Serotonin analogs for use in the treatment of metallothiasis-related disorders

Abstract

The present invention relates to serotonin derivatives of general formula (I) and their use in the pharmaceutical field, in particular for the prevention or treatment of metallothionein-related disorders. The present invention also relates to new serotonin derivatives of general formula (I) and their use for the prevention or treatment of iron and / or copper-related disorders.

Description

Technical Field

[0001] The present invention is an invention in the pharmaceutical field. In particular, the present invention relates to novel serotonin analogs and their use as drugs for preventing and / or treating metalloptosis-related disorders.

Background Art

[0002] In addition to classical apoptosis, several forms of regulated cell death (RCD) have been identified. These RCD subroutines differ in the initiating stimulus, intermediate activation events, and effectors. Various metals can induce regulated cell death, i.e., metalloptosis, via different subroutines. Metal ions are essential micronutrients, but both insufficient and excessive amounts of metals can cause cell death. Metalloptosis particularly includes ferroptosis and cuproptosis, which are dependent on iron and copper, respectively.

[0003] Ferroptosis is a type of programmed cell death that is iron-dependent and characterized by the accumulation of lipid peroxides, and is genetically and biochemically distinct from other forms of regulated cell death such as apoptosis. Ferroptosis is initiated by the failure of glutathione-dependent antioxidant defense, leading to unregulated lipid peroxidation and ultimately cell death. The field of ferroptosis research has experienced exponential growth over the past few years since the term was coined in 2012. This unique modality of cell death driven by iron-dependent phospholipid peroxidation is regulated by multiple cellular metabolic pathways including redox homeostasis, iron handling, mitochondrial activity and metabolism of amino acids, lipids and sugars, in addition to various signaling pathways associated with diseases (Xuejun Jiang et al., Nature Reviews Molecular Cell Biology 22, 266 - 282 (25.01.2021)). A number of organ injuries and degenerative pathologies are driven by ferroptosis. Recent studies have shown that ferroptosis is closely associated with the pathophysiological processes of many diseases such as tumors, nervous system diseases, ischemia-reperfusion injury, kidney injury, and blood diseases (Jie Li et al., Cell Death & Disease 11, 88 (03.02.2020)).

[0004] Recent studies have shown that intracellular copper (Cu) induces a new form of RCD called "cuproptosis", which is distinct from oxidative stress-related cell death (e.g., apoptosis, ferroptosis, and necroptosis) (Tsvetkov, P. et al., Science 375, 1254 - 1261 (2022)). In contrast, mitochondrial stress, particularly the aggregation of lipoylated mitochondrial enzymes and the decrease in Fe-S cluster proteins, fuels cuproptosis.

Prior Art Documents

Patent Documents

[0005]

Patent Document 1

Non-Patent Documents

[0006]

Non-Patent Document 1

Non-Patent Document 2

Non-Patent Document 3

Non-Patent Document 4

Non-Patent Document 5

Summary of the Invention

Problems to be Solved by the Invention

[0007] Therefore, there is a need to find new compounds that can activate or block the metallothionein pathway to alleviate the progression of diseases and thus provide promising treatment strategies for many diseases.

Means for Solving the Problems

[0008] The present inventors have discovered and developed serotonin analogs that can activate or block the metallothionein pathway and thus can prevent and / or treat diseases related to metallothionein. The present inventors have also discovered that these serotonin analogs are effective for preventing or treating iron and / or copper-related disorders.

[0009] Accordingly, the present invention relates to compounds of general formula (I) or pharmaceutically acceptable salts and / or solvates thereof for use in the prevention or treatment of metallopotosis-related disorders, wherein formula (I) is

[0010] [ka]

[0011] [In the formula, R 1 , R 2 , R 3 and R 4 -H, -OH, -C(O)OR 9 -, -S(O)2R 10 -, -C(O)R 9 -, -S(O)R 10 -, -NR 11 R 12 -, optionally substituted (C1-C 24 ) alkyl, optionally substituted (C2-C 24 ) alkenyl, optionally substituted (C2-C 24 ) alkynyl, optionally substituted (C3-C 10 ) independently selected from the group consisting of cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl, with the proviso that R 1 , R 2 and R 3 at least one of is not H; or R 1 and R 4 -H, -OH, -C(O)OR 9 -, -S(O)2R 10 -, -C(O)R 9 -, -S(O)R 10 -, -NR 11 R 12 -, optionally substituted (C1-C 24 ) alkyl, optionally substituted (C2-C 24 ) alkenyl, optionally substituted (C2-C 24) alkynyl, optionally substituted (C3 - C 10 ) cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl and optionally substituted heteroaryl, independently selected from the group consisting of, R 2 and R 3 together with the nitrogen atom to which they are attached form an optionally substituted heterocycloalkyl; X is selected from the group consisting of (C1 - C 12 ) alkyl, -O-(C1 - C 12 ) alkyl-, -C(O)-, -C(O)-(C1 - C 12 ) alkyl-, -NH-C(O)-(C1 - C 12 ) alkyl-, -S-(C1 - C 12 ) alkyl-, -S(O)-(C1 - C 12 ) alkyl-, and -S(O)2-(C1 - C 12 ) alkyl-; the (C1 - C 12 ) alkyl group may be optionally substituted by a heteroatom and / or may be optionally interrupted; Y 0 , Y 1 , Y 2 and Y 3 are each independently absent or -NH-, -O-, -S-, -S(O)-, -S(O)2-, -C(O)-, -C(O)O-, -OC(O)-, -NHC(O)-, -C(O)NH-; -C(O)NR 14 -, (C1 - C 24 ) alkyl, -(C1 - C 24 ) alkyl-NH-, -(C1 - C 24 ) alkyl-O-, -(C1 - C 24 ) alkyl-S-, (C1 - C 24 ) alkyl-NR 13 -, -(C1 - C 24 ) alkyl-S(O)-, -(C1 - C 24 ) alkyl-S(O)2-, -(C1 - C 24 ) alkyl-C(O)-, -(C1 - C 24 ) alkyl-C(O)O-, -(C1 - C 24 ) alkyl-OC(O)-, -(C1 - C24 ) Alkyl-NHC(O)-, -(C1-C 24 ) Alkyl-C(O)NH-, -(C1-C 24 ) Alkyl-C(O)NR 14-, -NH-C(O)-NH-, -NH-S(O)-NH-, -NH-S(O2)-NH-, -S-C(O)-NH-, -O-C(O)-NH-, -O-S(O)-NH-, -O-S(O2)-NH-, -S-CH2-C(O)-NH-, -S-CH2-S(O)-NH-, -S-CH2-S(O2)-NH-, -S(O)-CH2-C(O)-NH-, -S(O2)-CH2-C(O)-NH-, -O-CH2-C(O)-NH-, -O-CH2-S(O)-NH-, -O-CH2-S(O2)-NH-, -NH-CH2-C(O)-NH-, -NH-CH2-S(O)-NH-, -NH-CH2-S(O2)-NH-, -O-(CH2)2-NH-C(O)-, -O-(CH2)2-N(CH3)-C(O)-, -O-(CH2)2-NH-S(O)-, -O-(CH2)2-N(CH3)-S(O)-, -O-(CH2)2-NH-S(O2)-, -O-(CH2)2-N(CH3)-S(O2)-, -S-(CH2)2-NH-C(O)-, -S-(CH2)2-N(CH3)-C(O)-, -S-(CH2)2-NH-S(O)-, -S-(CH2)2-N(CH3)-S(O)-, -S-(CH2)2-NH-S(O2)-, -S-(CH2)2-N(CH3)-S(O2)-, -NH-(CH2)2-NH-C(O)-, -NH-(CH2)2-N(CH3)-C(O)-, -NH-(CH2)2-NH-S(O)-, -NH-(CH2)2-N(CH3)-S(O)-, -NH-(CH2)2-NH-S(O2)-, -NH-(CH2)2-N(CH3)-S(O2)-, -O-CH2-CH(CH2-OH)-NH-C(O)-, -O-CH2-CH(CH2-OCH3)-NH-C(O)-, -O-CH2-CH(CH3)-NH-C(O)-, -O-CH(CH3)-CH2-NH-C(O)-, -O-CH2-CH(CH2-OH)-NH-S(O)-, -O-CH2-CH(CH2-OCH3)-NH-S(O)-, -O-CH2-CH(CH3)-NH-S(O)-, -O-CH(CH3)-CH2-NH-S(O)-, -O-CH2-CH(CH2-OH)-NH-S(O2)-, -O-CH2-CH(CH2-OCH3)-NH-S(O2)-, -O-CH2-CH(CH3)-NH-S(O2)-, -O-CH(CH3)-CH2-NH-S(O2)-,-S-CH2-CH(CH2-OH)-NH-C(O)-, -S-CH2-CH(CH2-OCH3)-NH-C(O)-, -S-CH2-CH(CH3)-NH-C(O)-, -S-CH(CH3)-CH2-NH-C(O)-, -S-CH2-CH(CH2-OH)-NH-S(O)-, -S-CH2-CH(CH2-OCH3)-NH-S(O)-, -S-CH2-CH(CH3)-NH-S(O)-, -S-CH(CH3)-CH2-NH-S(O)-, -S-CH2-CH(CH2-OH)-NH-S(O2)-, -S-CH2-CH(CH2-OCH3)-NH-S(O2)-, -S-CH2-CH(CH3)-NH-S(O2)-, -S-CH(CH3)-CH2-NH-S(O2)-, -NH-CH2-CH(CH2-OH)-NH-C(O)-, -NH-CH2-CH(CH2-OCH3)-NH-C(O)-, -NH-CH2-CH(CH3)-NH-C(O)-, -NH-CH(CH3)-CH2-NH-C(O)-, -NH-CH2-CH(CH2-OH)-NH-S(O)-, -NH-CH2-CH(CH2-OCH3)-NH-S(O)-, -NH-CH2-CH(CH3)-NH-S(O)-, -NH-CH(CH3)-CH2-NH-S(O)-, -NH-CH2-CH(CH2-OH)-NH-S(O2)-, -NH-CH2-CH(CH2-OCH3)-NH-S(O2)-, -NH-CH2-CH(CH3)-NH-S(O2)-, -NH-CH(CH3)-CH2-NH-S(O2)-, -O-(CH2)2-NH-, -S-(CH2)2-NH-, and -NH-(CH2)2-NH-; (C1-C, 24 ) The alkyl group may be substituted; R 5 、R 6 、R 7 and R 8 are H, halogen, optionally substituted (C1-C 24 ) alkyl, optionally substituted (C2-C 24 ) alkenyl, optionally substituted (C2-C 24 ) alkynyl, optionally substituted (C3-C 10) Independently selected from the group consisting of cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; R 9 ~R 14 is independently selected from the group consisting of optionally substituted (C1-C 12 ) alkyl, optionally substituted (C2-C 12 ) alkenyl, optionally substituted (C2-C 12 ) alkynyl, and optionally substituted aryl]. Preferably, R 9 is selected from the group consisting of optionally substituted (C1-C 12 ) alkyl, optionally substituted (C2-C 12 ) alkenyl, optionally substituted (C2-C 12 ) alkynyl, and aryl optionally substituted with (C1-C6) alkyl; R 10 ~R 14 is independently selected from the group consisting of optionally substituted (C1-C 12 ) alkyl, optionally substituted (C2-C 12 ) alkenyl, optionally substituted (C2-C 12 ) alkynyl, and optionally substituted aryl.

[0012] In certain embodiments, the metallosis-related disorder is a disorder associated with ferroptosis and / or cuproptosis.

[0013] In certain embodiments, the metallosis-related disorder is selected from hemorrhagic stroke; ischemic heart injury; ischemic kidney injury; ischemia-reperfusion injury (IRI); neurodegenerative diseases such as Huntington's disease, dementia, and amyotrophic lateral sclerosis (ALS); age-related diseases or disorders; sepsis; ischemia-reperfusion; and diabetes.

[0014] The present invention also relates to a compound of general formula (I):

[0015]

Chemical formula

[0016] [wherein, R 1 、R 2 、R 3 and R 4 are independently selected from the group consisting of H, OH, -C(O)OR 9 -, -S(O)2R 10 -, -C(O)R 9 -, -S(O)R 10 -, -NR 11 R 12 -, optionally substituted (C1-C 24 ) alkyl, optionally substituted (C2-C 24 ) alkenyl, optionally substituted (C2-C 24 ) alkynyl, optionally substituted (C3-C 10 ) cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl and optionally substituted heteroaryl, provided that at least one of R 2 and R 3 is not H; or R 1 and R 4 are independently selected from the group consisting of H, OH, -C(O)OR 9 -, -S(O)2R 10 -, -C(O)R 9 -, -S(O)R 10 -, -NR 11 R 12 -, optionally substituted (C1-C 24 ) alkyl, optionally substituted (C2-C 24 ) alkenyl, optionally substituted (C2-C 24 ) alkynyl, optionally substituted (C3-C 10 ) cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl and optionally substituted heteroaryl, and R 2 and R 3Together with the nitrogen atom to which they are attached, halogen; CN; NO2; (C1-C6) alkyl; (C1-C6) haloalkyl; (C1-C6) haloalkoxy, (C1-C6) halothioalkoxy, optionally substituted aryl (in particular, optionally substituted with one or two (C1-C6) alkyl or NO2); heteroaryl; oxo; NR a R b ; COR c ; CO2R d ; CONR e R f ; OR g ; SR h ; SO2R i ; SO2NR j R k ; NR l COR m ; R n NR O R P ; NR q SO2R r (wherein R a ~R r are, independently of one another, H, (C1-C6) alkyl, (C1-C6) haloalkyl, aryl, (C1-C6) alkyl-aryl, heteroaryl or (C1-C6) alkyl-heteroaryl); in particular, halogen, CN, NO2, (C1-C6) alkyl, (C1-C6) haloalkyl, oxo, NR a R b , COR c , C(O)OR d , CONR e R f , and OR g (wherein R a ~R g are, independently of one another, H or (C1-C6) alkyl) and is optionally substituted with at least one substituent selected from the group consisting of; X is (C1-C 12 ) alkyl, -O-(C1-C 12 ) alkyl-, -C(O)-, -C(O)-(C1-C 12 ) alkyl-, -NH-C(O)-(C1-C 12 ) alkyl-, -S-(C1-C12 ) alkyl-, -S(O)-(C1-C 12 ) alkyl-, and -S(O)2-(C1-C 12 ) selected from the group consisting of alkyl-; (C1-C 12 ) the alkyl group may be substituted by a heteroatom and / or may be interrupted; Y 0 、Y 1 、Y 2 and Y 3 are independently absent or are -NH-, -O-, -S-, -S(O)-, -S(O)2-, -C(O)-, -C(O)O-, -OC(O)-, -NHC(O)-, -C(O)NH-; -C(O)NR 14 - -(C1-C 24 ) alkyl-NH-, -(C1-C 24 ) alkyl-O-, -(C1-C 24 ) alkyl-S-, (C1-C 24 ) alkyl-NR 13 -, -(C1-C 24 ) alkyl-S(O)-, -(C1-C 24 ) alkyl-S(O)2-, -(C1-C 24 ) alkyl-C(O)-, -(C1-C 24 ) alkyl-C(O)O-, -(C1-C 24 ) alkyl-OC(O)-, -(C1-C 24 ) alkyl-NHC(O)-, -(C1-C 24 ) alkyl-C(O)NH-, -(C1-C 24 ) alkyl-C(O)NR 14 -, (C1-C 24)Alkyl, -NH-C(O)-NH-, -NH-S(O)-NH-, -NH-S(O2)-NH-, -S-C(O)-NH-, -O-C(O)-NH-, -O-S(O)-NH-, -O-S(O2)-NH-, -S-CH2-C(O)-NH-, -S-CH2-S(O)-NH-, -S-CH2-S(O2)-NH-, -S(O)-CH2-C(O)-NH-, -S(O2)-CH2-C(O)-NH-, -O-CH2-C(O)-NH-, -O-CH2-S(O)-NH-, -O-CH2-S(O2)-NH-, -NH-CH2-C(O)-NH-, -NH-CH2-S(O)-NH-, -NH-CH2-S(O2)-NH-, -O-(CH2)2-NH-C(O)-, -O-(CH2)2-N(CH3)-C(O)-, -O-(CH2)2-NH-S(O)-, -O-(CH2)2-N(CH3)-S(O)-, -O-(CH2)2-NH-S(O2)-, -O-(CH2)2-N(CH3)-S(O2)-, -S-(CH2)2-NH-C(O)-, -S-(CH2)2-N(CH3)-C(O)-, -S-(CH2)2-NH-S(O)-, -S-(CH2)2-N(CH3)-S(O)-, -S-(CH2)2-NH-S(O2)-, -S-(CH2)2-N(CH3)-S(O2)-, -NH-(CH2)2-NH-C(O)-, -NH-(CH2)2-N(CH3)-C(O)-, -NH-(CH2)2-NH-S(O)-, -NH-(CH2)2-N(CH3)-S(O)-, -NH-(CH2)2-NH-S(O2)-, -NH-(CH2)2-N(CH3)-S(O2)-, -O-CH2-CH(CH2-OH)-NH-C(O)-, -O-CH2-CH(CH2-OCH3)-NH-C(O)-, -O-CH2-CH(CH3)-NH-C(O)-, -O-CH(CH3)-CH2-NH-C(O)-, -O-CH2-CH(CH2-OH)-NH-S(O)-, -O-CH2-CH(CH2-OCH3)-NH-S(O)-, -O-CH2-CH(CH3)-NH-S(O)-, -O-CH(CH3)-CH2-NH-S(O)-, -O-CH2-CH(CH2-OH)-NH-S(O2)-, -O-CH2-CH(CH2-OCH3)-NH-S(O2)-, -O-CH2-CH(CH3)-NH-S(O2)-, -O-CH(CH3)-CH2-NH-S(O2)-,-S-CH2-CH(CH2-OH)-NH-C(O)-, -S-CH2-CH(CH2-OCH3)-NH-C(O)-, -S-CH2-CH(CH3)-NH-C(O)-, -S-CH(CH3)-CH2-NH-C(O)-, -S-CH2-CH(CH2-OH)-NH-S(O)-, -S-CH2-CH(CH2-OCH3)-NH-S(O)-, -S-CH2-CH(CH3)-NH-S(O)-, -S-CH(CH3)-CH2-NH-S(O)-, -S-CH2-CH(CH2-OH)-NH-S(O2)-, -S-CH2-CH(CH2-OCH3)-NH-S(O2)-, -S-CH2-CH(CH3)-NH-S(O2)-, -S-CH(CH3)-CH2-NH-S(O2)-, -NH-CH2-CH(CH2-OH)-NH-C(O)-, -NH-CH2-CH(CH2-OCH3)-NH-C(O)-, -NH-CH2-CH(CH3)-NH-C(O)-, -NH-CH(CH3)-CH2-NH-C(O)-, -NH-CH2-CH(CH2-OH)-NH-S(O)-, -NH-CH2-CH(CH2-OCH3)-NH-S(O)-, -NH-CH2-CH(CH3)-NH-S(O)-, -NH-CH(CH3)-CH2-NH-S(O)-, -NH-CH2-CH(CH2-OH)-NH-S(O2)-, -NH-CH2-CH(CH2-OCH3)-NH-S(O2)-, -NH-CH2-CH(CH3)-NH-S(O2)-, -NH-CH(CH3)-CH2-NH-S(O2)-, -O-(CH2)2-NH-, -S-(CH2)2-NH-, and -NH-(CH2)2-NH-; (C1-C, 24 ) the alkyl group may be substituted; R 5 、R 6 、R 7 and R 8 are H, halogen, optionally substituted (C1-C 24 ) alkyl, optionally substituted (C2-C 24 ) alkenyl, optionally substituted (C2-C 24 ) alkynyl, optionally substituted (C3-C 10) Independently selected from the group consisting of cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; R 9 ~R 14 is optionally substituted (C1-C 12 ) alkyl, optionally substituted (C2-C 12 ) alkenyl, optionally substituted (C2-C 12 ) alkynyl, independently selected from the group consisting of optionally substituted aryl; provided that R 5 , R 6 , R 7 and R 8 are H, Y 0 is -O-, Y 1 , Y 2 and Y 3 are absent, R 1 , R 2 and R 3 are not optionally substituted (C2-C 24 ) alkynyl] or a pharmaceutically acceptable salt and / or solvate thereof.

[0017] Preferably, Y 1 , Y 2 and Y 3 are each independently absent or selected from the following list, and Y 0 is selected from the following list; the list is -NH-, -O-, -S-, -S(O)-, -S(O)2-, -C(O)-, -C(O)O-, -OC(O)-, -NHC(O)-, -C(O)NH-; -C(O)NR 14 - -(C1-C 24 ) alkyl-NH-, -(C1-C 24 ) alkyl-O-, -(C1-C 24 ) alkyl-S-, (C1-C 24 ) alkyl-NR 13 -, -(C1-C 24 ) alkyl-S(O)-, -(C1-C 24 ) alkyl-S(O)2-, -(C1-C 24) Alkyl-C(O)-, -(C1-C 24 ) Alkyl-C(O)O-, -(C1-C 24 ) Alkyl-OC(O)-, -(C1-C 24 ) Alkyl-NHC(O)-, -(C1-C 24 ) Alkyl-C(O)NH-, -(C1-C 24 ) Alkyl-C(O)NR 14 -, (C1-C 24)alkyl, -NH-C(O)-NH-, -NH-S(O)-NH-, -NH-S(O2)-NH-, -S-C(O)-NH-, -O-C(O)-NH-, -O-S(O)-NH-, -O-S(O2)-NH-, -S-CH2-C(O)-NH-, -S-CH2-S(O)-NH-, -S-CH2-S(O2)-NH-, -S(O)-CH2-C(O)-NH-, -S(O2)-CH2-C(O)-NH-, -O-CH2-C(O)-NH-, -O-CH2-S(O)-NH-, -O-CH2-S(O2)-NH-, -NH-CH2-C(O)-NH-, -NH-CH2-S(O)-NH-, -NH-CH2-S(O2)-NH-, -O-(CH2)2-NH-C(O)-, -O-(CH2)2-N(CH3)-C(O)-, -O-(CH2)2-NH-S(O)-, -O-(CH2)2-N(CH3)-S(O)-, -O-(CH2)2-NH-S(O2)-, -O-(CH2)2-N(CH3)-S(O2)-, -S-(CH2)2-NH-C(O)-, -S-(CH2)2-N(CH3)-C(O)-, -S-(CH2)2-NH-S(O)-, -S-(CH2)2-N(CH3)-S(O)-, -S-(CH2)2-NH-S(O2)-, -S-(CH2)2-N(CH3)-S(O2)-, -NH-(CH2)2-NH-C(O)-, -NH-(CH2)2-N(CH3)-C(O)-, -NH-(CH2)2-NH-S(O)-, -NH-(CH2)2-N(CH3)-S(O)-, -NH-(CH2)2-NH-S(O2)-, -NH-(CH2)2-N(CH3)-S(O2)-, -O-CH2-CH(CH2-OH)-NH-C(O)-, -O-CH2-CH(CH2-OCH3)-NH-C(O)-, -O-CH2-CH(CH3)-NH-C(O)-, -O-CH(CH......-S-CH2-CH(CH2-OH)-NH-C(O)-, -S-CH2-CH(CH2-OCH3)-NH-C(O)-, -S-CH2-CH(CH3)-NH-C(O)-, -S-CH(CH3)-CH2-NH-C(O)-, -S-CH2-CH(CH2-OH)-NH-S(O)-, -S-CH2-CH(CH2-OCH3)-NH-S(O)-, -S-CH2-CH(CH3)-NH-S(O)-, -S-CH(CH3)-CH2-NH-S(O)-, -S-CH2-CH(CH2-OH)-NH-S(O2)-, -S-CH2-CH(CH2-OCH3)-NH-S(O2)-, -S-CH2-CH(CH3)-NH-S(O2)-, -S-CH(CH3)-CH2-NH-S(O2)-, -NH-CH2-CH(CH2-OH)-NH-C(O)-, -NH-CH2-CH(CH2-OCH3)-NH-C(O)-, -NH-CH2-CH(CH3)-NH-C(O)-, -NH-CH(CH3)-CH2-NH-C(O)-, -NH-CH2-CH(CH2-OH)-NH-S(O)-, -NH-CH2-CH(CH2-OCH3)-NH-S(O)-, -NH-CH2-CH(CH3)-NH-S(O)-, -NH-CH(CH3)-CH2-NH-S(O)-, -NH-CH2-CH(CH2-OH)-NH-S(O2)-, -NH-CH2-CH(CH2-OCH3)-NH-S(O2)-, -NH-CH2-CH(CH3)-NH-S(O2)-, -NH-CH(CH3)-CH2-NH-S(O2)-, -O-(CH2)2-NH-, -S-(CH2)2-NH-, and -NH-(CH2)2-NH-; (C1-C, 24 ) The alkyl group may be substituted.

[0018] Preferably, R 9 is selected from the group consisting of optionally substituted (C1-C 12 ) alkyl, optionally substituted (C2-C 12 ) alkenyl, optionally substituted (C2-C 12 ) alkynyl, and aryl optionally substituted with (C1-C6) alkyl; R 10 ~R 14 are optionally substituted (C1-C12 ) alkyl, which may be substituted, (C2-C 12 ) alkenyl, which may be substituted, (C2-C 12 ) alkynyl, and aryl which may be substituted, and are independently selected from the group consisting of.

[0019] The present invention also relates to a compound as defined above, or a pharmaceutically acceptable salt and / or solvate thereof, for use as a drug.

[0020] The present invention also relates to a pharmaceutical composition comprising a compound as defined above, or a pharmaceutically acceptable salt and / or solvate thereof, and at least one pharmaceutically acceptable excipient.

[0021] The present invention also relates to a compound for use as defined above, or a pharmaceutical composition as defined above, for use in the prevention or treatment of iron and / or copper-related disorders, particularly iron and / or copper overload-related disorders; or metal-dependent cell death-related disorders.

[0022] In a particular aspect, the iron and / or copper-related disorders are selected from HFE-related iron overload; non-HFE-related iron overload; congenital atransferrinemia; iron overload-related anemia such as thalassemia, myelodysplasia, and hematopoietic stem cell transplantation-related disorders; chronic liver disease; chronic inflammation associated with cancer; autoimmune or inflammatory diseases; neurodegeneration associated with brain iron accumulation-related diseases such as Wilson's disease; and polygenic neurodegeneration-related diseases such as Parkinson's disease and Alzheimer's disease.

[0023] In a particular aspect, the metal-dependent cell death-related disorders are disorders related to ferroptosis, particularly disorders related to ferroptosis and / or cuproptosis; preferably, selected from hemorrhagic stroke; ischemic heart injury; ischemic kidney injury; ischemia-reperfusion injury (IRI); neurodegenerative diseases selected from Huntington's disease, dementia, amyotrophic lateral sclerosis (ALS); age-related diseases or disorders; sepsis; ischemia-reperfusion; and diabetes.

[0024] In a specific embodiment, in the compounds of the present invention, X is an optionally heteroatom-substituted and / or optionally interrupted (C1-C 12 ) alkyl, preferably an optionally heteroatom-substituted and / or optionally interrupted (C1-C6) alkyl, more preferably X is ethyl.

[0025] In a specific embodiment, in the compounds of the present invention, R 5 , R 6 , R 7 and R 8 are independently selected from the group consisting of H, halogen, optionally substituted (C1-C 24 ) alkyl, optionally substituted (C2-C 24 ) alkenyl, optionally substituted (C2-C 24 ) alkynyl, preferably H, halogen, haloalkyl, or (C1-C 24 ) alkyl.

[0026] In a specific embodiment, in the compounds of the present invention, R 4 is H.

[0027] In a specific embodiment, in the compounds of the present invention, R 1 is H.

[0028] In a specific embodiment, in the compounds of the present invention, R 2 and R 3 are independently selected from the group consisting of H, -C(O)OR 9 -, -S(O)2R 10 -, optionally substituted (C1-C 12 ] ) alkyl, optionally substituted (C2-C 12 ) alkenyl, optionally substituted (C2-C 12 ) alkynyl, optionally substituted (C3-C 12 ) cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl and optionally substituted heteroaryl, provided that R 2 and R 3at least one of which is not H; or R 2 and R 3 together with the nitrogen atom to which they are attached form an optionally substituted nitrogen - heterocycloalkyl containing 3 to 10 ring atoms; R 9 ~R 12 are as defined above.

[0029] In a particular embodiment, in the compounds of the present invention, Y 0 , Y 1 , Y 2 and Y 3 are independently absent or are selected from the group consisting of NH -, - O -, - S -, - S(O) -, - S(O)2 -, - C(O) -, - C(O)O -, - OC(O) -, - NHC(O) -, - C(O)NH -, - C(O)NR 14 -, (C1 - C 24 )alkyl, -(C1 - C 24 )alkyl - NH -, -(C1 - C 24 )alkyl - O -, -(C1 - C 24 )alkyl - S -, (C1 - C 24 )alkyl - NR 13 -, -(C1 - C 24 )alkyl - S(O) -, -(C1 - C 24 )alkyl - S(O)2 -, -(C1 - C 24 )alkyl - C(O) -, -(C1 - C 24 )alkyl - C(O)O -, -(C1 - C 24 )alkyl - OC(O) -, -(C1 - C 24 )alkyl - NHC(O) -, -(C1 - C 24 )alkyl - C(O)NH -, -(C1 - C 24 )alkyl - C(O)NR 14 -; the (C1 - C 24 )alkyl group may be substituted; R 13 and R 14 are as defined above.

[0030] In a particular embodiment, in the compounds of the present invention, Y 0 , Y 1 , Y 2and Y 3 is independently absent or is -O-; -NH-; -S- or optionally substituted (C1-C 24 ) alkyl; preferably, Y 0 , Y 1 , Y 2 and Y 3 is independently absent or is -O-; more preferably Y 0 is -O-, Y 1 , Y 2 and Y 3 is independently absent or is -O-.

[0031] In a particular embodiment, the compounds for use according to the invention are selected from the compounds (001)-(064) and (A1)-(A4) of Table 1, or pharmaceutically acceptable salts and / or solvates thereof.

[0032] In a particular embodiment, the compounds for use according to the invention are selected from the compounds (001)-(038) and (A1)-(A4) of Table 1, or pharmaceutically acceptable salts and / or solvates thereof.

[0033] In a particular embodiment, the compounds according to the invention are selected from the compounds (001)-(064) of Table 1; preferably from the compounds (002), (003), (004), (008), (009), (010), (012), (013), (014), (015), (016), (017), (018), (019), (020), (022), (023), (024), (025), (026), (028), (029), (036), (039), (040), (043), (045), (049), (051), (052), (054), (057), (058), (059), (061), (063), and (064) of Table 1; more preferably from the compounds (003)-(007), (013), (014), (021), (022), (029) and (031)-(038) of Table 1; or pharmaceutically acceptable salts and / or solvates thereof.

[0034] In a particular embodiment, the compounds according to the invention are selected from the compounds (001)-(038) of Table 1; preferably, the compounds (003)-(007), (013), (014), (021), (029) and (031)-(038) of Table 1; or selected from their pharmaceutically acceptable salts and / or solvates.

Brief Description of the Drawings

[0035]

Figure 1

Figure 2A

Figure 2B

Figure 2C

Figure 2D

Figure 2E

Figure 2F

Figure 2G

Figure 2H

Figure 2I

Figure 2J

Figure 2K

Figure 2L

Figure 2M

Figure 2N

Figure 2O

Figure 2P

Figure 2Q

Figure 2R

Figure 2S

Figure 2T

Figure 2U

Figure 2V

Figure 2W

Figure 2X

Figure 2Y

Figure 2Z

Figure 2AA

Figure 2AB

Figure 2AC

Figure 2AD

Figure 3

Figure 4

Figure 5

Figure 6

Figure 7

Figure 8

Figure 9

Figure 10

Mode for Carrying Out the Invention

[0036] Definition For the purposes of the present invention, the term "pharmaceutically acceptable" is intended to mean those which are useful in the preparation of pharmaceutical compositions and which are generally safe and non-toxic for pharmaceutical use.

[0037] The term "pharmaceutically acceptable salt" is intended to mean, within the framework of the present invention, salts of compounds which are pharmaceutically acceptable as defined above and which possess the pharmacological activity of the corresponding compounds.

[0038] Pharmaceutically acceptable salts are (1) Formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or acid addition salts formed with organic acids such as acetic acid, benzenesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, glutamic acid, glycolic acid, hydroxynaphthoic acid, 2-hydroxyethanesulfonic acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, muconic acid, 2-naphthalenesulfonic acid, propionic acid, succinic acid, dibenzoyl-L-tartaric acid, tartaric acid, p-toluenesulfonic acid, trimethylacetic acid, and trifluoroacetic acid, and the like, and (2) Salts formed when the acid protons present in the compound are replaced by metal ions such as alkali metal ions, alkaline earth metal ions, etc., or aluminum ions; or when coordinated with organic or inorganic bases are included. Acceptable organic bases include diethanolamine, ethanolamine, N-methylglucamine, triethanolamine, tromethamine, and the like. Acceptable inorganic bases include aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, and sodium hydroxide.

[0039] "Stereoisomers" are isomeric compounds that have the same molecular formula and sequence of bonded atoms but differ in the three-dimensional coordination of those atoms in space. Stereoisomers include enantiomers, diastereoisomers, cis-trans and E-Z isomers, conformational isomers, and anomers. In a specific aspect of the present disclosure, stereoisomers include diastereoisomers and enantiomers.

[0040] "Tautomers" are isomeric compounds that differ only in the position of protons and electrons.

[0041] The "solvates" of the present disclosure include ordinary solvates such as those formed during the final step of preparing the compounds of the present invention due to the presence of a solvent. This may be, for example, a hydrate or an alcoholate such as an ethanolate.

[0042] The term "halogen" or "halo", when used in the present invention, refers to a fluorine, bromine, chlorine or iodine atom.

[0043] The term "C x ~C y ", when used in the present disclosure, means that the corresponding hydrocarbon chain contains from x to y carbon atoms. For example, if the term "C1~C3" is used, this means that the corresponding hydrocarbon chain may contain from 1 to 3 carbon atoms, in particular 1, 2 or 3 carbon atoms. For example, if the term C1~C6 is used, this means that the corresponding hydrocarbon chain may contain from 1 to 6 carbon atoms, in particular 1, 2, 3, 4, 5 or 6 carbon atoms. Thus, the term "C0" means that no hydrocarbon chain is present and only a single bond is present.

[0044] The term "alkyl", when used in the present invention, refers to a monovalent straight-chain or branched saturated hydrocarbon chain. For example, the term "(C1~C3)alkyl" more specifically means methyl, ethyl, n-propyl, or isopropyl. The term "(C1~C6)alkyl" more specifically means methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, pentyl or a straight-chain or branched hexyl.

[0045] The term "heteroalkyl" refers to an alkyl as defined herein, wherein the aliphatic carbon chain contains at least one heteroatom such as O, N or S at one or both of its two ends (especially the end bonded to the rest of the molecule) and / or is interrupted thereby. Examples of heteroalkyl are in particular alkoxy (-O-alkyl), alkylthio (-S-alkyl), and alkylamino (-NH(alkyl) or -N(alkyl)2). "C1-C6 heteroalkyl" refers to a heteroalkyl having 1 to 6 carbon atoms and at least one heteroatom such as O, N or S. Examples of heteroalkyl (or C1-C6 heteroalkyl) include, but are not limited to, methoxy, ethoxy, propyloxy, isopropyloxy, butyloxy, isobutyloxy, tert-butyloxy, pentyloxy, hexyloxy, methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, tert-butylthio, pentylthio, hexylthio, methylamino, ethylamino, propylamino, isopropylamino, butylamino, isobutylamino, tert-butylamino, pentylamino, or hexylamino.

[0046] The term "alkoxy" or "alkyloxy", as used in the present invention, refers to an alkyl group as defined above, which is bonded to the molecule via an oxygen atom. (C1-C3) alkoxy includes methoxy, ethoxy, propyloxy, and isopropyloxy. (C1-C6) alkoxy includes methoxy, ethoxy, propyloxy, isopropyloxy, butyloxy, isobutyloxy, tert-butyloxy, pentyloxy and hexyloxy. In a particular embodiment, "alkoxy" or "alkyloxy" is methoxy.

[0047] The term "haloalkyl" refers to an alkyl as defined herein, substituted with at least one halogen, for example 1, 2 or 3 halogens. "(C1-C6) haloalkyl" refers to a haloalkyl having 1 to 6 carbon atoms and at least one halogen such as 1 fluorine, chlorine, bromine, or iodine atom. Haloalkyl includes fluoromethyl (-CH2F), difluoromethyl (-CHF2), or trifluoromethyl (-CF3).

[0048] The term "alkenyl", as used in the present invention, includes, but is not limited to, a straight-chain or branched monounsaturated hydrocarbon chain containing at least one double bond, including ethenyl, propenyl, butenyl, pentenyl, hexenyl and the like.

[0049] The term "alkynyl", as used in the present invention, includes, but is not limited to, a straight-chain or branched monounsaturated hydrocarbon chain containing at least one triple bond, including ethynyl, propynyl, butynyl, pentynyl, hexynyl and the like. Preferably, the alkynyl group, when used in the present disclosure, contains one triple bond.

[0050] In particular, the term "(C0-C6) alkyl-ethynyl", when used in the present disclosure, refers to an alkynyl as defined above containing one terminal triple bond; that is, (C0-C6) alkyl substituted at the terminal with ethynyl.

[0051] The term "cycloalkyl" corresponds to a saturated or unsaturated monocyclic, bicyclic or tricyclic alkyl group containing between 3 and 20 carbon atoms. This includes fused, bridged, or spiro-linked cycloalkyl groups. The term "cycloalkyl" includes, for example, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, preferably cyclopropyl. The term "spirocycloalkyl" includes, for example, spirocyclopentyl. In a particular embodiment, the term "cycloalkyl" corresponds to a saturated monocycloalkyl group containing between 3 and 7 carbon atoms. In a particular embodiment, the cycloalkyl group is cyclohexyl.

[0052] The term "heterocycloalkyl" corresponds to a saturated or unsaturated cycloalkyl group as defined above, further containing at least one heteroatom such as a nitrogen, oxygen, or sulfur atom. This includes fused, bridged, or spiro-linked heterocycloalkyl groups. Representative heterocycloalkyl groups include, but are not limited to, 3-dioxolane, benzo[1,3]dioxolyl, pyrazolinyl, pyranyl, thiomorpholinyl, pyrazolidinyl, piperidyl, piperazinyl, 1,4-dioxanyl, imidazolinyl, pyrrolinyl, pyrrolidinyl, piperidinyl, imidazolidinyl, morpholinyl, 1,4-dithianyl, pyrrolidinyl, oxazolinyl, oxazolidinyl, isoxazolinyl, isoxazolidinyl, thiazolinyl, thiazolidinyl, isothiazolinyl, isothiazolidinyl, dihydropyranyl, tetrahydro-2H-pyranyl, tetrahydrofuranyl, and tetrahydrothiophenyl. The term "heterocycloalkyl" can also refer to a 5- to 10-membered bridged heterocyclyl such as 7-oxabicyclo[2,2,1]heptanyl.

