Wash the organic layer with saturated brine (80 mL), dry over magnesium sulfate, filter and concentrate under reduced pressure. Purify the residue by column chromatography (silica, 3% ethyl acetate in petroleum ether) to give 4-bromo-l-(tetrahydro-2H-pyran-2-yl)-lH-indazole-5-carboxylic acid tert-butyl ester (4-5) as a yellow syrup (4.5 g, 11.6 mmol, 76.7% yield). LCMS: (ESI) m / z = 240.9 / 242.9 [M+H-THP-tBu] + ; 1 H NMR (400 MHz, CDC13) δ (ppm) 8.16 (s, 1H), 7.81 (d, 1H), 7.55 (d, 1H), 5.72 (dd, 1H), 3.93 - 4.03 (m, 1H), 3.67 - 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)

[0182] Step 9:Intermediate 4-5: tert-Butyl 4-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-5- carboxylate. To a solution of 4-bromo-1H-indazole-5-carboxylic acid (1.0 g, 3.97 mmol) in DMF (10 mL) was added EDCI (1.0 g, 5.97 mmol), HOBt (0.82 g, 6.0 mmol), and triethylamine (1.0 mL, 7.0 mmol). The reaction mixture was stirred at room temperature for 10 min, and then tert-butyl 4-hydroxypiperidine-1-carboxylate (0.82 g, 4.0 mmol) was added. The reaction mixture was stirred at room temperature for 16 h. LC-MS indicated that the starting material was consumed completely, and the target product was generated. The reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (20 mL) for 3 times. The organic layer was washed with saturated brine (20 mL), dried over magnesium sulfate, filtered, and concentrated to dryness under reduced pressure. The residue was purified by column chromatography (silica, 3% ethyl acetate in petroleum ether) to give tert-butyl 4-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-5-carboxylate (Intermediate 4-5) (1.0 g, 2.62 mmol, 66.0% yield) as a yellow syrup. LCMS: (ESI) m / z = 374.3 [M+H] + ;

[0183] Synthesis of N1-((2-(4,5-dihydro-1 H-benzo[d]azepin-3(2H)-yl)-6-methylpyridin-3- yl)methyl)-N1,N2-dimethylethan-1,2-diamine (Compound P110): Intermediate 4-6: tert-Butyl 1-(tetrahydro-2H-pyran-2-yl)-4-(1-(m-tolyl)-1,2,3,6- tetrahydropyridin-4-yl)-1H-indazole-5-carboxylate. tert-Butyl 4-bromo-1-(tetrahydro-2H- pyran-2-yl)-1H-indazole-5-carboxylate (Intermediate 4-5) (1.0 g, 2.62 mmol, 1.0 eq.) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(m-tolyl)-1,2,3,6-tetrahydropyridine (Intermediate B) (863 mg, 2.89 mmol) were dissolved in tetrahydrofuran (8 mL) and added with an aqueous solution of potassium phosphate (1.67 g, 7.87 mmol) (2 mL). The reaction mixture was degassed under reduced pressure and replaced with nitrogen several times. (2-Dicyclohexylphosphino-2,4,6-triisopropyl-1,1- biphenyl)[2-(2-amino-1,1-biphenyl)]palladium(II) methanesulfonate (XPhos-Pd-G3) (67 mg, 78.7 μmol) was added. The reaction mixture was stirred at 80 °C under nitrogen protection for 16 h. LC-MS indicated that the starting material was consumed completely, and the target product was generated. The reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (20 mL) for 3 times. The organic layer was washed with saturated brine (20 mL), dried over magnesium sulfate, filtered, and concentrated to dryness under reduced pressure. The residue was purified by column chromatography (silica, 3% ethyl acetate in petroleum ether) to give tert-butyl 1-(tetrahydro-2H-pyran-2-yl)-4-(1-(m-tolyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H- indazole-5-carboxylate (Intermediate 4-6) (800 mg, 1.55 mmol, 59.0% yield) as a yellow syrup. LCMS: (ESI) m / z = 474.4 [M+H] + ; RT = 0.857 min

[0184] 1H NMR (400 MHz, CDC13) δ (ppm) 8.31 (s, 1H), 7.64 (d, 1H), 7.45 (d, 1H), 7.19 (t, 1H), 6.80-6.91 (m, 2H), 6.71 (d 1H), 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)

[0185] Example 7: Synthesis of N1-((4-(4,4-bis(ethoxymethyl)cyclohexyl)-1 H-indol-5-yl)methyl)- N1,N2-dimethylethan-1,2-diamine (Compound P266) tert-Butyl 1-(tetrahydro-2H-pyran-2-yl)-4-(1-(m-tolyl)piperidin-4-yl)-1H-indazole-5- carboxylate (4-7) (630 mg, 1.32 mmol) was dissolved in tetrahydrofuran (6 mL) and lithium aluminum hydride (1 M in THF, 5.5 mL) was added dropwise at -5 °C. The reaction was stirred at 20 °C for 3 h. TLC (petroleum ether / ethyl acetate = 1:1) showed that the starting material was consumed completely and a new spot was generated. The reaction was quenched with water (10 mL) at -5 °C and diluted with water (5 mL) and extracted with ethyl acetate (30 mL) twice. The organic layer was washed with saturated brine (20 mL), dried over magnesium sulfate, filtered, and concentrated to dryness under reduced pressure. The residue was purified by column chromatography (silica, 50% ethyl acetate in petroleum ether) to give (1-(tetrahydro-2H-pyran-2-yl)-4-(1-(m-tolyl)piperidin-4-yl)-1H-indazol-5- yl)methanol (4-8) (500 mg, 849 μmol, 64.1% yield) LCMS: (ESI) m / z = 406.3 [M+H] + ;

[0186] Example 8: Synthesis of N1-((4-(2,3-difluoro-6,7,8,9-tetrahydro-5H- benzo[7]annulen-7-yl)-1 H-indol-5-yl)methyl)-N1,N2-dimethylethan-1,2-diamine (Compound P167)Dess-Martin periodinane (220 mg, 518 μιηοΐ) was added. The reaction was stirred at 25 °C for 6 h. LC-MS showed the starting material was consumed completely and the desired product was formed. The reaction was quenched with 10% sodium thiosulfate solution (20 mL) and stirred at room temperature for 0.5 h. The reaction was added to saturated sodium bicarbonate (50 mL) and extracted with dichloromethane (50 mL) for 3 times. The organic layer was washed with saturated brine (50 mL), dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure. The residue was purified by column chromatography (silica, 30% ethyl acetate in petroleum ether) to give 1-(tetrahydro-2H-pyran-2-yl)-4-(1-(m-tolyl)piperidin-4-yl)-1H-indazole-5- carbaldehyde (4-9) (140 mg, 293 μιηοΐ, 59.4% yield) as yellow syrup. LCMS: (ESI) m / z = 404.3 [M+H] + ;

[0187] Example 9: Synthesis of N1-((6-amino-2-(4,4-bis(ethoxymethyl)cyclohexyl)pyridin-3- yl)methyl)-N1,N2-dimethylethan-1,2-diamine (Compound P268) Dess-Martin periodinane (220 mg, 518 μιηοΐ) was added. The reaction was stirred at 25 °C for 6 h. LC-MS showed the starting material was consumed completely and the desired product was formed. The reaction was quenched with 10% sodium thiosulfate solution (20 mL) and stirred at room temperature for 0.5 h. The reaction was added to saturated sodium bicarbonate (50 mL) and extracted with dichloromethane (50 mL) for 3 times. The organic layer was washed with saturated brine (50 mL), dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure. The residue was purified by column chromatography (silica, 30% ethyl acetate in petroleum ether) to give 1-(tetrahydro-2H-pyran-2-yl)-4-(1-(m-tolyl)piperidin-4-yl)-1H-indazole-5- carbaldehyde (4-9) (140 mg, 293 μιηοΐ, 59.4% yield) as yellow syrup. LCMS: (ESI) m / z = 404.3 [M+H] + ;

[0188] Example 9: Synthesis of N1-((6-amino-2-(4,4-bis(ethoxymethyl)cyclohexyl)pyridin-3- yl)methyl)-N1,N2-dimethylethan-1,2-diamine (Compound P268)Tert-butyl methyl(2-(methyl((l-(tetrahydro-2H-pyran-2-yl)-4-(l-(m-tolyl)piperidin-4- yl)-lH-indazol-5-yl)methyl)amino)ethyl)carbamate (4-10) (210 mg, 365 μmol) was dissolved in methanol (2 mL) and hydrogen chloride / 1,4-dioxane (4 M, 2.10 mL) was added. The reaction was stirred at 25 °C for 16 h. LC-MS indicated complete consumption of starting material and formation of the desired product. The reaction was concentrated to dryness under reduced pressure and purified by preparative liquid chromatography (Boston Green ODS column, 5 um silica, 30 mm diameter, 150 mm length; using a mixture of water (containing 0.05% hydrochloric acid) and acetonitrile with decreasing polarity as eluent) to give N1,N2-dimethyl-N1-(((4-(l-(m-tolyl)piperidin-4-yl)-lH-indazol-5- yl)methyl)ethane-l,2-diamine (P190, Example 4) as a white solid (hydrochloride salt, 105 mg, 245 μmol, 67.3% yield). LCMS: (ESI) m / z = 392.2 [M+H] + ; 1 H NMR (400 MHz, D20) 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)

[0189] ​ ​

[0190]

[0191] ​Dissolve 4-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-5-carboxylic acid tert-butyl ester (4-5) (1.95 g, 5.11 mmol), (2,3-difluoro-6,9-dihydro-5H-benzo[7]annulen-7-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (Intermediate A) (1.80 g, 5.88 mmol, 1.15 eq), toluene (45 mL) and potassium phosphate (2.18 g, 10.3 mmol) dissolved in water (6.5 mL) into a reaction flask, purge with nitrogen several times, then add chloro(2-dicyclohexylphosphino-2,4,6-triisopropyl-1,1- biphenyl)[2-(2-amino-1,1-biphenyl)]palladium(II) (0.03 eq). Protect the reaction from light and heat, and stir at 60 °C for 24 h. Check LCMS for the formation of the desired product. Cool the reaction to 25 °C, dissolve in water (50 mL) and ethyl acetate (50 mL), separate the organic phase, then extract 3 times with ethyl acetate (50 mL). Combine the organic phases, dry over magnesium sulfate, filter, and concentrate the filtrate to dryness under reduced pressure. Purify by column chromatography (silica, 15% ethyl acetate in petroleum ether) to give crude 4-(2,3-difluoro-6,9-dihydro-5H-benzo[7]annulen-7-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-5-carboxylic acid tert-butyl ester (5-1) as a yellow oil. LCMS: (ESI) m / z = 481.2 [M+H] + ;

