Indole phthalocyanine compound, preparation method thereof and application of indole phthalocyanine compound in tumor diagnosis imaging

Abstract

The invention relates to an indole phthalocyanine compound, a preparation method thereof and application of the indole phthalocyanine compound in tumor diagnosis imaging. Specifically, the invention relates to a compound with a structure shown in a general formula (I) or a pharmaceutically acceptable salt thereof, and an application of the compound as a contrast agent. Near-infrared real-time imaging # imgabs0 # capable of realizing high contrast and clear and distinguishable imaging result by using contrast agent provided by the invention

Description

Indolephthalocyanine compounds, preparation methods thereof, and applications in tumor diagnostic imaging Technical Field

[0001] The present invention relates to an indolephthalocyanine compound, a preparation method thereof and an application thereof in tumor diagnostic imaging. Background Art

[0002] Molecular imaging is an interdisciplinary subject formed by the integration of molecular biology and medical imaging. Compared with traditional imaging examinations, molecular imaging technology has the advantages of high sensitivity and quantification. Molecular imaging technology or molecular imaging technology mainly includes magnetic resonance (MR) molecular imaging, nuclear medicine molecular imaging technology and optical molecular imaging. Among them, near-infrared fluorescence (NIRF) imaging technology in optical molecular imaging technology has been widely used in clinical surgical operations. Its basic principle is to use the near-infrared light emitted by fluorescent tracers after excitation to mark blood vessels, lymph nodes, tumor lesions and other parts, thereby assisting clinicians in performing surgical operations.

[0003] Currently, indocyanine green (ICG) is widely used in clinical practice as a near-infrared fluorescent tracer. However, because ICG lacks specific recognition for tumor tissue, its use during surgical tumor resection can only indirectly label tumor lesions through vascular and tissue differences. This imaging yields poor results, characterized by insufficient sensitivity, poor tumor specificity, and short imaging times. There are no clinically specific imaging diagnostic reagents for bladder cancer tissue.

[0004] Problem to be solved: Find a contrast agent that has strong targeting ability for tumors and can be clearly distinguished from surrounding normal tissues, especially for bladder instillation, can shorten the imaging time, has sufficient duration in the tumor, and has good biological adaptability without obvious toxicity and accumulation.

[0005] Summary of the Invention

[0006] The present invention provides a new near-infrared fluorescent tumor marking technology.

[0007] Therefore, the object of the present invention is to provide a compound having a structure represented by general formula (I) or a pharmaceutically acceptable salt thereof,

[0008] in:

[0009] X is C, O, S or N + ;

[0010] R 1 and R 2 Each independently selected from L1-L2-L3-Q;

[0011] L1 is selected from a bond, -(CH2) p -、-(CH2O) q -、-(CH2CH2O) v -、-(CH2O) q -(CH2) p -, -(CH2) p -(CH2O) q -、-(CH2) p -(CH2O) q -(CH2) p -、-(CH2CH2O) v -(CH2) p -、-(CH2CH2O) v -(CH2O) q -;

[0012] L2 is selected from a bond, an aryl group, a heteroaryl group, a cycloalkyl group, a heterocyclyl group;

[0013] L3 is selected from a bond, -(CH2) p -、-(CH2O) q -、-(CH2CH2O) v -、-(CH2O) q -(CH2) p -、-(CH2) p -(CH2O) q -、-(CH2) p -(CH2O) q -(CH2) p -、-(CH2CH2O) v -(CH2) p -、-(CH2CH2O) v -(CH2O) q -;

[0014] Q is selected from R 12 、-OR 13 、-C(O)R 12 、-C(O)OR 13 、-C(O)NHR 13 、-SO3H、

[0015] R 12is selected from hydrogen, halogen, amino, hydroxy, mercapto, alkyl, alkylamino, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl; said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted with one or more groups selected from halogen, amino, cyano, hydroxy, mercapto, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl;

[0016] R 13 is selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl; said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted with one or more groups selected from halogen, amino, cyano, hydroxy, mercapto, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl;

[0017] R 3 、R 4 each independently selected from hydrogen, halogen, amino, nitro, cyano, hydroxy, thiol, oxo, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein said alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from halogen, amino, oxo, thiol, nitro, cyano, hydroxy, thiol, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

[0018] R 5 、R 6 each independently selected from hydrogen, halogen, amino, nitro, cyano, hydroxy, thiol, oxo, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein said alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from halogen, amino, oxo, thiol, nitro, cyano, hydroxy, thiol, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

[0019] R 7 Selected from hydrogen, halogen, nitro, cyano, hydroxyl, mercapto, oxo, alkyl, OR a NR b R c, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from halogen, amino, oxo, thioxo, nitro, cyano, hydroxyl, mercapto, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

[0020] R 8 、R 9 are independently selected from hydrogen, halogen, nitro, cyano, hydroxyl, mercapto, oxo, alkyl, OR a NR b R c , alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from halogen, amino, oxo, thio, nitro, cyano, hydroxyl, sulfhydryl, carboxyl, ester, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

[0021] R 8a 、R 9a each independently selected from hydrogen, halogen, amino, nitro, cyano, hydroxy, thiol, oxo, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein said alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from halogen, amino, oxo, thiol, nitro, cyano, hydroxy, thiol, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

[0022] R 8b 、R 9b each independently selected from hydrogen, halogen, amino, nitro, cyano, hydroxy, thiol, oxo, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein said alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from halogen, amino, oxo, thiol, nitro, cyano, hydroxy, thiol, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

[0023] R 10a 、R 10b 、R 10c 、R 10dEach is independently selected from hydrogen, halogen, nitro, cyano, hydroxyl, mercapto, oxo, alkyl, OR a NR b R c , alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from halogen, amino, oxo, thio, nitro, cyano, hydroxyl, sulfhydryl, carboxyl, ester, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

[0024] or R 10a 、R 10b 、R 10c 、R 10d Any two adjacent atoms to which they are attached together form an aryl or heteroaryl group, wherein the aryl or heteroaryl group is optionally further substituted with one or more substituents selected from halogen, amino, oxo, thio, nitro, cyano, hydroxyl, sulfhydryl, carboxyl, ester, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

[0025] R 11a 、R 11b 、R 11c 、R 11d Each is independently selected from hydrogen, halogen, nitro, cyano, hydroxyl, mercapto, oxo, alkyl, OR a NR b R c 、-SO3H、-S(O)2R a 、-C(O)OR a , alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from halogen, amino, oxo, thio, nitro, cyano, hydroxyl, sulfhydryl, carboxyl, ester, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

[0026] or R 11a 、R 11b 、R 11c 、R 11dAny two adjacent atoms to which they are attached together form an aryl or heteroaryl group, wherein the aryl or heteroaryl group is optionally further substituted with one or more substituents selected from halogen, amino, oxo, thio, nitro, cyano, hydroxyl, sulfhydryl, carboxyl, ester, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

[0027] R a selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further selected from halogen, amino, oxo, thio, nitro, cyano, hydroxyl, sulfhydryl, carboxyl, ester, sulfonic acid, -NHC(O)-L4-NR b R c 、-OC(O)-L4-NR b R c , alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; wherein -L4- is alkenylene;

[0028] R b and R c each independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from halogen, amino, oxo, thio, nitro, cyano, hydroxy, thiol, carboxyl, ester, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

[0029] m is 0 or 1;

[0030] p is an integer from 1 to 10;

[0031] q is an integer from 1 to 10;

[0032] v is an integer from 1 to 10.

[0033] Another aspect of the present invention provides a compound represented by general formula (IA) or a pharmaceutically acceptable salt thereof,

[0034] in:

[0035] X is C, O, S or N + ;

[0036] M -is an acid ion, preferably a chloride ion, a bromide ion, an iodide ion, a formate ion, an acetate ion, or a trifluoroacetate ion;

[0037] n is 1 or 2, and when X is an N + When n is 2, when X is C, O or S, n is 1;

[0038] R 1 and R 2 Each independently selected from L1-L2-L3-Q;

[0039] L1 is selected from a bond, -(CH2) p -、-(CH2O) q -、-(CH2CH2O) v -、-(CH2O) q -(CH2) p -、-(CH2) p -(CH2O) q -、-(CH2) p -(CH2O) q -(CH2) p -、-(CH2CH2O) v -(CH2) p -、-(CH2CH2O) v -(CH2O) q -;

[0040] L2 is selected from a bond, an aryl group, a heteroaryl group, a cycloalkyl group, a heterocyclyl group;

[0041] L3 is selected from a bond, -(CH2) p -、-(CH2O) q -、-(CH2CH2O) v -、-(CH2O) q -(CH2) p -, -(CH2) p -(CH2O) q -、-(CH2) p -(CH2O) q -(CH2) p -、-(CH2CH2O) v -(CH2) p -、-(CH2CH2O) v -(CH2O) q -;

[0042] Q is selected from R 12 、-OR 13 、-C(O)R 12 、-C(O)OR 13、-C(O)NHR 13 、-SO3H、

[0043] R 12 is selected from hydrogen, halogen, amino, hydroxy, mercapto, alkyl, alkylamino, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl; said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted with one or more groups selected from halogen, amino, cyano, hydroxy, mercapto, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl;

[0044] R 13 is selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl; said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted with one or more groups selected from halogen, amino, cyano, hydroxy, mercapto, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl;

[0045] R 3 、R 4 each independently selected from hydrogen, halogen, amino, nitro, cyano, hydroxy, thiol, oxo, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein said alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from halogen, amino, oxo, thiol, nitro, cyano, hydroxy, thiol, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

[0046] R 5 、R 6 each independently selected from hydrogen, halogen, amino, nitro, cyano, hydroxy, thiol, oxo, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein said alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from halogen, amino, oxo, thiol, nitro, cyano, hydroxy, thiol, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

[0047] R 7 Selected from hydrogen, halogen, nitro, cyano, hydroxyl, mercapto, oxo, alkyl, OR a SR a NR b R c, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from halogen, amino, oxo, thioxo, nitro, cyano, hydroxyl, mercapto, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

[0048] R 8 、R 9 Each is independently selected from hydrogen, halogen, nitro, cyano, hydroxyl, mercapto, oxo, alkyl, OR a NR b R c , alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from halogen, amino, oxo, thio, nitro, cyano, hydroxyl, sulfhydryl, carboxyl, ester, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

[0049] R 8a 、R 9a each independently selected from hydrogen, halogen, amino, nitro, cyano, hydroxy, thiol, oxo, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein said alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from halogen, amino, oxo, thiol, nitro, cyano, hydroxy, thiol, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

[0050] R 8b 、R 9b each independently selected from hydrogen, halogen, amino, nitro, cyano, hydroxy, thiol, oxo, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein said alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from halogen, amino, oxo, thiol, nitro, cyano, hydroxy, thiol, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

[0051] R 10a 、R 10b 、R 10c 、R 10dEach is independently selected from hydrogen, halogen, nitro, cyano, hydroxyl, mercapto, oxo, alkyl, OR a NR b R c , alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from halogen, amino, oxo, thio, nitro, cyano, hydroxyl, sulfhydryl, carboxyl, ester, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

[0052] or R 10a 、R 10b 、R 10c 、R 10d Any two adjacent atoms to which they are attached together form an aryl or heteroaryl group, wherein the aryl or heteroaryl group is optionally further substituted with one or more substituents selected from halogen, amino, oxo, thio, nitro, cyano, hydroxyl, sulfhydryl, carboxyl, ester, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

[0053] R 11a 、R 11b 、R 11c 、R 11d Each is independently selected from hydrogen, halogen, nitro, cyano, hydroxyl, mercapto, oxo, alkyl, OR a NR b R c 、-SO3H、-S(O)2R a 、-C(O)OR a , alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from halogen, amino, oxo, thio, nitro, cyano, hydroxyl, sulfhydryl, carboxyl, ester, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

[0054] or R 11a 、R 11b 、R 11c 、R 11dAny two adjacent atoms to which they are attached together form an aryl or heteroaryl group, wherein the aryl or heteroaryl group is optionally further substituted with one or more substituents selected from halogen, amino, oxo, thio, nitro, cyano, hydroxyl, sulfhydryl, carboxyl, ester, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

[0055] R a selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further selected from halogen, amino, oxo, thio, nitro, cyano, hydroxyl, sulfhydryl, carboxyl, ester, sulfonic acid, -NHC(O)-L4-NR b R c 、-OC(O)-L4-NR b R c , alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; wherein -L4- is alkenylene;

[0056] R b and R c each independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from halogen, amino, oxo, thio, nitro, cyano, hydroxy, thiol, carboxyl, ester, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

[0057] m is 0 or 1;

[0058] p is an integer from 1 to 10;

[0059] q is an integer from 1 to 10;

[0060] v is an integer from 1 to 10.

[0061] In one embodiment, the compound having the structure represented by general formula (I) or a pharmaceutically acceptable salt thereof is a compound having the structure represented by general formula (II) or a pharmaceutically acceptable salt thereof,

[0062] Among them, R 1 ~R 7 、R 8a 、R 8b 、R 9a 、R 9b 、R10a 、R 10b 、R 10c 、R 10d 、R 11a 、R 11b 、R 11c 、R 11d As defined in general formula (I).

[0063] In another embodiment, the compound having the structure represented by general formula (I) or a pharmaceutically acceptable salt thereof is a compound having the structure represented by general formula (III) or a pharmaceutically acceptable salt thereof,

[0064] Among them, R 1 ~R 9 、R 8a 、R 8b 、R 9a 、R 9b 、R 10a 、R 10b 、R 10c 、R 10d 、R 11a 、R 11b 、R 11c 、R 11d As defined in general formula (I).

[0065] In another embodiment, the compound represented by the general formula (IA) or a pharmaceutically acceptable salt thereof is a compound represented by the general formula (IIA) or (IIIA) or a pharmaceutically acceptable salt thereof,

[0066] Among them, M - 、R 1 ~R 9 、R 8a 、R 8b 、R 9a 、R 9b 、R 10a 、R 10b 、R 10c 、R 10d 、R 11a 、R 11b 、R 11c 、R 11d As defined in general formula (IA).

[0067] In another embodiment, the compound having the structure represented by general formula (I) or a pharmaceutically acceptable salt thereof is a compound having the structure represented by general formula (IV) or a pharmaceutically acceptable salt thereof,

[0068] Among them, R1 ~R 9 、R 8a 、R 8b 、R 9a 、R 9b 、R 10a 、R 10b 、R 10c 、R 10d 、R 11a 、R 11b 、R 11c 、R 11d As defined in general formula (I).

[0069] In another embodiment, the compound represented by the general formula (IA) or a pharmaceutically acceptable salt thereof is a compound represented by the general formula (IVA) or a pharmaceutically acceptable salt thereof,

[0070] Among them, M - 、R 1 ~R 9 、R 8a 、R 8b 、R 9a 、R 9b 、R 10a 、R 10b 、R 10c 、R 10d 、R 11a 、R 11b 、R 11c 、R 11d As defined in general formula (IA).

[0071] In another embodiment, the compound having the structure shown in the general formula (I), (II), (III), (IV), (IA), (IIA), (IIIA), (IVA) or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from L1-L2-Q;

[0072] L1 is selected from -(CH2) p -、-(CH2O) q -(CH2) p -;

[0073] L2 is selected from a bond, C 6-10 Aryl, 5- to 10-membered heteroaryl; preferably a bond and phenyl;

[0074] Q is selected from R 12 、-C(O)OR 13 、-C(O)NHR 13 、-SO3H、

[0075] R 12 Selected from hydrogen, hydroxyl, C 1-6 alkyl;

[0076] R 13 Selected from hydrogen, C 6-10 Aryl or 5- to 10-membered heteroaryl; preferably hydrogen and phenyl.

[0077] p is an integer from 1 to 10, preferably an integer from 1 to 6;

[0078] q is an integer of 1 to 10, preferably an integer of 1 to 6.

[0079] In another embodiment, the compound having the structure represented by the general formula (I), (II), (III), (IV), (IA), (IIA), (IIIA), (IVA) or a pharmaceutically acceptable salt thereof, wherein:

[0080] R 2 Selected from L1-Q;

[0081] L1 is selected from -(CH2) p -;

[0082] Q is selected from R 12 、-C(O)OR 13 、-C(O)NHR 13 、-SO3H、

[0083] R 12 Selected from hydrogen, hydroxyl, C 1-6 alkyl;

[0084] R 13 Selected from hydrogen, C 6-10 Aryl or 5- to 10-membered heteroaryl; preferably hydrogen and phenyl.

[0085] p is an integer of 1 to 10, preferably an integer of 1 to 6.

[0086] In another embodiment, the compound having the structure shown in the general formula (I), (II), (III), (IV), (IA), (IIA), (IIIA), (IVA) or a pharmaceutically acceptable salt thereof, wherein R 10a 、R 10b 、R 10c 、R 10d are each independently selected from hydrogen, OR a , R a C 1-6 alkyl.

[0087] In another embodiment, the compound having the structure shown in the general formula (I), (II), (III), (IV), (IA), (IIA), (IIIA), (IVA) or a pharmaceutically acceptable salt thereof, wherein R 11a 、R 11b 、R 11c 、R 11d Each independently selected from hydrogen, carboxyl, OR a NR b R c 、-SO3H、-S(O)2R a 、-C(O)OR a ,

[0088] R a Selected from C 1-6 alkyl;

[0089] R b and R c Each independently selected from C 1-6 alkyl.

[0090] In another embodiment, the compound having the structure shown in the general formula (I), (II), (III), (IV), (IA), (IIA), (IIIA), (IVA) or a pharmaceutically acceptable salt thereof, wherein R 10a 、R 10b 、R 10c 、R 10d Any two adjacent atoms in the 6-10 Aryl or 5- to 10-membered heteroaryl, preferably phenyl; the aryl or heteroaryl is optionally further substituted by one or more substituents selected from halogen, amino, oxo, thio, nitro, cyano, hydroxyl, sulfhydryl, carboxyl, ester, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl.

[0091] In another embodiment, the compound having the structure shown in the general formula (I), (II), (III), (IV), (IA), (IIA), (IIIA), (IVA) or a pharmaceutically acceptable salt thereof, wherein R 11a 、R 11b 、R 11c 、R 11d Any two adjacent atoms in the 6-10Aryl or 5- to 10-membered heteroaryl, preferably phenyl; the aryl or heteroaryl is optionally further substituted by one or more substituents selected from halogen, amino, oxo, thio, nitro, cyano, hydroxyl, sulfhydryl, carboxyl, ester, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl.

[0092] In another embodiment, the compound having the structure represented by the general formula (I) or a pharmaceutically acceptable salt thereof is a compound having the structure represented by the general formula (V) or a pharmaceutically acceptable salt thereof,

[0093] Among them, R 1 ~R 9 、R 8a 、R 8b 、R 9a 、R 9b , X, and m are as defined in the general formula (I).

[0094] In another embodiment, the compound having the structure represented by the general formula (I), (II), (III), (IV), (V), (IA), (IIA), (IIIA), (IVA) or a pharmaceutically acceptable salt thereof, wherein:

[0095] R 1 Selected from L1-Q;

[0096] L1 is selected from -(CH2) p -;

[0097] Q is selected from -C(O)OR 13 、-C(O)NHR 13 、-SO3H、

[0098] R 13 Selected from hydrogen, C 6-10 Aryl or 5- to 10-membered heteroaryl; preferably hydrogen and phenyl;

[0099] p is an integer from 1 to 10, preferably an integer from 1 to 6;

[0100] R 2 Selected from C 1-6 alkyl.

[0101] In another embodiment, the compound having the structure represented by the general formula (I), (II), (III), (IV), (V), (IA), (IIA), (IIIA), (IVA) or a pharmaceutically acceptable salt thereof, wherein:

[0102] R 1Selected from L1-Q;

[0103] L1 is selected from -(CH2O) q -(CH2) p -;

[0104] Q is selected from -C(O)OR 13 、-C(O)NHR 13 ;

[0105] R 13 Selected from hydrogen, C 6-10 Aryl or 5- to 10-membered heteroaryl; preferably phenyl;

[0106] p is an integer from 1 to 6, preferably an integer from 1 to 4, more preferably 1 or 2;

[0107] q is an integer from 1 to 6, preferably an integer from 1 to 4, more preferably 1 or 2;

[0108] R 2 Selected from C 1-6 alkyl.

[0109] In another embodiment, the compound having the structure represented by the general formula (I), (II), (III), (IV), (V), (IA), (IIA), (IIIA), (IVA) or a pharmaceutically acceptable salt thereof, wherein:

[0110] R 1 Selected from L1-L2-Q;

[0111] L1 is selected from -(CH2) p -;

[0112] L2 is selected from C 6-10 Aryl, 5- to 10-membered heteroaryl, preferably phenyl;

[0113] Q is selected from -C(O)OR 13 ;

[0114] R 13 Selected from hydrogen, C 6-10 Aryl or 5- to 10-membered heteroaryl; preferably phenyl;

[0115] p is an integer from 1 to 4, preferably an integer from 1 to 2;

[0116] R 2 Selected from C 1-6 alkyl.

[0117] In another embodiment, the compound having the structure represented by the general formula (I), (II), (III), (IV), (V), (IA), (IIA), (IIIA), (IVA) or a pharmaceutically acceptable salt thereof, wherein:

[0118] R 1 Selected from C 1-6 alkyl;

[0119] R 2 Selected from C 1-6 alkyl.

[0120] In another embodiment, the compound having the structure represented by the general formula (I), (II), (III), (IV), (V), (IA), (IIA), (IIIA), (IVA) or a pharmaceutically acceptable salt thereof, wherein:

[0121] R 1 and R 2 Each independently selected from L1-Q;

[0122] L1 is selected from -(CH2) p -;

[0123] Q is selected from R 12 、-C(O)OR 13 、-C(O)NHR 13 、-SO3H、

[0124] R 12 Selected from hydrogen, hydroxyl, C 1-6 alkyl;

[0125] R 13 Selected from hydrogen, C 6-10 Aryl or 5- to 10-membered heteroaryl; preferably hydrogen and phenyl;

[0126] p is an integer of 1 to 10, preferably an integer of 1 to 6.

[0127] In another embodiment, the compound having the structure shown in the general formula (I), (II), (III), (IV), (V), (IA), (IIA), (IIIA), (IVA) or a pharmaceutically acceptable salt thereof, wherein R 7 Selected from hydrogen, halogen, hydroxyl, OR a SR a NR b R c ;

[0128] R a Selected from C 6-10 Aryl and 5-10 membered heteroaryl, preferably phenyl; wherein the aryl and heteroaryl are optionally further selected from halogen, amino, oxo, thio, nitro, cyano, hydroxyl, sulfhydryl, carboxyl, ester, sulfonic acid, -NHC (O) -L4 -NR b Rc 、-OC(O)-L4-NR b R c , alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; wherein -L4- is alkenylene;

[0129] R b and R c are each independently selected from hydrogen, C 1-10 Alkyl, wherein the C 1-10 The alkyl group is optionally further substituted with a carboxyl group.

[0130] In another embodiment, the compound having the structure shown in the general formula (I), (II), (III), (IV), (V), (IA), (IIA), (IIIA), (IVA) or a pharmaceutically acceptable salt thereof, wherein R 7 Selected from SR a ; R a Selected from C 1-6 Alkyl, the C 1-6 The alkyl group is optionally substituted with a carboxyl group.

[0131] In another embodiment, the compound having the structure shown in the general formula (I), (II), (III), (IV), (V), (IA), (IIA), (IIIA), (IVA) or a pharmaceutically acceptable salt thereof, wherein R 8 、R 9 are each independently selected from hydrogen and C 1-6 alkyl.

[0132] In another embodiment, the compound having the structure shown in the general formula (I), (II), (III), (IV), (V), (IA), (IIA), (IIIA), (IVA) or a pharmaceutically acceptable salt thereof, wherein R 8a 、R 9a are each independently selected from hydrogen.

[0133] In another embodiment, the compound having the structure shown in the general formula (I), (II), (III), (IV), (V), (IA), (IIA), (IIIA), (IVA) or a pharmaceutically acceptable salt thereof, wherein R 8b 、R 9b are each independently selected from hydrogen.

[0134] In another embodiment, the compound having the structure shown in the general formula (I), (II), (III), (IV), (V), (IA), (IIA), (IIIA), (IVA) or a pharmaceutically acceptable salt thereof, wherein R 3 、R 4 are each independently selected from hydrogen and C 1-6 alkyl.

[0135] In another embodiment, the compound having the structure shown in the general formula (I), (II), (III), (IV), (V), (IA), (IIA), (IIIA), (IVA) or a pharmaceutically acceptable salt thereof, wherein R 5 、R 6 are each independently selected from hydrogen and C 1-6 alkyl.

[0136] In another embodiment, the compound having the structure represented by the general formula (I), (II), (III), (IV), (V), (IA), (IIA), (IIIA), (IVA) or a pharmaceutically acceptable salt thereof, wherein the pharmaceutically acceptable salt is a halide, a carboxylate, preferably a hydrochloride, a formate, an acetate, or a trifluoroacetate.

[0137] Typical compounds of the present invention include, but are not limited to:

[0138] Another aspect of the present invention provides a compound having a structure represented by general formula (VI) or a pharmaceutically acceptable salt thereof,

[0139] Among them, R 1 ~R 9 、R 8a 、R 8b 、R 9a 、R 9b 、R 10a 、R 10b 、R 10c 、R 10d 、R 11a 、R 11b 、R 11c , as defined in general formula (I); s is 0 or 1;

[0140] Preferably,

[0141] R1 Selected from L1-L2-Q;

[0142] L1 is selected from -(CH2) p -;

[0143] L2 is selected from a bond;

[0144] Q is selected from -C(O)OR 13 ;

[0145] R 13 selected from hydrogen and phenyl;

[0146] R 2 Selected from C 1-6 alkyl;

[0147] R 3 、R 4 are each independently selected from hydrogen and C 1-6 Alkyl, preferably C 1-6 alkyl;

[0148] R 5 、R 6 are each independently selected from hydrogen and C 1-6 Alkyl, preferably C 1-6 alkyl;

[0149] R 7 selected from halogen;

[0150] R 8 、R 9 are each independently selected from hydrogen;

[0151] R 8a 、R 9a are each independently selected from hydrogen;

[0152] R 8b 、R 9b are each independently selected from hydrogen;

[0153] R 10a 、R 10b 、R 10c 、R 10d are each independently selected from hydrogen;

[0154] R 11a 、R 11b 、R 11c are each independently selected from hydrogen.

[0155] In a specific embodiment, the compound having the structure represented by general formula (VI) or a pharmaceutically acceptable salt thereof is selected from:

[0156] Another aspect of the present invention provides a compound having a structure represented by general formula (VII) or a pharmaceutically acceptable salt thereof,

[0157] Among them, R 2 ~R 9 、R 8a 、R 8b 、R 9a 、R 9b 、R 10a 、R 10b 、R 10c 、R 10d 、R 11a 、R 11b 、R 11c , as defined in general formula (I);

[0158] t is 0 or 1;

[0159] L5 is selected from -(CH2) t1 -C(O)NH-(CH2) t2 -NHC(O)-(CH2) t3 -;

[0160] t1, t2, t3 are each independently selected from an integer of 1 to 10; preferably an integer of 2 to 6;

[0161] Preferably,

[0162] R 2 Selected from C 1-6 alkyl;

[0163] R 3 、R 4 are each independently selected from hydrogen and C 1-6 Alkyl, preferably C 1-6 alkyl;

[0164] R 5 、R 6 are each independently selected from hydrogen and C 1-6 Alkyl, preferably C 1-6 alkyl;

[0165] R 7 selected from halogen;

[0166] R 8 、R 9 are each independently selected from hydrogen;

[0167] R 8a 、R 9a are each independently selected from hydrogen;

[0168] R 8b 、R 9bare each independently selected from hydrogen;

[0169] R 10a 、R 10b 、R 10c 、R 10d are each independently selected from hydrogen;

[0170] R 11a 、R 11b 、R 11c are each independently selected from hydrogen.

[0171] In a specific embodiment, the compound having the structure represented by general formula (VII) or a pharmaceutically acceptable salt thereof is selected from:

[0172] Another aspect of the present invention provides a compound having a structure represented by general formula (VIII) or a pharmaceutically acceptable salt thereof,

[0173] Among them, X, R 1 ~R 4 、R 7 ~R 9 、R 8a 、R 8b 、R 9a 、R 9b 、R 10a 、R 10b 、R 10c 、R 10d 、R 11a 、R 11b 、R 11c 、R 11d As defined in general formula (I); s is 0 or 1;

[0174] Preferably,

[0175] X is N + ;

[0176] s is 1;

[0177] R 1 Selected from L1-L2-Q;

[0178] L1 is selected from -(CH2) p -;

[0179] L2 is selected from a bond;

[0180] Q is selected from -C(O)OR 13 ;

[0181] R 13 selected from hydrogen and phenyl;

[0182] R2 Selected from C 1-6 alkyl;

[0183] R 3 、R 4 are each independently selected from hydrogen and C 1-6 Alkyl, preferably C 1-6 alkyl;

[0184] R 7 selected from halogen;

[0185] R 8 、R 9 Each independently selected from C 1-6 alkyl;

[0186] R 8a 、R 9a are each independently selected from hydrogen;

[0187] R 8b 、R 9b are each independently selected from hydrogen;

[0188] R 10a 、R 10b 、R 10c 、R 10d are each independently selected from hydrogen;

[0189] R 11a 、R 11b 、R 11c are each independently selected from hydrogen.

[0190] In a specific embodiment, the compound having the structure represented by general formula (VIII) or a pharmaceutically acceptable salt thereof is selected from:

[0191] Another aspect of the present invention provides a contrast agent comprising the compound according to the present invention or a pharmaceutically acceptable salt thereof and an anionic surfactant.

[0192] In one embodiment, the contrast agent, wherein the anionic surfactant is selected from carboxylates, sulfonates, sulfates, phosphates and lipopeptide anionic surfactants, preferably sulfonates or lipopeptide anionic surfactants, more preferably surfactin, sodium dodecyl sulfonate and / or sodium dodecylbenzene sulfonate.

[0193] In another embodiment, the contrast agent, wherein the molar ratio of the compound or a pharmaceutically acceptable salt thereof to the anionic surfactant is 1:20 to 10:1, preferably 1:10 to 10:1, and further preferably 1:5 to 5:1.

[0194] In another embodiment, the contrast agent, wherein the final concentration of the compound or a pharmaceutically acceptable salt thereof is in the range of 1 to 100 μM, preferably 5 to 50 μM or 10 to 30 μM.

