Aromatic ring-fused heterocyclic compound, preparation method therefor and use thereof

Abstract

Disclosed in the present invention are an aromatic ring-fused heterocyclic compound, a preparation method therefor and the use thereof. The aromatic ring-fused heterocyclic compound of the present invention is a compound as represented by formula (I) or (II), or a pharmaceutically acceptable salt thereof. The aromatic ring-fused heterocyclic compound of the present invention has a good agonistic activity against GPR40, and has good pharmaceutical prospects.

Description

Aryl ring fused heterocyclic compounds, methods for preparing the same, and uses thereof TECHNICAL FIELD

[0001] The present application relates to an aryl ring fused heterocyclic compound, a method for preparing the same, and uses thereof. BACKGROUND

[0002] GPR40 is a member of the GPCR family, also known as FFA1 receptor, which is a class A G protein-coupled receptor that can be activated by endogenous medium- and long-chain fatty acids (such as caprylic acid, soft acid, oleic acid, docosahexaenoic acid, etc.) in vivo. GPR40 is mainly highly expressed in islet beta cells, intestinal endocrine cells and brain, and also expressed in tissues such as gastrointestinal tract, liver, heart, skeletal muscle, taste bud, etc. When GPR40 is activated by its endogenous ligand, it can only induce insulin secretion (GPR40 promotes islet beta cell Ca 2+ influx, and secretes insulin) at a high blood glucose level, so there is no risk of hypoglycemia. GPR40 partial agonists activate the Gq / IP3 pathway to promote insulin secretion; complete agonists can also activate the Gs / cAMP pathway to promote the release of GLP-1 and GIP, thereby achieving a stronger hypoglycemic effect. These make GPR40 an important therapeutic target for diseases such as diabetes, obesity, cardiovascular disease, dyslipidemia, etc. The distribution of GPR40 in the brain may be related to pain regulation, neuroprotection, behavior regulation, etc., and is a potential target for the treatment of nervous system diseases.

[0003] In view of the importance of GPR40, it is of great significance to develop drugs that can activate GPR40.

[0004] SUMMARY

[0005] The technical problem to be solved by the present application is to overcome the limitation of the types of drugs with GPR40 agonistic activity in the prior art, and therefore, an aryl ring fused heterocyclic compound, a method for preparing the same, and uses thereof are provided. The compound of the present application has good GPR40 agonistic activity.

[0006] The present application solves the above technical problems by the following technical solutions.

[0007] The present application provides an aryl ring fused heterocyclic compound or a pharmaceutically acceptable salt thereof, wherein the aryl ring fused heterocyclic compound is a compound as shown in formula I or II:

[0008] wherein each n1, each n2, each n3 and each n4 is independently 0, 1, 2, 3 or 4;

[0009] each R 1 , each R 2 , each R3 and each R 4 independently is deuterium, halogen, cyano, hydroxyl, nitro, amino, -NR 1a-1 R 1a-2 , C 1- 6alkyl, C 1a-3 6alkyl substituted by one or more R 1-6 , C 1-6 6alkyl, C 1a-4 6alkoxy, C 1-6 6alkoxy substituted by one or more R 1-6 , -S-C 1-6 6alkyl, C 3-6 cycloalkyl, C 1a-5 cycloalkyl substituted by one or more R 3-6 , -O-C 3-6 cycloalkyl, -O-C 1a-6 cycloalkyl substituted by one or more R 3-6 , 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkyl substituted by one or more R 1a-7 , C 6-10 aryl, C 1a-8 aryl substituted by one or more R 6-10 , 5-10 membered heteroaryl, or 5-10 membered heteroaryl substituted by one or more R 1a-9 , or any two adjacent R 1 form -(CH2) n6 , n6 is 1, 2, 3 or 4, any one or two -CH2- in -(CH2) n6 may be replaced by one or two of N, S and O;

[0010] the 3-6 membered heterocycloalkyl, the 3-6 membered heterocycloalkyl substituted by one or more R 1a-7 , the 5-10 membered heteroaryl and the 5-10 membered heteroaryl substituted by one or more R 1a-9 are independently one or more of N, S or O, in a number of 1, 2, 3 or 4;

[0011] R 1a-1 and R 1a-2 are independently H or C 1-6 alkyl;

[0012] each R 1a-3 , each R 1a-4 , each R 1a-5 , each R 1a-6 , each R 1a-7 , each R 1a-8 and each R 1a-9 are independently halogen, cyano, hydroxyl, nitro, amino, C1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl or halogenated C 1-6 Alkoxy;

[0013] Each ring A, each ring C, and each ring D is independently C. 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 6-10 Aryl or 5-10 heteroaryl groups;

[0014] Each ring B is independently a 5-6 membered heterocyclic alkyl group or C. 4-6 Cycloalkenyl;

[0015] The heteroatoms in the 3-6 membered heterocyclic alkyl group, the 5-6 membered heterocyclic alkyl group, and the 5-10 membered heteroaryl group are independently one or more of N, S, or O, and the number is 1, 2, 3, or 4.

[0016] Each L 1 Independently for the connector key or C 1-6 Alkylene;

[0017] Each n5 is independently 0, 1, or 2;

[0018] Each R 5 Independently hydrogen, deuterium, halogen, amino, nitro, cyano, C 1-6 Alkyl or C 1-6 Alkoxy;

[0019] Each X 1 and each X 2 Independently C, CH, or N;

[0020] Each X 3 Independently for O or NR 7 R 7 For H or C 1-6 alkyl;

[0021] Each Y is independently a connecting bond, -C(=O)O- or -C(=O)NH-;

[0022] Each L 3 Independently -(CH2) m -, m is 1, 2, 3, 4, 5, 6, 7, 8 or 9, -(CH2) m Any 1, 2, 3, or 4 -CH2- atoms may be optionally replaced by 1, 2, 3, or 4 atoms or groups selected from the following: O, -CR 8 R 9 -, -CH=CH-, -C(=O)O- and -C(=O)NR 10 -;

[0023] R 8and R 9 independently H or C 1-6 alkyl, or R 8 and R 9 together with the C to which they are attached form a C 3-6 carbocycle, and R 8 and R 9 are not simultaneously H;

[0024] R 10 is H, C 1-6 alkyl, phenyl, phenyl substituted with one or more R 10a-1 substituted phenyl, 5-10 membered heteroaryl, 5-10 membered heteroaryl substituted with one or more R 10a-2 substituted 5-10 membered heteroaryl; the heteroatoms in said 5-10 membered heteroaryl and said 5-10 membered heteroaryl substituted with one or more R 10a-2 are independently one or more of N, S, or O, in a number ranging from 1, 2, 3, or 4;

[0025] each R 10a-1 and each R 10a-2 is independently halogen, C 1-6 alkyl, or C 1-6 alkoxy;

[0026] each L 2 is independently C 1-6 alkylene, C 2-1 alkylene substituted with one or more L 1-6 , C 3-6 cycloalkylene, or C 2-2 cycloalkylene substituted with one or more L 3-6 ;

[0027] each L 2-1 and each L 2-2 is independently halogen, C 1-6 alkyl, C 1-6 alkoxy, or C 3-6 cycloalkyl;

[0028] each R 6 is independently -C(=O)OH or -C(=O)NOH.

[0029] In one aspect, each R 1 , each R 2 , each R 3 , each R 4 , each R 1a-3 , each R 1a-4 , each R 1a-5 , each R 1a-6 , each R 1a-7 , each R 1a-8 , each R 1a-9 , each R5 , each R 10a-1 , each R 10a-2 , each L 2-1 , and each L 2-2 , the halogen is F, Cl, Br, or I.

[0030] In one embodiment, each R 1 , each R 2 , each R 3 , and each R 4 , the C 1-6 alkyl, the C 1a-3 alkyl substituted with one or more R 1-6 , the C 1-6 alkyl of -S-C 1-6 alkyl, the C 1-6 alkyl of -S(=O)2-C 1-6 alkyl, and the C 1-6 alkyl of -NR 1 -C 2 alkyl is independently methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl, or hexyl.

[0031] In one embodiment, each R 3 , each R 4 , each R 1-6 , and each R 1a- , the C 4 alkoxy, and the C 1-6 alkoxy of -NR 1-6 -C 1 alkoxy substituted with one or more R 2 3 is independently methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy, t-butoxy, pentoxy, or hexoxy.

[0032] In one embodiment, each R 4 , each R 3-6 , each R 1a- , and each R 5 , the C 3-6 cycloalkyl, the C 3-6 cycloalkyl of -O-C 3-6 cycloalkyl, the C 3-6 cycloalkyl of -O-C 1a-6 cycloalkyl substituted with one or more R 3-6 3-6 is independently cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0033] In one embodiment, each R1 Each R 2 Each R 3 and each R 4 In the context, the 3-6 membered heterocyclic alkyl group and the group with one or more R 1a-7 The 3-6 membered heterocyclic alkyl group in the substituted 3-6 membered heterocyclic alkyl group is independently a 5-6 membered heterocyclic alkyl group, with one or two heteroatoms N, and may also be piperidinyl.

[0034] In a certain scheme, each R 1 Each R 2 Each R 3 and each R 4 In the context, C 6-10 aryl and the aforementioned one or more R 1a- 8 Replacement C 6-10 C in aryl 6-10 The aryl group can be phenyl or naphthyl independently.

[0035] In a certain scheme, each R 1 Each R 2 Each R 3 and each R 4 In the context, the 5-10 membered heteroaryl group and the group with one or more R groups 1a-9 The 5-10 membered heteroaryl group in the substituted 5-10 membered heteroaryl group is independently a 5-6 membered monocyclic heteroaryl group or an 8-10 membered heteroaryl group.

[0036] In one particular scheme, R 1a-1 R 1a-2 Each R 1a-3 Each R 1a-4 Each R 1a-5 Each R 1a-6 Each R 1a-7 Each R 1a-8 Each R 1a-9 R 5 R 7 R 8 R 9 R 10 Each R 10a-1 Each R 10a-2 Each L 2-1 and each L 2-2 In the context, C 1-6 The alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, or hexyl.

[0037] In a certain scheme, each R 1a-3 Each R 1a-4 Each R 1a-5 Each R 1a-6, each R 1a-7 , each R 1a-8 , each R 1a-9 , R 5 , each R 10a-1 , each R 10a-2 , each L 2-1 , and each L 2-2 , the C 1-6 alkyl is methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, or t-butyl.

[0038] In one aspect, each R 1a-3 , each R 1a-4 , each R 1a-5 , each R 1a-6 , each R 1a-7 , each R 1a-8 , and each R 1a-9 , the haloC 1-6 alkyl is C 1-6 alkyl substituted with one or more halogens, which can be -CF3.

[0039] In one aspect, each R 1a-3 , each R 1a-4 , each R 1a-5 , each R 1a-6 , each R 1a-7 , each R 1a-8 , and each R 1a-9 , the C 1- 6alkoxy is methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy, or t-butoxy.

[0040] In one aspect, each R 1 , each R 2 , each R 3 , and each R 4 , the C 1a-3 alkyl substituted with one or more R 1-6 is C 1-4 alkyl substituted with one or more halogens, which can be -CF3.

[0041] In one aspect, each R 1 , each R 2 , each R 3 , and each R 4 , the C 1a-4 alkoxy substituted with one or more R 1-6 is C 1-4 alkoxy substituted with one or more halogens, which can be -OCF3.

[0042] In one aspect, each R1 , each R 2 , each R 3 , and each R 4 , the haloC 1a-8 alkyl is fluoroC 6-10 alkyl, which can be -CF3. 1a-8 , R 1a-8 is halo, C 1-6 alkyl, C 1-6 alkoxy, haloC 1-6 alkyl, or haloC 1- 6alkoxy; can be -OCF3.

[0043] In one embodiment, each R 1a-3 , each R 1a-4 , each R 1a-5 , each R 1a-6 , each R 1a-7 , each R 1a-8 , and each R 1a-9 , the haloC 1-6 alkyl is fluoroC 1-4 alkyl, which can be -CF3.

[0044] In one embodiment, each R 1a-3 , each R 1a-4 , each R 1a-5 , each R 1a-6 , each R 1a-7 , each R 1a-8 , and each R 1a-9 , the haloC 1-6 alkoxy is fluoroC 1-4 alkoxy, which can be -OCF3.

[0045] In one embodiment, each ring A, each ring C, and each ring D, the C 3-6 cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0046] In one embodiment, each ring A, each ring C, and each ring D, the 5-6 membered heterocycloalkyl is a 6 membered heterocycloalkyl, the number of heteroatoms N is 1 or 2, and the heterocycloalkyl is also piperidinyl.

[0047] In one embodiment, each ring A, each ring C, and each ring D, the C 6-10 aryl is phenyl or naphthyl.

[0048] Preferably, when ring A is phenyl and n1 is 1 or 2, R 1 substituted phenyl is at the ortho position, meta position, para position, "ortho and para positions" or "ortho and para positions".

[0049] Preferably, when ring D is phenyl and n1 is 1, R 1 The substituted phenyl group can be located at the ortho, para, or meta position.

[0050] In one embodiment, in each ring A, each ring C, and each ring D, the 5-10 membered heteroaryl group is a 5-6 membered monocyclic heteroaryl group or an 8-10 membered bicyclic heteroaryl group, and the heteroatoms N and / or O are 1, 2, or 3 in number, and can be imidazolyl, 1,3,4-oxadiazolyl, 4H-pyrazolyl, 1H-1,2,3-triazolyl, pyridinyl, or indoleyl.

[0051] In one embodiment, in each ring B, the 5-6 membered heterocyclic alkyl group is a 5-6 membered heterocyclic alkyl group, and the heteroatom N can be piperidinyl.

[0052] In a certain scheme, in each ring B, the aforementioned C 4-6 The cycloalkenyl group is C 5-6 Cycloalkenyl groups contain one double bond and can be cyclohexenyl groups.

[0053] In a certain scheme, when R 8 and R 9 Together with the C connected to it, they form C 3-6 When carbon rings are used, the C... 3-6 The carbon ring is cyclopropane, cyclobutane, cyclopentane, or cyclohexane.

[0054] In one particular scheme, R 10 In the context, the 5-10 membered heteroaryl group and the group with one or more R groups 10a The 5-10 membered heteroaryl group in the substituted 5-10 membered heteroaryl group is independently a 5-6 membered monocyclic heteroaryl group, the heteroatom is N, and it can be pyridyl.

[0055] In one particular scheme, R 10 In the context, the term "by one or more R" refers to... 10a-2 The substituted 5-10 heteroaryl group is replaced by one or more R groups. 10a- 2 Substituted 5-6 membered monocyclic heteroaryl groups, with nitrogen atom; can be

[0056] In a certain scheme, each L 2 In the context, C 1-6 Alkylene, the one or more L 2-1 Replacement C 1-6 C in alkylene 1-6 The alkylene group is independently methylene, ethylene, n-propylene, isopropylene, n-butylene, isobutylene, sec-butylene, or tert-butylene, such as methyl, ethyl, n-propyl, or isopropyl, such as methylene or ethylene.

[0057] In one aspect, each L 2 is C 1-6 alkylene, preferably S-configured C 1-6 alkylene. alkylene is non-chiral C, S-configured C or R-configured C, preferably S-configured C.

[0058] In one aspect, each L 2 is C 2-1 alkylene substituted with one or more L 1-6 alkylene is C 3-6 cycloalkyl substituted C 1-4 alkylene.

[0059] In one aspect, each R 1 is independently halogen or C 1-6 alkoxy, or any two adjacent R 1 have formed -(CH2) n6 , n6 is 1, 2, 3 or 4, any 1 or 2 -CH2- in -(CH2) n6 may be replaced with 1 or 2 of N, S and O, can be F, Cl or -OCH3, or any two adjacent R 1 have formed

[0060] In one aspect, each ring A is C 6-10 aryl, which can be phenyl.

[0061] In one aspect, is

[0062] In one aspect, is

[0063] In one aspect, each R 3 is independently halogen, C 1-6 alkyl or C 1-6 alkoxy, which can be F, Cl, -CH3 or -OCH3.

[0064] In one aspect, ring C is C 6-10 aryl or 5-10 membered heteroaryl, which can be phenyl, 1,3,4-oxadiazolyl, 1H- pyrazolyl or indolyl.

[0065] In one aspect, is

[0066] In one aspect, ring D is independently 5-6 membered heterocycloalkyl, C6-10 aryl or 5-10 membered heteroaryl, which can be piperidinyl, phenyl, imidazolyl, 4H-pyrazolyl, 1 H-1,2,3-triazolyl or pyridinyl.

[0067] In one aspect, each R 4 independently halogen, C 1-6 alkyl, C 1a-3 alkyl substituted by 1 or more R 1-6 alkyl, C 1-6 alkoxy, C 1a-4 alkyl substituted by 1 or more R 1-6 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C 6-10 aryl, C 1a-8 alkyl substituted by 1 or more R 6-10 aryl or C 1a-8 alkyl substituted by 1 or more R 6-10 aryl, each R 1a-3 , each R 1a-4 , each R 1a-8 and each R 1a-9 independently halogen, C 1-6 alkyl, C 1-6 alkoxy, haloC 1-6 alkyl or haloC 1-6 alkoxy;

[0068] may be F, -CH3, -CH2CH3, isopropyl, n-butyl, t-butyl, -C5H 11 (n-pentyl), -C6H 13 (n-hexyl), -CF3, -OCH3, -OC5H 11 , -OCF3, phenyl, In one aspect, L is any one of the following:

[0069] In one aspect, L 3 is -(CH2) m -, m is 1, 2, 3, 4, 5, 6, 7, 8 or 9, any one of the -CH2- groups in -(CH2) m - can optionally be replaced by O, -CR 8 R 9 -, -CH=CH-, -C(=O)O- or -C(=O)NR 10 -, 2 -CH2- groups can optionally be replaced by a group from group a, 3 -CH2- groups can optionally be replaced by a group from group b or 4 -CH2- groups can optionally be replaced by a group from group c;

[0070] Group a: 2 O or "O and -CR 8 R 9 - ", group b: 3 O, "2 O and -CR 8 R 9 - ", "2 O and -C(=O)NR 10 " or "O, -C(=O)NR 10 and -CR 8 R 9 - ", group c: 2 O, -C(=O)NR 10 and -CR 8 R 9 -;

[0071] L 3 may be any one of the following groups:

[0072] In one aspect, -L 2 - is C 2-1 alkylene substituted with one or more L 1-6 , each L 2-1 is independently C 3-6 cycloalkyl, which can be

[0073] In one aspect, -L 2 -G is for example

[0074] In one aspect, the aromatic ring and heterocyclic ring compound is a compound of formula Ia, IIb, Ia-1 or IIb-2:

[0075] In one aspect, the aromatic ring and heterocyclic ring compound is a compound of formula Ia, IIb, Ia-1 or IIb-2:

[0076] wherein each group is as defined above.

[0077] Preferably, in formula Ia, IIb, Ia-1 and IIb-2, each is independently is attached to ring A (the phenyl ring) at the 1 -position.

[0078] Preferably, in formula Ia, IIb, Ia-1 and IIb-2, each ring C is independently C 6-10 aryl or 5-10 membered heteroaryl. More preferably, each ring C is independently

[0079] Preferably, in formula Ia, IIb, Ia-1 and IIb-2, each ring D is independently 3-6 membered heterocycloalkyl, C​6-10 Aryl or 5-10 aryl compounds. More preferably, each ring D is independently...

[0080] Preferably, in formulas Ia, IIb, Ia-1 and IIb-2, each -L 2 - Independently for a C 3-6 Cycloalkyl-substituted C 1-6 Alkylene. More preferably, -L 2 -for

[0081] In one embodiment, the aromatic cyclic heterocyclic compound is of formula Ia-1-1 or Ia-1-2:

[0082] The definitions of each group are as described above.

[0083] Preferably, as in formula Ia-1-1 or Ia-1-2,

[0084] Each R 1 Independently for C 1-6 Alkoxy;

[0085] Each R 3 For Cl;

[0086] Each ring D is independently phenyl or piperidinyl;

[0087] Each R 4 Independently halogenated, methylated, or surrounded by one or more R atoms 1a-8 Substituted phenyl;

[0088] Each L 2 Independently for one or more L 2-1 Replacement C 1-6 Alkylene;

[0089] Each L 3 Independently -(CH2) m -, m is 1, 2 or 3;

[0090] When each ring D is phenyl, each R 4 When it is methyl, R 4 The substitution occurs at the meta position of the phenyl group.

[0091] In one embodiment, the aromatic cyclic heterocyclic compound is any of the following compounds:

[0092] Its isomers or mixtures of the two in any proportion (e.g., racemic mixtures).

[0093] The aromatic ring and heterocycle compound has the structural formula shown in the above formula (I), wherein -C6H 13 may be n-hexyl, -C5H 11 may be n-pentyl, and -C4H9may be n-butyl.

[0094] The present application also provides a preparation method of the aromatic ring and heterocycle compound or the pharmaceutically acceptable salt thereof, which is method 1 or method 2.

[0095] When R 6 is -C(=O)OH, it is method 1.

[0096] Method 1 comprises the following step: performing hydrolysis reaction on a compound shown in the following formula IIIa or IVa to obtain the aromatic ring and heterocycle compound.

[0097] wherein each R 11 is independently C 1-6 alkyl, and the definitions of other groups are the same as described above.

[0098] When R 6 is -C(=O)NOH, it is method 2.

[0099] Method 2 comprises the following step: performing deprotection reaction on a compound shown in the following formula IIIb or IVb to obtain the aromatic ring and heterocycle compound.

[0100] wherein each R 12 is independently a hydroxyl protecting group (for example (-THP), and the definitions of other groups are the same as described above.

[0101] The present application also provides a pharmaceutical composition comprising the aromatic ring and heterocycle compound or the pharmaceutically acceptable salt thereof (such as an effective treatment amount) and a pharmaceutically acceptable excipient.

[0102] The present application also provides application of the aromatic ring and heterocycle compound or the pharmaceutically acceptable salt thereof in preparation of a GPR40 agonist (in vivo or in vitro).

[0103] The present application also provides application of the aromatic ring and heterocycle compound or the pharmaceutically acceptable salt thereof in preparation of a drug for treating or preventing a disease related to GPR40.

[0104] In the application, the disease related to GPR40 is preferably diabetes.

[0105] The present application also provides a method for treating a disease related to GPR40 (preferably diabetes) comprising administering to a patient an effective amount of the aromatic ring and heterocyclic compound or a pharmaceutically acceptable salt thereof.

[0106] The present application also provides a compound as shown in Formula IIIa, IIIb, IVa or IVb (which can prepare the aromatic ring and heterocyclic compound described above):

[0107] wherein each R 11 independently is C 1-6 alkyl, each R 12 independently is a hydroxyl protecting group (for example (-THP)), and the definitions of other groups are the same as described above.

[0108] The compound as shown in Formula IIIa, IIIb, IVa or IVb is preferably any one of the following compounds:

[0109] The plurality in the expression "group B substituted with 1 or more groups A" refers to 2, 3, 4 or 5. The expression "group B substituted with 1 or more groups A" refers to 1, 2, 3, 4 or 5 hydrogen atoms in group B being independently replaced with group A. When multiple A groups appear simultaneously, their definitions are independent of each other and do not affect each other, unless otherwise specified. For example, "C6-C 10 aryl" refers to C6-C 10 The C6-C aryl" can be substituted with 2 halogens, 3 halogens, the definitions of which are independent of each other and do not affect each other, including but not limited to:

[0110] The term "pharmaceutically acceptable salt" refers to a salt of a compound with a pharmaceutically acceptable acid or base. When a compound contains a relatively acidic functionality, a base addition salt can be obtained by contacting the compound with a sufficient amount of the pharmaceutically acceptable base in a suitable inert solvent. When a compound contains a relatively basic functionality, an acid addition salt can be obtained by contacting the compound with a sufficient amount of the pharmaceutically acceptable acid in a suitable inert solvent. For details see Handbook of Pharmaceutical Salts: Properties, Selection, and Use (P. Heinrich Stahl, Camille G. Wermuth, 2011, 2nd Revised Edition).

[0111] The " is intended to mean that the structural fragment is attached to the remainder of the molecule through this site. For example, " is intended to mean cyclohexyl.

[0112] "-" at the end of a group is intended to mean that the group is attached to the remainder of the molecule through this site.

[0113] The term "halogen" means fluorine, chlorine, bromine, or iodine.

[0114] The term "alkyl" means a straight or branched, saturated, monovalent hydrocarbon group having the indicated number of carbon atoms (e.g., C 1-6 ). Alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, n-hexyl, and the like. In structural formulas, -C6H 13 may be n-hexyl, -C5H 11 may be n-pentyl, and -C4H9may be n-butyl.

[0115] The term "alkenyl" means a straight or branched, unsaturated, monovalent hydrocarbon group having the indicated number of carbon atoms (e.g., C 2-6 ) and having one or more (e.g., 1, 2, or 3) carbon-carbon sp2bonds. Alkenyl groups include, but are not limited to, ethenyl, propenyl, n-buten-2-yl, i-buten-2-yl, t-buten-2-yl, n-penten-2-yl, n-hexen-2-yl, and the like.

[0116] The term "cycloalkenyl" means a cyclic, unsaturated, monovalent hydrocarbon group having the indicated number of ring atoms (e.g., 5-14 membered or 5-10 membered) and having one or more (e.g., 1, 2, or 3) carbon-carbon sp2bonds, which is not aromatic. (Monocyclic)heterocycloalkenyl groups are attached to the molecule through a carbon atom or a heteroatom.

[0117] The term "heterocycloalkyl" means a cyclic group having the indicated number of ring atoms (e.g., 3-6 membered, or 5-6 membered), the indicated number of heteroatoms (e.g., 1, 2, 3, or 4), and the indicated type of heteroatoms (one or more of N, O, and S), which is monocyclic and each ring is saturated. Heterocycloalkyl groups include, but are not limited to, azetidinyl, tetrahydropyrrolyl, tetrahydrofuranyl, morpholinyl, piperidinyl, and the like.

[0118] The term "alkoxy" means the group R X -O-, R X is defined as the term "alkyl". Alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propyloxy, i-propyloxy, and the like.

[0119] The term "alkylene" is a divalent group that is attached to the remainder of the molecule through two single bonds, and the remaining definition is the same as the term "alkyl".

[0120] The term "cycloalkyl" means a cyclic group having the indicated number of carbon atoms (e.g., C 3-6 ​) that is cyclic, saturated, monovalent, and is monocyclic. Cycloalkyl groups include, but are not limited to: etc.

[0121] The term "carbocyclic (cycloalkane)" satisfies either of the following conditions: shares 1 atom with the rest of the molecule, and the rest of the definition is the same as the term "cycloalkyl". Carbocyclic (cycloalkane) includes, but is not limited to: etc. which is connected to the rest of the molecule by the carbon atom marked with an asterisk.

[0122] The term "aryl" refers to a cyclic, unsaturated, monovalent hydrocarbon group having the specified number of carbon atoms (e.g., C 6-10 ) that is cyclic, unsaturated, monovalent, and is monocyclic or polycyclic (e.g., 2 or 3), shares 2 atoms and 1 bond between monocyclic rings, and each ring is aromatic. Aryl groups include, but are not limited to: phenyl, naphthyl, and the like.

[0123] The term "heterocycloalkyl" refers to a cyclic, saturated, monovalent group having the specified number of ring atoms (e.g., 5-6 membered), the specified number of heteroatoms (e.g., 1, 2, 3, or 4), the specified type of heteroatoms (one or more of N, O, and S), that is monocyclic. Heterocycloalkyl groups include, but are not limited to: etc.

[0124] The term "heteroaryl" refers to a cyclic, unsaturated, monovalent group having the specified number of ring atoms (e.g., 5-10 membered, 5-6 membered), the specified number of heteroatoms (e.g., 1, 2, 3, or 4), the specified type of heteroatoms (one or more of N, O, and S), that is monocyclic or polycyclic (e.g., 2 or 3), shares 2 atoms and 1 bond between monocyclic rings, and each ring is aromatic. Heteroaryl groups are connected to the rest of the molecule by a carbon atom or a heteroatom; heteroaryl groups are connected to the rest of the molecule by a ring with heteroatoms or a ring without heteroatoms. Heteroaryl groups include, but are not limited to: etc.

[0125] The term "pharmaceutically acceptable excipient" refers to all substances contained in a pharmaceutical preparation in addition to the active pharmaceutical ingredient, which is generally divided into two categories: excipients and additives. For details, please refer to the "People's Republic of China Pharmacopoeia (2020 Edition)", Handbook of Pharmaceutical Excipients (Paul J Sheskey, Bruno C Hancock, Gary P Moss, David J Goldfarb, 2020, 9th Edition).

[0126] On the basis of common sense in the art, the above-mentioned preferred conditions can be combined arbitrarily, i.e. the preferred examples of the present application.

[0127] The reagents and materials used in the present application are commercially available.

[0128] The positive progress effect of the present application is that the GPR40 agonistic activity of the aromatic ring and heterocyclic compound of the present application or its pharmaceutically acceptable salt is good. DETAILED DESCRIPTION

[0129] The present application is further illustrated by the following examples, but the present application is not limited to the scope of the examples. The experimental methods in the following examples, if not otherwise specified, are selected according to the conventional methods and conditions, or according to the instructions of the commercial products.

[0130] In the following examples, -C6H 13 refers to n-hexyl, -C5H 11 refers to n-pentyl, -C4H9 refers to n-butyl.

[0131] Synthesis of intermediate M1

[0132] Synthetic route:

[0133] In a 1000 mL three-necked flask, compound M1-1 (40 g, 181.6 mmol) and dichloromethane (250 mL) were added under ice water bath condition, then N-iodosuccinimide (49 g, 217.9 mmol) was slowly added, then stirred for 1 hour, after the reaction was completed by LCMS monitoring, water (250 mL) was added to the reaction system, then extracted with dichloromethane (3 x 150 mL), the organic phase was washed with saturated ammonium chloride (250 mL x 3), then dried over anhydrous sodium sulfate and concentrated, the obtained crude product was purified by normal phase column chromatography (ethyl acetate: petroleum ether = 0% ~ 100%) to obtain brown solid compound M1-2 (28.7 g, yield 46%). MS (ESI, m / z): 347.2 [M+H] + .

[0134] A mixture of compound M1-2 (14.7 g, 42.5 mmol), cuprous iodide (0.8 g, 4.25 mmol) and dichlorobis(triphenylphosphine)palladium (1.7 g, 2.12 mmol) was stirred in acetonitrile (100 mL) under nitrogen. After the addition of triethylamine (5.9 mL, 42.5 mmol), the reaction was stirred at 80 °C for 2 minutes. Then compound M1-3 (8.9 g, 42.5 mmol) was added and the reaction was stirred at 80 °C for 90 minutes. After the reaction was completed by LCMS, the reaction was cooled to room temperature, water (150 mL) was added, and then extracted with dichloromethane (3 x 150 mL). The combined organic phase was dried over anhydrous sodium sulfate and concentrated. The crude product was purified by normal phase column chromatography (ethyl acetate: petroleum ether = 0% ~ 100%) to give compound M1-4 (16.9 g, yield 93%) as a brown solid. MS (ESI, m / z): 428.3 [M+H] + .

[0135] To a solution of compound M1-4 (16.9 g, 40.5 mmol) in anhydrous dichloromethane (200 mL) was slowly added N-bromosuccinimide (10.8 g, 60.8 mmol) under ice water bath condition. The reaction was stirred in ice water bath for 2 hours. After the reaction was completed by LCMS, water (250 mL) was added to the reaction system, and then extracted with dichloromethane (3 x 150 mL). The combined organic phase was dried over anhydrous sodium sulfate and concentrated. The crude product was purified by normal phase column chromatography (ethyl acetate: petroleum ether = 0% ~ 100%) to give compound M1-5 (14.8 g, yield 72%) as a brownish red solid. MS (ESI, m / z): 506.3 [M+H] + .

[0136] A mixture of compound M1-5 (7.6 g, 15.0 mmol), trifluoroacetic acid (5.13 g, 45.0 mmol), dichloromethane (100 mL) was stirred at room temperature for 2 hours. After the reaction was completed by LCMS, saturated sodium bicarbonate solution (100 mL) was added, and then extracted with dichloromethane (200 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate and concentrated. The crude product was purified by normal phase column chromatography (ethyl acetate: petroleum ether = 0% ~ 100%) to give compound M1-6 (5.65 g, yield 93%) as a yellow oil. MS (ESI, m / z): 406.2 [M+H] + .

[0137] To a mixture of compound M1-6 (5.65 g, 13.9 mmol), 1,1'-binaphthalene-2,2'-diphenylphosphine (1.21 g, 1.9 mmol), palladium acetate (400 mg, 1.9 mmol), compound M1-7 (4.28 g, 20.8 mmol) and cesium carbonate (18.12 g, 55.6 mol) in toluene (100 mL) was stirred at 100 °C overnight. After the reaction was completed by LCMS, water (200 mL) was added to the reaction mixture, which was then extracted with dichloromethane (200 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate and concentrated. The obtained crude product was purified by normal phase column chromatography (ethyl acetate: petroleum ether = 0% ~ 100%) to give compound M1-8 (949 mg, yield 13%) as a white solid. MS (ESI, m / z): 512.1 [M+H] + .

[0138] To a mixture of compound M1-8 (525 mg, 1.0 mmol), compound M1-9 (385 mg, 2.5 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (40 mg, 0.5 mmol), cesium carbonate (975 mg, 3 mmol) in 1,4-dioxane: water = 5:1 (25 mL) was stirred at 80 °C for 16 hours. After the reaction was completed by LCMS, the reaction mixture was extracted with ethyl acetate (25 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate and concentrated. The obtained crude product was purified by normal phase column chromatography (ethyl acetate: petroleum ether = 0% ~ 100%) to give compound M1-10 (390 mg, yield 97%) as a yellow oil. MS (ESI, m / z): 460.2 [M+H] + .

[0139] To a mixture of compound M1-10 (390 mg, 0.85 mmol), 2,6-dimethylpyridine (182 mg, 1.7 mmol) in 1,4-dioxane: water = 3:1 (40 mL) was added potassium osmate dihydrate (15.5 mg, 0.0425 mmol) and sodium periodate (910 mg, 4.25 mmol) at 0 °C. The mixture was stirred at 0 °C for 4 hours. After the reaction was completed by LCMS, saturated aqueous sodium thiosulfate (25 mL) was added to the reaction mixture at 0 °C. The reaction mixture was extracted with ethyl acetate (50 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate and concentrated. The obtained crude product was purified by normal phase column chromatography (ethyl acetate: petroleum ether = 0% ~ 100%) to give compound M1-11 (195 mg, yield 49%) as a yellow oil. MS (ESI, m / z): 462.2 [M+H] + .

[0140] To a solution of compound M1-11 (195 mg, 0.425 mmol), 2-methyl-2-butene (600 mg, 8.5 mmol) in tetrahydrofuran:tert-butanol = 1:1 (20 mL), a solution of sodium phosphate monobasic (700 mg, 5.1 mmol), sodium chlorite (192 mg, 2.15 mmol) in water (10 mL) was added dropwise at 25 °C. The reaction was stirred at 25 °C for 4 h. The reaction was monitored by LCMS. After the reaction was completed, the reaction mixture was extracted with ethyl acetate (20 mL x 3). The organic phase was combined, dried over anhydrous sodium sulfate and concentrated. The residue was purified by column chromatography (ethyl acetate: petroleum ether = 0%~100%) to give compound M1 (128 mg, yield 63%) as yellow oil. MS (ESI, m / z): 478.2 [M+H] + .

[0141] Example 1

[0142] Synthetic route:

[0143] Intermediate M2 (120 mg, 0.25 mmol) was synthesized according to the synthesis of intermediate M1.

[0144] To a solution of intermediate M2 (120 mg, 0.25 mmol), triethylamine (76 mg, 0.75 mmol), 2-(7-azobenzotriazol)-N,N,N',N'-tetramethyluronium hexafluorophosphate (191 mg, 0.50 mmol) in N,N-dimethylformamide (5 mL) was stirred, then tert-butyl carbazate (66 mg, 0.50 mmol) was added. The reaction was stirred at room temperature for 16 h. After the reaction was completed, the reaction mixture was diluted with ethyl acetate (20 mL), washed with saturated brine (40 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (ethyl acetate: petroleum ether = 50%) to give 1-1 (145.4 mg, yield 97%) as yellow oil. MS (ESI, m / z): 592.2 [M+H] + .

[0145] To a solution of compound 1-1 (145 mg, 0.25 mmol) in 1,4-dioxane (2 mL) was stirred, then hydrogen chloride solution in 1,4-dioxane (4 M, 4 mL) was added. The reaction was stirred at room temperature for 4 h. After the reaction was completed, the reaction mixture was concentrated. The residue was purified by column chromatography [acetonitrile / water (0.1% triethylamine) = 0~100%] to give 1-2 (128.1 mg, yield 99%) as yellow oil. MS (ESI, m / z): 492.2 [M+H] + .

[0146] Compound 1-2 (70 mg, 0.157 mmol), compound 1-3 (26 mg, 0.157 mmol), N,N,N,N-tetramethyl-O-(7-azabenzotriazol-1-yl) uronium hexafluorophosphate (66 mg, 0.172 mmol) and triethylamine (44 mg, 0.430 mmol) were dissolved in dichloromethane (5 mL) and reacted at room temperature overnight. After the reaction was completed as shown by TLC, the reaction solution was concentrated, and the obtained crude product was subjected to normal phase column chromatography (ethyl acetate: petroleum ether = 0-100%) to obtain white solid 1-4 (93.2 mg, yield 99%), MS (ESI, m / z): 637.3 [M+H] + .

[0147] Compound 1-4 (80 mg, 0.126 mmol), p-toluenesulfonyl chloride (42 mg, 0.221 mmol) and triethylamine (45 mg, 0.441 mmol) were dissolved in dichloromethane (5 mL) and reacted at room temperature for 2 hours. After the reaction was completed as shown by TLC, the reaction solution was concentrated, and the obtained crude product was subjected to normal phase column chromatography (ethyl acetate: petroleum ether = 0-100%) to obtain white solid 1-5 (70.1 mg, yield 83%), MS (ESI, m / z): 620.3 [M+H] + .

[0148] Compound 1-5 (42 mg, 0.0677 mmol), lithium hydroxide (19 mg, 0.773 mmol), tetrahydrofuran (3 mL), methanol (3 mL) and water (3 mL) were added to a reaction tube and reacted at 50°C for 2 hours. After the reaction was completed as shown by TLC, the reaction solution was concentrated, and the obtained crude product was subjected to reverse phase column chromatography [acetonitrile / water (0.05% formic acid) = 0-100%] to obtain white solid 1 (20.2 mg, yield 47%), MS (ESI, m / z): 606.3 [M+H] + .

[0149] 1H NMR (400 MHz, CDC13) δ 7.83 (d, J = 8.0 Hz, 1H), 7.40 - 7.36 (m, 5H), 7.32 - 7.29 (m, 1H), 7.25 - 7.20 (m, 2H), 6.67 - 6.61 (m, 1H), 6.58 - 6.54 (m, 1H), 6.50 - 6.45 (m, 1H), 3.86 - 3.79 (m, 5H), 3.71 - 3.62 (m, 1H), 2.91 - 2.80 (m, 4H), 2.56 - 2.47 (m, 1H), 2.20 - 2.12 (m, 2H), 1.99 - 1.95 (m, 8H), 1.16 - 1.07 (m, 1H), 0.69 - 0.59 (m, 1H), 0.51 - 0.41 (m, 1H), 0.38 - 0.31 (m, 1H), 0.22 - 0.14 (m, 1H).

[0150] Example 2

[0151] Synthetic route:

[0152] The synthesis of Reference Compound 1 was performed by replacing Compound 1-3 with Compound 2-1 to synthesize and purify Compound 2 (32.2 mg, yield 76%) as a white solid by reverse phase column chromatography [acetonitrile / water (0.05% formic acid) = 0% ~ 100%]. MS (ESI, m / z): 620.3 [M+H] + .

[0153] 1 H NMR (400 MHz, CDC13) δ 7.83 (d, J = 8.0 Hz, 1H), 7.40 - 7.36 (m, 5H), 7.32 - 7.29 (m, 1H), 7.25 - 7.20 (m, 2H), 6.67 - 6.61 (m, 1H), 6.58 - 6.54 (m, 1H), 6.50 - 6.45 (m, 1H), 3.86 - 3.79 (m, 5H), 3.71 - 3.62 (m, 1H), 2.91 - 2.80 (m, 4H), 2.56 - 2.47 (m, 1H), 2.20 - 2.12 (m, 2H), 1.99 - 1.95 (m, 8H), 1.16 - 1.07 (m, 1H), 0.69 - 0.59 (m, 1H), 0.51 - 0.41 (m, 1H), 0.38 - 0.31 (m, 1H), 0.22 - 0.14 (m, 1H).

