Compound for preventing and treating related diseases caused by aldehyde metabolism disorder and use thereof

Abstract

Disclosed in the present invention are a compound for preventing and treating related diseases caused by an aldehyde metabolism disorder and the use thereof. The compound is a compound as shown in formula (I), or a stereoisomer, a tautomer, a solvate, and a pharmaceutically acceptable salt of the compound as shown in formula (I).

Description

Compounds for preventing and treating related diseases caused by aldehyde metabolism disorders and uses thereof

[0001] Priority information

[0002] This application claims priority and benefits of patent application 202410255858.6 filed with the State Intellectual Property Office of China on March 6, 2024, and incorporates the entire text of it herein by reference. Technical Field

[0003] The present invention belongs to the technical field of biopharmaceuticals, and in particular, relates to compounds for preventing and treating related diseases caused by aldehyde metabolism disorders and uses thereof. Background Art

[0004] Reactive aldehydes are common bioactive molecules in the body, such as malondialdehyde (MDA) and 4-hydroxynonenal (4-HNE). They primarily originate from lipid and carbohydrate metabolism and inflammatory cells. Reactive aldehydes are chemically active and readily diffuse across membranes. They can regulate gene transcription and expression, alter protein epigenetic modifications, and participate in a variety of biological processes.

[0005] Under pathological conditions, aldehyde metabolism disorders lead to excessive aldehyde accumulation. These aldehydes can react with biological macromolecules (such as proteins, lipids, sugars, and DNA), chemically modifying them and changing their structure and function, thereby affecting cell proliferation and survival, energy metabolism, inflammatory response, oxidative stress, and other cellular stress responses, causing "aldehyde damage" and then participating in the occurrence and development of cardiovascular, nervous, digestive, respiratory, endocrine, rheumatic and immunological, genitourinary and other multi-system diseases. "Aldehyde damage" is an important pathological mechanism for the occurrence and development of diseases in various systems.

[0006] Therefore, it is urgent to develop a drug that can eliminate active aldehydes by competitively covalently binding with the active carbonyl groups of aldehydes. Summary of the Invention

[0007] The present invention aims to, at least to some extent, address at least one of the technical problems existing in the prior art. To this end, the present invention provides a compound that can bind to reactive aldehydes, reduce the production of reactive aldehyde-biomacromolecule adducts, and exert an aldehyde-scavenging effect. The compound can be used to treat various systemic diseases caused by aldehyde metabolism disorders.

[0008] In the first aspect of the present invention, the present invention provides a compound. According to an embodiment of the present invention, the compound is a compound represented by formula (I) or a stereoisomer, tautomer, solvate, or pharmaceutically acceptable salt of the compound represented by formula (I):

[0009] Wherein, R1 is empty, H, halogen, -CN, -C(O)OH, carbamoyl, aminosulfonamide, optionally replaced by one or more R 1a Substituted -C 1～10 Alkyl, optionally substituted by one or more R 1a Substituted -C 1～10 Oxyalkyl, optionally substituted by one or more R 1a Substituted 3-10 membered cycloalkyl, optionally substituted by one or more R 1a substituted 3-10 membered heterocycloalkyl, optionally substituted by one or more R 1a substituted 6-10 membered aromatic group, or optionally substituted by one or more R 1a substituted 5- to 10-membered heteroaromatic groups;

[0010] R2 is empty, H, halogen, -CN, -C(O)OH, carbamoyl, aminosulfonamide, optionally replaced by one or more R 2a Substituted -C 1～10 Alkyl, optionally substituted by one or more R 2a Substituted -C 1～10 Oxyalkyl, optionally substituted by one or more R 2a Substituted 3-10 membered cycloalkyl, optionally substituted by one or more R 2a substituted 3-10 membered heterocycloalkyl, optionally substituted by one or more R 2a substituted 6-10 membered aromatic group, or optionally substituted by one or more R 2a substituted 5- to 10-membered heteroaromatic groups;

[0011] R3 is empty, H, halogen, -CN, -C(O)OH, carbamoyl, aminosulfonamide, optionally replaced by one or more R 3a Substituted -C 1～10 Alkyl, optionally substituted by one or more R 3a Substituted -C 1～10 Oxyalkyl, optionally substituted by one or more R 3a Substituted 3-10 membered cycloalkyl, optionally substituted by one or more R 3a substituted 3-10 membered heterocycloalkyl, optionally substituted by one or more R 3a substituted 6-10 membered aromatic group, or optionally substituted by one or more R 3a a substituted 5- to 10-membered heteroaromatic group; or, R1 and R2 are linked together with the atoms to which they are connected to form a ring B, or R2 and R3 are linked together with the atoms to which they are connected to form a ring B; or, one of R1, R2 and R3 is linked to at least one of the following structures through A:

[0012] One or more One or more One or more or one or more

[0013] R1' is empty, H, halogen, -CN, -C(O)OH, carbamoyl, aminosulfonamide, optionally replaced by one or more R 1b Substituted -C 1～10 Alkyl, optionally substituted by one or more R 1b Substituted -C 1～10 Oxyalkyl, optionally substituted by one or more R 1b Substituted 3-10 membered cycloalkyl, optionally substituted by one or more R 1b substituted 3-10 membered heterocycloalkyl, optionally substituted by one or more R 1b substituted 6-10 membered aromatic group, or optionally substituted by one or more R 1b substituted 5- to 10-membered heteroaromatic groups;

[0014] R2' is empty, H, halogen, -CN, -C(O)OH, carbamoyl, aminosulfonamide, optionally replaced by one or more R 2b Substituted -C 1～10 Alkyl, optionally substituted by one or more R 2b Substituted -C 1～10 Oxyalkyl, optionally substituted by one or more R 2b Substituted 3-10 membered cycloalkyl, optionally substituted by one or more R 2b substituted 3-10 membered heterocycloalkyl, optionally substituted by one or more R 2b substituted 6-10 membered aromatic group, or optionally substituted by one or more R 2b substituted 5- to 10-membered heteroaromatic groups;

[0015] R3' is empty, H, halogen, -CN, -C(O)OH, carbamoyl, aminosulfonamide, optionally replaced by one or more R 3b Substituted -C 1～10 Alkyl, optionally substituted by one or more R 3b Substituted -C 1～10 Oxyalkyl, optionally substituted by one or more R 3b Substituted 3-10 membered cycloalkyl, optionally substituted by one or more R 3b substituted 3-10 membered heterocycloalkyl, optionally substituted by one or more R 3b substituted 6-10 membered aromatic group, or optionally substituted by one or more R 3b substituted 5- to 10-membered heteroaromatic groups;

[0016] Each R 1a 、R 2a 、R 3a 、R 1b 、R 2b and R 3bEach independently selected from halogen, -OH, -C(O)OH, -SH, -NH2, -NO2, -CN, -C 1～10 Alkyl, -C 1～10 Oxyalkyl, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, 6-10 membered aromatic group, or 5-10 membered heteroaromatic group, wherein the 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, 6-10 membered aromatic group, or 5-10 membered heteroaromatic group is optionally substituted by at least one of one or more of the following groups: halogen, -OH, -C(O)OH, -SH, -NH2, -NO2, -CN ... 1～10 alkyl;

[0017] A is empty, optionally replaced by one or more R 1c Replaced Optionally one or more R 1c Replaced Optionally one or more R 1c Replaced -OC 0～10 Alkylene-, -S-, optionally with one or more R 1c -NH-, optionally substituted with one or more R 1c Substituted-N(C 1～10 Alkyl)-, optionally substituted by one or more R 1c Substituted -C 1～10 Alkylene-, optionally substituted by one or more R 1c Substituted -C(O)C 0～10 Alkylene-, optionally substituted by one or more R 1c Substituted 3-10 membered cycloalkyl, optionally substituted by one or more R 1c substituted 3-10 membered heterocycloalkyl, optionally substituted by one or more R 1c substituted 6-10 membered aromatic group, or optionally substituted by one or more R 1c Substituted 5- to 10-membered heteroaromatic group, each R 1c are independently selected from halogen, -CN, -C 1～10 Alkyl, -C 1～6 Oxyalkyl;

[0018] Ring A' is a 6- to 10-membered aromatic group or a 5- to 10-membered heteroaromatic group;

[0019] n1 and n2 are each independently 1, 2 or 3;

[0020] Ring B and Ring B' are each independently selected from optionally substituted by one or more R 2c substituted 6-10 membered aromatic ring group, or optionally substituted with one or more R 2cA substituted 5- to 10-membered heteroaromatic ring group containing at least one heteroatom selected from O, N, and S, wherein each R 2c Each independently selected from halogen, -OH, -C(O)OH, -SH, -NH2, -NO2, -CN, -C 1～6 Alkyl, -C 1～6 Oxyalkyl;

[0021] R4 and R4' are each independently selected from optionally replaced by one or more R 4a -NH2, optionally substituted with one or more R 4a -NHNH2, optionally substituted with one or more R 4a Substituted -C 0～6 Alkylene-CO-NH2, optionally with one or more R 4a Substituted -C 0～10 Alkylene-CO-NHNH2, optionally with one or more R 4a Substituted -C 1～10 Alkyl, optionally substituted by one or more R 4a Substituted 3-10 membered cycloalkyl, optionally substituted by one or more R 4a Substituted 3-10 membered heterocycloalkyl, each R 4a Each independently selected from -C 1～10 Alkyl, -OH, -SH, -NH2;

[0022] R5 and R5' are each independently selected from optionally substituted by one or more R 5a -NH2, optionally substituted with one or more R 5a -NHNH2, optionally substituted with one or more R 5a Substituted -C 1～10 Alkyl, optionally substituted by one or more R 5a substituted 3-10 membered cycloalkyl, or optionally substituted with one or more R 5a Substituted 3-10 membered heterocycloalkyl, each R 5a Each independently selected from -C 1～10 Alkyl, -OH, -SH, or -NH2;

[0023] R6 and R6' are each independently selected from the group consisting of: null, =O, halogen, -CN, -C(O)OH, carbamoyl, aminosulfonamide, optionally substituted by one or more R 6a Substituted -C 1～10 Alkyl, or optionally one or more R 6a Substituted -C 1～10 Oxyalkyl, each R 6a Each independently selected from halogen, -OH, -C(O)OH, -SH, -NH2, -NO2, -CN, -C1～10 Alkyl, -C 1～10 Oxyalkyl;

[0024] Each are each independently selected from single bonds and double bonds;

[0025] Each Each is independently a single bond and absent;

[0026] X1, X2, X3, X4, X5, X1′, X2′, X3′, X4′ and X5′ are each independently selected from C or N.

[0027] According to the embodiments of the present application, the compound represented by formula (I) is not optionally substituted by one or more halogens. Optionally substituted with one or more halogens Optionally substituted with one or more halogens

[0028] The present invention provides a compound. According to an embodiment of the present invention, the compound is a compound represented by formula (I) or a stereoisomer, tautomer, solvate, or pharmaceutically acceptable salt of the compound represented by formula (I):

[0029] Wherein, R1 is empty, H, halogen, -CN, -C(O)OH, carbamoyl, aminosulfonamide, optionally replaced by one or more R 1a Substituted -C 1～6 Alkyl, optionally substituted by one or more R 1a Substituted -C 1～6 Oxyalkyl, optionally substituted by one or more R 1a Substituted 3-10 membered cycloalkyl, optionally substituted by one or more R 1a substituted 3-10 membered heterocycloalkyl, optionally substituted by one or more R 1a substituted 6-10 membered aromatic group, or optionally substituted by one or more R 1a substituted 5- to 10-membered heteroaromatic groups;

[0030] R2 is empty, H, halogen, -CN, -C(O)OH, carbamoyl, aminosulfonamide, optionally replaced by one or more R 2a Substituted -C 1～6 Alkyl, optionally substituted by one or more R 2a Substituted -C 1～6 Oxyalkyl, optionally substituted by one or more R 2a Substituted 3-10 membered cycloalkyl, optionally substituted by one or more R 2a substituted 3-10 membered heterocycloalkyl, optionally substituted by one or more R 2asubstituted 6-10 membered aromatic group, or optionally substituted by one or more R 2a substituted 5- to 10-membered heteroaromatic groups;

[0031] R3 is empty, H, halogen, -CN, -C(O)OH, carbamoyl, aminosulfonamide, optionally replaced by one or more R 3a Substituted -C 1～6 Alkyl, optionally substituted by one or more R 3a Substituted -C 1～6 Oxyalkyl, optionally substituted by one or more R 3a Substituted 3-10 membered cycloalkyl, optionally substituted by one or more R 3a substituted 3-10 membered heterocycloalkyl, optionally substituted by one or more R 3a substituted 6-10 membered aromatic group, or optionally substituted by one or more R 3a a substituted 5- to 10-membered heteroaromatic group; or, R1 and R2 are linked together with the atoms to which they are connected to form a ring B, or R2 and R3 are linked together with the atoms to which they are connected to form a ring B; or, one of R1, R2 and R3 is linked to at least one of the following structures through A:

[0032] One or more One or more One or more or one or more

[0033] R1' is empty, H, halogen, -CN, -C(O)OH, carbamoyl, aminosulfonamide, optionally replaced by one or more R 1b Substituted -C 1～6 Alkyl, optionally substituted by one or more R 1b Substituted -C 1～6 Oxyalkyl, optionally substituted by one or more R 1b Substituted 3-10 membered cycloalkyl, optionally substituted by one or more R 1b substituted 3-10 membered heterocycloalkyl, optionally substituted by one or more R 1b substituted 6-10 membered aromatic group, or optionally substituted by one or more R 1b substituted 5- to 10-membered heteroaromatic groups;

[0034] R2' is empty, H, halogen, -CN, -C(O)OH, carbamoyl, aminosulfonamide, optionally replaced by one or more R 2b Substituted -C 1～6 Alkyl, optionally substituted by one or more R 2b Substituted -C 1～6 Oxyalkyl, optionally substituted by one or more R 2b Substituted 3-10 membered cycloalkyl, optionally substituted by one or more R2b substituted 3-10 membered heterocycloalkyl, optionally substituted by one or more R 2b substituted 6-10 membered aromatic group, or optionally substituted by one or more R 2b substituted 5- to 10-membered heteroaromatic groups;

[0035] R3' is empty, H, halogen, -CN, -C(O)OH, carbamoyl, aminosulfonamide, optionally replaced by one or more R 3b Substituted -C 1～6 Alkyl, optionally substituted by one or more R 3b Substituted -C 1～6 Oxyalkyl, optionally substituted by one or more R 3b Substituted 3-10 membered cycloalkyl, optionally substituted by one or more R 3b substituted 3-10 membered heterocycloalkyl, optionally substituted by one or more R 3b substituted 6-10 membered aromatic group, or optionally substituted by one or more R 3b substituted 5- to 10-membered heteroaromatic groups;

[0036] Each R 1a 、R 2a 、R 3a 、R 1b 、R 2b and R 3b Each independently selected from halogen, -OH, -C(O)OH, -SH, -NH2, -NO2, -CN, -C 1～6 Alkyl, -C 1～6 Oxyalkyl, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, 6-10 membered aromatic group, or 5-10 membered heteroaromatic group, wherein the 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, 6-10 membered aromatic group, or 5-10 membered heteroaromatic group is optionally substituted by at least one of one or more of the following groups: halogen, -OH, -C(O)OH, -SH, -NH2, -NO2, -CN ... 1～6 alkyl;

[0037] A is empty, optionally replaced by one or more R 1c Replaced Optionally one or more R 1c Replaced Optionally one or more R 1c Replaced -OC 0～3 Alkylene-, -S-, optionally with one or more R 1c -NH-, optionally substituted with one or more R 1c Substituted-N(C 1～3 Alkyl)-, optionally substituted by one or more R 1cSubstituted -C 1～3 Alkylene-, optionally substituted by one or more R 1c Substituted -C(O)C 0～3 Alkylene-, optionally substituted by one or more R 1c Substituted 3-10 membered cycloalkyl, optionally substituted by one or more R 1c substituted 3-10 membered heterocycloalkyl, optionally substituted by one or more R 1c substituted 6-10 membered aromatic group, or optionally substituted by one or more R 1c Substituted 5- to 10-membered heteroaromatic group, each R 1c are independently selected from halogen, -CN, -C 1～6 Alkyl, -C 1～6 Oxyalkyl;

[0038] Ring A' is a 6- to 10-membered aromatic group or a 5- to 10-membered heteroaromatic group;

[0039] n1 and n2 are each independently 1, 2 or 3;

[0040] Ring B and Ring B' are each independently selected from optionally substituted by one or more R 2c substituted 6-10 membered aromatic ring group, or optionally substituted with one or more R 2c A substituted 5- to 10-membered heteroaromatic ring group containing at least one heteroatom selected from O, N, and S, wherein each R 2c Each independently selected from halogen, -OH, -C(O)OH, -SH, -NH2, -NO2, -CN, -C 1～6 Alkyl, -C 1～6 Oxyalkyl;

[0041] R4 and R4' are each independently selected from optionally replaced by one or more R 4a -NH2, optionally substituted with one or more R 4a -NHNH2, optionally substituted with one or more R 4a Substituted -C 0～6 Alkylene-CO-NH2, optionally with one or more R 4a Substituted -C 0～6 Alkylene-CO-NHNH2, optionally with one or more R 4a Substituted -C 1～6 Alkyl, optionally substituted by one or more R 4a Substituted 3-10 membered cycloalkyl, optionally substituted by one or more R 4a Substituted 3-10 membered heterocycloalkyl, each R 4a Each independently selected from -C 1～6 Alkyl, -OH, -SH, -NH2;

[0042] R5 and R5' are each independently selected from optionally substituted by one or more R 5a -NH2, optionally substituted with one or more R 5a -NHNH2, optionally substituted with one or more R 5a Substituted -C 1～6 Alkyl, optionally substituted by one or more R 5a substituted 3-10 membered cycloalkyl, or optionally substituted with one or more R 5a Substituted 3-10 membered heterocycloalkyl, each R 5a Each independently selected from -C 1～6 Alkyl, -OH, -SH, or -NH2;

[0043] R6 and R6' are each independently selected from the group consisting of: null, =O, halogen, -CN, -C(O)OH, carbamoyl, aminosulfonamide, optionally substituted by one or more R 6a Substituted -C 1～6 Alkyl, or optionally one or more R 6a Substituted -C 1～6 Oxyalkyl, each R 6a Each independently selected from halogen, -OH, -C(O)OH, -SH, -NH2, -NO2, -CN, -C 1～6 Alkyl, -C 1～6 Oxyalkyl;

[0044] Each are each independently selected from single bonds and double bonds;

[0045] Each Each is independently a single bond and absent;

[0046] X1, X2, X3, X4, X5, X1', X2', X3', X4' and X5' are each independently selected from C or N;

[0047] The compound represented by formula (I) is not optionally substituted by one or more halogens. Optionally substituted with one or more halogens Optionally substituted with one or more halogens

[0048] According to an embodiment of the present invention, the above compound may further include at least one of the following technical features:

[0049] According to an embodiment of the present invention, X1 is N and R5 is -NH2.

[0050] According to an embodiment of the present invention, X5 is C, and R6 is ═O.