[0192] ​ Dissolve the crude product 4-(2,3-difluoro-6,9-dihydro-5H-benzo[7]annulen-7-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-5-carboxylic acid tert-butyl ester (5-1) in ethyl acetate (50 mL), and add palladium hydroxide on carbon (520 mg, 10%) under a nitrogen atmosphere. Purge the reaction with hydrogen several times, and stir at 30 °C for 12 h. Check LCMS for the consumption of starting material and the formation of the desired product. Filter the reaction to give 4-(2,3-difluoro-6,7,8,9-tetrahydro-5H-benzo[7]annulen-7-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-5-carboxylic acid tert-butyl ester (5-2) as a white solid, which was used directly in the next reaction without further purification. LCMS: (ESI) m / z = 399.3 [M+H-THP] + ; 1H NMR (400 MHz, CDC13) 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)

[0193] ​ 4-(2,3-Difluoro-6,7,8,9-tetrahydro-5H-benzo[7]annulene-7-yl)-1-(tetrahydro-2H-pyran-2- yl)-1H-indazole-5-carboxylic acid tert-butyl ester (5-2) (1.9 g, 3.94 mmol) was dissolved in methanol (30 mL) and tetrahydrofuran (30 mL), and p-toluenesulfonic acid monohydrate (297 mg, 1.56 mmol) was added. The reaction was stirred at 30 °C for 3.5 days. LCMS indicated that the desired product was formed and starting material was remaining. The reaction was quenched with saturated sodium bicarbonate solution (20 mL) and concentrated under reduced pressure to remove the methanol. Ethyl acetate (100 mL) and water (50 mL) were added, the organic phase was separated and extracted with ethyl acetate (50 mL) twice. The organic phases were combined and dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure to dryness. Purification by thin layer chromatography (silica, 35% ethyl acetate in petroleum ether). Concentrated to dryness under reduced pressure to give 4-(2,3-difluoro-6,7,8,9-tetrahydro-5H-benzo[7]annulene-7-yl)-1H-indazole-5- carboxylic acid tert-butyl ester (5-3) as a white solid (827 mg, 2.08 mmol, 52.7% yield). LCMS: (ESI) m / z = 399.2 [M+H] + ; 1 H NMR (400 MHz, CDC13) 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)

[0194] ​4-(2,3-difluoro-6,7,8,9-tetrahydro-5H-benzo[7]annulen-7-yl)-lH-indazole-5- carboxylic acid tert-butyl ester (5-3) (424 mg, 1.06 mmol) was dissolved in dimethylformamide (10 mL) with potassium carbonate (458 mg, 3.31 mmol) and iodine (459 mg, 1.81 mmol) added. The reaction was stirred at 15-20 °C for 16 hours. LCMS indicated 69% of the desired product and 30% of the starting material remaining. Additional iodine (135 mg, 532 μmol) and potassium carbonate (180 mg, 1.30 mmol) were added to the reaction and stirring was continued at 15-30 °C for 3 hours. LCMS indicated 10% of the starting material remaining and formation of the desired product. The reaction was combined with the previous 50 mg of crude product and worked up. Ethyl acetate (50 mL) and 10% sodium thiosulfate solution (50 mL) were added to the reaction and the organic phase was separated. The aqueous phase was extracted with ethyl acetate (50 mL) three times. The organic phases were combined and washed once with 10% sodium thiosulfate solution, three times with 10% lithium chloride (25 mL), and once with saturated brine. The solution was dried, filtered, and concentrated under reduced pressure to give the crude product 4-(2,3-difluoro-6,7,8,9-tetrahydro-5H-benzo[7]annulen-7-yl)-3-iodo-lH-indazole-5- carboxylic acid tert-butyl ester (5-4) as a light yellow foamy solid. The material was used without further purification in the next reaction. LCMS: (ESI) m / z = 525.0 [M+H] + ;

[0195] ​4-(2,3-difluoro-6,7,8,9-tetrahydro-5H-benzo[7]annulen-7-yl)-3-iodo-1-(tetrahydro- 2H-pyran-2-yl)-1H-indazole-5-carboxylic acid tert-butyl ester (5-5) (564 mg, 742 μmol, 66.0% yield, 80% purity) was dissolved in dichloromethane (10 mL) and trifluoroacetic acid (5 mL) was added. The reaction was stirred at 15-20 °C for 3 hours. LCMS showed complete consumption of starting material and formation of the desired product. The reaction was diluted with dichloromethane (50 mL) and the organic phase was washed with 5% sodium bicarbonate solution (50 mL). The organic phase was separated and the aqueous phase was extracted with dichloromethane (50 mL) twice. The combined organic phase was dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure. Purification by column chromatography (silica, 12% ethyl acetate in petroleum ether) gave 4-(2,3-difluoro-6,7,8,9-tetrahydro-5H-benzo[7]annulen-7-yl)-3-iodo-1H- indazole-5-carboxylic acid tert-butyl ester (5-6) as a white solid (400 mg, 600 μmol, 85.0% yield, 95% purity). LCMS: (ESI) m / z = 489.1 [M+H-THP] + ; 1 H NMR (400 MHz, CDC13) 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)

[0196] ​Parallel run of two reactions: tert-butyl 4-(2,3-difluoro-6,7,8,9-tetrahydro- 5H-benzo[7]annulen-7-yl)-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-5- carboxylate (5-5) (225 mg, 370 μmol, 1.0 eq.), 1,4-dioxane (5 mL) and potassium phosphate (236 mg, 1.11 mmol) dissolved in water (1 mL). After the reaction was purged with nitrogen, 2,4,6-trimethyl-1,3,5,2,4,6- trioxatriborinane (292 mg, 1.16 mmol, 50% in THF) and [1,1-bis(ditert- butylphosphino)ferrocene]dichloropalladium (17 mg, 26.1 μmol, 0.07 eq.) were added and the reaction was stirred at 80 °C for 2 h. LCMS showed complete consumption of starting material and formation of the desired product. The reaction was cooled to 20 °C and partitioned between saturated brine (50 mL) and ethyl acetate (50 mL). The organic layer was separated and the aqueous phase was extracted with ethyl acetate (50 mL) twice. The combined organic phases were dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure. Purification by column chromatography (silica, 0-5%-7% ethyl acetate in petroleum ether) gave the deiodinated side product tert-butyl 4-(2,3-difluoro-6,9-dihydro-5H- benzo[7]annulen-7-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-5-carboxylate (5-1) as a bright yellow oil (124 mg, 257 μmol, 34.7% yield) and the desired product tert-butyl 4-(2,3-difluoro-6,7,8,9-tetrahydro-5H-benzo[7]annulen-7-yl)-3-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-5-carboxylate (5-6) as a bright yellow oil (244 mg, 442 μmol, 59.8% yield). LCMS: (ESI) m / z = 497.2 [M+H] + ; 1 H NMR (400 MHz, CDC13) 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), 2.06-2.18 (m, 3H), 1.95-2.04 (m, 1H), 1.70-1.84 (m, 2H), 1.62-1.70 (m, 2H), 1.58 (s, 9H)

[0197] ​ tert-Butyl 4-(2,3-difluoro-6,7,8,9-tetrahydro-5H-benzo[7]annulen-7-yl)-3-methyl- 1 -(tetrahydro-2H-pyran-2-yl)-1 H-indazole-5-carboxylate (5-6) (239 mg, 481 μιηοΐ) and tetrahydrofuran (8 mL) were charged into a reaction flask. Lithium aluminum hydride (1 M tetrahydrofuran solution, 0.9 mL) was added at 15-2 °C, and the reaction was stirred for 2 h. TLC indicated that starting material was still present, and a new spot was formed. Lithium aluminum hydride (1 M tetrahydrofuran, 300 μί) was added, and the reaction was stirred for 1 h at 15-20 °C. TLC (petroleum ether: ethyl acetate = 3: 1) indicated that most of the starting material was consumed, and a new spot was formed. The reaction was quenched with water (50 mL) and 15% sodium hydroxide solution. The reaction was dissolved with ethyl acetate (50 mL), dried over magnesium sulfate, and stirred for 10 min. It was filtered, and concentrated under reduced pressure to dryness to give crude product (4-(2,3-difluoro-6,7,8,9-tetrahydro-5H- benzo[7]annulen-7-yl)-3-methyl-1 -(tetrahydro-2H-pyran-2-yl)-1 H-indazol-5-yl)methanol (5-7) as a yellow solid (221 mg, 518 μιηοΐ). This crude product was used directly in the next reaction without further purification. LCMS: (ESI) m / z = 427.3 [M+H] + ;

[0198] ​ (4-(2,3-difluoro-6,7,8,9-tetrahydro-5H-benzo[7]annulen-7-yl)-3-methyl-1- (tetrahydro-2H-pyran-2-yl)-1 H-indazol-5-yl)methanol (5-7) (210 mg, 492 μιηοΐ) was dissolved in dichloromethane (15 mL), and manganese dioxide (530 mg, 6.10 mmol) was added. The reaction was stirred at 40 °C for 3.5 h. It was filtered, and concentrated under reduced pressure to dryness to give crude product 4-(2,3-difluoro-6,7,8,9-tetrahydro-5H-benzo[7]annulen-7-yl)-3-methyl-1- (tetrahydro-2H-pyran-2-yl)-1 H-indazole-5-carbaldehyde (5-8) as a white solid (210 mg, 495 μιηοΐ). This crude product was used directly in the next reaction without further purification. LCMS: (ESI) m / z = 425.1 [M+H] + ;

[0199] ​4-(2,3-difluoro-6,7,8,9-tetrahydro-5H-benzo[7]annulen-7-yl)-3-methyl-1- (tetrahydro-2H-pyran-2-yl)-1H-indazole-5-carbaldehyde (5-8) (204 mg, 480 μmol), tert-butyl methyl(2-(methylamino)ethyl)carbamate (186 mg, 987 μmol) and acetic acid (62 mg, 1.03 mmol, 2.15 eq.) were dissolved in dichloromethane (3 mL). After stirring at 25 °C for 2 h, sodium triethoxycarbonylborohydride (340 mg, 1.60 mmol) was added. The reaction was stirred at 25 °C for 14 h. LCMS indicated that the starting material was consumed and the desired product was formed. The reaction was partitioned between 5% sodium bicarbonate (15 mL) and dichloromethane. The organic phase was separated. The aqueous phase was extracted with ethyl acetate (10 mL) three times. The combined organic phases were dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure. Purification by column chromatography (silica, 30% ethyl acetate in dichloromethane) gave tert-butyl 2-((4-(2,3-difluoro-6,7,8,9-tetrahydro-5H-benzo[7]annulen-7-yl)-3-methyl-1- (tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)methyl)(methyl)amino)ethyl)(methyl)carbamic acid (5-9) as a light yellow oil (204 mg, 325 μmol, 67.6% yield). LCMS: (ESI) m / z = 597.4 [M+H] + ;