[0154] Example 3

[0155] Synthetic route:

[0156] Referring to the synthesis of Compound 1, Compound 1-3 was replaced by Compound 3-1 to synthesize and purify Compound 3 (37.3 mg, yield 75%) as a white solid by reverse phase column chromatography [acetonitrile / water (0.05% formic acid) = 0% ~ 100%]. MS (ESI, m / z): 634.3 [M+H] + .

[0157] 1 H NMR (400 MHz, CDC13) δ 7.96 (d, J = 8.0 Hz, 1H), 7.44 (s, 1H), 7.29 - 7.13 (m, 7H), 6.67 - 6.62 (m, 1H), 6.60 - 6.55 (m, 1H), 6.51 - 6.44 (m, 1H), 3.89 - 3.80 (m, 6H), 2.99 - 2.84 (m, 4H), 2.70 - 2.62 (m, 2H), 2.58 - 2.50 (m, 1H), 2.28 - 2.20 (m, 2H), 2.20 - 2.15 (m, 2H), 2.12 - 2.05 (m, 2H), 1.61 (s, 6H), 1.17 - 1.09 (m, 1H), 0.72 - 0.63 (m, 1H), 0.53 - 0.44 (m, 1H), 0.41 - 0.34 (m, 1H), 0.28 - 0.19 (m, 1H).

[0158] Example 4

[0159] Synthesis route:

[0160] Referring to the synthesis of Compound 1, Compound 1-3 was replaced by Compound 4-1 to synthesize and purify Compound 4 (16.1 mg, yield 47%) as a white solid by reverse phase column chromatography [acetonitrile / water (0.05% formic acid) = 0% ~ 100%]. MS (ESI, m / z): 648.3 [M+H] + .

[0161] 1H NMR (400 MHz, CDC13) δ 7.89 (d, J = 7.2 Hz, 1H), 7.45 (s, 1H), 7.29 - 7.24 (m, 4H), 7.18 - 7.14 (m, 3H), 6.87 - 6.38 (m, 3H), 3.89 - 3.82 (m, 6H), 3.01 - 2.83 (m, 4H), 2.64 (t, J = 7.6 Hz, 2H), 2.57 - 2.50 (m, 1H), 2.35 - 2.18 (m, 2H), 2.13 - 2.05 (m, 2H), 1.89 - 1.84 (m, 2H), 1.69 - 1.64 (m, 2H), 1.52 (s, 6H), 1.16 - 1.10 (m, 1H), 0.71 - 0.64 (m, 1H), 0.52 - 0.46 (m, 1H), 0.42 - 0.36 (m, 1H), 0.26 - 0.20 (m, 1H).

[0162] Example 5

[0163] Synthetic route:

[0164] Referring to the synthesis of Compound 1, Compound 1-3 is replaced with Compound 5-1 to synthesize and purify Compound 5 (14.2 mg, yield 24%) as a white solid by reverse phase column chromatography [acetonitrile / water (0.05% formic acid) = 0% ~ 100%]. MS (ESI, m / z): 662.3 [M+H] + .

[0165] 1H NMR (400 MHz, CDC13) δ 7.91 (d, J = 8.0 Hz, 1H), 7.43 (s, 1H), 7.29 - 7.19 (m, 2H), 7.10 - 7.02 (m, 4H), 6.64 (d, J = 8.0 Hz, 1H), 6.57 (s, 1H), 6.47 (d, J = 7.2 Hz, 1H), 3.85 - 3.77 (m, 6H), 2.98 - 2.86 (m, 4H), 2.64 - 2.51 (m, 3H), 2.28 (s, 3H), 2.27 - 2.15 (m, 2H), 2.11 - 2.01 (m, 2H), 1.88 - 1.82 (m, 2H), 1.70 - 1.59 (m, 2H), 1.51 (s, 6H), 1.16 - 1.09 (m, 1H), 0.71 - 0.65 (m, 1H), 0.51 - 0.45 (m, 1H), 0.40 - 0.34 (m, 1H), 0.26 - 0.17 (m, 1H).

[0166] Example 6

[0167] Synthetic route:

[0168] Referring to the synthesis of Compound 1, Compound 1-3 is replaced with Compound 6-1 to synthesize and purify Compound 6 (23.1 mg, yield 58%) as a white solid by reverse phase column chromatography [acetonitrile / water (0.05% formic acid) = 0%~100%] to obtain Compound 6. MS (ESI, m / z): 666.3 [M+H] + .

[0169] 1 H NMR (400 MHz, CDC13) δ 7.90 - 7.86 (m, 1H), 7.44 (s, 1H), 7.29 - 7.20 (m, 2H), 7.10 (dd, J = 8.4, 5.6 Hz, 2H), 6.97 - 6.90 (m, 2H), 6.67 - 6.62 (m, 1H), 6.59 - 6.56 (m, 1H), 6.50 - 6.45 (m, 1H), 3.88 - 3.80 (m, 6H), 2.98 - 2.87 (m, 4H), 2.65 - 2.51 (m, 3H), 2.26 - 2.16 (m, 2H), 2.06 (d, J = 12.8 Hz, 2H), 1.83 (d, J = 7.6 Hz, 2H), 1.65 (d, J = 7.6 Hz, 2H), 1.52 (s, 6H), 1.16 - 1.12 (m, 1H), 0.68 - 0.66 (m, 1H), 0.49 - 0.47 (m, 1H), 0.40 - 0.37 (m, 1H), 0.27 - 0.20 (m, 1H).

[0170] Example 7

[0171] Synthesis route:

[0172] Referring to the synthesis of Compound 1, Compound 1-3 is replaced with Compound 7-1 to synthesize and purify Compound 7 (9.8 mg, yield 17%) as a white solid by reverse phase column chromatography [acetonitrile / water (0.05% formic acid) = 0%~100%]. MS (ESI, m / z): 666.3 [M+H] + .

[0173] 1H NMR (400 MHz, CDC13) δ 7.89 (d, J = 8.0 Hz, 1H), 7.43 (s, 1H), 7.28 - 7.17 (m, 3H), 6.93 (d, J = 7.6 Hz, 1H), 6.86 (d, J = 9.2 Hz, 2H), 6.64 (d, J = 8.0 Hz, 1H), 6.57 (s, 1H), 6.48 (d, J = 8.0 Hz, 1H), 3.87 - 3.80 (m, 6H), 2.98 - 2.85 (m, 4H), 2.64 (t, J = 7.6 Hz, 2H), 2.57 - 2.50 (m, 1H), 2.28 - 2.17 (m, 2H), 2.06 (d, J = 11.6 Hz, 2H), 1.87 - 1.83 (m, 2H), 1.71 - 1.64 (m, 2H), 1.52 (s, 6H), 1.16 - 1.06 (m, 1H), 0.74 - 0.62 (m, 1H), 0.53 - 0.44 (m, 1H), 0.41 - 0.35 (m, 1H), 0.25 - 0.19 (m, 1H).

[0174] Example 8

[0175] Synthesis route:

[0176] Referring to the synthesis of Compound 1, Compound 1-3 was replaced with Compound 8-1 to synthesize and purify Compound 8 (12.9 mg, yield 41%) as a white solid by reverse phase column chromatography [acetonitrile / water (0.05% formic acid) = 0% ~ 100%]. MS (ESI, m / z): 666.3 [M+H] + .

[0177] 1H NMR (400 MHz, CDC13) δ 7.91 (d, J = 8.0 Hz, 1H), 7.43 (s, 1H), 7.28 - 7.20 (m, 2H), 7.17 - 7.12 (m, 2H), 7.06 - 6.95 (m, 2H), 6.64 (d, J = 8.0 Hz, 1H), 6.57 (s, 1H), 6.47 (dd, J = 8.0, 2.0 Hz, 1H), 3.87 - 3.81 (m, 6H), 2.98 - 2.84 (m, 4H), 2.67 (t, J = 7.6 Hz, 2H), 2.59 - 2.52 (m, 1H), 2.22 (d, J = 10.4 Hz, 2H), 2.06 (d, J = 12.0 Hz, 2H), 1.90 - 1.86 (m, 2H), 1.71 - 1.63 (m, 2H), 1.52 (s, 6H), 1.17 - 1.07 (m, 1H), 0.72 - 0.62 (m, 1H), 0.50 - 0.47 (m, 1H), 0.39 - 0.36 (m, 1H), 0.25 - 0.20 (m, 1H).

[0178] Example 9

[0179] Synthesis route:

[0180] Referring to the synthesis of Compound 1, Compound 1-3 is replaced with Compound 9-1 to synthesize and purify by reverse phase column chromatography [acetonitrile / water (0.05% formic acid) = 0% ~ 100%] to obtain white solid Compound 9 (18.1 mg, yield 60%). MS (ESI, m / z): 704.3 [M+H] + .

[0181] 1H NMR (400 MHz, CDC13) δ 7.94 (d, J = 8.0 Hz, 1H), 7.44 (s, 1H), 7.31 - 7.26 (m, 3H), 7.26 - 7.19 (m, 1H), 7.10 (d, J = 8.0 Hz, 2H), 6.64 (d, J = 8.0 Hz, 1H), 6.57 (s, 1H), 6.47 (d, J = 8.0 Hz, 1H), 3.87 - 3.82 (m, 6H), 2.97 - 2.87 (m, 4H), 2.63 - 2.53 (m, 3H), 2.23 - 2.18 (m, 2H), 2.08 - 2.05 (m, 2H), 1.91 - 1.86 (m, 2H), 1.69 - 1.67 (m, 2H), 1.53 (s, 6H), 1.30 (s, 9H), 1.16 - 1.13 (m, 1H), 0.69 - 0.65 (m, 1H), 0.51 - 0.47 (m, 1H), 0.40 - 0.36 (m, 1H), 0.24 - 0.21 (m, 1H).

[0182] Example 10

[0183] Synthetic route:

[0184] Referring to the synthesis of compound 1, compound 1-3 is replaced by compound 10-1 to synthesize white solid 10-2 (30 mg, 0.0474 mmol), which is dissolved in dichloromethane (2 ml) with p-tolylsulfonyl chloride (11 mg, 0.0568 mmol) and triethylamine (23 mg, 0.176 mmol) at room temperature for 2 hours. After TLC shows that the reaction is completed, the reaction solution is concentrated, and the obtained crude product is subjected to normal phase column chromatography (ethyl acetate: petroleum ether = 0-100%) to obtain white solid 10-3 (18.5 mg, yield 66%), MS (ESI, m / z): 574.0 [M+H] + .

[0185] Compound 10-4 (300 mg, 2.97 mmol), compound 10-5 (392 mg, 3.56 mmol), copper sulfate (141 mg, 0.713 mmol) and sodium ascorbate (356 mg, 1.43 mmol) are dissolved in tert-butyl alcohol (8 mL) and water (8 mL) at room temperature for 2 hours. After TLC shows that the reaction is completed, water (30 mL) is added for dilution, and ethyl acetate (30 mL x 3) is extracted. The organic phase is dried with anhydrous sodium sulfate, filtered, and concentrated. The obtained crude product is subjected to normal phase column chromatography (ethyl acetate: petroleum ether = 0-100%) to obtain white solid 10-6 (599.8 mg, yield 99%), MS (ESI, m / z): 198.0 [M+H] + .

[0186] Compound 10-6 (200 mg, 1.01 mmol), triphenylphosphine (532 mg, 2.03 mg), iodine (515 mg, 2.03 mmol) and imidazole (138 mg, 2.03 mmol) were dissolved in dichloromethane (10 mL) and reacted at room temperature overnight. After the reaction was completed as shown by TLC, the reaction solution was concentrated, and the obtained crude product was subjected to normal phase column chromatography (ethyl acetate: petroleum ether = 0-100%) to obtain white solid 10-7 (218.5 mg, yield 69%), MS (ESI, m / z): 308.0 [M+H] + .

[0187] Compound 10-3 (10 mg, 0.0175 mmol) was dissolved in dimethyl sulfoxide (2 mL), and potassium tert-butoxide (3.0 mg, 0.0262 mmol) and 18-crown-6 (4.6 mg, 0.0175 mmol) were added, and the mixture was reacted at room temperature for 1 hour. Compound 10-7 (11 mg, 0.035 mmol) was added, and the mixture was reacted at room temperature overnight. After the reaction was completed as shown by TLC, the reaction solution was concentrated, and the obtained crude product was subjected to reverse phase column chromatography [acetonitrile / water (0.05% formic acid) = 0-100%] to obtain white solid 10 (2.4 mg, yield 18%), MS (ESI, m / z): 739.0 [M+H] + .

[0188] 1 H NMR (400 MHz, CDC13) δ 7.76 - 7.67 (m, 1H), 7.50 - 7.41 (m, 2H), 7.40 - 7.34 (m, 1H), 7.27 - 7.22 (m, 1H), 6.81 - 6.45 (m, 3H), 4.74 - 4.64 (m, 2H), 4.49 - 4.36 (m, 2H), 3.88 - 3.79 (m, 5H), 3.71 - 3.39 (m, 3H), 3.01 - 2.84 (m, 4H), 2.78 - 2.72 (m, 2H), 2.56 - 2.51 (m, 1H), 2.04 - 1.99 (m, 2H), 1.71 - 1.68 (m, 2H), 1.37 - 1.31 (m, 8H), 1.16 - 1.11 (m, 1H), 1.01 (s, 6H), 0.93 - 0.90 (m, 3H), 0.71 - 0.67 (m, 1H), 0.53 - 0.47 (m, 1H), 0.43 - 0.37 (m, 1H), 0.27 - 0.20 (m, 1H).

[0189] Example 11

[0190] Synthetic route:

[0191] The compound 11 was synthesized by referring to the synthesis of compound 1, replacing compound 1-3 with compound 11-1, and purified by reverse phase column chromatography [acetonitrile / water (0.05% formic acid) = 0%~100%] to obtain compound 11 (31.2 mg, yield 37%) as a white solid. MS (ESI, m / z): 646.3 [M+H] + .

[0192] 1 H NMR (400 MHz, CDC13) δ 7.82 (d, J = 8.0 Hz, 1H), 7.46 - 7.32 (m, 5H), 7.27 - 7.18 (m, 3H), 6.72 - 6.34 (m, 3H), 3.83 (s, 3H), 3.80 (d, J = 1.6 Hz, 2H), 3.76 - 3.63 (m, 1H), 2.91 - 2.78 (m, 4H), 2.73 (d, J = 13.6 Hz, 2H), 2.48 (q, J = 8.0 Hz, 1H), 2.28 - 2.08 (m, 4H), 2.05 - 1.93 (m, 2H), 1.78 (t, J = 8.8 Hz, 2H), 1.73 - 1.52 (m, 4H), 1.13 - 1.01 (m, 1H), 0.65 - 0.58 (m, 1H), 0.46 - 0.40 (m, 1H), 0.37 - 0.28 (m, 1H), 0.19 - 0.13 (m, 1H).

[0193] Example 12

[0194] Synthetic route:

[0195] The compound 12 was synthesized by referring to the synthesis of compound M2, replacing compound M1-9 with compound 12-1, and then referring to the synthesis of compound 10, replacing compound 10-3 with compound 12-2, and purified by reverse phase column chromatography [acetonitrile / water (0.05% formic acid) = 0%~100%] to obtain compound 12 (6.2 mg, yield 63%) as a white solid. MS (ESI, m / z): 737.3 [M+H] + .

[0196] 1H NMR (400 MHz, CDC13) δ 7.73 - 7.65 (m, 2H), 7.44 (d, J = 8.0 Hz, 1H), 7.33 (s, 1H), 7.23 - 7.17 (m, 1H), 7.13 (s, 1H), 7.09 (d, J = 8.0 Hz, 1H), 6.65 - 6.59 (m, 1H), 6.58 - 6.51 (m, 1H), 6.48 - 6.41 (m, 1H), 4.52 - 4.41 (m, 2H), 4.40 - 4.36 (m, 2H), 3.89 (s, 2H), 3.85 - 3.80 (m, 5H), 3.13 - 3.02 (m, 1H), 2.90 - 2.76 (m, 4H), 2.67 (t, J = 7.6 Hz, 2H), 2.49 - 2.41 (m, 1H), 2.29 - 2.18 (m, 2H), 1.96 - 1.90 (m, 2H), 1.67 - 1.62 (m, 8H), 1.35 - 1.28 (m, 6H), 1.12 - 1.04 (m, 1H), 0.89 (t, J = 6.0 Hz, 3H), 0.63 - 0.55 (m, 1H), 0.49 - 0.41 (m, 1H), 0.29 - 0.24 (m, 1H), 0.22 - 0.15 (m, 1H).

[0197] Example 13

[0198] Synthetic route:

[0199] To a mixture of sodium hydride (708 mg, 17.7 mmol) and tetrahydrofuran (10 ml) was added compound 13-1 (2 g, 11.8 mmol), a solution of compound 13-2 (2.41 g, 12.4 mmol) in tetrahydrofuran (5 ml) at -30 °C, stirred at room temperature for 2 hours, TLC showed that the reaction was completed, the reaction solution was concentrated, the obtained crude product was purified by normal phase column chromatography (ethyl acetate: petroleum ether = 0-100%) to obtain white solid 13-3 (2.4 g, yield 65%), MS (ESI, m / z): 210.0 [M+H] + .

[0200] Compound 13-3 (716 mg, 3.43 mmol), sodium hydroxide (1.37 g, 34.3 mmol) and ethylene glycol (15 ml) were stirred at 120 °C for 1 hour, then stirred at 160 °C for 2 hours, TLC showed that the reaction was completed, the reaction solution was concentrated, the obtained crude product was purified by normal phase column chromatography (ethyl acetate: petroleum ether = 0-100%) to obtain white solid 13-4 (450.2 mg, yield 86%), MS (ESI, m / z): 152.0 [M+H] + .

[0201] Referring to the synthesis of compound M2, compound 13-6 (140 mg, 0.27 mmol) was synthesized by replacing compound M1-9 with compound 13-5, then compound 13-7 (66.4 mg, 0.40 mmol), tributylphosphine (108 mg, 0.53 mmol) and azodicarboxylic acid dipeperidine (134 mg, 0.53 mmol) were added to tetrahydrofuran (10 mL) and warmed to 60 °C with stirring overnight. TLC showed that the reaction was completed, the reaction solution was concentrated, and the obtained crude product was purified by normal phase column chromatography (ethyl acetate: petroleum ether = 0-100%) to obtain white solid 13-8 (70.3 mg, yield 39%), MS (ESI, m / z): 674.2 [M+H] + .

[0202] Compound 13-8 (70.3 mg, 0.104 mmol), compound 13-4 (21.8 mg, 0.104 mmol), sodium hydride (3.8 mg, 0.157 mmol) and N,N-dimethylformamide (2 ml) were stirred at 0 °C for 3 hours, TLC showed that the reaction was completed, water (0.5 ml) was added to quench the reaction, the reaction solution was concentrated, and the obtained crude product was purified by reverse phase column chromatography [acetonitrile / water (0.05% formic acid) = 0%-100%] to obtain white solid compound 13 (2.2 mg, yield 3%). MS (ESI, m / z): 731.3 [M+H] + .

[0203] 1H NMR (400 MHz, CDC13) δ 7.48 (d, J = 8.0 Hz, 1H), 7.42 - 7.34 (m, 2H), 7.22 - 7.16 (m, 1H), 7.13 (d, J = 8.0 Hz, 1H), 7.05 - 6.96 (m, 2H), 6.92 (d, J = 10.0 Hz, 1H), 6.60 (d, J = 8.8 Hz, 1H), 6.57 - 6.50 (m, 2H), 6.46 - 6.40 (m, 2H), 5.99 - 5.96 (m, 1H), 4.00 (t, J = 6.4 Hz, 2H), 3.88 - 3.83 (m, 2H), 3.82 - 3.77 (m, 5H), 3.17 - 3.04 (m, 1H), 2.94 - 2.74 (m, 4H), 2.54 - 2.47 (m, 1H), 2.47 - 2.40 (m, 2H), 2.33 - 2.16 (m, 2H), 1.92 (d, J = 12.0 Hz, 2H), 1.88 - 1.77 (m, 4H), 1.60 - 1.45 (m, 4H), 1.39 - 1.28 (m, 6H), 1.13 - 1.06 (m, 1H), 0.91 - 0.87 (m, 3H), 0.68 - 0.54 (m, 1H), 0.51 - 0.40 (m, 1H), 0.39 - 0.30 (m, 1H), 0.27 - 0.17 (m, 1H).

[0204] Example 14

[0205] Synthesis route:

[0206] The compound 14 was synthesized by the same method of the synthesis of the reference compound 13, replacing the compound 13-4 with the compound 14-1, and purified by reverse phase column chromatography [acetonitrile / water (0.05% formic acid) = 0% ~ 100%] to obtain a white solid compound 14 (22.1 mg, yield 85%). MS (ESI, m / z): 732.3 [M+H] + .

[0207] 1H NMR (400 MHz, CDC13) δ 7.46 (d, J = 8.0 Hz, 1H), 7.42 - 7.35 (m, 2H), 7.33 (s, 1H), 7.23 - 7.16 (m, 1H), 7.16 - 7.10 (m, 2H), 7.04 - 6.97 (m, 2H), 6.90 (d, J = 8.0 Hz, 1H), 6.65 - 6.57 (m, 1H), 6.57 - 6.50 (m, 1H), 6.48 - 6.40 (m, 1H), 4.10 (t, J = 7.2 Hz, 2H), 3.99 (t, J = 6.4 Hz, 2H), 3.85 - 3.76 (m, 5H), 3.16 - 3.06 (m, 1H), 2.94 - 2.74 (m, 4H), 2.55 - 2.47 (m, 1H), 2.43 (t, J = 7.6 Hz, 2H), 2.33 - 2.17 (m, 2H), 1.98 - 1.88 (m, 4H), 1.88 - 1.81 (m, 2H), 1.57 - 1.43 (m, 4H), 1.36 - 1.24 (m, 6H), 1.15 - 1.08 (m, 1H), 0.92 - 0.84 (m, 3H), 0.68 - 0.58 (m, 1H), 0.52 - 0.41 (m, 1H), 0.40 - 0.30 (m, 1H), 0.26 - 0.16 (m, 1H).

[0208] Example 15

[0209] Synthetic route:

[0210] Referring to the synthesis of compound 13, compound 13-7 was replaced by compound 15-1 to synthesize compound 15-2 (60 mg, 0.094 mmol) as a yellow oil. Compound 15-2, compound 15-3 (12 mg, 0.11 mmol), copper sulfate pentahydrate (5 mg, 0.018 mmol), and sodium salt of vitamin C (7 mg, 0.038 mmol) were added to a mixture of tert-butanol (10 mL) and water (10 mL), and stirred at 45 °C for 2 hours. After TLC showed that the reaction was completed, ethyl acetate (100 mL) was added, and the organic phase was washed with saturated brine. The organic phases were combined and concentrated to obtain a crude product, which was subjected to normal phase column chromatography (ethyl acetate: petroleum ether = 0-100%) to obtain compound 15-4 (69.3 mg, yield 98%) as a yellow oil, MS (ESI, m / z): 746.7 [M+H] + .

[0211] Compound 15-4 (69.3 mg, 0.092 mmol) was added to a mixture of tetrahydrofuran (4 mL) and methanol (4 mL), and then a solution of lithium hydroxide (26 mg, 0.92 mmol) in water (1.5 mL) was added to the reaction solution, which was stirred at 60 °C for 1 hour. After the reaction was completed as indicated by TLC, the reaction solution was concentrated, and the resulting crude product was purified by reverse-phase column chromatography [acetonitrile / water (0.05% formic acid) = 0% to 100%] to obtain compound 15 as a white solid (29.8 mg, yield 44%). MS (ESI, m / z): 732.8 [M+H] + .

[0212] 1 H NMR (400 MHz, CDCl3) δ 7.42 (d, J = 7.6 Hz, 1H), 7.38 - 7.31 (m, 2H), 7.27 (s, 1H), 7.18 - 7.12 (m, 1H), 7.11 (d, J = 7.6 Hz, 1H), 7.01 - 6.93 (m, 2H), 6.89 - 6.83 (m, 1H), 6.60 - 6.35 (m, 3H), 4.38 (t, J = 7.2 Hz, 2H), 4.02 (t, J = 6.0 Hz, 2H), 3.83 - 3.76 (m, 5H), 3.14 - 3.03 (m, 1H), 2.95 - 2.79 (m, 4H), 2.72 (t, J = 7.6 Hz, 2H), 2.54 - 2.46 (m, 1H), 2.37 - 2.23 (m, 2H), 2.06 - 1.82 (m, 6H), 1.71 - 1.63 (m, 2H), 1.59 - 1.52 (m, 2H), 1.37 - 1.27 (m, 6H), 1.13 - 1.04 (m, 1H), 0.88 (t, J = 5.6 Hz, 3H), 0.66 - 0.57 (m, 1H), 0.49 - 0.40 (m, 1H), 0.37 - 0.31 (m, 1H), 0.23 - 0.16 (m, 1H).

[0213] Example 16

[0214] Synthetic route:

[0215] Referring to the synthesis of compound 15, compound 15-1 was replaced by compound 16-1 to synthesize and purify compound 16 as a white solid (35.5 mg, yield 26%) by reverse-phase column chromatography [acetonitrile / water (0.05% formic acid) = 0% to 100%]. MS (ESI, m / z): 718.8 [M+H] + .

[0216] 1H NMR (400 MHz, CDC13) δ 7.46 (s, 1H), 7.42 - 7.34 (m, 2H), 7.29 (s, 1H), 7.22 - 7.15 (m, 1H), 7.13 (d, J = 8.0 Hz, 1H), 7.03 (d, J = 7.6 Hz, 1H), 7.00 (s, 1H), 6.90 (d, J = 8.0 Hz, 1H), 6.59 (d, J = 7.6 Hz, 1H), 6.52 (s, 1H), 6.43 (d, J = 8.0 Hz, 1H), 4.43 (t, J = 7.2 Hz, 2H), 4.03 (t, J = 5.6 Hz, 2H), 3.85 - 3.73 (m, 5H), 3.13 - 3.03 (m, 1H), 2.92 - 2.77 (m, 4H), 2.70 (t, J = 7.6 Hz, 2H), 2.54 - 2.46 (m, 1H), 2.30 - 2.07 (m, 4H), 1.96 - 1.79 (m, 4H), 1.69 - 1.61 (m, 2H), 1.34 - 1.24 (m, 6H), 1.14 - 1.05 (m, 1H), 0.91 - 0.83 (m, 3H), 0.66 - 0.58 (m, 1H), 0.48 - 0.40 (m, 1H), 0.38 - 0.30 (m, 1H), 0.24 - 0.15 (m, 1H).

[0217] Example 17

[0218] Synthesis route:

[0219] Referring to the synthesis of Compound 15, Compound 15-1 was replaced with Compound 17-1 to synthesize and purify Compound 17 (25.8 mg, yield 20%) as a white solid by reverse phase column chromatography [acetonitrile / water (0.05% formic acid) = 0% ~ 100%]. MS (ESI, m / z): 690.7 [M+H] + .

[0220] 1H NMR (400 MHz, CDC13) δ 7.49 (s, 1H), 7.46 - 7.35 (m, 3H), 7.22 - 7.15 (m, 1H), 7.13 (d, J = 8.0 Hz, 1H), 7.06 (d, J = 8.0 Hz, 1H), 7.00 (s, 1H), 6.90 (d, J = 8.0 Hz, 1H), 6.59 (d, J = 8.0 Hz, 1H), 6.52 (s, 1H), 6.43 (d, J = 8.4 Hz, 1H), 4.76 (t, J = 8.0 Hz, 2H), 4.39 (t, J = 8.0 Hz, 2H), 3.84 - 3.74 (m, 5H), 3.06 (t, J = 12.0 Hz, 1H), 2.91 - 2.77 (m, 4H), 2.71 (t, J = 7.6 Hz, 2H), 2.55 - 2.46 (m, 1H), 2.30 - 2.16 (m, 2H), 1.95 - 1.86 (m, 2H), 1.70 - 1.60 (m, 2H), 1.36 - 1.28 (m, 6H), 1.13 - 1.06 (m, 1H), 0.88 - 0.81 (m, 3H), 0.66 - 0.58 (m, 1H), 0.48 - 0.40 (m, 1H), 0.38 - 0.31 (m, 1H), 0.24 - 0.15 (m, 1H).

[0221] Example 18

[0222] Synthetic route:

[0223] Referring to the synthesis of compound 15, compound 15-2 (23 mg, 0.036 mmol) was synthesized with compound 15-3 (4 mg, 0.036 mmol) and pentamethylcyclopentadienyl bis(triphenylphosphine) ruthenium chloride (2 mg) was added to 1,4-dioxane (2 mL), stirred at 60 °C for 16 h. TLC showed that the reaction was completed, then ethyl acetate (50 mL) was added, the organic phase was washed with saturated brine, and the organic phase was concentrated to obtain a crude product, which was purified by normal phase column chromatography (ethyl acetate: petroleum ether = 0-100%) to obtain yellow oil 18-1 (9.5 mg, yield 35%), MS (ESI, m / z): 747.2 [M+H] + .

[0224] Referring to the synthesis of compound 15, compound 15-2 (23 mg, 0.036 mmol) was synthesized with compound 15-3 (4 mg, 0.036 mmol) and pentamethylcyclopentadienyl bis(triphenylphosphine) ruthenium chloride (2 mg) was added to 1,4-dioxane (2 mL), stirred at 60 °C for 16 h. TLC showed that the reaction was completed, then ethyl acetate (50 mL) was added, the organic phase was washed with saturated brine, and the organic phase was concentrated to obtain a crude product, which was purified by normal phase column chromatography (ethyl acetate: petroleum ether = 0-100%) to obtain yellow oil 18-1 (9.5 mg, yield 35%), MS (ESI, m / z): 747.2 [M+H] + .

[0225] 1H NMR (400 MHz, CDC13) δ 7.46 - 7.37 (m, 4H), 7.25 - 7.21 (m, 1H), 7.15 (d, J = 8.0 Hz, 1H), 7.03 - 6.98 (m, 2H), 6.92 (d, J = 8.0 Hz, 1H), 6.71 - 6.36 (m, 3H), 4.26 (t, J = 7.6 Hz, 2H), 4.01 (t, J = 6.4 Hz, 2H), 3.86 - 3.76 (m, 5H), 3.17 - 3.03 (m, 1H), 2.96 - 2.76 (m, 4H), 2.61 (t, J = 8.0 Hz, 2H), 2.56 - 2.47 (m, 1H), 2.28 - 2.17 (m, 2H), 2.04 - 1.93 (m, 4H), 1.91 - 1.83 (m, 2H), 1.71 - 1.54 (m, 4H), 1.41 - 1.24 (m, 6H), 1.18 - 1.07 (m, 1H), 0.93 - 0.86 (m, 3H), 0.70 - 0.60 (m, 1H), 0.51 - 0.42 (m, 1H), 0.40 - 0.31 (m, 1H), 0.26 - 0.16 (m, 1H).

[0226] Example 19

[0227] The synthesis of Reference Compound 15 was performed by replacing Compound 15-3 with Compound 19-1 to give Compound 19 (29.5 mg, 37% yield) as a white solid after purification by reverse phase column chromatography [acetonitrile / water (0.05% formic acid) = 0% ~ 100%]. MS (ESI, m / z): 738.9 [M+H] + .

[0228] 1H NMR (400 MHz, CDC13) δ 7.75 - 7.67 (m, 3H), 7.47 (d, J = 7.6 Hz, 1H), 7.41 - 7.34 (m, 2H), 7.23 - 7.17 (m, 3H), 7.12 (d, J = 7.6 Hz, 1H), 7.04 - 6.98 (m, 2H), 6.91 (dd, J = 8.0 Hz, 1.6 Hz, 1H), 6.60 (d, J = 8.4 Hz, 1H), 6.53 (s, 1H), 6.43 (dd, J = 8.4 Hz, 1.6 Hz, 1H), 4.44 (t, J = 7.2 Hz, 2H), 4.01 (t, J = 6.4 Hz, 2H), 3.83 - 3.76 (m, 5H), 3.10 (t, J = 12.0 Hz, 1H), 2.92 - 2.77 (m, 4H), 2.53 - 2.47 (m, 1H), 2.38 (s, 3H), 2.28 - 2.19 (m, 2H), 2.09 - 2.02 (m, 2H), 1.93 - 1.85 (m, 4H), 1.62 - 1.54 (m, 2H), 1.15 - 1.05 (m, 1H), 0.66 - 0.57 (m, 1H), 0.48 - 0.40 (m, 1H), 0.39 - 0.30 (m, 1H), 0.24 - 0.16 (m, 1H).

[0229] Example 20

[0230] Synthesis route:

[0231] The compound 20 was synthesized by the same method of the synthesis of the reference compound 15, by replacing the compound 15-3 with the compound 20-1, and purified by reverse phase column chromatography [acetonitrile / water (0.05% formic acid) = 0% ~ 100%] to obtain a white solid compound 20 (18.6 mg, yield 32%). MS (ESI, m / z): 738.9 [M+H] + .

[0232] 1H NMR (400 MHz, CDC13) δ 7.79 - 7.73 (m, 1H), 7.65 (s, 1H), 7.47 (d, J = 8.0 Hz, 1H), 7.41 - 7.34 (m, 2H), 7.29 - 7.26 (m, 3H), 7.22 - 7.15 (m, 1H), 7.12 (d, J = 8.0 Hz, 1H), 7.04 - 7.00 (m, 2H), 6.91 (dd, J = 8.0 Hz, 1.6 Hz, 1H), 6.60 (d, J = 7.6 Hz, 1H), 6.53 (s, 1H), 6.43 (d, J = 7.6 Hz, 1H), 4.47 (t, J = 7.2 Hz, 2H), 4.03 (t, J = 6.0 Hz, 2H), 3.83 - 3.77 (m, 5H), 3.10 (t, J = 12.0 Hz, 1H), 2.91 - 2.78 (m, 4H), 2.53 - 2.47 (m, 4H), 2.29 - 2.19 (m, 2H), 2.13 - 2.04 (m, 2H), 1.94 - 1.86 (m, 4H), 1.64 - 1.56 (m, 2H), 1.14 - 1.06 (m, 1H), 0.66 - 0.58 (m, 1H), 0.49 - 0.41 (m, 1H), 0.38 - 0.31 (m, 1H), 0.23 - 0.16 (m, 1H).

[0233] Example 21

[0234] Synthesis route:

[0235] Referring to the synthesis of Compound 15, Compound 15-3 is replaced with Compound 21-1 to synthesize and purify white solid Compound 21 (26.2 mg, yield 34%) by reverse phase column chromatography [acetonitrile / water (0.05% formic acid) = 0% ~ 100%] to synthesize and purify white solid Compound 21 (26.2 mg, yield 34%) by reverse phase column chromatography [acetonitrile / water (0.05% formic acid) = 0% ~ 100%]. MS (ESI, m / z): 738.9 [M+H] + .

[0236] 1H NMR (400 MHz, CDC13) δ 7.75 (s, 1H), 7.69 (s, 1H), 7.60 (d, J = 7.6 Hz, 1H), 7.47 (d, J = 8.0 Hz, 1H), 7.41 - 7.37 (m, 2H), 7.33 - 7.27 (m, 1H), 7.21 - 7.11 (m, 3H), 7.03 - 6.97 (m, 2H), 6.91 (dd, J = 8.4 Hz, 2.0 Hz, 1H), 6.60 (d, J = 7.6 Hz, 1H), 6.53 (s, 1H), 6.43 (d, J = 7.6 Hz, 1H), 4.45 (t, J = 7.2 Hz, 2H), 4.02 (t, J = 6.0 Hz, 2H), 3.84 - 3.75 (m, 5H), 3.10 (t, J = 12.0 Hz, 1H), 2.93 - 2.74 (m, 4H), 2.53 - 2.47 (m, 1H), 2.40 (s, 3H), 2.29 - 2.18 (m, 2H), 2.10 - 2.02 (m, 2H), 1.94 - 1.86 (m, 4H), 1.62 - 1.54 (m, 2H), 1.16 - 1.05 (m, 1H), 0.66 - 0.58 (m, 1H), 0.49 - 0.40 (m, 1H), 0.39 - 0.31 (m, 1H), 0.23 - 0.16 (m, 1H).

[0237] Example 22

[0238] Synthesis route:

[0239] Referring to the synthesis of Compound 15, Compound 22-1 was used instead of Compound 15-3 to synthesize and purify by reverse phase column chromatography [acetonitrile / water (0.05% formic acid) = 0% ~ 100%] to obtain Compound 22 as a white solid (47.8 mg, yield 56%). MS (ESI, m / z): 792.9 [M+H] + .

[0240] 1H NMR (400 MHz, CDC13) δ 7.94 (d, J = 8.0 Hz, 2H), 7.84 (s, 1H), 7.67 (d, J = 8.0 Hz, 2H), 7.47 (d, J = 8.0 Hz, 1H), 7.41 - 7.34 (m, 2H), 7.22 - 7.16 (m, 1H), 7.12 (d, J = 8.4 Hz, 1H), 7.04 - 7.00 (m, 2H), 6.91 (dd, J = 8.0 Hz, 1.6 Hz, 1H), 6.60 (d, J = 8.0 Hz, 1H), 6.52 (s, 1H), 6.43 (d, J = 7.2 Hz, 1H), 4.47 (t, J = 7.2 Hz, 2H), 4.02 (t, J = 6.4 Hz, 2H), 3.83 - 3.77 (m, 5H), 3.09 (t, J = 12.0 Hz, 1H), 2.92 - 2.77 (m, 4H), 2.53 - 2.47 (m, 1H), 2.29 - 2.19 (m, 2H), 2.12 - 2.05 (m, 2H), 1.93 - 1.87 (m, 4H), 1.64 - 1.56 (m, 2H), 1.15 - 1.06 (m, 1H), 0.67 - 0.58 (m, 1H), 0.49 - 0.41 (m, 1H), 0.38 - 0.29 (m, 1H), 0.24 - 0.16 (m, 1H).

[0241] Example 23

[0242] Synthesis route:

[0243] Referring to the synthesis of Compound 15, Compound 15-3 is replaced with Compound 23-1 to synthesize and purify white solid Compound 23 (24.4 mg, yield 40%) by reverse phase column chromatography [acetonitrile / water (0.05% formic acid) = 0% ~ 100%] to synthesize and purify white solid Compound 23 (24.4 mg, yield 40%) by reverse phase column chromatography [acetonitrile / water (0.05% formic acid) = 0% ~ 100%]. MS (ESI, m / z): 792.9 [M+H] + .

[0244] 1H NMR (400 MHz, CDC13) δ 8.07 (s, 1H), 8.04 (d, J = 7.6 Hz, 1H), 7.84 (s, 1H), 7.60 - 7.52 (m, 2H), 7.46 (d, J = 8.0 Hz, 1H), 7.41 - 7.37 (m, 2H), 7.24 - 7.15 (m, 1H), 7.12 (d, J = 8.4 Hz, 1H), 7.00 - 7.00 (m, 2H), 6.91 (dd, J = 8.0 Hz, 2.0 Hz, 1H), 6.76 - 6.38 (m, 3H), 4.48 (t, J = 7.2 Hz, 2H), 4.02 (t, J = 6.0 Hz, 2H), 3.85 - 3.72 (m, 5H), 3.10 (t, J = 12.0 Hz, 1H), 2.92 - 2.80 (m, 4H), 2.53 - 2.47 (m, 1H), 2.36 - 2.15 (m, 2H), 2.12 - 2.05 (m, 2H), 1.97 - 1.85 (m, 4H), 1.65 - 1.53 (m, 2H), 1.15 - 1.05 (m, 1H), 0.65 - 0.58 (m, 1H), 0.49 - 0.41 (m, 1H), 0.38 - 0.30 (m, 1H), 0.26 - 0.13 (m, 1H).

[0245] Example 24

[0246] Synthesis route:

[0247] Referring to the synthesis of Compound 15, Compound 15-3 was replaced with Compound 24-1 to synthesize and purify Compound 24 (37.5 mg, yield 71%) as a white solid by reverse phase column chromatography [acetonitrile / water (0.05% formic acid) = 0% ~ 100%]. MS (ESI, m / z): 742.9 [M+H] + .