[0051] According to an embodiment of the present invention, one of R1, R2 and R3 is connected to at least one of the following structures through A:

[0052] one one or one

[0053] X1 is N, R5 is -NH2, X5 is C, and R6 is ═O; or, X1′ is N, R5′ is -NH2, X5′ is C, and R6′ is ═O.

[0054] According to an embodiment of the present invention, the compound represented by formula (I) is not

[0055] According to an embodiment of the present invention, R1 and R2 are not When connected, X1, X2, X3, X4 and X5 are not C at the same time.

[0056] According to an embodiment of the present invention, R1 and R2 are not When connected, X1, X2, X3, X4 and X5 are not C at the same time.

[0057] According to an embodiment of the present invention, A is empty, optionally replaced by one or more R 1c Replaced Optionally one or more R 1c Replaced Optionally one or more R 1c Replaced -OC 0～3 Alkylene-, -S-, optionally with one or more R 1c Substituted -C 1～3 Alkylene-, optionally substituted by one or more R 1c Substituted 6- to 10-membered aromatic group.

[0058] According to an embodiment of the present invention, A is empty, -O-, -S-, optionally replaced by one or more R 1c Replaced Optionally one or more R 1c Replaced Optionally one or more R 1c Substituted -C 1～3 Alkylene-, optionally substituted by one or more R 1c Substituted 6- to 8-membered aromatic group.

[0059] According to an embodiment of the present invention, A is empty, optionally replaced by one or more R 1c Replaced -OC0～3 Alkylene-, -S-, or optionally substituted by one or more R 1c Substituted -C 1～3 Alkylene-.

[0060] According to an embodiment of the present invention, A is empty, optionally replaced by one or more R 1c Replaced Optionally one or more R 1c Replaced or optionally one or more R 1c Substituted 6- to 10-membered aromatic group.

[0061] According to an embodiment of the present invention, A is optionally replaced by one or more R 1c Replaced Optionally one or more R 1c Replaced or optionally one or more R 1c Substituted 6- to 8-membered aromatic group.

[0062] According to an embodiment of the present invention, A is empty, optionally replaced by one or more R 1c Replaced Optionally one or more R 1c Replaced or optionally one or more R 1c substituted 6-8 membered aromatic group, or optionally substituted by one or more R 1c substituted 5- to 8-membered heteroaromatic groups.

[0063] According to an embodiment of the present invention, ring A' is a 6- to 10-membered aromatic group, preferably a 6- to 8-membered aromatic group.

[0064] According to an embodiment of the present invention, n1 and n2 are each independently 1 or 2.

[0065] According to an embodiment of the present invention, each R 1c are each independently selected from halogen, -C 1～3 Haloalkyl, -C 1～3 Alkyl, or -C 1～3 Oxyalkyl.

[0066] According to an embodiment of the present invention, each R 1c Each independently selected from halogen, -CF3, -C 1～3 Alkyl, or -C 1～3 Oxyalkyl.

[0067] According to an embodiment of the present invention, A is empty, -O-, -S-, -C 1～3 Alkylene-, 6-10 membered aromatic group, or

[0068] According to an embodiment of the present invention, A is empty, 6-10 membered aromatic group, or

[0069] According to an embodiment of the present invention, A is empty, -O-, or -OC 1～3 Alkylene-, or -S-.

[0070] According to an embodiment of the present invention, A is empty, -O-, -S-,

[0071] According to an embodiment of the present invention, A is empty, -O-, or -S-.

[0072] According to an embodiment of the present invention, A is empty,

[0073] According to an embodiment of the present invention, A is empty,

[0074] According to an embodiment of the present invention, each R 2c are each independently selected from halogen, -C 1～3 Haloalkyl, -OH, -SH, -NH2, -NO2, -CN, -C 1～6 Alkyl, or -C 1～6 Oxyalkyl.

[0075] According to an embodiment of the present invention, each R 2c are each independently selected from halogen, -C 1～3 Alkyl, or -C 1～3 Oxyalkyl.

[0076] According to an embodiment of the present invention, each R 2c are each independently selected from halogen or -C 1～3 Oxyalkyl.

[0077] According to an embodiment of the present invention, ring B and ring B' are each independently selected from optionally substituted by one or more R 2c A substituted 6- to 10-membered heteroaromatic ring group, wherein the 6- to 10-membered heteroaromatic ring group contains one or more N heteroatoms.

[0078] According to an embodiment of the present invention, ring B and ring B' are each independently selected from optionally substituted by one or more R 2c A substituted 6- to 10-membered aromatic ring group.

[0079] According to an embodiment of the present invention, ring B is selected from the group consisting of 1～3 A 6- to 10-membered aromatic ring group substituted with an oxyalkyl group.

[0080] According to an embodiment of the present invention, ring B is selected from the group consisting of 1～3 A 6- to 7-membered aromatic ring group substituted with an oxyalkyl group.

[0081] According to an embodiment of the present invention, ring B is selected from the group consisting of 1～3 A 6-membered aromatic ring group substituted with an oxyalkyl group.

[0082] According to an embodiment of the present invention, ring B is optionally substituted with one or more halogen or -C 1～3 Oxyalkyl-substituted phenyl.

[0083] According to an embodiment of the present invention, ring B' is selected from a 6-10 membered aromatic ring group optionally substituted by one or more halogens.

[0084] According to an embodiment of the present invention, ring B' is selected from a 6-7 membered aromatic ring group optionally substituted by one or more halogens.

[0085] According to an embodiment of the present invention, ring B' is a phenyl group optionally substituted by one or more halogens.

[0086] According to an embodiment of the present invention, ring B' is a phenyl group.

[0087] According to an embodiment of the present invention, X1, X2, X1' and X2' are each independently selected from C or N.

[0088] According to an embodiment of the present invention, X1, X2, X1′ and X2′ are each independently selected from C or N, and X1′ and X2′ are not C at the same time.

[0089] According to an embodiment of the present invention, X1 and X2 are each independently selected from C or N, and X1 and X2 are not C at the same time.

[0090] According to an embodiment of the present invention, X1, X2 and X1′ are C, and X2′ is N.

[0091] According to an embodiment of the present invention, X1 and X1' are C, and X2 and X2' are N.

[0092] According to an embodiment of the present invention, X1 and X1' are C.

[0093] According to an embodiment of the present invention, X2 and X2' are each independently selected from C or N.

[0094] According to an embodiment of the present invention, X2 and X2' are C.

[0095] According to an embodiment of the present invention, X2 and X2' are N.

[0096] According to an embodiment of the present invention, R1 is H, halogen, optionally replaced by one or more R 1a Substituted -C1～3 Alkyl, optionally substituted by one or more R 1a Substituted 6- to 10-membered aromatic group.

[0097] According to an embodiment of the present invention, each R 1a Each independently selected from halogen, -OH, -C(O)OH, -SH, -NH2, -NO2, -CN, -C 1～3 Alkyl, -C 1～3 Oxyalkyl, 6-10 membered aromatic group, or 5-10 membered heteroaromatic group; the 6-10 membered aromatic group or 5-10 membered heteroaromatic group is optionally substituted by at least one of the following groups: halogen, -NH2, -C optionally substituted by one or more -OH 1～3 alkyl.

[0098] According to an embodiment of the present invention, R1 is H, optionally substituted by halogen, -C 1～3 Haloalkyl, -C 1～3 Alkyl, or -C 1～3 A 6- to 8-membered aromatic group substituted with an oxyalkyl group.

[0099] According to an embodiment of the present invention, R1 is R7 is selected from H, halogen, -C 1～3 Haloalkyl, -C 1～3 Alkyl, or -C 1～3 Oxyalkyl.

[0100] According to an embodiment of the present invention, R2 and R2' are each independently selected from H or halogen.

[0101] According to an embodiment of the present invention, R3 and R3' are each independently selected from the group consisting of space, H, halogen, -C 1～3 Haloalkyl, -C 1～3 Alkyl, or -C 1～3 Oxyalkyl.

[0102] According to an embodiment of the present invention, R3 is selected from the group consisting of space, H, halogen, -C 1～3 Haloalkyl, or -C 1～3 Oxyalkyl.

[0103] According to an embodiment of the present invention, R3 is selected from space, H, or halogen.

[0104] According to an embodiment of the present invention, X2 is N and R3 is empty.

[0105] According to an embodiment of the present invention, X2 is C, and R3 is H.

[0106] According to an embodiment of the present invention, X2' is N, and R3' is empty.

[0107] According to an embodiment of the present invention, X2' is C, and R3' is H.

[0108] According to an embodiment of the present invention, R4 and R4' are each independently selected from optionally one or more R 4a Substituted -C 0～3 Alkylene-CO-NH2, optionally with one or more R 4a Substituted -C 0～3 Alkylene-CO-NHNH2, optionally with one or more R 4a -NHNH2, optionally substituted with one or more R 4a -NH2, or optionally substituted with one or more R 4a Substituted -C 3～6 Alkyl, or optionally one or more R 4a Substituted -C 3～6 Cycloalkyl, or optionally substituted by one or more R 4a Substituted -C 3～6 Heterocycloalkyl.

[0109] According to an embodiment of the present invention, R4 is selected from the group consisting of one or more R 4a Substituted -C 0～3 Alkylene-CO-NH2, optionally with one or more R 4a Substituted -C 0～3 Alkylene-CO-NHNH2, or optionally one or more R 4a Substituted -C 3～6 alkyl.

[0110] According to an embodiment of the present invention, R4 and R4' are each independently selected from optionally one or more R 4a Substituted -C 3～6 alkyl.

[0111] According to an embodiment of the present invention, each R 4a Each is independently selected from halogen, -OH, or -NH2.

[0112] According to an embodiment of the present invention, R4 is selected from -CO-NH2, -CO-NHNH2, -C 1～3 Alkylene-CO-NH2, -C 1～3 Alkylene-CO-NHNH2, optionally substituted with one or more -OH or one or more -NH2- 2～6 alkyl.

[0113] According to an embodiment of the present invention, R4 is selected from -CO-NH2-, -CO-NHNH2-, -C optionally substituted with one or more -OH or one or more -NH2 3～6 alkyl.

[0114] According to an embodiment of the present invention, R4 and R4' are each independently selected from -C optionally substituted by one or more -OH 3～6 Alkyl, or one or more -NH2 substituted -C 3～6 alkyl.

[0115] According to an embodiment of the present invention, R4 and R4' are each independently selected from -C optionally substituted by one or more -OH 3～6 alkyl.

[0116] According to an embodiment of the present invention, R4, R4', R5 and R5' are each independently selected from optionally substituted by one or more R 4a Substituted -NH2, R 4a -C 1～6 alkyl.

[0117] According to an embodiment of the present invention, at least one of R4, R4', R5 and R5' is selected from the group consisting of 4a Substituted -NH2, R 4a -C 1～6 alkyl.

[0118] According to an embodiment of the present invention, R5 is selected from -NH2 or -NHNH2.

[0119] According to an embodiment of the present invention, R5 is selected from -NH2.

[0120] According to an embodiment of the present invention, at least one of R4 and R5 contains -NHNH2 or -CO-NHNH2.

[0121] According to an embodiment of the present invention, when X1 is N, R5 is selected from -NH2.

[0122] According to an embodiment of the present invention, R4 is selected from -NH2, -CO-NH2, or -C 1～6 Alkyl-NH2, and R5 is selected from -NH2, -CO-NH2, or -C 1～6 Alkyl-NH2.

[0123] According to an embodiment of the present invention, one of R4 and R5 is selected from -NH2, -CO-NH2, or -C 1～6 Alkyl-NH2, one of R4' and R5' is selected from -NH2, -CO-NH2, or -C 1～6 Alkyl-NH2.

[0124] According to an embodiment of the present invention, the compound represented by formula (I) satisfies at least one of the following conditions:

[0125] 1) At least one of R4 and R5 contains -NHNH2 or -CO-NHNH2;

[0126] 2) When X1 is N, R5 is selected from -NH2;

[0127] 3) R4 is selected from -NH2, -CO-NH2, or -C 1～6 Alkyl-NH2, and R5 is selected from -NH2, -CO-NH2, or -C 1～6 Alkyl-NH2;

[0128] 5) One of R4 and R5 is selected from -NH2, -CO-NH2, or -C 1～6 Alkyl-NH2, one of R4' and R5' is selected from -NH2, -CO-NH2, or -C 1～6 Alkyl-NH2;

[0129] 6) At least one of R4, R4', R5 and R5' is selected from the group consisting of 4a Substituted -NH2, R 4a -C 1～6 alkyl.

[0130] According to an embodiment of the present invention, R6 and R6' are each independently selected from H, =O, halogen, -C 1～3 Alkyl, or -C 1～3 Oxyalkyl.

[0131] According to an embodiment of the present invention, R6 is selected from H or ═O.

[0132] According to an embodiment of the present invention, X5 is C, R6 is =O, X1 is N, For a single bond.

[0133] According to an embodiment of the present invention, R6 and R6′ are both H.

[0134] According to an embodiment of the present invention, X5 is C, R6 is =O, X1 is N, is a single bond, and R5 is -NH2-.

[0135] According to an embodiment of the present invention, the compound represented by formula (I) has a structure represented by formula (II):

[0136] According to an embodiment of the present invention, the compound represented by formula (I) has a structure represented by formula (III):

[0137] According to an embodiment of the present invention, the compound represented by formula (I) has a structure represented by formula (IIIa):

[0138] Wherein, R8 is H, halogen, -C 1～6Alkyl, -C 1～6 Oxyalkyl, or -C 1～6 Halogenated alkyl.

[0139] According to an embodiment of the present invention, the compound represented by formula (I) has a structure represented by formula (IV):

[0140] According to an embodiment of the present invention, the structure wherein H is optionally substituted by halogen.

[0141] According to an embodiment of the present invention, the compound represented by formula (I) has a structure represented by formula (IVa):

[0142] According to an embodiment of the present invention, the compound represented by formula (I) has a structure represented by formula (V):

[0143] According to an embodiment of the present invention, the compound represented by formula (I) has the following structure:

[0144] In a second aspect of the present invention, the present invention provides a pharmaceutical composition. According to an embodiment of the present invention, the pharmaceutical composition comprises the compound described in the first aspect.

[0145] According to an embodiment of the present invention, the pharmaceutical composition may further include a pharmaceutically acceptable carrier, excipient, or vehicle.

[0146] In the third aspect of the present invention, the present invention proposes the use of the compound described in the first aspect and the pharmaceutical composition described in the second aspect in preparing a drug for preventing and / or treating related diseases caused by aldehyde metabolism disorders.

[0147] In the fourth aspect of the present invention, the present invention proposes the use of the compound described in the first aspect and the pharmaceutical composition described in the second aspect in preventing and / or treating related diseases caused by aldehyde metabolism disorders.

[0148] In the fifth aspect of the present invention, the present invention provides the compound described in the first aspect and the pharmaceutical composition described in the second aspect for use in preventing and / or treating related diseases caused by aldehyde metabolism disorders.

[0149] In a sixth aspect, the present invention provides a method for preventing and / or treating diseases related to aldehyde metabolism disorders. According to an embodiment of the present invention, the method comprises: administering a pharmaceutically acceptable dose of the compound of the first aspect or the pharmaceutical composition of the second aspect to a subject.

[0150] According to an embodiment of the present invention, the uses described in the third aspect, the fourth method, and the fifth method, and the method described in the sixth aspect may further include at least one of the following technical features:

[0151] According to an embodiment of the present invention, the related diseases caused by aldehyde metabolism disorder include eye diseases, skin diseases, autoimmune diseases, inflammatory diseases, nervous system diseases, metabolic disorders, cardiovascular diseases, sclerosis, fibrotic diseases, aging-related diseases, tumors, or related diseases caused by blistering agents.

[0152] According to an embodiment of the present invention, the eye diseases include dry eye, allergic conjunctivitis, bullous keratopathy, uveitis, scleritis, conjunctivitis, diabetic retinopathy, and cataract.

[0153] According to an embodiment of the present invention, the skin diseases include atopic dermatitis, psoriasis, eczema, alopecia areata, acne, and rosacea.

[0154] According to an embodiment of the present invention, the autoimmunity includes arthritis, rheumatoid arthritis, Sjögren's syndrome, systemic lupus erythematosus, Crohn's disease, celiac disease, ulcerative colitis, hyperthyroidism, Hashimoto's thyroiditis, Addison's disease, dermatomyositis, chronic inflammatory demyelinating polyneuropathy, Guillain-Barré syndrome, multiple sclerosis, myasthenia gravis, autoimmune vasculitis, pernicious anemia, and vasculitis.

[0155] According to an embodiment of the present invention, the inflammatory diseases include asthma, arthritis, Alzheimer's disease, and nonspecific intestinal inflammation.

[0156] According to an embodiment of the present invention, the nervous system diseases include dementia-type diseases, demyelinating diseases, Parkinson's diseases, motor neuron diseases, prion diseases, cerebral infarction, and amyotrophic lateral sclerosis.

[0157] According to an embodiment of the present invention, the metabolic disorder includes non-alcoholic fatty liver disease, steatohepatitis, cirrhosis, and diabetes.

[0158] According to an embodiment of the present invention, the cardiovascular diseases include coronary heart disease, arrhythmia, cardiomyopathy, heart failure, congenital heart disease, and pericarditis. Beneficial effects:

[0159] 1) The compounds and pharmaceutical compositions of the present invention can bind to active aldehydes, reduce the production of active aldehyde-biomacromolecule adducts, exert an aldehyde scavenging effect, and can be used to treat various systemic diseases caused by aldehyde metabolism disorders, such as dry eye.

[0160] 2) The compounds and pharmaceutical compositions of the present invention have the advantages of rapid onset of action and high safety.

[0161] Additional aspects and advantages of the present invention will be set forth in part in the description which follows and, in part, will be obvious from the description which follows, or may be learned by practice of the present invention. BRIEF DESCRIPTION OF THE DRAWINGS

[0162] The above and / or additional aspects and advantages of the present invention will become apparent and readily understood from the following description of the embodiments with reference to the accompanying drawings, in which:

[0163] FIG1 is a tear secretion test result of some compounds in Test Example 3 of the present invention;

[0164] FIG2 shows the staining score results of some compounds in Test Example 3 of the present invention. DETAILED DESCRIPTION

[0165] The embodiments of the present invention are described in detail below. The embodiments described below are exemplary and are only used to explain the present invention, and should not be understood as limiting the present invention.

[0166] It should be noted that the terms "first" and "second" are used for descriptive purposes only and should not be understood to indicate or imply relative importance or implicitly specify the number of the technical features indicated. Therefore, features defined as "first" or "second" may explicitly or implicitly include one or more of such features. Furthermore, in the description of the present invention, unless otherwise specified, "plurality" means two or more.

[0167] Detailed description of the invention

[0168] Definitions and General Terms

[0169] It should be noted that, for the structural formula and chemical formula descriptions in the embodiments or embodiments of the present invention, the present invention is intended to cover all replacements, modifications and equivalent technical solutions, which are all within the scope of the present invention as defined in the claims. Those skilled in the art will recognize that many methods and materials similar or equivalent to those described in the present invention can be used to practice the present invention. The present invention is in no way limited to the methods and materials described in the present invention. In the event that one or more of the combined documents, patents and similar materials differ from or contradict the present application (including but not limited to defined terms, term applications, described technologies, etc.), the present invention shall prevail.

