Novel compound and use thereof

Abstract

The present invention provides a novel compound or a pharmaceutically acceptable salt thereof, and a use thereof, the compound, on the basis of an MMP-9 inhibitory function, can be used as an initial response drug and protect against subsequent neuronal cell damage.

Description

Novel compounds and their uses

[0001] The present invention relates to a novel compound and its use, and more particularly, to a novel compound based on MMP-9 inhibitory function and its use.

[0002] Ischemic brain injury includes brain damage caused by stroke, cardiac arrest, epilepsy, traumatic brain injury, and hypoglycemia. While the causes vary, they all share similar pathogenesis. Stroke has the highest mortality rate among brain diseases, affecting an estimated 25-30 million people worldwide, with approximately 25% of these patients dying annually. In Korea, the annual number of stroke patients is approximately 500,000-600,000, with a high incidence in people over 60 years of age. It is the second leading cause of death in Korea, after cancer. Ischemic stroke, which accounts for 80% of strokes, occurs when a blood vessel supplying oxygen and nutrients to the brain becomes blocked by a blood clot or other cause. There is no effective treatment. Brain damage caused by cardiac arrest is also caused by ischemia and can lead to serious sequelae even after cardiac arrest is resolved. Because this condition is an acute brain injury, early intervention and treatment are crucial. More than 50% of patients experience permanent functional impairment, and post-onset treatment and management pose a significant social challenge. Because there is no fundamental treatment capable of minimizing acute lesions and protecting brain tissue after ischemic brain injury, the development of a treatment that can control these effects is essential.

[0003] Multiple sclerosis (MS) is an autoimmune inflammatory disease of the central nervous system caused by a malfunction of the immune system and the destruction of the myelin sheath surrounding nerve axons. Various neurotoxic mechanisms are involved. Treatment for MS has primarily involved steroids and immunosuppressants. This approach, based on the fact that the primary mechanism of MS is autoimmune, attempts to control the disease by weakening the body's immune system. However, recent studies have shown that while these treatments are effective in the acute phase of the disease, they do not prevent or reduce relapses in the long term. Therefore, the only treatment proven effective is the infusion of large doses of steroids or immunosuppressants at regular intervals over several days during the acute phase. Recently, many treatments have been attempted to prevent relapse and alleviate chronic degeneration by injecting beta-globulin into the spinal fluid or through the skin. While this treatment is currently recognized as effective without major side effects, it has the disadvantage of having to be continuously administered.

[0004] Meanwhile, it has been reported that the level of MMP-9 in the blood can be used as a biomarker for multiple sclerosis (Fainardi, E. et al., Mult. Scler. 12(3): 294-301, 2006). Increased MMP-9 causes damage to the blood-brain barrier (BBB) ​​by degrading the proteins that constitute the tight junctions that make up the BBB. Through the damaged BBB, blood immune cells such as neutrophils, macrophages, and monocytes infiltrate the brain tissue, aggravating the inflammatory response and accelerating the damage to the brain nerves. This neuroinflammation is recognized as a factor that worsens the symptoms of neurological diseases such as stroke and multiple sclerosis. Therefore, substances that can inhibit the activity or expression of MMP-9 can be considered as candidates for the treatment of stroke and multiple sclerosis.

[0005] Korean Patent No. 1283416 discloses a neuroprotective method in which a novel AMPK inhibitor compound is administered to ischemic mice to significantly reduce the size of the infarct area, thereby preserving function after stroke or ischemic injury.

[0006] However, in the case of the above prior art, the patient group eligible for administration is very limited, and there is no neuroprotective treatment that has yet been proven effective in humans.

[0007] The present invention aims to address various issues, including those described above, by providing a novel compound and its use that can protect against neuronal damage, as well as an initial response drug, based on its MMP-9 inhibitory function. However, these tasks are exemplary and should not be construed as limiting the scope of the present invention.

[0008] According to one aspect of the present invention, a novel compound having a structure represented by the following chemical formula 1 or a pharmaceutically acceptable salt thereof is provided:

[0009] . (Chemical formula 1)

[0010]

[0011] *(In the above formula, R1 is , , , or and the above R2 is , hydrogen, a hydroxyl group, a substituted or unsubstituted aryl, a heteroaryl, a substituted or unsubstituted alkyl group having 1 to 4 carbon atoms, a halogen, or a substituted or unsubstituted alkoxy group having 1 to 4 carbon atoms, wherein R3 is hydrogen, hydroxy, halogen, a substituted or unsubstituted alkyl group having 1 to 4 carbon atoms, a substituted or unsubstituted alkoxy group having 1 to 4 carbon atoms, or a substituted or unsubstituted arylalkoxy group, wherein R4 is hydrogen, hydroxy, halogen, methyl, ethyl, methoxy, or ethoxy, wherein A is -CH2NHCO- or heteroaryl, wherein B is -CH2CH2NH-, or a 5 to 7 membered cycloalkyl group containing at least one nitrogen atom, wherein R5 and R6 are each independently hydrogen, halogen, an amine group, a C1 a substituted or unsubstituted alkyl group having 1 to 4 carbon atoms, a substituted or unsubstituted alkoxy group having 1 to 4 carbon atoms, a 5 to 7 membered cycloalkyl group containing 0 to 2 substituted or unsubstituted oxygen atoms and / or at least one nitrogen atom, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, a substituted or unsubstituted alkylaryl group having 7 to 12 carbon atoms.

[0012] According to another aspect of the present invention, a pharmaceutical composition for treating a brain nerve disease is provided, comprising the novel compound or a pharmaceutically acceptable salt thereof as an active ingredient.

[0013] According to another aspect of the present invention, a method for treating a neurological disease is provided, comprising administering a therapeutically effective amount of the compound or a pharmaceutically acceptable salt thereof to a patient suffering from a neurological disease in need of treatment.

[0014] According to another aspect of the present invention, there is provided the above-described compound for use in the treatment of brain nerve diseases.

[0015] According to another aspect of the present invention, there is provided a use of the compound for the preparation of a therapeutic agent for a neurological disease.

[0016] As described above, the novel compound of the present invention can be expected to have a therapeutic effect differentiated from existing therapeutic agents due to its multi-target mechanism that can control the activity of MMP-9, a representative biomarker of ischemic brain damage, thereby maintaining the blood-brain barrier (BBB) ​​function, blocking the early occurrence of neuroinflammation, and controlling various neurotoxicities in brain neurons. In addition, considering the characteristics of target diseases that compete for time until drug administration, it shows the effect of developing an easily administrable emergency medicine and extending the drug efficacy time range. In addition, since the compound of the present invention can be administered by subcutaneous injection and intravenous injection to maximize exposure, it enables efficient treatment of brain nerve diseases. However, the scope of the present invention is not limited by the above effects of the present invention.

[0017] Figure 1a is a schematic diagram schematically showing the manufacturing process of a major intermediate.

[0018] (tert-butyl (2-((2-(1H-indol-3-yl)ethyl)amino)-2-oxoethyl)carbamate)

[0019] Figure 1b is a graph showing the results of purifying the intermediate of Figure 1a using column chromatography.

[0020] Figure 2a is a schematic diagram schematically showing the manufacturing process of a major intermediate.

[0021] (N-(2-(1H-indol-3-yl)ethyl)-2-aminoacetamide)

[0022] Figure 2b is a graph showing the results of purifying the intermediate of Figure 2a using column chromatography.

[0023] Figure 3a is a schematic diagram schematically showing the manufacturing process of a major intermediate.

[0024] (tert-butyl(2-((2-(6-fluoro-1H-indol-3-yl)ethyl)amino)-2-oxoethyl)carbamate)

[0025] Figure 3b is a graph showing the results of purifying the intermediate of Figure 3a using column chromatography.

[0026] Figure 4a is a schematic diagram schematically showing the manufacturing process of a major intermediate.

[0027] (N-(2-(1H-indol-3-yl)ethyl)-4-nitrobenzamide)

[0028] Figure 4b is a graph showing the results of purifying the intermediate of Figure 4a using column chromatography.

[0029] Figure 5a is a schematic diagram schematically showing the manufacturing process of the novel compound PS36.

[0030] Figure 5b is a graph showing the results of purifying the novel compound PS36 by column chromatography.

[0031] Figure 6a is a schematic diagram schematically showing the manufacturing process of the novel compound PS37.

[0032] Figure 6b is a graph showing the results of purifying the novel compound PS37 by column chromatography.

[0033] Figure 7a is a schematic diagram schematically showing the manufacturing process of the novel compound PS38.

[0034] Figure 7b is a graph showing the results of purifying the novel compound PS38 by column chromatography.

[0035] Figure 8a is a schematic diagram schematically showing the manufacturing process of the novel compound PS39.

[0036] Figure 8b is a graph showing the results of purifying the novel compound PS39 by column chromatography.

[0037] Figure 9a is a schematic diagram schematically showing the manufacturing process of the novel compound PS40.

[0038] Figure 9b is a graph showing the results of purifying the novel compound PS40 by column chromatography.

[0039] Figure 10a is a schematic diagram schematically showing the manufacturing process of the novel compound PS47.

[0040] Figure 10b is a graph showing the results of purifying the novel compound PS47 by column chromatography.

[0041] Figure 11a is a schematic diagram schematically showing the manufacturing process of the novel compound PS48.

[0042] Figure 11b is a graph showing the results of purifying the novel compound PS48 by column chromatography.

[0043] Figure 12a is a schematic diagram schematically showing the manufacturing process of the novel compound PS49.

[0044] Figure 12b is a graph showing the results of purifying the novel compound PS49 by column chromatography.

[0045] Figure 13a is a schematic diagram schematically showing the manufacturing process of the novel compound PS50.

[0046] Figure 13b is a graph showing the results of purifying the novel compound PS50 by column chromatography.

[0047] Figure 14 is a schematic diagram schematically showing the manufacturing process of the novel compound PS52.

[0048] Figure 15 is a schematic diagram schematically showing the manufacturing process of the novel compound PS53.

[0049] Figure 16 is a schematic diagram schematically showing the manufacturing process of the novel compound PS54.

[0050] Figure 17a is a schematic diagram schematically showing the manufacturing process of the novel compound PS55.

[0051] Figure 17b is a graph showing the results of purifying the novel compound PS55 by column chromatography.

[0052] Figure 18 is a schematic diagram schematically showing the manufacturing process of the novel compound PS56.

[0053] Figure 19a is a schematic diagram schematically showing the manufacturing process of the novel compound MS33.

[0054] Figure 19b is a graph showing the results of purifying the novel compound MS33 by column chromatography.

[0055] Figure 20a is a schematic diagram schematically showing the manufacturing process of the novel compound MS34.

[0056] Figure 20b is a graph showing the results of purifying the new compound MS34 by column chromatography.

[0057] Figure 21a is a schematic diagram schematically showing the manufacturing process of the novel compound K0116.

[0058] Figure 21b is a graph showing the results of purifying the novel compound K0116 by column chromatography.

[0059] Figure 22a is a schematic diagram schematically showing the manufacturing process of the novel compound K0117.

[0060] Figure 22b is a graph showing the results of purifying the novel compound K0117 by column chromatography.

[0061] Figure 23a is a schematic diagram schematically showing the manufacturing process of the novel compound K0119.

[0062] Figure 23b is a graph showing the results of purifying the novel compound K0119 by column chromatography.

[0063] Figure 24a is a schematic diagram schematically showing the manufacturing process of the novel compound K01144.

[0064] Figure 24b is a graph showing the results of purifying the novel compound K01144 by column chromatography.

[0065] Figure 25a is a schematic diagram schematically showing the manufacturing process of the novel compound K01145.

[0066] Figure 25b is a graph showing the results of purifying the novel compound K01145 by column chromatography.

[0067] Figure 26a is a schematic diagram schematically showing the manufacturing process of the novel compound K01146.

[0068] Figure 26b is a graph showing the results of purifying the novel compound K01146 by column chromatography.

[0069] Figure 27a is a schematic diagram schematically showing the manufacturing process of the novel compound K01165.

[0070] Figure 27b is a graph showing the results of purifying the novel compound K01165 by column chromatography.

[0071] Figure 28a is a schematic diagram schematically showing the manufacturing process of the novel compound K01166.

[0072] Figure 28b is a graph showing the results of purifying the novel compound K01166 by column chromatography.

[0073] Figure 29a is a schematic diagram schematically showing the manufacturing process of the novel compound K01180.

[0074] Figure 29b is a graph showing the results of purifying the novel compound K01180 by column chromatography.

[0075] Figure 30a is a schematic diagram schematically showing the manufacturing process of the novel compound K01181.

[0076] Figure 30b is a graph showing the results of purifying the novel compound K01181 by column chromatography.

[0077] Figure 31a is a schematic diagram schematically showing the first step manufacturing process of the first template of a novel compound intermediate.

[0078] Figure 31b is a graph showing the results of purifying an indole derivative using column chromatography.

[0079] Figure 32a is a schematic diagram schematically showing the two-step manufacturing process of the first template of a novel compound intermediate (1T1S).

[0080] Figure 32b is a graph showing the results of purifying an indole derivative using column chromatography.

[0081] Figure 33a is a schematic diagram schematically showing the three-step manufacturing process of the first template of a novel compound intermediate.

[0082] Figure 33b is a graph showing the results of purifying an indole derivative using column chromatography.

[0083] Figure 34a is a schematic diagram schematically showing the first step manufacturing process of the second template of a novel compound intermediate.

[0084] Figure 34b is a graph showing the results of purifying an indole derivative using column chromatography.

[0085] Figure 35a is a schematic diagram schematically showing a two-step manufacturing process of a second template of a novel compound intermediate.

[0086] Figure 35b is a graph showing the results of purifying an indole derivative using column chromatography.

[0087] Figure 36a is a schematic diagram schematically showing a three-step manufacturing process of a second template of a novel compound intermediate.

[0088] Figure 36b is a graph showing the results of purifying an indole derivative using column chromatography.

[0089] Figure 37a is a schematic diagram schematically showing the manufacturing process of the novel derivative ZW001.

[0090] Figure 37b is a graph showing the results of purifying the novel derivative ZW001 by column chromatography.

[0091] Figure 38a is a schematic diagram schematically showing the manufacturing process of the novel derivative ZW002.

[0092] Figure 38b is a graph showing the results of purifying the novel derivative ZW002 by column chromatography.

[0093] Figure 39a is a schematic diagram schematically showing the manufacturing process of the novel derivative ZW003.

[0094] Figure 39b is a graph showing the results of purifying the novel derivative ZW003 by column chromatography.

[0095] Figure 40a is a schematic diagram schematically showing the manufacturing process of the novel derivative ZW004.

[0096] Figure 40b is a graph showing the results of purifying the novel derivative ZW004 by column chromatography.

[0097] Figure 41a is a schematic diagram schematically showing the manufacturing process of the novel derivative ZW005.

[0098] Figure 41b is a graph showing the results of purifying the novel derivative ZW005 by column chromatography.

[0099] Figure 42a is a schematic diagram schematically showing the manufacturing process of the novel derivative ZW014.

[0100] Figure 42b is a graph showing the results of purifying the novel derivative ZW014 by column chromatography.

[0101] Figure 43a is a schematic diagram schematically showing the manufacturing process of the novel derivative ZW006.

[0102] Figure 43b is a graph showing the results of purifying the novel derivative ZW006 by column chromatography.

[0103] Figure 44a is a schematic diagram schematically showing the manufacturing process of the novel derivative ZW007.

[0104] Figure 44b is a graph showing the results of purifying the novel derivative ZW007 by column chromatography.

[0105] Figure 45a is a schematic diagram schematically showing the manufacturing process of the novel derivative ZW008.

[0106] Figure 45b is a graph showing the results of purifying the novel derivative ZW008 by column chromatography.

[0107] Figure 46a is a schematic diagram schematically showing the manufacturing process of the novel derivative ZW009.

[0108] Figure 46b is a graph showing the results of purifying the novel derivative ZW009 by column chromatography.

[0109] Figure 47 is a schematic diagram schematically showing the manufacturing process of the novel derivative ZW010.

[0110] Figure 48 is a schematic diagram schematically showing the manufacturing process of the novel derivative ZW011.

[0111] Figure 49 is a graph showing the results of purifying the novel derivative ZW012 by column chromatography.

[0112] Figure 50a is a schematic diagram schematically showing the manufacturing process of the novel derivative ZW013.

[0113] Figure 50b is a graph showing the results of purifying the novel derivative ZW013 by column chromatography.

[0114] Figure 51a is a schematic diagram schematically showing the manufacturing process of the novel derivative ZW015.

[0115] Figure 51b is a graph showing the results of purifying the novel derivative ZW015 by column chromatography.

[0116] Figure 52a is a schematic diagram schematically showing the manufacturing process of the novel derivative ZW016.

[0117] Figure 52b is a graph showing the results of purifying the novel derivative ZW016 by column chromatography.

[0118] Figure 53a is a schematic diagram schematically showing the manufacturing process of the novel derivative ZW017.

[0119] Figure 53b is a graph showing the results of purifying the novel derivative ZW017 by column chromatography.

[0120] Figure 54a is a schematic diagram schematically showing the manufacturing process of the novel derivative ZW018.

[0121] Figure 54b is a graph showing the results of purifying the novel derivative ZW018 by column chromatography.

[0122] Figure 55 is a graph showing the results of confirming the MMP-9 inhibitory activity of compounds according to one embodiment of the present invention.

[0123] Figures 56a and 56b are graphs showing the results of confirming the zinc toxicity inhibitory activity of compounds according to one embodiment of the present invention. The numerical values ​​in the graphs are relative values, with the values ​​measured in the control group treated with only a Zn aqueous solution set as 100%.

[0124] Figure 57 is a series of graphs showing the results of examining the autotoxicity of compounds at a concentration of 20 μM according to one embodiment of the present invention, and shows the results of analyzing the degree of cell death using LDH analysis 24 hours after drug treatment. The numbers in the graph are relative values, with 100% being the value measured when the control group (BL) was not treated with anything and when all nerve cells were treated with 100 μM NMDA to induce death.

[0125] Figure 58 is a graph showing the results of confirming the H2O2 toxicity inhibition activity of compounds according to one embodiment of the present invention. The numerical values ​​in the graph are relative values, with the values ​​measured after treating only H2O2 and the untreated control group (BL) as 100%.

[0126] Figure 59 is a graph showing the results of confirming the glutamate toxicity inhibitory activity of compounds according to one embodiment of the present invention. The numerical values ​​in the graph are relative values, with the values ​​measured in the group treated only with glutamate set as 100%.

[0127] Figure 60 is a graph showing the results of confirming the neuroinflammation inhibitory activity of compounds according to one embodiment of the present invention. The upper part shows the results of examining the effect of nutrients on the expression of IL-1β in the cytoplasm, the middle part shows the results of measuring the expression amount of proIL-1β secreted extracellularly, and the lower part shows the results of measuring the expression amount of mature IL-1β secreted extracellularly. All values ​​are normalized values ​​expressed relatively, taking the value of IL-1β measured in the control group treated only with LPS as 1.

[0128] Figure 61a is a schematic diagram schematically showing the manufacturing process of MCAO rats, a stroke animal model for verifying the in vivo effects of a compound according to one embodiment of the present invention.

[0129] Figure 61b is a schematic diagram schematically showing an experimental schedule for an animal experiment to verify the stroke treatment effect when administered 1 hour after MCAO treatment of a compound according to one embodiment of the present invention.

[0130] Figure 61c is a schematic diagram schematically showing an experimental schedule for an animal experiment to verify the stroke treatment effect when administered 3 hours after MCAO treatment of a compound according to one embodiment of the present invention.

[0131] Figure 61d is a graph showing the results of measuring the volume of the cerebral infarction area when a compound (ZC200081) according to one embodiment of the present invention was administered at different concentrations (5, 15, 25 mg / kg) 1 hour after MCAO treatment.

[0132] Figure 61e is a graph showing the results of measuring the degree of brain edema when a compound (ZC200081) according to one embodiment of the present invention was administered at different concentrations (5, 15, 25 mg / kg) 1 hour after MCAO treatment.

[0133] Figure 61f is a graph showing the results of measuring the volume of a cerebral infarction area when a compound (ZC200081) according to one embodiment of the present invention was subcutaneously administered at 15 mg / kg 3 hours after MCAO treatment.

[0134] Figure 61g is a representative photograph showing the results of TTC staining of brain sections extracted from experimental animals when a compound (ZC200081) according to one embodiment of the present invention was subcutaneously administered at 15 mg / kg 3 hours after MCAO treatment.

[0135] Figure 61h is a graph showing the results of measuring the degree of brain edema when a compound (ZC200081) according to one embodiment of the present invention was subcutaneously administered at 15 mg / kg 3 hours after MCAO treatment.

[0136] Figure 61i is a graph showing the results of measuring the mNSS index of experimental animals when a compound (ZC200081) according to one embodiment of the present invention was administered at different concentrations (5, 15, 25 mg / kg) 1 hour after MCAO treatment.

[0137] Figure 61j is a graph showing the results of measuring the mNSS index of experimental animals when a compound (ZC200081) according to one embodiment of the present invention was administered subcutaneously at 15 mg / kg 3 hours after MCAO treatment.