[0200] ​ Hydrochloric acid-1,4 dioxane (4 M, 5 mL) was added to a solution of tert-butyl 2-((4-(2,3-difluoro-6,7,8,9-tetrahydro-5H-benzo[7]annulen-7-yl)-3-methyl-1- (tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)methyl)(methyl)amino)ethyl)(methyl)carbamic acid (5-9) (202 mg, 338 μmol) in methanol. The reaction was stirred at 10-15 °C for 12 h. LCMS indicated that the starting material was consumed and the desired product was formed. The reaction was concentrated to dryness under reduced pressure. Purification by reverse phase preparative liquid chromatography (YMC-Actus Triart C18 column, 5 um silica, 30 mm diameter, 150 mm length; using a mixture of water (containing 0.05% ammonia) and acetonitrile of decreasing polarity as eluent) gave N1-((4-(2,3-difluoro-6,7,8,9-tetrahydro-5H-benzo[7]annulen-7-yl)-3-methyl-1H- indazol-5-yl)methyl-N1,N2-dimethylethane-1,2-diamine (P146, Example 5) as a white solid (hydrochloride salt, 105 mg, 214 μmol, 63.3% yield, 99% purity). LCMS: (ESI) m / z = 413.4 [M+H]+ ; 1 H NMR (400 MHz, 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, 1H), 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); 19 F NMR (376 MHz, CD3OD) tautomer mixture δ (ppm) -144.96, -145.32

[0201] Example 6: N 1 , N 2 - dimethyl-N 1 - ((3-(7-(trifluoromethyl)-4,5-dihydro-1 H-benzo[d]azepin-3 ​

[0202]

[0203] The synthesis of compound P088 was carried out by 3-fluoropyridine carboxaldehyde and intermediate D, see example 1. LCMS: (ESI) m / z = 393.4 [M+H] + ; 1 H NMR (400 MHz, D20) 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)

[0204] ​ ​

[0205]

[0206] The synthesis of compound P266 was performed according to Example 4 by using intermediate 4-4 and 2-(4,4-bis(ethoxymethyl)cyclohex-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane. LCMS: (ESI) m / z = 417.4 [M+H] + ; 1 H NMR (400 MHz, D20) 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), 1.63-1.75 (m, 2H), 1.48-1.58 (m, 2H), 1.33-1.46 (m, 2H), 1.20 (t, 3H), 1.16 (t, 3H)

[0207] ​ ​

[0208]

[0209] The synthesis of compound P167 was performed according to Example 4 by using intermediate 4-5 and intermediate A. LCMS: (ESI) m / z = 399.2 [M+H] + ; 1 H NMR (400 MHz, D20) 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), 1.63-1.75 (m, 2H), 1.48-1.58 (m, 2H), 1.33-1.46 (m, 2H), 1.20 (t, 3H), 1.16 (t, 3H)

[0210] ​ Synthesis of N2-dimethylethane-1,2-diamine (P293)

[0211]

[0212] The synthesis method of compound P293 is referred to the synthesis method of Example 3, which is synthesized from intermediate 3-2 and 2-(4,4-bis(ethoxymethyl)cyclohex-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane. LCMS: (ESI) m / z = 393.3 [M+H] + ; 1 H NMR (400 MHz, CD3OD) d (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)

[0213] Example 10: Synthesis of N1-((2-(2,3-difluoro-6,7,8,9-tetrahydro-5H- benzo[7]cyclopenta-7-yl-6-methylpyridin-3-yl)methyl)-N1,N2-dimethylethane-1,2- diamine (P038) Example 11: Synthesis of compound N,N'-dimethyl-N'-[[2-morpholino-4-[1-(m- tolyl)-4-piperidinyl]-1H-benzo[d]imidazol-5-yl]methyl]ethane-1,2-diamine (P406):

[0214]

[0215] Compound P038 was synthesized by the synthetic method of Example 2 from intermediate 2-2 and intermediate A. LCMS: (ESI) m / z = 374.2 [M+H] + ; 1 H NMR (400 MHz, D2O) d (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)

[0216] Example 12: Synthesis of compound 5-((methyl(2-(methylamino)ethyl)amino)methyl)- 4-(1-m-tolylpiperidin-4-yl)indolin-2-one (P180): Example 13: Synthesis of compound N-((5-amino-3-(1-(m-tolyl)piperidin-4-yl)pyrazin- 2-yl)methyl)-N,N'-dimethyl-1,2-ethanediamine (P407):

[0217]

[0218] 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) was heated to reflux for about 2 hours until the starting material 11-1 was consumed. The reaction mixture was cooled and poured into 3600 mL of water. The precipitate was filtered, dried in vacuum, dissolved in ethyl acetate, washed with water, saturated brine, and extracted with ethyl acetate. The organic phase was dried over anhydrous magnesium sulfate. The filtrate was concentrated and purified by silica gel column chromatography to give 2-nitro-3-bromo-4-iodoaniline (11-2) as a brown solid (178 g). 1 H NMR (400 MHz, DMSO-d6) δ (ppm) 7.66 (d, 1H), 6.70 (d, 1H), 6.23 (s, 2H).

[0219] Step 2: Compound 2-nitro-3-bromo-4-iodoaniline (11-2) (80.0 g, 233.29 mmol) was dissolved in a mixture of tetrahydrofuran (640 mL) / ethanol (640 mL) / water (320 mL). NH4Cl (187 g, 3.50 mol) was added. The mixture was heated to 90 °C and iron powder (52.1 g, 933.17 mmol) was added portionwise. The reaction was continued for 2 hours until it was complete. The reaction mixture was cooled to 60 °C and celite was added. The mixture was stirred for 10 minutes and then cooled to room temperature. The mixture was filtered. The filtrate was extracted with ethyl acetate. The organic phase was dried over anhydrous magnesium sulfate. The filtrate was concentrated and dissolved in a large amount of ethyl acetate. The solution was washed with saturated brine. The organic phase was dried over anhydrous magnesium sulfate, filtered and concentrated to give 3-bromo-4-iodo- o-phenylenediamine (11-3) as a brown solid (73.8 g, 224.04 mmol, 96.03% yield, 95% purity). The product was used in the next step without further purification. + ; 1 H NMR (400 MHz, DMSO-d6) δ (ppm) 6.92 (d, 1H), 6.35 (d, 1H), 4.99 (s, 2H), 4.90 (s, 2H).

[0220] Step 3: Compound 3-bromo-4-iodo-o-phenylenediamine (11-3) (35.0 g, 111.85 mmol) was dissolved in tetrahydrofuran (350 mL) and cooled in an ice water bath. Carbonyldiimidazole (27.2 g, 167.77 mmol) was added. The reaction mixture was allowed to warm to room temperature and stirred for about 2 hours until it was complete. The reaction mixture was concentrated and slurried in water (500 mL) for half an hour. The mixture was filtered and lyophilized to give 4-bromo-5-iodo-1,3-dihydro-2H- benzo[d]imidazol-2-one (11-4) as a brown solid (37.8 g, 111.53 mmol, 99.72% yield). The product was used in the next step without further purification. 1H NMR (400 MHz, DMSO-d6) d (ppm) 11.12 (s, 1H), 11.02 (s, 1H), 7.47 (d, 1H), 6.75 (d, 1H).

[0221] Step 4: Compound 4-bromo-5-iodo-l,3-dihydro-2H-benzo[d]imidazol-2-one (11-4) (28.0 g, 82.61 mmol) was carefully added to phosphorus oxychloride (130 mL) and the mixture was heated to 100 °C for 3 h, then heated to 120 °C for 16 h, the reaction was almost complete. After cooling to room temperature, it was distilled to half volume under pressure. After carefully pouring into 2 L of ice water, it was stirred and the pH was carefully adjusted to 8 with potassium carbonate, a brown solid was precipitated and filtered and dried to give the crude product 2-chloro-4-bromo-5-iodo-lH- benzo[d]imidazole (11-5) (30.0 g, crude), without further purification, it was used directly in the next step. LCMS: (ESI) m / z = 358.9 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) d (ppm) 13.77 (br s, 1H), 7.72 (d, 1H), 7.32 (br d, 1H).

[0222] Step 5: To a suspension of compound 2-chloro-4-bromo-5-iodo-lH-benzo[d]imidazole (11-5) (30.0 g, 83.95 mmol, 2.05 mL) in isopropanol (150 mL) and tetrahydrofuran (150 mL) was added morpholine (37.0 g, 424.70 mmol, 37.37 mL). The mixture was heated to 90 °C for 4 days, after the starting material was completely converted, it was cooled to room temperature, the organic solvent was removed by rotary evaporation, then it was slurried in water (300 mL), the solid was filtered and purified by silica gel column chromatography to give a brown sticky liquid, which was slurried in ethanol to give 30.1 g of yellow solid crude product, further recrystallization from ethanol gave white solid 2-(4-morpholinyl)-4-bromo-5-iodo-lH-benzo[d]imidazole (11-6) (15.5 g, 37.99 mmol, 45.25% yield). LCMS: (ESI) m / z = 407.9, 409.9 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) d (ppm) 11.82 (s, 0.85H), 11.40 (s, 0.15H), 7.48 (d, 0.15H), 7.40 (d, 0.85H), 6.97 - 7.05 (m, 1H), 3.65 - 3.81 (m, 4H), 3.44 - 3.59 (m, 4H),

[0223] Step 6: 2-(4-Morpholinyl)-4-bromo-5-iodo-lH-benzo[d]imidazole (11-6) (15.5 g, 37.99 mmol) was added to a solution of sodium ethoxide in ethanol (20% purity, 180 mL). After the reaction solution was deoxygenated, CO (balloon) was introduced for 3 times, Pd(dppf)Cl2(1.11 g, 1.52 mmol) was added, and the system was deoxygenated again and replaced with CO for 3 times; the system was heated to 45 °C for 16 h. After cooling in an ice water bath, acetic acid (8 mL, pH = 6-7) was carefully added to quench the reaction. After concentration, the product was diluted with ethyl acetate, washed with saturated sodium bicarbonate, and brine; the organic phase was dried over anhydrous magnesium sulfate, filtered, concentrated, and purified by silica gel column chromatography to give 4-bromo-2-(4-morpholinyl)-lH-benzo[d]imidazole-5-carboxylic acid ethyl ester (11-7) as a light yellow amorphous solid (16.5 g, 46.58 mmol, 77.12% yield). LCMS: (ESI) m / z = 356.0 [M+H] +