[0170] It will be further appreciated that certain features of the invention, which for clarity are described in the context of separate embodiments or implementations, may also be provided in combination in a single embodiment or implementation. Conversely, various features of the invention, which for brevity are described in the context of a single embodiment or implementation, may also be provided separately or in any suitable subcombination.

[0171] Unless otherwise specified, technical and scientific terms used in the present invention have the same meanings as commonly understood by those skilled in the art to which the present invention belongs, and unless otherwise specified, all patent publications cited in the entire disclosure of the present invention are incorporated herein by reference in their entirety.

[0172] Unless otherwise indicated, the following definitions apply. For purposes of this invention, the chemical elements are defined according to the Periodic Table of the Elements, CAS version, and the Chemical Handbook, 75th Ed, 1994. Additionally, general principles of organic chemistry are found in "Organic Chemistry," Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry," by Michael B. Smith and Jerry March, John Wiley & Sons, New York: 2007, all of which are hereby incorporated by reference.

[0173] In this document, the terms “include” or “comprising” are open expressions, that is, including the contents specified in the present invention, but not excluding other contents.

[0174] As used herein, the compounds of the present invention also include isotopically labeled compounds of the present invention, which are identical to those described herein except for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Exemplary isotopes that may also be incorporated into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as 2 H. 3 H. 13 C. 14 C. 15 N. 16 O. 17 O. 31 P. 32 P. 36 S. 18 F and 37 Cl.

[0175] Compounds of the invention containing the aforementioned isotopes and / or other isotopes of other atoms, as well as pharmaceutically acceptable salts of the compounds, are encompassed within the scope of the invention. Isotopically labeled compounds of the invention, for example radioactive isotopes, such as 3 H and 14 C is incorporated into the compounds of the present invention for drug and / or substrate tissue distribution analysis. 3H), and carbon-14 (i.e. 14 C), isotopes are particularly preferred. In addition, heavy isotopes, such as deuterium (i.e. 2 H substitutions), may offer some therapeutic advantages resulting from greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements. Thus, in some circumstances, it may be preferred.

[0176] The stereochemical definitions and conventions used herein are generally in accordance with SP Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc., New York, 1994. The compounds of the present invention may contain asymmetric centers or chiral centers and therefore exist in different stereoisomeric forms. It is contemplated that all stereoisomeric forms of the compounds of the present invention, including but not limited to diastereomers, enantiomers and atropisomers, and mixtures thereof, such as racemic mixtures, are encompassed by the present invention. Many organic compounds exist in optically active forms, i.e., they have the ability to rotate the plane of plane-polarized light. When describing an optically active compound, the prefixes D and L or R and S are used to denote the absolute configuration of the molecule with respect to the chiral center(s) in the molecule. The prefixes d and l, or (+) and (-), are symbols used to designate the rotation of plane-polarized light caused by a compound, where (-) or l indicates that the compound is levorotatory. A compound prefixed with (+) or d is dextrorotatory. With respect to a given chemical structure, these stereoisomers are identical except that they are mirror images of one another. Specific stereoisomers may also be referred to as enantiomers, and a mixture of such isomers is often referred to as a mixture of enantiomers. A 50:50 mixture of enantiomers is called a racemic mixture or racemate, which can occur when there is no stereoselectivity or stereospecificity in a chemical reaction or process.

[0177] Depending on the choice of starting materials and process, the compounds of the present invention may exist as one of the possible isomers or as a mixture thereof, for example as pure optical isomers, or as a mixture of isomers, such as a racemic and diastereomeric mixture, depending on the number of asymmetric carbon atoms. Optically active (R)- or (S)-isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. If the compound contains a double bond, the substituents may be in the E or Z configuration; if the compound contains a disubstituted cycloalkyl group, the cycloalkyl substituents may be in the cis or trans configuration.

[0178] The compounds of the present invention may contain asymmetric centers or chiral centers and therefore exist in different stereoisomeric forms. It is contemplated that all stereoisomeric forms of the compounds of the present invention, including but not limited to diastereomers, enantiomers and atropisomers and geometric (or conformational) isomers and mixtures thereof, such as racemic mixtures, are within the scope of the present invention.

[0179] Unless otherwise indicated, structures depicted herein are also meant to include all isomers (e.g., enantiomers, diastereomeric atropisomers, and geometric (or conformational) forms of such structures; for example, R and S configurations at various asymmetric centers, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers. Therefore, single stereochemical isomers as well as enantiomeric mixtures, diastereomeric mixtures, and geometric (or conformational) mixtures of the present compounds are within the scope of the invention.

[0180] Any asymmetric atom (e.g., carbon, etc.) of the compounds of the present invention may exist in a racemic or enantiomerically enriched form, such as in the (R)-, (S)-, or (R,S)-configuration. In certain embodiments, each asymmetric atom has at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess in terms of (R)- or (S)-configuration. Substituents on atoms with unsaturated double bonds may exist in cis-(Z)- or trans-(E)-form, if possible.

[0181] Thus, as described herein, the compounds of the invention may exist in the form of one of the possible isomers, rotamers, atropisomers, tautomers or mixtures thereof, for example, as substantially pure geometric (cis or trans) isomers, diastereomers, optical isomers (enantiomers), racemates or mixtures thereof.

[0182] Any resulting mixtures of isomers can be separated on the basis of the physicochemical differences of the constituents into the pure or substantially pure geometric or optical isomers, diastereomers, racemates, for example, by chromatography and / or fractional crystallization.

[0183] Any racemate of the resulting final product or intermediate can be resolved into its optical antipodes by methods familiar to those skilled in the art using known methods, such as by separation of the resulting diastereoisomer salts thereof. Racemic products can also be separated by chiral chromatography, such as high pressure liquid chromatography (HPLC) using a chiral adsorbent. In particular, enantiomers can be prepared by asymmetric synthesis (e.g., Jacques, et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Principles of Asymmetric Synthesis (2nd Ed. Robert E. Gawley, Jeffrey Aubé, Elsevier, Oxford, UK, 2012); Eliel, EL Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, SH Tables of Resolving Agents and Optical Resolutions p. 268 (EL Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972).

[0184] As used herein, the term "tautomer" or "tautomeric form" refers to structural isomers with different energies that can be converted into each other through a low energy barrier. If tautomerism is possible (such as in solution), a chemical equilibrium of the tautomers can be reached. For example, proton tautomers (also known as prototropic tautomers) include interconversions that occur through proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers include interconversions that occur through the reorganization of some bonding electrons. Unless otherwise indicated, all tautomeric forms of the compounds of the invention are within the scope of the invention.

[0185] As used herein, the term "solvate" refers to an association formed between one or more solvent molecules and a compound of the present invention. Solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, and aminoethanol. The term "hydrate" refers to an association formed when the solvent molecule is water.

[0186] As used herein, the term "pharmaceutically acceptable" means that the substance or composition must be compatible chemically and / or toxicologically with the other ingredients comprising the formulation and / or the mammal to be treated therewith.

[0187] As used herein, the term "pharmaceutically acceptable salts" refers to organic and inorganic salts of the compounds of the present invention. Pharmaceutically acceptable salts are well known in the art, as described in SM Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66: 1-19.

[0188] As used herein, the terms "optionally," "optional," or "optionally" generally mean that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not.

[0189] As used herein, the terms "optionally substituted," "optionally substituted by," and "substituted or unsubstituted" are used interchangeably. Generally, the term "optionally," whether or not preceded by the term "substituted," indicates that one or more hydrogen atoms in a given structure are replaced by a specified substituent. Unless otherwise indicated, an optional substituent group may be substituted at each substitutable position of the group. When more than one position in a given structural formula can be substituted by one or more substituents selected from a specified group, the substituents may be the same or different at each position. Such substituents may include, but are not limited to, F, Cl, Br, CN, OH, NH2, NO2, and the like.

[0190] As used herein, the term "one or more" (e.g. in the definition of substituents of compounds of the general formula of the invention) means "one, two, three, four or five, in particular one, two, three or four, more in particular one, two or three, even more in particular one or two".

[0191] In addition, it should be noted that, unless otherwise explicitly stated, the description methods used in the present invention such as "each...independently is" and "...each independently is" and "...independently is" can be interchanged and should be understood in a broad sense. They can mean that in different groups, the specific options expressed by the same symbols do not affect each other, or that in the same group, the specific options expressed by the same symbols do not affect each other.

[0192] As used herein, the term "halogen" refers to a fluorine, chlorine, bromine or iodine atom.

[0193] In this document, the minimum and maximum carbon atom content in a hydrocarbon group is indicated by a prefix, for example, the prefix C a～b Refers to a carbon atom containing "a" to "b". For example, "C 1～n ” refers to a linear or branched saturated / unsaturated carbon chain containing 1, 2, 3, 4, 5, ... or n carbon atoms; it is further understood that “C 1～n " shall be interpreted as including any sub-ranges therein, such as C 1～10 Including C 1～10 、C 1～9 、C 1～8 、C 1～7 、C 1～6 、C 1～5 、C 1～4 、C 1～3 、C 1～2 、C 2～10 、C 2～9 、C 2～8 、C 2～7 、C 2～6 、C 2～5 、C 2～4 、C 2～3 、C 3～10 、C 3～9 、C 3～8 、C 3～7 、C 3～6 、C 3～5 、C 3～4 、C 4～5 .

[0194] It should be noted that the term "C 1～10 ”, for example, in “C 1～10 Alkyl" or "C 1～10 In the context of the definition of "alkoxy", it refers to an alkyl group having a limited number of carbon atoms from 1 to 10, i.e., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms. It is further understood that the term "C 1～10 " shall be interpreted as including any sub-ranges therein, such as C 1～10 、C1～9 、C 1～8 、C 1～7 、C 1～6 、C 2～10 、C 2～9 、C 2～8 、C 2～7 、C 2～6 、C 2～5 、C 3～10 、C 3～9 、C 3～8 、C 3～7 、C 3～6 、C 3～5 、C 3～4 、C 1～2 、C 1～3 、C 1～4 、C 1～5 ; especially C 1～2 、C 1～3 、C 1～4 、C 1～5 、C 1～6 ; especially C 1～4 .

[0195] In this article, the term “C 1～10 "Alkyl" refers to a linear or branched saturated monovalent hydrocarbon group having 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms, such as C 1～6 Alkyl, C 1～5 Alkyl, C 1～4 Alkyl, C 1～3 Alkyl, C 2～5 Alkyl, C 2～4 Alkyl, C 2～3Alkyl. These include, but are not limited to, methyl, ethyl, n-propyl (n-Pr, -CH2CH2CH3), isopropyl (i-Pr, -CH(CH3)2), n-butyl (n-Bu, -CH2CH2CH2CH3), isobutyl (i-Bu, -CH2CH(CH3)2), sec-butyl (s-Bu, -CH(CH3)CH2CH3), tert-butyl (t-Bu, -C(CH3)3), n-pentyl (-CH2CH2CH2C H2CH3), 2-pentyl (-CH(CH3)CH2CH2CH3), 3-pentyl (-CH(CH2CH3)2), 2-methyl-2-butyl (-C(CH3)2CH2CH3), 3-methyl-2-butyl (-CH(CH3)CH(CH3)2), 3-methyl-1-butyl (-CH2CH2CH(CH3)2), 2-methyl-1-butyl (-CH2CH(CH3)CH2CH3), n-hexyl ( -CH2CH2CH2CH2CH2CH3), 2-hexyl (-CH(CH3)CH2CH2CH2CH3), 3-hexyl (-CH(CH2CH3)(CH2CH2CH3)), 2-methyl-2-pentyl (-C(CH3)2CH2CH2CH3), 3-methyl-2-pentyl (-CH(CH3)CH(CH3)CH2CH3), 4-methyl-2-pentyl (-CH(CH3)CH2CH(CH3)2), 3-methyl-3-pentyl (-C(CH3)(CH2CH3)2), 2-methyl-3-pentyl (-CH(CH2CH3)CH(CH3)2), 2,3-dimethyl-2-butyl (-C(CH3)2CH(CH3)2), 3,3-dimethyl-2-butyl (-CH(CH3)C(CH3)3), wherein the alkyl groups may independently be unsubstituted or substituted with one or more substituents described herein.

[0196] In this article, the term “C 1～10 Alkoxy" and "C 1～10 "Oxyalkyl" refers to a C 1～10 Alkyl, wherein the term "alkyl" is as defined above. For example: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, sec-butoxy, pentyloxy, isopentyloxy and n-hexyloxy, or isomers of the above groups. In particular, the "C 1～10 An "alkoxy" group may contain 1, 2, 3, 4, 5, or 6 carbon atoms ("C 1～6 Alkoxy”), preferably, may contain 1, 2, 3 or 4 carbon atoms (“C 1～4 (alkoxy").

[0197] In this article, the term “C 1～6"Cycloalkyl" or "1 to 6-membered cycloalkyl" refers to a saturated monovalent mono- or bicyclic hydrocarbon ring containing 1, 2, 3, 4, 5 or 6 carbon atoms. 3～6 Cycloalkyl is a monocyclic hydrocarbon ring, for example, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0198] In this context, the term "alkylene" refers to a group formed by removing a hydrogen atom from an "alkyl" group, wherein "C 1～6 "Alkylene" includes methylene, ethylene, propylene, isopropylene (such as ), butylene (such as ), pentylene (such as ), hexamethylene (such as )wait.

[0199] As used herein, the term "cycloalkylene" refers to a group formed by removing a hydrogen atom from a "cycloalkyl" group.

[0200] As used herein, the terms "heterocycloalkyl", "heterocycle" and "heterocycloalkane" all refer to saturated or non-aromatic unsaturated rings containing at least one heteroatom; wherein a heteroatom refers to a nitrogen atom, an oxygen atom, a sulfur atom, etc. Generally, it refers to a monovalent saturated or partially unsaturated monocyclic or bicyclic ring system with multiple ring atoms, which contains 1, 2 or 3 ring heteroatoms selected from N, O and S, and the remaining ring atoms are carbon.

[0201] The 4- to 10-membered heterocycle described in the present invention refers to a 4-, 5-, 6-, 7-, 8-, 9- or 10-membered saturated or unsaturated heterocycle, wherein the unsaturated refers to a group or molecule containing a carbon-carbon double bond, a carbon-carbon triple bond, a carbon-oxygen double bond, a carbon-sulfur double bond, a carbon-nitrogen triple bond, etc.

[0202] As used herein, the term "heterocycloalkylene" refers to a group formed by removing a hydrogen atom from a "heterocycloalkyl" group.

[0203] As used herein, the term "aromatic" or "aryl" refers to monocyclic, bicyclic, and tricyclic carbocyclic ring systems containing 6-10 ring atoms, or 6-9 ring atoms, or 6-8 ring atoms, wherein at least one ring system is aromatic and each ring system comprises a ring of 3-7 atoms. An aryl group is typically, but not necessarily, attached to the parent molecule via the aromatic ring of the aryl group. The terms "aromatic" or "aryl" may be used interchangeably with the terms "aromatic ring" or "aromatic ring." Examples of aryl groups include, but are not limited to, phenyl.

[0204] As used herein, the term "heteroaromatic" or "heteroaryl" refers to monocyclic, bicyclic, and tricyclic ring systems containing 5-10 ring atoms, or 5-9 ring atoms, or 5-8 ring atoms, wherein at least one ring system is aromatic and at least one ring system contains one or more heteroatoms, wherein each ring system contains a ring consisting of 5-7 atoms. The heteroaryl group is usually, but not necessarily, attached to the parent molecule through the aromatic ring of the heteroaryl group. The term "heteroaromatic" or "heteroaryl" can be used interchangeably with the term "heteroaromatic ring", "aromatic heterocycle" or "heteroaromatic compound". In one embodiment of the present invention, the 5-10 atom heteroaryl group contains 1, 2, 3 or 4 heteroatoms independently selected from O, S and N.

[0205] Examples of heteroaryl groups include, but are not limited to, 2-furyl, 3-furyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, pyridazinyl (e.g., 3-pyridazinyl), 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazolyl (such as 5-tetrazolyl), triazolyl (such as 2-triazolyl and 5-triazolyl), 2-thienyl, 3-thienyl, pyrazolyl (such as 2-pyrazolyl), isothiazolyl, 1,2,3-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,3-thiodiazolyl, 1,3,4-thiodiazolyl, 1,2,5-thiodiazolyl, pyrazinyl, 1,3,5-triazinyl.

[0206] As used herein, the term "arylene group" refers to a group formed by removing a hydrogen atom from an "aryl group".

[0207] As used herein, the term "heteroarylene" refers to a group formed by removing a hydrogen atom from a "heteroaryl".

[0208] Unless otherwise specified, use a solid wedge key. and dotted wedge key To indicate the absolute configuration of a stereocenter, use a straight solid bond and straight dashed bond Indicates the relative configuration of a stereocenter.

[0209] In the chemical structure of the ligand or compound disclosed herein, the bond Indicates that the configuration is not specified. If chiral isomers exist in the chemical structure, the bond Can be or include both Although all of the above structural formulae are drawn as certain isomers for simplicity, the present disclosure may include all isomers, such as tautomers, rotational isomers, geometric isomers, diastereomers, racemates, and enantiomers.

[0210] The group description of the present invention It is used to describe the position of group substitution.

[0211] As used herein, the term "pharmaceutically acceptable excipient" includes any solvent, dispersion medium, coating material, surfactant, antioxidant, preservative (e.g., antibacterial agent, antifungal agent), isotonic agent, salt, pharmaceutical stabilizer, binder, excipient, dispersant, lubricant, sweetener, flavoring agent, colorant, or combination thereof, which are known to those skilled in the art (e.g., Remington's Pharmaceutical Sciences, 18th Ed. Mack Printing Company, 1990, pp. 1289-1329). Except in the case where any conventional carrier is incompatible with the active ingredient, its use in treatment or pharmaceutical composition is encompassed.

[0212] As used herein, the term "administration" refers to the introduction of a predetermined amount of a substance into a patient by a suitable means. The compound or pharmaceutical composition of the present invention can be administered by any common route as long as it reaches the desired tissue. Various modes of administration are contemplated, including peritoneal, intravenous, intramuscular, subcutaneous, and the like, but the present invention is not limited to these exemplified modes of administration. Preferably, the composition of the present invention is administered by intravenous or subcutaneous injection.

[0213] As used herein, the term "treatment" refers to any agent used to obtain a desired pharmacological and / or physiological effect. The effect may be preventive in terms of completely or partially preventing a disease or its symptoms, and / or therapeutic in terms of partially or completely curing a disease and / or the adverse effects caused by the disease. "Treatment" as used herein covers diseases in mammals, particularly humans, and includes: (a) preventing the occurrence of a disease or condition in individuals who are susceptible to the disease but have not yet been diagnosed with the disease; (b) inhibiting the disease, such as arresting the progression of the disease; or (c) alleviating the disease, such as alleviating the symptoms associated with the disease. "Treatment" as used herein covers any medication that administers a drug or compound to an individual to treat, cure, alleviate, improve, reduce or inhibit the individual's disease, including but not limited to administering a drug containing a compound described herein to an individual in need.