[0248] 1H NMR (400 MHz, CDC13) δ 7.85 - 7.76 (m, 2H), 7.72 (s, 1H), 7.47 (d, J = 8.0 Hz, 1H), 7.43 - 7.37 (m, 2H), 7.23 - 7.17 (m, 1H), 7.16 - 7.08 (m, 3H), 7.07 - 6.99 (m, 2H), 6.92 (d, J = 8.4 Hz, 1H), 6.61 (d, J = 8.0 Hz, 1H), 6.53 (s, 1H), 6.44 (d, J = 8.0 Hz, 1H), 4.46 (t, J = 7.2 Hz, 2H), 4.03 (t, J = 6.0 Hz, 2H), 3.87 - 3.76 (m, 5H), 3.16 - 3.05 (m, 1H), 2.95 - 2.75 (m, 4H), 2.57 - 2.47 (m, 1H), 2.32 - 2.18 (m, 2H), 2.15 - 2.04 (m, 2H), 1.98 - 1.86 (m, 4H), 1.65 - 1.55 (m, 2H), 1.18 - 1.06 (m, 1H), 0.69 - 0.60 (m, 1H), 0.51 - 0.41 (m, 1H), 0.40 - 0.32 (m, 1H), 0.26 - 0.17 (m, 1H).

[0249] Example 25

[0250] Synthesis route:

[0251] Referring to the synthesis of Compound 15, Compound 15-3 is replaced with Compound 25-1 to synthesize and purify Compound 25 (20.2 mg, yield 34%) as a white solid by reverse phase column chromatography [acetonitrile / water (0.05% formic acid) = 0% ~ 100%]. MS (ESI, m / z): 781.1 [M+H] + .

[0252] 1H NMR (400 MHz, CDC13) δ 7.79 - 7.70 (m, 3H), 7.49 - 7.43 (m, 3H), 7.41 - 7.37 (m, 2H), 7.23 - 7.16 (m, 1H), 7.13 (d, J = 8.0 Hz, 1H), 7.04 - 6.99 (m, 2H), 6.91 (dd, J = 8.0 Hz, 2.0 Hz, 1H), 6.65 - 6.51 (m, 2H), 6.47 - 6.41 (m, 1H), 4.44 (t, J = 7.2 Hz, 2H), 4.01 (t, J = 6.0 Hz, 2H), 3.84 - 3.75 (m, 5H), 3.10 (t, J = 12.0 Hz, 1H), 2.93 - 2.74 (m, 4H), 2.54 - 2.48 (m, 1H), 2.35 - 2.16 (m, 2H), 2.10 - 2.02 (m, 2H), 1.96 - 1.84 (m, 4H), 1.63 - 1.51 (m, 2H), 1.35 (s, 9H), 1.14 - 1.05 (m, 1H), 0.66 - 0.58 (m, 1H), 0.48 - 0.41 (m, 1H), 0.38 - 0.31 (m, 1H), 0.24 - 0.16 (m, 1H).

[0253] Example 26

[0254] Synthetic route:

[0255] Compound 15-2 (84 mg, 0.13 mmol), compound 26-1 (13 mg, 0.13 mmol), tetrabutylammonium iodide (49 mg, 0.13 mmol), selective fluorinating reagent (47 mg, 0.13 mmol), N,N-diisopropylethylamine (17 mg, 0.13 mmol) and cuprous iodide (3 mg, 0.013 mmol) were added to water (2 mL) and stirred at 30 °C for 16 hours under nitrogen protection. TLC showed that the reaction was completed, then ethyl acetate (100 mL) was added, the organic phase was washed with saturated brine, and the organic phase was concentrated to obtain a crude product, which was further purified by normal phase column chromatography (ethyl acetate: petroleum ether = 0-100%) to obtain yellow oil 26-2 (31.2 mg, yield 27%), MS (ESI, m / z): 865.2 [M+H] + .

[0256] Compound 26-2 (28 mg, 0.036 mmol), phenylboronic acid pinacol ester (11 mg, 0.054 mmol), tetrakis triphenyl phosphine palladium (4 mg, 0.0036 mmol) and sodium carbonate (19 mg, 0.18 mmol) were added to 1,4-dioxane / water (4 mL / 1 mL) under nitrogen and stirred at 100 °C for 16 hours. TLC showed the reaction was completed, ethyl acetate (100 mL) was added, the organic phase was washed with saturated brine, the organic phase was combined and concentrated to get the crude product, which was purified by normal phase column chromatography (ethyl acetate: petroleum ether = 0-100%) to get yellow oil 26-3 (28.1 mg, yield 96%), MS (ESI, m / z): 815.2 [M+H] + .

[0257] Compound 26-3 (28 mg, 0.034 mmol) was added to a mixture of tetrahydrofuran (4 mL) and methanol (2 mL), then a solution of lithium hydroxide (19 mg, 0.39 mmol) in water (1 mL) was added to the reaction solution and stirred at 60 °C for 1 hour. TLC showed that the reaction was completed, and the obtained crude product was directly concentrated and purified by reverse phase column chromatography [acetonitrile / water (0.05% formic acid) = 0%-100%] to obtain white solid compound 26 (2.9 mg, yield 11%), MS (ESI, m / z): 801.2 [M+H] + .

[0258] 1 H NMR (400 MHz, CDC13) δ 7.56 - 7.46 (m, 6H), 7.41 - 7.33 (m, 4H), 7.27 - 7.18 (m, 4H), 7.14 (d, J = 8.0 Hz, 1H), 7.02 (d, J = 8.0 Hz, 1H), 6.98 (s, 1H), 6.89 (d, J = 8.0 Hz, 1H), 6.64 - 6.59 (m, 1H), 6.56 - 6.50 (m, 1H), 6.47 - 6.41 (m, 1H), 4.26 (t, J = 7.2 Hz, 2H), 3.95 (t, J = 6.4 Hz, 2H), 3.85 - 3.76 (m, 5H), 3.10 (t, J = 12.0 Hz, 1H), 2.94 - 2.74 (m, 4H), 2.56 - 2.47 (m, 1H), 2.31 - 2.16 (m, 2H), 1.96 - 1.87 (m, 4H), 1.82 - 1.75 (m, 2H), 1.52 - 1.43 (m, 2H), 1.15 - 1.07 (m, 1H), 0.68 - 0.59 (m, 1H), 0.50 - 0.43 (m, 1H), 0.39 - 0.32 (m, 1H), 0.24 - 0.18 (m, 1H)

[0259] Example 27

[0260] Synthetic route:

[0261] Referring to the synthesis of compound 26, compound 27 was synthesized by replacing pinacol benzeneboronic acid with pinacol methylboronic acid and purified by reverse phase column chromatography [acetonitrile / water (0.05% formic acid) = 0% ~ 100%] to obtain white solid compound 27 (58.6 mg, yield 48%). MS (ESI, m / z): 739.4 [M+H] + .

[0262] 1 H NMR (400 MHz, CDC13) δ 7.71 (d, J = 7.6 Hz, 2H), 7.50 - 7.35 (m, 6H), 7.24 - 7.18 (m, 1H), 7.15 (d, J = 8.0 Hz, 1H), 7.05 - 7.03 (m, 2H), 6.93 (dd, J = 8.4 Hz, 2.4 Hz, 1H), 6.68 - 6.43 (m, 3H), 4.36 (t, J = 7.2 Hz, 2H), 4.05 (t, J = 6.0 Hz, 2H), 3.88 - 3.78 (m, 5H), 3.13 (t, J = 12.0 Hz, 1H), 2.93 - 2.81 (m, 4H), 2.55 - 2.49 (m, 4H), 2.38 - 2.19 (m, 2H), 2.08 - 1.89 (m, 6H), 1.67 - 1.59 (m, 2H), 1.18 - 1.07 (m, 1H), 0.69 - 0.59 (m, 1H), 0.50 - 0.43 (m, 1H), 0.39 - 0.33 (m, 1H), 0.25 - 0.19 (m, 1H).

[0263] Example 28

[0264] Synthetic route:

[0265] Referring to the synthesis of compound 13, compound 28-3 was synthesized by replacing compound M1-7 with compound 28-1, and referring to the synthesis of compound 15, compound 28 was synthesized and purified by reverse phase column chromatography [acetonitrile / water (0.05% formic acid) = 0% ~ 100%] to obtain white solid compound 28 (25.1 mg, yield 51%). MS (ESI, m / z): 748.1 [M+H] + .

[0266] 1H NMR (400 MHz, CDC13) δ 7.48 (d, J = 8.0 Hz, 1H), 7.42 - 7.35 (m, 2H), 7.15 (d, J = 8.0 Hz, 1H), 7.05 (d, J = 8.0 Hz, 1H), 7.03 - 6.99 (m, 2H), 6.93 - 6.80 (m, 4H), 6.02 - 5.96 (m, 1H), 4.36 (t, J = 7.2 Hz, 2H), 4.01 (t, J = 6.4 Hz, 2H), 3.89 (s, 3H), 3.36 - 3.25 (m, 1H), 2.93 - 2.77 (m, 2H), 2.73 - 2.68 (m, 2H), 2.61 - 2.40 (m, 3H), 2.26 - 2.16 (m, 1H), 2.13 - 2.06 (m, 1H), 2.02 - 1.97 (m, 2H), 1.90 - 1.84 (m, 2H), 1.67 - 1.61 (m, 2H), 1.57 - 1.51 (m, 2H), 1.37 - 1.23 (m, 8H), 1.15 - 1.11 (m, 1H), 0.88 (t, J = 6.4 Hz, 3H), 0.66 - 0.60 (m, 1H), 0.50 - 0.43 (m, 1H), 0.41 - 0.34 (m, 1H), 0.26 - 0.19 (m, 1H).

[0267] Example 29

[0268] Synthesis route:

[0269] Compound 29-1 (550 mg, 4.78 mmol), p-toluenesulfonyl chloride (1100 mg, 5.74 mmol), 4-dimethylaminopyridine (58 mg, 0.478 mmol) were dissolved in dichloromethane (10 mL), triethylamine (966 mg, 9.57 mmol) was added, and the reaction was allowed to proceed at room temperature for 2 hours. After TLC showed that the reaction was complete, the reaction mixture was concentrated to obtain a crude product, which was purified by normal phase column chromatography (ethyl acetate: petroleum ether = 0-100%) to obtain compound 29-2 (1.5 g, yield 98%) as a white solid, MS (ESI, m / z): 256.1 [M+H] + .

[0270] Compound 29-2 (700 mg, 2.60 mmol), compound 26-1 (318 mg, 3.11 mmol), copper sulfate (130 mg, 0.528 mmol) and sodium ascorbate (206 mg, 1.04 mmol) were dissolved in tert-butanol (8 mL) and water (8 mL) and reacted at room temperature for 2 hours. After TLC showed that the reaction was completed, water (30 mL) was added for dilution, and ethyl acetate (30 mL x 3) was extracted. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and the obtained crude was purified by normal phase column chromatography (ethyl acetate: petroleum ether = 0-100%) to obtain white solid 29-3 (1.0 g, yield 99%), MS (ESI, m / z): 358.1 [M+H] + .

[0271] Compound 29-4 (220 mg, 1.05 mmol) was dissolved in dimethyl sulfoxide (3 mL), and potassium tert-butoxide (128 mg, 1.14 mmol) and 18-crown-6 ether (252 mg, 0.952 mmol) were added and reacted at room temperature for 30 minutes. Compound 29-3 (340 mg, 0.952 mmol) was added and reacted at room temperature for 2 hours. After TLC showed that the reaction was completed, water (30 mL) was added for dilution, and ethyl acetate (30 mL x 3) was extracted. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and the obtained crude was purified by normal phase column chromatography (ethyl acetate: petroleum ether = 0-100%) to obtain white solid 29-5 (80.3 mg, yield 20%), MS (ESI, m / z): 414.1 [M+H] + .

[0272] Compound 29-5 (80 mg, 0.194 mmol), pinacol diboronic acid (74 mg, 0.291 mmol), potassium acetate (38 mg, 0.387 mmol), and 1,1-bis(diphenylphosphino)ferrocene palladium dichloride (14 mg, 0.0194 mmol) were dissolved in 1,4-dioxane (4 mL) and reacted at 100°C overnight. After TLC showed that the reaction was completed, the obtained crude was concentrated and purified by normal phase column chromatography (ethyl acetate: petroleum ether = 0-100%) to obtain white solid 29-6 (75.2 mg, yield 84%), MS (ESI, m / z): 335.1 [M+H] + .

[0273] Compound 29-6 (75 mg, 0.163 mmol), compound M2-8 (64 mg, 0.125 mmol), potassium phosphate (80 mg, 0.375 mmol), tetrakis triphenylphosphine palladium (15 mg, 0.0125 mmol) were dissolved in 1,4-dioxane (4 mL) and water (1 mL), and reacted at 100 °C overnight. After TLC showed that the reaction was completed, the crude product was concentrated to obtain a white solid 29-7 (20.1 mg, yield 16%), MS (ESI, m / z): 767.1 [M+H] + .

[0274] A reaction tube was taken, and compound 29-7 (20 mg, 0.0260 mmol), lithium hydroxide (6.2 mg, 0.26 mmol), tetrahydrofuran (3 mL), methanol (3 mL) and water (3 mL) were added, and reacted at 50 °C for 2 hours. After TLC showed that the reaction was completed, the obtained crude product was directly concentrated and purified by reverse phase column chromatography [acetonitrile / water (0.05% formic acid) = 0%~100%] to obtain a white solid compound 29 (3.9 mg, yield 19%), MS (ESI, m / z): 753.2 [M+H] + .

[0275] 1 H NMR (400 MHz, CDC13) δ 7.77 - 7.72 (m, 2H), 7.62 (s, 1H), 7.55 - 7.31 (m, 9H), 7.28 - 7.21 (m, 1H), 7.13 (d, J = 8.0 Hz, 1H), 6.93 - 6.49 (m, 3H), 4.33 (t, J = 6.8 Hz, 2H), 3.87 - 3.76 (m, 5H), 3.49 (s, 2H), 3.39 (t, J = 5.6 Hz, 2H), 3.17 - 3.03 (m, 1H), 2.94 - 2.81 (m, 4H), 2.53 - 2.49 (m, 1H), 2.42 - 2.27 (m, 2H), 2.17 - 2.12 (m, 2H), 1.99 - 1.86 (m, 2H), 1.46 (s, 6H), 1.15 - 1.07 (m, 1H), 0.68 - 0.61 (m, 1H), 0.51 - 0.43 (m, 1H), 0.40 - 0.33 (m, 1H), 0.25 - 0.18 (m, 1H).

[0276] Example 30

[0277] Synthetic route:

[0278] The compound M3-8 was obtained by referring to the synthesis of intermediate M2, and then the compound 30 was synthesized by referring to the synthesis of compound 29, replacing compound 26-1 with compound 19-1 and replacing compound M2-8 with compound M3-8, and purified by reverse phase column chromatography [acetonitrile / water (0.05% formic acid) = 0% to 100%] to obtain compound 30 (4.7 mg, yield 14%) as a white solid. MS (ESI, m / z): 767.1 [M+H] + .

[0279] 1 H NMR (400 MHz, CDC13) δ 7.64 (s, 1H), 7.63 - 7.60 (m, 2H), 7.53 - 7.44 (m, 3H), 7.41 (s, 1H), 7.37 - 7.33 (m, 2H), 7.25 - 7.18 (m, 3H), 7.13 (d, J = 8.0 Hz, 1H), 6.65 - 6.58 (m, 1H), 6.57 - 6.51 (m, 1H), 6.50 - 6.42 (m, 1H), 4.33 (t, J = 6.8 Hz, 2H), 3.85 - 3.77 (m, 5H), 3.49 (s, 2H), 3.40 (t, J = 5.6 Hz, 2H), 3.14 - 3.04 (m, 1H), 2.94 - 2.82 (m, 2H), 2.82 - 2.69 (m, 2H), 2.55 - 2.48 (m, 1H), 2.39 (s, 3H), 2.31 - 2.24 (m, 2H), 2.19 - 2.14 (m, 2H), 1.92 (d, J = 12.8 Hz, 2H), 1.45 (s, 6H), 1.17 - 1.07 (m, 1H), 0.69 - 0.60 (m, 1H), 0.51 - 0.42 (m, 1H), 0.42 - 0.31 (m, 1H), 0.27 - 0.18 (m, 1H).

[0280] Example 31

[0281] Synthetic route:

[0282] Compound 31-1 (1.71 g, 7.1 mmol), compound 31-2 (715 mg, 8.5 mmol), cuprous iodide (135 mg, 0.71 mmol), [1,1-bis(diphenylphosphino)ferrocene]palladium dichloride (249 mg, 0.35 mmol) and triethylamine (2.1 g, 21.3 mmol) were added into acetonitrile (15 mL) and stirred at 90 °C for 8 h. After TLC showed the reaction was completed, ethyl acetate (100 mL) was added, the organic phase was washed with saturated brine, the organic phases were combined and concentrated to get the crude product, which was purified by normal phase column chromatography (ethyl acetate: petroleum ether = 0-100%) to give white solid 31-3 (966.2 mg, yield 56%), MS (ESI, m / z): 245.2 [M+H] + .

[0283] Compound 31-3 (774 mg, 3.17 mmol) and carbon tetrabromide (1.37 g, 4.12 mmol) were added into dichloromethane (15 mL), then a solution of triphenylphosphine (1 g, 4.12 mmol) in dichloromethane (5 mL) was added into the reaction solution under ice bath and stirred at room temperature for 3 h. After TLC showed the reaction was completed, dichloromethane (100 mL) was added, the organic phase was washed with saturated brine, the organic phases were combined and concentrated to get the crude product, which was purified by normal phase column chromatography (ethyl acetate: petroleum ether = 0-100%) to give white solid 31-3 (945.2 mg, yield 97%), MS (ESI, m / z): 307.2 [M+H] + .

[0284] Compound 31-3 (88 mg, 0.29 mmol), compound 13-6 (100 mg, 0.19 mmol) and potassium carbonate (53 mg, 0.38 mmol) were added into N,N-dimethylformamide (4 mL) and stirred at 60 °C overnight. After TLC showed the reaction was completed, ethyl acetate (100 mL) was added, the organic phase was washed with saturated brine, the organic phases were combined and concentrated to get the crude product, which was purified by normal phase column chromatography (ethyl acetate: petroleum ether = 0-100%) to give white solid 31-5 (70.1 mg, yield 49%), MS (ESI, m / z): 751.9 [M+H] + .

[0285] Compound 31-5 (70 mg, 0.093 mmol) and platinum carbon (15 mg) were added into a mixture of methanol (4 mL) and ethyl acetate (4 mL) and stirred at 50 °C overnight. After TLC showed the reaction was completed, the crude product was concentrated, which was purified by normal phase column chromatography (ethyl acetate: petroleum ether = 0-100%) to give white solid 31-6 (69.8 mg, yield 99%), MS (ESI, m / z): 755.9 [M+H]+ .

[0286] Compound 31-6 (70 mg, 0.093 mmol) was added to a mixture solution of tetrahydrofuran (2 mL) and methanol (2 mL), then a solution of lithium hydroxide (26 mg, 0.93 mmol) in water (0.5 mL) was added to the reaction solution and warmed to 60 °C for 1 hour. After TLC showed the reaction was completed, the resulting crude product was directly concentrated and purified by reverse phase column chromatography [acetonitrile / water (0.05% formic acid) = 0% ~ 100%] to give compound 31 (3.9 mg, yield 6%) as a white solid, MS (ESI, m / z): 741.9 [M+H] + .

[0287] 1 H NMR (400 MHz, CDC13) δ 7.49 (d, J = 8.0 Hz, 2H), 7.42 - 7.36 (m, 2H), 7.23 - 7.17 (m, 1H), 7.14 - 7.08 (m, 5H), 7.04 - 6.99 (m, 2H), 6.93 (dd, J = 8.0 Hz, 2.0 Hz, 1H), 6.65 - 6.39 (m, 3H), 4.01 (t, J = 6.4 Hz, 2H), 3.85 - 3.76 (m, 5H), 3.12 (t, J = 12.0 Hz, 1H), 2.93 - 2.75 (m, 4H), 2.65 - 2.55 (m, 4H), 2.54 - 2.47 (m, 1H), 2.38 - 2.16 (m, 2H), 1.96 - 1.82 (m, 4H), 1.73 - 1.68 (m, 2H), 1.64 - 1.51 (m, 4H), 1.36 - 1.27 (m, 6H), 1.12 - 1.07 (m, 1H), 0.90 - 0.87 (m, 3H), 0.67 - 0.59 (m, 1H), 0.50 - 0.40 (m, 1H), 0.39 - 0.30 (m, 1H), 0.24 - 0.17 (m, 1H).

[0288] Example 32

[0289] Synthetic route:

[0290] Compound 32-1 (1.0 g, 8.1 mmol) was added to dichlorosulfoxide (15 mL) and warmed to 70 °C for 2 hours. After TLC showed the reaction was completed, the resulting crude product was directly concentrated to give brown solid 32-2 (1.0 g, yield 87%), MS (ESI, m / z): 138.2 [M+H] + .

[0291] Compound 32-2 (397 mg, 2.8 mmol) and triethylamine (47 mg, 0.46 mmol) were added to a solution of compound 32-3 (200 mg, 0.93 mmol) in dichloromethane (10 mL) and stirred at room temperature for 16 hours. After TLC showed the reaction was completed, the crude was directly concentrated to give a yellow solid 32-4 (280.4 mg, yield 94%), MS (ESI, m / z): 319.2 [M+H] + .

[0292] Compound 32-4 (360 mg, 1.12 mmol), bis(pinacolato)diboron (286 mg, 1.12 mmol), potassium acetate (332 mg, 3.38 mmol) and 1,1'-bis(diphenylphosphino)ferrocene palladium dichloride (82 mg, 0.11 mmol) were dissolved in 1,4-dioxane (20 mL) and reacted at 100 °C overnight. After TLC showed the reaction was completed, the crude was concentrated to give a white solid 32-5 (340.2 mg, yield 82%), MS (ESI, m / z): 367.2 [M+H] + .

[0293] Then, referring to the synthesis of compound 29, compound 29-6 was replaced by compound 32-5, and compound M2-8 was replaced by compound 32-7, to synthesize and purify a white solid compound 32 (14.8 mg, yield 30%) by reverse phase column chromatography [acetonitrile / water (0.05% formic acid) = 0% ~ 100%]. MS (ESI, m / z): 676.3 [M+H] + .

[0294] 1H NMR (400 MHz, MeOD) d 8.41 - 8.25 (m, 1H), 7.76 - 7.64 (m, 1H), 7.50 - 7.03 (m, 9H), 6.95 (dd, J = 12.0, 8.8 Hz, 1H), 6.58 (dd, J = 7.2, 2.8 Hz, 1H), 6.52 - 6.45 (m, 1H), 5.22 - 4.99 (m, 1H), 3.75 (s, 3H), 3.55 - 3.45 (m, 2H), 3.01 - 2.85 (m, 1H), 2.80 - 2.66 (m, 4H), 2.52 - 2.43 (m, 1H), 2.25 - 2.10 (m, 2H), 1.95 - 1.81 (m, 2H), 1.31 (d, J = 6.8 Hz, 6H), 1.14 - 1.06 (m, 1H), 0.64 - 0.55 (m, 1H), 0.44 - 0.32 (m, 2H), 0.19 - 0.12 (m, 1H).

[0295] Example 33

[0296] Synthesis route:

[0297] The compound 33 was synthesized by the same method as for Reference Compound 19, using compound 33-1 instead of compound 13-5 and compound 26-1 instead of compound 19-1, and purified by reverse phase column chromatography [acetonitrile / water (0.05% formic acid) = 0% to 100%] to give compound 33 as a white solid (69.9 mg, yield 50%). MS (ESI, m / z): 748.1 [M+H] + .

[0298] 1 H NMR (400 MHz, CDCl3) d 7.81 - 7.66 (m, 5H), 7.47 - 7.33 (m, 9H), 7.19 - 7.11 (m, 3H), 6.55 (s, 1H), 4.40 - 4.31 (m, 2H), 4.16 (t, J = 6.4 Hz, 2H), 3.91 - 3.70 (m, 6H), 2.99 - 2.77 (m, 4H), 2.53 - 2.48 (m, 1H), 2.07 - 1.83 (m, 8H), 1.47 - 1.35 (m, 2H), 1.17 - 1.09 (m, 1H), 0.68 - 0.62 (m, 1H), 0.52 - 0.45 (m, 1H), 0.41 - 0.33 (m, 1H), 0.22 (s, 1H).

[0299] Example 34

[0300] Synthesis route:

[0301] Compound 34-1 (3 g, 17.3 mmol), compound 34-2 (14.5 g, 104 mmol) and potassium carbonate (6 g, 43.4 mmol) were added to N,N-dimethylformamide (15 mL) and stirred at 60 °C overnight. After TLC showed the reaction was completed, the crude product was directly concentrated to get yellow oil 34-3 (3.1 g, yield 78%), MS (ESI, m / z): 231.2 [M+H] + .

[0302] Compound 34-1 (3 g, 17.3 mmol), compound 34-2 (14.5 g, 104 mmol) and potassium carbonate (6 g, 43.4 mmol) were added to N,N-dimethylformamide (15 mL) and stirred at 60 °C overnight. After TLC showed the reaction was completed, the crude product was directly concentrated to get yellow oil 34-3 (3.1 g, yield 78%), MS (ESI, m / z): 231.2 [M+H] + .

[0303] Compound 34-1 (3 g, 17.3 mmol), compound 34-2 (14.5 g, 104 mmol) and potassium carbonate (6 g, 43.4 mmol) were added to N,N-dimethylformamide (15 mL) and stirred at 60 °C overnight. After TLC showed the reaction was completed, the crude product was directly concentrated to get yellow oil 34-3 (3.1 g, yield 78%), MS (ESI, m / z): 231.2 [M+H] + .

[0304] Dimethylsulfoxide (1.7 g, 21.8 mmol) was slowly added to oxalyl chloride (1.85 g, 14.6 mmol) in dichloromethane (30 mL) at -78 °C and stirred at -78 °C for 1 h. Then a solution of compound 34-6 (2.3 g, 7.28 mmol) in dichloromethane (20 mL) was added to the reaction and stirred at -78 °C for 2 h. Finally, triethylamine (3.7 g, 36.4 mmol) was added to the reaction and stirred at room temperature for 2 h. After TLC showed the reaction was completed, dichloromethane (100 mL) was added, the organic phase was washed with saturated brine, and the combined organic phase was concentrated to give a crude product, which was further purified by normal phase column chromatography (ethyl acetate: petroleum ether = 0-100%) to give yellow oil 34-7 (1.7 g, yield 74%), MS (ESI, m / z): 315.2 [M+H] + .

[0305] Compound 34-7 (1.75 g, 5.56 mmol), compound 34-8 (900 mg, 8.33 mmol) and acetic acid (1.15 g, 16.7 mmol) were added to dichloromethane (20 mL) and stirred at room temperature for 3 h. Then sodium triacetylboration hydride (1.77 g, 8.33 mmol) was added to the reaction and stirred at room temperature overnight. After TLC showed the reaction was completed, dichloromethane (100 mL) was added, the organic phase was washed with saturated brine, and the combined organic phase was concentrated to give a crude product, which was further purified by normal phase column chromatography (ethyl acetate: petroleum ether = 0-100%) to give yellow oil 34-9 (1.5 g, yield 67%), MS (ESI, m / z): 407.2 [M+H] + .

[0306] Lithium bis(trimethylsilyl)amide (1.3 mL, 1.35 mmol, 1 mol / L) was slowly added to compound 34-9 (367 mg, 0.9 mmol) in tetrahydrofuran (3 mL) at -78 °C and stirred at -78 °C for 1 h. Then acetyl chloride (142 mg, 1.8 mmol) was added to the reaction and stirred at -78 °C for 5 h. After TLC showed the reaction was completed, ethyl acetate (100 mL) was added, the organic phase was washed with saturated brine, and the combined organic phase was concentrated to give a crude product, which was further purified by normal phase column chromatography (ethyl acetate: petroleum ether = 0-100%) to give yellow oil 34-10 (300.5 mg, yield 74%), MS (ESI, m / z): 449.2 [M+H] + .

[0307] Compound 34-10 (300 mg, 0.67 mmol), bis(pinacolato)diboron (254 mg, 1 mmol), l,l'-bis(diphenylphosphino)ferrocene palladium dichloride (49 mg, 0.067 mmol) and potassium acetate (131 mg, 1.34 mmol) were added into 1,4-dioxane (5 mL) and stirred at 90 °C for 5 h under nitrogen. After TLC showed the reaction was completed, ethyl acetate (100 mL) was added and the organic phase was washed with saturated brine. The combined organic phase was concentrated to give a crude product, which was purified by normal phase column chromatography (ethyl acetate: petroleum ether = 0-100%) to give yellow oil 34-11 (330.8 mg, yield 99%) MS (ESI, m / z): 497.2 [M+H] + .

[0308] Compound 34-11 (331 mg, 0.67 mmol), compound M1-8 (342 mg, 0.67 mmol), tetrakis(triphenylphosphine)palladium (80 mg, 0.069 mmol) and sodium carbonate (221 mg, 2.08 mmol) were added into a mixture of 1,4-dioxane (6 mL) and water (1.5 mL) and stirred at 100 °C overnight under nitrogen. After TLC showed the reaction was completed, ethyl acetate (100 mL) was added and the organic phase was washed with saturated brine. The combined organic phase was concentrated to give a crude product, which was purified by normal phase column chromatography (ethyl acetate: petroleum ether = 0-100%) to give yellow oil 34-12 (330.4 mg, yield 62%) MS (ESI, m / z): 801.9 [M+H] + .

[0309] Compound 34-12 (330 mg, 0.41 mmol) was added into a mixture of tetrahydrofuran (4 mL) and methanol (4 mL), then a solution of lithium hydroxide (99 mg, 4.13 mmol) in water (1 mL) was added into the reaction solution and stirred at 60 °C for 1 h. After TLC showed the reaction was completed, the resulting crude product was directly concentrated and purified by reverse phase column chromatography [acetonitrile / water (0.05% formic acid) = 0%-100%] to give white solid compound 34 (125.2 mg, yield 39%) MS (ESI, m / z): 787.9 [M+H] + .

[0310] 1H NMR (400 MHz, CDC13) δ 7.62 - 7.56 (m, 1H), 7.49 (d, J = 8.0 Hz, 1H), 7.45 - 7.38 (m, 2H), 7.25 - 7.18 (m, 1H), 7.15 (d, J = 8.0 Hz, 1H), 7.06 - 6.91 (m, 5H), 6.63 (d, J = 8.4 Hz, 1H), 6.56 (s, 1H), 6.46 (d, J = 8.0 Hz, 1H), 4.05 (t, J = 6.4 Hz, 2H), 3.90 - 3.77 (m, 7H), 3.28 (t, J = 5.6 Hz, 2H), 3.18 - 3.08 (m, 1H), 3.02 (s, 2H), 2.94 - 2.78 (m, 4H), 2.58 - 2.48 (m, 4H), 2.34 - 2.21 (m, 2H), 2.02 - 1.88 (m, 7H), 1.17 - 1.08 (m, 1H), 0.90 - 0.80 (m, 6H), 0.69 - 0.60 (m, 1H), 0.52 - 0.44 (m, 1H), 0.40 - 0.33 (m, 1H), 0.27 - 0.19 (m, 1H).

[0311] Example 35

[0312] Synthesis route:

[0313] Intermediate Ml (710 mg, 1.49 mmol), N,N-dimethylformamide (0.2 mL) were stirred in dichloromethane (30 mL) at 0 °C, and oxalyl chloride (283 mg, 2.23 mmol) was added dropwise under nitrogen protection, and reacted for 4 hours. After the reaction was monitored to end by LCMS (detected by methanol), the reaction solution was directly used for the next step reaction, MS (ESI, m / z): 491.2 [M-Cl+OH+Na] + .

[0314] The reaction solution containing compound 35-1 (366 mg, 0.74 mmol) obtained in the previous step was slowly added dropwise into dichloromethane (40 mL) mixed with compound 35-2 (159 mg, 1.48 mmol) and triethylamine (375 mg, 3.71 mmol) at 0 °C under nitrogen protection, and stirred at room temperature for 16 hours. After TLC showed that the reaction was completed, the crude product was concentrated, and purified by normal phase column chromatography (ethyl acetate: petroleum ether = 0-100%) to obtain yellow oil 35-3 (410.0 mg, yield 97%), MS (ESI, m / z): 665.2 [M+H] + .

[0315] Compound 35-3 (52 mg, 0.078 mmol), compound 35-4 (28 mg, 0.12 mmol), tetrakis triphenylphosphine palladium (9 mg, 0.0078 mmol) and potassium phosphate (33 mg, 0.16 mmol) were added to a mixture solution of 1,4-dioxane (4 mL) and water (1 mL) and stirred at 100 °C for 8 h. TLC showed the reaction was completed, concentrated to get the crude product, purified by normal phase column chromatography (ethyl acetate: petroleum ether = 0-100%) to get yellow oil 35-5 (30.9 mg, yield 57%), MS (ESI, m / z): 695.2 [M+H] + .

[0316] Compound 35-5 (31 mg, 0.045 mmol) was added to a mixture solution of tetrahydrofuran (2 mL) and methanol (2 mL), then a solution of lithium hydroxide (19 mg, 0.67 mmol) in water (0.5 mL) was added to the reaction solution and stirred at 60 °C for 2 h. TLC showed the reaction was completed, the crude product was directly concentrated and purified by reverse phase column chromatography [acetonitrile / water (0.05% formic acid) = 0%-100%] to get white solid compound 35 (8.9 mg, yield 29%), MS (ESI, m / z): 681.2 [M+H] + .

[0317] 1 H NMR (400 MHz, CDC13) d 8.33 (d, J = 1.6 Hz, 1H), 8.11 (s, 1H), 7.61 (d, J = 8.0 Hz, 1H), 7.23 (s, 1H), 7.13 (d, J = 8.0 Hz, 1H), 7.08 - 7.05 (m, 1H), 7.02 - 6.94 (m, 3H), 6.81 - 6.74 (m, 2H), 6.65 (dd, J = 8.4 Hz, 2.0 Hz, 1H), 6.42 (d, J = 7.2 Hz, 1H), 6.34 (s, 1H), 6.24 (d, J = 7.2 Hz, 1H), 3.78 (s, 2H), 3.67 - 3.58 (m, 6H), 2.82 - 2.57 (m, 4H), 2.35 - 2.25 (m, 1H), 2.07 - 1.91 (m, 2H), 1.87 - 1.79 (m, 2H), 0.93 - 0.83 (m, 1H), 0.48 - 0.39 (m, 1H), 0.32 - 0.23 (m, 1H), 0.18 - 0.11 (m, 1H), 0.04 - -0.05 (m, 1H).

[0318] Example 36

[0319] Synthetic route:

[0320] Compound 36-1 (2 g, 10.6 mmol) and triphenylphosphine (2.77 g, 10.6 mmol) were added to acetonitrile (20 mL) and stirred at 80 °C for 5 hours. TLC showed that the reaction was completed, and the crude product 36-2 (4.77 g, yield 99%) was obtained as yellow oil after concentration, MS (ESI, m / z): 371.2 [M+H] + .

[0321] Compound 36-2 (900 mg, 2 mmol) was dissolved in tetrahydrofuran (15 mL) under ice bath, and a solution of potassium tert-butoxide (3 mL, 3 mmol) in tetrahydrofuran was added to the reaction solution and stirred for half an hour. Finally, a solution of compound 36-3 (408 mg, 2.2 mmol) in tetrahydrofuran (5 mL) was added to the reaction solution and stirred at room temperature overnight. TLC showed that the reaction was completed, and ethyl acetate (100 mL) was added. The organic phase was washed with saturated brine, and the combined organic phase was concentrated to obtain the crude product. Yellow oil 36-4 (549.6 mg, yield 99%) was obtained by normal phase column chromatography (ethyl acetate: petroleum ether = 0-100%), MS (ESI, m / z): 278.2 [M+H] + .

[0322] Compound 36-4 (550 mg, 1.98 mmol) and palladium on carbon (50 mg) were added to ethyl acetate (20 mL) under nitrogen protection. After the system was replaced with hydrogen under vacuum, it was warmed to 45 °C and stirred for 3 hours. TLC showed that the reaction was completed, and yellow oil 36-5 (493.2 mg, yield 99%) was obtained after direct filtration and concentration, MS (ESI, m / z): 250.2 [M+H] + .

[0323] Compound 36-5 (77 mg, 0.31 mmol), compound 35-1 (73 mg, 0.15 mmol), N-methylimidazole (37 mg, 0.46 mmol), and N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate (214 mg, 0.77 mmol) were added to acetonitrile (20 mL) and stirred at 80 °C for 5 hours. TLC showed that the reaction was completed, and the crude product was obtained after concentration. Yellow oil 36-6 (62.1 mg, yield 57%) was obtained by normal phase column chromatography (ethyl acetate: petroleum ether = 0-100%), MS (ESI, m / z): 709.2 [M+H] + .

[0324] Compound 36-6 (31 mg, 0.045 mmol) was added to a mixture of tetrahydrofuran (2 mL) and methanol (2 mL), and a solution of lithium hydroxide (19 mg, 0.67 mmol) in water (0.5 mL) was added to the reaction and warmed to 60 °C with stirring for 2 h. After the reaction was shown to be complete by TLC, the resulting crude product was directly concentrated and purified by reverse phase column chromatography [acetonitrile / water (0.05% formic acid) = 0%~100%] to give compound 36 (19.7 mg, yield 32%) as a white solid, MS (ESI, m / z): 695.2 [M+H] + .

[0325] 1 H NMR (400 MHz, CDC13) δ 8.31 (d, J = 2.0 Hz, 1H), 8.12 (s, 1H), 7.63 (d, J = 8.4 Hz, 1H), 7.13 - 7.05 (m, 3H), 7.02 - 6.92 (m, 3H), 6.80 - 6.73 (m, 2H), 6.65 (dd, J = 8.0 Hz, 2.0 Hz, 1H), 6.42 (d, J = 8.4 Hz, 1H), 6.35 (s, 1H), 6.24 (dd, J = 8.0 Hz, 2.0 Hz, 1H), 3.70 - 3.57 (m, 6H), 2.82 - 2.57 (m, 8H), 2.34 - 2.26 (m, 1H), 2.07 - 1.94 (m, 2H), 1.88 - 1.81 (m, 2H), 0.93 - 0.85 (m, 1H), 0.48 - 0.39 (m, 1H), 0.31 - 0.22 (m, 1H), 0.18 - 0.10 (m, 1H), 0.03 - -0.05 (m, 1H).

[0326] Example 37

[0327] Synthetic route:

[0328] Referring to the synthesis of compound 36, compound 36-1 was replaced by compound 37-1 to synthesize and purify compound 37 (50.4 mg, yield 54%) as a white solid by reverse phase column chromatography [acetonitrile / water (0.05% formic acid) = 0%~100%]. MS (ESI, m / z): 709.3 [M+H] + .

[0329] 1H NMR (400 MHz, CDC13) δ 8.48 (d, J = 2.0 Hz, 1H), 8.31 (s, 1H), 7.83 (d, J = 8.0 Hz, 1H), 7.43 (s, 1H), 7.33 (d, J = 8.0 Hz, 1H), 7.28 (d, J = 1.2 Hz, 1H), 7.24 - 7.17 (m, 1H), 7.17 - 7.11 (m, 2H), 7.00 - 6.93 (m, 2H), 6.90 (dd, J = 8.0, 2.0 Hz, 1H), 6.61 (d, J = 6.4 Hz, 1H), 6.54 (s, 1H), 6.44 (d, J = 6.4 Hz, 1H), 3.90 - 3.77 (m, 6H), 3.02 - 2.78 (m, 4H), 2.73 - 2.60 (m, 4H), 2.56 - 2.45 (m, 1H), 2.20 (d, J = 10.4 Hz, 2H), 2.10 - 1.91 (m, 4H), 1.15 - 1.04 (m, 1H), 0.68 - 0.59 (m, 1H), 0.51 - 0.42 (m, 1H), 0.38 - 0.31 (m, 1H), 0.24 - 0.16 (m, 1H).

[0330] Example 38

[0331] Synthesis route:

[0332] The compound 38 was synthesized by the same method of the synthesis of compound 36, using compound 38-1 instead of compound 36-1, and purified by reverse phase column chromatography [acetonitrile / water (0.05% formic acid) = 0% ~ 100%] to give compound 38 as a white solid (24.7 mg, yield 39%). MS (ESI, m / z): 723.2 [M+H] + .

[0333] 1H NMR (400 MHz, CDC13) δ 8.46 (d, J = 2.0 Hz, 1H), 8.30 (s, 1H), 7.82 (d, J = 8.0 Hz, 1H), 7.43 (s, 1H), 7.32 (d, J = 8.0 Hz, 1H), 7.28 - 7.26 (m, 1H), 7.22 - 7.16 (m, 1H), 7.15 - 7.08 (m, 2H), 6.98 - 6.86 (m, 3H), 6.61 (d, J = 7.6 Hz, 1H), 6.54 (s, 1H), 6.43 (d, J = 7.6 Hz, 1H), 3.90 - 3.76 (m, 6H), 2.99 - 2.79 (m, 4H), 2.70 - 2.58 (m, 4H), 2.54 - 2.45 (m, 1H), 2.27 - 2.14 (m, 2H), 2.07 - 1.98 (m, 2H), 1.72 - 1.62 (m, 4H), 1.13 - 1.05 (m, 1H), 0.68 - 0.59 (m, 1H), 0.51 - 0.42 (m, 1H), 0.37 - 0.31 (m, 1H), 0.23 - 0.16 (m, 1H).