[0138] Figure 62a is a schematic diagram schematically illustrating an animal experiment schedule for verifying the multiple sclerosis therapeutic effect of a compound according to one embodiment of the present invention.

[0139] Figure 62b is a graph showing changes in EAE clinical scores over time in experimental autoimmune encephalomyelitis (EAE) animals, which are multiple sclerosis model animals, when administered a compound (ZC200081) according to one embodiment of the present invention.

[0140] Figure 62c is a graph showing changes in the incidence rate of EAE over time in experimental autoimmune encephalomyelitis (EAE), a multiple sclerosis model animal, when administered a compound (ZC200081) according to one embodiment of the present invention.

[0141] FIG. 62d is a series of photographs captured at 1-second intervals from a 5-second video showing changes in motor ability on the 40th day of an experimental autoimmune encephalomyelitis (EAE) animal, which is a multiple sclerosis model animal, upon administration of a compound (ZC200081) according to one embodiment of the present invention.

[0142] FIG. 62e is a polyacrylamide gel staining photograph showing the results of analyzing the activity of MMP-9 in plasma obtained from an experimental autoimmune encephalomyelitis (EAE) animal, which is a multiple sclerosis model animal, upon administration of a compound (ZC200081) according to one embodiment of the present invention, using Geltin Zymography.

[0143] Figure 62f is a graph that quantifies the results of Figure 62e.

[0144] FIG. 62g is a series of photographs showing the results of tissue immunofluorescence staining of spinal cord sections obtained from experimental autoimmune encephalomyelitis (EAE), a multiple sclerosis model animal, stained with an anti-MMP-9 antibody when administered a compound (ZC200081) according to one embodiment of the present invention.

[0145] FIG. 62h is a series of photographs showing the results of histochemical staining showing the results of staining with anti-IgG antibodies for IgG that has penetrated into spinal cord tissue in an experimental autoimmune encephalomyelitis (EAE) animal, which is a multiple sclerosis model animal, when administered a compound (ZC200081) according to one embodiment of the present invention.

[0146] FIG. 62i is a series of photographs showing the results of analyzing mononuclear cells infiltrating the spinal cord tissue of an experimental autoimmune encephalomyelitis (EAE) animal, a multiple sclerosis model animal, by cresyl violet staining when administered a compound (ZC200081) according to one embodiment of the present invention.

[0147] Figure 62j is a graph that quantifies the results of Figure 62i.

[0148] Definition of terms:

[0149] The term "stroke" used in this document refers to a sudden, localized neurological symptom caused by cerebral blood flow abnormalities. Although the brain accounts for only 2% of body weight, its blood flow accounts for 15% of cardiac output and its oxygen consumption accounts for 20% of total body oxygen consumption. Furthermore, because the brain relies solely on glucose for energy, even a brief interruption in its energy supply can lead to necrosis. Therefore, cerebral blood flow abnormalities are closely related to brain damage.

[0150] The term "multiple sclerosis (MS)" used in this document is an autoimmune inflammatory disease of the central nervous system caused by abnormal control of the body's immune system and destruction of the myelin sheath surrounding the axons of nerve cells. It is known that various forms of neurotoxic mechanisms are involved.

[0151] The term "Matrix metalloproteinase-9 (MMP-9)" used in this document refers to a type of proteolytic enzyme that primarily degrades the extracellular matrix (ECM). MMP-9, also known as gelatinase B, has the ability to degrade gelatin and collagen types IV and V. It plays a crucial role in various physiological and pathological processes, including tissue remodeling, inflammatory responses, wound healing, and cancer metastasis. In particular, it plays a crucial role in cancer metastasis, enabling cancer cells to invade surrounding tissues and spread to other sites via the blood vessels.

[0152] Detailed description of the invention:

[0153] According to one aspect of the present invention, a novel compound having a structure represented by the following chemical formula 1 or a pharmaceutically acceptable salt thereof is provided:

[0154] (Chemical formula 1)

[0155] (In the above formula, R1 is , , , or and the above R2 is , hydrogen, a hydroxyl group, a substituted or unsubstituted aryl, a heteroaryl, a substituted or unsubstituted alkyl group having 1 to 4 carbon atoms, a halogen, or a substituted or unsubstituted alkoxy group having 1 to 4 carbon atoms, wherein R3 is hydrogen, hydroxy, halogen, a substituted or unsubstituted alkyl group having 1 to 4 carbon atoms, a substituted or unsubstituted alkoxy group having 1 to 4 carbon atoms, or a substituted or unsubstituted arylalkoxy group, wherein R4 is hydrogen, hydroxy, halogen, methyl, ethyl, methoxy, or ethoxy, wherein A is -CH2NHCO- or heteroaryl, wherein B is -CH2CH2NH-, or a 5 to 7 membered cycloalkyl group containing at least one nitrogen atom, wherein R5 and R6 are each independently hydrogen, halogen, an amine group, a C1 a substituted or unsubstituted alkyl group having 1 to 4 carbon atoms, a substituted or unsubstituted alkoxy group having 1 to 4 carbon atoms, a 5 to 7 membered cycloalkyl group containing 0 to 2 substituted or unsubstituted oxygen atoms and / or at least one nitrogen atom, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, a substituted or unsubstituted alkylaryl group having 7 to 12 carbon atoms.

[0156] In the novel compound or its pharmaceutically acceptable salt, R1 is , , , , or It could be.

[0157] In a preferred embodiment, R2 may be hydrogen, a phenyl group, a fluorophenyl group, a chlorophenyl group, a methoxyphenyl group, a trifluoromethyl group, a trifluoromethoxy group, a difluorophenyl group, a dimethoxyphenyl group, a dimethylaminophenyl group, a morpholinophenyl group, or a pyrrolidinylphenyl group.

[0158] In a preferred embodiment, R3 may be hydrogen, fluorine, chlorine, a methoxy group, a phenylmethoxy group, a hydroxy group, or a methoxy group.

[0159] In a preferred embodiment, the heteroaryl of A is , , or It can be, and more preferably It could be.

[0160] In a preferred embodiment, B is -CH2CH2-(ethylene) or It may be (piperidinylene).

[0161] In the novel compound of the present invention or a pharmaceutically acceptable salt thereof, R5 and R6 may each independently be hydrogen, halogen, a substituted or unsubstituted alkyl group having 1 to 4 carbon atoms, a substituted or unsubstituted alkoxy group having 1 to 4 carbon atoms, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, a substituted or unsubstituted 5 to 7-membered cycloalkyl group containing 0 to 2 oxygen atoms and / or at least one nitrogen atom, or a substituted or unsubstituted alkylaryl group having 7 to 12 carbon atoms.

[0162] The above substituted alkyl means that a hydrogen atom attached to a carbon skeleton is replaced by another element or functional group, such as a hydroxyl group, a halogen group, an amine group, a carboxyl group, a cyano group, an alkylthio group, a thiol group, etc. In addition, the above substituted aryl means that a carbon atom constituting an aryl ring (an aromatic ring structure such as a benzene ring) is replaced by an element or functional group other than a hydrogen atom. Examples include hydroxy aryl, halogen aryl, amino aryl, carboxy aryl, and methoxy aryl. The above substituted alkoxy means that a hydrogen atom attached to a carbon skeleton is replaced by another element or functional group, such as a hydroxyl group, a halogen group, an amine group, a carboxyl group, a cyano group, an alkylthio group, a thiol group, etc. The above alkyl group may be a methyl group, an ethyl group, a propyl group, or a butyl group. The above alkoxy group may be a methoxy group, an ethoxy group, a propoxy group or a butoxy group.

[0163] In a more preferred embodiment, R5 and R6 can each independently be hydrogen, fluorine, chlorine, methoxy, dimethylamine, morpholine, pyrrolidine, trifluoromethyl, or trifluoromethoxy.

[0164] In a preferred embodiment, R2 may be a fluorophenyl group, a chlorophenyl group, a methoxyphenyl group, a trifluoromethyl group, a trifluoromethoxy group, a difluorophenyl group, a dimethoxyphenyl group, a dimethylaminophenyl group, a morpholinophenyl group, or a pyrrolidinylphenyl group.

[0165] In the above compound or a pharmaceutically acceptable salt thereof, the amine group may be a primary amine group, a secondary amine group or a tertiary amine group, and the tertiary amine group may be a dimethylamine group or a diethylamine group.

[0166] In addition, in the novel compound of the above heteroaryl invention or a pharmaceutically acceptable salt thereof, R5 and R6 may each independently be hydrogen, halogen, a substituted or unsubstituted alkyl group having 1 to 4 carbon atoms, a substituted or unsubstituted alkoxy group having 1 to 4 carbon atoms, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, a substituted or unsubstituted 5 to 7-membered cycloalkyl group containing 0 to 2 oxygen atoms and / or at least one nitrogen atom, or a substituted or unsubstituted alkylaryl group having 7 to 12 carbon atoms.

[0167] The above substituted alkyl means that a hydrogen atom attached to a carbon skeleton is replaced by another element or functional group, such as a hydroxyl group, a halogen group, an amine group, a carboxyl group, a cyano group, an alkylthio group, a thiol group, etc. In addition, the above substituted aryl means that a carbon atom constituting an aryl ring (an aromatic ring structure such as a benzene ring) is replaced by an element or functional group other than a hydrogen atom. Examples include hydroxy aryl, halogen aryl, amino aryl, carboxy aryl, and methoxy aryl. The above substituted alkoxy means that a hydrogen atom attached to a carbon skeleton is replaced by another element or functional group, such as a hydroxyl group, a halogen group, an amine group, a carboxyl group, a cyano group, an alkylthio group, a thiol group, etc. The above alkyl group may be a methyl group, an ethyl group, a propyl group, or a butyl group. The above alkoxy group may be a methoxy group, an ethoxy group, a propoxy group or a butoxy group.

[0168] In a more preferred embodiment, R5 and R6 can each independently be hydrogen, fluorine, chlorine, methoxy, dimethylamine, morpholine, pyrrolidine, trifluoromethyl, or trifluoromethoxy.

[0169] In a preferred embodiment, R2 may be a fluorophenyl group, a chlorophenyl group, a methoxyphenyl group, a trifluoromethyl group, a trifluoromethoxy group, a difluorophenyl group, a dimethoxyphenyl group, a dimethylaminophenyl group, a morpholinophenyl group, or a pyrrolidinylphenyl group.

[0170] In the above compound or a pharmaceutically acceptable salt thereof, the amine group may be a primary amine group, a secondary amine group or a tertiary amine group, and the tertiary amine group may be a dimethylamine group or a diethylamine group.

[0171] In addition, the heteroaryl group refers to a ring structure that includes one or more heteroatoms (e.g., nitrogen, oxygen, sulfur, etc.) in addition to carbon atoms in an aromatic ring structure (aryl group), and the alkylaryl group refers to a structure in which an aryl group (aromatic ring structure) and an alkyl group (hydrocarbon chain) are bonded. The aryl group refers to an aromatic ring structure such as a benzene ring, and the alkyl group refers to a chain hydrocarbon such as a methyl group (-CH3), an ethyl group (-C2H5), etc. The expression "substituted or unsubstituted" means that a hydrogen atom in the aryl part or alkyl part of the alkylaryl group may or may not be replaced by another element or functional group.

[0172] In the above compound or a pharmaceutically acceptable salt thereof, the halogen may be fluorine (F), iodine (I), bromine (Br) or chlorine (Cl), and the compound may be a compound selected from the group consisting of:

[0173] N-(2-((2-(1H-indol-3-yl)ethyl)amino)-2-oxoethyl)-1H-indole-5-carboxamide,

[0174] N-(2-((2-(1H-indol-3-yl)ethyl)amino)-2-oxoethyl)-3-phenyl-1H-indole-5-carboxamide,

[0175] N-(2-((2-(1H-indol-3-yl)ethyl)amino)-2-oxoethyl)-3-(4-methoxyphenyl)-1H-indole-5-carboxamide,

[0176] N-(2-((2-(1H-indol-3-yl)ethyl)amino)-2-oxoethyl)-3-(4-fluorophenyl)-1H-indole-5-carboxamide,

[0177] N-(2-((2-(1H-indol-3-yl)ethyl)amino)-2-oxoethyl)-3-(4-chlorophenyl)-1H-indole-5-carboxamide,

[0178] N-(2-((2-(5-chloro-1H-indol-3-yl)ethyl)amino)-2-oxoethyl)-3-phenyl-1H-indole-5-carboxamide,

[0179] N-(2-((2-(5-chloro-1H-indol-3-yl)ethyl)amino)-2-oxoethyl)-3-(4-methoxyphenyl)-1H-indole-5-carboxamide,

[0180] N-(2-((2-(5-chloro-1H-indol-3-yl)ethyl)amino)-2-oxoethyl)-3-(4-fluorophenyl)-1H-indole-5-carboxamide,

[0181] N-(2-((2-(5-chloro-1H-indol-3-yl)ethyl)amino)-2-oxoethyl)-3-(4-chlorophenyl)-1H-indole-5-carboxamide,

[0182] N-(2-((2-(5-fluoro-1H-indol-3-yl)ethyl)amino)-2-oxoethyl)-1H-indole-5-carboxamide,

[0183] N-(2-((2-(5-fluoro-1H-indol-3-yl)ethyl)amino)-2-oxoethyl)-3-phenyl-1H-indole-5-carboxamide,

[0184] N-(2-((2-(5-fluoro-1H-indol-3-yl)ethyl)amino)-2-oxoethyl)-3-(4-methoxyphenyl)-1H-indole-5-carboxamide,

[0185] N-(2-((2-(5-fluoro-1H-indol-3-yl)ethyl)amino)-2-oxoethyl)-3-(4-fluorophenyl)-1H-indole-5-carboxamide,

[0186] 3-(4-chlorophenyl)-N-(2-((2-(5-fluoro-1H-indol-3-yl)ethyl)-amino)-2-oxoethyl)-1H-indole-5-carboxamide,

[0187] N-(2-((2-(5-fluoro-1H-indol-3-yl)ethyl)amino)-2-oxoethyl)-3-(4-(trifluoromethyl)phenyl)-1H-indole-5-carboxamide,

[0188] N-(2-((2-(5-fluoro-1H-indol-3-yl)ethyl)amino)-2-oxoethyl)-3-(4-(trifluoromethoxy)phenyl)-1H-indole-5-carboxamide,

[0189] 3-(3,5-difluorophenyl)-N-(2-((2-(5-fluoro-1H-indol-3-yl)ethyl)amino)-2-oxoethyl)-1H-indole-5-carboxamide,

[0190] 3-(3,5-dimethoxyphenyl)-N-(2-((2-(5-fluoro-1H-indol-3-yl)ethyl)amino)-2-oxoethyl)-1H-indole-5-carboxamide,

[0191] 3-(4-(dimethylamino)phenyl)-N-(2-((2-(5-fluoro-1H-indol-3-yl)ethyl)amino)-2-oxoethyl)-1H-indole-5-carboxamide,

[0192] 3-(3,4-dimethoxyphenyl)-N-(2-((2-(5-fluoro-1H-indol-3-yl)ethyl)amino)-2-oxoethyl)-1H-indole-5-carboxamide,

[0193] N-(2-((2-(5-fluoro-1H-indol-3-yl)ethyl)amino)-2-oxoethyl)-3-(3-methoxyphenyl)-1H-indole-5-carboxamide,

[0194] N-(2-((2-(5-fluoro-1H-indol-3-yl)ethyl)amino)-2-oxoethyl)-3-(4-morpholinophenyl)-1H-indole-5-carboxamide,

[0195] N-(2-((2-(5-fluoro-1H-indol-3-yl)ethyl)amino)-2-oxoethyl)-3-(3-fluorophenyl)-1H-indole-5-carboxamide,

[0196] N-(2-((2-(5-fluoro-1H-indol-3-yl)ethyl)amino)-2-oxoethyl)-3-(4-(pyrrolidin-1-yl)phenyl)-1H-indole-5-carboxamide,

[0197] 3-(4-fluorophenyl)-N-(2-((2-(5-methoxy-1-methyl-1H-indol-3-yl)ethyl)amino)-2-oxoethyl)-1H-indole-5-carboxamide,

[0198] N-(2-((2-(5-fluoro-1H-indol-3-yl)ethyl)amino)-2-oxoethyl)-3-(3-morpholinophenyl)-1H-indole-5-carboxamide,

[0199] 3-(4-fluorophenyl)-N-(2-((2-(5-methoxy-1H-indol-3-yl)ethyl)amino)-2-oxoethyl)-1H-indole-5-carboxamide,

[0200] N-(2-(1H-indol-3-yl)ethyl)-2-(3-phenyl-1H-indol-5-yl)isonicotinamide,

[0201] (4-(1H-indol-3-yl)piperidin-1-yl)(2-(3-phenyl-1H-indol-5-yl)pyridin-4-yl)methanone,

[0202] N-(2-(6-fluoro-1H-indol-3-yl)ethyl)-2-(3-phenyl-1H-indol-5-yl)isonicotinamide,

[0203] N-(2-(6-methoxy-1H-indol-3-yl)ethyl)-2-(3-phenyl-1H-indol-5-yl)isonicotinamide,

[0204] N-(2-(5-methoxy-1H-indol-3-yl)ethyl)-2-(3-phenyl-1H-indol-5-yl)isonicotinamide,

[0205] N-(2-(5-fluoro-1H-indol-3-yl)ethyl)-2-(3-phenyl-1H-indol-5-yl)isonicotinamide,

[0206] N-(2-(5-chloro-1H-indol-3-yl)ethyl)-2-(3-phenyl-1H-indol-5-yl)isonicotinamide,

[0207] N-(2-(5-(benzyloxy)-1H-indol-3-yl)ethyl)-2-(3-phenyl-1H-indol-5-yl)isonicotinamide,

[0208] N-(2-(5-hydroxy-1H-indol-3-yl)ethyl)-2-(3-phenyl-1H-indol-5-yl)isonicotinamide,

[0209] N-(2-(1H-indol-3-yl)ethyl)-2-(3-(4-fluorophenyl)-1H-indol-5-yl)isonicotinamide,

[0210] (4-(1H-indol-3-yl)piperidin-1-yl)(2-(3-(4-fluorophenyl)-1H-indol-5-yl)pyridin-4-yl)methanone,

[0211] 2-(3-(4-fluorophenyl)-1H-indol-5-yl)-N-(2-(5-methoxy-1H-indol-3-yl)ethyl)isonicotinamide,

[0212] N-(2-(5-fluoro-1H-indol-3-yl)ethyl)-2-(3-(4-fluorophenyl)-1H-indol-5-yl)isonicotinamide,

[0213] N-(2-(6-fluoro-1H-indol-3-yl)ethyl)-2-(3-(4-fluorophenyl)-1H-indol-5-yl)isonicotinamide,

[0214] 2-(3-(4-fluorophenyl)-1H-indol-5-yl)-N-(2-(4-methylpiperazin-1-yl)ethyl)isonicotinamide,

[0215] 2-(3-(4-fluorophenyl)-1H-indol-5-yl)-N-(2-morpholinoethyl)isonicotinamide,

[0216] 2-(3-(4-fluorophenyl)-1H-indol-5-yl)-N-(2-(pyrrolidin-1-yl)ethyl)isonicotinamide and

[0217] 2-(3-(4-fluorophenyl)-1H-indol-5-yl)-N-(2-(indolin-1-yl)ethyl)isonicotinamide.

[0218] According to another aspect of the present invention, a pharmaceutical composition for treating a brain nerve disease is provided, comprising the novel compound or a pharmaceutically acceptable salt thereof as an active ingredient.

[0219] In the pharmaceutical composition, the brain disease may be a stroke, epilepsy, traumatic brain injury, brain damage due to hypoglycemia, or multiple sclerosis, and the stroke may be a hemorrhagic stroke, an ischemic stroke, a global cerebaral ischemia stroke, or a metal toxicity stroke.

[0220] In the above pharmaceutical composition, the ischemic stroke may be caused by excitatory neuronal cell death or oxidative neuronal cell death.

[0221] In the pharmaceutical composition of the present invention, the effective amount of the compound may vary depending on the type of the patient's affected area, application site, number of treatments, treatment time, formulation, patient's condition, type of adjuvant, etc. The amount used is not particularly limited, but may be 0.01 μg / kg / day to 10 mg / kg / day. The daily amount may be administered once a day, or divided into 2 to 3 times a day at appropriate intervals, or intermittently at intervals of several days.

[0222] In the pharmaceutical composition of the present invention, the compound or its pharmaceutically acceptable salt may be contained in an amount of 0.1 to 100 wt% based on the total weight of the composition. The pharmaceutical composition of the present invention may further include suitable carriers, excipients, and diluents commonly used in the manufacture of pharmaceutical compositions. In addition, solid or liquid additives for formulations may be used in the manufacture of the pharmaceutical composition. Suspending agents, solubilizing agents, stabilizers, isotonic agents, preservatives, anti-adsorption agents, surfactants, diluents, excipients, pH adjusters, analgesics, buffers, sulfur-containing reducing agents, antioxidants, etc. may be appropriately included. For example, the composition may include sterile water, physiological saline, conventional buffers (such as phosphoric acid, citric acid, and other organic acids), stabilizers, salts, antioxidants (such as ascorbic acid), surfactants, suspending agents, isotonic agents, or preservatives. Examples of aqueous solutions for injection include saline solution, isotonic solutions containing glucose or other auxiliary agents, such as D-sorbitol, D-mannose, D-mannitol, and sodium chloride, and may also be combined with buffers, such as phosphate buffer, sodium acetate buffer, analgesics, such as procaine hydrochloride, stabilizers, such as benzyl alcohol, phenol, and antioxidants. Pharmaceutically acceptable carriers and formulations suitable for the present invention are described in detail in the literature [Remington's Pharmaceutical Sciences, 19th ed., 1995].