[0195] In another embodiment, the particle size of the contrast agent solution is 10 to 200 nm, preferably 30 to 150 nm, and more preferably 50 to 100 nm.

[0196] In another embodiment, the contrast agent is in the form of a solution or a lyophilized powder.

[0197] The present invention also provides a detection kit, which contains the compound according to the present invention or a pharmaceutically acceptable salt thereof and an anionic surfactant.

[0198] In one embodiment, the kit, wherein the anionic surfactant is selected from carboxylates, sulfonates, sulfates, phosphates and lipopeptide anionic surfactants, preferably sulfonates or lipopeptide anionic surfactants, more preferably surfactin, sodium dodecyl sulfonate and / or sodium dodecylbenzene sulfonate.

[0199] In another embodiment, in the kit, the molar ratio of the compound or pharmaceutically acceptable salt thereof to the anionic surfactant is 1:20 to 10:1, preferably 1:10 to 10:1, and further preferably 1:5 to 5:1.

[0200] In another embodiment, the final concentration of the compound or its pharmaceutically acceptable salt in the kit is in the range of 1 to 100 μM, preferably 5 to 50 μM or 10 to 30 μM.

[0201] In another embodiment, in the kit, the particle size of the contrast agent solution is 10 to 200 nm, preferably 30 to 150 nm, and more preferably 50 to 100 nm.

[0202] In another embodiment, the kit, wherein the contrast agent is in the form of a solution or a lyophilized powder.

[0203] The present invention also relates to a pharmaceutical composition comprising the compound according to the present invention or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers.

[0204] The present invention also relates to use of the compound according to the present invention or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, in the preparation of a tumor contrast agent, wherein the tumor is preferably bladder cancer.

[0205] The present invention also relates to the compound according to the present invention or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising the same, for use as a contrast agent.

[0206] The present invention also relates to a tumor imaging method, which comprises administering the compound according to the present invention or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, to a subject in need thereof.

[0207] In a cell model, the molecules of the present invention have obvious differences in uptake ability between normal cells and tumor cells, and tumor cells can increase their uptake exponentially, forming a significant difference from other cells.

[0208] The molecules of the present invention show good tumor-specific targeting effects in animal subcutaneous tumor models, forming obvious differences from surrounding normal tissues, thereby facilitating tumor diagnosis.

[0209] Terminology

[0210] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0211] The carbon, hydrogen, oxygen, sulfur, nitrogen or halogen involved in the groups and compounds of the present invention include their isotopes, that is, the carbon, hydrogen, oxygen, sulfur, nitrogen or halogen involved in the groups and compounds of the present invention are optionally further replaced by one or more of their corresponding isotopes, wherein the isotopes of carbon include 12 C. 13 C and 14 C, hydrogen isotopes include protium (H), deuterium (D, also known as heavy hydrogen), tritium (T, also known as super tritium), oxygen isotopes include 16 O. 17 O and 18 O, sulfur isotopes include 32 S. 33 S. 34 S and 36 S, nitrogen isotopes include 14 N and 15 N, fluorine isotopes include 19 F, chlorine isotopes include 35 Cl and 37 Isotopes of Cl, bromine include 79 Br and 81 Br.

[0212] The term "alkyl" refers to a saturated aliphatic hydrocarbon group, which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 12 carbon atoms, more preferably an alkyl group containing 1 to 6 carbon atoms, an alkyl group containing 1 to 4 carbon atoms or an alkyl group containing 1 to 3 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2, 3-Dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched-chain isomers thereof. More preferred are lower alkyl groups containing 1 to 6 carbon atoms, non-limiting examples of which include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, and the like. The alkyl group may be substituted or unsubstituted. When substituted, the substituent may be substituted at any available point of attachment and may be one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl, or carboxylate.

[0213] The term "alkylene" refers to a divalent alkyl group, wherein alkyl is as defined above, having from 1 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) carbon atoms (i.e., C 1-20 The alkylene group is preferably an alkylene group having 1 to 12 carbon atoms (i.e., C 1-12 alkylene), more preferably an alkylene containing 1 to 6 carbon atoms (i.e., C 1-6 Alkylene), further preferably an alkylene containing 1 to 4 carbon atoms (i.e., C 1-6 Alkylene). Non-limiting examples of alkylene include, but are not limited to, methylene (—CH—), 1,1-ethylene (—CH(CH)—), 1,2-ethylene (—CHCH)—, 1,1-propylene (—CH(CHCH)—), 1,2-propylene (—CHCH(CH)—), 1,3-propylene (—CHCHCHCH—), and 1,4-butylene (—CHCHCHCHCH—). Alkylene may be substituted or unsubstituted. When substituted, it may be substituted at any available point of attachment. The substituent may be selected from one or more of alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, and oxo.

[0214] The term "alkenyl" refers to a monovalent hydrocarbon group consisting of at least two carbon atoms and at least one carbon-carbon double bond, preferably an alkenyl group containing 2 to 4 carbon atoms, such as ethenyl, 1-propenyl, 2-propenyl, 1-, 2- or 3-butenyl, etc. The alkenyl group may be substituted or unsubstituted, and when substituted, the substituent may be one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, and heterocycloalkylthio.

[0215] The term "alkynyl" refers to a monovalent hydrocarbon group consisting of at least two carbon atoms and at least one carbon-carbon triple bond, preferably an alkynyl group containing 2 to 4 carbon atoms or preferably an alkynyl group containing 3 to 4 carbon atoms, such as ethynyl, propynyl, butynyl, etc. The alkynyl group may be substituted or unsubstituted, and when substituted, the substituent may be one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio.

[0216] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent, wherein the cycloalkyl ring contains 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, and more preferably 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like; polycyclic cycloalkyls include spirocyclic, fused, and bridged cycloalkyls.

[0217] The term "spiroalkyl" refers to a polycyclic group having a carbon atom (called a spiro atom) shared between 5 to 20 monocyclic rings, which may contain one or more double bonds, but no ring has a completely conjugated π electron system. Preferably, it is 6 to 14 yuan, more preferably 7 to 10 yuan. According to the number of spiro atoms shared between the rings, the spiroalkyl group is divided into a single spiroalkyl group, a double spiroalkyl group or a multi-spiroalkyl group, preferably a single spiroalkyl group and a double spiroalkyl group. More preferably, it is a 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 5 yuan or 5 yuan / 6 yuan single spiroalkyl group. Non-limiting examples of spiroalkyl groups include:

[0218] The term "fused cycloalkyl" refers to a 5 to 20-membered, all-carbon polycyclic group in which each ring in the system shares a pair of adjacent carbon atoms with the other rings in the system, wherein one or more rings may contain one or more double bonds, but no ring has a completely conjugated π electron system. Preferably, it is 6 to 14 members, more preferably 7 to 10 members. Depending on the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused cycloalkyl groups, preferably bicyclic or tricyclic, more preferably 5-membered / 5-membered or 5-membered / 6-membered bicyclic alkyl groups. Non-limiting examples of fused cycloalkyl groups include:

[0219] The term "bridged cycloalkyl" refers to a 5-20 membered, all-carbon polycyclic group in which any two rings share two carbon atoms that are not directly connected, which may contain one or more double bonds, but no ring has a completely conjugated π electron system. Preferably, it is 6-14 members, more preferably 7-10 members. Depending on the number of constituent rings, it can be classified as a bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl group, preferably a bicyclic, tricyclic or tetracyclic group, more preferably a bicyclic or tricyclic group. Non-limiting examples of bridged cycloalkyl groups include:

[0220] The cycloalkyl ring may be fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein the ring attached to the parent structure is a cycloalkyl, non-limiting examples of which include indanyl, tetrahydronaphthyl, benzocycloheptanyl, etc. The cycloalkyl may be optionally substituted or unsubstituted, and when substituted, the substituent may be one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl or carboxylate.

[0221] The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent containing 3 to 20 ring atoms, one or more of which is selected from nitrogen, oxygen or S(O) m (wherein m is an integer from 0 to 2) heteroatoms, but excluding the ring portion of -OO-, -OS- or -SS-, the remaining ring atoms are carbon. Preferably, it contains 4 to 12 ring atoms, of which 1 to 4 are heteroatoms; more preferably, it contains 7 to 12 ring atoms, of which 1 to 4 are heteroatoms. Non-limiting examples of monocyclic heterocyclic groups include pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl, etc., preferably 1, 2, 5-oxadiazolyl, pyranyl or morpholinyl. Polycyclic heterocyclic groups include spirocyclic, fused ring and bridged heterocyclic groups.

[0222] The term "spiroheterocyclyl" refers to a polycyclic heterocyclic group in which the monocyclic rings of 5 to 20 members share one atom (called a spiro atom), wherein one or more ring atoms are selected from nitrogen, oxygen or S(O) m (wherein m is an integer 0 to 2) heteroatom, and the remaining ring atoms are carbon. It may contain one or more double bonds, but no ring has a completely conjugated π electron system. It is preferably 6 to 14 members, more preferably 7 to 12 members. According to the number of shared spiral atoms between the rings, the spiro heterocyclic group is divided into a single spiral heterocyclic group, a double spiral heterocyclic group or a multi-spiro heterocyclic group, preferably a single spiral heterocyclic group and a double spiral heterocyclic group. More preferably 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 5 yuan or 5 yuan / 6 yuan single spiral heterocyclic group. Non-limiting examples of spiro heterocyclic groups include:

[0223] The term "fused heterocyclyl" refers to a polycyclic heterocyclic group of 5 to 20 members, wherein each ring in the system shares a pair of adjacent atoms with other rings in the system, one or more rings may contain one or more double bonds, but no ring has a completely conjugated π electron system, wherein one or more ring atoms are selected from nitrogen, oxygen or S(O) m(wherein m is an integer from 0 to 2) heteroatoms, the remaining ring atoms being carbon. Preferably, it is 6 to 14 members, more preferably 7 to 12 members. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic groups, preferably bicyclic or tricyclic, more preferably 5-membered / 5-membered or 5-membered / 6-membered bicyclic fused heterocyclic groups. Non-limiting examples of fused heterocyclic groups include:

[0224] The term "bridged heterocyclyl" refers to a 5- to 14-membered polycyclic heterocyclic group in which any two rings share two atoms that are not directly connected, which may contain one or more double bonds but no ring has a completely conjugated π electron system, wherein one or more ring atoms are selected from nitrogen, oxygen or S(O) m (wherein m is an integer from 0 to 2) heteroatoms, the remaining ring atoms being carbon. Preferably, it is 6 to 14 members, more preferably 7 to 12 members. Depending on the number of constituent rings, it can be classified as a bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic group, preferably a bicyclic, tricyclic or tetracyclic group, more preferably a bicyclic or tricyclic group. Non-limiting examples of bridged heterocyclic groups include:

[0225] The heterocyclyl ring may be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring attached to the parent structure is a heterocyclyl, non-limiting examples of which include:

[0226] wait.

[0227] The heterocyclyl group may be optionally substituted or unsubstituted, and when substituted, the substituent may be one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl, or carboxylate.

[0228] The term "aryl" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (i.e., rings sharing adjacent pairs of carbon atoms) group having a conjugated π electron system, preferably 6- to 10-membered, such as phenyl and naphthyl. More preferably, phenyl. The aryl ring may be fused to a heteroaryl, heterocyclyl, or cycloalkyl ring, wherein the ring attached to the parent structure is the aryl ring, non-limiting examples of which include:

[0229] The aryl group may be substituted or unsubstituted, and when substituted, the substituent may be one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.

[0230] The term "heteroaryl" refers to a heteroaromatic system containing 1 to 4 heteroatoms and 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen. The heteroaryl group is preferably 5 to 10-membered, containing 1 to 3 heteroatoms; more preferably 5 or 6-membered, containing 1 to 2 heteroatoms; preferably, for example, imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, tetrazolyl, pyridinyl, pyrimidinyl, thiadiazole, pyrazinyl, etc., preferably imidazolyl, thiazolyl, pyrazolyl or pyrimidinyl, thiazolyl; more preferably pyrazolyl or thiazolyl. The heteroaryl ring can be fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring, non-limiting examples of which include:

[0231] The heteroaryl group may be optionally substituted or unsubstituted, and when substituted, the substituent may be one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl, or carboxylate.

[0232] The term "alkoxy" refers to -O-(alkyl), wherein the definition of alkyl is as described above. The limiting examples of alkoxy include: methoxy, ethoxy, propoxy, butoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy. Alkoxy can be optionally substituted or unsubstituted, and when substituted, substituents can be one or more following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, sulfydryl, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.

[0233] The alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups mentioned above include residues derived by removing one hydrogen atom from a parent ring atom, or residues derived by removing two hydrogen atoms from the same ring atom or two different ring atoms of the parent, namely, "alkenylene", "alkynylene", "cycloalkylene", "heterocyclylene", "arylene" and "heteroarylene".

[0234] The term "cycloalkoxy" refers to an -O-(cycloalkyl) group, wherein cycloalkyl is as defined above.

[0235] The term "heterocycloalkoxy" refers to -O-(heterocyclyl), wherein heterocyclyl is as defined above.

[0236] The term "haloalkyl" refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined above.

[0237] The term "haloalkoxy" refers to an alkoxy group substituted with one or more halogens, wherein alkoxy is as defined above.

[0238] The term "hydroxyalkyl" refers to an alkyl group substituted with a hydroxy group, wherein alkyl is as defined above.

[0239] The term "hydroxy" refers to -OH.

[0240] The term "halogen" refers to fluorine, chlorine, bromine or iodine.

[0241] The term "amino" refers to -NH2.

[0242] The term "cyano" refers to -CN.

[0243] The term "nitro" refers to -NO2.

[0244] The term "oxo" refers to =0.

[0245] The term "thio" refers to =S.

[0246] The term "carboxy" refers to -C(O)OH.

[0247] The term "mercapto" refers to -SH.

[0248] The term "ester group" refers to -C(O)O(alkyl) or -C(O)O(cycloalkyl), wherein alkyl and cycloalkyl are as defined above.

[0249] The term "acyl" refers to a compound of the group -C(O)R, where R is alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl.

[0250] The term "sulfonic acid" refers to a -SO3H group.

[0251] "Optional" or "optionally" means 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. For example, "a heterocyclic group optionally substituted with an alkyl group" means that the alkyl group may but need not be present, and that the description includes instances where the heterocyclic group is substituted with an alkyl group and instances where the heterocyclic group is not substituted with an alkyl group.

[0252] "Substituted" means that one or more hydrogen atoms, preferably up to 5, more preferably 1 to 3 hydrogen atoms, in a group are replaced independently of one another by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and a person skilled in the art can determine (by experiment or theory) which substitutions are possible or impossible without undue effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when combined with a carbon atom with an unsaturated (e.g., olefinic) bond.

[0253] A "pharmaceutical composition" refers to a mixture containing one or more compounds described herein, or their physiologically / pharmaceutically acceptable salts or prodrugs, together with other chemical components, as well as other components such as physiologically / pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to an organism, facilitating absorption of the active ingredient and thereby exerting its biological activity.

[0254] "Pharmaceutically acceptable salts" or "pharmaceutically acceptable salts" refer to salts of the compounds of the present invention that are safe and effective when used in mammals and have the desired biological activity.

[0255] "Carrier" refers to a vehicle or diluent that does not cause significant irritation to an organism and does not abrogate the biological activity and properties of the administered compound. BRIEF DESCRIPTION OF THE DRAWINGS

[0256] FIG1 is a fluorescence microscopic image of the compound of the present invention in the human bladder cancer cell line RT112.

[0257] FIG2 is a fluorescence microscopic image of the compound of the present invention in the human bladder cancer cell line UM-UC-3.

[0258] FIG3 is a fluorescence microscopic image of the compound of the present invention in the human bladder cancer cell line RT112 with or without the addition of BSP.

[0259] FIG4 is a fluorescence microscopic image of the compound of the present invention in the human bladder cancer cell line UM-UC-3 with or without the addition of BSP.

[0260] FIG5 is the fluorescence imaging of the compound of the present invention in bladder cancer tumor model mice. DETAILED DESCRIPTION

[0261] The compounds of the present invention and their preparation will be further understood by way of the examples, which illustrate some methods of preparing or using the compounds. However, it will be understood that these examples do not limit the present invention. Variations of the present invention now known or further developed are considered to fall within the scope of the invention described herein and claimed.

[0262] The compounds of the present invention are prepared using convenient starting materials and general preparation procedures. Typical or preferred reaction conditions, such as reaction temperature, time, solvent, pressure, and molar ratio of reactants, are provided herein. However, other reaction conditions may be employed unless otherwise specified. Optimized conditions may vary depending on the specific reactants or solvents used, but generally, optimized reaction procedures and conditions are determined.

[0263] In addition, some protecting groups may be used in the present invention to protect certain functional groups from unwanted reactions. Protecting groups suitable for various functional groups and their protection or deprotection conditions are widely known to those skilled in the art. For example, TW Greene and GM Wuts's "Protective Groups in Organic Preparations" (3rd edition, Wiley, New York, 1999 and references therein) describes in detail the protection or deprotection of a large number of protecting groups.

[0264] The separation and purification of compounds and intermediates can be performed using appropriate methods and steps depending on specific needs, such as filtration, extraction, distillation, crystallization, column chromatography, preparative thin layer plate chromatography, preparative high performance liquid chromatography, or a combination of the above methods. Specific methods of use can be found in the examples described herein. Of course, other similar separation and purification methods can also be used. Conventional methods (including physical constants and spectral data) can be used to characterize the compounds and intermediates.

[0265] The structures of the compounds were determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). -6 The unit of ppm is given. NMR measurements were performed using a Brukerdps 300 NMR spectrometer. The solvents used were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD), with tetramethylsilane (TMS) as the internal standard.

[0266] MS was measured using LC (Agilent 1260 Infinity) / MS (G6125B) mass spectrometer (manufacturer: Agilent).

[0267] Preparative liquid chromatography was performed using an LC6000 high performance liquid chromatograph (manufacturer: Chuangxin Tongheng), with a Daisogel C18 10 μm 100A column (30 mm × 250 mm) and acetonitrile / water as the mobile phase.

[0268] Thin layer chromatography (TLC) used Qingdao Ocean Chemical GF254 silica gel plates. The silica gel plates used for reaction monitoring were of a size of 0.20 mm to 0.25 mm, and the silica gel plates used for separation and purification were of a size of 0.5 mm.

[0269] Silica gel column chromatography method uses Qingdao marine silica gel 100-200 mesh, 200-300 mesh and 300-400 mesh silica gel as the carrier.

[0270] The known starting materials of the present invention can be synthesized by methods known in the art, or can be purchased from online shopping malls, Beijing Coupling, Sigma, Bailingwei, Yishiming, Shanghai Shuya, Shanghai Yinuokai, Anaiji Chemical, Shanghai Bid, Nanjing Yaoshi and other companies.

[0271] Unless otherwise specified in the examples, all reactions were carried out under a nitrogen atmosphere.

[0272] Argon atmosphere or nitrogen atmosphere means that the reaction bottle is connected to an argon or nitrogen balloon with a capacity of about 1 L.

[0273] Reaction solvent, organic solvent or inert solvent are each expressed as the solvent used that does not participate in the reaction under the described reaction conditions, including, for example, benzene, toluene, acetonitrile, tetrahydrofuran (THF), dimethylformamide (DMF), chloroform, dichloromethane, ether, methanol, nitrogen-methylpyrrolidone (NMP), pyridine, etc. Unless otherwise specified in the examples, the solution refers to an aqueous solution.

[0274] The chemical reactions described herein are generally carried out under normal pressure. Reaction times and conditions are, for example, between -78°C and 200°C at atmospheric pressure, and are complete within approximately 1 to 24 hours. If the reaction is allowed to proceed overnight, the reaction time is generally 16 hours. Unless otherwise specified in the examples, the reaction temperature is room temperature, 20°C to 30°C.

[0275] The reaction progress in the examples was monitored by thin layer chromatography (TLC). The developing solvent systems used in the reactions were: A: dichloromethane and methanol system, B: petroleum ether and ethyl acetate system, and C: acetone. The volume ratio of the solvents was adjusted according to the polarity of the compounds.

[0276] The eluent system for column chromatography and the developing solvent system for thin-layer chromatography used to purify the compound include: A: dichloromethane and methanol system, B: petroleum ether and ethyl acetate system. The volume ratio of the solvent is adjusted according to the polarity of the compound, and a small amount of alkaline or acidic reagents such as triethylamine and trifluoroacetic acid can also be added for adjustment.

[0277] Unless otherwise defined, all professional and scientific terms used herein have the same meaning as those familiar to those skilled in the art. In addition, any methods and materials similar or equivalent to those described herein can be applied to the methods of the present invention.

[0278] Preparation Example 1: Preparation of 2,3,3-trimethylindole-5-carboxylic acid (A8A)

[0279] To a solution of 4-hydrazinobenzoic acid hydrochloride (50.0 g, 265 mmol, 1.00 eq) in AcOH (250 mL) was added 3-methylbutan-2-one (25.1 g, 292 mmol, 31.2 mL, 1.10 eq). The mixture was stirred at 120°C for 12 hours. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with DCM (200 mL) and adjusted to pH 7 with saturated NaHCO₃ solution. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (SiO₂, petroleum ether / ethyl acetate = 100 / 1 to 1 / 1) to afford compound A8A (25.0 g, 123 mmol, 46.4% yield) as a yellow solid.

[0280] 1 H NMR (400MHz, DMSO) δ12.8 (s, 1H), 7.99 (s, 1H), 7.90-7.93 (m, 1H), 7.50 (d, J = 7.6Hz, 1H), 2.25 (s, 3H), 1.27 (s, 6H).

[0281] LCMS: m / z=204.0 (M+H) + .

[0282] The following compounds were prepared by the above-mentioned preparation method using the corresponding substituted hydrazine:

[0283] Preparation Example 2: Preparation of 1-ethyl-2,3,3-trimethyl-indol-1-ium-5-carboxylic acid tert-butyl ester iodide (A8)

[0284] A mixture of compound A8B (prepared as described in Preparation 3) (9.00 g, 34.7 mmol, 1.00 eq), iodoethane (10.8 g, 69.4 mmol, 5.55 mL, 2.00 eq), and MeCN (90.0 mL) was stirred at 100°C for 32 hours. The reaction was concentrated under reduced pressure, and the residue was slurried with MTBE (30.0 mL) at 25°C for 30 minutes. The mixture was then purified by reverse-phase chromatography (Phenomenex luna C18 250 × 50 mm × 15 μm; mobile phase: [water (FA)-ACN]; B%: 50%-80%, 10 min) to afford compound A8 (10.0 g) as a red solid.

[0285] LCMS: m / z=288.3 (M+H) + .

[0286] The following compounds were prepared using the corresponding raw materials according to the above preparation method:

[0287] Preparation Example 3: Preparation of tert-butyl 2,3,3-trimethylindole-5-carboxylate (A8B)

[0288] To a solution of 2,3,3-trimethylindole-5-carboxylic acid (8.00 g, 39.4 mmol, 1.00 eq) and tert-butyl trichloroacetimidate (17.2 g, 78.7 mmol, 14.1 mL, 2.00 eq) in DCM (80.0 mL) and THF (40.0 mL) was added BF3·Et2O (4.75 g, 15.8 mmol, 4.12 mL, 47.0% purity, 0.400 eq). The mixture was stirred at 25°C for 12 hours. Maintaining the temperature at about 0°C, NaHCO3 (50.0 mL) solution was added dropwise, diluted with H2O (100 mL) and extracted with EA (200 mL×2), washed with brine (50.0 mL×2), dried over anhydrous Na2SO4, filtered, concentrated, and the residue was slurried with PE (50.0 mL) at 25°C for 30 min to give compound A8B (9.00 g, crude product) as a yellow oil.

[0289] LCMS: m / z=260.4 (M+H) + .

[0290] Preparation Example 4: Preparation of 5-amino-1,2,3,3-tetramethyl-3H-indol-1-ium iodide (A11B)

[0291] To a solution of compound A11A (12.5 g, 36.1 mmol, 1.00 eq) in HCl (60.0 mL) was added SnCl2·2H2O (57.0 g, 253 mmol, 7.00 eq). The mixture was stirred at 20°C for 16 hours. The mixture was diluted with 300 mL of water, adjusted to pH 10 with 5 M NaOH, and filtered. The mother liquor was extracted with DCM (600 mL). The organic phase was washed with 300 mL of brine, dried over anhydrous Na2SO4, and filtered. The aqueous phase was lyophilized and stirred with DCM (200 mL). The organic phases were combined, dried over anhydrous Na2SO4, filtered, and concentrated to afford compound A11B (7.05 g) as a green solid.

[0292] 1 H NMR (400MHz, CDCl3) δ6.57 (s, 1H), 6.52 (d, J = 7.2Hz, 1H), 6.37 (s, 1H), 3.82 (s, 2H), 3.17 (s, 3H), 1.33 (s, 9H).

[0293] LCMS: m / z = 189.3, C 12H 17 N2 + .

[0294] Preparation Example 5: Preparation of 5-(dimethylamino)-1,2,3,3-tetramethyl-3H-indol-1-ium iodide (A11)

[0295] A mixture of compound A11B (4.00 g, 12.7 mmol, 1.00 eq), MeI (8.98 g, 63.3 mmol, 3.94 mL, 5.00 eq), and ACN (20.0 mL) was incubated in a sealed tube at 15 psi and 80°C for 12 hours. The mixture was concentrated under reduced pressure, and the residue was purified by reverse-phase chromatography (Phenomenex luna C18 column (250 mm × 70 mm, 10 μm); mobile phase: [water (HCl)-ACN]; gradient: 1% to 35% B over 22 min) to afford compound A11 (1.40 g, 3.97 mmol, 15.7% yield, 97.7% purity) as a yellow solid.

[0296] 1 H NMR (400 MHz, DMSO- d6 )δ7.68(d,J=8.8Hz,1H),7.18(s,1H),6.88(d,J=8.4Hz,1H),3.90(s,3H),2.65(s,3H),1.47(s,6H).

[0297] LCMS: m / z = 217.1, C 14 H 21 N2 + .

[0298] In addition, trimethyl-(1,2,3,3-tetramethylindol-1-ium-5-yl)amine diiodide (720 mg, 1.38 mmol, 10.93% yield, 93.4% purity) was obtained as a yellow solid. LCMS: m / z = 231.0, C 15 H 24 N2 2+ .

[0299] Preparation Example 6: Preparation of (4-methylsulfonylphenyl)hydrazine (A13A)

[0300] A solution of 1-fluoro-4-methylsulfonatobenzene (20.0 g, 115 mmol, 1.00 eq), hydrazine hydrate (13.0 g, 221 mmol, 12.6 mL, 85.0% purity, 1.92 eq), and EtOH (200 mL) was stirred at 80°C for 16 hours. The mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (SiO2, PE:EA = 1:0 to 1:1) to afford compound A13A (7.80 g, 41.9 mmol, 36.5% yield) as a yellow solid.

[0301] 1 H NMR (400MHz, CDCl3) δ7.74(s,1H),7.71(s,1H),6.90(s,1H),6.87(s,1H),5.74(s,1H),3.70(s,2H),3.01(s,3H).

[0302] Preparation Example 7: Preparation of (E)-2-chloro-5-(dimethylamino)-3-(hydroxymethylene)cyclohex-1-ene-1-carbaldehyde (B4)

[0303] To DMF (10.0 mL) at 0°C was added POCl3 (16.3 g, 106 mmol, 9.90 mL, 3.00 eq) and stirred at 0-5°C for 30 minutes. 4-(Dimethylamino)cyclohexanone (5.00 g, 35.4 mmol, 1.00 eq) was added to the solution, and the temperature was raised to 80°C and stirred for 3 hours. The reaction mixture was added to HCl (1.00 M, 100 mL), stirred at 20°C for 12 hours, filtered, and the filter cake dried to afford compound B4 (3.90 g, crude) as a yellow solid.

[0304] 1 H NMR (400MHz, DMSO) δ8.89 (s, 2H), 3.40-3.44 (m, 1H), 3.02-3.07 (m, 2H), 2.76 (s, 6H), 2.36-2.40 (m, 2H).

[0305] LCMS: m / z=216.3 (M+H) + .

[0306] Preparation Example 8: Preparation of phenyl 3-[2-(2,3,3-trimethylindolin-1-ium-1-yl)ethoxy]propionate bromide (C4)

[0307] To a solution of 3-[2-(2,3,3-trimethylindolin-1-yl)ethoxy]propanoic acid bromide (C4A) (prepared as described in Preparation 13) (5.80 g, 16.3 mmol, 1.00 eq) in DMF (50.0 mL) were added HBTU (7.41 g, 19.5 mmol, 1.20 eq) and DIEA (5.26 g, 40.7 mmol, 7.09 mL, 2.50 eq). The mixture was stirred at 25°C for 30 minutes. Phenol (1.69 g, 17.9 mmol, 1.57 mL, 1.10 eq) was then added, and the mixture was stirred at 25°C for 12 hours. The reactants were added with H2O (300 mL) and extracted with EA (200 mL x 3). The organic phase was dried over Na2SO4 and concentrated. The residue was purified by reverse-phase HPLC (0.1% HCl; column: Phenomenex luna C18 250 mm x 50 mm x 15 μm; mobile phase: [water (FA)-ACN]; B%: 50%-80%, 10 min) and lyophilized to give compound C4 (3.10 g) as a brown oil.

[0308] LCMS: m / z=352.2, C 22 H 26 NO3 + .

[0309] Preparation Example 9: Preparation of 1-(6-(2,6-dimethylphenoxy)-6-oxohexyl)-2,3,3-trimethyl-3H-indol-1-ium chloride (C11)

[0310] According to the method of Preparation Example 8, compound C11 was prepared by replacing C4A with 1-(5-carboxypentyl)-2,3,3-trimethyl-3H-indol-1-ium and replacing phenol with 2,6-dimethylphenol.

[0311] Preparation Example 10: Preparation of 2,3,3-trimethyl-1-(5-(trimethylammonio)pentyl)-3H-indol-1-ium bromide (C14)

[0312] A mixture of 1-(5-bromopentyl)-2,3,3-trimethylindol-1-ium bromide (C14A) (prepared as described in Preparation 22) (8.00 g, 20.6 mmol, 1.00 eq), N,N-dimethylmethanamine (14.7 g, 82.2 mmol, 17.2 mL, 4.00 eq), and MeCN (80.0 mL) was stirred at 25°C for 12 hours. The mixture was concentrated under reduced pressure and purified by reverse-phase HPLC (column: Phenomenex Luna, C18 150 mm × 40 mm × 15 μm; mobile phase: [water (HCl)-ACN]; B%: 30%-60%, 10 min) to afford compound C14 (2.30 g, 5.13 mmol, 24.7% yield) as a pink oil.