[0334] Example 39

[0335] Synthesis route:

[0336] The compound 39 was synthesized by referring to the synthesis of compound 36, replacing compound 36-1 with compound 39-1, and purified by reverse phase column chromatography [acetonitrile / water (0.05% formic acid) = 0% ~ 100%] to obtain white solid compound 39 (84.2 mg, yield 41%). MS (ESI, m / z): 737.2 [M+H] + .

[0337] 1H NMR (400 MHz, CDC13) δ 8.26 (d, J = 2.0 Hz, 1H), 8.10 (s, 1H), 7.63 (d, J = 8.0 Hz, 1H), 7.12 (d, J = 8.0 Hz, 1H), 7.09 - 7.03 (m, 2H), 7.03 - 6.96 (m, 1H), 6.94 - 6.87 (m, 2H), 6.79 - 6.66 (m, 3H), 6.41 (d, J = 8.0 Hz, 1H), 6.34 (s, 1H), 6.23 (dd, J = 8.0, 1.6 Hz, 1H), 3.71 - 3.56 (m, 6H), 2.79 - 2.59 (m, 4H), 2.48 - 2.35 (m, 4H), 2.33 - 2.27 (m, 1H), 2.06 - 1.93 (m, 2H), 1.87 - 1.79 (m, 2H), 1.53 - 1.37 (m, 4H), 1.26 - 1.15 (m, 2H), 0.95 - 0.83 (m, 1H), 0.48 - 0.38 (m, 1H), 0.30 - 0.21 (m, 1H), 0.17 - 0.11 (m, 1H), 0.025 - -0.036 (m, 1H).

[0338] Example 40

[0339] Synthesis route:

[0340] The compound 40 was synthesized by referring to the synthesis of compound 36, replacing compound 36-1 with compound 40-1, and purified by reverse phase column chromatography [acetonitrile / water (0.05% formic acid) = 0% ~ 100%] to obtain white solid compound 40 (19.1 mg, yield 14%). MS (ESI, m / z): 709.3 [M+H] + .

[0341] 1H NMR (400 MHz, CDC13) δ 8.53 - 8.50 (m, 1H), 8.34 (s, 1H), 7.87 (d, J = 8.0 Hz, 1H), 7.47 (s, 1H), 7.37 (d, J = 8.0 Hz, 1H), 7.33 - 7.31 (m, 1H), 7.26 - 7.18 (m, 3H), 7.13 - 7.07 (m, 1H), 7.07 - 7.01 (m, 1H), 6.97 (dd, J = 8.0, 2.0 Hz, 1H), 6.69 - 6.62 (m, 1H), 6.58 (s, 1H), 6.50 - 6.43 (m, 1H), 3.92 - 3.81 (m, 6H), 3.02 - 2.82 (m, 4H), 2.78 - 2.71 (m, 4H), 2.60 - 2.48 (m, 1H), 2.29 - 2.16 (m, 2H), 2.10 - 1.98 (m, 4H), 1.17 - 1.09 (m, 1H), 0.73 - 0.63 (m, 1H), 0.55 - 0.46 (m, 1H), 0.43 - 0.34 (m, 1H), 0.29 - 0.20 (m, 1H).

[0342] Example 41

[0343] Synthesis route:

[0344] The compound 41 was synthesized by referring to the synthesis of compound 36, replacing compound 36-1 with compound 41-1, and purified by reverse phase column chromatography [acetonitrile / water (0.05% formic acid) = 0% ~ 100%] to obtain white solid compound 41 (76.2 mg, yield 81%). MS (ESI, m / z): 709.3 [M+H] + .

[0345] 1 H NMR (400 MHz, CDC13) δ 8.53 - 8.50 (m, 1H), 8.34 (s, 1H), 7.87 (d, J = 8.0 Hz, 1H), 7.47 (s, 1H), 7.37 (d, J = 8.0 Hz, 1H), 7.33 - 7.31 (m, 1H), 7.26 - 7.18 (m, 3H), 7.13 - 7.07 (m, 1H), 7.07 - 7.01 (m, 1H), 6.97 (dd, J = 8.0, 2.0 Hz, 1H), 6.69 - 6.62 (m, 1H), 6.58 (s, 1H), 6.50 - 6.43 (m, 1H), 3.92 - 3.81 (m, 6H), 3.02 - 2.82 (m, 4H), 2.78 - 2.71 (m, 4H), 2.60 - 2.48 (m, 1H), 2.29 - 2.16 (m, 2H), 2.10 - 1.98 (m, 4H), 1.17 - 1.09 (m, 1H), 0.73 - 0.63 (m, 1H), 0.55 - 0.46 (m, 1H), 0.43 - 0.34 (m, 1H), 0.29 - 0.20 (m, 1H).

[0346] 3.91 - 3.78 (m, 6H), 2.99 - 2.81 (m, 4H), 2.72 - 2.64 (m, 4H), 2.54 - 2.46 (m, 1H), 2.27 - 2.15 (m, 2H), 2.07 - 1.96 (m, 4H), 1.13 - 1.04 (m, 1H), 0.67 - 0.59 (m, 1H), 0.52 - 0.42 (m, 1H), 0.39 - 0.29 (m, 1H), 0.26 - 0.16 (m, 1H).

[0347] Example 42

[0348] Synthesis route:

[0349] The synthesis of Reference Compound 36 was performed by replacing Compound 36-1 with Compound 42-1 to give Compound 42 (20.3 mg, 77% yield) as a white solid, which was purified by reverse phase column chromatography [acetonitrile / water (0.05% formic acid) = 0% to 100%]. MS (ESI, m / z): 705.3 [M+H] + .

[0350] 1 H NMR (400 MHz, CDC13) δ 8.52 (d, J = 1.6 Hz, 1H), 8.35 (s, 1H), 7.87 (d, J = 8.0 Hz, 1H), 7.47 (s, 1H), 7.37 (d, J = 8.0 Hz, 1H), 7.34 - 7.30 (m, 1H), 7.27 - 7.20 (m, 1H), 7.17 - 7.10 (m, 4H), 6.95 (dd, J = 8.0, 1.6 Hz, 1H), 6.66 (d, J = 8.0 Hz, 1H), 6.59 (s, 1H), 6.48 (d, J = 7.6 Hz, 1H), 3.95 - 3.84 (m, 6H), 3.04 - 2.82 (m, 4H), 2.75 - 2.65 (m, 4H), 2.59 - 2.48 (m, 1H), 2.36 (s, 3H), 2.32 - 2.17 (m, 2H), 2.11 - 1.96 (m, 4H), 1.18 - 1.06 (m, 1H), 0.72 - 0.62 (m, 1H), 0.55 - 0.45 (m, 1H), 0.42 - 0.33 (m, 1H), 0.27 - 0.19 (m, 1H).

[0351] Example 43

[0352] Synthesis route:

[0353] The synthesis of Reference Compound 36 was followed by replacing Compound 36-1 with Compound 43-1 to give Compound 43 (68.1 mg, 71% yield) as a white solid after purification by reverse phase column chromatography [acetonitrile / water (0.05% formic acid) = 0% ~ 100%]. MS (ESI, m / z): 705.3 [M+H] + .

[0354] 1 H NMR (400 MHz, CDC13) δ 8.53 (d, J = 2.0 Hz, 1H), 8.34 (s, 1H), 7.86 (d, J = 8.0 Hz, 1H), 7.46 (s, 1H), 7.37 (d, J = 8.0 Hz, 1H), 7.32 - 7.29 (m, 1H), 7.26 - 7.19 (m, 1H), 7.20 - 7.10 (m, 4H), 6.97 (dd, J = 8.0, 2.0 Hz, 1H), 6.65 (d, J = 7.6 Hz, 1H), 6.58 (s, 1H), 6.47 (d, J = 7.2 Hz, 1H),

[0355] 3.97 - 3.76 (m, 6H), 3.04 - 2.82 (m, 4H), 2.81 - 2.74 (m, 2H), 2.73 - 2.67 (m, 2H), 2.58 - 2.47 (m, 1H), 2.33 (s, 3H), 2.30 - 2.15 (m, 2H), 2.13 - 2.04 (m, 2H), 2.02 - 1.91 (m, 2H), 1.18 - 1.05 (m, 1H), 0.72 - 0.61 (m, 1H), 0.55 - 0.45 (m, 1H), 0.42 - 0.32 (m, 1H), 0.29 - 0.19 (m, 1H).

[0356] Example 44

[0357] Synthesis route:

[0358] The synthesis of Reference Compound 36 was followed by replacing Compound 36-1 with Compound 44-1 to give Compound 44 (86.4 mg, 83% yield) as a white solid after purification by reverse phase column chromatography [acetonitrile / water (0.05% formic acid) = 0% ~ 100%]. MS (ESI, m / z): 705.3 [M+H] + .

[0359] 1H NMR (400 MHz, CDC13) δ 8.28 (d, J = 2.0 Hz, 1H), 8.10 (s, 1H), 7.63 (d, J = 8.0 Hz, 1H), 7.23 (s, 1H), 7.13 (d, J = 8.0 Hz, 1H), 7.08 - 7.06 (m, 1H), 7.02 - 6.95 (m, 2H), 6.85 - 6.78 (m, 3H), 6.72 (dd, J = 8.0, 2.0 Hz, 1H), 6.41 (d, J = 8.0 Hz, 1H), 6.34 (s, 1H), 6.23 (d, J = 7.6 Hz, 1H),

[0360] 3.71 - 3.58 (m, 6H), 2.79 - 2.59 (m, 4H), 2.53 - 2.40 (m, 4H), 2.34 - 2.25 (m, 1H), 2.13 (s, 3H), 2.06 - 1.92 (m, 2H), 1.89 - 1.73 (m, 4H), 0.95 - 0.83 (m, 1H), 0.49 - 0.39 (m, 1H), 0.31 - 0.22 (m, 1H), 0.19 - 0.10 (m, 1H), 0.04 - -0.04 (m, 1H).

[0361] Example 45

[0362] Synthesis route:

[0363] The synthesis of Reference Compound 36 was performed by replacing Compound 36-1 with Compound 45-1 to give Compound 45 (8.3 mg, 31% yield) as a white solid, which was purified by reverse phase column chromatography [acetonitrile / water (0.05% formic acid) = 0% ~ 100%]. MS (ESI, m / z): 759.3 [M+H] + .

[0364] 1H NMR (400 MHz, CDC13) δ 8.55 - 8.51 (m, 1H), 8.35 (s, 1H), 7.87 (d, J = 8.0 Hz, 1H), 7.58 (d, J = 8.0 Hz, 2H), 7.47 (s, 1H), 7.38 (d, J = 8.0 Hz, 1H), 7.36 - 7.29 (m, 3H), 7.26 - 7.20 (m, 1H), 6.95 (dd, J = 8.0, 2.0 Hz, 1H), 6.69 - 6.61 (m, 1H), 6.61 - 6.54 (m, 1H), 6.52 - 6.44 (m, 1H), 3.92 - 3.81 (m, 6H), 3.04 - 2.83 (m, 4H), 2.81 - 2.70 (m, 4H), 2.60 - 2.49 (m, 1H), 2.31 - 2.17 (m, 2H), 2.14 - 1.99 (m, 4H), 1.19 - 1.07 (m, 1H), 0.73 - 0.63 (m, 1H), 0.56 - 0.46 (m, 1H), 0.43 - 0.34 (m, 1H), 0.29 - 0.20 (m, 1H).

[0365] Example 46

[0366] Synthesis route:

[0367] The compound 46 was synthesized by referring to the synthesis of compound 36, replacing compound 36-1 with compound 46-1, and purified by reverse phase column chromatography [acetonitrile / water (0.05% formic acid) = 0% ~ 100%] to obtain white solid compound 46 (34.1 mg, yield 48%). MS (ESI, m / z): 759.3 [M+H] + .

[0368] 1H NMR (400 MHz, CDC13) δ 8.53 (d, J = 1.6 Hz, 1H), 8.36 (s, 1H), 7.87 (d, J = 8.0 Hz, 1H), 7.50 - 7.45 (m, 3H), 7.45 - 7.32 (m, 4H), 7.27 - 7.20 (m, 1H), 6.95 (dd, J = 8.4, 2.0 Hz, 1H), 6.65 (d, J = 9.2 Hz, 1H), 6.57 (s, 1H), 6.47 (d, J = 7.6 Hz, 1H), 3.90 - 3.84 (m, 6H), 3.02 - 2.88 (m, 4H), 2.79 - 2.71 (m, 4H), 2.57 - 2.52 (m, 1H), 2.28 - 2.20 (m, 2H), 2.10 - 2.03 (m, 4H), 1.19 - 1.11 (m, 1H), 0.76 - 0.64 (m, 1H), 0.57 - 0.47 (m, 1H), 0.46 - 0.36 (m, 1H), 0.33 - 0.19 (m, 1H).

[0369] Example 47

[0370] Synthesis route:

[0371] The compound 47 was synthesized according to the synthesis of compound 36 by replacing compound 36-1 with compound 47-1, and purified by reverse phase column chromatography [acetonitrile / water (0.05% formic acid) = 0% ~ 100%] to give compound 47 (10.2 mg, yield 55%) as a white solid. MS (ESI, m / z): 719.3 [M+H] + .

[0372] 1H NMR (400 MHz, CDC13) δ 8.53 (s, 1H), 8.35 (s, 1H), 7.87 (d, J = 8.0 Hz, 1H), 7.47 (s, 1H), 7.37 (d, J = 8.0 Hz, 1H), 7.32 (d, J = 8.0 Hz, 1H), 7.27 - 7.21 (m, 2H), 7.09 - 7.02 (m, 3H), 6.96 (d, J = 8.4 Hz, 1H), 6.72 - 6.41 (m, 3H), 3.92 - 3.83 (m, 6H), 3.06 - 2.87 (m, 4H), 2.79 - 2.63 (m, 6H), 2.58 - 2.50 (m, 1H), 2.31 - 2.19 (m, 2H), 2.11 - 1.99 (m, 4H), 1.26 (t, J = 7.6 Hz, 3H), 1.16 - 1.08 (m, 1H), 0.74 - 0.64 (m, 1H), 0.56 - 0.46 (m, 1H), 0.43 - 0.34 (m, 1H), 0.29 - 0.22 (m, 1H).

[0373] Example 48

[0374] Synthesis route:

[0375] The synthesis of Reference Compound 36 was performed by replacing Compound 36-1 with Compound 48-1 to give Compound 48 (9.9 mg, 54% yield) as a white solid, which was purified by reverse phase column chromatography [acetonitrile / water (0.05% formic acid) = 0% ~ 100%]. MS (ESI, m / z): 731.3 [M+H] + .

[0376] 1H NMR (400 MHz, CDC13) δ 8.52 (s, 1H), 8.35 (s, 1H), 7.87 (d, J = 8.0 Hz, 1H), 7.47 (s, 1H), 7.37 (d, J = 8.0 Hz, 1H), 7.32 (d, J = 8.0 Hz, 1H), 7.26 - 7.18 (m, 2H), 7.02 (d, J = 7.6 Hz, 1H), 6.98 - 6.90 (m, 3H), 6.75 - 6.41 (m, 3H), 3.94 - 3.84 (m, 6H), 3.05 - 2.85 (m, 4H), 2.77 - 2.64 (m, 4H), 2.59 - 2.48 (m, 1H), 2.34 - 2.19 (m, 2H), 2.12 - 1.97 (m, 4H), 1.93 - 1.85 (m, 1H), 1.21 - 1.07 (m, 1H), 1.02 - 0.93 (m, 2H), 0.76 - 0.64 (m, 3H), 0.53 - 0.43 (m, 1H), 0.41 - 0.35 (m, 1H), 0.29 - 0.21 (m, 1H).

[0377] Example 49

[0378] Synthesis route:

[0379] The compound 49 was synthesized by referring to the synthesis of compound 36, replacing compound 36-1 with compound 49-1, and purified by reverse phase column chromatography [acetonitrile / water (0.05% formic acid) = 0% ~ 100%] to obtain white solid compound 49 (8.1 mg, yield 44%). MS (ESI, m / z): 733.3 [M+H] + .

[0380] 1H NMR (400 MHz, CDC13) δ 8.53 (s, 1H), 8.35 (s, 1H), 7.87 (d, J = 8.0 Hz, 1H), 7.47 (s, 1H), 7.37 (d, J = 8.0 Hz, 1H), 7.32 (d, J = 8.0 Hz, 1H), 7.27 - 7.20 (m, 2H), 7.12 - 7.04 (m, 3H), 6.99 - 6.93 (m, 1H), 6.70 - 6.62 (m, 1H), 6.60 - 6.55 (m, 1H), 6.49 - 6.43 (m, 1H), 3.92 - 3.83 (m, 6H), 3.02 - 2.85 (m, 5H), 2.76 - 2.63 (m, 4H), 2.59 - 2.49 (m, 1H), 2.29 - 2.17 (m, 2H), 2.11 - 1.99 (m, 4H), 1.29 (d, J = 6.8 Hz, 6H), 1.18 - 1.11 (m, 1H), 0.73 - 0.60 (m, 1H), 0.56 - 0.47 (m, 1H), 0.43 - 0.34 (m, 1H), 0.28 - 0.20 (m, 1H).

[0381] Example 50

[0382] Synthesis route:

[0383] The compound 50 was synthesized by referring to the synthesis of compound 36, replacing compound 36-1 with compound 50-1, and replacing compound 36-3 with compound 50-3, and purified by reverse phase column chromatography [acetonitrile / water (0.05% formic acid) = 0% ~ 100%] to obtain white solid compound 50 (6.1 mg, yield 8%). MS (ESI, m / z): 775.3 [M+H] + .

[0384] 1 H NMR (400 MHz, CDC13) δ 8.52 (d, J = 2.0 Hz, 1H), 8.34 (s, 1H), 7.87 (d, J = 8.0 Hz, 1H), 7.47 (s, 1H), 7.36 (d, J = 8.0 Hz, 1H), 7.34 - 7.29 (m, 1H), 7.26 - 7.20 (m, 1H), 7.18 - 7.08 (m, 4H), 6.95 (dd, J = 8.0, 2.0 Hz, 1H), 6.66 (d, J = 8.0 Hz, 1H), 6.59 (s, 1H), 6.48 (d, J = 8.0 Hz, 1H),

[0385] 3.88 - 3.84 (m, 6H), 3.04 - 2.84 (m, 4H), 2.74 - 2.66 (m, 4H), 2.61 (t, J = 8.0 Hz, 2H), 2.54 (q, J = 8.0 Hz, 1H), 2.33 - 2.18 (m, 2H), 2.12 - 1.98 (m, 4H), 1.67 - 1.59 (m, 2H), 1.35 - 1.31 (m, 6H), 1.18 - 1.09 (m, 1H), 0.93 - 0.89 (m, 3H), 0.72 - 0.63 (m, 1H), 0.55 - 0.46 (m, 1H), 0.41 - 0.35 (m, 1H), 0.28 - 0.20 (m, 1H).

[0386] Example 51

[0387] Synthesis route:

[0388] Referring to the synthesis of compound 36, replace compound 36-1 with compound 51-1, compound 51-3 (171 mg, 0.59 mmol) and 1-bromopentane (134 mg, 0.89 mmol), potassium carbonate (122 mg, 0.89 mmol) were added to a solution of N,N-dimethylformamide (5 mL) and heated to 80 °C and stirred overnight. TLC showed that the reaction was completed, concentrated to get the crude product, purified by normal phase column chromatography (ethyl acetate: petroleum ether = 0-100%) to get yellow oil 51-4 (68.1 mg, yield 32%), MS (ESI, m / z): 360.2 [M+H] + .

[0389] Referring again to the synthesis of compound 36, replace compound 36-4 with compound 51-4, synthesize and purify by reverse phase column chromatography [acetonitrile / water (0.05% formic acid) = 0%-100%] to get white solid compound 51 (11.5 mg, yield 69%), MS (ESI, m / z): 777.2 [M+H] + .

[0390] 1H NMR (400 MHz, CDC13) δ 8.51 (d, J = 1.6 Hz, 1H), 8.34 (s, 1H), 7.86 (d, J = 8.4 Hz, 1H), 7.47 (s, 1H), 7.36 (d, J = 8.4 Hz, 1H), 7.32 - 7.30 (m, 1H), 7.26 - 7.20 (m, 1H), 7.13 (d, J = 8.4 Hz, 2H), 6.94 (dd, J = 8.0 Hz, 2.0 Hz, 1H), 6.86 (d, J = 8.4 Hz, 2H), 6.69 - 6.62 (m, 1H), 6.58 (s, 1H), 6.51 - 6.44 (m, 1H), 3.96 (t, J = 6.8 Hz, 2H), 3.92 - 3.82 (m, 6H), 3.06 - 2.83 (m, 4H), 2.75 - 2.61 (m, 4H), 2.58 - 2.49 (m, 1H), 2.32 - 2.16 (m, 2H), 2.12 - 2.04 (m, 2H), 2.03 - 1.94 (m, 2H), 1.84 - 1.77 (m, 2H), 1.50 - 1.39 (m, 4H), 1.18 - 1.09 (m, 1H), 0.96 (t, J = 7.2 Hz, 3H), 0.72 - 0.62 (m, 1H), 0.55 - 0.46 (m, 1H), 0.42 - 0.35 (m, 1H), 0.27 - 0.21 (m, 1H).

[0391] Example 52

[0392] Synthesis route:

[0393] The compound 52 was synthesized by referring to the synthesis of compound 38, replacing compound 38-1 with compound 52-1, and purified by reverse phase column chromatography [acetonitrile / water (0.05% formic acid) = 0% ~ 100%] to obtain white solid compound 52 (47.9 mg, yield 44%). MS (ESI, m / z): 719.2 [M+H] + .

[0394] 1H NMR (400 MHz, CDC13) δ 8.52 (d, J = 2.0 Hz, 1H), 8.34 (s, 1H), 7.87 (d, J = 8.0 Hz, 1H), 7.46 (d, J = 1.6 Hz, 1H), 7.36 (d, J = 8.0 Hz, 1H), 7.32 (d, J = 1.6 Hz, 1H), 7.26 - 7.20 (m, 1H), 7.17 - 7.11 (m, 4H), 6.95 (dd, J = 8.0, 2.0 Hz, 1H), 6.65 (dd, J = 8.0, 2.4 Hz, 1H), 6.58 (t, J = 2.4 Hz, 1H), 6.47 (dd, J = 8.0, 2.4 Hz, 1H), 3.91 - 3.85 (m, 6H), 3.03 - 2.82 (m, 4H), 2.74 - 2.64 (m, 4H), 2.53 (q, J = 8.0 Hz, 1H), 2.34 (s, 3H), 2.24 (q, J = 13.2 Hz, 2H), 2.07 (d, J = 12.8 Hz, 2H), 1.82 - 1.75 (m, 2H), 1.71 - 1.63 (m, 2H), 1.18 - 1.07 (m, 1H), 0.70 - 0.64 (m, 1H), 0.53 - 0.46 (m, 1H), 0.41 - 0.35 (m, 1H), 0.29 - 0.19 (m, 1H).

[0395] Example 53

[0396] Synthesis route:

[0397] The compound 53 was synthesized by referring to the synthesis of compound 38, replacing compound 38-1 with compound 53-1, and purified by reverse phase column chromatography [acetonitrile / water (0.05% formic acid) = 0% ~ 100%] to obtain white solid compound 53 (39.1 mg, yield 36%). MS (ESI, m / z): 719.2 [M+H] + .

[0398] 1H NMR (400 MHz, CDC13) δ 8.51 (s, 1H), 8.35 (s, 1H), 7.87 (d, J = 8.0 Hz, 1H), 7.47 (s, 1H), 7.42 - 7.30 (m, 2H), 7.26 - 7.18 (m, 2H), 7.03 - 7.01 (m, 3H), 6.94 (d, J = 8.0 Hz, 1H), 6.66 (d, J = 8.0 Hz, 1H), 6.59 (s, 1H), 6.48 (d, J = 8.0 Hz, 1H), 3.88 - 3.85 (m, 6H), 3.07 - 2.83 (m, 4H), 2.73 - 2.63 (m, 4H), 2.54 (q, J = 8.0 Hz, 1H), 2.37 (s, 3H), 2.31 - 2.17 (m, 2H), 2.08 (d, J = 12.8 Hz, 2H), 1.73 (s, 4H), 1.17 - 1.06 (m, 1H), 0.71 - 0.65 (m, 1H), 0.53 - 0.46 (m, 1H), 0.41 - 0.36 (m, 1H), 0.28 - 0.19 (m, 1H).

[0399] Example 54

[0400] Synthesis route:

[0401] The compound 54 was synthesized by referring to the synthesis of compound 39, replacing compound 39-1 with compound 54-1, and purified by reverse phase column chromatography [acetonitrile / water (0.05% formic acid) = 0% ~ 100%] to obtain white solid compound 54 (28.2 mg, yield 56%). MS (ESI, m / z): 733.3 [M+H] + .

[0402] 1H NMR (400 MHz, CDC13) δ 8.50 (s, 1H), 8.34 (s, 1H), 7.87 (d, J = 8.0 Hz, 1H), 7.47 (s, 1H), 7.36 (d, J = 8.0 Hz, 1H), 7.31 (d, J = 6.8 Hz, 1H), 7.26 - 7.17 (m, 2H), 7.07 - 6.98 (m, 3H), 6.96 - 6.91 (m, 1H), 6.70 - 6.61 (m, 1H), 6.61 - 6.54 (m, 1H), 6.50 - 6.44 (m, 1H), 3.90 - 3.82 (m, 6H), 3.02 - 2.78 (m, 4H), 2.68 (t, J = 8.0 Hz, 2H), 2.61 (t, J = 8.0 Hz, 2H), 2.57 - 2.49 (m, 1H), 2.37 (s, 3H), 2.31 - 2.17 (m, 2H), 2.12 - 2.04 (m, 2H), 1.76 - 1.63 (m, 4H), 1.51 - 1.41 (m, 2H), 1.17 - 1.06 (m, 1H), 0.73 - 0.60 (m, 1H), 0.56 - 0.42 (m, 1H), 0.41 - 0.32 (m, 1H), 0.27 - 0.19 (m, 1H).

[0403] Example 55

[0404] Synthesis route:

[0405] The compound 55 was synthesized by referring to the synthesis of compound 39, replacing compound 39-1 with compound 55-1, and purified by reverse phase column chromatography [acetonitrile / water (0.05% formic acid) = 0% ~ 100%] to obtain white solid compound 55 (27.9 mg, yield 55%). MS (ESI, m / z): 733.3 [M+H] + .

[0406] 1H NMR (400 MHz, CDC13) δ 8.51 (d, J = 1.6 Hz, 1H), 8.34 (s, 1H), 7.87 (d, J = 8.0 Hz, 1H), 7.46 (s, 1H), 7.36 (d, J = 8.0 Hz, 1H), 7.31 (d, J = 7.6 Hz, 1H), 7.26 - 7.20 (m, 1H), 7.18 - 7.11 (m, 4H), 6.94 (dd, J = 8.0, 2.0 Hz, 1H), 6.65 (d, J = 8.0 Hz, 1H), 6.58 (s, 1H), 6.47 (d, J = 7.6 Hz, 1H), 3.91 - 3.83 (m, 6H), 3.03 - 2.83 (m, 4H), 2.73 - 2.60 (m, 4H), 2.57 - 2.49 (m, 1H), 2.34 (s, 3H), 2.32 - 2.18 (m, 2H), 2.13 - 2.05 (m, 2H), 1.76 - 1.69 (m, 2H), 1.68 - 1.59 (m, 2H), 1.54 - 1.43 (m, 2H), 1.19 - 1.08 (m, 1H), 0.73 - 0.63 (m, 1H), 0.55 - 0.43 (m, 1H), 0.42 - 0.33 (m, 1H), 0.29 - 0.18 (m, 1H).

[0407] Example 56

[0408] Synthesis route:

[0409] Compound 56-1 (2 g, 10.7 mmol) and compound 56-2 (3.6 g, 11.8 mmol) were added to a solution of tetrahydrofuran (20 mL) under nitrogen and stirred at 80 °C overnight. TLC showed that the reaction was completed after concentration to give a crude product, which was obtained by normal phase column chromatography (ethyl acetate: petroleum ether = 0-100%) as yellow oil 56-3 (2.1 g, yield 88%), MS (ESI, m / z): 212.2 [M+H] + .

[0410] 56-4 (700 mg, 3.65 mmol), triphenylphosphine (1.43 g, 5.47 mmol) were added to dichloromethane (20 mL) and stirred, carbon tetrabromide (1.81 g, 5.47 mmol) was added at 0 °C, and the reaction was carried out at room temperature for 3 hours. After the reaction was completed, the crude product was concentrated. Then, yellow oil 56-5 (900 mg, yield 97%) was obtained by normal phase column chromatography (ethyl acetate: petroleum ether = 0-100%), MS (ESI, m / z): 255.2 [M+H] + .

[0411] Referring to the synthesis of compound 36 again, compound 36-1 is replaced by compound 56-5, and compound 36-3 is replaced by compound 56-3, to synthesize and purify by reverse phase column chromatography [acetonitrile / water (0.05% formic acid) = 0%~100%] to obtain white solid compound 56 (13.9 mg, yield 18%), MS (ESI, m / z): 789.2 [M+H] + .

[0412] 1 H NMR (400 MHz, CDC13) δ 8.51 (t, J = 2.4 Hz, 1H), 8.35 (s, 1H), 7.88 (d, J = 8.0 Hz, 1H), 7.48 (s, 1H), 7.36 (d, J = 8.0 Hz, 1H), 7.34 - 7.29 (m, 1H), 7.28 - 7.19 (m, 2H), 7.08 - 7.00 (m, 3H), 6.94 (dd, J = 8.0, 2.0 Hz, 1H), 6.67 (d, J = 8.0 Hz, 1H), 6.60 (s, 1H), 6.49 (dd, J = 8.0, 2.4 Hz, 1H), 3.92 - 3.85 (m, 6H), 3.05 - 2.84 (m, 4H), 2.74 - 2.59 (m, 6H), 2.54 (q, J = 8.0 Hz, 1H), 2.26 (q, J = 12.8 Hz, 2H), 2.09 (d, J = 12.4 Hz, 2H), 1.76 - 1.62 (m, 6H), 1.49 - 1.35 (m, 6H), 1.17 - 1.10 (m, 1H), 0.94 - 0.91 (m, 3H), 0.71 - 0.64 (m, 1H), 0.54 - 0.47 (m, 1H), 0.42 - 0.36 (m, 1H), 0.27 - 0.22 (m, 1H).

[0413] Example 57

[0414] Synthesis route:

[0415] Referring to the synthesis of compound 56, compound 56-4 is replaced by compound 57-1 to synthesize compound 57-3. Referring to the synthesis of compound 51 again, compound 51-3 is replaced by compound 57-3 to synthesize and purify by reverse phase column chromatography [acetonitrile / water (0.05% formic acid) = 0%~100%] to obtain white solid compound 57 (13.5 mg, yield 17%), MS (ESI, m / z): 791.2 [M+H] + .

[0416] 1H NMR (400 MHz, CDC13) δ 8.51 (s, 1H), 8.35 (s, 1H), 7.92-7.84 (m, 1H), 7.47 (s, 1H), 7.15-7.40 (m, 4H), 6.99-6.91 (m, 1H), 6.85-6.71 (m, 3H), 6.71-6.43 (m, 3H), 4.05-3.94 (m, 2H), 3.94-3.76 (m, 6H), 3.08-2.81 (m, 4H), 2.78-2.60 (m, 4H), 2.60-2.50 (m, 1H), 2.33-2.17 (m, 2H), 2.15-2.02 (m, 2H), 1.90-1.66 (m, 6H), 1.54-1.35 (m, 4H), 1.20-1.08 (m, 1H), 1.04-0.90 (m, 3H), 0.74-0.63 (m, 1H), 0.58-0.47 (m, 1H), 0.43-0.35 (m, 1H), 0.30-0.20 (m, 1H).

[0417] Example 58

[0418] Synthesis route:

[0419] The compound 58 was synthesized by the same method of synthesis of compound 50, replacing compound 50-3 with compound 58-1, and purified by reverse phase column chromatography [acetonitrile / water (0.05% formic acid) = 0% ~ 100%] to give compound 58 (4.6 mg, yield 4%) as a white solid. MS (ESI, m / z): 773.3 [M+H] + .

[0420] 1H NMR (400 MHz, CDC13) δ 8.51 (d, J = 2.0 Hz, 1H), 8.33 (s, 1H), 7.86 (d, J = 8.0 Hz, 1H), 7.46 (s, 1H), 7.35 (d, J = 8.0 Hz, 1H), 7.33 - 7.27 (m, 1H), 7.25 - 7.19 (m, 1H), 7.18 - 7.13 (m, 4H), 6.95 (dd, J = 8.0, 2.0 Hz, 1H), 6.64 (d, J = 8.0 Hz, 1H), 6.57 (s, 1H), 6.46 (dd, J = 8.0, 2.4 Hz, 1H), 3.93 - 3.84 (m, 6H), 3.05 - 2.83 (m, 4H), 2.76 - 2.65 (m, 4H), 2.56 - 2.47 (m, 2H), 2.29 - 2.19 (m, 2H), 2.13 - 1.98 (m, 4H), 1.93 - 1.83 (m, 4H), 1.49 - 1.37 (m, 6H), 1.17 - 1.07 (m, 1H), 0.72 - 0.60 (m, 1H), 0.57 - 0.43 (m, 1H), 0.41 - 0.35 (m, 1H), 0.25 - 0.21 (m, 1H).

[0421] Example 59

[0422] Synthesis route:

[0423] Compound 59-1 (2.0 g, 8.37 mmol) was stirred in anhydrous tetrahydrofuran (15 mL), and a solution of n-butyllithium (2.5 M, 3.34 mL, 8.37 mmol) was added under nitrogen protection at -78 °C, and reacted for 1 hour, a solution of N,N-dimethylformamide (610 mg, 8.37 mmol) in tetrahydrofuran (5 mL) was slowly added at -78 °C, and reacted for 16 hours at -30 °C. After the reaction was completed by TLC monitoring, it was quenched with saturated ammonium chloride solution (1.0 mL), and concentrated to obtain a crude product. Then, yellow oil 59-2 (1.4 g, yield 88%) was separated by normal phase column chromatography (ethyl acetate: petroleum ether = 0-100%). MS (ESI, m / z): 190.1 [M+H] + .

[0424] Referring to the synthesis of compound 58, compound 58-1 was replaced by compound 59-2 to synthesize and purify compound 59 (11.5 mg, yield 15%) by reverse phase column chromatography [acetonitrile / water (0.05% formic acid) = 0%-100%] to obtain a white solid. MS (ESI, m / z): 774.3 [M+H] + .

[0425] 1H NMR (400 MHz, CDC13) δ 8.51 (d, J = 2.0 Hz, 1H), 8.34 (s, 1H), 7.86 (d, J = 8.0 Hz, 1H), 7.47 (s, 1H), 7.38 - 7.31 (m, 2H), 7.24 (d, J = 8.0 Hz, 1H), 7.12 (d, J = 8.0 Hz, 2H), 6.97 - 6.90 (m, 3H), 6.68 - 6.61 (m, 1H), 6.59 - 6.56 (m, 1H), 6.47 (d, J = 8.0 Hz, 1H), 3.91 - 3.84 (m, 6H), 3.17 - 3.12 (m, 4H), 3.01 - 2.93 (m, 2H), 2.93 - 2.82 (m, 2H), 2.71 (t, J = 7.6 Hz, 2H), 2.63 (t, J = 7.6 Hz, 2H), 2.58 - 2.50 (m, 1H), 2.27 - 2.18 (m, 2H), 2.07 (d, J = 12.8 Hz, 2H), 2.02 - 1.94 (m, 2H), 1.75 - 1.69 (m, 4H), 1.61 - 1.56 (m, 2H), 1.15 - 1.03 (m, 1H), 0.70 - 0.62 (m, 1H), 0.55 - 0.46 (m, 1H), 0.42 - 0.35 (m, 1H), 0.27 - 0.17 (m, 1H).

[0426] Example 60

[0427] Synthesis route:

[0428] The compound 60 was synthesized by replacing compound 36-3 with compound 60-1 in the synthesis of Reference Compound 37 and purified by reverse phase column chromatography [acetonitrile / water (0.05% formic acid) = 0% ~ 100%] to give a white solid compound 60 (36.1 mg, yield 57%). MS (ESI, m / z): 693.3 [M+H] + .

[0429] 1H NMR (400 MHz, CDC13) δ 8.34 (dd, J = 7.6, 2.0 Hz, 1H), 7.97 (d, J = 3.6 Hz, 1H), 7.68 (d, J = 8.0 Hz, 1H), 7.43 (s, 1H), 7.29 - 7.26 (m, 1H), 7.22 - 7.17 (m, 1H), 7.16 - 7.11 (m, 2H), 7.09 - 7.02 (m, 1H), 7.00 - 6.93 (m, 2H), 6.92 - 6.86 (m, 1H), 6.61 (d, J = 8.0 Hz, 1H), 6.54 (s, 1H), 6.44 (d, J = 7.6 Hz, 1H), 3.91 - 3.76 (m, 6H), 3.00 - 2.77 (m, 4H), 2.70 - 2.60 (m, 4H), 2.56 - 2.45 (m, 1H), 2.28 - 2.11 (m, 2H), 2.08 - 1.90 (m, 4H), 1.15 - 1.02 (m, 1H), 0.69 - 0.59 (m, 1H), 0.52 - 0.41 (m, 1H), 0.40 - 0.30 (m, 1H), 0.25 - 0.15 (m, 1H).

[0430] Example 61

[0431] The synthesis of Reference Compound 42 was carried out by replacing Compound 36-3 with Compound 60-1 to give Compound 61 (75.9 mg, 84% yield) as a white solid, which was purified by reverse phase column chromatography [acetonitrile / water (0.05% formic acid) = 0% to 100%]. MS (ESI, m / z): 689.3 [M+H] + .

[0432] 1H NMR (400 MHz, CDC13) δ 8.34 (dd, J = 7.6, 2.0 Hz, 1H), 7.97 (d, J = 3.6 Hz, 1H), 7.68 (d, J = 8.0 Hz, 1H), 7.43 (s, 1H), 7.28 - 7.26 (m, 1H), 7.23 - 7.16 (m, 1H), 7.12 - 7.02 (m, 5H), 6.93 - 6.87 (m, 1H), 6.63 (d, J = 7.6 Hz, 1H), 6.56 (s, 1H), 6.45 (d, J = 7.6 Hz, 1H), 3.92 - 3.77 (m, 6H), 3.01 - 2.78 (m, 4H), 2.71 - 2.60 (m, 4H), 2.54 - 2.46 (m, 1H), 2.32 (s, 3H), 2.28 - 2.13 (m, 2H), 2.08 - 1.91 (m, 4H), 1.14 - 1.03 (m, 1H), 0.68 - 0.59 (m, 1H), 0.50 - 0.41 (m, 1H), 0.38 - 0.30 (m, 1H), 0.23 - 0.15 (m, 1H).

[0433] Example 62

[0434] Synthesis route:

[0435] The compound 62 was synthesized by the same method of the synthesis of compound 45, using compound 36-3 instead of compound 60-1, and purified by reverse phase column chromatography [acetonitrile / water (0.05% formic acid) = 0% ~ 100%] to give compound 62 (34.2 mg, yield 48%) as a white solid. MS (ESI, m / z): 743.3 [M+H] + .

[0436] 1H NMR (400 MHz, CDC13) δ 8.39 (d, J = 7.2 Hz, 1H), 8.02 (d, J = 3.2 Hz, 1H), 7.72 (d, J = 8.0 Hz, 1H), 7.57 (d, J = 8.0 Hz, 2H), 7.47 (s, 1H), 7.38 - 7.30 (m, 3H), 7.26 - 7.20 (m, 1H), 7.10 (dd, J = 10.8, 8.4 Hz, 1H), 6.97 - 6.90 (m, 1H), 6.70 - 6.44 (m, 3H), 3.89 - 3.81 (m, 6H), 3.04 - 2.84 (m, 4H), 2.79 - 2.70 (m, 4H), 2.60 - 2.48 (m, 1H), 2.30 - 2.16 (m, 2H), 2.09 - 1.99 (m, 4H), 1.17 - 1.08 (m, 1H), 0.72 - 0.61 (m, 1H), 0.55 - 0.44 (m, 1H), 0.43 - 0.31 (m, 1H), 0.31 - 0.13 (m, 1H).