[0223] The pharmaceutical composition of the present invention can be prepared in any dosage form commonly prepared in the art (e.g., see Remington's Pharmaceutical Science, latest edition; Mack Publishing Company, Easton PA), and the form of the preparation is not particularly limited. These dosage forms are generally known to all pharmaceutical chemists as described in Remington's Pharmaceutical Science, 15th Edition, 1975, Mack Publishing Company, Easton, Pennsylvania 18042 (Chapter 87: Blaug, Seymour).

[0224] In the pharmaceutical composition of the present invention, the compound can be administered orally or parenterally, and preferably parenterally, by intravenous injection, subcutaneous injection, intracerebroventricular injection, intracerebrospinal fluid injection, intramuscular injection, and intraperitoneal injection.

[0225] According to another aspect of the present invention, a method for treating a neurological disease is provided, comprising administering a therapeutically effective amount of the compound or a pharmaceutically acceptable salt thereof to a patient suffering from a neurological disease in need of treatment.

[0226] In the above treatment method, the brain nerve disease may be a stroke, epilepsy, traumatic brain injury, brain damage due to hypoglycemia, or multiple sclerosis, and the stroke may be a hemorrhagic stroke, an ischemic stroke, a global cerebral ischemia stroke, or a metal toxicity stroke.

[0227] According to another aspect of the present invention, there is provided the above-described compound for use in the treatment of brain nerve diseases.

[0228] According to another aspect of the present invention, there is provided a use of the compound for the preparation of a therapeutic agent for a neurological disease.

[0229] Hereinafter, the present invention will be described in more detail through examples. However, the present invention is not limited to the examples disclosed below, but can be implemented in various different forms. The following examples are provided to ensure that the disclosure of the present invention is complete and to fully inform those skilled in the art of the scope of the invention.

[0230] Example 1: Synthesis of key intermediates and novel compounds

[0231] 1-1:tert-butyl (2-((2-(1H-indol-3-yl)ethyl)amino)-2-oxoethyl)carbamate

[0232] To a solution of N-Boc-glycine (0.26 mg, 1.0 eq) in dimethylformamide (7 mL) were successively added HATU (0.60 mg, 1.1 eq) and triethylamine (0.22 mg, 1.5 eq) (Figure 1a). Tryptamine (0.26 mg, 1.1 eq) was added to the mixture. The mixture was stirred at room temperature overnight, and the reaction was nearly completed after 24 h. The reaction mixture was diluted with EtOAc (20 mL), and the organic phase was washed successively with saturated aqueous NaHCO3 and brine. The organic extract was dried over Na2SO4, and the organic extract was filtered. The organic extract was concentrated under vacuum and the product was further purified by column chromatography using a 1:4 hexane / EtOAc solvent system as the eluent to obtain 0.41 mg (yield 87.6%) of a white solid (Fig. 1b).

[0233] 1-2:N-(2-(1H-indol-3-yl)ethyl)-2-aminoacetamide

[0234] To a solution of tert-butyl (2-((2-(1H-indol-3-yl)ethyl)amino)-2-oxoethyl)carbamate (0.4 mg, 1.26 mmol) in anhydrous CH2Cl2 (5 mL) was added TFA (1.0 mL) and stirred at room temperature until the reaction was completed (Figure 2a). After completion of the reaction, the reaction mixture was directly evaporated under vacuum until TFA completely evaporated. Subsequently, it was washed with ethyl acetate and dried again on a rotary evaporator. The crude product was further dried under vacuum and used directly in the next step without further purification. The product was obtained in an amount of 0.28 mg (yield 102%) (Figure 2b).

[0235] 1-3:tert-butyl(2-((2-(6-fluoro-1H-indol-3-yl)ethyl)amino)-2-oxoethyl) carbamate

[0236] To a solution of acid (2.00 g, 11.4 mmol) in DMF (22.0 mL) was added TEA (3.1 mL, 22.8 mmol), followed by HATU (6.5 g, 17.1 mmol) (Figure 3a). The mixture was stirred at room temperature for 10 min, and the dark, transparent mixture was treated with amine (2.63 g, 11.4 mmol). The reaction mixture was stirred at room temperature for 15 h. After the reaction was completed, the reaction mixture was quenched with ice-cold water (distilled water) and stirred for 5 min. It was extracted with EtOAc (3 X 25 mL). The combined organic layers were washed with saturated aqueous NaHCO3 solution, then brine solution, dried over anhydrous Na2SO4, filtered, and evaporated under vacuum at 40 °C. Afterwards, the crude product was purified using HPLC eluted with 70% EA / HE, and the pure fraction was evaporated under reduced pressure at 40°C to obtain 2.8 g (yield 75%) of a white solid product (Fig. 3b).

[0237] 1H NMR (300 MHz, CDCl3) δ 8.28 (s, 1H), 7.30 - 7.24 (m, 1H), 7.20 (dd, J = 9.5, 2.5 Hz, 1H), 7.07 (t,J= 1.3 Hz, 1H), 6.93 (td,J= 9.0, 2.5 Hz, 1H), 6.35 (s, 1H), 5.16 (s, 1H), 3.74 (s, 2H), 3.58 (q,J= 6.6 Hz, 2H), 2.92 (td,J= 6.8, 0.8 Hz, 2H), 1.41 (s, 9H).

[0238] 1-4:N-(2-(1H-indol-3-yl)ethyl)-4-nitrobenzamide

[0239] 4-Nitrobenzoic acid (0.501 mg, 1 eq) was charged into a reaction tube. HATU (1.25 g, 1.1 eq) and triethylamine (0.628 mL, 1.5 eq) were added sequentially (Figure 4a). After stirring for approximately 15 min, tryptamine (0.485 mg, 1.1 eq) was added to the reaction mixture. The reaction mixture was stirred at room temperature for 12 min. The reaction progress was monitored by TLC using EA:hexane = 1:1 as the eluent. Upon completion of the reaction, the reaction mixture was diluted with ice-cold water (20 mL) and then with EtOAc. The organic phase was washed sequentially with brine solution. The organic extract was dried over Na2SO4 and concentrated under vacuum. The product was further purified by column chromatography using a 30% hexane / EtOAc solvent system as the eluent. The above product was obtained in an amount of 0.44 mg (yield 47%) (Fig. 4b).

[0240] 1-5:N-(2-((2-(1H-indol-3-yl)ethyl)amino)-2-oxoethyl)-1H-indole-5-carboxamide (K01183)(PS36)

[0241] 1H-indole-5-carboxylic acid (16 mg, 0.1 mmol) was dissolved in DMF (1 mL) in a vial equipped with a stir bar at room temperature. DCC (31 mg, 0.15 mmol), HOBt (15 mg, 0.1 mmol), and DIPEA (13 mg, 0.1 mmol) were then successively added to the reaction mixture (Figure 5a). N-(2-(1H-indol-3-yl)ethyl)-2-aminoacetamide was then added to the reaction mixture, and the reaction was stirred in a microwave at 70°C for 30 min. After completion, cold water was added, extracted three times with EtOAc, and the combined organic layers were dried over anhydrous MgSO4. The solvent was removed using a rotary evaporator, and the product was separated using a column using a hexane / EA solvent system. 15.5 mg (yield 43.3%) of the product was obtained (Figure 5b).

[0242] 1 H NMR (300 MHz, DMSO) δ 11.34 (s, 1H), 10.82 (d,J= 2.4 Hz, 1H), 8.56 (t,J= 5.9 Hz, 1H), 8.23 ​​- 8.17 (m, 1H), 8.06 - 7.93 (m, 1H), 7.69 (dd,J= 8.6, 1.7 Hz, 1H), 7.56 (d,J= 7.8 Hz, 1H), 7.50 - 7.40 (m, 2H), 7.34 (dt,J= 8.1, 1.0 Hz, 1H), 7.18 (d,J= 2.3 Hz, 1H), 7.02 (dddd,J= 26.6, 8.0, 7.0, 1.2 Hz, 2H), 6.56 (ddd,J= 3.0, 1.9, 0.9 Hz, 1H), 4.04 (q,J= 7.1 Hz, 1H), 3.89 (d,J= 5.8 Hz, 2H), 3.45 - 3.32 (m, 1H), 2.92 - 2.80 (m, 2H), 2.00 (s, 1H), 1.37 - 1.13 (m, 1H).

[0243] 1-6:N-(2-((2-(1H-indol-3-yl)ethyl)amino)-2-oxoethyl)-3-phenyl-1H-indole-5-carboxamide (K01184)(PS37)

[0244] 3-Phenyl-1H-indole-5-carboxylic acid (30 mg, 0.13 mmol) was dissolved in DMF (1 mL) in a vial equipped with a stir bar at room temperature. DCC (40 mg, 0.195 mmol), HOBt (20 mg, 0.13 mmol), and DIPEA (17 mg, 0.13 mmol) were then successively added to the reaction mixture (Figure 6a). N-(2-(1H-indol-3-yl)ethyl)-2-aminoacetamide (30 mg, 0.14 mmol) was then added to the reaction mixture. The reaction was stirred in a microwave at 70 °C for 30 min. Upon completion, cold water (5 mL) was added and extracted three times with EtOAc. The combined organic layers were dried over anhydrous MgSO4 and the solvent was removed using a rotary evaporator. The product was separated using a column with a hexane / EA solvent system. 16.4 mg (yield 29.8%) of the above product was obtained (Fig. 6b).

[0245] 1 H NMR (300 MHz, DMSO) δ 11.62 (s, 1H), 10.82 (s, 1H), 8.74 (t, J = 6.0 Hz, 1H), 8.49 (s, 1H), 8.03 (t, J = 5.9 Hz, 1H), 7.76 (dt, J = 11.9, 2.9 Hz, 4H), 7.52 - 7.45 (m, 4H), 7.34 - 7.23 (m, 2H), 7.18 (dd, J = 7.3, 3.7 Hz, 1H), 7.06 (t, J = 7.2 Hz, 1H), 7.01 - 6.94 (m, 1H), 3.90 (d, J = 5.8 Hz, 2H), 3.39 (qd, J = 6.4, 3.4 Hz, 2H), 2.85 (t, 2H).

[0246] 1-7:N-(2-((2-(1H-indol-3-yl)ethyl)amino)-2-oxoethyl)-3-(4-methoxyphenyl)-1H-indole-5-carboxamide (K01185)(PS38)

[0247] 3-(4-methoxyphenyl)-1H-indole-5-carboxylic acid (30 mg, 0.112 mmol) was dissolved in DMF (1 mL) in a 5 mL vial with a stir bar at room temperature. DCC (35 mg, 0.168 mmol), HOBt (17 mg, 0.112 mmol), and DIPEA (14.5 mg, 0.112 mmol) were then added successively to the reaction mixture (Figure 7a). N-(2-(1H-indol-3-yl)ethyl)-2-aminoacetamide (27 mg, 0.123 mmol) was then added to the reaction mixture. The reaction was then stirred in a microwave at 70 °C for 30 min. After completion, cold water (5 mL) was added and the mixture was extracted three times with EtOAc (3 × 5 mL). The combined organic layers were dried over anhydrous MgSO4, and the solvent was removed using a rotary evaporator. The product was separated using a column using a hexane / EA solvent system. 26.6 mg of the product (yield 50.8%) was obtained (Fig. 7b).

[0248] 1-8:N-(2-((2-(1H-indol-3-yl)ethyl)amino)-2-oxoethyl)-3-(4-fluorophenyl)-1H-indole-5-carboxamide (K01186)(PS39)

[0249] 3-(4-fluorophenyl)-1H-indole-5-carboxylic acid (30 mg, 0.12 mmol) was placed in a 5 mL vial with a stir bar and dissolved in DMF (1 mL) at room temperature. DCC (36 mg, 0.176 mmol), HOBt (18 mg, 0.12 mmol), and DIPEA (15 mg, 0.12 mmol) were successively added to the reaction mixture. N-(2-(1H-indol-3-yl)ethyl)-2-aminoacetamide (28 mg, 0.13 mmol) was then added to the reaction mixture (Figure 8a). The reaction was then stirred in a microwave at 70 °C for 30 min. After completion, cold water (5 mL) was added and extracted three times with EtOAc (3 × 5 mL). The combined organic layers were dried over anhydrous MgSO4. The solvent was removed using a rotary evaporator. The product was separated using a column using a hexane / EA solvent system. 15.5 mg of the product (yield 28.9%) was obtained (Fig. 8b).

[0250] 1-9:N-(2-((2-(1H-indol-3-yl)ethyl)amino)-2-oxoethyl)-3-(4-chlorophenyl)-1H-indole-5-carboxamide (K01187)(PS40)

[0251] 3-(4-chlorophenyl)-1H-indole-5-carboxylic acid (30 mg, 0.11 mmol) was placed in a 5 mL vial with a stir bar and dissolved in DMF (1 mL) at room temperature. DCC (34 mg, 0.165 mmol), HOBt (17 mg, 0.11 mmol), and DIPEA (14 mg, 0.11 mmol) were successively added to the reaction mixture (Figure 9a). N-(2-(1H-indol-3-yl)ethyl)-2-aminoacetamide (26 mg, 0.12 mmol) was then added to the reaction mixture. The reaction was then stirred in a microwave at 70 °C for 30 min. After completion, cold water (5 mL) was added and extracted three times with EtOAc (3 × 5 mL). The combined organic layers were dried over anhydrous MgSO4. The solvent was removed using a rotary evaporator, and the product was separated using a column using a hexane / EA solvent system. 19 mg of the product (yield 37%) was obtained (Fig. 9b).

[0252] 1-10:N-(2-((2-(5-chloro-1H-indol-3-yl)ethyl)amino)-2-oxoethyl)-3-phenyl-1H-indole-5-carboxamide (K01190)(PS47)

[0253] 3-Phenyl-1H-indole-5-carboxylic acid (30 mg, 0.126 mmol) was dissolved in DMF (1 mL) in a 5 mL vial with a stir bar at room temperature. DCC (39 mg, 0.19 mmol), HOBt (19.4 mg, 0.126 mmol), and DIPEA (16.3 mg, 0.126 mmol) were successively added to the reaction mixture (Figure 10a). 2-Amino-N-(2-(5-chloro-1H-indol-3-yl)ethyl)acetamide (35 mg, 0.139 mmol) was then added to the reaction mixture. The reaction was then stirred in a microwave at 70 °C for 30 min. After completion, cold water (5 mL) was added and extracted three times with EtOAc (3 × 5 mL). The combined organic layers were dried over anhydrous MgSO4. The solvent was removed using a rotary evaporator. The product was separated using a column using a hexane / EA solvent system. 26 mg of the product (38% yield) was obtained (Fig. 10b).

[0254] 1 H NMR (300 MHz, DMSO) δ 11.61 (d,J= 2.6 Hz, 1H), 11.03 (s, 1H), 8.74 (t,J= 5.8 Hz, 1H), 8.49 (d, J = 1.6 Hz, 1H), 8.03 (t,J= 5.7 Hz, 1H), 7.76 (ddd,J= 8.6, 2.8, 1.5 Hz, 4H), 7.59 (dd,J= 4.9, 2.1 Hz, 1H), 7.54 - 7.43 (m, 4H), 7.39 - 7.32 (m, 1H), 7.29 - 7.23 (m, 2H), 7.06 (ddd,J=8.6, 3.3, 1.9 Hz, 1H), 5.58 (d,J= 8.0 Hz, 1H), 3.89 (d,J= 5.8 Hz, 2H), 3.31 (d,J= 13.8 Hz, 2H), 2.91 - 2.75 (m, 2H).

[0255] 1-11:N-(2-((2-(5-chloro-1H-indol-3-yl)ethyl)amino)-2-oxoethyl)-3-(4-methoxyphenyl)-1H-indole-5-carboxamide (K01191)(PS48)

[0256] 3-(4-methoxyphenyl)-1H-indole-5-carboxylic acid (30 mg, 0.112 mmol) was dissolved in DMF (1 mL) in a 5 mL vial with a stir bar at room temperature. DCC (35 mg, 0.168 mmol), HOBt (17 mg, 0.11 mmol), and DIPEA (14.5 mg, 0.11 mmol) were then added successively to the reaction mixture (Figure 11a). 2-amino-N-(2-(5-chloro-1H-indol-3-yl)ethyl)acetamide (31 mg, 0.12 mmol) was then added to the reaction mixture. The reaction was then stirred in a microwave at 70 °C for 30 min. After completion, cold water (5 mL) was added and extracted three times with EtOAc (3 x 5 mL). The combined organic layers were dried over anhydrous MgSO4. The solvent was removed using a rotary evaporator. The product was separated using a column with a hexane / EA solvent system. 8 mg of the product (14% yield) was obtained (Fig. 11b).

[0257] 1H NMR (300 MHz, DMSO) δ 11.50 (d,J= 2.5 Hz, 1H), 11.07 - 11.00 (m, 1H), 8.72 (t,J= 5.9 Hz, 1H), 8.47 - 8.40 (m, 1H), 8.08 - 7.93 (m, 1H), 7.74 (dd,J= 8.5, 1.6 Hz, 1H), 7.71 - 7.63 (m, 3H), 7.60 (d,J= 2.1 Hz, 1H), 7.49 (d,J= 8.5 Hz, 1H), 7.35 (d,J= 8.6 Hz, 1H), 7.26 (d,J= 2.3 Hz, 1H), 7.11 - 6.99 (m, 3H), 3.89 (d,J= 5.7 Hz, 2H), 3.80 (s, 3H), 3.41 - 3.29 (m, 2H), 2.92 - 2.77 (m, 2H).

[0258] 1-12:N-(2-((2-(5-chloro-1H-indol-3-yl)ethyl)amino)-2-oxoethyl)-3-(4-fluorophenyl)-1H-indole-5-carboxamide (K01192)(PS49)

[0259] 3-(4-fluorophenyl)-1H-indole-5-carboxylic acid (30 mg, 0.12 mmol) was placed in a 5 mL vial with a stir bar and dissolved in DMF (1 mL) at room temperature. DCC (36.4 mg, 0.176 mmol), HOBt (18 mg, 0.12 mmol), and DIPEA (15 mg, 0.12 mmol) were successively added to the reaction mixture (Figure 12a). 2-amino-N-(2-(5-chloro-1H-indol-3-yl)ethyl)acetamide (32.5 mg, 0.13 mmol) was then added to the reaction mixture. The reaction mixture was then stirred in a microwave at 70 °C for 30 min. After completion, cold water (5 mL) was added, extracted three times with EtOAc (3 × 5 mL), and the combined organic layers were dried over anhydrous MgSO4. The solvent was removed using a rotary evaporator, and the product was separated using a column using a hexane / EA solvent system. 22 mg of the product (yield 37%) was obtained (Fig. 12b).

[0260] 1H NMR (300 MHz, DMSO) δ 11.62 (d, J = 2.6 Hz, 1H), 11.04 (d, J = 2.4 Hz, 1H), 8.76 (t, J = 5.9 Hz, 1H), 8.46 (d, J = 1.6 Hz, 1H), 8.05 (t, J = 5.8 Hz, 1H), 7.85 - 7.72 (m, 4H), 7.61 (d, J = 2.1 Hz, 1H), 7.52 (dd, J = 8.5, 0.6 Hz, 1H), 7.36 (dd, J = 8.6, 0.5 Hz, 1H), 7.37 - 7.23 (m, 3H), 7.07 (dd, J = 8.6, 2.1 Hz, 1H), 4.03 (q, J = 7.1 Hz, 1H), 3.92 (d, J = 5.8 Hz, 2H), 3.41 - 3.30 (m, 2H), 2.91 - 2.78 (m, 2H), 1.99 (s, 1H), 1.22 (s, 1H), 1.21 - 1.01 (m, 1H).

[0261] 1-13:N-(2-((2-(5-chloro-1H-indol-3-yl)ethyl)amino)-2-oxoethyl)-3-(4-chlorophenyl)-1H-indole-5-carboxamide (K01193)(PS50)

[0262] 3-(4-chlorophenyl)-1H-indole-5-carboxylic acid (30 mg, 0.11 mmol) was placed in a 5 mL vial with a stir bar and dissolved in DMF (1 mL) at room temperature. DCC (34 mg, 0.165 mmol), HOBt (17 mg, 0.11 mmol), and DIPEA (14 mg, 0.11 mmol) were successively added to the reaction mixture (Figure 13a). 2-amino-N-(2-(5-chloro-1H-indol-3-yl)ethyl)acetamide (30.6 mg, 0.12 mmol) was then added to the reaction mixture. The reaction was then stirred in a microwave at 70 °C for 30 min. After completion, cold water (5 mL) was added and the mixture was extracted three times with EtOAc (3 × 5 mL). The combined organic layers were dried over anhydrous MgSO4 and the solvent was removed using a rotary evaporator. The product was separated using a column using a hexane / EA solvent system. 7 mg of the product (12% yield) was obtained (Fig. 13b).

