5-HT 4 receptor agonist, preparation method therefor, intermediate, pharmaceutical composition and use thereof

Abstract

A 5-HT4 receptor agonist represented by formula I-A, a preparation method therefor, an intermediate thereof, a pharmaceutical composition containing the compound, and the use thereof in the preparation of a drug for 5-HT4 receptor-mediated diseases or peripheral gastrointestinal diseases.

Description

5-HT4 receptor agonists, methods of preparation, intermediates, pharmaceutical compositions and uses thereof

[0001] This application claims priority to Chinese patent application 2024112947097 with a filing date of 2024 / 9 / 14. This application incorporates the entirety of the aforementioned Chinese patent application. TECHNICAL FIELD

[0002] The present application relates to 5-HT4 receptor agonists, methods of preparation, intermediates, pharmaceutical compositions and uses thereof. BACKGROUND

[0003] There are several 5-HT4 receptor agonists on the market, all of which are gastrointestinal motility agents for the treatment of peripheral gastrointestinal related diseases such as indigestion and constipation. Early 5-HT4 receptor agonists such as Cisapride and Tegaserod were withdrawn from the market or used with restrictions due to poor target selectivity leading to cardiotoxicity. Prucalopride, as the first highly selective 5-HT4 receptor agonist, was first approved by EMA in Europe in 2009 (trade name: Resolor) for the treatment of chronic idiopathic constipation (CIC) where laxatives cannot relieve symptoms. Prucalopride has high target selectivity and good safety, and no other related cardiovascular effects have been observed at the clinical treatment concentration. However, given that 5-HT4 receptors are expressed throughout the central and peripheral nervous system, possible central side effects remain a concern, and in the FDA's drug label for prucalopride, the generation of suicidal ideation and behavior in some patients in clinical trials has also been reported.

[0004] In 2022, Japan's Takeda Pharmaceutical reported two types of small-molecule compounds targeting the 5-HT4 receptor of the colonic mucosal epithelial cells for intestinal local action (CN115515933A). These small molecules are derived from the 5-HT4 agonists Prucalopride and Naronapride (such as 5-HT4-LA1 and 5-HT4-LA2), which basically maintain the in vitro receptor affinity and agonistic efficacy comparable to the original molecules. It is worth noting that traditional pharmacology considers that 5-HT4 receptor agonists are absorbed into the blood through the intestinal tract to stimulate neurons in the enteric nervous system to release acetylcholine, thereby playing a role in promoting intestinal propulsive movement. Hoffman et al. first demonstrated that local stimulation of 5-HT4 receptors on the intestinal mucosal epithelial cells can also promote intestinal propulsive movement and inhibit visceral hypersensitivity. Immunofluorescence staining results of in vitro intestinal tissue and reverse transcription-polymerase chain reaction (RT-PCR) results of intestinal mucosal biopsy samples consistently showed that 5-HT4 receptors are highly expressed in the intestinal mucosa of mice, rats, guinea pigs, and humans. In animal oral bioavailability test experiments, after oral administration of 5-HT4-LA1, the compound was found to have the highest content in the colon and negligible content in the blood, indicating that the compound is locally acting in the intestinal tract. In animal efficacy experiments, intragastrically administered 5-HT4-LA1 resulted in accelerated whole intestinal transit and colonic movement in young mice, increased fecal output, and increased fecal water content, and the same phenomenon was observed in elderly mice. The above preliminary experimental results indicate that the design of 5-HT4 agonists for intestinal mucosal local action is feasible for the treatment of chronic idiopathic constipation.

[0005] Traditional 5-HT4 receptor small-molecule agonists such as Prucalopride have many limitations in clinical applications, such as central side effects, off-target risks, and the inability to meet the medication needs of special populations. In view of the clinical limitations exposed by these drugs, developing an intestinal-restricted 5-HT4 receptor agonist for the treatment of chronic idiopathic constipation becomes a feasible strategy. Due to its limited passive permeability, this type of drug is still limited to the gastrointestinal tract after oral administration and is not absorbed by the human body, thereby increasing the local concentration at the site of action and minimizing exposure to other parts of the body, reducing side effects caused by off-target drug effects. Since the compound does not enter the blood, it is not metabolized by the human liver and excreted by the kidneys, significantly reducing the metabolic pressure on the liver and kidneys and improving the safety of clinical drug use in patients, meeting the medication needs of special populations (such as elderly patients and patients with kidney dysfunction), and having potential clinical treatment characteristics. There is currently no active compound with this mechanism of action targeting the 5-HT4 receptor that has entered clinical research. SUMMARY

[0006] The present application provides a 5-HT4 receptor agonist, a preparation method thereof, an intermediate, a pharmaceutical composition and use thereof, which overcomes the problems of central side effects and easy off-target of the prior art 5-HT4 receptor agonist, and provides a 5-HT4 receptor agonist, a preparation method thereof, an intermediate, a pharmaceutical composition and use thereof. The 5-HT4 receptor agonist of the present application has excellent ability to activate 5-HT4 receptors, can stably exist in digestive juice, accelerates the whole intestinal transport rate, accelerates the colon transport rate, increases the fecal volume and fecal water content, has almost no trans-biological membrane property, thereby ensuring that it basically does not enter the blood in the form of a prototype drug, and avoids or reduces various side effects.

[0007] The present application provides a 5-HT4 receptor agonist, which is a compound as shown in formula I-A or a pharmaceutically acceptable salt thereof:

[0008] wherein,

[0009] R 1 is methyl;

[0010] R 2 is hydrogen or methyl;

[0011] or R 1 , R 2 and the atoms to which they are attached form a 3-6 membered heterocycloalkyl group;

[0012] R 3 is methyl;

[0013] R 4 is hydrogen or methyl;

[0014] or R 3 , R 4 and the atoms to which they are attached form a 3-6 membered heterocycloalkyl group;

[0015] L 1 and L 2 are independently selected from a single bond, methylene and ethylene;

[0016] L 3 and L 4 are independently selected from a single bond and -(CH2) m2 -, said -(CH2) m2 - is optionally substituted with 1, 2, 3, 4, 5 or 6 R L3 , m2 is an integer in the range of 1-6;

[0017] X a and X b are independently selected from k represents the connection site of L 3 and X a or L4 with the connection site of X b ; a denotes L 5 with the connection site of X a or L 6 with the connection site of X b ;

[0018] L 5 and L 6 are independently selected from the group consisting of a single bond, 3-6 membered heterocycloalkylene and 5-6 membered heteroarylene, said 3-6 membered heterocycloalkylene and 5-6 membered heteroarylene being optionally substituted with 1, 2 or 3 R L5 ; m3, m4 and m5 are independently integers in the range of 1 to 6, a denotes L 5 with the connection site of X a or L 6 with the connection site of X b , b denotes L 5 with the connection site of L 7 or L 6 with the connection site of L 8 ;

[0019] L 7 and L 8 are independently selected from the group consisting of a single bond and wherein n1 is an integer in the range of 1 to 6, m6 is an integer in the range of 1 to 6, wherein is optionally substituted with 1, 2 or 3 R L7 , b denotes L 7 with the connection site of L 5 or L 8 with the connection site of L 6 , c denotes L 7 with the connection site of L 9 or L 8 with the connection site of L 10 ;

[0020] L 9 and L 10 are independently selected from the group consisting of a single bond, said is optionally substituted with 1, 2 or 3 R L9 , each m7, each m8 and each m9 are independently integers in the range of 0 to 6, c denotes L 7 with the connection site of L 9 or L 8 with the connection site of L 10 , d denotes L 9the point of attachment to Y or L 10 the point of attachment to Y;

[0021] Y is a single bond, C 3-10 cycloalkylene, 3-10 membered heterocycloalkylene, C 1-6 alkylene, C 2-6 alkenylene, C 2-6 alkynylene, C 6-10 arylene or 5-12 membered heteroarylene, said C 1-6 heteroalkylene, C 3-10 cycloalkylene, 3-10 membered heterocycloalkylene, C 1-6 alkylene, C 2-6 alkenylene, C 2-6 alkynylene, C 6-10 arylene and 5-12 membered heteroarylene are optionally substituted with 1, 2, 3, or 4 R Y each m10 and each m11 is an integer ranging from 0 to 3;

[0022] Z is 3-6 membered heterocycloalkylene;

[0023] R L3 , R L5 , R L5-1 , R L7 , R L9 , R Y-1 , and R Y are independently selected from the group consisting of -H, halogen, -OH, -CN, -COOH, -CONH2, C 1- 6alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 alkylthio, -NR", and 3-6 membered heterocycloalkyl, said C 1-6 alkyl, C 1-6 alkenyl, C 1-6 alkynyl, C 1-6 alkoxy, C 1-6 alkylthio, -NR", and 3-6 membered heterocycloalkyl are optionally substituted with 1, 2, 3, 4, or 5 R';

[0024] R' and R" are selected from the group consisting of H, halogen, -OH, -NH2, C 1-6 alkyl, -COOH, and 3-6 membered heterocycloalkyl;

[0025] said 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkylene, 5-6 membered heteroarylene, 3-10 membered heterocycloalkylene, C6-C 10In the arylene and 5-12 membered heteroarylene group, the heteroatoms or heteroatom groups are independently selected from O, NH, S, C(=O), C(=O)O, S(=O), S(=O)2, and N, and the number of heteroatoms or heteroatom groups is 1, 2, or 3;

[0026] L 1 , L 2 , L 3 , L 4 , L 5 , L 6 , L 7 , L 8 , L 9 , L 10 and Y are not simultaneously a single bond.

[0027] In the present application, the compound as shown in formula I-A or a pharmaceutically acceptable salt thereof is a compound as shown in formula I or a pharmaceutically acceptable salt thereof:

[0028] X 1 and X 2 are independently selected from k represents the connection site of L 3 to X 1 or the connection site of L 4 to X 2 ; a represents the connection site of L 5 to X 1 or the connection site of L 6 to X 2 .

[0029] In the present application, the compound as shown in formula I-A or a pharmaceutically acceptable salt thereof is a compound as shown in formula I-1 or a pharmaceutically acceptable salt thereof:

[0030] X 1-1 and X 2-1 are independently k represents the connection site of L 3 to X 1-1 or the connection site of L 4 to X 2-1 ; a represents the connection site of L 7 to X 1-1 or the connection site of L 8 to X 2-1 .

[0031] In the present application, the heteroatom of each 3-6 membered heterocycloalkyl group is independently selected from one or two of N, O and S, and the number of heteroatoms is independently 1, 2 or 3, preferably the heteroatom is O and the number of heteroatoms is 1, for example wherein denotes the formation of a fused ring structure with the benzene ring in the parent molecule via this bond.

[0032] In the present application, each 3-6 membered heterocycloalkylene is a 6 membered heterocycloalkylene, wherein the heteroatoms are independently selected from one or two of N, O and S, and the number of heteroatoms is independently 1, 2 or 3, preferably the heteroatoms are N and the number of heteroatoms is 1.

[0033] In the present application, each 5-6 membered heteroarylene is a 6 membered heteroarylene, wherein the heteroatoms are independently selected from one or two of N, O and S, and the number of heteroatoms is independently 1, 2 or 3, preferably the heteroatoms are N or O and the number of heteroatoms is 1 or 2, for example pyridine, pyrimidine or pyran.

[0034] In the present application, each C 3-10 Cycloalkylene is independently monocyclic or polycyclic; the polycyclic ring can be a bridged, fused or spirocyclic ring; preferably, each C 3-10 Cycloalkylene is independently C 3-6 Monocycloalkylene or C 8-10 Bridged cycloalkylene, preferably cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene or bridged cyclooctylene, for example (eg ), (eg ), (eg ), (eg ), (eg ),

[0035] In the present application, the heteroatoms of each 3-10 membered heterocycloalkylene are independently selected from one or two of N, O and S, and the number of heteroatoms is independently 1, 2 or 3.

[0036] In the present application, each 3-10 membered heterocycloalkylene is independently monocyclic or polycyclic; the polycyclic ring can be a bridged, fused or spirocyclic ring; preferably, each 3-10 membered heterocycloalkylene is independently a 4-7 membered monocyclic heterocycloalkylene, a 7-8 membered spirocyclic heterocycloalkylene or an 8-10 membered fused heterocycloalkylene; for example

[0037] In the present application, each C 1-6 Alkylene is independently methylene,

[0038] In the present application, each C2-6 Alkenylene is independently

[0039] In the present application, each C 2-6 Alkynylene is independently

[0040] In the present application, each C 6-10 Arylene is independently phenylene or naphthylene, for example phenylene.

[0041] In the present application, each heteroatom in a 5-12 membered heteroarylene is independently selected from one or two of N, O and S, the number of heteroatoms being independently 1, 2 or 3.

[0042] In the present application, each halogen is independently fluorine, chlorine, bromine or iodine, preferably fluorine, chlorine or bromine.

[0043] In the present application, each C 1-6 Alkyl is independently methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, i-butyl or sec-butyl, for example methyl, ethyl or i-propyl.

[0044] In the present application, each C2-C6alkenyl is independently

[0045] In the present application, each C 2-6 In the present application, each C2-C6alkenyl is independently In the present application, each C 1-6 Alkoxy is -OCH3, -OCH2CH3, -O(CH2)2CH3, -OC(CH3)3, -O(CH2)2CH(CH3)2 or -O(CH2)4CH3.

[0046] In certain embodiments, the R L3 , R L5 , R L5-1 , R L7 , R L9 , R Y-1 and R Y are independently selected from -H, halogen, -OH, -CONH2, C 1-6 alkyl, C 1-6 alkoxy, -NR” and 3-6 membered heterocycloalkyl.

[0047] In certain embodiments, the R' and R” are independently selected from -H, halogen and C 1-6 alkyl.

[0048] In certain embodiments, the R L3 , RL5 , R L5-1 , R L7 , R L9 , R Y-1 , and R Y are independently -H, -F, -Cl, -Br, -I, -OH, -NH2, -CONH2, -Me, -Et, -OMe, -NHMe, or -N(Me)2.

[0049] In a certain embodiment, when R 1 is methyl, R 2 is hydrogen.

[0050] In a certain embodiment, R 1 , R 2 , and the atom to which they are attached together form a 6-membered heterocyclic ring, the heteroatom of which is one or two of N, O, and S, the number of heteroatoms being independently 1, 2, or 3.

[0051] In a certain embodiment, R 1 , R 2 , and the atom to which they are attached together form a 5-membered heterocyclic ring, the heteroatom of which is O, the number of heteroatoms being 1.

[0052] In a certain embodiment, R 1 , R 2 , and the atom to which they are attached together form

[0053] In a certain embodiment, the L 1 and L 2 are independently a single bond or is preferably

[0054] In a certain embodiment, the L 3 and L 4 are independently is preferably

[0055] In a certain embodiment, the L 3 and L 4 are independently a single bond or is preferably

[0056] In a certain embodiment, the X 1 and X 2 are independently is preferably wherein a represents the connection site of L 5 to X 1 or L6 with the connection site of X 2 , k represents L 3 with the connection site of X 1 or L 4 with the connection site of X 2 .

[0057] In certain embodiments, L 5 and L 6 are independently or 3-6 membered heterocycloalkylene, which is optionally substituted with 1, 2, or 3 R L5 , m3 is an integer in the range of 1-6, a represents L 5 with the connection site of X 1 or L 6 with the connection site of X 2 , b represents L 5 with the connection site of L 7 or L 6 with the connection site of L 8 .

[0058] In certain embodiments, the R L5 is -H or C 1-6 alkyl, preferably -H or -CH3.

[0059] In certain embodiments, the R L5-1 is -H or C 1-6 alkyl, preferably -H or -CH3.

[0060] In certain embodiments, the Z is 3-6 membered heterocycloalkylene, wherein the heteroatoms are independently selected from one or two of N, O, and S, and the number of heteroatoms is independently 1, 2, or 3.

[0061] In certain embodiments, in the Z, the heteroatoms are N, and the number of heteroatoms is 1.

[0062] In certain embodiments, L 5 and L 6 are independently preferably -NH(CH2)2-, wherein a represents L 5 with the connection site of X 1 or L 6 with the connection site of X 2 , b represents L 5 with the connection site of L 7 or L 6 with the connection site of L8 the connection site of L

[0063] In certain embodiments, L 5 and L 6 are independently a single bond.

[0064] In certain embodiments, L 7 and L 8 are independently a single bond or wherein m6is an integer in the range of 1 to 5, n1is 1, 2, 3, 4 or 5, preferably wherein m6is an integer in the range of 1 to 3, n1is 1, 2, 3, 4 or 5, wherein b denotes the connection site of L 7 to L 5 or the connection site of L 8 to L 6 or the connection site of L 7 to L 9 or the connection site of L 8 to L 10 .

[0065] In certain embodiments, L 7 and L 8 are independently a single bond, wherein b denotes the connection site of L 7 to L 5 or the connection site of L 8 to L 6 or the connection site of L 7 to L 9 or the connection site of L 8 to L 10 .

[0066] In certain embodiments, L 7 and L 8 are independently wherein b denotes the connection site of L 7 to L 5 or the connection site of L 8 to L 6 or the connection site of L 7 to L 9 or the connection site of L 8 to L 10 .

[0067] In certain embodiments, L 9 and L 10 are independently a single bond, each m7, each m8, and each m9 is independently an integer ranging from 0 to 6, c represents a bonding site to L 7 with a bonding site to L 9 , or a bonding site to L 8 with a bonding site to L 10 , or a bonding site to L 9 with a bonding site to Y, or L 10 with a bonding site to Y.

[0068] In a certain embodiment, L 9 and L 10 are each independently a single bond, c represents a bonding site to L 7 with a bonding site to L 9 , or a bonding site to L 8 with a bonding site to L 10 , or a bonding site to L 9 with a bonding site to Y, or L 10 with a bonding site to Y.

[0069] In a certain embodiment, L 9 and L 10 are each independently c represents a bonding site to L 7 with a bonding site to L 9 , or a bonding site to L 8 with a bonding site to L 10 , or a bonding site to L 9 with a bonding site to Y, or L 10 with a bonding site to Y.

[0070] In a certain embodiment, Y is a single bond, C 1-6 heteroalkylene, C 1-6 alkylene, C 2-6 alkenylene, C 2-6 alkynylene, C 3-10 cycloalkylene, 3-10 membered heterocycloalkylene, or C 6-10 arylene, said C 1-6 alkylene is optionally substituted with 1, 2, 3, or 4 R Y , preferably a single bond, C 1-6 alkylene, or C 3-10 cycloalkylene, each m10 and each m11 is an integer ranging from 0 to 3.

[0071] In a certain embodiment, in Y, R Y-1 is -H or C 1-6 alkyl, preferably -H or methyl.

[0072] In a certain embodiment, in Y, RY is -OH.

[0073] In a certain embodiment, Y is a single bond, (e.g. ), (e.g. ), (e.g. ), (e.g. ), (e.g. ), is preferably

[0074] In a certain embodiment, the is independently wherein are the same or different, d represents L 9 at the point of attachment to Y or L 10 at the point of attachment to Y.

[0075] In a certain embodiment, the is independently wherein are the same or different, d represents L 9 at the point of attachment to Y or L 10 at the point of attachment to Y.

[0076] In a certain embodiment, the is independently wherein are the same or different, d represents L 9 at the point of attachment to Y or L 10 at the point of attachment to Y.

[0077] In a certain embodiment, X 1 -L 5 or X 2 -L 6 is -NHCO- b , -CONH- b , is preferably -NHCO- b , -CONH-b 、 b denotes the attachment site of L 7 to L 5 or the attachment site of L 8 to L 6 .

[0078] In a certain embodiment, X 1 -L 5 or X 2 -L 6 is

[0079] In a certain embodiment, in the compound of formula I,

[0080] R 1 is methyl;

[0081] R 2 is hydrogen or methyl;

[0082] or R 1 , R 2 and the atoms to which they are attached form a 3-6 membered heterocycloalkyl group;

[0083] R 3 is methyl;

[0084] R 4 is hydrogen or methyl;

[0085] or R 3 , R 4 and the atoms to which they are attached form a 3-6 membered heterocycloalkyl group;

[0086] L 1 and L 2 are independently selected from a single bond, methylene and ethylene;

[0087] L 3 and L 4 are independently selected from a single bond and -(CH2) m2 -, m2 is an integer in the range of 1-6;

[0088] X 1 and X 2 are independently selected from

[0089] L 5 and L 6 are independently selected from a single bond, m3 is independently an integer in the range of 1-6, a denotes the attachment site of L 5 to X 1 or the attachment site of L 6 to X 2 , b denotes the attachment site of L5 with a linking site of L 7 or L 6 with a linking site of L 8 ;

[0090] L 7 and L 8 are independently selected from a single bond and wherein n1 is an integer in the range of 1-5, m6 is an integer in the range of 1-3, b represents a linking site of L 7 with a linking site of L 5 or L 8 with a linking site of L 6 , c represents a linking site of L 7 with a linking site of L 9 or L 8 with a linking site of L 10 ;

[0091] L 9 and L 10 are independently selected from a single bond, each m7, each m8 and each m9 is independently an integer in the range of 0-6, c represents a linking site of L 7 with a linking site of L 9 or L 8 with a linking site of L 10 , d represents a linking site of L 9 with a linking site of Y or L 10 with a linking site of Y;

[0092] Y is a single bond, C 3-10 cycloalkylene, 3-10 membered heterocycloalkylene, C 1-6 alkylene, C 2-6 alkenylene, C 2-6 alkynylene or C 6-10 arylene, said C 1-6 alkylene is optionally substituted with 1, 2, 3 or 4 R Y each m10 and each m11 is an integer in the range of 0-3;

[0093] R L5-1 is -H or methyl;

[0094] Z is 3-6 membered heterocycloalkylene;

[0095] R Y-1 is C 1-6 alkyl;

[0096] R Y is -H, -OH or C 1-6 alkyl.

[0097] said 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkylene, 3-10 membered heterocycloalkylene or C 6- C 10 arylene, the kind of heteroatom group is independently selected from N, O and S, the number of heteroatom groups is 1, 2 or 3;

[0098] L 1 , L 2 , L 3 , L 4 , X 1 , X 2 , L 5 , L 6 , L 7 , L 8 , L 9 , L 10 and Y are not simultaneously a single bond.

[0099] In a certain embodiment, when L 1 and L 2 are a single bond, L 3 and L 4 are independently -(CH2) m2 - with m2 being an integer in the range of 1-6;

[0100] L 5 and L 6 are independently selected from 3-6 membered heterocycloalkylene and 5-6 membered heteroarylene, m3 is an integer in the range of 1-6, a represents the connection site of L 5 to X 1 or the connection site of L 6 to X 2 , b represents the connection site of L 5 to L 7 or the connection site of L 6 to L 8 .

[0101] In a certain embodiment, when L 7 or L 8 are a single bond, L 3 and L 4 are independently -(CH2) m2 - with m2 being an integer in the range of 1-6;

[0102] L 5 and L 6 are independently selected from m3 is an integer in the range of 1-6, a represents the connection site of L 5 to X 1 or the connection site of L 6with the attachment site of X 2 , b represents the attachment site of L 5 with the attachment site of L 7 or L 6 with the attachment site of L 8 ;

[0103] L 9 is , the each m7, each m8, and each m9 is independently an integer in the range of 0-6, c represents the attachment site of L 7 with the attachment site of L 9 or L 8 with the attachment site of L 10 , d represents the attachment site of L 9 with the attachment site of Y or L 10 with the attachment site of Y.