[0437] Example 63

[0438] Synthesis route:

[0439] The compound 63 was synthesized by the same method of synthesis of compound 50, replacing compound 50-1 with compound 63-1, and purified by reverse phase column chromatography [acetonitrile / water (0.05% formic acid) = 0% ~ 100%] to give compound 63 as a white solid (28.1 mg, yield 56%). MS (ESI, m / z): 759.4 [M+H] + .

[0440] 1H NMR (400 MHz, CDC13) δ 8.37 (d, J = 6.0 Hz, 1H), 8.01 (s, 1H), 7.72 (d, J = 8.0 Hz, 1H), 7.47 (s, 1H), 7.34 - 7.31 (m, 1H), 7.27 - 7.20 (m, 1H), 7.16 - 7.04 (m, 5H), 6.97 - 6.90 (m, 1H), 6.69 - 6.61 (m, 1H), 6.61 - 6.53 (m, 1H), 6.52 - 6.41 (m, 1H), 3.93 - 3.82 (m, 6H), 3.03 - 2.82 (m, 4H), 2.73 - 2.65 (m, 4H), 2.60 (t, J = 7.6 Hz, 2H), 2.57 - 2.50 (m, 1H), 2.28 - 2.16 (m, 2H), 2.11 - 2.04 (m, 2H), 2.03 - 1.98 (m, 2H), 1.65 - 1.62 (m, 2H), 1.36 - 1.31 (m, 6H), 1.16 - 1.11 (m, 1H), 0.91 (t, J = 6.8 Hz, 3H), 0.72 - 0.64 (m, 1H), 0.58 - 0.46 (m, 1H), 0.43 - 0.31 (m, 1H), 0.28 - 0.19 (m, 1H).

[0441] Example 64

[0442] Synthesis route:

[0443] The compound 64 was synthesized by the same method as described in synthesis of Reference Compound 51, using compound 60-1 instead of compound 36-3, and purified by reverse phase column chromatography [acetonitrile / water (0.05% formic acid) = 0% ~ 100%] to give compound 64 (11.9 mg, yield 67%) as a white solid. MS (ESI, m / z): 761.4 [M+H] + .

[0444] 1 H NMR (400 MHz, CDC13) δ 8.37 (d, J = 7.6 Hz, 1H), 8.00 (d, J = 3.2 Hz, 1H), 7.72 (d, J = 8.0 Hz, 1H), 7.47 (s, 1H), 7.34 - 7.29 (m, 1H), 7.26 - 7.20 (m, 1H), 7.16 - 7.05 (m, 3H), 6.97 - 6.90 (m, 1H), 6.89 - 6.84 (m, 2H), 6.66 (d, J = 8.4 Hz, 1H), 6.59 (s, 1H), 6.48 (d, J = 7.2 Hz, 1H),

[0445] 3.97 (t, J = 6.4 Hz, 2H), 3.89 - 3.81 (m, 6H), 3.04 - 2.85 (m, 4H), 2.74 - 2.61 (m, 4H), 2.59 - 2.49 (m, 1H), 2.27 - 2.16 (m, 2H), 2.12 - 2.04 (m, 2H), 2.00 - 1.93 (m, 2H), 1.89 - 1.77 (m, 2H), 1.53 - 1.38 (m, 4H), 1.18 - 1.08 (m, 1H), 0.96 (t, J = 7.2 Hz, 3H), 0.72 - 0.64 (m, 1H), 0.54 - 0.46 (m, 1H), 0.42 - 0.34 (m, 1H), 0.26 - 0.19 (m, 1H).

[0446] Example 65

[0447] Synthesis route:

[0448] The compound 65 was synthesized by replacing compound 60-1 with compound 65-1 in the synthesis of compound 62, and purified by reverse phase column chromatography [acetonitrile / water (0.05% formic acid) = 0% ~ 100%] to give a white solid compound 65 (58.2 mg, yield 77%). MS (ESI, m / z): 755.4 [M+H] + .

[0449] 1 H NMR (400 MHz, CDC13) δ 8.49 (s, 1H), 8.42 (d, J = 1.6 Hz, 1H), 7.77 (d, J = 8.8 Hz, 1H), 7.54 (d, J = 8.0 Hz, 2H), 7.42 (s, 1H), 7.30 (d, J = 8.8 Hz, 2H), 7.28 - 7.23 (m, 1H), 7.23 - 7.17 (m, 1H), 6.93 - 6.83 (m, 2H), 6.62 (d, J = 8.0 Hz, 1H), 6.55 (s, 1H), 6.44 (d, J = 8.8 Hz, 1H), 3.96 - 3.77 (m, 9H), 3.02 - 2.79 (m, 4H), 2.76 - 2.64 (m, 4H), 2.54 - 2.45 (m, 1H), 2.27 - 2.13 (m, 2H), 2.08 - 1.96 (m, 4H), 1.15 - 1.04 (m, 1H), 0.69 - 0.60 (m, 1H), 0.51 - 0.42 (m, 1H), 0.38 - 0.30 (m, 1H), 0.24 - 0.16 (m, 1H)

[0450] Example 66

[0451] Synthesis route:

[0452] The compound 64 was synthesized by referring to the synthesis of compound 42, and purified by reverse phase column chromatography [acetonitrile / water (0.05% formic acid) = 0% ~ 100%] to give compound 65 as a white solid (75.9 mg, yield 70%). MS (ESI, m / z): 773.4 [M+H] + .

[0453] 1 H NMR (400 MHz, CDC13) δ 8.47 (s, 1H), 8.40 (d, J = 2.0 Hz, 1H), 7.78 (dd, J = 8.0, 2.0 Hz, 1H), 7.41 (s, 1H), 7.35 - 7.27 (m, 1H), 7.26 - 7.19 (m, 1H), 7.15 - 7.02 (m, 2H), 6.96 - 6.75 (m, 4H), 6.61 (d, J = 8.4 Hz, 1H), 6.54 (s, 1H), 6.43 (d, J = 8.4 Hz, 1H), 3.99 - 3.76 (m, 11H), 3.02 - 2.78 (m, 4H), 2.68 - 2.58 (m, 4H), 2.55 - 2.46 (m, 1H), 2.26 - 2.12 (m, 2H), 2.08 - 1.99 (m, 2H), 1.97 - 1.88 (m, 2H), 1.84 - 1.73 (m, 2H), 1.50 - 1.33 (m, 4H), 1.15 - 1.05 (m, 1H), 0.96 - 0.86 (m, 3H), 0.69 - 0.58 (m, 1H), 0.51 - 0.42 (m, 1H), 0.40 - 0.30 (m, 1H), 0.25 - 0.15 (m, 1H).

[0454] Example 67

[0455] Synthesis route:

[0456] The compound 64 was synthesized by referring to the synthesis of compound 42, and purified by reverse phase column chromatography [acetonitrile / water (0.05% formic acid) = 0% ~ 100%] to give compound 65 as a white solid (75.9 mg, yield 70%). MS (ESI, m / z): 773.4 [M+H] + .

[0457] 1H NMR (400 MHz, CDC13) δ 7.87 (s, 1H), 7.66 (d, J = 8.0 Hz, 1H), 7.55 (s, 1H), 7.43 (s, 1H), 7.25 - 7.12 (m, 3H), 7.11 - 7.06 (m, 4H), 6.95 (d, J = 7.6 Hz, 1H), 6.64 - 6.58 (m, 1H), 6.53 (s, 1H), 6.46 - 6.39 (m, 1H), 3.88 - 3.72 (m, 6H), 2.99 - 2.77 (m, 4H), 2.72 - 2.58 (m, 4H), 2.54 - 2.44 (m, 1H), 2.35 - 2.29 (m, 6H), 2.25 - 2.11 (m, 2H), 2.05 - 1.91 (m, 4H), 1.15 - 1.02 (m, 1H), 0.70 - 0.60 (m, 1H), 0.51 - 0.41 (m, 1H), 0.39 - 0.29 (m, 1H), 0.25 - 0.14 (m, 1H).

[0458] Example 68

[0459] Synthesis route:

[0460] The compound 68 was synthesized by referring to the synthesis of compound 37, replacing compound 36-3 with compound 67-1, and purified by reverse phase column chromatography [acetonitrile / water (0.05% formic acid) = 0% ~ 100%] to obtain a white solid (63.5 mg, yield 66%). MS (ESI, m / z): 689.3 [M+H] + .

[0461] 1 H NMR (400 MHz, CDC13) δ 7.87 (s, 1H), 7.66 (d, J = 8.0 Hz, 1H), 7.55 (s, 1H), 7.43 (s, 1H), 7.25 - 7.12 (m, 3H), 7.11 - 7.06 (m, 4H), 6.95 (d, J = 7.6 Hz, 1H), 6.64 - 6.58 (m, 1H), 6.53 (s, 1H), 6.46 - 6.39 (m, 1H), 3.88 - 3.72 (m, 6H), 2.99 - 2.77 (m, 4H), 2.72 - 2.58 (m, 4H), 2.54 - 2.44 (m, 1H), 2.35 - 2.29 (m, 6H), 2.25 - 2.11 (m, 2H), 2.05 - 1.91 (m, 4H), 1.15 - 1.02 (m, 1H), 0.70 - 0.60 (m, 1H), 0.51 - 0.41 (m, 1H), 0.39 - 0.29 (m, 1H), 0.25 - 0.14 (m, 1H).

[0462] Example 69

[0463] Synthesis route:

[0464] Referring to the synthesis of compound 45, compound 36-3 is replaced by compound 67-1 to synthesize and purify by reverse phase column chromatography [acetonitrile / water (0.05% formic acid) = 0% ~ 100%] to obtain white solid compound 69 (50.9 mg, yield 81%). MS (ESI, m / z): 739.3 [M+H] + .

[0465] 1 H NMR (400 MHz, CDC13) d 7.90 (s, 1H), 7.66 (d, J = 8.0 Hz, 1H), 7.60 - 7.49 (m, 3H), 7.44 (s, 1H), 7.30 (d, J = 8.0 Hz, 2H), 7.25 - 7.14 (m, 3H), 6.94 (d, J = 8.0 Hz, 1H), 6.68 - 6.37 (m, 3H), 3.90 - 3.74 (m, 6H), 2.98 - 2.78 (m, 4H), 2.75 - 2.64 (m, 4H), 2.54 - 2.45 (m, 1H), 2.32 (s, 3H), 2.27 - 2.10 (m, 2H), 2.07 - 1.94 (m, 4H), 1.13 - 1.04 (m, 1H), 0.68 - 0.60 (m, 1H), 0.50 - 0.42 (m, 1H), 0.38 - 0.30 (m, 1H), 0.24 - 0.15 (m, 1H).

[0466] Example 70

[0467] Synthesis route:

[0468] Referring to the synthesis of compound 64, compound 60-1 is replaced by compound 67-1 to synthesize and purify by reverse phase column chromatography [acetonitrile / water (0.05% formic acid) = 0% ~ 100%] to obtain white solid compound 70 (85.2 mg, yield 61%). MS (ESI, m / z): 757.4 [M+H] + .

[0469] 1H NMR (400 MHz, CDC13) δ 7.86 (s, 1H), 7.65 (d, J = 8.8 Hz, 1H), 7.55 (s, 1H), 7.42 (s, 1H), 7.26 - 7.07 (m, 5H), 6.95 (d, J = 8.0 Hz, 1H), 6.81 (d, J = 8.8 Hz, 2H), 6.63 - 6.57 (m, 1H), 6.52 (s, 1H), 6.42 (d, J = 8.0, 1H), 3.92 (t, J = 6.8 Hz, 2H), 3.92 - 3.78 (m, 6H), 2.95 - 2.81 (m, 4H), 2.70 - 2.57 (m, 4H), 2.53 - 2.43 (m, 1H), 2.31 (s, 3H), 2.24 - 2.10 (m, 2H), 2.06 - 1.87 (m, 4H), 1.83 - 1.74 (m, 2H), 1.49 - 1.32 (m, 4H), 1.13 - 1.03 (m, 1H), 0.92 (t, J = 6.8 Hz, 3H), 0.69 - 0.54 (m, 1H), 0.51 - 0.40 (m, 1H), 0.39 - 0.28 (m, 1H), 0.24 - 0.14 (m, 1H).

[0470] Example 71

[0471] Synthesis route:

[0472] The compound 71 was synthesized by referring to the synthesis of compound 57, replacing compound 57-3 with compound 71-1, and purified by reverse phase column chromatography [acetonitrile / water (0.05% formic acid) = 0% ~ 100%] to obtain white solid compound 71 (38.1 mg, yield 31%), MS (ESI, m / z): 757.2 [M+H] + .

[0473] 1H NMR (400 MHz, CDC13) δ 7.73 (s, 1H), 7.64 (d, J = 8.0 Hz, 1H), 7.53 (s, 1H), 7.50 - 7.41 (m, 2H), 7.35 - 7.19 (m, 3H), 7.03 (d, J = 7.6 Hz, 1H), 6.81 - 6.74 (m, 3H), 6.65 (d, J = 8.2 Hz, 1H), 6.58 (s, 1H), 6.48 (d, J = 8.0 Hz, 1H), 4.06 - 3.93 (m, 2H), 3.91 - 3.74 (m, 6H), 3.04 - 2.83 (m, 4H), 2.77 - 2.60 (m, 4H), 2.59 - 2.47 (m, 1H), 2.27 - 2.13 (m, 2H), 2.10 - 1.96 (m, 2H), 1.87 - 1.66 (m, 6H), 1.54 - 1.36 (m, 4H), 1.17 - 1.07 (m, 1H), 1.04 - 0.90 (m, 3H), 0.73 - 0.63 (m, 1H), 0.55 - 0.45 (m, 1H), 0.43 - 0.33 (m, 1H), 0.29 - 0.18 (m, 1H).

[0474] Example 72

[0475] Synthesis route:

[0476] The compound 72 was synthesized by the same method as for Reference Compound 49, using compound 72-1 instead of compound 36-1, and purified by reverse phase column chromatography [acetonitrile / water (0.05% formic acid) = 0%~100%] to give compound 72 (16.1 mg, yield 47%) as a white solid. MS (ESI, m / z): 741.4 [M+H] + .

[0477] 1H NMR (400 MHz, CDC13) δ 7.75 (s, 1H), 7.68 (d, J = 8.0 Hz, 1H), 7.63 (s, 1H), 7.48 (s, 1H), 7.31 - 7.22 (m, 4H), 7.13 - 7.04 (m, 4H), 6.65 (d, J = 7.6 Hz, 1H), 6.58 (s, 1H), 6.47 (d, J = 7.6 Hz, 1H), 3.89 - 3.82 (m, 6H), 3.15 - 3.06 (m, 1H), 2.96 - 2.87 (m, 5H), 2.76 - 2.68 (m, 4H), 2.59 - 2.48 (m, 1H), 2.30 - 2.16 (m, 2H), 2.08 - 2.01 (m, 4H), 1.34 - 1.22 (m, 12H), 1.19 - 1.07 (m, 1H), 0.74 - 0.63 (m, 1H), 0.57 - 0.43 (m, 1H), 0.43 - 0.33 (m, 1H), 0.31 - 0.18 (m, 1H).

[0478] Example 73

[0479] Synthesis route:

[0480] Compound 73-1 (1.2 g, 5.24 mmol), compound 73-2 (1.02 g, 7.86 mmol), potassium phosphate (3.33 g, 15.72 mmol) were added to 1.4 dioxane (10 mL) / water (2 mL) and stirred, then tetrakis triphenylphosphine palladium (1.21 g, 1.04 mmol) was added and reacted at 100 °C for 16 hours under nitrogen protection. After the reaction was completed by TLC monitoring, the crude product was concentrated. Then compound 73-3 (480.2 mg, yield 39%) was obtained as colorless oil by normal phase column chromatography (petroleum ether: ethyl acetate = 0-100%). MS (ESI, m / z): 235.3 [M+H] + .

[0481] Compound 73-3 (480 mg, 2.05 mmol) was added to tetrahydrofuran (5 mL) and stirred, then borane dimethyl sulfide solution (2.0 M, 10.26 mL, 20.51 mmol) was added, and then reacted at 80 °C for 16 hours. After the reaction was completed by TLC monitoring, methanol (20 mL) was slowly added at 0 °C to quench the reaction, and then concentrated to obtain the crude product, which was separated by normal phase column chromatography (petroleum ether: ethyl acetate = 0-100%) to obtain compound 73-4 (250.5 mg, yield 59%) as colorless oil. MS (ESI, m / z): 189.2 [M-18+H] + .

[0482] Compound 35-1 (400 mg, 0.84 mmol) was added to 1,2-dichloroethane (15 mL) and compound 73-5 (215 mg, 1.26 mmol) was added and stirred at 90 °C for 16 h under nitrogen protection. After the reaction was completed by TLC monitoring, the reaction mixture was concentrated to give a crude product. Then the compound 73-6 (340.8 mg, yield 64%) was obtained as a yellow solid by normal phase column chromatography (petroleum ether: ethyl acetate = 0-100%). MS (ESI, m / z): 631.3 [M+H] + .

[0483] Compound 73-6 (100 mg, 0.16 mmol), 4-dimethylaminopyridine (19 mg, 0.16 mmol), N,N'-dicyclohexylcarbodiimide (65 mg, 0.32 mmol) were added to dichloromethane (15 mL) and stirred at room temperature for 2 h. Compound 73-4 (39 mg, 0.19 mmol) was added and stirred at room temperature for 16 h under nitrogen protection. After the reaction was completed by TLC monitoring, the reaction mixture was concentrated to give a crude product. Then the compound 73-7 (105.3 mg, yield 81%) was obtained as a yellow oil by normal phase column chromatography (petroleum ether: ethyl acetate = 0-100%). MS (ESI, m / z): 819.3 [M+H] + .

[0484] Compound 73-7 (105 mg, 0.13 mmol) was added to 1,2-dichloroethane (10 mL) and stirred. Trimethyltin hydroxide (232 mg, 1.28 mmol) was added and then stirred at 90 °C for 48 h under nitrogen protection. After the reaction was completed by TLC monitoring, the reaction mixture was concentrated to give a crude product. Then the compound 73 (1.4 mg, yield 1%) was obtained as a white solid by reverse phase column chromatography [acetonitrile / water (0.05% formic acid) = 0%-100%]. MS (ESI, m / z): 805.3 [M+H] + .

[0485] 1H NMR (400 MHz, CDC13) δ 9.29 (d, J = 2.0 Hz, 1H), 8.36 (s, 1H), 7.85 (d, J = 8.0 Hz, 1H), 7.79 (dd, J = 8.4, 2.0 Hz, 1H), 7.54 (d, J = 8.4 Hz, 1H), 7.49 (s, 1H), 7.37 - 7.28 (m, 1H), 7.28 - 7.20 (m, 2H), 7.20 - 7.13 (m, 2H), 7.09 (d, J = 7.6 Hz, 1H), 6.65 (d, J = 8.4 Hz, 1H), 6.58 (s, 1H), 6.47 (d, J = 8.0 Hz, 1H), 4.57 (t, J = 7.2 Hz, 2H), 3.95 - 3.81 (m, 6H), 3.12 (t, J = 7.2 Hz, 2H), 3.05 - 2.85 (m, 4H), 2.66 - 2.52 (m, 3H), 2.24 - 2.22 (m, 2H), 2.09 (d, J = 12.0 Hz, 2H), 1.65 - 1.25 (m, 8H), 1.18 - 1.11 (m, 1H), 0.93 - 0.88 (m, 3H), 0.74 - 0.64 (m, 1H), 0.53 - 0.49 (m, 1H), 0.41 - 0.38 (m, 1H), 0.27 - 0.22 (m, 1H).

[0486] Example 74

[0487] Synthetic route:

[0488] Compound 74-1 (1200 mg, 4.93 mmol), compound 74-2 (1600 mg, 8.12 mmol), potassium phosphate (2600 mg, 12.26 mmol) and tetrakis triphenyl phosphine palladium (480 mg, 0.416 mmol) were dissolved in 1,4-dioxane solution (60 mL) and water (4 mL) and reacted at 100 °C overnight. After the reaction was completed, the reaction was monitored by TLC and concentrated to obtain a crude product. Then, yellow oil 74-3 (1.0 g, yield 99%) was separated by normal phase column chromatography (petroleum ether: ethyl acetate = 0-100%) MS (ESI, m / z): 203.3 [M+H] + .

[0489] Compound 74-6 was obtained by referring to the synthesis of intermediate M1, and then compound 74-9 (260 mg, 0.367 mmol) and compound 74-3 (150 mg, 0.734 mmol) were synthesized by referring to the synthesis of compound 35, replacing compound 35-2 with compound 74-8, tetra- triphenylphosphine palladium (85 mg, 0.734 mmol) was dissolved in triethylamine (1 mL) and N, N-dimethylformamide (4 mL), and reacted at 100 °C overnight. After the reaction was completed by TLC monitoring, water (20 mL) was added for dilution, and ethyl acetate (20 x 3) was extracted, and concentrated to obtain a crude product. Yellow oil 74-10 (180.3 mg, yield 61%) was obtained by normal phase column chromatography (ethyl acetate: petroleum ether = 0~100%), MS (ESI, m / z): 805.3 [M+H] + .

[0490] Compound 74-10 (60 mg, 0.0745 mmol), lithium hydroxide (8.2 mg, 0.341 mmol) was added to tetrahydrofuran (3 mL), methanol (3 mL) and water (3 ml), and reacted at 50 °C for 2 hours. After the reaction was completed by TLC monitoring, the crude product was concentrated. Then purified by reverse phase column chromatography [acetonitrile / water (0.05% formic acid) = 0%~100%] to obtain white solid 74 (43.2 mg, yield 71%), MS (ESI, m / z): 791.4 [M+H] + .

[0491] 1 H NMR (400 MHz, CDCl3) δ 8.69-8.55 (m, 1H), 8.39-8.31 (m, 1H), 7.92-7.83 (m, 1H), 7.49 (s, 1H), 7.43-7.37 (m, 1H), 7.34-7.30 (m, 1H), 7.28-7.20 (m, 2H), 7.17-6.99 (m, 4H), 6.76-6.62 (m, 2H), 6.55-6.34 (m, 2H), 3.99-3.84 (m, 4H), 3.68-3.54 (m, 4H), 3.02-2.86 (m, 4H), 2.69-2.50 (m, 3H), 2.41-2.28 (m, 2H), 2.16-2.05 (m, 2H), 1.68-1.61 (m, 2H), 1.36-1.29 (m, 6H), 1.22-1.10 (m, 1H), 0.90 (t, J = 6.8 Hz, 3H), 0.73-0.64 (m, 1H), 0.56-0.48 (m, 1H), 0.42-0.36 (m, 1H), 0.30-0.20 (m, 1H).

[0492] Example 75

[0493] Synthesis route:

[0494] Referring to the synthesis of compound 74, compound 74-10 (180 mg, 0.224 mmol) was dissolved in tetrahydrofuran (15 mL), 10% palladium on carbon (50 mg) was added, and the reaction was carried out under 1 atm of hydrogen at room temperature overnight. After the reaction was completed as monitored by TLC, the mixture was filtered and concentrated to give white solid 75-1 (160.2 mg, yield 88%), MS (ESI, m / z): 807.3 [M+H] + .

[0495] Referring to the synthesis of compound 74, compound 74-10 (180 mg, 0.224 mmol) was dissolved in tetrahydrofuran (15 mL), 10% palladium on carbon (50 mg) was added, and the reaction was carried out under 1 atm of hydrogen at room temperature overnight. After the reaction was completed as monitored by TLC, the mixture was filtered and concentrated to give white solid 75-1 (160.2 mg, yield 88%), MS (ESI, m / z): 807.3 [M+H] + .

[0496] 1 H NMR (400 MHz, CDC13) δ 8.53 (s, 1H), 8.35 (s, 1H), 7.87 (d, J = 8.0 Hz, 1H), 7.48 (s, 1H), 7.36 (d, J = 8.0 Hz, 1H), 7.32 (d, J = 8.0 Hz, 1H), 7.26 - 7.19 (m, 1H), 7.06 - 7.01 (m, 4H), 6.97 - 6.93 (m, 1H), 6.72 - 6.65 (m, 2H), 3.95 - 3.82 (m, 4H), 3.67 - 3.59 (m, 2H), 3.00 - 2.87 (m, 4H), 2.77 - 2.65 (m, 4H), 2.62 - 2.54 (m, 3H), 2.37 - 2.33 (m, 2H), 2.13 - 1.98 (m, 4H), 1.67 - 1.59 (m, 2H), 1.36 - 1.30 (m, 6H), 1.19 - 1.09 (m, 1H), 0.90 (t, J = 6.0 Hz, 3H), 0.73 - 0.65 (m, 1H), 0.56 - 0.47 (m, 1H), 0.45 - 0.36 (m, 1H), 0.28 - 0.20 (m, 1H).

[0497] Example 76

[0498] Synthesis route:

[0499] The compound 76-4 was synthesized by referring to the synthesis of the compound 36, replacing the compound 36-1 with the compound 76-1, and the compound 76-10 was synthesized by referring to the synthesis of the intermediate M1, and the compound 76 was synthesized by referring to the synthesis of the compound 36, and purified by reverse phase column chromatography [acetonitrile / water (0.05% formic acid) = 0% ~ 100%] to obtain a white solid 76 (35.1 mg, yield 62%), MS (ESI, m / z): 809.3 [M+H] + .

[0500] 1 H NMR (400 MHz, CDC13) δ 8.53 (d, J = 1.6 Hz, 1H), 8.35 (s, 1H), 7.87 (d, J = 8.0 Hz, 1H), 7.50 (s, 1H), 7.36 (d, J = 8.0 Hz, 1H), 7.31 (d, J = 8.0 Hz, 2H), 7.26 - 7.20 (m, 1H), 7.08 - 7.02 (m, 3H), 6.98 - 6.92 (m, 1H), 6.72 - 6.67 (m, 1H), 6.56 (dd, J = 8.8, 2.8 Hz, 1H), 3.90 - 3.81 (m, 4H), 3.62 - 3.55 (m, 2H), 2.94 - 2.85 (m, 4H), 2.76 - 2.66 (m, 4H), 2.64 - 2.49 (m, 3H), 2.40 - 2.26 (m, 2H), 2.11 - 1.99 (m, 4H), 1.67 - 1.60 (m, 2H), 1.37 - 1.31 (m, 6H), 1.18 - 1.09 (m, 1H), 0.90 (t, J = 6.8 Hz, 3H), 0.73 - 0.64 (m, 1H), 0.55 - 0.44 (m, 1H), 0.44 - 0.35 (m, 1H), 0.29 - 0.20 (m, 1H).

[0501] Example 77

[0502] The compound 77 was synthesized by referring to the synthesis of the compound 76, replacing the compound 76-6 with the compound 32-7, and purified by reverse phase column chromatography [acetonitrile / water (0.05% formic acid) = 0% ~ 100%] to obtain a white solid 77 (70.4 mg, yield 78%), MS (ESI, m / z): 793.4 [M+H] + .

[0503] 1H NMR (400 MHz, CDC13) δ 8.53 (d, J = 1.6 Hz, 1H), 8.35 (s, 1H), 7.87 (d, J = 8.0 Hz, 1H), 7.48 (s, 1H), 7.39 - 7.31 (m, 2H), 7.26 - 7.20 (m, 1H), 7.06 - 6.95 (m, 5H), 6.64 - 6.54 (m, 1H), 6.51 - 6.44 (m, 1H), 3.87 - 3.81 (m, 4H), 3.68 - 3.60 (m, 2H), 2.95 - 2.86 (m, 4H), 2.74 - 2.66 (m, 4H), 2.63 - 2.49 (m, 3H), 2.36 - 2.25 (m, 2H), 2.11 - 2.02 (m, 4H), 1.67 - 1.61 (m, 2H), 1.36 - 1.31 (m, 6H), 1.18 - 1.11 (m, 1H), 0.91 - 0.88 (m, 3H), 0.72 - 0.67 (m, 1H), 0.55 - 0.49 (m, 1H), 0.43 - 0.36 (m, 1H), 0.29 - 0.21 (m, 1H).

[0504] Example 78

[0505] Synthesis route:

[0506] The synthesis of Reference Compound 76 was performed by replacing Compound 76-5 with Compound 78-1 to give Compound 78 (18.5 mg, yield 61%) as a white solid, which was purified by reverse phase column chromatography [acetonitrile / water (0.05% formic acid) = 0% ~ 100%] and MS (ESI, m / z): 789.4 [M+H] + .

[0507] 1H NMR (400 MHz, CDC13) δ 8.52 (s, 1H), 8.34 (s, 1H), 7.87 (d, J = 8.0 Hz, 1H), 7.48 (s, 1H), 7.39 - 7.30 (m, 2H), 7.26 - 7.20 (m, 1H), 7.07 - 7.02 (m, 3H), 6.95 (d, J = 8.4 Hz, 1H), 6.78 (d, J = 8.4 Hz, 1H), 6.71 - 6.63 (m, 1H), 6.53 - 6.43 (m, 1H), 5.95 (s, 2H), 3.89 - 3.77 (m, 1H), 3.71 - 3.58 (m, 2H), 2.97 - 2.84 (m, 4H), 2.77 - 2.65 (m, 4H), 2.64 - 2.51 (m, 3H), 2.33 - 2.21 (m, 2H), 2.11 - 2.01 (m, 4H), 1.68 - 1.62 (m, 2H), 1.36 - 1.29 (m, 6H), 1.17 - 1.11 (m, 1H), 0.91 (t, J = 6.8 Hz, 3H), 0.71 - 0.66 (m, 1H), 0.55 - 0.46 (m, 1H), 0.44 - 0.35 (m, 1H), 0.28 - 0.19 (m, 1H).

[0508] Example 79

[0509] Compound 79-1 (1.0 g, 9.26 mmol), compound 79-2 (3.86 g, 27.8 mmol) and potassium carbonate (2.56 g, 18.5 mmol) were dissolved in N,N-dimethylformamide (15 mL) and reacted at 60 °C overnight. After the reaction was completed, the reaction mixture was concentrated to obtain a crude product. Then, the crude product was separated by normal phase column chromatography (petroleum ether: ethyl acetate = 0-100%) to obtain compound 79-3 (1.27 g, yield 83%) as a yellow oil, MS (ESI, m / z): 167.1 [M+H] + .

[0510] Compound 79-3 (1.27 g, 7.66 mmol), p-toluenesulfonyl chloride (1.76 g, 9.2 mmol), triethylamine (1.55 g, 15.3 mmol) and 4-dimethylaminopyridine (93 mg, 0.766 mmol) were dissolved in dichloromethane (20 mL) and reacted at 25 °C for 4 hours. After the reaction was completed, the reaction mixture was concentrated to obtain a crude product. Then, the crude product was separated by normal phase column chromatography (petroleum ether: ethyl acetate = 0-100%) to obtain compound 79-4 (2.26 g, yield 92%) as a yellow oil, MS (ESI, m / z): 321.3 [M+H] + .

[0511] Compound 79-4 (2.26 g, 7.06 mmol), compound 79-5 (1.23 g, 7.06 mmol), potassium carbonate (1.95 g, 14.1 mmol) were dissolved in N,N-dimethylformamide (10 mL) and reacted at 60 °C for 4 hours. After the reaction was completed, the reaction mixture was concentrated to obtain a crude product. The crude product was separated by normal phase column chromatography (petroleum ether: ethyl acetate = 0 ~ 100%) to obtain compound 79-6 (1.64 g, yield 72%) as a yellow oil, MS (ESI, m / z): 322.1 [M+H] + .

[0512] Compound 79-6 (1.64 g, 5.11 mmol), iron powder (2.86 g, 51.1 mmol), ammonium chloride (2.76 g, 51.1 mmol) were dissolved in a mixed solution of ethanol (20 mL) / water (4 mL) and reacted at 80 °C for 8 hours. After the reaction was completed, the reaction mixture was concentrated to obtain a crude product. The crude product was separated by normal phase column chromatography (petroleum ether: ethyl acetate = 0 ~ 100%) to obtain compound 79-7 (1.4 g, yield 94%) as a yellow oil, MS (ESI, m / z): 292.1 [M+H] + .

[0513] Compound 79-7 (58 mg, 0.2 mmol), compound 35-1 (95 mg, 0.2 mmol), N,N,N',N'-tetramethylchloroformamidium hexafluorophosphate (84 mg, 0.3 mmol), and 1-methylimidazole (74 mg, 0.9 mmol) were dissolved in acetonitrile (2 mL) and reacted at 70 °C for 24 hours. After the reaction was completed, the reaction mixture was concentrated to obtain a crude product. The crude product was separated by normal phase column chromatography (petroleum ether: ethyl acetate = 0 ~ 100%) to obtain compound 79-8 (61 mg, yield 41%) as a yellow oil, MS (ESI, m / z): 751.3 [M+H] + .

[0514] Compound 79-8 (61 mg, 0.0813 mmol), lithium hydroxide (396 mg, 1.63 mmol) were added to a mixed solution of tetrahydrofuran (2 mL), methanol (2 mL), and water (1 mL) and reacted at 60 °C for 3 hours. After the reaction was completed, the reaction mixture was concentrated to obtain a crude product. The crude product was purified by reverse phase column chromatography [acetonitrile / water (0.05% formic acid) = 0% ~ 100%] to obtain compound 79 (33.2 mg, yield 55%) as a white solid, MS (ESI, m / z): 737.3 [M+H] + .

[0515] 1H NMR (400 MHz, CDC13) δ 8.35 - 8.29 (m, 2H), 7.83 (d, J = 8.0 Hz, 1H), 7.43 (s, 1H), 7.31 - 7.26 (m, 2H), 7.23 - 7.12 (m, 2H), 6.79 - 6.70 (m, 3H), 6.69 - 6.58 (m, 2H), 6.57 - 6.51 (m, 1H), 6.48 - 6.40 (m, 1H), 4.21 (t, J = 6.0 Hz, 2H), 4.16 (t, J = 6.0 Hz, 2H), 3.89 - 3.76 (m, 6H), 3.01 - 2.78 (m, 4H), 2.54 - 2.46 (m, 1H), 2.32 (s, 3H), 2.31 - 2.13 (m, 4H), 2.08 - 2.00 (m, 2H), 1.17 - 1.03 (m, 1H), 0.70 - 0.60 (m, 1H), 0.53 - 0.41 (m, 1H), 0.39 - 0.30 (m, 1H), 0.25 - 0.13 (m, 1H).

[0516] Example 80

[0517] Synthesis route:

[0518] The synthesis of Reference Compound 79 was performed by replacing Compound 79-2 with Compound 80-1 to give Compound 80 (40.8 mg, yield 42%) as a white solid, which was purified by reverse phase column chromatography [acetonitrile / water (0.05% formic acid) = 0% ~ 100%] and MS (ESI, m / z): 723.4 [M+H] + .

[0519] 1H NMR (400 MHz, CDC13) δ 8.38 (d, J = 2.4 Hz, 1H), 8.32 (s, 1H), 7.83 (d, J = 8.4 Hz, 1H), 7.43 (s, 1H), 7.34 - 7.27 (m, 2H), 7.22 - 7.15 (m, 2H), 6.82 - 6.75 (m, 3H), 6.74 - 6.69 (m, 1H), 6.62 (d, J = 8.4 Hz, 1H), 6.54 (s, 1H), 6.44 (d, J = 8.0 Hz, 1H), 4.41 - 4.29 (m, 4H), 3.87 - 3.77 (m, 6H), 2.99 - 2.77 (m, 4H), 2.54 - 2.44 (m, 1H), 2.34 (s, 3H), 2.27 - 2.13 (m, 2H), 2.07 - 1.99 (m, 2H), 1.14 - 1.04 (m, 1H), 0.66 - 0.59 (m, 1H), 0.50 - 0.42 (m, 1H), 0.38 - 0.30 (m, 1H), 0.24 - 0.16 (m, 1H).

[0520] Example 81

[0521] Synthesis route:

[0522] The synthesis of Reference Compound 80 was performed by replacing Compound 80-1 with Compound 81-1 to give Compound 81 (78.2 mg, yield 57%) as a white solid, which was purified by reverse phase column chromatography [acetonitrile / water (0.05% formic acid) = 0% ~ 100%] and MS (ESI, m / z): 765.4 [M+H] + .

[0523] 1H NMR (400 MHz, CDC13) δ 8.37 - 8.31 (m, 2H), 7.86 (d, J = 8.0 Hz, 1H), 7.47 (s, 1H), 7.34 - 7.30 (m, 2H), 7.27 - 7.20 (m, 1H), 7.20 - 7.15 (m, 1H), 6.81 - 6.73 (m, 3H), 6.71 - 6.63 (m, 2H), 6.61 - 6.54 (m, 1H), 6.51 - 6.44 (m, 1H), 3.92 (s, 2H), 3.90 - 3.82 (m, 8H), 3.06 - 2.80 (m, 4H), 2.57 - 2.49 (m, 1H), 2.34 (s, 3H), 2.30 - 2.18 (m, 2H), 2.12 - 2.03 (m, 2H), 1.19 (s, 6H), 1.17 - 1.08 (m, 1H), 0.72 - 0.63 (m, 1H), 0.53 - 0.45 (m, 1H), 0.41 - 0.34 (m, 1H), 0.27 - 0.18 (m, 1H).

[0524] Example 82

[0525] Synthesis route:

[0526] Compound 56-3 (250 mg, 1.18 mmol), compound 82-1 (250 mg, 1.18 mmol), acetic acid (0.2 mL), 3A molecular sieves (250 mg) were added to 1,2-dichloroethane (20 mL) and stirred, reacted at 60 °C for 2 hours, sodium borohydride (502 mg, 2.37 mmol) was added, reacted at 60 °C for 16 hours, after TLC monitoring the reaction was completed, concentrated to obtain the crude product. Then separated by normal phase column chromatography (petroleum ether: ethyl acetate = 0-100%) to obtain yellow oil 82-2 (270.4 mg, yield 62%), MS (ESI, m / z): 371.3 [M+H] + .

[0527] Compound 82-2 (180 mg, 0.49 mmol), iron filings (136 mg, 2.43 mmol), ammonium chloride (131 mg, 2.43 mmol) were added to a mixture of ethanol (10 mL) / water (2 mL) and stirred, reacted at 80 °C for 16 hours under nitrogen protection, diluted with ethyl acetate (80 mL) and filtered after the reaction was completed, concentrated to obtain the crude product. Then separated by normal phase column chromatography (petroleum ether: ethyl acetate = 0-100%) to obtain yellow oil 82-3 (160.5 mg, yield 97%), MS (ESI, m / z): 341.3 [M+H] + .

[0528] Then referring to the synthesis of compound 36, compound 36-5 was replaced by compound 82-3, compound 82-4 (130 mg, 0.16 mmol) was synthesized and added into ethyl acetate (10 mL) and stirred, then palladium on carbon (10%) (20 mg) was added, and the reaction was carried out under the protection of hydrogen (1.5 atm) at room temperature for 16 hours. After the reaction was completed, TLC was used for monitoring, and then the crude product was concentrated. Then yellow oil 82-5 (129.6 mg, yield 99%) was separated by normal phase column chromatography (petroleum ether: ethyl acetate = 0-100%) and MS (ESI, m / z): 802.3 [M+H] + .

[0529] Then referring to the synthesis of compound 36, compound 36-5 was replaced by compound 82-3, compound 82-4 (130 mg, 0.16 mmol) was synthesized and added into ethyl acetate (10 mL) and stirred, then palladium on carbon (10%) (20 mg) was added, and the reaction was carried out under the protection of hydrogen (1.5 atm) at room temperature for 16 hours. After the reaction was completed, TLC was used for monitoring, and then the crude product was concentrated. Then yellow oil 82-5 (129.6 mg, yield 99%) was separated by normal phase column chromatography (petroleum ether: ethyl acetate = 0-100%) and MS (ESI, m / z): 802.3 [M+H] + .

[0530] 1 H NMR (400 MHz, CDC13) δ 8.54 - 8.17 (m, 1H), 8.05 (s, 1H), 7.77 - 7.65 (m, 1H), 7.51 (s, 1H), 7.34 (d, J = 7.6 Hz, 1H), 7.25 - 7.16 (m, 3H), 7.09 - 6.98 (m, 3H), 6.66 - 6.59 (m, 2H), 6.56 (s, 1H), 6.49 - 6.42 (m, 1H), 3.89 - 3.80 (m, 6H), 3.62 - 3.49 (m, 2H), 2.98 - 2.74 (m, 6H), 2.67 - 2.49 (m, 4H), 2.36 (s, 3H), 2.32 - 2.28 (m, 2H), 2.24 - 2.11 (m, 4H), 2.05 - 2.01 (m, 2H), 1.95 - 1.83 (m, 4H), 1.16 - 1.02 (m, 1H), 0.70 - 0.57 (m, 1H), 0.51 - 0.35 (m, 2H), 0.31 - 0.20 (m, 1H).