[0053] The term "aryl" corresponds to a monocyclic or bicyclic aromatic hydrocarbon having 6 to 12 carbon atoms. For example, the term "aryl" includes phenyl, biphenyl, or naphthyl. In a particular embodiment, aryl is phenyl.

[0054] As used herein, the term "heteroaryl" corresponds to an aromatic, monocyclic or polycyclic group containing from 5 to 14 atoms including at least one heteroatom such as a nitrogen, oxygen or sulfur atom. Examples of such monocyclic and polycyclic heteroaryl groups are pyridinyl, thiazolyl, thiophenyl, furanyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, benzofuranyl, thianaphthalenyl, indolyl, indolinyl, quinolinyl, isoquinolinyl, benzimidazolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, triazinyl, thianthrenyl, isobenzofuranyl, chromenyl, xanthenyl, phenoxanthinyl, isothiazolyl, isoxazolyl, pyrazinyl, pyridazinyl, indolizinyl, isoindolyl, indazolyl, purinyl, quinolidinyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, pteridinyl, carbazolyl, β-carbolinyl, phenanthridinyl, acridinyl, pyrimidinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, furoxanyl, phenoxazinyl, isochromanyl, chromanyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, indolinyl, isoindolinyl, oxazolidinyl, benzotriazolyl, benzisoxazolyl, oxindolyl, benzoxazolinyl, benzothienyl, benzothiazolyl, isatinyl, dihydropyridyl, pyrimidinyl, s-triazinyl, oxazolyl, or thiophenyl. In a particular embodiment, the heteroaryl group is thiophenyl, pyridinyl, pyrazinyl, or thiazolyl.

[0055] As used herein, the term "(C1-C6)alkyl-aryl" refers to a (C1-C6)alkyl group as defined above substituted with an aryl group as defined above. In particular, this can be a benzyl group.

[0056] As used herein, the term "(C1-C6)alkyl - heterocyclic ring" refers to a (C1-C6)alkyl group as defined above substituted with a heterocyclic ring group as defined above. In particular, "(C1-C6)alkyl - heteroaryl" refers to a (C1-C6)alkyl group as defined above substituted with a heteroaryl group as defined above.

[0057] The expression "substituted by at least~" or "substituted by" means that the group is substituted by one or more substituents in the list. For example, the expression "C1-C6 alkyl substituted by at least one halogen" or "C1-C6 alkyl substituted by one halogen" may include fluoromethyl (-CH2F), difluoromethyl (-CHF2), or trifluoromethyl (-CF3).

[0058] The expression "optionally substituted" means that the group is either unsubstituted or substituted by one or more substituents in the list.

[0059] In the context of the present invention, substituents are halogen; CN; NO2; (C1-C6)alkyl; (C1-C6)haloalkyl; (C1-C6)haloalkoxy, (C1-C6)halothioalkoxy, optionally substituted aryl (in particular, optionally substituted by 1 or 2 (C1-C6)alkyl or NO2); heteroaryl; oxo; NR a R b ; COR c ; CO2R d ; CONR e R f ; OR g ; SR h ; SO2R i ; SO2NR j R k ; NR l COR m ; R n NR O R P ; NR q SO2R rmay be selected from the group consisting of; R a ~R r are, independently of each other, H, (C1-C6)alkyl, (C1-C6)haloalkyl, aryl, (C1-C6)alkyl-aryl, heteroaryl or (C1-C6)alkyl-heteroaryl.

[0060] "-CO-" or "-C(O)-" refers to an oxo group. "-SO-" or "-S(O)-" refers to a sulfinyl group. "-SO2-" or "-S(O2)-" refers to a sulfonyl group.

[0061] As used herein, the terms "subject", "individual" or "patient" are interchangeable and refer to animals, preferably mammals, and even more preferably humans including adults and children. However, the term "subject" can also refer, inter alia, to non-human animals, particularly mammals such as dogs, cats, horses, cows, pigs, sheep and non-human primates.

[0062] In the context of the present disclosure, the term "treatment" refers to curative, symptomatic, and prophylactic treatment. The pharmaceutical compositions, kits, products and combination preparations of the present invention can be used in humans having a disease or disorder. The pharmaceutical compositions, kits, products and combination formulations of the present invention do not necessarily cure the patient, but rather delay or slow progression, or prevent further progression of the disease or disorder, and / or thereby improve the patient's condition. In the treatment of a disease or disorder, the pharmaceutical composition of the present invention is administered in a therapeutically effective amount.

[0063] Throughout this specification, "treatment of a disease or disorder" or the like, as described with respect to the pharmaceutical compositions of the present invention, means: a) a method for treating a disease or disorder, comprising administering to a subject in need of such treatment a therapeutically effective amount of a compound of the present invention or a pharmaceutical composition comprising said compound; b) the use of a compound of the present invention or a pharmaceutical composition comprising said compound for treating a disease or disorder; c) the use of a compound of the present invention or a pharmaceutical composition comprising said compound for manufacturing a medicament for treating a disease or disorder; and / or d) a compound of the present invention or a pharmaceutical composition comprising said compound for use in the treatment of a disease or disorder.

[0064] As used herein, the term "therapeutic effect" refers to an effect induced by an active ingredient according to the present invention, or a pharmaceutical composition, which can prevent or delay the appearance or occurrence of a disease or disorder, or cure or attenuate the effects of a disease or disorder.

[0065] "Therapeutically effective amount" or "active amount" or "effective amount" means, in mammals including humans, an amount of the pharmaceutical composition of the present invention that, alone or in combination with other active ingredients of a pharmaceutical composition, kit, product or combination preparation, prevents, eliminates or reduces the adverse effects of a disease or disorder. It is understood that the dosage administered may be less than the "therapeutically effective amount" defined for each compound in the composition, whether used alone or for each compound used in combination with treatments other than those described herein. The "therapeutically effective amount" of the composition will be adapted by those skilled in the art according to the patient, the condition, the mode of administration, etc.

[0066] As used herein, the term "pharmaceutically acceptable excipient" refers to any component other than the active ingredient present in a pharmaceutical composition. Its addition may be for the purpose of imparting a particular consistency or other physical or gustatory characteristics to the final product. A pharmaceutically acceptable excipient must be devoid of any interaction with the active ingredient, especially a chemical interaction.

[0067] In the context of the present invention, a range of values represented by "from X to XX" or "between X and XX" includes the upper and lower limits.

[0068] Compounds for use As described, the present invention relates to a compound of the following general formula (I) for use in preventing and / or treating metallothionein-related disorders, or a pharmaceutically acceptable salt, stereoisomer, tautomer or solvate thereof, or a pharmaceutically acceptable salt and / or solvate thereof, formula (I) being:

[0069]

Chemical formula

[0070] [wherein, R 1 , R 2 , R 3 and R 4 are independently selected from the group consisting of H, OH, -C(O)OR 9 -, -S(O)2R 10 -, -C(O)R 9 -, -S(O)R 10 -, -NR 11 R 12 -, optionally substituted (C1-C 24 ) alkyl, optionally substituted (C2-C 24 ) alkenyl, optionally substituted (C2-C 24 ) alkynyl, optionally substituted (C3-C 10 ) cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl and optionally substituted heteroaryl, provided that at least one of R 1 , R 2 and R 3 is not H; or R 1 and R 4 are H, OH, -C(O)OR 9 -, -S(O)2R 10 -, -C(O)R 9-, -S(O)R 10 -, -NR 11 R 12 -, optionally substituted (C1 - C 24 ) alkyl, optionally substituted (C2 - C 24 ) alkenyl, optionally substituted (C2 - C 24 ) alkynyl, optionally substituted (C3 - C 10 ) cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl and optionally substituted heteroaryl, independently selected from the group consisting of; R 2 and R 3 together with the nitrogen atom to which they are attached form an optionally substituted heterocycloalkyl; X is (C1 - C 12 ) alkyl, -O-(C1 - C 12 ) alkyl-, -C(O)-, -C(O)-(C1 - C 12 ) alkyl- and -NH-C(O)-(C1 - C 12 ) alkyl-, -S-(C1 - C 12 ) alkyl-, -S(O)-(C1 - C 12 ) alkyl-, -S(O)2-(C1 - C 12 ) alkyl-, selected from the group consisting of; (C1 - C 12 ) alkyl group may be substituted by one heteroatom and / or may be interrupted; Y 0 , Y 1 , Y 2 and Y 3 are each independently absent or -NH-, -O-, -S-, -S(O)-, -S(O)2-, -C(O)-, -C(O)O-, -OC(O)-, -NHC(O)-, -C(O)NH-; -C(O)NR 14 - -(C1 - C 24 ) alkyl - NH-, -(C1 - C 24 ) alkyl - O-, -(C1 - C 24 ) alkyl - S-, (C1 - C 24 ) alkyl - NR 13 -, -(C1 - C 24 ) alkyl - S(O)-, -(C1 - C24 ) alkyl-S(O)2-, -(C1-C 24 ) alkyl-C(O)-, -(C1-C 24 ) alkyl-C(O)O-, -(C1-C 24 ) alkyl-OC(O)-, -(C1-C 24 ) alkyl-NHC(O)-, -(C1-C 24 ) alkyl-C(O)NH-, -(C1-C 24 ) alkyl-C(O)NR 14 -, (C1-C 24)alkyl, -NH-C(O)-NH-, -NH-S(O)-NH-, -NH-S(O2)-NH-, -S-C(O)-NH-, -O-C(O)-NH-, -O-S(O)-NH-, -O-S(O2)-NH-, -S-CH2-C(O)-NH-, -S-CH2-S(O)-NH-, -S-CH2-S(O2)-NH-, -S(O)-CH2-C(O)-NH-, -S(O2)-CH2-C(O)-NH-, -O-CH2-C(O)-NH-, -O-CH2-S(O)-NH-, -O-CH2-S(O2)-NH-, -NH-CH2-C(O)-NH-, -NH-CH2-S(O)-NH-, -NH-CH2-S(O2)-NH-, -O-(CH2)2-NH-C(O)-, -O-(CH2)2-N(CH3)-C(O)-, -O-(CH2)2-NH-S(O)-, -O-(CH2)2-N(CH3)-S(O)-, -O-(CH2)2-NH-S(O2)-, -O-(CH2)2-N(CH3)-S(O2)-, -S-(CH2)2-NH-C(O)-, -S-(CH2)2-N(CH3)-C(O)-, -S-(CH2)2-NH-S(O)-, -S-(CH2)2-N(CH3)-S(O)-, -S-(CH2)2-NH-S(O2)-, -S-(CH2)2-N(CH3)-S(O2)-, -NH-(CH2)2-NH-C(O)-, -NH-(CH2)2-N(CH3)-C(O)-, -NH-(CH2)2-NH-S(O)-, -NH-(CH2)2-N(CH3)-S(O)-, -NH-(CH2)2-NH-S(O2)-, -NH-(CH2)2-N(CH3)-S(O2)-, -O-CH2-CH(CH2-OH)-NH-C(O)-, -O-CH2-CH(CH2-OCH3)-NH-C(O)-, -O-CH2-CH(CH3)-NH-C(O)-, -O-CH(CH3)-CH2-NH-C(O)-, -O-CH2-CH(CH2-OH)-NH-S(O)-, -O-CH2-CH(CH2-OCH3)-NH-S(O)-, -O-CH2-CH(CH3)-NH-S(O)-, -O-CH(CH3)-CH2-NH-S(O)-, -O-CH2-CH(CH2-OH)-NH-S(O2)-, -O-CH2-CH(CH2-OCH3)-NH-S(O2)-, -O-CH2-CH(CH3)-NH-S(O2)-, -O-CH(CH3)-CH2-NH-S(O2)-,-S-CH2-CH(CH2-OH)-NH-C(O)-, -S-CH2-CH(CH2-OCH3)-NH-C(O)-, -S-CH2-CH(CH3)-NH-C(O)-, -S-CH(CH3)-CH2-NH-C(O)-, -S-CH2-CH(CH2-OH)-NH-S(O)-, -S-CH2-CH(CH2-OCH3)-NH-S(O)-, -S-CH2-CH(CH3)-NH-S(O)-, -S-CH(CH3)-CH2-NH-S(O)-, -S-CH2-CH(CH2-OH)-NH-S(O2)-, -S-CH2-CH(CH2-OCH3)-NH-S(O2)-, -S-CH2-CH(CH3)-NH-S(O2)-, -S-CH(CH3)-CH2-NH-S(O2)-, -NH-CH2-CH(CH2-OH)-NH-C(O)-, -NH-CH2-CH(CH2-OCH3)-NH-C(O)-, -NH-CH2-CH(CH3)-NH-C(O)-, -NH-CH(CH3)-CH2-NH-C(O)-, -NH-CH2-CH(CH2-OH)-NH-S(O)-, -NH-CH2-CH(CH2-OCH3)-NH-S(O)-, -NH-CH2-CH(CH3)-NH-S(O)-, -NH-CH(CH3)-CH2-NH-S(O)-, -NH-CH2-CH(CH2-OH)-NH-S(O2)-, -NH-CH2-CH(CH2-OCH3)-NH-S(O2)-, -NH-CH2-CH(CH3)-NH-S(O2)-, -NH-CH(CH3)-CH2-NH-S(O2)-, -O-(CH2)2-NH-, -S-(CH2)2-NH-, and -NH-(CH2)2-NH-; (C1-C, 24 ) The alkyl group may be substituted; R 5 、R 6 、R 7 and R 8 are H, halogen, optionally substituted (C1-C 24 ) alkyl, optionally substituted (C2-C 24 ) alkenyl, optionally substituted (C2-C 24 ) alkynyl, optionally substituted (C3-C 10) Independently selected from the group consisting of cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; R 9 ~R 14 is optionally substituted (C1-C 12 ) alkyl, optionally substituted (C2-C 12 ) alkenyl, optionally substituted (C2-C 12 ) alkynyl, and is independently selected from the group consisting of optionally substituted aryl].

[0071] In particular, R 9 is optionally substituted (C1-C 12 ) alkyl, optionally substituted (C2-C 12 ) alkenyl, optionally substituted (C2-C 12 ) alkynyl, and is selected from the group consisting of aryl optionally substituted with (C1-C6) alkyl; R 10 ~R 14 is optionally substituted (C1-C 12 ) alkyl, optionally substituted (C2-C 12 ) alkenyl, optionally substituted (C2-C 12 ) alkynyl, and is independently selected from the group consisting of optionally substituted aryl.

[0072] The present invention also relates to the use of a compound of general formula (I) as defined above, in particular one of those disclosed in Table 1 (Table 1), or a pharmaceutically acceptable salt and / or solvate thereof, or a pharmaceutical composition containing the same, for the manufacture of a medicament for preventing and / or treating a metallothiasis-related disorder.

[0073] The present invention further relates to a method for preventing and / or treating a metallothionein-related disorder in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of general formula (I) as defined above, in particular one of those disclosed in Table 1, or a pharmaceutically acceptable salt and / or solvate thereof, or a pharmaceutical composition comprising the same.

[0074] In a specific embodiment, the metallothionein-related disorder is a disorder associated with ferroptosis and / or cuproptosis. Advantageously, the metallothionein-related disorder is selected from hemorrhagic stroke; ischemic heart injury; ischemic kidney injury; ischemia-reperfusion injury (IRI) such as IRI occurring during organ transplantation (liver, lung, heart, kidney, pancreas, intestine); neurodegenerative diseases selected from Huntington's disease, dementia, and amyotrophic lateral sclerosis (ALS); age-related diseases or disorders; sepsis; ischemia-reperfusion; and diabetes. In particular, the use of the compounds according to the invention is specifically disclosed below in the present specification.

[0075] In the context of the present invention, a compound of general formula (I) as defined above, or a pharmaceutically acceptable salt and / or solvate thereof, can also be used for preventing and / or treating iron and / or copper-related disorders. The present invention also relates to the use of a compound of general formula (I) as defined above, or a pharmaceutically acceptable salt and / or solvate thereof, or a pharmaceutical composition comprising the same, for manufacturing a medicament for use in preventing and / or treating iron and / or copper-related disorders. The present invention also relates to a method for preventing and / or treating iron and / or copper-related disorders in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of general formula (I) as defined above, or a pharmaceutically acceptable salt and / or solvate thereof, or a pharmaceutical composition comprising the same.

[0076] In this context, iron and / or copper-related disorders can be selected from HFE-related iron overload; non-HFE-related iron overload; congenital atransferrinemia; iron overload-related anemia such as thalassemia, spinal dysplasia, and hematopoietic stem cell transplantation-related disorders; chronic liver disease; chronic inflammation associated with cancer; autoimmune or inflammatory diseases; neurodegeneration with brain copper or iron accumulation-related diseases such as Wilson's disease; and polygenic neurodegeneration-related diseases such as Parkinson's disease and Alzheimer's disease.

[0077] In particular, iron-related disorders can be selected from HFE-related iron overload; non-HFE-related iron overload; congenital atransferrinemia; iron overload-related anemia such as thalassemia, spinal dysplasia, and hematopoietic stem cell transplantation-related disorders; chronic liver disease; chronic inflammation associated with cancer; autoimmune or inflammatory diseases; neurodegeneration with brain iron accumulation-related diseases such as Wilson's disease; and polygenic neurodegeneration-related diseases such as Parkinson's disease and Alzheimer's disease.

[0078] In particular, copper-related disorders can be selected from HFE-related iron overload; non-HFE-related iron overload; congenital atransferrinemia; iron overload-related anemia such as thalassemia, spinal dysplasia, and hematopoietic stem cell transplantation-related disorders; chronic liver disease; chronic inflammation associated with cancer; autoimmune or inflammatory diseases; neurodegeneration with brain copper accumulation-related diseases such as Wilson's disease; and polygenic neurodegeneration-related diseases such as Parkinson's disease and Alzheimer's disease.

[0079] In the compound of general formula (I), X is selected from the group consisting of (C1-C 12 [[ID=!4]]) alkyl, -O-(C1-C 12 ) alkyl-, -C(O)-, -C(O)-(C1-C 12 ) alkyl-, -NH-C(O)-(C1-C 12 ) alkyl-, -S-(C1-C 12 ) alkyl-, -S(O)-(C1-C 12 ) alkyl-, and -S(O)2-(C1-C 12 ) alkyl-; (C1-C 12) The alkyl group may be substituted by a heteroatom and / or may be interrupted. Preferably, X is selected from the group consisting of (C1-C 12 ) alkyl, -O-(C1-C 12 ) alkyl-, -C(O)-, -C(O)-(C1-C 12 ) alkyl-, -NH-C(O)-(C1-C 12 ) alkyl-; the (C1-C 12 ) alkyl group may be substituted by a heteroatom and / or may be interrupted. Preferably, X is selected from the group consisting of (C1-C6) alkyl, -O-(C1-C6) alkyl-, -C(O)-, -C(O)-(C1-C6) alkyl- and -NH-C(O)-(C1-C6) alkyl-; the (C1-C6) alkyl group may be substituted by a heteroatom and / or may be interrupted. More preferably, X is selected from the group consisting of (C1-C3) alkyl, -O-(C1-C3) alkyl-, -C(O)-(C1-C3) alkyl- and -NH-C(O)-(C1-C3) alkyl-; the (C1-C3) alkyl group may be substituted by a heteroatom and / or may be interrupted.

[0080] In a specific embodiment, X is (C1-C6) alkyl. Preferably, X is methyl, ethyl or n-propyl, more preferably ethyl.

[0081] In the compound of general formula (I), Y 0 , Y 1 , Y 2 and Y 3 are each independently absent or -NH-, -O-, -S-, -S(O)-, -S(O)2-, -C(O)-, -C(O)O-, -OC(O)-, -NHC(O)-, -C(O)NH-; -C(O)NR 14 -, -(C1-C 24 ) alkyl-NH-, -(C1-C 24 ) alkyl-O-, -(C1-C 24 ) alkyl-S-, (C1-C 24 ) alkyl-NR 13 -, -(C1-C24 ) alkyl-S(O)-, -(C1-C 24 ) alkyl-S(O)2-, -(C1-C 24 ) alkyl-C(O)-, -(C1-C 24 ) alkyl-C(O)O-, -(C1-C 24 ) alkyl-OC(O)-, -(C1-C 24 ) alkyl-NHC(O)-, -(C1-C 24 ) alkyl-C(O)NH-, -(C1-C 24 ) alkyl-C(O)NR 14 -, optionally substituted (C1-C 24)alkyl, -NH-C(O)-NH-, -NH-S(O)-NH-, -NH-S(O2)-NH-, -S-C(O)-NH-, -O-C(O)-NH-, -O-S(O)-NH-, -O-S(O2)-NH-, -S-CH2-C(O)-NH-, -S-CH2-S(O)-NH-, -S-CH2-S(O2)-NH-, -S(O)-CH2-C(O)-NH-, -S(O2)-CH2-C(O)-NH-, -O-CH2-C(O)-NH-, -O-CH2-S(O)-NH-, -O-CH2-S(O2)-NH-, -NH-CH2-C(O)-NH-, -NH-CH2-S(O)-NH-, -NH-CH2-S(O2)-NH-, -O-(CH2)2-NH-C(O)-, -O-(CH2)2-N(CH3)-C(O)-, -O-(CH2)2-NH-S(O)-, -O-(CH2)2-N(CH3)-S(O)-, -O-(CH2)2-NH-S(O2)-, -O-(CH2)2-N(CH3)-S(O2)-, -S-(CH2)2-NH-C(O)-, -S-(CH2)2-N(CH3)-C(O)-, -S-(CH2)2-NH-S(O)-, -S-(CH2)2-N(CH3)-S(O)-, -S-(CH2)2-NH-S(O2)-, -S-(CH2)2-N(CH3)-S(O2)-, -NH-(CH2)2-NH-C(O)-, -NH-(CH2)2-N(CH3)-C(O)-, -NH-(CH2)2-NH-S(O)-, -NH-(CH2)2-N(CH3)-S(O)-, -NH-(CH2)2-NH-S(O2)-, -NH-(CH2)2-N(CH3)-S(O2)-, -O-CH2-CH(CH2-OH)-NH-C(O)-, -O-CH2-CH(CH2-OCH3)-NH-C(O)-, -O-CH2-CH(CH3)-NH-C(O)-, -O-CH(CH3)-CH2-NH-C(O)-, -O-CH2-CH(CH2-OH)-NH-S(O)-, -O-CH2-CH(CH2-OCH3)-NH-S(O)-, -O-CH2-CH(CH3)-NH-S(O)-, -O-CH(CH3)-CH2-NH-S(O)-, -O-CH2-CH(CH2-OH)-NH-S(O2)-, -O-CH2-CH(CH2-OCH3)-NH-S(O2)-, -O-CH2-CH(CH3)-NH-S(O2)-, -O-CH(CH3)-CH2-NH-S(O2)-,-S-CH2-CH(CH2-OH)-NH-C(O)-, -S-CH2-CH(CH2-OCH3)-NH-C(O)-, -S-CH2-CH(CH3)-NH-C(O)-, -S-CH(CH3)-CH2-NH-C(O)-, -S-CH2-CH(CH2-OH)-NH-S(O)-, -S-CH2-CH(CH2-OCH3)-NH-S(O)-, -S-CH2-CH(CH3)-NH-S(O)-, -S-CH(CH3)-CH2-NH-S(O)-, -S-CH2-CH(CH2-OH)-NH-S(O2)-, -S-CH2-CH(CH2-OCH3)-NH-S(O2)-, -S-CH2-CH(CH3)-NH-S(O2)-, -S-CH(CH3)-CH2-NH-S(O2)-, -NH-CH2-CH(CH2-OH)-NH-C(O)-, -NH-CH2-CH(CH2-OCH3)-NH-C(O)-, -NH-CH2-CH(CH3)-NH-C(O)-, -NH-CH(CH3)-CH2-NH-C(O)-, -NH-CH2-CH(CH2-OH)-NH-S(O)-, -NH-CH2-CH(CH2-OCH3)-NH-S(O)-, -NH-CH2-CH(CH3)-NH-S(O)-, -NH-CH(CH3)-CH2-NH-S(O)-, -NH-CH2-CH(CH2-OH)-NH-S(O2)-, -NH-CH2-CH(CH2-OCH3)-NH-S(O2)-, -NH-CH2-CH(CH3)-NH-S(O2)-, -NH-CH(CH3)-CH2-NH-S(O2)-, -O-(CH2)2-NH-, -S-(CH2)2-NH-, and -NH-(CH2)2-NH-; (C1-C, 24 ) The alkyl group may be substituted.

[0082] In a specific embodiment, in the compound of general formula (I), Y 0 , Y 1 , Y 2 and Y 3 are independently absent or -NH-, -O-, -S-, -S(O)-, -S(O)2-, -C(O)-, -C(O)O-, -OC(O)-, -NHC(O)-, -C(O)NH-; -C(O)NR 14 -, -(C1-C 24 ) alkyl-NH-, -(C1-C24 ) alkyl - O -, -(C1 - C 24 ) alkyl - S -, (C1 - C 24 ) alkyl - NR 13 -, -(C1 - C 24 ) alkyl - S(O)-, -(C1 - C 24 ) alkyl - S(O)2 -, -(C1 - C 24 ) alkyl - C(O)-, -(C1 - C 24 ) alkyl - C(O)O -, -(C1 - C 24 ) alkyl - OC(O)-, -(C1 - C 24 ) alkyl - NHC(O)-, -(C1 - C 24 ) alkyl - C(O)NH -, -(C1 - C 24 ) alkyl - C(O)NR 14 -, optionally substituted (C1 - C 24 ) alkyl, -NH - C(O)-NH -, -NH - S(O)-NH -, -NH - S(O2)-NH -, -S - C(O)-NH -, -O - C(O)-NH -, -O - S(O)-NH -, -O - S(O2)-NH -, -O -(CH2)2 - NH -, -S -(CH2)2 - NH -, and -NH -(CH2)2 - NH -; (C1 - C 24 ) the alkyl group may be substituted.

[0083] In a specific embodiment, in the compound of general formula (I), Y 0 , Y 1 , Y 2 and Y 3 are each independently absent or -NH -, -O -, -S -, -S(O)-, -S(O2)-, -C(O)-, -C(O)O -, -OC(O)-, -NHC(O)-, -C(O)NH -; -C(O)NR 14 -, -(C1 - C 24 ) alkyl - NH -, -(C1 - C 24 ) alkyl - O -, -(C1 - C 24 ) alkyl - S -, (C1 - C 24 ) alkyl - NR 13 -, -(C1 - C 24 ) alkyl - S(O)-, -(C1 - C 24 ) alkyl - S(O)2 -, -(C1 - C24 ) Alkyl-C(O)-, -(C1-C 24 ) Alkyl-C(O)O-, -(C1-C 24 ) Alkyl-OC(O)-, -(C1-C 24 ) Alkyl-NHC(O)-, -(C1-C 24 ) Alkyl-C(O)NH-, -(C1-C 24 ) Alkyl-C(O)NR 14 -, and optionally substituted (C1-C 24 ) selected from alkyl; (C1-C 24 ) the alkyl group may be substituted. In particular, Y 0 , Y 1 , Y 2 and Y 3 are each independently absent or -NH-, -O-, -S-, -S(O)-, -S(O)2-, -C(O)-, -C(O)O-, -OC(O)-, -NHC(O)-, -C(O)NH-; -C(O)NR 14 -, -(C1-C 12 ) Alkyl-NH-, -(C1-C 12 ) Alkyl-O-, -(C1-C 12 ) Alkyl-S-, (C1-C 12 ) Alkyl-NR 13 -, -(C1-C 12 ) Alkyl-S(O)-, -(C1-C 12 ) Alkyl-S(O)2-, -(C1-C 12 ) Alkyl-C(O)-, -(C1-C 12 ) Alkyl-C(O)O-, -(C1-C 12 ) Alkyl-OC(O)-, -(C1-C 12 ) Alkyl-NHC(O)-, -(C1-C 12 ) Alkyl-C(O)NH-, -(C1-C 12 ) Alkyl-C(O)NR 14 -, and optionally substituted (C1-C 12 ) selected from alkyl; (C1-C 12 ) the alkyl group may be substituted. More particularly, Y 0 , Y 1 , Y 2 and Y 3is independently absent, or -NH-, -O-, -S-, -S(O)-, -S(O)2-, -C(O)-, -C(O)O-, -OC(O)-, -NHC(O)-, -C(O)NH-; -C(O)NR 14 -, -(C1-C6)alkyl-NH-, -(C1-C6)alkyl-O-, -(C1-C6)alkyl-S-, (C1-C6)alkyl-NR 13 -, -(C1-C6)alkyl-S(O)-, -(C1-C6)alkyl-S(O)2-, -(C1-C6)alkyl-C(O)-, -(C1-C6)alkyl-C(O)O-, -(C1-C6)alkyl-OC(O)-, -(C1-C6)alkyl-NHC(O)-, -(C1-C6)alkyl-C(O)NH-, -(C1-C6)alkyl-C(O)NR 14 -, and is selected from optionally substituted (C1-C6)alkyl; the (C1-C6)alkyl group may be substituted. Preferably, Y 0 , Y 1 , Y 2 and Y 3 is independently absent, or is selected from -O-, and optionally substituted (C1-C6)alkyl.

[0084] In a specific embodiment, Y 0 , Y 1 , Y 2 and Y 3 is independently absent, or is -O-. Preferably, Y 0 is -O-, and Y 1 , Y 2 and Y 3 is independently absent, or is -O-, and preferably is absent.

[0085] In a specific embodiment, in the compound of general formula (I), X is (C1-C6)alkyl, and Y 0 is -O-, and Y 1 , Y 2 and Y 3 is independently absent, or is -O-.

[0086] In a specific embodiment, X is methyl, ethyl or n-propyl, and Y 0 is -O-, and Y 1 , Y 2 and Y 3 are each independently absent or -O-. Preferably, X is methyl, ethyl or n-propyl, and Y 0 is -O-, and Y 1 , Y 2 and Y 3 are absent. More preferably, X is ethyl, and Y 0 is -O-, and Y 1 , Y 2 and Y 3 are absent.

[0087] In the compound of general formula (I), R 5 , R 6 , R 7 and R 8 are each independently selected from the group consisting of H, halogen, optionally substituted (C1-C 24 ) alkyl, optionally substituted (C2-C 24 ) alkenyl, optionally substituted (C2-C 24 ) alkynyl, optionally substituted (C3-C 10 ) cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl and optionally substituted heteroaryl.

[0088] In a specific embodiment, R 5 , R 6 , R 7 and R 8 are independently selected from the group consisting of H, halogen, optionally substituted (C1-C 24 ) alkyl, optionally substituted (C2-C 24 ) alkenyl, optionally substituted (C2-C 24 ) alkynyl. In particular, R 5 , R 6 , R 7 and R 8 are H, halogen, optionally substituted (C1-C 12) Alkyl, optionally substituted (C2 - C 12 ) Alkenyl, optionally substituted (C2 - C 12 ) Alkynyl, independently selected from the group consisting of. More particularly, R 5 , R 6 , R 7 and R 8 are independently selected from the group consisting of H, halogen, optionally substituted (C1 - C6) alkyl, optionally substituted (C2 - C6) alkenyl, and optionally substituted (C2 - C6) alkynyl. Preferably, R 5 , R 6 , R 7 and R 8 are independently selected from the group consisting of H, halogen, haloalkyl, or (C1 - C 24 ) alkyl. More preferably, R 5 , R 6 , R 7 and R 8 are independently selected from the group consisting of H, halogen, haloalkyl such as CF3, or (C1 - C6) alkyl.

[0089] In a specific embodiment, three of R 5 , R 6 , R 7 and R 8 are H, and at least one is as defined above.

[0090] In another specific embodiment, two of R 5 , R 6 , R 7 and R 8 are H, and two are as defined above.

[0091] In another specific embodiment, three of R 5 , R 6 , R 7 and R 8 are H, and one is as defined above.

[0092] In another specific embodiment, R 5 , R6 and R 7 and R 8 is H.

[0093] In another specific embodiment, R 5 and R 6 and R 7 and R 8 are as defined above, but not H.

[0094] In a specific embodiment, one or two of R 5 and R 6 and R 7 and R 8 are selected from the group consisting of H, halogen, haloalkyl such as CF3, or (C1-C6) alkyl, and the others are H.

[0095] In a specific embodiment, Y 0 is -O-, and Y 1 and Y 2 and Y 3 do not exist, - R 5 and R 6 and R 7 and R 8 three of them are H, and the last one is as defined above; or - R 5 and R 6 and R 7 and R 8 two of them are H, and two are as defined above; or - R 5 and R 6 and R 7 and R 8 three of them are H, and one is as defined above; or - R 5 and R 6 and R 7 and R 8 are H; or - R 5 and R 6 and R 7 and R 8 are as defined above, but not H.

[0096] In a specific embodiment, Y 0 is -O-, and Y 1 , Y 2 and Y 3 do not exist, and one or two of R 5 , R 6 , R 7 and R 8 are selected from the group consisting of H, halogen, haloalkyl such as CF3, or (C1-C6) alkyl, and the others are H.

[0097] In one embodiment of the compound of general formula (I), R 1 , R 2 , R 3 and R 4 are H, OH, -C(O)OR 9 -, -S(O)2R 10 -, -C(O)R 9 -, -S(O)R 10 -, -NR 11 R 12 -, optionally substituted (C1-C 24 ) alkyl, optionally substituted (C2-C 24 ) alkenyl, optionally substituted (C2-C 24 ) alkynyl, optionally substituted (C3-C 10 ) cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted (C1-C6) alkyl-aryl, and optionally substituted heteroaryl, independently selected from the group, provided that at least one of R 1 , R 2 and R 3 is not H.

[0098] In a specific embodiment of the compound of general formula (I), R 1 , R 2 , R 3 and R 4 are H, OH, -C(O)OR 9 -, -S(O)2R 10 -, optionally substituted (C1-C 24Alkyl, optionally substituted (C2 - C 24 ), alkenyl, optionally substituted (C2 - C 24 ), alkynyl, optionally substituted (C3 - C 10 ), cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted (C1 - C6) alkyl - aryl, and optionally substituted heteroaryl, independently selected from the group consisting of, provided that R 1 , R 2 and R 3 are such that at least one of them is not H.

[0099] In this definition, "optionally substituted" preferably means unsubstituted or halogen; CN; NO2; (C1 - C6) alkyl; (C1 - C6) haloalkyl; (C1 - C6) haloalkoxy, (C1 - C6) halothioalkoxy, optionally substituted aryl (in particular, optionally substituted with 1 or 2 (C1 - C6) alkyl or NO2); heteroaryl; halogeno - heteroaryl, in particular, halogeno - furanyl; oxo; NR a R b ; COR c ; CO2R d ; CONR e R f ; OR g ; SR h ; SO2R i ; SO2NR j R k ; NR l COR m ; R n NR O R P ; NR q SO2R r ; (wherein R a - R rare, independently of each other, H, (C1-C6)alkyl, (C1-C6)haloalkyl, aryl, (C1-C6)alkyl-aryl, heteroaryl or (C1-C6)alkyl-heteroaryl; in particular, halogen; CN; NO2; (C1-C6)alkyl; (C1-C6)haloalkyl; aryl optionally substituted with 1 or 2 (C1-C6)alkyl or NO2; heteroaryl; oxo; NR a R b ; COR c ; CO2R d ; CONR e R f ; and OR g (wherein R a ~R g are independently of each other selected from the group consisting of H, (C1-C6)alkyl, (C1-C6)haloalkyl, aryl, (C1-C6)alkyl-aryl, heteroaryl or (C1-C6)alkyl-heteroaryl) and may be substituted with at least 1, for example 1, 2 or 3 substituents selected from the group consisting of

[0100] In a specific embodiment, R 1 is preferably selected from the group consisting of H, (C1-C 24 )alkyl, (C2-C 24 )alkenyl, (C2-C 24 )alkynyl, (C3-C 12 )cycloalkyl and aryl; said alkyl, alkenyl, alkynyl, aryl or cycloalkyl group may be substituted with one or more halogens, (C1-C6)alkyl, aryl, oxo, -NH2, -CO2H or -OH. In particular, R 1 is selected from the group consisting of H, (C1-C 12 )alkyl, (C2-C 12 )alkenyl, (C2-C 12 )alkynyl and aryl. Preferably, R 1 is H.

[0101] In a specific embodiment, R 4 is preferably H, (C1-C 24alkyl, (C2-C 24 ) alkenyl, (C2-C 24 ) alkynyl, (C3-C 12 ) cycloalkyl and aryl, and is selected from the group consisting of; the alkyl, alkenyl, alkynyl, aryl or cycloalkyl group may be substituted with one or more halogen, (C1-C6) alkyl, aryl, oxo, -NH2, -CO2H or -OH. In particular, R 4 is selected from the group consisting of H, (C1-C 12 ) alkyl and aryl. Preferably, R 4 is H.

[0102] In a specific embodiment, R 2 and R 3 are H, OH, -C(O)OR 9 -, -S(O)2R 10 -, optionally substituted (C1-C 12 ) alkyl, optionally substituted (C2-C 12 ) alkenyl, optionally substituted (C2-C 12 ) alkynyl, optionally substituted (C3-C 12 ) cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl and optionally substituted heteroaryl, and are independently selected from the group consisting of, provided that at least one of R 1 , R 2 and R 3 is not H, preferably at least one of R 2 and R 3 is not H; or at least one of R 2 and R 3together with the nitrogen atom to which they are attached, form an optionally substituted heterocycloalkyl. In this definition, "optionally substituted" preferably means unsubstituted or preferably halogen; CN; NO2; (C1-C6) alkyl; (C1-C6) haloalkyl; (C1-C6) haloalkoxy, (C1-C6) halothioalkoxy, optionally substituted aryl (in particular optionally substituted with 1 or 2 (C1-C6) alkyl or NO2); heteroaryl; halogeno-heteroaryl, in particular halogeno-furanyl; oxo; NR a R b ; COR c ; CO2R d ; CONR e R f ; OR g ; SR h ; SO2R i ; SO2NR j R k ; NR l COR m ; R n NR O R P ; NR q SO2R r ; (wherein R a ~R r are, independently of one another, H, (C1-C6) alkyl, (C1-C6) haloalkyl, aryl, (C1-C6) alkyl-aryl, heteroaryl or (C1-C6) alkyl-heteroaryl); in particular, (C1-C6) alkyl; halogen; CN; NO2; (C1-C6) haloalkyl; phenyl optionally substituted with 1 or 2 (C1-C6) alkyl or NO2; heteroaryl optionally substituted with -OH; oxo; NR a R b ; (C1-C 12 ) alkyl-NR a R b ; COR c ; CO2R d ; CONR e R f ; and OR g ; (wherein R a ~R gMeans that it may be substituted with at least one, for example 1, 2 or 3 substituents, which are, independently of each other, H, (C1-C6) alkyl, (C1-C6) haloalkyl, aryl, (C1-C6) alkyl-aryl, heteroaryl or (C1-C6) alkyl-heteroaryl.

