Novel serotonin derivatives and their use for treating iron-related disorders - Patents.com

Abstract

The present invention relates to novel serotonin derivatives of formula (I) or their pharma- ceutically acceptable salts and / or solvates. Another object of the present invention relates to the use of compounds of formula (I) as medicaments, especially in the prevention and / or treatment of disorders related to iron overload. TIFF2024531311000052.tif29128

Description

[Technical field]

[0001] The present invention relates to novel serotonin derivatives and their use as medicaments, in particular for preventing and / or treating iron-related disorders. [Background technology]

[0002] Iron is essential for carrying out biological processes, particularly erythropoiesis, the process of producing red blood cells.

[0003] Many diseases have iron-related disorders associated with ineffective erythropoiesis. In particular, the disorders may be associated with iron overload in the body. Among the most common iron overload-related disorders are iron overload-related anemias, such as β-thalassemia, myelodysplasia, or hematopoietic stem cell transplant-related disorders.

[0004] β-thalassemia is a type of genetic hemolytic anemia, associated with abnormal synthesis of B-hemoglobin, which induces apoptosis of erythrocyte precursor cells. The disease affects 1.5% of the world's population, with a high prevalence in the poorest countries, Africa and India. It is responsible for 50 000 to 100 000 deaths per year. Current treatment consists of regular blood transfusions to maintain normal hemoglobin levels. However, repeated transfusions and hemoglobin apoptosis lead to iron overload in the organism, causing high toxicity. It is therefore essential to eliminate this excess iron. Iron chelators (e.g., deferoxamine) may be used for this purpose and have proven effective in reducing mortality. However, deferoxamine requires severe treatment conditions such as daily injections and infusions. For more convenient use, oral iron chelators such as deferiprone or deferasinox also exist, but they are less effective. A new drug, luspatercept, was approved by the FDA in 2019 for transfusion-dependent thalassemia. Luspatercept is a recombinant protein that has been shown to be effective in reducing anemia, decreasing the need for blood transfusions, and lowering ferritin levels. However, the price of luspatercept is particularly high, making it difficult to reach disadvantaged populations.

[0005] Myelodysplasia or myelodysplastic syndrome (MDS) is a clonal hematopoietic disease characterized by anemia associated with inefficient hematopoiesis and progression to acute myeloid leukemia. The syndrome mainly affects people over 60 years of age. With regard to β-thalassemia, blood transfusions help maintain normal hemoglobin levels, but result in iron overload in the organism. This iron overload is also caused by the suppression of the production of hepcidin, a hormone that regulates iron metabolism in the body, due to this syndrome. Iron chelators are not recommended in view of their toxicity and the vulnerability of the patient. Luspatercept has also been recently approved for the treatment of this disease.

[0006] Approximately 40,000 allogeneic transplants are performed annually worldwide, including about 2,500 in France, with an estimated growth rate of 7% per year. Allogeneic transplantation refers to transplants in which the donor and recipient are two separate individuals. Hematopoietic stem cell allogeneic transplantation is an evolving technique that offers the prospect of a cure for hematologic malignancies (leukemia, lymphoma, myeloma) and other hematological disorders (e.g., primary immunodeficiency, bone marrow aplasia, myelodysplasia). Post-transfusion iron overload is relatively common in the setting of hematopoietic stem cell transplantation. The use of iron chelators is very limited after allogeneic transplant procedures due to their toxicity. Currently, there are no alternative treatments to reduce post-transplant iron overload and support hematopoiesis to increase post-transplant survival.

[0007] Thus, an alternative treatment for iron-related disorders, in particular for preventing and / or treating iron overload as observed, for example, in β-thalassemia, MSD or post-transplant patients, is provided. There is a need for alternative treatments that can be obtained at a reasonable cost and with a satisfactory safety and efficacy profile at least as good as the treatment of luspatercept used in β-thalassemia and MSD.