[0531] Example 83

[0532] Synthesis route:

[0533] Then referring to the synthesis of compound 36, compound 36-5 was replaced by compound 82-3, compound 82-4 (130 mg, 0.16 mmol) was synthesized and added into ethyl acetate (10 mL) and stirred, then palladium on carbon (10%) (20 mg) was added, and the reaction was carried out under the protection of hydrogen (1.5 atm) at room temperature for 16 hours. After the reaction was completed, TLC was used for monitoring, and then the crude product was concentrated. Then yellow oil 82-5 (129.6 mg, yield 99%) was separated by normal phase column chromatography (petroleum ether: ethyl acetate = 0-100%) and MS (ESI, m / z): 802.3 [M+H] + .

[0534] 1 H NMR (400 MHz, CDC13) δ 8.52 (s, 1H), 8.16 (s, 1H), 7.73 (d, J = 8.0 Hz, 1H), 7.54 (s, 1H), 7.35 (d, J = 8.4 Hz, 1H), 7.25 - 7.16 (m, 3H), 7.05 - 6.95 (m, 4H), 6.68 - 6.61 (m, 1H), 6.58 - 6.55 (m, 1H), 6.49 - 6.44 (m, 1H), 3.87 - 3.82 (m, 6H), 3.77 - 3.54 (m, 2H), 3.33 - 3.19 (m, 4H), 3.02 - 2.81 (m, 4H), 2.62 - 2.49 (m, 2H), 2.35 (s, 3H), 2.23 - 2.14 (m, 2H), 2.08 - 1.93 (m, 4H), 1.92 - 1.77 (m, 2H), 1.19 - 1.11 (m, 1H), 0.71 - 0.65 (m, 1H), 0.53 - 0.46 (m, 1H), 0.43 - 0.39 (m, 1H), 0.28 - 0.22 (m, 1H).

[0535] Example 84

[0536] Synthetic route:

[0537] Compound 84-1 (2.0 g, 9.95 mmol), triphenylphosphine (3.91 g, 14.93 mmol) were added to dichloromethane (20 mL) and stirred, carbon tetrabromide (4.94 g, 14.93 mmol) was added at 0 °C, and the reaction was allowed to proceed at room temperature for 3 hours. After the reaction was completed as monitored by TLC, the crude product was concentrated. Then, yellow oil 84-2 (2.2 g, yield 84%) was isolated by normal phase column chromatography (petroleum ether: ethyl acetate = 0-100%). Then, according to the synthesis of compound 82, compound 56-3 was replaced by compound 84-2, and white solid 84 (10.8 mg, yield 14%) was synthesized and purified by reverse phase column chromatography [acetonitrile / water (0.05% formic acid) = 0%-100%], MS (ESI, m / z): 774.3 [M+H] + .

[0538] 1H NMR (400 MHz, CDC13) δ 8.36 (s, 1H), 7.87 (s, 1H), 7.65 (d, J = 8.0 Hz, 1H), 7.54 (s, 1H), 7.37 (d, J = 8.0 Hz, 1H), 7.26 - 7.21 (m, 2H), 7.11 - 7.03 (m, 4H), 6.70 - 6.64 (m, 1H), 6.61 - 6.57 (m, 1H), 6.50 - 6.45 (m, 1H), 6.44 - 6.38 (m, 1H), 3.90 - 3.84 (m, 6H), 3.62 - 3.53 (m, 2H), 3.04 - 2.96 (m, 2H), 2.92 - 2.82 (m, 2H), 2.80 - 2.72 (m, 1H), 2.68 - 2.31 (m, 9H), 2.24 - 2.05 (m, 6H), 2.04 - 1.78 (m, 3H), 1.12 - 1.04 (m, 1H), 0.70 - 0.59 (m, 1H), 0.51 - 0.35 (m, 2H), 0.30 - 0.22 (m, 1H).

[0539] Example 85

[0540] Synthesis route:

[0541] Intermediate M2-5 (1 g, 1.98 mmol), compound 85-1 (610 mg, 2.17 mmol), tetrakis triphenylphosphine palladium (228 mg, 0.2 mmol) and sodium carbonate (1 g, 9.88 mmol) were added to a mixture solution of 1,4-dioxane (20 mL) and water (5 mL) and stirred at 100 °C overnight. After monitoring the end of the reaction by TLC, ethyl acetate (100 mL) was added, the organic phase was washed with saturated brine, and the organic phase was combined and concentrated to obtain a crude product, which was separated by normal phase column chromatography (petroleum ether: ethyl acetate = 0-100%) to obtain 85-2 (1.05 g, yield 88%) as a yellow oil, MS (ESI, m / z): 576.2 [M+H] + .

[0542] Compound 85-2 (240 mg, 0.42 mmol) was added to dimethyl sulfoxide (5 mL), then potassium tert-butoxide (56 mg, 0.5 mmol) and 18-crown-6 (110 mg, 0.42 mmol) were added to the reaction solution and stirred at room temperature for 1 hour. Finally, a dimethyl sulfoxide (5 mL) solution of compound 85-3 (147 mg, 0.5 mmol) was added to the reaction solution and stirred at room temperature for 3 hours. After the reaction was completed by TLC monitoring, ethyl acetate (100 mL) was added, the organic phase was washed with saturated brine, and the combined organic phase was concentrated to obtain a crude product, which was separated by normal phase column chromatography (petroleum ether: ethyl acetate = 0-100%) to obtain yellow oil 85-4 (124.8 mg, yield 38%), MS (ESI, m / z): 788.2 [M+H] + .

[0543] Compound 85-4 (120 mg, 0.15 mmol) was added to dichloromethane (10 mL), then trifluoroacetic acid (0.5 mL) was slowly added to the reaction solution and stirred at room temperature for 4 hours. After the reaction was completed by TLC monitoring, it was directly concentrated, then ethyl acetate (100 mL) was added, the organic phase was washed with saturated sodium bicarbonate solution, dried, filtered and concentrated to obtain a crude product, which was separated by normal phase column chromatography (petroleum ether: ethyl acetate = 0-100%) to obtain yellow oil 85-5 (95.2 mg, yield 91%), MS (ESI, m / z): 688.2 [M+H] + .

[0544] Compound 85-5 (95 mg, 0.14 mmol), tris(dibenzylideneacetone)dipalladium (13 mg, 0.014 mmol), 2-dicyclohexylphospho-2',6'-diisopropoxy-1,1'-biphenyl (13 mg, 0.028 mmol) and cesium carbonate (89 mg, 0.27 mmol) were added to 1,4-dioxane (50 mL) and stirred at 100°C overnight. After the reaction was completed by TLC monitoring, ethyl acetate (200 mL) was added, the organic phase was washed with saturated brine, dried, filtered and concentrated to obtain a crude product, which was separated by normal phase column chromatography (petroleum ether: ethyl acetate = 0-100%) to obtain yellow oil 85-6 (84.2 mg, yield 99%), MS (ESI, m / z): 608.3 [M+H] + .

[0545] Compound 85-6 (84.2 mg, 0.139 mmol) was added to a mixture of tetrahydrofuran (3 mL) and methanol (3 mL), then a solution of lithium hydroxide (33 mg, 1.39 mmol) in water (1 mL) was added to the reaction solution and warmed to 60 °C for 1 hour. After the reaction was completed by TLC monitoring, the crude product was concentrated, then purified by reverse phase column chromatography [acetonitrile / water (0.05% formic acid) = 0% ~ 100%] to obtain compound 85 (3.8 mg, yield 4%) as a white solid, MS (ESI, m / z): 593.9 [M+H] + .

[0546] 1 H NMR (400 MHz, CDC13) δ 7.57 - 7.51 (m, 1H), 7.46 - 7.34 (m, 4H), 7.16 - 7.07 (m, 3H), 6.87 - 6.81 (m, 2H), 4.21 (t, J = 6.8 Hz, 2H), 3.80 (s, 3H), 3.65 - 3.52 (m, 2H), 3.25 - 3.15 (m, 1H), 3.10 - 2.96 (m, 2H), 2.90 - 2.75 (m, 6H), 2.54 - 2.36 (m, 3H), 2.15 - 2.03 (m, 2H), 1.55 (s, 6H), 1.14 - 1.05 (m, 1H), 0.64 - 0.57 (m, 1H), 0.50 - 0.43 (m, 1H), 0.33 - 0.25 (m, 1H), 0.23 - 0.15 (m, 1H).

[0547] Example 86

[0548] Synthetic route:

[0549] Compound 86-1 (1.5 g, 9.55 mmol), (3-bromopropoxy)tert-butyldimethylsilane (2.51 g, 10.5 mmol) and cesium carbonate (4.67 g, 14.3 mmol) were added to a solution of N,N-dimethylformamide (15 mL) and warmed to 60 °C for 3 hours. After the reaction was completed by TLC monitoring, ethyl acetate (100 mL) was added, the organic phase was washed with saturated brine, dried, filtered and concentrated to obtain the crude product, which was separated by normal phase column chromatography (petroleum ether: ethyl acetate = 0 ~ 100%) to obtain 86-2 (2.5 g, yield 76%) as a yellow oil, MS (ESI, m / z): 316.2 [M+H] + .

[0550] Compound 86-2 (958 mg, 3.04 mmol) and tetrabutylammonium fluoride (4.5 mL, 4.56 mmol, 1 mol / L) were added to a solution of tetrahydrofuran (15 mL) and stirred at room temperature for 3 hours. After the reaction was completed by TLC monitoring, ethyl acetate (100 mL) was added, the organic phase was washed with saturated brine, dried, filtered and concentrated to obtain a crude product, which was separated by normal phase column chromatography (petroleum ether: ethyl acetate = 0-100%) to obtain yellow oil 86-3 (611.2 mg, yield 99%), MS (ESI, m / z): 202.2 [M+H] + .

[0551] Compound 86-3 (611.2 mg, 3.03 mmol), p-toluenesulfonyl chloride (707 mg, 3.71 mmol) and triethylamine (681 mg, 6.74 mmol) were added to a solution of dichloromethane (10 mL) and stirred at room temperature for 8 hours. After the reaction was completed by TLC monitoring, dichloromethane (100 mL) was added to dilute, the organic phase was washed with saturated brine, dried, filtered and concentrated to obtain a crude product, which was separated by normal phase column chromatography (petroleum ether: ethyl acetate = 0-100%) to obtain yellow oil 86-4 (900.5 mg, yield 84%), MS (ESI, m / z): 356.2 [M+H] + .

[0552] Then, referring to the synthesis of intermediate M1, compound 86-7 (1.46 g, 3.1 mmol) was synthesized, and potassium carbonate (856 mg, 6.2 mmol) was added to N,N-dimethylformamide (20 mL) and stirred, then benzyl bromide (689 mg, 4.03 mmol) was slowly added, and the reaction was carried out at room temperature for 8 hours. After the reaction was completed by TLC monitoring, it was diluted with ethyl acetate (100 mL), the organic phase was washed with water (50 mL x 3), the organic phase was dried with anhydrous sodium sulfate, filtered and concentrated to obtain a crude product. Then, it was separated by normal phase column chromatography (petroleum ether: ethyl acetate = 0-100%) to obtain yellow oil 86-8 (1.73 g, yield 99%), MS (ESI, m / z): 562.3 [M+H] + .

[0553] 86-8 (1.73 g, 3.084 mmol) was added to dichloromethane (10 mL) and stirred. Then, trifluoroacetic acid (1.5 mL) was added, and the mixture was reacted at room temperature for 6 hours. After the reaction was completed by TLC monitoring, the mixture was concentrated, diluted with ethyl acetate (100 mL), and washed with saturated sodium bicarbonate solution (50 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. Then, the crude product was separated by normal-phase column chromatography (petroleum ether: ethyl acetate = 0–100%) to obtain a yellow oily substance 86-9 (1.42 g, yield 99%), MS (ESI, m / z): 462.2 [M+H]. + .

[0554] Compound 86-9 (1.42 g, 3.08 mmol), compound 86-10 (2 g, 8.33 mmol), tris(dibenzylacetone)palladium (381 mg, 0.42 mmol), 2-dicyclohexylphosphine-2',6'-diisopropoxy-1,1'-biphenyl (388 mg, 0.83 mmol), and cesium carbonate (2.7 g, 8.33 mmol) were added to 1,4-dioxane (20 mL) and the mixture was heated to 100 °C and stirred overnight. After the reaction was completed by TLC monitoring, ethyl acetate (200 mL) was added, the organic phase was washed with saturated brine, dried, filtered, and concentrated to obtain the crude product. Then, the crude product was separated by normal-phase column chromatography (petroleum ether: ethyl acetate = 0–100%) to obtain a yellow oily compound 86-11 (1.2 g, yield 62%), MS (ESI, m / z): 628.2 [M+H]. + .

[0555] Compound 86-11 (577 mg, 0.92 mmol) was added to tetrahydrofuran (9 mL), followed by the addition of 6N hydrochloric acid solution (1 mL). The mixture was heated to 50 °C and stirred for 2 hours. After the reaction was completed by TLC monitoring, ethyl acetate (100 mL) was added, and the organic phase was washed with saturated brine. The mixture was dried, filtered, and concentrated to obtain the crude product. The crude product was then separated by normal-phase column chromatography (petroleum ether:ethyl acetate = 0–100%) to obtain a yellow oily substance 86-12 (527.5 mg, yield 98%). MS (ESI, m / z): 584.2 [M+H] + .

[0556] Compound 86-12 (527 mg, 0.90 mmol), compound 86-4 (383 mg, 1.08 mmol) and cesium carbonate (589 mg, 1.81 mmol) were added to N,N-dimethylformamide (5 mL) and stirred at 60 °C for 3 h. After the reaction was completed by TLC monitoring, ethyl acetate (100 mL) was added, the organic phase was washed with saturated brine, dried, filtered and concentrated to give a crude product, which was separated by normal phase column chromatography (petroleum ether: ethyl acetate = 0-100%) to give yellow oil 86-13 (380.2 mg, yield 55%), MS (ESI, m / z): 767.2 [M+H] + .

[0557] Compound 86-13 (380 mg, 0.49 mmol), palladium on carbon (40 mg) and palladium hydroxide (40 mg) were added to ethyl acetate (5 mL) and stirred at 50 °C for overnight under hydrogen (1 atm). After the reaction was completed by TLC monitoring, it was directly filtered and concentrated to give a crude product, which was separated by normal phase column chromatography (petroleum ether: ethyl acetate = 0-100%) to give yellow oil 86-14 (250.5 mg, yield 79%), MS (ESI, m / z): 646.2 [M+H] + .

[0558] Compound 86-14 (250.5 mg, 0.38 mmol) was added to a solution of pyridine (25 mL) under ice bath, then phosphorus oxychloride (0.8 mL) was slowly added to the reaction solution and stirred at elevated temperature for 3 h. After the reaction was completed by TLC monitoring, it was directly filtered and concentrated to give a crude product, which was separated by normal phase column chromatography (petroleum ether: ethyl acetate = 0-100%) to give yellow solid compound 86-15 (15.3 mg, yield 6%), MS (ESI, m / z): 629.2 [M+H] + .

[0559] Compound 86-15 (15.3 mg, 0.023 mmol) was added to a mixture of tetrahydrofuran (4 mL) and methanol (2 mL), then a solution of lithium hydroxide (6 mg, 0.23 mmol) in water (1 mL) was added to the reaction solution and stirred at 60 °C for 3 h. After the reaction was completed by TLC monitoring, it was directly filtered and concentrated to give a crude product, which was purified by reverse phase column chromatography [acetonitrile / water (0.05% formic acid) = 0%-100%] to give white solid compound 86 (1.2 mg, yield 9%), MS (ESI, m / z): 615.2 [M+H] + .

[0560] 1H NMR (400 MHz, CDC13) δ 7.85 (s, 1H), 7.77 - 7.71 (m, 1H), 7.43 - 7.32 (m, 2H), 7.23 (d, J = 8.0 Hz, 1H), 7.14 - 7.05 (m, 1H), 6.95 - 6.88 (m, 1H), 6.83 (d, J = 8.8 Hz, 1H), 6.65 (s, 1H), 6.59 - 6.52 (m, 1H), 4.65 - 4.51 (m, 2H), 4.31 - 4.26 (m, 2H), 3.85 - 3.75 (m, 5H), 3.61 - 3.54 (m, 2H), 3.27 - 3.17 (m, 1H), 2.91 - 2.86 (m, 2H), 2.76 - 2.72 (m, 1H), 2.55 - 2.50 (m, 2H), 2.28 - 2.24 (m, 2H), 1.14 - 1.09 (m, 1H), 0.70 - 0.62 (m, 1H), 0.51 - 0.42 (m, 1H), 0.40 - 0.32 (m, 1H), 0.24 - 0.17 (m, 1H).

[0561] Example 87

[0562] Synthesis route:

[0563] Referring to the synthesis of Compound 86, (3-bromopropoxy)-tert-butyldimethylsilane was replaced by (2-bromoethoxy)-tert-butyldimethylsilane to synthesize and purify by reverse phase column chromatography [acetonitrile / water (0.05% formic acid) = 0% ~ 100%] to obtain white solid 87 (1.3 mg, yield 8%), MS (ESI, m / z): 629.2 [M+H] + .

[0564] 1H NMR (400 MHz, CDC13) δ 7.76 (s, 1H), 7.67 (s, 1H), 7.58 (d, J = 6.4 Hz, 1H), 7.33 (s, 1H), 7.20 (d, J = 6.0 Hz, 1H), 7.08 - 6.99 (m, 1H), 6.79 (d, J = 6.8 Hz, 1H), 6.74 - 6.69 (m, 1H), 6.57 (d, J = 2.0 Hz, 1H), 6.49 (dd, J = 6.8 Hz, 2.0 Hz, 1H), 4.47 - 4.31 (m, 2H), 4.07 - 3.96 (m, 2H), 3.77 (s, 3H), 3.60 - 3.51 (m, 2H), 3.07 - 2.98 (m, 1H), 2.90 - 2.78 (m, 2H), 2.70 - 2.51 (m, 4H), 2.49 - 2.44 (m, 1H), 2.25 - 2.19 (m, 2H), 2.13 - 2.07 (m, 2H), 1.10 - 1.03 (m, 1H), 0.66 - 0.57 (m, 1H), 0.46 - 0.40 (m, 1H), 0.34 - 0.28 (m, 1H), 0.20 - 0.14 (m, 1H).

[0565] Example 88

[0566] Synthetic route:

[0567] Compound M1-5 (4.8 g, 11.78 mmol), compound 88-1 (5.2 g, 14.13 mmol), cesium carbonate (7.7 g, 23.55 mmol), 2-dicyclohexylphospho-2',6'-diisopropoxy-1,1'-biphenyl (1.1 g, 2.35 mmol) and tris(dibenzylideneacetone)dipalladium (1.08 g, 1.18 mmol) were dissolved in 1,4-dioxane (100 mL) and reacted at 100 °C overnight. After the reaction was completed as monitored by TLC, it was directly filtered and concentrated to obtain a crude product, which was separated by normal phase column chromatography (petroleum ether: ethyl acetate = 0-100%) to obtain yellow oil 88-2 (5.1 g, yield 76%), MS (ESI, m / z): 568.2 [M+H] + .

[0568] Compound 88-2 (2.55 g, 4.50 mmol) was dissolved in methanol (100 mL), tetrahydroxydiboron (2.02 g, 22.5 mmol), potassium acetate (2.2 g, 22.5 mmol), methane sulfonic acid (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (177 mg, 0.225 mmol) and 2-dicyclohexylphospho-2',4',6'-triisopropyl biphenyl (382.7 mg, 0.45 mmol) were added, and the mixture was stirred at 80 °C for 2 h. After the reaction was completed by TLC monitoring, the mixture was directly filtered and concentrated to give a crude product, which was separated by normal phase column chromatography (petroleum ether: ethyl acetate = 0-100%) to give compound 88-3 (1.4 g, yield 51%) as a white solid, MS (ESI, m / z): 612.2 [M+H] + .

[0569] Compound 88-4 (500 mg, 2.89 mmol), compound 88-5 (1400 mg, 3.76 mmol), potassium carbonate (800 mg, 5.78 mmol) were dissolved in acetone (50 mL) and stirred at 50 °C overnight. After the reaction was completed by TLC monitoring, the mixture was quenched by adding water (50 mL), extracted with ethyl acetate (30 mL x 3), washed with saturated brine (30 mL), concentrated and dried to give compound 88-6 (0.8 g, yield 74%) as a yellow oil, MS (ESI, m / z): 371.1 [M+H] + .

[0570] Compound 88-7 (421 mg, 4.05 mmol) was dissolved in N,N-dimethylformamide (10 mL), sodium hydride (162 mg, 4.05 mmol) was added at 0 °C, and the mixture was stirred at room temperature for 1 h. Then, compound 88-6 (1 g, 2.7 mmol) was added, and the mixture was stirred at 50 °C overnight. After the reaction was completed by TLC monitoring, the mixture was quenched by adding water (50 mL), extracted with ethyl acetate (30 mL x 3), washed with saturated brine (30 mL), concentrated and dried to give compound 88-8 (523 mg, yield 64%) as a yellow oil, MS (ESI, m / z): 303.1 [M+H] + .

[0571] Compound 88-8 (482 mg, 1.6 mmol), Dess Martin oxidant (814 mg, 1.92 mmol) were dissolved in dichloromethane (10 mL), stirred at 0 °C for 4 h, TLC monitored the end of the reaction, directly filtered and concentrated to get the crude product, then separated by normal phase column chromatography (petroleum ether: ethyl acetate = 0-100%) to get yellow oil 88-9 (380.5 mg, yield 79%), MS (ESI, m / z): 301.1 [M+H] + .

[0572] Compound 88-9 (380 mg, 1.25 mmol), triphenylmethylamine (561 mg, 2.52 mmol), sodium borohydride (533 mg, 2.52 mmol) were dissolved in dichloromethane (4 mL), added a drop of acetic acid as catalyst, reacted at room temperature overnight, TLC monitored the end of the reaction, directly filtered and concentrated to get the crude product, then separated by normal phase column chromatography (petroleum ether: ethyl acetate = 0-100%) to get yellow oil 88-10 (400 mg, yield 58%), MS (ESI, m / z): 544.2 [M+H] + .

[0573] Compound 88-10 (300 mg, 0.552 mmol), compound 88-3 (680 mg, 1.1 mmol), sodium carbonate (300 mg, 2.76 mmol) and [1,1'-bis (di-tert-butylphosphino) ferrocene] dichloropalladium (40 mg, 0.0552 mmol) were dissolved in tetrahydrofuran (15 mL) and water (5 mL), reacted at room temperature overnight, TLC monitored the end of the reaction, directly filtered and concentrated to get the crude product, then separated by normal phase column chromatography (petroleum ether: ethyl acetate = 0-100%) to get yellow oil 88-11 (500 mg, yield 86%), MS (ESI, m / z): 516.2 [M+2H] / 2 + .

[0574] Compound 88-11 (500 mg, 0.485 mmol) was dissolved in dichloromethane (4 mL), added trifluoroacetic acid (2 mL), reacted at room temperature for 4 h, TLC monitored the end of the reaction, directly filtered and concentrated to get the crude product, then separated by normal phase column chromatography (petroleum ether: ethyl acetate = 0-100%) to get yellow oil 88-12 (350 mg, yield 92%), MS (ESI, m / z): 789.4 [M+H] + .

[0575] Compound 88-12 (350 mg, 0.44 mmol) was dissolved in tetrahydrofuran (5 mL), palladium on carbon (100 mg) was added, and the reaction was stirred under hydrogen (1 atm) at room temperature overnight. After the reaction was completed as monitored by TLC, the reaction mixture was filtered directly and concentrated to give a crude product, which was separated by normal phase column chromatography (petroleum ether: ethyl acetate = 0-100%) to give 88-13 (300 mg, 98% yield) as a red oil, MS (ESI, m / z): 699.4 [M+H] + .

[0576] Compound 88-13 (50 mg, 0.0716 mmol), N,N,N',N'-tetramethylchloroformamidium hexafluorophosphate (30 mg, 0.107 mmol), and 1-methylpyrazole (26 mg, 0.322 mmol) were dissolved in acetonitrile (3 mL) and the reaction was stirred at room temperature overnight. After the reaction was completed as monitored by TLC, the reaction mixture was filtered directly and concentrated to give a crude product, which was separated by normal phase column chromatography (petroleum ether: ethyl acetate = 0-100%) to give 88-14 (40 mg, 82% yield) as a yellow oil, MS (ESI, m / z): 681.3 [M+H] + .

[0577] A reaction tube was taken and compound 88-14 (40 mg, 0.0587 mmol), lithium hydroxide (8.2 mg, 0.341 mmol), tetrahydrofuran (3 mL), methanol (3 mL), and water (3 mL) were added, and the reaction was stirred at 50 °C for 2 hours. After the reaction was completed as monitored by TLC, the reaction mixture was filtered directly and concentrated to give a crude product, which was purified by reverse phase column chromatography [acetonitrile / water (0.05% formic acid) = 0%-100%] to give 88 (16 mg, 40% yield) as a white solid, MS (ESI, m / z): 667.3 [M+H] + .

[0578] 1H NMR (400 MHz, CDC13) δ 9.11 (t, J = 6.8 Hz, 1H), 8.00 (d, J = 9.2 Hz, 1H), 7.34 - 7.27 (m, 2H), 7.13 (d, J = 8.0 Hz, 1H), 7.08 - 7.03 (m, 2H), 7.01 - 6.96 (m, 1H), 6.90 (d, J = 7.6 Hz, 1H), 6.71 - 6.65 (m, 2H), 4.36 - 4.26 (m, 2H), 3.83 (s, 3H), 3.72 (t, J = 4.0 Hz, 2H), 3.27 - 3.16 (m, 6H), 3.06 - 2.99 (m, 1H), 2.88 - 2.82 (m, 2H), 2.74 (t, J = 11.6 Hz, 2H), 2.54 - 2.46 (m, 1H), 2.23 - 2.15 (m, 2H), 1.72 - 1.66 (m, 2H), 1.11 - 1.06 (m, 1H), 0.82 (s, 6H), 0.67 - 0.57 (m, 1H), 0.50 - 0.40 (m, 1H), 0.38 - 0.30 (m, 1H), 0.24 - 0.16 (m, 1H).

[0579] Example 89

[0580] Synthesis route:

[0581] Compound 88-14 (50 mg, 0.0735 mmol) was dissolved in N,N-dimethylformamide (4 mL), sodium hydride (5 mg, 0.110 mmol) was added, and the reaction was allowed to proceed at room temperature for 1 hour. Methyl iodide (31 mg, 0.220 mmol) was added, and the reaction was allowed to proceed at room temperature overnight. After the reaction was completed as monitored by TLC, the reaction mixture was directly filtered and concentrated to obtain a crude product, which was then purified by reverse phase column chromatography [acetonitrile / water (0.05% formic acid) = 0% to 100%] to obtain 89 (5.2 mg, yield 10%) as a white solid, MS (ESI, m / z): 681.3 [M+H] + .

[0582] 1H NMR (400 MHz, CDC13) δ 7.37 - 7.30 (m, 2H), 7.23 - 6.92 (m, 6H), 6.52 (dd, J = 8.4, 2.0 Hz, 1H), 6.46 - 6.38 (m, 1H), 4.46 - 4.33 (m, 1H), 4.26 - 4.18 (m, 1H), 3.83 - 3.70 (m, 5H), 3.51 - 3.11 (m, 4H), 3.04 - 2.69 (m, 9H), 2.58 - 2.43 (m, 2H), 2.23 - 1.81 (m, 2H), 1.77 - 1.51 (m, 2H), 1.11 - 1.03 (m, 1H), 0.99 (s, 3H), 0.66 - 0.47 (m, 4H), 0.47 - 0.38 (m, 1H), 0.36 - 0.28 (m, 1H), 0.22 - 0.14 (m, 1H).

[0583] Example 90

[0584] Synthesis route:

[0585] Compound M1-5 (5000 mg, 9.89 mmol) was dissolved in methanol (40 mL), tetrahydroxydiboron (4400 mg, 49.41 mmol), potassium acetate (4800 mg, 49.41 mmol), methane sulfonic acid (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (388 mg, 0.494 mmol) and 2-dicyclohexylphospho-2',4',6'-triisopropyl biphenyl (471 mg, 0.988 mmol) were added, and the mixture was stirred at 80 °C for 2 h. After the reaction was completed as monitored by TLC, the mixture was directly filtered and concentrated to give a crude product, which was separated by normal phase column chromatography (petroleum ether: ethyl acetate = 0-100%) to give 90-1 (3200 mg, yield 69%) as a white solid, MS (ESI, m / z): 472.2 [M+H] + .

[0586] Compound 88-9 (220 mg, 0.733 mmol), aniline (82 mg, 0.88 mmol), sodium borohydride (186 mg, 0.88 mmol) were dissolved in dichloromethane (4 mL), and a drop of acetic acid was added as a catalyst. The mixture was stirred at room temperature overnight. After the reaction was completed as monitored by TLC, the mixture was directly filtered and concentrated to give a crude product, which was separated by normal phase column chromatography (petroleum ether: ethyl acetate = 0-100%) to give 90-2 (240 mg, yield 87%) as a yellow oil, MS (ESI, m / z): 376.2 [M+H] + .

[0587] Compound 90-2 (240 mg, 0.638 mmol), compound 90-1 (450 mg, 0.957 mmol), sodium carbonate (340 mg, 3.20 mmol) and [1,1'-bis(di-tert-butylphosphino) ferrocene] dichloropalladium (42 mg, 0.0638 mmol) were dissolved in tetrahydrofuran (6 mL) and water (2 mL), and the reaction was allowed to proceed at room temperature overnight. After the reaction was completed as monitored by TLC, the reaction mixture was directly filtered and concentrated to give a crude product, which was separated by normal phase column chromatography (petroleum ether: ethyl acetate = 0-100%) to give yellow oil 90-3 (265 mg, yield 58%), MS (ESI, m / z): 725.4 [M+H] + .

[0588] Compound 90-3 (250 mg, 0.345 mmol), compound 90-4 (133 mg, 0.449 mmol) were dissolved in dichloromethane (4 mL), and triethylamine (70 mg, 0.690 mmol) was added. The reaction was allowed to proceed at room temperature overnight. After the reaction was completed as monitored by TLC, the reaction mixture was directly filtered and concentrated to give a crude product, which was separated by normal phase column chromatography (petroleum ether: ethyl acetate = 0-100%) to give yellow oil 90-5 (303 mg, yield 89%), MS (ESI, m / z): 985.3 [M+H] + .

[0589] Compound 90-5 (303 mg, 0.307 mmol) was dissolved in dichloromethane (5 mL), and trifluoroacetic acid (2 mL) was added. The reaction was allowed to proceed at room temperature for 2 hours. After the solvent was removed by rotary evaporation, red oil 90-6 (300 mg, yield 100%) was obtained, MS (ESI, m / z): 885.3 [M+H] + .

[0590] Compound 90-6 (151 mg, 0.171 mmol), cesium carbonate (111 mg, 0.341 mmol), 2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl (14 mg, 0.0341 mmol), and tris(dibenzylideneacetone)dipalladium (16 mg, 0.0171 mmol) were dissolved in 1,4-dioxane (8 mL), and the reaction was allowed to proceed at 100°C overnight. After the reaction was completed as monitored by TLC, the reaction mixture was directly filtered and concentrated to give a crude product, which was separated by normal phase column chromatography (petroleum ether: ethyl acetate = 0-100%) to give yellow oil 90-7 (90 mg, yield 70%), MS (ESI, m / z): 756.4 [M+H] + .

[0591] Take a reaction tube, add compound 90-7 (40 mg, 0.0530 mmol), lithium hydroxide (8.2 mg, 0.341 mmol), tetrahydrofuran (3 mL), methanol (3 mL) and water (3 ml), react at 50 °C for 2 hours, after TLC monitoring reaction is completed, directly filter and concentrate to obtain a crude product, then purify by reverse phase column chromatography [acetonitrile / water (0.05% formic acid) = 0%~100%] to obtain white solid 90 (16 mg, yield 40%), MS (ESI, m / z): 743.4 [M+H] + .

[0592] 1H NMR (400 MHz, CDCl3) δ 8.45 (d, J = 8.8 Hz, 2H), 8.18 (d, J = 8.0 Hz, 1H), 7.89 (d, J = 8.8 Hz, 1H), 7.63 (d, J = 2.0 Hz, 1H), 7.52 - 7.43 (m, 3H), 7.37 (t, J = 8.0 Hz, 1H), 7.26 - 7.20 (m, 1H), 7.17 - 7.12 (m, 2H), 7.04 - 6.98 (m, 2H), 6.85 (d, J = 7.6 Hz, 1H), 5.72 - 5.62 (m, 2H), 4.25 - 4.19 (m, 2H), 3.99 (s, 3H), 3.80 (s, 2H), 3.23 (s, 2H), 3.02 - 2.79 (m, 5H), 2.59 - 2.43 (m, 3H), 2.01 - 1.78 (m, 2H), 1.54 (d, J = 11.6 Hz, 1H), 1.43 (d, J = 11.6 Hz, 1H), 1.13 - 0.95 (m, 7H), 0.68 - 0.58 (m, 1H), 0.48 - 0.40 (m, 1H), 0.38 - 0.30 (m, 1H), 0.28 - 0.17 (m, 1H).

[0593] Example 91

[0594] Synthetic route:

[0595] The synthesis of reference compound 88, replace intermediate M1-5 with intermediate M2-5, replace tritylamine with compound 91-3, can synthesize and purify by reverse phase column chromatography [acetonitrile / water (0.05% formic acid) = 0%~100%] to obtain white solid 91 (5.8 mg, yield 41%), MS (ESI, m / z): 758.4 [M+H] + .

[0596] 1H NMR (400 MHz, CDC13) δ 7.45 - 7.38 (m, 2H), 7.36 (s, 1H), 7.29 - 7.26 (m, 1H), 7.22 - 7.15 (m, 2H), 7.14 - 7.08 (m, 2H), 7.00 (d, J = 7.6 Hz, 1H), 6.72 - 6.58 (m, 2H), 6.57 - 6.52 (m, 1H), 6.13 (s, 1H), 4.56 - 4.03 (m, 2H), 3.88 - 3.73 (m, 5H), 3.67 - 3.26 (m, 6H), 3.08 - 2.81 (m, 4H), 2.66 - 2.59 (m, 1H), 2.56 - 2.49 (m, 1H), 2.45 - 2.20 (m, 2H), 2.16 (s, 3H), 2.08 - 1.98 (m, 2H), 1.29 (s, 6H), 1.18 - 1.07 (m, 1H), 0.69 - 0.60 (m, 1H), 0.52 - 0.44 (m, 1H), 0.41 - 0.33 (m, 1H), 0.28 - 0.20 (m, 1H).

[0597] Example 92

[0598] Synthesis route:

[0599] The synthesis of Reference Compound 91 was carried out by replacing compound 88-5 with compound 92-1 and compound 91-2 with compound 88-3 to give compound 92 (4.1 mg, 41% yield) as a white solid, MS (ESI, m / z): 771.9 [M+H] after purification by reverse phase column chromatography [acetonitrile / water (0.05% formic acid) = 0% ~ 100%]. + .

[0600] 1H NMR (400 MHz, CDC13) δ 7.44 - 7.35 (m, 3H), 7.16 (d, J = 8.0 Hz, 1H), 7.13 - 7.01 (m, 4H), 6.97 (d, J = 7.2 Hz, 1H), 6.68 - 6.62 (m, 1H), 6.56 (dd, J = 8.8 Hz, 2.0 Hz, 1H), 6.51 - 6.45 (m, 1H), 6.12 (s, 1H), 4.30 - 4.06 (m, 4H), 3.77 (s, 3H), 3.51 - 3.43 (m, 1H), 3.39 - 3.29 (m, 2H), 3.01 - 2.80 (m, 4H), 2.77 - 2.70 (m, 1H), 2.63 - 2.36 (m, 4H), 2.29 - 2.13 (m, 5H), 2.05 - 1.97 (m, 2H), 1.93 - 1.88 (m, 2H), 1.34 - 1.27 (m, 6H), 1.17 - 1.10 (m, 1H), 0.71 - 0.62 (m, 1H), 0.53 - 0.45 (m, 1H), 0.42 - 0.34 (m, 1H), 0.28 - 0.21 (m, 1H).

[0601] Example 93

[0602] Synthesis route:

[0603] The synthesis of Reference Compound 91 was carried out by replacing compound 88-7 with compound 93-1, and replacing compound 91-2 with compound 88-3 to give compound 93 (7.7 mg, yield 11%) as a white solid, which was purified by reverse phase column chromatography [acetonitrile / water (0.05% formic acid) = 0% ~ 100%] MS (ESI, m / z): 730.2 [M+H] + .

[0604] 1H NMR (400 MHz, CDC13) δ 7.45 - 7.38 (m, 2H), 7.35 (s, 1H), 7.23 - 7.15 (m, 3H), 7.11 - 7.08 (m, 1H), 7.01 (d, J = 8.0 Hz, 2.0 Hz, 2H), 6.71 (d, J = 8.0 Hz, 1H), 6.55 (dd, J = 8.8 Hz, 2.0 Hz, 1H), 6.50 - 6.39 (m, 1H), 6.20 (s, 1H), 4.35 - 4.05 (m, 4H), 3.92 - 3.70 (m, 6H), 3.67 - 3.58 (m, 2H), 2.92 - 2.83 (m, 3H), 2.70 - 2.40 (m, 4H), 2.23 (s, 3H), 1.99 - 1.65 (m, 6H), 1.17 - 1.08 (m, 1H), 0.69 - 0.61 (m, 1H), 0.52 - 0.44 (m, 1H), 0.40 - 0.33 (m, 1H), 0.27 - 0.19 (m, 1H).

[0605] Example 94

[0606] Synthesis route:

[0607] Compound 87-2 (3.0 g, 13.95 mmol) was dissolved in dichloromethane (15 mL), and Dess-Martin oxidizing agent (7.1 g, 16.74 mmol) was added at 0 °C. The reaction was carried out at room temperature for 1 hour. After the reaction was completed by TLC monitoring, the crude product was directly filtered and concentrated, and then separated by normal phase column chromatography (petroleum ether: ethyl acetate = 0-100%) to obtain 94-1 (2.95 g, yield 99%) as a yellow oil, MS (ESI, m / z): 214.1 [M+H] + .

[0608] Compound 94-1 (1.5 g, 7.04 mmol), compound 91-3 (988 mg, 9.15 mmol), and sodium borohydride acetate (2.3 g, 9.15 mmol) were dissolved in dichloromethane (40 mL), and the reaction was carried out at room temperature overnight. After the reaction was completed by TLC monitoring, the crude product was directly filtered and concentrated, and then separated by normal phase column chromatography (petroleum ether: ethyl acetate = 0-100%) to obtain 94-2 (1.3 g, yield 60%) as a yellow oil, MS (ESI, m / z): 306.1 [M+H] + .

[0609] Compound 94-3 (2.5 g, 17.98 mmol) and compound 94-4 (36.5 mL) were dissolved in toluene (20 mL) and reacted at 85 °C overnight. After the reaction was completed as monitored by TLC, the crude product was obtained by direct filtration and concentration, and then separated by normal phase column chromatography (petroleum ether: ethyl acetate = 0-100%) to obtain compound 94-5 (2.52 g, yield 84%) in yellow oil, MS (ESI, m / z): 335.1 [M+H] + .

[0610] Compound 94-5 (2.5 g, 7.49 mmol), compound 86-9 (2.9 g, 6.24 mmol), tris(dibenzylideneacetone)dipalladium (570 mg, 0.624 mmol), 2-dicyclohexylphospho-2',6'-diisopropoxy-1,1'-biphenyl (595 mg, 1.25 mmol) and cesium carbonate (4.1 g, 12.48 mmol) were dissolved in 1,4-dioxane (50 mL) and reacted at 100 °C overnight. After the reaction was completed as monitored by TLC, the crude product was obtained by direct filtration and concentration, and then separated by normal phase column chromatography (petroleum ether: ethyl acetate = 0-100%) to obtain compound 94-6 (2.01 g, yield 48%) in yellow oil, MS (ESI, m / z): 668.3 [M+H] + .

[0611] Compound 94-6 (2.01 g, 3.01 mmol) was dissolved in dichloromethane (8 mL), and trifluoroacetic acid (16 mL) was added. The mixture was reacted at 35 °C overnight. After the reaction was completed as monitored by TLC, the crude product was obtained by direct filtration and concentration, and then separated by normal phase column chromatography (petroleum ether: ethyl acetate = 0-100%) to obtain compound 94-7 (1.5 g, yield 81%) in yellow oil, MS (ESI, m / z): 612.3 [M+H] + .