[0224] Step 7: Compound 4-bromo-2-(4-morpholinyl)-lH-benzo[d]imidazole-5-carboxylic acid ethyl ester (11-7) (16.5 g, 46.58 mmol), 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l-(m-tolyl)-l,2,3,6-tetrahydropyridine (Intermediate B) (15.3 g, 51.24 mmol), and potassium phosphate (19.8 g, 93.17 mmol) were added to tetrahydrofuran (165 mL) and water (33 mL), the reaction was deoxygenated, XPhos-PD-G2 (1.10 g, 1.40 mmol) was added, and the reaction was heated at 65 °C for 5 h under nitrogen protection. The reaction solution was cooled to 40 °C, and sodium diethylaminomethylthiothiolate (997.25 mg, 5.82 mmol) was added, and the stirring was continued for 1 h. The reaction was diluted with water (200 mL), extracted with ethyl acetate, and the organic phase was dried over anhydrous magnesium sulfate, filtered, concentrated, and the crude product was purified by silica gel column chromatography to give 2-(4-morpholinyl)-4-(l-m-tolyl-l,2,3,6-tetrahydropyridin-4-yl)-lH-benzo[d]imidazole-5-carboxylic acid ethyl ester (11-8) as a yellow solid (18.5 g, 41.43 mmol, 88.94% yield). LCMS: (ESI) m / z = 447.3 [M+H] + ; 1H NMR (400 MHz, CDC13) 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)

[0225] Step 8: To a suspension of compound ethyl 2-(4-morpholinyl)-4-(1-m-methylphenyl- 1,2,3,6-tetrahydropyridin-4-yl)-1H-benzo[d]imidazole-5-carboxylate (11-8) (18.5 g, 41.43 mmol) in tetrahydrofuran (600 mL) was added Pd(OH)2 / C (7.0 g, 41.43 mmol, 10% purity), after hydrogen gas displacement, the reaction was stirred at 30 °C under hydrogen gas atmosphere (balloon) for 16 h. The reaction was almost complete. The mixture was filtered, the filter cake was washed with tetrahydrofuran (200 mL*2), the combined filtrate was concentrated to dryness to give the crude ethyl 2-(4-morpholinyl)-4-(1-m-methylphenyl-4-piperidinyl)-3H- benzo[d]imidazole-5-carboxylate (11-9) (19 g). It was used in the next step without further purification. LCMS: (ESI) m / z = 449.3 [M+H] + ;

[0226] Step 9: Ethyl 2-(4-morpholinyl)-4-(1-m-methylphenyl-4-piperidinyl)-3H- benzo[d]imidazole-5-carboxylate (11-9) (19 g, 42.36 mmol) was dissolved in CH3CN (550 mL), cesium carbonate (69.0 g, 211.79 mmol) was added, then SEM-Cl (19 g, 113.96 mmol, 20.17 mL) was added dropwise with stirring. The reaction mixture was stirred at 30 °C for 24 h. The reaction was almost complete. The mixture was filtered, washed with ethyl acetate, the combined organic phase was concentrated, then purified by silica gel column chromatography to give compound ethyl 2-(4-morpholinyl)-4-(1-m-methylphenyl-4-piperidinyl)-1-(2- trimethylsilylethoxymethyliden)benzo[d]imidazole-5-carboxylate (11-10) (22.3 g, 38.53 mmol, 90.96% yield) as colorless oil. LCMS: (ESI) m / z = 580.2 [M+H] + ; 1H NMR (400 MHz, CDC13) 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)

[0227] Step 10: To a solution of lithium aluminum hydride (3.0 g, 79.05 mmol, 79.05 mL) in tetrahydrofuran (300 mL) was added dropwise a solution of compound ethyl 2-(4-morpholinyl)-4-(1-m- tolyl-4-piperidinyl)-1-(2-trimethylsilylethoxymethylene)benzo[d]imidazole-5-carboxylate (11-10) (22.0 g, 38.01 mmol) in tetrahydrofuran (100 mL) under ice water bath cooling. After the addition was completed, the reaction was gradually returned to room temperature and heated to 30 °C for 1 h. The reaction was almost complete. The reaction was quenched by careful dropwise addition of 3 mL of water, 3 mL of 15% sodium hydroxide aqueous solution, and 6 mL of water under ice water bath cooling, respectively. The reaction was then dried by stirring with anhydrous magnesium sulfate for 15 min at room temperature. After filtration, the organic phase was concentrated to give the crude product 2-(4-morpholinyl)-4-(1-m-tolyl-4-piperidinyl)-1-(2- trimethylsilylethoxymethylene)benzo[d]imidazole-5-methanol (11-11) (19.3 g, 35.96 mmol, 94.60% yield) as a colorless viscous liquid. Without further purification, it was used directly in the next step. LCMS: (ESI) m / z = 537.3 [M+H] + ; 1 H NMR (400 MHz, CDC13) 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)

[0228] Step 11 : To a solution of compound 2-(4-morpholinyl)-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) was added DMP (9.01 g, 21.24 mmol, 6.58 mL) and the reaction was stirred at 30 °C for half an hour. The reaction was almost complete. 100 mL of saturated sodium bicarbonate and 100 mL of sodium thiosulfate were added and stirred for 30 minutes. The organic phase was dried over anhydrous magnesium sulfate after extraction with dichloromethane. After filtration, concentration and purification on silica gel column, compound 2-(4-morpholinyl)-4-(1-m-methylphenyl-4-piperidinyl)-1-(2- trimethylsilylethoxymethylene)benzo[d]imidazole-5-carbaldehyde (11-12) was obtained as a white amorphous solid (11.7 g, 21.88 mmol, 61.81% yield). LCMS: (ESI) m / z = 535.3 [M+H] + ; 1 H NMR (400 MHz, CDC13) 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)

[0229] Step 12: Compound 2-(4-morpholinyl)-4-(1-m-tolyl-4-piperidinyl)-1-(2- trimethylsilylethoxymethylenyl)benzo[d]imidazole-5-carboxaldehyde (11-12) (10.7 g, 20.01 mmol) and tert-butyl N-methyl-N-[2-(methylamino)ethyl]carbamate (4.52 g, 24.01 mmol) were dissolved in 150 mL of dichloromethane, acetic acid (1.44 g, 24.01 mmol, 1.37 mL) was added, the reaction was stirred at 30 °C for 1 h, sodium borohydride (12.7 g, 60.03 mmol) was added in portions, and stirred at 30 °C for 15 h. The reaction was almost complete, 100 mL of saturated aqueous sodium bicarbonate solution was added carefully to quench the reaction, and stirred for 1 h. The organic phase was extracted with dichloromethane, the combined organic phase was dried over anhydrous magnesium sulfate, filtered, concentrated, and purified by silica gel column chromatography to give the product tert-butyl N-tert-butoxycarbonyl-N,N'-dimethyl-N'-[[2-morpholin-4-yl-1-(m-tolyl)-4- piperidinyl]methyl]ethane-1,2-diamine (11-13) (10.6 g, 14.99 mmol, 68.12% yield) and the by-product product 2-(4-morpholinyl)-4-(1-m-tolyl-4-piperidinyl)-1-(2- trimethylsilylethoxymethylenyl)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 (400 MHz, CDC13) 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)

[0230] Step 13: Compound N-tert-butoxycarbonyl-N,N'-dimethyl-N'-[[2-morpholin-4-yl- 1 -(m-tolyl)-4-piperidinyl]methyl]ethane-1,2-diamine (11-13) (10.6 g, 14.99 mmol) was dissolved in 50 mL of 1,4-dioxane, HCl / dioxane (50 mL) solution was added and stirred at 70 °C for 2 h, a white solid precipitated. After cooling to room temperature, 10 mL of methanol was added, concentrated, 50 mL of methanol was added, 500 mL of isopropyl ether was added dropwise with stirring, a white precipitate was precipitated, after continuing to stir and slurry at room temperature for 16 h, filtration, freeze-drying gave white solid N,N'-dimethyl-N'-[[2-morpholin-4-yl-1-(m-tolyl)-4-piperidinyl]methyl]ethane-1,2-diamine hydrochloride (quantitative determination of hydrochloride coefficient is 4). LCMS: (ESI) m / z = 477.3 [M+H] + ; 1 H NMR (400 MHz, D20) d (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)

[0231] To N,N'-dimethyl-N'-[[2-morpholin-4-yl-1-(m-tolyl)-4-piperidinyl]methyl]ethane-1,2-diamine hydrochloride (400 mg) was added 5 mL of water, then a saturated aqueous sodium carbonate solution was added dropwise to adjust the pH to 8-10, then extracted with ethyl acetate, the organic phase was washed with saturated brine and dried over anhydrous magnesium sulfate, filtered, concentrated, and the crude product was freeze-dried to give a light yellow free compound N,N'-dimethyl-N'-[[2-morpholin-4-yl-1-(m-tolyl)-4-piperidinyl]methyl]ethane-1,2-diamine (P406, Example 11 ) (270 mg, 0.566 mmol, 88.15% yield). LCMS: (ESI) m / z = 477.3 [M+H] + ; 1H NMR (400 MHz, DMSO-d6) d (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)

[0232] Synthesis of N,N'-dimethyl-1,2-ethanediamine (P292): Compound

[0233]

[0234] Step 1: Compound 4-bromoindolin-2-one (12-1) (2.00 g, 9.43 mmol), 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-l(2H)-carboxylic acid tert-butyl ester (2.92 g, 9.43 mmol) and potassium phosphate (6.01 g, 28.30 mmol) were added to a mixture of 100 mL of tetrahydrofuran and 20 mL of water, purged with nitrogen, and Xphos Pd G3 (239 mg, 0.28 mmol) was added. After purging with nitrogen again, the reaction was heated to 65 °C with stirring under nitrogen for 2 hours. The reaction was diluted with saturated brine and extracted with ethyl acetate; the combined organic phase was dried over anhydrous magnesium sulfate, filtered, concentrated, and the crude product was purified by silica gel column chromatography to give brown solid compound 4-(l-tert-butoxycarbonyl-l,2,3,6-tetrahydropyridin-4-yl)-indolin-2-one (12-2) (2.8 g, 8.91 mmol, 94.43% yield). LCMS: (ESI) m / z = 214.9 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) d (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)

[0235] Step 2: To a solution of compound 4-(l-tert-butoxycarbonyl-l,2,3,6-tetrahydropyridin-4- yl)-lH-indol-2-one (12-2) (2.30 g, 7.32 mmol) in 50 mL of methanol, nitrogen was bubbled through the solution for 10 min, then 10% palladium-carbon (460 mg, 0.43 mmol) was added. The reaction mixture was then hydrogenated by bubbling hydrogen gas through the solution for 10 min, and stirred at room temperature under a hydrogen atmosphere (balloon) for 16 h. The reaction was essentially complete, and the mixture was filtered and concentrated to give a yellow crude product 4-(l-tert-butoxycarbonyl-piperidin-4-yl)-lH-indol-2-one (12-3) (2.2 g, 6.95 mmol, 95.04% yield), which was used in the next step without further purification. LCMS: (ESI) m / z = 216.9 [M+H] + ; 1 H NMR (400 MHz, CDC13) 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).