[0263] 1 H NMR (300 MHz, DMSO) δ 11.68 (d,J= 2.6 Hz, 1H), 11.03 (s, 1H), 8.74 (t,J= 5.9 Hz, 1H), 8.46 (d,J= 1.5 Hz, 1H), 8.03 (t,J= 5.7 Hz, 1H), 7.84 (d,J= 2.6 Hz, 1H), 7.78 (td,J= 8.6, 1.8 Hz, 3H), 7.59 (d,J= 2.1 Hz, 1H), 7.51 (d,J= 8.5 Hz, 3H), 7.35 (d,J= 8.6 Hz, 1H), 7.26 (d,J= 2.4 Hz, 1H), 7.06 (dd,J= 8.6, 2.1 Hz, 1H), 3.89 (d,J= 5.8 Hz, 2H), 3.29 (s, 2H), 2.82 (t,J= 7.5 Hz, 2H).

[0264] 1-14:N-(2-((2-(5-fluoro-1H-indol-3-yl)ethyl)amino)-2-oxoethyl)-1H-indole-5-carboxamide (K01194)(PS52)

[0265] 1H-indole-5-carboxylic acid (48 mg, 0.3 mmol) was dissolved in DMF (1 mL) in a 5 mL vial with a stir bar at room temperature. DCC (93 mg, 0.45 mmol), HOBt (46 mg, 0.3 mmol), and DIPEA (39 mg, 0.3 mmol) were successively added to the reaction mixture. 2-amino-N-(2-(5-fluoro-1H-indol-3-yl)ethyl)acetamide (77.6 mg, 0.33 mmol) was then added to the reaction mixture (Figure 14). The reaction was then stirred in a microwave at 70 °C for 30 min. After completion, cold water (5 mL) was added and extracted three times with EtOAc (3 x 5 mL). The combined organic layers were dried over anhydrous MgSO4. The solvent was removed using a rotary evaporator. The product was separated using a column using a hexane / EA solvent system.

[0266] 1-15:N-(2-((2-(5-fluoro-1H-indol-3-yl)ethyl)amino)-2-oxoethyl)-3-phenyl-1H-indole-5-carboxamide (K01195)(PS53)

[0267] 3-Phenyl-1H-indole-5-carboxylic acid (30 mg, 0.126 mmol) was dissolved in DMF (1 mL) in a 5 mL vial with a stir bar at room temperature. DCC (39 mg, 0.19 mmol), HOBt (19.4 mg, 0.126 mmol), and DIPEA (16.3 mg, 0.126 mmol) were successively added to the reaction mixture. 2-amino-N-(2-(5-fluoro-1H-indol-3-yl)ethyl)acetamide (32.7 mg, 0.139 mmol) was then added to the reaction mixture. The reaction was then stirred in a microwave at 70 °C for 30 min. After completion, cold water (5 mL) was added and the mixture was extracted three times with EtOAc (3 x 5 mL). The combined organic layers were dried over anhydrous MgSO4 and the solvent was removed using a rotary evaporator. The product was separated using a column using a hexane / EA solvent system (Fig. 15).

[0268] 1-16:N-(2-((2-(5-fluoro-1H-indol-3-yl)ethyl)amino)-2-oxoethyl)-3-(4-methoxyphenyl)-1H-indole-5-carboxamide (K01196)(PS54)

[0269] 3-(4-methoxyphenyl)-1H-indole-5-carboxylic acid (30 mg, 0.112 mmol) was dissolved in DMF (1 mL) in a 5 mL vial with a stir bar at room temperature. DCC (35 mg, 0.168 mmol), HOBt (17 mg, 0.11 mmol), and DIPEA (14.5 mg, 0.11 mmol) were then added successively to the reaction mixture. 2-amino-N-(2-(5-fluoro-1H-indol-3-yl)ethyl)acetamide (28 mg, 0.12 mmol) was then added to the reaction mixture. The reaction was stirred in a microwave at 70 °C for 30 min. After completion, cold water (5 mL) was added and extracted three times with EtOAc (3 x 5 mL). The combined organic layers were dried over anhydrous MgSO4. The solvent was removed under a rotary evaporator. The product was separated using a column with a hexane / EA solvent system (Fig. 16).

[0270] 1-17:N-(2-((2-(5-fluoro-1H-indol-3-yl)ethyl)amino)-2-oxoethyl)-3-(4-fluorophenyl)-1H-indole-5-carboxamide (K01108)(PS55)

[0271] 3-(4-fluorophenyl)-1H-indole-5-carboxylic acid (638.1 mg, 2.5 mmol) was placed in a vial with a stir bar and dissolved in 10 mL of DMF at room temperature. DCC (773.7 mg, 3.75 mmol), HOBt (421.1 mg, 2.75 mmol), and DIPEA (355.4 mg, 2.75 mmol) were added successively to the reaction mixture, followed by 2-amino-N-(2-(5-fluoro-1H-indol-3-yl)ethyl)acetamide (882.2 mg, 3.75 mmol) (Figure 17a). The reaction was then stirred at 70 °C in a microwave for 1 h. After completion, cold water (20 mL) was added and extracted three times with EtOAc (3 × 20 mL). The combined organic layers were dried over anhydrous MgSO4. The solvent was removed using a rotary evaporator. The compound was purified by MPLC (80% EA / Hex) to obtain 537.3 mg (yield 61%) of a white solid (Fig. 17b).

[0272] 1 H NMR (300 MHz, DMSO) δ 11.62 (d, J = 2.6 Hz, 1H), 11.25 - 10.48 (m, 1H), 8.76 (t, J = 5.9 Hz, 1H), 8.46 (d, J = 1.6 Hz, 1H), 8.04 (t, J = 5.8) Hz, 1H), 7.84 - 7.72 (m, 4H), 7.53 (s, 1H), 7.37 - 7.24 (m, 5H), 6.91 (td, J = 9.2, 2.5 Hz, 1H), 3.92 (d, J = 5.8 Hz, 2H), 3.44 - 3.30 (m, 2H), 2.82 (t, J = 7.5 Hz, 2H).

[0273] 1-18:3-(4-chlorophenyl)-N-(2-((2-(5-fluoro-1H-indol-3-yl)ethyl)-amino)-2-oxoethyl)-1H-indole-5-carboxamide (K01198)(PS56)

[0274] 3-(4-chlorophenyl)-1H-indole-5-carboxylic acid (30 mg, 0.11 mmol) was placed in a 5 mL vial with a stir bar and dissolved in DMF (1 mL) at room temperature. DCC (34 mg, 0.165 mmol), HOBt (17 mg, 0.11 mmol), and DIPEA (14 mg, 0.11 mmol) were successively added to the reaction mixture. 2-amino-N-(2-(5-fluoro-1H-indol-3-yl)ethyl)acetamide (28 mg, 0.12 mmol) was then added to the reaction mixture (Figure 18). The reaction was then stirred in a microwave at 70 °C for 30 min. After completion, cold water (5 mL) was added and extracted three times with EtOAc (3 × 5 mL). The combined organic layers were dried over anhydrous MgSO4. The solvent was removed under a rotary evaporator. The product was separated using a column with a hexane / EA solvent system.

[0275] 1-19:N-(2-((2-(5-fluoro-1H-indol-3-yl)ethyl)amino)-2-oxoethyl)-3-(4-(trifluoromethyl)phenyl)-1H-indole-5-carboxamide (K01203)(MS33)

[0276] 3-(4-(trifluoromethyl)phenyl)-1H-indole-5-carboxylic acid (28 mg, 0.09 mmol) was placed in a 0.5 mL vial with a stir bar and dissolved in DMF (1 mL) at room temperature. DCC (28 mg, 0.14 mmol), HOBt (12 mg, 0.09 mmol), and DIPEA (0.02 mL, 0.09 mmol) were added successively to the reaction mixture. Then, 2-amino-N-(2-(5-fluoro-1H-indol-3-yl)ethyl)acetamide (81 mg, 0.34 mmol) was added to the reaction mixture (Figure 19a). The reaction was then stirred in a microwave at 70 °C for 30 min. After completion, cold water (5 mL) was added and extracted three times with EtOAc (3 × 5 mL). The combined organic layers were dried over anhydrous Na2SO4. The solvent was removed using a rotary evaporator. The product was separated using a column with a hexane / EA 80% solvent system, obtaining 10 mg of the product (yield 21%) (Fig. 19b).

[0277] 1 H NMR (300 MHz, DMSO) δ 11.81 (d,J= 2.9 Hz, 1H), 10.52 (s, 1H), 8.79 (dd,J= 9.6, 5.2 Hz, 1H), 8.54 (dd,J= 7.7, 1.6 Hz, 1H), 8.06 - 7.90 (m, 4H), 7.86 - 7.73 (m, 4H), 7.54 (dd,J= 8.6, 3.9 Hz, 1H), 7.37 - 7.29 (m, 1H), 7.29 - 7.23 (m, 1H), 6.86 (dtd,J= 26.5, 9.2, 2.6 Hz, 1H), 3.92 (t,J= 6.3 Hz, 2H), 3.22 (d,J= 11.0 Hz, 2H), 2.85 (dt,J= 34.6, 8.3 Hz, 2H).

[0278] 1-20:N-(2-((2-(5-fluoro-1H-indol-3-yl)ethyl)amino)-2-oxoethyl)-3-(4-(trifluoromethoxy)phenyl)-1H-indole-5-carboxamide (K01120)(MS34)

[0279] Acid (80 mg, 0.25 mmol) was dissolved in DMF (1 mL) in a 0.5 mL - 2 mL MW vial with a stir bar at room temperature. DCC (77.37 mg, 0.375 mmol), HOBt (42 mg, 0.275 mmol), and DIPEA (36 mg, 0.275 mmol) were successively added to the reaction mixture, followed by the addition of 2-amino-N-(2-(5-fluoro-1H-indol-3-yl)ethyl)acetamide (88.22 mg, 0.375 mmol) (Figure 20a). The reaction was then stirred at 70 °C in a microwave for 60 min. After completion, cold water (10 mL) was added and extracted three times with EtOAc (3 x 10 mL). The combined organic layers were dried over anhydrous Na2SO4. The solvent was removed using a rotary evaporator. The product was separated using a column with a hexane / EA solvent system by MPLC. The product was obtained as 120 mg (89% yield) of a white solid (Fig. 20b).

[0280] 1H NMR (300 MHz, DMSO) δ 11.70 (d,J= 2.6 Hz, 1H), 10.92 (s, 1H), 8.75 (t,J= 5.9 Hz, 1H), 8.47 (d,J= 1.6 Hz, 1H), 8.02 (t,J= 5.7 Hz, 1H), 7.89 (d,J= 2.1 Hz, 1H), 7.86 (q,J= 2.3 Hz, 2H), 7.77 (dd,J= 8.6, 1.6 Hz, 1H), 7.52 (d,J= 8.6 Hz, 1H), 7.49 - 7.41 (m, 2H), 7.31 (ddd,J= 10.5, 6.6, 3.6 Hz, 2H), 7.25 (d,J= 2.4 Hz, 1H), 6.90 (td,J= 9.2, 2.6 Hz, 1H), 3.89 (d,J= 5.8 Hz, 2H), 3.38 (s, 2H), 2.80 (t,J= 7.5 Hz, 2H).

[0281] 1-21:3-(3,5-difluorophenyl)-N-(2-((2-(5-fluoro-1H-indol-3-yl)ethyl)amino)-2-oxoethyl)-1H-indole-5-carboxamide (K01116)

[0282] 3-(3,5-difluorophenyl)-1H-indole-5-carboxylic acid (68 mg, 0.25 mmol) was dissolved in DMF (1 mL) in a 0.5-2 mL vial with a stir bar at room temperature. DCC (77 mg, 0.375 mmol), HOBt (42 mg, 0.275 mmol), and DIPEA (36 mg, 0.275 mmol) were added successively to the reaction mixture, followed by 2-amino-N-(2-(5-fluoro-1H-indol-3-yl)ethyl)acetamide (88.22 mg, 0.375 mmol) (Figure 21a). The reaction was then stirred at 70 °C in a microwave for 60 min. After completion, cold water (10 mL) was added, and the mixture was extracted three times with EtOAc (3 × 10 mL). The combined organic layers were dried over anhydrous Na2SO4. The solvent was removed using a rotary evaporator. The product was separated using a column with a hexane / EA solvent system by MPLC. 68 mg (56% yield) of the product was obtained (Fig. 21b).

[0283] 1 H NMR (300 MHz, DMSO) δ 11.82 (d,J= 2.8 Hz, 1H), 10.92 (s, 1H), 8.84 (t,J= 5.9 Hz, 1H), 8.48 (d,J= 1.6 Hz, 1H), 8.04 (t,J= 5.7 Hz, 1H), 8.00 (d,J= 2.5 Hz, 1H), 7.78 (dd,J= 8.6, 1.6 Hz, 1H), 7.56 - 7.47 (m, 3H), 7.36 - 7.27 (m, 2H), 7.26 (d,J= 2.4 Hz, 1H), 7.09 (tt,J=9.5, 2.3 Hz, 1H), 6.90 (td,J= 9.2, 2.6 Hz, 1H), 3.91 (d,J= 5.9 Hz, 2H), 3.38 (d,J= 6.8 Hz, 2H), 2.81 (t,J= 7.5 Hz, 2H).

[0284] 1-22:3-(3,5-dimethoxyphenyl)-N-(2-((2-(5-fluoro-1H-indol-3-yl)ethyl)amino)-2-oxoethyl)-1H-indole-5-carboxamide (K01117)

[0285] 3-(3,5-dimethoxyphenyl)-1H-indole-5-carboxylic acid (70 mg, 0.24 mmol) was dissolved in DMF (1 mL) at room temperature in a 0.5 mL - 2 mL MW vial with a stir bar. DCC (74.3 mg, 0.36 mmol), HOBt (40 mg, 0.264 mmol), and DIPEA (34 mg, 0.264 mmol) were added successively to the reaction mixture, followed by the addition of 2-amino-N-(2-(5-fluoro-1H-indol-3-yl)ethyl)acetamide (84.7 mg, 0.36 mmol) (Figure 22a). The reaction was then stirred at 70 °C in a microwave for 60 min. After completion, cold water (10 mL) was added and the mixture was extracted three times with EtOAc (3 × 10 mL). The combined organic layers were dried over anhydrous Na2SO4. The solvent was removed using a rotary evaporator. The product was separated using a column with a hexane / EA solvent system by MPLC. 75 mg of the product (yield 61%) was obtained (Fig. 22b).

[0286] 1H NMR (300 MHz, DMSO) δ 11.61 (d,J= 2.6 Hz, 1H), 10.92 (s, 1H), 8.73 (t,J= 5.9 Hz, 1H), 8.50 - 8.45 (m, 1H), 8.02 (t,J= 5.8 Hz, 1H), 7.80 (d,J= 2.5 Hz, 1H), 7.74 (dd,J= 8.6, 1.6 Hz, 1H), 7.49 (d,J= 8.5 Hz, 1H), 7.37 - 7.27 (m, 2H), 7.25 (d,J= 2.4 Hz, 1H), 6.96 - 6.89 (m, 1H), 6.88 (s, 2H), 6.44 (t,J= 2.2 Hz, 1H), 3.88 (d,J= 5.7 Hz, 2H), 3.83 (s, 6H), 3.37 (d,J= 7.2 Hz, 2H), 2.80 (t,J= 7.5 Hz, 2H).

[0287] 1-23:3-(4-(dimethylamino)phenyl)-N-(2-((2-(5-fluoro-1H-indol-3-yl)ethyl)amino)-2-oxoethyl)-1H-indole-5-carboxamide (K01119)

[0288] 3-(4-(dimethylamino)phenyl)-1H-indole-5-carboxylic acid (70 mg, 0.25 mmol) was dissolved in DMF (1 mL) at room temperature in a 0.5 mL-2 mL MW vial with a stir bar. DCC (77.37 mg, 0.375 mmol), HOBt (42 mg, 0.275 mmol), and DIPEA (36 mg, 0.275 mmol) were added successively to the reaction mixture, followed by 2-amino-N-(2-(5-fluoro-1H-indol-3-yl)ethyl)acetamide (88.22 mg, 0.375 mmol) (Figure 23a). The reaction was then stirred at 70 °C in a microwave for 60 min. After completion, cold water (10 mL) was added and the mixture was extracted three times with EtOAc (3 × 10 mL). The combined organic layers were dried over anhydrous Na2SO4. The solvent was removed using a rotary evaporator. The product was separated using a column with a hexane / EA solvent system by MPLC. 56 mg of the product (45% yield) was obtained (Fig. 23b).

[0289] 1H NMR (300 MHz, DMSO) δ 11.40 (d,J= 2.5 Hz, 1H), 10.92 (s, 1H), 8.68 (t,J= 5.9 Hz, 1H), 8.42 (d,J= 1.6 Hz, 1H), 8.01 (t,J= 5.8 Hz, 1H), 7.96 (s, 1H), 7.71 (dd,J= 8.6, 1.6 Hz, 1H), 7.59 (s, 1H), 7.57 (d,J= 6.9 Hz, 2H), 7.46 (d,J= 8.6 Hz, 1H), 7.36 - 7.27 (m, 2H), 7.25 (d,J= 2.4 Hz, 1H), 6.91 (dd,J= 9.2, 2.4 Hz, 1H), 6.85 (d,J= 8.7 Hz, 2H), 3.88 (d, J = 5.8 Hz, 2H), 3.37 (d,J= 7.5 Hz, 2H), 2.93 (s, 6H), 2.80 (t,J= 7.5 Hz, 2H).

[0290] 1-24:N-(2-((2-(5-fluoro-1H-indol-3-yl)ethyl)amino)-2-oxoethyl)-3-(3-methoxyphenyl)-1H-indole-5-carboxamide (K01144)

[0291] 3-(3-methoxyphenyl)-1H-indole-5-carboxylic acid (70 mg, 0.26 mmol) was dissolved in DMF (1 mL) at room temperature in a 0.5 mL-2 mL MW vial with a stir bar. DCC (80 mg, 0.39 mmol), HOBt (44 mg, 0.29 mmol), and DIPEA (37 mg, 0.29 mmol) were added successively to the reaction mixture, followed by 2-amino-N-(2-(5-fluoro-1H-indol-3-yl)ethyl)acetamide (91 mg, 0.39 mmol) (Figure 24a). The reaction was then stirred at 70 °C in a microwave for 60 min. After completion, cold water (10 mL) was added and extracted three times with EtOAc (3 × 10 mL). The combined organic layers were dried over anhydrous Na2SO4. The solvent was removed using a rotary evaporator. The product was separated using a column with a hexane / EA solvent system by MPLC. 79 mg of the product (yield 63%) was obtained (Fig. 24b).

[0292] 1 H NMR (300 MHz, DMSO) δ 11.62 (d,J= 2.6 Hz, 1H), 10.92 (s, 1H), 8.74 (t,J= 5.9 Hz, 1H), 8.48 (d,J= 1.6 Hz, 1H), 8.02 (t,J= 5.8 Hz, 1H), 7.80 (d,J= 2.4 Hz, 1H), 7.75 (dd,J= 8.6, 1.6 Hz, 1H), 7.50 (d,J= 8.6 Hz, 1H), 7.43 - 7.22 (m, 7H), 6.98 - 6.80 (m, 2H), 3.89 (d,J= 5.8 Hz, 2H), 3.84 (s, 3H), 3.34 (s, 2H), 2.81 (t,J= 7.5 Hz, 2H).

[0293] 1-25:N-(2-((2-(5-fluoro-1H-indol-3-yl)ethyl)amino)-2-oxoethyl)-3-(4-morpholinophenyl)-1H-indole-5-carboxamide (K01145)

[0294] 3-(4-morpholinophenyl)-1H-indole-5-carboxylic acid (81 mg, 0.25 mmol) was dissolved in DMF (1.2 mL) at room temperature in a 0.5 mL - 2 mL MW vial with a stir bar. DCC (78 mg, 0.38 mmol), HOBt (42 mg, 0.28 mmol), and DIPEA (35 mg, 0.28 mmol) were added successively to the reaction mixture, followed by 2-amino-N-(2-(5-fluoro-1H-indol-3-yl)ethyl)acetamide (89 mg, 0.38 mmol) (Figure 25a). The reaction was then stirred at 70 °C in a microwave for 60 min. After completion, cold water (10 mL) was added and the mixture was extracted three times with EtOAc (3 × 10 mL). The combined organic layers were dried over anhydrous Na2SO4. The solvent was removed using a rotary evaporator. The product was separated using a column with a hexane / EA solvent system by MPLC. 65 mg of the product (yield 48.2%) was obtained (Fig. 25b).