[0103] In the compound of general formula (I), R 1 , R 2 , R 3 and R 4 One or more of are -C(O)OR 9 -, -S(O)2R 10 -, -C(O)R 9 -, -S(O)R 10 -, or -NR 11 R 12 -, preferably, -C(O)OR 9 - or -S(O)2R 10 - When, R 9 ~R 12 are independently selected from the group consisting of optionally substituted (C1-C 12 ) alkyl, optionally substituted (C2-C 12 ) alkenyl, optionally substituted (C2-C 12 ) alkynyl, and optionally substituted aryl.

[0104] In the compound of general formula (I), R 1 , R 2 , R 3 and R 4 One or more of are -C(O)OR 9 -, -S(O)2R 10 -, -C(O)R 9 -, -S(O)R 10 -, or -NR 11 R 12 -, preferably, -C(O)OR 9 - or -S(O)2R 10 - When, R 9 is optionally substituted (C1-C 12 ) alkyl, optionally substituted (C2-C 12)Alkenyl, optionally substituted (C2 - C 12 )alkynyl, and aryl optionally substituted with (C1 - C6) alkyl, selected from the group consisting of; R 10 ~R 12 are independently selected from the group consisting of optionally substituted (C1 - C 12 )alkyl, optionally substituted (C2 - C 12 )alkenyl, optionally substituted (C2 - C 12 )alkynyl, and optionally substituted aryl.

[0105] In this definition, "optionally substituted" preferably means unsubstituted or substituted with at least 1, for example 1, 2 or 3 substituents which may preferably be (C1 - C6) alkyl.

[0106] In a specific embodiment, R 9 ~R 12 are independently selected from the group consisting of optionally substituted (C1 - C6) alkyl, optionally substituted (C2 - C6) alkenyl, optionally substituted (C2 - C6) alkynyl, and optionally substituted aryl.

[0107] In particular, R 9 is selected from the group consisting of optionally substituted (C1 - C6) alkyl, optionally substituted (C2 - C6) alkenyl, optionally substituted (C2 - C6) alkynyl, and aryl optionally substituted with (C1 - C6) alkyl such as methyl; R 10 ~R 12 are independently selected from the group consisting of optionally substituted (C1 - C6) alkyl, optionally substituted (C2 - C6) alkenyl, optionally substituted (C2 - C6) alkynyl, and optionally substituted aryl.

[0108] Preferably, R 9 ~R 12is independently selected from the group consisting of (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, aryl or aryl substituted with (C1-C6) alkyl such as methyl.

[0109] In another embodiment of the compound of general formula (I), R 1 and R 4 are H, OH, -C(O)OR 9 -, -S(O)2R 10 -, optionally substituted (C1-C 24 ) alkyl, optionally substituted (C2-C 24 ) alkenyl, optionally substituted (C2-C 24 ) alkynyl, optionally substituted (C3-C 10 ) cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl and optionally substituted heteroaryl, independently selected from the group consisting of; R 2 and R 3 together with the nitrogen atom to which they are attached form an optionally substituted heterocycloalkyl.

[0110] In a specific embodiment, the optionally substituted heterocycloalkyl formed by R 2 and R 3 together with the nitrogen atom to which they are attached is preferably an optionally substituted nitrogen-heterocycloalkyl containing 3 to 10 ring atoms; preferably an optionally substituted nitrogen-heterocycloalkyl containing 1 nitrogen atom and 3 to 10 ring atoms. In particular, the nitrogen-heterocycloalkyl is unsubstituted or halogen; CN; NO2; (C1-C6) alkyl; (C1-C6) haloalkyl; (C1-C6) haloalkoxy, (C1-C6) halothioalkoxy, optionally substituted aryl (especially optionally substituted with 1 or 2 (C1-C6) alkyl or NO2); heteroaryl; oxo; NR a R b ; COR c ; CO2R d ; CONR e Rf ; OR g ; SR h ; SO2R i ; SO2NR j R k ; NR l COR m ; R n NR O R P ; NR q SO2R r ; (wherein, R a ~R r are, independently of one another, H, (C1-C6) alkyl, (C1-C6) haloalkyl, aryl, (C1-C6) alkyl-aryl, heteroaryl or (C1-C6) alkyl-heteroaryl); in particular, they are substituted with one or more substituents selected from the list consisting of halogen, (C1-C6) alkyl, aryl, oxo, -NH2, -CO2H or -OH).

[0111] In a specific embodiment, when R 2 and R 3 together with the nitrogen atom to which they are attached form an optionally substituted heterocycloalkyl, R 4 is preferably selected from the group consisting of H, (C1-C 24 ) alkyl, (C2-C 24 ) alkenyl, (C2-C 24 ) alkynyl, (C3-C 12 ) cycloalkyl and aryl; the alkyl, alkenyl, alkynyl, aryl or cycloalkyl group may be substituted with one or more halogen, (C1-C6) alkyl, aryl, oxo, -NH2, -CO2H or -OH; in particular, R 4 is selected from the group consisting of H, (C1-C 12 ) alkyl and aryl; preferably, R 4 is H.

[0112] In a specific embodiment, R 2 and R 3When, together with the nitrogen atom to which they are attached, they form an optionally substituted heterocycloalkyl, R 1 is preferably selected from the group consisting of H, (C1-C 24 )alkyl, (C2-C 24 )alkenyl, (C2-C 24 )alkynyl, (C3-C 12 )cycloalkyl and aryl; said alkyl, alkenyl, alkynyl, aryl or cycloalkyl group may be substituted with one or more halogens, (C1-C6)alkyl, aryl, oxo, -NH2, -CO2H or -OH; in particular, R 1 is selected from the group consisting of H, (C1-C 12 )alkyl, (C2-C 12 )alkenyl, (C2-C 12 )alkynyl and aryl; preferably, R 1 is H.

[0113] In a specific embodiment, when R 2 and R 3 , together with the nitrogen atom to which they are attached, form an optionally substituted heterocycloalkyl: - R 4 is preferably selected from the group consisting of H, (C1-C 24 )alkyl, (C2-C 24 )alkenyl, (C2-C 24 )alkynyl, (C3-C 12 )cycloalkyl and aryl; said alkyl, alkenyl, alkynyl, aryl or cycloalkyl group may be substituted with one or more halogens, (C1-C6)alkyl, aryl, oxo, -NH2, -CO2H or -OH; - R 1 is preferably selected from the group consisting of H, (C1-C 24 )alkyl, (C2-C 24 )alkenyl, (C2-C 24 )alkynyl, (C3-C 12)Selected from the group consisting of cycloalkyl and aryl; said alkyl, alkenyl, alkynyl, aryl or cycloalkyl group may be substituted with one or more halogens, (C1-C6) alkyl, aryl, oxo, -NH2, -CO2H or -OH.

[0114] In a specific embodiment, R 2 and R 3 when, together with the nitrogen atom to which they are attached, form an optionally substituted heterocycloalkyl: - R 4 is preferably selected from the group consisting of H, (C1-C 12 ) alkyl and aryl; - R 1 is preferably selected from the group consisting of H, (C1-C 12 ) alkyl, (C2-C 12 ) alkenyl, (C2-C 12 ) alkynyl and aryl.

[0115] In a specific embodiment, R 2 and R 3 when, together with the nitrogen atom to which they are attached, form an optionally substituted heterocycloalkyl: - R 4 is preferably H; - R 1 is preferably selected from the group consisting of H, (C1-C 12 ) alkyl, (C2-C 12 ) alkenyl, (C2-C 12 ) alkynyl and aryl; more preferably, R 1 is H.

[0116] In a specific embodiment, - X is methyl, ethyl or n-propyl; and / or Y 0 is -O-; and / or Y 1 , Y 2 and Y 3 are independently absent or -O-. - R 2 and R 3 together with the nitrogen atom to which they are attached form an optionally substituted nitrogen - heterocycloalkyl containing 3 to 10 ring atoms; - R 4 is preferably selected from the group consisting of H, (C1 - C 24 )alkyl, (C2 - C 24 )alkenyl, (C2 - C 24 )alkynyl, (C3 - C 12 )cycloalkyl and aryl; said alkyl, alkenyl, alkynyl, aryl or cycloalkyl group may be substituted with one or more halogens, (C1 - C6)alkyl, aryl, oxo, -NH2, -CO2H or -OH; and / or R 1 is preferably selected from the group consisting of H, (C1 - C 24 )alkyl, (C2 - C 24 )alkenyl, (C2 - C 24 )alkynyl, (C3 - C 12 )cycloalkyl and aryl; said alkyl, alkenyl, alkynyl, aryl or cycloalkyl group may be substituted with one or more halogens, (C1 - C6)alkyl, aryl, oxo, -NH2, -CO2H or -OH.

[0117] In a specific embodiment, - X is methyl, ethyl or n - propyl; and / or Y 0 is -O-; and / or Y 1 , Y 2 and Y 3 are independently absent or are -O-; - R 2 and R 3 together with the nitrogen atom to which they are attached form an optionally substituted nitrogen - heterocycloalkyl containing 1 nitrogen atom and 3 to 10 ring atoms; - R 4 is preferably selected from the group consisting of H, (C1 - C 12 )alkyl and aryl; and / or R1 is preferably selected from the group consisting of H, (C1-C 12 ) alkyl, (C2-C 12 ) alkenyl, (C2-C 12 ) alkynyl and aryl.

[0118] In a specific embodiment, - X is methyl, ethyl or n-propyl; and / or Y 0 is -O-; and / or Y 1 , Y 2 and Y 3 are independently absent or -O-; - R 2 and R 3 together with the nitrogen atom to which they are attached form a nitrogen-heterocycloalkyl containing one nitrogen atom and 3 to 10 ring atoms; - R 4 is preferably H; and / or R 1 is preferably selected from the group consisting of H, (C1-C 12 ) alkyl, (C2-C 12 ) alkenyl, (C2-C 12 ) alkynyl and aryl; more preferably, R 1 is H.

[0119] In a specific embodiment, R 2 and R 3 are H, -C(O)OR 9 -, -S(O)2R 10 -, -C(O)R 9 -, -S(O)R 10 -, -NR 11 R 12 -, optionally substituted (C1-C 12 ) alkyl, optionally substituted (C2-C 12 ) alkenyl, optionally substituted (C2-C 12 ) alkynyl, optionally substituted (C3-C 12)When independently selected from the group consisting of cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl and optionally substituted heteroaryl (R 9 ~R 12 is as defined above), R 4 is preferably H, (C1-C 24 )alkyl, (C2-C 24 )alkenyl, (C2-C 24 )alkynyl, (C3-C 12 )cycloalkyl and aryl; said alkyl, alkenyl, alkynyl, aryl or cycloalkyl group may be substituted with one or more halogens, (C1-C6)alkyl, aryl, oxo, -NH2, -CO2H or -OH; in particular, R 4 is selected from the group consisting of H, (C1-C 12 )alkyl and aryl; preferably, R 4 is H.

[0120] In a specific embodiment, R 2 and R 3 are independently selected from the group consisting of H, -C(O)OR 9 -, -S(O)2R 10 -, optionally substituted (C1-C 12 )alkyl, optionally substituted (C2-C 12 )alkenyl, optionally substituted (C2-C 12 )alkynyl, optionally substituted (C3-C 12 )cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl and optionally substituted heteroaryl (R 9 and R 10 are as defined above), R 1 is preferably H, (C1-C 24 )alkyl, (C2-C 24 )alkenyl, (C2-C 24 )alkynyl, (C3-C 12) cycloalkyl and aryl; wherein said alkyl, alkenyl, alkynyl, aryl or cycloalkyl group is optionally substituted with one or more halogen, (C1-C6) alkyl, aryl, oxo, —NH2, —CO2H or —OH; provided that R 1 , R 2 and R 3 At least one of is not H, preferably R 2 and R 3 At least one of is not H; in particular, R 1 is H, (C1~C 12 ) Alkyl, (C2-C 12 ) alkenyl, (C2-C 12 ) selected from the group consisting of alkynyl and aryl; preferably, R 1 is H.

[0121] In one specific embodiment, R 2 and R 3 H, -C(O)OR 9 -, -S(O)2R 10 -, optionally substituted (C1-C 12 ) alkyl, optionally substituted (C2-C 12 ) alkenyl, optionally substituted (C2-C 12 ) alkynyl, optionally substituted (C3-C 12 ) independently selected from the group consisting of cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; R 9 and R 10 is as defined above: -R 4 is preferably H, (C1 to C 24 ) Alkyl, (C2-C 24 ) alkenyl, (C2-C 24 ) alkynyl, (C3-C 12)selected from the group consisting of cycloalkyl and aryl; said alkyl, alkenyl, alkynyl, aryl or cycloalkyl group may be substituted with one or more halogens, (C1-C6)alkyl, aryl, oxo, -NH2, -CO2H or -OH; and / or - R 1 is preferably H, (C1-C 24 )alkyl, (C2-C 24 )alkenyl, (C2-C 24 )alkynyl, (C3-C 12 )selected from the group consisting of cycloalkyl and aryl; said alkyl, alkenyl, alkynyl, aryl or cycloalkyl group may be substituted with one or more halogens, (C1-C6)alkyl, aryl, oxo, -NH2, -CO2H or -OH; provided that R 1 , R 2 and R 3 at least one of which is not H, preferably at least one of R 2 and R 3 is not H.

[0122] In a specific embodiment, R 2 and R 3 are independently selected from the group consisting of H, -C(O)OR 9 -, -S(O)2R 10 -, optionally substituted (C1-C 12 )alkyl, optionally substituted (C2-C 12 )alkenyl, optionally substituted (C2-C 12 )alkynyl, optionally substituted (C3-C 12 )cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl and optionally substituted heteroaryl; when R 9 and R 10 are as defined above: - R 4 is preferably H, (C1-C 12) selected from the group consisting of alkyl and aryl; and / or - R 1 is preferably H, (C1 - C 12 ) alkyl, (C2 - C 12 ) alkenyl, (C2 - C 12 ) alkynyl and aryl; provided that R 1 , R 2 and R 3 at least one of them is not H, preferably, R 2 and R 3 at least one of them is not H.

[0123] In a specific embodiment, R 2 and R 3 are H, -C(O)OR 9 -, -S(O)2R 10 -, optionally substituted (C1 - C 12 ) alkyl, optionally substituted (C2 - C 12 ) alkenyl, optionally substituted (C2 - C 12 ) alkynyl, optionally substituted (C3 - C 12 ) cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl and optionally substituted heteroaryl, independently selected from the group consisting of; R 9 and R 10 are as defined above: - R 4 is preferably H; and / or - R 1 is preferably H, (C1 - C 12 ) alkyl, (C2 - C 12 ) alkenyl, (C2 - C 12 ) alkynyl and aryl; more preferably, R 1 is H; provided that R 1 , R 2 and R 3 at least one of them is not H, preferably, R 2 and R3 At least one of them is not H.

[0124] In a specific embodiment, - X is methyl, ethyl or n-propyl; and / or Y 0 is -O-; and / or Y 1 Y 2 Y 3 and Y - R [[ID=IP18]] 2 and R 3 are independently selected from the group consisting of H, -C(O)OR 9 -, -S(O)₂R 10 -, optionally substituted (C₁-C 12 ) alkyl, optionally substituted (C₂-C 12 ) alkenyl, optionally substituted (C₂-C 12 ) alkynyl, optionally substituted (C₃-C 12 ) cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl and optionally substituted heteroaryl (R 9 and R 10 are as defined above); - R 4 is preferably selected from the group consisting of H, (C₁-C 24 ) alkyl, (C₂-C 24 ) alkenyl, (C₂-C 24 ) alkynyl, (C₃-C 12 ) cycloalkyl and aryl; the alkyl, alkenyl, alkynyl, aryl or cycloalkyl group may be substituted with one or more halogens, (C₁-C₆) alkyl, aryl, oxo, -NH₂, -CO₂H or -OH; and / or R 1 is preferably selected from the group consisting of H, (C₁-C 24 ) alkyl, (C₂-C 24 ) alkenyl, (C₂-C 24 ) alkynyl, (C₃-C 12)Selected from the group consisting of cycloalkyl and aryl; said alkyl, alkenyl, alkynyl, aryl or cycloalkyl group may be substituted with one or more halogens, (C1-C6) alkyl, aryl, oxo, -NH2, -CO2H or -OH; However, R 1 , R 2 and R 3 at least one of which is not H, preferably, R 2 and R 3 at least one of which is not H.

[0125] In a specific embodiment, - X is methyl, ethyl or n-propyl; and / or Y 0 is -O-; and / or Y 1 , Y 2 and Y 3 are independently absent or -O-; - R 2 and R 3 are independently selected from the group consisting of H, -C(O)OR 9 -, -S(O)2R 10 -, optionally substituted (C1-C 12 ) alkyl, optionally substituted (C2-C 12 ) alkenyl, optionally substituted (C2-C 12 ) alkynyl, optionally substituted (C3-C 12 ) cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl and optionally substituted heteroaryl (R 9 and R 10 are as defined above); - R 4 is preferably selected from the group consisting of H, (C1-C 12 ) alkyl and aryl; and / or R 1 is preferably selected from the group consisting of H, (C1-C 12 ) alkyl, (C2-C 12 ) alkenyl, (C2-C 12) selected from the group consisting of alkynyl and aryl; provided that R 1 , R 2 and R 3 at least one of which is not H, preferably, R 2 and R 3 at least one of which is not H.

[0126] In a specific embodiment, - X is methyl, ethyl or n-propyl; and / or Y 0 is -O-; and / or Y 1 , Y 2 and Y 3 are independently absent or -O-; - R 2 and R 3 are H, -C(O)OR 9 -, -S(O)2R 10 -, optionally substituted (C1-C 12 ) alkyl, optionally substituted (C2-C 12 ) alkenyl, optionally substituted (C2-C 12 ) alkynyl, optionally substituted (C3-C 12 ) cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl and optionally substituted heteroaryl, independently selected from the group consisting of (R 9 and R 10 are as defined above); - R 4 is preferably H; and / or R 1 is preferably H, (C1-C 12 ) alkyl, (C2-C 12 ) alkenyl, (C2-C 12 ) alkynyl and aryl, selected from the group consisting of; more preferably, R 1 is H; provided that R 1 , R 2 and R 3 at least one of which is not H, preferably, R 2 and R3 At least one of them is not H.

[0127] In the context of the present invention, compounds of formula (I) for use according to the invention are preferably selected from compounds (001) to (064) and (A1) to (A4) in Table 1 below, or pharmaceutically acceptable salts and / or solvates thereof. Preferably, compounds of formula (I) for use according to the invention are preferably compounds (A1), (A2), (A3), (A4), (002), (003), (004), (008), (009), (010), (012), (013), (014), (015), (016), (017), (018), (019), (2000), (2010), (2011), (2012), (2013), (2014), (2015), (2016), (2017), (2018), (2019), (210), (211), (212), (213), (214), (215), (216), (217), (218), (219), (220), (221), (222), (223), (224), (225), (226), (227), (228), (229), (230), (231), (232), (233), (234), (235), (236), (237), (238), (239), (240), (241), (242), (243), (244), (245), (246), (247), (248), (249), (250), (251), (252), (253), (254), (255), (256), (257), (258), (259), (260), (261), (262), (263), (264), (

[009] More preferably, the compound of formula (I) for use according to the present invention is preferably selected from compounds (001) to (038) of Table 1, or a pharmaceutically acceptable salt and / or solvate thereof. More preferably, the compound of formula (I) for use according to the present invention is preferably selected from compounds (003) to (007), (013), (014), (021), (031) and (034) to (038) of Table 1, or a pharmaceutically acceptable salt and / or solvate thereof. In the context of the present invention, the compound of formula (I) for use according to the present invention is preferably selected from compounds (001) to (038) and (A1) to (A4) of Table 1 below, or a pharmaceutically acceptable salt and / or solvate thereof. Preferably, the compound of formula (I) for use according to the present invention is preferably selected from compounds (001) to (038) of Table 1, or a pharmaceutically acceptable salt and / or solvate thereof. More preferably, the compounds of formula (I) for use according to the present invention are preferably selected from compounds (003) to (007), (013), (014), (021), (029) and (031) to (038) of Table 1, or a pharmaceutically acceptable salt and / or solvate thereof.

[0128] In a specific embodiment, in the compound of formula (I) for use according to the present invention, R 5 , R 6 , R 7 and R 8 are H, Y 0 is -O-, Y 1 , Y 2 and Y 3 are absent, R 1 , R 2 and R 3 are not (C2-C 24 ) alkynyl which may be substituted.

[0129] In a specific embodiment, the compound of formula (I) for use according to the present invention is not compound (A1), (A2), (A3) or (A4).

[0130] New compound The present invention also relates to a compound of general formula (I), or a pharmaceutically acceptable salt, stereoisomer, tautomer or solvate thereof

[0131]

Chemical formula

[0132] or a pharmaceutically acceptable salt and / or solvate thereof [wherein, R 1 , R 2 , R 3 and R 4 are H, -OH, -C(O)OR 9 -, -S(O)2R 10 -, -C(O)R 9 -, -S(O)R 10 -, -NR 11 R 12 -, optionally substituted (C1-C 24 ) alkyl, optionally substituted (C2-C 24 ) alkenyl, optionally substituted (C2-C 24 ) alkynyl, optionally substituted (C3-C 10Independently selected from the group consisting of cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl, provided that R 2 and R 3 at least one of which is not H; or R 1 and R 4 are H, OH, -C(O)OR 9 -, -S(O)2R 10 -, -C(O)R 9 -, -S(O)R 10 -, -NR 11 R 12 -, optionally substituted (C1-C 24 ) alkyl, optionally substituted (C2-C 24 ) alkenyl, optionally substituted (C2-C 24 ) alkynyl, optionally substituted (C3-C 10 ) cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl, independently selected from the group, R 2 and R 3 together with the nitrogen atom to which they are attached, are halogen; CN; NO2; (C1-C6) alkyl; (C1-C6) haloalkyl; (C1-C6) haloalkoxy, (C1-C6) halothioalkoxy, optionally substituted aryl (in particular, optionally substituted with one or two (C1-C6) alkyl or NO2); heteroaryl; oxo; NR a R b ; COR c ; CO2R d ; CONR e R f ; OR g ; SR h ; SO2R i ; SO2NR j R k ; NR l COR m ; R n NR O R P ; NR q SO2Rr ; (wherein, R a ~R r are, independently of one another, H, (C1-C6)alkyl, (C1-C6)haloalkyl, aryl, (C1-C6)alkyl-aryl, heteroaryl or (C1-C6)alkyl-heteroaryl); in particular, halogen, CN, NO2, (C1-C6)alkyl, (C1-C6)haloalkyl, oxo, NR a R b , COR c , C(O)OR d , CONR e R f , and OR g (wherein, R a ~R g are, independently of one another, H or (C1-C6)alkyl) and is optionally substituted with at least one substituent selected from the group consisting of nitrogen-heterocycloalkyl; X is (C1-C 12 )alkyl, -O-(C1-C 12 )alkyl-, -C(O)-, -C(O)-(C1-C 12 )alkyl-, -NH-C(O)-(C1-C 12 )alkyl-, -S-(C1-C 12 )alkyl-, -S(O)-(C1-C 12 )alkyl-, and -S(O)2-(C1-C 12 )alkyl- and is selected from the group consisting of; (C1-C 12 )alkyl group may be substituted by a heteroatom and / or may be interrupted; Y 0 , Y 1 , Y 2 and Y 3 are independently absent or -NH-, -O-, -S-, -S(O)-, -S(O)2-, -C(O)-, -C(O)O-, -OC(O)-, -NHC(O)-, -C(O)NH-; -C(O)NR 14 - -(C1-C 24 )alkyl-NH-, -(C1-C 24 )alkyl-O-, -(C1-C 24 )alkyl-S-, (C1-C24 ) Alkyl-NR 13 -, -(C1-C 24 ) Alkyl-S(O)-, -(C1-C 24 ) Alkyl-S(O)2-, -(C1-C 24 ) Alkyl-C(O)-, -(C1-C 24 ) Alkyl-C(O)O-, -(C1-C 24 ) Alkyl-OC(O)-, -(C1-C 24 ) Alkyl-NHC(O)-, -(C1-C 24 ) Alkyl-C(O)NH-, -(C1-C 24 ) Alkyl-C(O)NR 14 -, (C1-C 24)Alkyl, -NH-C(O)-NH-, -NH-S(O)-NH-, -NH-S(O2)-NH-, -S-C(O)-NH-, -O-C(O)-NH-, -O-S(O)-NH-, -O-S(O2)-NH-, -S-CH2-C(O)-NH-, -S-CH2-S(O)-NH-, -S-CH2-S(O2)-NH-, -S(O)-CH2-C(O)-NH-, -S(O2)-CH2-C(O)-NH-, -O-CH2-C(O)-NH-, -O-CH2-S(O)-NH-, -O-CH2-S(O2)-NH-, -NH-CH2-C(O)-NH-, -NH-CH2-S(O)-NH-, -NH-CH2-S(O2)-NH-, -O-(CH2)2-NH-C(O)-, -O-(CH2)2-N(CH3)-C(O)-, -O-(CH2)2-NH-S(O)-, -O-(CH2)2-N(CH3)-S(O)-, -O-(CH2)2-NH-S(O2)-, -O-(CH2)2-N(CH3)-S(O2)-, -S-(CH2)2-NH-C(O)-, -S-(CH2)2-N(CH3)-C(O)-, -S-(CH2)2-NH-S(O)-, -S-(CH2)2-N(CH3)-S(O)-, -S-(CH2)2-NH-S(O2)-, -S-(CH2)2-N(CH3)-S(O2)-, -NH-(CH2)2-NH-C(O)-, -NH-(CH2)2-N(CH3)-C(O)-, -NH-(CH2)2-NH-S(O)-, -NH-(CH2)2-N(CH3)-S(O)-, -NH-(CH2)2-NH-S(O2)-, -NH-(CH2)2-N(CH3)-S(O2)-, -O-CH2-CH(CH2-OH)-NH-C(O)-, -O-CH2-CH(CH2-OCH3)-NH-C(O)-, -O-CH2-CH(CH3)-NH-C(O)-, -O-CH(CH3)-CH2-NH-C(O)-, -O-CH2-CH(CH2-OH)-NH-S(O)-, -O-CH2-CH(CH2-OCH3)-NH-S(O)-, -O-CH2-CH(CH3)-NH-S(O)-, -O-CH(CH3)-CH2-NH-S(O)-, -O-CH2-CH(CH2-OH)-NH-S(O2)-, -O-CH2-CH(CH2-OCH3)-NH-S(O2)-, -O-CH2-CH(CH3)-NH-S(O2)-, -O-CH(CH3)-CH2-NH-S(O2)-,-S-CH2-CH(CH2-OH)-NH-C(O)-, -S-CH2-CH(CH2-OCH3)-NH-C(O)-, -S-CH2-CH(CH3)-NH-C(O)-, -S-CH(CH3)-CH2-NH-C(O)-, -S-CH2-CH(CH2-OH)-NH-S(O)-, -S-CH2-CH(CH2-OCH3)-NH-S(O)-, -S-CH2-CH(CH3)-NH-S(O)-, -S-CH(CH3)-CH2-NH-S(O)-, -S-CH2-CH(CH2-OH)-NH-S(O2)-, -S-CH2-CH(CH2-OCH3)-NH-S(O2)-, -S-CH2-CH(CH3)-NH-S(O2)-, -S-CH(CH3)-CH2-NH-S(O2)-, -NH-CH2-CH(CH2-OH)-NH-C(O)-, -NH-CH2-CH(CH2-OCH3)-NH-C(O)-, -NH-CH2-CH(CH3)-NH-C(O)-, -NH-CH(CH3)-CH2-NH-C(O)-, -NH-CH2-CH(CH2-OH)-NH-S(O)-, -NH-CH2-CH(CH2-OCH3)-NH-S(O)-, -NH-CH2-CH(CH3)-NH-S(O)-, -NH-CH(CH3)-CH2-NH-S(O)-, -NH-CH2-CH(CH2-OH)-NH-S(O2)-, -NH-CH2-CH(CH2-OCH3)-NH-S(O2)-, -NH-CH2-CH(CH3)-NH-S(O2)-, -NH-CH(CH3)-CH2-NH-S(O2)-, -O-(CH2)2-NH-, -S-(CH2)2-NH-, and -NH-(CH2)2-NH-; (C1-C, 24 ) The alkyl group may be substituted; preferably, Y 0 is not non-existent, R 5 、R 6 、R 7 and R 8 are H, halogen, optionally substituted (C1-C 24 ) alkyl, optionally substituted (C2-C 24 ) alkenyl, optionally substituted (C2-C 24 ) alkynyl, optionally substituted (C3-C 10) Independently selected from the group consisting of cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; R 9 ~R 14 is optionally substituted (C1-C 12 ) alkyl, optionally substituted (C2-C 12 ) alkenyl, optionally substituted (C2-C 12 ) alkynyl, independently selected from the group consisting of optionally substituted aryl; provided that R 5 , R 6 , R 7 and R 8 are H, Y 0 is -O-, Y 1 , Y 2 and Y 3 do not exist, R 1 , R 2 and R 3 are not optionally substituted (C2-C 24 ) alkynyl].

[0133] In particular, R 9 is selected from the group consisting of optionally substituted (C1-C 12 ) alkyl, optionally substituted (C2-C 12 ) alkenyl, optionally substituted (C2-C 12 ) alkynyl, and aryl optionally substituted with (C1-C6) alkyl; R 10 ~R 14 are independently selected from the group consisting of optionally substituted (C1-C 12 ) alkyl, optionally substituted (C2-C 12 ) alkenyl, optionally substituted (C2-C 12 ) alkynyl, and optionally substituted aryl.

[0134] In the compound of general formula (I), X is (C1-C 12 ) alkyl, -O-(C1-C 12) alkyl-, -C(O)-, -C(O)-(C1-C 12 ) alkyl-, -NH-C(O)-(C1-C 12 ) alkyl-, -S-(C1-C 12 ) alkyl-, -S(O)-(C1-C 12 ) alkyl-, and -S(O)2-(C1-C 12 ) selected from the group consisting of alkyl-; (C1-C 12 ) the alkyl group may be substituted by a heteroatom and / or may be interrupted. Preferably, X is (C1-C 12 ) alkyl, -O-(C1-C 12 ) alkyl-, -C(O)-, -C(O)-(C1-C 12 ) alkyl-, -NH-C(O)-(C1-C 12 ) selected from the group consisting of alkyl-; (C1-C 12 ) the alkyl group may be substituted by a heteroatom and / or may be interrupted; (C1-C 12 ) the alkyl group may be substituted by a heteroatom and / or may be interrupted. Preferably, X is selected from the group consisting of (C1-C6)alkyl, -O-(C1-C6)alkyl-, -C(O)-, -C(O)-(C1-C6)alkyl- and -NH-C(O)-(C1-C6)alkyl-; the (C1-C6)alkyl group may be substituted by a heteroatom and / or may be interrupted. More preferably, X is selected from the group consisting of (C1-C3)alkyl, -O-(C1-C3)alkyl-, -C(O)-(C1-C3)alkyl- and -NH-C(O)-(C1-C3)alkyl-; the (C1-C3)alkyl group may be substituted by a heteroatom and / or may be interrupted.

[0135] In a specific embodiment, X is (C1-C6)alkyl. Preferably, X is methyl, ethyl or n-propyl, more preferably ethyl.

[0136] In the compound of general formula (I), Y 0 , Y 1 , Y2 and Y 3 each independently does not exist, or is -NH-, -O-, -S-, -S(O)-, -S(O)2-, -C(O)-, -C(O)O-, -OC(O)-, -NHC(O)-, -C(O)NH-; -C(O)NR 14 -, -(C1-C 24 )alkyl-NH-, -(C1-C 24 )alkyl-O-, -(C1-C 24 )alkyl-S-, (C1-C 24 )alkyl-NR 13 -, -(C1-C 24 )alkyl-, S(O)-, -(C1-C 24 )alkyl-S(O)2-, -(C1-C 24 )alkyl-C(O)-, -(C1-C 24 )alkyl-C(O)O-, -(C1-C 24 )alkyl-OC(O)-, -(C1-C 24 )alkyl-NHC(O)-, -(C1-C 24 )alkyl-C(O)NH-, -(C1-C 24 )alkyl-C(O)NR 14 -, optionally substituted (C1-C 24)Alkyl, -NH-C(O)-NH-, -NH-S(O)-NH-, -NH-S(O2)-NH-, -S-C(O)-NH-, -O-C(O)-NH-, -O-S(O)-NH-, -O-S(O2)-NH-, -S-CH2-C(O)-NH-, -S-CH2-S(O)-NH-, -S-CH2-S(O2)-NH-, -S(O)-CH2-C(O)-NH-, -S(O2)-CH2-C(O)-NH-, -O-CH2-C(O)-NH-, -O-CH2-S(O)-NH-, -O-CH2-S(O2)-NH-, -NH-CH2-C(O)-NH-, -NH-CH2-S(O)-NH-, -NH-CH2-S(O2)-NH-, -O-(CH2)2-NH-C(O)-, -O-(CH2)2-N(CH3)-C(O)-, -O-(CH2)2-NH-S(O)-, -O-(CH2)2-N(CH3)-S(O)-, -O-(CH2)2-NH-S(O2)-, -O-(CH2)2-N(CH3)-S(O2)-, -S-(CH2)2-NH-C(O)-, -S-(CH2)2-N(CH3)-C(O)-, -S-(CH2)2-NH-S(O)-, -S-(CH2)2-N(CH3)-S(O)-, -S-(CH2)2-NH-S(O2)-, -S-(CH2)2-N(CH3)-S(O2)-, -NH-(CH2)2-NH-C(O)-, -NH-(CH2)2-N(CH3)-C(O)-, -NH-(CH2)2-NH-S(O)-, -NH-(CH2)2-N(CH3)-S(O)-, -NH-(CH2)2-NH-S(O2)-, -NH-(CH2)2-N(CH3)-S(O2)-, -O-CH2-CH(CH2-OH)-NH-C(O)-, -O-CH2-CH(CH2-OCH3)-NH-C(O)-, -O-CH2-CH(CH3)-NH-C(O)-, -O-CH(CH3)-CH2-NH-C(O)-, -O-CH2-CH(CH2-OH)-NH-S(O)-, -O-CH2-CH(CH2-OCH3)-NH-S(O)-, -O-CH2-CH(CH3)-NH-S(O)-, -O-CH(CH3)-CH2-NH-S(O)-, -O-CH2-CH(CH2-OH)-NH-S(O2)-, -O-CH2-CH(CH2-OCH3)-NH-S(O2)-, -O-CH2-CH(CH3)-NH-S(O2)-, -O-CH(CH3)-CH2-NH-S(O2)-,-S-CH2-CH(CH2-OH)-NH-C(O)-, -S-CH2-CH(CH2-OCH3)-NH-C(O)-, -S-CH2-CH(CH3)-NH-C(O)-, -S-CH(CH3)-CH2-NH-C(O)-, -S-CH2-CH(CH2-OH)-NH-S(O)-, -S-CH2-CH(CH2-OCH3)-NH-S(O)-, -S-CH2-CH(CH3)-NH-S(O)-, -S-CH(CH3)-CH2-NH-S(O)-, -S-CH2-CH(CH2-OH)-NH-S(O2)-, -S-CH2-CH(CH2-OCH3)-NH-S(O2)-, -S-CH2-CH(CH3)-NH-S(O2)-, -S-CH(CH3)-CH2-NH-S(O2)-, -NH-CH2-CH(CH2-OH)-NH-C(O)-, -NH-CH2-CH(CH2-OCH3)-NH-C(O)-, -NH-CH2-CH(CH3)-NH-C(O)-, -NH-CH(CH3)-CH2-NH-C(O)-, -NH-CH2-CH(CH2-OH)-NH-S(O)-, -NH-CH2-CH(CH2-OCH3)-NH-S(O)-, -NH-CH2-CH(CH3)-NH-S(O)-, -NH-CH(CH3)-CH2-NH-S(O)-, -NH-CH2-CH(CH2-OH)-NH-S(O2)-, -NH-CH2-CH(CH2-OCH3)-NH-S(O2)-, -NH-CH2-CH(CH3)-NH-S(O2)-, -NH-CH(CH3)-CH2-NH-S(O2)-, -O-(CH2)2-NH-, -S-(CH2)2-NH-, and -NH-(CH2)2-NH-; (C1-C, 24 ) The alkyl group may be substituted. In particular, Y 0 is not non-existent.

[0137] In a specific embodiment, in the compound of general formula (I), Y 0 , Y 1 , Y 2 and Y 3 are independently non-existent or -NH-, -O-, -S-, -S(O)-, -S(O)2-, -C(O)-, -C(O)O-, -OC(O)-, -NHC(O)-, -C(O)NH-; -C(O)NR 14 -, -(C1-C24 ) Alkyl-NH-, -(C1-C 24 ) Alkyl-O-, -(C1-C 24 ) Alkyl-S-, (C1-C 24 ) Alkyl-NR 13 -, -(C1-C 24 ) Alkyl-S(O)-, -(C1-C 24 ) Alkyl-S(O)2-, -(C1-C 24 ) Alkyl-C(O)-, -(C1-C 24 ) Alkyl-C(O)O-, -(C1-C 24 ) Alkyl-OC(O)-, -(C1-C 24 ) Alkyl-NHC(O)-, -(C1-C 24 ) Alkyl-C(O)NH-, -(C1-C 24 ) Alkyl-C(O)NR 14 -, Optionally substituted (C1-C 24 ) Alkyl, -NH-C(O)-NH-, -NH-S(O)-NH-, -NH-S(O2)-NH-, -S-C(O)-NH-, -O-C(O)-NH-, -O-S(O)-NH-, -O-S(O2)-NH-, -O-(CH2)2-NH-, -S-(CH2)2-NH-, and -NH-(CH2)2-NH-; (C1-C 24 ) The alkyl group may be optionally substituted. In particular, Y 0 is not non-existent.