[0313] 1 H NMR: (400MHz, DMSO) δ8.01-8.03(m,1H),7.85-7.87(m,1H),7.62-7.65(m,2H),4.51(t,J=7.6Hz,2H),3.30-3 .34(m,2H),3.07(s,9H),2.88(s,3H),1.86-1.94(m,2H),1.72-1.80(m,2H),1.55(s,6H),1.39-1.47(m,2H).

[0314] LCMS: m / z=144.3, C 19 H 32 N2 2+ / 2.

[0315] Preparation Example 11: Preparation of 2,3,3-trimethyl-1-(4-(trimethylammonio)butyl)-3H-indol-1-ium chloride (C15)

[0316] Compound C15 was prepared by the same method as in Preparation Example 10, except that compound C15A was used instead of C14A.

[0317] LCMS: m / z = 273.3, C 18 H 30 N 22 + .

[0318] Preparation Example 12: Preparation of 5-methoxy-2,3,3-trimethyl-1-(6-oxo-6-phenoxyhexyl)-3H-indol-1-ium bromide (C21B)

[0319] According to the method of Preparation Example 8, C21 was used to replace C4A to prepare compound C21B.

[0320] LCMS: m / z=380.3, C 24 H 30 NO3 + .

[0321] Preparation Example 13: Preparation of Compound C4A

[0322] LCMS: m / z = 276.2, C 16 H 22 NO3 + . Yellow oil.

[0323] Preparation Example 14: Preparation of Compound A7

[0324] 1 H NMR: (400MHz, D2O) δ8.11(s,1H),8.02(d,J=8.4Hz,1H),7.92(d,J=8.4Hz,1H),4 .65(d,J=16.4Hz,2H),3.31(s,3H),2.38-2.34(m,2H),2.04(s,1H),1.59(s,6H).

[0325] LCMS: m / z = 362. Purple solid.

[0326] Preparation Example 15: Preparation of Compound C10

[0327] LCMS: m / z=336.2, C 22 H 26 NO2 + . Purple solid.

[0328] Preparation Example 16: Preparation of Compound C7

[0329] LCMS: m / z=394.3, C 25 H 32 NO3 + . Red oily substance.

[0330] Preparation Example 17: Preparation of Compound C8

[0331] LCMS: m / z=366.2, C 23 H 28 NO3 + . Yellow oil.

[0332] Preparation Example 18: Preparation of Compound C9

[0333] LCMS: m / z=380.2, C 24 H 30 NO3 + . Yellow oil.

[0334] Preparation Example 19: Preparation of Compound C21

[0335] LCMS: m / z=304.2, C 18 H 26 NO3 + . Green solid.

[0336] Preparation Example 20: Preparation of Compound C13

[0337] LCMS: m / z=396.3, C 24 H 30 NO4 + . Yellow oil.

[0338] Preparation Example 21: Preparation of Compound C12

[0339] 1 H NMR (400MHz, CDCl3) δ7.66-7.58(m,1H),7.57-7.56(m,2H),7.55-7.54(m,1H),7.37-7.32(m,5H),5.83-5.57(m,4H),4.8 0(t,J=4.80Hz,2H),4.51(s,2H),3.97(d,J=4.40Hz,2H),3.56-3.54(m,2H),3.51-3.50(m,2H),2.74(s,3H),1.47(s,6H).

[0340] LCMS: m / z=382.2, C 24 H 32 NO3 + . Brown-black solid.

[0341] Preparation Example 22: Preparation of Compound C14A

[0342] LCMS: m / z=310.2, C 16 H 23 BrN + . Red solid.

[0343] Preparation Example 23: Preparation of Compound C15A

[0344] LCMS: m / z = 296.1, C 15 H 21 BrN + . Brown oil.

[0345] Preparation Example 24: Preparation of Compound C16

[0346] 1 H NMR (400MHz, CDCl3) δ7.55-7.68(m,4H),4.85(t,J=6.8Hz,2H),4.04-4.10(m,4 H), 3.18 (s, 3H), 1.98-2.00 (m, 3H), 1.64-1.78 (m, 11H), 1.30 (t, J = 7.2Hz, 6H).

[0347] LCMS: m / z=366.3, C 20 H 33 NO3P + . Brown oil.

[0348] Preparation Example 25: Preparation of Compound C17

[0349] LCMS: m / z = 259.3, C 17 H 28 N 22 + . Yellow solid.

[0350] Preparation Example 26: Preparation of Compound C18

[0351] LCMS: m / z = 262.2, C 16 H 24 NO2 + . Green solid.

[0352] Preparation Example 27: Preparation of Compound C19

[0353] 1 H NMR (400MHz, CDCl3) δ7.62-7.64(m,1H),7.49-7.53(m,3H),4.76(s,2H),3.95(t,J=5.2Hz,2H), 3.55-3.57(m,2H),3.48-3.52(m,4H),3.42-3.44(m,2H),3.32(s,3H),2.00(s,6H),1.55(s,3H).

[0354] LCMS: m / z=306.3, C 18H 28 NO3 + . Red oily substance.

[0355] Preparation Example 28: Preparation of Compound C20

[0356] LCMS: m / z=350.3, C 20 H 32 NO4 + . Yellow oil.

[0357] Preparation Example 29: Preparation of Compound C23

[0358] LCMS: m / z=394.2, C 22 H 36 NO5 + . Brown oil.

[0359] Example 1: 2-((E)-2-((E)-2-chloro-3-((E)-2-(1,1-dimethyl-3-(6-oxo-6-phenoxyhexyl)-1,3-dihydro-2H-benzo[e]indol-2-ylenyl)vinyl)cyclopent-1-en-1-yl)vinyl)-3-ethyl-1,1-dimethyl-1H-benzo[e]indol-3-onium chloride Preparation of (1A) and 2-((E)-2-((E)-3-((E)-2-(3-(5-carboxypentyl)-1,1-dimethyl-1,3-dihydro-2H-benzo[e]indol-2-ylenyl)vinyl)-2-chlorocyclopent-1-en-1-yl)vinyl)-3-ethyl-1,1-dimethyl-1H-benzo[e]indol-3-ium chloride (1B)

[0360] Step 1: Preparation of 1-ethyl-2,3,3-trimethyl-3H-indole-1-bromide salt (A1)

[0361] A solution of 2,3,3-trimethylindole (A0) (10.0 g, 62.8 mmol, 1.00 eq), ethyl bromide (10.3 g, 94.2 mmol, 7.03 mL, 1.50 eq), and acetonitrile (80.0 mL) was heated to 85°C and stirred for 24 hours. The reaction mixture was concentrated and slurried with MTBE (60.0 mL) to afford compound A1 (12.7 g, 47.4 mmol, 75.4% yield) as a brown solid.

[0362] 1H NMR (400MHz, CDCl3) δ7.99-8.01(m,1H),7.85-7.87(m,1H),7.61-7.64(m,2H),4.49-4.55(m,2H),2.86(s,3H),1.54(s,6H),1.45(t,J=7.4Hz,3H).

[0363] LCMS: m / z = 188.1 (positive ion).

[0364] Step 2: Preparation of 3-ethyl-1,1,2-trimethyl-1H-benzo[e]indole-3-bromonium salt (A2)

[0365] 1,1,2-Trimethylbenz[e]indole (20.0 g, 95.5 mmol, 1.00 eq) and ethyl bromide (15.6 g, 143 mmol, 10.7 mL, 1.50 eq) were mixed in ACN (200 mL). The mixture was evacuated and replaced with N2 three times, then heated at 85°C for 36 hours. LCMS analysis showed approximately 56% yield of the desired product. The reaction mixture was concentrated and slurried with MTBE / DCM = 6:1 (300 mL / 50.0 mL) at 25°C for 12 hours. The filter cake was filtered to obtain the product, Compound A2 (16.0 g, 47.9 mmol, 50.2% yield, 95.4% purity).

[0366] Step 3: Preparation of 6-(1,1,2-trimethylbenz[e]indol-3-yl)phenyl hexanoate chloride (C2)

[0367] 6-(1,1,2-Trimethylbenz[e]indol-3-yl)hexanoic acid bromide (5.00 g, 15.4 mmol, 1.00 eq) was dissolved in a mixture of DMF (15.0 mL) and DCM (20.0 mL). EDCI (7.01 g, 18.4 mmol, 1.20 eq) and DIEA (4.98 g, 38.5 mmol, 6.71 mL, 2.50 eq) were added. The mixture was stirred at 25°C for 0.5 h, followed by the addition of phenol (1.60 g, 16.9 mmol, 1.49 mL, 1.10 eq). The reaction was continued at this temperature for 12 h. Assays indicated that the 6-(1,1,2-trimethylbenz[e]indol-3-yl)hexanoic acid bromide was completely consumed. The reaction solution was concentrated, separated and purified by reverse phase HPLC (0.1% HCl), and lyophilized to obtain compound C2 (2.40 g, 5.99 mmol, 38.9% yield) as a brown solid.

[0368] LCMS: m / z = 400.2, C 27 H 30 NO2 +.

[0369] Step 4: Preparation of Compound 1B

[0370] A solution of compound A2 (1.00 g, 3.15 mmol, 1.00 eq), compound C2 (1.89 g, 4.72 mmol, 1.50 eq) and acetic anhydride (30.0 mL) was stirred at 70°C for 1 hour, and then NaOAc (776 mg, 9.45 mmol, 3.00 eq) was added. Then, (E)-2-chloro-3-(hydroxymethylene)cyclopent-1-ene-1-carbaldehyde (compound B1) (500 mg, 3.15 mmol, 1.00 eq) was added in batches. After stirring at 80°C for 1 hour, the solvent was concentrated. The residue was separated and purified by reverse phase chromatography (0.1% HCl condition) to give compound 1A (53.7 mg, 68.4 μmol, 2.17% yield, 96.8% purity) as a brown solid and compound 1B (4.90 mg, 6.80 μmol, 0.22% yield, 95.0% purity) as a white solid.

[0371] Compound 1A:

[0372] 1 H NMR (400MHz, CDCl3) δ8.11-8.15(m,2H),7.93-7.98(m,5H),7.60-7.62(m,2H) ,7.44-7.47(m,4H),7.28-7.32(m,3H),7.19-7.20(m,1H),6.97-6.99(m,2H),6 .25-6.30(m,2H),4.41-4.49(m,4H),3.11-3.16(m,4H),2.61-2.65(m,2H),2. 01(d,J=4.8Hz,12H),1.85-1.87(m,2H),1.67-1.69(m,3H),1.51-1.55(m,4H).

[0373] LCMS: m / z=759.6 (M+H) + .

[0374] Compound 1B:

[0375] LCMS: m / z=683.5 (M+H) + .

[0376] Example 2: Preparation of 6-[(2E)-2-[(2E)-2-[2-chloro-3-[(E)-2-(3-ethyl-1,1-dimethyl-phenylpropano[e]indol-3-yl)vinyl]cyclohexyl-2-en-1-yl]ethylidene]-1,1-dimethyl-phenylpropano[e]indol-3-yl]phenyl hexanoate (2)

[0377] To a solution of compound A2 (1.01 g, 3.16 mmol, 1.00 eq) in Ac2O (12.0 mL) was added a solution of compound C2 (1.90 g, 4.74 mmol, 1.50 eq) in Ac2O (12.0 mL). After incubation at 70°C for 3 hours, the reaction solution was concentrated and the residue was dissolved in EtOH (40.0 mL). The mixture was heated to 80°C and compound B2 (purchased from WuXi AppTec, 545 mg, 3.16 mmol, 1 eq) and NaOAc (778 mg, 9.49 mmol, 3.00 eq) were added. Stirring was continued at 80°C for 2 hours. After the reaction solution was concentrated, the residue was purified by preparative chromatography (chromatographic column: YMC Triart C18 150 mm × 25 mm × 5 μm; mobile phase [water (HCl)-ACN]; B%: 76%-100%, 10 min) and lyophilized to obtain compound 2 (52.47 mg, 65.9 μmol, 34.0% yield, 97.3% purity) as a green solid.

[0378] 1 H NMR: (400MHz, CDCl3) δ8.47-8.41(m,1H),8.13(d,J=8.0Hz,2H),7.98-7.94(m, 4H),7.62(d,J=7.2Hz,2H),7.53-7.46(m,3H),7.31-7.27(m,2H),7.20-7.15(m ,1H),6.98-6.95(m,2H),6.41-6.22(m,1H),4.41(s,3H),2.95-2.57(m,5H),2. 02-1.96(m,20H),1.89-1.80(m,3H),1.70-1.62(m,2H),1.53(t,J=5.1Hz,3H).

[0379] Example 3: Preparation of 2-((E)-2-((E)-2-chloro-3-((E)-2-(1,1-dimethyl-3-(4-(phenoxycarbonyl)phenyl)-1,3-dihydro-2H-benzo[e]indol-2-ylenyl)vinyl)cyclohex-1-en-1-yl)vinyl)-3-ethyl-1,1-dimethyl-1H-benzo[e]indol-3-onium chloride (3)

[0380] Step 1: Preparation of 3-(4-carboxybromo)-1,1,2-trimethyl-1H-benzo[e]indol-3-ium bromide (3a)

[0381] To a solution of 1,1,2-trimethylbenz[e]indole (3.75 g, 17.90 mmol, 1.00 eq) in ACN (50.0 mL) was added 4-(bromomethyl)benzoic acid (3.85 g, 17.9 mmol, 1.00 eq). The mixture was stirred at 85°C for 12 hours. The reaction mixture was concentrated under reduced pressure, and the residue was slurried with MTBE / DCM = 1:2 (210 mL / 30 mL) at 25°C for 30 minutes. The filter cake was filtered to obtain the product, compound 3a (6.50 g, 15.3 mmol, 85.5% yield), as a brown solid.

[0382] 1 H NMR: (400MHz, CDCl3) δ8.41 (d, J = 8.4Hz, 1H), 8.22-8.16 (m, 2H), 7.97-7.91 (m, 3H), 7.82- 7.73(m,2H),4.22-4.16(m,4H),7.57-7.52(m,2H),6.06(s,2H),3.07(s,3H),1.85(s,6H).

[0383] Step 2: Preparation of 1,1,2-trimethyl-3-(4-(phenoxycarbonyl)bromo)-1H-benzo[e]indol-3-ium chloride (C3)

[0384] Compound 3a (4.50 g, 10.6 mmol, 1.00 eq) was dissolved in DMF (10.0 mL) and DCM (60.0 mL). HBTU (4.83 g, 12.7 mmol, 1.20 eq) and DIEA (3.43 g, 26.5 mmol, 4.62 mL, 2.50 eq) were added. The mixture was stirred at 25°C for 0.5 h, followed by the addition of phenol (1.10 g, 11.6 mmol, 1.03 mL, 1.10 eq). The mixture was then stirred at 25°C for 12 h. The reaction mixture was concentrated, and the residue was purified by reverse phase chromatography (0.1% HCl) to afford compound C3 (1.7 g, 4.04 mmol, 38.12% yield) as a brown solid.

[0385] LCMS: m / z = 420.2C 29 H 26 ClNO2 - .

[0386] Step 3: Preparation of compound 3

[0387] A mixture of compound A2 (353 mg, 1.11 mmol, 1.00 eq), 1,1,2-trimethyl-3-(4-(phenoxycarbonyl)bromo)-1H-benz[e]indole-3-ium chloride (C3) (0.700 g, 1.66 mmol, 1.50 eq), and Ac2O (14.0 mL) was stirred at 70°C for 1 hour. NaOAc (273 mg, 3.33 mmol, 3.00 eq) and compound B2 (192 mg, 1.11 mmol, 1.00 eq) were then added. The mixture was heated to 80°C and stirred for 1 hour. The reaction mixture was concentrated, and the residue was purified by preparative chromatography (HCl) to afford compound 3 (104.57 mg, 126 μmol, 11.4% yield, 95.7% purity) as a green solid.

[0388] 1 H NMR (400MHz, CDCl3) δ8.51-8.55(m,1H),8.29-8.32(m,1H),8.14-8.22(m,4H),7.89 -8.02(m,2H),7.40-7.67(m,2H),7.40-7.58(m,9H),7.31-7.34(m,1H),7.19-7.21( m,2H),6.50-6.57(m,1H),6.15-6.18(m,1H),5.65(s,2H),4.58-4.60(m,2H),2.80( s,2H),2.63(s,2H),2.10(s,6H),2.03(s,6H),2.00-2.01(m,2H),1.50-1.60(m,3H).

[0389] LCMS: m / z = 793.3.

[0390] Example 4: Preparation of 2-((E)-2-((E)-2-chloro-3-(2-((E)-3,3-dimethyl-1-(6-oxo-6-phenoxyhexyl)indolin-2-ylalkenyl)vinyl)cyclopent-1-en-1-yl)vinyl)-1-ethyl-3,3-dimethyl-3H-indole-1-onium chloride (4)

[0391] Step 1: Preparation of 1-(5-carboxypentyl)-2,3,3-trimethyl-3H-indol-1-ium bromide (C0)

[0392] A solution of 2,3,3-trimethylindole (5 g, 31.40 mmol, 1 eq) and 6-bromohexanoic acid (12.25 g, 62.80 mmol, 2 eq) in ACN (40 mL) was stirred at 85°C for 24 hours. The reaction mixture was concentrated under reduced pressure to remove the solvent to afford the crude product. The product was then slurried with DCM:MTBE (1:1) (60 mL) at 0°C for 30 minutes to afford compound C0 (6.9 g, 19.48 mmol, 62.02% yield) as a pink solid.

[0393] 1 H NMR: (400MHz, CDCl3) δ7.99-7.97(m,1H),7.86-7.83(m,1H),7.63-7.61(m,2H),4.48-4.44(m,2H), 2.85(s,,3H),2.24-2.20(t,J=7.2Hz,2H),1.86–1.80(m,2H),1.57–1.54(m,8H),1.44–1.41(m,2H).

[0394] Step 2: Preparation of 2,3,3-trimethyl-1-(6-oxo-6-phenoxyhexyl)-3H-indol-1-ium chloride (C1)

[0395] Compound C0 (4.00 g, 11.3 mmol, 1.00 eq) was mixed in DCM (50.0 mL), followed by the addition of HBTU (5.14 g, 13.5 mmol, 1.20 eq) and DIEA (3.65 g, 28.2 mmol, 4.92 mL, 2.50 eq). The mixture was stirred at 25°C for 0.5 h, followed by the addition of phenol (1.06 g, 11.3 mmol, 993 μL, 1.00 eq), and the reaction was continued at 25°C for 12 h. The product, compound C1 (2.00 g, 4.53 mmol, 40.1% yield, 79.3% purity), was purified by reverse-phase HPLC (0.1% HCl) and lyophilized to obtain a brown solid.

[0396] LCMS: m / z=350.1, C 23 H 28 NO2 + .

[0397] Step 3: Preparation of compound 4

[0398] A solution of compound C1 (1.32 g, 3.78 mmol, 1.50 eq), compound A1 (676 mg, 2.52 mmol, 1.00 eq), and Ac2O (20.0 mL) was stirred at 70°C for 1 hour, then NaOAc (621 mg, 7.56 mmol, 3.00 eq) and compound B1 (400 mg, 2.52 mmol, 1.00 eq) were added. The mixture was heated to 80°C and stirred for 1 hour, then concentrated under reduced pressure. The residue was purified by preparative chromatography (HCl conditions: column: YMC Triart C18 150 mm × 25 mm × 5 μm; mobile phase: [water (HCl)-ACN]; B%: 70%-100%, 10 min) and lyophilized to obtain compound 4 (68.07 mg, 89.0 μmol, 3.53% yield, 91% purity) as a green solid.

[0399] 1 H NMR (400MHz, DMSO) δ7.83 (t, J = 14Hz, 2H), 7.34-7.43 (m, 6H), 7.22-7.23 (m, 3H), 7.11-7.16 (m, 2H), 7.02-7.06 (m, 2H), 6.05-6.11 (m ,2H),4.16-4.21(m,4H),2.63(t,J=7.2Hz,2H),1.78-1.93(m,8H),1.71(d,J=4.4Hz,12H),1.60-1.64(m,2H),1.46(t,J=7.2Hz,3H).

[0400] LCMS: m / z=659.2, C 43 H 48 ClN2O2 + .

[0401] Example 5: Preparation of 2-((E)-2-((E)-2-chloro-3-(2-((E)-3,3-dimethyl-1-(6-oxo-6-phenoxyhexyl)indolin-2-ylalkenyl)vinyl)cyclohex-1-en-1-yl)vinyl)-3,3-dimethyl-1-(6-oxo-6-phenoxyhexyl)-3H-indole-1-onium chloride (5)

[0402] Compound C1 (3.05 g, 8.69 mmol, 2.00 eq) was added to a solution of compound B2 (750 mg, 4.35 mmol, 1.00 eq), NaOAc (1.07 g, 13.0 mmol, 3.00 eq), and Ac2O (30.0 mL). The mixture was stirred at 70°C for 40 minutes. The solvent was concentrated and the product was purified by preparative chromatography (HCl conditions: column: Phenomenex luna C18 150 mm × 40 mm × 15 μm; mobile phase: [water (HCl)-ACN]; B%: 70%-100%, 10 min). Compound 5 (263 mg, 288 μmol, 6.62% yield, 95.4% purity) was obtained as a green solid.

[0403] 1 H NMR (400MHz, CDCl3) δ8.36 (d, J = 14Hz, 2H), 7.35-7.42 (m, 8H), 7.27- 7.28(m,1H),7.24-7.26(m,5H),7.03(d,J=7.6Hz,4H),6.30(d,J=13.6Hz,2H),4.25(s,4H),2.72( s,4H),2.60-2.64(m,4H),1.93-1.95(m,6H),1.83-1.89(m,4H),1.72(s,12H),1.63-1.64(m,4H).

[0404] LCMS: m / z=835.5 (M+H) + .

[0405] Example 6: Preparation of 2-((E)-2-((E)-2-chloro-3-(2-((E)-3,3-dimethyl-1-(4-(phenoxycarbonyl)bromo)indolin-2-ylalkenyl)vinyl)cyclohex-1-en-1-yl)vinyl)-1-ethyl-3,3-dimethyl-3H-indole-1-onium chloride (6)

[0406] Step 1: Preparation of 1-(4-carboxybromo-2,3,3-trimethyl-3H-indol-1-ium bromide (6b)

[0407] Compound A0 (6.00 g, 37.6 mmol, 1.00 eq) was added with acetonitrile (50.0 mL), followed by 4-(bromomethyl)benzoic acid (6a, purchased from Shanghai Bid Pharmaceutical Technology Co., Ltd.) (12.1 g, 56.5 mmol, 1.50 eq). The mixture was heated at 85°C for 12 hours. The reaction mixture was concentrated under reduced pressure and then slurried with MTBE / DCM = 1:2 (60.0 mL / 120 mL) at 25°C for 30 minutes. The mixture was filtered to obtain compound 6b (11.0 g, 28.1 mmol, 74.6% yield, 95.7% purity) as a yellow solid.

[0408] 1 H NMR (400MHz, DMSO) δ7.97 (d, J = 8.0 Hz, 2H), 7.88 (d, J = 7.2 Hz, 1H), 7.77 (d, J = 7.2 Hz, 1H), 7.63-7.51 (m, 4H), 5.92 (s, 2H), 2.97 (s, 3H), 1.62 (s, 6H).

[0409] Step 2: Preparation of 2,3,3-trimethyl-1-(4-(phenoxycarbonyl)bromo)-3H-indol-1-ium chloride (6c)

[0410] Compound 6b (6.00 g, 16.0 mmol, 1.00 eq) was dissolved in DMF (10.0 mL) and DCM (40.0 mL), followed by the addition of HBTU (7.30 g, 19.2 mmol, 1.20 eq) and DIEA (5.18 g, 40.0 mmol, 6.98 mL, 2.50 eq). The mixture was stirred at 25°C for 0.5 h. Phenol (1.66 g, 17.6 mmol, 1.55 mL, 1.10 eq) was then added to the reaction mixture, and stirring was continued for 12 h. The reaction mixture was concentrated, and the residue was purified by reverse-phase preparative chromatography (0.1% HCl) and freeze-dried to afford compound 6c (3.6 g, 8.85 mmol, 55.22% yield, 91.1% purity) as a red solid.

[0411] LCMS: m / z=370.1, C 25 H 24 NO2 + .

[0412] Step 3: Preparation of compound 6

[0413] Compound 6c (965 mg, 2.61 mmol, 1.50 eq) and 1-ethyl-2,3,3-methyl-3H-indol-1-ium bromide (A1) (466 mg, 1.74 mmol, 1.00 eq) were dissolved in AcO (20.0 mL) and stirred at 70°C for 1 hour. Compound B2 (300 mg, 1.74 mmol, 1.00 eq) was added, followed by NaOAc (427 mg, 5.21 mmol, 16.3 μL, 3.00 eq), and the mixture was stirred at 80°C for 1 hour. The reaction solution was concentrated, and the resulting residue was separated by reverse-phase preparative chromatography to afford green compound 6 (200 mg, 187 μmol, 10.7% yield, 65.0% purity). Further purification afforded 83.47 mg, 113 μmol, 39.2% yield, 94.1% purity) as a green solid.

[0414] 1 H NMR (400MHz, CDCl3) δ8.45 (d, J = 14.4Hz, 2H), 8.26-8.19 (m, 3H), 7.47-7.38 (m, 7H), 7.3 5-7.28(m,3H),7.26-7.22(m,2H),7.20-7.18(m,2H),7.01(d,J=8.0Hz,2H),6.44(d,J=1 4.4Hz,1H),6.03(d,J=13.2Hz,1H),5.79-5.52(m,1H),5.41(s,2H),4.43-4.35(m,2H), 2.72(s,2H),2.55(s,2H),1.91(s,2H),1.77(s,6H),1.73(s,6H),1.48(t,J=5.1Hz,3H).

[0415] Example 7: Preparation of 2-((E)-2-((E)-2-chloro-3-(2-((E)-3,3-dimethyl-1-(2-(3-oxo-3-phenoxypropoxy)ethyl)indolin-2-ylalkenyl)vinyl)cyclohex-1-en-1-yl)vinyl)-1-ethyl-3,3-dimethyl-3H-indol-1-ium trifluoroacetate (7)

[0416] Step 1: Preparation of 1-(2-(2-carbonylethoxy)ethyl)-2,3,3-trimethyl-3H-indol-1-ium chloride (7b)

[0417] To a solution of compound A0 (1.20 g, 7.54 mmol, 1.00 eq) and acetonitrile (15.0 mL) was added 3-(2-bromoethoxy)propanoic acid (7a) (2.97 g, 15.1 mmol, 2.00 eq). The mixture was stirred at 90°C for 36 hours. The solvent was concentrated and purified by preparative chromatography (HCl) to afford compound 7b (1.60 g, 4.49 mmol, 59.6% yield) as a colorless paste.

[0418] LCMS: m / z=276.1 (M+H) + .

[0419] Step 2: Preparation of 2,3,3-trimethyl-1-(2-(3-oxo-3-phenoxypropoxy)ethyl)-3H-indol-1-ium chloride (7c)

[0420] To a solution of compound 7b (1.60 g, 4.49 mmol, 1.00 eq), DMF (3.00 mL), and DCM (22.0 mL) were added HBTU (2.04 g, 5.39 mmol, 1.20 eq) and DIEA (1.45 g, 11.2 mmol, 1.96 mL, 2.50 eq). The mixture was stirred at 25°C for 30 minutes. Phenol (465 mg, 4.94 mmol, 435 μL, 1.10 eq) was added, and the mixture was stirred at 25°C for 12 hours. The mixture was concentrated under reduced pressure, and the residue was purified by preparative chromatography (0.1% HCl) to afford compound 7c (1.40 g, 3.97 mmol, 88.5% yield) as a yellow oil.

[0421] LCMS: m / z=352.2 (M+H) + .

[0422] Step 3: Preparation of compound 7

[0423] A solution of compound 7c (306 mg, 869 μmol, 1.00 eq), compound A1 (350 mg, 1.30 mmol, 1.50 eq), and acetic anhydride (8.00 mL) was stirred at 80°C for 1.5 hours. NaOAc (214 mg, 2.61 mmol, 3.00 eq) and compound B2 (150 mg, 869 μmol, 1.00 eq) were then added at 80°C and stirring continued for 1.5 hours. The reaction mixture was concentrated, and the residue was purified by preparative chromatography (TFA conditions) to afford compound 7 (60.0 mg, 80.3 μmol, 9.24% yield, 90.5% purity) as a brown solid.

[0424] 1H NMR (400MHz, CDCl3) δ8.34 (t, J = 14Hz, 2H), 7.36-7.40 (m, 4H), 7.29-7.35 (m, 3H), 7.26-7.27 ( m,2H),7.25-7.26(m,1H),7.13-7.25(m,1H),6.85(d,J=7.6Hz,2H),6.37(d,J=14Hz,1H),6.13 (d,J=14Hz,1H),4.41(s,2H),4.12-4.17(m,2H),3.97(s,2H),3.82-3.85(m,2H),2.70-2.74( m,2H),2.65-2.68(m,4H),1.91-1.93(m,2H),1.74(s,6H),1.72(s,6H),1.44(t,J=7.2Hz,3H).

[0425] LCMS: m / z=675.4 (M+H) + .

[0426] Example 8: Preparation of 2-((E)-2-((E)-2-chloro-3-(2-((E)-3,3-dimethyl-1-(2-(2-oxo-2-phenoxyethoxy)ethyl)indolin-2-ylalkenyl)vinyl)cyclohex-1-en-1-yl)vinyl)-1-ethyl-3,3-dimethyl-3H-indol-1-ium trifluoroacetate (8)

[0427] Step 1: Preparation of 2-(2-chloroethoxy)phenyl acetate (8a)

[0428] To a solution of 2-(2-chloroethoxy)acetic acid (5.00 g, 36.1 mmol, 1.00 eq) in DCM (70.0 mL) were added HBTU (16.4 g, 43.3 mmol, 1.20 eq) and DIEA (11.7 g, 90.2 mmol, 15.7 mL, 2.50 eq). After stirring at 25°C for 30 minutes, phenol (3.74 g, 39.7 mmol, 3.49 mL, 1.10 eq) was added and stirred at 25°C for 12 hours. The solvent was concentrated, water (100 mL) was added, and the mixture was extracted with ethyl acetate (100 mL x 3). The organic phases were combined, dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 100 / 1 to 1 / 1) and thin layer chromatography (petroleum ether / ethyl acetate = 3 / 1, R f = 0.5, KMnO4) to give compound 8a (6.40 g, 29.8 mmol, yield 82.6%) as a yellow solid.