[0295] 1H NMR (300 MHz, DMSO) δ 11.46 (d,J= 2.6 Hz, 1H), 10.92 (s, 1H), 8.70 (t,J= 5.9 Hz, 1H), 8.44 (d, J = 1.6 Hz, 1H), 8.01 (t,J= 5.8 Hz, 1H), 7.72 (dd,J= 8.6, 1.6 Hz, 1H), 7.64 (d,J= 2.6 Hz, 2H), 7.61 (s, 1H), 7.47 (d,J= 8.6 Hz, 1H), 7.36 - 7.28 (m, 2H), 7.26 (d,J= 2.4 Hz, 1H), 7.05 (d, J = 8.8 Hz, 2H), 6.90 (td,J= 9.2, 2.5 Hz, 1H), 3.88 (d,J= 5.8 Hz, 2H), 3.77 (dd,J= 6.0, 3.5 Hz, 4H), 3.38 (t,J= 5.4 Hz, 2H), 3.18 - 3.09 (m, 4H), 2.80 (t,J= 7.5 Hz, 2H).

[0296] 1-26:N-(2-((2-(5-fluoro-1H-indol-3-yl)ethyl)amino)-2-oxoethyl)-3-(3-fluorophenyl)-1H-indole-5-carboxamide (K01146)

[0297] 3-(3-fluorophenyl)-1H-indole-5-carboxylic acid (128 mg, 0.5 mmol) was dissolved in DMF (2 mL) at room temperature in a 0.5 mL - 2 mL MW vial with a stir bar. DCC (155 mg, 0.75 mmol), HOBt (84 mg, 0.55 mmol), and DIPEA (71 mg, 0.5 mmol) were added successively to the reaction mixture, followed by 2-amino-N-(2-(5-fluoro-1H-indol-3-yl)ethyl)acetamide (176 mg, 0.75 mmol) (Figure 26a). The reaction was then stirred at 70 °C in a microwave for 60 min. After completion, cold water (10 mL) was added and extracted three times with EtOAc (3 × 10 mL). The combined organic layers were dried over anhydrous Na2SO4. The solvent was removed using a rotary evaporator. The product was separated by MPLC using a column with a hexane / EA solvent system. The product was obtained in an amount of 111 mg, in a yield of 47% (Fig. 26b).

[0298] 1 H NMR (300 MHz, DMSO) δ 11.72 (d,J= 2.6 Hz, 1H), 10.92 (s, 1H), 8.79 (t,J= 5.9 Hz, 1H), 8.49 (d,J= 1.6 Hz, 1H), 8.03 (t,J= 5.7 Hz, 1H), 7.90 (d,J= 2.2 Hz, 1H), 7.77 (dd,J= 8.5, 1.6 Hz, 1H), 7.68 - 7.55 (m, 2H), 7.54 - 7.46 (m, 2H), 7.35 - 7.27 (m, 2H), 7.26 (d,J= 2.3 Hz, 1H), 7.13 - 7.05 (m, 1H), 6.90 (td,J= 9.2, 2.6 Hz, 1H), 3.90 (d,J= 5.8 Hz, 2H), 3.34 (q,J= 6.1 Hz, 2H), 2.81 (t,J= 7.5 Hz, 2H).

[0299] 1-27:N-(2-((2-(5-fluoro-1H-indol-3-yl)ethyl)amino)-2-oxoethyl)-3-(4-(pyrrolidin-1-yl)phenyl)-1H-indole-5-carboxamide (K01165)

[0300] 3-(4-(pyrrolidin-1-yl)phenyl)-1H-indole-5-carboxylic acid (65 mg, 0.212 mmol) was dissolved in DMF (1.2 mL) in a 0.5 mL - 2 mL MW vial with a stir bar at room temperature. DCC (66 mg, 0.32 mmol), HOBt (36 mg, 0.233 mmol), and DIPEA (30 mg, 0.233 mmol) were added sequentially to the reaction mixture, followed by 2-amino-N-(2-(5-fluoro-1H-indol-3-yl)ethyl)acetamide (60 mg, 0.254 mmol) (Figure 27a). The reaction was then stirred at 70 °C in a microwave for 60 min. After completion, cold water (10 mL) was added and the mixture was extracted three times with EtOAc (3 × 10 mL). The combined organic layers were dried over anhydrous Na2SO4. The solvent was removed using a rotary evaporator. The product was separated using a column with a hexane / EA solvent system by MPLC. 65 mg of the product (58% yield) was obtained (Fig. 27b).

[0301] 1H NMR (300 MHz, DMSO) δ 11.38 (d,J= 2.5 Hz, 1H), 10.92 (s, 1H), 8.83 - 8.61 (m, 1H), 8.42 (s, 1H), 8.01 (t,J= 5.5 Hz, 1H), 7.82 - 7.64 (m, 2H), 7.61 - 7.41 (m, 4H), 7.37 - 7.25 (m, 3H), 6.90 (td,J= 9.2, 2.6 Hz, 1H), 6.66 (d,J= 8.4 Hz, 2H), 3.88 (d,J= 4.7 Hz, 2H), 3.38 (d,J= 10.6 Hz, 2H), 3.28 (d,J= 4.3 Hz, 4H), 2.80 (t,J= 7.4 Hz, 2H), 2.07 - 1.88 (m, 4H).

[0302] 1-28:3-(4-fluorophenyl)-N-(2-((2-(5-methoxy-1H-indol-3-yl)ethyl)amino)-2-oxoethyl)-1H-indole 5-carboxamide (K01166)

[0303] 3-(4-fluorophenyl)-1H-indole-5-carboxylic acid (77 mg, 0.30 mmol) was dissolved in DMF (1.2 mL) in a 0.5 mL - 2 mL MW vial with a stir bar at room temperature. DCC (93 mg, 0.45 mmol), HOBt (50 mg, 0.33 mmol), and DIPEA (43 mg, 0.33 mmol) were added successively to the reaction mixture, followed by 2-amino-N-(2-(5-methoxy-1-methyl-1H-indol-3-yl)ethyl)acetamide (117 mg, 0.45 mmol) (Figure 28a). The reaction was then stirred at 70 °C in a microwave for 60 min. After completion, cold water (10 mL) was added and the mixture was extracted three times with EtOAc (3 × 10 mL). The combined organic layers were dried over anhydrous Na2SO4. The solvent was removed using a rotary evaporator. The product was separated using a column with a hexane / EA solvent system by MPLC. 61 mg of the product (yield 41%) was obtained (Fig. 28b).

[0304] 1 H NMR (300 MHz, DMSO) δ 11.61 (d,J= 2.5 Hz, 1H), 8.74 (s, 1H), 8.44 (t,J= 1.0 Hz, 1H), 7.98 (t,J= 5.8 Hz, 1H), 7.87 - 7.71 (m, 4H), 7.51 (d,J= 8.6 Hz, 1H), 7.37 - 7.19 (m, 3H), 7.11 - 7.02 (m, 2H), 6.77 (dd,J= 8.8, 2.4 Hz, 1H), 3.89 (d,J= 5.8 Hz, 2H), 3.76 (s, 3H), 3.64 (s, 3H), 3.32 (s, 2H), 2.79 (t,J= 7.4 Hz, 2H).

[0305] 1-29:N-(2-((2-(5-fluoro-1H-indol-3-yl)ethyl)amino)-2-oxoethyl)-3-(3-morpholinophenyl)-1H-indole-5-carboxamide (K01180)

[0306] 3-(3-morpholinophenyl)-1H-indole-5-carboxylic acid (81 mg, 0.25 mmol) was dissolved in DMF (1.2 mL) in a 0.5 mL - 2 mL MW vial with a stir bar at room temperature. DCC (78 mg, 0.38 mmol), HOBt (42 mg, 0.275 mmol), and DIPEA (35 mg, 0.275 mmol) were added successively to the reaction mixture, followed by 2-amino-N-(2-(5-fluoro-1H-indol-3-yl)ethyl)acetamide (89 mg, 0.38 mmol) (Figure 29a). The reaction was then stirred at 70 °C in a microwave for 60 min. After completion, cold water (10 mL) was added and the mixture was extracted three times with EtOAc (3 × 10 mL). The combined organic layers were dried over anhydrous Na2SO4. The solvent was removed using a rotary evaporator. The product was separated using a column with a hexane / EA solvent system by MPLC. 65 mg of the product (yield 48.2%) was obtained (Fig. 29b).

[0307] 1H NMR (300 MHz, DMSO) δ 11.76 - 11.40 (m, 1H), 10.92 (s, 1H), 8.69 (t,J= 5.9 Hz, 1H), 8.46 (s, 1H), 8.11 - 7.96 (m, 1H), 7.82 - 7.67 (m, 2H), 7.49 (d,J= 8.5 Hz, 1H), 7.28 (dtd,J= 19.1, 7.4, 2.9 Hz, 7H), 6.90 (td,J= 9.3, 2.5 Hz, 2H), 3.88 (d,J= 5.7 Hz, 2H), 3.78 (t,J= 4.5 Hz, 4H), 3.32 (s, 2H), 3.20 (t,J= 4.7 Hz, 4H), 2.81 (t,J= 7.4 Hz, 2H).

[0308] 1-30:3-(4-fluorophenyl)-N-(2-((2-(5-methoxy-1H-indol-3-yl)ethyl)amino)-2-oxoethyl)-1H-indole-5-carboxamide (K01181)

[0309] 3-(4-fluorophenyl)-1H-indole-5-carboxylic acid (64 mg, 0.25 mmol) was dissolved in DMF (1 mL) in a 0.5 mL–2 mL MW vial with a stir bar at room temperature. DCC (77 mg, 0.375 mmol), HOBt (42 mg, 0.275 mmol), and DIPEA (35 mg, 0.275 mmol) were added sequentially to the reaction mixture, followed by 2-amino-N-(2-(5-methoxy-1H-indol-3-yl)ethyl)acetamide (93 mg, 0.375 mmol) (Figure 30a). The reaction mixture was then stirred in a microwave at 70 °C for 60 min. After completion, cold water (10 mL) was added and extracted three times with EtOAc (3 x 10 mL). The combined organic layers were dried over anhydrous Na2SO4. The solvent was removed under a rotary evaporator (Figure 30b).

[0310] 1H NMR (300 MHz, DMSO) δ 11.61 (d,J= 2.5 Hz, 1H), 10.65 (d,J= 2.3 Hz, 1H), 8.73 (t,J= 5.8 Hz, 1H), 8.49 - 8.40 (m, 1H), 8.02 (t,J= 5.7 Hz, 1H), 7.84 - 7.71 (m, 4H), 7.50 (d,J= 8.5 Hz, 1H), 7.35 - 7.24 (m, 2H), 7.22 (d,J= 8.7 Hz, 1H), 7.08 (dd,J= 26.8, 2.4 Hz, 2H), 6.71 (dd,J=8.7, 2.4 Hz, 1H), 3.90 (d,J= 5.8 Hz, 2H), 3.76 (s, 3H), 3.43 - 3.35 (m, 2H), 2.81 (t,J= 7.5 Hz, 2H).

[0311] The names and structures of the 26 compounds manufactured above are shown in Table 1 below.

[0312] Code name: Structural formula: IUPAC designation: PS36 N-(2-((2-(1H-indol-3-yl)ethyl)amino)-2-oxoethyl)-1H-indole-5-carboxamidePS37 N-(2-((2-(1H-indol-3-yl)ethyl)amino)-2-oxoethyl)-3-phenyl-1H-indole-5-carboxamidePS38 N-(2-((2-(1H-indol-3-yl)ethyl)amino)-2-oxoethyl)-3-(4-methoxyphenyl)-1H-indole-5-carboxamidePS39 N-(2-((2-(1H-indol-3-yl)ethyl)amino)-2-oxoethyl)-3-(4-fluorophenyl)-1H-indole-5-carboxamidePS40 N-(2-((2-(1H-indol-3-yl)ethyl)amino)-2-oxoethyl)-3-(4-chlorophenyl)-1H-indole-5-carboxamidePS47 N-(2-((2-(5-chloro-1H-indol-3-yl)ethyl)amino)-2-oxoethyl)-3-phenyl-1H-indole-5-carboxamidePS48 N-(2-((2-(5-chloro-1H-indol-3-yl)ethyl)amino)-2-oxoethyl)-3-(4-methoxyphenyl)-1H-indole-5-carboxamidePS49 N-(2-((2-(5-chloro-1H-indol-3-yl)ethyl)amino)-2-oxoethyl)-3-(4-fluorophenyl)-1H-indole-5-carboxamidePS50 N-(2-((2-(5-chloro-1H-indol-3-yl)ethyl)amino)-2-oxoethyl)-3-(4-chlorophenyl)-1H-indole-5-carboxamidePS52 N-(2-((2-(5-fluoro-1H-indol-3-yl)ethyl)amino)-2-oxoethyl)-1H-indole-5-carboxamidePS53 N-(2-((2-(5-fluoro-1H-indol-3-yl)ethyl)amino)-2-oxoethyl)-3-phenyl-1H-indole-5-carboxamidePS54 N-(2-((2-(5-fluoro-1H-indol-3-yl)ethyl)amino)-2-oxoethyl)-3-(4-methoxyphenyl)-1H-indole-5-carboxamidePS55 N-(2-((2-(5-fluoro-1H-indol-3-yl)ethyl)amino)-2-oxoethyl)-3-(4-fluorophenyl)-1H-indole-5-carboxamidePS56 3-(4-chlorophenyl)-N-(2-((2-(5-fluoro-1H-indol-3-yl)ethyl)-amino)-2-oxoethyl)-1H-indole-5-carboxamideMS33 N-(2-((2-(5-fluoro-1H-indol-3-yl)ethyl)amino)-2-oxoethyl)-3-(4-(trifluoromethyl)phenyl)-1H-indole-5-carboxamideMS34 N-(2-((2-(5-fluoro-1H-indol-3-yl)ethyl)amino)-2-oxoethyl)-3-(4-(trifluoromethoxy)phenyl)-1H-indole-5-carboxamideK0116 3-(3,5-difluorophenyl)-N-(2-((2-(5-fluoro-1H-indol-3-yl)ethyl)amino)-2-oxoethyl)-1H-indole-5-carboxamideK0117 3-(3,5-dimethoxyphenyl)-N-(2-((2-(5-fluoro-1H-indol-3-yl)ethyl)amino)-2-oxoethyl)-1H-indole-5-carboxamideK0119 3-(4-(dimethylamino)phenyl)-N-(2-((2-(5-fluoro-1H-indol-3-yl)ethyl)amino)-2-oxoethyl)-1H-indole-5-carboxamideK01144 N-(2-((2-(5-fluoro-1H-indol-3-yl)ethyl)amino)-2-oxoethyl)-3-(3-methoxyphenyl)-1H-indole-5-carboxamideK01145 N-(2-((2-(5-fluoro-1H-indol-3-yl)ethyl)amino)-2-oxoethyl)-3-(4-morpholinophenyl)-1H-indole-5-carboxamidK01146 N-(2-((2-(5-fluoro-1H-indol-3-yl)ethyl)amino)-2-oxoethyl)-3-(3-fluorophenyl)-1H-indole-5-carboxamideK01165 N-(2-((2-(5-fluoro-1H-indol-3-yl)ethyl)amino)-2-oxoethyl)-3-(4-(pyrrolidin-1-yl)phenyl)-1H-indole-5-carboxamideK01166 3-(4-fluorophenyl)-N-(2-((2-(5-methoxy-1-methyl-1H-indol-3-yl)ethyl)amino)-2-oxoethyl)-1H-indole-5-carboxamideK01180 N-(2-((2-(5-fluoro-1H-indol-3-yl)ethyl)amino)-2-oxoethyl)-3-(3-morpholinophenyl)-1H-indole-5-carboxamideK01181 3-(4-fluorophenyl)-N-(2-((2-(5-methoxy-1H-indol-3-yl)ethyl)amino)-2-oxoethyl)-1H-indole-5-carboxamide

[0313] Example 2: ZW001 to ZW020, a total of 20 new compounds and synthetic methods

[0314] The synthesis of intermediates (ZW019 and ZW020) and new compounds (ZW001 to ZW018) based on them was performed with reference to the previous literature (Wu, J.et al., Adv. Synth. Catal.364(15): 2565-2570, 2020).

[0315] Intermediate Synthesis (1T1S) Step 1 (Method 1)

[0316] 4-Bromophenylhydrazine hydrochloride (5 g, 22.4 mmol, 1.05 equiv) was dissolved in 100 mL of ethanol, and phenylacetaldehyde (2.56 g, 21.3 mmol, 1.0 equiv) was added. The reflux reaction was carried out for 3 h under nitrogen protection, and then poured into water (200 mL). The suspension was extracted with ethyl acetate (50 mL x 3), and the organic layer was combined, concentrated, and then separated by silica gel column chromatography eluted with EA: n-HEX = 1:5 (v / v) (Fig. 31a). The resulting intermediate (1T1S) was 5-bromo-3-phenyl-1H-indoled, and the total production amount (TY) was 6.09 g, the purified amount (PY) was 5.2 g, and the yield was 86%.

[0317] Intermediate Synthesis (1T1S) Step 1 (Method 2)

[0318] The intermediate (1T1S) was synthesized using another procedure for preparing indole derivatives (Gore, S. et al., Org. Lett. 14(17): 4568-4571, 2012). In a typical experiment, 30 g of a mixture of 9 g of L-(+)-tartaric acid and 21 g of DMU (30:70) was heated to 70°C to obtain a clear melt. To this melt was added 20 mmol (4.47 g) of 4-bromophenylhydrazine hydrochloride and 20 mmol (2.4 g = 2.22 mL) of phenylacetaldehyde at 70°C. The reaction was monitored by thin layer chromatography. Upon completion, the reaction mixture was quenched by adding water while still hot. After the reaction mixture was cooled to room temperature, the suspension was extracted with ethyl acetate (50 mLx3), the organic layer was collected, concentrated, and separated by silica gel column chromatography eluted with EA:n-HEX=1:5 (v / v) (Fig. 31b). TY 5.4 g, PY 4.84 g, yield 89%.

[0319] Intermediate Synthesis (1T2S) Step 2

[0320] The intermediate (5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-phenyl-1H-indole, 1T2S) was synthesized using the method described in the literature (Billingsley, K. Let et al., Angewandte Chemie- International Edition, 46(28): 5359-5363, 2007).

[0321] A mixture of 5-bromo-3-phenylindole (0.85 mg, 3.12 mmol), bis(pinacolato)diboron (2.38 mg, 9.37 mmol, 3 eq), KOAc (0.92 mg, 9.37 mmol, 3 eq), Pd(OAc) (14 mg, 0.062 mmol, 0.02 eq), and x-phos (60 mg, 0.125 mmol, 0.04 eq) in 1,4-dioxane was heated to 110 °C with stirring for 1 h (Figure 32a). The crude product was purified by flash column chromatography on silica gel (10% EtOAc / hexanes) to afford the title compound in 67% yield (670 mg) as a white solid (mp 91-92 °C) (Figure 32b).

[0322] Intermediate Synthesis (1T3S) Method 1 (1T3S, ZW019) (2-(3-phenyl-1H-indol-5-yl)isonicotinic acid)

[0323] The intermediate (2-(3-phenyl-1H-indol-5-yl)isonicotinic acid, 1T3S) was synthesized by referring to the method described in the literature (Pu, C. et al., Bioorg. Med. Chem. Lett., 27(17): 4150-4155, 2017). The synthesized intermediate was designated ZW019.

[0324] 5-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-3-phenyl-1H-indole (450 mg, 1.4 mmol) and 2-chloroisonicotinic acid (245 mg, 1.55 mmol) were added to a 1,4-dioxane / H2O mixture (3:2–4 mL) dissolved in a solution of tetrakis(triphenylphosphine)palladium (81 mg, 0.07 mmol) and K2CO3 (414 mg, 4.2 mmol), and the suspension was bubbled with nitrogen for 20 min and heated at 110 °C for 10 h (Fig. 33a). After cooling to room temperature, the pH of the reaction mixture was adjusted to 4.5–5.5 with acetic acid to obtain a heavy yellow solid, which was collected by filtration and dried in vacuo. The above solid was purified by silica gel column chromatography eluted with MC:MeOH=4:1 (v / v) (Fig. 33b). TY 0.440 g, PY 0.206 g, yield 47%.

[0325] Intermediate Synthesis (1T3S) Method 2

[0326] 5-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-3-phenyl-1H-indole (1 g, 3.13 mmol) and 2-bromoisonicotinic acid 202.01 (0.7 g, 1.1 eq) were added to a solution of tetrakis(triphenylphosphine)palladium 1155.59 (0.19 g, 0.05 eq) and K2CO3 138.205 (1.29 g, 3 eq) in a 1,4-dioxane / H2O mixture (6:4–10 mL). The suspension was bubbled with nitrogen for 20 min and then heated at 110°C for 10 h. The reaction process was the same as above. TY 0.983 g, PY 0.482 g, yield 49%.

[0327] Intermediate Synthesis (1T3S) Method 3

[0328] 5-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-3-phenyl-1H-indole (450 mg, 1.4 mmol) and 2-bromoisonicotinic acid 202.01 (313 mg, 1.55 mmol) were added to a solution of tetrakis(triphenylphosphine)palladium 1155.59 (0.19 g, 0.05 eq) and K2CO3 138.205 (1.29 g, 3 eq) in a 1,4-dioxane / H2O mixture (3:2–5 mL). The suspension was bubbled with nitrogen for 20 min and then heated at 110°C for 10 h. The reaction procedure was the same as above. TY 0.440 g, PT 0.220 g, yield 50%.