[0214] Below, the scheme of the present invention will be explained in conjunction with embodiment.It will be understood by those skilled in the art that the following examples are only used to illustrate the present invention and should not be regarded as limiting the scope of the present invention.In the embodiment, if specific technology or conditions are not indicated, the technology or conditions described in the literature in this area or the product instructions are used.The reagents or instruments used are not indicated by the manufacturer, and are all conventional products that can be obtained by commercial purchase.

[0215] Example 1: Synthesis of Compound 1

[0216] Synthesis route of compound 1:

[0217] Step 1: Synthesis of compound 1-2

[0218] Compound 1-1 (1.0 g, 5.68 mmol, 1 eq) was dissolved in DMF (25 mL), cesium carbonate (3.68 g, 11.3 mmol, 2 eq) was added, and the mixture was stirred at room temperature for 15 min. Diphenylphosphonic acid hydroxylamine (3.7 g, 11.4 mmol, 2 eq) was added and stirred for 1 h under the same conditions. The reaction solution was added to water (50 mL), extracted with dichloromethane (30 mL × 3), and the organic layer was collected. The mixture was washed with water (50 mL × 3) and saturated brine (50 mL × 2) in sequence, and the organic layer was dried over anhydrous sodium sulfate. Anhydrous sodium sulfate was filtered, and the organic layer was concentrated. The crude product was purified by flash silica gel column (n-hexane: ethyl acetate = 4:1) to give compound 1-2 (0.65 g, 63%).

[0219] LCMS(ESI):[M+H] + =183.0.

[0220] Step 2: Synthesis of compound 1

[0221] Hydrazine hydrate (6 mmol, 10 eq) was added dropwise to a suspension of compound 1-2 (109 mg, 0.6 mmol, 1 eq) in ethanol (15 mL) at room temperature. After stirring for ten minutes, the system was sealed and heated to 80°C. After overnight reaction, heating was stopped and the system was gradually cooled to room temperature. A large amount of white solid precipitated in the reaction solution. The solution was filtered and the filter cake was washed with an appropriate amount of ethanol (5 mL × 3). The filter cake was collected and dried in vacuo to obtain compound 1 (53.6 mg, 53%).

[0222] LCMS(ESI):[M+H] + =169.0.

[0223] 1H NMR (400MHz, DMSO-d6) δ9.97 (s, 1H, NH), 7.39 (dd, J = 9.0, 9.0Hz, 1H), 6.56 (d, J=9.0Hz,1H),6.35(d,J=6.9Hz,1H),6.23–6.00(m,2H,NH2),4.63(s,1H,NH2).

[0224] Example 2: Synthesis of Compound 2

[0225] Synthesis route of compound 2:

[0226] Under argon conditions, compound 1-2 (54.6 mg, 0.3 mmol, 1 eq) was dissolved in anhydrous THF, cooled to 0°C, and methylmagnesium bromide (3 M, 2.4 mmol, 0.8 mL, 8 eq) was slowly added dropwise. The mixture was stirred for half an hour, warmed to room temperature, and reacted for three hours, then cooled to 0°C. Water (15 mL) was slowly added to quench the mixture. 1N HCl was used to adjust the pH of the system to 6-7. The mixture was extracted with ethyl acetate (10 mL × 3) and washed with saturated brine (15 mL × 1). The organic layer was dried over sodium sulfate, filtered, concentrated, slurried with methyl tert-butyl ether, filtered, and the filter cake was rinsed with a small amount of methyl tert-butyl ether and dried under reduced pressure to give compound 2 (13 mg, 26%).

[0227] LCMS(ESI):[M+H] + =169.1.

[0228] 1 H NMR (400MHz, DMSO-d6) δ7.32(dd,J=8.9,7.4Hz,1H),6.51(s,2H),6.41(dd,J=8.9,1.4Hz,1H),6.32(dd,J=7.4,1.4Hz,1H),6.20(s,1H),1.58(s,6H).

[0229] Example 3: Synthesis of Compound 3

[0230] Synthesis route of compound 3:

[0231] A methanol solution of ammonia (7M, 1.9 mL, 13.5 mmol, 45 eq) was added dropwise to a suspension of compound 1-2 (54.6 mg, 0.3 mmol, 1 eq) in methanol (8 mL) at room temperature. After stirring for ten minutes, the system was sealed and heated to 80°C. After overnight reaction, heating was stopped and the system was gradually cooled to room temperature. A large amount of white solid precipitated in the reaction solution. The solution was filtered and the filter cake was washed with an appropriate amount of methanol (1 mL × 3). The filter cake was collected and dried in vacuo to obtain compound 3 (14.6 mg, 26%).

[0232] LCMS(ESI):[M+H] + =154.0.

[0233] 1 H NMR (400MHz, DMSO-d6) δ8.28(s,1H),7.93(s,1H),7.40(dd,J=9.1,7.1,2.8Hz,1H),6.55(dd,J=9.1,2.1Hz,1H),6.42(dd,J=7.1,1.5Hz,1H),6.20(s,2H).

[0234] Example 4: Synthesis of Compound 4

[0235] Synthesis route of compound 4:

[0236] Step 1: Synthesis of compound 4-3

[0237] Compound 4-1 (346 mg, 1.5 mmol, 1 eq), 3-methoxyphenylboronic acid 4-2 (274 mg, 1.8 mmol, 1.2 eq), tetrakis(triphenylphosphine)palladium (173 mg, 0.15 mmol, 0.1 eq) and potassium carbonate (622 mg, 4.5 mmol, 3 eq) were dissolved in 1,4-dioxane (12 mL), replaced with argon three times, stirred at 100 ° C for 3.5 hours, cooled, filtered, extracted with dichloromethane (20 mL × 3), the organic phases were combined, washed with saturated brine (30 mL × 1), dried over sodium sulfate, concentrated, and the crude product was purified by flash silica gel column (n-hexane: ethyl acetate = 4: 1) to give compound 4-3 (136 mg, 35%).

[0238] LCMS(ESI):[M+H] + =260.1.

[0239] Step 2: Synthesis of compound 4-4

[0240] Compound 4-3 (136 mg, 0.5 mmol, 1 eq) was dissolved in DMF (10 mL), cesium carbonate (342 mg, 1.1 mmol, 2 eq) was added, and the mixture was stirred at room temperature for 15 min. Diphenylphosphonic acid hydroxylamine (256 mg, 1.1 mmol, 2 eq) was added and stirred for 1 h under the same conditions. The reaction solution was added to water (30 mL), extracted with dichloromethane (20 mL × 3), and the organic layer was collected. The mixture was washed with water (30 mL × 3) and saturated brine (30 mL × 2) in sequence, and the organic layer was dried over anhydrous sodium sulfate. Anhydrous sodium sulfate was filtered, and the organic layer was concentrated. The crude product was purified by flash silica gel column (n-hexane: ethyl acetate = 4:1) to give the compound (79 mg, 57%).

[0241] LCMS(ESI):[M+H] + =275.1.

[0242] Step 3: Synthesis of compound 4

[0243] Under argon conditions, compound 4-4 (79 mg, 0.29 mmol, 1 eq) was dissolved in anhydrous THF (6 mL), cooled to 0°C, and methylmagnesium bromide (3 M, 2.3 mmol, 0.77 mL, 8 eq) was slowly added dropwise. The mixture was stirred for half an hour, warmed to room temperature, and reacted for three hours, then cooled to 0°C. Water (10 mL) was slowly added to quench the mixture. 1N HCl was used to adjust the pH of the system to 6-7. The mixture was extracted with ethyl acetate (10 mL × 3) and washed with saturated brine (15 mL × 1). The organic layer was dried over sodium sulfate, filtered, and the organic layer was concentrated. The mixture was slurried with methyl tert-butyl ether, filtered, and the filter cake was rinsed with a small amount of methyl tert-butyl ether. The mixture was dried under reduced pressure to give compound 4 (30 mg, 38%).

[0244] LCMS(ESI):[M+H] + =275.1.

[0245] 1 H NMR (600MHz, CDCl3) δ7.47(d,J=7.5Hz,1H),7.32(dd,J=7.8,7.8Hz,1H),7.28(s,1H),7.24(d,J=7.8Hz,1H),6 .90(dd,J=8.3,2.4Hz,1H),6.32(d,J=7.6Hz,1H),5.94(s,1H,OH),5.43(s,2H,NH2),3.84(s,3H),1.67(s,6H).

[0246] Example 5: Synthesis of Compound 5

[0247] Synthesis route of compound 5:

[0248] Step 1: Synthesis of compound 5-2

[0249] Compound 4-1 (346 mg, 1.5 mmol, 1 eq), 3-trifluoromethylphenylboronic acid 5-1 (342 mg, 1.8 mmol, 1.2 eq), tetrakis(triphenylphosphine)palladium (173 mg, 0.15 mmol, 0.1 eq) and potassium carbonate (622 mg, 4.5 mmol, 3 eq) were dissolved in dioxane (12 mL), replaced with argon three times, stirred at 100 ° C for 3.5 hours, cooled, filtered, extracted with dichloromethane (20 mL × 3), and the organic phases were combined, washed with saturated brine (30 mL × 1), dried over sodium sulfate, and concentrated. The crude product was purified by flash silica gel column (n-hexane: ethyl acetate = 4: 1), compound 5-2 (133.6 mg, 30%).

[0250] LCMS(ESI):[M+H] + =298.0.

[0251] Step 2: Synthesis of compound 5-3

[0252] Compound 5-2 (133 mg, 0.45 mmol, 1 eq) was dissolved in DMF (10 mL), cesium carbonate (292 mg, 0.9 mmol, 2 eq) was added, and the mixture was stirred at room temperature for 15 min. Diphenylphosphonic acid hydroxylamine (210 mg, 0.9 mmol, 2 eq) was added and continued to stir under this condition for 1 h. The reaction solution was added to water (30 mL), extracted with dichloromethane (20 mL × 3), and the organic layer was collected. It was washed with water (30 mL × 3) and saturated brine (30 mL × 2) in sequence, and the organic layer was dried over anhydrous sodium sulfate. Anhydrous sodium sulfate was filtered and concentrated. The crude product was purified by flash silica gel column (n-hexane: ethyl acetate = 4:1), compound 5-3 (91 mg, 65%).

[0253] LCMS(ESI):[M+H] + =313.0.

[0254] Step 3: Synthesis of compound 5

[0255] Under argon conditions, compound 5-3 (91 mg, 0.29 mmol, 1 eq) was dissolved in anhydrous THF (6 mL), cooled to 0°C, and methylmagnesium bromide (3 M, 2.3 mmol, 0.77 mL, 8 eq) was slowly added dropwise. Stirring was continued for half an hour, and the temperature was raised to room temperature. After three hours of reaction, the temperature was lowered to 0°C, and water (10 mL) was slowly added to quench the mixture. 1N HCl was used to adjust the pH of the system to 6-7. The mixture was extracted with ethyl acetate (10 mL × 3) and washed with saturated brine (15 mL × 1). The organic layer was dried over sodium sulfate, and sodium sulfate was filtered. The organic layer was concentrated, slurried with methyl tert-butyl ether, filtered, and the filter cake was washed with a small amount of methyl tert-butyl ether. It was dried under reduced pressure to obtain compound 5 (47 mg, 52%).

[0256] LCMS(ESI):[M+H] + =313.1.

[0257] 1 H NMR (600MHz, CDCl3) δ7.95 (s, 1H), 7.91 (d, J = 7.8Hz, 1H), 7.60 (d, J = 7.8Hz, 1H), 7.53 (dd, J=14.9,7.6Hz,2H),6.36(d,J=7.6Hz,1H),5.79(s,1H,OH),5.44(s,2H,NH2),1.69(s,6H).

[0258] Example 6: Synthesis of Compound 6:

[0259] Synthesis route of compound 6:

[0260] In an argon environment and at -78 ° C, methyl lithium (1.6M, 18mmol, 15mL, 9eq) was slowly added to a suspension of cerium trichloride (4.9g, 14mmol, 7eq) in anhydrous THF (20mL). After the addition was complete, stirring was continued for 1 hour under this condition, and a solution of compound 6-1 (240mg, 2mmol, 1eq) in anhydrous THF (10mL) was added. The temperature was slowly raised to room temperature and stirred overnight. 28-30% wt. NH4OH (in The reaction mixture was quenched with H2O, 50 mL), stirred at room temperature for 1 h, filtered through celite, and the filter cake was rinsed with an appropriate amount of THF (10 mL); the mother liquor was allowed to stand and then separated into layers, the organic layer was collected, the aqueous phase was extracted with THF (30 mL × 2), the organic phases were combined, and washed once with saturated brine (40 mL × 1), the organic phase was dried over anhydrous sodium sulfate, and spin-dried. The crude product was purified by flash silica gel column (Et3N:DCM=0.5% to Et3N:EA:DCM:MeOH=0.5%:30:70:1), compound 6 (117 mg, 39%).

[0261] LCMS(ESI):[M+H] + =152.1.

[0262] 1 H NMR (600MHz, CDCl3) δ7.90 (m, 1H), 6.96–6.94 (m, 1H), 6.85 (d, J = 7.9Hz, 1H), 1.58 (s, 6H).

[0263] Example 7: Synthesis of Compound 7:

[0264] Synthesis route of compound 7:

[0265] Step 1: Synthesis of compound 7-3

[0266] Quinoline-N-oxide compound 7-1 (2.38 g, 16.4 mmol, 1.0 eq) was dissolved in acetonitrile (25 mL). The reaction system was purged with argon three times. Under argon protection, tert-butyl nitrite (5.9 g, 57.38 mmol, 3.5 eq) was added to the solution. The mixture was heated to reflux and stirred overnight at this temperature. After completion of the reaction, the mixture was concentrated under reduced pressure to obtain the crude product. The crude product was purified on a flash silica gel column (n-hexane:ethyl acetate = 1:1) to obtain 3-nitroquinoline-N-oxide 7-3 (2.3 g, 73.8%).

[0267] LCMS(ESI):[M+H] + =191.0.

[0268] Step 2: Synthesis of compound 7-4

[0269] 3-Nitroquinoline-N-oxide 7-3 (2.3 g, 12.1 mmol, 1.0 eq) was mixed with TMSCN (2.64 g, 26.62 mmol, 2.2 eq), reacted under microwave conditions at 130 ° C for 5 minutes, returned to room temperature, and the crude product was purified by flash silica gel column to obtain 3-nitroquinoline-2-carbonitrile 7-4 (417 mg, 17.3%).

[0270] LCMS(ESI):[M+H] + =200.0.

[0271] Step 3: Synthesis of compound 7-5

[0272] 3-Nitroquinoline-2-carbonitrile 7-4 (417 mg, 2.09 mmol, 1.0 eq) was dissolved in ethanol (30 mL), and iron powder (351 mg, 6.28 mmol, 3.0 eq) and dilute hydrochloric acid (0.7 mL) were added to the solution. The temperature was raised to reflux, and the mixture was stirred at this temperature for 4 hours, then the heating was stopped and filtered. A saturated sodium carbonate solution was added to the filtrate, and the pH was adjusted to 8. The mixture was extracted with dichloromethane (20 mL × 3), and the organic phases were combined, washed with saturated brine (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by flash silica gel column (n-hexane: ethyl acetate = 3:1) to give 3-aminoquinoline-2-carbonitrile 7-5 (210 mg, 59.4%).

[0273] LCMS(ESI):[M+H] + =170.0.

[0274] Step 4: Synthesis of compound 7

[0275] Cerium trichloride (3.06 g, 12.4 mmol, 10.0 eq) was dissolved in 20 mL of dry tetrahydrofuran solution. The reaction system was cooled to -78 ° C under argon protection after evacuation of argon three times. Methyl lithium (ether solution) (1.6 M, 7.75 mL, 12.4 mmol, 10.0 eq) was added to the reaction solution. After stirring at this temperature for 1 hour, a THF solution (8 mL) of 3-aminoquinoline-2-carbonitrile 7-5 (210 mg, 1.24 mmol, 1.0 eq) was added to the reaction solution. After the addition was complete, the reaction system was transferred to room temperature. After stirring for half an hour, ammonium hydroxide (ppm: 35%, 10 mL) was added to the system and filtered. The filtrate was extracted with dichloromethane (20 mL×3). The organic phases were combined, washed with saturated sodium chloride solution (20 mL×2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by flash silica gel column chromatography (n-hexane:ethyl acetate=2:1) ​​to obtain compound 7 (175 mg, 70.1%).

[0276] LCMS(ESI):[M+H] + =202.1.

[0277] 1 H NMR (400MHz, DMSO-d6) δ7.69(d,J=8.0Hz,1H),7.52(d,J=7.9Hz,1H),7.32–7.24(m,2H),7.13(s,1H),6.60(s,2H),1.55(s,6H).

[0278] Example 8: Synthesis of Compound 8:

[0279] Synthesis route of compound 8:

[0280] Step 1: Synthesis of compound 8-7

[0281] Slowly add ethyl 3-bromopyruvate 8-1 (7 mL, 55.7 mmol, 1.0 eq) to an ethanol solution (25 mL) of pyridine 8-2 (5 mL, 61.3 mmol, 1.1 eq). Stir for 10 minutes at room temperature, then heat to 70°C and react for 2 hours.

[0282] The reaction mixture was slowly cooled to room temperature, and 2-amino-5-chlorobenzaldehyde 8-4 (7.77 g, 50.1 mmol, 0.9 eq) solid was slowly added to the reaction solution, followed by pyridine (10.5 mL, 128.1 mmol, 2.3 eq) and ethanol (10 mL). The temperature was raised to 80°C and the reaction was continued for 16 hours.

[0283] The reaction mixture was cooled to 70°C, and morpholine 8-6 (13 mL, 150.4 mmol, 2.7 eq) was added. The temperature was then raised to 80°C and the reaction was allowed to react for 2 hours. The mixture was then cooled to 0°C, and an appropriate amount of water (50 mL) was added. After stirring for 10 minutes, the mixture was filtered and washed with water (5 mL x 3). The filter cake was collected and dried under vacuum to obtain compound 8-7 (2.5 g, total yield 18%).

[0284] LCMS(ESI):[M+H] + =251.0.

[0285] Step 2: Synthesis of compound 8

[0286] Hydrazine hydrate (2 mL, 8 mmol, 10 eq) was added dropwise to a suspension of compound 8-7 (200 mg, 0.8 mmol, 1 eq) in ethanol (8 mL) at room temperature. After stirring for ten minutes, the system was sealed and heated to 80 ° C. After overnight reaction, heating was stopped and the system was gradually cooled to room temperature. A large amount of white solid precipitated in the reaction solution. It was filtered and the filter cake was rinsed with an appropriate amount of ethanol (1 mL × 3). The filter cake was collected and dried in vacuo to obtain compound 8 (150 mg, 79%).

[0287] LCMS(ESI):[M+H] + =237.0.

[0288] 1H NMR (400MHz, DMSO-d6) δ9.99–9.96(m,1H),7.82–7.78(m,2H),7.38–7.35(m,2H),6.84(s,2H),4.59(d,J=4.7Hz,2H).