[0104] In certain embodiments, when Y is a single bond, L 3 and L 4 are independently -(CH2) m2 -, m2 is an integer in the range of 1-6;

[0105] L 5 and L 6 are independently selected from m3 is an integer in the range of 1-6, a represents the attachment site of L 5 with the attachment site of X 1 or L 6 with the attachment site of X 2 , b represents the attachment site of L 5 with the attachment site of L 7 or L 6 with the attachment site of L 8 .

[0106] In certain embodiments, each substituent in the compound of Formula I is according to Scheme 1 or Scheme 2:

[0107] Scheme 1:

[0108] R 1 , R 2 and the atoms to which they are attached form a 5-membered heterocycloalkyl group;

[0109] R 3 , R 4 and the atoms to which they are attached form a 5-membered heterocycloalkyl group;

[0110] L 1 and L 2 are independently -CH2-;

[0111] L 3 and L4 Independently -(CH2) m2 - where m2 is an integer in the range of 1-6;

[0112] L 5 and L 6 Independently Or a 3-6 membered heterocyclic alkylene group, wherein the 3-6 membered heterocyclic alkylene group is optionally surrounded by 1, 2 or 3 R groups. L5 Replacement, m3 is an integer in the range of 1-6, a represents L 5 With X 1 Connection site or L 6 With X 2 The connection site, b represents L 5 With L 7 Connection site or L 6 With L 8 Connection sites;

[0113] L 7 and L 8 Selected independently n1 is an integer in the range of 1-5, m6 is an integer in the range of 1-3, and b represents L. 7 With L 5 Connection site or L 8 With L 6 The connection site, c represents L 7 With L 9 Connection site or L 8 With L 10 Connection sites;

[0114] L 9 and L 10 Selected independently Each m7, each m8, and each m9 is an independent integer in the range 0-6, and c represents L. 7 With L 9 Connection site or L 8 With L 10 The connection site, d represents L 9 Connection site with Y or L 10 Connection site with Y;

[0115] Y is

[0116] Option 2:

[0117] R 1 R 2 Together with the atoms attached to it, it forms a 6-membered heterocyclic alkyl group;

[0118] R 3 R4 and together with the atom to which they are attached form a 6-membered heterocycloalkyl group;

[0119] L 1 and L 2 are independently a single bond;

[0120] L 3 and L 4 are independently -(CH2) m2 -, wherein m2 is an integer in the range of 1 to 6;

[0121] L 5 and L 6 are independently or a 3-6 membered heterocycloalkylene group, which is optionally substituted with 1, 2 or 3 R L5 substituted, m3 is an integer in the range of 1 to 6, a represents the attachment site of L 5 to X 1 or the attachment site of L 6 to X 2 , b represents the attachment site of L 5 to L 7 or the attachment site of L 6 to L 8 ;

[0122] L 7 and L 8 are independently selected from wherein n1 is an integer in the range of 1 to 5, m6 is an integer in the range of 1 to 3, b represents the attachment site of L 7 to L 5 or the attachment site of L 8 to L 6 , c represents the attachment site of L 7 to L 9 or the attachment site of L 8 to L 10 ;

[0123] L 9 and L 10 are independently selected from each m7, each m8 and each m9 are independently an integer in the range of 0 to 6, c represents the attachment site of L 7 to L 9 or the attachment site of L 8 to L 10 , d represents the attachment site of L 9 to Y or the attachment site of L 10 to Y;

[0124] Y is

[0125] In certain embodiments, each substituent in the compound of formula I is according to Scheme 3:

[0126] Scheme 3:

[0127] R 1 , R 2 and the atoms to which they are attached form a 5-membered heterocycloalkyl group;

[0128] R 3 , R 4 and the atoms to which they are attached form a 5-membered heterocycloalkyl group;

[0129] L 1 and L 2 are independently a single bond or -CH2-;

[0130] L 3 and L 4 are independently -(CH2) m2 -, wherein m2 is an integer in the range of 1 to 6;

[0131] X 1 and X 2 are independently k represents the point of attachment of L 3 to X 1 or the point of attachment of L 4 to X 2 ; a represents the point of attachment of L 5 to X 1 or the point of attachment of L 6 to X 2 ;

[0132] L 5 and L 6 are independently a single bond, or 3-6 membered heterocycloalkylene, which is optionally substituted with 1, 2, or 3 R L5 , a represents the point of attachment of L 5 to X 1 or the point of attachment of L 6 to X 2 , b represents the point of attachment of L 5 to L 7 or the point of attachment of L 6 to L 8 ;

[0133] L 7 and L 8 are independently a single bond or n1 is an integer in the range of 1 to 6, m6 is an integer in the range of 1 to 3, b represents the point of attachment of L 7 to L5 Connection site or L 8 With L 6 The connection site, c represents L 7 With L 9 Connection site or L 8 With L 10 Connection sites;

[0134] L 9 and L 10 Independently as a single bond or Each m7 is an independent integer in the range of 0-6;

[0135] Y represents a single bond.

[0136] In one embodiment, the substituents in the compound of formula I-1 are those of scheme 4:

[0137] Option 4:

[0138] R 1 R 2 Together with the atoms attached to it, they form a 5-membered heterocyclic alkyl group;

[0139] R 3 R 4 Together with the atoms attached to it, they form a 5-membered heterocyclic alkyl group;

[0140] L 1 and L 2 Independently -CH2-;

[0141] L 3 and L 4 Independently a single bond or -(CH2) m2 - where m2 is an integer in the range of 1-6;

[0142] X 1-1 and X 2-1 Independently k represents L 3 With X 1-1 Connection site or L 4 With X 2-1 The connection site; a represents L 7 With X 1-1 Connection site or L 8 With X 2-1 Connection sites;

[0143] L 7 and L 8 Independently n1 is an integer in the range of 1-5, m6 is an integer in the range of 1-3, and b represents L. 7 With X1-1 L 8 L 2-1 L 7 L 9 L 8 L 10 L

[0144] L 9 L 10 L each m7 is independently an integer in the range of 0-6;

[0145] Y is a single bond, or C 1-6 alkylene; for example, said C 1-6 alkylene is

[0146] In one embodiment, the pharmaceutically acceptable salt of the compound of Formula I-A, Formula I, or Formula I-1 is a hydrochloride salt or a fumarate salt.

[0147] The present application provides a 5-HT4 receptor agonist which is any one of the following compounds: A1-A25, A5-1, B1-B14, C1-C14, D1-D9, D3-1, E1-E3, F1-F10, or G1-G6.

[0148] The present application provides a method for preparing a compound of Formula I-A or a pharmaceutically acceptable salt thereof, which is a method A or a method B:

[0149] Method A: condensing a compound of Formula A-a with a compound of Formula B to obtain a compound of Formula I-A;

[0150] wherein R 1 , R 2 , R 3 , R 4 , L 1 , L 2 , L 3 , L 4 , X a , X b , L 5 , L 6 , L 7 , L 8 , L 9 , L 10 and Y are as described above, and R 6 is -COOH, -NH2, -NCO, or

[0151] Method B: condensing a compound of Formula C-a with a compound of Formula D to produce a compound of Formula I-A;

[0152] wherein R 1 , R 2 , R 3 , R 4 , L 1 , L 2 , L 3 , L 4 , X a , X b , L 5 , L 6 , L 7 , L 8 , L 9 , L 10 and Y are as described in any of the preceding embodiments.

[0153] In one embodiment, the method of preparing a compound of Formula I-A, or a pharmaceutically acceptable salt thereof, is a method of preparing a compound of Formula I, or a pharmaceutically acceptable salt thereof,

[0154] Method One: condensing a compound of Formula A with a compound of Formula B to produce a compound of Formula I;

[0155] wherein R 1 , R 2 , R 3 , R 4 , L 1 , L 2 , L 3 , L 4 , X 1 , X 2 , L 5 , L 6 , L 7 , L 8 , L 9 , L 10 and Y are as described above, R 6 is -COOH, -NH2, or -NCO;

[0156] Method Two: condensing a compound of Formula C with a compound of Formula D to produce a compound of Formula I;

[0157] wherein R 1 , R 2 , R 3 , R 4 , L 1 , L 2, L 3 , L 4 , X 1 , X 2 , L 5 , L 6 , L 7 , L 8 , L 9 , L 10 and Y are as described above.

[0158] In certain embodiments, in the method, R 6 is

[0159] In certain embodiments, the method of preparing the compound of formula I-A or a pharmaceutically acceptable salt thereof is a method of preparing a compound of formula I-1 or a pharmaceutically acceptable salt thereof,

[0160] condensing a compound of formula A-1 with a compound of formula B to produce a compound of formula I-1;

[0161] wherein, R 1 , R 2 , R 3 , R 4 , L 1 , L 2 , L 3 , L 4 , X 1-1 , X 2-1 , L 7 , L 8 , L 9 , L 10 and Y are as described above, R 6 is -COOH, -NH2, -NCO or

[0162] The present application also provides a compound of formula A,

[0163] wherein, R 1 , R 2 , L 1 , L 3 , X 1 , L 5 , L 7 and L 9 are as described above.

[0164] The present application also provides a compound of formula A-1,

[0165] wherein, R 1 , R2 , L 1 , L 3 , X 1-1 , L 7 and L 9 As described above.

[0166] The present application provides a pharmaceutical composition comprising a compound represented by Formula I, I-A or I-1 or a pharmaceutically acceptable salt thereof as described above, and a pharmaceutical adjuvant.

[0167] The present application also provides the use of a compound represented by Formula I, I-A or I-1 or a pharmaceutically acceptable salt thereof as described above, or the pharmaceutical composition as described above in the preparation of a medicament for treating and / or preventing a 5-HT4 receptor-mediated disease, which can be a peripheral gastrointestinal tract-related disease, such as chronic idiopathic constipation, slow-transit constipation, opioid-induced constipation, irritable bowel syndrome, Crohn's disease, ulcerative colitis, enteral feeding intolerance, postoperative ileus, postoperative gastrointestinal dysfunction, diabetic gastroparesis, idiopathic gastroparesis, functional abdominal pain, chronic intestinal pseudo-obstruction, Sjogren's syndrome, celiac disease and short bowel syndrome.

[0168] The present application also provides the use of a compound represented by Formula I, I-A or I-1 or a pharmaceutically acceptable salt thereof as described above, or the pharmaceutical composition as described above in the preparation of a medicament for treating and / or preventing a peripheral gastrointestinal tract disease.

[0169] The compound of the present application has a preferable activation activity on 5-HT4 receptor, with an EC 50 of 0.01-17.6 nM, such as 0.01-1.93 nM, and for example 0.01-0.66 nM;

[0170] The test method is Cisbio cAMP assay kit for measuring cAMP level.

[0171] Definitions

[0172] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. Furthermore, the following definitions are set out to illustrate and define the meanings of various terms used to describe the present application.

[0173] The term "C 1-6 alkyl" alone or in combination means a saturated, straight-chain or branched alkyl group containing 1 to 6, in particular 1 to 4 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, in particular "C 1-6 alkyl" means methyl or ethyl.

[0174] The term "C 1-6"Alkoxy" refers to a group consisting of a C 1-6 "Alkyl" refers to a group consisting of a C

[0175] The term "C 6-10 "Arylene" refers to a group consisting of an aromatic group containing 6 to 10 carbon atoms, including but not limited to phenylene, naphthylene, etc.

[0176] The term "C 3-10 "Cycloalkylene" refers to a group consisting of a saturated cyclic alkyl group containing 3 to 10 carbon atoms, such as (e.g. ).

[0177] The term "5-12 membered heteroarylene" refers to a group consisting of an aromatic group containing at least one heteroatom incorporated within the ring of the aromatic group. Examples of heteroatoms include, but are not limited to, nitrogen, oxygen, sulfur, and phosphorus.

[0178] The term "pharmaceutically acceptable salt" includes "a pharmaceutically acceptable salt formed with an organic or inorganic acid" and "a pharmaceutically acceptable salt formed with an organic or inorganic base". The inorganic acid includes, but is not limited to, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, or phosphoric acid, and the organic acid includes, but is not limited to, formic acid, acetic acid, trifluoroacetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, benzoic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, naphthalenesulfonic acid, proline, phenylalanine, aspartic acid, or glutamic acid. The inorganic base includes, but is not limited to, alkali metal or alkaline earth metal. The organic base includes, but is not limited to, such as methylamine salt, ethylamine salt, propylamine salt, dimethylamine salt, trimethylamine salt, diethylamine salt, triethylamine salt, t-butylamine salt, ethylenediamine salt, hydroxyethylamine salt, dihydroxyethylamine salt, or trihydroxyethylamine salt.

[0179] The term "pharmaceutical composition" means a mixture or solution of a therapeutically effective amount of an active pharmaceutical ingredient with a pharmaceutically acceptable excipient, ready for administration to a mammal, such as a human, in need thereof.

[0180] The above-mentioned preferred conditions can be combined in any manner, based on common general knowledge in the art, to obtain each preferred embodiment of the present application.

[0181] The reagents and materials used in the present application are commercially available.

[0182] The positive progress effect of the present application is that:

[0183] 1) The compound of the present application has good activation ability (EC 50 ) on 5-HT4 receptor.

[0184] 2) The compound of the present application or its pharmaceutically acceptable salt can significantly improve the whole intestinal transport capacity, especially the transport capacity of the distal colon, while increasing the fecal content and water content in animal tests. The compound is basically excreted in the form of the original prototype, which meets the basic pharmacokinetic characteristics of the intestinal restricted drugs.

[0185] 3) The compound of the present application or its pharmaceutically acceptable salt shows that it is basically impermeable to the membrane in the in vitro permeability experiment, and shows that it is basically not entered into the blood in the animal in vivo pharmacokinetic test; and can stably exist in the in vitro digestive juice, and has a long degradation half-life, and the content of the compound after 24h in the artificial simulated gastric juice and the artificial simulated intestinal juice is greater than 70%.

[0186] 4) The compound of the present application or its pharmaceutically acceptable salt has no obvious inhibitory activity on the hERG potassium channel, and the IC 50 value is greater than 30μM, and the possibility of causing cardiotoxicity is low.

[0187] In summary, the compound of the present application is a new structural type of 5-HT4 receptor agonist compound, which has good activation ability to 5-HT4 receptor in vitro, can significantly improve the whole intestinal transport capacity and is basically not entered into the blood in animal tests, and has excellent clinical value. BRIEF DESCRIPTION OF DRAWINGS

[0188] Figure 1 is the stability of compound A5 in the artificial simulated gastric juice and the artificial simulated intestinal juice in vitro at different time points within 24 hours;

[0189] Figure 2 is the concentration of compound A5 in the blood of mice after oral administration of 10mg / kg of the compound within 12 hours at different time points;

[0190] Figure 3 is the time of discharging carmine of mice after oral administration of different dosages of the drug, wherein the vertical coordinate of figure 3 is the absolute value of the time of discharging carmine of mice after administration (i.e. the whole intestinal transport time), the horizontal coordinate is different dosages of the drug, the positive drug is Prucalopride, the data is expressed by mean ± standard error (Mean ± SEM), 10 mice in each group, and the data significance analysis method uses unpaired two-tailed t test (*p≤0.05; **p≤0.01; ***p≤0.001);

[0191] Figure 4 is the time of discharging steel balls of mice after oral administration of different dosages of the drug, wherein the vertical coordinate of figure 4 is the absolute value of the time of discharging steel balls of mice after administration, the horizontal coordinate is different dosages of the drug, the positive drug is Prucalopride, the data is expressed by mean ± standard error (Mean ± SEM), 10 mice in each group, and the data significance analysis method uses unpaired two-tailed t test (*p≤0.05; **p≤0.01).

[0192] Figure 5 is a graph showing the wet weight of feces excreted by mice after oral administration of different doses of the drug, wherein the vertical axis of Figure 5 represents the absolute value of the wet weight of feces excreted by mice after oral administration of different doses of the drug, the horizontal axis of Figure 5 represents different doses of the drug, the positive drug is Prucalopride, the data are expressed as Mean ± SEM, 10 mice in each group, and the data were analyzed by unpaired two-tailed t test for significance (*p < 0.05; **p < 0.01).

[0193] Figure 6 is a graph showing the dry weight of feces excreted by mice after oral administration of different doses of the drug, wherein the vertical axis of Figure 6 represents the absolute value of the dry weight of feces excreted by mice after oral administration of different doses of the drug, the horizontal axis of Figure 6 represents different doses of the drug, the positive drug is Prucalopride, the data are expressed as Mean ± SEM, 10 mice in each group, and the data were analyzed by unpaired two-tailed t test for significance (*p < 0.05; **p < 0.01).

[0194] Figure 7 is a graph showing the water content of feces excreted by mice after oral administration of different doses of the drug, wherein the vertical axis of Figure 7 represents the absolute value of the water content of feces excreted by mice after oral administration of different doses of the drug, the horizontal axis of Figure 7 represents different doses of the drug, the positive drug is Prucalopride, the data are expressed as Mean ± SEM, 10 mice in each group, and the data were analyzed by unpaired two-tailed t test for significance (*p < 0.05; **p < 0.01).

[0195] Figure 8 is a graph showing the time of excretion of carmine by mice after oral administration of different doses of the drug, wherein the vertical axis of Figure 8 represents the absolute value of the time of excretion of carmine by mice after oral administration of different doses of the drug, the horizontal axis of Figure 8 represents different doses of the drug, the positive drug is Prucalopride, the data are expressed as Mean ± SEM, 10 mice in each group, and the data were analyzed by unpaired two-tailed t test for significance (**p < 0.01; ***p < 0.001).

[0196] Figure 9 is a graph showing the recovery rate of compound G3 in feces at different time points within 96 hours after oral administration of 5 mg / kg of compound G3 to rats.

[0197] Figure 10 is a graph showing the inhibition rate of hERG potassium channel by compound G3 at different concentrations of compound G3. DETAILED DESCRIPTION

[0198] The present invention is further illustrated below by way of embodiments, but the invention is not limited to the scope of the embodiments described herein. Experimental methods in the following embodiments that do not specify specific conditions were performed according to conventional methods and conditions, or as selected according to the product instructions.

[0199] In the following examples, many compounds were obtained. 1 H NMR spectroscopy. Characteristic chemical shifts (δ) are given by tetramethylsilane in parts per million (ppm) low-field units. Common abbreviations are used to denote major peaks, including s (singleton), d (doublet), t (triplet), q (quartet), m (multiplex), dd (doublet), dt (doubletuplet), and br (broad peak). The following abbreviations are used for common solvents: CDCl3 (deuterated chloroform), DMSO-d6 (deuterated dimethyl sulfoxide), and CD3OD (deuterated methanol). Mass spectrometry (for [M+H] + The m / z values ​​were recorded using electrospray ionization (ESI-MS) mass spectrometry.

[0200] When indicated, the products of certain preparations and examples were purified by semi-preparative HPLC, rapid chromatography, or preparative TLC. Reversed-phase chromatography was typically performed on a column under acidic conditions, eluting with a mobile phase of water and methanol containing 0.1% trifluoroacetic acid or 0.1% formic acid, respectively; or under alkaline conditions, eluting with a mobile phase of water and methanol containing 10 mM NH4HCO3. Preparative TLC was typically performed on silica gel 60F. 254 The reaction is carried out on a plate. After separation by chromatography, the solvent is removed, and the product is obtained by drying in a centrifugal evaporator, rotary evaporator, vacuum flask, or similar apparatus. The reaction is typically carried out at approximately 1 atmosphere (14.7 psi) under an inert atmosphere (e.g., nitrogen).

[0201] Example 1: Synthesis of compound A1

[0202] Step 1: Synthesis of compound A1-3

[0203] Compound A1-1 (5.00 g, 23.40 mmol) was dissolved in DMF (100 ml), and EDCI (6.73 g, 35.10 mmol), HOBt (4.74 g, 35.10 mmol) and TEA (4.74 g, 46.80 mmol) were added. The reaction mixture was stirred at room temperature (25 °C) for 0.5 h. To the above reaction solution, A1-2 (5.63 g, 28.10 mmol) was added, and the reaction mixture was stirred at 20 °C for 4 h. After the reaction was completed, 10 volumes of H2O (1000 ml) was added to the reaction solution, and a large amount of white solid was precipitated, which was filtered and dried to obtain white solid compound A1-3 (10.20 g, crude), which was used directly in the next step without further purification.

[0204] 1 H NMR (400 MHz, DMSO-d6) δ 9.08 (s, 2H), 7.44 (s, 1H), 7.31 (d, J = 7.2 Hz, 1H), 5.90 (s, 2H), 4.73 (t, J = 8.6 Hz, 2H), 4.05 - 3.91 (m, 1H), 3.23 (d, J = 12.2 Hz, 2H), 3.01 (dt, J = 17.7, 9.4 Hz, 4H), 1.99 (dd, J = 13.9, 3.8 Hz, 2H), 1.68 (q, J = 10.4 Hz, 2H).

[0205] ESI-MS m / z [M+H] + = 396.2

[0206] Step two: synthesis of compound A1-4

[0207] Compound A1-3 crude (10.20 g, 25.76 mmol) was dissolved in MeOH (100 ml), and HCl EA solution (2 mol / L, 25.77 ml, 51.53 mmol) was added dropwise at 0 °C, and the reaction was stirred at 40 °C overnight. After the reaction was completed, white solid was precipitated, which was filtered to obtain white solid compound A1-4 (8.40 g, crude), which was used directly in the next step without further purification, and the yield of the first two steps was 86%.

[0208] 1 H NMR (400 MHz, DMSO-d6) δ 9.08 (s, 2H), 7.44 (s, 1H), 7.31 (d, J = 7.2 Hz, 1H), 5.90 (s, 2H), 4.73 (t, J = 8.6 Hz, 2H), 4.05 - 3.91 (m, 1H), 3.23 (d, J = 12.2 Hz, 2H), 3.01 (dt, J = 17.7, 9.4 Hz, 4H), 1.99 (dd, J = 13.9, 3.8 Hz, 2H), 1.68 (q, J = 10.4 Hz, 2H).

[0209] ESI-MS m / z [M+H] + = 296.2

[0210] Step three: synthesis of compound A1-6

[0211] Compound A1-4 (2.00 g, 6.00 mmol) was dissolved in DMF (20 ml) at room temperature, K2CO3 (1.66 g, 12.00 mmol) and a catalytic amount of NaI (90.00 mg, 0.60 mmol) were added, A1-5 (1.10 g, 6.60 mmol) was added, the reaction mixture was heated to 80 °C, and stirred at 80 °C for 2 h. After the reaction was completed, the reaction was cooled to room temperature, water (40 ml) was added to dilute the reaction and extracted with EA (40 ml x 3), the combined organic layer was washed with water (120 ml x 3), washed with saturated brine (120 ml x 2), the organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was separated by normal phase silica gel column chromatography (DCM / MeOH = 40:1-20:1), and dried to give compound A1-6 (2.06 g, yield 90%) as a colorless oil.

[0212] 1 H NMR (400 MHz, CDCl3) δ 7.81 (s, 1H), 7.24 (d, J = 7.8 Hz, 1H), 4.74 (t, J = 8.7 Hz, 2H), 4.28 (s, 2H), 4.02-3.88 (m, 1H), 3.67 (s, 3H), 3.03 (t, J = 8.9 Hz, 2H), 2.80 (d, J = 12.2 Hz, 2H), 2.69 (t, J = 7.3 Hz, 2H), 2.50 (t, J = 7.3 Hz, 2H), 2.24-2.17 (m, 2H), 2.02-1.92 (m, 2H), 1.60-1.45 (m, 2H).