[0429] 1 H NMR (400MHz, CDCl3) δ7.39-7.43(m,2H),7.27-7.29(m,1H),7.13-7.15(m,2H),4.45(s,2H),3.95(t,J=5.8Hz,2H),3.73(t,J=5.6Hz,2H).

[0430] Step 2: Preparation of 2,3,3-trimethyl-1-(2-(2-oxo-2-phenoxyethoxy)ethyl)-3H-indol-1-ium trifluoroacetate (8b)

[0431] A mixture of compound 8a (4.44 g, 20.7 mmol, 2.00 eq), compound A0 (1.65 g, 10.4 mmol, 1.00 eq), and NaI (7.77 g, 51.8 mmol, 5.00 eq) was heated to 180°C and stirred for 1 hour. After cooling, the mixture was diluted with ACN (30.0 mL), filtered, and the mother liquor was concentrated. The concentrate was purified by preparative chromatography (TFA) to afford compound 8b (1.20 g, 3.55 mmol) as a brown oil.

[0432] LCMS: m / z=338.1 (M+H) + .

[0433] Step 3: Preparation of compound 8

[0434] A solution of compound 8b (588 mg, 1.74 mmol, 1.50 eq) and compound A1 (366 mg, 1.16 mmol, 1.00 eq) in acetic anhydride (2.00 mL) was stirred at 70 ° C for 1.5 hours, and then NaOAc (285 mg, 3.48 mmol, 3.00 eq) and compound B2 (200 mg, 1.16 mmol, 1.00 eq) were added. The mixture was stirred at 80 ° C for another 1.5 hours, and the mixture was concentrated under reduced pressure. The residue was purified by preparative chromatography (0.1% TFA conditions) to give compound 8 (92.0 mg, 106 μmol, 9.17% yield, 89.8% purity, TFA) as a green solid.

[0435] 1H NMR (400MHz, CDCl3) δ8.30-8.39(m,2H),7.35-7.42(m,7H),7.24-7.26(m, 3H),7.12(d,8.0Hz,1H),7.00-7.02(m,2H),6.44(d,J=14.4Hz,1H),6.13(d ,J=14Hz,1H),4.49-4.51(m,2H),4.35(s,2H),4.10-4.17(m,4H),2.63-2.6 9(m,4H),1.92(s,1H),1.90-1.91(m,2H),1.72(s,12H),1.42-1.46(m,3H).

[0436] LCMS: m / z=661.5 (M+H) + .

[0437] Example 9: Preparation of 2-((E)-2-((E)-2-chloro-3-(2-((E)-3,3-dimethyl-1-(6-oxo-6-phenoxyhexyl)indolin-2-ylalkenyl)vinyl)cyclopent-1-en-1-yl)vinyl)-1,3,3-trimethyl-3H-indole-1-onium chloride (9)

[0438] Step 1: Preparation of 1,2,3,3-tetramethyl-3H-indol-1-iodide (A3)

[0439] A solution of 2,3,3-trimethylindole (3.00 g, 18.8 mmol, 1.00 eq) and MeI (4.01 g, 28.2 mmol, 1.76 mL, 1.50 eq) in ACN (30.0 mL) was evacuated and replaced with nitrogen three times. The mixture was stirred at 90°C under a nitrogen atmosphere for 12 hours. The reaction mixture was concentrated under reduced pressure to remove the solvent to obtain the crude product. The product was then slurried with MTBE / DCM (5:1) (20 mL) at 25°C for 30 minutes and filtered to obtain the filter cake, which was the product, Compound A3 (3.50 g, 11.4 mmol, 60.4% yield, 98% purity), as a purple solid.

[0440] Step 2: Preparation of compound 9

[0441] A mixture of compound C1 (2.00 g, 5.71 mmol, 1.50 eq), compound A3 (1.15 g, 3.80 mmol, 1.00 eq), and Ac2O (30.0 mL) was stirred at 70°C for 1 hour, followed by the addition of NaOAc (936 mg, 11.4 mmol, 3.00 eq) and compound B1 (603 mg, 3.80 mmol, 1.00 eq). The reaction mixture was stirred at 80°C for 1 hour, concentrated under reduced pressure, and the residue was purified by preparative chromatography (0.1% HCl) to afford compound 9 (900 mg, 1.23 mmol, 32.21% yield, 88% purity) as a green solid.

[0442] LCMS: m / z=645.2, C 42 H 46 ClN2O2 + .

[0443] Example 10: Preparation of 2-((E)-2-((E)-3-(2-((E)-1-(5-carboxypentyl)-3,3-dimethylindolin-2-ylalkenyl)vinyl)-2-chlorocyclopent-1-en-1-yl)vinyl)-1,3,3-trimethyl-3H-indole-1-onium chloride (10)

[0444] To a solution of compound 9 (200 mg, 309 μmol, 1.00 eq) in dioxane (2.00 mL) was added HCl / dioxane solution (1 M, 1.86 mL, 6.00 eq). The mixture was stirred at 50°C for 2 hours. The reaction solution was concentrated and the residue was purified by preparative chromatography (column: YMC Triart C18 150 mm × 25 mm × 5 μm; mobile phase: [water (HCl)-ACN]; B%: 58%-88%, 10 min) to give compound 10 (41.0 mg, 71.0 μmol, 23.0% yield, 98.7% purity) as a green solid.

[0445] 1 H NMR (400MHz, CDCl3) δ7.85-7.81(m,2H),7.41-7.36(m,4H),7.25-7.22(m,2H),7.15-7.13(m,2H),6.08-6.03(m,2H), 4.08-4.06(m,2H),3.67(s,3H),3.03(s,4H),2.54-2.49(m,2H),1.87-1.76(m,4H),1.71(s,12H),1.60-1.54(m,2H).

[0446] LCMS: m / z=569.4, C36 H 42 ClN2O2 + .

[0447] Example 11: Preparation of 1-(5-carboxyphenyl)-2-((E)-2-((E)-2-chloro-3-(2-((E)-3,3-dimethyl-1-(6-oxo-6-phenoxyhexyl)indolin-2-ylalkenyl)vinyl)cyclohex-1-en-1-yl)vinyl)-3,3-dimethyl-3H-indole-1-onium chloride (11)

[0448] To a solution of compound B2 (0.400 g, 2.32 mmol, 1.00 eq) and compound C1 (812 mg, 2.32 mmol, 1.00 eq) in EtOH (2.00 mL) were added NaOAc (570 mg, 6.95 mmol, 3.00 eq) and compound C0 (635 mg, 2.32 mmol, 1.00 eq). After stirring at 85°C for 2 hours, the reaction solution was concentrated and the residue was purified by preparative chromatography (column: YMC Triart C18 150 mm × 25 mm × 5 μm; mobile phase: [water (HCl)-ACN]; B%: 56%-86%, 8.5 min) to give compound 11 (94.0 mg, 111 μmol, 4.81% yield, 90.2% purity) as a green solid.

[0449] 1 H NMR(400MHz, CDCl3) δ8.40(d,J=14.0Hz,1H),8.31(d,J=14.0Hz,1H),7.38-7. 43(m,6H),7.35-7.37(m,1H),7.21-7.23(m,3H),7.02-7.04(m,3H),6.31(d,J= 14.0Hz,1H),6.10(d,J=14.0Hz,1H),4.06-4.19(m,4H),2.69-2.75(m,4H),2.6 1-2.64(m,4H),1.82-1.99(m,10H),1.72(d,J=5.6Hz,12H),1.59-1.64(m,4H).

[0450] LCMS: m / z=759.4, C 48 H 56 ClN2O4 + .

[0451] Example 12: Preparation of 2-((E)-2-((E)-3-(2-((E)-3,3-dimethyl-1-(6-oxo-6-phenoxyhexyl)indolin-2-ylalkenyl)vinyl)-2-phenoxycyclohex-1-en-1-yl)vinyl)-1-ethyl-3,3-dimethyl-3H-indole-1-onium chloride (12)

[0452] To a solution of phenol (209 mg, 2.22 mmol, 196 μL, 2.50 eq) in THF (50.0 mL) was added NaH (88.9 mg, 2.22 mmol, 60.0% purity, 2.50 eq) at 0°C, and then the temperature was raised to 25°C and stirred for 30 minutes. Then, a solution of 2-((E)-2-((E)-2-chloro-3-(2-((E)-3,3-dimethyl-1-(6-oxo-6-phenoxyhexyl)indolin-2-ylalkenyl)vinyl)cyclohex-1-en-1-yl)vinyl)-1-ethyl-3,3-dimethyl-3H-indole-1-ium chloride (12a) (preparation method see Comparative Example 1) (600 mg, 890 μmol, 1.00 eq) in THF (10.0 mL) was added and stirred for 4 hours, cooled to 0° C., quenched by addition of saturated NH 4 Cl solution (4.00 mL), and concentrated under reduced pressure. The residue was purified by preparative chromatography (HCl conditions: column: Phenomenex luna C18 150mm×40mm×15μm; mobile phase: [water (HCl)-ACN]; B%: 60%-90%, 10min) to give compound 12 (84.7mg, 110μmol, 12.4% yield, purity 95.3%) as a green solid.

[0453] 1 H NMR: (400MHz, CDCl3)δ7.91(t,J=13.8Hz,2H),7.34-7.37(m,6H),7.23-7.27(m,5H),7.02-7.08(m,7H),6.08(t,J=14.4Hz,2H),4.06-4.16( m,4H),2.72(s,4H),2.59-2.71(m,2H),2.02-2.03(m,2H),1.82-1.86(m,4H),1.58-1.60(m,2H),1.38-1.43(m,3H),1.33(d,J=2.0Hz,12H).

[0454] LCMS: m / z=731.6 (M+H) + .

[0455] Example 13: Preparation of 2-((E)-2-((E)-2-((5-carboxypentyl)amino)-3-(2-((E)-1-ethyl-3,3-dimethylindolin-2-ylalkenyl)vinyl)cyclohex-1-en-1-yl)vinyl)-1-ethyl-3,3-dimethyl-3H-indol-1-ium formate (13)

[0456] Step 1: Preparation of 2-((E)-2-((E)-2-chloro-3-(2-((E)-1-ethyl-3,3-dimethyl-indolin-2-ylenyl)vinyl)cyclohex-1-en-1-yl]vinyl]-1-ethyl-3,3-dimethyl-indol-1-ium bromide (13A)

[0457] To a mixture of compound A1 (3.88 g, 14.5 mmol, 2.50 eq) and Ac2O (50.0 mL) were added NaOAc (1.43 g, 17.4 mmol, 3.00 eq) and compound B2 (1.00 g, 5.79 mmol, 1.00 eq) at 70°C, and the mixture was heated to 80°C and stirred for 1 hour. The reaction solution was concentrated and purified by preparative chromatography (neutral conditions) and lyophilized to give compound 13A (1.30 g) as a green solid.

[0458] LCMS: m / z = 511.2.

[0459] Step 2: Preparation of compound 13

[0460] To a solution of compound 13A (0.100 g, 195 μmol, 1.00 eq), 6-aminohexanoic acid (169 mg, 1.29 mmol, 166 μL, 6.60 eq), and MeOH (5.50 mL) was added triethylamine (324 mg, 3.20 mmol, 446 μL, 16.4 eq). The reaction mixture was stirred at 70°C for 4 hours. After concentration under reduced pressure, the product was purified by preparative chromatography (column: Phenomenex luna C18 150 mm × 25 mm × 10 μm; mobile phase: [water (FA)-ACN]; B%: 38%-68%, 10 min) to afford compound 13 (56.0 mg, 83.9 μmol, 42.9% yield, 90.9% purity) as a green solid.

[0461] 1H NMR(400MHz, CDCl3)δ8.70(s,1H),7.64-7.67(m,2H),7.28(s,1H),7.23- 7.26(m,3H),7.02-7.06(m,2H),6.81(d,J=8.4Hz,2H),5.52-5.55(m,2H), 3.79-3.83(m,6H),2.49-2.53(m,6H),1.95-1.98(m,2H),1.81-1.84(m,2H ),1.75-1.79(m,2H),1.66(s,12H),1.45-1.49(m,2H),1.31-1.37(m,6H).

[0462] LCMS: m / z = 606.5.

[0463] Example 14: Preparation of 2-((E)-2-((E)-4-chloro-5-(2-((E)-3,3-dimethyl-1-(6-oxo-6-phenoxyhexyl)indolin-2-ylalkenyl)vinyl)-1,1-dimethyl-1,2,5,6-tetrahydropyridin-1-ium-3-yl)vinyl)-3,3-dimethyl-1-(6-oxo-6-phenoxyhexyl)-3H-indol-1-ium dichloride (14)

[0464] Step 1: Preparation of 1,1-dimethyl-4-oxopiperidinium-1-iodide (14a)

[0465] To a solution of 1-methyl-4-piperidone (15 g, 132.56 mmol, 15.42 mL, 1 eq) in acetone (210 mL) at 0°C was added MeI (41.02 g, 288.98 mmol, 17.99 mL, 2.18 eq) and the mixture was stirred at 25°C for 4 hours. The reaction mixture was filtered, and the filter cake was washed with glacial acetone (20.0 mL) and then concentrated under reduced pressure to yield the product (33 g, 129.36 mmol, 97.59% yield) as a yellow solid.

[0466] 1 H NMR (400MHz, CDCl3) δ3.77-3.74 (t, J=6.8Hz, 4H), 3.28 (s, 6H), 2.73–2.69 (m, 4H).

[0467] Step 2: Preparation of (E)-4-chloro-5-formyl-3-(hydroxymethylene)-1,1-dimethyl-1,2,3,6-tetrahydropyridinium-1-chloride (B3)

[0468] A mixture of DMF (210 mL) and POCl3 (209.17 g, 1.36 mol, 126.77 mL, 3 eq) was stirred for 0.5 hours. The product from the previous step (116 g, 454.73 mmol, 1 eq) was then added to the mixture, followed by stirring at 80°C for 3 hours. TLC (ethyl acetate:methanol = 5:1) indicated the disappearance of the product from the previous step. The reaction mixture was quenched with 20% HCl (700 mL) at 35-40°C, then rapidly cooled to -20°C. The suspension was filtered, and the filtrate was incubated at 25°C for 12 hours. The filtrate was then cooled to -20°C for 4 hours, filtered, and the filter cake was concentrated under reduced pressure to obtain a residue. The residue was diluted with toluene (30.0 mL) and concentrated under reduced pressure to yield two residues, namely, Compound B3 (24.2 g, 110.50 mmol, 26.26% yield), as a yellow solid.

[0469] 1 H NMR (400MHz, CDCl3) δ9.00 (s, 2H), 4.27 (s, 4H), 3.18 (s, 6H).

[0470] Step 3: Preparation of compound 14

[0471] A mixture of compound C1 (865 mg, 2.47 mmol, 2.00 eq) and Ac2O (10.0 mL) was stirred at 70°C for 30 minutes, and then NaOAc (304 mg, 3.70 mmol, 3.00 eq) and compound B3 (250 mg, 1.23 mmol, 1.00 eq) were added. After stirring at 80°C for 1 hour, the mixture was concentrated under reduced pressure. The residue was purified by preparative chromatography (0.1% HCl) to give compound 14 (182.57 mg, 190 μmol, 15.4% yield, 90.1% purity) as a green solid.

[0472] 1 H NMR (400MHz, CDCl3) δ8.28(d,J=7.4Hz,2H),7.34-7.44(m,10H),7.19-7.25(m,4H),7.04(d,J=8.0Hz,4H),6.22-6.26(m,2H),4.39(s,4H) ),4.24-4.33(m,4H),3.08(s,6H),2.60(t,J=4.0Hz,4H),2.02(s,2H),1.88-1.95(m,4H),1.82-1.86(m,4H),1.73(s,12H),1.66(s,2H).

[0473] LCMS: m / z = 433.4, C 55 H64 ClN3O4 2+ .

[0474] Example 15: Preparation of 2-((E)-2-((E)-5-(2-((E)-1-(5-carboxypentyl)-3,3-dimethylindolin-2-ylalkenyl)vinyl)-4-chloro-1,1-dimethyl-1,2,5,6-tetrahydropyridin-1-ium-3-yl)vinyl)-3,3-dimethyl-1-(6-oxo-6-phenoxyhexyl)-3H-indol-1-ium ditrifluoroacetate (15)

[0475] To a solution of compound 14 (100 mg, 115 μmol, 1.00 eq) in MeCN (2.00 mL) was added a solution of hydrogen chloride in dioxane (4.00 M, 86.6 μL, 3.00 eq). The mixture was stirred at 25°C for 12 hours, and then a solution of hydrogen chloride in dioxane (4.00 M, 289 μL, 10.0 eq) was added. Stirring was continued at 25°C for 12 hours. The solvent was concentrated and the residue was purified by preparative chromatography (TFA conditions; column: Phenomenex Synergi Polar-RP 100 mm × 25 mm × 4 μm; mobile phase: [water (TFA)-ACN]; B%: 38%-68%, 9 min) and lyophilized to give compound 15 (43.44 mg, 43.0 μmol, 37.3% yield, 89.5% purity, TFA) as a blue paste.

[0476] 1 H NMR (400MHz, CDCl3) δ8.30(d,J=14.8Hz,2H),7.34-7.42(m,8H),7.18-7.23(m,3H),7.00-7.23(m,2H),6.39-6.45(m,2H),4.76(d,J=1 4.8Hz,4H),4.24-4.25(m,4H),3.34(s,6H),2.53-2.63(m,2H),2.32-2.42(m,2H),1.82-1.87(m,7H),1.72(s,12H),1.54-1.59(m,5H).

[0477] LCMS: m / z = 395.0C 49 H 60 ClN3O4 2+ .

[0478] Example 16: 2-((E)-2-((E)-4-chloro-5-(2-((E)-3,3-dimethyl-1-(6-oxo-6-phenoxyhexyl)indolin-2-ylalkenyl)vinyl)-1,1-dimethyl-1,2,5,6-tetrahydropyridin-1-ium-3-yl)vinyl)-1-ethyl-3,3-dimethyl-3H-indol-1-ium dichloride (16)

[0479] A mixture of compound C1 (2.00 g, 5.71 mmol, 1.50 eq), compound A1 (716 mg, 3.81 mmol, 1.00 eq, based on cations only), and Ac2O (30.0 mL) was heated to 80°C and stirred for 1 hour. Sodium acetate (936 mg, 11.4 mmol, 3.00 eq) and compound B3 (771 mg, 3.81 mmol, 1.00 eq) were then added sequentially, and the mixture was stirred at 80°C for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative chromatography (column: Phenomenex luna C18, 150 mm × 40 mm × 15 μm; mobile phase: [water (HCl)-ACN]; B%: 30%-60%, 10 min) to afford compound 16 (121 mg, 166 μmol, 4.38% yield, 97.1% purity) as a green solid.

[0480] 1 H NMR: (400MHz, CDCl3) δ8.28-8.33(m,2H),7.34-7.45(m,9H),7.24-7.26(m,2H),7.04-7.06(m,2H),6.20-6.28(m,2H),4.43(d,J=10.8Hz,4H ),4.27-4.32(m,4H),3.20(s,6H),2.61(t,J=14.0Hz,2H),1.83-1.93(m,4H),1.74(d,J=2.4Hz,12H),1.59-1.64(m,2H),1.47-1.50(s,3H).

[0481] LCMS: m / z=352.0, C 45 H 54 ClN3O2 2+ .

[0482] Example 17: Preparation of 1-(2-carboxyethyl)-2-((E)-2-((E)-5-(2-((E)-1-(2-carboxyethyl)-3,3-dimethylindolin-2-ylalkenyl)vinyl)-4-chloro-1,1-dimethyl-1,2,5,6-tetrahydropyridin-1-ium-3-yl)vinyl)-3,3-dimethyl-3H-indol-1-ium ditrifluoroacetate (17)

[0483] Step 1: Preparation of 1-(2-carboxyethyl)-2,3,3-trimethyl-3H-indol-1-ium bromide

[0484] To a solution of 3-bromopropionic acid (5.76 g, 37.7 mmol, 3.89 mL, 2.00 eq) in ACN (30 mL) was added 2,3,3-trimethylindole (A0) (3.00 g, 18.8 mmol, 1.00 eq). After stirring at 80 °C for 24 h, the reaction mixture was concentrated under reduced pressure and the residue was slurried with DCM:MTBE = 5:1 (10.0 mL) to give the title compound (1.50 g, 5.94 mmol, 31.5% yield, 92.0% purity) as a pink solid.

[0485] LCMS: m / z = 232.2, C 14 H 18 NO2 + .

[0486] Step 2: Preparation of compound 17

[0487] To a solution of the compound obtained in step 1 (1.00 g, 4.30 mmol, 1.00 eq) in EtOH (50.0 mL) was added NaOAc (353 mg, 4.30 mmol, 1.00 eq). The reaction mixture was stirred at 25°C for 0.5 h, and compound B3 (436 mg, 2.15 mmol, 0.500 eq) was added. The mixture was reacted at 80°C for 5 h. Purification by preparative chromatography (column: Phenomenex Synergi Polar-RP 100 mm × 25 mm × 4 μm; mobile phase: [water (TFA)-ACN]; B%: 30%-60%, 9 min) afforded compound 17 (174 mg, 247 μmol, 5.73% yield, 89.4% purity) as a green solid.

[0488] 1H NMR(400MHz,DMSO-d6)δ8.30-8.26(m,2H),7.44-7.37(m,4H),7.32-7.28(m,4H),6. 56-6.52(m,2H),4.78(s,4H),4.54(s,4H),3.43(s,6H),2.91(s,4H),1.71(s,12H).

[0489] LCMS: m / z=314.8, C 37 H 44 ClN3O 42 + .

[0490] Example 18: Preparation of 2-((E)-2-((E)-4-chloro-5-(2-((E)-1-ethyl-3,3-dimethylindolin-2-ylalkenyl)vinyl)-1,1-dimethyl-1,2,5,6-tetrahydropyridin-1-ium-3-yl)vinyl)-1-ethyl-3,3-dimethyl-3H-indol-1-ium ditrifluoroacetate (18)

[0491] A solution of compound A1 (1.86 g, 9.87 mmol, 2.00 eq) in Ac2O (15.0 mL) was stirred at 70°C for 0.5 h, and then NaOAc (1.21 g, 14.8 mmol, 3.00 eq) and compound B3 (1.00 g, 4.93 mmol, 1.00 eq) were added. The reaction mixture was stirred at 80°C for 1 hour and then concentrated under reduced pressure. The residue was slurried with water for 15 minutes and filtered. The crude product was purified by preparative chromatography (column: YMC Triart C18 150 mm×25 mm×5 μm; mobile phase: [water (TFA)-ACN]; B%: 41%-61%, 10 min) to give compound 18 (150 mg, 272 μmol, 5.51% yield, 98.2% purity) as a green solid.

[0492] 1 H NMR(400MHz, CDCl3)δ8.32(d,J=14.8Hz,2H),7.41-7.46(m,4H),7.36-7.34(m,2H),7.22(d,J=8.0Hz,2H), 6.68(d,J=14.8Hz,2H),4.98(s,4H),4.38-4.43(m,4H),3.53(s,6H),1.76(s,12H),1.46(t,J=7.2Hz,6H).

[0493] LCMS: m / z = 271.0, C 35 H44 ClN3 2+ .

[0494] Example 19: Preparation of 2-((E)-2-((E)-4-chloro-5-(2-((E)-1-(2-hydroxyethyl)-3,3-dimethylindolin-2-ylalkenyl)vinyl)-1,1-dimethyl-1,2,5,6-tetrahydropyridin-1-ium-3-yl)vinyl)-1-(2-hydroxyethyl)-3,3-dimethyl-3H-indol-1-ium ditrifluoroacetate (19)

[0495] Step 1: Preparation of 1-(2-hydroxyethyl)-2,3,3-trimethyl-3H-indol-1-iodide (A5)

[0496] A mixture of compound A0 (5.00 g, 31.4 mmol, 1.00 eq), 2-iodoethanol (5.40 g, 31.4 mmol, 2.45 mL, 1.00 eq) and EtOH (50.0 mL) was stirred at 80°C for 12 hours. The reaction solution was then concentrated under reduced pressure and the residue was slurried with petroleum ether (100 mL) to give compound A5 (2.80 g, 11.2 mmol, 35.8% yield, 82.0% purity) as a pink solid.

[0497] 1 H NMR (400MHz, CDCl3) δ7.81-7.79(m,1H),7.60-7.57(m,3H),4.90-4.88(m,2H),4.21(s,2H),3.12(s,3H),1.66(s,6H).

[0498] LCMS: m / z = 204.2C 13 H 18 NO + .

[0499] Step 2: Preparation of compound 19

[0500] Compound A5 (1.00 g, 4.90 mmol, 1.00 eq) was dissolved in EtOH (50 mL), and NaOAc (402 mg, 4.90 mmol, 1.00 eq) was added. The mixture was stirred at 25°C for 0.5 h, followed by the addition of compound B3 (496 mg, 2.45 mmol, 0.500 eq). The mixture was then stirred at 80°C for 5 h. The mixture was concentrated under reduced pressure, and the residue was purified by preparative chromatography (column: Phenomenex Synergi Polar-RP 100 mm × 25 mm × 4 μm; mobile phase: [water (TFA)-ACN]; B%: 28%-58%, 9 min) to afford compound 19 (90.1 mg, 145.38 μmol, 3.34% yield, 92.65% purity) as a brown solid.

[0501] 1 H NMR (400MHz, DMSO-d6) δ8.24-8.22(m,2H),7.70-7.68(m,2H),7.55-7.53(m,2H),7.49-7.45(m,2H),7.38-7. 34(m,2H),6.41-6.37(m,2H),4.65(s,4H),4.38-4.34(m,4H),3.86-3.83(m,6H),3.27(s,6H),1.70(s,12H).

[0502] LCMS: m / z = 286.9, C 35 H 44 ClN3O2 2+ .

[0503] Example 20: Preparation of 2-((E)-2-((E)-3-(2-((E)-3,3-dimethyl-1-(6-oxo-6-phenoxyhexyl)indol-2-methylene)vinyl)-2-(4-sulfonic acid phenoxy)cyclohex-1-en-1-yl)vinyl)-1-ethyl-3,3-dimethyl-3H-indol-1-ium formate (20)

[0504] To a mixture of (4-phenoxysulfonic acid) sodium (52.3 mg, 266 μmol, 1.20 eq), compound 12a (150 mg, 222 μmol, 1.00 eq) and DMSO (3.00 mL) was added K2CO3 (30.7 mg, 222 μmol, 1.00 eq). The mixture was stirred at 40°C for 12 hours and filtered. The filtrate was purified by preparative chromatography (column: UniSil 3-100C18UItra (150 mm × 25 mm × 3 μm); mobile phase [water (FA)-ACN]; B%: 67%-97%, 10 min) and lyophilized to give compound 20 (85.43 mg, 100 μmol, 45.2% yield, 95.5% purity) as a green solid.

[0505] 1 H NMR (400MHz, CDCl3) δ8.03 (d, J=8.8Hz, 2H), 7.92 (dd, J=14.0, 9.6Hz, 2H), 7.3 9-7.29(m,5H),7.26-7.15(m,4H),7.07-7.02(m,4H),6.98-6.96(m,2H),5.92( dd,J=14.0,11.6Hz,2H),4.05–3.95(m,4H),2.65-2.59(m,6H),1.02-1.99(m,2 H), 1.91-1.82 (m, 4H), 1.60-1.55 (m, 2H), 1.39 (t, J = 5.4Hz, 3H), 1.33 (s, 12H).

[0506] LCMS: m / z=811.37, C 50 H 55 N2O6S + .

[0507] Example 21. Preparation of 2-((E)-2-((E)-2-chloro-3-(2-((E)-3,3-dimethyl-1-(2-(3-oxo-3-phenoxypropoxy)ethyl)indol-2-methylene)ethylidene)cyclopentyl-1-en-1-yl)vinyl)-1-ethyl-3,3-dimethyl-3H-indol-1-ium trifluoroacetate (21)

[0508] To a solution of compound B1 (500 mg, 3.15 mmol, 1.00 eq), compound A1 (994 mg, 2.29 mmol, 1.00 eq), and compound C4 (1.36 g, 3.15 mmol, 1.00 eq) in acetic anhydride (20.0 mL) was added NaOAc (776 mg, 9.46 mmol, 3.00 eq). The mixture was stirred at 80°C for 3 hours. The reaction was concentrated under reduced pressure, and the residue was purified by reverse-phase HPLC (Phenomenex luna C18 150 × 40 mm × 15 μm, mobile phase: [water (TFA)-ACN]; B%: 25%-55%, 10 min, 0.1% HCl) to obtain a crude product (400 mg). The product was then purified by reverse-phase HPLC (TFA conditions, column: Phenomenex luna C18 150 mm × 40 mm × 15 μm; mobile phase: [water (TFA)-ACN]; gradient: 60%-90% B 10 min) and lyophilized to give compound 21 (66.41 mg, 80.4 μmol, 2.55% yield, 93.8% purity) as a green solid.

[0509] 1 H NMR (400MHz, CDCl3) δ7.88 (t, J = 11.2Hz, 2H), 7.40-7.47 (m, 4H), 7.31-7.36 (m, 5H),7.17-7.24(m,2H),6.90(d,J=8.0Hz,2H),5.96-6.21(m,2H),4.38(s,2H),4 .13-4.21(m,2H),4.02(t,J=4.8Hz,2H),3.88(t,J=6.0Hz,2H),2.97(br,2H),2 .78(t,J=5.6Hz,2H),1.80(s,2H),1.75(d,J=14Hz,12H),1.49(t,J=7.2Hz,2H).

[0510] LCMS: m / z=661.3, C 42 H 46 ClN2O3 + .

[0511] Example 22: Preparation of 2-((E)-2-((E)-2-chloro-3-(2-((E)-3,3-dimethyl-1-(6-oxo-6-phenoxyhexyl)indolin-2-ylalkenyl)vinyl)cyclopent-1-en-1-yl)vinyl)-1-ethyl-3,3-dimethyl-5-sulfonyl-3H-indol-1-ium chloride (22)

[0512] The preparation method of Example 21 was adopted to prepare Compound 22 as a green solid using Compounds A12, B1 and C1 as raw materials.