[0138] In a particular embodiment, in the compound of general formula (I), Y 0 , Y 1 , Y 2 and Y 3 are independently either non-existent or -NH-, -O-, -S-, -S(O)-, -S(O)2-, -C(O)-, -C(O)O-, -OC(O)-, -NHC(O)-, -C(O)NH-; -C(O)NR 14 -, -(C1-C 24 ) Alkyl-NH-, -(C1-C 24 ) Alkyl-O-, -(C1-C 24 ) Alkyl-S-, (C1-C 24 ) Alkyl-NR 13 -, -(C1-C24 ) alkyl-S(O)-, -(C1-C 24 ) alkyl-S(O)2-, -(C1-C 24 ) alkyl-C(O)-, -(C1-C 24 ) alkyl-C(O)O-, -(C1-C 24 ) alkyl-OC(O)-, -(C1-C 24 ) alkyl-NHC(O)-, -(C1-C 24 ) alkyl-C(O)NH-, -(C1-C 24 ) alkyl-C(O)NR 14 -, and optionally substituted (C1-C 24 ) alkyl selected from; (C1-C 24 ) the alkyl group may be optionally substituted; preferably, Y 0 is not non-existent. In particular, Y 0 , Y 1 , Y 2 and Y 3 are each independently either non-existent or -NH-, -O-, -S-, -S(O)-, -S(O)2-, -C(O)-, -C(O)O-, -OC(O)-, -NHC(O)-, -C(O)NH-; -C(O)NR 14 -, -(C1-C 12 ) alkyl-NH-, -(C1-C 12 ) alkyl-O-, -(C1-C 12 ) alkyl-S-, (C1-C 12 ) alkyl-NR 13 -, -(C1-C 12 ) alkyl-S(O)-, -(C1-C 12 ) alkyl-S(O)2-, -(C1-C 12 ) alkyl-C(O)-, -(C1-C 12 ) alkyl-C(O)O-, -(C1-C 12 ) alkyl-OC(O)-, -(C1-C 12 ) alkyl-NHC(O)-, -(C1-C 12 ) alkyl-C(O)NH-, -(C1-C 12 ) alkyl-C(O)NR 14 -, and optionally substituted (C1-C 12 ) alkyl selected from; (C1-C 12) The alkyl group may be substituted; preferably, Y 0 is not non-existent. More particularly, Y 0 , Y 1 , Y 2 and Y 3 are each independently either non-existent or -NH-, -O-, -S-, -S(O)-, -S(O)2-, -C(O)-, -C(O)O-, -OC(O)-, -NHC(O)-, -C(O)NH-; -C(O)NR 14 -, -(C1-C6)alkyl-NH-, -(C1-C6)alkyl-O-, -(C1-C6)alkyl-S-, (C1-C6)alkyl-NR 13 -, -(C1-C6)alkyl-S(O)-, -(C1-C6)alkyl-S(O)2-, -(C1-C6)alkyl-C(O)-, -(C1-C6)alkyl-C(O)O-, -(C1-C6)alkyl-OC(O)-, -(C1-C6)alkyl-NHC(O)-, -(C1-C6)alkyl-C(O)NH-, -(C1-C6)alkyl-C(O)NR 14 -, and are selected from optionally substituted (C1-C6)alkyl; the (C1-C6)alkyl group may be substituted; preferably, Y 0 is not non-existent. Preferably, Y 0 , Y 1 , Y 2 and Y 3 are each independently either non-existent or selected from -O- and optionally substituted (C1-C6)alkyl; preferably, Y 0 is not non-existent. In particular, Y 0 is not non-existent.

[0139] In a specific embodiment, Y 0 , Y 1 , Y 2 and Y 3 are each independently either non-existent or -O-. Preferably, Y 0 is -O-, and Y 1 , Y 2 and Y 3 are each independently either non-existent or -O-, and preferably non-existent.

[0140] In a specific embodiment, in the compound of general formula (I), X is (C1-C6) alkyl, and Y 0 is -O-, and Y 1 , Y 2 and Y 3 are independently absent or -O-.

[0141] In a specific embodiment, X is methyl, ethyl or n-propyl, and Y 0 is -O-, and Y 1 , Y 2 and Y 3 are independently absent or -O-. Preferably, X is methyl, ethyl or n-propyl, and Y 0 is -O-, and Y 1 , Y 2 and Y 3 are absent. More preferably, X is ethyl, and Y 0 is -O-, and Y 1 , Y 2 and Y 3 are absent.

[0142] In the compound of general formula (I), R 5 , R 6 , R 7 and R 8 are independently selected from the group consisting of H, halogen, optionally substituted (C1-C 24 ) alkyl, optionally substituted (C2-C 24 ) alkenyl, optionally substituted (C2-C 24 ) alkynyl, optionally substituted (C3-C 10 ) cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl and optionally substituted heteroaryl. Preferably, at least one of R 5 , R 6 , R 7 and R 8 is not H.

[0143] In a specific embodiment, R 5, R 6 , R 7 and R 8 is H, halogen, optionally substituted (C1-C 24 ) alkyl, optionally substituted (C2-C 24 ) alkenyl, optionally substituted (C2-C 24 ) alkynyl. In particular, R 5 , R 6 , R 7 and R 8 is H, halogen, optionally substituted (C1-C 12 ) alkyl, optionally substituted (C2-C 12 ) alkenyl, optionally substituted (C2-C 12 )alkynyl. More particularly, R 5 , R 6 , R 7 and R 8 are independently selected from the group consisting of H, halogen, optionally substituted (C1-C6) alkyl, optionally substituted (C2-C6) alkenyl, and optionally substituted (C2-C6) alkynyl. Preferably, R 5 , R 6 , R 7 and R 8 is H, halogen, haloalkyl, or (C1-C 24 ) alkyl. More preferably, R 5 , R 6 , R 7 and R 8 are independently selected from the group consisting of H, halogen, haloalkyl such as CF3, or (C1-C6) alkyl. Preferably, R 5 , R 6 , R 7 and R 8 At least one of them is not H.

[0144] In one specific embodiment, R 5 , R 6 , R 7 and R 8Three of them are H, and the last one is as defined above, except for H.

[0145] In another specific embodiment, R 5 , R 6 , R 7 and R 8 Two of them are H, and two are as defined above, except for H.

[0146] In another specific embodiment, R 5 , R 6 , R 7 and R 8 Three of them are H, and one is as defined above, except for H.

[0147] In another specific embodiment, R 5 , R 6 , R 7 and R 8 are H.

[0148] In another specific embodiment, R 5 , R 6 , R 7 and R 8 are as defined above, but not H.

[0149] In a specific embodiment, one or two of R 5 , R 6 , R 7 and R 8 are selected from the group consisting of H, halogen, haloalkyl such as CF3, or (C1-C6) alkyl, and the others are H.

[0150] In a specific embodiment, one or two of R 5 , R 6 , R 7 and R 8 are selected from the group consisting of halogen, haloalkyl such as CF3, or (C1-C6) alkyl, and the others are H.

[0151] In a specific embodiment, Y0 is -O-, and Y 1 , Y 2 and Y 3 do not exist: - R 5 , R 6 , R 7 and R 8 Among them, 3 are H, and the last 1, excluding H, is as defined above; or - R 5 , R 6 , R 7 and R 8 Among them, 2 are H, and 2, excluding H, are as defined above; or - R 5 , R 6 , R 7 and R 8 Among them, 3 are H, and 1, excluding H, is as defined above; or - R 5 , R 6 , R 7 and R 8 are H; or - R 5 , R 6 , R 7 and R 8 are as defined above but not H.

[0152] In a specific embodiment, Y 0 is -O-, and Y 1 , Y 2 and Y 3 do not exist, and R 5 , R 6 , R 7 and R 8 Among them, 1 or 2 are selected from the group consisting of H, halogen, haloalkyl such as CF3, or (C1 - C6) alkyl, and the others are H.

[0153] In a specific embodiment, Y 0 is -O-, and Y 1 , Y 2 and Y 3 do not exist, and R 5 , R 6, R 7 and R 8 One or two of them are selected from the group consisting of halogen, haloalkyl such as CF3, or (C1-C6) alkyl, and the others are H.

[0154] In the above embodiment, when R 5 , R 6 , R 7 and R 8 are H and Y 1 , Y 2 and Y 3 are absent, R 1 , R 2 and R 3 are not optionally substituted (C2-C 24 ) alkynyl. The new compound of general formula (I) cannot be compound (A1), (A2), (A3) or (A4).

[0155] In one embodiment of the compound of general formula (I), R 1 , R 2 , R 3 and R 4 are independently selected from the group consisting of H, OH, -C(O)OR 9 -, -S(O)2R 10 -, -C(O)R 9 -, -S(O)R 10 -, -NR 11 R 12 -, optionally substituted (C1-C 24 ) alkyl, optionally substituted (C2-C 24 ) alkenyl, optionally substituted (C2-C 24 ) alkynyl, optionally substituted (C3-C 10 ) cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted (C1-C6) alkyl-aryl, and optionally substituted heteroaryl, provided that at least one of R 2 and R 3 is not H.

[0156] In a specific embodiment of the compound of general formula (I), R1 , R 2 , R 3 and R 4 are each independently selected from the group consisting of H, OH, -C(O)OR 9 -, -S(O)2R 10 -, optionally substituted (C1-C 24 ) alkyl, optionally substituted (C2-C 24 ) alkenyl, optionally substituted (C2-C 24 ) alkynyl, optionally substituted (C3-C 10 ) cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted (C1-C6) alkyl-aryl, and optionally substituted heteroaryl, provided that at least one of R 2 and R 3 is not H.

[0157] In this definition, "optionally substituted" preferably means unsubstituted or halogen; CN; NO2; (C1-C6) alkyl; (C1-C6) haloalkyl; (C1-C6) haloalkoxy, (C1-C6) halothioalkoxy, optionally substituted aryl (especially optionally substituted with 1 or 2 (C1-C6) alkyl or NO2); heteroaryl; halogeno-heteroaryl, especially halogeno-furanyl; oxo; NR a R b ; COR c ; CO2R d ; CONR e R f ; OR g ; SR h ; SO2R i ; SO2NR j R k ; NR l COR m ; R n NR O R P ; NR q SO2R r ; (wherein R a ~R rwhich consists of, independently of one another, H, (C1-C6)alkyl, (C1-C6)haloalkyl, aryl, (C1-C6)alkyl-aryl, heteroaryl or (C1-C6)alkyl-heteroaryl; in particular, halogen; CN; NO2; (C1-C6)alkyl; (C1-C6)haloalkyl; aryl optionally substituted with 1 or 2 (C1-C6)alkyl or NO2; heteroaryl; oxo; NR a R b ; COR c ; CO2R d ; CONR e R f ; and OR g ; (wherein R a ~R g are independently of one another selected from the group consisting of H, (C1-C6)alkyl, (C1-C6)haloalkyl, aryl, (C1-C6)alkyl-aryl, heteroaryl or (C1-C6)alkyl-heteroaryl) and may be substituted with at least 1, for example 1, 2 or 3 substituents selected from the group consisting of

[0158] In a specific embodiment, R 1 is preferably selected from the group consisting of H, (C1-C 24 )alkyl, (C2-C 24 )alkenyl, (C2-C 24 )alkynyl, (C3-C 12 )cycloalkyl and aryl; said alkyl, alkenyl, alkynyl, aryl or cycloalkyl group may be substituted with one or more halogens, (C1-C6)alkyl, aryl, oxo, -NH2, -CO2H or -OH. In particular, R 1 is selected from the group consisting of H, (C1-C 12 )alkyl, (C2-C 12 )alkenyl, (C2-C 12 )alkynyl and aryl. Preferably, R 1 is H.

[0159] In a specific embodiment, R 4 is preferably selected from the group consisting of H, (C1-C 24) Alkyl, (C2 - C 24 ) Alkenyl, (C2 - C 24 ) Alkynyl, (C3 - C 12 ) Selected from the group consisting of cycloalkyl and aryl; said alkyl, alkenyl, alkynyl, aryl or cycloalkyl group may be substituted with one or more halogens, (C1 - C6) alkyl, aryl, oxo, -NH2, -CO2H or -OH. In particular, R 4 is selected from the group consisting of H, (C1 - C 12 ) alkyl and aryl. Preferably, R 4 is H.

[0160] In a specific embodiment, R 2 and R 3 are independently selected from the group consisting of H, OH, -C(O)OR 9 -, -S(O)2R 10 -, -C(O)R 9 -, -S(O)R 10 -, -NR 11 R 12 -, optionally substituted (C1 - C 12 ) alkyl, optionally substituted (C2 - C 12 ) alkenyl, optionally substituted (C2 - C 12 ) alkynyl, optionally substituted (C3 - C 12 ) cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl and optionally substituted heteroaryl, provided that at least one of R 2 and R 3 is not H; or R 2 and R 3Together with the nitrogen atom to which they are attached, they form an optionally substituted heterocycloalkyl. In this definition, "optionally substituted" preferably means unsubstituted or preferably halogen; CN; NO2; (C1-C6) alkyl; (C1-C6) haloalkyl; (C1-C6) haloalkoxy, (C1-C6) halothioalkoxy, optionally substituted aryl (especially optionally substituted with 1 or 2 (C1-C6) alkyl or NO2); heteroaryl; halogeno-heteroaryl, especially halogeno-furanyl; oxo; NR a R b ; COR c ; CO2R d ; CONR C e R f ; OR g ; SR h ; SO2R i ; SO2NR j R k ; NR l COR m ; R n NR O R P ; NR q SO2R r ; (wherein R a ~R r are independently of each other H, (C1-C6) alkyl, (C1-C6) haloalkyl, aryl, (C1-C6) alkyl-aryl, heteroaryl or (C1-C6) alkyl-heteroaryl); especially (C1-C6) alkyl; halogen; CN; NO2; (C1-C6) haloalkyl; phenyl optionally substituted with 1 or 2 (C1-C6) alkyl or NO2; heteroaryl optionally substituted with -OH; oxo; NR a R b ; (C1-C 12 ) alkyl-NR a R b ; COR c ; CO2R d ; CONR e R f ; and OR g ; (wherein R a ~R gMeans that it may be substituted with at least one, for example, 1, 2 or 3 substituents, which are, independently of each other, H, (C1-C6) alkyl, (C1-C6) haloalkyl, aryl, (C1-C6) alkyl-aryl, heteroaryl or (C1-C6) alkyl-heteroaryl.

[0161] In the compound of general formula (I), R 1 , R 2 , R 3 and R 4 One or more of are -C(O)OR 9 -, -S(O)2R 10 -, -C(O)R 9 -, -S(O)R 10 -, or -NR 11 R 12 -, preferably -C(O)OR 9 - or -S(O)2R 10 - When it is, R 9 ~R 12 are independently selected from the group consisting of optionally substituted (C1-C 12 ) alkyl, optionally substituted (C2-C 12 ) alkenyl, optionally substituted (C2-C 12 ) alkynyl, and optionally substituted aryl.

[0162] In the compound of general formula (I), R 1 , R 2 , R 3 and R 4 One or more of are -C(O)OR 9 -, -S(O)2R 10 -, -C(O)R 9 -, -S(O)R 10 -, or -NR 11 R 12 -, preferably -C(O)OR 9 - or -S(O)2R 10 - When it is, R 9 is optionally substituted (C1-C 12 ) alkyl, optionally substituted (C2-C 12)Alkenyl, optionally substituted (C2-C 12 )alkynyl, and optionally substituted by (C1-C6) alkyl aryl selected from the group consisting of; R 10 ~R 12 are each independently selected from the group consisting of optionally substituted (C1-C 12 )alkyl, optionally substituted (C2-C 12 )alkenyl, optionally substituted (C2-C 12 )alkynyl, and optionally substituted aryl.

[0163] In this definition, "optionally substituted" preferably means unsubstituted or preferably substituted by at least one, for example 1, 2 or 3 substituents which may be (C1-C6) alkyl.

[0164] In a specific embodiment, R 9 ~R 12 are each independently selected from the group consisting of optionally substituted (C1-C6) alkyl, optionally substituted (C2-C6) alkenyl, optionally substituted (C2-C6) alkynyl, and optionally substituted aryl.

[0165] In particular, R 9 is selected from the group consisting of optionally substituted (C1-C6) alkyl, optionally substituted (C2-C6) alkenyl, optionally substituted (C2-C6) alkynyl, and aryl optionally substituted by (C1-C6) alkyl such as methyl; R 10 ~R 12 are each independently selected from the group consisting of optionally substituted (C1-C6) alkyl, optionally substituted (C2-C6) alkenyl, optionally substituted (C2-C6) alkynyl, and optionally substituted aryl.

[0166] Preferably, R 9 ~R 12is independently selected from the group consisting of (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, aryl, or aryl substituted with (C1-C6) alkyl such as methyl.

[0167] In another embodiment of the compound of general formula (I), R 1 and R 4 are H, OH, -C(O)OR 9 -, -S(O)2R 10 -, optionally substituted (C1-C 24 ) alkyl, optionally substituted (C2-C 24 ) alkenyl, optionally substituted (C2-C 24 ) alkynyl, optionally substituted (C3-C 10 ) cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl and optionally substituted heteroaryl, independently selected from the group consisting of; R 2 and R 3 together with the nitrogen atom to which they are attached form an optionally substituted heterocycloalkyl.

[0168] In a specific embodiment, the optionally substituted heterocycloalkyl formed by R 2 and R 3 together with the nitrogen atom to which they are attached is preferably an optionally substituted nitrogen-heterocycloalkyl containing 3 to 10 ring atoms; preferably an optionally substituted nitrogen-heterocycloalkyl containing 1 nitrogen atom and 3 to 10 ring atoms. In particular, the nitrogen-heterocycloalkyl is unsubstituted or halogen; CN; NO2; (C1-C6) alkyl; (C1-C6) haloalkyl; (C1-C6) haloalkoxy, (C1-C6) halothioalkoxy, optionally substituted aryl (especially optionally substituted with 1 or 2 (C1-C6) alkyl or NO2); heteroaryl; oxo; NR a R b ; COR c ; CO2R d ; CONR e Rf ; OR g ; SR h ; SO2R i ; SO2NR j R k ; NR l COR m ; R n NR O R P ; NR q SO2R r ; (wherein, R a ~R r are each independently H, (C1-C6) alkyl, (C1-C6) haloalkyl, aryl, (C1-C6) alkyl-aryl, heteroaryl or (C1-C6) alkyl-heteroaryl); in particular, substituted with one or more substituents selected from the list consisting of halogen, (C1-C6) alkyl, aryl, oxo, -NH2, -CO2H or -OH.

[0169] In a specific embodiment, when R 2 and R 3 together with the nitrogen atom to which they are attached form an optionally substituted heterocycloalkyl, R 4 is preferably selected from the group consisting of H, (C1-C 24 ) alkyl, (C2-C 24 ) alkenyl, (C2-C 24 ) alkynyl, (C3-C 12 ) cycloalkyl and aryl; said alkyl, alkenyl, alkynyl, aryl or cycloalkyl group may be substituted with one or more halogen, (C1-C6) alkyl, aryl, oxo, -NH2, -CO2H or -OH; in particular, R 4 is selected from the group consisting of H, (C1-C 12 ) alkyl and aryl; preferably, R 4 is H.

[0170] In a specific embodiment, R 2 and R 3When they together with the nitrogen atom to which they are attached form an optionally substituted heterocycloalkyl, R 1 is preferably selected from the group consisting of H, (C1-C 24 )alkyl, (C2-C 24 )alkenyl, (C2-C 24 )alkynyl, (C3-C 12 )cycloalkyl and aryl; said alkyl, alkenyl, alkynyl, aryl or cycloalkyl group may be substituted with one or more halogens, (C1-C6)alkyl, aryl, oxo, -NH2, -CO2H or -OH; in particular, R 1 is selected from the group consisting of H, (C1-C 12 )alkyl, (C2-C 12 )alkenyl, (C2-C 12 )alkynyl and aryl; preferably, R 1 is H.

[0171] In a specific embodiment, when R 2 and R 3 together with the nitrogen atom to which they are attached form an optionally substituted heterocycloalkyl: - R 4 is preferably selected from the group consisting of H, (C1-C 24 )alkyl, (C2-C 24 )alkenyl, (C2-C 24 )alkynyl, (C3-C 12 )cycloalkyl and aryl; said alkyl, alkenyl, alkynyl, aryl or cycloalkyl group may be substituted with one or more halogens, (C1-C6)alkyl, aryl, oxo, -NH2, -CO2H or -OH; - R 1 is preferably selected from the group consisting of H, (C1-C 24 )alkyl, (C2-C 24 )alkenyl, (C2-C 24 )alkynyl, (C3-C 12)Selected from the group consisting of cycloalkyl and aryl; said alkyl, alkenyl, alkynyl, aryl or cycloalkyl group may be substituted with one or more halogens, (C1-C6) alkyl, aryl, oxo, -NH2, -CO2H or -OH.

[0172] In a specific embodiment, R 2 and R 3 when, together with the nitrogen atom to which they are attached, form an optionally substituted heterocycloalkyl: - R 4 is preferably selected from the group consisting of H, (C1-C 12 ) alkyl and aryl; - R 1 is preferably selected from the group consisting of H, (C1-C 12 ) alkyl, (C2-C 12 ) alkenyl, (C2-C 12 ) alkynyl and aryl.

[0173] In a specific embodiment, R 2 and R 3 when, together with the nitrogen atom to which they are attached, form an optionally substituted heterocycloalkyl: - R 4 is preferably H; - R 1 is preferably selected from the group consisting of H, (C1-C 12 ) alkyl, (C2-C 12 ) alkenyl, (C2-C 12 ) alkynyl and aryl; more preferably, R 1 is H.

[0174] In a specific embodiment, - X is methyl, ethyl or n-propyl; and / or Y 0 is -O-; and / or Y 1 , Y 2 and Y 3 are each independently absent or -O-. - R 2 and R 3 together with the nitrogen atom to which they are attached form an optionally substituted nitrogen - heterocycloalkyl containing 3 to 10 ring atoms; - R 4 is preferably selected from the group consisting of H, (C1 - C 24 ) alkyl, (C2 - C 24 ) alkenyl, (C2 - C 24 ) alkynyl, (C3 - C 12 ) cycloalkyl and aryl; said alkyl, alkenyl, alkynyl, aryl or cycloalkyl group may be substituted with one or more halogens, (C1 - C6) alkyl, aryl, oxo, -NH2, -CO2H or -OH; and / or R 1 is preferably selected from the group consisting of H, (C1 - C 24 ) alkyl, (C2 - C 24 ) alkenyl, (C2 - C 24 ) alkynyl, (C3 - C 12 ) cycloalkyl and aryl; said alkyl, alkenyl, alkynyl, aryl or cycloalkyl group may be substituted with one or more halogens, (C1 - C6) alkyl, aryl, oxo, -NH2, -CO2H or -OH.

[0175] In a specific embodiment, - X is methyl, ethyl or n - propyl; and / or Y 0 is -O-; and / or Y 1 , Y 2 and Y 3 are independently absent or are -O-; - R 2 and R 3 together with the nitrogen atom to which they are attached form an optionally substituted nitrogen - heterocycloalkyl containing 1 nitrogen atom and 3 to 10 ring atoms; - R 4 is preferably selected from the group consisting of H, (C1 - C 12 ) alkyl and aryl; and / or R1 is preferably selected from the group consisting of H, (C1-C 12 ) alkyl, (C2-C 12 ) alkenyl, (C2-C 12 ) alkynyl, and aryl.

[0176] In a specific embodiment, - X is methyl, ethyl or n-propyl; and / or Y 0 is -O-; and / or Y 1 , Y 2 and Y 3 are independently absent or -O-; - R 2 and R 3 together with the nitrogen atom to which they are attached form a nitrogen-heterocycloalkyl containing one nitrogen atom and 3 to 10 ring atoms; - R 4 is preferably H; and / or R 1 is preferably selected from the group consisting of H, (C1-C 12 ) alkyl, (C2-C 12 ) alkenyl, (C2-C 12 ) alkynyl, and aryl; more preferably, R 1 is H.

[0177] In a specific embodiment, R 2 and R 3 are H, -C(O)OR 9 -, -S(O)2R 10 -, -C(O)R 9 -, -S(O)R 10 -, -NR 11 R 12 -, optionally substituted (C1-C 12 ) alkyl, optionally substituted (C2-C 12 ) alkenyl, optionally substituted (C2-C 12 ) alkynyl, optionally substituted (C3-C[[ID=6)] 12)Cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl and optionally substituted heteroaryl (R 9 ~R 12 is independently selected from the group consisting of those defined above), R 4 is preferably H, (C1-C 24 )alkyl, (C2-C 24 )alkenyl, (C2-C 24 )alkynyl, (C3-C 12 )cycloalkyl and aryl; said alkyl, alkenyl, alkynyl, aryl or cycloalkyl group may be substituted with one or more halogens, (C1-C6)alkyl, aryl, oxo, -NH2, -CO2H or -OH; in particular, R 4 is selected from the group consisting of H, (C1-C 12 )alkyl and aryl; preferably, R 4 is H.

[0178] In a specific embodiment, R 2 and R 3 are H, -C(O)OR 9 -, -S(O)2R 10 -, optionally substituted (C1-C 12 )alkyl, optionally substituted (C2-C 12 )alkenyl, optionally substituted (C2-C 12 )alkynyl, optionally substituted (C3-C 12 )cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl and optionally substituted heteroaryl (R 9 and R 10 are as defined above), when independently selected from the group consisting of, R 1 is preferably H, (C1-C 24 )alkyl, (C2-C 24 )alkenyl, (C2-C 24 )alkynyl, (C3-C 12) cycloalkyl and aryl; wherein said alkyl, alkenyl, alkynyl, aryl or cycloalkyl group is optionally substituted with one or more halogen, (C1-C6) alkyl, aryl, oxo, —NH2, —CO2H or —OH; provided that R 2 and R 3 At least one of is not H; in particular, R 1 is H, (C1~C 12 ) Alkyl, (C2-C 12 ) alkenyl, (C2-C 12 ) selected from the group consisting of alkynyl and aryl; preferably, R 1 is H.

[0179] In one specific embodiment, R 2 and R 3 H, -C(O)OR 9 -, -S(O)2R 10 -, optionally substituted (C1-C 12 ) alkyl, optionally substituted (C2-C 12 ) alkenyl, optionally substituted (C2-C 12 ) alkynyl, optionally substituted (C3-C 12 ) independently selected from the group consisting of cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; R 9 and R 10 is as defined above: -R 4 is preferably H, (C1 to C 24 ) Alkyl, (C2-C 24 ) alkenyl, (C2-C 24 ) alkynyl, (C3-C 12 ) cycloalkyl and aryl; wherein said alkyl, alkenyl, alkynyl, aryl or cycloalkyl group is optionally substituted with one or more halogen, (C1-C6) alkyl, aryl, oxo, -NH2, -CO2H or -OH; and / or -R1 is preferably selected from the group consisting of H, (C1-C 24 ) alkyl, (C2-C 24 ) alkenyl, (C2-C 24 ) alkynyl, (C3-C 12 ) cycloalkyl and aryl; said alkyl, alkenyl, alkynyl, aryl or cycloalkyl group may be substituted with one or more halogens, (C1-C6) alkyl, aryl, oxo, -NH2, -CO2H or -OH; provided that at least one of R 2 and R 3 is not H.

[0180] In a specific embodiment, R 2 and R 3 are independently selected from the group consisting of H, -C(O)OR 9 -, -S(O)2R 10 -, optionally substituted (C1-C 12 ) alkyl, optionally substituted (C2-C 12 ) alkenyl, optionally substituted (C2-C 12 ) alkynyl, optionally substituted (C3-C 12 ) cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl and optionally substituted heteroaryl; when R 9 and R 10 are as defined above: - R 4 is preferably selected from the group consisting of H, (C1-C 12 ) alkyl and aryl; and / or - R 1 is preferably selected from the group consisting of H, (C1-C 12 ) alkyl, (C2-C 12 ) alkenyl, (C2-C 12 ) alkynyl and aryl; provided that at least one of R 2 and R 3 is not H.

[0181] In a specific embodiment, R 2 and R 3 are independently selected from the group consisting of H, -C(O)OR 9 -, -S(O)2R 10 -, optionally substituted (C1-C 12 ) alkyl, optionally substituted (C2-C 12 ) alkenyl, optionally substituted (C2-C 12 ) alkynyl, optionally substituted (C3-C 12 ) cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl and optionally substituted heteroaryl; R 9 and R 10 are as defined above: - R 4 is preferably H; and / or - R 1 is preferably selected from the group consisting of H, (C1-C 12 ) alkyl, (C2-C 12 ) alkenyl, (C2-C 12 ) alkynyl and aryl; more preferably, R 1 is H; provided that at least one of R 2 and R 3 is not H.

[0182] In a specific embodiment, - X is methyl, ethyl or n-propyl; and / or Y 0 is -O-; and / or Y 1 , Y 2 and Y 3 are independently absent or -O-; - R 2 and R 3 are H, -C(O)OR 9 -, -S(O)2R 10 -, optionally substituted (C1-C 12 ) alkyl, optionally substituted (C2-C 12 ) alkenyl, optionally substituted (C2-C12 ) alkynyl, optionally substituted (C3-C 12 ) cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl and optionally substituted heteroaryl (R 9 and R 10 are independently selected from the group consisting of as defined above); - R 4 is preferably selected from the group consisting of H, (C1-C 24 ) alkyl, (C2-C 24 ) alkenyl, (C2-C 24 ) alkynyl, (C3-C 12 ) cycloalkyl and aryl; the alkyl, alkenyl, alkynyl, aryl or cycloalkyl group may be substituted with one or more halogens, (C1-C6) alkyl, aryl, oxo, -NH2, -CO2H or -OH; and / or R 1 is preferably selected from the group consisting of H, (C1-C 24 ) alkyl, (C2-C 24 ) alkenyl, (C2-C 24 ) alkynyl, (C3-C 12 ) cycloalkyl and aryl; the alkyl, alkenyl, alkynyl, aryl or cycloalkyl group may be substituted with one or more halogens, (C1-C6) alkyl, aryl, oxo, -NH2, -CO2H or -OH; provided that at least one of R 2 and R 3 is not H.

[0183] In a specific embodiment, - X is methyl, ethyl or n-propyl; and / or Y 0 is -O-; and / or Y 1 , Y 2 and Y 3 are independently absent or -O-; - R 2 and R 3 are H, -C(O)OR 9-、 -S(O)2R 10 -、 Optionally substituted (C1-C 12 ) alkyl, optionally substituted (C2-C 12 ) alkenyl, optionally substituted (C2-C 12 ) alkynyl, optionally substituted (C3-C 12 ) cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl and optionally substituted heteroaryl (R 9 and R 10 are as defined above) and are independently selected from the group consisting of; - R 4 is preferably selected from the group consisting of H, (C1-C 12 ) alkyl and aryl; and / or R 1 is preferably selected from the group consisting of H, (C1-C 12 ) alkyl, (C2-C 12 ) alkenyl, (C2-C 12 ) alkynyl and aryl; Provided that at least one of R 2 and R 3 is not H.

[0184] In a specific embodiment, - X is methyl, ethyl or n-propyl; and / or Y 0 is -O-; and / or Y 1 , Y 2 and Y 3 are independently absent or -O-; - R 2 and R 3 are H, -C(O)OR 9 -, -S(O)2R 10 -, optionally substituted (C1-C 12 ) alkyl, optionally substituted (C2-C 12 ) alkenyl, optionally substituted (C2-C 12 ) alkynyl, optionally substituted (C3-C 12Cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl (R 9 and R 10 are independently selected from the group consisting of those defined above); - R 4 is preferably H; and / or R 1 is preferably H, (C1-C 12 )alkyl, (C2-C 12 )alkenyl, (C2-C 12 )alkynyl, and aryl; more preferably, R 1 is H; provided that at least one of R 2 and R 3 is not H.

[0185] In the context of the present invention, the novel compounds of formula (I) according to the present invention are preferably selected from the compounds (001)-(064) of Table 1 below, or pharmaceutically acceptable salts and / or solvates thereof. Preferably, the novel compounds of formula (I) for use according to the present invention are selected from the compounds (002), (003), (004), (008), (009), (010), (012), (013), (014), (015), (016), (017), (018), (019), (020), (022), (023), (024), (025), (026), (028), (029), (036), (039), (040), (043), (045), (049), (051), (052), (054), (057), (058), (059), (061), (063), and (064) of Table 1. Preferably, the novel compounds of formula (I) for use according to the present invention are preferably selected from the compounds (003)-(007), (013), (014), (021), (029), (031), and (034)-(038) of Table 1, or pharmaceutically acceptable salts and / or solvates thereof.

[0186] In the context of the present invention, the novel compounds of formula (I) according to the present invention are preferably selected from the compounds (001) to (038) of Table 1 below, or pharmaceutically acceptable salts and / or solvates thereof. Preferably, the novel compounds of formula (I) for use according to the present invention are preferably selected from the compounds (003) to (007), (013), (014), (021), (029), (031) to (038) of Table 1, or pharmaceutically acceptable salts and / or solvates thereof.

[0187] The present invention also relates to a pharmaceutical composition comprising a compound of general formula (I) as defined above, in particular one selected from the compounds (001) to (064) as disclosed in Table 1, or a pharmaceutically acceptable salt and / or solvate thereof.

[0188] The present invention also relates to a pharmaceutical composition comprising a compound of general formula (I) as defined above, in particular one selected from the compounds (001) to (038) as disclosed in Table 1, or a pharmaceutically acceptable salt and / or solvate thereof.

[0189] The present invention also relates to a compound of general formula (I) as defined above for use as a drug, in particular one selected from the compounds (001) to (064) as disclosed in Table 1, or a pharmaceutically acceptable salt and / or solvate thereof, or a pharmaceutical composition comprising the same.

[0190] The present invention also relates to a compound of general formula (I) as defined above for use as a drug, in particular one selected from the compounds (001) to (038) as disclosed in Table 1, or a pharmaceutically acceptable salt and / or solvate thereof, or a pharmaceutical composition comprising the same.

[0191] The present invention also relates to the use of a compound of general formula (I) as defined above, in particular one selected from compounds (001) to (064) as disclosed in Table 1, or a pharmaceutically acceptable salt and / or solvate thereof, or a pharmaceutical composition containing the same, for the manufacture of a medicament.

[0192] The present invention also relates to the use of a compound of general formula (I) as defined above, in particular one selected from compounds (001) to (038) as disclosed in Table 1, or a pharmaceutically acceptable salt and / or solvate thereof, or a pharmaceutical composition containing the same, for the manufacture of a medicament.

[0193] The present invention further relates to a method for treating a disease or disorder in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of general formula (I) as defined above, in particular one selected from compounds (001) to (064) as disclosed in Table 1, or a pharmaceutically acceptable salt and / or solvate thereof, or a pharmaceutical composition containing the same.

[0194] The present invention further relates to a method for treating a disease or disorder in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of general formula (I) as defined above, in particular one selected from compounds (001) to (038) as disclosed in Table 1, or a pharmaceutically acceptable salt and / or solvate thereof, or a pharmaceutical composition containing the same.

[0195] The present invention also relates to a parts kit and / or combination comprising (i) a compound of general formula (I) according to the invention, in particular one selected from compounds (001) to (064) as disclosed in Table 1, or a pharmaceutically acceptable salt thereof, and (ii) an additional active ingredient, for use separately, sequentially or simultaneously.

[0196] The present invention also relates to a parts kit and / or combination comprising (i) a compound of general formula (I) according to the invention, in particular one selected from compounds (001) to (038) as disclosed in Table 1, or a pharmaceutically acceptable salt thereof, and (ii) an additional active ingredient, for use separately, sequentially or simultaneously.

[0197] The present invention also relates to a compound of general formula (I) as defined above, in particular one of those disclosed in Table 1, or a pharmaceutically acceptable salt and / or solvate thereof, or a pharmaceutical composition comprising the same, for use in the prevention or treatment of iron and / or copper-related disorders, in particular iron and / or copper overload-related disorders; or metal-dependent cell death-related disorders.

[0198] The present invention also relates to the use of a compound of general formula (I) as defined above, in particular one of those disclosed in Table 1, or a pharmaceutically acceptable salt and / or solvate thereof, or a pharmaceutical composition comprising the same, for the manufacture of a medicament for the prevention or treatment of iron and / or copper-related disorders, in particular iron and / or copper overload-related disorders; or metal-dependent cell death-related disorders.

[0199] The present invention further relates to a method for preventing or treating iron and / or copper-related disorders, in particular iron and / or copper overload-related disorders; or metal-dependent cell death-related disorders, in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of general formula (I) as defined above, in particular one of those disclosed in Table 1, or a pharmaceutically acceptable salt and / or solvate thereof, or a pharmaceutical composition comprising the same.

[0200] In a specific embodiment, the metallothasis-related disorder is a disorder related to ferroptosis and / or cuproptosis. Advantageously, the metallothasis-related disorder is selected from hemorrhagic stroke; ischemic heart injury; ischemic kidney injury; ischemia-reperfusion injury (IRI) such as IRI occurring during organ transplantation (liver, lung, heart, kidney, pancreas, intestine); neurodegenerative diseases selected from Huntington's disease, dementia, and amyotrophic lateral sclerosis (ALS); age-related diseases or disorders; sepsis; ischemia-reperfusion; and diabetes. In particular, the use of the compounds according to the invention is specifically disclosed herein below.

[0201] In a specific embodiment, the iron and / or copper-related disorder is selected from HFE-related hemochromatosis; non-HFE-related hemochromatosis; congenital atransferrinemia; iron overload-related anemia such as thalassemia, myelodysplasia, and hematopoietic stem cell transplantation-related disorders; chronic liver disease; chronic inflammation associated with cancer; autoimmune or inflammatory diseases; neurodegeneration associated with brain iron accumulation-related diseases such as Wilson's disease; and polygenic neurodegeneration-related diseases such as Parkinson's disease and Alzheimer's disease.

[0202] Therapeutic use As exemplified by the examples, the inventors have demonstrated the therapeutic importance of the novel compounds of the present invention. Accordingly, the present invention relates to a pharmaceutical or veterinary composition comprising any novel compound according to the present invention, or a pharmaceutically acceptable salt and / or solvate thereof. Preferably, the pharmaceutical or veterinary composition further comprises a pharmaceutically or veterinarily acceptable carrier or excipient. The present invention relates to the use of any novel compound according to the present invention, or a pharmaceutically acceptable salt and / or solvate thereof, as a drug or as a medicament. The present invention further relates to a method for treating a disease in a subject, the method comprising administering a therapeutically effective amount of any novel compound according to the present invention, or a pharmaceutically acceptable salt and / or solvate thereof, to the subject in need thereof. The present invention also relates to the use of any novel compound according to the present invention, or a pharmaceutically acceptable salt and / or solvate thereof, for the manufacture of a medicament. The present invention also relates to a pharmaceutical composition comprising any novel compound according to the present invention, or a pharmaceutically acceptable salt and / or solvate thereof, for use as a drug. The term "any novel compound according to the present invention" or "any novel compound of general formula (I)" as used herein means any compound as defined herein in the above section "Novel Compounds". The term "any compound according to the present invention" or "any compound of general formula (I)" as used herein means any compound of general formula (I) as defined herein, particularly as defined herein in the above sections "Compounds for Use" and "Novel Compounds".

[0203] The present invention relates to a compound of any of general formula (I) according to the present invention for use in preventing and / or treating metallothionein-related disorders, in particular one of those as disclosed in Table 1, or a pharmaceutically acceptable salt and / or solvate thereof, or a pharmaceutical composition comprising the same. The present invention further relates to the use of a compound of any of general formula (I) according to the present invention for the manufacture of a medicament for use in preventing and / or treating metallothionein-related disorders, in particular one of those as disclosed in Table 1, or a pharmaceutically acceptable salt and / or solvate thereof, or a pharmaceutical composition comprising the same. The present invention also relates to a method for preventing and / or treating metallothionein-related disorders in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of any of general formula (I) according to the present invention, in particular one of those as disclosed in Table 1, or a pharmaceutically acceptable salt and / or solvate thereof, or a pharmaceutical composition comprising the same.

[0204] In the context of the present invention, a metallothionein-related disorder is a metal-dependent cell death-related disorder. In particular, a metallothionein-related disorder is a disorder associated with ferroptosis and / or cuproptosis.