[0213] ESI-MS m / z [M+H] + = 382.2

[0214] Step four: synthesis of compound A1-7

[0215] A1-6 (2.06 g, 5.40 mmol) was dissolved in methanol (16 ml), and 8 ml of aqueous NaOH (containing NaOH 0.65 g, 16.20 mmol) was added dropwise, and the reaction mixture was heated to 40 °C for 0.5 h. After the reaction was completed, the methanol was removed by rotary evaporation under reduced pressure, and the water layer was adjusted to pH 7.0 with 1N HCl at 0 °C, and a white solid was precipitated, which was filtered, the filter cake was washed with cold water, and the filter cake was dried to give compound A1-7 (1.69 g, yield 85%) as a white solid.

[0216] 1 H NMR (400 MHz, DMSO-d6) δ 7.45 (s, 1H), 7.32 (d, J = 7.3 Hz, 1H), 5.90 (s, 2H), 4.73 (t, J = 8.8 Hz, 2H), 4.02 - 3.92 (m, 1H), 3.35 (d, J = 11.8 Hz, 2H), 3.19 (t, J = 7.7 Hz, 2H), 3.03 (t, J = 8.8 Hz, 4H), 2.82 (t, J = 7.7 Hz, 2H), 2.01 (dd, J = 13.9, 4.0 Hz, 2H), 1.89 - 1.74 (m, 2H).

[0217] ESI-MS m / z [M+H] + = 368.2

[0218] Step five: synthesis of compound A1-9

[0219] A1-7 (1.00 g, 2.72 mmol), EDCI (0.78 g, 4.07 mmol), HOBt (0.55 g, 4.07 mmol) were dissolved in DMF (10 ml), TEA (0.55 g, 5.43 mmol) was added, and the reaction was carried out at room temperature under nitrogen protection for 0.5 h. A1-8 (0.74 g, 2.99 mmol) was added to the reaction solution, and the reaction was continued for 5 h. After the reaction was completed, most of the DMF was removed by concentration, diluted with water (20 ml) and extracted with DCM (20 ml x 3), the combined organic layer was washed with water (60 ml x 3), washed with saturated brine (60 ml), the organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was separated by basic alumina column chromatography (DCM / MeOH = 60:1-20:1), and rotary evaporation gave compound A1-9 (1.44 g, yield 89%) as a light yellow foaming solid.

[0220] 1H NMR (400 MHz, CD3OD) δ 7.60 (s, 1H), 4.80 (t, J = 8.8 Hz, 2H), 3.93 - 3.82 (m, 1H), 3.62 (s, 4H), 3.56 (t, J = 5.4 Hz, 2H), 3.51 (t, J = 5.7 Hz, 2H), 3.38 (t, J = 5.4 Hz, 2H), 3.22 (t, J = 5.6 Hz, 2H), 3.10 (t, J = 8.8 Hz, 2H), 2.88 (d, J = 11.8 Hz, 2H), 2.69 (t, J = 7.1 Hz, 2H), 2.42 (t, J = 7.1 Hz, 2H), 2.25 (d, J = 11.3 Hz, 2H), 1.98 (dd, J = 12.8, 4.2 Hz, 2H), 1.64 - 1.53 (m, 2H), 1.43 (s, 9H).

[0221] ESI-MS m / z [M+H] + = 598.3

[0222] Step six: synthesis of compound A1-10

[0223] Compound A1-9 (0.54 g, 0.90 mmol) was dissolved in EA, HCl EA solution (2 N, 0.90 ml, 1.80 mmol) was added dropwise at 0 °C, and stirred at room temperature overnight. After the reaction was completed, a white solid was precipitated, and the filter cake was easily hygroscopic. After being dissolved in methanol and concentrated under reduced pressure, compound A1-10 (0.51 g, yield 98%) was obtained as a light yellow foaming solid.

[0224] 1 H NMR (400 MHz, DMSO-d6) δ 11.00 (s, 1H), 8.32 (t, J = 5.6 Hz, 1H), 8.14 (s, 3H), 7.44 (s, 1H), 7.28 (d, J = 7.3 Hz, 1H), 4.72 (t, J = 8.7 Hz, 2H), 4.38 (s, 2H), 4.01 - 3.90 (m, 1H), 3.63 (t, J = 5.3 Hz, 2H), 3.54 (d, J = 3.2 Hz, 4H), 3.43 (t, J = 5.7 Hz, 4H), 3.22 (q, J = 5.4 Hz, 4H), 3.04 (q, J = 10.6, 8.7 Hz, 4H), 2.94 (q, J = 5.5 Hz, 2H), 2.72 (t, J = 7.7 Hz, 2H), 2.03 (d, J = 12.5 Hz, 2H), 1.91 - 1.77 (m, 2H).

[0225] ESI-MS m / z [M+H] + = 498.3

[0226] Step seven: synthesis of compound A1

[0227] Compound A1-10 (0.36 g, 0.63 mmol) was dissolved in DMF (2 ml), TEA (0.13 g, 1.26 mmol) was added, A1-11 (44.00 mg, 0.31 mmol) was added, and the reaction was allowed to proceed at room temperature for 10 min; or A1-12 (86.00 mg, 0.31 mmol) was added, and the reaction was allowed to proceed at 60 °C for 6 h. After the reaction was completed, the precipitated triethylamine hydrochloride was removed by suction filtration, and the filtrate was concentrated to remove most of the DMF to obtain a crude product. The crude product was dissolved in analytical methanol and purified by semi-preparative high performance liquid chromatography (separation conditions: column: Thermo HYPERSIL PREP HS C18 150 x 10 mm 10 μm; column temperature: 30 °C; mobile phase: water (containing 10 mmol / L NH4HCO3) - methanol; gradient: methanol: 50% - 90% 10 min, 90%, 10 min; flow rate: 8 ml / min), and the solution was lyophilized to obtain compound A1 as a white powder.

[0228] 1 H NMR (600 MHz, CD3OD) δ 7.59 (s, 2H), 4.78 (t, J = 8.7 Hz, 4H), 3.91 - 3.83 (m, 2H), 3.62 (s, 8H), 3.55 (t, J = 5.4 Hz, 4H), 3.51 (t, J = 5.5 Hz, 4H), 3.38 (t, J = 5.4 Hz, 4H), 3.28 (t, J = 5.5 Hz, 4H), 3.13 - 3.07 (m, 8H), 2.87 (d, J = 11.2 Hz, 4H), 2.69 (t, J = 7.1 Hz, 4H), 2.41 (t, J = 7.1 Hz, 4H), 2.26 (t, J = 9.9 Hz, 4H), 1.98 (dd, J = 13.4, 4.0 Hz, 4H), 1.62 - 1.54 (m, 4H), 1.50 - 1.45 (m, 4H).

[0229] ESI-MS m / z [M+H] + = 1135.6

[0230] Example 2: synthesis of compound A2

[0231] The title compound was prepared in analogy to Example 1 using 4-bromobutanoic acid methyl ester instead of A1-5 (3-bromopropionic acid methyl ester) to give compound A2 as a white powder.

[0232] 1H NMR (400 MHz, CD3OD) δ 7.59 (s, 2H), 4.78 (t, J = 8.8 Hz, 4H), 3.93 - 3.82 (m, 2H), 3.61 (s, 8H), 3.57 - 3.49 (m, 8H), 3.36 (t, J = 5.6 Hz, 4H), 3.29 (t, J = 5.6 Hz, 4H), 3.15 - 3.05 (m, 8H), 2.88 (d, J = 11.5 Hz, 4H), 2.40 (t, J = 7.7 Hz, 4H), 2.23 (t, J = 7.2 Hz, 8H), 2.02 - 1.91 (m, 4H), 1.87 - 1.76 (m, 4H), 1.63 - 1.52 (m, 4H), 1.52 - 1.43 (m, 4H).

[0233] ESI-MS m / z [M+H] + = 1163.6

[0234] Example 3: Synthesis of compound A3

[0235] The title compound was prepared in analogy to Example 1 using 5-bromovaleric acid methyl ester instead of A1-5 (3-bromopropionic acid methyl ester) to give compound A3 as a white powder.

[0236] 1 H NMR (600 MHz, CD3OD) δ 7.59 (s, 2H), 4.78 (t, J = 8.7 Hz, 4H), 3.95 - 3.88 (m, 2H), 3.61 (s, 8H), 3.53 (dt, J = 15.9, 5.5 Hz, 8H), 3.36 (t, J = 5.6 Hz, 4H), 3.29 (t, J = 5.5 Hz, 4H), 3.13 - 3.08 (m, 8H), 3.03 - 2.93 (m, 4H), 2.51 (t, J = 7.8 Hz, 4H), 2.36 (t, J = 11.6 Hz, 4H), 2.25 (t, J = 7.1 Hz, 4H), 2.01 (d, J = 11.5 Hz, 4H), 1.65 - 1.56 (m, 12H), 1.52 - 1.44 (m, 4H).

[0237] ESI-MS m / z [M+H] + = 1191.6

[0238] Example 4: Synthesis of compound A4

[0239] The title compound was prepared in analogy to Example 1 using 6-bromohexanoic acid methyl ester instead of A1-5 (3-bromopropionic acid methyl ester) to give compound A4 as a white powder.

[0240] 1 H NMR (600 MHz, CD3OD) δ 7.59 (s, 2H), 4.79 (t, J = 8.7 Hz, 4H), 3.92 - 3.84 (m, 2H), 3.61 (s, 8H), 3.53 (dt, J = 13.9, 5.6 Hz, 8H), 3.36 (t, J = 5.5 Hz, 4H), 3.29 (t, J = 5.5 Hz, 4H), 3.15 - 3.06 (m, 8H), 2.96 - 2.83 (m, 4H), 2.40 (t, J = 7.9 Hz, 4H), 2.21 (t, J = 7.5 Hz, 8H), 1.98 (d, J = 11.9 Hz, 4H), 1.67 - 1.62 (m, 4H), 1.61 - 1.52 (m, 8H), 1.51 - 1.46 (m, 4H), 1.37 - 1.32 (m, 4H).

[0241] ESI-MS m / z [M+H] + = 1219.6

[0242] Example 5: Synthesis of compound A5

[0243] The title compound was prepared in analogy to Example 1 using 1-tert- butyloxycarbonyl-4-aminomethylpiperidine instead of A1-2 (1-tert- butyloxycarbonyl-4-aminopiperidine) and 6-bromohexanoic acid methyl ester instead of A1-5 (3-bromopropionic acid methyl ester), which resulted in compound A5 as a white powder.

[0244] 1 H NMR (400 MHz, CD3OD) δ 7.61 (s, 2H), 4.81 (t, J = 8.7 Hz, 4H), 3.62 (s, 10H), 3.56 (q, J = 5.3 Hz, 10H), 3.41 - 3.33 (m, 12H), 3.21 (t, J = 6.7, 5.8 Hz, 4H), 3.15 (t, J = 8.5 Hz, 4H), 3.13 - 3.04 (m, 4H), 2.96 (t, J = 12.6 Hz, 4H), 2.29 (t, J = 7.2 Hz, 4H), 1.97 (t, J = 15.8 Hz, 6H), 1.78 (s, 4H), 1.73 - 1.61 (m, 6H), 1.60 - 1.50 (m, 6H), 1.46 - 1.35 (m, 4H).

[0245] ESI-MS m / z [M+H] + = 1247.7

[0246] Example 6: Synthesis of compound A6

[0247] The title compound was prepared in analogy to Example 1 by using 1-tert- butyloxycarbonyl-1,8-diaminooctane instead of A1-8 (tert-butyl 2-(2-(2- aminoethoxy)ethoxy)ethylcarbamate) as a white powder.

[0248] 1 H NMR (400 MHz, CD3OD) δ 7.60 (s, 2H), 4.79 (t, J = 8.7 Hz, 4H), 4.20 - 4.05 (m, 2H), 3.67 (d, J = 11.3 Hz, 4H), 3.52 (s, 2H), 3.43 (t, J = 6.8 Hz, 4H), 3.23 - 3.11 (m, 18H), 2.77 (t, J = 6.7 Hz, 4H), 2.28 - 2.15 (m, 4H), 1.92 (q, J = 12.6 Hz, 4H), 1.59 - 1.48 (m, 12H), 1.34 (s, 16H).

[0249] ESI-MS m / z [M+H] + = 1227.6

[0250] Example 7: Synthesis of compound A7

[0251] Compound A1-10 (0.36 g, 0.63 mmol) was dissolved in DMF (2 ml), TEA (0.13 g, 1.26 mmol) was added, and CDI (50.00 mg, 0.31 mmol) was added. The reaction was stirred at room temperature for 8 h. After the reaction was completed, triethylamine hydrochloride was removed by suction filtration, and the filtrate was concentrated to remove most of the DMF to obtain a crude product. The crude product was dissolved in analytical methanol and purified by semi-preparative high performance liquid chromatography (separation conditions: column: Thermo HYPERSIL PREP HS C18 150 x 10 mm 10 μm; column temperature: 30 °C; mobile phase: water (containing 10 mmol / L NH4HCO3) - methanol; gradient: methanol: 50% - 90% 10 min, 90%, 10 min; flow rate: 8 ml / min), and the solution was lyophilized to obtain compound A7 as a white powder.

[0252] 1H NMR (400 MHz, CD3OD) δ 7.59 (s, 2H), 4.78 (t, J = 8.8 Hz, 4H), 3.92 - 3.82 (m, 2H), 3.61 (s, 8H), 3.55 (t, J = 5.4 Hz, 4H), 3.51 (t, J = 5.5 Hz, 4H), 3.37 (t, J = 5.4 Hz, 4H), 3.29 (t, J = 5.4 Hz, 4H), 3.09 (t, J = 8.7 Hz, 4H), 2.87 (d, J = 11.0 Hz, 4H), 2.68 (t, J = 7.1 Hz, 4H), 2.41 (t, J = 7.0 Hz, 4H), 2.26 (t, J = 10.8 Hz, 4H), 1.97 (dd, J = 13.5, 3.8 Hz, 4H), 1.63 - 1.52 (m, 4H).

[0253] ESI-MS m / z [M+H] + = 1021.5

[0254] Example 8: Synthesis of compound A8

[0255] The title compound was prepared in analogy to example 7 using tert-butyl [2-(2- aminoethoxy)ethy l] carbamate instead of A1-8 (tert-butyl 2-(2-(2- aminoethoxy)ethoxy)ethylcarbamate) as a white powder.

[0256] 1 H NMR (400 MHz, CD3OD) δ 7.60 (s, 2H), 4.79 (t, J = 8.8 Hz, 4H), 3.96 - 3.81 (m, 2H), 3.53 (dt, J = 10.9, 5.4 Hz, 8H), 3.39 (t, J = 5.4 Hz, 4H), 3.30 (s, 4H), 3.09 (t, J = 8.7 Hz, 4H), 2.91 (d, J = 10.9 Hz, 4H), 2.72 (t, J = 7.1 Hz, 4H), 2.44 (t, J = 7.0 Hz, 4H), 2.36 - 2.21 (m, 4H), 2.05 - 1.94 (m, 4H), 1.68 - 1.52 (m, 4H).

[0257] ESI-MS m / z [M+H] + = 933.4

[0258] Example 9: Synthesis of compound A9

[0259] The title compound was prepared in analogy to Example 7 using 13-amino-5,8,11- trioxa-2-azatridecanoic acid 1,1 -dimethylethyl ester instead of A1-8 (tert-buty\ 2-(2-(2- aminoethoxy)ethoxy)ethylcarbamate), which yielded compound A9 as a white powder.

[0260] 1 H NMR (400 MHz, CD3OD) δ 7.59 (s, 2H), 4.78 (t, J = 8.8 Hz, 4H), 3.91 - 3.82 (m, 2H), 3.65 - 3.53 (m, 20H), 3.49 (t, J = 5.4 Hz, 4H), 3.37 (t, J = 5.3 Hz, 4H), 3.28 (t, J = 5.4 Hz, 4H), 3.08 (t, J = 8.7 Hz, 4H), 2.88 (d, J = 11.3 Hz, 4H), 2.69 (t, J = 7.1 Hz, 4H), 2.41 (t, J = 7.0 Hz, 4H), 2.32 - 2.19 (m, 4H), 2.04 - 1.92 (m, 4H), 1.63 - 1.53 (m, 4H).

[0261] ESI-MS m / z [M+H] + = 1109.5

[0262] Example 10: Synthesis of compound A10

[0263] Compound A1-7 (0.50 g, 1.36 mmol) was dissolved in DMF (5 ml), HATU (0.78 g, 2.04 mmol) and DIPEA (0.35 g, 2.72 mmol) were added. The reaction mixture was stirred at room temperature for 0.5 h. To the above reaction solution, A16-1 (71.00 mg, 0.68 mmol) was added, and the reaction mixture was stirred at room temperature for 2 h. After the reaction was completed, the precipitated DIPEA hydrochloride was removed by suction filtration, and the filtrate was concentrated to remove most of the DMF to obtain a crude product. The crude product was dissolved in analytical methanol and purified by semi-preparative high performance liquid chromatography (separation conditions: column: Thermo HYPERSIL PREP HS C18 150 x 10 mm 10 μm; column temperature: 30 °C; mobile phase: water (containing 10 mmol / L NH4HCO3) - methanol; gradient: methanol: 50% - 90% 10 min, 90%, 10 min; flow rate: 8 ml / min), and the solution was lyophilized to obtain compound A10 as a white powder.

[0264] 1H NMR (400 MHz, CD3OD) δ 7.58 (s, 2H), 4.77 (t, J = 8.8 Hz, 4H), 3.94 - 3.76 (m, 2H), 3.55 (t, J = 5.4 Hz, 4H), 3.39 (t, J = 5.4 Hz, 4H), 3.07 (t, J = 8.8 Hz, 4H), 2.86 (d, J = 11.7 Hz, 4H), 2.66 (t, J = 7.1 Hz, 4H), 2.40 (t, J = 7.0 Hz, 4H), 2.24 (dt, J = 6.0, 11.9 Hz, 4H), 1.97 (dd, J = 3.5, 13.2 Hz, 4H), 1.62 - 1.50 (m, 4H).

[0265] ESI-MS m / z [M+H] + = 803.4

[0266] Example 11: Synthesis of compound A11

[0267] The title compound was prepared in analogy to Example 10 using 1,8-diamino-3,6-dioxaoctane instead of A16-1 (2,2'-oxobisethylamine), which yielded compound A11 as a white powder.

[0268] 1 H NMR (400 MHz, CD3OD) δ 7.58 (s, 2H), 4.77 (t, J = 8.8 Hz, 4H), 3.92 - 3.81 (m, 2H), 3.64 (s, 4H), 3.55 (t, J = 5.4 Hz, 4H), 3.37 (t, J = 5.4 Hz, 4H), 3.07 (t, J = 8.7 Hz, 4H), 2.86 (d, J = 11.5 Hz, 4H), 2.67 (t, J = 7.1 Hz, 4H), 2.39 (t, J = 7.0 Hz, 4H), 2.31 - 2.17 (m, 4H), 2.02 - 1.91 (m, 4H), 1.63 - 1.51 (m, 4H).

[0269] ESI-MS m / z [M+H] + = 847.4

[0270] Example 12: Synthesis of compound A12

[0271] The title compound was prepared in analogy to Example 10 using 3,6,9-trioxaundecane-1,11-diamine instead of A16-1 (2,2'-oxobisethylamine), which yielded compound A12 as a white powder.

[0272] 1H NMR (400 MHz, CD3OD) δ 7.59 (s, 2H), 4.77 (t, J = 8.8 Hz, 4H), 3.93 - 3.81 (m, 2H), 3.66 - 3.59 (m, 8H), 3.53 (t, J = 5.4 Hz, 4H), 3.36 (t, J = 5.5 Hz, 4H), 3.08 (t, J = 8.7 Hz, 4H), 2.92 - 2.80 (m, 4H), 2.68 (t, J = 7.0 Hz, 4H), 2.40 (t, J = 7.0 Hz, 4H), 2.25 (t, J = 10.7 Hz, 4H), 2.02 - 1.91 (m, 4H), 1.65 - 1.50 (m, 4H).

[0273] ESI-MS m / z [M+H] + = 891.4

[0274] Example 13: Synthesis of compound A13

[0275] The title compound was prepared in analogy to Example 10 using 3,6,9,12- tetraoxatetradecane-l,14-diamine instead of A16-1 (2,2'-oxobisethylamine) to give compound A13 as a white powder.

[0276] 1 H NMR (400 MHz, CD3OD) δ 7.59 (s, 2H), 4.78 (t, J = 8.8 Hz, 4H), 3.93 - 3.80 (m, 2H), 3.64 - 3.58 (m, 12H), 3.54 (t, J = 5.4 Hz, 4H), 3.37 (t, J = 5.3 Hz, 4H), 3.08 (t, J = 8.7 Hz, 4H), 2.87 (d, J = 11.6 Hz, 4H), 2.67 (t, J = 7.0 Hz, 4H), 2.40 (t, J = 7.0 Hz, 4H), 2.29 - 2.18 (m, 4H), 2.02 - 1.92 (m, 4H), 1.63 - 1.52 (m, 4H).

[0277] ESI-MS m / z [M+H] + = 935.4

[0278] Example 14: Synthesis of compound A14

[0279] The title compound was prepared in analogy to Example 10 using 1,17-diamino- 3,6,9,12,15-pentaoxahexadecane instead of A16-1 (2,2'-oxobisethylamine) to give compound A14 as a white powder.

[0280] 1 H NMR (400 MHz, CD3OD) δ 7.59 (s, 2H), 4.78 (t, J = 8.8 Hz, 4H), 3.93 - 3.81 (m, 2H), 3.64 - 3.58 (m, 16H), 3.54 (t, J = 5.3 Hz, 4H), 3.37 (t, J = 5.3 Hz, 4H), 3.08 (t, J = 8.7 Hz, 4H), 2.87 (d, J = 11.6 Hz, 4H), 2.67 (t, J = 7.0 Hz, 4H), 2.40 (t, J = 7.1 Hz, 4H), 2.26 - 2.19 (m, 4H), 2.02 - 1.93 (m, 4H), 1.64 - 1.50 (m, 4H).

[0281] ESI-MS m / z [M+H] + = 979.5

[0282] Example 15: Synthesis of compound B1

[0283] Compound A1-10 (0.78 g, 1.36 mmol) and compound B1-1 (0.08 g, 0.68 mmol) were dissolved in DMF (8 ml), HATU (0.78 g, 2.04 mmol) and DIPEA (0.35 g, 2.72 mmol) were added successively into the solution at room temperature, after the addition, the system was stirred at room temperature for 2 h. After the reaction was completed, the precipitated DIPEA hydrochloride was removed by suction filtration, and the filtrate was concentrated to remove most of the DMF to obtain a crude product. The crude product was dissolved in analytical methanol and purified by semi-preparative high performance liquid chromatography (separation conditions: column: Thermo HYPERSIL PREP HS CI 8 150 x 10 mm 10 μm; column temperature: 30 °C; mobile phase: water (containing 10 mmol / L NH4HCO3) - methanol; gradient: methanol: 50% - 90% 10 min, 90%, 10 min; flow rate: 8 ml / min), and the solution was freeze-dried to obtain compound B1 as a white powder.

[0284] 1H NMR (400 MHz, CD3OD) δ 7.59 (s, 2H), 4.78 (t, J = 8.8 Hz, 4H), 3.94 - 3.82 (m, 2H), 3.61 (s, 8H), 3.58 - 3.50 (m, 8H), 3.40 - 3.32 (m, 8H), 3.08 (t, J = 8.8 Hz, 4H), 2.88 (d, J = 11.5 Hz, 4H), 2.70 (t, J = 7.1 Hz, 4H), 2.47 (s, 4H), 2.41 (t, J = 7.1 Hz, 4H), 2.34 - 2.17 (m, 4H), 2.04 - 1.92 (m, 4H), 1.64 - 1.52 (m, 4H).