[0513] 1 H NMR(400MHz,DMSO-d6)δ7.70-7.79(m,3H),7.62-7.64(m,2H),7.36-7.46(m ,5H),7.24-7.34(m,2H),7.02(d,J=7.6Hz,2H),6.10-6.20(m,2H),4.19-4. 23(m,4H),2.91-2.94(m,4H),2.56-2.58(m,2H),1.78-1.80(m,2H),1.69-1 .73(m,2H),1.66(d,J=1.6Hz,12H),1.48-1.50(m,2H),1.29(d,J=7.2Hz,3H)

[0514] LCMS: m / z ==739.4, C 43 H 48 ClN2O5S + .

[0515] Example 23: Preparation of 2-((E)-2-((E)-2-chloro-3-(2-((E)-1-(6-(2,6-dimethylphenoxy)-6-oxohexyl)-3,3-dimethylindolin-2-ylalkenyl)vinyl)cyclopent-1-en-1-yl)vinyl)-1-(6-(2,6-dimethylphenoxy)-6-oxohexyl)-3,3-dimethyl-3H-indol-1-ium chloride (23)

[0516] The preparation method of Example 21 was adopted to prepare Compound 23 as a green solid using Compounds B1 and C11 as raw materials.

[0517] LCMS: m / z=877.5, C 57 H 66 ClN2O4 + .

[0518] Example 24: Preparation of 2-((E)-2-((E)-2-chloro-3-(2-((E)-3,3-dimethyl-1-(6-oxo-6-phenoxyhexyl)indolin-2-ylenyl)vinyl)cyclopent-1-en-1-yl)vinyl)-3,3-dimethyl-1-(6-oxo-6-phenoxyhexyl)-3H-indol-1-ium chloride (24)

[0519] The preparation method of Example 21 was adopted, and Compound B1 and C1B (prepared according to the preparation method of Compound C1) were used as raw materials to prepare Compound 24 as a blue paste.

[0520] LCMS: m / z=821.3, C 53 H 58 ClN2O4 + .

[0521] Example 25: Preparation of Compound 25

[0522] The preparation method of Example 21 was adopted, and Compound B3 and C0 were used as raw materials to prepare Compound 25 as a purple oil.

[0523] 1 H NMR (400MHz, CDCl3) δ8.30 (d, J = 14.4Hz, 2H), 7.40-7.45 (m, 4H), 7.30-7.34 (m, 2H), 7.18-7.20 (m, 2H), 6.38-6.42 (m ,2H),4.83(s,4H),4.24(s,4H),4.48(s,6H),2.33-2.37(m,4H),1.78-1.87(m,5H),1.73(s,12H),1.44-1.54(m,7H).

[0524] LCMS: m / z=357.2, C 43 H 56 ClN3O4 2+ .

[0525] Example 26: Preparation of 2-((E)-2-((E)-2-chloro-3-(2-((E)-3,3-dimethyl-1-(6-oxo-6-(phenylamino)hexyl)indolin-2-ylenyl)vinyl)cyclohex-1-en-1-yl)vinyl)-3,3-dimethyl-1-(4-sulfonylbutyl)-3H-indol-1-ium formate (26)

[0526] The preparation method of Example 21 was adopted, and Compounds A6, B2, and C1C were used as raw materials (Compounds A6 and C1C were purchased from Bidex Pharmaceuticals, batch number 221007) to prepare Compound 26 as a green solid.

[0527] 1H NMR: (400MHz, CDCl3) δ9.62 (s, 1H), 8.32 (dd, J = 14.0, 2.0Hz, 2H), 7.77 (d, J = 7.6Hz, 2H) ,7.40-7.33(m,4H),7.25-7.20(m,4H),7.15-7.11(m,2H),7.02-6.99(m,1H),6.20(dd,J =13.6,4.8Hz,2H),4.13-4.04(m,4H),3.04-3.01(m,2H),2.67-2.60(m,6H),2.11-2.01( m,4H),1.95-1.91(m,4H),1.85-1.83(m,1H),1.69(d,J=2.4Hz,12H),1.64-1.60(m,3H).

[0528] LCMS: m / z = 780.3, C 46 H 55 ClN3O4S + .

[0529] Examples 27A and 27B: 1-(5-carboxypentyl)-2-((E)-2-((E)-2-chloro-3-(2-((E)-3,3-dimethyl-1-(6-oxo-6-(phenylamino)hexyl)indolin-2-ylenyl)vinyl)cyclohex-1-en-1-yl)vinyl)-3,3-dimethyl-3H-indol-1-ium 2,2,2-trifluoroacetate (27A) and Preparation of 2-((E)-2-((E)-2-chloro-3-(2-((E)-3,3-dimethyl-1-(6-oxo-6-(phenylamino)hexyl)indolin-2-ylenyl)vinyl)cyclohex-1-en-1-yl)vinyl)-3,3-dimethyl-1-(6-oxo-6-(phenylamino)hexyl)-3H-indol-1-ium 2,2,2-trifluoroacetate (27B)

[0530] The preparation method of Example 21 was adopted and Compounds C1B, B2 and C1C were used as raw materials to prepare Compounds 27A and 27B, both of which were green solids.

[0531] Compound 27A:

[0532] 1H NMR (400MHz, CDCl3) δ9.11 (s, 1H), 8.34 (t, J = 14.4Hz, 2H), 7.67 (d, J = 8.0Hz, 2H), 7.36-7.40 ( m,4H),7.28-7.29(s,1H),7.21-7.25(m,3H),7.15(d,J=8.0Hz,1H),7.07(d,J=8.0Hz,1H),6. 99(d,J=7.6Hz,1H),6.03-6.02(m,2H),3..98-4.09(m,4H),2.63-2.64(m,4H),2.51(t,J=6.8 Hz, 2H), 2.42 (d, J = 6.8 Hz, 2H), 1.76-1.92 (m, 9H), 1.70 (d, J = 12.0 Hz, 12H), 1.53-1.55 (m, 5H).

[0533] LCMS: m / z=758.8, C 48 H 57 ClN3O3 + .

[0534] Compound 27B:

[0535] 1 H NMR (400MHz, CDCl3) δ9.19 (brs, 1H), 8.31-8.34 (m, 2H), 7.65 (d, J = 6.8Hz, 2H), 7 .36-7.40(m,4H),7.22-7.26(m,3H),7.14(d,J=8.4Hz,1H),7.07(d,J=7.6Hz,1H) ,6.99(d,J=6.4Hz,1H),6.08-6.21(m,2H),3.99-4.08(m,4H),2.63(s,4H),2.49( t,J=6.8Hz,4H),1.79-1.88(m,10H),1.71(d,J=14.4Hz,12H),1.53-1.55(m,4H).

[0536] LCMS: m / z=758.4, C 48 H 57 ClN3O3 + .

[0537] Example 28: Preparation of Compound 28

[0538] The preparation method of Example 21 was adopted, and compounds C1B, B3, and A1B (prepared according to the preparation method of compound A1) were used as raw materials to prepare compound 28 as a blue solid.

[0539] 1 H NMR (400MHz, CDCl3) δ8.30-8.28(m,2H),7.47-7.30(m,8H),7.29-7.28(m,2H),7.25-7.18(m,3H),7.04(d,J=7.6Hz,2H),5.2 8-5.20(m,2H),4.69-4.59(m,2H),3.62-3.54(m,4H),2.62-2.59(m,1H),1.98-1.81(m,5H),1.72(s,20H),1.53-1.48(m,3H).

[0540] LCMS: m / z=352.0, C 45 H 54 ClN3O2 2+ .

[0541] Example 29: Preparation of 2-((E)-2-((E)-4-chloro-5-(2-((E)-3,3-dimethyl-1-(6-oxo-6-phenoxyhexyl)indolin-2-ylalkenyl)vinyl)-1,1-dimethyl-1,2,5,6-tetrahydropyridin-1-ium-3-yl)vinyl)-3,3-dimethyl-1-(6-oxo-6-phenoxyhexyl)-3H-indol-1-ium chloride (29)

[0542] The preparation method of Example 21 was adopted to prepare Compound 29 as a green paste using Compounds C1B and B3 as raw materials.

[0543] LCMS: m / z = 433.1, C 55 H 64 ClN3O4 2+ .

[0544] Example 30: Preparation of 2-((E)-2-((E)-3-(2-((E)-1-(5-carboxypentyl)-3,3-dimethylindolin-2-ylalkenyl)vinyl)-2-chlorocyclohex-1-en-1-yl)vinyl)-1-ethyl-3,3-dimethyl-3H-indol-1-ium chloride (30)

[0545] The preparation method of Example 21 was adopted to prepare compound 30 as a green solid using compounds A1B, B2 and C0 as raw materials.

[0546] LCMS: m / z=597.5, C 38 H 46 ClN2O2 + .

[0547] Example 33: Preparation of 2-((E)-2-((E)-2-chloro-3-(2-((E)-3,3-dimethyl-1-(5-oxo-5-phenoxypentyl)indolin-2-ylalkenyl)vinyl)cyclohex-1-en-1-yl)vinyl)-3,3-dimethyl-1-(5-oxo-5-phenoxypentyl)-3H-indol-1-ium chloride (33)

[0548] The preparation method of Example 21 was adopted, and Compounds B2, A1, and C10 were used as raw materials to prepare Compound 33 as a green solid.

[0549] 1 H NMR (400MHz, CDCl3) δ8.34(d,J=14.0Hz,2H),7.34-7.38(m,8H),7.20-7.26(m,6H),7.03(d,J=7.6Hz, 4H), 6.32 (d, J = 14.0Hz, 2H), 4.31-4.35 (m, 4H), 2.70-2.75 (m, 8H), 1.90-2.03 (m, 10H), 1.73 (s, 12H).

[0550] LCMS: m / z=807.4, C 52 H 56 ClN2O4 + .

[0551] Example 34: Preparation of 2-((E)-2-((E)-2-chloro-3-(2-((E)-3,3-dimethyl-1-(5-oxo-5-phenoxypentyl)indolin-2-ylalkenyl)vinyl)cyclohex-1-en-1-yl)vinyl)-1-ethyl-3,3-dimethyl-3H-indol-1-ium chloride (34)

[0552] The preparation method of Example 21 was adopted to prepare compound 34 as a green solid using compounds B2, A1B and C10 as raw materials.

[0553] 1 H NMR (400MHz, CDCl3) δ8.32-8.37(m,2H),7.34-7.42(m,6H),7.20-7.25(m,5H),7.02-7.04(m,2H),6.25-6 .35(m,2H),4.26-4.35(m,4H),2.70-2.78(m,6H),1.94-2.02(m,6H),1.73(s,12H),1.47(t,J=7.2Hz,3H).

[0554] LCMS: m / z=659.3, C 43 H 48 ClN2O2 + .

[0555] Example 35: Preparation of 2-((E)-2-((E)-2-chloro-3-(2-((E)-3,3-dimethyl-1-(2-((6-oxo-6-phenoxyhexyl)oxy)ethyl)indolin-2-ylenyl)vinyl)cyclohex-1-en-1-yl)vinyl)-1-ethyl-3,3-dimethyl-3H-indol-1-ium 2,2,2-trifluoroacetate (35)

[0556] The preparation method of Example 21 was adopted to prepare compound 35 as a blue solid using compounds B2, A1B and C7 as raw materials.

[0557] 1 H NMR: (400MHz, CDCl3) δ8.37 (t, J = 31.6Hz, 2H), 7.37-7.40 (m, 6H), 7.32-7.34 (m, 4H), 7.24-7.25 (m, 1 H),7.02-7.04(m,2H),6.33(d,J=14.4Hz,1H),6.10(d,J=14Hz,1H),4.31-4.34(m,2H),4.09-4.14(m ,2H),3.83-3.86(m,2H),3.42(t,J=6.4Hz,2H),2.67(s,4H),2.44(t,J=7.6Hz,2H),1.95-1.97(m,2H ), 1.71 (d, J = 10Hz, 12H), 1.64-1.66 (m, 2H), 1.62-1.64 (m, 2H), 1.42-1.44 (m, 3H), 1.31-1.40 (m, 2H).

[0558] LCMS: m / z = 717.4, C 46 H 54 ClN2O3 + .

[0559] Example 36: Preparation of 2-((E)-2-((E)-2-chloro-3-(2-((E)-3,3-dimethyl-1-(2-(4-oxo-4-phenoxybutoxy)ethyl)indolin-2-ylalkenyl)vinyl)cyclohex-1-en-1-yl)vinyl)-1-ethyl-3,3-dimethyl-3H-indol-1-ium 2,2,2-trifluoroacetate (36)

[0560] The preparation method of Example 21 was adopted, and Compound B2, A1B, and C8 were used as raw materials to prepare Compound 36 as a blue solid.

[0561] 1 H NMR (400MHz, CDCl3) δ8.28-8.39(m,2H),7.36-7.43(m,5H),7.30-7.34(m,2H),7.1 4-7.26(m,4H),6.97-7.01(m,2H),6.49-6.55(m,1H),6.14-6.17(m,1H),4.58(s,2 H),4.21(s,2H),3.93-3.99(m,2H),3.53(t,J=6.0Hz,2H),2.62-2.81(m,4H),2.47 (t,J=7.6Hz,2H),1.86-1.96(m,4H),1.72(d,J=8.4Hz,12H),1.44(t,J=7.2Hz,3H).

[0562] 19 F NMR (400MHz, CDCl3) δ75.946.

[0563] LCMS: m / z=689.4, C 44 H 50 ClN2O3 + .

[0564] Example 37: 2-((E)-2-((E)-2-chloro-3-(2-((E)-3,3-dimethyl-1-(2-((5-oxo-5-phenoxypentyl)oxy)ethyl)indolin-2-ylenyl)vinyl)cyclohex-1-en-1-yl)vinyl)-1-ethyl-3,3-dimethyl-3H-indol-1-ium 2,2,2-trifluoroacetate (37A) YH-065 6 and 2-((E)-2-((E)-2-chloro-3-(2-((E)-3,3-dimethyl-1-(2-((5-oxo-5-phenoxypentyl)oxy)ethyl)indolin-2-ylenyl)vinyl)cyclohex-1-en-1-yl)vinyl)-3,3-dimethyl-1-(2-((5-oxo-5-phenoxypentyl)oxy)ethyl)-3H-indol-1-ium (37B)

[0565] The preparation method of Example 21 was adopted, and Compound B2, A1B, and C9 were used as raw materials to prepare Compound 37A and Compound 37B, both of which were green solids.

[0566] Compound 37A:

[0567] LCMS: m / z=703.4, C 45 H 52 ClN2O3 + .

[0568] Compound 37B:

[0569] 1 H NMR (400MHz, CDCl3) δ8.27 (d, J = 14.4Hz, 2H), 7.28-7.31 (m, 7H), 7.16-7.20 (m, 7H),6.95(d,J=7.6Hz,4H),6.24(d,J=14.0Hz,2H),4.27(t,J=4.4Hz,4H),3.79 (t,J=4.8Hz,4H),3.40(t,J=6.0Hz,4H),2.59(t,J=5.2Hz,4H),2.39(t,J=7.2H z,4H),1.85-1.86(m,2H),1.65(s,12H),1.58-1.62(m,4H),.1.53-1.54(m,4H).

[0570] LCMS: m / z=859.6, C 56 H 64 ClN2O6 + .

[0571] Example 38: Preparation of (E)-4-chloro-3-(2-((E)-3,3-dimethyl-1-(5-oxo-5-phenoxypentyl)indolin-2-ylalkenyl)vinyl)-1,1-dimethyl-5-(((Z)-1-methyl-2-oxoindolin-3-ylalkenyl)methyl)-1,2,3,6-tetrahydropyridin-1-ium chloride (38)

[0572] The preparation method of Example 21 was adopted, and compound B3, A14 (purchased from Bidex Pharmaceuticals, batch number 220918), and C10 were used as raw materials to prepare compound 38 as a blue solid.

[0573] 1H NMR (400MHz, CDCl3) δ8.68(s,2H),7.93(d,J=13.6Hz,1H),7.74(s,1H),7.49(d,J= 7.6Hz,1H),7.36(t,J=7.6Hz,3H),7.22-7.25(m,2H),7.03-7.06(m,3H),6.86-6.8 8(m,1H),6.81-6.83(m,1H),5.96-6.00(m,1H),4.95(s,2H),4.85(s,2H),3.99-4. 06(m,2H),3.33(s,6H),3.26(s,3H),2.67-2.75(m,2H),1.92(s,4H),1.67(s,6H).

[0574] LCMS: m / z=648.4, C 40 H 43 ClN3O3 + .

[0575] Example 39: Preparation of 2-((E)-2-((E)-2-chloro-3-(2-((E)-1-(6-(2,6-dimethylphenoxy)-6-oxohexyl)-3,3-dimethylindolin-2-ylalkenyl)vinyl)cyclohex-1-en-1-yl)vinyl)-1-ethyl-3,3-dimethyl-5-(methylsulfonyl)-3H-indol-1-ium chloride (39)

[0576] The preparation method of Example 21 was adopted, and Compounds B2, A13, and C11 were used as raw materials to prepare Compound 39 as a blue solid.

[0577] 1 H NMR(400MHz,MeOD)δ8.66(d,J=14.8Hz,1H),8.18(d,J=13.2Hz,1H),7.93-7.90(m,2H),7.68-7.47(m, 4H),7.26(d,J=8.4Hz,1H),7.05-7.01(m,3H),6.70(d,J=14.8Hz,1H),6.08(d,J=13.2Hz,1H),4.46(t ,J=6.8Hz,2H),4.07(dd,J1=7.2Hz,J2=7.2Hz,2H),3.14(s,3H),2.73-2.67(m,6H),2.05(s,6H),2.03 -1.99(m,2H),1.91-1.81(m,4H),1.78(s,6H),1.74(s,6H),1.65-1.59(m,2H),1.35(t,J=7.2Hz,3H).

[0578] LCMS: m / z=779.5, C 47 H 56 ClN2O4S + .

[0579] Example 40: Preparation of 2-((E)-2-((E)-2-chloro-3-(2-((E)-3,3-dimethyl-1-(6-oxo-6-phenoxyhexyl)indolin-2-ylalkenyl)vinyl)cyclohex-1-en-1-yl)vinyl)-1-ethyl-3,3-dimethyl-5-(methylsulfonyl)-3H-indol-1-ium chloride (40)

[0580] The preparation method of Example 21 was adopted, and Compounds B2, A13, and C1B were used as raw materials to prepare Compound 40 as a blue solid.

[0581] 1 H NMR (400MHz, DMSO-d6) δ8.45(d,J=14.8Hz,1H),8.05-8.01(m,2H),7.87(dd,J1=1.6Hz,J2=6.4Hz,1H),7.76(dd,J1=7.6Hz,J2=10.0Hz,2H),7.55(t,J= 7.2Hz,1H),7.48(t,J=7.6Hz,1H),7.41-7.37(m,3H),7.27-7.25(m,1H),7. 03(d,J=8.4Hz,2H),6.73(d,J=14.8Hz,1H),6.10(d,J=13.6Hz,1H),4.48(t J=2.8Hz,2H),4.10-4.08(m,2H),3.21(s,3H),2.73-2.68(m,4H),2.59(t,J=7.2Hz,2 H),1.88-1.82(m,4H),1.75-1.68(m,14H),1.52-1.50(m,2H),1.24(t,J=7.2Hz,3H).

[0582] LCMS: m / z=751.4, C 45 H 52 ClN2O4S + .

[0583] Example 41: Preparation of 5-(tert-Butoxycarbonyl)-2-((E)-2-((E)-2-chloro-3-(2-((E)-3,3-dimethyl-1-(6-oxo-6-phenoxyhexyl)indolin-2-ylenyl)vinyl)cyclohex-1-en-1-yl)vinyl)-1-ethyl-3,3-dimethyl-3H-indol-1-ium bromide (41)

[0584] The preparation method of Example 21 was adopted to prepare compound 41 as a green oil using compounds B2, A8 and C1B as raw materials.

[0585] LCMS: m / z=773.5, C 49 H 58 ClN2O4 + .

[0586] Example 42: Preparation of 5-(tert-Butoxycarbonyl)-2-((E)-2-((E)-2-chloro-3-(2-((E)-3,3-dimethyl-1-(6-oxo-6-phenoxyhexyl)indolin-2-ylenyl)vinyl)cyclopent-1-en-1-yl)vinyl)-1-ethyl-3,3-dimethyl-3H-indol-1-ium bromide (42)

[0587] The preparation method of Example 21 was adopted to prepare compound 42 as a green oil using compounds B1, A8 and C1B as raw materials.

[0588] LCMS: m / z=759.3, C 48 H 56 ClN2O4 + .

[0589] Example 43: Preparation of 5-(tert-Butoxycarbonyl)-2-((E)-2-((E)-3-(2-((E)-1-(5-carboxypentyl)-3,3-dimethylindolin-2-ylenyl)vinyl)-2-chlorocyclohex-1-en-1-yl)vinyl)-1,3,3-trimethyl-3H-indol-1-ium bromide (43)

[0590] The preparation method of Example 21 was adopted to prepare compound 43 as a green paste using compounds B1, A9 and C0 as raw materials.

[0591] LCMS: m / z=683.4, C 42 H 52 ClN2O4 + .

[0592] Example 44: Preparation of 5-(tert-Butoxycarbonyl)-2-((E)-2-((E)-2-chloro-3-(2-((E)-3,3-dimethyl-1-(6-oxo-6-phenoxyhexyl)indolin-2-ylenyl)vinyl)cyclohex-1-en-1-yl)vinyl)-1,3,3-trimethyl-3H-indol-1-ium bromide (44)

[0593] The preparation method of Example 21 was adopted to prepare compound 44 as a green paste using compounds B2, A9 and C1B as raw materials.

[0594] LCMS: m / z=759.6, C 48 H 56 ClN2O4 + .

[0595] Example 45: Preparation of 2-((E)-2-((E)-2-chloro-3-(2-((E)-1-(6-(2,6-dimethylphenoxy)-6-oxohexyl)-3,3-dimethylindolin-2-ylalkenyl)vinyl)cyclohex-1-en-1-yl)vinyl)-1-ethyl-3,3-dimethyl-3H-indol-1-ium chloride (45)

[0596] The preparation method of Example 21 was adopted, and Compound B2, A1B, and C11 were used as raw materials to prepare Compound 45 as a dark brown solid.

[0597] LCMS: m / z=701.4, C 46 H 54 ClN2O2 + .

[0598] Example 46: Preparation of 5-(tert-Butoxycarbonyl)-2-((E)-2-((E)-4-chloro-5-(2-((E)-3,3-dimethyl-1-(6-oxo-6-phenoxyhexyl)indolin-2-ylalkenyl)vinyl)-1,1-dimethyl-1,2,5,6-tetrahydropyridin-1-ium-3-yl)vinyl)-1-ethyl-3,3-dimethyl-3H-indol-1-ium chloride (46)

[0599] The preparation method of Example 21 was adopted, and Compounds B3, A8, and C1 were used as raw materials to prepare a crude compound 46 as a purple oil.

[0600] LCMS: m / z = 402.0, C 50 H 62 ClN3O4 2+ / 2.

[0601] Example 47: Preparation of 2-((E)-2-((E)-2-chloro-3-(2-((E)-5-methoxy-3,3-dimethyl-1-(6-oxo-6-phenoxyhexyl)indolin-2-ylenyl)vinyl)cyclohex-1-en-1-yl)vinyl)-5-methoxy-1,3,3-trimethyl-3H-indol-1-ium (47)

[0602] The preparation method of Example 21 was adopted to prepare compound 47 as a blue solid using compounds B2, A10 and C21B as raw materials.

[0603] 1 H NMR(400MHz,DMSO)δ8.15-8.21(m,2H),7.56-7.41(m,4H),7.29-7.31(m,2H),7 .25(t,J=7.2Hz,1H),6.96-7.03(m,4H),6.20-6.26(m,2H),4.18-4.22(m,2H), 3.81(d,J=2.8Hz,6H),3.67(s,3H),2.66-2.67(m,4H),2.58(t,J=7.2Hz,2H),1 .77-1.82(m,4H),1.68-1.74(m,2H),1.66(d,J=3.6Hz,12H),1.46-1.50(m,2H).

[0604] LCMS: m / z=719.3, C 45 H 52 ClN2O4 + .

[0605] Example 48: 2-((E)-2-((E)-2-chloro-3-(2-((E)-3,3-dimethyl-1-(6-oxo-6-phenoxyhexyl)indolin-2-ylenyl)vinyl)cyclohex-1-en-1-yl)vinyl)-1-(2-hydroxyethyl)-3,3-dimethyl-3H-indol-1-ium formate (48)

[0606] The preparation method of Example 21 was adopted to prepare compound 48 as a blue solid using compound B2, A5B (prepared according to the preparation method of compound A5) and C1B as starting materials.

[0607] 1H NMR (400MHz, MeOD) δ8.44 (dd, J1=14.4Hz, J2=26.4Hz, 2H), 7.53 (t, J=7.6Hz, 2H), 7.41-7.45 (m, 2H) ,7.26-7.38(m,6H),7.19-7.23(m,1H),6.98-7.00(m,2H),6.45(d,J=14.4Hz,1H),6.27(d,J=14.4Hz ,1H),4.32(t,J=5.2Hz,2H),4.20(t,J=7.2Hz,2H),3.97(t,J=5.2Hz,2H),2.67-2.72(m,4H),2.61( t,J=6.4Hz,2H),1.88-1.93(m,4H),1.81-1.85(m,2H),1.77(s,6H),1.72(s,6H),1.55-1.61(m,2H).

[0608] LCMS: m / z=689.4, C 44 H 50 ClN2O3 + .

[0609] Example 49: Preparation of 2-((E)-2-((E)-3-(2-((E)-1-(5-carboxypentyl)-3,3-dimethylindolin-2-ylenyl)vinyl)-2-chlorocyclohex-1-en-1-yl)vinyl)-1-(2-hydroxyethyl)-3,3-dimethyl-3H-indol-1-ium chloride (49)

[0610] The preparation method of Example 21 was adopted to prepare compound 49 as a blue solid using compounds B2, A5B and C0 as starting materials.

[0611] 1 H NMR(400MHz,MeOD)δ8.45(br,2H),7.53(d,J=8.0Hz,2H),7.36-7.45(m,3H),7 .24-7.32(m,3H),6.45(br,1H),6.27(br,1H),4.40(s,2H),4.17(s,2H),3.98( t,J=5.2Hz,2H),2.74(br,4H),2.32(t,J=7.6Hz,2H),1.93-2.01(m,2H),1.83 -1.90(m,2H),1.77(s,6H),1.73(s,6H),1.67-1.71(m,2H),1.47-1.55(m,2H).

[0612] LCMS: m / z=613.3, C38 H 46 ClN2O3 + .

[0613] Example 50: Preparation of 2-((E)-2-((E)-2-chloro-3-(2-((E)-3,3-dimethyl-1-(6-oxo-6-phenoxyhexyl)indolin-2-ylenyl)vinyl)-5-(dimethylamino)cyclohex-1-en-1-yl)vinyl)-1,3,3-trimethyl-3H-indol-1-ium formate (50)

[0614] The preparation method of Example 21 was adopted to prepare compound 50 as a green solid using compounds B4, A3 and C1B as raw materials.

[0615] 1 H NMR(400MHz,MeOD)δ8.46(t,J=14.0Hz,2H),7.55-7.57(m,2H),7.44-7.49( m,2H),7.31-7.42(m,6H),7.20-7.24(m,1H),6.99-7.03(m,2H),6.37-6.43 (m,2H),4.32-4.34(m,2H),3.81(s,3H),3.60-3.72(m,1H),3.00(s,6H),2.82-2.91(m,2H),2. 64(t,J=7.2Hz,2H),1.81-2.00(m,6H),1.75(dd,J1=0.8Hz,J2=6.4Hz,12H),1.61-1.66(m,2H).

[0616] LCMS: m / z=702.4, C 45 H 53 ClN3O2 + .

[0617] Example 51: Preparation of 2-((E)-2-((E)-2-chloro-3-(2-((E)-3,3-dimethyl-1-(2-(2-(3-oxo-3-phenoxypropoxy)ethoxy)ethyl)indolin-2-ylalkenyl)vinyl)cyclohex-1-en-1-yl)vinyl)-1,3,3-trimethyl-3H-indol-1-ium formate (51)

[0618] The preparation method of Example 21 was adopted, and Compounds B2, A3, and C13 were used as raw materials to prepare Compound 51 as a green solid.

[0619] 1H NMR (400MHz, CDCl3) δ8.26-8.31(m,2H),7.29-7.31(m,5H),7.15-7.22(m,6H),7.00(d,J=8.0Hz,2H),6.27(d,J=14.0Hz,1H),6.10(d,J=14.0Hz,1 H),4.31(m,2H),3.87(s,2H),3.67(t,J=6.0Hz,2H),3.62(s,3H),3.52-3 .56(m,4H),2.62-2.68(m,6H),1.89-1.90(m,2H),1.65(d,J=6.8Hz,12H).

[0620] LCMS: m / z=705.3, C 44 H 50 ClN2O4 + .

[0621] Example 52: Preparation of 2-((E)-2-((E)-2-chloro-3-(2-((E)-3,3-dimethyl-1-(2-(3-oxo-3-phenoxypropoxy)ethyl)indolin-2-ylalkenyl)vinyl)cyclohex-1-en-1-yl)vinyl)-1,3,3-trimethyl-3H-indol-1-ium chloride (52)

[0622] The preparation method of Example 21 was adopted, and Compounds B2, A3, and C4 were used as raw materials to prepare Compound 52 as a green solid.

[0623] 1 H NMR (400MHz, MeOD); δ7.52-7.42(m,8H),7.29-7.26(m,4H),7.18-7.14(m,2H),6.85-6.83(m,3H),3.9 8-3.90(m,2H),3.80(t,J=5.60Hz,4H),2.74(t,J=5.60Hz,4H),1.73(d,J=6.00Hz,10H),1.69(s,9H).

[0624] LCMS: m / z=661.4, C 42 H 46 ClN2O3 + .

[0625] Example 53: Preparation of 2-((E)-2-((E)-2-chloro-3-(2-((E)-3,3-dimethyl-1-(6-oxo-6-phenoxyhexyl)indolin-2-ylenyl)vinyl)cyclohex-1-en-1-yl)vinyl)-3,3,7-trimethyl-3H-pyrrolo[2,3-b]pyridin-7-ium 2,2,2-trifluoroacetate (53)

[0626] The preparation method of Example 21 was adopted to prepare compound 53 as a green solid using compounds B2, A3 and C1B as raw materials.