[0205] In the context of the present invention, the metallothionein-related disorder is selected from hemorrhagic stroke; ischemic heart injury; ischemic kidney injury; ischemia-reperfusion injury (IRI) such as IRI occurring during organ transplantation (liver, lung, heart, kidney, pancreas, intestine); neurodegenerative diseases selected from Huntington's disease, dementia, and amyotrophic lateral sclerosis (ALS); age-related diseases or disorders; sepsis; ischemia-reperfusion; and diabetes.

[0206] In another embodiment, the present invention relates to any novel compound of general formula (I) according to the present invention, or a pharmaceutically acceptable salt and / or solvate thereof, or a pharmaceutical composition containing the same, for use in preventing and / or treating iron and / or copper-related disorders. The present invention further relates to the use of any novel compound of general formula (I) according to the present invention, or a pharmaceutically acceptable salt and / or solvate thereof, or a pharmaceutical composition containing the same, for manufacturing a medicament for use in preventing and / or treating iron and / or copper-related disorders. The present invention also relates to a method for preventing and / or treating iron and / or copper-related disorders in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of any novel compound of general formula (I) according to the present invention, or a pharmaceutically acceptable salt and / or solvate thereof, or a pharmaceutical composition containing the same.

[0207] In the context of the present invention, the iron and / or copper-related disorders are selected from HFE-related hemochromatosis; non-HFE-related hemochromatosis; congenital atransferrinemia; iron overload-related anemia such as thalassemia, myelodysplasia and hematopoietic stem cell transplantation-related disorders; chronic liver disease; chronic inflammation associated with cancer; autoimmune or inflammatory diseases; neurodegeneration associated with brain copper- or iron-accumulation-related diseases such as Wilson's disease; and polygenic neurodegeneration-related diseases such as Parkinson's disease and Alzheimer's disease.

[0208] In particular, the iron-related disorders are selected from HFE-related hemochromatosis; non-HFE-related hemochromatosis; congenital atransferrinemia; iron overload-related anemia such as thalassemia, myelodysplasia and hematopoietic stem cell transplantation-related disorders; chronic liver disease; chronic inflammation associated with cancer; autoimmune or inflammatory diseases; neurodegeneration associated with brain iron-accumulation-related diseases such as Wilson's disease; and polygenic neurodegeneration-related diseases such as Parkinson's disease and Alzheimer's disease.

[0209] In particular, copper-related disorders are selected from HFE-related hemochromatosis; non-HFE-related hemochromatosis; congenital atransferrinemia; iron overload-related anemias such as thalassemia, myelodysplasia, and hematopoietic stem cell transplantation-related disorders; chronic liver disease; chronic inflammation associated with cancer; autoimmune or inflammatory diseases; neurodegeneration associated with brain copper accumulation-related diseases such as Wilson's disease; and polygenic neurodegeneration-related diseases such as Parkinson's disease and Alzheimer's disease.

[0210] HFE-related hemochromatosis is obtained, inter alia, by C282Y homozygosity or C282 / H63D heterozygosity. Non-HFE-related hemochromatosis is obtained, for example, by including juvenile hemochromatosis type 2A or 2B, or by mutant transferrin receptor 2 or mutant ferroportin 1 genes.

[0211] Neurodegeneration including brain iron accumulation-related diseases includes aceruloplasminemia, neuroferritinopathy, pantothenate kinase-associated neurodegeneration, Wilson's disease, and beta-propeller protein-associated neurodegeneration (BPAN).

[0212] Polygenic neurodegenerative disorders include Parkinson's disease and Alzheimer's disease. In particular, iron-overload-related disorders are iron-overload-related anemias such as thalassemia, myelodysplasia, aplastic anemia, Diamond-Blackfan anemia, congenital dyserythropoietic anemia, chronic hemolytic anemia, in particular sickle cell anemia, hematopoietic stem cell transplantation-related disorders, and chronic liver diseases including viral hepatitis, alcoholic hepatitis, non-alcoholic steatohepatitis (NASH), and metabolic iron overload syndrome.

[0213] Pharmaceutical composition The pharmaceutical compositions contemplated herein may include a pharmaceutically acceptable carrier in addition to the active ingredient. The term "pharmaceutically acceptable carrier" is intended to encompass any carrier (e.g., a support, substance, solvent, etc.) that does not interfere with the effectiveness of the biological activity of the active ingredient and is not toxic to the host to which it is administered. For example, for parenteral administration, the active compound can be formulated into unit dosage forms for injection in vehicles such as physiological saline, dextrose solution, serum albumin, and Ringer's solution.

[0214] The pharmaceutical composition can be formulated by methods known in the art as a solution in a pharmaceutically compatible solvent, or as an emulsion, suspension or dispersion in a suitable pharmaceutical solvent or vehicle, or as a pill, tablet or capsule containing a solid vehicle. The formulations of the present invention suitable for oral administration are in the form of separate units such as capsules, sachets, tablets or lozenges each containing a predetermined amount of the active ingredient; in the form of powders or granules; in the form of solutions or suspensions in aqueous or non-aqueous liquids; or in the form of oil-in-water or water-in-oil emulsions. Formulations suitable for parenteral administration conveniently include sterile oily or aqueous preparations of the active ingredient which are preferably isotonic with the blood of the recipient. Any such formulations may also contain other pharmaceutically compatible and non-toxic adjuvants such as stabilizers, antioxidants, binders, coloring agents, emulsifying agents or flavoring substances. The formulations of the present invention thus contain an active ingredient in association with a pharmaceutically acceptable carrier and optionally with other therapeutic components. The carrier needs to be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not toxic to its recipient. The pharmaceutical composition is advantageously applied by injection or intravenous infusion of a suitable sterile solution or as oral medication through the gastrointestinal tract. Methods for the safe and effective administration of many of these chemotherapeutic agents are known to those skilled in the art. In addition, their administration is described in standard literature.

[0215] The pharmaceutical or veterinary composition as disclosed herein may further contain additional active ingredients or drugs.

[0216] Further aspects and advantages of the present invention are illustrated in the following examples, which should be regarded as illustrative and not restrictive.

Examples

[0217]

Table 1A

[0218] [Table 1B]

[0219] [Table 1C]

[0220] [Table 1D]

[0221] [Table 1E]

[0222] [Table 1F]

[0223] [Table 1G]

[0224] [Table 1H]

[0225] Example 1 Compound synthesis 1- General information All solvents and chemicals were purchased from commercially available sources and used without further purification or were collected by Purification of Laboratory Chemicals (Armarego, WLF; Chai, CLL 5 th The reaction was purified according to the procedure outlined in (Ed.). The solvent was dried under standard conditions. The reaction was purified by thin layer chromatography (TLC) on precoated silica (60F) on aluminum plates (Merck). 254) was used for monitoring. The TLC plates were visualized by treatment with UV light and / or ammonium molybdate cerium solution (CAM) and heating. The product was purified by column chromatography using silica gel 60 (0.036 - 0.071 mm; 215 - 400 mesh) from Macherey Nagel, a CombiFlash Rf+ Teledyne Isco system equipped with a prepacked column silica gel column (Interchim), or / and preparative HPLC Quaternary Gradient 2545 equipped with a Photodiode Array detector (Waters) with a reversed-phase column (XBridge Prep C18 5μm OBD, 30×150 mm).

[0226] NMR spectroscopy was performed on a Bruker spectrometer. The spectra were operated at 298 K in DMSO-d6 or D2O or CD3OD, CD2Cl2. 1 1H NMR was recorded at 400 or 500 MHz, and the chemical shift δ is expressed in ppm using the residual non-deuterated solvent signal as an internal standard, and the coupling constant J is specified in Hz. The following abbreviations are used: s, singlet; brs, broad singlet; d, doublet; dd, doublet of doublets; dt, doublet of triplets; dq, doublet of quartets; ddd, doublet of doublets of doublets; dqd, doublet of doublets of quartets; t, triplet; td, triplet of doublets; tdd, triplet of doublets of doublets; q, quartet; m, multiplet. The inventors have only reported the labile protons that could be clearly identified in the spectra. 13 13C NMR was recorded at 101 or 126 MHz, and the chemical shift δ is expressed in ppm using the deuterated solvent signal as an internal standard.

[0227] The purity of the final compound determined to be >95% by UPLC MS was recorded on a Waters Acquity H-class equipped with a Photodiode Array detector and SQ detector 2 with a reversed-phase column (Aquity UPLC® BEH C18 1.7μm, 2.1×50 mm).

[0228] "Classical System": ACN (+FA 0.1%) and MilliQ water (+FA 0.1%): constant composition (0.2 minutes) with 5% ACN, then a linear gradient from 5% to 100% ACN in 2.3 minutes, and then constant composition (0.5 minutes) with 100% ACN.

[0229] 2 - Abbreviations ACN, acetonitrile; AcOH, acetic acid; aq., aqueous; Boc2O, di - tert - butyl dicarbonate; DCM, dichloromethane; equiv., equivalent; ESI, electrospray ionization; EtOAc, ethyl acetate; EtOH, ethanol; Et2O, diethyl ether; Et3N, triethylamine; FA, formic acid; HPLC, high - performance liquid chromatography; HRMS, high - resolution mass spectrometry; K2CO3, potassium carbonate; MeOH, methanol; MgSO4, magnesium sulfate; MS, mass spectrometry; NaH, sodium hydride; NMR, nuclear magnetic resonance; RT, room temperature; THF, tetrahydrofuran; TLC, thin - layer chromatography; UPLC, ultra - performance liquid chromatography; UV, ultraviolet.

[0230] 3 - Chemical Synthesis 3 - 1 - Synthesis by Nucleophilic Substitution 3 - 1 - 1 Procedure for NH - Monoalkylated Compounds Under darkness and in an inert atmosphere, serotonin hydrochloride (200 mg, 0.940 mmol, 1 equivalent) was dissolved in THF (10 mL). NaH (45 mg, 1.128 mmol, 1.2 equivalents) was added to the mixture. The mixture was stirred for 30 minutes, then an alkyl bromide (0.6 equivalent) was added. The mixture was stirred for 3.5 hours and then quenched with water. The resulting solution was extracted with DCM, dried over MgSO4, and concentrated. The crude product was purified by flash chromatography using DCM / MeOH (from 100 / 0 to 80 / 20) as the eluent and by preparative HPLC to obtain the desired product after lyophilization. The resulting compound was a formate salt.

[0231]

Chemical Structure

[0232] Yield: 44 mg, 21%. Isolated as a light gray powder with purity >95% by NMR and a single spot by TLC; R f : 0.44 in DCM / MeOH 90 / 10. Strain that stains green with CAM. 1 H NMR (DMSO-d6, 500 MHz): δ ppm= 10.51 (1H, s); 7.12 (1H, d, J = 8.6 Hz); 7.04 (1H, d, J = 2.4 Hz); 6.82 (1H, d, J = 2.4 Hz); 6.60 (1H, dd, J = 2.3, J = 8.6 Hz); 3.52 (2H, d, J = 2.4 Hz); 3.21 (1H, t, J = 2.4 Hz); 2.92 (2H, m); 2.79 (2H, m). 13 C NMR (DMSO-d6, 126 MHz): δ ppm= 150.2; 130.8; 127.8; 123.2; 111.7; 111.3; 110.5; 102.2; 80.8; 75.2; 47.9; 36.7; 24.2.UPLC: R T : 0.8 to 1.0 (classical system). MS (ESI + ) m / z [M+H] + C 13 H 15 N2O + Calculated value: 215.11; measured value: 215.22.

[0233] LC419(=Compound (039))

[0234] [ka]

[0235] Yield: 28 mg, 12%. Isolated as a light gray powder with purity >95% by NMR and a single spot by TLC; R f : 0.56 in DCM / MeOH, 80 / 20. Strains that stain green with CAM; 1 1H NMR (CD3OD, 500 MHz): δ ppm = 8.51 (1H, s, FA); 7.19 (1H, d, J = 8.8 Hz); 7.11 (1H, s); 6.93 (1H, d, J = 2.1 Hz); 6.70 (1H, dd, J = 2.2, J = 8.8 Hz); 3.32 - 3.29 (2H, m); 3.18 (2H, t, J = 7.4 Hz); 3.09 (2H, t, J = 7.5 Hz); 2.62 (2H, dt, J = 2.7 Hz, J = 6.8 Hz); 2.52 (1H, t, J = 2.6 Hz). 13 13C NMR (CD3OD, 126 MHz): δ ppm = 169.8 (FA); 151.5; 133.2; 128.8; 124.9; 113.0; 112.9; 109.3; 103.1; 79.4; 73.1; 49.7; 47.1; 23.4; 16.9. UPLC: R T : 0.74 (classical system) MS (ESI + ) m / z [M + H] + C 14 H 17 N2O + Calculated value for C14H15N2O: 229.13; Measured value: 229.28.

[0236] LYS6(LC344)(= Compound (002))

[0237]

Chem.

[0238] Yield: 43 mg, 19%. Isolated as a pale - gray powder with purity > 95% by NMR and a single spot by TLC; R f : 0.5 in DCM / MeOH / Et3N, 95 / 5 / 2. Strains stained green with CAM. 11H NMR (CD3OD, 400 MHz): δ ppm = 7.16 (1H, d, J = 8.4 Hz); 7.00 (1H, s); 6.92 (1H, d, J = 2.1 Hz); 6.67 (1H, dd, J = 2.3 Hz, J = 8.4 Hz); 5.21 (1H, m); 3.23 (2H, d, J = 7.2 Hz); 2.89 (4H, s); 1.71 (3H, brs); 1.62 (3H, brs). 13 13C NMR (CD3OD, 101 MHz): δ ppm = 151.2; 136.8; 133.2; 129.3; 124.3; 122.3; 112.7; 112.5; 112.4; 103.5; 50.0; 47.4; 26.0; 25.9; 17.9. UPLC: R T : 1.45 (classical system) MS (ESI + ) m / z [M+H] + C 15 H 21 N2O + Calculated value for 245.16; Measured value 245.17.

[0239] LC342 (= Compound 040)

[0240]

Chem.

[0241] Yield: 24 mg, 10%. Isolated as a light gray powder with purity > 95% by NMR and a single spot by TLC; R f : In DCM / MeOH / Et3N, 90 / 10 / 2, 0.49. Stains green with CAM; 1H NMR (CD3OD, 400 MHz): δ ppm = 7.16 (1H, dd, J = 0.5 Hz, J = 8.5 Hz); 7.08 (1H, s,); 6.85 (1H, dd, J = 0.5 Hz, J = 2.3 Hz); 6.67 (1H, dd, J = 2.4 Hz, J = 8.7 Hz); 5.29 (2H, m); 3.72 (4H, d, J = 7.5 Hz); 3.27 (2H, m); 3.08 (2H, m); 1.81 (6H, brs); 1.72 (6H, d, J = 0.9 Hz). 13 C NMR (CD3OD, 101 MHz): δ ppm = 151.6; 145.3 (2C); 133.2; 128.8; 125.0 (2C); 114.3; 113.1; 112.9; 109.2; 103.2; 53.3; 51.9 (2C); 26.2 (2C); 22.0; 18.5 (2C). UPLC: R T : 1.81 (classical system) MS (ESI + ) m / z [M+H] + C 20 H 29 N2O + Calculated value: 313.22; measured value: 313.04.

[0242] LYS7(LC330)(=Compound(003))

[0243] [ka]

[0244] Yield: 124 mg, 37%. Isolated as an orange powder with purity >95% by NMR and a single spot by TLC; R f : 0.48 in DCM / MeOH, 90 / 10. Strains that stain green with CAM; 11H NMR (DMSO-d6, 400 MHz): δ ppm = 10.43 (1H, brs); 8.68 (1H, t, J = 2.2 Hz); 8.60 (2H, d, J = 2.1 Hz); 8.51 (1H, s); 7.08 (1H, d, J = 8.5 Hz); 7.01 (1H, d, J = 2.5 Hz); 6.74 (1H, d, J = 2.2 Hz); 6.55 (1H, dd, J = 2.3 Hz, J = 8.6 Hz); 3.98 (2H, s); 2.77 (4H, m). 13 13C NMR (DMSO-d6, 101 MHz): δ ppm = 150.5; 148.4 (2C); 146.9; 131.3; 128.5 (2C); 128.3; 123.5; 117.2; 112.0; 111.8; 111.6; 102.6; 51.7; 49.6; 26.2. UPLC: R T : 1.48 (classical system) MS (ESI + ) m / z [M+H] + C 17 H 17 N4O5 + Calculated value for 357.11; measured value 357.13.

[0245] Procedure for 3-1-2-polyalkylated compounds Under dark and in an inert atmosphere, serotonin hydrochloride (500 mg, 2.35 mmol, 1 equivalent) was dissolved in THF (25 mL). NaH (188 mg, 2 equivalents) was added to the mixture. The mixture was stirred for 30 minutes, then propargyl bromide (524 μL, 2 equivalents) was added. The mixture was stirred for 4 hours and then quenched with water. The resulting solution was extracted with DCM, dried over MgSO4, and concentrated. The crude product was purified by flash chromatography using DCM / MeOH (from 99 / 1 to 80 / 20) as the eluent. Three fractions were obtained and purified by preparative HPLC to obtain three products after lyophilization.

[0246] A1 (LYS1) (NMR-SD095A1):

[0247]

Chem.

[0248] Yield: 5.5 mg, 0.8%. Isolated as a light grey powder with purity >95% by NMR and a single spot by TLC; R f : 0.71 in DCM / MeOH, 95 / 5. Stains green with CAM, 1 1H NMR (CD3OD, 500 MHz): δ ppm = 7.23 (1H, d, J = 8.8 Hz); 7.16 (1H, d, J = 2.3 Hz); 7.06 (1H, s); 6.80 (1H, dd, J = 2.3 Hz, J = 8.8 Hz); 4.72 (2H, d, J = 2.4 Hz); 3.56 (4H, d, J = 2.5 Hz); 2.90 (4H, m); 2.89 (1H, t, J = 2.4 Hz); 2.69 (2H, t, J = 2.5 Hz). 13 13C NMR (CD3OD, 126 MHz): δ ppm = 152.9; 133.9; 128.9; 124.2; 113.3 (2C); 112.9; 103.6; 80.7; 79.0 (2C); 76.2; 75.1 (2C); 57.8; 54.7; 42.8 (2C); 24.2. UPLC: R T : 1.88 (classical system). MS (ESI + ) m / z [M+H] + C 19 H 19 N2O + Calculated value for 291.14; Measured value 291.18.

[0249] A3 (LYS3) (NMR-SD095A3 - formate):

[0250]

Chem.

[0251] Yield: 29 mg, 6%. Isolated as a light gray powder with purity >95% by NMR and a single spot by TLC; R f : 0.14 in DCM / MeOH, 95 / 5. Strains stained green with CAM. 1 1H NMR (DMSO-d6, 500 MHz): δ ppm = 10.51 (1H, s); 7.12 (1H, d, J = 8.6 Hz); 7.04 (1H, d, J = 2.4 Hz); 6.82 (1H, d, J = 2.4 Hz); 6.60 (1H, dd, J = 2.3, J = 8.6 Hz); 3.52 (2H, d, J = 2.4 Hz); 3.21 (1H, t, J = 2.4 Hz); 2.92 (2H, m); 2.79 (2H, m). 13 13C NMR (DMSO-d6, 126 MHz): δ ppm = 150.2; 130.8; 127.8; 123.2; 111.7; 111.3; 110.5; 102.2; 80.8; 75.2; 47.9; 36.7; 24.2. UPLC: R T : 0.8 to 1.0 (classical system). MS (ESI + ) m / z [M+H-HCOOH] + C 13 H 15 N2O + Calculated value of 215.11; Measured value of 215.22.

[0252] A4(LYS4)(NMR-SD095A4):

[0253]

Chemical Structure

[0254] Yield: 57 mg, 10%. Isolated as a light gray powder with purity >95% by NMR and a single spot by TLC; R f : 0.43 in DCM / MeOH, 95 / 5. Strains stained green with CAM. 11H NMR (CD3OD, 500 MHz): δ ppm = 7.15 (1H, d, J = 8.3 Hz); 6.99 (1H, s); 6.95 (1H, d, J = 2.3 Hz); 6.67 (1H, dd, J = 2.3 Hz, J = 8.6 Hz); 3.55 (4H, d, J = 2.5 Hz); 2.90 - 2.85 (4H, m); 2.70 (2H, t, J = 2.5 Hz). 13 13C NMR (CD3OD, 126 MHz): δ ppm = 151.0; 133.1; 129.3; 1234.1; 112.7; 112.5; 112.4; 103.6; 78.7 (2C); 75.3 (2C); 54.7; 42.8 (2C); 24.2. UPLC: R T : 1.42 (classical system). MS (ESI + ) m / z [M + H] + C 16 H 17 N2O + Calculated value for 253.13; Measured value 253.15.

[0255] A0(LC431F1):

[0256]

Chem.

[0257] Yield: 67 mg, 9%. Isolated as a light gray powder with purity >95% by NMR and a single spot by TLC; R f : DCM / MeOH, 98 / 2, 0.68. Stains green with CAM; 11H NMR (CD2Cl2, 500 MHz): δ ppm = 7.29 (1H, d, J = 8.8 Hz); 7.16 (1H, d, J = 2.5 Hz); 7.06 (1H, s); 6.92 (1H, dd, J = 2.4 Hz, J = 8.8 Hz); 4.82 (2H, d, J = 2.4 Hz); 4.74 (2H, d, J = 2.5 Hz); 3.52 (4H, d, J = 2.5 Hz); 2.90 - 2.85 (4H, m); 2.56 (1H, t, J = 2.5 Hz); 2.44 (1H, t, J = 2.5 Hz); 2.30 (2H, t, J = 2.5 Hz). 13 13C NMR (CD2Cl2, 126 MHz): δ ppm = 151.9; 131.9; 128.7; 125.9; 113.3; 112.5; 110.2; 103.4; 79.3; 78.9 (2C); 78.1; 74.8; 72.9; 72.7 (2C); 56.8; 53.3; 42.1 (2C); 35.8; 23.4. UPLC: R T : 2.02 (classical system) MS (ESI + ) m / z [M + H] + C 22 H 21 N2O + Calculated value for 329.16; Measured value 329.20.

[0258] Procedure for 3 - 1 - 3 - O - alkylated compounds In the dark, serotonin hydrochloride (500 mg, 2.35 mmol, 1 equiv) was dissolved in water (9 mL). K2CO3 (665 mg, 4.81 mmol, 2.1 equiv) and Boc2O (538 mg, 2.46 mmol, 1.05 equiv) were added to the solution. The solution was stirred overnight and then extracted with DCM. The organic phase was washed with 5% aqueous HCl and brine, then dried over MgSO4 and concentrated. The crude product was purified by flash chromatography using DCM / MeOH (from 100 / 0 to 90 / 10) as the eluent to obtain the desired product (485 mg), which was carried on to the next step.

[0259] In the dark and under an inert atmosphere, the product of the previous step (138 mg, 0.5 mmol, 1 equiv) was dissolved in anhydrous acetonitrile (4 mL). K2CO3 (138 mg, 2 equiv) and propargyl bromide (59 μL, 1.06 equiv) were added to the solution. The mixture was stirred and heated at reflux overnight, cooled to room temperature, then filtered with acetonitrile and concentrated. The crude product was purified by flash chromatography using cyclohexane / EtOAC (from 90 / 10 to 0 / 100) as the eluent to obtain LC466.

[0260] The product was then dissolved in CH2Cl2 / TFA, 4 / 1 (4 mL) and stirred for 2 h until the product was predominant in the UPLC analysis. The mixture was then concentrated and the crude product was purified directly by preparative HPLC to obtain the desired product after lyophilization.

[0261] A2(LYS2)(NMR-SD08801-formate):

[0262]

Chemical Structure

[0263] Yield: 39 mg, 17%. Isolated as a light grey powder with >95% purity by NMR and a single spot by TLC; R f : 0.68 in DCM / MeOH / Et3N, 90 / 10 / 2. Strains that stain green with CAM.1 1H NMR (D2O, 500 MHz): δ ppm = 8.45 (1H, s, (FA)); 7.47 (1H, d, J = 8.7 Hz); 7.31 (1H, s); 7.29 (1H, d, J = 2.5 Hz); 7.00 (1H, dd, J = 8.9 Hz, J = 2.4 Hz); 4.84 (2H, d, J = 2.4 Hz); 3.32 (2H, t, J = 7.1 Hz); 3.14 (2H, t, J = 7.1 Hz); 2.95 (1H, t, J = 2.4 Hz). UPLC: R T : 1.57 (classical system). MS (ESI + ) m / z [M+H] + C 13 H 15 N2O + Calculated value for 215.11; Measured value 215.23.

[0264] Procedure for 3-1-4-carbamate Under dark and inert atmosphere, serotonin hydrochloride (75 mg, 0.315 mmol, 1 equivalent) was dissolved in DCM / H2O, 1 / 2 (1 / 4 mL). Na2CO3 (�6 mg, 0.740 mmol, 2.1 equivalents) was added to the mixture. The mixture was stirred for 30 minutes and then alkyl chloroformate (1 equivalent) was added. The mixture was stirred for 18 hours and then quenched with water. The resulting solution was extracted with DCM, dried over MgSO4 and concentrated. The crude product was purified by flash chromatography using heptane / EtOAc (100 / 0 to 50 / 50) as the eluent and then by preparative HPLC.

[0265] LYS8=LC406F2 (= Compound (004))

[0266]

Chemical Structure

[0267] Yield: 39 mg, 17%. Isolated as a light gray powder with purity >95% by NMR and a single spot by TLC; R f : 0.68 in DCM / MeOH / Et3N, 90 / 10 / 2. Stains green with CAM. 1 1H NMR (CD3OD, 500 MHz): δ ppm = 7.15 (1H, d, J = 8.7 Hz); 6.98 (1H, s,); 6.95 (1H, d, J = 2.2 Hz); 6.67 (1H, dd, J = 2.2 Hz, J = 8.7 Hz); 4.63 (2H, d, J = 2.2 Hz); 3.36 (2H, t, J = 7.4 Hz); 2.85 (2H, t, J = 7.4 Hz); 2.83 (1H, t, J = 2.4 Hz). 13 13C NMR (CD3OD, 126 MHz): δ ppm = 157.9; 151.0; 133.0; 129.3; 124.2; 112.6; 112.3 (2C); 103.5; 79.5; 75.6; 53.0; 42.6; 26.7. UPLC: R T : 1.83 (classical system). MS (ESI + ) m / z [M+H] + C 14 H 15 N2O + Calculated value for 259.10; measured value 259.24.

[0268] Procedure for 3-1-5-sulfonamide: In the dark, serotonin hydrochloride (200 mg, 0.94 mmol) was dissolved in DCM (9 mL). Triethylamine (210 μL, 1.5 mmol, 1.6 eq) was added to the mixture. The mixture was stirred for 30 minutes, then methanesulfonyl chloride (43 μL, 0.56 mmol, 0.6 eq) was added slowly. The mixture was stirred for 18 hours, then quenched with water. The resulting solution was extracted with DCM, dried over MgSO4, and concentrated. The crude product was purified by flash chromatography using n-hexane / EtOAc (from 20 / 80 to 0 / 100) as the eluent to obtain a white solid.

[0269] LYS9 (= Compound (041))

[0270]

Chem.

[0271] Yield: 15 mg, 7%. Isolated as a pale yellow oil with purity > 95% by NMR and a single spot by TLC; R f : 0.23 in n-Hex / EtOAc, 10 / 90. Stains green with CAM; 1 1H NMR (CD3OD, 500 MHz): δ ppm = 7.54 (1H, d, J = 2.2 Hz); 7.39 (1H, d, J = 8.7 Hz); 7.25 (1H, s,); 7.07 (1H, dd, J = 2.3 Hz, J = 8.6 Hz); 3.36 (2H, t, J = 7.2 Hz); 3.18 (3H, s); 2.99 (2H, t, J = 7.2 Hz); 2.81 (3H, s). 13 13C NMR (CD3OD, 126 MHz): δ ppm = 144.3; 136.6; 128.9; 126.2; 116.8; 113.7; 113.1; 112.5; 44.9; 39.9; 36.9; 27.3. UPLC: R T : 1.45 (classical system) MS (ESI + ) m / z [M+H] + C 12 H 17 N2O5S2 + Calculated value for 333.05; Measured value 333.18.

[0272] Procedure for 3-1-6-NH-alkylated tryptamine derivatives In the dark and under an inert atmosphere, tryptamine (160 mg, 1 mmol, 1 equiv) was dissolved in DMF (10 mL). K2CO3 (138 mg, 1 equiv) was added to the mixture. The mixture was stirred for 5 minutes and then alkyl bromide (0.6 equiv) was added. The mixture was stirred for 4 hours and then quenched with water. The resulting solution was extracted with DCM, dried over MgSO4, and concentrated. The crude product was purified by flash chromatography using DCM / MeOH (from 100 / 0 to 80 / 20) as the eluent and by preparative HPLC to obtain the desired product after lyophilization. The resulting compound was a formate salt.

[0273] [Chemical formula]

[0274] Yield: 25 mg, 13%. Isolated as a white powder with >95% purity by NMR and a single spot by TLC; R f : 0.26 in DCM / MeOH, 95 / 5. Stains green with CAM; 1 1H NMR (CD3OD, 500 MHz): δ ppm = 8.51 (1H, s, FA); 7.58 (1H, td, J = 0.9 Hz, J = 7.9 Hz); 7.38 (1H, td, J = 0.8 Hz, J = 8.1 Hz); 7.17 (1H, brs); 7.13 (1H, dt, J = 0.9 Hz, J = 7.9 Hz); 7.05 (1H, dt, J = 0.9 Hz, J = 8.1 Hz); 3.87 (2H, d, J = 2.5 Hz); 3.36 (2H, t, J = 7.5 Hz); 3.15 (2H, t, J = 7.4 Hz); 3.13 (1H, t, J = 2.5 Hz). 1313C NMR (CD3OD, 126 MHz): δ ppm = 169.7 (FA); 138.3; 128.1; 124.2; 122.7; 120.0; 118.9; 112.5; 110.3; 78.4; 75.6; 48.4; 37.4; 23.5. UPLC: R T : 1.45 (Classical system) MS (ESI + ) m / z [M+H] + C 13 H 15 N2 + Calculated value for 199.12; Measured value 199.23.

[0275]

Chemical Structure

[0276] Yield: 160 mg, 67%. Isolated as a white powder with purity > 95% by NMR and a single spot by TLC; R f : 0.63 in DCM / MeOH, 95 / 5. Strains stained green with CAM; 1 1H NMR (CD2Cl2, 500 MHz): δ ppm = 8.11 (1H, brs); 8.09 (1H, s, FA); 7.61 (1H, dd, J = 0.9 Hz, J = 7.8 Hz); 7.36 (1H, td, J = 0.9 Hz, J = 8.2 Hz); 7.16 (1H, dt, J = 1.0 Hz, J = 7.9 Hz); 7.08 (2H, m); 3.53 (4H, d, J = 2.5 Hz); 2.94 (2H, m); 2.89 (2H, m); 2.29 (2H, t, J = 2.5 Hz). 13 13C NMR (CD2Cl2, 126 MHz): δ ppm = 136.7; 127.9; 122.2; 122.1; 119.5; 119.1; 114.2; 111.5; 79.2 (2C); 73.2 (2C); 53.8; 42.4 (2C); 23.8. UPLC: R T : 1.68 (Classical system) MS (ESI + ) m / z [M+H] + C 16 H 17 N2 + Calculated value of 237.13; measured value of 237.19.

[0277] Synthesis by 3-2-Reductive amination Procedure from 3-Compound 1-7]:

[0278]

Chemical formula

[0279] Under dark and inert atmosphere, serotonin hydrochloride (213 mg, 1 mmol) was dissolved in anhydrous MeOH (10 mL). Et3N (153 μL, 1.1 equivalents) was added to the mixture. The mixture was stirred at room temperature for 30 minutes and then the corresponding ketone (1.1 equivalents) was added. The mixture was stirred overnight and after that time, NaBH3CN (1.1 equivalents) was added. The reaction mixture was stirred at room temperature for an additional 60 minutes. Next, the solvent was evaporated under reduced pressure. The crude product was placed in a mixture of Et2O / water, 1 / 1 (10 / 10 mL), and the resulting solution was alkalized with NaOH [2M] until pH = 10 was obtained, and then extracted with Et2O (2 × 20 mL) and then with DCM (1 × 20 mL). The organic phase was dehydrated over MgSO4 and concentrated. The crude product was purified by flash chromatography using DCM / MeOH / Et3N (from 100 / 0 / 2 to 80 / 20 / 2) as the eluent.

[0280] LYS12 Compound 1: LC332-333-338 ((= Compound (008))

[0281]

Chemical formula

[0282] Yield: 39 mg, 17%. Isolated as a light gray powder with purity >95% by NMR and a single spot by TLC; R f : In DCM / MeOH / Et3N, 90 / 10 / 2, 0.68. A strain that stains green with CAM. 1 1H NMR (CD3OD, 400 MHz): δ ppm = 7.16 (1H, d, J = 8 Hz); 7.00 (1H, s,); 6.91 (1H, d, J = 4 Hz); 6.67 (1H, dd, J = 4 Hz, J = 8 Hz); 3.33 (1H, m); 2.84 (4H, m); 2.20 (2H, m); 1.72 (4H, m). 13 13C NMR (CD3OD, 101 MHz): δ ppm = 151.2; 133.2; 129.2; 124.3; 112.7; 112.5; 112.4; 103.4; 54.6; 47.7; 30.8 (2C); 26.1; 15.6. UPLC: R T : 1.21 (classical system). MS (ESI + ) m / z [M+H] + C 14 H 19 N2O + Calculated value for C

[0283] LC348 (= compound (009))

[0284]

Chemical formula

[0285] Yield: 138 mg, 48%. Isolated as a light gray powder with purity >95% by NMR and a single spot by TLC; R f : In DCM / MeOH / Et3N, 98 / 2 / 2, 0.62. A strain that stains green with CAM; 11H NMR (CD3OD, 400 MHz): δ ppm = 8.54 (1H, s, FA) 7.20 (1H, dd, J = 0.5 Hz, J = 8.6 Hz); 7.11 (1H, s,); 6.88 (1H, dd, J = 0.5 Hz, J = 2.3 Hz); 6.71 (1H, dd, J = 2.3 Hz, J = 8.6 Hz); 3.88 (2H, quintet, J = 8.5 Hz); 3.19 (2H, m); 3.03 (2H, m); 2.33 (8H, m); 1.86 (4H, m). 13 13C NMR (CD3OD, 101 MHz): δ ppm = 169.9 (FA); 151.6; 133.1; 128.7; 124.9; 113.1; 112.8; 109.6; 102.8; 58.2 (2C); 50.2; 28.9 (4C); 20.4; 15.7 (2C). UPLC: R T : 1.49 (classical system) MS (ESI + ) m / z [M+H] + C 18 H 25 N2O + Calculated value for 285.18, measured value 285.34.

[0286] LYS13 Compound 2: LC335((=Compound(010))

[0287]

Chem.

[0288] Yield: 195 mg, 80%. Isolated as a light gray powder with purity >95% by NMR and a single spot by TLC; R f : DCM / MeOH / Et3N, 95 / 5 / 2, 0.51. Strains stained green with CAM. 1H NMR (CD3OD, 400 MHz): δ ppm= 7.16 (1H, d, J = 8 Hz); 7.01 (1H, s,); 6.92 (1H, d, J = 4 Hz); 6.67 (1H, dd, J = 4 Hz, J = 8 Hz); 3.11 (1H, m); 2.90 (4H, s); 1.90 (2H, m); 1.66 (2H, m); 1.54 (2H, m); 1.36 (2H, m). 13 C NMR (CD3OD, 101 MHz): δ ppm= 151.2; 133.2; 129.3; 124.3; 112.7; 112.5 (2C); 103.5; 60.7; 49.6; 33.2 (2C); 26.1; 25.0 (2C). UPLC: R T : 1.34 (classical system). MS (ESI + ) m / z [M+H] + C 15 H 21 N2O + Calculated value: 245.16; measured value: 245.10.

[0289] LYS14 Compound 3:LC336(=Compound (011))

[0290] [ka]

[0291] Yield: 253 mg, 98%. Isolated as a light gray powder with purity >95% by NMR and a single spot by TLC; R f : 0.53 in DCM / MeOH / Et3N, 95 / 5 / 2. Strain staining green with CAM. 11H NMR (CD3OD, 400 MHz): δ ppm = 7.16 (1H, d, J = 8 Hz); 7.01 (1H, s); 6.93 (1H, d, J = 4 Hz); 6.67 (1H, dd, J = 4 Hz, J = 8 Hz); 2.90 (4H, m); 2.50 (1H, m); 1.90 (2H, m); 1.73 (2H, m); 1.63 (1H, m); 1.21 (5H, m). 13 13C NMR (CD3OD, 101 MHz): δ ppm = 151.2; 133.2; 129.3; 124.3; 112.8; 112.5; 112.4; 103.5; 57.9; 47.6; 33.5 (2C); 27.1; 26.1 (3C). UPLC: R T : 1.46 (classical system). MS (ESI + ) m / z [M+H] + C 16 H 23 N2O + calculated value 259.17; measured value 259.24.

[0292] LYS15 compound: LC356 (= compound (012))

[0293]

Chemical Structure

[0294] Yield: 120 mg, 44%. Isolated as a light gray powder with purity > 95% by NMR and a single spot by TLC; R f : 0.43 in DCM / MeOH / Et3N, 95 / 5 / 2. Strains stained green with CMA. 11H NMR (CD3OD, 400 MHz): δ ppm = 7.17 (1H, d, J = 8.6 Hz); 7.02 (1H, s); 6.93 (1H, d, J = 2.5 Hz); 6.67 (1H, dd, J = 2.4 Hz, J = 8.6 Hz); 2.91 (4H, m); 2.71 (1H, m); 1.89 - 1.80 (2H, m); 1.71 - 1.32 (10H, m). 13 13C NMR (CD3OD, 101 MHz): δ ppm = 151.2; 133.2; 129.2; 124.4; 112.8; 112.5; 112.2; 103.4; 60.2; 48.0; 34.8 (2C); 29.1 (2C); 25.8; 25.5 (2C). UPLC: R T : 1.57 (classical system) MS (ESI + ) m / z [M+H] + C 17 H 25 N2O + calculated value for 273.19; measured value 273.30.

[0295] LYS16 Compound 4: LC337 (= Compound 013)

[0296]

Chemical Structure

[0297] Yield: 212 mg, 74%. Isolated as a light grey powder with >95% purity by NMR and a single spot by TLC; R f : 0.6 in DCM / MeOH / Et3N, 90 / 10 / 2. Strains stained green with CMA; 11H NMR (CD3OD, 400 MHz): δ ppm = 7.17 (1H, d, J = 8 Hz); 7.02 (1H, s); 6.93 (1H, d, J = 4 Hz); 6.67 (1H, dd, J = 4 Hz, J = 8 Hz); 2.94 (4H, m); 2.78 (1H, m); 1.73 (4H, m); 1.48 (10H, m). 13 13C NMR (CD3OD, 101 MHz): δ ppm = 151.2; 133.2; 129.2; 124.4; 112.8; 112.6; 112.1; 103.4; 59.1; 47.9; 32.9 (2C); 27.9 (2C); 26.9; 25.8; 25.3 (2C). UPLC: R T : 1.66 (classical system) MS (ESI + ) m / z [M+H] + C 18 H 27 N2O + Calculated value for C15H22N2O: 287.20; Measured value: 287.30.