[0285] ESI-MS m / z [M+H] + = 1077.5

[0286] Example 16: Synthesis of compound B2

[0287] The title compound was prepared in analogy to example 15 using tartaric acid instead of B1-1 (succinic acid) to yield compound B2 as a white powder.

[0288] 1 H NMR (400 MHz, CD3OD) δ 7.59 (s, 2H), 4.78 (t, J = 8.8 Hz, 4H), 4.48 (s, 2H), 3.88 (tt, J = 9.6, 4.1 Hz, 2H), 3.62 (s, 8H), 3.57 (dt, J = 9.4, 5.5 Hz, 8H), 3.50 - 3.35 (m, 8H), 3.09 (t, J = 8.7 Hz, 4H), 2.89 (d, J = 11.8 Hz, 4H), 2.71 (t, J = 7.1 Hz, 4H), 2.42 (t, J = 7.1 Hz, 4H), 2.35 - 2.21 (m, 4H), 2.05 - 1.92 (m, 4H), 1.67 - 1.48 (m, 4H).

[0289] ESI-MS m / z [M+H] + = 1109.5

[0290] Example 17: Synthesis of compound B3

[0291] The title compound was prepared in analogy to example 15 using terephthalic acid instead of B1-1 (succinic acid) to yield compound B3 as a white powder.

[0292] 1H NMR (400 MHz, CD3OD) δ 7.87 (s, 4H), 7.57 (s, 2H), 4.76 (t, J = 8.8 Hz, 4H), 3.89 - 3.80 (m, 2H), 3.69 - 3.62 (m, 12H), 3.56 (dt, J = 10.7, 5.4 Hz, 8H), 3.35 (t, J = 5.4 Hz, 4H), 3.06 (t, J = 8.7 Hz, 4H), 2.84 (d, J = 11.5 Hz, 4H), 2.65 (t, J = 7.0 Hz, 4H), 2.38 (t, J = 7.0 Hz, 4H), 2.28 - 2.15 (m, 4H), 2.01 - 1.88 (m, 4H), 1.64 - 1.48 (m, 4H).

[0293] ESI-MS m / z [M+H] + = 1125.5

[0294] Example 18: Synthesis of compound B4

[0295] The title compound was prepared in analogy to example 15 using diethylene glycol acid instead of Bl-1 (succinic acid) to yield compound B4 as a white powder.

[0296] 1 H NMR (400 MHz, CD3OD) δ 7.59 (s, 2H), 4.78 (t, J = 8.8 Hz, 4H), 4.04 (s, 4H), 3.93 - 3.80 (m, 2H), 3.62 (s, 8H), 3.56 (dt, J = 8.2, 5.6 Hz, 8H), 3.43 (t, J = 5.7 Hz, 4H), 3.37 (t, J = 5.4 Hz, 4H), 3.08 (t, J = 8.8 Hz, 4H), 2.89 (d, J = 11.8 Hz, 4H), 2.70 (t, J = 7.1 Hz, 4H), 2.41 (t, J = 7.0 Hz, 4H), 2.33 - 2.21 (m, 4H), 2.04 - 1.92 (m, 4H), 1.64 - 1.52 (m, 4H).

[0297] ESI-MS m / z [M+H] + = 1093.5

[0298] Example 19: Synthesis of compound B5

[0299] The title compound was prepared in analogy to example 15 using dimethyl malonic acid instead of Bl-1 (succinic acid) to yield compound B5 as a white powder.

[0300] 1H NMR (400 MHz, CD3OD) δ 7.59 (s, 2H), 4.78 (t, J = 8.8 Hz, 4H), 3.94 - 3.83 (m, 2H), 3.61 (s, 8H), 3.55 (q, J = 5.4 Hz, 8H), 3.41 - 3.35 (m, 8H), 3.08 (t, J = 8.7 Hz, 4H), 2.89 (d, J = 10.9 Hz, 4H), 2.70 (t, J = 7.1 Hz, 4H), 2.42 (t, J = 7.0 Hz, 4H), 2.27 (t, J = 11.4 Hz, 4H), 1.98 (dd, J = 13.1, 3.9 Hz, 4H), 1.65 - 1.51 (m, 4H), 1.35 (s, 4H).

[0301] ESI-MS m / z [M+H] + = 1091.5

[0302] Example 20: Synthesis of compound B6

[0303] The title compound was prepared in analogy to example 15 using 1,1- cyclopropyl dicarboxylic acid instead of B1-1 (succinic acid) to give compound B6 as a white powder.

[0304] 1 H NMR (400 MHz, CD3OD) δ 7.59 (s, 2H), 4.78 (t, J = 8.8 Hz, 4H), 3.94 - 3.83 (m, 2H), 3.61 (s, 8H), 3.55 (q, J = 5.4 Hz, 8H), 3.41 - 3.35 (m, 8H), 3.08 (t, J = 8.7 Hz, 4H), 2.89 (d, J = 10.9 Hz, 4H), 2.70 (t, J = 7.1 Hz, 4H), 2.42 (t, J = 7.0 Hz, 4H), 2.27 (t, J = 11.4 Hz, 4H), 1.98 (dd, J = 13.1, 3.9 Hz, 4H), 1.65 - 1.51 (m, 4H), 1.35 (s, 4H).

[0305] ESI-MS m / z [M+H] + = 1089.5

[0306] Example 21: Synthesis of compound B7

[0307] The title compound was prepared in analogy to example 15 using 1,1- cyclobutyl dicarboxylic acid instead of B1-1 (succinic acid) to give compound B7 as a white powder.

[0308] 1H NMR (400 MHz, CD3OD) δ 7.59 (s, 2H), 4.78 (t, J = 8.8 Hz, 4H), 3.94 - 3.80 (m, 2H), 3.61 (s, 8H), 3.54 (q, J = 5.5 Hz, 8H), 3.41 - 3.35 (m, 8H), 3.09 (t, J = 8.7 Hz, 4H), 2.88 (d, J = 10.8 Hz, 4H), 2.70 (t, J = 7.1 Hz, 4H), 2.50 (t, J = 7.8 Hz, 4H), 2.42 (t, J = 7.1 Hz, 4H), 2.36 - 2.19 (m, 4H), 2.03 - 1.93 (m, 4H), 1.92 - 1.79 (m, 2H), 1.63 - 1.53 (m, 4H).

[0309] ESI-MS m / z [M+H] + = 1103.5

[0310] Example 22: Synthesis of compound B8

[0311] The title compound was prepared in analogy to example 15 using 1,1- cyclopentyldicarboxylic acid instead of B1-1 (succinic acid) to give compound B8 as a white powder.

[0312] 1 H NMR (400 MHz, CD3OD) δ 7.59 (s, 2H), 4.78 (t, J = 8.8 Hz, 4H), 3.94 - 3.81 (m, 2H), 3.60 (s, 8H), 3.53 (dt, J = 11.1, 5.5 Hz, 8H), 3.42 - 3.32 (m, 8H), 3.09 (t, J = 8.7 Hz, 4H), 2.88 (d, J = 11.7 Hz, 4H), 2.70 (t, J = 7.2 Hz, 4H), 2.43 (t, J = 7.1 Hz, 4H), 2.32 - 2.22 (m, 4H), 2.17 - 2.10 (m, 4H), 2.02 - 1.93 (m, 4H), 1.67 - 1.52 (m, 8H).

[0313] ESI-MS m / z [M+H] + = 1117.5

[0314] Example 23: Synthesis of compound B9

[0315] The title compound was prepared in analogy to example 15 using 1,1- cyclohexyldicarboxylic acid instead of B1-1 (succinic acid) to give compound B9 as a white powder.

[0316] 1H NMR (400 MHz, CD3OD) δ 7.59 (s, 2H), 4.78 (t, J = 8.7 Hz, 4H), 3.93 - 3.82 (m, 2H), 3.61 (s, 8H), 3.53 (dt, J = 10.7, 5.5 Hz, 8H), 3.40 - 3.35 (m, 8H), 3.09 (t, J = 8.7 Hz, 4H), 2.87 (d, J = 11.8 Hz, 4H), 2.69 (t, J = 7.1 Hz, 4H), 2.42 (t, J = 7.1 Hz, 4H), 2.31 - 2.20 (m, 4H), 2.03 - 1.92 (m, 8H), 1.63 - 1.38 (m, 10H).

[0317] ESI-MS m / z [M+H] + = 1131.5

[0318] Example 24: Synthesis of compound C1

[0319] Compound A1-10 (0.36 g, 0.63 mmol) was dissolved in DMF (2 ml), to which TEA (0.13 g, 1.26 mmol) and CDI (0.10 g, 0.63 mmol) were added, after addition, the system was stirred at room temperature for 1 h. After monitoring the complete conversion to the active intermediate, C1-1 (19.00 mg, 0.31 mmol) was added to the reaction solution, after addition, the system was reacted at 60 °C for 6 h. After the reaction was completed, the precipitated triethylamine hydrochloride was filtered off, and the filtrate was concentrated to remove most of the DMF to obtain the crude product. The crude product was dissolved in analytical methanol and purified by semi-preparative high performance liquid chromatography (separation conditions: column: Thermo HYPERSIL PREP HS C18 150 x 10 mm 10 μm; column temperature: 30 °C; mobile phase: water (containing 10 mmol / L NH4HCO3) - methanol; gradient: methanol: 50% - 90% 10 min, 90%, 10 min; flow rate: 8 ml / min), and the solution was freeze-dried to obtain compound C1 as a white powder.

[0320] 1H NMR (400 MHz, CD3OD) δ 7.59 (s, 2H), 4.78 (t, J = 8.8 Hz, 4H), 3.93 - 3.82 (m, 2H), 3.62 (s, 8H), 3.55 (t, J = 5.4 Hz, 4H), 3.51 (t, J = 5.5 Hz, 4H), 3.38 (t, J = 5.4 Hz, 4H), 3.28 (t, J = 5.4 Hz, 4H), 3.19 (s, 4H), 3.09 (t, J = 8.7 Hz, 4H), 2.88 (d, J = 12.0 Hz, 4H), 2.69 (t, J = 7.1 Hz, 4H), 2.41 (t, J = 7.1 Hz, 4H), 2.27 (t, J = 11.0 Hz, 4H), 2.03 - 1.92 (m, 4H), 1.65 - 1.51 (m, 4H).

[0321] ESI-MS m / z [M+H] + = 1107.5

[0322] Example 25: Synthesis of compound C2

[0323] The title compound was prepared in analogy to Example 24 using hexanediamine instead of C1-1 (ethylenediamine), which resulted in compound C2 as a white powder.

[0324] 1 H NMR (400 MHz, CD3OD) δ 7.59 (s, 2H), 4.78 (t, J = 8.8 Hz, 4H), 3.93 - 3.82 (m, 2H), 3.62 (s, 8H), 3.55 (t, J = 5.4 Hz, 4H), 3.51 (t, J = 5.5 Hz, 4H), 3.38 (t, J = 5.4 Hz, 4H), 3.28 (t, J = 5.4 Hz, 4H), 3.09 (t, J = 7.6 Hz, 8H), 2.94 - 2.81 (m, 4H), 2.69 (t, J = 7.1 Hz, 4H), 2.41 (t, J = 7.0 Hz, 4H), 2.26 (t, J = 10.6 Hz, 4H), 1.98 (dd, J = 13.0, 3.9 Hz, 4H), 1.63 - 1.53 (m, 4H), 1.50 - 1.42 (m, 4H), 1.36 - 1.29 (m, 4H).

[0325] ESI-MS m / z [M+H] + = 1163.6

[0326] Example 26: Synthesis of compound C3

[0327] The title compound was prepared in analogy to Example 24 using p-phenylenediamine instead of CI-1 (ethylenediamine), yielding compound C3 as a white powder.

[0328] 1 H NMR (400 MHz, CD3OD) δ 7.59 (s, 2H), 7.24 (s, 4H), 4.76 (t, J = 8.8 Hz, 4H), 3.90 - 3.80 (m, 2H), 3.63 (s, 8H), 3.56 (t, J = 5.3 Hz, 8H), 3.37 (t, J = 5.3 Hz, 8H), 3.07 (t, J = 8.7 Hz, 4H), 2.84 (d, J = 11.5 Hz, 4H), 2.67 (t, J = 7.1 Hz, 4H), 2.39 (t, J = 7.1 Hz, 4H), 2.23 (t, J = 11.1 Hz, 4H), 2.00 - 1.90 (m, 4H), 1.61 - 1.50 (m, 4H).

[0329] ESI-MS m / z [M+H] + = 1155.5

[0330] Example 27: Synthesis of compound C4

[0331] The title compound was prepared in analogy to Example 24 using trans-1,4- cyclohexanediamine instead of CI-1 (ethylenediamine), yielding compound C4 as a white powder.

[0332] 1 H NMR (400 MHz, CD3OD) δ 7.62 (s, 2H), 4.81 (t, J = 8.7 Hz, 4H), 4.23 - 4.07 (m, 2H), 3.63 (s, 12H), 3.61 - 3.49 (m, 12H), 3.47 - 3.34 (m, 12H), 3.18 (q, J = 9.4, 8.3 Hz, 8H), 2.86 - 2.76 (m, 4H), 2.25 (d, J = 13.6 Hz, 4H), 2.07 - 1.85 (m, 8H), 1.47 - 1.36 (m, 4H).

[0333] ESI-MS m / z [M+H] + = 1161.6

[0334] Example 28: Synthesis of compound C5

[0335] The title compound was prepared in analogy to Example 24 using cis-1,4- cyclohexanediamine instead of CI-1 (ethylenediamine), yielding compound C5 as a white powder.

[0336] 1 H NMR (400 MHz, CD3OD) δ 7.59 (s, 2H), 4.78 (t, J = 8.7 Hz, 4H), 3.95 - 3.80 (m, 2H), 3.62 (s, 10H), 3.55 (t, J = 5.4 Hz, 4H), 3.51 (t, J = 5.4 Hz, 4H), 3.38 (t, J = 5.4 Hz, 4H), 3.28 (d, J = 5.4 Hz, 4H), 3.08 (t, J = 8.7 Hz, 4H), 2.87 (d, J = 11.7 Hz, 4H), 2.69 (t, J = 7.1 Hz, 4H), 2.41 (t, J = 7.0 Hz, 4H), 2.34 - 2.17 (m, 4H), 2.03 - 1.92 (m, 4H), 1.72 - 1.64 (m, 4H), 1.63 - 1.51 (m, 8H).

[0337] ESI-MS m / z [M+H] + = 1161.6

[0338] Example 29: Synthesis of compound C6

[0339] The title compound was prepared in analogy to Example 24 using piperazine instead of C1-1 (ethylenediamine) to give compound C6 as a white powder.

[0340] 1 H NMR (400 MHz, CD3OD) δ 7.59 (s, 2H), 4.78 (t, J = 8.8 Hz, 4H), 3.94 - 3.82 (m, 2H), 3.62 (s, 8H), 3.54 (dt, J = 9.8, 5.5 Hz, 8H), 3.40 - 3.32 (m, 16H), 3.08 (t, J = 8.7 Hz, 4H), 2.90 (d, J = 11.7 Hz, 4H), 2.71 (t, J = 7.0 Hz, 4H), 2.42 (t, J = 7.0 Hz, 4H), 2.35 - 2.23 (m, 4H), 2.03 - 1.92 (m, 4H), 1.66 - 1.51 (m, 4H).

[0341] ESI-MS m / z [M+H] + = 1133.5

[0342] Example 30: Synthesis of compound C7

[0343] The title compound was prepared in analogy to Example 24 using 2,6-diazaspiro[3,3]heptane instead of C1-1 (ethylenediamine) to give compound C7 as a white powder.

[0344] 1 H NMR (400 MHz, CD3OD) δ 7.59 (s, 2H), 4.78 (t, J = 8.8 Hz, 4H), 4.01 (s, 8H), 3.95 - 3.82 (m, 2H), 3.61 (s, 8H), 3.56 (t, J = 5.4 Hz, 4H), 3.50 (t, J = 5.8 Hz, 4H), 3.38 (t, J = 5.4 Hz, 4H), 3.28 (t, J = 5.7 Hz, 4H), 3.09 (t, J = 8.7 Hz, 4H), 2.94 (d, J = 11.9 Hz, 4H), 2.75 (t, J = 7.0 Hz, 4H), 2.44 (t, J = 7.0 Hz, 4H), 2.34 (t, J = 11.1 Hz, 4H), 2.00 (dd, J = 13.0, 3.7 Hz, 4H), 1.68 - 1.54 (m, 4H).

[0345] ESI-MS m / z [M+H] + = 1145.5

[0346] Example 31: Synthesis of compound C8

[0347] The title compound was prepared in analogy to example 24 using trans-1,3- cyclobutanediamine instead of C1-1 (ethylenediamine) to give compound C8 as a white powder.

[0348] 1 H NMR (400 MHz, CD3OD) δ 7.59 (s, 2H), 4.78 (t, J = 8.8 Hz, 4H), 4.95 - 3.85 (m, 2H), 3.61 (s, 8H), 3.55 (t, J = 5.4 Hz, 4H), 3.49 (t, J = 5.5 Hz, 4H), 3.38 (t, J = 5.4 Hz, 4H), 3.30 - 3.20 (m, 4H), 3.09 (t, J = 8.7 Hz, 4H), 2.94 (d, J = 11.7 Hz, 4H), 2.76 (t, J = 7.0 Hz, 4H), 2.45 (t, J = 7.0 Hz, 4H), 2.36 (t, J = 11.3 Hz, 4H), 2.05 - 1.92 (m, 6H), 1.72 - 1.55 (m, 6H), 1.36 - 1.15 (m, 6H).

[0349] ESI-MS m / z [M+H] + = 1161.6

[0350] Example 32: Synthesis of compound C9

[0351] The title compound was prepared in analogy to Example 24 by using trans-1,3- cyclohexanediamine instead of CI-1 (ethylenediamine) to afford compound C9 as a white powder.

[0352] 1 H NMR (400 MHz, CD3OD) δ 7.59 (s, 2H), 4.78 (t, J = 8.8 Hz, 4H), 4.20 - 4.10 (m, 2H), 3.94 - 3.81 (m, 2H), 3.61 (s, 8H), 3.55 (t, J = 5.4 Hz, 4H), 3.50 (t, J = 5.4 Hz, 4H), 3.38 (t, J = 5.4 Hz, 4H), 3.28 (t, J = 5.4 Hz, 4H), 3.08 (t, J = 8.7 Hz, 4H), 2.88 (d, J = 10.5 Hz, 4H), 2.70 (t, J = 7.1 Hz, 4H), 2.42 (t, J = 7.0 Hz, 4H), 2.34 - 2.23 (m, 4H), 2.20 (t, J = 6.6 Hz, 4H), 2.03 - 1.93 (m, 4H), 1.64 - 1.53 (m, 4H).

[0353] ESI-MS m / z [M+H] + = 1133.5

[0354] Example 33: Synthesis of compound D1

[0355] Step one: Synthesis of compound D1-2

[0356] Compound A1-7 (2.00 g, 5.44 mmol) was dissolved in DMF (30 ml), and EDCI (1.56 g, 8.16 mmol), HOBt (1.10 g, 8.16 mmol) and TEA (1.10 g, 10.88 mmol) were added. The reaction mixture was stirred at room temperature (25 °C) for 0.5 h. To the above reaction solution, D1-1 (1.20 g, 5.98 mmol) was added, and the reaction mixture was stirred at 25 °C for 4 h. After the reaction was completed, 10 times volume of H2O (300 ml) was added to the reaction solution, and a large amount of white solid was precipitated, which was filtered and dried to obtain white solid compound D1-2, which was used in the next step without further purification.

[0357] 1H NMR (400 MHz, CDC13) δ 8.46 (d, J = 7.7 Hz, 1H), 7.83 (s, 1H), 7.25 (s, 1H), 4.80 (t, J = 8.7 Hz, 2H), 4.29 (s, 2H), 4.00 - 3.91 (m, 2H), 3.06 (t, J = 8.7 Hz, 2H), 2.99 - 2.81 (m, 4H), 2.62 (t, J = 6.0 Hz, 2H), 2.37 (t, J = 6.0 Hz, 2H), 2.24 (t, J = 11.3 Hz, 2H), 2.08 - 1.99 (m, 4H), 1.94 - 1.85 (m, 2H), 1.55 - 1.47 (m, 2H), 1.45 (s, 9H), 1.38 - 1.26 (m, 2H).

[0358] ESI-MS m / z [M+H] + = 550.3

[0359] Step two: synthesis of compound D1-3

[0360] The compound D1-2 crude (2.00 g, 3.85 mmol) was dissolved in MeOH (20 ml), HCl EA solution (2 mol / L, 5.77 ml, 11.55 mmol) was added dropwise at 0 °C, after adding, the reaction was stirred at 40 °C overnight. After the reaction was completed, white solid was precipitated, suction filtration, and the filter cake was dried to obtain white solid compound D1-3, which was directly used in the next step without further purification, the yield of the first two steps was 88%.

[0361] 1 H NMR (400 MHz, CDC13) δ 8.46 (d, J = 7.7 Hz, 1H), 7.83 (s, 1H), 7.25 (s, 1H), 4.80 (t, J = 8.7 Hz, 2H), 4.29 (s, 2H), 4.00 - 3.91 (m, 2H), 3.06 (t, J = 8.7 Hz, 2H), 2.99 - 2.81 (m, 4H), 2.62 (t, J = 6.0 Hz, 2H), 2.37 (t, J = 6.0 Hz, 2H), 2.24 (t, J = 11.3 Hz, 2H), 2.08 - 1.99 (m, 4H), 1.94 - 1.85 (m, 2H), 1.55 - 1.47 (m, 2H), 1.45 (s, 9H), 1.38 - 1.26 (m, 2H).

[0362] ESI-MS m / z [M+H] + = 550.3

[0363] Step three: synthesis of compound D1-5

[0364] Compound D1-3 (2.00 g, 3.36 mmol) was dissolved in DMF (20 ml), K2CO3 (1.39 g, 10.07 mmol) and catalytic amount of NaI (50.00 mg, 0.34 mmol) were added, D1-4 (0.99 g, 3.70 mmol) was added, the reaction mixture was heated to 80 °C, and stirred at 80 °C for 2 h. Upon completion of the reaction, the reaction was cooled to room temperature, water (40 ml) was added to dilute the reaction and extracted with EA (40 ml x 3), the combined organic layer was washed with water (120 ml x 3), washed with saturated brine (120 ml x 2), the organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was separated by normal phase silica gel column chromatography (DCM / MeOH = 40:1-20:1), and dried under vacuum to give compound D1-5 (1.90 g, yield 89%) as a colorless oil.

[0365] 1 H NMR (400 MHz, CDCl3) δ 8.46 (d, J = 7.9 Hz, 1H), 7.82 (s, 1H), 7.26 (d, J = 7.9 Hz, 1H), 5.09 (s, 1H), 4.81 (t, J = 8.7 Hz, 2H), 4.30 (s, 2H), 4.05-3.91 (m, 1H), 3.86-3.70 (m, 1H), 3.57 (t, J = 5.7 Hz, 2H), 3.49 (t, J = 5.2 Hz, 2H), 3.28 (q, J = 5.4 Hz, 2H), 3.06 (t, J = 8.7 Hz, 2H), 2.86 (d, J = 11.4 Hz, 4H), 2.58 (q, J = 5.3 Hz, 4H), 2.34 (t, J = 5.9 Hz, 2H), 2.19 (t, J = 11.3 Hz, 4H), 2.07-1.99 (m, 2H), 1.95-1.88 (m, 2H), 1.55-1.45 (m, 4H), 1.41 (s, 9H).