[0612] Compound 94-2 (400 mg, 0.654 mmol) was dissolved in tetrahydrofuran (5 mL), and lithium bis(trimethylsilyl)amide (1.96 mL, 1M in THF) was added at -78 °C. The mixture was reacted at -78 °C for 1 hour. Compound 94-7 (400 mg, 0.605 mmol) was dissolved in dichloromethane (5 mL), and oxalyl chloride (166 mg, 1.31 mmol) was added at 0 °C. The mixture was reacted at room temperature for 1 hour, concentrated, dissolved in tetrahydrofuran (3 mL), and added dropwise to the above reaction solution at -78 °C. The mixture was reacted at -78 °C overnight. After the reaction was completed as monitored by TLC, methanol (3 mL) was added to quench the reaction, and the crude product was obtained by direct filtration and concentration. Then, the crude product was separated by normal phase column chromatography (petroleum ether: ethyl acetate = 0-100%) to obtain compound 94-8 (500 mg, yield 86%) in yellow oil, MS (ESI, m / z): 899.4 [M+H] + .

[0613] Compound 94-8 (500 mg, 0.558 mmol) was dissolved in methanol (10 mL), 10% palladium on carbon (100 mg) was added, and the reaction was stirred at room temperature under hydrogen (1 atm) overnight. After the reaction was completed as monitored by TLC, the reaction mixture was filtered directly and concentrated to give a crude product, which was separated by normal phase column chromatography (petroleum ether: ethyl acetate = 0-100%) to give compound 94-9 (380 mg, 87% yield) as a yellow oil, MS (ESI, m / z): 800.4 [M+H] + .

[0614] Compound 94-9 (100 mg, 0.128 mmol) was dissolved in acetonitrile (5 mL), N,N,N',N'-tetramethylchloroformamidium hexafluorophosphate (54 mg, 0.193 mmol) and 1-methylpyrazole (47 mg, 0.578 mmol) were added, and the reaction was stirred at room temperature overnight. After the reaction was completed as monitored by TLC, the reaction mixture was filtered directly and concentrated to give a crude product, which was separated by normal phase column chromatography (petroleum ether: ethyl acetate = 0-100%) to give compound 94-10 (62 g, 63% yield) as a yellow oil, MS (ESI, m / z): 761.2 [M+H] + .

[0615] A reaction tube was taken, compound 94-10 (34 mg, 0.045 mmol), lithium hydroxide (8.2 mg, 0.341 mmol), tetrahydrofuran (3 mL), methanol (3 mL) and water (3 mL) were added, and the reaction was stirred at 50 °C for 2 hours. After the reaction was completed as monitored by TLC, the reaction mixture was filtered directly and concentrated to give a crude product, which was purified by reverse phase column chromatography [acetonitrile / water (0.05% formic acid) = 0%-100%] to give compound 94 (22.1 mg, 65% yield) as a white solid, MS (ESI, m / z): 747.2 [M+H] + .

[0616] 1H NMR (400 MHz, DMSO-d6) δ 11.80 (s, 1H), 10.19 (s, 1H), 7.36 - 7.28 (m, 3H), 7.26 - 7.11 (m, 1H), 7.09 (d, J = 8.0 Hz, 1H), 7.04 - 6.96 (m, 1H), 6.78 (d, J = 7.6 Hz, 1H), 6.71 (d, J = 8.0 Hz, 1H), 6.63 - 6.52 (m, 2H), 6.37 (d, J = 2.0 Hz, 1H), 6.12 (dd, J = 8.8, 2.0 Hz, 1H), 4.31 - 3.70 (m, 4H), 3.51 (s, 3H), 3.46 - 3.30 (m, 2H), 2.93 - 2.84 (m, 1H), 2.74 - 2.63 (m, 2H), 2.64 - 2.49 (m, 2H), 2.27 - 2.21 (m, 1H), 2.12 (s, 3H), 2.02 - 1.81 (m, 4H), 1.77 - 1.68 (m, 2H), 0.97 - 0.88 (m, 1H), 0.44 - 0.34 (m, 1H), 0.20 - 0.08 (m, 2H), 0.03 - -0.05 (m, 1H).

[0617] Example 95

[0618] Synthesis route:

[0619] The compound 95 was synthesized by referring to the synthesis of compound 92, replacing compound 92-4 with compound 95-1, and purified by reverse phase column chromatography [acetonitrile / water (0.05% formic acid) = 0% ~ 100%] to give white solid 95 (1.1 mg, yield 7%), MS (ESI, m / z): 685.9 [M+H] + .

[0620] 1H NMR (400 MHz, CDC13) δ 7.53 (d, J = 8.0 Hz, 1H), 7.41 - 7.35 (m, 2H), 7.27 (s, 1H), 7.20 (d, J = 8.0 Hz, 1H), 7.18 - 7.13 (m, 2H), 6.91 (d, J = 8.0 Hz, 1H), 6.86 (d, J = 8.4 Hz, 1H), 6.82 (d, J = 8.0 Hz, 1H), 6.62 (s, 1H), 6.41 - 6.30 (m, 2H), 5.55 - 5.33 (m, 1H), 4.90 - 4.61 (m, 1H), 4.49 - 4.29 (m, 1H), 4.24 - 4.11 (m, 1H), 4.02 - 3.83 (m, 2H), 3.74 (s, 3H), 3.18 - 3.06 (m, 1H), 2.99 - 2.78 (m, 4H), 2.59 - 2.50 (m, 1H), 2.46 (s, 3H), 2.44 - 2.08 (m, 6H), 1.15 - 1.12 (m, 1H), 0.68 - 0.64 (m, 1H), 0.52 - 0.45 (m, 1H), 0.41 - 0.35 (m, 1H), 0.29 - 0.21 (m, 1H).

[0621] Example 96

[0622] Synthesis route:

[0623] Compound 96-1 (8.0 g, 54.42 mmol), cesium carbonate (35.48 g, 108.84 mmol) were added to N,N-dimethylformamide (150 mL) and stirred, then compound 96-2 (14.56 g, 65.31 mmol) was added, and reacted at 100 °C for 16 hours under nitrogen protection. After the reaction was completed by TLC monitoring, the organic phase was diluted with ethyl acetate (1.0 L), washed with brine (400 mL x 3), dried over anhydrous sodium sulfate, and concentrated to obtain a crude product. Then separated by normal phase column chromatography (petroleum ether: ethyl acetate = 0-100%) to obtain white solid 96-3 (11.7 g, yield 75%), MS (ESI, m / z): 289.2 [M+H] + .

[0624] Compound 96-3 (11.7 g, 40.63 mmol) was added to anhydrous tetrahydrofuran (150 mL) under nitrogen protection, and lithium aluminum hydride (3.86 g, 101.56 mmol) was added at 0 °C. The reaction was stirred at room temperature for 3 h. After the reaction was completed by TLC monitoring, sodium sulfate decahydrate was added to quench the reaction, and ethyl acetate (200 mL) was added to dilute the reaction. After filtration, the filtrate was concentrated to obtain a crude product. Then, normal phase column chromatography (petroleum ether: ethyl acetate = 0-100%) was used to separate the yellow oil 96-4 (4.4 g, yield 50%) to obtain a yellow oil, MS (ESI, m / z): 219.2 [M+H] + .

[0625] Compound 96-4 (3.0 g, 13.76 mmol) was added to anhydrous tetrahydrofuran (30 mL) and stirred, and sodium hydride (1.38 g, 34.40 mmol) was added at room temperature. The reaction was stirred at room temperature for 1 h, and 2-bromo-1,1-dimethoxyethane (5.78 g, 34.40 mmol) was slowly added dropwise. The reaction was stirred at room temperature for 16 h under nitrogen protection. After the reaction was completed by TLC monitoring, water (2 mL) was added to quench the reaction, and the reaction was concentrated to obtain a crude product. Then, normal phase column chromatography (dichloromethane:methanol = 0-100%) was used to obtain a yellow oil 96-5 (3.6 g, yield 85%) to obtain a yellow oil, MS (ESI, m / z): 307.2 [M+H] + .

[0626] Compound 96-5 (1.9 g, 6.21 mmol) was added to acetone (20 mL) and stirred, and p-toluenesulfonic acid monohydrate (3.54 g, 18.63 mmol) was added under nitrogen protection. The reaction was stirred at room temperature for 4 h. After the reaction was completed by TLC monitoring, the reaction was concentrated to obtain a crude product. The crude product was diluted with ethyl acetate (200 mL), and the organic phase was washed with saturated brine (80 mL x 3). After drying over anhydrous sodium sulfate, the reaction was concentrated to obtain a yellow oil 96-6 (1.6 g, yield 97%) to obtain a yellow oil, MS (ESI, m / z): 261.2 [M+H] + .

[0627] Referring to the synthesis of compound 92, compound 96-6 was used instead of compound 92-4 to synthesize compound 96 (3.8 mg, yield 5%) in the form of a yellow solid, which was purified by reverse phase column chromatography [acetonitrile / water (0.05% formic acid) = 0%-100%], MS (ESI, m / z): 718.2 [M+H] + .

[0628] 1H NMR (400 MHz, CDC13) δ 8.46 - 8.32 (m, 1H), 8.28 (d, J = 8.8 Hz, 1H), 8.12 (d, J = 8.0 Hz, 1H), 7.75 (d, J = 7.6 Hz, 1H), 7.60 (s, 1H), 7.47 (s, 1H), 7.39 - 7.32 (m, 2H), 7.19 - 7.12 (m, 2H), 7.02 - 6.95 (m, 1H), 4.74 (t, J = 6.0 Hz, 1H), 4.01 - 3.82 (m, 3H), 3.83 - 3.66 (m, 6H), 3.32 - 3.16 (m, 2H), 3.06 - 2.99 (m, 1H), 2.92 - 2.78 (m, 4H), 2.54 (s, 3H), 2.48 - 2.37 (m, 4H), 1.62 - 1.49 (m, 6H), 1.09 - 0.96 (m, 1H), 0.65 - 0.55 (m, 1H), 0.49 - 0.37 (m, 1H), 0.38 - 0.27 (m, 1H), 0.26 - 0.14 (m, 1H).

[0629] Example 97

[0630] Synthesis route:

[0631] The compound 97 was synthesized by referring to the synthesis of compound 15, replacing compound 15-1 with compound 97-1, and purified by reverse phase column chromatography [acetonitrile / water (0.05% formic acid) = 0% ~ 100%] to obtain white solid compound 97 (29.2 mg, yield 43%). MS (ESI, m / z): 732.8 [M+H] + .

[0632] 1H NMR (400 MHz, CDC13) δ 7.42 (d, J = 7.6 Hz, 1H), 7.38 - 7.32 (m, 3H), 7.30 - 7.26 (m, 1H), 7.25 - 7.19 (m, 1H), 7.11 (d, J = 7.6 Hz, 1H), 6.99 (d, J = 8.4 Hz, 2H), 6.71 - 6.62 (m, 2H), 6.52 (d, J = 8.0 Hz, 1H), 4.38 (t, J = 7.2 Hz, 2H), 4.02 (t, J = 6.0 Hz, 2H), 3.83 - 3.76 (m, 5H), 3.14 - 3.03 (m, 1H), 2.95 - 2.79 (m, 4H), 2.72 (t, J = 7.6 Hz, 2H), 2.54 - 2.46 (m, 1H), 2.37 - 2.23 (m, 2H), 2.06 - 1.92 (m, 4H), 1.91 - 1.83 (m, 2H), 1.71 - 1.63 (m, 2H), 1.59 - 1.52 (m, 2H), 1.37-1.27 (m, 6H), 1.13 - 1.04 (m, 1H), 0.88 (t, J = 5.6 Hz, 3H), 0.66 - 0.57 (m, 1H), 0.49 - 0.40 (m, 1H), 0.37 - 0.31 (m, 1H), 0.23 - 0.16 (m, 1H).

[0633] Example 98

[0634] Synthetic route:

[0635] Compound 98-1 (1 g, 4.85 mmol), ammonium chloride (1.3 g, 24.3 mmol), 2-(7-azobenzotriazole)-N,N,N,N'-tetramethyluronium hexafluorophosphate (2.2 g, 5.83 mmol) and triethylamine (2.94 g, 29.1 mmol) were added to N,N-dimethylformamide (10 mL) and stirred at room temperature for 24 hours. After monitoring the end of the reaction by TLC, 1 N dilute hydrochloric acid (50 mL) was added, filtered and dried to obtain white solid compound 98-2 (920 mg, yield 92%), MS (ESI, m / z): 206.1 [M+H] + .

[0636] Compound 98-2 (920 mg, 4.49 mmol) was added to tetrahydrofuran (15 mL), then lithium aluminum hydride (341 mg, 8.98 mmol) was added to the reaction solution under ice bath cooling and warmed to 80 °C for stirring for 4 hours. After the reaction was completed by TLC monitoring, water (0.3 mL), 15% sodium hydroxide solution (0.3 mL) and water (0.9 mL) were added in turn to quench the reaction, then dried by adding anhydrous sodium sulfate, concentrated after filtration to obtain a crude product. Then separated by normal phase column chromatography (petroleum ether: ethyl acetate = 0~100%) to obtain compound 98-3 (600 mg, yield 70%) as a white solid, MS (ESI, m / z): 192.1 [M+H] + .

[0637] Compound M2-8 (173 mg, 0.34 mmol), compound 98-4 (100 mg, 0.41 mmol), tetrakis triphenylphosphine palladium (39 mg, 0.034 mmol) and sodium carbonate (108 mg, 1.0 mmol) were added to a mixed solution of 1,4-dioxane (4 mL) and water (0.5 mL) and warmed to 100 °C for stirring overnight. After the reaction was completed by TLC monitoring, the crude product was directly concentrated. Then separated by normal phase column chromatography (petroleum ether: ethyl acetate = 0~100%) to obtain compound 98-5 (180 mg, yield 96%) as a yellow oil, MS (ESI, m / z): 554.1 [M+H] + .

[0638] Compound 98-5 (180 mg, 0.33 mmol), compound 98-3 (124 mg, 0.65 mmol), 2-(7-azobenzotriazole)-N,N,N,N'-tetramethyluronium hexafluorophosphate (186 mg, 0.49 mmol) and N,N-diisopropyl ethylamine (126 mg, 0.98 mmol) were added to N,N-dimethylformamide (10 mL) and stirred at room temperature for 4 hours. After the reaction was completed by TLC monitoring, ethyl acetate (50 mL) was added, the organic phase was washed with saturated brine, the combined organic phase was concentrated to obtain a crude product, then separated by normal phase column chromatography (petroleum ether: ethyl acetate = 0~100%) to obtain compound 98-6 (115 mg, yield 49%) as a yellow oil, MS (ESI, m / z): 727.1 [M+H] + .

[0639] Compound 98-6 (115 mg, 0.16 mmol) was added to a mixture of tetrahydrofuran (2 mL) and methanol (2 mL), then a solution of lithium hydroxide (38 mg, 1.58 mmol) in water (1 mL) was added to the reaction solution and warmed to 60 °C for 1 hour. After the reaction was completed by TLC monitoring, the crude product was directly concentrated. Then purified by reverse phase column chromatography [acetonitrile / water (0.05% formic acid) = 0% ~ 100%] to give compound 98 (64.2 mg, yield 57%) as a white solid, MS (ESI, m / z): 713.1 [M+H] + .

[0640] 1 H NMR (400 MHz, CDC13) δ 7.92 (d, J = 8.0 Hz, 2H), 7.52 (d, J = 7.6 Hz, 2H), 7.43 - 7.38 (m, 2H), 7.33 - 7.26 (m, 2H), 7.22 - 7.18 (m, 3H), 7.13 (d, J = 8.0 Hz, 1H), 6.60 (d, J = 8.0 Hz, 1H), 6.55 - 6.50 (m, 2H), 6.44 (d, J = 8.0 Hz, 1H), 4.66 (d, J = 5.6 Hz, 2H), 3.84 - 3.77 (m, 5H), 3.11 - 2.99 (m, 1H), 2.94 - 2.73 (m, 4H), 2.62 (t, J = 8.0 Hz, 2H), 2.52 - 2.46 (m, 1H), 2.28 - 2.19 (m, 2H), 1.90 (d, J = 12.4 Hz, 2H), 1.67 - 1.55 (m, 2H), 1.37 - 1.28 (m, 6H), 1.15 - 1.04 (m, 1H), 0.90 (t, J = 6.4 Hz, 3H), 0.69 - 0.56 (m, 1H), 0.50 - 0.41 (m, 1H), 0.38 - 0.29 (m, 1H), 0.24 - 0.16 (m, 1H).

[0641] Example 99

[0642] Synthesis route:

[0643] The compound 99 was synthesized by referring to the synthesis of compound 15, replacing compound 15-1 with compound 99-1, and purified by reverse phase column chromatography [acetonitrile / water (0.05% formic acid) = 0% ~ 100%] to give compound 99 (42.5 mg, yield 43%) as a white solid. MS (ESI, m / z): 704.9 [M+H] + .

[0644] 1H NMR (400 MHz, CDC13) δ 7.49 - 7.35 (m, 3H), 7.31 (s, 1H), 7.23 - 7.17 (m, 1H), 7.14 (d, J = 8.0 Hz, 1H), 7.06 (d, J = 7.6 Hz, 1H), 7.02 (s, 1H), 6.92 (d, J = 8.0 Hz, 1H), 6.61 (d, J = 8.0 Hz, 1H), 6.54 (s, 1H), 6.44 (d, J = 7.6 Hz, 1H), 4.58 (t, J = 6.4 Hz, 2H), 4.03 (t, J = 5.2 Hz, 2H), 3.87 - 3.76 (m, 5H), 3.10 (t, J = 12.0 Hz, 1H), 2.93 - 2.77 (m, 4H), 2.71 (t, J = 7.6 Hz, 2H), 2.56 - 2.38 (m, 3H), 2.33 - 2.18 (m, 2H), 1.93 (d, J = 12.4 Hz, 2H), 1.70 - 1.59 (m, 2H), 1.37 - 1.28 (m, 6H), 1.16 - 1.06 (m, 1H), 0.88 (t, J = 6.4 Hz, 3H), 0.68 - 0.58 (m, 1H), 0.49 - 0.41 (m, 1H), 0.40 - 0.31 (m, 1H), 0.25 - 0.17 (m, 1H).

[0645] Example 100

[0646] Synthesis route:

[0647] Referring to the synthesis of Compound 15, Compound 15-3 was replaced with Compound 100-1 to synthesize and purify Compound 100 (80.8 mg, yield 75%) as a white solid by reverse phase column chromatography [acetonitrile / water (0.05% formic acid) = 0% ~ 100%]. MS (ESI, m / z): 719.2 [M+H] + .

[0648] 1H NMR (400 MHz, CDC13) δ 7.46 (d, J = 8.0 Hz, 1H), 7.42 - 7.34 (m, 2H), 7.27 - 7.25 (m, 1H), 7.22 - 7.16 (m, 1H), 7.13 (d, J = 8.0 Hz, 1H), 7.05 - 6.96 (m, 2H), 6.90 (d, J = 8.0 Hz, 1H), 6.66 - 6.39 (m, 3H), 4.35 (t, J = 7.2 Hz, 2H), 4.00 (t, J = 6.0 Hz, 2H), 3.85 - 3.74 (m, 5H), 3.16 - 3.04 (m, 1H), 2.94 - 2.75 (m, 4H), 2.70 (t, J = 7.2 Hz, 2H), 2.57 - 2.45 (m, 1H), 2.35 - 2.17 (m, 2H), 2.06 - 1.80 (m, 6H), 1.71 - 1.60 (m, 2H), 1.59 - 1.48 (m, 2H), 1.36 - 1.30 (m, 4H), 1.17 - 1.05 (m, 1H), 0.92 - 0.84 (m, 3H), 0.68 - 0.57 (m, 1H), 0.51 - 0.40 (m, 1H), 0.39 - 0.31 (m, 1H), 0.25 - 0.16 (m, 1H).

[0649] Example 101

[0650] Synthesis route:

[0651] Referring to the synthesis of Compound 15, Compound 15-3 was replaced with Compound 101-1 to synthesize and purify Compound 101 (35.8 mg, yield 20%) as a white solid by reverse phase column chromatography [acetonitrile / water (0.05% formic acid) = 0% ~ 100%]. MS (ESI, m / z): 705.2 [M+H] + .

[0652] 1H NMR (400 MHz, CDC13) δ 7.46 (d, J = 8.0 Hz, 1H), 7.42 - 7.35 (m, 2H), 7.27 - 7.24 (m, 1H), 7.22 - 7.15 (m, 1H), 7.13 (d, J = 8.0 Hz, 1H), 7.04 - 6.98 (m, 2H), 6.90 (d, J = 7.6 Hz, 1H), 6.60 (d, J = 7.6 Hz, 1H), 6.52 (s, 1H), 6.43 (d, J = 8.0 Hz, 1H), 4.35 (t, J = 7.2 Hz, 2H), 4.00 (t, J = 6.0 Hz, 2H), 3.86 - 3.73 (m, 5H), 3.16 - 3.02 (m, 1H), 2.94 - 2.74 (m, 4H), 2.71 (t, J = 7.6 Hz, 2H), 2.56 - 2.45 (m, 1H), 2.32 - 2.16 (m, 2H), 2.05 - 1.96 (m, 2H), 1.95 - 1.82 (m, 4H), 1.71 - 1.59 (m, 2H), 1.59 - 1.49 (m, 2H), 1.43 - 1.33 (m, 2H), 1.16 - 1.05 (m, 1H), 0.92 (t, J = 7.2 Hz, 3H), 0.68 - 0.57 (m, 1H), 0.51 - 0.40 (m, 1H), 0.39 - 0.30 (m, 1H), 0.26 - 0.15 (m, 1H).

[0653] Example 102

[0654] Synthesis route:

[0655] The compound 102 was synthesized by replacing compound 15-3 with compound 102-1 in the synthesis of compound 15, and purified by reverse phase column chromatography [acetonitrile / water (0.05% formic acid) = 0% ~ 100%] to obtain white solid compound 102 (21.9 mg, yield 50%). MS (ESI, m / z): 731.2 [M+H] + .

[0656] 1H NMR (400 MHz, CDC13) δ 7.46 (d, J = 7.6 Hz, 1H), 7.42 - 7.34 (m, 2H), 7.23 (s, 1H), 7.22 - 7.15 (m, 1H), 7.13 (d, J = 7.6 Hz, 1H), 7.05 - 6.97 (m, 2H), 6.93 - 6.87 (m, 1H), 6.60 (d, J = 7.2 Hz, 1H), 6.53 (s, 1H), 6.43 (d, J = 7.6 Hz, 1H), 4.35 (t, J = 6.8 Hz, 2H), 4.01 (t, J = 6.0 Hz, 2H), 3.85 - 3.74 (m, 5H), 3.16 - 3.02 (m, 1H), 2.94 - 2.70 (m, 5H), 2.57 - 2.45 (m, 1H), 2.33 - 2.17 (m, 2H), 2.10 - 1.97 (m, 4H), 1.96 - 1.82 (m, 4H), 1.81 - 1.66 (m, 3H), 1.60 - 1.47 (m, 2H), 1.46 - 1.32 (m, 4H), 1.27 - 1.20 (m, 1H), 1.16 - 1.04 (m, 1H), 0.68 - 0.57 (m, 1H), 0.49 - 0.40 (m, 1H), 0.40 - 0.31 (m, 1H), 0.25 - 0.15 (m, 1H).

[0657] Example 103

[0658] Synthesis route:

[0659] Referring to the synthesis of Compound 15, Compound 15-3 was replaced with Compound 103-1 to synthesize and purify Compound 103 (32.1 mg, yield 49%) as a white solid by reverse phase column chromatography [acetonitrile / water (0.05% formic acid) = 0% ~ 100%]. MS (ESI, m / z): 725.2 [M+H] + .

[0660] 1H NMR (400 MHz, CDC13) δ 7.82 (d, J = 7.2 Hz, 2H), 7.76 (s, 1H), 7.49 - 7.29 (m, 6H), 7.22 - 7.07 (m, 2H), 7.06 - 6.95 (m, 2H), 6.91 (d, J = 7.2 Hz, 1H), 6.60 (d, J = 7.2 Hz, 1H), 6.52 (s, 1H), 6.43 (d, J = 7.2 Hz, 1H), 4.49 - 4.39 (m, 2H), 4.05 - 3.97 (m, 2H), 3.84 - 3.74 (m, 5H), 3.16 - 2.97 (m, 1H), 2.93 - 2.72 (m, 4H), 2.56 - 2.43 (m, 1H), 2.32 - 2.15 (m, 2H), 2.11 - 1.99 (m, 2H), 1.96 - 1.82 (m, 4H), 1.66 - 1.52 (m, 2H), 1.16 - 1.03 (m, 1H), 0.68 - 0.56 (m, 1H), 0.52 - 0.39 (m, 1H), 0.39 - 0.28 (m, 1H), 0.25 - 0.11 (m, 1H).

[0661] Example 104

[0662] Synthesis route:

[0663] Referring to the synthesis of Compound 15, Compound 15-3 was replaced by Compound 104-1 to synthesize and purify by reverse phase column chromatography [acetonitrile / water (0.05% formic acid) = 0% ~ 100%] to obtain white solid Compound 104 (22.2 mg, yield 44%). MS (ESI, m / z): 705.2 [M+H] + .

[0664] 1H NMR (400 MHz, CDC13) δ 7.47 (d, J = 8.0 Hz, 1H), 7.43 - 7.35 (m, 2H), 7.28 - 7.23 (m, 1H), 7.22 - 7.15 (m, 1H), 7.14 (d, J = 8.0 Hz, 1H), 7.05 - 6.98 (m, 2H), 6.91 (d, J = 8.0 Hz, 1H), 6.60 (d, J = 8.0 Hz, 1H), 6.53 (s, 1H), 6.43 (d, J = 8.0 Hz, 1H), 4.35 (t, J = 7.2 Hz, 2H), 4.01 (t, J = 5.6 Hz, 2H), 3.88 - 3.70 (m, 5H), 3.10 (t, J = 11.6 Hz, 1H), 2.96 - 2.75 (m, 4H), 2.57 - 2.47 (m, 1H), 2.33 - 2.17 (m, 2H), 2.07 - 1.96 (m, 2H), 1.96 - 1.80 (m, 4H), 1.62 - 1.51 (m, 2H), 1.32 (s, 9H), 1.17 - 1.05 (m, 1H), 0.67 - 0.58 (m, 1H), 0.50 - 0.40 (m, 1H), 0.40 - 0.32 (m, 1H), 0.25 - 0.15 (m, 1H).

[0665] Example 105

[0666] Synthetic Route:

[0667] Referring to the synthesis of intermediate M1, compound M1-3 is replaced by compound 105-1 to synthesize compound 105-3 (813 mg, 1.76 mmol), which is added to tetrahydrofuran (15 mL), and then a 2N hydrochloric acid (10 mL) solution is added to the reaction solution and stirred at 50°C for 3 hours. After the reaction is completed, ethyl acetate (100 mL) is added, the organic phase is washed with saturated brine (50 mL), and the combined organic phase is concentrated to obtain a crude product, which is purified by normal phase column chromatography (ethyl acetate: petroleum ether = 0% ~ 50%) to obtain compound 105-4 (630.5 mg, yield 86%) as a yellow oil, MS (ESI, m / z): 419.3 [M+H] + .

[0668] Compound 105-4 (460 mg, 1.10 mmol) was added to tetrahydrofuran (15 mL) under nitrogen protection and cooled to -78 °C, then lithium bis(trimethylsilyl)amide (1.2 mL, 1.21 mmol) was slowly added to the reaction solution under nitrogen protection and stirred at -78 °C for 1 hour, then a solution of N-phenyl bis(trifluoromethanesulfonyl)imide (432 mg, 1.21 mmol) in tetrahydrofuran (3 mL) was slowly added to the reaction solution and stirred at -78 °C for 30 minutes, after warming to room temperature, stirred for 1 hour. After the reaction was completed, ethyl acetate (100 mL) was added, the organic phase was washed with saturated brine (50 mL), the organic phase was concentrated to obtain a crude product, which was purified by normal phase column chromatography (ethyl acetate: petroleum ether = 0% ~ 50%) to obtain compound 105-5 (563.2 mg, yield 93%) as colorless oil, MS (ESI, m / z): 551.3 [M+H] + .

[0669] Compound 105-5 (280.7 mg, 0.51 mmol), compound 105-6 (94.2 mg, 0.62 mmol), tetrakis(triphenylphosphine)palladium (59 mg, 0.05 mmol) and sodium carbonate (163 mg, 1.54 mmol) were added to a mixture of 1,4-dioxane (8 mL) and water (1 mL) under nitrogen protection and stirred at 90 °C for 5 hours. After the reaction was completed, ethyl acetate (100 mL) was added, the organic phase was washed with saturated brine (50 mL), the organic phase was concentrated to obtain a crude product, which was purified by normal phase column chromatography (ethyl acetate: petroleum ether = 0% ~ 50%) to obtain compound 105-7 (158.3 mg, yield 61%) as yellow oil, MS (ESI, m / z): 509.4 [M+H] + .

[0670] Referring to the synthesis of compound 4, compound M2-8 was replaced by compound 105-7 to synthesize and purify compound 105 (44.1 mg, yield 41%) as white solid by reverse phase column chromatography [acetonitrile / water (0.05% formic acid) = 0% ~ 100%]. MS (ESI, m / z): 645.3 [M+H] + .

[0671] 1H NMR (400 MHz, CDC13) δ 7.93 (d, J = 7.6 Hz, 1H), 7.44 (s, 1H), 7.30 - 7.23 (m, 4H), 7.20 - 7.12 (m, 3H), 7.06 (d, J = 7.6 Hz, 1H), 7.00 (s, 1H), 6.85 (d, J = 8.0 Hz, 1H), 6.27 - 6.17 (m, 1H), 3.98 - 3.82 (m, 4H), 2.97 - 2.83 (m, 2H), 2.78 - 2.54 (m, 7H), 2.29 - 2.14 (m, 2H), 1.90 - 1.80 (m, 2H), 1.73 - 1.62 (m, 2H), 1.51 (s, 6H), 1.20 - 1.08 (m, 1H), 0.72 - 0.61 (m, 1H), 0.54 - 0.45 (m, 1H), 0.42 - 0.34 (m, 1H), 0.28 - 0.18 (m, 1H).

[0672] Example 106

[0673] Synthesis route:

[0674] The compound 106 was synthesized by the same method as for Reference Compound 30, using compound 105-7 instead of compound M3-8, and purified by reverse phase column chromatography [acetonitrile / water (0.05% formic acid) = 0% to 100%] to give compound 106 (10.8 mg, 53% yield) as a white solid. MS (ESI, m / z): 764.2 [M+H] + .

[0675] 1H NMR (400 MHz, CDC13) δ 7.67 (d, J = 8.0 Hz, 2H), 7.54 - 7.50 (m, 2H), 7.49 - 7.47 (m, 1H), 7.45 - 7.41 (m, 3H), 7.31 - 7.24 (m, 2H), 7.24 - 7.20 (m, 2H), 7.18 (d, J = 8.0 Hz, 1H), 7.01 (d, J = 7.8 Hz, 1H), 6.97 - 6.94 (m, 1H), 6.85 - 6.81 (m, 1H), 6.20 - 6.14 (m, 1H), 4.18 - 4.02 (m, 4H), 3.86 (s, 3H), 3.69 (s, 2H), 3.28 - 3.19 (m, 1H), 2.96 - 2.87 (m, 2H), 2.80 - 2.67 (m, 1H), 2.65 - 2.43 (m, 4H), 2.40 (s, 3H), 2.26 - 2.06 (m, 4H), 1.40 (s, 6H), 1.18 - 1.08 (m, 1H), 0.71 - 0.62 (m, 1H), 0.55 - 0.46 (m, 1H), 0.39 - 0.32 (m, 1H), 0.31 - 0.23 (m, 1H).

[0676] Example 107

[0677] Synthesis route:

[0678] The compound 99 was synthesized according to the procedure for the synthesis of compound 98 by replacing compound M2-8 with compound 105-7, which was purified by reverse phase column chromatography [acetonitrile / water (0.05% formic acid) = 0% ~ 100%] to give compound 107 (9.6 mg, yield 17%) as a white solid. MS (ESI, m / z): 730.2 [M+H] + .

[0679] 1H NMR (400 MHz, CDC13) δ 7.50 (d, J = 8.0 Hz, 1H), 7.43 - 7.41 (m, 1H), 7.39 (d, J = 8.0 Hz, 1H), 7.29 - 7.24 (m, 2H), 7.17 (d, J = 8.0 Hz, 1H), 7.08 - 7.01 (m, 3H), 6.99 - 6.96 (m, 1H), 6.94 - 6.89 (m, 1H), 6.85 - 6.80 (m, 1H), 6.24 - 6.18 (m, 1H), 4.36 (t, J = 7.2 Hz, 2H), 4.03 (t, J = 6.4 Hz, 2H), 3.85 (s, 3H), 3.35 - 3.24 (m, 1H), 2.96 - 2.82 (m, 2H), 2.75 - 2.70 (m, 2H), 2.63 - 2.45 (m, 4H), 2.29 - 2.20 (m, 1H), 2.20 - 2.10 (m, 2H), 2.05 - 1.98 (m, 2H), 1.92 - 1.85 (m, 2H), 1.72 - 1.64 (m, 2H), 1.61 - 1.50 (m, 2H), 1.41 - 1.32 (m, 6H), 1.21 - 1.09 (m, 1H), 0.90 (t, J = 6.8 Hz, 3H), 0.70 - 0.62 (m, 1H), 0.53 - 0.44 (m, 1H), 0.42 - 0.34 (m, 1H), 0.29 - 0.20 (m, 1H).

[0680] Example 108

[0681] Synthesis route:

[0682] The compound 108 was synthesized by the same method of synthesis of compound 106, replacing compound 30-3 with compound 108-1, and purified by reverse phase column chromatography [acetonitrile / water (0.05% formic acid) = 0% ~ 100%] to give compound 108 (14.7 mg, yield 25%) as a white solid. MS (ESI, m / z): 667.3 [M+H] + .

[0683] 1H NMR (400 MHz, CDC13) δ 7.58 - 7.55 (m, 1H), 7.53 (d, J = 8.0 Hz, 1H), 7.50 - 7.41 (m, 3H), 7.35 (d, J = 7.2 Hz, 1H), 7.29 - 7.24 (m, 1H), 7.16 (d, J = 7.2 Hz, 1H), 7.03 - 6.94 (m, 3H), 6.91 (s, 1H), 6.88 - 6.80 (m, 2H), 6.25 - 6.19 (m, 1H), 3.85 (s, 3H), 3.37 - 3.27 (m, 1H), 2.96 - 2.84 (m, 2H), 2.83 - 2.75 (m, 1H), 2.67 - 2.47 (m, 4H), 2.43 - 2.36 (m, 2H), 2.29 - 2.18 (m, 8H), 2.02 - 1.95 (m, 2H), 1.46 (s, 6H), 1.19 - 1.07 (m, 1H), 0.71 - 0.61 (m, 1H), 0.54 - 0.45 (m, 1H), 0.42 - 0.33 (m, 1H), 0.30 - 0.20 (m, 1H).

[0684] Example 109

[0685] Synthesis route:

[0686] Compound 109-1 (400 mg, 1.43 mmol), compound 109-2 (190 mg, 1.86 mmol), tris(dibenzylideneacetone)dipalladium (26 mg, 0.0287 mmol), cuprous iodide (14 mg, 0.0720 mmol), 1,8-diazabicyclo[5,4,0]undec-7-ene (217 mg, 1.43 mmol) were dissolved in N,N-dimethylformamide (5 mL) and reacted at 80 °C overnight. After the reaction was completed by TLC monitoring, the crude product was obtained by filtration and concentration, and then separated by normal phase column chromatography (petroleum ether: ethyl acetate = 0-100%) to obtain white solid 109-3 (360 mg, yield 82%). MS (ESI, m / z): 307.1 [M+H] + .

[0687] Compound 109-3 (360 mg, 1.24 mmol) was dissolved in tetrahydrofuran (4 mL) and methanol (4 mL), and 10% palladium-carbon (30 mg) was added. The reaction was carried out at room temperature under hydrogen gas (1 atm) overnight. After the reaction was completed by TLC monitoring, the crude product was obtained by filtration and concentration, and then separated by normal phase column chromatography (petroleum ether: ethyl acetate = 0-100%) to obtain colorless oil 109-4 (250 mg, yield 93%). MS (ESI, m / z): 217.1 [M+H] + .

[0688] Intermediate M2 (200 mg, 0.420 mmol) was dissolved in toluene (5 mL), sodium hydride (50 mg, 1.66 mmol) was added at 0 °C, and the reaction was stirred at room temperature for 1 h. Compound 109-5 (346 mg, 2.94 mmol) was added, and the reaction was stirred at 50 °C for 1 h. After the reaction was completed as monitored by TLC, the reaction was diluted with 1 N aqueous hydrochloric acid (30 mL) and extracted with ethyl acetate (30 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was separated by normal phase column chromatography (petroleum ether: ethyl acetate = 0-100%) to give 109-6 (200 mg, 84% yield) as a white solid. MS (ESI, m / z): 564.2 [M+H] + .

[0689] Compound 109-6 (200 mg, 0.380 mmol) was dissolved in dichloromethane (3 mL), and oxalyl chloride (90 mg, 0.712 mmol) was added at 0 °C. The reaction was stirred at room temperature for 1 h. After concentration, the crude product was dissolved in dichloromethane (3 mL), and compound 109-4 (82 mg, 0.380 mmol), and triethylamine (115 mg, 1.14 mmol) were added at 0 °C. After the reaction was completed as monitored by TLC, the reaction was filtered and concentrated to give a crude product. The crude product was separated by normal phase column chromatography (petroleum ether: ethyl acetate = 0-100%) to give 109-7 (85 mg, 30% yield) as a yellow oil. MS (ESI, m / z): 762.2 [M+H] + .

[0690] A reaction tube was taken, and compound 109-7 (85 mg, 0.122 mmol), tetrahydrofuran (3 mL), and N,N-dimethylformamide (1 mL) were added. Tetrabutylammonium fluoride (0.34 mL, 1 M) was added, and the reaction was stirred at room temperature for 1 h. After the reaction was completed as monitored by TLC, the reaction was directly concentrated to give a crude product. The crude product was purified by reverse phase column chromatography [acetonitrile / water (0.05% formic acid) = 0%-100%] to give 109 (18.5 mg, 24% yield) as a white solid. MS (ESI, m / z): 662.2 [M+H] + .

[0691] 1H NMR (400 MHz, CDC13) δ 8.02 (d, J = 8.0 Hz, 1H), 7.44 (s, 1H), 7.36 - 7.31 (m, 2H), 7.28 - 7.12 (m, 7H), 7.10 - 7.04 (m, 1H), 6.66 - 6.62 (m, 1H), 6.57 - 6.55 (m, 1H), 6.49 - 6.44 (m, 1H), 3.93 - 3.82 (m, 6H), 2.98 - 2.97 (m, 4H), 2.96 - 2.85 (m, 4H), 2.60 - 2.51 (m, 1H), 2.30 - 2.18 (m, 2H), 2.12 - 2.06 (m, 2H), 1.17 - 1.10 (m, 1H), 0.71 - 0.63 (m, 1H), 0.53 - 0.46 (m, 1H), 0.44 - 0.35 (m, 1H), 0.27 - 0.20 (m, 1H).

[0692] Example 110

[0693] Synthetic route:

[0694] Compound 109-1 (400 mg, 1.43 mmol), compound 110-1 (472 mg, 1.72 mmol), palladium acetate (16 mg, 0.0720 mmol), tricyclohexylphosphonium hexafluorophosphate (106 mg, 0.287 mmol), cesium carbonate (1.4 g, 4.30 mmol) were dissolved in toluene (20 mL) and isopropyl alcohol (2 mL) and reacted at 80 °C overnight. After the reaction was completed by TLC monitoring, the filtrate was concentrated to obtain a crude product, which was then separated by normal phase column chromatography (petroleum ether: ethyl acetate = 0-100%) to obtain white solid 110-2 (200 mg, yield 68%). MS (ESI, m / z): 293.2 [M+H] + .

[0695] Then, according to the synthesis of compound 109, compound 109-3 was replaced by compound 110-2 to synthesize and purify white solid compound 110 (14.7 mg, yield 34%) by reverse phase column chromatography [acetonitrile / water (0.05% formic acid) = 0%-100%]. MS (ESI, m / z): 648.3 [M+H] + .