[0329] Intermediate Synthesis (2T1S) Step 1

[0330] 4-Bromophenylhydrazine hydrochloride (1.27 g, 5.7 mmol, 1.05 equiv) was dissolved in 50 mL of ethanol, and 4-fluorophenylacetaldehyde dimethylacetal (1.0 g, 5.42 mmol, 1.0 equiv) was added (Figure 34a). The reflux reaction was carried out for 3 h under nitrogen protection. After the reaction was completed, the entire mixture was evaporated, and the residue was dissolved in ethyl acetate (50 mL), washed with water and brine, and dried over Na2SO4. After filtration, the filtrate was concentrated, and the red solution was purified by column chromatography EA:n-HEX=8:1-->6:1-->5:1 (v / v) (Figure 34b). The synthesized intermediate (2T1S) was 5-bromo-3-(4-fluorophenyl)-1H-indole, with TY of 1.57 g, PY of 1.485 g, and a yield of 94.2%.

[0331] Intermediate Synthesis (2T2S) Step 2

[0332] The intermediate (5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(4-fluorophenyl)-1H-indole, 2T2S) was synthesized using the method described in the literature (Billingsley, K. Let et al., Angewandte Chemie- International Edition, 46(28): 5359-5363, 2007).

[0333] Specifically, a mixture of 5-bromo-3-(4-fluorophenyl)-1H-indole (1.485 g, 5.1 mmol), bis(pinacolato)diboron (3.9 g, 15.3 mmol, 3 eq), KOAc (1.51 g, 15.3 mmol, 3 eq), Pd(OAc)2 (0.023 g, 0.102 mmol, 0.02 eq), and x-phos (0.098 g, 0.2 mmol, 0.04 eq) was heated to 110 °C in 1,4-dioxane (10 mL) with stirring for 1 h (Figure 35a). The crude product was purified by flash column chromatography on silica gel (10% EtOAc / hexanes) to afford the title compound as a solid in yield (g) (Figure 35b). TY 1.72 g primary product, 0.7576 g secondary product, 4 0.3847 g, PY 1.1423 g yield 66.4%.

[0334] Intermediate synthesis (2T3S) Step 3 (2T3S, ZW020) (2-(3-(4-fluorophenyl)-1H-indol-5-yl)isonicotinic acid)

[0335] To a solution of tetrakis(triphenylphosphine)palladium (0.19 g, 0.05 eq) and K2CO3 (1.29 g, 3 eq) in a 1,4-dioxane / H2O mixture (6:4–10 mL) were added 2T2S (1.06 g, 3.13 mmol) and 2-bromoisonicotinic acid (0.7 g, 1.1 eq) (Fig. 36a). The suspension was bubbled with nitrogen for 20 min and heated at 110°C for 10 h. After cooling to room temperature, the whole was evaporated to dryness and suspended in water (100 mL). The solid was filtered off, and the pH of the filtrate was adjusted to 5–6 with acetic acid to obtain a heavy yellow solid, which was collected by filtration and dried in the air. The crude product (100 mg) was purified by silica gel column chromatography eluted with MC:MeOH = 4:1 (v / v) (Fig. 36b). The resulting intermediate (2T3S) was 2-(3-(4-fluorophenyl)-1H-indol-5-yl)isonicotinic acid, with a total production amount (TY) of 1.04 g, a purified amount (PY) of 1.135 g (crude product), and a yield of 109%. The present inventors designated the intermediate (2T3S) as ZW020.

[0336] Acquisition of new derivatives

[0337] 2-1: ZW001 manufactured (N-(2-(1H-indol-3-yl)ethyl)-2-(3-phenyl-1H-indol-5-yl)isonicotinamide)

[0338] Ingredients 1T3S 0.06 g 0.19 mmole Tryptamine 160.22 1.1 eq 0.21 mmole 0.034 g TBTU 0.072 g DMF 5 mL DIPEA 2 eq 0.049 g, 0.07 mL

[0339] To a solution of 1T3S (0.06 g, 0.19 mmole), tryptamine (0.045 g, 1.1 eq, 0.21 mmole), and TBTU (0.080 g, 1.1 eq) in DMF (5 mL) was added DIPEA (0.12 mL, 3.3 eq) at room temperature, and the mixture was stirred overnight at room temperature (Fig. 37a). Water (50 mL) was added, precipitating a pale yellow solid, which was filtered and vacuum-dried. The solid was purified by silica gel column chromatography eluted with MC:MeOH = 10:1 (v / v) (Fig. 37b). TY 0.086 g, PY 0.053 g, yield 62%.

[0340] 2-2: ZW002 manufactured ((4-(1H-indol-3-yl)piperidin-1-yl)(2-(3-phenyl-1H-indol-5-yl)pyridin-4-yl)methanone)

[0341] Ingredient content1T3S0.06 g 0.19 mmole3-(4-Piperidyl)indole1.1 eq 0.21 mmole 0.042 gTBTU0.072 gDMF3 mLDIPEA2 eq 0.049 g, 0.07 mL

[0342] To a solution of 1T3S (0.06 g, 0.19 mmole), 3-(4-piperidyl)indole (0.042 g, 1.1 eq, 0.21 mmole), and TBTU (0.072 g, 1.1 eq) in DMF (3 mL) was added DIPEA (0.07 mL, 2.0 eq) at room temperature (Fig. 37a). The whole was stirred at room temperature overnight. Water (50 mL) was added to precipitate a solid, which was collected by filtration and dried in vacuo. The solid was purified by silica gel column chromatography eluted with MC:MeOH = 10:1 (v / v) (Fig. 38b). TY 0.0943 g, PY 0.0903 g, yield 95.7%.

[0343] 2-3: manufactured by ZW003 (N-(2-(6-fluoro-1H-indol-3-yl)ethyl)-2-(3-phenyl-1H-indol-5-yl)isonicotinamide)

[0344] Ingredient content1T3S0.06 g 0.19 mmole6-Fluorotryptamine HCl1.1eq 0.21 mmole 0.042 gTBTU0.072 gDMF2 mLDIPEA2eq 0.049 g, 0.07 mL

[0345] To a solution of 1T3S (0.06 g, 0.19 mmole), 6-fluorotryptamine HCl (0.045 g, 1.1 eq, 0.21 mmole), and TBTU (0.080 g, 1.1 eq) in DMF (2 mL) was added DIPEA (0.12 mL, 3.3 eq) at room temperature (Fig. 39a). The mixture was stirred overnight at room temperature. Water (50 mL) was added to precipitate a solid, which was collected by filtration and dried in vacuo. The solid was purified by silica gel column chromatography eluted with MC:MeOH = 10:1 (v / v) (Fig. 39b). TY 0.0901 g, PY 0.064 g, yield 71.0%.

[0346] 2-4: manufactured by ZW004 (N-(2-(6-methoxy-1H-indol-3-yl)ethyl)-2-(3-phenyl-1H-indol-5-yl)isonicotinamide)

[0347] Ingredient content1T3S0.06 g 0.19 mmole6-Methoxytryptamine190.24 1.1 eq 0.21 mmole 0.046 gTBTU0.08 gDMF2 mLDIPEA2 eq 0.049 g, 0.08 mL

[0348] To a solution of 1T3S (0.06 g, 0.19 mmole), 6-methoxytryptamine (0.046 g, 1.1 eq, 0.21 mmole), and TBTU (0.080 g, 1.1 eq) in DMF (2 mL) was added DIPEA (0.08 mL, 2.2 eq) at room temperature (Fig. 40a). The whole was stirred at room temperature overnight. Water (50 mL) was added to precipitate a solid, which was collected by filtration and dried in vacuo. The solid was purified by silica gel column chromatography eluted with MC:MeOH = 10:1 (v / v) (Fig. 40b). TY 0.0924 g, PY 0.0643 g, yield 69.5%.

[0349] 2-5: manufactured by ZW005 (N-(2-(5-methoxy-1H-indol-3-yl)ethyl)-2-(3-phenyl-1H-indol-5-yl)isonicotinamide)

[0350] Ingredient content1T3S0.0437 g 0.139 mmole5-Methoxytryptamine190.24 1.1eq 0.1 5mmole 0.029 gTBTU0.064 gDMF2 mLDIPEA2eq 0.036 g, 0.049 mL

[0351] To a solution of 1T3S (0.0437 g, 0.139 mmole), 5-methoxytryptamine (0.029 g, 1.1 eq, 0.15 mmole), and TBTU (0.064 g, 1.2 eq) in DMF (2 mL) was added DIPEA (0.048 mL, 2 eq) at room temperature (Fig. 41a). The whole was stirred at room temperature overnight. Water (50 mL) was added to precipitate a solid, which was collected by filtration and dried in vacuo. The solid was purified by silica gel column chromatography eluted with MC:MeOH = 10:1 (v / v) (Fig. 41b). TY 0.0924 g, PY 0.0437 g, yield 47.2%.

[0352] 2-6: manufactured by ZW014 (N-(2-(5-fluoro-1H-indol-3-yl)ethyl)-2-(3-phenyl-1H-indol-5-yl)isonicotinamide)

[0353] Ingredient content1T3S0.06 g 0.19 mmole5-Fluorotryptamine1.1 eq 0.21 mmole 0.037 gTBTU0.072 gDMF2 mLDIPEA2 eq 0.049 g, 0.07 mL

[0354] Step 1: Tem 3 (0.06 g, 0.19 mmole), 5-fluorotryptamine (0.037 g, 1.1 eq, 0.21 mmole), and TBTU (0.080 g, 1.1 eq) were dissolved in DMF (2 mL). DIPEA (0.12 mL, 3.3 eq) was added at room temperature (Fig. 42a). The whole was stirred overnight at room temperature. Pour into water (30 mL), and a pale yellow solid was precipitated. It was collected by filtration and dried to yield 0.08 g TY, 0.09 g 88.9%. The solid was purified by silica gel column chromatography eluted with MC:MeOH = 15:1 (v / v) (Fig. 42b). TY 0.090 g, PY 0.0789 g, yield 87.6%.

[0355] 2-7: manufactured by ZW006 (N-(2-(5-chloro-1H-indol-3-yl)ethyl)-2-(3-phenyl-1H-indol-5-yl)isonicotinamide)

[0356] Ingredient content 1T3S0.06g 0.19 mmole5-Chlorotryptamine HClMW 231.12 1.1 eq 0.21 mmole 0.048 gTBTU0.072 gDMF2 mLDIPEA2 eq 0.049 g, 0.07 mL

[0357] To a solution of 1T3S (0.06 g, 0.19 mmole), 5-chlorotryptamine HCl (0.048 g, 1.1 eq 0.21 mmole), and TBTU (0.080 g, 1.1 eq) in DMF (2 mL) was added DIPEA (0.14 mL, 3.3 eq) at room temperature (Figure 43a). The mixture was stirred overnight at room temperature. Pour into water (30 mL), and a pale yellow solid was precipitated, which was filtered and dried. TY 0.093 g. The solid was purified by silica gel column chromatography eluted with MC:MeOH = 15:1 (v / v) (Figure 43b). TY 0.090 g, PY 0.0886 g, yield 98.4%.

[0358] 2-8: manufactured by ZW007 (N-(2-(5-(benzyloxy)-1H-indol-3-yl)ethyl)-2-(3-phenyl-1H-indol-5-yl)isonicotinamide)

[0359] Ingredient content 1T3S0.1257 g 0.4 mmole5-Benzyloxytryptamine HClMW 302.80 1.1eq 0.133 gTBTU1.1 eq 0.1668 gDMF4 mLDIPEA3.3 eq 0.23 mL

[0360] To a solution of 1T3S (0.1257 g, 0.4 mmole), 5-benzyloxytryptamine HCl (0.133 g, 1.1 eq), and TBTU (0.1668 g, 1.1 eq) in DMF (4 mL) was added DIPEA (0.23 mL, 3.3 eq) at room temperature (Fig. 44a). The mixture was stirred overnight at room temperature. Pour into water (30 mL), and a pale yellow solid precipitated, which was filtered and dried. The solid was purified by silica gel column chromatography eluting with MC:MeOH = 15:1 (v / v) (Fig. 44b). TY 0.225 g, PY 0.18 g, yield 80%.

[0361] 2-9: manufactured by ZW008 (N-(2-(5-hydroxy-1H-indol-3-yl)ethyl)-2-(3-phenyl-1H-indol-5-yl)isonicotinamide)

[0362] To a solution of ZW007 (90 mg, 0.16 mmol) in MeOH (30 mL) was added 5% Pd / C (10 mg) (Fig. 45a). The mixture was stirred overnight under a H2 gas atmosphere (balloon). The mixture was filled through Celite, and the filtrate was evaporated. The residue was purified by silica gel column chromatography eluting with MC:MeOH = 15:1 (v / v) (Fig. 45b). TY 76 mg, PY 70 mg, yield 93%.

[0363] 2-10: manufactured by ZW009 (N-(2-(1H-indol-3-yl)ethyl)-2-(3-(4-fluorophenyl)-1H-indol-5-yl)isonicotinamide)

[0364] Ingredient content1T3S0.1257 g 0.4 mmole5-Benzyloxytryptamine HClMW 302.80 1.1 eq 0.133 gTBTU1.1 eq 0.1668 gDMF4 mLDIPEA3.3 eq 0.23 mL

[0365] To a solution of 2T3S (0.063 g, 0.19 mmole), tryptamine HCl (0.041 g, 1.1 eq 0.21 mmole), and TBTU (0.080 g, 1.1 eq) in DMF (2 mL) was added DIPEA (0.14 mL, 3.3 eq) at room temperature (Fig. 46a). The mixture was stirred overnight at room temperature. Pour into water (30 mL) to precipitate a pale yellow solid, which was filtered and dried. The solid was purified by silica gel column chromatography eluted with MC:MeOH = 15:1 (v / v) (Fig. 46b). TY 0.090 g, PY 0.0576 g, yield 64%. 1H-NMR.

[0366] 2-11: ZW010 manufactured ((4-(1H-indol-3-yl)piperidin-1-yl)(2-(3-(4-fluorophenyl)-1H-indol-5-yl)pyridin-4-yl)methanone)

[0367] Ingredient content2T3S0.0332 g 0.1 mmole3-(4-Piperidyl)indole1.1 eq 0.11 mmole 0.021 gTBTU0.036 gDMF3 mLDIPEA2 eq 0.049 g, 0.07 mL

[0368] To a solution of 2T3S (0.0332 g, 0.10 mmole), 3-(4-piperidyl)indole (0.022 g, 1.1 eq, 0.11 mmole), and TBTU (0.036 g, 1.1 eq) in DMF (3 mL) was added DIPEA (0.04 mL, 2.0 eq) at room temperature (Fig. 47). The whole was stirred at room temperature overnight. Water (50 mL) was added to precipitate a solid, which was collected by filtration and dried in vacuo. The solid was purified by silica gel column chromatography eluted with MC:MeOH = 10:1 (v / v). TY 0.0472 g, PY 0.0354 g, yield 75%.

[0369] 2-12: ZW011 manufactured (2-(3-(4-fluorophenyl)-1H-indol-5-yl)-N-(2-(5-methoxy-1H-indol-3-yl)ethyl)isonicotinamide)

[0370] Ingredient content2T3S0.0332 g 0.1 mmole5-MethoxytryptamineMW 190.25 1.5 eq 0.15 mmole 0.029 gTBTU0.064 gDMF2 mLDIPEA2 eq 0.036 g, 0.049 mL

[0371] To a solution of 2T3S (0.0332 g, 0.10 mmole), 5-methoxytryptamine (0.029 g, 1.5 eq, 0.15 mmole), and TBTU (0.064 g, 1.2 eq) in DMF (2 mL) was added DIPEA (0.048 mL, 2 eq) at room temperature (Fig. 48). The whole was stirred at room temperature overnight. Water (50 mL) was added to precipitate a solid, which was collected by filtration and dried in vacuo. The solid was purified by silica gel column chromatography eluted with MC:MeOH = 10:1 (v / v). TY 0.0504 g, PY 0.0238 g, yield 47.2%.

[0372] 2-13: ZW012 manufactured (N-(2-(5-fluoro-1H-indol-3-yl)ethyl)-2-(3-(4-fluorophenyl)-1H-indol-5-yl)isonicotinamide)

[0373] Ingredient content2T3S0.0332 g 0.1 mmole5-fluorotryptamine HCl214.67 1.1 eq 0.11 mmole 0.0236 gTBTU1.1 eq 0.042 gDMF2 mLDIPEA2 eq 0.03 5 mL

[0374] To a solution of 2T3S (0.0332 g, 0.1 mmole), 5-fluorotryptamine HCl (0.0236 g, 1.1 eq, 0.11 mmole), and TBTU (0.042 g, 1.1 eq) in DMF (2 mL) was added DIPEA (0.035 mL, 2 eq) at room temperature. The mixture was stirred overnight at room temperature. The mixture was poured into water (30 mL), and a pale yellow solid precipitated, which was filtered and dried. The solid was purified by silica gel column chromatography eluting with MC:MeOH = 15:1 (v / v) (Fig. 49). TY 0.0492 g, PY 0.0305 g, yield 62%.

[0375] 2-14: ZW013 manufactured (N-(2-(6-fluoro-1H-indol-3-yl)ethyl)-2-(3-(4-fluorophenyl)-1H-indol-5-yl)isonicotinamide)

[0376] Ingredient content2T3S0.0332 g 0.1 mmole5-fluorotryptamine HCl214.67 1.1eq 0.11 mmole 0.0236 gTBTU1.1 eq 0.042 gDMF2 mLDIPEA2 eq 0.035 mL

[0377] To a solution of 2T3S (0.0332 g, 0.1 mmole), 6-fluorotryptamine HCl (0.0236 g, 1.1 eq, 0.11 mmole), and TBTU (0.042 g, 1.1 eq) dissolved in DMF (2 mL) was added DIPEA (0.035 mL, 2 eq) at room temperature (Fig. 50a). The whole mixture was stirred overnight at room temperature. The mixture was poured into water (30 mL), and a pale yellow solid precipitated, which was filtered and dried. The solid was purified by silica gel column chromatography eluted with MC:MeOH = 15:1 (v / v) (Fig. 50b). TY 0.0492 g, PY 0.0295 g, yield 60.0%.

[0378] 2-15: ZW015 manufactured (2-(3-(4-fluorophenyl)-1H-indol-5-yl)-N-(2-(4-methylpiperazin-1-yl)ethyl)isonicotinamide)

[0379] Ingredient content2T3S0.0332 g 0.1 mmole1-(2-aminoethyl)-4-methypyperazine HCl179.69 1.1 eq 0.11 mmole 0.02 gTBTU1.1 eq 0.042 gDMF2 mLDIPEA2 eq 0.035 mL

[0380] To a solution of 2T3S (0.0332 g, 0.1 mmole), 1-(2-aminoethyl)-4-methypyperazine HCl (0.02 g, 1.1 eq, 0.11 mmole), and TBTU (0.042 g, 1.1 eq) in DMF (2 mL) was added DIPEA (0.035 mL, 2 eq) at room temperature (Fig. 51a). The whole was stirred at room temperature overnight. The mixture was poured into water (30 mL), and a pale yellow solid precipitated, which was filtered and dried. The solid was purified by silica gel column chromatography eluted with MC:MeOH = 15:1 (v / v) (Fig. 51b). TY 0.0457 g, PY 0.316 g, yield 69%.

[0381] 2-16: ZW016 manufactured (2-(3-(4-fluorophenyl)-1H-indol-5-yl)-N-(2-morpholinoethyl)isonicotinamide)

[0382] Ingredient content2T3S0.0332 g 0.1 mmole4-(2-aminoethyl)morpholine166.65 1.1 eq 0.11 mmole 0.0183 g 0.992 g / mL at 25°C 0.184 mLTBTU1.1 eq 0.042 gDMF2 mLDIPEA2 eq 0.035 mL

[0383] To a solution of 2T3S (0.0332 g, 0.1 mmole), 4-(2-aminoethyl)morpholine (0.02 g, 1.1 eq, 0.11 mmole), and TBTU (0.042 g, 1.1 eq) in DMF (2 mL) was added DIPEA (0.035 mL, 2 eq) at room temperature (Fig. 52a). The whole was stirred at room temperature overnight. Pour into water (30 mL), and a pale yellow solid precipitated, which was filtered and dried. Pour into water (30 mL), and a pale yellow solid precipitated, which was filtered and dried. The solid was purified by silica gel column chromatography eluted with MC:MeOH = 15:1 (v / v) (Fig. 52b). TY 0.0444 g, PY 295 g, yield 66%.

[0384] 2-17: manufactured by ZW017 (2-(3-(4-fluorophenyl)-1H-indol-5-yl)-N-(2-(pyrrolidin-1-yl)ethyl)isonicotinamide)

[0385] Ingredient content2T3S0.0332 g 0.1 mmole1-(2-aminoethyl)pyrrolidine1.1 eq 0.11 mmole 0.0125 gd 0.901 0.0137 mLTBTU1.1 eq 0.042 gDMF2 mLDIPEA2 eq 0.035 mL

[0386] To a solution of 2T3S (0.0332 g, 0.1 mmole), 1-(2-aminoethyl)pyrrolidine (0.0125 g, 1.1 eq, 0.11 mmole), and TBTU (0.042 g, 1.1 eq) in DMF (2 mL) was added DIPEA (0.035 mL, 2 eq) at room temperature (Fig. 53a). The whole was stirred at room temperature overnight. Pour into water (30 mL), and a pale yellow solid precipitated, which was filtered and dried. The solid was purified by silica gel column chromatography eluted with MC:MeOH = 15:1 (v / v) (Fig. 53b). TY 0.0428 g, PY 0.0216 g, yield 50%.