[0289] Example 9: Synthesis of Compound 9:

[0290] Synthesis route of compound 9:

[0291] A methanol solution of ammonia (7M, 7 mL, 48.7 mmol, 28 eq) was added dropwise to a suspension of compound 8-7 (410 mg, 1.74 mmol) in methanol (10 mL) at room temperature. After stirring for ten minutes, the system was sealed and heated to 80°C. After overnight reaction, heating was stopped and the system was gradually cooled to room temperature. A large amount of white solid precipitated in the reaction solution. The solution was filtered and the filter cake was washed with an appropriate amount of methanol (1 mL × 3). The filter cake was collected and dried in vacuo to obtain compound 9 (276.8 mg, 72%).

[0292] LCMS(ESI):[M+H] + =222.0.

[0293] 1 H NMR (600MHz, CDCl3) δ8.17(s,1H),7.80(d,J=9.0Hz,1H),7.55(s,1H),7.33(dd,J=8.9,2.1Hz,1H),7.19(s,2H).

[0294] Example 10: Synthesis of Compound 10:

[0295] Synthesis route of compound 10:

[0296] Step 1: Synthesis of compound 10-1

[0297] Under argon, compound 8-7 (1.0 g, 4 mmol, 1 eq) was dissolved in anhydrous THF (30 mL), cooled to 0°C, and methylmagnesium bromide (3 M, 32 mmol, 11 mL, 8 eq) was slowly added dropwise. Stirring was continued for half an hour, and the mixture was warmed to room temperature. After reacting for three hours, the mixture was cooled to 0°C and quenched by slowly adding water (40 mL). 1N HCl was used to adjust the pH of the system to 6-7. The mixture was extracted with ethyl acetate (30 mL × 3) and washed with saturated brine (50 mL × 1). The organic layer was dried over sodium sulfate, filtered, and the organic layer was concentrated. The crude product was purified by flash silica gel column (n-hexane: ethyl acetate = 1:1) to give compound 10-1 (302 mg, 32%).

[0298] LCMS(ESI):[M+H] + =237.0.

[0299] Step 2: Synthesis of compound 10

[0300] At 0°C under argon, an aqueous solution of NaNO2 (44 mg, 0.53 mmol, 1.05 eq) (7 mL) was slowly added to a 6 M HCl solution (20 mL) of compound 10-1 (120 mg, 0.51 mmol, 1.0 eq), and stirring was continued under the same conditions for half an hour. A 6 M HCl solution (15 mL) of SnCl2·H2O (350 mg, 1.27 mmol, 2.5 eq) was slowly added to the above reaction solution, and stirring was continued under the same conditions for one hour; the pH was adjusted to 12 using a 40% w / w KOH aqueous solution, extracted with ethyl acetate (mL×3), washed with saturated brine (mL×1), the organic layer was dried over sodium sulfate, sodium sulfate was filtered, and the organic layer was concentrated. The crude product was purified by flash silica gel column (n-hexane:ethyl acetate) and dried under reduced pressure to obtain compound 10 (41 mg, 33%).

[0301] LCMS(ESI):[M+H] + =252.0.

[0302] 1 H NMR (400MHz, CDCl3) δ7.82(d,J=8.8Hz,1H),7.63(d,J=2.3Hz,1H),7.52(s,1H),7.35(dd,J=8.9,2.3Hz,1H),1.73(d,J=6.4Hz,8H).

[0303] Example 11: Synthesis of Compound 11:

[0304] Synthesis route of compound 11:

[0305] Step 1: Synthesis of compound 11-2

[0306] Compound 11-1 (1.0 g, 4.9 mmol, 1.0 eq) was dissolved in DMF (20 mL), cesium carbonate (3.2 g, 9.8 mmol, 2.0 eq) was added, and the mixture was stirred at room temperature for 15 min. Diphenylphosphonic acid hydroxylamine (2.28 g, 9.8 mmol, 2.0 eq) was added and stirred for 1 h under the same conditions. The reaction solution was added to water (40 mL), extracted with dichloromethane (30 mL × 3), and the organic layer was collected. It was washed with water (50 mL × 3) and saturated brine (50 mL × 2) in sequence, and the organic layer was dried over anhydrous sodium sulfate. Anhydrous sodium sulfate was filtered and concentrated. The crude product was purified by flash silica gel column (n-hexane: ethyl acetate = 3:1) to give compound 11-2 (0.69 g, 65%).

[0307] LCMS(ESI):[M+H] + =219.1.

[0308] Step 2: Synthesis of compound 11

[0309] Under argon conditions, compound 11-2 (60 mg, 0.28 mmol, 1.0 eq) was dissolved in anhydrous THF, cooled to 0°C, and methylmagnesium bromide (3 M, 2.24 mmol, 0.75 mL, 8.0 eq) was slowly added dropwise. Stirring was continued for half an hour, and the temperature was raised to room temperature. After reacting for three hours, the temperature was lowered to 0°C, and water (10 mL) was slowly added to quench the reaction; extraction was performed with dichloromethane (10 mL × 3), and the mixture was washed with saturated brine (15 mL × 1). The organic layer was dried over sodium sulfate, and sodium sulfate was filtered. The organic layer was concentrated, and the crude product was purified by flash silica gel column purification (n-hexane: ethyl acetate = 3:1) and dried under reduced pressure to obtain compound 11 (41 mg, 68%).

[0310] LCMS(ESI):[M+H] + =219.1.

[0311] 1 H NMR (600MHz, CDCl3) δ8.35(d,J=7.9Hz,1H),7.66–7.63(m,1H),7.52–7.46(m,2H),6.55(s,1H),6.26(s,1H),5.19(s,2H),1.71(s,6H).

[0312] Example 12: Synthesis of Compound 12:

[0313] Synthesis route of compound 12:

[0314] Hydrazine hydrate (2.27 mmol, 20.0 eq) was added dropwise to a suspension of compound 11-2 (24 mg, 0.11 mmol, 1.0 eq) in ethanol (7 mL) at room temperature. After stirring for ten minutes, the system was sealed and heated to 80°C. After overnight reaction, heating was stopped and the system was gradually cooled to room temperature. A large amount of white solid precipitated in the reaction solution. The solution was filtered and the filter cake was rinsed with an appropriate amount of ethanol (0.5 mL × 3). The filter cake was collected and dried in vacuo to obtain compound 12 (21 mg, 85%).

[0315] LCMS(ESI):[M+H] + =219.1.

[0316] 1 H NMR (600MHz, DMSO-d6) δ8.23(d,J=8.4Hz,1H),7.78–7.73(m,2H),7.59(dd,J=7.8,7.2Hz,1H),6.87(s,1H),5.94(s,2H).

[0317] Example 13: Synthesis of Compound 13:

[0318] Synthesis route of compound 13:

[0319] Step 1: Synthesis of compound 13-3

[0320] Compound 2-bromo-5-fluorobenzoic acid methyl ester 13-1 (14 g, 60 mmol, 3.0 eq), 2-acetamido methyl acrylate 13-2 (2.8 g, 20 mmol, 1.0 eq), Pd2(dba)3 (1.4 g, 1.5 mmol, 0.076 eq), tri-tert-butylphosphine boron tetrafluoride (1.8 g, 6 mmol, 0.3 eq) and N, N-dihexylmethylamine (11.7 g, 60 mmol, 3.0 eq) were dissolved in toluene (50 mL), replaced with argon three times, stirred at 100 ° C for 18 hours, cooled, dried, filtered, and the filter cake was washed with n-hexane (5 mL×3), dried over sodium sulfate, concentrated, and the crude product was purified by flash silica gel column (n-hexane: ethyl acetate = 2:1) to obtain compound 13-3 (0.9 g, 7%).

[0321] LCMS(ESI):[M+H] + =222.

[0322] Step 2: Synthesis of compound 13-4

[0323] Compound 13-3 (0.55 g, 2.5 mmol, 1.0 eq) was dissolved in DMF (10 mL), cesium carbonate (1.6 g, 5 mmol, 2.0 eq) was added, and the mixture was stirred at room temperature for 15 min. Diphenylphosphonic acid hydroxylamine (1.2 g, 5 mmol, 2.0 eq) was added and stirred for 1 h under the same conditions. The reaction solution was added to water (20 mL), extracted with dichloromethane (15 mL × 3), and the organic layer was collected. The mixture was washed with water (20 mL × 3) and saturated brine (20 mL × 2) in sequence, and the organic layer was dried over anhydrous sodium sulfate. Anhydrous sodium sulfate was filtered, and the organic layer was concentrated. The crude product was purified by flash silica gel column (n-hexane: ethyl acetate = 2: 1) to give compound 13-4 (0.33 g, 56%).

[0324] LCMS(ESI):[M+H] + =222.

[0325] Step 3: Synthesis of compound 13

[0326] Hydrazine hydrate (3.4 mL, 70 mmol, 50.0 eq) was added dropwise to a suspension of compound 13-4 (0.33 g, 1.4 mmol, 1.0 eq) in ethanol (7 mL) at room temperature. After stirring for ten minutes, the system was sealed and heated to 80°C. After overnight reaction, heating was stopped and the system was gradually cooled to room temperature. A large amount of white solid precipitated in the reaction solution. The solution was filtered and the filter cake was rinsed with an appropriate amount of ethanol (0.5 mL × 3). The filter cake was collected and dried in vacuo to obtain compound 13 (192 mg, 58%).

[0327] LCMS(ESI):[M+H] + =237.1.

[0328] 1 H NMR (600MHz, DMSO-d6) δ10.07(s,1H),7.91–7.89(m,2H),7.66(td,J=8.7,2.8Hz,1H),6.93(s,1H),5.99(s,2H),4.62(s,2H).

[0329] Example 14: Synthesis of Compound 14:

[0330] Synthesis route of compound 14:

[0331] Step 1: Synthesis of compound 14-3

[0332] Methyl 2-bromo-5-chlorobenzoate 14-1 (15 g, 60 mmol, 3.0 eq), methyl 2-acetamidoacrylate 13-2 (2.8 g, 20 mmol, 1.0 eq), Pd2(dba)3 (1.4 g, 1.5 mmol, 0.076 eq), tri-tert-butylphosphine boron tetrafluoride (1.8 g, 6 mmol, 0.3 eq) and N,N-dihexylmethylamine (11.7 g, 60 mmol, 3.0 eq) were dissolved in toluene (50 mL), replaced with argon three times, stirred at 100 ° C for 18 hours, cooled, dried, filtered, and the filter cake was washed with n-hexane (5 mL×3), dried over sodium sulfate, concentrated, and the crude product was purified by flash silica gel column (n-hexane: ethyl acetate = 2:1) to give compound 14-2 (1.74 g, 12%).

[0333] LCMS(ESI):[M+H] + =238.0.

[0334] Step 2: Synthesis of compound 14-3

[0335] Compound 14-2 (0.87 g, 3.7 mmol, 1.0 eq) was dissolved in DMF (10 mL), cesium carbonate (2.41 g, 7.4 mmol, 2.0 eq) was added, and the mixture was stirred at room temperature for 15 min. Diphenylphosphonic acid hydroxylamine (1.72 g, 7.4 mmol, 2.0 eq) was added and stirred for 1 h under the same conditions. The reaction solution was added to water (20 mL), extracted with dichloromethane (15 mL×3), and the organic layer was collected. The mixture was washed with water (20 mL×3) and saturated brine (20 mL×2) in sequence, and the organic layer was dried over anhydrous sodium sulfate. Anhydrous sodium sulfate was filtered, and the organic layer was concentrated. The crude product was purified by flash silica gel column (n-hexane:ethyl acetate) to give compound 14-3 (0.65 g, 70%).

[0336] LCMS(ESI):[M+H] + =253.0.

[0337] Step 3: Synthesis of compound 14

[0338] Hydrazine hydrate (6 mL, 125 mmol, 50.0 eq) was added dropwise to a suspension of compound 14-3 (0.65 g, 2.5 mmol, 1.0 eq) in ethanol (12 mL) at room temperature. After stirring for ten minutes, the system was sealed and heated to 80°C. After overnight reaction, heating was stopped and the system was gradually cooled to room temperature. A large amount of white solid precipitated in the reaction solution. The solution was filtered and the filter cake was washed with an appropriate amount of ethanol (0.5 mL × 3). The filter cake was collected and dried in vacuo to obtain compound 14 (0.59 g, 90%).

[0339] LCMS(ESI):[M+H] + =253.0.

[0340] 1 H NMR (400MHz, DMSO-d6) δ10.07(s,1H),8.18(d,J=2.2Hz,1H),7.85(d,J=8.6Hz,1H),7.80(dd,J=8.6,2.2Hz,1H),6.91(s,1H),5.98(s,2H),4.63(s,2H).

[0341] Example 15: Synthesis of Compound 15:

[0342] Synthesis route of compound 15:

[0343] Step 1: Synthesis of compound 15-2

[0344] Compound 2-bromo-5-methoxybenzoic acid methyl ester 15-1 (14.7 g, 60 mmol, 3.0 eq), 2-acetamidoacrylate methyl ester 13-2 (2.8 g, 20 mmol, 1.0 eq), Pd2(dba)3 (1.4 g, 1.5 mmol, 0.076 eq), tri-tert-butylphosphine boron tetrafluoride (1.8 g, 6 mmol, 0.3 eq) and N,N-dihexylmethylamine (11.7 g, 60 mmol, 3.0 eq) were dissolved in toluene (50 mL), replaced with argon three times, stirred at 100 ° C for 18 hours, cooled, dried, filtered, and the filter cake was washed with n-hexane (5 mL×3), dried over sodium sulfate, concentrated, and the crude product was purified by flash silica gel column (n-hexane: ethyl acetate = 2:1) to obtain compound 15-2 (1.9 g, 14%).

[0345] LCMS(ESI):[M+H] + =234.0.

[0346] Step 2: Synthesis of compound 15-3

[0347] Compound 15-2 (1.86 g, 8 mmol, 1.0 eq) was dissolved in DMF (20 mL), cesium carbonate (5.21 g, 16 mmol, 2.0 eq) was added, and the mixture was stirred at room temperature for 15 min. Diphenylphosphonic acid hydroxylamine (3.73 g, 16 mmol, 2.0 eq) was added and continued to stir under this condition for 1 h. The reaction solution was added to water (40 mL), extracted with dichloromethane (30 mL×3), and the organic layer was collected. It was washed with water (50 mL×3) and saturated brine (50 mL×2) in sequence, and the organic layer was dried over anhydrous sodium sulfate. Anhydrous sodium sulfate was filtered and concentrated. The crude product was purified by flash silica gel column (n-hexane: ethyl acetate = 2:1) to give compound 15-3 (1.2 g, 61%).

[0348] LCMS(ESI):[M+H] + =249.1.

[0349] Step 3: Synthesis of compound 15

[0350] Hydrazine hydrate (1 mL, 20 mmol, 50.0 eq) was added dropwise to a suspension of compound 15-3 (100 mg, 0.4 mmol, 1.0 eq) in ethanol (2 mL) at room temperature. After stirring for ten minutes, the system was sealed and heated to 80°C. After overnight reaction, heating was stopped and the system was gradually cooled to room temperature. A large amount of white solid precipitated in the reaction solution. The solution was filtered and the filter cake was rinsed with an appropriate amount of ethanol (0.5 mL × 3). The filter cake was collected and dried in vacuo to obtain compound 15 (21 mg, 85%).

[0351] LCMS(ESI):[M+H] + =249.1.

[0352] 1 H NMR (600MHz, DMSO-d6) δ10.08(s,1H),7.74(d,J=8.7Hz,1H),7.64(t,J=5.7Hz,1H),7.37(dd ,J=8.7,2.7Hz,1H),6.89(s,1H),6.01(d,J=10.6Hz,2H),4.60(s,2H),3.89(d,J=8.6Hz,3H).

[0353] Example 16: Synthesis of Compound 16:

[0354] Synthesis route of compound 16:

[0355] Step 1: Synthesis of compound 16-3

[0356] Under argon environment, sodium carbonate (2.2 g, 20 mmol, 2 eq) was added to a mixed solution of compound 16-1 (1.67 g, 10 mmol, 1 eq) and compound 16-2 (2.5 g, 10 mmol, 1 eq) in acetonitrile (20 mL), the temperature was raised to reflux, the reaction was allowed to react overnight, and the temperature was lowered to room temperature. After the reaction solution was concentrated, the crude product was purified by flash silica gel column (n-hexane: ethyl acetate = 5:1 to 2:1) to give compound 16-3 (2.9 g, 80%).

[0357] LCMS(ESI):[M+H] + =362.0.

[0358] Step 2: Synthesis of compound 16-4

[0359] Under argon environment, reduced iron powder (930 mg, 16.7 mmol, 10 eq) was added to a solution of compound 16-3 (600 mg, 1.67 mmol, 1 eq) in EtOH / 20% HOAc (v / v = 10 / 1, 15 mL), the temperature was raised to reflux, the reaction was carried out for two hours, the temperature was lowered to room temperature, the mixture was added to water (20 mL), the pH was adjusted to 9-10 with 1N NaOH, and the mixture was filtered through diatomaceous earth. The mother liquor was extracted with dichloromethane (30 mL × 3), washed with water (40 mL × 1) and saturated brine (40 mL × 1) in sequence, the organic layer was collected, dried over anhydrous sodium sulfate, anhydrous sodium sulfate was filtered, the organic layer was concentrated, and the crude product was purified by flash silica gel column (n-hexane: ethyl acetate = 2: 1) to give compound 16-4 (190 mg, 38%).

[0360] LCMS(ESI):[M+H] + =302.1.

[0361] Step 3: Synthesis of compound 16-6

[0362] Slowly add ethyl 3-bromopyruvate 8-1 (0.176 mL, 0.48 mmol, 1 eq) to an ethanol solution (2.5 mL) of pyridine 8-2 (0.124 mL, 0.53 mmol, 1.1 eq). Stir for 10 minutes at room temperature, then heat to 70°C and react for 2 hours.

[0363] The reaction mixture was slowly cooled to room temperature, and compound 16-4 (0.19 g, 0.43 mmol, 0.9 eq) was slowly added to the reaction solution. Pyridine (0.13 mL, 1.1 mmol, 2.3 eq) was then added, and the temperature was raised to 85° C. for 16 hours.

[0364] The reaction mixture was cooled to 70°C, morpholine 8-6 (0.17 mL, 1.3 mmol, 2.7 eq) was added, and then the temperature was raised to 85°C and the reaction was allowed to proceed for 3 hours. The mixture was cooled to room temperature, an appropriate amount of water (30 mL) was added, and the mother liquor was extracted with dichloromethane (20 mL × 3). The mixture was washed with water (30 mL × 3) and saturated brine (30 mL × 2) in that order. The organic layer was collected and dried over anhydrous sodium sulfate. The anhydrous sodium sulfate was filtered, and the organic layer was concentrated. The crude product was purified by flash silica gel column chromatography (n-hexane:ethyl acetate = 3 / 1 to dichloromethane:methanol = 60 / 1) to obtain compound 16-6 (120 mg, 70%).

[0365] LCMS(ESI):[M+H] + =397.1.