[0627] 1 H NMR (400MHz, DMSO-d6) δ8.42-8.47(m,2H),8.30(d,J=7.2Hz,1H),7.94(d,J=13.2Hz,1H ),7.49-7.51(m,2H),7.32-7.41(m,3H),7.25(d,J=7.2Hz,2H),7.14(d,J=7.2Hz,1H),7. 03(d,J=7.6Hz,2H),6.57(d,J=14.4Hz,1H),6.05(d,J=14.4Hz,1H),4.23(s,3H),4.07( s, 2H), 2.66 (s, 4H), 2.58 (d, J = 7.2Hz, 2H), 1.67-1.78 (m, 6H), 1.62 (s, 6H), 1.49 (s, 8H).

[0628] LCMS: m / z=660.3, C 42 H 47 ClN3O2 + .

[0629] Example 54: Preparation of 2-((E)-2-((E)-2-bromo-3-(2-((E)-3,3-dimethyl-1-(6-oxo-6-phenoxyhexyl)indolin-2-ylenyl)vinyl)cyclohex-1-en-1-yl)vinyl)-1-ethyl-3,3-dimethyl-3H-indol-1-ium formate (54)

[0630] The preparation method of Example 21 was adopted to prepare compound 54 as a green solid using compounds B5, A1B and C1B as raw materials.

[0631] 1H NMR(400MHz,MeOD)δ8.46(t,J=13.2Hz,2H),7.53-7.56(m,2H),7.42-7.47(m,2H ),7.30-7.37(m,6H),7.19-7.23(m,1H),6.98-7.01(m,2H),6.31(d,J=13.6Hz,2H ),4.15-4.30(m,4H),2.72(s,4H),2.62(t,J=7.2Hz,2H),1.90-1.97(m,4H),1.8 1-1.84(m,2H),1.75(d,J=4.4Hz,12H),1.55-1.61(m,2H),1.42(t,J=6.8Hz,3H).

[0632] LCMS: m / z = 719.4, C 44 H 50 BrN2O2 + .

[0633] Example 55: Preparation of 2-((E)-2-((E)-3-(2-((E)-1-(2-(2-(benzyloxy)ethoxy)ethoxy)ethyl)-3,3-dimethylindolin-2-ylalkenyl)vinyl)-2-chlorocyclopent-1-en-1-yl)vinyl)-1,3,3-trimethyl-3H-indol-1-ium carboxylate (55)

[0634] The preparation method of Example 21 was adopted to prepare compound 55 as a green solid using compounds B1, A3 and C12 as raw materials.

[0635] 1 H NMR(400MHz,MeOD)δ7.95-7.92(m,2H),7.51-7.49(m,2H),7.43-7.39(m,2H),7.35-7.34(m, 2H),7.32-7.29(m,6H),7.28-7.25(m,1H),6.28(d,J=14.0Hz,1H),6.04(d,J=14.0Hz,1H),4 .58(s,1H),4.47(d,J=5.60Hz,2H),4.36(t,J=4.80Hz,2H),3.92(t,J=4.80Hz,2H),3.64(s, 3H), 3.61-3.55 (m, 2H), 3.53-3.51 (m, 5H), 2.95 (d, J = 2.80Hz, 4H), 1.71 (d, J = 2.00Hz, 12H).

[0636] LCMS: m / z=677.2, C43 H 50 ClN2O3 + .

[0637] Example 56: Preparation of 2-((E)-2-((E)-3-(2-((E)-1-(2-(2-(benzyloxy)ethoxy)ethoxy)ethyl)-3,3-dimethylindolin-2-ylalkenyl)vinyl)-2-chlorocyclohex-1-en-1-yl)vinyl)-1,3,3-trimethyl-3H-indol-1-ium 2,2,2-trifluoroacetate (56)

[0638] The preparation method of Example 21 was adopted, and Compounds B2, A3, and C12 were used as raw materials to prepare Compound 56 as a green solid.

[0639] 1 H NMR (400MHz, CDCl3) δ8.32(d,J=13.2Hz,2H),7.37-7.23(m,13H),6.27-6.11(m,2H),4.48(s,2H),4.27(s,2H),3.87(t,J =4.80Hz,2H),3.71-3.62(m,4H),3.49-3.48(m,8H),2.62(d,J=1.60Hz,2H),1.90-1.80(m,3H),1.68(d,J=2.80Hz,12H).

[0640] LCMS: m / z=691.6, C 44 H 52 ClN2O3 + .

[0641] Example 57: Preparation of 2-((E)-2-((E)-3-(2-((E)-1-(2-(2-(benzyloxy)ethoxy)ethoxy)ethyl)-3,3-dimethylindolin-2-ylalkenyl)vinyl)-2-chloro-5-(dimethylamino)cyclohex-1-en-1-yl)vinyl)-1,3,3-trimethyl-3H-indol-1-ium 2,2,2-trifluoroacetate (57)

[0642] The preparation method of Example 21 was adopted, and Compounds B4, A3, and C12 were used as raw materials to prepare Compound 57 as a blue paste.

[0643] 1H NMR: (400MHz, MeOD) δ8.70-8.42(m,2H),7.50-7.52(m,2H),7.30-7.32(m,4H),7.30-7.28(m,7H),6.50(d,J=14.4H z,1H),6.34(d,J=14.4Hz,1H),4.48(t,J=14.8Hz,2H),4.44(s,2H),3.9-3.92(t,J=5.20Hz,2H),3.75(s,3H),2.70- 3.67(m,1H),3.60-3.58(m,8H),3.3-3.33(m,2H),3.05(s,6H),2.88-2.79(dd,J1=12.0Hz,J2=26.4Hz,2H),1.73(d,J=2.00Hz,2H).

[0644] LCMS: m / z=734.4, C 46 H 57 ClN3O3 + .

[0645] Example 58: Preparation of 2-((E)-2-((E)-2-bromo-3-(2-((E)-3,3-dimethyl-1-(6-oxo-6-phenoxyhexyl)indolin-2-ylenyl)vinyl)cyclohex-1-en-1-yl)vinyl)-1,3,3-trimethyl-3H-indol-1-ium 2,2,2-trifluoroacetate (58)

[0646] The preparation method of Example 21 was adopted to prepare compound 58 as a green solid using compounds B5, A3 and C1B as raw materials.

[0647] 1 H NMR (400MHz, CDCl3) δ8.34-8.41(m,2H),7.37-7.42(m,4H),7.27-7.30(m,2H ),7.14-7.19(m,2H),6.18(dd,J1=14.4Hz,J2=33.2Hz,2H),4.11(t,J=7.2Hz, 2H),3.65(s,3H),2.71(t,J=5.6Hz,4H),2.46(t,J=6.8Hz,2H),1.96-1.99(m ,2H),1.85-1.89(m,2H),1.76-1.81(m,2H),1.74(s,12H),1.53-1.57(m,2H).

[0648] LCMS: m / z=629.3, C 37 H 44BrN2O2 + .

[0649] Example 60: Preparation of 2-((E)-2-((E)-2-chloro-3-(2-((E)-3,3-dimethyl-1-(6-oxo-6-phenoxyhexyl)indolin-2-ylenyl)vinyl)cyclohex-1-en-1-yl)vinyl)-3,3-dimethyl-1-(5-(trimethylammonio)pentyl)-3H-indol-1-ium 2,2,2-trifluoroacetate (60)

[0650] The preparation method of Example 21 was adopted, and Compounds B2, C1, and C14 were used as raw materials to prepare Compound 60 as a green solid.

[0651] 1 H NMR (400MHz, DMSO) δ8.27 (t, J=14.8Hz, 2H), 7.65 (dd, J1=7.6Hz, J2=11.2Hz, 2H), 7.3 7-7.52(m,6H),7.23-7.34(m,3H),7.02-7.04(m,2H),6.35(dd,J1=14.0Hz,J2=33.2Hz ,2H),4.22-4.30(m,4H),3.22-3.26(m,4H),3.01(s,9H),2.67-2.72(m,4H),2.58(t, J=7.2Hz,2H),1.71-1.82(m,8H),1.67(s,12H),1.47-1.57(m,2H),1.36-1.40(m,2H).

[0652] LCMS: m / z=387.6, C 50 H 64 ClN3O2 2+ / 2.

[0653] Example 61: Preparation of 2-((E)-2-((E)-2-chloro-3-(2-((E)-3,3-dimethyl-1-(6-oxo-6-phenoxyhexyl)indolin-2-ylenyl)vinyl)cyclohex-1-en-1-yl)vinyl)-3,3-dimethyl-1-(4-(trimethylammonio)butyl)-3H-indol-1-ium 2,2,2-trifluoroacetate (61)

[0654] The preparation method of Example 21 was adopted, and Compounds B2, C1, and C15 were used as raw materials to prepare Compound 61 as a green solid.

[0655] 1H NMR: (400MHz, CDCl3)δ8.43(d,J=14.4Hz,1H),8.27(t,J=13.2Hz,1H),7.40-7.43(m,2H),7. 33-7.37(m,5H),7.19-7.20(m,3H),7.00-7.05(m,3H),6.32(t,J=13.6Hz,1H),6.05(t,J=13 .6Hz,1H),4.00-4.16(m,4H),3.39-3.43(m,2H),3.13(s,9H),2.75(s,2H),2.57-2.64(m,4H ),2.05-2.10(m,2H),1.92-1.94(m,3H),1.81-1.88(m,5H),1.70(s,12H),1.58-1.69(m,2H).

[0656] LCMS: m / z=380.2, C 49 H 62 ClN3O 22 + / 2.

[0657] Example 62: Preparation of 2-((E)-2-((E)-2-chloro-3-(2-((E)-1-(5-(diethoxyphosphino)pentyl)-3,3-dimethylindolin-2-ylalkenyl)vinyl)cyclohex-1-en-1-yl)vinyl)-1,3,3-trimethyl-3H-indol-1-ium 2,2,2-trifluoroacetate (62)

[0658] The preparation method of Example 21 was adopted, and Compounds B1, A3, and C16 were used as raw materials to prepare Compound 62 as a green solid.

[0659] LCMS: m / z=675.4, C 40 H 53 ClN2O3P + .

[0660] Example 63: Preparation of 2-((E)-2-((E)-3-(2-((E)-1-(5-carboxypentyl)-3,3-dimethylindolin-2-ylenyl)vinyl)-2-chlorocyclopent-1-en-1-yl)vinyl)-3,3,7-trimethyl-3H-pyrrolo[2,3-b]pyridin-7-ium chloride (63)

[0661] The preparation method of Example 21 was adopted, and Compounds B1, A3, and C0 were used as raw materials to prepare Compound 63 as a blue paste.

[0662] 1 H NMR(400MHz,MeOD)δ8.29(d,J=15.2Hz,1H),8.01(s,2H),7.83-7.78(m,2H) ,7.67-7.56(m,3H),7.17(s,1H),6.92(d,J=15.6Hz,1H),5.83(d,J=11.6Hz ,1H),4.63(s,2H),4.16(s,3H),3.04(d,J=20.0Hz,4H),2.33(t,J=11.2Hz, 2H),2.04-2.00(m,2H),1.82(s,6H),1.73-1.67(m,3H),1.62-1.55(m,7H).

[0663] LCMS: m / z=570.4, C 35 H 41 ClN3O2 + .

[0664] Example 64: Preparation of 2-((E)-2-((E)-3-(2-((E)-1-(5-carboxypentyl)-3,3-dimethylindolin-2-ylenyl)vinyl)-2-chlorocyclohex-1-en-1-yl)vinyl)-3,3,7-trimethyl-3H-pyrrolo[2,3-b]pyridin-7-ium chloride (64)

[0665] The preparation method of Example 21 was adopted, and Compounds B2, A3, and C0 were used as raw materials to prepare Compound 64 as a blue solid.

[0666] 1 H NMR(400MHz,MeOD)8.75(d,J=15.6Hz,1H),8.01(d,J=7.20Hz,2H),7.81–7.78(m, 3H),7.65–7.63(m,2H),7.18(t,J=6.80Hz,1H),7.03(d,J=15.6Hz,1H),6.04(t,J= 5.60Hz,1H),4.62(t,J=7.20Hz,2H),4.15(s,3H),2.83–2.80(m,4H),2.33(t,J=7 .20Hz,2H),1.99–1.98(m,4H),1.83(s,6H),1.73–1.67(m,3H),1.58–1.56(m,7H).

[0667] LCMS: m / z=584.4, C 36 H 43 ClN3O2 + .

[0668] Example 65: Preparation of 2-((E)-2-((E)-2-chloro-3-(2-((E)-3,3-dimethyl-1-(6-oxo-6-phenoxyhexyl)indolin-2-ylenyl)vinyl)cyclohex-1-en-1-yl)vinyl)-3,3-dimethyl-1-(3-(trimethylammonio)propyl)-3H-indol-1-ium 2,2,2-trifluoroacetate (65)

[0669] The preparation method of Example 21 was adopted to use compounds B2, C1 and C17 as raw materials to prepare compound 65 as a blue paste.

[0670] 1 H NMR: (400MHz, CDCl3)δ8.46(d,J=14.4Hz,1H),8.29(d,J=13.6Hz,1H),7.61(d,J=7.6Hz,1H),7.46(t,J=7.6Hz,1H),7.34-7.38(m,5H),7.29(s,1H), 7.19-7.21(m,2H),7.00-7.03(m,3H),6.54(d,J=14.0Hz,1H),6.01(d,J=14.0Hz,1H),4.36(s,2H),4.00-4.02(m,4H),3 .24(s,9H),2.77(s,2H),2.59-2.62(m,4H),2.38(s,2H),1.82-1.91(m,6H),1.72(d,J=10.0Hz,12H),1.56-1.58(m,2H).

[0671] LCMS: m / z=373.1, C 48 H 60 ClN3O 22 + / 2.

[0672] Example 66: Preparation of 2-((E)-2-((E)-2-chloro-3-(2-((E)-3,3-dimethyl-1-(6-oxo-6-phenoxyhexyl)indolin-2-ylenyl)vinyl)cyclohex-1-en-1-yl)vinyl)-5-(dimethylamino)-1,3,3-trimethyl-3H-indol-1-ium chloride (66)

[0673] The preparation method of Example 21 was adopted, and Compounds B2, A11, and C1 were used as raw materials to prepare Compound 66 as a blue solid.

[0674] 1 H NMR (400 MHz, DMSO-d6 )δ8.26(d,J=14.8Hz,1H),7.92(d,J=13.6Hz,1H),7.51-7.46(m,2H),7.41-7.37(m,2H),7.32-7 .23(m,2H),7.16(d,J=8.0Hz,1H),7.09-7.04(m,2H),7.03(d,J=7.6Hz,2H),6.82(d,J=8.0Hz,1 H),6.58(d,J=15.2Hz,1H),5.92(d,J=13.2Hz,1H),4.00(s,2H),3.85(s,3H),3.03(s,6H),2.66 (s,4H),2.58(t,J=7.2Hz,2H),1.84-1.73(m,6H),1.68(s,6H),1.61(s,6H),1.51-1.45(m,2H).

[0675] LCMS: m / z=702.4, C 45 H 53 ClN3O2 + .

[0676] Example 67: Preparation of 2-((E)-2-((E)-2-chloro-3-(2-((E)-1-(2-(2-methoxyethoxy)ethyl)-3,3-dimethylindolin-2-ylalkenyl)vinyl)cyclohex-1-en-1-yl)vinyl)-3,3-dimethyl-1-(2-(2-(3-oxo-3-phenoxypropoxy)ethoxy)ethyl)-3H-indol-1-ium 2,2,2-trifluoroacetate (67)

[0677] The preparation method of Example 21 was adopted to prepare Compound 67 as a green paste using Compounds B2, C13 and C18 as raw materials.

[0678] 1 H NMR (400MHz, CDCl3) δ8.35(d,J=14.4Hz,2H),7.36-7.39(m,6H),7.23-7.25(m,5H),7.06(d,J=8.4Hz,2H),6.30(d,J=14.0Hz,2H),4.33-4.35(m,4H ),3.89-3.93(m,4H),3.76(t,J=6.4Hz,2H),3.58-3.63(m,6H),3.43-3.46 (m,2H),3.28(s,3H),2.67-2.75(s,6H),1.95-1.96(m,2H),1.73(s,12H).

[0679] LCMS: m / z=793.5, C 48 H 58 ClN2O6 + .

[0680] Example 68: Preparation of 1-(2-(2-(2-carboxyethoxy)ethoxy)ethyl)-2-((E)-2-((E)-2-chloro-3-(2-((E)-1-(2-(2-methoxyethoxy)ethyl)-3,3-dimethylindolin-2-ylalkenyl)vinyl)cyclohex-1-en-1-yl)vinyl)-3,3-dimethyl-3H-indol-1-ium 2,2,2-trifluoroacetate (68)

[0681] The preparation method of Example 21 was used to prepare Compound 68 as a green paste using Compound B2, C13B (purchased from Bidex Pharmaceuticals, batch number 220503), and C18 as raw materials.

[0682] 1 H NMR (400MHz, CDCl3) δ8.43(d,J=14.4Hz,1H),8.25(d,J=13.6Hz,1H),7.30-7.43(m,6H),7.19(d,J=7.2Hz,1 H),7.11(d,J=8.0Hz,1H),6.57(d,J=14.4Hz,1H),6.14(d,J=14.0Hz,1H),4.46(t,J=4.8Hz,2H),4.22(t,J= 5.2Hz,2H),4.00(t,J=5.2Hz,2H),3.88(t,J=5.2Hz,2H),3.74(t,J=6.0Hz,2H),3.57-3.63(m,4H),3.48-3. 49(m,4H),3.31(s,3H),2.73(t,J=4.0Hz,2H),2.60-2.66(m,4H),1.95-1.97(m,2H),1.73(d,J=9.2Hz,12H).

[0683] LCMS: m / z = 717.4C 42 H 54 ClN2O6 + .

[0684] Example 69: Preparation of 2-((E)-2-((E)-2-chloro-3-(2-((E)-1-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)-3,3-dimethylindolin-2-ylalkenyl)vinyl)cyclohex-1-en-1-yl)vinyl)-3,3-dimethyl-1-(2-(2-(3-oxo-3-phenoxypropoxy)ethoxy)ethyl)-3H-indol-1-ium 2,2,2-trifluoroacetate (69)

[0685] The preparation method of Example 21 was adopted, and Compounds B2, C13, and C19 were used as raw materials to prepare Compound 69 as a green paste.

[0686] 1 H NMR (400MHz, CDCl3) δ8.35 (d, J = 14.0Hz, 2H), 7.34-7.40 (m, 6H), 7.20-7.26 (m, 5H), 7.0 5-7.07(m,2H),6.29(d,J=14.0Hz,2H),4.29-4.35(m,4H),3.87-3.95(m,4H),3.75(t,J= 6.0Hz,2H),3.60-3.64(m,4H),3.55-3.59(m,4H),3.51-3.53(m,2H),3.44-3.46(m,2H), 3.33(s,3H),2.73(t,J=6.4Hz,2H),2.62-2.69(m,4H),1.88-1.99(m,2H),1.73(s,12H).

[0687] LCMS: m / z=837.4, C 50 H 62 ClN2O7 + .

[0688] Example 70: Preparation of 1-(2-(2-(2-carboxyethoxy)ethoxy)ethyl)-2-((E)-2-((E)-2-chloro-3-(2-((E)-1-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)-3,3-dimethylindolin-2-ylalkenyl)vinyl)cyclohex-1-en-1-yl)vinyl)-3,3-dimethyl-3H-indol-1-ium 2,2,2-trifluoroacetate (70)

[0689] The preparation method of Example 21 was adopted to prepare Compound 70 as a blue paste using Compounds B2, C13B and C19 as raw materials.

[0690] 1H NMR (400MHz, CDCl3) δ8.41(d,J=14.0Hz,1H),8.28(d,J=14.0Hz,1H),7.33-7.43(m,4H),7.28-7.31(m,2H),7.20(d ,J=7.2Hz,1H),7.13-7.15(m,1H),6.47(d,J=14.4Hz,1H),6.17(d,J=14.0Hz,1H),4.36-4.42(m,2H),4.24(t,J=5.2 Hz,2H),3.96(t,J=4.8Hz,2H),3.88(t,J=4.4Hz,2H),3.70(t,J=6.0Hz,2H),3.61-2.63(m,2H),3.52-3.58(m,8H),3 .45-3.47(m,2H),3.34(s,3H),3.64-3.71(m,4H),2.59(t,J=6.0Hz,2H),1.90-1.98(m,2H),1.72(d,J=6.8Hz,12H).

[0691] LCMS: m / z=761.5, C 44 H 58 ClN2O7 + .

[0692] Example 71: Preparation of 2-((E)-2-((E)-2-chloro-3-(2-((E)-1-(2-(2-methoxyethoxy)ethyl)-3,3-dimethylindolin-2-ylalkenyl)vinyl)cyclohex-1-en-1-yl)vinyl)-1-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)-3,3-dimethyl-3H-indol-1-ium 2,2,2-trifluoroacetate (71)

[0693] The preparation method of Example 21 was adopted to prepare Compound 71 as a green paste using Compounds B2, C18 and C19 as raw materials.

[0694] 1H NMR (400MHz, CDCl3) δ8.33 (dd, J1=5.6Hz, J2=14.0Hz, 2H), 7.35-7.71 (m, 4H), 7 .23-7.25(m,4H),6.36(t,J1=13.6Hz,2H),4.36-4.42(m,4H),3.91-3.95(m,4H ),3.60-3.65(m,4H),3.56-3.58(m,2H),3.53-3.55(m,2H),3.45-3.47(m,4H), 3.35(s,3H),3.28(s,3H),2.64-2.72(m,4H),1.93-1.96(m,2H),1.73(s,12H).

[0695] LCMS: m / z=703.3, C 42 H 56 ClN2O5 + .

[0696] Example 72: Preparation of 2-((E)-2-((E)-2-chloro-3-(2-((E)-3,3-dimethyl-1-(2,5,8,11-tetraoxatridecan-13-yl)indolin-2-ylenyl)vinyl)cyclohex-1-en-1-yl)vinyl)-3,3-dimethyl-1-(2-(2-(3-oxo-3-phenoxypropoxy)ethoxy)ethyl)-3H-indol-1-ium 2,2,2-trifluoroacetate (72)

[0697] The preparation method of Example 21 was adopted to prepare Compound 72 as a green paste using Compounds B2, C13 and C20 as raw materials.

[0698] 1 H NMR (400MHz, CDCl3) δ8.35 (d, J = 14.0Hz, 2H), 7.33-7.38 (m, 6H), 7.20-7.26 (m ,5H),7.05-7.07(m,2H),6.27(d,J=14.0Hz,2H),4.25-4.34(m,4H),3.88-3.96 (m,4H),3.74(t,J=6.4Hz,2H),2.58-2.63(m,8H),2.52-2.57(m,8H),3.35(s,3 H), 2.72 (t, J = 6.0Hz, 2H), 2.63-2.69 (m, 4H), 1.91-1.99 (m, 2H), 1.72 (s, 12H).

[0699] LCMS: m / z=881.6, C 52 H 66ClN2O8 + .

[0700] Example 73: Preparation of 1-(2-(2-(2-carboxyethoxy)ethoxy)ethyl)-2-((E)-2-((E)-2-chloro-3-(2-((E)-3,3-dimethyl-1-(2,5,8,11-tetraoxatridecan-13-yl)indolin-2-ylenyl)vinyl)cyclohex-1-en-1-yl)vinyl)-3,3-dimethyl-3H-indol-1-ium chloride (73)

[0701] The preparation method of Example 21 was adopted to prepare Compound 73 as a green paste using Compounds B2, C13B and C20 as raw materials.

[0702] 1 H NMR(400MHz, CDCl3)δ8.42(d,J=14.0Hz,1H),8.23(d,J=13.6Hz,1H),7.29-7.45(m,6H),7.13-7 .19(m,2H),6.61(d,J=14.4Hz,1H),6.17(d,J=13.6Hz,1H),4.53-4.60(m,2H),4.23-4.30(m,2H) ,4.00-4.07(m,2H),3.86-3.96(m,2H),3.73-3.76(m,2H),3.57-3.63(m,14H),3.51-3.54(m,2H) ,3.36(s,3H),2.76-2.83(m,2H),2.64-2.72(m,4H),1.93-2.02(m,2H),1.72(d,J=10.0Hz,12H).

[0703] LCMS: m / z = 805.5, C 46 H 62 ClN2O8 + .

[0704] Example 74: Preparation of 5-(tert-Butoxycarbonyl)-2-((E)-2-((E)-2-chloro-3-(2-((E)-3,3-dimethyl-1-(2-(3-oxo-3-phenoxypropoxy)ethyl)indolin-2-ylalkenyl)vinyl)cyclohex-1-en-1-yl)vinyl)-1-ethyl-3,3-dimethyl-3H-indol-1-ium bromide (74)

[0705] The preparation method of Example 21 was adopted to prepare compound 74 as a green oil using compounds B2, A8 and C4 as raw materials.

[0706] LCMS: m / z=775.3, C 48 H 56 ClN2O5 + .

[0707] Examples 75A and 75B: 2-((E)-2-((E)-3-(2-((E)-1-(2,5,8,11,14-pentaoxahexadecan-16-yl)-3,3-dimethylindolin-2-ylenyl)vinyl)-2-chlorocyclohex-1-en-1-yl)vinyl)-3,3-dimethyl-1-(2-(2-(3-oxo-3-phenoxypropoxy)ethoxy)ethyl)-3H-indol-1-ium 2,2,2-trifluoroacetate (75 Preparation of 2-((E)-2-((E)-2-chloro-3-(2-((E)-3,3-dimethyl-1-(2-(2-(3-oxo-3-phenoxypropoxy)ethoxy)ethyl)indolin-2-ylalkenyl)vinyl)cyclohex-1-en-1-yl)vinyl)-3,3-dimethyl-1-(2-(2-(3-oxo-3-phenoxypropoxy)ethoxy)ethyl)-3H-indol-1-ium 2,2,2-trifluoroacetate (75B)

[0708] The preparation method of Example 21 was adopted, and Compounds B2, C13, and C23 were used as raw materials to prepare Compounds 75A and 75B, both of which were blue pastes.

[0709] Compound 75A:

[0710] 1 H NMR(400MHz, DMSO-d6); δ8.25(d,J=14.0Hz,2H),7.62(d,J=7.2Hz,2H),7.36-7.44( m,6H),7.23-7.28(m,3H),7.05(d,J=7.6Hz,2H),6.42(d,J=14.4Hz,2H),4.42(d,J=4 .8Hz,4H),3.81-3.82(m,4H),3.62(d,J=6.0Hz,2H),3.50-3.55(m,4H),3.37-3.47(m ,16H),3.21(s,3H),2.68(t,J=2.8Hz,6H),1.83-1.86(m,2H)1.66(t,J=2.4Hz,12H).

[0711] LCMS: m / z = 925.6, C 54 H 70 ClN2O9 + .

[0712] Compound 75B:

[0713] 1 H NMR (400MHz, CDCl3) δ8.34(d,J=13.6Hz,2H),7.34-7.38(m,8H),7.22-7.26(m,6H),7.06(d,J=7.6Hz,4H),6.29(d,J=14.0Hz,2H), 4.32(s,4H),3.92(s,4H),3.75(t,J=6.4Hz,4H),3.58-3.63(m,8H),2.73(t,J=6.0Hz,4H),2.66(s,4H),1.94(s,2H),1.72(s,12H).

[0714] LCMS: m / z = 928.0, C 56 H 64 ClN2O8 + .

[0715] Example 76: Preparation of 2-((E)-2-((E)-3-(2-((E)-1-(2,5,8,11,14-pentaoxahexadecan-16-yl)-3,3-dimethylindolin-2-ylenyl)vinyl)-2-chlorocyclohex-1-en-1-yl)vinyl)-1-(2-(2-(2-carboxyethoxy)ethoxy)ethyl)-3,3-dimethyl-3H-indol-1-ium 2,2,2-trifluoroacetate (76)

[0716] The preparation method of Example 21 was adopted, and Compounds B2, C13B, and C23 were used as raw materials to prepare Compound 76 as a green paste.

[0717] 1 H NMR (400MHz, CDCl3); δ8.35 (dd, J1=14.0Hz, J2=29.2Hz, 2H), 7.37-7.42(m, 4H), 7.33-7.35( m,2H),7.15-7.21(m,2H),6.42(d,J=14.4Hz,1H),6.18(d,J=14.0Hz,1H),4.25-4.37(m,4H) ,3.87-3.96(m,4H),3.69(t,J=6.0Hz,2H),3.60-3.64(m,9H),3.52-3.56(m,11H),3.36(s,3 H), 2.65-2.69 (m, 4H), 2.56 (t, J = 6.4Hz, 2H), 1.94 (t, J = 5.6Hz, 2H), 1.72 (d, J = 5.6Hz, 12H).

[0718] LCMS: m / z=849.5, C 48 H 66 ClN2O9 + .

[0719] Example 77: Preparation of 2,2'-((1E,1'E)-((3E,3'E)-(((2E,2'E)-((pentane-1,5-diylbis(azanediyl))bis(6-oxohexane-6,1-diyl))bis(3,3-dimethylindolin-1-yl-2-ylalkenyl))bis(ethane-2,1-diylalkenyl))bis(2-chlorocyclohex-1-en-1-yl-3-ylalkenyl))bis(ethylene-2,1-diyl))bis(1-ethyl-3,3-dimethyl-3H-indol-1-ium) chloride (77)

[0720] Under a nitrogen atmosphere, a mixture of compound 30 (206 mg, 324 μmol, 2.00 eq), pentane-1,5-diamine (16.6 mg, 162 μmol, 19.0 μL, 1.00 eq), DIEA (62.9 mg, 486 μmol, 84.7 μL, 3.00 eq), 2-chloro-1-methyl-pyridinium-1-ammonium iodide (62.1 mg, 243 μmol, 1.50 eq), and DMF (3.00 mL) was stirred at 25°C for 12 hours. 2-chloro-1-methyl-pyridinium-1-ammonium iodide (20.7 mg, 81.0 μmol, 0.500 eq) was then added, and stirring was continued for 6 hours. Filtration afforded the crude product (400 mg). The crude product was purified by reverse phase HPLC (HCl conditions; column: Phenomenex luna C18 150 mm × 40 mm × 15 μm; mobile phase: [water (HCl)-ACN]; gradient: 60%-90% B, 10 min) to give compound 77 (25.27 mg, 18.4 μmol, 6.13% yield, 97.0% purity) as a blue solid.