[0008] Serotonin, also called 5-hydroxytryptamine (5-HT), is a neurotransmitter that responds to the following:

[0009] [ka]

[0010] This molecule is essential for metabolism and allows to regulate numerous physiological processes such as mood, cognition, reward, learning, memory, as well as emesis and vasoconstriction. Serotonin is synthesized in neurons starting from tryptophan, an essential amino acid that is transported to the brain via the blood circulation. It has been shown that the rate-limiting enzyme tryptophan hydroxylase involved in serotonin synthesis is highly expressed in erythroid precursors and that serotonin is synthesized at a critical transition checkpoint during the proliferation of erythroid precursor cells (Coman et al., Cell Reports, 2019, 26, 3246-3256). Recently, it has been demonstrated that serotonin levels in the bone marrow directly affect erythropoiesis. High levels of serotonin are capable of enhancing the renewal of erythroid precursor cells and thus promoting the production of red blood cells (Coman et al., Cell Reports, 2019). In contrast, reduced serotonin levels have been observed in patients suffering from myelodysplastic syndromes.

[0011] Without wishing to be bound by theory, the inventors hypothesize that serotonin can regulate erythropoiesis by affecting the availability of iron required for the production of erythrocytes.Therefore, serotonin is an interesting therapeutic target for the treatment of anemia.However, serotonin has vasoconstrictor / vasodilator properties via serotonin receptors, and therefore cannot be injected.

[0012] To improve the shortcomings of existing treatments, and based on the above hypothesis, the inventors have developed a small serotonin derivative that is easy to prepare, can act as an iron chelator to normalize iron stores, and makes iron available for biological processes in the body without exhibiting the toxicity observed with current iron chelators. Summary of the Invention

[0013] In a first aspect, the present invention provides a compound of formula (I):

[0014] [ka] or a pharma- ceutically acceptable salt and / or solvate thereof, During the ceremony, R 1 , R 2 , and R 4 are independently H, 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 7 selected from the group consisting of cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; R3 is H, 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 Cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted -C(O)OC 1 -C 24 Alkyl, optionally substituted -C(O)OC 2 -C 24 Alkenyl, optionally substituted -C(O)OC 2 -C 24 Alkynyl, -C(O)O-optionally substituted aryl, optionally substituted -C(O)O-heteroaryl, optionally substituted -S(O) 2 -C 1 -C 24 Alkyl, optionally substituted -S(O) 2 -C 2 -C 24 Alkenyl, optionally substituted -S(O) 2 -C 2 -C 24 Alkynyl, -S(O)2 -optionally substituted aryl and optionally substituted -S(O) 2 -heteroaryl, where R 1 , R 2 and R 3 At least one of them is not H, X is C 1 -C 12 Alkyl, OC 1 -C 12 Alkyl, C(O), C(O)-C 1 -C 12 Alkyl and NH-C(O)-C 1 -C 12 Alkyl is selected from the group consisting of:

[0015] In a second aspect, the present invention relates to a compound of formula (I) for use as a medicament.

[0016] According to a third aspect, the present invention relates to a pharmaceutical composition comprising a compound of formula (I) and at least one pharma- ceutically acceptable excipient.

[0017] A fourth aspect of the invention resides in a pharmaceutical composition comprising a compound of formula (I) and at least one pharma- ceutically acceptable excipient for use as a medicament.

[0018] Detailed Description For purposes of the present invention, the term "pharmaceutical acceptable" is intended to mean something that is useful in the preparation of a pharmaceutical composition and that is generally safe and non-toxic for pharmaceutical use.

[0019] The term "pharmaceutically acceptable salts and / or solvates" is intended, in the framework of the present invention, to mean salts and / or solvates of compounds which are pharmaceutically acceptable as defined above and which possess the pharmacological activity of the corresponding compounds.

[0020] Pharmaceutically acceptable salts include the following: (1) Acid addition salts formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid, or 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-L25-tartaric acid, tartaric acid, p-toluenesulfonic acid, trimethylacetic acid, and trifluoroacetic acid, and (2) Base addition salts, which are formed when an acid proton present in a compound is replaced by a metal ion, such as an alkali metal ion, an alkaline earth metal ion, or an aluminum ion, or is coordinated with an organic or inorganic base. Acceptable organic bases and Examples include diethanolamine, ethanolamine, N-methylglucamine, triethanolamine, tromethamine, etc. Acceptable inorganic bases include aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, and sodium hydroxide.