[0366] Step 4: Synthesis of compound 16

[0367] Under argon conditions, compound 16-6 (120 mg, 0.3 mmol, 1 eq) was dissolved in anhydrous THF (7 mL), cooled to 0°C, and methylmagnesium bromide (3 M, 2.4 mmol, 0.8 mL, 12 eq) was slowly added dropwise. The mixture was stirred for half an hour, warmed to room temperature, and reacted for three hours, then cooled to 0°C. Water (15 mL) was slowly added to quench the mixture; the mixture was extracted with dichloromethane (10 mL × 3) and washed with saturated brine (10 mL × 1). The organic layer was dried over sodium sulfate, filtered, and the organic layer was concentrated. The crude product was purified by flash silica gel column (n-hexane: ethyl acetate = 1.5: 1) and dried under reduced pressure to give compound 16 (34 mg, 31%).

[0368] LCMS(ESI):[M+H] + =369.2.

[0369] 1 H NMR (400MHz, CDCl3) δ7.84(d,J=9.0Hz,1H),7.17(dd,J=9.0,2.7Hz,1H),7.14(d,J=2.7Hz ,1H),7.07(s,1H),7.00(d,J=8.4Hz,1H),6.65(d,J=8.4Hz,1H),1.73(s,6H),1.57(s,6H).

[0370] Example 17: Synthesis of Compound 17:

[0371] Synthesis route of compound 17:

[0372] Step 1: Synthesis of compound 17-2

[0373] Compound 17-1 (2.0 g, 7.2 mmol, 1 eq), Pd(dppf)Cl2·CH2Cl2 (0.17 g, 0.2 mmol, 0.03 eq), potassium acetate (2.2 g, 21.7 mmol, 3 eq) and diboronic acid pinacol ester (2.4 g, 8.7 mmol, 1.2 eq) were added to anhydrous dioxane solution (15 mL). Argon was bubbled continuously at room temperature for ten minutes. Then, under argon, the temperature was raised to 80°C and reacted for two hours. The temperature was cooled to room temperature and added to water (30 mL). The mixture was extracted with dichloromethane (25 mL×3). The organic layer was collected and washed with water (30 mL×1) and saturated brine (30 mL×1) in sequence. The organic layer was dried over sodium sulfate, filtered, and concentrated. The crude product was purified by flash silica gel column (n-hexane:ethyl acetate = 4:1) to obtain compound 17-2 (1.7 g, 64%).

[0374] LCMS(ESI):[M+H] + =326.1.

[0375] 1 H NMR (600MHz, CDCl3) δ8.37 (d, J = 4.7Hz, 1H), 7.32 (d, J = 7.9Hz, 1H), 3.93 (s, 3H), 1.37 (s, 12H).

[0376] Step 2: Synthesis of compound 17-4

[0377] Compound 17-2 (340 mg, 1.05 mmol, 1.2 eq), compound 17-3 (270 mg, 0.87 mmol, 1 eq), Pd(dppf)Cl2 (73 mg, 0.09 mmol, 0.1 eq) and potassium carbonate (350 mg, 2.2 mmol, 2.5 eq) were added to a dioxane / water (v / v = 50 / 1, 12 mL) solution, and argon was continuously bubbled in at room temperature for ten minutes. Then, under argon, the temperature was raised to 70°C and reacted for three hours. The temperature was cooled to room temperature and added to water (30 mL). The mixture was extracted with dichloromethane (20 mL × 3), the organic layer was collected, and washed with water (30 mL × 1) and saturated brine (30 mL × 1) in sequence. The organic layer was dried over sodium sulfate, filtered, and concentrated. The crude product was purified by flash silica gel column (n-hexane: ethyl acetate = 7:1 to 3:1) to give compound 17-4 (390 mg, 82%).

[0378] LCMS(ESI):[M+H] + =414.1.

[0379] Step 3: Synthesis of compound 17-5

[0380] Under argon environment, reduced iron powder (260 mg, 4.72 mmol, 5 eq) was added to a solution of compound 17-4 (390 mg, 0.94 mmol, 1 eq) in EtOH / 20% HOAc (v / v = 10 / 1, 15 mL), the temperature was raised to reflux, the reaction was carried out for two hours, the temperature was lowered to room temperature, the solution was added to water (25 mL), the pH was adjusted to 9-10 with 1N NaOH, and the mixture was filtered through diatomaceous earth. The mother liquor was extracted with dichloromethane (15 mL × 3), washed with water (20 mL × 1) and saturated brine (20 mL × 1) in sequence, the organic layer was collected, dried over anhydrous sodium sulfate, and the crude product was purified by flash silica gel column (dichloromethane: methanol = 80 / 1) to give compound 17-5 (190 mg, 53%).

[0381] LCMS(ESI):[M+H] + =384.1.

[0382] Step 4: Synthesis of compound 17

[0383] Under argon conditions, compound 17-5 (180 mg, 0.47 mmol, 1 eq) was dissolved in anhydrous THF (10 mL), cooled to 0°C, and methylmagnesium bromide (3 M, 5.64 mmol, 1.88 mL, 12 eq) was slowly added dropwise. Stirring was continued for half an hour, and the temperature was raised to room temperature. After reacting for three hours, the temperature was lowered to 0°C, and water (20 mL) was slowly added to quench the reaction; extraction was performed with dichloromethane (15 mL × 3), and the mixture was washed with saturated brine (20 mL × 1). The organic layer was dried over sodium sulfate, and sodium sulfate was filtered. The organic layer was concentrated, and the crude product was purified by flash silica gel column (dichloromethane: methanol = 60 / 1) to give compound 17 (62.4 mg, 36%).

[0384] LCMS(ESI):[M+H] + =370.2.

[0385] 1 H NMR (600MHz, DMSO-d6) δ7.85(s,1H),7.65(d,J=8.5Hz,1H),7.53(d,J=8.4Hz,1H),6.96(d,J=12.9Hz,1 H),6.91(d,J=7.5Hz,1H),5.79(s,1H),5.37(d,J=12.1Hz,2H),5.35(s,1H),1.65(s,6H),1.56(s,6H).

[0386] Example 18: Synthesis of Compound 18:

[0387] Synthesis route of compound 18:

[0388] Step 1: Synthesis of compound 18-2

[0389] In a 50 mL reaction flask, ethyl 3-amino-7-bromoquinoline-2-carboxylate 17-3 (620 mg, 2.1 mmol, 1.0 eq) and methyl 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate 18-1 (698 mg, 2.52 mmol, 1.2 eq) were dissolved in 1,4-dioxane (8 mL) and water (0.5 mL). Potassium carbonate (870 mg, 6.3 mmol, 3.0 eq) and Pd(dppf)Cl2 (92 mg, 0.126 mmol, 0.06 eq) were then added. The reaction system was purged with argon three times and then stirred in an oil bath at 90°C for 3 hours under argon protection. After the reaction was complete, 20 mL of water was added to the reaction solution, and the mixture was extracted with dichloromethane (20 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified on a flash silica gel column (n-hexane:ethyl acetate = 5:1) to obtain compound 18-2 (584 mg, 76%).

[0390] LCMS(ESI):[M+H] + =366.1.

[0391] Step 2: Synthesis of compound 18

[0392] Compound 18-2 (549 mg, 1.5 mmol, 1.0 eq) was dissolved in anhydrous tetrahydrofuran (5 mL) solution. After the reaction system was purged of argon three times, methylmagnesium bromide reagent (3.0 M tetrahydrofuran solution) (6 mL, 18 mmol, 12.0 eq) was added dropwise at -78 ° C. After the addition was complete, the reaction system was warmed to room temperature and reacted at room temperature for 1 hour to stop the reaction. Water (10 mL) was added to the reaction solution to quench it, and it was extracted with dichloromethane (20 mL × 3). The organic phases were combined and washed with saturated sodium chloride solution (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by flash silica gel column (n-hexane: ethyl acetate = 3:1) to obtain compound 18 (305 mg, 58%).

[0393] LCMS(ESI):[M+H] + =352.1.

[0394] 1 H NMR(600MHz,DMSO-d6)δ7.81(d,J=1.7Hz,1H),7.61–7.58(m,2H),7.40(d,J=2.2Hz,1H),7.37(dd,J=8.2,2.2Hz,1H) ,7.21(s,1H),6.72(d,J=8.2Hz,1H),5.85(s,2H),5.74(s,1H),5.57(s,2H),5.28(s,1H),1.63(s,6H),1.59(s,6H).

[0395] Example 19: Synthesis of Compound 19:

[0396] Synthesis route of compound 19:

[0397] Step 1: Synthesis of compound 19-1

[0398] Ethyl 3-amino-7-bromoquinoline-2-carboxylate 17-3 (590 mg, 2 mmol, 1.0 eq), pinacol diboron (559 mg, 2.2 mmol, 1.1 eq), potassium acetate (589 mg, 6 mmol, 3.0 eq), and Pd(dppf)Cl2 (74 mg, 0.1 mmol, 0.05 eq) were dissolved in anhydrous 1,4-dioxane (10 mL). The reaction system was purged with argon three times and stirred in an oil bath at 110°C for 2 hours. After completion of the reaction, 20 mL of water was added to the reaction solution, and the mixture was extracted with dichloromethane (20 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain crude compound 19-1 (684 mg, 100%).

[0399] LCMS(ESI):[M+H] + =343.1.

[0400] Step 2: Synthesis of compound 19-3

[0401] In a 50 mL reaction flask, compound 19-1 (684 mg, 2 mmol, 1.0 eq) and methyl 3-amino-5-bromo-pyridine-2-carboxylate 19-2 (555 mg, 2.4 mmol, 1.2 eq) were dissolved in 1,4-dioxane (8 mL) and water (0.5 mL). Cesium carbonate (1.3 g, 4 mmol, 2.0 eq) and Pd(dppf)Cl2 (88 mg, 0.12 mmol, 0.06 eq) were added. The reaction system was purged with argon three times and then stirred in an oil bath at 90°C for 3 hours under argon protection. After completion of the reaction, water (20 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (20 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by flash silica gel column (n-hexane: ethyl acetate = 5:1) to give compound 19-3 (620 mg, 84.7%).

[0402] LCMS(ESI):[M+H] + =367.1.

[0403] Step 3: Synthesis of compound 19

[0404] Compound 19-3 (137 mg, 0.37 mmol, 1.0 eq) was dissolved in anhydrous tetrahydrofuran (3 mL) solution. After the reaction system was replaced with argon three times, methylmagnesium bromide reagent (3.0 M tetrahydrofuran solution) (2 mL, 5.92 mmol, 16.0 eq) was added dropwise at -78 ° C. After the addition was complete, the reaction system was warmed to room temperature and reacted at room temperature for 1 hour; water (10 mL) was added to the reaction solution, quenched, extracted with dichloromethane (20 mL × 3), and the organic phases were combined, washed with saturated sodium chloride solution (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by flash silica gel column (n-hexane: ethyl acetate = 3:1) to obtain compound 19 (52 mg, 39.5%).

[0405] LCMS(ESI):[M+H] + =353.1.

[0406] 1 H NMR (400MHz, DMSO-d6) δ8.11(d,J=2.0Hz,1H),7.91(d,J=1.5Hz,1H),7.67–7.62(m,2H),7.37(d,J=2. 1Hz,1H),7.24(s,1H),5.98(s,2H),5.77(s,1H),5.62(s,2H),5.48(s,1H),1.63(s,6H),1.53(s,6H).

[0407] Example 20: Synthesis of Compound 20:

[0408] Synthesis route of compound 20:

[0409] Step 1: Synthesis of compound 20-3

[0410] 3-Bromopyruvic acid ethyl ester 8-1 (0.113 mL, 0.7 mmol, 1.0 eq) and pyridine 8-2 (0.07 mL, 0.77 mmol, 1.1 eq) were dissolved in ethanol (5 mL), stirred at 65 ° C for 2 hours and then returned to room temperature. 2-Amino-5-bromobenzaldehyde compound 20-1 (127 mg, 0.63 mmol, 0.9 eq) and pyridine (0.14 mL, 1.54 mmol, 2.2 eq) were added to the reaction system, then heated to 80 ° C and stirred overnight, cooled to 65 ° C, added morpholine 8-6 (0.17 mL, 1.89 mmol, 2.7 eq) and heated to 80 ° C again and stirred for 2 hours. After the reaction is completed, the reaction solution was concentrated under reduced pressure and the crude product was purified by flash silica gel column (n-hexane: ethyl acetate = 5:1) to obtain compound 20-3 (152 mg, 81.4%)

[0411] LCMS(ESI):[M+H] + =295.0.

[0412] Step 2: Synthesis of compound 20-4

[0413] In a 50 mL reaction flask, ethyl 3-amino-6-bromoquinoline-2-carboxylate 20-3 (152 mg, 0.52 mmol, 1.0 eq) and methyl 2-amino-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate 18-1 (172 mg, 1.62 mmol, 1.2 eq) were dissolved in 8 mL of 1,4-dioxane and 0.5 mL of water. Potassium carbonate (213 mg, 1.55 mmol, 3.0 eq) and Pd(dppf)Cl2 (38 mg, 0.05 mmol, 0.1 eq) were then added. The reaction system was purged with argon three times and then stirred in an oil bath at 90°C for 3 hours under argon protection. After the reaction was complete, 20 mL of water was added to the reaction solution, and the mixture was extracted with dichloromethane (20 mL x 3). The organic phases were combined, washed with saturated sodium chloride solution (20 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified on a flash silica gel column (n-hexane:ethyl acetate = 5:1) to obtain compound 20-4 (137 mg, yield: 72.9%).

[0414] LCMS(ESI):[M+H] + =366.1.

[0415] Step 3: Synthesis of compound 20

[0416] Compound 20-4 (137 mg, 0.375 mmol, 1.0 eq) was dissolved in dry tetrahydrofuran (5 mL). After purging the reaction system with argon three times, methylmagnesium bromide (3.0 M in tetrahydrofuran) (2 mL, 6 mmol, 16.0 eq) was added dropwise at -78°C. After the addition was complete, the reaction system was warmed to room temperature and allowed to react for 1 hour to terminate the reaction. The reaction solution was quenched with water (10 mL) and extracted with dichloromethane (20 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure to obtain the crude product. The crude product was purified on a flash silica gel column (n-hexane:ethyl acetate = 3:1) to obtain compound 20 (56 mg, yield: 42.6%).

[0417] LCMS(ESI):[M+H] + =352.1.

[0418] 1 H NMR (600MHz, DMSO-d6) δ7.71(d,J=8.6Hz,1H),7.67(d,J=2.1Hz,1H),7.53(dd,J=8.7,2.1Hz,1H),7.41(d,J=2.3Hz,1H),7.37(dd,J=8.2 ,2.2Hz,1H),7.22(d,J=0.8Hz,1H),6.72(d,J=8.2Hz,1H),5.86(s,2H),5.71(s,1H),5.59(s,2H),5.27(s,1H),1.61(s,6H),1.59(s,6H).

[0419] Example 21: Synthesis of Compound 21:

[0420] Synthesis route of compound 21:

[0421] Step 1: Synthesis of compound 21-1

[0422] Ethyl 3-amino-6-bromoquinoline-2-carboxylate 20-3 (560 mg, 1.9 mmol, 1.0 eq), bis(pinacolato) borate (578 mg, 2.28 mmol, 1.2 eq), potassium acetate (560 mg, 5.7 mmol, 3.0 eq), and Pd(dppf)Cl2 (137 mg, 0.19 mmol, 0.1 eq) were dissolved in dry 1,4-dioxane (10 mL). The reaction system was purged with argon three times and then stirred in an oil bath at 110°C for 2 hours under argon protection. After completion of the reaction, water (20 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (20 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain crude compound 21-1 (650 mg, 100%), which was directly used in the next step.

[0423] LCMS(ESI):[M+H] + =343.1.

[0424] Step 2: Synthesis of compound 21-3

[0425] Compound 21-1 (650 mg, 1.9 mmol, 1.0 eq) and 3-amino-5-bromo-pyridine-2-carboxylic acid methyl ester 19-2 (527 mg, 2.28 mmol, 1.2 eq) were dissolved in 1,4-dioxane (8 mL) and water (0.5 mL), and cesium carbonate (1.235 g, 3.8 mmol, 2.0 eq) and Pd(dppf)Cl2·CH2Cl2 (310 mg, 0.38 mmol, 0.2 eq) were added. The reaction system was purged with argon three times and then stirred in an oil bath at 90°C for 3 hours under argon protection. After the reaction was completed, water (20 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (20 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by flash silica gel column (n-hexane: ethyl acetate = 5:1) to give compound 21-2 (517 mg, 74.3%).

[0426] LCMS(ESI):[M+H] + =367.1.

[0427] Step 3: Synthesis of compound 21

[0428] Compound 21-2 (517 mg, 1.41 mmol, 1.0 eq) was dissolved in anhydrous tetrahydrofuran solution (20 mL). After the reaction system was purged of argon three times, methylmagnesium bromide reagent (3.0 M tetrahydrofuran solution) (7.5 mL, 22.58 mmol, 16.0 eq) was added dropwise at -78°C. After the addition was complete, the reaction system was warmed to room temperature and reacted at room temperature for 1 hour to stop the reaction. Water (10 mL) was added to the reaction solution to quench the mixture, and the mixture was extracted with dichloromethane (20 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by flash silica gel column chromatography (n-hexane:ethyl acetate = 3:1) to obtain compound 21 (200 mg, 40%).

[0429] LCMS(ESI):[M+H] + =353.1.

[0430] 1 H NMR (400MHz, DMSO-d6) δ8.09(d,J=2.0Hz,1H),7.79(d,J=8.3Hz,2H),7.54(dd,J=8.5,2.1Hz,1H),7.3 2(s,1H),7.27(s,1H),5.96(s,2H),5.76(s,1H),5.65(s,2H),5.49(s,1H),1.62(s,6H),1.53(s,6H).

[0431] Example 22: Synthesis of Compound 22:

[0432] Synthesis route of compound 22:

[0433] Step 1: Synthesis of compound 22-3

[0434] Compound 22-1 (100 mg, 0.32 mmol, 1.0 eq), compound 22-2 (528 mg, 1.9 mmol, 5.9 eq), Pd(dppf)Cl2 (38.6 mg, 0.05 mmol, 0.15 eq) and cesium carbonate (621 mg, 1.9 mmol, 5.9 eq) were added to a dioxane / water (v / v=4 / 1, 15 mL) solution and argon was continuously bubbled in at room temperature for 10 min. The mixture was heated to 80°C under argon atmosphere for three hours, cooled to room temperature, added to water (30 mL), extracted with dichloromethane (15 mL × 3), and the organic layer was collected and washed with water (20 mL × 1) and saturated brine (30 mL × 1) in sequence. The organic layer was dried over sodium sulfate, filtered, and concentrated, and subjected to column chromatography (n-hexane: ethyl acetate = 4:1). The mixture was dried under reduced pressure to give compound 22-3 (120 mg, 60%).

[0435] LCMS(ESI):[M+H] + =525.7.

[0436] Step 2: Synthesis of compound 22

[0437] Under argon, compound 22-3 (120 mg, 0.23 mmol, 1.0 eq) was dissolved in anhydrous THF (12 mL), cooled to 0°C, and methylmagnesium bromide (3 M, 2.74 mmol, 0.9 mL, 12 eq) was slowly added dropwise. The mixture was stirred for half an hour, warmed to room temperature, and reacted for three hours. The mixture was cooled to 0°C and quenched by slowly adding water (2 mL); extracted with dichloromethane (15 mL × 3), washed with saturated brine (20 mL × 1), and the organic layer was dried over anhydrous sodium sulfate, filtered, and the organic layer was concentrated, column chromatography (n-hexane: ethyl acetate = 3:1), and dried under reduced pressure to give compound 22 (50 mg, 42%).