[0366] ESI-MS m / z [M+H] + = 637.3

[0367] Step four: synthesis of compound D1-6

[0368] Compound D1-5 (1.00 g, 1.57 mmol) was dissolved in MeOH (10 ml), HCl EA solution (2 mol / L, 2.35 ml, 4.71 mmol) was added dropwise at 0 °C, after the addition was completed, the reaction was stirred at 40 °C overnight. Upon completion of the reaction, the reaction was directly dried under vacuum to give compound D1-6 as an oil, which was directly used in the next step without further purification.

[0369] 1H NMR (400 MHz, CD3OD) δ 7.59 (s, 1H), 4.78 (t, J = 8.8 Hz, 2H), 3.93 - 3.81 (m, 1H), 3.72 - 3.64 (m, 1H), 3.61 (t, J = 5.6 Hz, 2H), 3.49 (t, J = 5.3 Hz, 2H), 3.09 (t, J = 8.7 Hz, 2H), 2.99 - 2.91 (m, 2H), 2.87 (d, J = 10.4 Hz, 2H), 2.80 (t, J = 5.3 Hz, 2H), 2.68 (t, J = 7.2 Hz, 2H), 2.61 (t, J = 5.6 Hz, 2H), 2.38 (t, J = 7.2 Hz, 2H), 2.32 - 2.14 (m, 4H), 2.03 - 1.93 (m, 2H), 1.92 - 1.82 (m, 2H), 1.64 - 1.47 (m, 4H).

[0370] ESI-MS m / z [M+H] + = 537.3

[0371] Step four: synthesis of compound D1

[0372] Compound D1-6 (0.30 g, 0.44 mmol) was dissolved in DMF (2 ml), to which TEA (45.00 mg, 0.88 mmol) and CDI (78.00 mg, 0.48 mmol) were added, after addition, the system was stirred at room temperature for 1 h. After monitoring by sampling that the complete conversion to the active intermediate, D1-7 (25.00 mg, 0.22 mmol) was added to the reaction solution, after addition, the system was reacted at 60 °C for 6 h. After the reaction was completed, the precipitated triethylamine hydrochloride was removed by suction filtration, and the filtrate was concentrated to remove most of the DMF to obtain a crude product. The crude product was dissolved in analytical methanol and purified by semi-preparative high performance liquid chromatography (separation conditions: column: Thermo HYPERSIL PREP HS C18 150 x 10 mm 10 μm; column temperature: 30 °C; mobile phase: water (containing 0.1% TFA) - methanol; gradient: methanol: 20% - 80% 30 min; flow rate: 5 ml / min), and the solution was freeze-dried to obtain compound D1 as a light yellow powder.

[0373] 1H NMR (400 MHz, CD3OD) δ 7.58 (s, 2H), 4.78 (t, J = 8.7 Hz, 4H), 4.17 - 4.06 (m, 2H), 4.00 - 3.87 (m, 2H), 3.79 (t, J = 5.3 Hz, 4H), 3.66 (d, J = 12.5 Hz, 6H), 3.53 (t, J = 5.1 Hz, 6H), 3.43 (t, J = 7.1 Hz, 6H), 3.39 - 3.31 (m, 8H), 3.19 - 3.06 (m, 10H), 2.85 - 2.70 (m, 4H), 2.31 - 2.11 (m, 8H), 2.06 - 1.76 (m, 12H), 1.42 - 1.13 (m, 6H).

[0374] ESI-MS m / z [M+H] + = 1239.7

[0375] Example 34: Synthesis of compound E1

[0376] Step one: Synthesis of compound E1-2

[0377] Compound A1-7 (2.00 g, 5.44 mmol) was dissolved in DMF (30 ml), and EDCI (1.56 g, 8.16 mmol), HOBt (1.10 g, 8.16 mmol) and TEA (1.65 g, 16.32 mmol) were added. The reaction mixture was stirred at room temperature (25 °C) for 0.5 h. To the above reaction solution, the hydrochloride salt of E1-1 (0.81 g, 5.98 mmol) was added, and the reaction mixture was stirred at 25 °C for 4 h. After the reaction was completed, 10 times the volume of H2O (300 ml) was added to the reaction solution, and a large amount of white solid was precipitated, which was filtered and dried to obtain white solid compound E1-2, which was used directly in the next step without further purification.

[0378] 1 H NMR (400 MHz, CD3OD) δ 7.58 (s, 2H), 4.78 (t, J = 8.7 Hz, 4H), 4.17 - 4.06 (m, 2H), 4.00 - 3.87 (m, 2H), 3.79 (t, J = 5.3 Hz, 4H), 3.66 (d, J = 12.5 Hz, 6H), 3.53 (t, J = 5.1 Hz, 6H), 3.43 (t, J = 7.1 Hz, 6H), 3.39 - 3.31 (m, 8H), 3.19 - 3.06 (m, 10H), 2.85 - 2.70 (m, 4H), 2.31 - 2.11 (m, 8H), 2.06 - 1.76 (m, 12H), 1.42 - 1.13 (m, 6H).

[0379] ESI-MS m / z [M+H] + = 449.2

[0380] Step two: synthesis of compound E1-4

[0381] Compound E1-2 (2.00 g, 4.45 mmol) was dissolved in DCM (30 ml) under nitrogen protection, DIPEA (0.58 g, 4.45 mmol) and DCM solution of E1-3 (1.17 g, 5.35 mmol) were added. NaBH(OAc)3 (1.42 g, 6.68 mmol) was added portionwise, after addition, the reaction mixture was stirred at room temperature (25 °C) for 4 h. After the reaction was completed, the reaction was quenched with water (30 ml) and extracted with DCM (20 ml x 3), the combined organic layer was washed with saturated brine (60 ml), the organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was separated by basic alumina column chromatography (DCM / MeOH = 60:1-20:1), rotary evaporation to give compound E1-4 as a light yellow oil.

[0382] 1 H NMR (400 MHz, CDCl3) δ 7.80 (s, 1H), 7.26 (d, J = 7.9 Hz, 1H), 4.74 (t, J = 8.7 Hz, 2H), 4.69-4.57 (m, 1H), 4.31 (s, 2H), 4.04-3.94 (m, 1H), 3.90 (d, J = 14.8 Hz, 1H), 3.64 (t, J = 5.0 Hz, 1H), 3.54-3.44 (m, 5H), 3.31-3.22 (m, 3H), 3.05 (d, J = 9.3 Hz, 3H), 2.84 (d, J = 10.9 Hz, 2H), 2.77-2.69 (m, 2H), 2.61 (t, J = 5.8 Hz, 2H), 2.56-2.54 (m, 2H), 2.33-2.22 (m, 5H), 2.03-1.95 (m, 2H), 1.88-1.73 (m, 2H), 1.63-1.50 (m, 2H), 1.41 (s, 9H), 1.39-1.34 (m, 2H).

[0383] ESI-MS m / z [M+H] + = 651.4

[0384] Step three: synthesis of compound E1-5

[0385] Compound E1-4 (1.00 g, 1.54 mmol) was dissolved in MeOH (10 ml), HCl in EA (2 mol / L, 3.07 ml, 6.14 mmol) was added dropwise at 0 °C, after addition, the reaction was stirred at 40 °C overnight. After the reaction was completed, it was directly rotary evaporated to obtain oily compound E1-5, which was directly used in the next step without further purification.

[0386] 1 H NMR (400 MHz, CD3OD) δ 7.59 (s, 1H), 4.78 (t, J = 8.8 Hz, 2H), 4.63 - 4.55 (m, 1H), 4.11 - 4.00 (m, 1H), 3.94 - 3.82 (m, 1H), 3.57 (t, J = 5.7 Hz, 2H), 3.48 (t, J = 5.3 Hz, 2H), 3.14 - 3.04 (m, 3H), 2.88 (d, J = 10.9 Hz, 2H), 2.78 (t, J = 5.3 Hz, 2H), 2.74 - 2.65 (m, 5H), 2.66 - 2.53 (m, 3H), 2.35 - 2.22 (m, 5H), 2.03 - 1.81 (m, 4H), 1.63 - 1.51 (m, 2H), 1.50 - 1.43 (m, 1H), 1.39 - 1.29 (m, 1H).

[0387] ESI-MS m / z [M+H] + = 551.3

[0388] Step four: synthesis of compound E1

[0389] Compound E1-5 (0.30 g, 0.45 mmol) was dissolved in DMF (2 ml), TEA (138.00 mg, 1.36 mmol) and CDI (81.00 mg, 0.50 mmol) were added, after addition, the system was stirred at room temperature for 1 h. After the sample was monitored to be completely converted into the active intermediate, D1-7 (25.00 mg, 0.22 mmol) was added to the reaction solution, after addition, the system was reacted at 60 °C for 6 h. After the reaction was completed, the precipitated triethylamine hydrochloride was removed by suction filtration, and the filtrate was concentrated to remove most of the DMF to obtain a crude product. The crude product was dissolved in analytical methanol and purified by semi-preparative high performance liquid chromatography (separation conditions: column: Thermo HYPERSIL PREP HS C18 150 x 10 mm 10 μm; column temperature: 30 °C; mobile phase: water (containing 0.1% TFA) - methanol; gradient: methanol: 20% - 80% 30 min; flow rate: 5 ml / min), and the solution was freeze-dried to obtain compound E1 as a light yellow powder.

[0390] 1H NMR (400 MHz, CD3OD) δ 7.58 (s, 2H), 4.78 (t, J = 8.8 Hz, 4H), 4.17 - 4.06 (m, 4H), 3.80 (t, J = 5.0 Hz, 4H), 3.71 (d, J = 12.5 Hz, 4H), 3.65 - 3.59 (m, 2H), 3.55 (t, J = 4.9 Hz, 8H), 3.44 (t, J = 6.7 Hz, 8H), 3.27 - 3.13 (m, 8H), 3.09 (t, J = 8.7 Hz, 4H), 3.03 - 2.94 (m, 4H), 2.89 (s, 6H), 2.75 - 2.66 (m, 2H), 2.25 (d, J = 12.8 Hz, 4H), 2.19 - 2.05 (m, 6H), 1.98 - 1.88 (m, 6H), 1.87 - 1.75 (m, 4H), 1.71 - 1.61 (m, 2H), 1.36 - 1.20 (m, 6H).

[0391] ESI-MS m / z [M+H] + = 1267.7

[0392] Example 35: Synthesis of compound A15

[0393] The title compound was prepared in analogy to example 7 using 4-bromobutanoic acid methyl ester instead of A1-5 (methyl 3-bromopropionate), which resulted in compound A15 as a white powder.

[0394] 1 H NMR (400 MHz, CD3OD) δ 7.59 (s, 2H), 4.78 (t, J = 8.8 Hz, 4H), 3.93 - 3.81 (m, 2H), 3.61 (s, 8H), 3.53 (dt, J = 5.5, 11.0 Hz, 8H), 3.36 (t, J = 5.5 Hz, 4H), 3.29 (d, J = 5.5 Hz, 4H), 3.08 (t, J = 8.7 Hz, 4H), 2.89 (d, J = 12.7 Hz, 4H), 2.41 (t, J = 7.5 Hz, 4H), 2.24 (t, J = 7.3 Hz, 8H), 1.97 (dd, J = 3.6, 13.4 Hz, 4H), 1.82 (p, J = 7.4 Hz, 4H), 1.65 - 1.50 (m, 4H).

[0395] ESI-MS m / z [M+H] + = 1049.5

[0396] Example 36: Synthesis of compound A16

[0397] The title compound was prepared in analogy to example 35 by using N-tert- butoxycarbonyl-1,2-ethanediamine instead of A1-8 (tert-butyl 2-(2-(2- aminoethoxy)ethoxy)ethylcarbamate) as white powder.

[0398] 1 H NMR (400 MHz, CD3OD) δ 7.58 (s, 2H), 4.77 (t, J = 8.8 Hz, 4H), 3.95 - 3.81 (m, 2H), 3.25 (dt, J = 4.9, 10.0 Hz, 8H), 3.08 (t, J = 8.8 Hz, 4H), 2.90 (d, J = 11.1 Hz, 4H), 2.42 (t, J = 7.5 Hz, 4H), 2.23 (t, J = 7.4 Hz, 8H), 1.97 (dd, J = 3.8, 12.6 Hz, 4H), 1.82 (dt, J = 7.4, 14.9 Hz, 4H), 1.66 - 1.51 (m, 4H).

[0399] ESI-MS m / z [M+H] + = 873.4

[0400] Example 37: Synthesis of compound A17

[0401] The title compound was prepared in analogy to example 10 by using 3,6,9,12,15,18-hexaoxaeicosane-1,20-diamine instead of A16-1 (2,2'-oxobisethylamine) as white powder.

[0402] 1 H NMR (400 MHz, CD3OD) δ 7.59 (s, 2H), 4.78 (t, J = 8.8 Hz, 4H), 3.91 - 3.82 (m, 2H), 3.64 - 3.58 (m, 20H), 3.54 (t, J = 5.4 Hz, 4H), 3.37 (t, J = 5.3 Hz, 4H), 3.08 (t, J = 8.7 Hz, 4H), 2.87 (d, J = 11.4 Hz, 4H), 2.68 (t, J = 7.0 Hz, 4H), 2.40 (t, J = 7.0 Hz, 4H), 2.23 (dt, J = 12.1, 6.0 Hz, 4H), 1.97 (dd, J = 13.3, 3.5 Hz, 4H), 1.62 - 1.53 (m, 4H).

[0403] ESI-MS m / z [M+H] + = 1023.5

[0404] Example 38: Synthesis of compound A18

[0405] The title compound was prepared in analogy to Example 10 using 3,6,9,12,15,18,21- heptaoxatricosane-1,23-diamine instead of A16-1 (2,2'-oxobisethylamine), yielding compound A18 as a white powder.

[0406] 1 H NMR (400 MHz, CD3OD) δ 7.59 (s, 2H), 4.78 (t, J = 8.8 Hz, 4H), 3.91 - 3.80 (m, 2H), 3.64 - 3.57 (m, 24H), 3.54 (t, J = 5.3 Hz, 4H), 3.37 (t, J = 5.3 Hz, 4H), 3.08 (t, J = 8.7 Hz, 4H), 2.87 (d, J = 11.2 Hz, 4H), 2.67 (t, J = 7.0 Hz, 4H), 2.40 (t, J = 7.0 Hz, 4H), 2.28 - 2.18 (m, 4H), 1.96 (dt, J = 12.1, 3.9 Hz, 4H), 1.62 - 1.52 (m, 4H).

[0407] ESI-MS m / z [M+H] + = 1067.5

[0408] Example 39: Synthesis of compound D2

[0409] The title compound was prepared in analogy to Example 33 using butanediamine instead of D1 -7 (trans-1,4-cyclohexyl diamine), yielding compound D2 as a white powder.

[0410] 1 H NMR (400 MHz, CD3OD) δ 7.58 (s, 2H), 4.78 (t, J = 8.7 Hz, 4H), 4.14 - 4.07 (m, 2H), 3.99 - 3.89 (m, 2H), 3.80 (t, J = 4.7 Hz, 4H), 3.67 (d, J = 12.5 Hz, 8H), 3.54 (t, J = 5.2 Hz, 8H), 3.43 (t, J = 7.0 Hz, 4H), 3.15 - 3.06 (m, 16H), 2.75 (t, J = 7.0 Hz, 4H), 2.26 (d, J = 13.4 Hz, 4H), 2.16 (d, J = 14.6 Hz, 6H), 1.94 - 1.75 (m, 8H), 1.52 - 1.47 (m, 4H).

[0411] ESI-MS m / z [M+H] + = 1213.6

[0412] Example 40: Synthesis of compound D3

[0413] The title compound was prepared in analogy to Example 33 using 1-tert- butyloxycarbonyl-4-aminomethylpiperidine instead of A1-2 (1-tert-butoxycarbonyl-4- aminopiperidine), which resulted in compound D3 as a white powder.

[0414] 1 H NMR (400 MHz, CD3OD) δ 7.63 (s, 2H), 4.83 (t, J = 8.7 Hz, 4H), 4.14 - 3.89 (m, 2H), 3.84 (q, J = 4.8 Hz, 4H), 3.74 - 3.53 (m, 12H), 3.52 - 3.44 (m, 4H), 3.44 - 3.32 (m, 16H), 3.25 - 3.10 (m, 7H), 3.02 (t, J = 12.6 Hz, 3H), 2.92 - 2.74 (m, 4H), 2.15 (d, J = 14.0 Hz, 4H), 1.97 (q, J = 13.3, 11.8 Hz, 14H), 1.62 (q, J = 11.2 Hz, 4H), 1.47 - 1.34 (m, 4H).

[0415] ESI-MS m / z [M+H] + = 1267.7

[0416] Example 41: Synthesis of compound D4

[0417] The title compound was prepared in analogy to Example 33 using 4-bromobutanoic acid methyl ester instead of A1-5 (methyl 3-bromopropionate), which resulted in compound D4 as a white powder.

[0418] 1 H NMR (400 MHz, CD3OD) δ 7.64 (s, 2H), 4.83 (t, J = 8.6 Hz, 4H), 4.22 - 3.91 (m, 4H), 3.85 (s, 4H), 3.69 (d, J = 11.5 Hz, 6H), 3.61 (t, J = 4.5 Hz, 4H), 3.52 (d, J = 20.4 Hz, 4H), 3.47 - 3.34 (m, 9H), 3.28 - 3.08 (m, 15H), 2.52 (d, J = 7.7 Hz, 1H), 2.43 (t, J = 6.6 Hz, 3H), 2.26 (d, J = 13.5 Hz, 4H), 2.16 (d, J = 14.4 Hz, 4H), 2.12 - 2.04 (m, 4H), 2.04 - 1.80 (m, 12H), 1.42 (t, J = 8.8 Hz, 4H).

[0419] ESI-MS m / z [M+H] + = 1267.7

[0420] Example 42: Synthesis of compound D5

[0421] The title compound was prepared in analogy to Example 33 using 1-tert-butoxycarbonyl-4-aminomethylpiperidine instead of A1-2 (1-tert-butoxycarbonyl-4-aminopiperidine) and methyl 6-bromohexanoate instead of A1-5 (methyl 3-bromopropionate), which resulted in compound D5 as a white powder.

[0422] 1 H NMR (400 MHz, CD3OD) δ 7.59 (s, 2H), 4.78 (t, J = 8.8 Hz, 4H), 3.69 - 3.62 (m, 2H), 3.59 (t, J = 5.5 Hz, 4H), 3.46 (t, J = 5.3 Hz, 4H), 3.44 - 3.37 (m, 2H), 3.30 - 3.24 (m, 8H), 3.13 - 3.03 (m, 8H), 2.96 (d, J = 12.2 Hz, 4H), 2.60 (t, J = 5.5 Hz, 4H), 2.52 - 2.41 (m, 4H), 2.23 - 2.11 (m, 12H), 1.98 - 1.89 (m, 4H), 1.84 (dd, J = 13.4, 3.9 Hz, 4H), 1.80 - 1.73 (m, 4H), 1.65 - 1.51 (m, 12H), 1.40 - 1.23 (m, 14H).

[0423] ESI-MS m / z [M+H] + = 1351.8

[0424] Example 43: Synthesis of compound D6

[0425] The title compound was prepared in analogy to Example 33 using 1-tert-butoxycarbonyl-4-aminomethylpiperidine instead of A1-2 (1-tert-butoxycarbonyl-4-aminopiperidine), which resulted in compound D6 as a white powder.

[0426] 1H NMR (400 MHz, CD3OD) δ 7.64 (s, 2H), 4.83 (t, J = 8.7 Hz, 4H), 3.87 - 3.80 (m, 4H), 3.79 - 3.64 (m, 8H), 3.60 (t, J = 5.2 Hz, 4H), 3.57 - 3.45 (m, 8H), 3.41 (t, J = 5.0 Hz, 6H), 3.36 (d, J = 5.7 Hz, 8H), 3.25 - 3.17 (m, 8H), 3.13 (s, 2H), 3.01 (t, J = 12.3 Hz, 4H), 2.23 - 2.10 (m, 4H), 2.05 - 1.86 (m, 14H), 1.61 (q, J = 12.9, 12.2 Hz, 4H), 1.49 - 1.36 (m, 4H).

[0427] ESI-MS m / z [M+H] + = 1297.7

[0428] Example 44: Synthesis of compound D7

[0429] The title compound was prepared in analogy to example 33 using 4-bromobutanoic acid methyl ester instead of A1-5 (3-bromopropionic acid methyl ester), N-Boc-5-bromo-1-pentylamine instead of D1-4 (bromo-mono- polyethylene glycol-amino tert-butyl ester), to yield compound D7 as a white powder.

[0430] 1 H NMR (400 MHz, CD3OD) δ 7.61 (s, 2H), 4.81 (t, J = 7.2 Hz, 4H), 4.05 (d, J = 70.6 Hz, 4H), 3.66 (t, J = 14.3 Hz, 6H), 3.51 (s, 4H), 3.23 - 3.07 (m, 22H), 2.53 (s, 1H), 2.42 (t, J = 6.6 Hz, 3H), 2.26 (d, J = 13.2 Hz, 4H), 2.16 (d, J = 11.5 Hz, 4H), 2.06 (s, 6H), 2.00 - 1.78 (m, 16H), 1.61 (s, 4H), 1.42 (s, 8H).

[0431] ESI-MS m / z [M+H] + = 1263.7

[0432] Example 45: Synthesis of compound D8

[0433] The title compound was prepared in analogy to example 33 using 4-bromobutyric acid methyl ester instead of A1-5 (3-bromopropionic acid methyl ester), N-Boc- bromoethylamine instead of D1-4 (bromo-mono-PEG-amino tert-butyl ester), which yielded compound D8 as a white powder.

[0434] 1 H NMR (400 MHz, CD3OD) δ 7.64 (s, 2H), 4.83 (t, J = 8.6 Hz, 4H), 4.16 (d, J = 13.9 Hz, 2H), 3.97 (t, J = 9.9 Hz, 2H), 3.70 (t, J = 11.6 Hz, 6H), 3.61 - 3.33 (m, 10H), 3.30 - 3.04 (m, 18H), 2.53 (s, 1H), 2.44 (t, J = 6.3 Hz, 3H), 2.22 (dd, J = 32.1, 12.3 Hz, 8H), 2.12 - 1.80 (m, 16H), 1.36 - 1.28 (m, 4H).

[0435] ESI-MS m / z [M+H] + = 1179.6

[0436] Example 46: Synthesis of compound E2

[0437] The title compound was prepared in analogy to example 34 using butanediamine instead of D1-7 (trans-1,4-cyclohexyl diamine), which yielded compound E2 as a white powder.

[0438] 1 H NMR (400 MHz, CD3OD) δ 7.59 (s, 2H), 4.79 (t, J = 8.7 Hz, 4H), 4.60 (d, J = 13.7 Hz, 2H), 4.05 (d, J = 15.8 Hz, 2H), 3.95 - 3.83 (m, 2H), 3.58 (t, J = 5.6 Hz, 4H), 3.48 (t, J = 5.4 Hz, 4H), 3.28 (d, J = 5.4 Hz, 4H), 3.14 - 3.07 (m, 8H), 2.91 (d, J = 12.2 Hz, 4H), 2.77 - 2.70 (m, 8H), 2.65 - 2.60 (m, 4H), 2.36 (s, 6H), 2.29 (d, J = 11.1 Hz, 2H), 2.08 - 1.94 (m, 6H), 1.92 - 1.85 (m, 2H), 1.64 - 1.55 (m, 4H), 1.51 - 1.47 (m, 4H), 1.38 - 1.26 (m, 12H).