[0021] Acceptable solvates of the compounds of the invention include conventional solvates, such as those formed during the final steps of the preparation of the compounds of the invention due to the presence of solvents. By way of example, mention may be made of solvates due to the presence of water (these solvates are also called hydrates) or solvates due to the presence of ethanol.

[0022] As used herein, the term "halogen" refers to a fluorine, bromine, chlorine or iodine atom.

[0023] As used in the present invention, "C x -C y The term "alkyl" refers to a linear or branched monovalent saturated hydrocarbon chain containing x to y carbon atoms. 1 -C 24Examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, n-hexyl, and the like.

[0024] As used in the present invention, "C x -C y The term "alkenyl" refers to a linear or branched monovalent unsaturated hydrocarbon chain containing x to y carbon atoms and at least one double bond. 2 -C 24 Examples of alkenyl include, but are not limited to, ethenyl, propenyl, butenyl, pentenyl, hexenyl, and the like.

[0025] As used in the present invention, "C x -C y The term "alkynyl" refers to a linear or branched monovalent unsaturated hydrocarbon chain containing x to y carbon atoms and containing at least one triple bond. 2 -C 24 Examples of alkynyl include, but are not limited to, ethynyl, propynyl (or propargyl), butynyl, pentynyl, hexynyl, and the like.

[0026] "C x -C y The term "haloalkyl" refers to a C alkyl group as defined above, in which one or more hydrogen atoms are replaced by a halogen atom selected from fluorine, chlorine, bromine or iodine, preferably a fluorine atom. x -C y It refers to an alkyl chain. For example, it is CF 3 It is based on

[0027] The term "cycloalkyl" refers to a saturated non-aromatic hydrocarbon ring, typically containing 3 to 10, preferably 3 to 7, carbons and containing one or more fused or bridged rings. 3 -C 10Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, and the like.

[0028] The term "heterocycloalkyl" as used in the present invention refers to a non-aromatic, saturated or unsaturated monocyclic or polycyclic ring (including fused, bridged or spiro rings) containing preferably 5 to 10, especially 5 or 6 atoms in the ring(s), the ring(s) atoms being composed of carbon atoms and one or more, advantageously 1 to 4, more advantageously 1 or 2 heteroatoms, such as nitrogen, oxygen or sulfur atoms, with the remainder being carbon atoms. In particular, it can be an unsaturated ring, such as an unsaturated 5- or 6-membered monocyclic ring. Preferably, it contains 1 or 2, especially 1, nitrogen. Heterocyclic rings include, inter alia, piperidinyl ... piperizinyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, azepanyl, It can be thiazolidinyl, isothiazolidinyl, oxazocanyl, thiazepanyl, benzimidazolonyl, 1,3-benzodioxole.

[0029] The term "aryl" refers to an aromatic hydrocarbon group, preferably containing 6 to 12 carbon atoms and containing one or more fused rings, such as, for example, a phenyl, naphthyl or anthracenyl group. Advantageously, it is a phenyl group.

[0030] The term "heteroaryl" as used in the present invention refers to an aromatic group containing one or several, especially one or two fused hydrocarbon rings, in which one or several, especially one to four, advantageously one or two carbon atoms are each replaced by a heteroatom selected from sulfur, oxygen and nitrogen atoms, preferably oxygen and nitrogen atoms. Preferably, heteroaryl contains 5 to 12 carbon atoms, especially 5 to 10 carbon atoms. It can be furyl, thienyl, pyrrolyl, pyridyl, benzofuranyl, benzopyrrolyl, benzothiohenyl, isobenzofuranyl, isobenzopyrrolyl, isobenzothiophenyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, quinolyl, isoquinolyl, quinoxalyl or indyl.

[0031] In the context of the present invention, "unsaturated" means that the hydrocarbon chain may contain one or more unsaturations, ie double bonds C=C, advantageously one.