[0721] 1H NMR: (400MHz, MeOD)δ8.44(t,J=16.0Hz,4H),7.51-7.55(m,4H),7.42-7.45(m,4H),7. 26-7.37(m,8H),6.24-6.33(m,4H),4.21-4.26(m,4H),4.15-4.19(m,4H),3.11(t,J=6 .8Hz,4H),2.73-2.77(m,8H),2.19(t,J=7.2Hz,4H),1.93-1.99(m,4H),1.82-1.89(m, 4H), 1.73 (d, J = 2.4Hz, 24H), 1.65-1.70 (m, 4H), 1.40-1.49 (m, 14H), 1.27-1.33 (m, 2H).

[0722] LCMS: m / z=631.3, C 81 H 102 Cl2N6O2 2+ / 2.

[0723] The following compound was prepared from the corresponding acid and diamine according to the preparation method of Example 77:

[0724] Example 83: Preparation of 2-((E)-2-((E)-2-chloro-3-(2-((E)-3,3-dimethyl-1-(6-oxo-6-(anilino)hexyl)indol-2-methylene)ethylidene)cyclopentyl-1-en-1yl)vinyl)-1,3,3-trimethyl-3H-indole-1-chloroium salt (83)

[0725] To a mixture of compound 10 (100 mg, 175 μmol, 1.00 eq) and T3P (3.36 g, 5.28 mmol, 3.14 mL, 50% purity, 30.1 eq) were added aniline (16.3 mg, 175 μmol, 16.0 μL, 1.00 eq) and DIEA (113 mg, 877 μmol, 153 μL, 5.00 eq). The mixture was stirred at 50°C for 12 hours. The mixture was concentrated under reduced pressure, and the residue was purified by preparative HPLC (HCl conditions; column: YMC Triart C18 150 mm × 25 mm × 5 μm; mobile phase: [water (HCl)-ACN]; B%: 56%-86%, 8.5 min) and lyophilized to afford compound 83 (21.57 mg, 30.3 μmol, 9.76% yield, 90.5% purity) as a green solid.

[0726] 1H NMR (400MHz, CDCl3) δ10.8 (s, 1H), 7.96-7.98 (m, 2H), 7.86 (d, J = 14Hz, 1H), 7. 67(d,J=13.6Hz,1H),7.37-7.44(m,3H),7.30-7.34(m,2H),7.17-7.24(m,4H), 6.95-7.03(m,2H),6.39(d,J=14.4Hz,1H),5.68(d,J=14.4Hz,1H),4.31-4.34( m,2H),3.52(s,3H),3.04-3.12(m,2H),2.69-2.77(m,4H),1.61-1.71(m,18H).

[0727] LCMS: m / z=644.3, C 42 H 47 ClN3O + .

[0728] Example 84: Preparation of 1-(5-carboxypentyl)-2-((E)-2-((E)-3-(2-((E)-1-(5-carboxypentyl)-3,3-dimethylindolin-2-ylenyl)vinyl)-2-chlorocyclopent-1-en-1-yl)vinyl)-3,3-dimethyl-3H-indol-1-ium chloride (84)

[0729] To a solution of compound 24 (350 mg, 407 μmol, 1.00 eq) in ACN (1.00 mL) and H₂O (73.5 mg, 4.08 mmol, 73.5 μL, 10.0 eq) was added a solution of HCl / dioxane (4.00 M, 5.10 mL, 50.0 eq), and the mixture was stirred at 15°C for 2 hours. The mixture was concentrated under reduced pressure and purified by preparative chromatography (column: Phenomenex luna C₁₈ 150 mm × 40 mm × 15 μm; mobile phase: [water (HCl)-ACN]; gradient: 45%-75% B over 10 min) to afford compound 84 (55.0 mg, 76.5 μmol, 18.7% yield, 98.2% purity) as a green solid.

[0730] 1H NMR (400MHz, DMSO-d6) δ12.04(brs,2H),7.76(d,J=13.6Hz,2H),7.61(d,J=7.2Hz,2H),7.42-7.44(m,4H),7.25-7.29(m,2H),6.15(d,J=14. 0Hz,2H),4.19(t,J=6.8Hz,4H),2.94(s,4H),2.21(t,J=7.2Hz,4H),1.72–1.76(m,4H),1.66(s,12H),1.55-1.58(m,4H),1.40-1.42(m,4H).

[0731] LCMS: m / z=699.4, C 41 H 50 ClN2O4 + .

[0732] According to the preparation method of Example 84 above, the following compound was prepared from the corresponding raw materials:

[0733] Example 88: Preparation of 2-((E)-2-((E)-3-(2-((E)-1-(5-carboxypentyl)-3,3-dimethylindolin-2-ylenyl)vinyl)-2-chlorocyclopent-1-en-1-yl)vinyl)-1-(6-(2,6-dimethylphenoxy)-6-oxohexyl)-3,3-dimethyl-3H-indol-1-ium acetate (88)

[0734] To a solution of compound 23 (150 mg, 164 μmol, 1.00 eq) in MeCN (3 mL) were added HCl / dioxane solution (4.00 M, 2.05 mL, 50.0 eq) and H₂O (29.6 mg, 1.64 mmol, 29.5 μL, 10.0 eq), and the mixture was stirred at 40°C for 12 hours. The mixture was filtered, concentrated, and purified by preparative HPLC (column: Phenomenex luna C₁₈ 150 mm × 25 mm × 10 μm; mobile phase: [water (TFA)-ACN]; gradient: 55%-85% B over 10 min) to afford compound 88 (24.0 mg, 24.5 μmol, 14.9% yield, 90.6% purity) as a green solid.

[0735] 1H NMR (400MHz, CDCl3) δ7.81-7.87(m,2H),7.36-7.40(m,4H),7.23-7.25(m,2H),7.07-7.11(m,2H),7.03(s,3H),6.00-6.05(m,2H),4. 05-4.08(m,4H),2.95(s,2H),2.65-2.67(m,2H),2.44(s,2H),2.10(s,6H),1.85-1.90(m,8H),1.71-1.76(m,12H),1.54-1.61(m,6H).

[0736] LCMS: m / z = 773.4, C 49 H 58 ClN2O4 + .

[0737] According to the preparation method of Example 88 above, the following compound was prepared from the corresponding raw materials:

[0738] Example 101: Preparation of 6-[(2E)-2-[(2E)-2-[3-[(E)-2-(1-ethyl-3,3-dimethyl-1-indol-1-ium-2-yl)vinyl]-2-thiophenol-cyclopentyl-2-ene-1-methylene]ethylidene]-3,3-dimethyl-indol-1-yl]hexanoate; 2,2,2-trifluoroacetate (101)

[0739] To a solution of compound 4 (200 mg, 258 μmol, 1.00 eq) in THF (1 mL) were added triethylamine (78.5 mg, 775 μmol, 107 μL, 3.00 eq) and sodium thiophenolate (41.0 mg, 310 μmol, 1.20 eq). The mixture was stirred at 25°C for 3 hours. After concentration under reduced pressure, the residue was purified by preparative HPLC (column: Phenomenex luna C18 150 mm × 40 mm × 15 μm; mobile phase: [water (TFA)-ACN]; gradient: 60%-90% B over 10 min) to afford compound 101 (86.0 mg, 96.0 μmol, 37.1% yield, 94.6% purity) as a blue solid.

[0740] 1H NMR(400MHz,MeOD)δ8.06-8.12(m,2H),7.36-7.45(m,10H),7.29-7.32(m,6H),6.99-7.01(m,2H),6.07-6.13(m,2H),4.41-4.19(m,4 H),2.96-3.02(m,4H),2.61(t,J=14.4Hz,2H),1.81-1.92(m,4H),1.56-1.57(m,2H),1.48(d,J=2.8Hz,12H),1.39(t,J=14.4Hz,3H).

[0741] LCMS: m / z = 733.3, C 49 H 53 N2O2S + .

[0742] According to the preparation method of Example 101 above, the following compound was prepared from the corresponding raw materials:

[0743] Example 117: Preparation of 5-carboxy-2-((E)-2-((E)-2-chloro-3-(2-((E)-3,3-dimethyl-1-(2-(3-oxo-3-phenoxypropoxy)ethyl)indolin-2-ylalkenyl)vinyl)cyclohex-1-en-1-yl)vinyl)-1-ethyl-3,3-dimethyl-3H-indol-1-ium 2,2,2-trifluoroacetate (117)

[0744] To a solution of compound 74 (3.00 g, 3.86 mmol, 1.00 eq) in DCM (10.0 mL) was added TFA (8.81 g, 77.3 mmol, 5.74 mL, 20.0 eq), and the mixture was stirred at 20°C for 4 hours. The mixture was concentrated under reduced pressure, and the residue was purified by reverse-phase HPLC (Phenomenex Synergi Polar-RP 100 mm × 25 mm × 4 μm; mobile phase: [water (TFA)-ACN]; B%: 25%-85%; 9 min) and lyophilized to afford compound 117 as a blue solid in a yield of 9.63%.

[0745] 1H NMR(400MHz,MeOD)δ8.50-8.65(m,1H),8.16-8.27(m,1H),8.03-8.07(m,2H),7.62(d,J=7.2Hz, 1H),7.51-7.57(m,2H),7.22-7.25(m,1H),7.42-7.46(m,2H),7.26-7.30(m,2H),7.14-7.19(m,2 H),6.83-6.85(m,1H),6.09(br,1H),4.60(s,2H),4.08(s,2H),3.99(t,J=4.4Hz,2H),3.79(t,J= 5.6Hz,2H),2.64-2.77(m,6H),1.85-1.88(m,2H),1.72(d,J=6.4Hz,12H),1.36(t,J=7.2Hz,3H).

[0746] LCMS: m / z = 719.4, C 44 H 48 ClN2O5.

[0747] Example 118: Preparation of 5-carboxy-2-((E)-2-((E)-2-chloro-3-(2-((E)-3,3-dimethyl-1-(6-oxo-6-phenoxyhexyl)indolin-2-ylenyl)vinyl)cyclohex-1-en-1-yl)vinyl)-1-ethyl-3,3-dimethyl-3H-indol-1-ium 2,2,2-trifluoroacetate (118)

[0748] Compound 118 was prepared similarly to Example 117, except that Compound 41 was used instead of Compound 74, to obtain Compound 118 as a blue solid.

[0749] 1H NMR(400MHz,MeOD)δ8.61(d,J=14.4Hz,1H),8.28(d,J=13.6Hz,1H),8.05-8.10(m,2H),7.63-7.65(m,1H),7.5 0-7.57(m,2H),7.42-7.46(m,1H),7.36(t,J=8.0Hz,2H),7.20-7.24(m,2H),6.99(d,J=7.6Hz,2H),6.59(d,J=1 4.8Hz,1H),6.14(d,J=13.6Hz,1H),4.36-4.41(m,2H),4.08-4.17(m,2H),2.70-2.75(m,4H),2.62(t,J=7.2Hz ,2H),1.90-2.00(m,4H),1.80-1.87(m,2H),1.75(d,J=13.2Hz,12H),1.58-1.64(m,2H),1.38(t,J=7.2Hz,3H).

[0750] LCMS: m / z=717.4, C 45 H 50 ClN2O4 + .

[0751] Example 119: Preparation of 5-carboxy-2-((E)-2-((E)-3-(2-((E)-1-(5-carboxypentyl)-3,3-dimethylindolin-2-ylenyl)vinyl)-2-chlorocyclohex-1-en-1-yl)vinyl)-1,3,3-trimethyl-3H-indol-1-ium 2,2,2-trifluoroacetate (119)

[0752] Compound 119 was prepared similarly to Example 117, except that Compound 43 was used instead of Compound 74.

[0753] 1H NMR(400MHz,MeOD)δ8.63(d,J=14.8Hz,1H),8.27(d,J=13.6Hz,1H),8.03-8.08(m,2H),7.64(d ,J=7.6Hz,1H),7.53-7.54(m,2H),7.44-7.46(m,1H),7.21(d,J=8.4Hz,1H),6.59(d,J=14.8Hz, 1H),6.11(d,J=13.6Hz,1H),4.36(t,J=7.2Hz,2H),3.55(s,3H),2.72-2.80(m,4H),2.33(t,J= 7.2Hz,2H),1.91-1.99(m,4H),1.78(s,6H),1.74(s,6H),1.67-1.71(m,2H),1.50-1.54(m,2H).

[0754] LCMS: m / z=627.3, C 38 H 44 ClN2O4 + .

[0755] Example 120: Preparation of 5-carboxy-2-((E)-2-((E)-2-chloro-3-(2-((E)-3,3-dimethyl-1-(6-oxo-6-phenoxyhexyl)indolin-2-ylenyl)vinyl)cyclohex-1-en-1-yl)vinyl)-1,3,3-trimethyl-3H-indol-1-ium 2,2,2-trifluoroacetate (120)

[0756] Compound 120 was prepared similarly to the preparation method of Example 117, except that Compound 44 was used instead of Compound 74.

[0757] 1H NMR (400MHz, MeOD) δ8.61(d,J=14.8Hz,1H),8.27(d,J=14.0Hz,1H),8.03-8.08(m,2H),7.64(d,J=7.2Hz,1H ),7.50-7.57(m,2H),7.43-7.46(m,1H),7.34-7.37(m,2H),7.20-7.23(m,2H),6.98-7.00(m,2H),6.59(d,J= 14.8Hz,1H),6.10(d,J=13.6Hz,1H),4.39(t,J=6.8Hz,2H),3.55(s,3H),2.67-2.76(m,4H),2.62(t,J=7.2Hz ,2H),1.96-2.00(m,2H),1.87-1.94(m,2H),1.80-1.85(m,2H),1.76(s,6H),1.73(s,6H),1.58-1.64(m,2H).

[0758] LCMS: m / z=703.3, C 44 H 48 ClN2O4 + .

[0759] Example 121: Preparation of 2-((E)-2-((E)-2-(((E)-4-(dimethylamino)but-2-enoyl)oxy)-3-(2-((E)-1-(6-(2,6-dimethylphenoxy)-6-oxohexyl)-3,3-dimethylindolin-2-ylenyl)vinyl)cyclohex-1-en-1-yl)vinyl)-1-ethyl-3,3-dimethyl-3H-indol-1-ium 2,2,2-trifluoroacetate (121)

[0760] To a solution of compound 116 (500 mg, 695 μmol, 1.00 eq) and (E)-4-(dimethylamino)but-2-enyl hydrochloride (820 mg, 5.56 mmol, 8.00 eq) in DCM (10 mL) was added pyridine (27.5 mg, 347 μmol, 28.1 μL, 0.500 eq). The reaction mixture was stirred at 45°C for 12 hours. The mixture was concentrated under reduced pressure, and the residue was purified by reverse-phase HPLC (column: Phenomenex luna C18 150 mm × 40 mm × 15 μm; mobile phase: [water (HCl)-ACN]; gradient: 35%-65% B over 10 min) to afford compound 121 (40.0 mg, 30.6 μmol, 4.40% yield, 69.5% purity) as a green solid.

[0761] 1 H NMR (400MHz, CDCl3) δ7.70-7.77(m,2H),7.55-7.61(m,1H),7.42-7.45(m,4H), 7.36-7.38(m,1H),7.23-7.25(m,1H),7.03-7.07(m,5H),6.83-6.87(m,1H),5.9 4-6.00(m,2H),4.33(d,J=3.6Hz,2H),3.97-4.06(m,4H),3.00(s,6H),2.61-2. 68(m,6H),2.12(s,6H),1.86-2.07(m,8H),1.59(s,12H),1.43(t,J=6.8Hz,3H).

[0762] LCMS: m / z=794.5, C 52 H 64 N3O4 + .

[0763] Example 122: Preparation of 2-((E)-2-((E)-2-chloro-3-(2-((E)-3,3-dimethyl-1-(5-phosphonopentyl)indolin-2-ylenyl)vinyl)cyclohex-1-en-1-yl)vinyl)-1,3,3-trimethyl-3H-indol-1-ium chloride (122)

[0764] To a solution of compound 62 (0.600 g, 760 μmol, 1.00 eq) in MeCN (3.00 mL) at 0°C was added HCl / dioxane (6.00 M, 1.27 mL, 10.0 eq), and the mixture was heated to 100°C and stirred for 24 hours. The mixture was filtered, concentrated, and purified by reverse-phase HPLC (column: Phenomenex luna C18 150 mm × 40 mm × 15 μm; mobile phase: [water (HCl)-ACN]; gradient: 45%-75% B over 10 min) to afford compound 122 (27.0 mg, 39.5 μmol, 5.20% yield, 95.9% purity) as a green solid.

[0765] 1H NMR (400MHz, DMSO-d6) δ8.24-8.28(m,2H),7.63(t,J=7.6Hz,2H),7.42-7.46(m,4H),7.27-7.30(m,2H),6.31(t,J=14.4Hz,2H ),4.17-4.20(m,2H),3.70(s,3H),2.70-2.72(m,4H),1.86-1.87(m,2H),1.71-1.73(m,2H),1.67(s,12H),1.47-1.55(m,8H).

[0766] LCMS: m / z=619.3, C 36 H 45 ClN2O3P + .

[0767] Example 123: Preparation of 5-carboxy-2-((E)-2-((E)-2-chloro-3-(2-((E)-3,3-dimethyl-1-(2-(3-oxo-3-phenoxypropoxy)ethyl)indolin-2-ylalkenyl)vinyl)cyclohex-1-en-1-yl)vinyl)-1-ethyl-3,3-dimethyl-3H-indol-1-ium 2,2,2-trifluoroacetate (123)

[0768] Similar to the preparation method of Example 118, compound 123 was prepared as a blue solid by replacing compound 41 with compound 42.

[0769] 1 H NMR (400MHz, CDCl3) δ8.04(d,J=8.4Hz,1H),7.98-8.01(m,2H),7.62(d,J=13.2Hz,1H),7.41-7.53 (m,2H),7.30-7.37(m,4H),7.21(t,J=16.0Hz,1H),7.01(d,J=7.6Hz,2H),6.95(d,J=8.0Hz,1H),6. 71(d,J=14.0Hz,1H),5.87(d,J=13.6Hz,1H),4.66(s,2H),4.07(br,2H),3.18(br,2H),2.96(br,2H ),2.60-2.67(m,2H),1.98(br,2H),1.76-1.87(m,4H),1.71(d,J=19.2Hz,12H),1.35-1.45(m,3H).

[0770] LCMS: m / z=703.3, C 44 H 48 ClN2O4+ .

[0771] The present invention also synthesized the following compounds:

[0772] Comparative Example 1: Preparation of 2-((E)-2-((E)-2-chloro-3-(2-((E)-3,3-dimethyl-1-(6-oxo-6-phenoxyhexyl)indolin-2-ylalkenyl)vinyl)cyclohex-1-en-1-yl)vinyl)-1-ethyl-3,3-dimethyl-3H-indole-1-onium chloride (12a)

[0773] Compound 12a was prepared in the same manner as in Example 34, except that compound C1 was used instead of compound C10.

[0774] 1 H NMR (400MHz, CDCl3) δ8.35(t,J=13.2Hz,2H),7.43-7.35(m,6H),7.25-7.13(m,5H),7.03(d,J=8.4Hz,2H),6.25-6.19(m,2H),4.22-4.16(m,4H) ,2.71-2.66(m,4H),2.62(t,J=6.8Hz,2H),2.01-1.88(m,4H),1.87-1.8 3(m,2H),1.73-1.72(m,12H),1.67-1.62(m,2H),1.46(t,J=6.8Hz,3H).

[0775] LCMS: m / z=673.4, C 44 H 50 N2O2Cl2.

[0776] Test Case

[0777] Test Example 1: Solubility, hERG, Optical Properties, and MRC5 Tests

[0778] (1) Solubility test method

[0779] An appropriate amount of compound was weighed and dissolved in DMSO to prepare a 10 mM stock solution. 30 μL of the stock solution was then added to 970 μL of phosphate-buffered saline (PBS). The mixture was shaken on a 25°C thermomixer for 2 hours. The mixture was centrifuged at 12,000 rpm for 10 minutes. The supernatant was collected and the kinetic solubility of each compound in phosphate-buffered saline (PBS) was determined using a Waters Acquity Arc HPLC. The results are shown in Table 1 below.

[0780] (2) hERG test method

[0781] 1) Materials and Instruments

[0782] 2) Cell lines and cell culture

[0783] The HEK 293 cell line (K1236) stably expressing hERG was purchased from Invitrogen. The cells were cultured in 85% DMEM, 10% dialyzed EBS, 0.1 mM NEAA, 25 mM HEPES, 100 U / mL penicillin-streptomycin, 5 μg / mL blasticidin, and 400 μg / mL geneticin. TrypLE TM Split cells approximately three times per week and maintain confluence between 40% and 80%. Prior to the assay, cells were plated at 5 × 10 5 The cells were cultured at a density of 100 μg / mL in 6 cm dishes and induced with 1 μg / mL doxycycline for 48 h.

[0784] 3) Solution preparation

[0785] Extracellular solution (mM): 132 NaCl, 4 KCl, 13 CaCl2, 0.5 MgCl2, 11.1 glucose, 10 HEPES (pH adjusted to 7.35 with NaOH);

[0786] Intercellular fluid (mM): 140KCl, 2MgCl2, 10EGTA, 10HEPES, 5MgATP (pH adjusted to 7.35 with KOH).

[0787] 4) Preparation of working solution of test compound

[0788] The test compounds were prepared in DMSO to a final concentration of 10 mM as stock solutions.

[0789] The stock solution of each compound was then serially diluted with DMSO at a ratio of 1:3 to prepare five intermediate solutions with concentrations of 3, 1, 0.33, 0.12, 0.04 mM or 3.33, 1.11, 0.37, 0.12 mM, respectively.

[0790] Before the experiment, the final working solution was prepared by diluting the above intermediate solution 1000 times with extracellular fluid. The DMSO concentration in the working solution was in the range of 0.1%.

[0791] Five working solutions with different concentration gradients of 3, 1, 0.33, 0.12, and 0.04 μM were used to determine the potential inhibitory effect of the compounds on hERG channels and to fit the dose-effect curves and calculate the IC 50 5) Experimental steps

[0792] Remove the coverslip from the cell culture medium and place it on the microscope stage.

[0793] Use a 10x objective to locate the cell to be observed. Position the electrode tip under the microscope using the 10x objective by focusing above the plane of the cell. Once the tip is in focus, use coarse control of the manipulator to push the electrode down toward the cell while moving the objective to keep the tip in focus.

[0794] When directly above the cell, switch to the 40x objective and use the fine control of the manipulator to gradually approach the cell surface.

[0795] Gently draw suction through the side port of the electrode holder to form a gigaohm seal.

[0796] Using C fast Eliminate the capacitive current in line with the voltage step by repeated, short, forceful suction until the membrane ruptures the entire cell structure.

[0797] At this point, the membrane potential was set to -60 mV to ensure that the hERG channels were not open. slow To eliminate the capacitive current spikes.

[0798] The holding potential was set to -90 mV for 500 ms; currents were recorded at 20 kHz and filtered at 10 kHz. Leakage currents were measured at -80 mV for 500 ms.

[0799] hERG currents were elicited by depolarizing at +30 mV for 4.8 seconds, then returning the voltage to -50 mV for 5.2 seconds to remove inactivation and observe the inactivation tail current. The maximum value of the tail current magnitude was used to determine the hERG current amplitude.

[0800] Current stability was assessed by recording the current for 120 seconds. Only cells with stable recording parameters above a threshold were used for drug administration.

[0801] First, the vehicle control is applied to the cells to establish the matrix. Once the hERC current documentation is found, the compound is applied 5 minutes later. The hERG current in the presence of the test compound is recorded for about 5 minutes to reach a steady state, and then 5 scans are captured. For dose-response tests, multiple compounds are applied to the cells cumulatively from low concentrations to high concentrations (multiple compounds are detected simultaneously). The positive control, dofetilide at a concentration of 150nM, is also applied to each cell after hERG current measurement at the highest concentration of the test compound as an internal low control for normalization of the percentage of inhibition. In order to ensure good performance of the cultured cells and operations, 5 doses of the positive control dofetilide are also used to test the same batch of cells used for the compound.

[0802] 6) Data Analysis

[0803] Data acceptance criteria:

[0804] The following criteria are used to determine the acceptability of data:

[0805] Initial seal resistance >1 GΩ;

[0806] Leakage current < 50% of the controlled peak tail current at any time;

[0807] Peak tail amplitude >250pA;

[0808] Membrane resistance Rm>200MΩ;

[0809] Access resistance Ra>15MΩ;

[0810] The apparent drop in peak current was <2.5% / min.

[0811] After filling blank solvent or compound gradient solution, obtain 5 stable continuous current values ​​and calculate the average current value.

[0812] The mean value is used as the tail current size. 空白 ” and “tail current size 化合物 ”.

[0813] Data meeting the above hERG current quality criteria were further analyzed according to the following steps:

[0814] The percentage of current inhibition was calculated using the following equation (PatchMaster or Clampfit software was used to extract the peak current from the raw data), where the blank control was the perfused blank solvent 0.1% DMSO;

[0815] Graphpad Prism 8.0 was used to fit the dose-effect curve of the test compound, and the concentration corresponding to 50% inhibition rate was obtained from the curve, which is the concentration in Table 1.

[0816] The hERG test results are shown in Table 1.

[0817] 7) References

[0818] [1]1: Roche et al. A Virtual Screening Method for Prediction of the hERG Potassium Channel Liability of Compound Libraries. (2002) ChemBioChem.3, 455-459.

[0819] [2]Glenn E.Kirsch et al.Variability in the measurement of hERG potassium channel inhibition:effects of temperature and stimulus pattern.(2004)Journal of Pharmacological and Toxicological Methods 50,93-101.

[0820] [3] Roger Marrannes et al. Computer programs to facilitate the estimation of time-dependent drug effects on ion channels. (2004) Computer Methods and Programs in Biomedicine 74,167-181.

[0821] Table 1 Solubility and hERG value of the compounds of the examples of the present invention and the comparative examples

[0822] (3) Optical property test method

[0823] The UV-visible absorption spectra of the compounds (10 μM, DMSO solution) were detected using a Shimadzu UV2600 spectrophotometer to obtain the maximum absorption peak and absorbance of each compound. The results are shown in Table 2.

[0824] Table 2

[0825] (4)MRC5 test

[0826] 1. Cell lines

[0827] MRC5 (ATCC; Catalog No.: CCL-171)

[0828] 2. Reagents

[0829] Culture medium EMEM (ATCC, 30-2003)

[0830] Fetal bovine serum (Gibco, 10091148)

[0831] Penicillin-streptomycin dual antibody (Gibco, S110JV)

[0832] DPBS (Gibco, 14190-144)

[0833] Detection kit (Promega, G7573)

[0834] Pancreatin (0.25%) (Gibco, 25200-056)

[0835] DMSO (Sigma, D2650)

[0836] 3. Instruments

[0837] Biological safety cabinet (Sujing Antai, BSC-1300A II)

[0838] Automated cell counter (Life Technologies, Countess II)

[0839] Multifunctional microplate reader (Biotek, H1FM)

[0840] Shaking table (Hangzhou Aosheng Instrument Co., Ltd., OS-100)

[0841] XLFIT 5.3 (Shanghai Jiuzhan Information Technology Co., Ltd.)

[0842] 4. Test Method

[0843] This test method is carried out in a biological safety cabinet. The specific steps are as follows:

[0844] (1) Cells were seeded in a 96-well plate (using EMEM as the culture medium). After one day, the previous EMEM culture medium was discarded and 5 mL of DPBS was added to wash the cells. The DPBS was then aspirated and discarded. An appropriate amount of trypsin was then added and the cells were incubated at 37°C in a cell culture incubator containing 5% CO2 for approximately 2-5 minutes. Fresh EMEM culture medium was added and the cells were pipetted up and down to resuspend them evenly. The cells were then counted using an automated cell counter.

[0845] (2) Each cell was seeded in a 96-well plate (Corning, Cat. No. 3610) at a density of 3,000 cells per well in 100 μL of EMEM medium in columns 1 to 11. 100 μL of cell-free EMEM medium was added to the well in column 12. The plates were then incubated at 37°C in a 5% CO2 incubator for 24 h.

[0846] (3) Then, the compound of the present invention was diluted 2-fold starting at 10 μM to 8 dose points. 10 μL of the diluted compound was taken with a pipette and added to 100 μL of cells in columns 1 to 10. 10 μL of EMEM containing 2% DMSO was added to columns 11 and 12. The cells were incubated in a 37°C, 5% CO2 incubator for 3 days (Note: Column 11 is the MAX well, which contains cells but no compound; Column 12 is the MIN well, which contains no cells and no compound).

[0847] (4) Then, follow the instructions to The cell activity detection reagent in the detection kit was added to a 96-well plate at 50 μL per well, placed on a shaker in the dark for 5-10 minutes, and then the cell activity was measured using a multifunctional microplate reader. Finally, the inhibition of cell proliferation by the compound of the present invention was plotted using XLFIT software and the half-inhibitory concentration (IC) of the compound of the present invention was calculated. 50 value.

[0848] The test results of the inhibition of MRC5 by the compounds of the present invention are shown in Table 3 below.

[0849] Table 3 Inhibitory effect of the compounds of the present invention on normal cell proliferation (IC 50 , nM)

[0850] The results showed that the compounds of the present invention had significantly improved solubility compared to the compound of Comparative Example 1. This greatly facilitates the use of injectable medications. Furthermore, the compounds of the present invention significantly reduced hERG values, i.e., cardiotoxicity, making them safer for blood or other systemic medications. Furthermore, the inventors evaluated the cytotoxicity of some of the compounds on normal cells and found that all were greater than 10 μM, indicating that they would not adversely affect normal tissues or cells.

[0851] Test Example 2: In vitro cellular uptake of imaging agent molecules

[0852] 2.1. Fluorescence localization imaging of comparative examples 1, 2, 6, 4, 7, 8 and 10 in the human bladder cancer cell line RT112 (Nanjing Kebai; catalog number: CBP60316).