[0439] ESI-MS m / z [M+H] + = 1241.7

[0440] Example 47: Synthesis of compound F1

[0441] The title compound was prepared in analogy to Example 5 using N-Boc-bromoethylamine instead of A1-5 (methyl 3-bromopropionate), N-tert-butoxycarbonyl-dipolyethylene glycol- carboxylic acid instead of A1-8 (tert-butyl 2-(2-(2-aminoethoxy)ethoxy)ethylcarbamate), to yield compound F1 as a white powder.

[0442] 1 H NMR (400 MHz, CD3OD) δ 7.62 (s, 2H), 4.82 (t, J = 8.6 Hz, 4H), 3.76 (t, J = 6.0 Hz, 4H), 3.70 (d, J = 11.5 Hz, 4H), 3.61 (d, J = 4.0 Hz, 12H), 3.56 (t, J = 4.9 Hz, 4H), 3.37 (dd, J = 9.4, 5.2 Hz, 8H), 3.29 - 3.14 (m, 12H), 3.03 (t, J = 12.3 Hz, 4H), 2.53 (t, J = 5.8 Hz, 4H), 2.00 (d, J = 14.8 Hz, 6H), 1.71 - 1.51 (m, 8H).

[0443] ESI-MS m / z [M+H] + = 1163.6

[0444] Example 48: Synthesis of compound F2

[0445] The title compound was prepared in analogy to Example 47 using trans-1,4- cyclohexyl diamine instead of butanediamine to yield compound F2 as a white powder.

[0446] 1 H NMR (400 MHz, CD3OD) δ 7.63 (s, 2H), 4.83 (t, J = 8.7 Hz, 4H), 3.76 (t, J = 5.9 Hz, 4H), 3.71 (s, 4H), 3.62 (d, J = 4.7 Hz, 12H), 3.57 (t, J = 5.0 Hz, 4H), 3.53 - 3.47 (m, 2H), 3.40 - 3.35 (m, 8H), 3.27 (t, J = 5.7 Hz, 4H), 3.20 (t, J = 8.6 Hz, 4H), 3.04 (t, J = 12.4 Hz, 4H), 2.54 (t, J = 5.9 Hz, 4H), 1.99 (t, J = 10.7 Hz, 10H), 1.77 - 1.53 (m, 4H), 1.46 - 1.35 (m, 4H).

[0447] ESI-MS m / z [M+H] + = 1189.6

[0448] Example 49: Synthesis of compound F3

[0449] The title compound was prepared in analogy to Example 5 using N-tert- butyloxycarbonyl-dipolyethylene glycol-carboxylic acid instead of A1-8 (tert- butyl 2-(2-(2-aminoethoxy)ethoxy)ethylcarbamate) as a white powder.

[0450] 1 H NMR (400 MHz, CD3OD) δ 7.59 (s, 2H), 4.77 (t, J = 8.8 Hz, 4H), 3.87 (t, J = 6.2 Hz, 4H), 3.63 - 3.59 (m, 4H), 3.58 - 3.54 (m, 4H), 3.46 (t, J = 5.4 Hz, 4H), 3.26 (q, J = 5.9, 5.4 Hz, 8H), 3.16 - 3.06 (m, 12H), 3.01 (dt, J = 12.2, 3.3 Hz, 4H), 2.86 (t, J = 7.5 Hz, 4H), 2.46 - 2.37 (m, 4H), 2.07 (td, J = 11.9, 2.5 Hz, 4H), 1.80 (dd, J = 15.3, 7.8 Hz, 4H), 1.67 - 1.55 (m, 6H), 1.51 - 1.46 (m, 4H), 1.41 - 1.29 (m, 10H).

[0451] ESI-MS m / z [M+H] + = 1297.7

[0452] Example 50: Synthesis of compound F4

[0453] The title compound was prepared in analogy to Example 47 using tert- butyl 2-(2-(2-aminoethoxy)ethoxy)ethylcarbamate instead of N-tert- butyloxycarbonyl-dipolyethylene glycol-carboxylic acid as a white powder.

[0454] 1H NMR (400 MHz, CD3OD) δ 7.64 (s, 2H), 4.83 (t, J = 8.7 Hz, 4H), 3.69 (d, J = 11.9 Hz, 4H), 3.63 (s, 8H), 3.59 (t, J = 5.3 Hz, 4H), 3.56 - 3.51 (m, 8H), 3.41 (t, J = 5.3 Hz, 4H), 3.35 (dd, J = 10.8, 5.8 Hz, 8H), 3.27 - 3.18 (m, 12H), 3.01 (t, J = 12.1 Hz, 4H), 2.05 - 1.90 (m, 6H), 1.66 - 1.51 (m, 8H).

[0455] ESI-MS m / z [M+H] + = 1193.6

[0456] Example 51: Synthesis of compound F5

[0457] The title compound was prepared in analogy to Example 50 using trans-1,4- cyclohexyl diamine instead of butanediamine to yield compound F5 as a white powder.

[0458] 1 H NMR (400 MHz, CD3OD) δ 7.63 (s, 2H), 4.82 (t, J = 8.7 Hz, 4H), 3.69 (d, J = 11.7 Hz, 4H), 3.62 (s, 8H), 3.58 (t, J = 5.1 Hz, 4H), 3.56 - 3.48 (m, 10H), 3.42 - 3.32 (m, 12H), 3.20 (q, J = 8.6, 7.8 Hz, 8H), 3.01 (t, J = 12.4 Hz, 4H), 2.09 - 1.91 (m, 10H), 1.61 (q, J = 11.6 Hz, 4H), 1.48 - 1.36 (m, 4H).

[0459] ESI-MS m / z [M+H] + = 1219.6

[0460] Example 52: Synthesis of compound F6

[0461] The title compound was prepared in analogy to Example 50 using N-Boc-5- bromo-1-pentylamine instead of N-Boc-bromoethylamine to yield compound F6 as a white powder.

[0462] 1H NMR (400 MHz, CD3OD) δ 7.59 (s, 2H), 4.77 (t, J = 8.8 Hz, 4H), 3.59 (s, 8H), 3.51 (t, J = 5.4 Hz, 8H), 3.28 (t, J = 5.5 Hz, 12H), 3.14 - 3.00 (m, 16H), 2.49 - 2.37 (m, 4H), 2.10 (td, J = 12.0, 2.6 Hz, 4H), 1.75 (dd, J = 13.8, 3.5 Hz, 4H), 1.70 - 1.60 (m, 2H), 1.58 - 1.46 (m, 12H), 1.38 - 1.29 (m, 8H).

[0463] ESI-MS m / z [M+H] + = 1277.7

[0464] Example 53: Synthesis of compound G1

[0465] Step one: synthesis of compound G1-3

[0466] Intermediate G1-1 (1.00 g, 2.88 mmol) was dissolved in DCM (20 ml) under nitrogen protection, DIPEA (0.37 g, 2.88 mmol) and G1-2 (0.74 g, 3.45 mmol) were added, the pH of the reaction solution was adjusted to 5.0 with glacial acetic acid, and stirred at room temperature for 1 hour. NaBH(OAc)3 (0.92 g, 4.32 mmol) was added portionwise to the reaction mixture, after addition, the reaction mixture was stirred at room temperature (25 °C) for 4 hours. After the reaction was completed, the reaction was quenched with water (30 ml) and extracted with DCM (20 ml x 3), the combined organic layer was washed with saturated brine (60 ml), the organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was separated by basic alumina column chromatography (DCM / MeOH = 60:1-20:1), and rotary evaporation to give white foaming compound G1-3 (1.37 g, yield 94%).

[0467] 1H NMR (400 MHz, CDC13) δ 7.84 (s, 1H), 7.38 (t, J = 5.9 Hz, 1H), 4.76 (t, J = 8.7 Hz, 2H), 4.27 (s, 2H), 4.12 - 4.00 (m, 2H), 3.29 (t, J = 6.3 Hz, 2H), 3.05 (t, J = 8.7 Hz, 2H), 2.83 (dt, J = 11.8, 3.2 Hz, 2H), 2.66 (t, J = 12.5 Hz, 2H), 2.12 (d, J = 6.9 Hz, 2H), 1.88 (t, J = 11.6 Hz, 2H), 1.72 - 1.66 (m, 4H), 1.64 - 1.52 (m, 2H), 1.43 (s, 9H), 1.34 - 1.23 (m, 2H), 1.09 - 0.98 (m, 2H).

[0468] ESI-MS m / z [M+H] + = 507.3.

[0469] Step two: synthesis of compound G1-4

[0470] Intermediate G1-3 (2.00 g, 3.95 mmol) was dissolved in EA (20 ml), HCl EA solution (2 mol / L, 5.90 ml, 11.85 mmol) was added dropwise at 0 °C, after the addition was completed, the reaction was stirred at 40 °C overnight. After the reaction was completed, white solid was precipitated, suction filtration, the filter cake was dried to give white solid intermediate G1-4, which was used directly in the next step without further purification.

[0471] 1 H NMR (400 MHz, CDC13) δ 7.84 (s, 1H), 7.38 (t, J = 5.9 Hz, 1H), 4.76 (t, J = 8.7 Hz, 2H), 4.27 (s, 2H), 4.12 - 4.00 (m, 2H), 3.29 (t, J = 6.3 Hz, 2H), 3.05 (t, J = 8.7 Hz, 2H), 2.83 (dt, J = 11.8, 3.2 Hz, 2H), 2.66 (t, J = 12.5 Hz, 2H), 2.12 (d, J = 6.9 Hz, 2H), 1.88 (t, J = 11.6 Hz, 2H), 1.72 - 1.66 (m, 4H), 1.64 - 1.52 (m, 2H), 1.43 (s, 9H), 1.34 - 1.23 (m, 2H), 1.09 - 0.98 (m, 2H).

[0472] ESI-MS m / z [M+H] + = 507.3.

[0473] Step three: synthesis of compound G1-5

[0474] Intermediate G1-4 (2.12 g, 4.42 mmol) was dissolved in DMF (30 ml) at room temperature, K2CO3 (1.83 g, 13.25 mmol) and a catalytic amount of NaI (66.00 mg, 0.44 mmol) were added, D1-4 (1.42 g, 5.30 mmol) was added, and the reaction mixture was heated to 80 °C and stirred for 3 h. After the reaction was completed, the reaction was cooled to room temperature, water (60 ml) was added to dilute the reaction, and EA (60 ml x 3) was used to extract, the organic layers were combined, washed with water (180 ml x 3), washed with saturated brine (180 ml x 2), the organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated by normal phase silica gel column chromatography (DCM / MeOH = 40:1-20:1), and dried under vacuum to obtain white foaming intermediate G1-5 (2.49 g, yield 95%).

[0475] 1 H NMR (400 MHz, CDCl3) δ 7.86 (s, 1H), 7.39 (t, J = 6.0 Hz, 1H), 4.78 (t, J = 8.6 Hz, 2H), 4.26 (s, 2H), 3.59 (t, J = 4.8 Hz, 2H), 3.51 (t, J = 5.4 Hz, 2H), 3.30 (t, J = 5.4 Hz, 4H), 3.07 (t, J = 8.7 Hz, 2H), 2.96 (d, J = 11.4 Hz, 2H), 2.86 (d, J = 11.4 Hz, 2H), 2.57 (t, J = 4.9 Hz, 2H), 2.16 (dd, J = 7.0, 2.1 Hz, 2H), 2.02 (t, J = 11.7 Hz, 5H), 1.90 (t, J = 11.6 Hz, 3H), 1.72 (t, J = 14.2 Hz, 5H), 1.44 (s, 9H), 1.34-1.31 (m, 2H).

[0476] ESI-MS m / z [M+H] + = 594.3.

[0477] Step four: synthesis of compound G1-6

[0478] Intermediate G1-5 (1.00 g, 1.68 mmol) was dissolved in EA (20 ml), and HCl EA solution (2 mol / L, 2.50 ml, 5.05 mmol) was added dropwise at 0 °C, after addition, the reaction was stirred at 40 °C overnight. After the reaction was completed, white solid was precipitated, and the filter cake was dried to obtain white solid intermediate G1-6, which was directly used in the next step without further purification.

[0479] 1H NMR (400 MHz, Methanol-d4) δ 7.60 (s, 1H), 4.80 (t, J = 8.7 Hz, 2H), 3.90 (t, J = 4.8 Hz, 2H), 3.78 (t, J = 4.8 Hz, 2H), 3.68 (s, 4H), 3.40 (t, J = 4.4 Hz, 2H), 3.36 (d, J = 5.8 Hz, 2H), 3.20 (t, J = 4.7 Hz, 3H), 3.12 (t, J = 7.8 Hz, 5H), 3.00 (t, J = 12.5 Hz, 2H), 2.31 (s, 1H), 2.11 (d, J = 13.6 Hz, 2H), 2.03 - 1.85 (m, 5H), 1.75 - 1.62 (m, 2H).

[0480] ESI-MS m / z [M+H] + = 494.3.

[0481] Step five: synthesis of compound G1

[0482] The title compound was prepared in analogy to example 7 using Boc-amino- monoethyleneglycol-carboxylic acid instead of D1-4 (bromo-mono polyethyleneglycol- amino tert-butyl ester) to give compound G1 as a white powder.

[0483] 1 H NMR (400 MHz, CD3OD) δ 7.59 (s, 2H), 4.77 (t, J = 8.8 Hz, 4H), 3.60 (t, J = 5.6 Hz, 4H), 3.47 (t, J = 5.3 Hz, 4H), 3.30 - 3.24 (m, 8H), 3.08 (t, J = 8.8 Hz, 4H), 3.00 (dt, J = 12.0, 3.3 Hz, 4H), 2.91 (dt, J = 11.7, 3.4 Hz, 4H), 2.62 (t, J = 5.6 Hz, 4H), 2.20 (d, J = 6.9 Hz, 4H), 2.11 (td, J = 12.0, 2.6 Hz, 4H), 1.94 (td, J = 11.9, 2.5 Hz, 4H), 1.79 - 1.67 (m, 8H), 1.62 - 1.51 (m, 4H), 1.35 - 1.24 (m, 8H).

[0484] ESI-MS m / z [M+H] + = 1013.6

[0485] Example 54: synthesis of compound G2

[0486] The title compound was prepared in analogy to example 53 using Boc-amino- monoethyleneglycol-carboxylic acid instead of D1-4 (bromo-mono polyethyleneglycol- amino tert-butyl ester) to give compound G2 as a white powder.

[0487] 1 H NMR (400 MHz, CD3OD) δ 7.59 (s, 2H), 4.77 (t, J = 8.8 Hz, 4H), 4.50 (d, J = 13.1 Hz, 2H), 3.97 (d, J = 13.6 Hz, 2H), 3.71 (t, J = 6.2 Hz, 4H), 3.48 (t, J = 5.4 Hz, 4H), 3.27 (t, J = 5.6 Hz, 8H), 3.08 (t, J = 8.8 Hz, 5H), 2.92 (d, J = 9.6 Hz, 4H), 2.64 (q, J = 6.1 Hz, 5H), 2.18 (d, J = 6.5 Hz, 4H), 1.99 - 1.89 (m, 4H), 1.88 - 1.65 (m, 11H), 1.62 - 1.51 (m, 2H), 1.38 - 1.26 (m, 5H), 1.17 - 0.97 (m, 4H).

[0488] ESI-MS m / z [M+H] + = 1069.5

[0489] Example 55: Synthesis of compound G3

[0490] The title compound was prepared in analogy to Example 53 using trans-1,4- cyclohexyl diamine instead of CDI to give compound G3 as a white powder.

[0491] 1 H NMR (400 MHz, CD3OD) δ 7.59 (s, 2H), 4.78 (t, J = 8.8 Hz, 4H), 3.59 (t, J = 5.5 Hz, 4H), 3.46 (t, J = 5.3 Hz, 4H), 3.27 (t, J = 6.1 Hz, 8H), 3.09 (t, J = 8.8 Hz, 4H), 2.99 (dt, J = 12.3, 3.3 Hz, 4H), 2.91 (dt, J = 12.1, 3.3 Hz, 4H), 2.60 (t, J = 5.5 Hz, 4H), 2.19 (d, J = 6.8 Hz, 4H), 2.09 (t, J = 11.0 Hz, 4H), 1.99 - 1.89 (m, 8H), 1.78 - 1.67 (m, 8H), 1.62 - 1.52 (m, 4H), 1.36 - 1.20 (m, 14H).

[0492] ESI-MS m / z [M+H] + = 1153.6

[0493] Example 56: Synthesis of compound G4

[0494] The title compound was prepared in analogy to Example 54 using trans-1,4- cyclohexyl diamine instead of CDI to give compound G4 as a white powder.

[0495] 1 H NMR (400 MHz, CD3OD) δ 7.59 (s, 2H), 4.78 (t, J = 8.7 Hz, 4H), 4.50 (d, J = 13.2 Hz, 2H), 3.97 (d, J = 13.7 Hz, 2H), 3.70 (t, J = 6.2 Hz, 4H), 3.47 (t, J = 5.3 Hz, 4H), 3.27 (dt, J = 7.2, 4.2 Hz, 8H), 3.09 (t, J = 8.7 Hz, 5H), 2.96 (d, J = 9.6 Hz, 4H), 2.66 - 2.59 (m, 5H), 2.24 (d, J = 6.6 Hz, 4H), 2.00 (t, J = 9.5 Hz, 4H), 1.93 (d, J = 6.1 Hz, 4H), 1.87 - 1.68 (m, 10H), 1.64 - 1.53 (m, 2H), 1.40 - 1.20 (m, 12H), 1.16 - 0.99 (m, 4H).

[0496] ESI-MS m / z [M+H] + = 1231.6

[0497] Example 57: Synthesis of compound G5

[0498] The title compound was prepared in analogy to Example 55 using 1 -Boc-4- piperidinone instead of G1 -2 (N-Boc-4-piperidinylcarboxaldehyde) to give compound G5 as a white powder.

[0499] 1 H NMR (400 MHz, CD3OD) δ 7.59 (s, 2H), 4.78 (t, J = 8.8 Hz, 4H), 3.58 (t, J = 5.5 Hz, 4H), 3.49 - 3.40 (m, 6H), 3.30 - 3.24 (m, 8H), 3.1 1 - 3.00 (m, 12H), 2.59 (t, J = 5.5 Hz, 4H), 2.36 (tt, J = 1 1.8, 3.7 Hz, 2H), 2.26 (td, J = 1 1.8, 2.5 Hz, 4H), 2.08 (t, J = 1 1.7 Hz, 4H), 1.93 (dt, J = 9.1, 3.9 Hz, 4H), 1.89 - 1.83 (m, 4H), 1.81 - 1.73 (m, 4H), 1.66 - 1.55 (m, 6H), 1.35 - 1.24 (m, 8H).

[0500] ESI-MS m / z [M+H]+ = 1125.6

[0501] Example 58: Synthesis of compound G6

[0502] The title compound was prepared in analogy to Example 55 using N-Boc-4-piperidine acetaldehyde instead of G1-2 (N-Boc-4-piperidine carboxaldehyde) to give compound G6 as a white powder.

[0503] 1 H NMR (400 MHz, CD3OD) d 7.59 (s, 2H), 4.78 (t, J = 8.7 Hz, 4H), 3.61 (t, J = 5.5 Hz, 4H), 3.48 - 3.39 (m, 6H), 3.30 - 3.25 (m, 8H), 3.12 - 2.99 (m, 12H), 2.66 (t, J = 5.3 Hz, 4H), 2.53 - 2.41 (m, 4H), 2.26 - 2.02 (m, 8H), 1.93 (d, J = 6.0 Hz, 4H), 1.80 - 1.70 (m, 8H), 1.68 - 1.59 (m, 2H), 1.54 - 1.43 (m, 4H), 1.38 - 1.25 (m, 14H).

[0504] ESI-MS m / z [M+H] + = 1181.7

[0505] Example 59: Synthesis of compound A19

[0506] The title compound was prepared in analogy to Example 1 using 4-amino-5-chloro-2- methoxybenzoic acid instead of A1-1 (4-amino-5-chloro-2,3-dihydrobenzofuran-7- carboxylic acid) to give compound A19 as a white powder.

[0507] 1H NMR (400 MHz, CD3OD) δ 7.79 (s, 2H), 6.50 (s, 2H), 3.91 (s, 6H), 3.90 - 3.83 (m, 2H), 3.60 (s, 8H), 3.55 (t, J = 5.4 Hz, 4H), 3.50 (t, J = 5.5 Hz, 4H), 3.37 (t, J = 5.4 Hz, 4H), 3.28 (t, J = 5.4 Hz, 4H), 3.15 - 3.07 (m, 4H), 2.84 (d, J = 11.5 Hz, 4H), 2.69 (t, J = 7.2 Hz, 4H), 2.42 (t, J = 7.1 Hz, 4H), 2.27 (t, J = 11.0 Hz, 4H), 2.02 - 1.92 (m, 4H), 1.65 - 1.54 (m, 4H), 1.52 - 1.43 (m, 4H).

[0508] ESI-MS m / z [M+H] + = 1111.5

[0509] Example 60: Synthesis of compound A20

[0510] The title compound was prepared in analogy to Example 1 using 1-tert- butyloxycarbonyl-4-aminomethylpiperidine instead of A1-2 (N-BOC-4- aminopiperidine) to give compound A20 as a white powder.

[0511] 1 H NMR (400 MHz, CD3OD) δ 7.59 (s, 2H), 4.78 (t, J = 8.7 Hz, 4H), 3.59 (s, 8H), 3.51 (dt, J = 13.2, 5.4 Hz, 8H), 3.36 (t, J = 5.4 Hz, 4H), 3.30 - 3.24 (m, 8H), 3.15 - 3.07 (m, 8H), 2.97 (dt, J = 12.1, 3.3 Hz, 4H), 2.66 (t, J = 7.1 Hz, 4H), 2.40 (t, J = 7.1 Hz, 4H), 2.05 (t, J = 10.9 Hz, 4H), 1.74 (d, J = 12.0 Hz, 4H), 1.64 - 1.55 (m, 2H), 1.50 - 1.45 (m, 4H), 1.37 - 1.29 (m, 4H).

[0512] ESI-MS m / z [M+H] + = 1185.6

[0513] Example 61: Synthesis of compound A21

[0514] The title compound was prepared in analogy to Example 1 by using tert-butyl [2-(2- aminoethoxy)ethoxy] carbamate instead of A1-8 (tert-butyl 2-(2-(2- aminoethoxy)ethoxy)ethylcarbamate) as a white powder.

[0515] 1 H NMR (400 MHz, CD3OD) δ 7.58 (s, 2H), 4.77 (t, J = 8.8 Hz, 4H), 3.60 (s, 8H), 3.52 (dt, J = 13.4, 5.5 Hz, 8H), 3.42 - 3.34 (m, 8H), 3.28 (t, J = 5.4 Hz, 4H), 3.13 - 3.05 (m, 8H), 3.02 - 2.96 (m, 4H), 2.72 (t, J = 7.2 Hz, 4H), 2.45 - 2.40 (m, 4H), 2.12 (t, J = 10.9 Hz, 4H), 1.78 (d, J = 11.1 Hz, 4H), 1.56 - 1.45 (m, 8H), 1.40 - 1.27 (m, 6H).

[0516] ESI-MS m / z [M+H] + = 1191.6

[0517] Example 62: Synthesis of compound A23

[0518] The title compound was prepared in analogy to Example 1 by using tert-butyl [2-(2- aminoethoxy)ethoxy] carbamate instead of A1-8 (tert-butyl 2-(2-(2- aminoethoxy)ethoxy)ethylcarbamate) as a white powder.