[0696] 1H NMR (400 MHz, CDC13) δ 7.99 (d, J = 8.0 Hz, 1H), 7.43 (s, 1H), 7.39 - 7.32 (m, 2H), 7.27 - 7.09 (m, 8H), 6.67 - 6.60 (m, 1H), 6.58 - 6.53 (m, 1H), 6.50 - 6.44 (m, 1H), 4.03 (s, 2H), 3.92 - 3.83 (m, 6H), 2.97 - 2.85 (m, 4H), 2.59 - 2.50 (m, 1H), 2.26 - 2.16 (m, 2H), 2.11 - 2.05 (m, 2H), 1.18 - 1.09 (m, 1H), 0.69 - 0.63 (m, 1H), 0.51 - 0.44 (m, 1H), 0.40 - 0.34 (m, 1H), 0.24 - 0.19 (m, 1H).

[0697] Example 111

[0698] Synthesis route:

[0699] The compound 111 was synthesized by referring to the synthesis of compound 51, replacing compound 51-1 with compound 111-1, and purified by reverse phase column chromatography [acetonitrile / water (0.05% formic acid) = 0% ~ 100%] to obtain compound 111 (33.2 mg, yield 66%) as a white solid. MS (ESI, m / z): 777.4 [M+H] + .

[0700] 1H NMR (400 MHz, CDC13) δ 8.51 (s, 1H), 8.34 (s, 1H), 7.86 (d, J = 8.0 Hz, 1H), 7.47 (s, 1H), 7.36 (d, J = 8.0 Hz, 1H), 7.31 (d, J = 8.0 Hz, 1H), 7.27 - 7.19 (m, 2H), 6.95 (dd, J = 8.0, 1.6 Hz, 1H), 6.82 - 6.73 (m, 3H), 6.73 - 6.36 (m, 3H), 3.97 (t, J = 6.8 Hz, 2H), 3.91 - 3.82 (m, 6H), 3.04 - 2.85 (m, 4H), 2.76 - 2.63 (m, 4H), 2.58 - 2.47 (m, 1H), 2.30 - 2.16 (m, 2H), 2.12 - 1.98 (m, 4H), 1.84 - 1.77 (m, 2H), 1.49 - 1.37 (m, 4H), 1.16 - 1.09 (m, 1H), 0.95 (t, J = 7.2 Hz, 3H), 0.70 - 0.62 (m, 1H), 0.57 - 0.46 (m, 1H), 0.42 - 0.33 (m, 1H), 0.28 - 0.18 (m, 1H).

[0701] Example 112

[0702] Synthesis route:

[0703] Compound 111 (70 mg, 0.1 mmol), compound 112-1 (16 mg, 0.13 mmol), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (46 mg, 0.12 mmol) were dissolved in dichloromethane (4 mL), triethylamine (30 mg, 0.30 mmol) was added, and the reaction was allowed to proceed at room temperature overnight. After the reaction was completed as monitored by TLC, the crude product was concentrated, and then separated by normal phase column chromatography (petroleum ether: ethyl acetate = 0-100%) to obtain compound 112-2 (50 mg, yield 57%) as a yellow oil. LCMS: [M+H] + = 876.4

[0704] Compound 112-2 (50 mg, 0.057 mmol) was dissolved in dichloromethane (2 mL), and a hydrochloric acid 1,4-dioxane solution (2 mL, 1M) was added. The reaction was allowed to proceed at room temperature overnight. After the reaction was completed as monitored by TLC, the crude product was directly concentrated. Then, purification by reverse phase column chromatography [acetonitrile / water (0.05% formic acid) = 0%-100%] gave compound 112 (32.3 mg, yield 71%) as a white solid. MS (ESI, m / z): 792.4 [M+H] + .

[0705] 1 H NMR (400 MHz, CDC13) δ 8.47 (s, 1H), 8.29 (d, J = 8.0 Hz, 1H), 7.83 (d, J = 6.4 Hz, 1H), 7.48 - 7.38 (m, 1H), 7.33 (dd, J = 8.0, 2.4 Hz, 1H), 7.23 - 7.14 (m, 3H), 6.91 (d, J = 8.0 Hz, 1H), 6.79 - 6.69 (m, 4H), 6.68 - 6.52 (m, 2H), 6.45 (d, J = 7.2 Hz, 1H), 3.95 (t, J = 6.8 Hz, 2H), 3.87 - 3.74 (m, 6H), 3.02 - 2.89 (m, 2H), 2.72 - 2.62 (m, 4H), 2.60 - 2.48 (m, 2H), 2.26 - 2.16 (m, 1H), 2.11 - 1.93 (m, 4H), 1.81 - 1.69 (m, 4H), 1.46 - 1.35 (m, 4H), 1.11 - 1.01 (m, 1H), 0.92 (t, J = 7.2 Hz, 3H), 0.71 - 0.58 (m, 1H), 0.52 - 0.30 (m, 2H), 0.24 - 0.12 (m, 1H).

[0706] Example 113

[0707] Synthetic route:

[0708] Compound 73-5 (900 mg, 5.26 mmol) was added to tetrahydrofuran (10 mL) stirring, borane dimethyl sulfide solution (2.0 M, 13.16 mL, 26.32 mmol) was added, then 80 °C for 16 hours. After monitoring the end of the reaction by TLC, methanol (30 mL) was added slowly at 0 °C to quench, and concentrated to get the crude product. Then purified by reverse phase column chromatography ([acetonitrile / water (0.05% formic acid) = 0% ~ 100%]) to get white solid 113-1 (670 mg, yield 81%), MS (ESI, m / z): 158.1 [M+H] + .

[0709] Then, referring to the synthesis of compound 73, compound 73-5 is replaced by compound 113-1 to synthesize compound 113-2 (80 mg, 0.13 mmol), and 1,8-diazabicyclo[5,4,0]undec-7-ene (4 mg, 0.03 mmol) is added to dichloromethane (5 mL), and trichloroacetonitrile (28 mg, 0.19 mmol) is added with stirring at 0 °C. After 2 hours of reaction at room temperature, it is concentrated, the obtained residue is dissolved in dichloromethane (5 mL) and added to a suspension of compound 73-4 (134 mg, 0.65 mmol, and 3Ao MS (80 mg) in dichloromethane (10 mL) with stirring at 0 °C, and trifluoromethanesulfonic acid (2 mg, 0.01 mmol) is further added, and it is reacted at room temperature for 16 hours. After completion of the reaction, it is concentrated to obtain a crude product, and then separated by normal phase column chromatography (dichloromethane:methanol = 0~100%) to obtain 113-3 (80 mg, yield 76%) as a yellow oil. LCMS: [M+H]=805.4. +

[0710] Compound 113-3 (80 mg, 0.10 mmol) is added to methanol (1 mL) / tetrahydrofuran (1 mL), and 4M sodium hydroxide solution (2 mL) is added with stirring at room temperature. It is stirred at 60 °C for 4 hours, and after completion of the reaction, it is concentrated to obtain a crude product, and purified by reverse phase column chromatography [acetonitrile / water (0.05% formic acid) = 0%~100%] to obtain compound 113 (6.3 mg, yield 8%) as a white solid. MS (ESI, m / z): 791.4 [M+H] + .

[0711] 1 ​H NMR (400 MHz, CDC13) d 8.61 (s, 1H), 8.36 (s, 1H), 7.86 (d, J = 8.0 Hz, 1H), 7.47 (s, 1H), 7.42 (d, J = 8.0 Hz, 1H), 7.34 - 7.29 (m, 1H), 7.28 - 7.20 (m, 2H), 7.14 - 7.04 (m, 4H), 6.72 - 6.43 (m, 3H), 4.59 (s, 2H), 3.96 - 3.81 (m, 6H), 3.75 (t, J = 7.2 Hz, 2H), 3.06 - 2.82 (m, 6H), 2.61 (t, J = 7.6 Hz, 2H), 2.59 - 2.50 (m, 1H), 2.32 - 2.16 (m, 2H), 2.13 - 2.02 (m, 2H), 1.68 - 1.57 (m, 2H), 1.40 - 1.27 (m, 6H), 1.17 - 1.09 (m, 1H), 0.96 - 0.88 (m, 3H), 0.72 - 0.62 (m, 1H), 0.55 - 0.45 (m, 1H), 0.43 - 0.34 (m, 1H), 0.29 - 0.19 (m, 1H).

[0712] Example 114

[0713] Synthesis route:

[0714] The compound 114 was synthesized according to the synthesis of compound 73 by replacing compound 73-1 with compound 114-1, and then synthesizing compound 114-3 according to the synthesis of compound 113 by replacing compound 73-4 with compound 114-3, and purifying to obtain white solid compound 114 (2.6 mg, yield 13%) by reverse phase column chromatography [acetonitrile / water (0.05% formic acid) = 0% ~ 100%]. MS (ESI, m / z): 791.4 [M+H] + .

[0715] 1H NMR (400 MHz, CDC13) δ 8.57 (d, J = 2.0 Hz, 1H), 8.32 (s, 1H), 7.82 (d, J = 8.4 Hz, 1H), 7.44 (s, 1H), 7.39 (d, J = 8.4 Hz, 1H), 7.30 - 7.26 (m, 1H), 7.23 - 7.16 (m, 1H), 7.15 - 7.05 (m, 5H), 6.64 - 6.52 (m, 2H), 6.48 - 6.41 (m, 1H), 4.55 (s, 2H), 3.88 - 3.79 (m, 6H), 3.70 (t, J = 7.2 Hz, 2H), 2.95 - 2.82 (m, 6H), 2.57 - 2.49 (m, 3H), 2.22 - 2.18 (m, 2H), 2.08 - 2.02 (m, 2H), 1.62 - 1.56 (m, 2H), 1.30 - 1.26 (m, 6H), 1.13 - 1.06 (m, 1H), 0.87 (t, J = 3.6 Hz, 3H), 0.67 - 0.62 (m, 1H), 0.53 - 0.43 (m, 1H), 0.37 - 0.31 (m, 1H), 0.25 - 0.18 (m, 1H).

[0716] Example 115

[0717] Synthesis route:

[0718] The compound 115 (3.5 mg, yield 10%) was synthesized by referring to the synthesis of compound 73, replacing compound 73-4 with compound 114-3, and purified by reverse phase column chromatography [acetonitrile / water (0.05% formic acid) = 0% ~ 100%] to obtain a white solid. MS (ESI, m / z): 805.4 [M+H] + .

[0719] 1H NMR (400 MHz, CDC13) δ 9.25 (d, J = 2.0 Hz, 1H), 8.32 (s, 1H), 7.82 (d, J = 8.0 Hz, 1H), 7.75 (dd, J = 8.4, 2.0 Hz, 1H), 7.50 (d, J = 8.4 Hz, 1H), 7.45 (s, 1H), 7.29 (dd, J = 8.0, 1.6 Hz, 1H), 7.25 - 7.16 (m, 3H), 7.16 - 7.11 (m, 2H), 6.65 - 6.57 (m, 1H), 6.54 (s, 1H), 6.47 - 6.41 (m, 1H), 4.52 (t, J = 7.2 Hz, 2H), 3.90 - 3.78 (m, 6H), 3.07 (t, J = 7.2 Hz, 2H), 2.99 - 2.82 (m, 4H), 2.60 - 2.50 (m, 3H), 2.25 - 2.15 (m, 2H), 2.10 - 2.04 (m, 2H), 1.62 - 1.56 (m, 2H), 1.29 - 1.26 (m, 6H), 1.13 - 1.04 (m, 1H), 0.88 - 0.85 (m, 3H), 0.69 - 0.60 (m, 1H), 0.51 - 0.42 (m, 1H), 0.38 - 0.32 (m, 1H), 0.26 - 0.16 (m, 1H).

[0720] Example 116

[0721] Synthesis route:

[0722] The compound 116 was synthesized by referring to the synthesis of compound 74, replacing compound 74-1 with compound 116-1, and replacing compound 74-7 with compound 35-1, and purified by reverse phase column chromatography [acetonitrile / water (0.05% formic acid) = 0% ~ 100%] to obtain white solid compound 116 (50.1 mg, yield 71%). MS (ESI, m / z): 721.3 [M+H] + .

[0723] 1H NMR (400 MHz, CDC13) δ 8.52 (s, 1H), 8.34 (s, 1H), 7.86 (d, J = 8.0 Hz, 1H), 7.46 (s, 1H), 7.36 (d, J = 8.0 Hz, 1H), 7.31 (d, J = 8.0 Hz, 1H), 7.26 - 7.18 (m, 2H), 6.98 - 6.92 (m, 1H), 6.83 (d, J = 7.6 Hz, 1H), 6.80 - 6.75 (m, 2H), 6.65 (d, J = 7.6 Hz, 1H), 6.57 (s, 1H), 6.47 (d, J = 8.0 Hz, 1H), 3.87 - 3.82 (m, 9H), 3.00 - 2.85 (m, 4H), 2.77 - 2.66 (m, 4H), 2.57 - 2.50 (m, 1H), 2.31 - 2.20 (m, 2H), 2.10 - 2.00 (m, 4H), 1.17 - 1.05 (m, 1H), 0.72 - 0.62 (m, 1H), 0.56 - 0.45 (m, 1H), 0.43 - 0.34 (m, 1H), 0.27 - 0.16 (m, 1H).

[0724] Example 117

[0725] Synthesis route:

[0726] The synthesis of Reference Compound 76 was performed by replacing Compound 76-10 with Compound 35-1 to give 117 (42.1 mg, yield 70%) as a white solid, MS (ESI, m / z): 775.4 [M+H] after purification by reverse phase column chromatography [acetonitrile / water (0.05% formic acid) = 0% ~ 100%]. + .

[0727] 1H NMR (400 MHz, CDC13) δ 8.49 (d, J = 2.0 Hz, 1H), 8.30 (s, 1H), 7.83 (d, J = 8.0 Hz, 1H), 7.43 (s, 1H), 7.33 (d, J = 8.0 Hz, 1H), 7.29 - 7.25 (m, 1H), 7.22 - 7.16 (m, 2H), 7.03 - 6.97 (m, 3H), 6.92 (dd, J = 8.0, 2.0 Hz, 1H), 6.61 (dd, J = 8.0, 2.0 Hz, 1H), 6.56 - 6.51 (m, 1H), 6.43 (dd, J = 8.0, 2.0 Hz, 1H), 3.92 - 3.76 (m, 6H), 3.01 - 2.78 (m, 4H), 2.75 - 2.63 (m, 4H), 2.61 - 2.55 (m, 2H), 2.54 - 2.45 (m, 1H), 2.27 - 2.14 (m, 2H), 2.08 - 1.94 (m, 4H), 1.65 - 1.55 (m, 2H), 1.36 - 1.27 (m, 6H), 1.14 - 1.03 (m, 1H), 0.93 - 0.81 (m, 3H), 0.68 - 0.58 (m, 1H), 0.50 - 0.41 (m, 1H), 0.38 - 0.30 (m, 1H), 0.23 - 0.14 (m, 1H).

[0728] Example 118

[0729] Synthesis route:

[0730] Referring to the synthesis of Compound 116, Compound 116-1 was replaced with Compound 118-1 to synthesize and purify Compound 118 (44.3 mg, yield 72%) as a white solid by reverse phase column chromatography [acetonitrile / water (0.05% formic acid) = 0% ~ 100%]. MS (ESI, m / z): 775.3 [M+H] + .

[0731] 1H NMR (400 MHz, CDC13) δ 8.49 (d, J = 2.0 Hz, 1H), 8.31 (s, 1H), 7.83 (d, J = 8.0 Hz, 1H), 7.43 (s, 1H), 7.36 - 7.26 (m, 3H), 7.22 - 7.15 (m, 1H), 7.13 (d, J = 8.0 Hz, 1H), 7.07 - 7.02 (m, 2H), 6.91 (dd, J = 8.0, 2.0 Hz, 1H), 6.61 (dd, J = 8.0, 2.0 Hz, 1H), 6.53 - 6.55 (m, 1H), 6.43 (dd, J = 8.0, 2.0 Hz, 1H), 3.93 - 3.74 (m, 6H), 3.01 - 2.78 (m, 4H), 2.76 - 2.63 (m, 4H), 2.55 - 2.45 (m, 1H), 2.26 - 2.13 (m, 2H), 2.08 - 1.94 (m, 4H), 1.14 - 1.04 (m, 1H), 0.68 - 0.59 (m, 1H), 0.51 - 0.42 (m, 1H), 0.38 - 0.30 (m, 1H), 0.24 - 0.15 (m, 1H).

[0732] Example 119

[0733] Synthesis route:

[0734] The compound 119 was synthesized by referring to the synthesis of compound 116, replacing compound 116-1 with compound 119-1, and purified by reverse phase column chromatography [acetonitrile / water (0.05% formic acid) = 0% ~ 100%] to obtain white solid compound 119 (53.5 mg, yield 79%). MS (ESI, m / z): 747.3 [M+H] + .

[0735] 1H NMR (400 MHz, CDC13) δ 8.49 (d, J = 2.0 Hz, 1H), 8.30 (s, 1H), 7.83 (d, J = 8.0 Hz, 1H), 7.42 (s, 1H), 7.33 (d, J = 8.0 Hz, 1H), 7.29 - 7.25 (m, 1H), 7.24 - 7.16 (m, 4H), 7.05 - 6.97 (m, 1H), 6.92 (dd, J = 8.0, 2.0 Hz, 1H), 6.61 (dd, J = 8.0, 2.0 Hz, 1H), 6.55 - 6.51 (m, 1H), 6.43 (dd, J = 8.0, 2.0 Hz, 1H), 3.92 - 3.75 (m, 6H), 3.00 - 2.77 (m, 4H), 2.75 - 2.63 (m, 4H), 2.54 - 2.46 (m, 1H), 2.26 - 1.13 (m, 2H), 2.09 - 1.94 (m, 4H), 1.32 (s, 9H), 1.14 - 1.04 (m, 1H), 0.69 - 0.57 (m, 1H), 0.51 - 0.41 (m, 1H), 0.38 - 0.29 (m, 1H), 0.24 - 0.14 (m, 1H).

[0736] I. In vitro activity test

[0737] Effect test example 1

[0738] Method for detecting agonistic activity of GPR40 of a compound based on NFAT-RE reporter gene activity detection

[0739] 1. Method

[0740] 1.1 Construction and preparation of plasmid pcDNA3.0-flag-FFAR1 (GPR40)

[0741] The pcDNA3.0-flag-FFAR1 (GPR40) plasmid was constructed according to the conventional molecular cloning method. The main steps are as follows: the full-length cDNA (NM_005303.3) sequence of human FFAR1 (GPR40) was inserted into the HindIII and XbaI enzyme digestion sites of the pcDNA3.0 vector by PCR technology to obtain the pcDNA3.0-flag-FFAR1 (GPR40) plasmid; the pGL4.30[luc2P NFAT-RE] (#E8481) and pRL-TK (#E2241) plasmids were purchased from Promega Company; the plasmid was transformed into DH5a Escherichia coli by CaCl2 method, and the corresponding plasmid DNA was obtained by further culture amplification and purification with plasmid extraction kit (TIANGEN, #DP117).

[0742] 1.2 Plasmid co-transfection of HEK293T cells and compound treatment

[0743] HEK293T cells were transfected with plasmid at a dose of 1×10⁻⁶ cells the day before transfection. 4 / well density was seeded in 96-well plates. Following the transfection reagent... Cell transfection was performed according to the HD (Promega, #E2311) instructions. The main steps were as follows: Using one well as an example, plasmids pcDNA3.0-flag-FFAR1 (GPR40), pGL4.30 [luc2P NFAT-RE], and pRL-TK were added to 10 μL of Opti-MEM at a ratio of 50 ng, 50 ng, and 5 ng, respectively. TM Mix well in medium I (Gibco, #11058021); then add 0.2 μL of... HD, mix well and let stand at room temperature for 5 minutes; then add 10 μL of this mixture to cell wells containing 100 μL of culture medium. 24 hours after cell co-transfection, the compound was serially diluted at a maximum concentration of 1 μM using a half-logarithmic dilution method, resulting in 10 concentrations added to cell culture medium and treated for 4 hours. The mixture was divided into 2 replicates, with compound TAK875 (which had previously entered Phase III clinical trials) and compound SCO267 (which had previously entered Phase I clinical trials) used as positive controls.

[0744] 1.3 Dual-Glo Luciferase Detection

[0745] Cells were treated with the compound for 4 hours, and then... The Luciferase Assay System (Promega, #E2940) was used for testing according to the instructions. The main steps were: aspirate 50 μL of culture medium from each well, then add 50 μL of dual-phase medium. Incubate with Luciferase reagent and shake at room temperature for 10 minutes; transfer 80 μL of the lysis reaction solution to a white, opaque OptiPlate-96 well plate and detect the luminescence signal (Firefly-Luc) of firefly luciferase using an MD i3x multi-microplate reader; then add 40 μL of Dual- Stop & Reagent, room temperature, 10 minutes; then use MD i3x multifunctional enzyme label instrument to detect the light signal value (Renilla-Luc) of Renilla luciferase. The ratio of Firefly-Luc / Renilla-Luc is used as the activation activity of the compound on GPR40, and the ratio of the solvent DMSO group is normalized. GraphPad Prism8.0 software is used to calculate the EC50 value by four-parameter fitting dose-response curve.

[0746] 2、Results

[0747] The experimental data is shown in Table 1 below.

[0748] Table 1

[0749] *: 1 μM > EC 50 > 0.1 μM; **: 0.1 μM ≥ EC 50 > 0.01 μM; ***: 0.01 μM ≥ EC 50 > 0.001 μM; ****: 0.001 μM ≥ EC 50 > 0.0001 μM; *****: 0.0001 μM ≥ EC 50 ; NA represents no activity.

[0750] 100 ≥ Efficacy (%) > 50; 125 ≥ Efficacy (%) > 100; Efficacy (%) > 125.

[0751] Conclusion: The compound of the present application generally has good GPR40 activity.

Claims

1. An aromatic ring and heterocyclic ring compound or a pharmaceutically acceptable salt thereof, characterized by, The aromatic ring and heterocyclic compound is a compound as shown in formula I or II: each n1, each n2, each n3, and each n4 are independently 1, 2, 3, or 4; Each R 1 Each R 2 Each R 3 and each R 4 Independently deuterium, halogen, cyano, hydroxyl, nitro, amino, -NR 1a-1 R 1a-2 C 1- 6-alkyl group, with one or more R 1a-3 Replacement C 1-6 Alkyl, C 1-6 alkoxy group, with one or more R groups 1a-4 Replacement C 1-6 Alkoxy, -SC 1-6 Alkyl group, -S(=O)2-C 1-6 Alkyl, C 3-6 cycloalkyl, with one or more R 1a-5 Replacement C 3-6 cycloalkyl, -OC 3-6 cycloalkyl, with one or more R 1a-6 Replacement -OC 3-6 Cycloalkyl, 3-6 membered heterocyclic alkyl, with one or more R 1a-7 Substituted 3-6 membered heterocyclic alkyl groups, C 6-10 aryl, with one or more R 1a-8 Replacement C 6-10 aryl, 5-10 aryl, or with one or more R 1a-9 Substituted 5-10 heteroaryl groups, or, any two R adjacent to each other 1 forming -(CH2) n6 n6 is 1, 2, 3 or 4, -(CH2) n6 any 1 or 2 -CH2- in -CH2- said 3-6 membered heterocycloalkyl, substituted 3-6 membered heterocycloalkyl, 5-10 membered heteroaryl and substituted 5-10 membered heteroaryl are each optionally substituted with one or more R 1a-7 said 3-6 membered heterocycloalkyl, substituted 3-6 membered heterocycloalkyl, 5-10 membered heteroaryl and substituted 5-10 membered heteroaryl are each optionally substituted with one or more R 1a-9 the heteroatoms in the substituted 5-10 membered heteroaryl are independently one or more of N, S or O, in a number of 1, 2, 3 or 4; R 1a-1 and R 1a-2 are independently H or C 1-6 alkyl; each R 1a-3 , each R 1a-4 , each R 1a-5 , each R 1a-6 , each R 1a-7 , each R 1a-8 , and each R 1a-9 is independently halogen, cyano, hydroxyl, nitro, amino, C 1-6 alkyl, C 1-6 alkoxy, haloC 1-6 alkyl, haloC 1-6 alkoxy, or C 6-10 aryl; each ring A, each ring C, and each ring D is independently C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C 6-10 aryl or 5-10 membered heteroaryl; each ring B is independently a 5-6 membered heterocycloalkyl or C 4-6 cycloalkenyl; the heteroatom in the 5-10 membered heterocycloalkyl group, the 5-6 membered heterocycloalkyl group, and the 5-10 membered heteroaryl group is independently one or more of N, S, or O, in a number of 1, 2, 3, or 4; each L 1 independently a bond or C 1-6 alkylene; each n5 is independently 0, 1, or 2; Each R 5 Independently hydrogen, deuterium, halogen, amino, nitro, cyano, C 1-6 Alkyl or C 1-6 Alkoxy; each X 1 and each X 2 is independently C, CH, or N; each X is independently O or NR 3 is independently O or NR 7 , R 7 is H or C 1-6 alkyl; each Y is independently a bond, -C(=O)O-, or -C(=O)NH-; each L 3 independently -(CH2) m -; m is 1, 2, 3, 4, 5, 6, 7, 8 or 9, and any 1, 2, 3 or 4 -CH2- in -(CH2) m - is optionally replaced by 1, 2, 3 or 4 atoms or atom groups selected from the group consisting of O, -CR 8 R 9 -, -CH=CH-, -C(=O)O- and -C(=O)NR 10 -; R 8 and R 9 are independently H or C 1-6 alkyl, or R 8 and R 9 together with the C to which they are attached form a C 3-6 carbocyclic ring, and R 8 and R 9 are not simultaneously H; R 10 is H, C 1-6 alkyl, phenyl, phenyl substituted with one or more R 10a-1 substituted phenyl, 5-10 membered heteroaryl, 5-10 membered heteroaryl substituted with one or more R 10a-2 substituted 5-10 membered heteroaryl; the heteroatoms in said 5-10 membered heteroaryl and in said 5-10 membered heteroaryl substituted with one or more R 10a-2 are independently one or more of N, S or O in a number of 1, 2, 3 or 4; each R 10a-1 and each R 10a-2 is independently halogen, C 1-6 alkyl or C 1-6 alkoxy; each L 2 independently C 1-6 alkylene, substituted C 2-1 alkylene, substituted C 1-6 alkylene, C 3-6 cycloalkylene, or substituted C 2-2 cycloalkylene, or substituted C 3-6 cycloalkylene; each L 2-1 and each L 2-2 independently halogen, C 1-6 alkyl, C 1-6 alkoxy or C 3-6 cycloalkyl; each R 6 independently -C(=O)OH or -C(=O)NOH.

2. The aromatic ring-fused heterocyclic compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein which satisfies one or more of the following conditions: (1) each R 1 (2) each R 2 (3) each R 3 (4) each R 4 (5) each R 1a-3 (6) each R 1a-4 (7) each R 1a-5 (8) each R 1a-6 (9) each R 1a-7 (10) each R 1a-8 (11) each R 1a- (12) each R 9 (13) each R 5 (14) each R 10a-1 (15) each R 10a-2 (16) each L 2-1 (17) each L 2-2 , and each L is F, Cl, Br, or I. (2) each R 1 , each R 2 , each R 3 , and each R 4 , the C 1-6 alkyl, the C 1a-3 alkyl substituted with one or more R 1-6 , the C 1-6 alkyl in the C 1-6 alkyl, the C 1-6 alkyl in the -S(=O)2-C 1-6 alkyl, and the C 1-6 alkyl are independently methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl, or hexyl; (3) each R 1 , each R 2 , each R 3 , and each R 4 , the C 1-6 alkyl of said C 1a-4 6alkyl and the C 1- 6alkyl of said C 1-6 6alkoxy independently is methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, t-butoxy, pentanecoxy, or hexanecoxy; (4) each R 1 , each R 2 , each R 3 , and each R 4 , in the group -C(=O)-R 3-6 , the C 1a-5 6 cycloalkyl in the group -C(=O)-R 3- 6 cycloalkyl substituted by one or more R 3-6 , the C 3-6 3 cycloalkyl in the group -O-C 3-6 3 cycloalkyl, and the C 1a-6 3 cycloalkyl in the group -O-C 3-6 3 cycloalkyl substituted by one or more R 3-6 , independently, is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; (5) each R 1 (6) each R 2 (7) each R 3 (8) each R 4 Among them, the 3-6 membered heterocycloalkyl in the 3-6 membered heterocycloalkyl of the 3-6 membered heterocycloalkyl and the 3-6 membered heterocycloalkyl substituted by one or more R 1a-7 is independently 5-6 membered heterocycloalkyl, heteroatom N, number is 1 or 2, and can also be piperidyl; (6) each R 1 , each R 2 , each R 3 , and each R 4 , the C 6-10 aryl and the C 1a-8 substituted with one or more R 6- 10 C 6-10 in the aryl group is independently phenyl or naphthyl; (7) each R 1 , each R 2 , each R 3 , and each R 4 , the 5-10 membered heteroaryl of the 5-10 membered heteroaryl group and the 5-10 membered heteroaryl group substituted by one or more R 1a-9 is independently a 5-6 membered monocyclic heteroaryl group or an 8-10 membered heterocyclic heteroaryl group; (8) R 1a-1 , R 1a-2 , each R 1a-3 , each R 1a-4 , each R 1a-5 , each R 1a-6 , each R 1a-7 , each R 1a-8 , each R 1a-9 , each R 5 , R 7 , R 8 , R 9 , R 10 , each R 10a-1 , each R 10a-2 , each L 2-1 , and each L 2-2 , the C 1-6 alkyl is methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl, or hexyl. (9) each R 1a-3 (9) each R 1a-4 (9) each R 1a-5 (9) each R 1a-6 (9) each R 1a-7 (9) each R 1a-8 (9) each R 1a-9 (9) each R 5 (9) each R 10a-1 (9) each R 10a-2 (9) each L 2-1 (9) each L 2-2 (9) each C 1-6 alkoxy is methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or t-butoxy; (10) each R 1a-3 (10) each R 1a-4 (10) each R 1a-5 (10) each R 1a-6 (10) each R 1a-7 (10) each R 1a-8 (10) each R 1a-9 (10) each R 1-6 (10) each R 1-6 (10) each R (11) each R 1a-3 (12) each R 1a-4 (13) each R 1a-5 (14) each R 1a-6 (15) each R 1a-7 (16) each R 1a-8 (17) each R 1a-9 (18) each R 1-6 haloalkoxy is methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or t-butoxy; (12) each ring A, each ring C, and each ring D is 3-6 Cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. (13) in each ring A, each ring C, and each ring D, the 5-6 membered heterocycloalkyl group is a 6 membered heterocycloalkyl group, the heteroatom N, in a number of 1 or 2, and can be a piperidinyl group; (14) each ring A, each ring C, and each ring D, said C 6-10 aryl is phenyl or naphthyl; (15) in each ring A, each ring C, and each ring D, the 5-10 membered heteroaryl group is a 5-6 membered monocyclic heteroaryl group or an 8-10 membered bicyclic heteroaryl group, the heteroatom N and / or O, in a number of 1, 2, or 3, and can be an imidazolyl group, a 1,3,4-oxadiazolyl group, a 4H-pyrazolyl group, a 1H-1,2,3-triazolyl group, a pyridyl group, or an indolyl group; (16) in each ring B, the 5-6 membered heterocycloalkyl group is a 5-6 membered heterocycloalkyl group, the heteroatom N, and can be a piperidinyl group; (17) each ring B, said C 4-6 Cycloalkenyl is a C 5-6 Cycloalkenyl is a C (18) when R 8 and R 9 together with C to which they are attached form a C 3-6 carbocyclic ring, said C 3-6 carbocyclic ring is cyclopropane, cyclobutane, cyclopentane or cyclohexane; (19) R 10 In particular, the 5-10 membered heteroaryl and the 5-10 membered heteroaryl substituted by one or more R 10a The 5-10 membered heteroaryl in the 5-10 membered heteroaryl group is independently a 5-6 membered monocyclic heteroaryl group, the heteroatom being N, which can be pyridyl. (20) Each L 2 In the context, C 1-6 Alkylene, the one or more L 2-1 Replacement C 1-6 C in alkylene 1-6 The alkylene group is independently methylene, ethylene, n-propylene, isopropylene, n-butylene, isobutylene, sec-butylene, or tert-butylene, for example, methyl, ethyl, n-propyl, or isopropyl; and (21) when L 2 is C 1-6 alkylene, said C 1-6 alkylene is the connected C is a non-chiral C, an S configuration C, or an R configuration C, preferably an S configuration C.

3. The aromatic ring-fused heterocyclic compound or a pharmaceutically acceptable salt thereof according to Claim 2, wherein which satisfies one or more of the following conditions: (1) each R 1 , each R 2 , each R 3 , and each R 4 , the C 1a-3 1-6 alkyl substituted by one or more R 1-6 , is C 1-4 1-6 alkyl substituted by one or more halogen, which can be -CF3; (2) each R 1 , each R 2 , each R 3 , and each R 4 , the C 1-6 alkoxy group is a C 1-4 alkoxy group substituted with 1 or C with multiple halogen substitutions 1-4 Alkyl groups can be -OCF3; (3) each R 1 , each R 2 , each R 3 , and each R 4 , the C 1a-8 6-10 aryl group substituted by one or more R 6-10 6, the phenyl group substituted by one or more R 1a-8 6, R 1a-8 6 is halogen, C 1-6 1-6 alkyl, C 1-6 1-6 alkoxy, halogenated C 1-6 1-6 alkyl, or halogenated C 1-6 1-6 alkoxy; and (4) each R 1a-3 (4) each R 1a-4 (4) each R 1a-5 (4) each R 1a-6 (4) each R 1a-7 (4) each R 1a-8 (4) each R 1a-9 (4) each R 1-6 (4) each R 1-4 (4) each R (5) each R 1a-3 (6) each R 1a-4 (7) each R 1a-5 (8) each R 1a-6 (9) each R 1a-7 (10) each R 1a-8 (11) each R 1a-9 (12) each R 1-6 haloalkoxy is fluoroC 1-4 alkoxy, which can be -OCF3; (6) when ring A is phenyl, n1 is 1 or 2, R 1 the ortho position, the meta position, the para position, the ortho and para positions, or the ortho and para positions of a substituted phenyl group; (7) when ring D is phenyl, n1 is 1, R 1 the ortho position, the para position, or the meta position of the substituted phenyl group; (8) R 10 In particular, the 5-10 membered heteroaryl group substituted with 1 or more R 10a-2 substituted with 1 or more R 10a-2 substituted with 1 or more R and (9) each L 2 In particular, the C 2-1 substituted with one or more L 1-6 alkylene, which can be 3-6 cycloalkyl, which can be 1-4 alkylene, which can be 4. The aromatic ring-fused heterocyclic compound or a pharmaceutically acceptable salt thereof according to Claim 1, wherein which satisfies one or more of the following conditions: (1) each R 1 independently halogen or C 1-6 alkoxy, or any two R 1 has formed -(CH2) n6 - n6 is 1, 2, 3 or 4, -(CH2) n6 - any 1 or 2 -CH2- in -CH2-CH2-CH2- can be replaced by 1 or 2 of N, S and O, can be F, Cl or -OCH3, or any two R 1 has formed (2) each ring A is C 6-10 aryl, which can be phenyl; (3) each R 3 independently halogen, C 1-6 alkyl or C 1-6 alkoxy, can be F, Cl, -CH3, or -OCH3; (4) Ring C is C 6-10 aryl or 5-10 membered heteroaryl, which can be phenyl, 1,3,4-oxadiazolyl, 1H- pyrazolyl, or indolyl; (5) each R 4 independently halogen, C 1-6 alkyl, C 1a-3 substituted C 1-6 alkyl, C 1-6 alkoxy, C 1a-4 substituted C 1-6 alkoxy, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C 6-10 aryl, C 1a- 8 substituted C 6-10 aryl or C 1a-8 substituted C 6-10 aryl, each R 1a-3 , each R 1a-4 , each R 1a-8 and each R 1a-9 independently halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkyl or C 1-6 alkoxy; may be F, -CH3, -CH2CH3, -C4H9, -C5H 11 , -C6H 13 , -CF3, -OCH3, -OC5H 11 , -OCF3, phenyl, (6) Ring D is independently 5-6 membered heterocycloalkyl, C 6-10 aryl or 5-10 membered heteroaryl, which can be piperidinyl, phenyl, imidazole the heteroatom N, and can be a piperidinyl group; and (7) L 3 -(CH2) m -; m is 1, 2, 3, 4, 5, 6, 7, 8 or 9, -(CH2) m -; any 1 of the -CH2- groups can optionally be replaced by O, -CR 8 R 9 -, -CH=CH-, -C(=O)O- or -C(=O)NR 10 -; 2 of the -CH2- groups can optionally be replaced by a group from group a, 3 of the -CH2- groups can optionally be replaced by a group from group b or 4 of the -CH2- groups can optionally be replaced by a group from group c; Group a: 2 O or "O and -CR 8 R 9 -”, group b: 3 O, "2 O and -CR 8 R 9 -”, "2 O and -C(=O)NR 10 ” or "O, -C(=O)NR 10 and -CR 8 R 9 -”, group c: 2 O, -C(=O)NR 10 and -CR 8 R 9 - 5. The aromatic ring-fused heterocyclic compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, wherein which satisfies one or more of the following conditions: (1) each of For (2) each of For (3) each of For (4) each of for any one of the following groups: (5) each L 3 is any one of the following groups: (6) each -L 2 -G is and (7) each For 6. The aromatic ring-fused heterocyclic compound or a pharmaceutically acceptable salt thereof according to Claim 1, wherein The aromatic ring and heterocyclic compound is a compound as shown in formula Ia, IIb, Ia-1 or IIb-2: preferably, As in formulae Ia, IIb, Ia-1 and IIb-2, each independently are 1 is connected to ring A; each ring C is independently C 6-10 aryl or 5-10 membered heteroaryl; each ring D is independently a 3-6 membered heterocycloalkyl, C 6-10 aryl or 5-10 membered heteroaryl; each -L 2 - is independently C 3-6 C 1-6 alkylene; more preferably, As in Formulas Ia, IIb, Ia-1, and IIb-2, each ring C is independently each ring D is independently each -L 2 - is 7. The aromatic ring-fused heterocyclic compound or a pharmaceutically acceptable salt thereof according to Claim 1 or 6, wherein The aromatic ring and heterocyclic compound is as formula Ia-1-1 or Ia-1-2: preferably, in formula Ia-1-1 or Ia-1-2, Each R 1 Independently for C 1-6 Alkoxy; Each R 3 For Cl; each ring D is independently a phenyl group or a piperidinyl group; each R is independently halogen, methyl or phenyl substituted with one or more R 4 independently halogen, methyl or phenyl substituted with one or more R 1a-8 substituted phenyl; each L 2 independently substituted C 2-1 alkylene; and 1-6 alkylene; and each L 3 independently -(CH2) m - and m is 1, 2 or 3; when each ring D is independently phenyl, each R 4 is methyl, R 4 is substituted meta to the phenyl group.

8. The aromatic ring-fused heterocyclic compound or a pharmaceutically acceptable salt thereof according to Claim 1, wherein The aromatic ring and heterocyclic compound is any one of the following compounds: an isomer thereof or a mixture of either at a ratio.

9. The method for producing an aromatic ring-fused heterocyclic compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 8, wherein which is method 1 or method 2: when R 6 is -C(=O)OH, it is Method 1; Method 1 comprises the following steps: subjecting a compound represented by the following formula IIIa or IVa to a hydrolysis reaction to obtain the aromatic ring and heterocyclic compound; wherein each R is independently C1-C6alkyl; 11 independently C1-C6alkyl; 1-6 alkyl; when R 6 is -C(=O)NOH, it is Method 2; Method 2 comprises the following steps: subjecting a compound as shown in the following formula IIIb or IVb to a deprotection reaction to obtain the aromatic ring and heterocyclic compound; wherein each R 12 independently is a hydroxyl protecting group.

10. A pharmaceutical composition, characterized by, which comprises the aromatic ring-fused heterocyclic compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-8, and a pharmaceutically acceptable excipient.

11. Use of the aromatic ring-fused heterocyclic compound according to any one of claims 1-8, a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 10, in the manufacture of a GPR40 agonist or in the manufacture of a medicament for treating or preventing a GPR40 related disease, the GPR40 related disease is preferably diabetes.

12. A compound of formula IIIa, IIIb, IVa or IVb: wherein Each R 11 Independently for C 1-6 Alkyl groups; each R 12 Independently protected by a hydroxyl group; each n1, each n2, each n3, each n4, each R 1 , each R 2 , each R 3 , each R 4 , each ring A, each ring B, each ring C, each ring D, each L 1 , each L 2 , each L 3 , each X 1 , each X 2 , each X 3 and each Y are as defined in any one of claims 1-9.

13. The compound of claim 12 of Formula IIIa, IIIb, IVa, or IVb, wherein The compound as shown in Formula IIIa, IIIb, IVa or IVb is any one of the following compounds: an isomer thereof or a mixture of both in any ratio.

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