[0298] LYS17 Compound 5: LC341 (= Compound (0014))

[0299]

Chemical Structure

[0300] Yield: 300 mg, 97%. Isolated as a light gray powder with purity > 95% by NMR and a single spot by TLC; R f : 0.53 in DCM / MeOH / Et3N, 95 / 5 / 2. Stains green with CMA; 11H NMR (CD3OD, 400 MHz): δ ppm = 7.17 (1H, d, J = 8.6 Hz); 7.04 (1H, s); 6.94 (1H, d, J = 2.3 Hz); 6.67 (1H, dd, J = 2.4 Hz, J = 8.6 Hz); 2.93 (4H, m); 2.79 (1H, brs); 1.91 - 1.83 (4H, m); 1.80 (1H, m); 1.74 - 1.68 (4H, m); 1.65 - 1.56 (3H, m); 1.47 - 1.41 (2H, m). 13 13C NMR (CD3OD, 101 MHz): δ ppm = 151.2; 133.2; 129.3; 124.4; 112.8; 112.5 (2C); 103.5; 62.4; 47.4; 38.8; 38.7 (2C); 32.4 (2C); 31.9 (2C); 29.1; 28.6; 26.0. UPLC: R T : 1.62 (classical system) MS (ESI + ) m / z [M + H] + C 20 H 27 N2O + Calculated value for 311.21; measured value 311.30.

[0301] LYS19 Compound 6: LC340 (= Compound (015))

[0302]

Chem.

[0303] Yield: 70 mg, 32%. Isolated as a white amorphous solid with purity > 95% by NMR and a single spot by TLC; R f : 0.29 in DCM / MeOH / Et3N, 90 / 10 / 2. Stains green with CMA; 11H NMR (CD3OD, 400 MHz): δ ppm = 7.18 (1H, d, J = 8.6 Hz); 7.04 (1H, s); 6.93 (1H, d, J = 2.3 Hz); 6.68 (1H, dd, J = 2.3 Hz, J = 8.6 Hz); 3.05 - 2.91 (5H, m); 1.14 (6H, d, J = 6.5 Hz). 13 13C NMR (CD3OD, 101 MHz): δ ppm = 151.3; 133.2; 129.2; 124.5; 112.8; 112.6; 111.6; 103.3; 50.3; 47.7; 25.4; 21.4 (2C). UPLC: R T : 1.13 (classical system) MS (ESI + ) m / z [M + H] + C 13 H 19 N2O + calculated value for 219.14; measured value 219.21.

[0304] LYS20 Compound 7: LC339 (= Compound (016))

[0305]

Chem.

[0306] Yield: 57 mg, 23%. Isolated as a white amorphous solid with > 95% purity by NMR and a single spot by TLC; R f : DCM / MeOH / Et3N, 90 / 10 / 2, 0.63. Stains green with CMA; 11H NMR (CD3OD, 400 MHz): δ ppm = 7.18 (1H, d, J = 8.6 Hz); 7.07 (1H, s); 6.94 (1H, d, J = 2.4 Hz); 6.69 (1H, dd, J = 2.3 Hz, J = 8.7 Hz); 3.06 (2H, m); 2.99 (2H, m); 2.68 (1H, quintet, J = 6.2 Hz); 1.56 (4H, m); 0.87 (6H, t, J = 7.5 Hz). 13 13C NMR (CD3OD, 101 MHz): δ ppm = 151.4; 133.2; 129.1; 124.7; 112.9; 112.7; 111.1; 103.3; 61.6; 47.3; 24.9 (3C); 9.8 (2C). UPLC: R T : 1.40 (classical system) MS (ESI + ) m / z [M+H] + C 15 H 23 N2O + Calculated value for C13H17N2O: 247.17; Measured value: 247.20.

[0307] LC347 (= compound (017))

[0308]

Chemical Structure

[0309] Yield: 115 mg, 44%. Isolated as a white amorphous solid with >95% purity by NMR and a single spot by TLC; R f : 0.8 in DCM / MeOH / Et3N, 90 / 10 / 2. Strains stained green with CMA; 11H NMR (CD3OD, 400 MHz): δ ppm = 7.17 (1H, dd, J = 0.5 Hz, J = 8.6 Hz); 7.05 (1H, s,); 6.93 (1H, dd, J = 0.5 Hz, J = 2.3 Hz); 6.68 (1H, dd, J = 2.3 Hz, J = 8.6 Hz); 3.08 - 2.85 (5H, m); 1.53 (1H, m); 1.36 (1H, m); 1.24 (1H, m); 1.12 (3H, m); 0.88 (6H, dd, J = 3.6 Hz, J = 6.6 Hz). 13 13C NMR (CD3OD, 101 MHz): δ ppm = 151.3; 133.2; 129.1; 124.6; 112.9; 112.6; 111.4; 103.3; 52.9; 47.3; 45.8; 25.9; 25.3; 23.4; 22.3; 18.8. UPLC: R T : 1.58 (classical system) MS (ESI + ) m / z [M + H] + C 15 H 23 N2O + Calculated value for 261.19; Measured value 261.27.

[0310] LYS23 Compound 8: LC349 (= Compound (019))

[0311]

Chemical Structure

[0312] Yield: 131 mg, 35%. Isolated as a white amorphous solid with purity > 95% by NMR and a single spot by TLC; R f : 0.33 in DCM / MeOH, 90 / 10. Strains stained green with CMA; 11H NMR (CD3OD, 400 MHz): δ ppm = 7.21 - 7.10 (7H, m); 7.01 (4H, m); 6.84 (1H, d, J = 2.4 Hz); 7.07 (1H, s,); 6.94 (1H, d, J = 2.4 Hz); 6.67 (1H, dd, J = 2.4 Hz, J = 8.6 Hz); 6.62 (1H, s); 3.04 (1H, p, J = 6.9 Hz); 2.92 (2H, t, J = 6.6 Hz); 2.78 (1H, t, J = 6.6 Hz); 2.72 (2H, dd, J = 6.9 Hz, J = 13.8 Hz); 2.61 (2H, dd, J = 6.6 Hz, J = 13.8 Hz). 13 13C NMR (CD3OD, 101 MHz): δ ppm = 151.1; 139.7 (2C); 133.2; 130.5 (4C); 129.6 (4C); 128.9; 127.5 (2C); 124.5; 112.8; 112.5; 111.3; 103.4; 62.5; 47.6; 40.8 (2C); 25.5. UPLC: R T : 1.91 (classical system) MS (ESI + ) m / z [M + H] + C 25 H 27 N2O + Calculated value for 371.20; Measured value 371.27.

[0313] LC350 (= compound (020))

[0314]

Chem.

[0315] Yield: 187 mg, 63%. Isolated as a white amorphous solid with purity > 95% by NMR and a single spot by TLC; R f : 0.6 in DCM / MeOH, 90 / 10. Strains stained green with CMA; 1 1H NMR (CD3OD, 400 MHz): δ ppm = 7.18 - 7.12 (4H, m); 7.01 (2H, dd, J = 2.0 Hz, J = 7.8 Hz); 6.90 (1H, d, J = 0.5 Hz, J = 2.3 Hz); 6.82 (1H, s,); 6.68 (1H, dd, J = 2.3 Hz, J = 8.6 Hz); 3.03 - 2.81 (5H, m); 2.69 (1H, J = 7.1 Hz, J = 12.9 Hz); 2.59 (1H, J = 7.1 Hz, J = 12.9 Hz); 1.06 (3H, d, J = 6.5 Hz). 13 13C NMR (CD3OD, 101 MHz): δ ppm = 151.1; 139.7; 133.2; 130.1 (2C); 129.5 (2C); 129.1; 127.4; 124.4; 112.8; 112.5; 111.8; 103.4; 55.8; 47.6; 43.5; 25.7; 19.4. UPLC: R T : 1.62 (classical system) MS (ESI + ) m / z [M + H] + C 15 H 23 N2O + Calculated value for C

[0316] LC354(= Compound (018))

[0317]

Chemical Structure

[0318] Yield: 273 mg, 95%. Isolated as a white amorphous solid with >95% purity by NMR and a single spot by TLC; R f : 0.12 in DCM / MeOH / Et3N (95 / 5 / 2). Strains stained green with CMA; 11H NMR (CD3OD, 400 MHz): δ ppm = 7.19 (1H, d, J = 0.4 Hz, J = 8.6 Hz); 7.08 (1H, s,); 6.94 (1H, d, J = 0.5 Hz, J = 2.2 Hz); 6.70 (1H, dd, J = 2.3 Hz, J = 8.7 Hz); 5.06 (1H, m); 3.14 - 2.91 (5H, m); 1.98 (2H, m); 1.66 (3H, J = 0.7 Hz); 1.65 - 1.60 (1H, m); 1.56 (3H, s); 1.46 - 1.36 (1H, m); 1.18 (3H, d, J = 6.5 Hz). 13 13C NMR (CD3OD, 101 MHz): δ ppm = 151.4; 133.5; 133.2; 129.1; 124.7; 124.2; 112.9; 112.7; 110.9; 103.3; 54.6; 47.1; 35.8; 25.8; 25.1; 24.9; 18.0; 17.7. UPLC: R T : 1.71 (classical system) MS (ESI + ) m / z [M+H] + C 15 H 23 N2O + Calculated value for 287.20; Measured value 287.30.

[0319] LYS25 Compound X: LC357 (= Compound (021))

[0320]

Chem.

[0321] Yield: 36 mg, 16%. Isolated as a white amorphous solid with purity > 95% by NMR and a single spot by TLC; R f : DCM / MeOH, 90 / 10 + 2% Et3N, 0.32. Stains green with CMA; 11H NMR (CD3OD, 500 MHz): δ ppm = 8.54 (2H, s, (FA)); 7.20 (2H, d, J = 8.6 Hz); 7.11 (2H, s); 6.92 (2H, d, J = 2.3 Hz); 6.71 (2H, dd, J = 2.3 Hz, J = 8.6 Hz); 3.29 - 3.16 (6H, m); 3.07 (4H, m); 1.71 (2H, m); 1.48 (2H, m); 1.41 - 1.22 (14H, m). 13 13C NMR (CD3OD, 126 MHz): δ ppm = 170.1 (FA) (2C); 151.6 (2C); 133.2 (2C); 128.8 (2C); 124.9 (2C); 113.1 (2C); 112.9 (2C); 109.4 (2C); 103.1 (2C); 55.5 (2C); 46.1 (2C); 34.1 (2C); 30.2 (2C); 26.4 (2C); 23.7 (2C); 16.6 (2C). UPLC: R T : 1.48 (classical system) MS (ESI + ) m / z [M + H] + C 30 H 42 N4O2 + Calculated value for C19H27N4O2 is 491.33; Measured value is 491.49.

[0322] Procedure from 3 - 2 - 2 - aldehyde (monosubstituted analog) [Compounds 8 - x]:

[0323]

Chemical Structure

[0324] In the dark and under an inert atmosphere, serotonin hydrochloride (213 mg, 1 mmol) was dissolved in anhydrous MeOH (10 mL), and the corresponding aldehyde (1.1 equiv) was added. The mixture was stirred for 3 h, and after that time, NaBH3CN (1.1 equiv) was added. The reaction mixture was stirred for an additional 30 min at room temperature. Next, the solvent was evaporated under reduced pressure. The crude product was taken up in a 1 / 1 mixture of Et2O / water (10 / 10 mL), and the resulting solution was alkalinized with NaOH [2M] until pH = 10 was obtained, then extracted with Et2O (2 × 20 mL), then with DCM (1 × 20 mL). The organic phase was dried over MgSO4 and concentrated. The crude product was purified by flash chromatography using DCM / MeOH / Et3N (from 100 / 0 / 2 to 80 / 20 / 2) as eluent.

[0325] LYS29(LC358)(= Compound (024))

[0326] [Chemical Formula]

[0327] Yield: 88 mg, 36%. Isolated as a white amorphous solid with >95% purity by NMR and a single spot by TLC; R f : 0.31 in DCM / MeOH / Et3N, 98 / 2 / 2. Stains green with CMA; 1 H NMR (CD3OD, 500 MHz): δ ppm = 8.58 (1H, s, (FA)); 7.19 (1H, d, J = 8.7 Hz); 7.09 (1H, s,); 6.95 (1H, d, J = 2.2 Hz); 6.71 (1H, dd, J = 2.2 Hz, J = 8.7 Hz); 3.21 (2H, t, J = 7.5 Hz); 3.07 (2H, t, J = 7.5 Hz); 2.94 (2H, t, J = 7.9 Hz); 1.65 (2H, quintet, J = 7.8 Hz); 1.33 (4H, m); 0.92 (3H, t, J = 6.7 Hz). 13 13C NMR (CD3OD, 126 MHz): δ ppm = 170.3; 151.5; 133.1; 128.9; 124.9; 113.0; 112.8; 109.4; 103.1; 49.0; 48.8; 29.7; 26.9; 23.4; 23.2; 14.1. UPLC: R T : 1.45 (classical system) MS (ESI + ) m / z [M+H] + C 15 H 22 N2O + Calculated value for 247.17; Measured value 247.27.

[0328] LYS30 Compound 9: LC343, LC345, LC346 (= Compound (025))

[0329]

Chem.

[0330] Yield: 122 mg, 47%. Isolated as a white amorphous solid with purity > 95% by NMR and a single spot by TLC; R f : DCM / MeOH / Et3N, 98 / 2 / 2, 0.16. Stains green with CMA; 1 1H NMR (CD3OD, 400 MHz): δ ppm = 7.16 (1H, d, J = 8.7 Hz); 7.01 (1H, s,); 6.92 (1H, d, J = 2.1 Hz); 6.67 (1H, dd, J = 2.1 Hz, J = 8.7 Hz); 2.91 (4H, s); 2.62 (2H, m); 1.48 (2H, m); 1.26 (6H, m); 0.88 (3H, t, J = 6.5 Hz). 1313C NMR (CD3OD, 101 MHz): δ ppm = 151.2; 133.2; 129.3; 124.3; 112.8; 112.5; 112.2; 1 "03.4; 50.6; 50.3; 32.8; 30.0; 27.9; 25.8; 23.6; 14.3. UPLC: R T : 1.68 (Classical system) MS (ESI + ) m / z [M+H] + C 16 H 25 N2O 10 + Calculated value of 261.19; Measured value 261.19.

[0331] LYS26 Compound 10: (exp:LT266A)(=Compound(022))

[0332]

Chem.

[0333] Yield: 10 mg, 4.5%. Isolated as a white amorphous solid with purity >95% by NMR and a single spot by TLC; R f : DCM / MeOH / Et3N, 80 / 20 / 2, 0.3. Stains green with CMA; 1 1H NMR (CD3OD, 400 MHz): δ ppm = 8.57 (1H, s, (FA)); 7.21 (1H, d, J = 8.6 Hz); 7.13 (1H, s); 6.95 (1H, d, J = 2.3 Hz); 6.72 (1H, dd, J = 8.6Hz, J =2.3 Hz); 3.28 (2H, t, J = 7.6 Hz); 3.10 (2H, t, J = "7.6 Hz); 2.99 (2H, d, J = 8.6 Hz). 1.72 (2H, d, J = 7.5 Hz); 1.02 (3H, t, J = 7.4 Hz). 1313C NMR (CD3OD, 126 MHz): δ ppm = 168.7 (FA); 150.2; 131.8; 127.5; 123.5; 111.6; 111.5; 108.0; 101.7; 49.0; 22.0; 19.2; 9.8. UPLC: R T : 0.9 to 1.12 (classical system) MS (ESI + ) m / z [M+H] + C 13 H 19 N2O + Calculated value for 219.14; Measured value 219.26.

[0334] LYS28 Compound 11: (exp:LT265B)(=Compound (023))

[0335]

Chemical Structure

[0336] Yield: 27.6 mg, 11.8%. Isolated as a white amorphous solid with purity >95% by NMR and a single spot by TLC; R f : 0.5 in DCM / MeOH / Et3N, 90 / 10 / 2. Stains green with CMA; 1 1H NMR (CD3OD, 500 MHz): δ ppm = 8.58 (s, 1H (FA)); 7.21 (1H, dd, J = 8.7 Hz, J = 2.7 Hz); 7.12 (1H, s); 6.96 (1H, d, J = 2.4 Hz); 6.72 (1H, dd, J = 8.6 Hz, J = 2.0 Hz); 3.27 (2H, t, J = 7.6 Hz,); 3.10 (2H, t, J = 7.6 Hz); 3.00 (2H, t, J = 8.2 Hz); 1.67 (2H, p, J = 7.9 Hz); 1.42 (2H, h, J = 7.4 Hz); 0.98 (3H, t, J = 7.4 Hz). 1313C NMR (CD3OD, 126 MHz): δ ppm = 168.9; 150.2; 131.8; 127.5; 123.5; 111.6; 111.5; 108.0; 101.7; 27.8; 22.1; 19.4; 12.5. UPLC: R T : 1.23 (classical system) MS (ESI + ) m / z [M+H] + C 14 H 21 N2O + Calculated value for 233.16; measured value 233.20.

[0337] LYS31 Compound 12: (exp:LT265C)(=Compound (026))

[0338]

Chem.

[0339] Yield: 71.8 mg, 26%. Isolated as a white amorphous solid with >95% purity by NMR and a single spot by TLC; R f : In DCM / MeOH / Et3N, 90 / 10 / 2, 0.6. Strains stained green with CMA; 1 1H NMR (CD3OD, 500 MHz): δ ppm = 8.59 (1H, s, (FA)); 7.21 (1H, d, J = 8.7 Hz); 7.12 (1H, s); 6.96 (1H, d, J = 2.5 Hz); 6.72 (1H, dd, J = 8.7 Hz, J = 2.0 Hz); 3.26 (2H, dd, J = 6.5 Hz, J = 5.5 Hz); 3.09 (2H, t, J = 7.6 Hz), 2.98 (2H, dd, J = 6.6 Hz, J = 5.3 Hz); 1.73 - 1.58 (2H, m); 1.44 - 1.25 (8H, m); 0.93 (3H, t, J = 7.6 Hz). 1313C NMR (CD3OD, 126 MHz): δ ppm = 169.0, 150.2, 131.8, 127.5, 123.5, 111.6, 111.5, 108.1, 101.7, 31.3, 28.5, 26.2, 25.9, 22.2, 22.1, 13.0 ppm. UPLC: R T : 1.61 (classical system) MS (ESI + ) m / z [M+H] + C 17 H 27 N2O + Calculated value for 275.20; Measured value 275.28.

[0340] LYS32 Compound 13: (exp:LT266B)(=Compound (063))

[0341]

Chemical Structure

[0342] Yield: 69 mg, 24%. Isolated as a white amorphous solid with purity >95% by NMR and a single spot by TLC; R f : 0.4 in DCM / MeOH / Et3N, 90 / 10 / 2. Stains green with CMA; 1 1H NMR (CD3OD, 500 MHz): δ ppm = 8.60 (1H, d, J = 2.3 Hz, (FA)); 7.21 (1H, d, J = 8.6 Hz); 7.11 (1H, s); 6.97 (1H, d, J = 2.4 Hz); 6.73 (1H, dd, J = 8.6 Hz, J = 2.3 Hz); 3.28 - 3.19 (2H, m); 3.08 (2H, t, J = 7.6 Hz); 3.04 - 2.88 (2H, m); 1.75 - 1.60 (2H, m); 1.43 - 1.23 (10H, m); 0.92 (3H, t, J = 6.7 Hz). 1313C NMR (CD3OD, 126 MHz): δ ppm = 169.0; 150.2; 131.8; 127.5; 123.5; 111.6; 111.5; 108.1; 101.8; 31.5; 28.8 (2C); 26.2; 25.8; 22.3; 22.1; 13.0. UPLC: R T : 1.85 (classical system) MS (ESI + ) m / z [M+H] + C 18 H 29 [[ID=1\4]]N2O + Calculated value for 289.22; Measured value 289.22.

[0343] LYS33 Compound 14: (exp:LT262A)(=Compound (027))

[0344]

Chemical Structure

[0345] Yield: 22 mg, 7%. Isolated as a white amorphous solid with purity >95% by NMR and a single spot by TLC; R f : 0.7 in DCM / MeOH / Et3N, 80 / 20 / 2. Strains stained green with CMA; 1 1H NMR (CD3OD, 500 MHz): δ ppm = 8.59 (1H, s, (FA)); 7.21 (1H, d, J = 8.6 Hz); 7.12 (1H, s); 6.96 (1H, d, J = 2.3 Hz); 6.72 (1H, dd, J = 8.6 Hz, J = 2.3 Hz); 3.26 (2H, t, J = 7.6 Hz); 3.09 (2H, t, J = 7.6 Hz); 2.99 (2H, t, J = 7.1 Hz); 1.67 (2H, p, J = 7.4 Hz); 1.46 - 1.19 (14H, m); 0.92 (3H, t, J = 6.8 Hz). 1313C NMR (CD3OD, 126 MHz): δ ppm = 169.0; 150.2; 131.8; 127.5; 123.5; 111.6; 111.5; 108.1; 101.7; 31.6; 29.2; 29.1; 29.0; 28.8; 26.2; 25.9; 22.3; 22.1; 13.0. UPLC: R T : 2.03 (classical system) MS (ESI + ) m / z [M+H] + C 20 H 33 N2O + Calculated value for 317.25; Measured value 317.03.

[0346] LYS34 Compound 15: (exp:LT266C)(=Compound(064))

[0347]

Chem.

[0348] Yield: 77 mg, 22%. Isolated as a white amorphous solid with purity >95% by NMR and a single spot by TLC; R f : 0.4 in DCM / MeOH / Et3N, 90 / 10 / 2. Strains stained green with CMA. 1 1H NMR (CD3OD, 500 MHz): δ ppm = 8.60 (1H, s, (FA)); 7.21 (1H, d, J = 8.7 Hz); 7.12 (1H, s); 6.96 (1H, d, J = 2.2 Hz); 6.72 (1H, dd, J = 8.7 Hz, J = 2.3 Hz); 3.25 (2H, t, J = 7.6 Hz); 3.09 (2H, t, J = 7.6 Hz); 2.97 (2H, t, J = 8.0 Hz); 1.67 (2H, p, J = 7.5 Hz); 1.47 - 1.21 (18H, m); 0.92 (3H, t, J = 6.9 Hz). 1313C NMR (CD3OD, 126 MHz): δ ppm = 169.0; 150.2; 131.8; 127.5; 123.5; 111.6; 111.5; 108.1; 101.8; 31.7; 29.3 (2C); 29.2; 29.1; 29.1; 28.8; 26.2; 25.9; 22.3; 22.2; 13.1. UPLC: R T : 2.32 (classical system). MS (ESI + ) m / z [M+H] + C 22 H 37 N2O + Calculated value for 345.28; measured value 345.16.

[0349] LYS35 Compound 16: LC355 (= Compound (028))

[0350]

Chem.

[0351] Yield: 93 mg, 35%. Isolated as a white amorphous solid with purity > 95% by NMR and a single spot by TLC; R f : 0.46 in DCM / MeOH / Et3N, 98 / 2 / 2. 1 1H NMR (CD3OD, 400 MHz): δ ppm = 7.31 - 7.21 (5 H, m); 7.16 (1H, d, J = 8.6 Hz); 6.98 (1H, s); 6.90 (1H, d, J = 2.4 Hz); 6.66 (1H, dd, J = 8.6 Hz, J = 2.4 Hz); 3.78 (2H, s); 2.91 (4H, s). 13 13C NMR (CD3OD, 101 MHz): δ ppm = 151.2; 139.9; 133.2; 129.6 (2C); 129.5 (2C); 129.3; 128.3; 124.3; 112.7; 112.5; 112.4; 103.5; 54.2; 50.1; 25.9. UPLC: R T: 1.48 (Classical system). MS (ESI + ) m / z [M+H] + C 17 H 19 N2O + Calculated value of 267.14; measured value of 267.21.

[0352] LYS36 Compound 17: LC353B (= Compound (029))

[0353]

Chem.

[0354] Yield: 154 mg, 49%. Isolated as a white amorphous solid with purity > 95% by NMR and a single spot by TLC; R f : In DCM / MeOH, 95 / 5, 0.10. 1 1H NMR (CD3OD, 400 MHz): δ ppm = 7.16 (1H, d, J = 8.8 Hz); 6.98 (1H, s); 6.89 (1H, d, J = 2.4 Hz); 6.98 (1H, s); 6.76 (1H, brs); 6.71 (2H, brs); 6.66 (1H, dd, J = 8.7 Hz, J = 2.4 Hz); 5.90 (2H, s); 3.68 (2H, s); 2.89 (4H, brt, J = 3.9 Hz). 13 13C NMR (CD3OD, 101 MHz): δ ppm = 151.1; 149.2; 148.3; 133.8; 133.2; 129.3; 124.3; 122.9; 112.7; 112.4 (2C); 109.8; 108.9; 103.5; 102.3; 53.9; 49.8; 25.9. UPLC: R T : 1.49 (Classical system). MS (ESI + ) m / z [M+H] + C 18 H 19 N2O + Calculated value of 311.13; measured value of 311.23.

[0355] LC353A (= Compound (043))

[0356] [Chemical formula]

[0357] Yield: 82 mg, 18%. Isolated as a white amorphous solid with purity > 95% by NMR and a single spot by TLC; R f : 0.49 in DCM / MeOH, 95 / 5. 1 1H NMR (CD3OD, 400 MHz): δ ppm = 7.12 (1H, d, J = 8.5 Hz); 6.88 (1H, s); 6.82 (2H, d, J = 1.6 Hz); 6.75 (3H, m); 6.70 (2H, m); 6.62 (1H, dd, J = 8.6 Hz, J = 2.3 Hz); 5.89 (4H, s); 3.53 (4H, s); 2.84 (2H, m); 2.70 (2H, s). 13 13C NMR (CD3OD, 101 MHz): δ ppm = 150.8; 149.1 (2C); 148.0 (2C); 134.8 (2C); 133.1; 129.5; 123.9; 123.1 (2C); 113.7; 112.5; 112.1; 110.1 (2C); 108.7 (2C); 103.7; 102.1 (2C); 58.9 (2C); 54.9; 24.0. UPLC: R T : 1.79 (classical system) MS (ESI + ) m / z [M+H] + C 26 H 25 N2O5 + Calculated value for 445.17; Measured value 445.23.

[0358] LYS37 Compound 18: (exp: LT262B) (= Compound (058))

[0359] [Chemical]

[0360] Yield: 31 mg, 12%. Isolated as a white amorphous solid with purity >95% by NMR and a single spot by TLC; R f : 0.5 in DCM / MeOH / Et3N, 90 / 10 / 2. A strain that stains green with CMA. 1 1H NMR (CD3OD, 500 MHz): δ ppm = 8.53 (1H, s); 7.63 (1H, d, J = 1.8 Hz); 7.21 (1H, d, J = 8.7 Hz); 7.11 (1H, s); 6.93 (1H, d, J = 2.3 Hz); 6.72 (1H, dd, J = 8.7 Hz, J = 2.3 Hz); 6.61 (1H, d, J = 3.3 Hz); 6.50 (1H, dd, J = 3.3, 1.8 Hz); 4.27 (2H, s); 3.27 (2H, t, J = 7.7 Hz); 3.09 (2H, t, J = 7.6 Hz). 13 13C NMR (CD3OD, 126 MHz): δ ppm = 168.4; 150.2; 145.4; 144.3; 131.8; 127.4; 123.5; 112.0; 111.6; 111.5; 110.7; 108.0; 101.8; 47.0; 42.7; 22.0. UPLC: R T : 1.22 (classical system). MS (ESI + ) m / z [M+H] + C 15 H 17 N2O + Calculated value for 257.12; Measured value 257.14.

[0361] LYS38 Compound 19: (exp:LT267C)(=Compound (059))

[0362] [Chemical]

[0363] Yield: 37.3 mg, 13%. Isolated as a white amorphous solid with purity > 95% by NMR and a single spot by TLC; R f : In DCM / MeOH / Et3N, 90 / 10 / 2, 0.4. Stains green with CMA. 1 1H NMR (CD3OD, 400 MHz): δ ppm = 8.41 (1H, s); 7.09 (1H, d, J = 8.6 Hz); 6.98 (1H, s); 6.81 (1H, d, J = 2.2 Hz); 6.60 (1H, dd, J = 8.7 Hz, J = 2.3 Hz); 6.48 (1H, d, J = 3.4 Hz); 6.22 (1H, d, J = 3.3 Hz); 4.06 (2H, s), 3.12 (2H, t, J = 7.6 Hz); 2.95 (2H, t, J = 7.5 Hz). 13 13C NMR (CD3OD, 101 MHz): δ ppm = 150.1; 146.4; 137.4; 131.8; 127.5; 123.5; 114.0; 111.6; 111.4; 108.3; 107.4; 101.8; 47.3; 43.0; 22.3. UPLC: R T : 1.43 (classical system). MS (ESI + ) m / z [M+H] + C 15 H 16 N2O + Calculated value for 291.08; Measured value 291.10.

[0364] 3-3 - N-Cycloalkylation Strategy: O-Silylation, then N-Cycloalkylation

[0365]

Chemical Structure

[0366] A mixture of serotonin hydrochloride (1.0 g, 4.7 mmol), tert-butyldimethylsilyl chloride (TBDMSCl, 3.97 g, 5.6 equivalents), and imidazole (640 mg, 2 equivalents) in acetonitrile (47 mL) was stirred at room temperature overnight under N2, then filtered. The solid residue was dissolved in 0.5 M aqueous NaOH (100 mL) and immediately extracted with CH2Cl2 (3 × 30 mL). The combined CH2Cl2 extracts were washed with deionized water (30 mL) and dried over Mg2SO4. The solvent was removed under reduced pressure to afford the desired compound LC423 as a grayish solid.

[0367] Under dark and in an inert atmosphere, the product LC423 (145 mg, 0.5 mmol, 1 equivalent) from the previous step was dissolved in anhydrous acetonitrile (4 mL). K2CO3 (276 mg, 4 equivalents) and dibromoalkyl (1 equivalent) were added to the solution. The mixture was stirred and heated at reflux overnight, cooled to room temperature, then filtered with acetonitrile and concentrated. The crude product was purified by flash chromatography using cyclohexane / EtOAC (from 90 / 10 to 0 / 100) as the eluent to obtain the O-silylated-N-cycloalkylated derivative.

[0368] The product was then dissolved in THF (C = 0.1 M), and 1.1 equivalents of TBAF (1 M in THF) were added. The mixture was stirred for 1 hour until the O-deprotected product predominated in the UPLC analysis. The mixture was then concentrated, and the crude product was purified directly by preparative HPLC to afford the desired product after lyophilization.

[0369] LC423 (5-((tert-butyldimethylsilyl)oxy-1H-indol-3-yl)ethanamine

[0370]

Chemical formula

[0371] Yield: 1.29 g, 94%. Isolated as a pale gray foam with >95% purity by NMR and a single spot by TLC; Rf : In DCM / MeOH, 95 / 5 + 2% Et3N, 0.15. Strains stained green with CAM; 1 1H NMR (CD2Cl2, 400 MHz): δ ppm = 8.17 (1H, brs); 7.20 (1H, dd, J = 0.6 Hz, J = 8.5 Hz); 7.01 (1H, d, J = 2.1 Hz); 6.99 (1H, d, J = 2.3 Hz); 6.73 (1H, dd, J = 2.3 Hz, J = 8.5 Hz); 2.95 (2H, t, J = 7.0 Hz); 2.80 (2H, t, J = 6.8 Hz); 1.31 (2H, brs); 1.01 (9H, s); 0.19 (6H, s). 13 13C NMR (CD2Cl2, 101 MHz): δ ppm = 148.9; 132.1; 128.3; 122.9; 115.9; 113.5; 111.3; 108.3; 42.5; 29.7; 25.6 (3C); 18.1; -3.8 (2C). UPLC: R T : 1.85 (classical system) MS (ESI + ) m / z [M+H] + C 16 H 28 N2OSi + Calculated value for C

[0372] LC434

[0373]

Chem.

[0374] Yield: 70 mg, 41%. Isolated as a pale gray foam with >95% purity by NMR and a single spot by TLC; R f : In DCM / MeOH, 95 / 5 + 2% Et3N, 0.67. Strains stained green with CAM; 11H NMR (CD3OD, 400 MHz): δ ppm = 7.19 (1H, dd, J = 0.5 Hz, J = 8.6 Hz); 7.04 (1H, s); 6.96 (1H, d, J = 2.1 Hz); 6.67 (1H, dd, J = 2.3 Hz, J = 8.6 Hz); 2.92 (4H, m); 2.78 (4H, m); 1.88 (4H, m); 1.02 (9H, s); 0.19 (6H, s). 13 13C NMR (CD3OD, 101 MHz): δ ppm = 149.7; 133.9; 129.1; 124.2; 116.5; 112.6 (2C); 108.7; 58.1; 55.1 (2C); 26.3 (3C); 25.3; 24.1 (2C); 19.1; -4.2 (2C). UPLC: R T : 2.05 (classical system) MS (ESI + ) m / z [M+H] + C 20 H 33 N2OSi + calculated value for 345.57; measured value 345.21.

[0375] LC437

[0376]

Chemical Structure

[0377] Yield: 35 mg, 76%. Isolated as a pale grey foam with >95% purity by NMR and a single spot by TLC; R f : DCM / MeOH, 95 / 5 + 2% Et3N, 0.41. Stains green with CAM; 11H NMR (CD3OD, 500 MHz): δ ppm = 8.51 (1H, s, FA); 7.19 (1H, d, J = 8.5 Hz); 7.10 (1H, s); 6.96 (1H, brs); 6.70 (1H, brd, J = 8.4 Hz); 3.37 (2H, d, J = 7.5 Hz); 3.29 (4H, m); 3.08 (2H, t, J = 7.8 Hz); 2.01 (4H, brs). 13 13C NMR (CD3OD, 101 MHz): δ ppm = 169.8 (FA); 151.6; 133.1; 128.8; 125.0; 113.1; 112.9; 109.2; 103.2; 56.5; 55.1 (2C); 23.9 (2C); 23.2. UPLC: R T : 0.61 (classical system) MS (ESI + ) m / z [M+H] + C 14 H 19 N2O + Calculated value for 231.14; Measured value 231.09.

[0378] LC432F2 - LC432 (= compound (045))

[0379]

Chem.

[0380] Comment: LC432F2 is obtained by directly deprotecting after the alkylation reaction. Yield: 65 mg, 53%. Isolated as a pale gray foam with >95% purity by NMR and a single spot by TLC; R f : DCM / MeOH, 95 / 5 + 2% Et3N, 0.59. Strains stained green with CAM; 11H NMR (CD3OD, 400 MHz): δ ppm = 8.56 (1H, brs, FA); 7.18 (1H, d, J = 8.6 Hz); 7.09 (1H, s); 6.93 (1H, d, J = 2.1 Hz); 6.70 (1H, dd, J = 2.4 Hz, J = 8.5 Hz); 3.33 - 3.15 (6H, m); 3.12 (2H, m); 1.85 (4H, m); 1.67 (2H, brs). 13 13C NMR (CD3OD, 101 MHz): δ ppm = 170.2 (FA); 151.6; 133.1; 128.8; 124.7; 113.0; 112.8; 109.5; 103.1; 58.6; 54.3 (2C); 24.4 (2C); 22.9; 22.6. UPLC: R T : 1.15 (classical system) MS (ESI + ) m / z [M + H] + C 15 H 21 N2O + Calculated value for C13H17N2O: 244.16; Measured value: 245.17.

[0381] 3 - 4 - N - dimer Strategy

[0382]

Chem.

[0383] Under dark conditions and in an inert atmosphere, LC423 (145 mg, 0.5 mmol) was dissolved in anhydrous DMF (1 mL). K2CO3 (76 mg, 1.1 equivalents) and 1,10 - dibromodecane (75 mg, 0.5 equivalents) were added to the solution. The mixture was stirred at 40 °C overnight, cooled to room temperature, and then concentrated to dryness. The crude product was purified by flash chromatography using DCM / MeOH (from 100 / 0 to 90 / 10) + 2% Et3N as the eluent, and then by preparative HPLC, and the desired product LC439 was obtained after lyophilization.

[0384] Subsequently, LC439 was dissolved in THF (C = 0.1 M), and 1.1 equivalents of TBAF (1 M in THF) was added. The mixture was stirred for 1 hour until the O-deprotected product became predominant in the UPLC analysis. The mixture was then concentrated, and the crude product was directly purified by preparative HPLC to obtain the desired product LC469 after lyophilization.

[0385] LC439

[0386]

Chemical Structure

[0387] Yield: 34 mg, 9.5%. Isolated as a light gray foam with >95% purity by NMR and a single spot by TLC; R f : 0.50 in DCM / MeOH, 90 / 10 + 2% Et3N. A strain that stains green with CAM; 1 1H NMR (CD3OD, 500 MHz): δ ppm = 8.59 (2H, brs, FA); 7.25 (2H, d, J = 8.7 Hz); 7.16 (2H, s); 7.00 (2H, d, J = 2.0 Hz); 6.72 (2H, dd, J = 2.3 Hz, J = 8.7 Hz); 3.25 (4H, t, J = 7.5 Hz); 3.10 (4H, t, J = 7.5 Hz); 2.98 (4H, m); 1.67 (4H, m); 1.34 (12H, m); 1.03 (18H, s); 0.21 (12 H, s). 1313C NMR (CD3OD, 126 MHz): δ ppm = 168.9 (FA); 148.7 (2C); 132.6 (2C); 127.4 (2C); 123.7 (2C); 115.5 (2C); 111.5 (2C); 108.5 (2C); 107.1 (2C); 47.8 (2C); 47.5 (2C); 28.9 (2C); 28.8 (2C); 26.2 (2C); 25.9 (2C); 24.9 (6C); 22.1 (2C); 17.7 (2C); -5.6 (4C). UPLC: R T : 2.43 (classical system) MS (ESI + ) m / z [M+H] + C 42 H 71 N4O2Si2 + Calculated value for 719.50; measured value 719.62.

[0388] LC469 (= compound (047))

[0389] [Chemical formula]

[0390] Yield: 18 mg, 78%. Isolated as a light gray foam with purity > 95% by NMR; 1 1H NMR (CD3OD, 400 MHz): δ ppm = 8.53 (2H, brs, FA); 7.19 (2H, d, J = 8.7 Hz); 7.10 (2H, s); 6.93 (2H, d, J = 2.2 Hz); 6.70 (2H, dd, J = 2.1 Hz, J = 8.7 Hz); 3.26 (4H, t, J = 7.5 Hz); 3.08 (4H, t, J = 7.5 Hz); 2.99 (4H, m); 1.66 (4H, m); 1.34 (12H, m). 1313C NMR (CD3OD, 101 MHz): δ ppm = 170.1 (FA); 1516 (2C); 133.2 (2C); 128.9 (2C); 124.9 (2C); 113.0 (2C); 112.8 (2C); 109.4 (2C); 103.1 (2C); 49.1 (2C); 48.9 (2C); 30.4 (2C); 30.2 (2C); 27.6 (2C); 27.2 (2C); 23.5 (2C). UPLC: R T : 1.49 (classical system) MS (ESI + ) m / z [M+H] + C 42 H 71 N4O2Si2 + Calculated value for 491.33; measured value 491.56.