[0519] 1 H NMR (400 MHz, CD3OD) δ 7.58 (s, 2H), 4.77 (t, J = 8.8 Hz, 4H), 3.60 (s, 8H), 3.52 (dt, J = 13.4, 5.5 Hz, 8H), 3.42 - 3.34 (m, 8H), 3.28 (t, J = 5.4 Hz, 4H), 3.13 - 3.05 (m, 8H), 3.02 - 2.96 (m, 4H), 2.72 (t, J = 7.2 Hz, 4H), 2.45 - 2.40 (m, 4H), 2.12 (t, J = 10.9 Hz, 4H), 1.78 (d, J = 11.1 Hz, 4H), 1.56 - 1.45 (m, 8H), 1.40 - 1.27 (m, 6H).

[0520] ESI-MS m / z [M+H] + = 1047.5

[0521] Example 63: Synthesis of compound A24

[0522] The title compound was prepared in analogy to Example 1 by using tert-butyl 2-(2-(2-(2- aminoethoxy)ethoxy)ethoxy)ethylcarbamate instead of A1-8 (tert-butyl 2-(2-(2- aminoethoxy)ethoxy)ethylcarbamate) to yield compound A24 as a white powder.

[0523] 1 H NMR (400 MHz, CD3OD) δ 7.59 (s, 2H), 4.78 (t, J = 8.8 Hz, 4H), 3.92 - 3.82 (m, 2H), 3.66 - 3.60 (m, 12H), 3.60 - 3.57 (m, 4H), 3.55 (t, J = 5.5 Hz, 4H), 3.49 (t, J = 5.4 Hz, 4H), 3.37 (t, J = 5.4 Hz, 4H), 3.27 (t, J = 5.4 Hz, 4H), 3.13 - 3.05 (m, 8H), 2.87 (d, J = 11.5 Hz, 4H), 2.68 (t, J = 7.1 Hz, 4H), 2.41 (t, J = 7.1 Hz, 4H), 2.25 (t, J = 10.5 Hz, 4H), 2.03 - 1.93 (m, 4H), 1.63 - 1.53 (m, 4H), 1.50 - 1.44 (m, 4H).

[0524] ESI-MS m / z [M+H] + = 1223.6

[0525] Example 64: Synthesis of compound B11

[0526] The title compound was prepared in analogy to Example 15 by using fumaric acid instead of B1-1 (succinic acid) to yield compound B11 as a white powder.

[0527] 1 H NMR (400 MHz, CD3OD) δ 7.58 (s, 2H), 6.90 (s, 2H), 4.77 (t, J = 8.8 Hz, 4H), 3.93 - 3.82 (m, 2H), 3.62 (s, 8H), 3.56 (dt, J = 12.2, 5.5 Hz, 8H), 3.45 (t, J = 5.4 Hz, 4H), 3.37 (t, J = 5.4 Hz, 4H), 3.08 (t, J = 8.8 Hz, 4H), 2.89 (d, J = 11.5 Hz, 4H), 2.71 (t, J = 7.1 Hz, 4H), 2.42 (t, J = 7.0 Hz, 4H), 2.28 (t, J = 10.6 Hz, 4H), 1.98 (dd, J = 13.0, 3.8 Hz, 4H), 1.65 - 1.52 (m, 4H).

[0528] ESI-MS m / z [M+H] + = 1075.5

[0529] Example 65: Synthesis of compound C12

[0530] The title compound was prepared in analogy to Example 5 by using trans-N-{4-[(imidazol-1- ylcarbonyl)amino]cyclohexyl}imidazole-1-carboxamide instead of A1-11 (isocyclohexanamide), which yielded compound C12 as a white powder.

[0531] 1 H NMR (400 MHz, CD3OD) δ 7.64 (s, 2H), 4.83 (t, J = 8.7 Hz, 4H), 3.63 (s, 10H), 3.61 - 3.48 (m, 12H), 3.46 - 3.33 (m, 12H), 3.21 (t, J = 8.6 Hz, 4H), 3.15 - 3.06 (m, 4H), 2.98 (t, J = 12.6 Hz, 4H), 2.35 (t, J = 7.2 Hz, 4H), 2.07 - 1.88 (m, 10H), 1.86 - 1.74 (m, 4H), 1.75 - 1.54 (m, 8H), 1.51 - 1.37 (m, 8H).

[0532] ESI-MS m / z [M+H] + = 1273.7

[0533] Example 66: Synthesis of compound F7

[0534] The title compound was prepared in analogy to Example 47 by using 1-tert-butoxycarbonyl-4- aminopiperidine instead of 1-tert-butoxycarbonyl-4-aminomethylpiperidine, which yielded compound F7 as a white powder.

[0535] 1H NMR (400 MHz, CD3OD) δ 7.58 (s, 2H), 4.77 (t, J = 8.8 Hz, 4H), 3.91 - 3.81 (m, 2H), 3.73 (t, J = 6.1 Hz, 4H), 3.59 (s, 8H), 3.50 (t, J = 5.4 Hz, 4H), 3.34 (t, J = 6.8 Hz, 4H), 3.28 (t, J = 5.4 Hz, 4H), 3.14 - 3.05 (m, 8H), 2.87 (d, J = 12.2 Hz, 4H), 2.51 (t, J = 6.8 Hz, 4H), 2.45 (t, J = 6.1 Hz, 4H), 2.25 (t, J = 10.5 Hz, 4H), 2.00 - 1.91 (m, 4H), 1.65 - 1.51 (m, 4H), 1.51 - 1.43 (m, 4H).

[0536] ESI-MS m / z [M+H] + = 1135.5

[0537] Example 67: Synthesis of compound F8

[0538] The title compound was prepared in analogy to Example 47 using N-BOC-5- bromo-1-pentylamine instead of N-Boc-bromoethylamine as a white powder.

[0539] 1 H NMR (400 MHz, CD3OD) δ 7.59 (s, 2H), 4.77 (t, J = 8.8 Hz, 4H), 3.72 (t, J = 6.1 Hz, 4H), 3.58 (s, 8H), 3.49 (t, J = 5.4 Hz, 4H), 3.27 (t, J = 5.4 Hz, 8H), 3.18 (t, J = 7.0 Hz, 4H), 3.13 - 3.06 (m, 8H), 3.02 (d, J = 11.9 Hz, 4H), 2.45 - 2.39 (m, 8H), 2.08 (t, J = 11.1 Hz, 4H), 1.75 (d, J = 12.2 Hz, 4H), 1.69 - 1.60 (m, 2H), 1.57 - 1.46 (m, 12H), 1.38 - 1.29 (m, 8H).

[0540] ESI-MS m / z [M+H] + = 1247.7

[0541] Example 1: Ability of compounds to activate 5-HT4receptors in HEK293 cells

[0542] A variety of methods, including in vitro and in vivo methods, can be used to measure the activity of the compounds of the present application. The following assay can be used to determine the ability of the example compounds to activate 5-HT4receptors.

[0543] Human embryonic kidney cells 293 (HEK293, provided by Shanghai GenScript Biotech Co., Ltd.) expressing full-length human 5-HT4receptors were cultured in DMEM containing 10% dialyzed fetal bovine serum (DFBS), 1% penicillin-streptomycin and 400 pg / ml geneticin (G418) according to the manufacturer's protocol and stored as frozen aliquots for use as cells for assays. On the day of the assay, cells were removed from liquid nitrogen tanks, resuspended in HBSS Hanks' Balanced Salt Buffer (Invitrogen) and washed once with HBSS Hanks' Balanced Salt Buffer (Invitrogen) before resuspension to 2 x 105cells / mL in assay buffer. Test compound solutions at a starting concentration of 10 mM were gradient diluted using a Bravo (Agilent) and transferred to 5 pL to a 384-well plate (PerkinElmer) followed by the addition of 1000 cells per well for a total volume of 10 pL. Cells and test compounds were incubated in the dark at room temperature for 30 minutes and cAMP levels were measured using a Cisbio cAMP assay kit according to the manufacturer's protocol. Anti-cAMP antibody and d2-cAMP tracer diluted in assay buffer were incubated in the dark at room temperature for 1 hour and results were measured on an Envision plate reader (PerkinElmer). Data were normalized using 1 mM 5-HT (Sigma Aldrich) as 100% activity and DMSO alone as 0% activity. Positive control 5-HT was at a starting concentration of 1 mM with a 4-fold gradient dilution and test compounds were at a starting concentration of 10 mM with a 3-fold gradient dilution with 10 test concentrations per sample, double replicates and three independent experiments. 5 50 50

[0544] The ability of the example compounds to activate 5-HT4receptors was evaluated using the above method. Table 1 lists the EC50values from the 5-HT4agonist assay for a portion of the example compounds. 50 where a smaller EC 50 value represents a higher potency.

[0545] Table 1. 5-HT4agonist assay

[0546] As can be seen from Table 1, the compounds of the present application have a good ability to activate 5-HT4receptors, with some of the compounds having a potency comparable to or slightly better than the positive drug Prucalopride.

[0547] Using the above detection conditions, the EC50values of the 5-HT4agonist assay of some of the example compounds were determined 50 As shown in Table 2 below:

[0548] Table 2. 5-HT4agonist assay

[0549] As shown in Table 2, the compounds of the present application have better ability to activate 5-HT4receptors, and some of the compounds have better potency than the positive drug Prucalopride.

[0550] Investigation of the in vitro permeability of the compounds of Example 2

[0551] In this study, the in vitro permeability (P e ) of the compounds was preliminarily evaluated using the parallel artificial membrane permeability assay (PAMPA) technique. 10 μL of a clear solution containing 5% (W / V) lecithin / dodecane was precisely pipetted onto the polyvinylidene fluoride (PVDF) hydrophobic membrane in each well of the donor plate. After uniform coating, 150 μL of a 5% DMSO / PBS buffer containing 10 μM of the test drug was added to each well of the donor plate, with 3 replicates in each group. 300 μL of 5% DMSO / PBS buffer was added to each well of the polytetrafluoroethylene (PTFE) receiver plate, after which the donor plate was placed on the receiver plate to ensure that the liquid in the receiver plate was in full contact with the artificial membrane. The lid was then closed, and the receiver plate was incubated at room temperature at 300 rpm for 4 h. After 4 h, the two plates were carefully separated, and samples were taken from the donor plate and the receiver plate. The drug concentrations in the donor plate and the receiver plate were determined by LC-MS / MS, and the in vitro permeability (P e ) of the compounds was calculated using the following formula. [drug]equilibrium=([drug] donor ×V D +[drug] acceptor ×V A ) / (V D +V A )

[0552] The test results showed that the PAMPA P e <0.185 nm / s, indicating that the compound has little trans-biological membrane property.

[0553] Table 3. In vitro permeability assay of the compounds

[0554] Investigation of the stability of the compounds in in vitro digestive juice in Example 3

[0555] Simulated Gastric Fluid (SGF, pH = 1.5) and Simulated Intestinal Fluid (SIF, pH = 6.8) were prepared according to the Chinese Pharmacopoeia. 285 μL of SGF or SIF was taken and 15 μL of Compound A5 stock solution (50 μg / ml in water) was added, the mixed solution was vortexed for 1 min, and then incubated at 37 °C on a shaker (120 rpm). Equal amounts of solution (50 μL) were extracted at 0 min, 30 min, 1 h, 2 h, 6 h and 24 h, and then diluted with 200 μL of analytical methanol. The samples were centrifuged, and the supernatant (100 μL, compound concentration about 500 ng / ml) was analyzed by LC-MS / MS. The content of Compound A5 in the solution was determined by the peak area size, and expressed as a percentage of the peak area at the 0 h time point (results in Table 4). Compound curve fitting used one-phase decay, and the compound half-life (t 1 / 2 ) was determined from the degradation curve and calculated using GraphPad Prism 10. The experimental results are shown in Figure 1, and Compound A5 has good stability in Simulated Gastric Fluid and Simulated Intestinal Fluid, with a degradation half-life t 1 / 2 > 24 h.

[0556] Table 4

[0557] As can be seen from Table 4, the compound provided by the present application can stably exist in the in vitro digestive fluid, and has a long degradation half-life.

[0558] Using the above detection conditions, the stability of Compound G3 was determined as shown in Table 5 below:

[0559] Table 5 Stability of Compound G3 in SGF and SIF within 0-24 hours

[0560] As can be seen from Table 5, the compound provided by the present application can stably exist in the in vitro digestive fluid, and has a long degradation half-life.

[0561] Example 4 Preliminary pharmacokinetic properties of the compound

[0562] Six male C57BL / 6J mice aged 7-9 weeks (provided by Yinuos Biotechnology Haimen Co., Ltd.) were fasted for 12 hours before drug administration, with free access to water. Free access to food and drink was resumed 12 hours after drug administration, i.e., after the last blood collection. Compound A5 was administered orally by gavage at a dose of 10 mg / kg. Blood samples were collected from the orbital vein at seven time points: 0h, 0.5h, 1h, 2h, 4h, 8h, and 12h. Six animals were divided into groups of three, with alternating blood collection. Approximately 50 μL of whole blood was collected at each time point. The whole blood was collected into tubes containing EDTA-K2 anticoagulant, immediately and gently inverted several times to mix thoroughly, placed at room temperature, and then centrifuged at 4°C (approximately 3000g, 5min). Centrifugation of samples at each time point was completed within 2 hours after collection. The collected plasma was transferred to labeled EP tubes (stored at -80°C for 1 hour). For plasma samples, proteins in 30 μL of plasma were precipitated with 120 μL of methanol containing an internal standard, vortexed, centrifuged, and the supernatant was collected for LC-MS / MS analysis. Drug production curves were obtained for N=3 animals at each time point. GraphPad Prism 10 was used to analyze the relationship between drug concentration and time and to calculate relevant pharmacokinetic parameters such as AUC. The test results are shown in Figure 2. At a dose of 10 mg / kg of compound A5, the maximum concentration C of the drug reaching the bloodstream was... max The concentration was 8.4 ng / mL, and the AUC was... 0- t The concentration was 18.8 ng / mL*h. After oral administration of the compound, the concentration of the original drug in the blood was less than one ten-thousandth of the total dose, and it basically did not enter the blood in the form of the original drug.

[0563] Experimental Example 5: The ability of the compound to promote whole intestinal transport

[0564] Male C57BL / 6J mice aged 6-8 weeks (provided by Yinuosi Biotechnology Haimen Co., Ltd.) were used as mice. Mice were orally administered 300 μL of the following mixture by gavage: 0.5% methylcellulose (Sigma Aldrich), 1%... Polyoxyethylene stearate (Sigma Aldrich), 5 mM citric acid monohydrate (Sigma Aldrich), and 6% carmine (Sigma Aldrich) were added to tap water at varying doses. Mice were then placed in individual cages without bedding but allowed free access to food and napaganol. TM The presence of carmine in fecal pellets was monitored every 5 minutes. When carmine dye was detected in the first fecal pellet, the total gastrointestinal transit time was measured. The total gastrointestinal transit time was considered to be the time interval between the start of tube feeding and the first observation of carmine in the feces.

[0565] The ability of the compounds to promote whole gut transit was evaluated using the above method. Figure 3 shows the ability of different doses of compound A5 and the positive drug prucalopride to promote whole gut transit in mice compared to the blank control group, where the more the time of reducing whole gut transit is reduced, the higher the ability of the compound to promote whole gut transit. Compound A5 (10 / 15 mg / kg) significantly reduced the time of ejection of the red bezoar in mice after administration compared to the blank control group, accelerating the rate of whole gut transit, and the efficacy between the 4 dose groups was dose-dependent, with the 3 / 10 / 15 mg / kg dose group being more effective than the 10 mg / kg positive drug prucalopride succinate.

[0566] Figure 8 shows the ability of different doses of compound G3 and the positive drug prucalopride to promote whole gut transit in mice compared to the blank control group, where the more the time of reducing whole gut transit is reduced, the higher the ability of the compound to promote whole gut transit. Compound G3 (1 / 3 mg / kg) significantly reduced the time of ejection of the red bezoar in mice after administration compared to the blank control group, accelerating the rate of whole gut transit.

[0567] Example 6 Effect of the ability of the compound to promote distal colon motility

[0568] 5-HT4 receptors are most highly expressed in the distal colon of mice, and the mouse steel ball test was used to evaluate the motility of the distal colon. Male C57BL / 6J mice aged 6-8 weeks (provided by Yinosu Biotechnology Co., Ltd., Haimen) were used, and the mice were orally administered with 100 μl of drug-containing vehicle or blank vehicle (blank vehicle formula as in Example 5). After a delay of 1 h, the mice were lightly anesthetized with isoflurane (1-2 min), and a glass bead with a diameter of 2.3 mm was inserted into the distal colon 20 mm with a blunt gavage needle. After inserting the bead, the mice were isolated in cages without food and water. The measurement of colon motility was based on the time the animal was able to stand independently, and the time from the animal waking up to the ejection of the glass bead was recorded, with the shorter the time, the faster the colon motility. The experimental results are shown in Figure 4, and compound A5 significantly reduced the time of ejection of the steel ball and significantly accelerated the rate of colon transit at a dose of 3 / 10 / 15 mg / kg compared to the blank control group, and the efficacy was comparable to that of the positive drug prucalopride succinate (10 mg / kg).

[0569] Example 7 Effect of the ability of the compound to increase the amount of feces and the water content of feces

[0570] Mice were selected from 6-8 week old male C57BL / 6J mice (provided by YINOSU Biotechnology Co., Ltd. Haimen), and the mice were orally administered with 100 μL of drug-containing solvent or blank solvent (blank solvent formula same as experimental example 5). Subsequently, the mice were placed in separate cages for 1 hour without bedding, but were allowed to freely obtain food and water. Fecal pellets were collected immediately after expulsion, counted and placed in sealed 1.5 ml microcentrifuge tubes for weighing to obtain the wet weight (Figure 5), and the wet feces were dried and weighed to obtain the dry weight (Figure 6). The difference between the two weights was the water content of the feces (Figure 7). The experimental results showed that compound A5 significantly increased the fecal output and water content of the mice at a dose of 3 mg / kg and 10 mg / kg, and the efficacy was comparable to that of the positive drug prucalopride succinate (10 mg / kg).

[0571] Effect experiment example 8 fecal recovery rate experiment of compound

[0572] Three male SD rats of 7-10 weeks old in each group were fasted for 12 h before administration and allowed free access to water. The compound was administered by oral gavage at a dose of 5 mg / kg, and the animals were allowed to freely eat 4 h after administration. Fecal samples were collected at the following time points (0 h, 0-4 h, 4-8 h, 8-12 h, 12-24 h, 24-48 h, 48-96 h) and stored on wet ice. The fecal samples were homogenized with 14 volumes of homogenization buffer (methanol: 15 mmol / L PBS = 1:2). During sample processing, 40 μL of each fecal homogenate was mixed with 400 μL of methanol containing an internal standard, shaken (10 min, 800 rpm), and centrifuged (3220 g, 15 min, 4°C). 50 μL of supernatant was taken, re-centrifuged (3220 g, 5 min, 4°C), and then the supernatant was directly injected into LC-MS / MS for analysis. The fecal recovery rate calculation method was the percentage of drug content in feces to the administered dose, and the data were analyzed using GraphPad Prism 7. Figure 9 shows the fecal recovery rate experiment results of compound G3 in rats. Compound G3 was almost completely excreted within 24 hours and did not stay in the body for a long time. The excretion peak appeared within 8 to 12 hours after administration. The fecal recovery rate of compound G3 was close to 100%, indicating that the compound was basically excreted in its original form, which met the basic pharmacokinetic characteristics of intestinal restricted drugs.

[0573] Effect experiment example 9 in vitro hERG potassium channel inhibition experiment of compound

[0574] Human embryonic kidney cells 293 (HEK293, provided by Nanjing Yitaisi Biological Technology Co., Ltd.) stably expressing hERG potassium channel were cultured in DMEM medium (Bio-Channel, containing 1% penicillin-streptomycin) containing 10% fetal bovine serum (Lonsera) at 37°C and 5% carbon dioxide concentration. The cells were normally passaged, and 5*103cells per well were inoculated into a 24-well plate with a cover glass. After 24 hours, the detection was performed. The test compound powder was prepared into a 30.628 mM stock solution with dimethyl sulfoxide (DMSO, Sigma Aldrich), and after aliquot, it was stored at -20°C in the dark. The positive control was cisapride (Sigma Aldrich). The negative control was a suitable volume of DMSO. On the experimental day, the negative control, positive control stock solution and test compound stock solution were gradient diluted into the corresponding volume of extracellular fluid as the working solution. The final concentration of the test compound was 1, 3, 10, 30 and 100 μM, and the DMSO content of the test solution was 0.1%. The current signal was collected by EPC10 amplifier (HEKA) with a sampling rate of 20 kHz. The negative control and the test compound were used to flow through the recording chamber from low concentration to high concentration in turn by gravity perfusion, so as to quickly act on the cells. The current detected in each cell negative control was used as the cell's own control group. Each drug concentration acted for 5 minutes or until the current was stable. All experiments were performed at room temperature. The online and offline analysis of data used PatchMaster software (HEKA). Curve fitting and IC 50 values were calculated using GraphPad Prism 7.0. IC 50 values were the average of two independent experiments (N=2).

[0575] Figure 10 is the IC 50 curve of the in vitro hERG potassium channel inhibition experiment of compound G3. The experimental results show that compound G3 has no obvious inhibition activity on the hERG potassium channel, and the IC 50 value is greater than 30 μM, and the possibility of causing cardiotoxicity is low.