[0853] RT112 cells (1.5×10 4Cells were cultured in DMEM (10% fetal bovine serum (FBS) and 1% antibiotics (100 U / mL penicillin and 100 U / mL streptomycin)) in 96-well plates and incubated overnight in a cell culture incubator at 37°C and 5% CO2. The next day, the culture medium was aspirated, and culture medium containing the appropriate concentration (1-20 μM) of the compound and surfactin (the molar ratio of the test compound to surfactin (OKA: Catalog No. A55976-1g) was 1:5) was added to the experimental wells. The cells were incubated for 30 minutes, washed three times with PBS, and the near-infrared fluorescence intensity of the bladder cancer cells was observed using a Keyence integrated fluorescence microscope. Near-infrared imaging conditions were Ex = 775 / 50 nm, Em = 845 / 55 nm. The results are shown in Figure 1.

[0854] 2.2. Fluorescence localization imaging of compounds 12a, 2, 6, 4, 7, 8, and 10 in the human bladder cancer cell line UM-UC-3 (ATCC; catalog number: CRL-1749).

[0855] UM-UC-3 cells (1.5×10 4 Cells were cultured in EMEM (10% fetal bovine serum (FBS) and 1% antibiotics (100 U / mL penicillin and 100 U / mL streptomycin)) in 96-well plates in advance and incubated overnight in a cell culture incubator at 37°C and 5% CO2. The next day, the culture medium was aspirated, and culture medium containing the appropriate concentration (1-20 μM) of the compound and surfactin (the molar ratio of the test compound to surfactin was 1:5) was added to the experimental wells. The cells were incubated for 30 minutes and washed three times with PBS. The near-infrared fluorescence intensity of the bladder cancer cells was observed using a Keyence integrated fluorescence microscope. The near-infrared imaging conditions were Ex = 775 / 50 nm and Em = 845 / 55 nm. The results are shown in Figure 2.

[0856] Test Example 3: In vitro cell development effect test with BSP

[0857] RT112 cells (1.5×10 4Cells were seeded in 96-well plates using DMEM (10% fetal bovine serum (FBS) and 1% antibiotics (100 U / mL penicillin and 100 U / mL streptomycin)) and cultured overnight in a cell culture incubator at 37°C and 5% CO2. The next day, the medium was aspirated, and the experimental wells were pretreated with 250 μM BSP (bromosulfophenolphthalein, purchased from MACKLIN; Catalog No. S914901) for 10 minutes. Appropriate concentrations (1-20 μM) of compound and surfactin (molar ratio of test compound to surfactin of 1:5) were then added to the wells. The wells were incubated for 30 minutes, washed three times with PBS, and the near-infrared fluorescence intensity of the bladder cancer cells was observed using a Keyence integrated fluorescence microscope. Near-infrared imaging conditions were Ex = 775 / 50 nm, Em = 845 / 55 nm. The results are shown in Figure 3.

[0858] As shown in Figure 3, the uptake of compounds 12a, 2, 6, 4, 7, 8, and 10 by the human bladder cancer cell line RT112 can be attenuated or enhanced by BSP.

[0859] UM-UC-3 cells (1.5×10 4 Cells were seeded in 96-well plates using EMEM (10% fetal bovine serum (FBS) and 1% antibiotics (100 U / mL penicillin and 100 U / mL streptomycin)) and cultured overnight in a cell culture incubator at 37°C and 5% CO2. The next day, the culture medium was aspirated, and the experimental wells were pretreated with 250 μM BSP for 10 minutes. The appropriate concentrations (1-20 μM) of compound and surfactin (the molar ratio of test compound to surfactin was 1:5) were then added to the culture medium with or without 250 μM BSP. The cells were incubated for 30 minutes, washed three times with PBS, and the near-infrared fluorescence intensity of the bladder cancer cells was observed using a Keyence integrated fluorescence microscope. Near-infrared imaging conditions were Ex = 775 / 50 nm, Em = 845 / 55 nm. The results are shown in Figure 4.

[0860] As shown in Figure 4, the uptake of compounds 12a, 2, 6, 4, 7, 8, and 10 by the human bladder cancer cell line UM-UC-3 can be attenuated or enhanced by BSP.

[0861] Test Example 4: Imaging of the Compounds of the Invention in a Bladder Cancer Tumor Model

[0862] Compounds 7, 8, and 10 were tested for imaging in a bladder cancer tumor model.

[0863] All animal experiments were performed in full compliance with the guidelines for the care and use of animals issued by the regional animal committee. 6-8 week-old female BALB / C nude mice (20-25 g) were injected subcutaneously in the right upper limb with a suspension of RT112 cells (2 × 10 6 A mouse model bearing RT112 tumors was established using a PBS-free (0.1 ml PBS per mouse) BABL / c nude mice (15-20 g) were purchased from Beijing Weitong Lihua Laboratory Animal Technology Co., Ltd. For in vivo near-infrared fluorescence (NIRF) imaging, mice with RT112 tumors were intraperitoneally injected with different doses of the free compound (2 mg / kg or 0.4 mg / kg). Near-infrared imaging was performed 48 hours after injection using an IVIS Lumina spectral imaging system (excitation / emission, 780 / 845 nm). The results are shown in Figure 5.

[0864] As shown in Figure 5, compounds 7, 8, and 10 were specifically enriched in the tumor site at either a 2 mg / kg or 0.4 mg / kg dose (NIR is a near-infrared fluorescence signal). The ratio of the fluorescence intensity at the tumor site to the background fluorescence intensity was greater than 1.5 times.

[0865] Test Example 5: Irradiance of the Compounds of the Invention

[0866] Compounds of the present invention, such as compound 10, are superior to ICG, a dye used in angiography.

[0867] Test Example 6: Tumor / normal cell signal ratio of the compound of the present invention

[0868] The compound of the present invention, for example, shows good contrast in different concentration ranges (1-20 μM), ie, the fluorescence intensity of tumor cells is significantly higher than that of normal cells.

[0869] Test Example 7: Tumor / background ratio of the compound of the present invention

[0870] Subcutaneous tumor model mice inoculated with RT112 tumors were selected. Each compound was administered at a dose of 2 mpk by intraperitoneal injection. 48 hours after injection, the ratio of the fluorescence intensity at the tumor site to the background fluorescence intensity was observed using a small animal imaging device. The results are shown in Table 4 below.

[0871] Table 4

[0872] In addition, the experimental results in an orthotopic tumor model showed that the compound of the present invention showed a good tumor-to-background ratio, and the fluorescence intensity in the tumor bladder was significantly higher than that in the normal bladder.

Claims

1. A compound having a structure represented by general formula (I) or a pharmaceutically acceptable salt thereof, in: X is C, O, S or N + ; R 1 and R 2 Each independently selected from L1-L2-L3-Q; L1 is selected from a bond, -(CH2) p -、-(CH2O) q -、-(CH2CH2O) v -、-(CH2O) q -(CH2) p -、-(CH2) p -(CH2O) q -、-(CH2) p -(CH2O) q -(CH2) p -、-(CH2CH2O) v -(CH2) p -、-(CH2CH2O) v -(CH2O) q -; L2 is selected from a bond, an aryl group, a heteroaryl group, a cycloalkyl group, a heterocyclyl group; L3 is selected from a bond, -(CH2) p -、-(CH2O) q -、-(CH2CH2O) v -、-(CH2O) q -(CH2) p -、-(CH2) p -(CH2O) q -、-(CH2) p -(CH2O) q -(CH2) p -、-(CH2CH2O) v -(CH2) p -、-(CH2CH2O) v -(CH2O) q -; Q is selected from R 12 、-OR 13 、-C(O)R 12 、-C(O)OR 13 、-C(O)NHR 13 、-SO3H、 R 12 is selected from hydrogen, halogen, amino, hydroxyl, mercapto, alkyl, alkylamino, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl; the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted with one or more groups selected from halogen, amino, cyano, hydroxyl, mercapto, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl; R 13 is selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl; the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted by one or more groups selected from halogen, amino, cyano, hydroxyl, mercapto, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl; R 3 , R 4 Each independently selected from hydrogen, halogen, amino, nitro, cyano, hydroxyl, mercapto, oxo, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further selected from halogen, amino, oxo, thio, nitro, cyano, hydroxyl, mercapto, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl. substituted with multiple substituents; R 5 , R 6 each independently selected from hydrogen, halogen, amino, nitro, cyano, hydroxyl, mercapto, oxo, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from halogen, amino, oxo, thio, nitro, cyano, hydroxyl, mercapto, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; R 7 Selected from hydrogen, halogen, nitro, cyano, hydroxyl, mercapto, oxo, alkyl, OR a , SR a NR b R c , alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from halogen, amino, oxo, thio, nitro, cyano, hydroxyl, mercapto, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; R 8 , R 9 are each independently selected from hydrogen, halogen, nitro, cyano, hydroxyl, mercapto, oxo, alkyl, OR a NR b R c , alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from halogen, amino, oxo, thio, nitro, cyano, hydroxyl, sulfhydryl, carboxyl, ester, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; R 8a , R 9a each independently selected from hydrogen, halogen, amino, nitro, cyano, hydroxyl, mercapto, oxo, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from halogen, amino, oxo, thio, nitro, cyano, hydroxyl, mercapto, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; R 8b , R 9b each independently selected from hydrogen, halogen, amino, nitro, cyano, hydroxyl, mercapto, oxo, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from halogen, amino, oxo, thio, nitro, cyano, hydroxyl, mercapto, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; R 10a , R 10b , R 10c , R 10d are each independently selected from hydrogen, halogen, nitro, cyano, hydroxyl, mercapto, oxo, alkyl, OR a NR b R c , alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further selected from halogen, amino, oxo, thio, nitro, cyano, hydroxyl, thiol, carboxyl, ester, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl. substituted by one or more substituents of aryl and heteroaryl; or R 10a , R 10b , R 10c , R 10d Any two adjacent atoms to which they are attached together form an aryl or heteroaryl group, wherein the aryl or heteroaryl group is optionally further substituted by one or more substituents selected from halogen, amino, oxo, thio, nitro, cyano, hydroxyl, sulfhydryl, carboxyl, ester, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; R 11a , R 11b , R 11c , R 11d are each independently selected from hydrogen, halogen, nitro, cyano, hydroxyl, mercapto, oxo, alkyl, OR a NR b R c 、-SO3H、-S(O)2R a 、-C(O)OR a , alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from halogen, amino, oxo, thio, nitro, cyano, hydroxyl, sulfhydryl, carboxyl, ester, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; or R 11a , R 11b , R 11c , R 11d Any two adjacent atoms to which they are attached together form an aryl or heteroaryl group, wherein the aryl or heteroaryl group is optionally further substituted by one or more substituents selected from halogen, amino, oxo, thio, nitro, cyano, hydroxyl, sulfhydryl, carboxyl, ester, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; R a is selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further selected from halogen, amino, oxo, thio, nitro, cyano, hydroxyl, sulfhydryl, carboxyl, ester, sulfonic acid, -NHC(O)-L4-NR b R c 、-OC(O)-L4-NR b R c , alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; wherein -L4- is alkenylene; R b and R c each independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from halogen, amino, oxo, thio, nitro, cyano, hydroxyl, thiol, carboxyl, ester, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; m is 0 or 1; p is an integer from 1 to 10; q is an integer from 1 to 10; v is an integer from 1 to 10.

2. A compound represented by general formula (IA) or a pharmaceutically acceptable salt thereof, in: X is C, O, S or N + ; M - is an acid ion, preferably a chloride ion, a bromide ion, an iodide ion, a formate ion, an acetate ion, or a trifluoroacetate ion; n is 1 or 2, and when X is an N + When X is C, O or S, n is 1; R 1 and R 2 Each independently selected from L1-L2-L3-Q; L1 is selected from a bond, -(CH2) p -、-(CH2O) q -、-(CH2CH2O) v -、-(CH2O) q -(CH2) p -、-(CH2) p -(CH2O) q -、-(CH2) p -(CH2O) q -(CH2) p -、-(CH2CH2O) v -(CH2) p -、-(CH2CH2O) v -(CH2O) q -; L2 is selected from a bond, an aryl group, a heteroaryl group, a cycloalkyl group, a heterocyclyl group; L3 is selected from a bond, -(CH2) p -、-(CH2O) q -、-(CH2CH2O) v -、-(CH2O) q -(CH2) p -、-(CH2) p -(CH2O) q -、-(CH2) p -(CH2O) q -(CH2) p -、-(CH2CH2O) v -(CH2) p -、-(CH2CH2O) v -(CH2O) q -; Q is selected from R 12 、 -OR 13 、 -C(O)R 12 、 -C(O)OR 13 、 -C(O)NHR 13 、 -SO3H、 R 12 is selected from hydrogen, halogen, amino, hydroxyl, mercapto, alkyl, alkylamino, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl; the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted with one or more groups selected from halogen, amino, cyano, hydroxyl, mercapto, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl; R 13 is selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl; the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted by one or more groups selected from halogen, amino, cyano, hydroxyl, mercapto, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl; R 3 , R 4 Each independently selected from hydrogen, halogen, amino, nitro, cyano, hydroxyl, mercapto, oxo, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further selected from halogen, amino, oxo, thio, nitro, cyano, hydroxyl, mercapto, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl. substituted with multiple substituents; R 5 , R 6 each independently selected from hydrogen, halogen, amino, nitro, cyano, hydroxyl, mercapto, oxo, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from halogen, amino, oxo, thio, nitro, cyano, hydroxyl, mercapto, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; R 7 Selected from hydrogen, halogen, nitro, cyano, hydroxyl, mercapto, oxo, alkyl, OR a , SR a NR b R c , alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from halogen, amino, oxo, thio, nitro, cyano, hydroxyl, mercapto, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; R 8 , R 9 are each independently selected from hydrogen, halogen, nitro, cyano, hydroxyl, mercapto, oxo, alkyl, OR a NR b R c , alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from halogen, amino, oxo, thio, nitro, cyano, hydroxyl, sulfhydryl, carboxyl, ester, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; R 8a , R 9a each independently selected from hydrogen, halogen, amino, nitro, cyano, hydroxyl, mercapto, oxo, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from halogen, amino, oxo, thio, nitro, cyano, hydroxyl, mercapto, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; R 8b , R 9b each independently selected from hydrogen, halogen, amino, nitro, cyano, hydroxyl, mercapto, oxo, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from halogen, amino, oxo, thio, nitro, cyano, hydroxyl, mercapto, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; R 10a , R 10b , R 10c , R 10d are each independently selected from hydrogen, halogen, nitro, cyano, hydroxyl, mercapto, oxo, alkyl, OR a NR b R c , alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further selected from halogen, amino, oxo, thio, nitro, cyano, hydroxyl, thiol, carboxyl, ester, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl. substituted by one or more substituents of aryl and heteroaryl; or R 10a , R 10b , R 10c , R 10d Any two adjacent atoms to which they are attached together form an aryl or heteroaryl group, wherein the aryl or heteroaryl group is optionally further substituted by one or more substituents selected from halogen, amino, oxo, thio, nitro, cyano, hydroxyl, sulfhydryl, carboxyl, ester, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; R 11a , R 11b , R 11c , R 11d are each independently selected from hydrogen, halogen, nitro, cyano, hydroxyl, mercapto, oxo, alkyl, OR a NR b R c 、-SO3H、-S(O)2R a 、-C(O)OR a , alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from halogen, amino, oxo, thio, nitro, cyano, hydroxyl, sulfhydryl, carboxyl, ester, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; or R 11a , R 11b , R 11c , R 11d Any two adjacent atoms to which they are attached together form an aryl or heteroaryl group, wherein the aryl or heteroaryl group is optionally further substituted by one or more substituents selected from halogen, amino, oxo, thio, nitro, cyano, hydroxyl, sulfhydryl, carboxyl, ester, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; R a is selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further selected from halogen, amino, oxo, thio, nitro, cyano, hydroxyl, sulfhydryl, carboxyl, ester, sulfonic acid, -NHC(O)-L4-NR b R c 、-OC(O)-L4-NR b R c , alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; wherein -L4- is alkenylene; R b and R c each independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from halogen, amino, oxo, thio, nitro, cyano, hydroxyl, thiol, carboxyl, ester, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; m is 0 or 1; p is an integer from 1 to 10; q is an integer from 1 to 10; v is an integer from 1 to 10.

3. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, which is a compound having a structure represented by general formula (II) or a pharmaceutically acceptable salt thereof, in, R 1 ~R 7 , R 8a , R 8b , R 9a , R 9b , R 10a , R 10b , R 10c , R 10d , R 11a , R 11b , R 11c , R 11d As defined in claim 1.

4. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, which is a compound having a structure represented by general formula (III) or a pharmaceutically acceptable salt thereof, in, R 1 ~R 9 , R 8a , R 8b , R 9a , R 9b , R 10a , R 10b , R 10c , R 10d , R 11a , R 11b , R 11c , R 11d As defined in claim 1.

5. The compound represented by the general formula (IA) or a pharmaceutically acceptable salt thereof according to claim 2, which is a compound represented by the general formula (IIA) or (IIIA) or a pharmaceutically acceptable salt thereof, in, M - , R 1 ~R 9 , R 8a , R 8b , R 9a , R 9b , R 10a , R 10b , R 10c , R 10d , R 11a , R 11b , R 11c , R 11d As defined in claim 2.

6. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, which is a compound having a structure represented by general formula (IV) or a pharmaceutically acceptable salt thereof, in, R 1 ~R 9 , R 8a , R 8b , R 9a , R 9b , R 10a , R 10b , R 10c , R 10d , R 11a , R 11b , R 11c , R 11d As defined in claim 1.

7. The compound represented by the general formula (IA) or a pharmaceutically acceptable salt thereof according to claim 2, which is a compound represented by the general formula (IVA) or a pharmaceutically acceptable salt thereof, in, M - 、R 1 ~R 9 、R 8a 、R 8b 、R 9a 、R 9b 、R 10a 、R 10b 、R 10c 、R 10d 、R 11a 、R 11b 、 R 11c , R 11d As defined in claim 2.

8. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, wherein R 1 Selected from L1-L2-Q; L1 is selected from -(CH2) p -、-(CH2O) q -(CH2) p -; L2 is selected from a bond, C 6-10 Aryl, 5- to 10-membered heteroaryl; preferably a bond and phenyl; Q is selected from R 12 、-C(O)OR 13 、-C(O)NHR 13 、-SO3H、 R 12 Selected from hydrogen, hydroxyl, C 1-6 alkyl; R 13 Selected from hydrogen, C 6-10 Aryl or 5- to 10-membered heteroaryl; preferably hydrogen and phenyl; p is an integer from 1 to 10, preferably an integer from 1 to 6; q is an integer of 1-10, preferably an integer of 1-6.

9. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 8, wherein R 2 Selected from L1-Q; L1 is selected from -(CH2) p -; Q is selected from R 12 、-C(O)OR 13 、-C(O)NHR 13 、-SO3H、 R 12 Selected from hydrogen, hydroxyl, C 1-6 alkyl; R 13 Selected from hydrogen, C 6-10 Aryl or 5- to 10-membered heteroaryl; preferably hydrogen and phenyl; p is an integer of 1-10, preferably an integer of 1-6.

10. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 9, wherein R 10a , R 10b , R 10c , R 10d are each independently selected from hydrogen, OR a , R a C 1-6 alkyl.

11. The compound according to any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof, wherein: R 11a , R 11b , R 11c , R 11d Each independently selected from hydrogen, carboxyl, OR a NR b R c 、-SO3H、-S(O)2R a 、-C(O)OR a , R a Selected from C 1-6 alkyl; R b and R c Each independently selected from C 1-6 alkyl.

12. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein: R 10a , R 10b , R 10c , R 10d Any two adjacent atoms in the 6-10 Aryl or 5 to 10 membered heteroaryl, preferably phenyl; the aryl or heteroaryl is optionally further substituted by one or more substituents selected from halogen, amino, oxo, thio, nitro, cyano, hydroxyl, sulfhydryl, carboxyl, ester, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl.

13. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein: R 11a , R 11b , R 11c , R 11d Any two adjacent atoms in the 6-10 Aryl or 5 to 10 membered heteroaryl, preferably phenyl; the aryl or heteroaryl is optionally further substituted by one or more substituents selected from halogen, amino, oxo, thio, nitro, cyano, hydroxyl, sulfhydryl, carboxyl, ester, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl.

14. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, which is a compound having a structure represented by general formula (V) or a pharmaceutically acceptable salt thereof, in, R 1 ~R 9 , R 8a , R 8b , R 9a , R 9b , X, m as defined in claim 1.

15. The compound according to any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof, wherein: R 1 Selected from L1-Q; L1 is selected from -(CH2) p -; Q is selected from -C(O)OR 13 、-C(O)NHR 13 、-SO3H、 R 13 Selected from hydrogen, C 6-10 Aryl or 5- to 10-membered heteroaryl; preferably hydrogen and phenyl; p is an integer from 1 to 10, preferably an integer from 1 to 6; R 2 Selected from C 1-6 alkyl.

16. The compound according to any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof, wherein: R 1 Selected from L1-Q; L1 is selected from -(CH2O) q -(CH2) p -; Q is selected from -C(O)OR 13 、-C(O)NHR 13 ; R 13 Selected from hydrogen, C 6-10 Aryl or 5- to 10-membered heteroaryl; preferably phenyl; p is an integer from 1 to 6, preferably an integer from 1 to 4, more preferably 1 or 2; q is an integer from 1 to 6, preferably an integer from 1 to 4, more preferably 1 or 2; R 2 Selected from C 1-6 alkyl.

17. The compound according to any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof, wherein: R 1 Selected from L1-L2-Q; L1 is selected from -(CH2) p -; L2 is selected from C 6-10 Aryl, 5- to 10-membered heteroaryl, preferably phenyl; Q is selected from -C(O)OR 13 ; R 13 Selected from hydrogen, C 6-10 Aryl or 5- to 10-membered heteroaryl; preferably phenyl; p is an integer from 1 to 4, preferably an integer from 1 to 2; R 2 Selected from C 1-6 alkyl.

18. The compound according to any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof, wherein: R 1 Selected from C 1-6 alkyl; R 2 Selected from C 1-6 alkyl.

19. The compound according to any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof, wherein: R 1 and R 2 Each independently selected from L1-Q; L1 is selected from -(CH2) p -; Q is selected from R 12 、-C(O)OR 13 、-C(O)NHR 13 、-SO3H、 R 12 Selected from hydrogen, hydroxyl, C 1-6 alkyl; R 13 Selected from hydrogen, C 6-10 Aryl or 5- to 10-membered heteroaryl; preferably hydrogen and phenyl; p is an integer of 1-10, preferably an integer of 1-6.

20. The compound according to any one of claims 1 to 19 or a pharmaceutically acceptable salt thereof, wherein: R 7 Selected from hydrogen, halogen, hydroxyl, OR a , SR a NR b R c ; R a Selected from C 6-10 Aryl and 5-10 membered heteroaryl, preferably phenyl; wherein the aryl and heteroaryl are optionally further selected from halogen, amino, oxo, thio, nitro, cyano, hydroxyl, sulfhydryl, carboxyl, ester, sulfonic acid, -NHC(O)-L4-NR b R c 、-OC(O)-L4-NR b R c , alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; wherein -L4- is alkenylene; R b and R c are each independently selected from hydrogen, C 1-10 Alkyl, wherein the C 1-10 The alkyl group is optionally further substituted with a carboxyl group.

21. The compound according to any one of claims 1 to 19 or a pharmaceutically acceptable salt thereof, wherein: R 7 Selected from SR a ; R a Selected from C 1-6 Alkyl, the C 1-6 The alkyl group is optionally substituted with a carboxyl group.

22. The compound according to any one of claims 1 to 21 or a pharmaceutically acceptable salt thereof, wherein: R 8 , R 9 are each independently selected from hydrogen, C 1-6 Alkyl, NR b R c ; R b , R c are each independently selected from hydrogen and C 1-6 alkyl.

23. The compound according to any one of claims 1 to 22 or a pharmaceutically acceptable salt thereof, wherein: R 8a , R 9a are each independently selected from hydrogen.

24. The compound according to any one of claims 1 to 23 or a pharmaceutically acceptable salt thereof, wherein: R 8b , R 9b are each independently selected from hydrogen.

25. The compound according to any one of claims 1 to 24 or a pharmaceutically acceptable salt thereof, wherein: R 3 , R 4 are each independently selected from hydrogen and C 1-6 alkyl.

26. The compound according to any one of claims 1 to 25 or a pharmaceutically acceptable salt thereof, wherein: R 5 , R 6 are each independently selected from hydrogen and C 1-6 alkyl.

27. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the pharmaceutically acceptable salt is a halide salt or a carboxylate salt, preferably a hydrochloride salt, a formate salt, an acetate salt or a trifluoroacetate salt.

28. A compound according to any one of claims 1 to 27 or a pharmaceutically acceptable salt thereof, selected from:

29. A compound having a structure represented by general formula (VI) or a pharmaceutically acceptable salt thereof, in, R 1 ~R 9 , R 8a , R 8b , R 9a , R 9b , R 10a , R 10b , R 10c , R 10d , R 11a , R 11b , R 11c , as defined in claim 1; s is 0 or 1; Preferably, R 1 Selected from L1-L2-Q; L1 is selected from -(CH2) p -; L2 is selected from a bond; Q is selected from -C(O)OR 13 ; R 13 is selected from hydrogen and phenyl; R 2 Selected from C 1-6 alkyl; R 3 , R 4 are each independently selected from hydrogen and C 1-6 Alkyl, preferably C 1-6 alkyl; R 5 , R 6 are each independently selected from hydrogen and C 1-6 Alkyl, preferably C 1-6 alkyl; R 7 is selected from halogen; R 8 , R 9 are each independently selected from hydrogen; R 8a , R 9a are each independently selected from hydrogen; R 8b , R 9b are each independently selected from hydrogen; R 10a , R 10b , R 10c , R 10d are each independently selected from hydrogen; R 11a , R 11b , R 11c are each independently selected from hydrogen.

30. The compound according to claim 29 or a pharmaceutically acceptable salt thereof, which is selected from:

31. A compound having a structure represented by general formula (VII) or a pharmaceutically acceptable salt thereof, in, R 2 ~R 9 , R 8a , R 8b , R 9a , R 9b , R 10a , R 10b , R 10c , R 10d , R 11a , R 11b , R 11c , R 11d As defined in claim 1; t is 0 or 1; L5 is selected from -(CH2) t1 -C(O)NH-(CH2) t2 -NHC(O)-(CH2) t3 -; t1, t2, t3 are each independently selected from an integer from 1 to 10; preferably an integer from 2 to 6; Preferably, R 2 Selected from C 1-6 alkyl; R 3 , R 4 are each independently selected from hydrogen and C 1-6 Alkyl, preferably C 1-6 alkyl; R 5 , R 6 are each independently selected from hydrogen and C 1-6 Alkyl, preferably C 1-6 alkyl; R 7 is selected from halogen; R 8 , R 9 are each independently selected from hydrogen; R 8a , R 9a are each independently selected from hydrogen; R 8b , R 9b are each independently selected from hydrogen; R 10a , R 10b , R 10c , R 10d are each independently selected from hydrogen; R 11a , R 11b , R 11c are each independently selected from hydrogen.

32. The compound according to claim 31 or a pharmaceutically acceptable salt thereof, selected from:

33. A compound having a structure represented by general formula (VIII) or a pharmaceutically acceptable salt thereof, in, X, R 1 ~R 4 , R 7 ~R 9 , R 8a , R 8b , R 9a , R 9b , R 10a , R 10b , R 10c , R 10d , R 11a , R 11b , R 11c , R 11d As defined in claim 1; s is 0 or 1; Preferably, X is N + ; s is 1; R 1 Selected from L1-L2-Q; L1 is selected from -(CH2) p -; L2 is selected from a bond; Q is selected from -C(O)OR 13 ; R 13 is selected from hydrogen and phenyl; R 2 Selected from C 1-6 alkyl; R 3 , R 4 are each independently selected from hydrogen and C 1-6 Alkyl, preferably C 1-6 alkyl; R 7 is selected from halogen; R 8 , R 9 Each independently selected from C 1-6 alkyl; R 8a , R 9a are each independently selected from hydrogen; R 8b , R 9b are each independently selected from hydrogen; R 10a , R 10b , R 10c , R 10d are each independently selected from hydrogen; R 11a , R 11b , R 11c are each independently selected from hydrogen.

34. The compound according to claim 33 or a pharmaceutically acceptable salt thereof, selected from:

35. A contrast agent comprising the compound according to any one of claims 1 to 34 or a pharmaceutically acceptable salt thereof and an anionic surfactant.

36. The contrast agent according to claim 35, wherein the anionic surfactant is selected from carboxylates, sulfonates, sulfates, phosphates and lipopeptide anionic surfactants, preferably sulfonates or lipopeptide anionic surfactants, more preferably surfactin, sodium dodecyl sulfonate and / or sodium dodecylbenzene sulfonate; and / or The molar ratio of the compound according to any one of claims 1 to 34 or a pharmaceutically acceptable salt thereof to the anionic surfactant is 1:20 to 10:1, preferably 1:10 to 10:1, and more preferably 1:5 to 5:1; and / or In the contrast agent, the final concentration of the compound according to any one of claims 1 to 34 or a pharmaceutically acceptable salt thereof is in the range of 1 to 100 μM, preferably 5 to 50 μM or 10 to 30 μM; and / or The particle size of the contrast agent solution is 10 to 200 nm, preferably 30 to 150 nm, more preferably 50 to 100 nm; and / or The contrast agent is in the form of a solution or a lyophilized powder.

37. A detection kit comprising a compound according to any one of claims 1 to 34 or a pharmaceutically acceptable salt thereof and an anionic surfactant; Preferably, the anionic surfactant is selected from carboxylates, sulfonates, sulfates, phosphates and lipopeptide anionic surfactants, preferably sulfonates or lipopeptide anionic surfactants, more preferably surfactin, sodium dodecyl sulfonate and / or sodium dodecylbenzene sulfonate; and / or The molar ratio of the compound according to any one of claims 1 to 34 or a pharmaceutically acceptable salt thereof to the anionic surfactant is 1:20 to 10:1, preferably 1:10 to 10:1, and further preferably 1:5 to 5:1; and / or In the contrast agent, the final concentration of the compound according to any one of claims 1 to 34 or a pharmaceutically acceptable salt thereof is in the range of 1 to 100 μM, preferably 5 to 50 μM or 10 to 30 μM; and / or The particle size of the contrast agent solution is 10 to 200 nm, preferably 30 to 150 nm, more preferably 50 to 100 nm; and / or The contrast agent is in the form of a solution or a lyophilized powder.

38. A pharmaceutical composition comprising a compound according to any one of claims 1 to 34 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers.

39. Use of the compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 34 or the pharmaceutical composition according to claim 38 in the preparation of a tumor contrast agent, wherein the tumor is preferably bladder cancer.

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