[0391] 3-5-Pyrrole C-alkylation 3-5-1-Strategy 1: N- and O-acetyl

[0392]

Chemical Structure

[0393] To a cold (0 °C) solution of serotonin hydrochloride (HCl·C10H12N2O, 2.5 g, 11.5 mmol) and triethylamine (8.25 mL, 5 equiv) in CH2Cl2 (80 mL), acetyl chloride (2.67 mL, 3. equiv) was added slowly over 10 min. After addition was complete, the reaction mixture was warmed to room temperature and stirred for 2 h. The reaction was diluted with CH2Cl2 (20 mL), washed with water (2 × 20 mL) and brine (30 mL), dried over MgSO4, and the solvent was evaporated to give compound LC377 as a pale yellow foam.

[0394] A mixture of diacetylserotonin derivative LC377 (130 mg, 0.50 mmol), norbornene (94 mg, 2.00 equivalents), K2CO3 (276 mg, 4.00 equivalents), and PdCl2 (8.9 mg, 10 mol%) was added with 2.5 mL of DMF (containing 0.5 M H2O) and 1-bromo-2-methylpropane (218 μL, 4.00 equivalents). The resulting suspension was stirred at 60 °C for 24 hours. After cooling to room temperature, the reaction mixture was diluted with Et2O (30 mL) and washed with water (50 mL). Then, the aqueous layer was extracted with Et2O (2 × 50 mL), and the combined organic extracts were dehydrated over MgSO4 and concentrated. The crude product was purified by flash column chromatography on silica gel to obtain the 2-alkylserotonin product LC385. Comment: Deacetylation of phenol occurs during the reaction.

[0395] LC377 (= compound (048))

[0396]

Chemical Structure

[0397] Yield: 3.06 g, 100%. Isolated as a pale yellow foam with >95% purity by NMR and a single spot by TLC; R f : 0.5 in DCM / MeOH, 95 / 5. A strain that stains green with CAM; 1 1H NMR (DMSO-d6, 500 MHz): δ ppm = 10.91 (1H, s); 7.92 (1H, brt, J = 5.4 Hz); 7.35 (1H, d, J = 8.6 Hz); 7.22 (2H, dd, J = 2.4 Hz, J = 7.9 Hz); 6.81 (1H, dd, J = 2.2 Hz, J = 8.6 Hz); 3.30 (2H, dd, J = 6.0 Hz, J = 7.0 Hz); 2.79 (2H, t, J = 7.4 Hz); 2.26 (3H, s); 1.80 (3H, s). 1313C NMR (DMSO-d6, 126 MHz): δ ppm = 169.9; 169.1; 143.3; 134.0; 127.4; 124.2; 115.3; 112.2; 111.7; 110.4; 54.9; 25.1; 22.7; 20.9. UPLC: R T : 1.70 (classical system) MS (ESI + ) m / z [M+H] + C 14 H 17 N2O3 + Calculated value for 261.12; Measured value 261.21.

[0398] LC385 (= compound (049))

[0399]

Chemical Structure

[0400] Yield: 19 mg, 12%. Isolated as a light gray powder with purity > 95% by NMR and a single spot by TLC; R f : In EtOAc / MeOH, 95 / 5, 0.64. Strains stained green with CAM; 1 1H NMR (CD3OD, 500 MHz): δ ppm = 7.06 (1H, d, J = 8.5 Hz); 6.87 (1H, d, J = 2.3 Hz); 6.58 (1H, dd, J = 2.3 Hz, J = 8.5 Hz); 3.34 (2H, t, J = 7.5 Hz); 2.81 (2H, t, J = 7.5 Hz); 2.55 (2H, d, J = 7.5 Hz); 1.99 (1H, quintet, J = 6.9 Hz); 1.91 (3H, s); 0.94 (6H, d, J = 6.7 Hz). 1313C NMR (CD3OD, 126 MHz): δ ppm = 173.2; 150.9; 137.9; 132.1; 130.5; 111.8; 111.1; 108.6; 103.2; 41.5; 36.3; 30.4; 25.4; 22.9 (2C); 22.7. UPLC: R T : 1.87 (classical system) MS (ESI + ) m / z [M+H] + C 16 H 23 N2O2 + Calculated value for 275.17; measured value 275.28.

[0401] 3-5-2-Strategy 2: NH-Boc and O-TBDMS

[0402]

Chemical Structure

[0403] In the dark, serotonin hydrochloride (500 mg, 2.35 mmol, 1 equiv) was dissolved in water (9 mL). K2CO3 (665 mg, 4.81 mmol, 2.1 equiv) and Boc2O (538 mg, 2.46 mmol, 1.05 equiv) were added to the solution. The solution was stirred overnight and then extracted with DCM. The organic phase was washed with 5% aqueous HCl and brine, then dried over MgSO4 and concentrated. The crude product was purified by flash chromatography using DCM / MeOH (from 100 / 0 to 90 / 10) as the eluent to obtain the desired product (485 mg), which was carried on to the next step.

[0404] In the dark and under an inert atmosphere, the product (553 mg, 2 mmol) of the preceding step, tert-butyldimethylsilyl chloride (TBDMSCl, 1.69 g, 5.6 equivalents), and imidazole (272 mg, 2 equivalents) in acetonitrile (20 mL) were stirred at room temperature overnight under N2 and then filtered. The solid residue was dissolved in 0.5 M aqueous NaOH (50 mL) and immediately extracted with CH2Cl2 (3 × 20 mL). The combined CH2Cl2 extracts were washed with deionized water (30 mL) and dried over Mg2SO4. The crude product was purified by flash chromatography using n-Hex / EtOAc (from 100 / 0 to 50 / 50) as the eluent to obtain the desired product LC429 as a white solid.

[0405] To a mixture of the LC429 serotonin derivative (117 mg, 0.30 mmol), norbornene (56 mg, 2.00 equivalents), K2CO3 (166 mg, 4.00 equivalents), and PdCl2 (5.3 mg, 10 mol%), 2.1 mL of DMF (containing 0.5 M H2O) and bromoethane (90 μL, 4.00 equivalents) were added. The resulting suspension was stirred at 60 °C for 24 h. After cooling to room temperature, the reaction mixture was diluted with Et2O (30 mL) and washed with water (50 mL). The aqueous layer was then extracted with Et2O (2 × 50 mL), and the combined organic extracts were dried over MgSO4 and concentrated. The crude product was purified by flash column chromatography on silica gel using n-Hex / EtOAc (from 100 / 0 to 50 / 50) as the eluent to obtain LC464.

[0406] LC464 was dissolved in THF (C = 0.1 M), and 1.1 equivalents of TBAF (1 M in THF) were added. The mixture was stirred for 1 h until the O-deprotected product became predominant in the UPLC analysis. The mixture was then concentrated, and the crude product was purified directly by preparative HPLC and lyophilized to obtain the desired product LC468.

[0407] LC468 was dissolved in CH2Cl2 / TFA, 4 / 1 (4 mL) and stirred for 2 hours until the product became predominant in the UPLC analysis. Then the mixture was concentrated and the crude product was purified directly by preparative HPLC to obtain the desired product LC470 after lyophilization.

[0408] LC429

[0409]

Chem.

[0410] Yield: 691 mg, 88%. Isolated as a light grey powder with >95% purity by NMR and a single spot by TLC; R f : 0.56 in n-Hex / EtOAc, 60 / 40. Stains green with ninhydrin; 1 1H NMR (CD3OD, 500 MHz): δ ppm = 7.17 (1H, d, J = 8.6 Hz); 7.02 (1H, s); 6.98 (1H, brd, J = 1.2 Hz); 6.66 (1H, dd, J = 2.3 Hz, J = 8.5 Hz); 3.29 (2H, t, J = 7.3 Hz); 2.83 (2H, t, J = 7.3 Hz); 1.43 (9H, s); 1;02 (9H, s); 0.19 (6H, s). 13 13C NMR (CD3OD, 126 MHz): δ ppm = 158.5; 149.7; 133.9; 129.4; 124.3; 116.4; 112.9; 112.5; 108.9; 79.9; 42.4; 28.8 (3C); 26.8; 26.3 (3C); 19.1; -4.2 (2C). UPLC: R T : 3.04 (classical system) MS (ESI + ) m / z [M+Na] + C 21 H 34 N2O3SiNa +Calculated value: 413.21; Measured value: 413.29.

[0411] LC464

[0412]

Chem.

[0413] Yield: 50 mg, 40%. Isolated as a light gray powder with purity > 95% by NMR and a single spot by TLC; R f : 0.65 in n-Hex / EtOAc, 70 / 30. A strain that stains green with ninhydrin; 1 1H NMR (CD3OD, 500 MHz): δ ppm = 7.09 (1H, d, J = 8.4 Hz); 6.90 (1H, brs); 6.57 (1H, dd, J = 2.4 Hz, J = 8.6 Hz); 3.20 (2H, t, J = 7.0 Hz); 2.79 (2H, t, J = 7.2 Hz); 2.73 (2H, q, J = 7.7 Hz); 1.43 (9H, s); 1.28 (3H, t, J = 7.5 Hz); 1.01 (9H, s); 0.18 (6H, s). 13 13C NMR (CD3OD, 126 MHz): δ ppm = 158.5; 149.6; 140.4; 132.9; 130.5; 115.2; 111.6; 108.5; 107.7; 79.8; 42.5; 28.8 (3C); 26.3 (3C); 25.7; 20.3; 19.1; 14.9; -4.2 (2C). UPLC: R T : 3.18 (classical system) MS (ESI + ) m / z [M+Na] + C 23 H 38 N2O3SiNa + Calculated value: 441.23; Measured value: 441.22.

[0414] LC468 (= Compound (046))

[0415]

Chem.

[0416] Yield: 20 mg, 56%. Isolated as a light gray powder with purity > 95% by NMR and a single spot by TLC; R f : 0.38 in n-Hex / EtOAc, 60 / 40. Stains green with ninhydrin; 1 1H NMR (CD3OD, 400 MHz): δ ppm = 7.06 (1H, dd, J = 0.5 Hz, J = 8.5 Hz); 6.85 (1H, brd, J = 1.8 Hz); 6.57 (1H, dd, J = 2.3 Hz, J = 8.5 Hz); 3.20 (2H, t, J = 7.0 Hz); 2.77 (2H, t, J = 7.5 Hz); 2.72 (2H, q, J = 7.7 Hz); 1.43 (9H, s); 1.27 (3H, t, J = 7.5 Hz). 13 13C NMR (CD3OD, 101 MHz): δ ppm = 158.5; 150.9; 140.2; 132.1; 130.6; 111.7; 111.0; 107.4; 103.3; 79.8; 42.3; 28.8 (3C); 25.8; 20.3; 14.9. UPLC: R T : 2.17 (classical system) MS (ESI + ) m / z [M+H] + C 17 H 24 N2O3Na + Calculated value for 327.18; Measured value 327.46.

[0417] LC470

[0418]

Chem.

[0419] Yield: 10 mg, 77%. Isolated as a light gray powder with purity >95% by NMR; 1 H NMR (CD3OD, 400 MHz): δ ppm = 7.11 (1H, dd, J = 0.5 Hz, J = 8.7 Hz); 6.84 (1H, d, J = 2.3 Hz); 6.62 (1H, dd, J = 2.4 Hz, J = 8.7 Hz); 3.10 (2H, m); 2.99 (2H, m); 2.75 (2H, q, J = 7.6 Hz); 1.29 (3H, t, J = 7.6 Hz). 13 C NMR (CD3OD, 101 MHz): δ ppm = 151.4; 140.9; 132.2; 130.0; 112.2; 111.5; 104.2; 102.8; 41.3; 23.5; 20.1; 14.8. UPLC: R T : 1.19 (classical system) MS (ESI + ) m / z [M+H] + C 12 H 17 N2O + Calculated value for 205.13; measured value 188.13.

[0420] 3-6-Serotonin / pyrrole C-trifluoromethylation Strategy

[0421]

Chemical Structure

[0422] For the trifluoromethylation of indole, LC429 (195 mg, 0.5 mmol) and Togni reagent (342 mg, 1.3 equiv) were added to a Schlenk tube. Under vacuum, DCM (5 mL) and TMSOTf (18 μL, 0.2 equiv) were added, and the mixture was stirred for 15 minutes. Saturated aqueous NaHCO3 solution (15 mL) was added to quench the reaction mixture, which was then extracted with CH2Cl2 (3 × 20 mL). The combined CH2Cl2 extracts were dried over Mg2SO4. The crude product was purified by flash chromatography using n-Hex / EtOAc (from 100 / 0 to 50 / 50) as the eluent to obtain the desired product LC471F1 and the by-product LC471F2 as white solids.

[0423] LC471F1 was dissolved in THF (C = 0.1 M), and 1.1 equiv of TBAF (1 M in THF) was added. The mixture was stirred for 1 hour until the O-deprotected product became predominant in the UPLC analysis. Saturated aqueous NH4Cl solution (15 mL) was added, and the mixture was extracted with EtOAc (3 × 20 mL). The combined organic phases were dried over MgSO4. The solvent was removed under reduced pressure to obtain the desired compound LC472, which was used for the next step without purification.

[0424] LC471F2 was dissolved in THF (C = 0.1 M), and 1.1 equiv of TBAF (1 M in THF) was added. The mixture was stirred for 1 hour until the O-deprotected product became predominant in the UPLC analysis. Saturated aqueous NH4Cl solution (15 mL) was added, and the mixture was extracted with EtOAc (3 × 20 mL). The combined organic phases were dried over MgSO4. The solvent was removed under reduced pressure to obtain the desired compound LC473, which was used for the next step without purification.

[0425] LC472 was dissolved in CH2Cl2 / TFA, 4 / 1 (4 mL), and the mixture was stirred for 2 hours until the product became predominant in the UPLC analysis. The mixture was then concentrated, and the crude product was directly purified by preparative HPLC to obtain the desired product LC474 after lyophilization.

[0426] LC473 was dissolved in CH2Cl2 / TFA, 4 / 1 (4 mL) and stirred for 2 hours until the product became predominant in the UPLC analysis. The mixture was then concentrated and the crude product was purified directly by preparative HPLC to obtain the desired product LC475 after lyophilization.

[0427] LC471F1

[0428]

Chem.

[0429] Yield: 59 mg, 22%. Isolated as a light gray powder with purity >95% by NMR and a single spot by TLC; R f : 0.64 in n-Hex / EtOAc, 80 / 20. Stains green with ninhydrin; 1 1H NMR (CD3OD, 400 MHz): δ ppm = 7.27 (1H, d, J = 8.2 Hz); 7.13 (1H, s); 6.84 (1H, dd, J = 2.3 Hz, J = 8.7 Hz); 3.26 (2H, t, J = 6.8 Hz); 2.98 (2H, t, J = 6.8 Hz); 1.44 (9H, s); 1.02 (9H, s); 0.21 (6H, s). 19 19F NMR (CD3OD, 376 MHz): δ ppm = -59.38. UPLC: R T : 3.21 (classical system) MS (ESI + ) m / z [M+Na] + C 22 H 34 F3N2O3SiNa + Calculated value for 481.22; Found 481.41.

[0430] LC471F2

[0431]

Chem.

[0432] Yield: 90 mg, 39%. Isolated as a light gray powder with purity >95% by NMR and a single spot by TLC; R f : 0.53 in n-Hex / EtOAc, 80 / 20. Stains green with ninhydrin; 1 1H NMR (CD3OD, 400 MHz): δ ppm = 7.55 (1H, d, J = 8.7 Hz); 6.96 (1H, d, J = 8.7 Hz); 3.21 (2H, t, J = 6.4 Hz); 3.05 (2H, t, J = 6.4 Hz); 1.42 (9H, s); 1.04 (9H, s); 0.26 (6H, s). 19 19F NMR (CD3OD, 376 MHz): δ ppm = -52.95; -59.38. UPLC: R T : 3.20 (classical system) MS (ESI + ) m / z [M+Na] + C 23 H 32 F6N2O3SiNa + Calculated value for 549.21; Measured value 549.48.

[0433] LC474

[0434]

Chemical Structure

[0435] Yield: 22 mg, 52%. Isolated as a light gray powder with purity >95% by NMR; 11H NMR (CD3OD, 500 MHz): δ ppm = 7.29 (1H, d, J = 8.6 Hz); 7.01 (1H, d, J = 2.2 Hz); 6.89 (1H, dd, J = 2.2 Hz, J = 8.7 Hz); 3.19 (2H, m); 3.14 (2H, m). 13 13C NMR (CD3OD, 126 MHz): δ ppm = 152.8; 132.3; 128.7; 124.2 (d, J = 38.2 Hz); 123.5 (d, J = 268.2 Hz); 116.6; 114.1; 111.1; 103.5; 41.1; 23.2. 19 19F NMR (CD3OD, 470 MHz): δ ppm = -59.4 UPLC: R T : 1.31 (classical system) MS (ESI + ) m / z [M+H] + C 11 H 12 F3N2O + Calculated value for C

[0436] LC475

[0437]

Chemical formula

[0438] Yield: 38 mg, 58%. Isolated as a light gray powder with purity >95% by NMR; 1 1H NMR (CD3OD, 500 MHz): δ ppm = 8.50 (1H, s, FA); 7.53 (1H, d, J = 8.8 Hz); 6.99 (1H, d, J = 8.8 Hz); 3.26 (2H, m); 3.06 (2H, m). 1313C NMR (CD3OD, 126 MHz): δ ppm = 168.2 (FA); 151.9; 131.2; 125.5 (d, J = 269.3 Hz); 125.3 (d, J = 39.4 Hz); 122.2; 121.9 (d, J = 268.2 Hz); 117.7; 116.3; 109.8; 104.8 (d, J = 31.2 Hz); 39.9; 22.9. 19 19F NMR (CD3OD, 470 MHz): δ ppm = -53.5; -59.6. UPLC: R T : 1.43 (classical system) MS (ESI + ) m / z [M+H] + 13 12 1 10 6F2N2O + Calculated value for 6F2N2O: 313.07; Measured value: 313.16.

[0439] 3-7-A3 / Pyrrole C-Trifluoromethylation Strategy

[0440]

Chemical Structure

[0441] Under dark and inert atmosphere, LC423 (145 mg, 0.5 mmol, 1 equiv.) was dissolved in anhydrous acetonitrile (5 mL). K2CO3 (83 mg, 1.2 equiv.) and propargyl bromide (56 μL, 1 equiv.) were added to the solution. The mixture was stirred and heated under reflux overnight, cooled to room temperature, then filtered with acetonitrile and concentrated. The crude product was purified by flash chromatography using DCM / MeOH (from 100 / 0 to 80 / 20) as the eluent to obtain LC451.

[0442] For the trifluoromethylation of indole, LC451 (67 mg, 0.2 mmol) and Togni reagent (140 mg, 1.3 equiv) were added to a Schlenk tube. Under vacuum, DCM (2 mL) and TMSOTf (7.4 μL, 0.2 equiv) were added and the mixture was stirred for 15 minutes. Saturated aqueous NaHCO3 (15 mL) was added to quench the reaction mixture, which was then extracted with CH2Cl2 (3 × 20 mL). The combined CH2Cl2 extracts were dried over Mg2SO4. The crude product was purified by flash chromatography using n-Hex / EtOAc (from 100 / 0 to 50 / 50) as the eluent to afford the desired product LC456 as a white solid.

[0443] LC456 was dissolved in THF (C = 0.1 M) and 1.1 equiv of TBAF (1 M in THF) was added. The mixture was stirred for 1 h until the O-deprotected product became predominant in the UPLC analysis. The mixture was then concentrated and the crude product was purified directly by preparative HPLC to afford the desired product LC458 after lyophilization.

[0444] LC451

[0445] [Chemical formula]

[0446] Yield: 67 mg, 41%. Isolated as a light gray powder with >95% purity by NMR and a single spot by TLC; R f : 0.67 in DCM / MeOH, 90 / 10. A strain that stains green with ninhydrin; 11H NMR (CD3OD, 400 MHz): δ ppm = 7.19 (1H, dd, J = 0.6 Hz, J = 8.6 Hz); 7.04 (1H, s); 6.98 (1H, dd, J = 0.6 Hz, J = 2.4 Hz); 6.67 (1H, dd, J = 2.3 Hz, J = 8.5 Hz); 3.41 (2H, d, J = 2.5 Hz); 2.97 (2H, m); 2.89 (2H, m); 2.56 (1H, t, J = 2.5 Hz); 1.01 (9H, s); 0.19 (6H, s). 13 13C NMR (CD3OD, 101 MHz): δ ppm = 149.7; 134.0; 129.2; 124.4; 116.6; 112.9; 112.6; 108.9; 81.9; 73.2; 49.8; 38.3; 26.3 (3C); 26.0; 19.1; -4.2 (2C). UPLC: R T : 2.10 (classical system) MS (ESI + [[ID=II]]) m / z [M+H] + C 19 H 28 N2OSi + Calculated value for 329.20; measured value 328.98.

[0447] LC456

[0448]

Chem.

[0449] Yield: 19 mg, 23%. Isolated as a pale gray powder with purity >95% by NMR and a single spot by TLC; R f : n-Hex / EtOAc, 60 / 40, 0.6. Stains green with ninhydrin; 11H NMR (CD3OD, 400 MHz): δ ppm = 7.30 (1H, d, J = 8.7 Hz); 7.09 (1H, d, J = 2.6 Hz); 6.86 (1H, dd, J = 2.4 Hz, J = 8.7 Hz); 3.59 (2H, d, J = 2.3 Hz); 3.08 (2H, m); 3.02 (2H, m); 2.76 (1H, t, J = 2.4 Hz); 1.02 (9H, s); 0.21 (6H, s). UPLC: R T : 2.23 (classical system) MS (ESI + ) m / z [M+H] + C 20 H 28 F3N2OSi + Calculated value for 397.18; measured value 397.40.

[0450] LC458 (= compound (036))

[0451]

Chemical Structure

[0452] Yield: 7 mg, 63%. Isolated as a light gray powder with purity > 95% by NMR; 1 1H NMR (CD3OD, 500 MHz): δ ppm = 8.41 (1H, s, FA); 7.28 (1H, d, J = 8.7 Hz); 7.01 (1H, d, J = 2.0 Hz); 6.88 (1H, dd, J = 2.0 Hz, J = 8.7 Hz); 3.82 (2H, d, J = 2.2 Hz); 3.18 (4H, m); 3.05 (1H, t, J = 2.1 Hz). 19 19F NMR (CD3OD, 470 MHz): δ ppm = -59.41. UPLC: R T : 1.45 (classical system) MS (ESI+ ) m / z [M+H] + C 14 H 14 F3N2OSi + Calculated value 283.10; Measured value 283.12.

[0453] 3-8-Bromination Strategy

[0454]

Chem.

[0455] To a cold solution (0 °C) of the diacetylated serotonin derivative LC377 (284 mg, 1.1 mmol) in AcOH (11 mL), the bromide (67 μL, 1.2 equiv) was added dropwise over 5 minutes. After the addition was complete, the reaction mixture was warmed to room temperature and stirred for 5 hours. The reaction was poured into cold water (30 mL), extracted with EtOAc (3 × 30 mL), dried over MgSO4, and the solvent was evaporated under reduced pressure. The crude product was purified directly by preparative HPLC and the desired products LC380F2 and LC380F3 were obtained after lyophilization.

[0456] LC380F2 (= Compound (051))

[0457]

Chem.

[0458] Yield: 7 mg, 1.5%. Isolated as a pale yellow foam with >95% purity by NMR and a single spot by TLC; R f : 0.5 in DCM / MeOH, 95 / 5. Stains green with CAM; 11H NMR (CD3OD, 500 MHz): δ ppm = 8.15 (1H, s, FA); 7.29 (1H, d, J = 8.7 Hz); 6.92 (1H, d, J = 8.7 Hz); 3.47 (2H, t, J = 6.9 Hz); 3.18 (2H, t, J = 7.0 Hz); 2.35 (3H, s); 1.92 (3H, s). 13 13C NMR (CD3OD, 126 MHz): δ ppm = 171.9; 169.7; 141.9; 135.4; 125.7; 116.7; 112.8; 112.3; 110.2; 105.6; 40.5; 24.7; 21.3; 19.3. UPLC: R T : 1.96 (classical system) MS (ESI + ) m / z [M+H] + C 14 H 15 Br2N2O3 + Calculated value for 419.05; measured value 419.02.

[0459] LC380F3 (= compound (052))

[0460]

Chemical Structure

[0461] Yield: 20 mg, 4.4%. Isolated as a pale yellow foam with >95% purity by NMR and a single spot by TLC; R f : 0.5 in DCM / MeOH, 95 / 5. Stains green with CAM; 1 H NMR (CD3OD, 500 MHz): δ ppm = 7.55 (1H, s); 7.35 (1H, s); 3.38 (2H, t, J = 6.9 Hz); 2.88 (2H, t, J = 7.0 Hz); 2.35 (3H, s); 1.88 (3H, s). 1313C NMR (CD3OD, 126 MHz): δ ppm = 172.1; 169.9; 141.3; 134.9; 127.4; 114.2; 112.0; 111.6; 110.7; 109.1; 39.1; 24.1; 21.2; 19.3. UPLC: R T : 2.01 (classical system) MS (ESI + ) m / z [M+H] + C 14 H 15 Br2N2O3 + Calculated value for 419.05; measured value 419.02.

[0462] LC380F4 (= compound (060))

[0463]

Chemical Structure

[0464] Yield: 4 mg, 0.7%. Isolated as a pale yellow foam with >95% purity by NMR and a single spot by TLC; R f : 0.5 in DCM / MeOH, 95 / 5. Strains stained green with CAM; 1 1H NMR (CD3OD, 500 MHz): Mixture of two isomers δ ppm = 7.38 (1H, s); 7.19 (1H, s); 3.47 (2H, t, J = 7.0 Hz); 3.39 (2H, t, J = 6.8 Hz); 3.18 (2H, t, J = 6.7 Hz); 2.89 (2H, t, J = 6.7 Hz); 2.35 (6H, s); 1.91 (3H, s); 1.87 (3H, s). 1313C NMR (CD3OD, 126 MHz): Mixture of 2 isomers δ ppm = 172.1; 171.9; 169.6; 169.3; 142.1; 142.0; 134.3; 134.1; 127.2; 126.2; 119.5; 114.4; 113.9; 113.5; 112.3; 112.0; 111.0; 110.7; 106.4; 105.4; 102.4; 40.3; 38.9; ; 24.9; 24.2; 21.3; 21.2; 19.3; 19.2. UPLC: R T : 2.05 (Classical system) MS (ESI + ) m / z [M+H] + C 14 H 14 Br3N2O3 + Calculated value for 494.85; Measured value 494.72.

[0465] 3-9-Melatonin and derivatives

[0466]

Chem.

[0467] Adapt the synthesis procedure from Patent WO2011 / 047156, PCT / US2010 / 052674. A suspension of LC377 (260 mg, 1 mmol) and K2CO3 (138 mg, equimolar) in MeOH (3.2 mL) was stirred at 26 °C for 2 hours. The reaction mixture was concentrated under reduced pressure, then the crude product was diluted in water (10 mL) and extracted with EtOAc (2 × 20 mL). The combined organic layers were washed with water (10 mL) and brine (10 mL), dried over MgSO4, and the solvent was evaporated under reduced pressure. The desired compound LC460 was obtained as a pale yellow foam.

[0468] LC460 (117 mg, 0.54 mmol) was solubilized in 30% NaOH solution (67 μL) and stirred at 26 °C. Dimethyl sulfate (86 μL, 1.7 equiv) was added dropwise, and the reaction mixture was stirred for 2 h. The reaction mixture was acidified with 2N HCl to obtain pH = 2, then diluted with water (10 mL) and extracted with EtOAc (2 × 20 mL). The combined organic layers were washed with water (2 × 10 mL) and brine (10 mL), dried over MgSO4, and the solvent was removed to obtain crude melatonin LC461. Melatonin was then purified by preparative HPLC to give a pale yellow rubbery solid.

[0469] LC460

[0470]

Chem.

[0471] Yield: 139 mg, 61%. Isolated as a pale yellow foamy solid with >95% purity by NMR and a single spot by TLC; R f : 0.2 in DCM / MeOH, 95 / 5. Stains green with CAM; 1 1H NMR (CD3OD, 400 MHz): δ ppm = 7.22 (1H, dd, J = 0.5 Hz, J = 8.5 Hz); 7.00 (1H, s); 6.92 (1H, dd, J = 0.5 Hz, J = 2.5 Hz); 6.65 (1H, dd, J = 2.3 Hz, J = 8.6 Hz); 3.43 (2H, t, J = 7.2 Hz); 2.86 (2H, dt, J = 0.6 Hz, J = 7.2 Hz); 1.91 (3H, s). 13 13C NMR (CD3OD, 101 MHz): δ ppm = 173.3; 151.1; 133.1; 129.5; 124.2; 112.6; 112.5; 112.3; 103.5; 41.5; 26.3; 22.6. UPLC: R T : 1.32 (classical system) MS (ESI + ) m / z [M+H] + C 12 H 15 N2O2 + Calculated value: 219.11; Measured value: 219.12.

[0472] LC461 = Melatonin (= Compound (054)

[0473]

Chem.

[0474] Yield: 76 mg, 61%. Isolated as a pale yellow foam with >95% purity by NMR and a single spot by TLC; R f : 0.5 in DCM / MeOH, 95 / 5. Strains stained green with CAM; 1 1H NMR (CD3OD, 400 MHz): δ ppm = 7.21 (1H, dd, J = 0.4 Hz, J = 8.7 Hz); 7.05 (1H, d, J = 2.5 Hz); 7.03 (1H, s); 6.75 (1H, dd, J = 2.5 Hz, J = 8.7 Hz); 3.82 (3H, s); 3.45 (2H, t, J = 7.5 Hz); 2.90 (2H, dt, J = 0.5 Hz, J = 7.5 Hz); 1.91 (3H, s).[[ID=3,3]] 13 13C NMR (CD3OD, 101 MHz): δ ppm = 173.3; 154.9; 133.4; 129.1; 124.1; 113.1; 112.9; 112.6; 101.3; 56.3; 41.5; 26.2; 22.6. UPLC: R T : 1.68 (classical system) MS (ESI + ) m / z [M+H] + C 13 H 17 N2O2 + Calculated value: 233.12; Measured value: 233.12.

[0475] 3 - 10 - phenylcarbamate Strategy:

[0476]

Chem.

[0477] In the dark, serotonin hydrochloride (500 mg, 2.35 mmol, 1 equiv) was dissolved in water (9 mL). K2CO3 (665 mg, 4.81 mmol, 2.1 equiv) and Boc2O (538 mg, 2.46 mmol, 1.05 equiv) were added to the solution. The solution was stirred overnight and then extracted with DCM. The organic phase was washed with 5% aqueous HCl and brine, then dried over MgSO4 and concentrated. The crude product was purified by flash chromatography using DCM / MeOH (from 100 / 0 to 90 / 10) as the eluent to obtain the desired product (485 mg), which was carried on to the next step.

[0478] In the dark and under an inert atmosphere, the product from the previous step (138 mg, 0.5 mmol, 1 equiv) was dissolved in anhydrous THF (4 mL). NMM (110 μL, 2 equiv) and propargyl chloroformate (97 μL, 2 equiv) were added to the solution. The mixture was stirred at room temperature for 1 hour. Then the reaction mixture was concentrated to dryness. The crude product was purified by flash chromatography using n - Hex / EtOAC (from 100 / 0 to 50 / 50) as the eluent to obtain LC483.

[0479] The product was then dissolved in CH2Cl2 / TFA, 4 / 1 (4 mL) and stirred for 2 hours until the product became predominant in the UPLC analysis. Then the mixture was concentrated and the crude product was directly purified by preparative HPLC to obtain the desired product LC487 after lyophilization.

[0480] LC483 (= Compound (055))

[0481]

Chem.

[0482] Yield: 125 mg, 69%. Isolated as a pale gray powder with purity > 95% by NMR and a single spot by TLC; R f : 0.58 in n-Hex / EtOAc, 60 / 40. Stains green with CAM; 1 [[ID=eleven]]1H NMR (CDCl3, 400 MHz): δ ppm = 8.34 (1H, s); 7.36 (2H, m); 7.10 (1H, d, J = 1.1 Hz); 6.98 (1H, dd, J = 2.3 Hz, J = 8.7 Hz); 4.84 (2H, d, J = 2.6 Hz); 4.65 (1H, brs); 3.39 (2H, q, J = 6.6 Hz); 2.90 (2H, t, J = 7.1 Hz); 2.65 (1H, t, J = 2.3 Hz); 1.41 (9H, s). 13 13C NMR (CDCl3, 101 MHz): δ ppm = 156.2; 154.4; 145.1; 134.7; 128.1; 124.4; 115.9; 114.0; 112.0; 110.8; 79.2; 77.3; 76.1; 56.1; 41.2; 28.5 (3C); 26.1. UPLC: R T : 2.36 (classical system) MS (ESI + ) m / z [M+Na] + C 19 H 23 N2O5Na + Calculated value for C

[0483] LC487 (= Compound (056))

[0484]

Chemical Structure

[0485] Note: In the translation of the NMR and MS data, the unit "ppm" is not translated as it is a standard unit in spectroscopy and is commonly used in English in this context. Also, the chemical formula and structure-related parts are translated as accurately as possible while maintaining the integrity of the original text. The specific chemical structure representation may need to be adjusted according to the actual chemical structure if it is to be presented more precisely in a different format.Yield: 75 mg, 87%. Isolated as a light gray powder with purity >95% by NMR; 1 1H NMR (CD3OD, 500 MHz): δ ppm = 7.38 (2H, m); 7.24 (1H, s); 6.95 (1H, dd, J = 2.3 Hz, J = 8.6 Hz); 4.86 (2H, d, J = 2.6 Hz); 3.19 (2H, t, J = 7.0 Hz); 3.07 (3H, m). 13 13C NMR (CD3OD, 126 MHz): δ ppm = 155.7; 145.9; 136.2; 128.3; 126.3; 116.2; 113.1; 110.8; 110.7; 78.1; 77.3; 56.7; 41.1; 24.3. UPLC: R T : 1.41 (classical system) MS (ESI + ) m / z [M+H] + C 14 H 15 N2O5 + Calculated value for C

[0486] LT273 (= Compound (057))

[0487]

Chem.

[0488] In the dark, serotonin hydrochloride (500 mg, 2.35 mmol, 1 equiv) was dissolved in water (9 mL). K2CO3 (665 mg, 4.81 mmol, 2.1 equiv) and Boc2O (538 mg, 2.46 mmol, 1.05 equiv) were added to the solution. The solution was stirred overnight and then extracted with DCM. The organic phase was washed with 5% aqueous HCl and brine, then dried over MgSO4 and concentrated. The crude product was purified by flash chromatography using DCM / MeOH (from 100 / 0 to 90 / 10) as the eluent to obtain the desired product (quantitative yield). It was then further purified by HPLC. 1 1H NMR (, CD2Cl2, 500 MHz) δ ppm = 8.12 (s, 1H), 7.26 (dd, J = 8.6, 0.6 Hz, 1H), 7.05 (d, J = 2.3 Hz, 1H), 7.03 (d, J = 2.4 Hz, 1H), 6.79 (dd, J = 8.7, 2.4 Hz, 1H), 4.76 (s, 1H), 3.43 (d, J = 6.9 Hz, 2H), 2.89 (t, J = 7.0 Hz, 2H), 1.46 (s, 9H). 13 13C NMR (, CD2Cl2, 126 MHz) δ ppm = 155.98, 149.66, 131.58, 128.15, 123.21, 112.37, 111.74, 103.11, 78.95, 40.77, 28.13, 25.82. MS (ESI + ) m / z [M+H] + C 15 H 21 N2O3 + Calculated value for 277.14; Measured value 277.24

[0489] LT282 (= Compound (061))

[0490]

Chemical formula

[0491] To a solution of LT273 (200 mg) in anhydrous acetone (8 mL), K2CO3 (300 mg, 3 equiv) and NaI (109 mg, 1 equiv) were added, and the mixture was stirred at room temperature for 5 minutes. Then, CH3I was added to the reaction mixture, and the mixture was refluxed for 5 hours. The solution was concentrated in vacuo and purified by flash chromatography with an EtOAc and cyclohexane gradient. It was then further purified by HPLC to give the pure final product (80 mg, 38%). 1 1H NMR (MeOD, 500 MHz) δ ppm = 7.23 (d, J = 8.7 Hz, 1H), 7.08 (s, 1H), 7.03 (s, 1H), 6.76 (dt, J = 8.7, 1.9 Hz, 1H), 3.84 (s, 3H), 3.33 (t, J = 7.4 Hz, 2H), 2.88 (t, J = 7.4 Hz, 2H), 1.44 (s, 9H). 13 13C NMR (MeOD, 126 MHz) δ ppm = 157.12, 153.54, 132.00, 127.74, 122.75, 111.84, 111.43, 111.14, 100.05, 78.50, 54.96, 41.04, 27.39, 25.53. MS (ESI + ) m / z [M+H] + C 16 H 23 N2O3 + Calculated for C14H19N2O3 291.16; found 291.32

[0492] LT299F1

[0493]

Chemical formula

[0494] To the diacetylated serotonin derivative LC337 (200 mg) in anhydrous DCM (4 mL), 0.6 equivalent of N-bromosuccinimide (96 mg) was added and stirred at room temperature for 20 minutes. Then, 0.1 equivalent of N-bromosuccinimide (15 mg) was further added and left for an additional 20 minutes. The reaction solution was concentrated in vacuo and purified by flash chromatography with an EtOAc and cyclohexane gradient, and then finally by HPLC to give the final product (13 mg, 5%). 1 H NMR (CD3CN, 500 MHz) δ ppm = 9.64 (s, 1H), 7.35 (dd, J = 8.7, 0.6 Hz, 1H), 7.28 - 7.19 (m, 1H), 6.89 (dd, J = 8.7, 2.2 Hz, 1H), 6.42 (s, 1H), 3.35 (td, J = 6.9, 6.1 Hz, 2H), 2.83 (t, J = 6.9 Hz, 2H), 2.28 (s, 3H), 1.81 (s, 3H). 13 C NMR (CD3CN, 126 MHz) δ ppm = 170.24, 169.65, 144.63, 134.15, 127.84, 116.35, 112.60, 111.15, 110.33, 109.92, 38.79, 24.73, 22.15, 20.28. MS (ESI + ) m / z [M+H] + C 14 H 16 BrN2O3 + Calculated for 339.03; found 339.21

[0495] (Example 2) Biological activity Materials and methods Complexation studies Calorimetric evaluation of complex formation: To an aqueous solution of serotonin hydrochloride (3 equivalents, C = 0.1 M) or A3 formate (3 equivalents, C = 0.1 M), iron(III) chloride (1 equivalent) or copper(II) sulfate (C = 0.1 M) was added. The color change characterizes the formation of the metal complex.