Claims

1. A 5-HT4 receptor agonist which is a compound of formula I-A: ###0001### I-A or a pharmaceutically acceptable salt thereof. wherein, R 1 is methyl; R 2 is hydrogen or methyl; or R 1 , R 2 and the atoms to which they are attached form a 3-6 membered heterocycloalkyl group; R 3 is methyl; R 4 is hydrogen or methyl; or R 3 , R 4 and the atoms to which they are attached form a 3-6 membered heterocycloalkyl group; L 1 and L 2 is independently selected from a single bond, methylene, and ethylene; L 3 and L 4 is independently selected from a single bond and -(CH2) m2 - -(CH2) m2 - is optionally substituted with 1, 2, 3, 4, 5, or 6 R L3 substituents, and m2 is an integer ranging from 1-6; X a and X b are independently selected from k represents L 3 with the attachment site of X a or L 4 with the attachment site of X b ; a represents L 5 with the attachment site of X a or L 6 with the attachment site of X b ; L 5 and L 6 is independently selected from a single bond, 3-6 membered heterocycloalkylene and 5-6 membered heteroarylene, said 3-6 membered heterocycloalkylene and 5-6 membered heteroarylene is optionally substituted with 1, 2, or 3 R L5 substituted; m3, m4, and m5 are independently integers in the range of 1-6, a represents L 5 at the connection site of X a at the connection site of L 6 at the connection site of X b at the connection site of L 5 at the connection site of L 7 at the connection site of L 6 at the connection site of L 8 at the connection site of L L 7 and L 8 are independently selected from a single bond and wherein n1 is an integer in the range of 1-6, m6 is an integer in the range of 1-6, wherein optionally substituted with 1, 2, or 3 R L7 substituted, b represents the attachment site of L 7 to L 5 to L 8 to L 6 to L 7 to L 9 to L 8 to L 10 to L L 9 and L 10 is independently selected from a single bond, The optionally substituted with 1, 2, or 3 R L9 substituted, each m7, each m8, and each m9 is independently an integer in the range of 0-6, c represents the point of attachment of L 7 to L 9 to L 8 to L 10 to L 9 to Y or L 10 to Y; Y is a single bond, C 3-10 cycloalkylene, 3-10 membered heterocycloalkylene, C 1-6 alkylene, C 2-6 alkenylene, C 2-6 alkynylene, C 6-10 arylene or 5-12 membered heteroarylene, said C 3-10 cycloalkylene, 3-10 membered heterocycloalkylene, C 1-6 alkylene, C 2-6 alkenylene, C 2-6 alkynylene, C 6-10 arylene and 5-12 membered heteroarylene are optionally substituted with 1, 2, 3, or 4 R Y each m10 and each m11 is an integer ranging from 0 to 3; Z is a 3-6 membered heterocycloalkylene; R L3 , R L5 , R L5-1 , R L7 , R L9 , R Y-1 and R Y are independently selected from -H, halogen, -OH, -CN, -COOH, -CONH2, C 1- 6alkyl, C 2-6 2-6alkenyl, C 2-6 2-6alkynyl, C 1-6 1-6alkoxy, C 1-6 1-6alkylthio, -NR" and a 3- to 6-membered heterocycloalkyl group, said C 1-6 6alkyl, C 1-6 2-6alkenyl, C 1-6 2-6alkynyl, C 1-6 1-6alkoxy, C 1-6 1-6alkylthio, -NR" and a 3- to 6-membered heterocycloalkyl group are optionally substituted with 1, 2, 3, 4 or 5 R'; R' and R" are selected from the group consisting of H, halogen, -OH, -NH2, C 1-6 alkyl, -COOH and 3-6 membered heterocycloalkyl; said 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkylene, 5-6 membered heteroarylene, 3-10 membered heterocycloalkylene, C6-C10 arylene and 5-12 membered heteroarylene, the heteroatoms or heteroatom groups are independently selected from O, NH, S, C(=O), C(=O)O, S(=O), S(=O)2and N, the number of heteroatoms or heteroatom groups is 1, 2 or 3; 10 said 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkylene, 5-6 membered heteroarylene, 3-10 membered heterocycloalkylene, C6-C10 arylene and 5-12 membered heteroarylene, the heteroatoms or heteroatom groups are independently selected from O, NH, S, C(=O), C(=O)O, S(=O), S(=O)2and N, the number of heteroatoms or heteroatom groups is 1, 2 or L 1 、L 2 、L 3 、L 4 、L 5 、L 6 、L 7 、L 8 、L 9 、L 10 and Y are not simultaneously a single bond.

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein which is a compound of Formula I: wherein, X 1 and X 2 are independently selected from k represents L 3 with the attachment site of X 1 or L 4 with the attachment site of X 2 ; a represents L 5 with the attachment site of X 1 or L 6 with the attachment site of X 2 .

3. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein which is a compound of Formula I-1 or a pharmaceutically acceptable salt thereof: wherein, X 1-1 and X 2-1 are independently k represents L 3 the attachment site of X 1-1 or L 4 the attachment site of X 2-1 or L 7 the attachment site of X 1-1 or L 8 the attachment site of X 2-1 .

4. The compound or pharmaceutically acceptable salt thereof for use according to claim 2 or 3, wherein which satisfies one or more of the following conditions: (1) the heteroatom(s) of the 3-6 membered heterocycloalkyl group is / are independently selected from one or two of N, O and S, the number of heteroatoms is independently 1, 2 or 3, preferably the heteroatom is O and the number of heteroatoms is 1, for example (2) the 3-6 membered heterocycloalkylene is a 6 membered heterocycloalkylene, wherein the heteroatoms are independently selected from one or two of N, O and S, and the number of heteroatoms is independently 1, 2 or 3, preferably the heteroatom is N and the number of heteroatoms is 1; (3) the 5-6 membered heteroarylene is a 6 membered heteroarylene, wherein the heteroatoms are independently selected from one or two of N, O and S, and the number of heteroatoms is independently 1, 2 or 3, preferably the heteroatom is N or O, and the number of heteroatoms is 1 or 2, for example pyridine, pyrimidine or pyran; (4) said C 3-10 Cycloalkylene is independently monocyclic or polycyclic; the polycyclic can be bridged, fused or spiro; preferably, each C 3-10 Cycloalkylene is independently C 3-6 Monocycloalkylene or C 8-10 Bridged cycloalkylene, preferably cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene or bridged cyclooctylene, for example Further preferred is (5) the heteroatoms of the 3-10 membered heterocycloalkylene are independently selected from one or two of N, O and S, and the number of heteroatoms is independently 1, 2 or 3; (6) the 3-10 membered heterocycloalkylene is independently monocyclic or polycyclic; the polycyclic can be bridged, annelated, or spirocyclic; preferably, each 3-10 membered heterocycloalkylene is independently 4-7 membered monocyclic heterocycloalkylene, 7-8 membered spirocyclic heterocycloalkylene, or 8-10 membered annelated heterocycloalkylene; for example (7) said C 1-6 alkylene is independently methylene, (8) said C 2-6 alkylene is independently (9) said C 2-6 alkynylene is independently (10) said C 6-10 arylene is independently phenylene or naphthylene, e.g., phenylene; (11) the heteroatoms of the 5-12 membered heteroarylene are independently selected from one or two of N, O and S, and the number of heteroatoms is independently 1, 2 or 3; (12) the halogen is independently fluorine, chlorine, bromine or iodine, preferably fluorine, chlorine or bromine; (13) C 1-6 alkyl is independently methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, i-butyl or s-butyl, for example methyl, ethyl or i-propyl; (14) said C2-C6alkenyl is independently (15) The C 2-6 The alkynyl group is independently ethynyl. (16) said C 1-6 Alkoxy is -OCH3, -OCH2CH3, -0(CH2)2CH3, -OC(CH3)3, -0(CH2)2CH(CH3)2, or -0(CH2)4CH3.

5. The compound of claim 2 or 3, or a pharmaceutically acceptable salt thereof, wherein which satisfies one or more of the following conditions: (1) said R L3 , R L5 , R L5-1 , R L7 , R L9 , R Y-1 and R Y are independently selected from -H, halogen, -OH, -CONH2, C 1-6 alkyl, C 1-6 alkoxy, -NR" and 3-6 membered heterocycloalkyl; preferably said R L3 , R L5 , R L5-1 , R L7 , R L9 , R Y-1 and R Y are independently -H, -F, -Cl, -Br, -I, -OH, -NH2, -CONH2, -Me, -Et, -OMe, -NHMe or -N(Me)2; (2) R' and R" are selected from -H, halogen, and C 1-6 alkyl; (3) when R 1 is methyl, R 2 is hydrogen; or, R 1 or, R 2 and together with the atoms to which they are attached form a 5- or 6-membered heterocyclic ring, the heteroatoms of the 5- or 6-membered heterocyclic ring being one or two of N, O and S, the number of heteroatoms being independently 1, 2 or 3; preferably the heteroatom species of the 5-membered heterocyclic ring is O and the number of heteroatoms is 1; (4) said L 1 and L 2 independently a single bond or Preferably (5) said L 3 and L 4 independently a single bond, Preferably (6) in the compound of Formula I, X 1 and X 2 are independently wherein a represents the attachment site of L 5 to X 1 or L 6 to X 2 , k represents the attachment site of L 3 to X 1 or L 4 to X 2 , preferably (7) said L 5 and L 6 are independently or 3-6 membered heterocycloalkylene, which is optionally substituted by 1, 2 or 3 R L5 substituted, m3is an integer in the range of 1 -6, a represents L 5 at the connection site of X 1 at the connection site of X 6 at the connection site of X 2 at the connection site of X 5 at the connection site of L 7 at the connection site of L 6 at the connection site of L 8 at the connection site of L (8) the Z is a 3-6 membered heterocycloalkylene, wherein the heteroatoms are independently selected from one or two of N, O and S, and the number of heteroatoms is independently 1, 2 or 3; preferably in the Z, the heteroatom is N and the number of heteroatoms is 1; (9) said L 7 and L 8 independently a single bond or wherein m6 is an integer in the range of 1-5, n1 is 1, 2, 3, 4, or 5, preferably wherein m6 is an integer in the range of 1-3, n1 is 1, 2, 3, 4, or 5, b represents the attachment site of L 7 to L 5 ; c represents the attachment site of L 8 to L 6 ; d represents the attachment site of L 7 to L 9 ; or e represents the attachment site of L 8 to L 10 ; (10) L 9 and L 10 is independently a single bond, each m7, each m8, and each m9 is independently an integer ranging from 0-6, c represents the attachment site of L 7 to L 9 ; d represents the attachment site of L 8 to L 10 ; d represents the attachment site of L 9 to Y; e represents the attachment site of L 10 to Y; (11) said Y is a single bond, C 1-6 heteroalkylene, C 1-6 alkylene, C 2-6 alkenylene, C 2-6 alkynylene, C 3-10 cycloalkylene, 3-10 membered heterocycloalkylene or C 6-10 aryl, said C 1-6 alkylene is optionally substituted with 1, 2, 3 or 4 R Y each m10 and each m11 is an integer in the range of 0-3, preferably a single bond, C 1- 6alkylene or C 3-10 cycloalkylene.

6. The compound of claim 5, or a pharmaceutically acceptable salt thereof, wherein which satisfies one or more of the following conditions: (1) said R 1 , R 2 and the atoms to which they are attached form (2) said R L5 is -H or C 1-6 alkyl, preferably -H or -CH3; (3) said R L5-1 is -H or C 1-6 alkyl, preferably -H or -CH3; (4) said L 5 and L 6 is independently a single bond, Preferably -NH(CH2)2-, wherein a represents L 5 and the connection site of L 1 to X 6 or the connection site of L 2 to X 5 and the connection site of L 7 to L 6 or the connection site of L 8 to L (5) said L 7 and L 8 independently a single bond, wherein b represents the attachment site of L 7 to L 5 ; c represents the attachment site of L 8 to L 6 ; d represents the attachment site of L 7 to L 9 ; or L 8 to L 10 ; (6) said L 9 and L 10 are each independently a single bond, c denotes L 7 with the attachment site of L 9 with the attachment site of L 8 with the attachment site of L 10 with the attachment site of L 9 with the attachment site of L 10 with the attachment site of L (7) In Y, R Y-1 is -H or C 1-6 alkyl, preferably -H or methyl; (8) In Y, R Y is -OH; (9) Y is a single bond, Further preferred is More preferably (10) the pharmaceutically acceptable salt of the compound is a hydrochloride or a fumarate; Further preferably, it satisfies one or more of the following conditions: (1) in the compound of formula I, the are independently wherein identical or different, d represents L 9 the point of attachment to Y or L 10 the point of attachment to Y; (2) In the compound represented by formula I-1, the are independently wherein identical or different, d represents L 9 the point of attachment to Y or L 10 the point of attachment to Y; (3) in the compound of formula I, X 1 -L 5 or X 2 -L 6 is -NHCO- b , -CONH- b , -NHCO- b , b , b represents L 7 with the attachment site of L 5 or L 8 with the attachment site of L 6 .

7. The compound of claim 2 or 3, or a pharmaceutically acceptable salt thereof, wherein which is any of the following schemes: Scheme A: in the compound of formula I, R 1 is methyl; R 2 is hydrogen or methyl; or R 1 , R 2 and the atoms to which they are attached form a 3-6 membered heterocycloalkyl group; R 3 is methyl; R 4 is hydrogen or methyl; or R 3 , R 4 and the atoms to which they are attached form a 3-6 membered heterocycloalkyl group; L 1 and L 2 is independently selected from a single bond, methylene, and ethylene; L 3 and L 4 is independently selected from a single bond and -(CH2) m2 - and m2 is an integer in the range of 1-6; X 1 and X 2 are independently selected from k represents L 3 with the attachment site of X 1 or L 4 with the attachment site of X 2 ; a represents L 5 with the attachment site of X 1 or L 6 with the attachment site of X 2 ; L 5 and L 6 is independently selected from a single bond, m3 is independently an integer in the range of 1-6, a represents L 5 with the connection site of X 1 or L 6 with the connection site of X 2 or L 5 with the connection site of L 7 or L 6 with the connection site of L 8 ; L 7 and L 8 are independently selected from a single bond and wherein nl is an integer in the range of 1-5, m6 is an integer in the range of 1-3, b represents the attachment site of L 7 with L 5 ; c represents the attachment site of L 8 with L 6 ; c represents the attachment site of L 7 with L 9 ; c represents the attachment site of L 8 with L 10 ; c represents the attachment site of L L 9 and L 10 is independently selected from a single bond, each m7, each m8, and each m9 is independently an integer in the range of 0-6, c represents the attachment site of L 7 to L 9 ; d represents the attachment site of L 8 to L 10 ; d represents the attachment site of L 9 to Y; e represents the attachment site of L 10 to Y; Y is a single bond, C 3-10 cycloalkylene, 3-10 membered heterocycloalkylene, C 1-6 alkylene, C 2-6 alkenylene, C 2-6 alkynylene, or C 6-10 arylene, said C 1-6 alkylene is optionally substituted with 1, 2, 3, or 4 R Y each m10 and each m11 is an integer in the range of 0-3; R L5-1 is -H or methyl; Z is a 3-6 membered heterocycloalkylene; R Y-1 is C 1-6 alkyl; R Y -H, -OH, or C 1-6 alkyl; said 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkylene, 3-10 membered heterocycloalkylene or C 6- C 10 arylene, the kind of heteroatom group is independently selected from N, O and S, the number of heteroatom groups is 1, 2 or 3; L 1 , L 2 , L 3 , L 4 , X 1 , X 2 , L 5 , L 6 , L 7 , L 8 , L 9 , L 10 and Y are not simultaneously a single bond; Scheme B: in the compound of formula I-1, R 1 , R 2 and together with the atom to which they are attached form a 5-membered heterocycloalkyl group; R 3 , R 4 and together with the atom to which they are attached form a 5-membered heterocycloalkyl group; L 1 and L 2 is independently -CH2-; L 3 and L 4 independently a single bond or -(CH2) m2 - wherein m2 is an integer in the range of 1-6; X 1-1 and X 2-1 are independently k represents L 3 with the attachment site of X 1-1 or L 4 with the attachment site of X 2-1 ; a represents L 7 with the attachment site of X 1-1 or L 8 with the attachment site of X 2-1 ; L 7 and L 8 are independently n1 is an integer in the range of 1-5, m6 is an integer in the range of 1-3, b represents the attachment site of L 7 to X 1-1 , c represents the attachment site of L 8 to X 2-1 , c represents the attachment site of L 7 to L 9 , c represents the attachment site of L 8 to L 10 , c represents the attachment site of L L 9 and L 10 independently a single bond or each m7 is independently an integer in the range of 0-6; Y is a single bond, or C 1-6 alkylene; for example, the C 1-6 alkylene is Further, the compound of formula I is any of the following schemes 1, 2 or 3: Scheme 1: R 1 , R 2 and together with the atom to which they are attached form a 5-membered heterocycloalkyl group; R 3 , R 4 and together with the atom to which they are attached form a 5-membered heterocycloalkyl group; L 1 and L 2 is independently -CH2-; L 3 and L 4 are independently -(CH2) m2 - wherein m2 is an integer in the range of 1-6; L 5 and L 6 are independently or 3-6 membered heterocycloalkylene, which is optionally substituted with 1, 2, or 3 R L5 substituted, m3 is an integer in the range of 1-6, a represents the attachment site of L 5 to X 1 or L 6 to X 2 or L 5 to L 7 or L 6 to L 8 to L L 7 and L 8 are independently selected from n1 is an integer in the range of 1-5, m6 is an integer in the range of 1-3, b denotes the attachment site of L 7 to L 5 ; c denotes the attachment site of L 8 to L 6 ; c denotes the attachment site of L 7 to L 9 ; c denotes the attachment site of L 8 to L 10 ; c denotes the attachment site of L L 9 and L 10 are independently selected from each m7, each m8, and each m9 is independently an integer in the range of 0-6, c represents the attachment site of L 7 to L 9 ; d represents the attachment site of L 8 to L 10 ; d represents the attachment site of L 9 to Y; e represents the attachment site of L 10 to Y; Y is Scheme 2: R 1 , R 2 and together with the atom to which they are attached form a 6-membered heterocycloalkyl group; R 3 , R 4 and together with the atom to which they are attached form a 6-membered heterocycloalkyl group; L 1 and L 2 is independently a single bond; L 3 and L 4 independently -(CH2) m2 - wherein m2 is an integer in the range of 1-6; L 5 and L 6 are independently or 3-6 membered heterocycloalkylene, which is optionally substituted by 1, 2 or 3 R L5 substituted, m3 is an integer in the range of 1 -6, a represents L 5 at the connection site of X 1 at the connection site of X 6 at the connection site of X 2 at the connection site of X 5 at the connection site of L 7 at the connection site of L 6 at the connection site of L 8 at the connection site of L L 7 and L 8 are independently selected from wherein nl is an integer in the range of 1-5, m6 is an integer in the range of 1-3, b represents the attachment site of L 7 with L 5 ; c represents the attachment site of L 8 with L 6 ; c represents the attachment site of L 7 with L 9 ; c represents the attachment site of L 8 with L 10 ; c represents the attachment site of L L 9 and L 10 are independently selected from each m7, each m8, and each m9 is independently an integer ranging from 0-6, c represents the attachment site of L 7 to L 9 , d represents the attachment site of L 8 to L 10 , d represents the attachment site of L 9 to Y 10 to Y Y is Scheme 3: R 1 , R 2 and the atom to which they are attached form a 5-membered heterocycloalkyl group; R 3 , R 4 and together with the atom to which they are attached form a 5-membered heterocycloalkyl group; L 1 and L 2 is independently a single bond or -CH2-; L 3 and L 4 are independently -(CH2) m2 - wherein m2 is an integer in the range of 1-6; X 1 and X 2 are independently k represents L 3 with the attachment site of X 1 or L 4 with the attachment site of X 2 ; a represents L 5 with the attachment site of X 1 or L 6 with the attachment site of X 2 ; L 5 and L 6 is independently a single bond, or 3-6 membered heterocycloalkylene, optionally substituted with 1, 2, or 3 R L5 substituted, a represents L 5 at the point of attachment to X 1 at the point of attachment to L 6 at the point of attachment to X 2 at the point of attachment to L 5 at the point of attachment to L 7 at the point of attachment to L 6 at the point of attachment to L 8 at the point of attachment to L L 7 and L 8 are independently a single bond or n1 is an integer in the range of 1-6, m6 is an integer in the range of 1-3, b denotes the attachment site of L 7 with L 5 or the attachment site of L 8 with L 6 or the attachment site of L 7 with L 9 or the attachment site of L 8 with L 10 or the attachment site of L L 9 and L 10 independently a single bond or each m7 is independently an integer in the range of 0-6; Y is a single bond, 8. The compound or a pharmaceutically acceptable salt thereof according to claim 2 or 3, wherein, (1) when L 1 and L 2 are single bonds, L 3 and L 4 are independently -(CH2) m2 -; m2 is an integer in the range of 1-6; L 5 and L 6 are independently selected from 3-6 membered heterocycloalkylene and 5-6 membered heteroarylene, m3, m4 and m5 are independently an integer in the range of 1-6, a represents L 5 with the connection site of X 1 , or L 6 with the connection site of X 2 , b represents L 5 with the connection site of L 7 , or L 6 with the connection site of L 8 ; (2) when L 7 or L 8 is a single bond, L 3 and L 4 are independently -(CH2) m2 -; m2 is an integer in the range of 1-6; L 5 and L 6 are independently selected from m3 is an integer in the range of 1-6, a denotes the attachment site of L 5 to X 1 , b denotes the attachment site of L 6 to X 2 , b denotes the attachment site of L 5 to L 7 , b denotes the attachment site of L 6 to L 8 , b denotes the attachment site of L L 9 for The each m7, each m8, and each m9 is independently an integer ranging from 0-6, c represents the attachment site of L 7 to L 9 ; d represents the attachment site of L 8 to L 10 ; d represents the attachment site of L 9 to Y; e represents the attachment site of L 10 to Y; e represents the attachment site of L (3) when Y is a single bond, L 3 and L 4 are independently -(CH2) m2 -, m2 is an integer in the range of 1-6; L 5 and L 6 are independently selected from m3 is an integer in the range of 1-6, a denotes the attachment site of L 5 to X 1 , b denotes the attachment site of L 6 to X 2 , b denotes the attachment site of L 5 to L 7 , b denotes the attachment site of L 6 to L 8 .

9. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-8, wherein The compound is any one of the following structures:

10. A method for preparing a compound according to any one of claims 1-9 or a pharmaceutically acceptable salt thereof, which is method A or method B: Method A: condensation of a compound of formula A-a with a compound of formula B to give a compound of formula I-A; wherein, R 1 , R 2 , R 3 , R 4 , L 1 , L 2 , L 3 , L 4 , X a , X b , L 5 , L 6 , L 7 , L 8 , L 9 , L 10 and Y are as described in any one of claims 1-8, R 6 -COOH, -NH2, -NCO or Method B: condensing a compound of Formula C-a with a compound of Formula D to produce a compound of Formula I-A; wherein R 1 , R 2 , R 3 , R 4 , L 1 , L 2 , L 3 , L 4 , X a , X b , L 5 , L 6 , L 7 , 7, L 8 , L 9 , L 10 and Y are as described in any one of claims 1-8.

11. The method for preparing according to claim 10, which satisfies any one of the following method one, method two or method three: When the compound of Formula I-A is a compound of Formula I, Method One: condensing a compound of Formula A with a compound of Formula B to produce a compound of Formula I; wherein R 1 , R 2 , R 3 , R 4 , L 1 , L 2 , L 3 , L 4 , X 1 , X 2 , L 5 , L 6 , L 7 , L 8 , L 9 , L 10 and Y are as described in any one of claims 1-8, R 6 -COOH, -NH2, -NCO or when the compound of formula I-A is a compound of formula I, method two: condensing a compound of Formula C with a compound of Formula D to produce a compound of Formula I; wherein R 1 , R 2 , R 3 , R 4 , L 1 , L 2 , L 3 , L 4 , X 1 , X 2 , L 5 , L 6 , L 7 , L 8 , L 9 , L 10 and Y are as described in any one of claims 1-8; when the compound of formula I-A is a compound of formula I-1, method three: condensing a compound of Formula A-1 with a compound of Formula B to produce a compound of Formula I-1; wherein R 1 , R 2 , R 3 , R 4 , L 1 , L 2 , L 3 , L 4 , X 1-1 , X 2-1 , L 5 , L 6 , L 7 , L 8 , L 9 , L 10 and Y are as described in any one of claims 1-8, R 6 is -COOH, -NH2, -NCO or 12. A compound of formula A or of formula A-1, wherein, R 1 , R 2 , L 1 , L 3 , X 1 , X 1-1 , L 5 , L 7 and L 9 as in any one of claims 1-8.

13. A pharmaceutical composition comprising a compound according to any one of claims 1-9 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

14. Use of a compound according to any one of claims 1-9 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 13, in the preparation of a medicament for the treatment and / or prevention of a 5-HT4 receptor mediated disease. The disease is a peripheral gastrointestinal related disease, such as chronic idiopathic constipation, slow transit constipation, opioid-induced constipation, irritable bowel syndrome, Crohn's disease, ulcerative colitis, enteral feeding intolerance, postoperative ileus, postoperative gastrointestinal dysfunction, diabetic gastroparesis, idiopathic gastroparesis, functional abdominal pain, chronic intestinal pseudo-obstruction, Sjogren's syndrome, celiac disease, or short bowel syndrome.

15. Use of a compound of any one of claims 1-9, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 13, in the manufacture of a medicament for the treatment and / or prevention of a peripheral gastrointestinal disease.

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