[0236] Step 3: To a solution of crude product 4-(l-tert-butoxycarbonyl-piperidin-4-yl)-lH-indol-2- one (12-3) (3.70 g, 11.69 mmol) in 100 mL of dichloromethane, N-bromosuccinimide (2.29 g, 12.86 mmol, 1.1 eq) was added in portions. The reaction mixture was stirred at room temperature for 16 h, and the reaction was essentially complete. The reaction mixture was carefully added to 50 mL of 15% aqueous potassium carbonate solution with stirring, and the organic phase was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated to give a white solid crude product 4-(l-tert-butoxycarbonyl-piperidin-4-yl)-5-bromo-lH-indol-2-one (12-4) (3.60 g, 9.11 mmol, 77.88% yield), which was used in the next step without further purification. 1 H NMR (400 MHz, CDC13) δ (ppm) 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).

[0237] Step 4: The crude product 4-(l-tert-butoxycarbonyl-piperidin-4-yl)-5-bromo- indolin-2-one (12-4) (3.60 g, 9.11 mmol) was dissolved in 20 mL of 1,4- dioxane, then 20 mL of 4 M concentration hydrochloric acid-1,4-dioxane solution was added. The reaction was stirred at room temperature for 16 hours and was almost complete. After filtration, the filter cake was washed with methyl tert-butyl ether. Concentration and drying gave the white crude product 5-bromo-4-(piperidin-4-yl)indolin-2-one (12-5) hydrochloride (3.00 g, 9.05 mmol, 99.33% yield), which was used directly in the next step without further purification. LCMS: (ESI) m / z = 295.0 [M+H] + ; 1 H NMR (400 MHz, D20) 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).

[0238] Step 5: To a stirred suspension of compound 5-bromo-4-(piperidin-4-yl)indolin-2- one (12-5) hydrochloride (1.90 g, 5.73 mmol) in acetonitrile (20 mL) was added N,N- diisopropylethylamine (1.55 g, 12.03 mmol, 2.10 mL), followed by dropwise addition of (4-nitrophenyl)2-trimethylsilylethyl carbonate (1.79 g, 6.30 mmol). After the reaction was stirred at room temperature for 15 hours, it was filtered, the filter cake was washed with acetonitrile, and the combined mother liquor was concentrated and purified on a silica gel column to give 5-bromo-4-(l- trimethylsilylethoxycarbonyl-piperidin-4-yl)-indolin-2-one (12-6) (2.50 g, 5.40 mmol, 94.34% yield, 95% purity) as a yellow solid. LCMS: (ESI) m / z = 413.1 [M-2Me+H] +

[0239] Step 6: To a mixture of compound 5-bromo-4-(l-trimethylsilylethoxycarbonyl-piperidin-4-yl)- indolin-2-one (12-6) (2.00 g, 4.55 mmol), anhydrous [2-(tert-butoxycarbonylmethylamino)ethyl] (methyl)amino] methyl potassium trifluoroborate (4.21 g, 13.65 mmol), potassium phosphate (2.90 g, 13.65 mmol), and Ruphos Pd G2 (353 mg, 0.455 mmol) was added 40 mL of tetrahydrofuran, 4 mL of water, purged with nitrogen, heated to 80 °C under nitrogen for 16 h. The reaction was substantially complete. After cooling to room temperature, 30 mL of saturated brine was added, and the organic phase was dried over anhydrous magnesium sulfate, filtered, concentrated, and purified by silica gel column chromatography to give compound 2-trimethylsilylethyl-4-(5-(((2-((tert- butoxycarbonyl)(methyl)amino)ethyl)(methyl)amino)methyl-2-oxoindolin-4-yl)piperidin-l- yl)carboxylate (12-7) (2.8 g, 4.49 mmol, 98.73% yield, 90% purity) as a yellow viscous liquid. LCMS: (ESI) m / z = 561.5 [M+H] + .

[0240] Step 7: To a mixture of compound 2-trimethylsilylethyl-4-(5-(((2-((tert- butoxycarbonyl)(methyl)amino)ethyl)(methyl)amino)methyl-2-oxoindolin-4-yl)piperidin-l- yl)carboxylate (12-7) (1.50 g, 2.41 mmol, 90% purity) and cesium carbonate (5.00 g, 15.35 mmol) was added 20 mL of acetonitrile and stirred for 3 h. To this was added 4-methoxybenzyl chloride (565 mg, 3.61 mmol, 0.49 mL) dropwise, and the reaction was stirred at room temperature for 1 h. The reaction was substantially complete. The reaction was filtered, concentrated, and purified by silica gel column chromatography to give compound 2-trimethylsilylethyl-4-(5-(((2-((tert- butoxycarbonyl)(methyl)amino)ethyl)(methyl)amino)methyl-l-(4-methoxybenzyl)-2,3-dioxoindolin- 4-yl)piperidin-l-yl)carboxylate (12-8) (1.32 g, 1.46 mmol, 60.76% yield, 77% purity) as a yellow solid. LCMS: (ESI) m / z = 695.6 [M+H] + .

[0241] Step 8: To a solution of compound tert-butyl (2-(((l-(4-methoxybenzyl)-2,3-dioxo-4- (piperidin-4-yl)indolin-5-yl)methyl)(methyl)amino)ethyl)(methyl)carbamate (12-9) (1.30 g, 2.36 mmol) in 20 mL of toluene was added cesium carbonate (1.54 g, 4.72 mmol) and the mixture was stirred at 100 °C for 16 h. The reaction was complete. The reaction mixture was filtered and concentrated. The residue was purified by silica gel column chromatography to give compound tert-butyl (2-(((l-(4-methoxybenzyl)-2,3-dioxo-4-(l-m-tolylpiperidin-4- yl)indolin-5-yl)methyl)(methyl)amino)ethyl)(methyl)carbamate (12-10) (900 mg, 1.40 mmol, 59.49% yield, 100% purity) as orange solid. LCMS: (ESI) m / z = 641.4 [M+H] + .

[0242] Step 9: To a mixture of compound tert-butyl (2-(((l-(4-methoxybenzyl)-2,3-dioxo-4- (piperidin-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) was added 20 mL of toluene, and the mixture was stirred under nitrogen. Then, RuPhos Pd G3 (200 mg, 0.24 mmol) was added, and the mixture was stirred under nitrogen at 100 °C for 16 h. The reaction was complete. The reaction mixture was filtered and concentrated. The residue was purified by silica gel column chromatography to give compound tert-butyl (2-(((l-(4-methoxybenzyl)-2,3-dioxo-4-(l-m-tolylpiperidin-4- yl)indolin-5-yl)methyl)(methyl)amino)ethyl)(methyl)carbamate (12-10) (900 mg, 1.40 mmol, 59.49% yield, 100% purity) as orange solid. LCMS: (ESI) m / z = 641.4 [M+H] + . 1H NMR (400 MHz, CD3OD) δ (ppm) 7.45 (br s, 1 H), 7.33 (br d, 2 H), 7.13 (t, 1 H), 6.72 - 6.94 (m, 5 H), 6.67 (d, 1 H), 3.68 - 3.91 (m, 5 H), 3.52 (s, 2 H), 3.25 - 3.40 (m, 5 H), 2.67 - 2.91 (m, 4 H), 2.37 - 2.67 (m, 4 H), 2.09 - 2.36 (m, 7 H), 1.60 (br d, 2 H), 1.17 - 1.41 (m, 9 H).

[0243] Step 10: Compound tert-butyl (2-(((1-(4-methoxybenzyl)-2,3-dioxo-4-(1-m- tolyl piperidin-4-yl)indolin-5-yl)methyl)(methyl)amino)ethyl)(methyl)carbamate (12-10) (190 mg, 0.30 mmol) was dissolved in 5 mL of ethanol, hydrazine hydrate (5.15 g, 87.44 mmol, 5.00 mL, 85% purity) and potassium hydroxide (332 mg, 5.93 mmol) were added. The mixture was heated to 80 °C and stirred for 3 hours, the reaction was almost complete. After most of the ethanol was removed by concentration, the aqueous phase was extracted with ethyl acetate, the combined organic phase was dried over anhydrous magnesium sulfate, filtered, concentrated to give the crude product tert-butyl (2-(((1-(4-methoxybenzyl)-2-oxo-4-(1-m-tolyl piperidin-4-yl)indolin-5- yl)methyl)(methyl)amino)ethyl)(methyl)carbamate (12-11) (220 mg) as a yellow viscous liquid, which was used in the next step without further purification. LCMS: (ESI) m / z = 627.5 [M+H] + .

[0244] Step 11: tert-butyl (2-(((1-(4-methoxybenzyl)-2-oxo-4-(1-m-tolylpiperidin-4- yl)indolin-5-yl)methyl)(methyl)amino)ethyl)(methyl)carbamate (12-11) (220 mg, 0.32 mmol, 92% purity) was dissolved in 5 mL of trifluoroacetic acid, then trifluoromethanesulfonic acid (200 mg, 1.33 mmol, 0.12 mL) was added dropwise with stirring at room temperature for 5 hours, then heated to 40 °C for 30 hours, and the reaction was substantially complete. The reaction solution was concentrated and diluted with 5 mL of dichloromethane, extracted with 0.5 M aqueous hydrochloric acid. The aqueous phase was combined and adjusted to pH 12 with 1 M aqueous sodium hydroxide solution, then extracted with dichloromethane. The combined organic phase was dried over anhydrous magnesium sulfate, filtered, and concentrated to give the free base product 5-((methyl(2-(methylamino)ethyl)amino)methyl)-4-(1-m-tolylpiperidin-4-yl)indolin-2-one (P180). This product was dissolved in 2 mL of 1,4-dioxane, then 2 mL of 4 M hydrochloric acid-1,4-dioxane solution was added dropwise with stirring. Concentration and lyophilization gave 5-((methyl(2-(methylamino)ethyl)amino)methyl)-4-(1-m-tolylpiperidin-4-yl)indolin-2-one (P180, Example 12) hydrochloride as a white solid (80 mg, 48.12% yield, quantified hydrochloride salt factor 3). LCMS: (ESI) m / z = 407.3 [M+H] + . 1 H NMR (400 MHz, 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).