[0496] Regarding the NMR experiment: NMR spectroscopy was performed on a 500 MHz Bruker spectrometer. The sample was dissolved in D2O or CD3OD at 298 K or 310 K. 1 1H-NMR was recorded at 500 MHz, and the chemical shift δ is expressed in ppm using the residual non-deuterated solvent signal as the internal standard. Titration of the sample up to 0.3, 0.6, or 1 mol equivalent of iron or copper was carried out using the conditions (solvent and temperature) as shown in the figure. For some samples, trifluoroacetic acid (TFA) was added as shown in the figure.

[0497] Cell culture All cells were grown in an incubator equilibrated at 37°C and 5% CO2 until confluent, and then split once or twice a week with trypsin / EDTA (Gibco, TRYPGIB01) depending on the confluency. HMLER cells (gender: female), which endogenously suppress E-cadherin and were obtained from human mammary epithelial cells infected with retroviruses carrying hTERT, SV40, and the oncogenic allele H-rasV12, and HMLER CD44 and TFRC ko clones, were cultured in DMEM / F12 (Thermo Fisher Scientific, 31331093) supplemented with 10% FBS (v / v) (Thermo Fisher Scientific, 10270106), 10 μg / mL insulin (Sigma-Aldrich, I0516), 0.5 μg / mL hydrocortisone (Sigma-Aldrich, H0888), and 0.5 μg / mL puromycin (Life Technologies, A11138-02), unless otherwise stated. PDAC053T cells were grown in serum-free ductal medium: DMEM / F12 supplemented with 0.61 g / 500 mL nicotinamide (Sigma-Aldrich, 3376), 2.50 g / 500 mL glucose (Sigma-Aldrich, G6152), 1:200 ITS+ (Corning, 354352), 1:20 Nu-serum IV (Corning, 355104), 100 ng / ml cholera toxin, 1 μM dexamethasone (Sigma-Aldrich, D4902), 50 nM 3,3',5-triiodo-L-thyronine (Sigma-Aldrich, T6397), and 1× PenStrep. BELA cells were cultured using the published procedure (Nat. Comm. doi:10.1038 / ncomms14750).

[0498] Fluorescence microscopy Immunofluorescence method. Cells were seeded on cover glasses 24 hours before the experiment. Subsequently, the cells were washed three times with 1×PBS, fixed with 2% paraformaldehyde (w / v) in 1×PBS for 12 minutes, and then washed three times with 1×PBS. After fixation, the cells were permeabilized with 0.1% Triton X-100 (v / v) in 1×PBS for 5 minutes and washed three times with 1×PBS. Then, the cells were blocked at room temperature for 20 minutes in 2% BSA, 0.2% Tween-20 (w / v) / 1×PBS (blocking buffer). The cells were incubated with the relevant antibody in the blocking buffer at room temperature for 1 hour and washed three times with the blocking buffer. Then, the cells were incubated with the secondary antibody for 1 hour. Finally, the cover glasses were washed three times with 1×PBS and mounted using VECTASHIELD (Vector Laboratories) containing DAPI.

[0499] Fluorescence microscopy of clickable serotonin analog A3: Cells were seeded on cover glasses 24 hours before the experiment. Cells were treated with 10 μM A3 for 3 hours and with LysoTracker Deep Red (Thermo Fisher Scientific, L12492, 1:10000) according to the manufacturer's protocol. Subsequently, cells were washed three times with 1×PBS, fixed with 2% paraformaldehyde (w / v) in 1×PBS for 12 minutes, and then washed three times with 1×PBS. After fixation, cells were permeabilized with 0.1% Triton X-100 (v / v) in 1×PBS for 5 minutes and washed three times with 1×PBS. Then, cells were blocked at room temperature for 20 minutes in 2% BSA, 0.2% Tween-20 (w / v) / 1×PBS (blocking buffer). The click reaction cocktail was prepared from Click-iT EdU Imaging Kits (ThermoFisher Scientific, C10337) according to the manufacturer's protocol. Briefly, 868 μL of 1×Click-iT reaction buffer was mixed with 40 μL of CuSO4 solution, 2 μL of Alexa Fluor azide, and 90 μL of reaction buffer additive (sodium ascorbate) to a final volume of 1 mL. The cover glasses were incubated with 50 μL of the click reaction cocktail in the dark at room temperature for 30 minutes and then washed three times with 1×PBS. The cover glasses were mounted using VECTASHIELD containing DAPI and sealed with Nail Enamel Express manicure (Maybelline, 16P201).

[0500] Flow cytometry Bodipy-C11 (Thermo Fisher Scientific, D3861) was used according to the manufacturer's protocol. RhoNox-M (in-house) was added to live cells at a concentration of 1 μM for 1 hour prior to flow cytometry analysis. In the annexin / PI assay (Thermo Fisher Scientific, V13245, manufacturer's protocol), BELA cells were treated with RSL3 for 24 hours in the presence or absence of 1 μM of liproxstatin-1 (Sigma-Aldrich, SML1414) or 10 μM of A3. The cells were then washed twice with ice-cold 1×PBS, suspended in incubation buffer, and then analyzed by flow cytometry according to the manufacturer's protocol. At least 10,000 cells were counted for each condition. Data were recorded on an Attune (Thermo Fisher Scientific) and processed using FlowJo (FLOWJO, LLC).

[0501] Inductively coupled plasma mass spectrometry Glass vials equipped with Teflon membranes were cleaned with 65% nitric acid (w / v) (VWR, Suprapur, 1.00441.0250), washed with ultrapure water (Sigma-Aldrich, 1012620500), and dried. Cells were seeded 24 hours prior to the experiment. Cells were harvested using trypsin treatment (TrypLE Express Enzyme, Life Technologies, 12605010) and subsequently washed twice with 1×PBS. The cells were then counted using an automated cell counter (Entek), transferred to a cleaned glass vial in 100 μL of 1×PBS, and the samples were lyophilized using a freeze dryer (CHRIST, 22080). Subsequently, the samples were mixed with 65% nitric acid (w / v) overnight and then heated at 80 °C for 2 hours. The samples were diluted with ultrapure water (Sigma-Aldrich, 1012620500) to a final concentration of 0.475 N nitric acid and then transferred to a metal-free centrifuge vial (VWR, 89049-172) for subsequent ICP-MS analysis. 56The Fe concentration was measured using an Agilent 7900 ICP-QMS in low-resolution mode. Sample introduction was achieved via a Scott spray chamber using a MicroMist nebulizer (0.2 mL / min). Isotopes were measured using a collision reaction interface with helium gas (5 mL / min) to remove polyatomic interferences. Scandium and indium internal standards were injected after in-line mixing with the sample to control for signal drift and matrix effects. A mixture of certified reference materials was measured at concentrations within the concentration range of the samples to convert the count measurements to concentrations in solution. The uncertainty at the sample concentration was calculated using algebraic propagation of the ICP-MS blank and sample count uncertainty. Values were normalized by dry mass and cell number.

[0502] Cell viability Cell viability was evaluated by seeding 4,000 cells / well in a 96-well plate and using the CellTiter-Blue Viability assay according to the manufacturer's protocol. Cells were treated as shown in the figure. CellTiter-Blue reagent (Promega, G8081) was added 72 hours after treatment, and the cells were incubated for 2 hours, after which the fluorescence intensity (E ex. 560 nm; E em. 590 nm) was recorded using a Perkin Elmer Wallac 1420 Victor2 Microplate Reader.

[0503] Results As demonstrated by calorimetric complexation studies in solution (Figure 1) and by NMR spectroscopy (Figure 2), serotonin and A3 readily form complexes with Fe(II), Fe(III), and Cu(II).

[0504] The inventors treated cells with 1 μM of the serotonin analog A3 for 3 hours and performed click chemistry using a technique previously developed by the inventors. 1,2Using co-staining with LysoTracker, the inventors found that these molecules accumulate in lysosomes (Figure 3).

[0505] Using a lysomotropic probe called RhoNox-M that specifically detects Fe(II) in lysosomes 3 the inventors observed an increase in RhoNox-M fluorescence measured by flow cytometry in cells treated with the serotonin analogs A3, LT262A, LC357, LC336 or LT265B (Figure 4a, b). This data indicates an increase in lysosomal Fe(II) when cells are treated with these compounds.

[0506] Treatment of cells with 100 nM A3 for 3 or 24 hours resulted in an increase in total intracellular iron and copper as measured by inductively coupled plasma mass spectrometry (Figure 5a, b).

[0507] A3 resulted in a decrease in lipid peroxidation induced by ferroptosis inducers (measured by BODIPY-C11 fluorescence) (Figure 6a) and also resulted in the rescue of cell survival from the toxicity caused by this ferroptosis inhibitor (Figure 6b).

[0508] The serotonin analog A3 rescued cell death induced by the ferroptosis inducer RSL-3 together with liproxstatin-1 as a control in the same experiment (Figure 7).

[0509] In summary, these results demonstrate that serotonin analogs can form complexes with iron and copper, accumulate in lysosomes, and sequester lysosomal iron and copper. This results in an increase in total intracellular iron and copper. The complexation of these metals protects cells from oxidative stress and protects them against ferroptosis and cuproptosis.

[0510] (Example 3) Anti-ferroptotic activity Method: Pancreatic ductal adenocarcinoma (PDAC) cells were grown at 37 °C and 5% CO2 using a medium prepared based on previous descriptions (https: / / doi.org / 10.1053 / j.gastro.2004.03.058).

[0511] Antibodies and reagents IF: Immunofluorescence Annexin / PI kit (Thermo Fisher Scientific, V13245, manufacturer protocol), BODIPY-C11 (Thermo Fisher Scientific, D3861, manufacturer protocol), Cyt c (Cell Signaling, 12963S, IF 1:200), EEA1 (Enzo Life Science, ALX210-239, IF 1:200), LysoTracker (LysoTracker Deep Red, Thermo Fisher Scientific, L12492, 45 minutes in live cells, then fixed), Rcas1 (Cell Signaling, 12290, IF 1:200), PDIA3 (Sigma-Aldrich, AMAB90988, IF 1:200), RSL3 (Sigma-Aldrich, SML2234-5MG).

[0512] Anti-ferroptosis activity (Figure 8) PDAC cells were seeded in 6-well plates at a density of 2 × 10 5 cells / well. The next day, RSL3 (200 nM) was added together with the compound (10 μM in screening), and after 23 hours, BODIPY (4 μM) was added for 1 hour. The medium was removed, the cells were washed twice with PBS, and then trypsinized. The cells were harvested, pelleted, washed with PBS, and finally, a PBS buffer containing 10% FBS and EDTA was added for flow cytometry.

[0513] The results are shown in Figure 8, which enabled the inventors to establish a strong structure-activity correlation in the serotonin scaffold.

[0514] Fluorescence microscopy (Fig. 9) Cells were seeded on cover glasses 24 hours before the experiment. Cells were treated with 10 μM of the compound for 3 hours and with LysoTracker Deep Red (ThermoFisher Scientific, L12492, 1:10000) according to the manufacturer's protocol. Subsequently, the cells were washed three times with 1×PBS, fixed with 2% paraformaldehyde (w / v) in 1×PBS for 12 minutes, and then washed three times with 1×PBS. After fixation, the cells were permeabilized with 0.1% Triton X-100 (v / v) in 1×PBS for 5 minutes and washed three times with 1×PBS. Then, the cells were blocked at room temperature for 20 minutes in 2% BSA, 0.2% Tween-20 (w / v) / 1×PBS (blocking buffer). The click reaction cocktail was prepared from Click-iT EdU Imaging Kits (ThermoFisher Scientific, C10337) according to the manufacturer's protocol. Briefly, 868 μL of 1×Click-iT reaction buffer was mixed with 40 μL of CuSO4 solution, 2 μL of Alexa Fluor azide, and 90 μL of reaction buffer additive (sodium ascorbate) to a final volume of 1 mL. The cover glasses were incubated with 50 μL of the click reaction cocktail in the dark at room temperature for 30 minutes and then washed three times with 1×PBS. Furthermore, the cells were incubated with the relevant antibody in the blocking buffer at room temperature for 1 hour and washed three times with the blocking buffer. Then, the cells were incubated with the secondary antibody for 1 hour. Finally, the cover glasses were washed three times with 1×PBS, mounted using VECTASHIELD containing DAPI (Vector Laboratories), and sealed with Nail Enamel Express manicure (Maybelline, 16P201). Fluorescent images were obtained using a Deltavision real-time microscope (Applied Precision).A 100× / 1.4NA objective lens was used for 2D and 3D acquisition, and they were deconvolved with SoftWorx (Ratio conservative-10 iterations, Applied Precision) and processed with ImageJ.

[0515] The results are shown in Figure 9, which shows that A3 enters lysosomes in cells and does not co-localize with other cell organelles. The active compounds A1 and A4 also localize in lysosomes, while the inactive compound A0 does not enter lysosomes, indicating the importance of lysosomes in targeting ferroptosis.

[0516] Cell apoptosis assay using annexin V and propidium iodide (PI) (Figure 10a) PDAC cells were seeded in 6-well plates at a density of 2×10 cells / well. 5 The next day, RSL3 (0.1, 0.5, 2, 10 μM) was added together with the compound (10 μM). After 24 hours, the medium was collected and the cells were trypsinized. The cells were harvested, the medium was collected and pelleted, and washed with 100 μL of 1× annexin binding buffer containing PBS and annexin V and PI (according to the manufacturer's protocol, Dead Cell Apoptosis Kits with Annexin V for Flow Cytometry (Invitrogen)). Finally, a PBS buffer containing 10% FBS and 1 mM EDTA was added for flow cytometry. Figure 10a shows the flow cytometry profiles of annexin / propidium iodide and their quantification for cells treated with various concentrations of RSL3 and cells co-treated with A3, A0 or reproxastatin-1. A3 protects against RSL3-induced ferroptosis.

[0517] Cyclic voltammetry experiment (Figure 10b) The cyclic voltammetry experiment was carried out under argon using a three - electrode cell. A saturated calomel electrode (SCE) was used as the reference, a stationary glassy carbon (GC) electrode with a diameter of 3 mm was used as the working electrode, and a platinum wire was selected as the counter electrode. All cyclic voltammograms were recorded at room temperature using a Metrohm μ - autolab III with Nova software at a scan rate of 2 V / s. MeCN was used as a degassed HPLC grade from Carlo Erba. The water was mQ H2O. Stock solutions of FeCl3 (100 mM) and Lip - 1, A3, A0, and DFO (20 mM) were prepared in 0.3 M nBu4NBF4 in MeCN. 1 mM FeCl3 (1 mL) in 0.3 M nBu4NBF4 in MeCN was used as the working solution for recording, and then an equivalent amount of the compound was added, stirred, and recorded.

[0518] Figure 10b shows the cyclic voltammetry curves after the addition of FeCl3 and the compound. This indicates that A3 chelates / binds to Fe, 3+ in contrast to the inert compound A0 which does not bind to Fe, 3+ similar to the known Fe 3+ chelating agent - DFO. (References)

Table 2

Claims

1. A pharmaceutical composition comprising a compound of general formula (I) or a pharmaceutically acceptable salt and / or solvate thereof for use in the prevention or treatment of a metallopotosis-related disorder, wherein formula (I) is: 【Chemistry 1】 [In the formula, R 1 , R 2 , R 3 and R 4 -H, -OH, -C(O)OR 9 -, -S(O) 2 R 10 -, -C(O)R 9 -, -S(O)R 10 -, -NR 11 R 12 -, optionally substituted (C 1 ~C 24 ) alkyl, optionally substituted (C 2 ~C 24 ) alkenyl, optionally substituted (C 2 ~C 24 ) alkynyl, optionally substituted (C 3 ~C 10 ) independently selected from the group consisting of cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl, with the proviso that R 1 , R 2 and R 3 is not H; or R 1 and R 4 -H, -OH, -C(O)OR 9 -, -S(O) 2 R 10 -, -C(O)R 9 -, -S(O)R 10 -, -NR 11 R 12 -, optionally substituted (C 1 ~C 24 ) alkyl, optionally substituted (C 2 ~C 24 ) alkenyl, optionally substituted (C 2 ~C 24 ) alkynyl, optionally substituted (C 3 ~C 10 ) independently selected from the group consisting of cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; R 2 and R 3 together with the nitrogen atom to which they are attached form an optionally substituted heterocycloalkyl; X is (C 1 ~C 12 ) alkyl, -O-(C 1 ~C 12 ) alkyl-, -C(O)-, -C(O)-(C 1 ~C 12 ) alkyl-, -NH-C(O)-(C 1 ~C 12 ) alkyl-, -S-(C 1 ~C 12 ) alkyl-, -S(O)-(C 1 ~C 12 ) alkyl-, and -S(O) 2 -(C 1 ~C 12 ) alkyl-; (C 1 ~C 12 ) the alkyl group may be substituted and / or interrupted by heteroatoms; Y 0 , Y 1 , Y 2 and Y 3 are independently absent or -NH-, -O-, -S-, -S(O)-, -S(O) 2 -, -C(O)-, -C(O)O-, -OC(O)-, -NHC(O)-, -C(O)NH-; -C(O)NR 14 -, (C 1 ~C 24 ) alkyl, -(C 1 ~C 24 ) alkyl-NH-, -(C 1 ~C 24 ) alkyl-O-, -(C 1 ~C 24 ) alkyl-S-, (C 1 ~C 24 )Alkyl-NR 13 -, -(C 1 ~C 24 ) alkyl-S(O)-, -(C 1 ~C 24 )Alkyl-S(O) 2 -, -(C 1 ~C 24 ) alkyl-C(O)-, -(C 1 ~C 24 ) alkyl-C(O)O-, -(C 1 ~C 24 ) alkyl-OC(O)-, -(C 1 ~C 24 ) alkyl-NHC(O)-, -(C 1 ~C 24 ) alkyl-C(O)NH-, -(C 1 ~C 24 )Alkyl-C(O)NR 14 -, -NH-C(O)-NH-, -NH-S(O)-NH-, -NH-S(O 2 )-NH-, -SC(O)-NH-, -OC(O)-NH-, -OS(O)-NH-, -OS(O 2 )-NH-, -S-CH 2 -C(O)-NH-, -S-CH 2 -S(O)-NH-, -S-CH 2 -S(O 2 )-NH-, -S(O)-CH 2 -C(O)-NH-、-S(O 2 )-CH 2 -C(O)-NH-、-O-CH 2 -C(O)-NH-、-O-CH 2 -S(O)-NH-、-O-CH 2 -S(O 2 )-NH-、-NH-CH 2 -C(O)-NH-,-NH-CH 2 -S(O)-NH-、-NH-CH 2 -S(O 2 )-NH-、-O-(CH 2 ) 2 -NH-C(O)-,-O-(CH 2 ) 2 -N(CH 3 )-C(O)-、-O-(CH 2 ) 2 -NH-S(O)-,-O-(CH 2 ) 2 -N(CH 3 )-S(O)-、-O-(CH 2 ) 2 -NH-S(O 2 )-、-O-(CH 2 ) 2 -N(CH 3 )-S(O 2 )-、-S-(CH 2 ) 2 -NH-C(O)-,-S-(CH 2 ) 2 -N(CH 3 )-C(O)-、-S-(CH 2 ) 2 -NH-S(O)-,-S-(CH 2 ) 2 -N(CH 3 )-S(O)-、-S-(CH 2 ) 2 -NH-S(O 2 )-、-S-(CH 2 ) 2 -N(CH 3 )-S(O 2 )-、-NH-(CH 2 ) 2 -NH-C(O)-,-NH-(CH 2 ) 2 -N(CH 3 )-C(O)-、-NH-(CH 2 ) 2 -NH-S(O)-,-NH-(CH 2 ) 2 -N(CH 3 )-S(O)-、-NH-(CH 2 ) 2 -NH-S(O 2 )-、-NH-(CH 2 ) 2 -N(CH 3 )-S(O 2 )-、-O-CH 2 -CH(CH 2 -OH)-NH-C(O)-、-O-CH 2 -CH(CH 2 -OCH 3 )-NH-C(O)-、-O-CH 2 -CH(CH 3 )-NH-C(O)-、-O-CH(CH 3 )-CH 2 -NH-C(O)-,-O-CH 2 -CH(CH 2 -OH)-NH-S(O)-、-O-CH 2 -CH(CH 2 -OCH 3 )-NH-S(O)-、-O-CH 2 -CH(CH 3 )-NH-S(O)-、-O-CH(CH 3 )-CH 2 -NH-S(O)-,-O-CH 2 -CH(CH 2 -OH)-NH-S(O 2 )-、-O-CH 2 -CH(CH 2 -OCH 3 )-NH-S(O 2 )-、-O-CH 2 -CH(CH 3 )-NH-S(O 2 )-、-O-CH(CH 3 )-CH 2 -NH-S(O 2 )-、-S-CH 2 -CH(CH 2 -OH)-NH-C(O)-、-S-CH 2 -CH(CH 2 -OCH 3 )-NH-C(O)-、-S-CH 2 -CH(CH 3 )-NH-C(O)-、-S-CH(CH 3 )-CH 2 -NH-C(O)-,-S-CH 2 -CH(CH 2 -OH)-NH-S(O)-、-S-CH 2 -CH(CH 2 -OCH 3 )-NH-S(O)-、-S-CH 2 -CH(CH 3 )-NH-S(O)-、-S-CH(CH 3 )-CH 2 -NH-S(O)-,-S-CH 2 -CH(CH 2 -OH)-NH-S(O 2 )-、-S-CH 2 -CH(CH 2 -OCH 3 )-NH-S(O 2 )-、-S-CH 2 -CH(CH 3 )-NH-S(O 2 )-、-S-CH(CH 3 )-CH 2 -NH-S(O 2 )-、-NH-CH 2 -CH(CH 2 -OH)-NH-C(O)-、-NH-CH 2 -CH(CH 2 -OCH 3 )-NH-C(O)-、-NH-CH 2 -CH(CH 3 )-NH-C(O)-、-NH-CH(CH 3 )-CH 2 -NH-C(O)-,-NH-CH 2 -CH(CH 2 -OH)-NH-S(O)-、-NH-CH 2 -CH(CH 2 -OCH 3 )-NH-S(O)-、-NH-CH 2 -CH(CH 3 )-NH-S(O)-, -NH-CH(CH 3 )-CH 2 -NH-S(O)-, -NH-CH 2 -CH(CH 2 -OH)-NH-S(O 2 )-, -NH-CH 2 -CH(CH 2 -OCH 3 )-NH-S(O 2 )-, -NH-CH 2 -CH(CH 3 )-NH-S(O 2 )-, -NH-CH(CH 3 )-CH 2 -NH-S(O 2 )-, -O-(CH 2 ) 2 -NH-, -S-(CH 2 ) 2 -NH- and -NH-(CH 2 ) 2 -NH-; (C 1 ~C 24 ) the alkyl group may be substituted; R 5 , R 6 , R 7 and R 8 is H, halogen, optionally substituted (C 1 ~C 24 ) alkyl, optionally substituted (C 2 ~C 24 ) alkenyl, optionally substituted (C 2 ~C 24 ) alkynyl, optionally substituted (C 3 ~C 10 ) independently selected from the group consisting of cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; R 9 ~R 14 may be substituted (C 1 ~C 12 ) alkyl, optionally substituted (C 2 ~C 12 ) alkenyl, optionally substituted (C 2 ~C 12 ) alkynyl, and optionally substituted aryl.

2. The pharmaceutical composition according to claim 1, wherein the metallopotosis-associated disorder is a disorder associated with ferroptosis and / or cuproptosis.

3. 2. The pharmaceutical composition of claim 1, wherein the metallopotosis-related disorder is selected from the group consisting of hemorrhagic stroke; ischemic cardiac injury; ischemic renal injury; ischemia-reperfusion injury (IRI); neurodegenerative diseases selected from Huntington's disease, dementia, and amyotrophic lateral sclerosis (ALS); age-related diseases or disorders; sepsis; ischemia-reperfusion; and diabetes.

4. Compounds of general formula (I): 【Chemistry 2】 [In the formula, R 1 , R 2 , R 3 and R 4 H, OH, -C(O)OR 9 -, -S(O) 2 R 10 -, -C(O)R 9 -, -S(O)R 10 -, -NR 11 R 12 -, optionally substituted (C 1 ~C 24 ) alkyl, optionally substituted (C 2 ~C 24 ) alkenyl, optionally substituted (C 2 ~C 24 ) alkynyl, optionally substituted (C 3 ~C 10 ) independently selected from the group consisting of cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl, with the proviso that R 2 and R 3 at least one of is not H; or R 1 and R 4 H, OH, -C(O)OR 9 -, -S(O) 2 R 10 -, -C(O)R 9 -, -S(O)R 10 -, -NR 11 R 12 -, optionally substituted (C 1 ~C 24 ) alkyl, optionally substituted (C 2 ~C 24 ) alkenyl, optionally substituted (C 2 ~C 24 ) alkynyl, optionally substituted (C 3 ~C 10 ) independently selected from the group consisting of cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; R 2 and R 3 together with the nitrogen atom to which they are attached, halogens; CN; NO 2 ;(C 1 ~C 6 ) alkyl; (C 1 ~C 6 ) haloalkyl; (C 1 ~C 6 ) haloalkoxy, (C 1 ~C 6 ) halothioalkoxy, optionally substituted aryl (especially aryl having one or two (C 1 ~C 6 ) alkyl or NO 2 optionally substituted with); heteroaryl; oxo; NR a R b ;COR c ;CO 2 R d ;CONR e R f ;OR g ;SR h ;SO 2 R i ;SO 2 NR j R k ;NR l COR m ;R n NR O R P ;NR q SO 2 R r ;(In the formula, R a ~R r are mutually independent, H, (C 1 ~C 6 ) alkyl, (C 1 ~C 6 ) haloalkyl, aryl, (C 1 ~C 6 ) alkyl-aryl, heteroaryl or (C 1 ~C 6 ) alkyl-heteroaryl); in particular halogen, CN, NO 2 , (C 1 ~C 6 ) alkyl, (C 1 ~C 6 ) Haloalkyl, oxo, NR a R b , C.O.R. c , C(O)OR d ,CONR e R f , and OR g (In the formula, R a ~R g are each independently H or (C 1 ~C 6 ) alkyl); X is (C 1 ~C 12 ) alkyl, -O-(C 1 ~C 12 ) alkyl-, -C(O)-, -C(O)-(C 1 ~C 12 ) alkyl-, -NH-C(O)-(C 1 ~C 12 ) alkyl-, -S-(C 1 ~C 12 ) alkyl-, -S(O)-(C 1 ~C 12 ) alkyl-, and -S(O) 2 -(C 1 ~C 12 ) alkyl-; (C 1 ~C 12 ) the alkyl group may be substituted and / or interrupted by heteroatoms; Y 0 , Y 1 , Y 2 and Y 3 are independently absent or -NH-, -O-, -S-, -S(O)-, -S(O) 2 -, -C(O)-, -C(O)O-, -OC(O)-, -NHC(O)-, -C(O)NH-; -C(O)NR 14 -, -(C 1 ~C 24 ) alkyl-NH-, -(C 1 ~C 24 ) alkyl-O-, -(C 1 ~C 24 ) alkyl-S-, (C 1 ~C 24 )Alkyl-NR 13 -, -(C 1 ~C 24 ) alkyl-S(O)-, -(C 1 ~C 24 )Alkyl-S(O) 2 -, -(C 1 ~C 24 ) alkyl-C(O)-, -(C 1 ~C 24 ) alkyl-C(O)O-, -(C 1 ~C 24 ) alkyl-OC(O)-, -(C 1 ~C 24 ) alkyl-NHC(O)-, -(C 1 ~C 24 ) alkyl-C(O)NH-, -(C 1 ~C 24 )Alkyl-C(O)NR 14 -, (C 1 ~C 24 )alkyl, -NH-C(O)-NH-, -NH-S(O)-NH-, -NH-S(O 2 )-NH-, -SC(O)-NH-, -OC(O)-NH-, -OS(O)-NH-, -OS(O 2 )-NH-, -S-CH 2 -C(O)-NH-, -S-CH 2 -S(O)-NH-, -S-CH 2 -S(O 2 )-NH-, -S(O)-CH 2 -C(O)-NH-、-S(O 2 )-CH 2 -C(O)-NH-、-O-CH 2 -C(O)-NH-、-O-CH 2 -S(O)-NH-、-O-CH 2 -S(O 2 )-NH-、-NH-CH 2 -C(O)-NH-,-NH-CH 2 -S(O)-NH-、-NH-CH 2 -S(O 2 )-NH-、-O-(CH 2 ) 2 -NH-C(O)-,-O-(CH 2 ) 2 -N(CH 3 )-C(O)-、-O-(CH 2 ) 2 -NH-S(O)-,-O-(CH 2 ) 2 -N(CH 3 )-S(O)-、-O-(CH 2 ) 2 -NH-S(O 2 )-、-O-(CH 2 ) 2 -N(CH 3 )-S(O 2 )-、-S-(CH 2 ) 2 -NH-C(O)-,-S-(CH 2 ) 2 -N(CH 3 )-C(O)-、-S-(CH 2 ) 2 -NH-S(O)-,-S-(CH 2 ) 2 -N(CH 3 )-S(O)-、-S-(CH 2 ) 2 -NH-S(O 2 )-、-S-(CH 2 ) 2 -N(CH 3 )-S(O 2 )-、-NH-(CH 2 ) 2 -NH-C(O)-,-NH-(CH 2 ) 2 -N(CH 3 )-C(O)-、-NH-(CH 2 ) 2 -NH-S(O)-,-NH-(CH 2 ) 2 -N(CH 3 )-S(O)-、-NH-(CH 2 ) 2 -NH-S(O 2 )-、-NH-(CH 2 ) 2 -N(CH 3 )-S(O 2 )-、-O-CH 2 -CH(CH 2 -OH)-NH-C(O)-、-O-CH 2 -CH(CH 2 -OCH 3 )-NH-C(O)-、-O-CH 2 -CH(CH 3 )-NH-C(O)-、-O-CH(CH 3 )-CH 2 -NH-C(O)-,-O-CH 2 -CH(CH 2 -OH)-NH-S(O)-、-O-CH 2 -CH(CH 2 -OCH 3 )-NH-S(O)-、-O-CH 2 -CH(CH 3 )-NH-S(O)-、-O-CH(CH 3 )-CH 2 -NH-S(O)-,-O-CH 2 -CH(CH 2 -OH)-NH-S(O 2 )-、-O-CH 2 -CH(CH 2 -OCH 3 )-NH-S(O 2 )-、-O-CH 2 -CH(CH 3 )-NH-S(O 2 )-、-O-CH(CH 3 )-CH 2 -NH-S(O 2 )-、-S-CH 2 -CH(CH 2 -OH)-NH-C(O)-、-S-CH 2 -CH(CH 2 -OCH 3 )-NH-C(O)-、-S-CH 2 -CH(CH 3 )-NH-C(O)-、-S-CH(CH 3 )-CH 2 -NH-C(O)-,-S-CH 2 -CH(CH 2 -OH)-NH-S(O)-、-S-CH 2 -CH(CH 2 -OCH 3 )-NH-S(O)-、-S-CH 2 -CH(CH 3 )-NH-S(O)-、-S-CH(CH 3 )-CH 2 -NH-S(O)-,-S-CH 2 -CH(CH 2 -OH)-NH-S(O 2 )-、-S-CH 2 -CH(CH 2 -OCH 3 )-NH-S(O 2 )-、-S-CH 2 -CH(CH 3 )-NH-S(O 2 )-、-S-CH(CH 3 )-CH 2 -NH-S(O 2 )-、-NH-CH 2 -CH(CH 2 -OH)-NH-C(O)-、-NH-CH 2 -CH(CH 2 -OCH 3 )-NH-C(O)-、-NH-CH 2 -CH(CH 3 )-NH-C(O)-、-NH-CH(CH 3 )-CH 2 -NH-C(O)-,-NH-CH 2 -CH(CH 2 -OH)-NH-S(O)-、-NH-CH 2 -CH(CH 2 -OCH 3 )-NH-S(O)-、-NH-CH 2 -CH(CH 3 )-NH-S(O)-, -NH-CH(CH 3 )-CH 2 -NH-S(O)-, -NH-CH 2 -CH(CH 2 -OH)-NH-S(O 2 )-, -NH-CH 2 -CH(CH 2 -OCH 3 )-NH-S(O 2 )-, -NH-CH 2 -CH(CH 3 )-NH-S(O 2 )-, -NH-CH(CH 3 )-CH 2 -NH-S(O 2 )-, -O-(CH 2 ) 2 -NH-, -S-(CH 2 ) 2 -NH- and -NH-(CH 2 ) 2 -NH-; (C 1 ~C 24 ) the alkyl group may be substituted; R 5 , R 6 , R 7 and R 8 is H, halogen, optionally substituted (C 1 ~C 24 ) alkyl, optionally substituted (C 2 ~C 24 ) alkenyl, optionally substituted (C 2 ~C 24 ) alkynyl, optionally substituted (C 3 ~C 10 ) independently selected from the group consisting of cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; R 9 ~R 14 may be substituted (C 1 ~C 12 ) alkyl, optionally substituted (C 2 ~C 12 ) alkenyl, optionally substituted (C 2 ~C 12 ) independently selected from the group consisting of alkynyl, optionally substituted aryl; However, R 5 , R 6 , R 7 and R 8 is H and Y 0 is -O- and Y 1 , Y 2 and Y 3 If does not exist, R 1 , R 2 and R 3 may be substituted (C 2 ~C 24 ) not alkynyl] or a pharmaceutical composition comprising a pharmaceutically acceptable salt and / or solvate thereof.

5. 5. The pharmaceutical composition of claim 4 for use as a medicament.

6. 5. The pharmaceutical composition of claim 4, further comprising at least one pharmaceutically acceptable excipient.

7. 7. A pharmaceutical composition according to claim 5 or 6 for use in preventing or treating iron and / or copper related disorders, in particular iron and / or copper excess related disorders; or metal dependent cell death related disorders.

8. 8. The pharmaceutical composition of claim 7, wherein the iron and / or copper-related disorder is selected from HFE-associated iron overload disorders; non-HFE-associated iron overload disorders; congenital atransferrin anemia; iron overload-related anemias such as thalassemia, myelodysplasia, and hematopoietic stem cell transplant-related disorders; chronic liver disease; chronic inflammation associated with cancer; autoimmune or inflammatory diseases; neurodegeneration associated with brain iron accumulation-related diseases such as Wilson's disease; and polygenic neurodegeneration-related diseases such as Parkinson's disease and Alzheimer's disease.

9. The pharmaceutical composition of claim 7, wherein the metal-dependent cell death-related disorder is a metallopotosis-related disorder, particularly a disorder associated with ferroptosis and / or cuproptosis; preferably selected from hemorrhagic stroke; ischemic cardiac injury; ischemic renal injury; ischemia-reperfusion injury (IRI); a neurodegenerative disease selected from Huntington's disease, dementia, and amyotrophic lateral sclerosis (ALS); an age-related disease or disorder; sepsis; ischemia-reperfusion; and diabetes.

10. X may be substituted and / or interrupted by heteroatoms (C 1 ~C 12 ) alkyl, preferably optionally substituted by heteroatoms and / or optionally interrupted (C 1 ~C 6 5. The pharmaceutical composition according to claim 1, wherein X is alkyl, more preferably X is ethyl.

11. R 5 , R 6 , R 7 and R 8 is H, halogen, optionally substituted (C 1 ~C 24 ) alkyl, optionally substituted (C 2 ~C 24 ) alkenyl, optionally substituted (C 2 ~C 24 ) alkynyl, preferably H, halogen, haloalkyl, or (C 1 ~C 24 10. The pharmaceutical composition of claim 1, wherein each of the aryl, aryl, aryls ...

12. R 4 The pharmaceutical composition of claim 1 or 4, wherein is H.

13. R 1 The pharmaceutical composition of claim 1 or 4, wherein is H.

14. R 2 and R 3 H, -C(O)OR 9 -, -S(O) 2 R 10 -, optionally substituted (C 1 ~C 12 ) alkyl, optionally substituted (C 2 ~C 12 ) alkenyl, optionally substituted (C 2 ~C 12 ) alkynyl, optionally substituted (C 3 ~C 12 ) independently selected from the group consisting of cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl, with the proviso that R 2 and R 3 at least one of is not H; or R 2 and R 3 together with the nitrogen atom to which they are attached form an optionally substituted nitrogen-heterocycloalkyl containing 3 to 10 ring atoms; R 9 ~R 12 5. The pharmaceutical composition according to claim 1 or 4, wherein:

15. Y 0 , Y 1 , Y 2 and Y 3 are independently absent or are selected from the group consisting of NH—, —O—, —S—, —S(O)—, and —S(O) 2 -, -C(O)-, -C(O)O-, -OC(O)-, -NHC(O)-, -C(O)NH-, -C(O)NR 14 -, (C 1 ~C 24 ) alkyl, -(C 1 ~C 24 ) alkyl-NH-, -(C 1 ~C 24 ) alkyl-O-, -(C 1 ~C 24 ) alkyl-S-, (C 1 ~C 24 )Alkyl-NR 13 -, -(C 1 ~C 24 ) alkyl-S(O)-, -(C 1 ~C 24 )Alkyl-S(O) 2 -, -(C 1 ~C 24 ) alkyl-C(O)-, -(C 1 ~C 24 ) alkyl-C(O)O-, -(C 1 ~C 24 ) alkyl-OC(O)-, -(C 1 ~C 24 ) alkyl-NHC(O)-, -(C 1 ~C 24 ) alkyl-C(O)NH-, -(C 1 ~C 24 )Alkyl-C(O)NR 14 - selected from the group consisting of: 1 ~C 24 ) the alkyl group may be substituted; R 13 and R 14 5. The pharmaceutical composition according to claim 1 or 4, wherein:

16. Y 0 , Y 1 , Y 2 and Y 3 are independently absent or -O-; -NH-, -S- or optionally substituted (C 1 ~C 24 ) alkyl; preferably Y 0 , Y 1 , Y 2 and Y 3 are independently absent or -O-; more preferably Y 0 is -O- and Y 1 , Y 2 and Y 3 The pharmaceutical composition of claim 1 or 4, wherein: is independently absent or -O-.

17. A compound listed in Table 1 below. Table 1A Table 1B 【Table 1C】 【Table 1D】 Table 1E Table 1F 【Table 1G】 Table 1H or a pharmaceutically acceptable salt and / or solvate thereof.

18. The compounds are selected from the compounds (001) to (064) in Table 1 below; in particular, the compounds (002), (003), (004), (008), (009), (010), (012), (013), (014), (015), (016), (017), (018), (019), (020), (022), (023), (024), (025), (026), (028), ( 029), (036), (039), (040), (043), (045), (049), (051), (052), (054), (057), (058), (059), (061), (063), and (064); in particular selected from compounds (003) to (007), (013), (014), (021), (029) and (031) to (038) of Table 1; Table 2A Table 2B Table 2C 【Table 2D】 Table 2E Table 2F 【Table 2G】 Table 2H 5. The pharmaceutical composition of claim 4.

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