[0438] LCMS(ESI):[M+H] + =526.9.

[0439] 1 H NMR (400MHz, MeOD) δ7.49 (s, 3H), 7.47 (d, J = 2.0Hz, 3H), 7.37 (dd, J = 8.2, 2.0Hz, 3H), 6.82 (d, J = 8.2Hz, 3H), 1.71 (s, 18H).

[0440] Example 23: Synthesis of Compound 23:

[0441] Synthesis route of compound 23:

[0442] Step 1: Synthesis of compound 23-1

[0443] Under argon, compound 19-2 (1.0 g, 4.3 mmol, 1.0 eq) was dissolved in anhydrous THF (8 mL), cooled to -78°C, and methylmagnesium bromide (3 M, 21.5 mmol, 7.2 mL, 5.0 eq) was slowly added dropwise. Stirring was continued for 2 hours. After completion of the reaction, water (2 mL) was slowly added to quench the reaction. The mixture was extracted with dichloromethane (15 mL × 3) and washed with saturated brine (20 mL × 1). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The organic layer was purified by column chromatography (n-hexane:ethyl acetate = 3:1) and dried under reduced pressure to obtain compound 23-1 (780 mg, 82%).

[0444] LCMS(ESI):[M+H] + =231.0.

[0445] Step 2: Synthesis of compound 23

[0446] Compound 23-1 (200 mg, 0.88 mmol, 4.0 eq), compound 23-2 (99 mg, 0.22 mmol, 1.0 eq), Pd(dppf)Cl2 (26.3 mg, 0.032 mmol, 0.15 eq) and cesium carbonate (423 mg, 1.3 mmol, 6.0 eq) were added to a dioxane / water (v / v=4 / 1, 15 mL) solution and argon was continuously bubbled into the solution at room temperature. The reaction mixture was heated to 80°C under argon for ten minutes, and then the temperature was raised to 80°C under argon, and the reaction was carried out for three hours. The mixture was cooled to room temperature, added to water (30 mL), and extracted with dichloromethane (15 mL × 3). The organic layer was collected and washed with water (20 mL × 1) and saturated brine (30 mL × 1) in that order. The organic layer was dried over sodium sulfate, filtered, and concentrated, and subjected to column chromatography (n-hexane: ethyl acetate = 3:1). The mixture was dried under reduced pressure to give compound 23 (92 mg, 79%).

[0447] LCMS(ESI):[M+H] + =529.0.

[0448] 1 H NMR (600MHz, MeOD) δ8.11 (d, J = 2.0 Hz, 3H), 7.79 (s, 3H), 7.41 (d, J = 2.0 Hz, 3H), 1.66 (s, 18H).

[0449] Test Example 1: In vitro aldehyde binding capacity evaluation

[0450] Experimental purpose: By simulating the in vivo environment, the binding ability of Compounds 1 to 23 prepared in Examples 1 to 23 and active aldehydes was investigated.

[0451] Experimental Method: Dissolve sulfobutyl-β-cyclodextrin (310 mg) in phosphate buffer (1.25 mL) to obtain Solution 1. At room temperature, add 4-hydroxynonenal (4-HNE, 5 mg, 32 mmol, 1 eq) and triolein (300 mg) to a reaction flask. Add the prepared Solution 1, then add linoleic acid (300 mg). Finally, add solutions containing Compounds 1 to 23 (32 mmol, 1 eq) of the present invention in dimethyl sulfoxide (0.15 mL). The reaction mixture is stirred for 10, 100, 200, and 300 minutes, then stand for 2 minutes to separate the layers. Samples are then collected for HPLC analysis.

[0452] Sampling method: Use a pipette to sample 25 μl of the upper emulsion layer and 50 μl of the lower aqueous phase, and dilute with 1 ml of methanol.

[0453] Experimental results: 4-Hydroxynonenal exhibits relatively weak UV absorption at a wavelength of 254 nm, which has a relatively small impact on the overall content of the conjugated product. Therefore, the percentage of conjugates at 254 nm was compared using HPLC to examine the compounds' ability to bind to the active aldehyde. The test results show that the compounds of the present invention all possess highly significant aldehyde-binding capacity and speed. This example demonstrates the aldehyde-binding capacity of some compounds; see Table 1 for specific results.

[0454] Taking compound 1 as an example, the binding reaction is as follows:

[0455] Table 1 Specific HPLC data of the percentage of aldehyde-binding products of some compounds

[0456] Test Example 2: Local irritation evaluation

[0457] Experimental purpose: Compounds 1 to 23 were prepared by administering Examples 1 to 23, respectively, and observing the irritation reaction, degree, and reversibility of the test substances on the rabbit eyes and surrounding tissues, so as to provide a reference for evaluating their safety in clinical use.

[0458] Experimental Methods: Two New Zealand rabbits, half male and half female, were randomly assigned to each group based on body weight. The rabbits were divided into a vehicle control group and multiple compound groups (the compound groups were given 0.2% of Compounds 1 to 23, respectively, prepared in Examples 1 to 23). Drug administration was performed three times daily for seven consecutive days. Slit lamp and sodium fluorescein examinations were performed before daily administration and 1, 2, 4, 24, 48, and 72 hours after the last dose, and irritation scores were calculated.

[0459] Clinical observation: During the trial, no obvious abnormalities were found in the appearance, general behavior, mental state, glandular secretion, skin and mucous membrane color, respiratory status, fecal properties and color, and genitals of the New Zealand rabbits in each group.

[0460] Body weight: During the experimental period, the body weight of animals in each group showed a normal growth trend and no obvious abnormalities were observed.

[0461] Slit lamp examination: Slit lamp examination before administration every day and 1, 2, 4, 24, 48, and 72 hours after the last administration (D7), and then to D14, showed that the cornea of ​​the New Zealand rabbits in each dose group had no opacity, the iris was normal, and the conjunctiva (congestion, edema, secretions) was normal. The irritation scores were all within the range of 0 to 3, indicating no irritation.

[0462] Fluorescein sodium examination: Fluorescein sodium examination 1 and 2 hours after the last dose (D7) revealed central corneal staining in the left eye of male New Zealand rabbits in the vehicle control group, with a score of 1; and in the compound group, with a score of 1. These sodium fluorescein staining and scores indicate normal corneal appearance in the animals. No sodium fluorescein staining was observed in the corneas of the animals in any of the groups at other time points.

[0463] In summary, under the conditions of this test, the compounds of the present invention are non-irritating.

[0464] Test Example 3: In vivo efficacy evaluation

[0465] Subcutaneous injection of scopolamine combined with benzalkonium chloride eye drops can induce dry eye in mice. Tear testing and corneal fluorescence staining scores reveal decreased tear secretion and inflammatory infiltration in mice. Furthermore, early in the modeling process, it is possible to predict whether the model will achieve the desired severity. The specific experiments are as follows:

[0466] 1) Female C57BL6 / J mice were randomly divided into groups according to body weight, with 5 animals in each group.

[0467] 2) From day 1 to day 14 of the experiment, mice were injected subcutaneously with scopolamine hydrobromide (0.2 mL / mouse / time) twice daily (4 ± 0.5 hours) to establish a dry eye model. Group 1 served as the blank control group and received PBS (0.2 mL / mouse / time) subcutaneously twice daily (4 ± 0.5 hours).

[0468] 3) On days 1 to 6 of the experiment, benzalkonium chloride was administered to both eyes twice daily (4 ± 0.5 hours) to establish a dry eye model in mice, at a dose of 5 μL / eye. Group 1 served as a blank control group and received PBS instillation into both eyes twice daily (4 ± 0.5 hours) at a dose of 5 μL / eye.

[0469] 4) On days 7 to 14 of the experiment, the drug was administered by eye drops in both eyes 4 times a day (3±0.5 h), 5 μL / eye / time. The first group was not administered and PBS was administered by eye drops in both eyes 4 times a day (3±0.5 h), 5 μL / eye / time. The second group was not administered and the vehicle was administered by eye drops in both eyes 4 times a day (3±0.5 h), 5 μL / eye / time. The other groups were administered Compounds 1 to 23 prepared in Examples 1 to 23, respectively.

[0470] 5) Before modeling, tear tests and corneal fluorescence staining scores were performed on all experimental animals on Day 7 and Day 14.

[0471] 6) Corneal fluorescein staining scoring criteria: Each cornea is divided into five zones (1-central, 2-superior, 3-temporal, 4-nasal, and 5-inferior). Each zone has a maximum score of 8 points. 1 point indicates that the area of ​​punctate staining is 1%-25% of the corresponding zone; 2 points indicate that the area of ​​punctate staining is 26%-50% of the corresponding zone; 3 points indicate that the area of ​​punctate staining is 51%-75% of the corresponding zone; and 4 points indicate that the area of ​​punctate staining is 76%-100% of the corresponding zone. If the staining area is dense and / or clearly fused, additional points of 1, 2, 3, or 4 will be awarded based on the area of ​​the staining area in the corresponding zone (i.e., 1%-25%, 26%-50%, 51%-75%, and 76%-100%, respectively). The maximum total score per eye is 40 points. The total corneal fluorescein sodium staining score for each eye was calculated.

[0472] 7) Tear analysis was performed on all experimental animals on Days 7 and 14 before dosing in the morning. Corneal fluorescence staining scores were performed on all animals on Days 7 and 14 after the second dose. The results show that the compounds of the present invention can improve tear secretion and corneal inflammation, demonstrating efficacy in improving dry eye. This example illustrates the therapeutic effects of some compounds, as shown in Figures 1 and 2.

[0473] Table 3: Experimental protocol for drug efficacy in dry eye disease in mice

[0474] In the description of this specification, the reference terms "one embodiment", "some embodiments", "example", "specific example", or "some examples" mean that the specific features, structures, materials or characteristics described in conjunction with the embodiment or example are included in at least one embodiment or example of the present invention. In this specification, the schematic representations of the above terms do not necessarily refer to the same embodiment or example. Moreover, the specific features, structures, materials or characteristics described can be combined in any one or more embodiments or examples in a suitable manner. In addition, those skilled in the art can combine and combine different embodiments or examples described in this specification and features of different embodiments or examples without contradiction.

[0475] Although the embodiments of the present invention have been shown and described above, it will be understood that the above embodiments are illustrative and are not to be construed as limitations on the present invention. A person skilled in the art may change, modify, replace and modify the above embodiments within the scope of the present invention.

Claims

1. A compound, which is a compound represented by formula (I) or a stereoisomer, tautomer, solvate, or pharmaceutically acceptable salt of the compound represented by formula (I): in, R1 is empty, H, halogen, -CN, -C(O)OH, carbamoyl, aminosulfonamide, optionally replaced by one or more R 1a Substituted -C 1～10 Alkyl, optionally substituted by one or more R 1a Substituted -C 1～10 Oxyalkyl, optionally substituted by one or more R 1a Substituted 3-10 membered cycloalkyl, optionally substituted by one or more R 1a substituted 3-10 membered heterocycloalkyl, optionally substituted by one or more R 1a substituted 6-10 membered aromatic group, or optionally substituted by one or more R 1a substituted 5- to 10-membered heteroaromatic groups; R2 is empty, H, halogen, -CN, -C(O)OH, carbamoyl, aminosulfonamide, optionally replaced by one or more R 2a Substituted -C 1～10 Alkyl, optionally substituted by one or more R 2a Substituted -C 1～10 Oxyalkyl, optionally substituted by one or more R 2a Substituted 3-10 membered cycloalkyl, optionally substituted by one or more R 2a substituted 3-10 membered heterocycloalkyl, optionally substituted by one or more R 2a substituted 6-10 membered aromatic group, or optionally substituted by one or more R 2a substituted 5- to 10-membered heteroaromatic groups; R3 is empty, H, halogen, -CN, -C(O)OH, carbamoyl, aminosulfonamide, optionally replaced by one or more R 3a Substituted -C 1～10 Alkyl, optionally substituted by one or more R 3a Substituted -C 1～10 Oxyalkyl, optionally substituted by one or more R 3a Substituted 3-10 membered cycloalkyl, optionally substituted by one or more R 3a substituted 3-10 membered heterocycloalkyl, optionally substituted by one or more R 3a substituted 6-10 membered aromatic group, or optionally substituted by one or more R 3a a substituted 5- to 10-membered heteroaromatic group; or, R1 and R2 are linked together with the atoms to which they are connected to form a ring B, or R2 and R3 are linked together with the atoms to which they are connected to form a ring B; or, one of R1, R2 and R3 is linked to at least one of the following structures through A: One or more One or more One or more or one or more R1' is empty, H, halogen, -CN, -C(O)OH, carbamoyl, aminosulfonamide, optionally replaced by one or more R 1b Substituted -C 1～10 Alkyl, optionally substituted by one or more R 1b Substituted -C 1～10 Oxyalkyl, optionally substituted by one or more R 1b Substituted 3-10 membered cycloalkyl, optionally substituted by one or more R 1b substituted 3-10 membered heterocycloalkyl, optionally substituted by one or more R 1b substituted 6-10 membered aromatic group, or optionally substituted by one or more R 1b substituted 5- to 10-membered heteroaromatic groups; R2' is empty, H, halogen, -CN, -C(O)OH, carbamoyl, aminosulfonamide, optionally replaced by one or more R 2b Substituted -C 1～10 Alkyl, optionally substituted by one or more R 2b Substituted -C 1～10 Oxyalkyl, optionally substituted by one or more R 2b Substituted 3-10 membered cycloalkyl, optionally substituted by one or more R 2b substituted 3-10 membered heterocycloalkyl, optionally substituted by one or more R 2b substituted 6-10 membered aromatic group, or optionally substituted by one or more R 2b substituted 5- to 10-membered heteroaromatic groups; R3' is empty, H, halogen, -CN, -C(O)OH, carbamoyl, aminosulfonamide, optionally replaced by one or more R 3b Substituted -C 1～10 Alkyl, optionally substituted by one or more R 3b Substituted -C 1～10 Oxyalkyl, optionally substituted by one or more R 3b Substituted 3-10 membered cycloalkyl, optionally substituted by one or more R 3b substituted 3-10 membered heterocycloalkyl, optionally substituted by one or more R 3b substituted 6-10 membered aromatic group, or optionally substituted by one or more R 3b substituted 5- to 10-membered heteroaromatic groups; Each R 1a 、R 2a 、R 3a 、R 1b 、R 2b and R 3b Each independently selected from halogen, -OH, -C(O)OH, -SH, -NH2, -NO2, -CN, -C 1～10 Alkyl, -C 1～10 Oxyalkyl, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, 6-10 membered aromatic group, or 5-10 membered heteroaromatic group, wherein the 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, 6-10 membered aromatic group, or 5-10 membered heteroaromatic group is optionally substituted by at least one of one or more of the following groups: halogen, -OH, -C(O)OH, -SH, -NH2, -NO2, -CN ... 1～10 alkyl; A is empty, optionally replaced by one or more R 1c Replaced Optionally one or more R 1c Replaced Optionally one or more R 1c Replaced -OC 0～10 Alkylene-, -S-, optionally with one or more R 1c -NH-, optionally substituted with one or more R 1c Substituted-N(C 1～10 Alkyl)-, optionally substituted by one or more R 1c Substituted -C 1～10 Alkylene-, optionally substituted by one or more R 1c Substituted -C(O)C 0～10 Alkylene-, optionally substituted by one or more R 1c Substituted 3-10 membered cycloalkyl, optionally substituted by one or more R 1c substituted 3-10 membered heterocycloalkyl, optionally substituted by one or more R 1c substituted 6-10 membered aromatic group, or optionally substituted by one or more R 1c Substituted 5- to 10-membered heteroaromatic group, each R 1c are independently selected from halogen, -CN, -C 1～10 Alkyl, -C 1～6 Oxyalkyl; Ring A' is a 6- to 10-membered aromatic group or a 5- to 10-membered heteroaromatic group; n1 and n2 are each independently 1, 2 or 3; Ring B and Ring B' are each independently selected from optionally substituted by one or more R 2c substituted 6-10 membered aromatic ring group, or optionally substituted with one or more R 2c A substituted 5- to 10-membered heteroaromatic ring group containing at least one heteroatom selected from O, N, and S, wherein each R 2c Each independently selected from halogen, -OH, -C(O)OH, -SH, -NH2, -NO2, -CN, -C 1～6 Alkyl, -C 1～6 Oxyalkyl; R4 and R4' are each independently selected from optionally replaced by one or more R 4a -NH2, optionally substituted with one or more R 4a -NHNH2, optionally substituted with one or more R 4a Substituted -C 0～6 Alkylene-CO-NH2, optionally with one or more R 4a Substituted -C 0～10 Alkylene-CO-NHNH2, optionally with one or more R 4a Substituted -C 1～10 Alkyl, optionally substituted by one or more R 4a Substituted 3-10 membered cycloalkyl, optionally substituted by one or more R 4a Substituted 3-10 membered heterocycloalkyl, each R 4a Each independently selected from -C 1～10 Alkyl, -OH, -SH, -NH2; R5 and R5' are each independently selected from optionally substituted by one or more R 5a -NH2, optionally substituted with one or more R 5a -NHNH2, optionally substituted with one or more R 5a Substituted -C 1～10 Alkyl, optionally substituted by one or more R 5a substituted 3-10 membered cycloalkyl, or optionally substituted with one or more R 5a Substituted 3-10 membered heterocycloalkyl, each R 5a Each independently selected from -C 1～10 Alkyl, -OH, -SH, or -NH2; R6 and R6' are each independently selected from the group consisting of: null, =O, halogen, -CN, -C(O)OH, carbamoyl, aminosulfonamide, optionally substituted by one or more R 6a Substituted -C 1～10 Alkyl, or optionally one or more R 6a Substituted -C 1～10 Oxyalkyl, each R 6a Each independently selected from halogen, -OH, -C(O)OH, -SH, -NH2, -NO2, -CN, -C 1～10 Alkyl, -C 1～10 Oxyalkyl; Each are each independently selected from single bonds and double bonds; Each Each is independently a single bond and absent; X1, X2, X3, X4, X5, X1′, X2′, X3′, X4′ and X5′ are each independently selected from C or N.