[0245] PRMT3 PRMT4

[0246]

[0247] Step 1 : Compound 2-cyano-3,5-dichloropyrazine (13-1) (145 g, 833.39 mmol) was dissolved in 1000 mL of N,N-dimethylformamide, then dropwise added diisopropylethylamine (109 g, 843.37 mmol, 146.90 mL) at room temperature. Then cooled to 5-10 degrees, then dropwise added a solution of di(4-methoxybenzyl)amine (217.50 g, 845.23 mmol) in 500 mL of N,N-dimethylformamide to it under stirring. Slowly warmed to room temperature, continue stirring for 3 hours, the reaction is substantially complete. Pour the reaction into 5000 mL of ice water mixture, stirring for 5 minutes, precipitate solid. After filtration, the solid was dissolved in 4000 mL of ethyl acetate, then washed with saturated brine, the organic phase was dried over anhydrous magnesium sulfate, filtered, concentrated, then the crude product was slurried in 700 mL of methyl tert-butyl ether at 20 degrees for 16 hours, filtered and dried the yellow solid compound 2-cyano-3-chloro-5-(di(4-methoxybenzyl)amino)pyrazine (13-2), without further purification, directly used in the next step reaction. 1 H NMR (400 MHz, CDC13) 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).

[0248] Step 2: Compound 2-cyano-3-chloro-5-(di(4-methoxybenzyl)amino)pyrazine (13-2) was dissolved in 600 mL of tetrahydrofuran, cooled to minus 78 degrees under nitrogen protection, then dropwise added DIBALH (1 mole / liter, 548 mL) under stirring, then continue stirring for 2 hours until the reaction is substantially complete. Carefully added 500 mL of 10% acetic acid aqueous solution under stirring at minus 78 degrees to quench the reaction, slowly warmed to room temperature, filtered through diatomite and washed with ethyl acetate, the filtrate was extracted with ethyl acetate, the combined organic phase was adjusted to pH 8-9 with saturated sodium bicarbonate aqueous solution, separated the organic phase, washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, concentrated, then the product was slurried in methyl tert-butyl ether / petroleum ether (volume ratio 1:2) for 3 hours to obtain yellow solid crude product 5-(di(4-methoxybenzyl)amino)-3-chloro-pyrazine-2-carbaldehyde (13-3) (100 g, 252.35 mmol, 92.69% yield), directly used in the next step reaction. 1 H NMR (400 MHz, CDC13) 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).

[0249] Step 3: To a solution of compound 5-(di(4-methoxybenzyl)amino)-3-chloro-pyrazine-2- carboxaldehyde (13-3) (53.0 g, 133.21 mmol), N-tert-butoxycarbonyl-N,N'- dimethylethylenediamine (30.0 g, 159.35 mmol) in 1000 mL of dichloromethane, acetic acid (9.60 g, 159.86 mmol, 9.14 mL) was added, followed by the addition of sodium borohydride (71.0 g, 335.00 mmol) in portions at room temperature. The reaction was stirred for 2 h, then quenched by the careful addition of 1000 mL of saturated aqueous sodium carbonate solution. The reaction mixture was extracted with ethyl acetate, and the organic phase was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, concentrated, and purified by silica gel column chromatography to give compound tert-butyl (2-((((5-(di(4-methoxybenzyl)amino)-3-chloropyrazin-2-yl)(methyl)amino)ethyl)(methyl)carbamate (13-4) (112 g, 196.45 mmol, 73.73% yield) as a yellow viscous liquid. The crude product was used in the next step without further purification. 1 H NMR (400 MHz, CDC13) 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).

[0250] Step 4: A mixture of tert-butyl (2-((((5-(di(4-methoxybenzyl)amino)-3- chloropyrazin-2-yl)(methyl)amino)ethyl)(methyl)carbamate (13-4) (37 g, 64.90 mmol), 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l-(m-tolyl)-l,2,3,6-tetrahydropyridine (Intermediate B) (25 g, 83.55 mmol) and potassium phosphate (35 g, 164.89 mmol) was taken up in tetrahydrofuran (250 mL) and water (50 mL), purged with nitrogen and XPhos-Pd-G2 (1.65 g, 1.95 mmol) was added. The reaction was stirred at 65 °C under nitrogen for 16 h. The reaction was substantially complete. The mixture was diluted with 500 mL of saturated brine and extracted with ethyl acetate. The organic phase was dried over anhydrous magnesium sulfate, filtered, concentrated and dissolved in 500 mL of methyl tert-butyl ether. The solution was washed with 10% aqueous phosphoric acid (150 mL x 3) and the aqueous phase was adjusted to pH 13-14 with 10-15% aqueous sodium hydroxide solution. The organic phase was dried over anhydrous magnesium sulfate, filtered, concentrated and 101 g of crude tert-butyl (2-(((5-(di(4-methoxybenzyl)amino)-3-(l-(m-tolyl)-l,2,3,6- tetrahydropyridin-4-yl)pyrazin-2-yl)methyl)(methyl)amino)ethyl)(methyl)carbamate (13-5) was obtained as a brownish viscous material which was used directly in the next step. 1 H NMR (400 MHz, CDC13) 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).

[0251] Step 5: To compound tert-butyl (2-(((5-(di(4-methoxybenzyl)amino)-3-(1-(m- methylphenyl)-1,2,3,6-tetrahydropyridin-4-yl)pyrazin-2-yl)methyl)(methyl)amino)ethyl)(methyl)carbamate (13-5) (46.5 g, 65.78 mmol) was dissolved in 600 mL of tetrahydrofuran and palladium on carbon (15 g, 21.36 mmol, 20% purity) was added under nitrogen. After purging with hydrogen, the reaction was stirred at room temperature under a hydrogen atmosphere (balloon) for 4 days. After filtration, the crude product was concentrated and purified by silica gel column chromatography to give compound tert-butyl (2-(((5-(di(4-methoxybenzyl)amino)-3-(1-(m- methylphenyl)piperidin-4-yl)pyrazin-2-yl)methyl)(methyl)amino)ethyl)(methyl)carbamate (13-6) as a yellow viscous liquid (83.5 g, 117.78 mmol, 89.53% yield). 1 H NMR (400 MHz, CDC13) 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).

[0252] Step 6: To compound tert-butyl (2-(((5-(di(4-methoxybenzyl)amino)-3-(1-(m- methylphenyl)piperidin-4-yl)pyrazin-2-yl)methyl)(methyl)amino)ethyl)(methyl)carbamate (13-6) (56 g, 78.99 mmol) was added 300 mL of trifluoroacetic acid followed by trifluoromethanesulfonic acid (30.0 g, 199.90 mmol, 17.65 mL). The reaction was stirred at room temperature for 16 hours and was essentially complete. The reaction was concentrated under reduced pressure, 1 L of water was added, and 2 L of ethyl acetate was added to dissolve the solids. After separation, the organic phase was extracted with 1 M hydrochloric acid solution, and the aqueous phase was neutralized to pH 9 with 30% sodium hydroxide aqueous solution. The organic phase was then extracted with ethyl acetate, dried, concentrated, and purified by silica gel column chromatography to give compound N-((5-amino-3-(1-(m- methylphenyl)piperidin-4-yl)pyrazin-2-yl)methyl)-N,N'-dimethyl-1,2-ethanediamine (P292, Example 13) as a white solid. LCMS: (ESI) m / z = 369.3 [M+H] + ; 1H NMR (400 MHz, methanol-d4) d (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).

[0253] Using similar methods described above, compounds P001-P448 were synthesized, and their characterization data are shown in the right column:

[0254]

[0255]

[0256]

[0257]

[0258]

[0259]

[0260]

[0261]

[0262]

[0263]

[0264]

[0265]

[0266]

[0267]

[0268]

[0269]

[0270]

[0271]

[0272]

[0273]

[0274]

[0275]

[0276]

[0277]

[0278]

[0279]

[0280]

[0281]

[0282]

[0283]

[0284] Biological test example

[0285] Test Example 1 PRMT1 enzyme activity test method

[0286] The PRMT1 enzyme activity assay was performed in a buffer prepared on the same day, consisting of 10 mM Tirs-HCl (pH 8.0), 0.01% Tween-20, and 1 mM DTT. The compound was prepared to the highest inhibitor concentration required for the final 100X reaction using 100% DMSO, and then transferred to one well of a 384-well Echo plate (Echo-qualified 384-well polypropylene microplate 2.0, clear, flat bottom) and subsequently diluted 3-fold with 100% DMSO in the next well, for a total of 10 concentrations based on precision. 100% DMSO was added to two empty wells as a control well without the compound and a control well without the enzyme in the same 384-well Echo plate. 250 nL of the compound was transferred from each well of the 384-well Echo plate to a 384-well assay plate (384-well polypropylene storage microplate) using an Echo 550 liquid processor. For control wells containing and without the compound, add 15 μL of the mixture containing the PRMT1 enzyme to the 384-well assay plate. For control wells without the enzyme, instead add 15 μL of the mixture containing the test buffer. Incubate the compound with PRMT1 at room temperature for 15 minutes, then add the mixture containing the test buffer. 3 A mixture of H-SAM and peptides (10 μL) was used to begin the reaction (final volume = 25 μL). The final concentrations of the components were as follows: PRMT1 was 0.5 nM. 3 The concentrations were 0.25 μM H-SAM, 0.1 μM peptide, and 1% DMSO. After incubation for 120 minutes, the assay was terminated by adding 5 μL of non-radioactively labeled SAM to a final concentration of 125 μM, which diluted the 3H-SAM to a level where its incorporation into the peptide substrate was no longer detectable. 25 μL of the reaction solution was then transferred from the 384-well assay plate to a 384-well assay plate (Streptavidin FlashPlate HTS PLUS, high capacity, 384 wells). The biotinylated peptide was allowed to bind to the streptavidin surface at room temperature for at least 60 minutes. The Flashplate was then washed three times with 0.1% Tween-20 in a BioTek plate washer. The plate was read on a microplate counter (MicroBeta2) to measure the amount of peptide bound to the assay plate surface. 3 The amount of H-labeled peptides was measured in counts per minute (cpm).