[0387] 2-18: manufactured by ZW018 (2-(3-(4-fluorophenyl)-1H-indol-5-yl)-N-(2-(indolin-1-yl)ethyl)isonicotinamide)

[0388] Ingredient content2T3S0.0332 g 0.1 mmole2-(indolin-1-yl)ethan-1-amine HClMW 162.24 1.1 eq 0.11 mmole 0.018 gTBTU1.1 eq 0.042 gAN5 mLDIPEA3 eq 0.053 mL

[0389] To a solution of 2T3S (0.0332 g 0.1 mmole), 2-(indolin-1-yl)ethan-1-amine HCl (0.018 g, 1.1 eq, 0.11 mmole), and TBTU (0.042 g, 1.1 eq) dissolved in AN (5 mL) was added DIPEA (0.053 mL, 3 eq) at room temperature (Figure 54a). The whole was stirred at room temperature overnight. The reaction mixture was evaporated, and the residue was purified by silica gel column chromatography eluted with MC:MeOH = 6:1 (v / v) (Figure 54b). TY 0.0477 g, PY 0.0280 g, yield 59%. Information on the compounds prepared above is summarized in Table 19 below.

[0390] 코드명구조식IUPAC 명칭ZW001 N-(2-(1H-indol-3-yl)ethyl)-2-(3-phenyl-1H-indol-5-yl)isonicotinamideZW002 (4-(1H-indol-3-yl)piperidin-1-yl)(2-(3-phenyl-1H-indol-5-yl)pyridin-4-yl)methanoneZW003 N-(2-(6-fluoro-1H-indol-3-yl)ethyl)-2-(3-phenyl-1H-indol-5-yl)isonicotinamideZW004 N-(2-(6-methoxy-1H-indol-3-yl)ethyl)-2-(3-phenyl-1H-indol-5-yl)isonicotinamideZW005 N-(2-(5-methoxy-1H-indol-3-yl)ethyl)-2-(3-phenyl-1H-indol-5-yl)isonicotinamideZW014 N-(2-(5-fluoro-1H-indol-3-yl)ethyl)-2-(3-phenyl-1H-indol-5-yl)isonicotinamideZW006 N-(2-(5-chloro-1H-indol-3-yl)ethyl)-2-(3-phenyl-1H-indol-5-yl)isonicotinamideZW007 N-(2-(5-(benzyloxy)-1H-indol-3-yl)ethyl)-2-(3-phenyl-1H-indol-5-yl)isonicotinamideZW008 N-(2-(5-hydroxy-1H-indol-3-yl)ethyl)-2-(3-phenyl-1H-indol-5-yl)isonicotinamideZW009 N-(2-(1H-indol-3-yl)ethyl)-2-(3-(4-fluorophenyl)-1H-indol-5-yl)isonicotinamideZW010 (4-(1H-indol-3-yl)piperidin-1-yl)(2-(3-(4-fluorophenyl)-1H-indol-5-yl)pyridin-4-yl)methanoneZW011 2-(3-(4-fluorophenyl)-1H-indol-5-yl)-N-(2-(5-methoxy-1H-indol-3-yl)ethyl)isonicotinamideZW012 N-(2-(5-fluoro-1H-indol-3-yl)ethyl)-2-(3-(4-fluorophenyl)-1H-indol-5-yl)isonicotinamideZW013 N-(2-(6-fluoro-1H-indol-3-yl)ethyl)-2-(3-(4-fluorophenyl)-1H-indol-5-yl)isonicotinamideZW015 2-(3-(4-fluorophenyl)-1H-indol-5-yl)-N-(2-(4-methylpiperazin-1-yl)ethyl)isonicotinamideZW016 2-(3-(4-fluorophenyl)-1H-indol-5-yl)-N-(2-morpholinoethyl)isonicotinamideZW017 2-(3-(4-fluorophenyl)-1H-indol-5-yl)-N-(2-(pyrrolidin-1-yl)ethyl)isonicotinamideZW018 2-(3-(4-fluorophenyl)-1H-indol-5-yl)-N-(2-(indolin-1-yl)ethyl)isonicotinamideZW019 2-(3-phenyl-1H-indol-5-yl)isonicotinic acidZW020 2-(3-(4-fluorophenyl)-1H-indol-5-yl)isonicotinic acid

[0391] Since the codes of the compounds synthesized in the above Examples 1 and 2 are notated in various ways, they are unified as shown in Table 20 below.

[0392] Existing codeNew codeExisting codeNew code

[0393] Experimental Example 1: Evaluation of MMP-9 Inhibitory Activity

[0394] The MMP-9 inhibitory activity was evaluated using a novel compound manufactured according to one embodiment of the present invention. In order to observe the activity of the proform MMP-9, proMMP-9 was reacted with active MMP-3 that can activate it. At this time, in order to screen the activity inhibitory effect of the existing drug group, proMMP-9 (20 nM) and the test compound (10 μM) were pre-reacted at 37°C for 30 minutes, and then active MMP-3 (10 nM) was added and reacted at 37°C for 1 hour. Next, 390 MMP FRET substrate (10 μM) was added, dispensed into a 384-well plate, and reacted at 37°C for 30 minutes. MMP-9 activity was measured by measuring the fluorescence of the substrate at a wavelength of Ex / Em: 325 / 393 nM in a fluorometer, and normalized using the MMP-9 activity value without the compound added.

[0395] As a result, most of the novel compounds of the present invention exhibited excellent inhibitory activity (see Table 20). The results of the MMP-9 inhibitory effect analysis are summarized in Table 21 and Figure 55 below.

[0396] Compound MMP-9 activity (%) at 10 μM STD Compound MMP-9 activity (%) at 10 μM STD ZC200067111.0821.59 ZC20009367.0011.77 ZC20006840.234.27 ZC20009560.6022.20 ZC20006989.100.90 ZC20009643.6818.84 ZC20007027.243.04 ZC20009764.0039.14 ZC20007181.1920.74 ZC20009853.4228.49 ZC20007498.4736.06 Z C20009971.1926.08ZC20007531.161.82ZC20010020.972.11ZC20007646.747.38ZC20010116.242.89ZC20007795.5354.6 1ZC20010290.0458.61ZC20007887.230.96ZC20010379.7967.72ZC20007980.3322,35ZC20010427.942.78ZC20008032.963 .57ZC20010512.108.47ZC20008146.6414.90ZC20010617.419.65ZC20008262.8838.46ZC20010796.2920.27ZC20008360. 6343.87ZC20010817.296.88ZC20008481.0846.01ZC20010912.486.09ZC20008626.0311.65ZC20011020.077.40ZC2000873 5.2844.70ZC20011189.5842.18ZC20008838.1247.99ZC20011243.8910.68ZC20008989.7258.73ZC20011347.3829.99ZC20 009048.0034.28ZC20011499.131.24ZC20009188.5728.73ZC200115101.8414.92ZC20009264.9834.52ZC20011696.984.36

[0397] Experimental Example 2: Evaluation of Zinc Toxicity and Autotoxicity

[0398] The present inventors analyzed the zinc toxicity inhibition activity of 11 candidate compounds (ZC200071, ZC200076, ZC200081, ZC20082, ZC200086, ZC200087, ZC200095, ZC200097, ZC200098, ZC200100, and ZC200101) with high MMP-9 inhibition activity based on the results of the MMP-9 inhibition activity analysis of Experimental Example 1 above.

[0399] Specifically, the brain cortex was obtained from a 15-day mouse embryo, disrupted, suspended in a growth medium, and seeded on a Poly-D-lysine-coated plate at a ratio of 8 hemispheres per plate. Cell culture was performed in a 37°C, 5% CO2 incubator, and used for zinc toxicity analysis from the 10th day of culture.

[0400] Zinc toxicity was induced by the following process:

[0401] The culture medium was first exchanged for minimal essential medium (MEM), and the cells were pretreated with the candidate drug at a final concentration of 20 μM for 30 minutes. The medium was then exchanged for a zinc aqueous solution (ZnCl 2,400 μM, NaCl 2,1.8 mM, glucose 1.94 mM, MgCl 2,3.15 mM, Hanks' Balanced Salt solution (HBSS)) and stimulated for 12 minutes. Subsequently, a posttreatment was performed with MEM medium containing the candidate drug at a concentration of 20 μM.

[0402] After 15 hours of post-treatment, cell death was analyzed using LDH (lactate dehydrogenase) release assay.

[0403] As a result, as confirmed in Figures 56a and 56b, it was confirmed that the compounds according to one embodiment of the present invention effectively suppress zinc toxicity.

[0404] Meanwhile, for the autotoxicity analysis, the stimulation process with a zinc aqueous solution for 12 minutes was omitted, and only the candidate drug was pretreated and posttreated, and the degree of cell death was analyzed (Fig. 57).

[0405] As a result of the autotoxicity analysis, the compounds according to one embodiment of the present invention were found to exhibit almost no cytotoxicity at a concentration of 20 μM.

[0406] Experimental Example 3: Evaluation of Hydrogen Peroxide-Induced Toxicity

[0407] The mouse brain neurons obtained in Experimental Example 2 above were also used in this analysis.

[0408] Specifically, mouse brain neurons were cultured in MEM in which the concentration of each test compound was adjusted to 20 μM, and then pretreated for 30 minutes. Subsequently, 150 μM of an aqueous H2O2 solution was treated, and after 15 hours, the degree of cell death was examined using an LDH assay in the same manner as in Experimental Example 2.

[0409] As a result, as shown in Figure 58, most of the compounds according to one embodiment of the present invention significantly suppressed H2O2 toxicity.

[0410] Experimental Example 4: Glutamate Toxicity Evaluation

[0411] Excessive glutamate exposure also causes cytotoxicity. Therefore, the inventors of the present invention sought to determine whether compounds according to one embodiment of the present invention could effectively suppress glutamate-induced toxicity.

[0412] Specifically, mouse brain neurons were cultured in MEM adjusted to a concentration of 20 μM for each test compound, and then pretreated for 30 minutes. Subsequently, 150 μM glutamate solution was treated, and after 15 hours, the degree of cell death was examined using LDH analysis in the same manner as in Experimental Example 2.

[0413] As a result, as shown in Figure 59, most of the compounds according to one embodiment of the present invention significantly suppressed glutamate toxicity.

[0414] Experimental Example 5: Neuroinflammation Analysis

[0415] Based on the results of Experimental Examples 1 to 4, the present inventors attempted to investigate whether compounds according to one embodiment of the present invention can suppress neuroinflammation in neural tissue by analyzing the expression level of IL-1β, a representative neuroinflammatory cytokine.

[0416] Specifically, the inventors of the present invention performed a two-step culture in which neurons were seeded in astrocyte-glial cell culture, and then prepared compounds of one embodiment of the present invention by dissolving them in MEM at a concentration of 20 μM, and then replaced the culture medium with the thus prepared MEM and performed an additional culture for 30 minutes.

[0417] Next, 10 μg / ml of LPS (lipopolysaccharide) was treated for 24 hours. Then, the culture medium was recovered and centrifuged at 1,500 xg for 5 minutes to obtain only the supernatant. After mixing 4 times the volume of acetone of the obtained supernatant and shaking well, the cells were incubated overnight at -20℃. The cells (pellet) were lysed with RIPA lysis buffer, and the obtained cell lysate was left on ice for 30 minutes and centrifuged at 10,000 rpm at 4℃ for 5 minutes to obtain the supernatant. The cell lysate supernatant was well quantified to have the same protein amount, and then sample buffer was added and heated at 95℃ for 5 minutes to obtain a cell lysate sample. The medium-acetone mixture was centrifuged at 3,000 rpm for 20 minutes, the supernatant was removed, and the precipitate was dried at room temperature for 30 minutes. The precipitate was dissolved in 1x sample buffer and heated at 95°C for 5 minutes to obtain a medium sample. The cell lysate and medium samples thus obtained were loaded onto a polyacrylamide gel, electrophoresed, and then transferred to a nylon membrane. Western blot analysis was performed using anti-IL-1βB antibodies and anti-proIL-1β antibodies.

[0418] As a result, as confirmed in FIG. 60, the compounds according to one embodiment of the present invention were found to not only suppress the expression of IL-1β within the cytoplasm, but also reduce the secretion amount of proIL-1B and mature IL-1B secreted extracellularly. Among them, the effects of ZC200071, ZC200081, ZC200086, ZC200095, and ZC200100 and ZC200101 were prominent, and the effects of ZC200081 and ZC20001 were particularly prominent.

[0419] Experimental Example 6: Analysis of the in vivo effects of stroke

[0420] Based on the above in vitro analysis results, the inventors of the present invention selected ZC200081 as a representative compound to investigate whether the compound according to one embodiment of the present invention can be effective in treating brain nerve diseases under actual in vivo conditions, and verified its therapeutic effect on a stroke model animal, a representative brain nerve disease.

[0421] 6-1: Preparation of stroke model animal (MCAO)

[0422] The MCAO (middle cerebral artery occulsion) model was used as a brain tumor model animal, and the specific manufacturing process is as follows (Figure 61a):

[0423] 8-9 week-old male Sprague-Dawley (SD) rats (290-320 g) were anesthetized with an intramuscular injection of atropine (0.05 mg / kg) and zoretil 50 (50 mg / kg). The hair on the lower right neck was disinfected with ethanol and shaved to remove any hair. Then, the endothelium was incised using a cotton swab, and the common carotid artery (CCA) and internal carotid artery (ICA) were located and tightly tied with suture (B-Brown, C0266841). In addition, the external carotid artery (ECA) was located and tied with suture, tightly (A) at the distal end and loosely (B) at the proximal end. Then, the blood vessel between the CCA and ECA was punctured using spring scissors or an 18G syringe needle. Next, a filament suture for MCAO was inserted into the s-shaped perforation, a loosely tied suture (B) was passed through it, and then the suture (B) was tied tightly. The suture (A) was loosened, a nylon suture was passed through the suture (A) to occlude the middle cerebral artery, and the suture (A) was tied tightly again to finish. Next, the filament suture was inserted up to 2 cm, and the incision site was sutured.

[0424] Effective drugs were injected intravenously or subcutaneously 30 minutes, 1 hour, or 3 hours after middle cerebral artery occlusion. The surgical animals were then allowed to recover under an infrared warming lamp while maintaining body temperature.

[0425] Anesthesia was achieved by intramuscular injection of Zoretyl 50 (10 mg / kg) 4 to 18 hours after surgery, and blood samples were collected.

[0426] After this, the animals were allowed to recover by maintaining their body temperature under an infrared heating lamp.

[0427] 6-2: Analysis of infarct volume using brain TTC staining

[0428] The present inventors administered a carrier (control group) or a compound (ZC200081) according to an embodiment of the present invention subcutaneously (sc) at a concentration of 5, 15, or 25 mg / kg 1 hour after MCAO treatment to MCAO model rats prepared in Experimental Example 6-1, collected blood from the experimental animals 18 to 24 hours after drug administration, performed a behavioral analysis, and sacrificed the animals after the behavioral analysis to examine the degree of cerebral infarction (Fig. 61b).

[0429] In addition, in order to confirm whether the compound according to one embodiment of the present invention exhibits efficacy even after a longer period of time has elapsed since the occurrence of infarction, the inventors subcutaneously injected the carrier (control group) or the compound according to one embodiment of the present invention (ZC200081) at a concentration of 15 mg / kg 3 hours after the MCAO procedure, collected blood from the experimental animals, performed a behavioral analysis, and sacrificed the animals after the behavioral analysis to examine the degree of cerebral infarction (Fig. 61c).

[0430] Specifically, the degree of cerebral infarction was assessed through the following process:

[0431] After the brains were removed from the sacrificed experimental animals, the removed brains were washed with cold phosphate-buffered saline (PBS) and coronally sectioned into 6-8 2-mm-thick sections. The brain sections were then darkened in a 2% 2,3,5-triphenyl tetrazolium chloride (TTC) solution for 15 minutes, washed with PBS (Longa, EZ et al., Stroke, 20: 81-91, 1989), aligned on a scanner, and the TTC staining images were scanned. The infarct volume was quantified using image analysis software (Image J). The direct infarct volume was calculated by adding up the infarct volumes measured in each section along the sagittal plane (AP axis). Brain edema was assessed by calculating the difference in volume between the normal hemisphere and the lesioned hemisphere. To correct for the possibility that edema may affect the infarct volume measurement, infarct volume was normalized to the volume of the normal hemisphere and expressed as indirect infarct volume.

[0432] As a result, as confirmed in FIG. 61d, the compound according to one embodiment of the present invention significantly reduced the area of ​​indirect and periarterial infarction sites in a concentration-dependent manner up to a concentration of 15 mg / kg, and no significant effect was observed compared to the carrier at a dose of 25 mg / kg. This is expected to be because the compound according to one embodiment of the present invention exhibited cytotoxicity at high concentrations. Meanwhile, as a result of measuring the edema area, as shown in FIG. 61e, although there was no significance, a tendency for the edema area to decrease was observed when the compound according to one embodiment of the present invention was administered.

[0433] Meanwhile, even when the compound according to one embodiment of the present invention was administered at a dose of 15 mg / kg 3 hours after MCAO treatment, the infarct area volume was significantly reduced, as confirmed in FIGS. 61f and 61g, and the change in the edema area was not significant, as confirmed in FIG. 61h.

[0434] 6-3: Behavioral Analysis

[0435] When middle cerebral artery occlusion (MCAO) is performed, experimental animals exhibit behavioral symptoms due to brain damage. We investigated whether a compound according to one embodiment of the present invention could improve the severity of these behavioral impairments.

[0436] Finally, the present inventors measured the degree of neurological damage after MCAO using the modified Neurological Severity Score (mNSS). The mNSS is a comprehensive neurobehavioral test that includes motor function, sensory function, reflexes, and balance, with higher scores indicating more severe neurological damage.

[0437] Behavioral assessments were conducted before surgery (baseline) and on the first day after MCAO. The assessments were conducted under blinded conditions to compare differences between groups randomly assigned to the experiment. The assessment items and criteria were as follows (Longa, EZ et al., Stroke, 20: 81-91, 1989; Chen, J. et al., Stroke 32(11): 2682-2688, 2001):

[0438] - Motor tests (0-6 points): abnormal forefoot flexion, rotation, walking abnormalities, etc.

[0439] - Sensory tests (0-2 points): tactile response, visual response

[0440] - Reflexes (0-4 points): auricular reflex, corneal reflex, etc.

[0441] - Balance (beam and balance tests) (0-6 points): Maintaining posture on a beam, etc.

[0442] The total score ranges from 0 (normal) to 18 (maximum deficit), and the scores are summed by awarding 1 point for each item that was not performed.

[0443] As a result, as shown in FIG. 61i, the compound according to one embodiment of the present invention succeeded in lowering the mNSS index to less than half compared to the control group at a dosage of 5 mg / kg when administered 1 hour after the onset of infarction, and the 15 mg / kg administration group also showed a lowering of the mNSS index compared to the control group, although it was not significant. In addition, as shown in FIG. 61j, it was confirmed that the mNSS index was significantly lower in the group administered the compound according to one embodiment of the present invention compared to the control group when administered 15 mg / kg 3 hours after the onset of infarction. This is a very encouraging result in that it was confirmed in the MCAO model, which typically causes more severe damage, and considering that the golden time for stroke is typically 4.5 hours, it suggests that the symptoms of stroke patients can be improved by administering the compound according to one embodiment of the present invention even after the golden time has elapsed.

[0444] Experimental Example 7: Analysis of the therapeutic effect on multiple sclerosis

[0445] 7-1: Preparation of EAE animal model and evaluation of clinical symptoms

[0446] The present inventors induced experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis, by subcutaneously injecting Myelin oligodendrocyte glycoprotein 35-55 (MOG35-55, hereinafter referred to as "MOG") peptide antigen into C57BL / 6 female mice (Fig. 62a). To this end, MOG35-55 (Ana spec, USA) and Complete Freund's adjuvant (CFA) were first prepared. MOG35-55 (2 mg / ml) was dissolved in phosphate-buffered saline (1x PBS, Sigma), and 25 ml of the CFA was added to a 50 ml conical tube with Incomplete Freund's adjuvant (IFA, Sigma). Next, an ampoule of Mycobacterium tuberculosis H37Ra (100 mg; Difco, USA) was carefully broken in the hood, added, vortexed, and stored in the refrigerator. Then, equal amounts of MOG and CFA containing Mycobacterium tuberculosis H37Ra were mixed and injected into both flanks of the mice. In addition, 4 μg / ml of pertussis toxin (List Biological Laboratories, USA) was injected intraperitoneally on the day of immunization and on day 2 after immunization. After the immunization, the body weight and clinical symptoms of the mice were measured daily, and the progression of EAE was evaluated based on specific clinical symptoms. Details are described below.