2. A compound, which is a compound represented by formula (I) or a stereoisomer, tautomer, solvate, or pharmaceutically acceptable salt of the compound represented by formula (I): in, R1 is empty, H, halogen, -CN, -C(O)OH, carbamoyl, aminosulfonamide, optionally replaced by one or more R 1a Substituted -C 1～6 Alkyl, optionally substituted by one or more R 1a Substituted -C 1～6 Oxyalkyl, optionally substituted by one or more R 1a Substituted 3-10 membered cycloalkyl, optionally substituted by one or more R 1a substituted 3-10 membered heterocycloalkyl, optionally substituted by one or more R 1a substituted 6-10 membered aromatic group, or optionally substituted by one or more R 1a substituted 5- to 10-membered heteroaromatic groups; R2 is empty, H, halogen, -CN, -C(O)OH, carbamoyl, aminosulfonamide, optionally replaced by one or more R 2a Substituted -C 1～6 Alkyl, optionally substituted by one or more R 2a Substituted -C 1～6 Oxyalkyl, optionally substituted by one or more R 2a Substituted 3-10 membered cycloalkyl, optionally substituted by one or more R 2a substituted 3-10 membered heterocycloalkyl, optionally substituted by one or more R 2a substituted 6-10 membered aromatic group, or optionally substituted by one or more R 2a substituted 5- to 10-membered heteroaromatic groups; R3 is empty, H, halogen, -CN, -C(O)OH, carbamoyl, aminosulfonamide, optionally replaced by one or more R 3a Substituted -C 1～6 Alkyl, optionally substituted by one or more R 3a Substituted -C 1～6 Oxyalkyl, optionally substituted by one or more R 3a Substituted 3-10 membered cycloalkyl, optionally substituted by one or more R 3a substituted 3-10 membered heterocycloalkyl, optionally substituted by one or more R 3a substituted 6-10 membered aromatic group, or optionally substituted by one or more R 3a a substituted 5- to 10-membered heteroaromatic group; or, R1 and R2 are linked together with the atoms to which they are connected to form a ring B, or R2 and R3 are linked together with the atoms to which they are connected to form a ring B; or, one of R1, R2 and R3 is linked to at least one of the following structures through A: One or more One or more One or more or one or more R1' is empty, H, halogen, -CN, -C(O)OH, carbamoyl, aminosulfonamide, optionally replaced by one or more R 1b Substituted -C 1～6 Alkyl, optionally substituted by one or more R 1b Substituted -C 1～6 Oxyalkyl, optionally substituted by one or more R 1b Substituted 3-10 membered cycloalkyl, optionally substituted by one or more R 1b substituted 3-10 membered heterocycloalkyl, optionally substituted by one or more R 1b substituted 6-10 membered aromatic group, or optionally substituted by one or more R 1b substituted 5- to 10-membered heteroaromatic groups; R2' is empty, H, halogen, -CN, -C(O)OH, carbamoyl, aminosulfonamide, optionally replaced by one or more R 2b Substituted -C 1～6 Alkyl, optionally substituted by one or more R 2b Substituted -C 1～6 Oxyalkyl, optionally substituted by one or more R 2b Substituted 3-10 membered cycloalkyl, optionally substituted by one or more R 2b substituted 3-10 membered heterocycloalkyl, optionally substituted by one or more R 2b substituted 6-10 membered aromatic group, or optionally substituted by one or more R 2b substituted 5- to 10-membered heteroaromatic groups; R3' is empty, H, halogen, -CN, -C(O)OH, carbamoyl, aminosulfonamide, optionally replaced by one or more R 3b Substituted -C 1～6 Alkyl, optionally substituted by one or more R 3b Substituted -C 1～6 Oxyalkyl, optionally substituted by one or more R 3b Substituted 3-10 membered cycloalkyl, optionally substituted by one or more R 3b substituted 3-10 membered heterocycloalkyl, optionally substituted by one or more R 3b substituted 6-10 membered aromatic group, or optionally substituted by one or more R 3b substituted 5- to 10-membered heteroaromatic groups; Each R 1a 、R 2a 、R 3a 、R 1b 、R 2b and R 3b Each independently selected from halogen, -OH, -C(O)OH, -SH, -NH2, -NO2, -CN, -C 1～6 Alkyl, -C 1～6 Oxyalkyl, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, 6-10 membered aromatic group, or 5-10 membered heteroaromatic group, wherein the 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, 6-10 membered aromatic group, or 5-10 membered heteroaromatic group is optionally substituted by at least one of one or more of the following groups: halogen, -OH, -C(O)OH, -SH, -NH2, -NO2, -CN ... 1～6 alkyl; A is empty, optionally replaced by one or more R 1c Replaced Optionally one or more R 1c Replaced Optionally one or more R 1c Replaced -OC 0～3 Alkylene-, -S-, optionally with one or more R 1c -NH-, optionally substituted with one or more R 1c Substituted-N(C 1～3 Alkyl)-, optionally substituted by one or more R 1c Substituted -C 1～3 Alkylene-, optionally substituted by one or more R 1c Substituted -C(O)C 0～3 Alkylene-, optionally substituted by one or more R 1c Substituted 3-10 membered cycloalkyl, optionally substituted by one or more R 1c substituted 3-10 membered heterocycloalkyl, optionally substituted by one or more R 1c substituted 6-10 membered aromatic group, or optionally substituted by one or more R 1c Substituted 5- to 10-membered heteroaromatic group, each R 1c are independently selected from halogen, -CN, -C 1～6 Alkyl, -C 1～6 Oxyalkyl; Ring A' is a 6- to 10-membered aromatic group or a 5- to 10-membered heteroaromatic group; n1 and n2 are each independently 1, 2 or 3; Ring B and Ring B' are each independently selected from optionally substituted by one or more R 2c substituted 6-10 membered aromatic ring group, or optionally substituted with one or more R 2c A substituted 5- to 10-membered heteroaromatic ring group containing at least one heteroatom selected from O, N, and S, wherein each R 2c Each independently selected from halogen, -OH, -C(O)OH, -SH, -NH2, -NO2, -CN, -C 1～6 Alkyl, -C 1～6 Oxyalkyl; R4 and R4' are each independently selected from optionally replaced by one or more R 4a -NH2, optionally substituted with one or more R 4a -NHNH2, optionally substituted with one or more R 4a Substituted -C 0～6 Alkylene-CO-NH2, optionally with one or more R 4a Substituted -C 0～6 Alkylene-CO-NHNH2, optionally with one or more R 4a Substituted -C 1～6 Alkyl, optionally substituted by one or more R 4a Substituted 3-10 membered cycloalkyl, optionally substituted by one or more R 4a Substituted 3-10 membered heterocycloalkyl, each R 4a Each independently selected from -C 1～6 Alkyl, -OH, -SH, -NH2; R5 and R5' are each independently selected from optionally substituted by one or more R 5a -NH2, optionally substituted with one or more R 5a -NHNH2, optionally substituted with one or more R 5a Substituted -C 1～6 Alkyl, optionally substituted by one or more R 5a substituted 3-10 membered cycloalkyl, or optionally substituted with one or more R 5a Substituted 3-10 membered heterocycloalkyl, each R 5a Each independently selected from -C 1～6 Alkyl, -OH, -SH, or -NH2; R6 and R6' are each independently selected from the group consisting of: null, =O, halogen, -CN, -C(O)OH, carbamoyl, aminosulfonamide, optionally substituted by one or more R 6a Substituted -C 1～6 Alkyl, or optionally one or more R 6a Substituted -C 1～6 Oxyalkyl, each R 6a Each independently selected from halogen, -OH, -C(O)OH, -SH, -NH2, -NO2, -CN, -C 1～6 Alkyl, -C 1～6 Oxyalkyl; Each are each independently selected from single bonds and double bonds; Each Each is independently a single bond and absent; X1, X2, X3, X4, X5, X1', X2', X3', X4' and X5' are each independently selected from C or N; The compound represented by formula (I) is not optionally substituted by one or more halogens. Optionally substituted with one or more halogens Optionally substituted with one or more halogens 3. The compound according to claim 1 or 2, characterized in that The compound represented by formula (I) is not optionally substituted by one or more halogens. Optionally substituted with one or more halogens Optionally substituted with one or more halogens Optionally, X1 is N, R5 is -NH2; Optionally, X5 is C, R6 is ═O; Optionally, one of R1, R2 and R3 is connected to at least one of the following structures through A: one one or one X1 is N, R5 is -NH2, X5 is C, R6 is =O; Alternatively, X1' is N, R5' is -NH2, X5' is C, and R6' is =O; Optionally, the compound represented by formula (I) is not Optionally, one of R1, R2 and R3 is connected to at least one of the following structures through A: Multiple Multiple Multiple or one or more Optionally, R1 and R2 are not When connected, X1, X2, X3, X4 and X5 are not C at the same time; Optionally, A is empty, optionally replaced by one or more R 1c Replaced Optionally one or more R 1c Replaced Optionally one or more R 1c Replaced -OC 0～3 Alkylene-, -S-, optionally with one or more R 1c Substituted -C 1～3 Alkylene-, optionally substituted by one or more R 1c Substituted 6- to 10-membered aromatic groups; Optionally, A is empty, -O-, -S-, optionally replaced by one or more R 1c Replaced Optionally one or more R 1c Replaced Optionally one or more R 1c Substituted -C 1～3 Alkylene-, optionally substituted by one or more R 1c Substituted 6- to 8-membered aromatic groups; Optionally, A is empty, optionally replaced by one or more R 1c Replaced -OC 0～3 Alkylene-, -S-, or optionally substituted by one or more R 1c Substituted -C 1～3 Alkylene-; Optionally, A is empty, optionally replaced by one or more R 1c Replaced Optionally one or more R 1c Replaced or optionally one or more R 1c Substituted 6- to 10-membered aromatic groups; Optionally, A is empty, optionally replaced by one or more R 1c Replaced Optionally one or more R 1c Replaced or optionally one or more R 1c substituted 6-8 membered aromatic group, or optionally substituted by one or more R 1c Substituted 5- to 8-membered heteroaromatic group; Optionally, ring A' is a 6- to 10-membered aromatic group, preferably a 6- to 8-membered aromatic group; Optionally, n1 and n2 are each independently 1 or 2; Optionally, each R 1c are each independently selected from halogen, -C 1～3 Haloalkyl, -C 1～3 Alkyl, or -C 1～3 Oxyalkyl; Optionally, each R 1c Each independently selected from halogen, -CF3, -C 1～3 Alkyl, or -C 1～3 Oxyalkyl; Optionally, A is empty, -O-, -S-, -C 1～3 Alkylene-, 6-10 membered aromatic group, or Optionally, A is empty, 6-10 membered aromatic group, or Optionally, A is empty, -O-, or -OC 1～3 Alkylene-, or -S-; Optionally, A is empty, -O-, -S-, Optionally, A is empty, -O-, or -S-; Optionally, A is empty, Optionally, A is empty, Optionally, each R 2c are each independently selected from halogen, -C 1～3 Haloalkyl, -OH, -SH, -NH2, -NO2, -CN, -C 1～6 Alkyl, or -C 1～6 Oxyalkyl; Optionally, each R 2c are each independently selected from halogen, -C 1～3 Alkyl, or -C 1～3 Oxyalkyl; Optionally, each R 2c are each independently selected from halogen or -C 1～3 Oxyalkyl; Optionally, Ring B and Ring B' are each independently selected from optionally substituted by one or more R 2c a substituted 6- to 10-membered heteroaromatic ring group containing one or more nitrogen heteroatoms; Optionally, Ring B and Ring B' are each independently selected from optionally substituted by one or more R 2c Substituted 6- to 10-membered aromatic ring group; Optionally, Ring B is selected from optionally substituted by one or more halogen or -C 1～3 an oxyalkyl-substituted 6- to 10-membered aromatic ring group; Optionally, Ring B is selected from optionally substituted by one or more halogen or -C 1～3 an oxyalkyl-substituted 6-membered aromatic ring group; Optionally, Ring B is optionally substituted with one or more halogen or -C 1～3 Oxyalkyl-substituted phenyl group; Optionally, ring B' is selected from a 6-10 membered aromatic ring group optionally substituted by one or more halogens; Optionally, ring B' is selected from a 6-7 membered aromatic ring group optionally substituted by one or more halogens; Optionally, Ring B' is phenyl optionally substituted with one or more halogens; Optionally, ring B' is phenyl; Optionally, X1, X2, X1' and X2' are each independently selected from C or N; Optionally, X1, X2, X1' and X2' are each independently selected from C or N, and X1' and X2' are not C at the same time; Optionally, X1 and X2 are each independently selected from C or N, and X1 and X2 are not C at the same time; Optionally, X1, X2 and X1' are C, and X2' is N; Optionally, X1 and X1' are C, X2 and X2' are N; Optionally, X1 and X1' are C; Optionally, X2 and X2' are each independently selected from C or N; Optionally, X2 and X2' are C; Optionally, X2 and X2' are N; Optionally, R1 is H, halogen, optionally substituted by one or more R 1a Substituted -C 1～3 Alkyl, optionally substituted by one or more R 1a Substituted 6- to 10-membered aromatic groups; Optionally, each R 1a Each independently selected from halogen, -OH, -C(O)OH, -SH, -NH2, -NO2, -CN, -C 1～3 Alkyl, -C 1～3 Oxyalkyl, 6-10 membered aromatic group, or 5-10 membered heteroaromatic group; the 6-10 membered aromatic group or 5-10 membered heteroaromatic group is optionally substituted by at least one of the following groups: halogen, -NH2, -C optionally substituted by one or more -OH 1～3 alkyl; Optionally, R1 is H, optionally substituted by halogen, -C 1～3 Haloalkyl, -C 1～3 Alkyl, or -C 1～3 6- to 8-membered aromatic groups substituted with oxyalkyl groups; Optionally, R1 is R7 is selected from H, halogen, -C 1～3 Haloalkyl, -C 1～3 Alkyl, or -C 1～3 Oxyalkyl; Optionally, R2 and R2' are each independently selected from H or halogen; Optionally, R3 and R3' are each independently selected from the group consisting of space, H, halogen, -C 1～3 Haloalkyl, -C 1～3 Alkyl, or -C 1～3 Oxyalkyl; Optionally, R3 is selected from the group consisting of space, H, halogen, -C 1～3 Haloalkyl, or -C 1～3 Oxyalkyl; Optionally, R3 is selected from space, H, or halogen; Optionally, X2 is N, and R3 is empty; Optionally, X2 is C, R3 is H; Optionally, X2' is N, and R3' is empty; Optionally, X2' is C, R3' is H; Optionally, R4 and R4' are each independently selected from optionally replaced by one or more R 4a Substituted -C 0～3 Alkylene-CO-NH2, optionally with one or more R 4a Substituted -C 0～3 Alkylene-CO-NHNH2, optionally with one or more R 4a -NHNH2, optionally substituted with one or more R 4a -NH2, or optionally substituted with one or more R 4a Substituted -C 3～6 Alkyl, or optionally one or more R 4a Substituted -C 3～6 Cycloalkyl, or optionally substituted by one or more R 4a Substituted -C 3～6 heterocycloalkyl; Optionally, R4 is selected from the group consisting of one or more R 4a Substituted -C 0～3 Alkylene-CO-NH2, optionally with one or more R 4a Substituted -C 0～3 Alkylene-CO-NHNH2, or optionally one or more R 4a Substituted -C 3～6 alkyl; Optionally, R4 and R4' are each independently selected from optionally replaced by one or more R 4a Substituted -C 3～6 alkyl; Optionally, each R 4a Each independently selected from halogen, -OH, -NH2; Optionally, R4 is selected from -CO-NH2, -CO-NHNH2, -C optionally substituted with one or more -OH or one or more -NH2 3～6 alkyl; Optionally, R4 and R4' are each independently selected from -C optionally substituted with one or more -OH 3～6 Alkyl, or one or more -NH2 substituted -C 3～6 alkyl; Optionally, R4 and R4' are each independently selected from -C optionally substituted with one or more -OH 3～6 alkyl; Optionally, R4, R4', R5 and R5' are each independently selected from optionally replaced by one or more R 4a Substituted -NH2, R 4a -C 1～6 alkyl; Optionally, R5 is selected from -NH2 or -NHNH2; Optionally, R5 is selected from -NH2; Optionally, R6 and R6' are each independently selected from H, =O, halogen, -C 1～3 Alkyl, or -C 1～3 Oxyalkyl; Optionally, R6 is selected from H or ═O; Optionally, X5 is C, R6 is ═O, X1 is N, is a single bond; Optionally, R6 and R6′ are both H.

4. The compound according to claim 1 or 2, characterized in that The compound represented by formula (I) has the structure represented by formula (II):

5. The compound according to claim 1 or 2, characterized in that The compound represented by formula (I) has the structure represented by formula (III): Alternatively, the compound represented by formula (I) has a structure represented by formula (IIIa): Wherein, R8 is H, halogen, -C 1～6 Alkyl, -C 1～6 Oxyalkyl, or -C 1～6 Halogenated alkyl.

6. The compound according to claim 1 or 2, characterized in that The compound represented by formula (I) has the structure represented by formula (IV): Optionally, the structure wherein H is optionally substituted by halogen; Optionally, the compound represented by formula (I) has a structure represented by formula (IVa):

7. The compound according to claim 1 or 2, characterized in that The compound represented by formula (I) has the structure represented by formula (V):

8. The compound according to claim 1 or 2, characterized in that The compound represented by formula (I) has the following structure:

9. A pharmaceutical composition, characterized in that The invention comprises the compound according to any one of claims 1 to 8.

10. The pharmaceutical composition according to claim 9, characterized in that The pharmaceutical composition may further include a pharmaceutically acceptable carrier, excipient, or vehicle.

11. The compound according to any one of claims 1 to 8, or the pharmaceutical composition according to any one of claims 9 to 10, for preventing and / or treating diseases related to aldehyde metabolism disorders, or for the following uses: Preventing and / or treating diseases caused by aldehyde metabolism disorders; and / or Preparation of medicines for preventing and / or treating related diseases caused by aldehyde metabolism disorders.

12. A method for preventing and / or treating diseases related to aldehyde metabolism disorders, characterized in that: include: A pharmaceutically acceptable dose of the compound according to any one of claims 1 to 8 or the pharmaceutical composition according to any one of claims 9 to 10 is administered to a subject.

13. The use according to claim 11 or the method according to claim 12, characterized in that The diseases caused by aldehyde metabolism disorders include eye diseases, skin diseases, autoimmune diseases, inflammatory diseases, nervous system diseases, metabolic disorders, cardiovascular diseases, sclerosis, fibrosis diseases, aging-related diseases, tumors, or diseases caused by blistering agents.

14. The use or method according to claim 12, characterized in that The eye diseases include dry eye, allergic conjunctivitis, bullous keratopathy, uveitis, scleritis, red eye, diabetic retinopathy, and cataracts; Optionally, the skin disease comprises atopic dermatitis, psoriasis, eczema, alopecia areata, acne, rosacea; Optionally, the autoimmune disease comprises arthritis, rheumatoid arthritis, Sjögren's syndrome, systemic lupus erythematosus, Crohn's disease, celiac disease, ulcerative colitis, hyperthyroidism, Hashimoto's thyroiditis, Addison's disease, dermatomyositis, chronic inflammatory demyelinating polyneuropathy, Guillain-Barré syndrome, multiple sclerosis, myasthenia gravis, autoimmune vasculitis, pernicious anemia, vasculitis; Optionally, the inflammatory disease comprises asthma, arthritis, Alzheimer's disease, nonspecific intestinal inflammation; Optionally, the nervous system disease comprises dementia-type disease, demyelinating disease, Parkinson's disease, motor neuron disease, prion disease, cerebral infarction, amyotrophic lateral sclerosis; Optionally, the metabolic disorder comprises nonalcoholic fatty liver disease, steatohepatitis, cirrhosis, diabetes; Optionally, the cardiovascular disease comprises coronary heart disease, arrhythmia, cardiomyopathy, heart failure, congenital heart disease, pericarditis.

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