[0287] Curve fitting:

[0288] The raw data was copied from the Reader, and the inhibition rate values were calculated in Excel by equation (1): Inh% = (CPMmax - CPMcmpd) / (CPMmax - CPMmin)*100; Max signal was obtained by enzyme and substrate, and Min signal was obtained by substrate. The IC50 values were obtained by fitting the data by equation (2) using XLFit plug-in of Excel version 45.4.0.8. Equation (2): Y = Bottom + (Top - Bottom) / (1+((IC50 / X)*HillSlope)), where Y represents the percentage of inhibition, and X represents the compound concentration.

[0289] Test Example 2:

[0290] Toledo cell proliferation inhibition experiment method

[0291] A. Purpose: To determine the effect of the compound on Toledo cells through a six-day cell proliferation experiment

[0292] B. Reagents and materials:

[0293] 1. Cell culture medium: RPMI 1640 + 10% FBS

[0294] 2. 384-well cell culture plate (Corning, item # 3764)

[0295] 3. 0.4% trypan blue staining solution (Thermo, item # T10282)

[0296] 4. Cell counting plate (Thermo, item # C10228)

[0297] 5. 50ml reagent reservoir (Corning, item # 4870)

[0298] 6. 50ml conical sterile polypropylene centrifuge tube (Thermo, item # 339653)

[0299] 7. Automatic cell counter (Thermo, item # AMQAX1000)

[0300] 8. CellTiter-Glo Luminescent Cell Viability Assay Reagent (Promega, item # G7572)

[0301] 9. SpectraMax i3x Multi-Mode Microplate Reader (Molecular Devices, item # 5024062)

[0302] C. Experimental method

[0303] 1. Resuspend the cells with a pipette

[0304] 2. Mix equal volumes of 0.4% trypan blue stain and Toledo cells and count cells using an automated cell counter

[0305] 3. Dilute Toledo cells to a final concentration of 2000 cells per well and transfer to a 50ml reagent reservoir

[0306] 4. Add diluted Toledo cells to a 384 well cell culture plate at 40ul per well

[0307] 5. Briefly centrifuge to settle cells

[0308] 6. Incubate cells in a cell culture incubator at 37°C, 5% CO2

[0309] 7. Mix the substrate in the CellTiter-Glo luminescent cell viability assay reagent with the solution

[0310] 8. After six days remove the 384 well cell culture plate from the incubator and add 20ul of the prepared CellTiter-Glo reagent to each well

[0311] 9. Place the 384 well cell culture plate on an orbital shaker and mix for 30 minutes

[0312] 10. Measure the luminescent signal using a SpectraMax i3x multimode microplate reader

[0313] MV-4-11 cell proliferation inhibition assay method

[0314] Similar to the Toledo cell proliferation inhibition assay method, except that MV-4-11 cells are used and the cell culture medium is IMDM + 10% FBS; and 250 cells per well in step 3 of the assay method

[0315] The results are shown in the table below. PRMT1 enzyme activity assay results are shown in the table below:

[0316] A represents IC 50 < 50 nM;

[0317] B represents 50 nM <= IC 50 < 500 nM;

[0318] C represents IC 50 > = 500 nM

[0319] Toledo and MV-4-11 cell proliferation inhibition assay results:

[0320] A represents IC 50 < 1 uM;

[0321] B represents 1 uM <= IC 50< 5 uM;

[0322] C represents IC 50 > = 5 uM

[0323] PRMT1 enzyme activity test and Toledo, MV-4-11 cell proliferation inhibition test results are shown in the following table:

[0324]

[0325]

[0326]

[0327]

[0328]

[0329]

[0330] Test Example 3 PRMT panel selectivity test

[0331] The test method of PRMT1 is as in Test Example 1, and the test and data processing method of PRMT5, PRMT7 are referenced to the test and data processing method of PRMT1 using the optimized parameters. The test method of PRMT3 is as follows:

[0332] PRMT3 experimental method:

[0333] This assay was run in buffer prepared on the day of the experiment consisting of 10 mM Tris-HCl (pH=8.0), 0.01% Tween-20 and 1 mM DTT. Compounds were prepared in 100% DMSO to the highest inhibitor concentration needed in the final reaction and then transferred to one well of a 384-well Echo plate (Echo qualified 384-well polypropylene microplate 2.0, clear, flat bottom) and diluted in the next well with 3-fold dilutions of 100% DMSO, and so on, for a total of 10 concentrations with Precision. 100% DMSO was added to two empty wells as a control well with no compound and a control well with no enzyme in the same 384-well Echo plate. 100 nL of compound was transferred from each well of the 384-well Echo plate to a 384-well assay plate (OptiPlate (384-well, white)) by an Echo 550 liquid handler. For the wells with compound and the control well with no compound, a mixture containing PRMT3 enzyme (5 uL) was added to the 384-well assay plate. For the control well with no enzyme, a mixture containing assay buffer (5 uL) was added instead. The compound was allowed to incubate with PRMT3 for 15 minutes at room temperature before adding a mixture containing cold SAM and peptide (5 uL) to start the reaction (final volume = 10 uL). The final concentrations of the components were as follows: PRMT3 was 0.1 nM, SAM was 15 uM, peptide was 0.05 uM, and DMSO concentration was 1%. After incubation for 60 minutes at room temperature, the reaction was stopped by adding donor and acceptor magnetic beads (15 uL) diluted to a final concentration of 10 ug / mL in AlphaLISA Epigenetics Buffer. The 384-well assay plate was incubated for 60 min at room temperature before measuring the relative fluorescence units (RFU) using a multimode plate reader in Alpha mode (Ex 680 / Em 615).

[0334] Curve fitting: Inhibition values were calculated in Excel from Reader copy raw data by equation (1). Equation (1): Inh% = (RFUmax - RFUcmpd) / (RFUmax - RFUmin)*100, where Max signal is obtained by enzyme with substrate and Min signal is obtained by substrate. IC50 values were fitted by equation (2) using XLFit add-in version 45.4.0.8 in Excel. Equation (2): Y = Bottom + (Top - Bottom) / (1 + ((IC50 / X)*HillSlope)), where Y represents percent inhibition and X represents compound concentration.

[0335] PRMT4, PRMT6, PRMT8 testing and curve fitting reference PRMT3 testing and data processing methods were performed with optimized parameters.

[0336] The results of the PRMT panel selectivity test are shown in the table below, where A represents IC50< 50 nM;

[0337] B represents 50 nM <= IC 50 < 500 nM;

[0338] C represents IC 50 > = 10 uM

[0339] PRMT5 PRMT6 PRMT7 PRMT8 Patent_ID RKO ICW_EC30 Patent_ID P207 B A C A C A P023 A A C A C A P118 B B C A C A

[0340] Test Example 4 RKO in cell western experimental procedure

[0341] RKO were seeded into poly-lysine coated 96 well plates (Corning #3599) at a concentration of 20000 cells / ml, 2000 cells per well and 100 μL media. 500 nL of compound was added to the 96 well plate. 3) The 96 well plate was placed in a 37 °C, 5% carbon dioxide incubator for 72 hours. After three days the 96 well plate was removed from the incubator and 100 μL of 8% paraformaldehyde solution was added to each well and left for 15 minutes at room temperature. After 15 minutes the liquid was flicked off the plate and the plate was washed three times with phosphate buffered saline (1* PBS). The liquid was flicked off the plate and 200 μL of lysis buffer (0.1% (v / v) Tween-20 in PBS) was added and incubated on a shaker for 30 minutes. After half an hour the liquid was flicked off the plate and blocking buffer was added and incubated for two hours at room temperature with shaking. After this time the liquid was flicked off the plate and primary antibody containing blocking buffer (MMA primary antibody, CST #8711S, 1 : 1000 v / v) was added to the 96 well plate and incubated overnight at 4 °C with shaking. The following day the plate was washed three times with wash buffer (0.05% (v / v) Tween-20 in PBS) and secondary antibody containing blocking buffer (goat anti-rabbit IgG (H+L) Invitrogen #31460, 1 : 10000 v / v) was added and incubated for two hours at room temperature. After this time the plate was washed four times with wash buffer. TMB mix was added to the 96 well plate and incubated for 15 minutes at room temperature with shaking. After this time the reaction was stopped by the addition of stop solution and the OD450nm was read on a microplate reader. The plate was washed three times with wash buffer and 50 μL of kinaview was added and incubated for 15 minutes at room temperature with shaking. The plate was washed ten times with water until no colour remained and 200 μL of 0.5M hydrochloric acid solution was added to each well and incubated for 10 minutes at room temperature. The OD595nm was read on a Flexstation.

[0342] Calculation:

[0343] The ratio OD450 / OD595 was first calculated for each well

[0344] Each plate has 6 DMSO negative controls (ZPE) and 6 positive controls at 10 μM (HPE). The average of the control ratios is used to determine the percent activation for each test well. The test compound is diluted in DMSO in triplicate, with a total of 8 concentration points, starting at 5 μM. The percent activation for each test well is calculated as follows:

[0345] Percent Activation = 100 - [(HPE Ratio - Well Ratio) / (HPE Ratio - ZPE Ratio)] * 100

[0346] Table 4 RKO ICW Results

[0347] A represents EC30< 250 nM

[0348] B represents 250 nM < = EC30< 2500 nM

[0349] C represents EC30> 2500 nM

[0350] RKO ICW_EC30 Patent_ID RKO ICW_EC30 Patent_ID P001 B P118 A P003 A P122 C P004 B P130 B P005 B P131 B P007 A P136 B P008 B P137 B P009 B P141 B P014 B P142 B P015 B P143 B P021 A P147 B P022 A P148 B P023 A P149 B P025 A P153 A P039 B P157 B P044 B P158 A P049 A P165 B

[0351] RKO ICW_EC30 ​ ​ ​ P050 B P167 A P051 B P170 B P052 B P171 B P053 B P179 B P054 A P184 C P056 B P185 B P057 B P186 B P069 B P187 A P074 B P198 A P075 B P202 B P078 A P206 B P079 A P207 A P080 B P208 B P081 A P225 A P083 A P226 A P085 A P236 B P088 B P240 B P089 A P243 B P094 A P250 B P095 A P251 B P106 B P252 B P107 B P258 A P112 B P323 C P114 A P325 B

[0352] All documents referred to in this disclosure are incorporated by reference herein as if each were individually incorporated by reference. In addition, it is to be understood that the application can be carried out by specifically different embodiments and that these equivalents ypes do not depart from the spirit and scope of the application. Accordingly, other than in the Examples, or where otherwise indicated, all numbers expressing quantities of ingredients, reaction conditions, and so forth used in the specification and associated claims are to be understood as modified in all instances by the term "about." Accordingly, unless indicated to the contrary, the numerical parameters are approximations. While the numerical parameters are not critical to the preferred embodiments of the application, the preferred specific numerical parameters provide preferable operational limits for the application. As used herein, the expression "consisting essentially of permits the inclusion of additional ingredients or steps, provided they do not change the fundamental nature of the application.