[0447] 7-2: EAE clinical score evaluation

[0448] The clinical symptom evaluation of EAE used in the present invention was evaluated based on a previous study (Jones et al., J. Neuroimmunol. 199(1-2):83-93. 2008). Specifically, to evaluate the clinical symptoms of EAE, the clinical score was evaluated daily according to the following criteria.

[0449] score 0, no symptoms;

[0450] score 0.5, partial paralysis of the tail or slightly abnormal gait;

[0451] score 1.0, complete or partial tail paralysis and mild hind limb weakness;

[0452] score 1.5, complete tail paralysis and mild hind limb weakness;

[0453] score 2.0, tail paralysis and moderate hind limb weakness (as evidenced by frequent paw drop while walking in the cage);

[0454] score 2.5, no weight in the hind legs but some movement;

[0455] score 3.0, complete hind limb paralysis;

[0456] score 3.5, hind limb paralysis and mild weakness in the forelimbs;

[0457] score 4.0, complete paralysis of the limbs but head movement;

[0458] score 4.5, moribund;

[0459] score 5.0, death

[0460] As described in Experimental Example 7-1 above, the animal test was conducted by inducing disease by injecting pertussis toxin together with MOG, and administering ZC200081 subcutaneously (sc) at a dose of 300 μg / kg once daily for the entire test period (60 days).

[0461] As a result, as shown in Fig. 62b, when the clinical score was measured through a behavioral test that evaluates mobility based on the movement of the animal's hind limbs, the drug (ZC200081) administration group showed a clear difference in mobility compared to the vehicle administration group (average maximum clinical score of 3.2) with an average clinical score of 1.7 or less during the entire test period.

[0462] 7-3: Incidence Rate Analysis

[0463] Within the test animal group, the incidence rate was calculated by reflecting an individual's clinical score of 0.5 (confirmed onset) as an onset. As a result, as confirmed in Figure 62c, in the vehicle-administered group, half of the animals developed the disease (clinical score > 0.5) on the 9th day of disease induction, showing an incidence rate of 50%. All animals developed the disease on the 10th day, which was maintained until the end of the test. On the other hand, in the drug-administered group, after one animal developed the disease on the 9th day, the incidence rate gradually increased, and by the 17th day, 9 out of 10 animals reached a clinical score of 0.5 or higher at least once, reaching an incidence rate of 90%, and this maximum incidence rate was maintained until the end of the test. In other words, by the 17th day, 9 out of 10 animals were in an onset state at least once during the entire test period, and 1 animal did not develop the disease during the entire test period.

[0464] In summary, the drug (ZC200081) administration group showed a 10% lower incidence of multiple sclerosis in the EAE model compared to the vehicle administration group, and the time to reach 50% incidence or maximum incidence was delayed by one week. In addition, the maximum average clinical score of individuals who developed the disease in the drug administration group was approximately 17, which was approximately half of the maximum clinical score of 32 in the vehicle administration group. In other words, although ZC200081 administration did not significantly affect the incidence of the disease, it was confirmed to delay the onset of the disease and show a significant difference in the severity of the disease.

[0465] 7-4: Behavioral Analysis

[0466] Multiple sclerosis causes a decline in motor ability. In order to confirm whether the compound according to one embodiment of the present invention can improve this decline in motor ability, on the 40th day of the animal experiment described in Experimental Example 7-2, the behavior of the test animal group was recorded as a video for 30 seconds, and the first 5 seconds of the recording were captured at 1-second intervals. As a result, as shown in Fig. 62d, the ZC200081-administered group showed active movement comparable to that of normal mice, but the vehicle-administered group showed a state of staying in one place, dragging its hind legs and barely moving.

[0467] In particular, when looking at the captured photo at the 5-second point, it was confirmed that the vehicle-administered group was unable to lift its hind legs, had poor mobility, and was huddled together in one place, whereas the ZC200081 300 μg / kg-administered group was able to move its hind legs freely, just like normal mice.

[0468] 7-5: Analysis of the inhibitory effect of MMP-9 activity in vivo

[0469] MMP-9, the target molecule of the compound according to one embodiment of the present invention, has long been reported to be associated with multiple sclerosis, and plasma MMP-9 levels have been reported to be useful as a biomarker for multiple sclerosis (Fainardi, E. et al., Mult. Scler. 12(3): 294-301, 2006). Therefore, gelatin zymography was performed to assess MMP-9 activity in plasma obtained from EAE test animals. Gelatin zymography was performed as follows:

[0470] Blood was obtained through venous blood collection from experimental animals administered vehicle and ZC200081 (300 μg / kg, SC) groups, centrifuged at 4°C and 1,000 xg for 20 minutes, and the supernatant (plasma) was obtained and stored at -80°C. The plasma was diluted 10-fold with MMP-9 reaction buffer ((Tris-HCl, pH 7.5, 50 mM, NaCl 150 mM, CaCl 25 mM, ZnCl 220 μM), and protein was quantified to adjust the sample concentration to 3 μg / ml. Subsequently, non-reducing 5x loading buffer was added to complete sample preparation.

[0471] Next, electrophoresis and gel staining were performed as follows:

[0472] Samples were loaded onto a 7.5% acrylamide gel containing 8 mg / ml gelatin and subjected to electrophoresis (120-150 V, 90-120 min). After electrophoresis, the gel was washed twice with washing buffer (2.5% Triton X-100, 50 mM Tris-HCl, 5 mM CaCl2, 1 μM ZnCl2) for 30 min each, and the reaction buffer (incubation buffer, 1% Triton X-100 50 mM Tris-HCl, 5 mM CaCl2, 1 μM ZnCl2) was added and the reaction was performed for 5-10 min at 37°C. After replacing with fresh reaction buffer, the reaction was performed for an additional 24-48 h at 37°C. The gel was immersed in a dye solution (40% MeOH, 10% acetic acid, 0.1% Comassie Brilliant Blue) and stirred for 30–60 minutes to stain. After washing with distilled water, the gel was stirred in a decolorizing solution (40% MeOH, 10% acetic acid) until the gel bands were clearly visible, removing the dye. After that, the gel was photographed.

[0473] As a result, as confirmed in Figures 62e and 62f, although there were individual differences among test animals, a significant decrease in MMP-9 activity was confirmed in the ZC200081 300 μg / kg administration group compared to the vehicle administration group.

[0474] Furthermore, the inventors performed immunofluorescence staining using an anti-MMP-9 antibody to determine the level of MMP-9 expression in spinal cord tissue. As shown in Figure 62g, MMP-9 expression was significantly reduced in the ZC200081-administered group compared to the vehicle-administered group.

[0475] This suggests that the compound according to one embodiment of the present invention is a substance that can not only inhibit the activity of MMP-9 under in vitro conditions but also inhibit the expression of MMP-9 under in vivo conditions.

[0476] 7-6: Analysis of blood-brain barrier (BBB) ​​protective effects

[0477] The spinal cord, as part of the central nervous system (CNS), is protected by the blood-brain barrier (BBB). Increased MMP-9 activity in the blood is known to degrade tight junction proteins, a component of the BBB, leading to BBB breakdown and the subsequent infiltration of immune cells, which accelerates nerve cell damage. IgG is an antibody produced by plasma B cells and is present in the blood. Therefore, staining spinal cord tissue with IgG is a representative test method for detecting BBB breakdown and inflammation.

[0478] To verify the BBB breakdown inhibitory effect of a compound according to one embodiment of the present invention, the inventors performed histological analysis of IgG secretion using the spinal cord of sham or EAE mice 60 days after MOG injection. Coronal sections of the spinal cord measuring 30 μm were immunostained with biotinylated horse anti-mouse IgG. In animals not induced with EAE, IgG staining due to BBB damage was not found in the white or gray matter. However, in animals injected with MOG 60 days ago, IgG infiltration was significantly increased in both the white and gray matter, and it was confirmed that this phenomenon was significantly reduced by administration of ZC200081.

[0479] In addition, when BBB damage occurs, infiltration of monocytes into the central nervous system occurs. Therefore, in order to confirm whether the compound according to one embodiment of the present invention can inhibit infiltration of monocytes into the central nervous system caused by BBB damage, cresyl violet staining was performed on spinal cord tissue sections of experimental animals obtained from test animals after completing a 60-day EAE animal test. Cresyl violet staining was performed according to the method described in the literature (Wang et al., Behav. Brain Res., 265: 171-180, 2014). As a result, as shown in Figures 62i and 62j, it was confirmed that monocyte infiltration in the ZC200081-administered group was reduced to the level of the Sham group that did not induce EAE.

[0480] The above-described results are all results that prove that the compound according to one embodiment of the present invention not only inhibits the in vivo activity and expression of MMP-9, but also very effectively inhibits the breakdown of the blood-brain barrier that may occur due to the action of MMP-9.

[0481] This invention was made possible with the support of the National New Drug Development Project of the National Drug Development Fund of the Republic of Korea with funds from the Ministry of Science and ICT, the Ministry of Trade, Industry and Energy, and the Ministry of Health and Welfare (Project No. OOOOOOOOO / RS-2025-02182973).

[0482] While the present invention has been described with reference to the above-described embodiments, these are merely exemplary, and those skilled in the art will understand that various modifications and equivalent alternative embodiments are possible. Therefore, the true scope of technical protection of the present invention should be determined by the technical spirit of the appended claims.

[0483] [Revised on July 16, 2025, pursuant to Article 91 of the Rules] The compound or a pharmaceutically acceptable salt thereof according to one embodiment of the present invention can be used in the manufacture of a medicine, particularly a therapeutic agent for brain and nerve diseases. <Acknowledgement> The present invention was made possible with the support of the National Drug Development Program of the National Drug Development Fund, funded by the Ministry of Science and ICT, the Ministry of Trade, Industry and Energy, and the Ministry of Health and Welfare. (Project Unique Number: 2710086721 / Project Number RS-2025-02182973).

Claims

1. A novel compound having a structure represented by the following chemical formula 1 or a pharmaceutically acceptable salt thereof: . (Chemical formula 1) (In the above formula, R1 is , , , or and the above R2 is , hydrogen, a hydroxyl group, a substituted or unsubstituted aryl, a heteroaryl, a substituted or unsubstituted alkyl group having 1 to 4 carbon atoms, a halogen, or a substituted or unsubstituted alkoxy group having 1 to 4 carbon atoms, wherein R3 is hydrogen, hydroxy, halogen, a substituted or unsubstituted alkyl group having 1 to 4 carbon atoms, a substituted or unsubstituted alkoxy group having 1 to 4 carbon atoms, or a substituted or unsubstituted arylalkoxy group, wherein R4 is hydrogen, hydroxy, halogen, methyl, ethyl, methoxy, or ethoxy, wherein A is -CH2NHCO- or heteroaryl, wherein B is -CH2CH2NH-, or a 5 to 7 membered cycloalkyl group containing at least one nitrogen atom, wherein R5 and R6 are each independently hydrogen, halogen, an amine group, a C1 a substituted or unsubstituted alkyl group having 1 to 4 carbon atoms, a substituted or unsubstituted alkoxy group having 1 to 4 carbon atoms, a 5 to 7 membered cycloalkyl group containing 0 to 2 substituted or unsubstituted oxygen atoms and / or at least one nitrogen atom, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, a substituted or unsubstituted alkylaryl group having 7 to 12 carbon atoms.

2. In paragraph 1, The above R1 is , , , , or A novel compound or a pharmaceutically acceptable salt thereof.

3. In paragraph 1, The heteroaryl of the above A is , , or A novel compound or a pharmaceutically acceptable salt thereof.

4. In paragraph 1, A novel compound or a pharmaceutically acceptable salt thereof, wherein R5 and R6 are each independently hydrogen, fluorine, chlorine, methoxy, dimethylamine, morpholine, pyrrolidine, trifluoromethyl, or trifluoromethoxy group.

5. In paragraph 1, A novel compound or a pharmaceutically acceptable salt thereof, wherein the halogen is fluorine (F), iodine (I), bromine (Br) or chlorine (Cl).

6. In paragraph 1, The above compound is N-(2-((2-(1H-indol-3-yl)ethyl)amino)-2-oxoethyl)-1H-indole-5-carboxamide, N-(2-((2-(1H-indol-3-yl)ethyl)amino)-2-oxoethyl)-3-phenyl-1H-indole-5-carboxamide, N-(2-((2-(1H-indol-3-yl)ethyl)amino)-2-oxoethyl)-3-(4-methoxyphenyl)-1H-indole-5-carboxamide, N-(2-((2-(1H-indol-3-yl)ethyl)amino)-2-oxoethyl)-3-(4-fluorophenyl)-1H-indole-5-carboxamide, N-(2-((2-(1H-indol-3-yl)ethyl)amino)-2-oxoethyl)-3-(4-chlorophenyl)-1H-indole-5-carboxamide, N-(2-((2-(5-chloro-1H-indol-3-yl)ethyl)amino)-2-oxoethyl)-3-phenyl-1H-indole-5-carboxamide, N-(2-((2-(5-chloro-1H-indol-3-yl)ethyl)amino)-2-oxoethyl)-3-(4-methoxyphenyl)-1H-indole-5-carboxamide, N-(2-((2-(5-chloro-1H-indol-3-yl)ethyl)amino)-2-oxoethyl)-3-(4-fluorophenyl)-1H-indole-5-carboxamide, N-(2-((2-(5-chloro-1H-indol-3-yl)ethyl)amino)-2-oxoethyl)-3-(4-chlorophenyl)-1H-indole-5-carboxamide, N-(2-((2-(5-fluoro-1H-indol-3-yl)ethyl)amino)-2-oxoethyl)-1H-indole-5-carboxamide, N-(2-((2-(5-fluoro-1H-indol-3-yl)ethyl)amino)-2-oxoethyl)-3-phenyl-1H-indole-5-carboxamide, N-(2-((2-(5-fluoro-1H-indol-3-yl)ethyl)amino)-2-oxoethyl)-3-(4-methoxyphenyl)-1H-indole-5-carboxamide, N-(2-((2-(5-fluoro-1H-indol-3-yl)ethyl)amino)-2-oxoethyl)-3-(4-fluorophenyl)-1H-indole-5-carboxamide, 3-(4-chlorophenyl)-N-(2-((2-(5-fluoro-1H-indol-3-yl)ethyl)-amino)-2-oxoethyl)-1H-indole-5-carboxamide, N-(2-((2-(5-fluoro-1H-indol-3-yl)ethyl)amino)-2-oxoethyl)-3-(4-(trifluoromethyl)phenyl)-1H-indole-5-carboxamide, N-(2-((2-(5-fluoro-1H-indol-3-yl)ethyl)amino)-2-oxoethyl)-3-(4-(trifluoromethoxy)phenyl)-1H-indole-5-carboxamide, 3-(3,5-difluorophenyl)-N-(2-((2-(5-fluoro-1H-indol-3-yl)ethyl)amino)-2-oxoethyl)-1H-indole-5-carboxamide, 3-(3,5-dimethoxyphenyl)-N-(2-((2-(5-fluoro-1H-indol-3-yl)ethyl)amino)-2-oxoethyl)-1H-indole-5-carboxamide, 3-(4-(dimethylamino)phenyl)-N-(2-((2-(5-fluoro-1H-indol-3-yl)ethyl)amino)-2-oxoethyl)-1H-indole-5-carboxamide, 3-(3,4-dimethoxyphenyl)-N-(2-((2-(5-fluoro-1H-indol-3-yl)ethyl)amino)-2-oxoethyl)-1H-indole-5-carboxamide, N-(2-((2-(5-fluoro-1H-indol-3-yl)ethyl)amino)-2-oxoethyl)-3-(3-methoxyphenyl)-1H-indole-5-carboxamide, N-(2-((2-(5-fluoro-1H-indol-3-yl)ethyl)amino)-2-oxoethyl)-3-(4-morpholinophenyl)-1H-indole-5-carboxamide, N-(2-((2-(5-fluoro-1H-indol-3-yl)ethyl)amino)-2-oxoethyl)-3-(3-fluorophenyl)-1H-indole-5-carboxamide, N-(2-((2-(5-fluoro-1H-indol-3-yl)ethyl)amino)-2-oxoethyl)-3-(4-(pyrrolidin-1-yl)phenyl)-1H-indole-5-carboxamide, 3-(4-fluorophenyl)-N-(2-((2-(5-methoxy-1-methyl-1H-indol-3-yl)ethyl)amino)-2-oxoethyl)-1H-indole-5-carboxamide, N-(2-((2-(5-fluoro-1H-indol-3-yl)ethyl)amino)-2-oxoethyl)-3-(3-morpholinophenyl)-1H-indole-5-carboxamide, 3-(4-fluorophenyl)-N-(2-((2-(5-methoxy-1H-indol-3-yl)ethyl)amino)-2-oxoethyl)-1H-indole-5-carboxamide, N-(2-(1H-indol-3-yl)ethyl)-2-(3-phenyl-1H-indol-5-yl)isonicotinamide, (4-(1H-indol-3-yl)piperidin-1-yl)(2-(3-phenyl-1H-indol-5-yl)pyridin-4-yl)methanone, N-(2-(6-fluoro-1H-indol-3-yl)ethyl)-2-(3-phenyl-1H-indol-5-yl)isonicotinamide, N-(2-(6-methoxy-1H-indol-3-yl)ethyl)-2-(3-phenyl-1H-indol-5-yl)isonicotinamide, N-(2-(5-methoxy-1H-indol-3-yl)ethyl)-2-(3-phenyl-1H-indol-5-yl)isonicotinamide, N-(2-(5-fluoro-1H-indol-3-yl)ethyl)-2-(3-phenyl-1H-indol-5-yl)isonicotinamide, N-(2-(5-chloro-1H-indol-3-yl)ethyl)-2-(3-phenyl-1H-indol-5-yl)isonicotinamide, N-(2-(5-(benzyloxy)-1H-indol-3-yl)ethyl)-2-(3-phenyl-1H-indol-5-yl)isonicotinamide, N-(2-(5-hydroxy-1H-indol-3-yl)ethyl)-2-(3-phenyl-1H-indol-5-yl)isonicotinamide, N-(2-(1H-indol-3-yl)ethyl)-2-(3-(4-fluorophenyl)-1H-indol-5-yl)isonicotinamide, (4-(1H-indol-3-yl)piperidin-1-yl)(2-(3-(4-fluorophenyl)-1H-indol-5-yl)pyridin-4-yl)methanone, 2-(3-(4-fluorophenyl)-1H-indol-5-yl)-N-(2-(5-methoxy-1H-indol-3-yl)ethyl)isonicotinamide, N-(2-(5-fluoro-1H-indol-3-yl)ethyl)-2-(3-(4-fluorophenyl)-1H-indol-5-yl)isonicotinamide, N-(2-(6-fluoro-1H-indol-3-yl)ethyl)-2-(3-(4-fluorophenyl)-1H-indol-5-yl)isonicotinamide, 2-(3-(4-fluorophenyl)-1H-indol-5-yl)-N-(2-(4-methylpiperazin-1-yl)ethyl)isonicotinamide, 2-(3-(4-fluorophenyl)-1H-indol-5-yl)-N-(2-morpholinoethyl)isonicotinamide, 2-(3-(4-fluorophenyl)-1H-indol-5-yl)-N-(2-(pyrrolidin-1-yl)ethyl)isonicotinamide or A novel compound, which is 2-(3-(4-fluorophenyl)-1H-indol-5-yl)-N-(2-(indolin-1-yl)ethyl)isonicotinamide, or a pharmaceutically acceptable salt thereof.

7. A novel compound or a pharmaceutically acceptable salt thereof for use in the treatment of a brain nerve disease according to any one of claims 1 to 6.

8. A pharmaceutical composition for treating a brain nerve disease, comprising a novel compound of any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof as an active ingredient.

9. In paragraph 8, The above brain disease is a pharmaceutical composition including stroke, epilepsy, traumatic brain injury, brain damage due to hypoglycemia, or multiple sclerosis.

10. In paragraph 9, A pharmaceutical composition, wherein the above stroke is a hemorrhagic stroke, an ischemic stroke, a global cerebral ischemia stroke, or a metal toxicity stroke.

11. In paragraph 10, A pharmaceutical composition wherein the brain damage caused by the above systemic ischemia is caused by cardiac arrest, hypotension, or excessive bleeding.

12. In paragraph 11, A pharmaceutical composition wherein the above ischemic stroke is caused by excitatory neuronal cell death or oxidative neuronal cell death.

13. A method for treating a neurological disease, comprising administering a therapeutically effective amount of a compound of any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof to a patient with a neurological disease in need of treatment.

14. In paragraph 13, A treatment method wherein the above brain disease may be a stroke, epilepsy, traumatic brain injury, brain damage due to hypoglycemia, or multiple sclerosis, and the stroke may be a hemorrhagic stroke, an ischemic stroke, a global cerebral ischemia stroke, or a metal toxicity stroke.

15. In paragraph 14, A treatment method wherein the brain damage caused by the above systemic ischemia is caused by cardiac arrest, hypotension or excessive bleeding.

16. Use of a compound according to any one of claims 1 to 6 for the manufacture of a therapeutic agent for neurological diseases.

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