Claims

1. A compound of the following Formula I: ###0001### or a pharmaceutically acceptable salt thereof. I X 1 and X 2 are each independently selected from the group consisting of CR, NR or N; X 3 and X 4 are each independently selected from CR' or N; the dotted line is a chemical bond or nothing; said A ring is selected from the group consisting of: ###0002### 、 、 、 、 wherein, when the connecting site to other structural fragments or substituents is NH, the hydrogen atom on NH is lost to form the connecting site; B ring is selected from the group consisting of C3-C 12 carbocyclic, 3-12 membered heterocyclic ring containing 1-3 heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen; m and n are each independently selected from the group consisting of 0, 1, 2, 3, or 4; L is selected from the group consisting of a direct bond, or -0-, -(CHR 6 ) p -0-, -CHR 6 -O-, or -NH-; p is selected from the group consisting of 1, 2 or 3; R 1 selected from the group consisting of substituted or unsubstituted C1-C4alkyl; R 2 is selected from the group consisting of H, substituted or unsubstituted C1-C4alkyl; and said R 1 , R 2 , wherein each of said substituted substitutents is independently selected from the group consisting of deuterium, halogen, C1-C2alkyl; R 3 R is selected from the group consisting of H, halogen, cyano, amino, hydroxyl, carboxyl, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6alkoxy, substituted or unsubstituted C1-C6alkylamino, substituted or unsubstituted 5-7 membered heterocycle containing 1-3 heteroatoms selected from oxygen, sulfur and nitrogen, substituted or unsubstituted C1-C6amido, substituted or unsubstituted C1-C4alkyl-S(O)2-; and said R 3 wherein said substituted substituent is selected from the group consisting of deuterium, halogen, hydroxyl, oxo (=0), cyano, unsubstituted or halogenated Ci-C6alkyl, Ci-C6alkoxy, or Ci-C6alkyl-aminyl; R is a group selected from the group consisting of H, halogen, amino, hydroxyl, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6alkoxy, substituted or unsubstituted C1-C6alkylamino, substituted or unsubstituted 4-7 membered heterocycle containing 1-3 heteroatoms selected from oxygen, sulfur and nitrogen, substituted or unsubstituted -C1-C6alkyl-phenyl, substituted or unsubstituted C6-C 10 substituted or unsubstituted C1-C6alkyl-S(O)2-; In the R, the substitution refers to the substitution of the hydrogen atom on the corresponding group by one or more substituents selected from the group consisting of: deuterium, halogen, hydroxyl, oxygen (=O), C1-C. 12 Alkoxycarbonyl, amino, C1-C6 amide, unsubstituted or halogenated C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkyl-amine, C1-C6 alkyl-sulfonamide, C1-C6 alkyl-urea, five- or six-membered non-aromatic heterocyclic groups; R' is a group selected from the group consisting of H, halogen, amino, hydroxyl, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C1-C6 alkylamino, substituted or unsubstituted C1-C6 acylamino; and in said R', the substituents are selected from the group consisting of deuterium, halogen, C1-C2 alkyl. or two R or R' located on adjacent ring atoms together with the ring atoms to which they are attached form a substituted or unsubstituted 5-11 membered carbocyclic or heterocyclic ring, said ring being partially unsaturated or saturated, or two adjacent ring atoms R or R' together with the ring atoms to which they are attached form a substituted or unsubstituted 5-9 membered aromatic carbocyclic or heterocyclic ring; said substitution means that a hydrogen atom in the respective group is replaced by one or more substituents selected from the group consisting of deuterium, halogen, hydroxy, oxygen (=0), amino, C1-C6 amido, unsubstituted or halogenated C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkyl- aminyl, C1-C6 alkyl-sulfonamidyl, C6-C10 aryl, five- or six-membered heteroaryl, five- or six-membered non-aromatic heterocyclyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, C1-C4 alkyl-S(O)2-; and 10 aryl, five- or six-membered heteroaryl, five- or six-membered non-aromatic heterocyclyl, unsubstituted or halogenated C2-C6 alkenyl, C1-C4 alkyl-S(O)2-; and 10 acyl, unsubstituted or halogenated C1-C4 alkyl-S(O)2-; R 4 R is selected from the group consisting of H, halogen, substituted or unsubstituted C1-C6alkyl, unsubstituted C1-C6alkoxy; said substituents are selected from the group consisting of deuterium, halogen, C1-C6alkoxy; R 6 is a group selected from the group consisting of H, halogen; Unless otherwise specified, in each of the above formulas, the heterocyclic or heteroaromatic ring has 1-3 heteroatoms selected from the group consisting of N, S or O.

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein B ring is selected from the group consisting of C6-Ci2aryl, 5-12 membered heteroaryl ring. 10 aryl, 5-12 membered heteroaryl ring.

3. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein said compound of Formula I has a structure selected from the group consisting of: ###0003### ###0004### V VI wherein C ring is a substituted or unsubstituted phenyl ring, a substituted or unsubstituted 5-7 membered heterocyclic ring; said substitution means that the hydrogen atom on the corresponding group is replaced by one or more substituents selected from the group consisting of deuterium, halogen, hydroxyl, oxygen (=0), amino, C1-C6 amido, unsubstituted or halogenated C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkyl- aminyl, C1-C6 alkyl-sulfonamido, C6-C 10 aryl, five- or six-membered heteroaryl, five- or six-membered non-aromatic heterocyclyl, unsubstituted or halogenated C2-C 10 acyl, unsubstituted or halogenated C1-C4 alkyl-S(O)2-.

4. The compound of claim 3, or a pharmaceutically acceptable salt thereof, wherein said C ring is a substituted or unsubstituted 5-6 membered heteroaromatic ring.

5. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R is selected from the group consisting of H, halogen, cyano, amino, hydroxyl, carboxyl, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6alkoxy, substituted or unsubstituted C1-C6alkylamino, substituted or unsubstituted 5-10 membered heteroaryl, substituted or unsubstituted 5-7 membered heterocycle, substituted or unsubstituted C1-C6amide; and / or 3 R is selected from the group consisting of H, halogen, cyano, amino, hydroxyl, carboxyl, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6alkoxy, substituted or unsubstituted C1-C6alkylamino, substituted or unsubstituted 5-10 membered heteroaryl, substituted or unsubstituted 5-7 membered heterocycle, substituted or unsubstituted C1-C6amide; and / or R is a group selected from the group consisting of H, halogen, amino, hydroxyl, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6alkoxy, substituted or unsubstituted C1-C6alkylamino, substituted or unsubstituted 5-7 membered heterocycle containing 1-3 heteroatoms selected from oxygen, sulfur and nitrogen, substituted or unsubstituted -C1-C6alkyl-phenyl, substituted or unsubstituted C6-C 10 substituted or unsubstituted C1-C6alkyl-S(O)2-; R' is a group selected from the group consisting of H, halogen, amino, hydroxyl, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkylamino; or two R on adjacent ring atoms, together with the ring atoms to which they are attached, form a substituted or unsubstituted 5-9 membered carbocyclic or heterocyclic ring, which is partially unsaturated, saturated or aromatic.

6. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein said B ring is selected from the group consisting of phenyl, 5-10 membered heteroaromatic ring.

7. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R is a group selected from the group consisting of H, halogen, amino, hydroxyl, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C1-C6 alkylamino, substituted or unsubstituted C1-C6 acylamino, substituted or unsubstituted C1-C4 alkyl-S(O)2-; R' is a group selected from the group consisting of H, halogen, amino, hydroxyl, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C1-C6 alkylamino.

8. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R 4 is a group selected from the group consisting of H, halogen, unsubstituted C1-C6alkyl.

9. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein The Ring is selected from the group consisting of: , , , , , , , , , , , , , , , , , , , , .

10. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein said compound has a structure of the following Formula III: ###0005### III wherein, A ring is selected from the group consisting of: , , , , wherein, when the point of attachment to the other structural fragment or substituent is NH, the hydrogen atom on the NH is lost to form the point of attachment; R 3 is a group selected from the group consisting of H, halogen, cyano, amino, hydroxy, carboxy, unsubstituted or halogenated C1-C6alkyl, substituted or unsubstituted C1-C6alkoxy, substituted or unsubstituted C1-C6alkylamino, substituted or unsubstituted C1-C4alkyl-S(O)2-; R 4 is a group selected from the group consisting of H, halogen, unsubstituted C1-C6alkyl, unsubstituted C1-C6alkoxy.

11. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein said compound has a structure of the following Formula V: ###0006### V R 3 is a group selected from the group consisting of H, halogen, cyano, amino, hydroxyl, carboxyl, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6alkoxy, substituted or unsubstituted C1-C6alkylamino; R 4 is a group selected from the group consisting of H, halogen, unsubstituted C1-C6alkyl, unsubstituted C1-C6alkoxy.

12. A compound selected from the group consisting of: ###0007### or a pharmaceutically acceptable salt thereof. 。 13. A pharmaceutical composition, characterized by, said pharmaceutical composition contains a therapeutically effective amount of a compound of claim 1, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable adjuvants.

14. Use of a compound of claim 1, or a pharmaceutically acceptable salt thereof, in the preparation of a pharmaceutical composition for treating or preventing a disease associated with PRMT.

15. The use according to claim 14, characterized in that, said PRMT is a type I PRMT.

16. The use of claim 14, wherein, said disease is selected from the group consisting of tumor, cardiovascular disease, neurodegenerative disease, malaria, gout, diabetes, renal failure, chronic pulmonary disease, cocaine addiction, alcoholic cirrhosis, viral infection.

17. The use of claim 14, wherein, said disease is selected from the group consisting of oculopharyngeal muscular dystrophy, amyotrophic lateral sclerosis, AIDS, pulmonary hypertension disease.

Images