[0032] In the context of this invention, an "optionally substituted group" is in particular a group optionally substituted with one or more substituents selected from the following: Halogen C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, Preferably 1 to 3, preferably 1 or 2 C 1 -C 4 Alkyl, halogen or -NO 2 aryl optionally substituted with Oxo, · NR a R b , C.O.R. C , CO 2 R d ,CONR e R f , ORg (In the formula, R a ~R g are, independently of each other, H, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl or aryl, preferably H or C 1 -C 6 Alkyl, C 1 -C 6 Alkyl, C 1 -C 6 haloalkyl or aryl is optionally substituted with aryl or heteroaryl, and aryl or heteroaryl is optionally substituted with -OH; -CN, -NO 2 .

[0033] The substituents may also have 1 to 3, preferably 1 or 2, C 1 -C 4 It may be heteroaryl optionally substituted with alkyl, halogen or -OH.

[0034] R a also includes C optionally substituted with aryl or heteroaryl. 1 -C 6 The heteroaryl may be optionally substituted with -OH. b is H.

[0035] Preferably, an "optionally substituted group" is a group optionally substituted with one or more substituents selected from the following: Halogen C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, Aryl Oxo, · NR a R b , C.O.R. C , CO 2 Rd ,CONR e R f , OR g (In the formula, R a ~R g are, independently of each other, H, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl or aryl, preferably H or C 1 -C 6 Alkyl, C 1 -C 6 Alkyl, C 1 -C 6 haloalkyl or aryl is optionally substituted with aryl or heteroaryl, and aryl or heteroaryl is optionally substituted with -OH; -CN, -NO 2 .

[0036] The term "oxo" refers to a substituent of the formula "C(=O)".

[0037] The term "pharmaceutical composition" means, in the framework of the present invention, a composition that has preventive and curative properties against cancer.

[0038] Compounds of formula (I) The compound of the present invention has the following formula (I):

[0039] [ka] or a pharma- ceutically acceptable salt and / or solvate thereof, During the ceremony, R 1 , R 2 , and R 4 are independently H, 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 7 selected from the group consisting of cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; R 3 is H, 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 Cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted -C(O)OC 1 -C 24 Alkyl, optionally substituted -C(O)OC 2 -C 24 Alkenyl, optionally substituted -C(O)OC 2 -C 24 Alkynyl, -C(O)O-optionally substituted aryl, optionally substituted -C(O)O-heteroaryl, optionally substituted -S(O) 2 -C 1 -C24 alkyl, optionally substituted -S(O) 2 -C 2 -C 24 Alkenyl, optionally substituted -S(O) 2 -C 2 -C 24 Alkynyl, -S(O) 2 -optionally substituted aryl and optionally substituted -S(O) 2 -heteroaryl, where R 1 , R 2 and R 3 At least one of them is not H, X is C 1 -C 12 Alkyl, OC 1 -C 12 Alkyl, C(O), C(O)-C 1 -C 12 Alkyl and NH-C(O)-C 1-C 12 Alkyl is selected from the group consisting of:

[0040] According to certain embodiments, the compound of formula (I) comprises at least one lipophilic group. The term "lipophilic group" (or "hydrophobic group") refers to a chemical group that confers lipophilic properties to the compound of formula (I). Such lipophilic properties may be useful for the identification of the lipophilic properties of biological membranes such as cell membranes, plasma membranes or lysosomes. The lipophilic group is preferably represented by a hydrocarbon group, such as a linear or branched, saturated or unsaturated aliphatic chain, containing at least three carbon atoms, a cycloalkyl or aromatic ring. 2 -C 12 Alkynes, especially C 2 -C 6 It corresponds to an alkyne, in particular a propynyl group.

[0041] According to a preferred embodiment, X is C 1 -C 6 Alkyl, OC 1 -C 6 Alkyl, C(O), C(O)-C 1 -C 6 Alkyl and NH-C(O)-C 1 -C 6 In particular, X is selected from the group consisting of C 1 -C 6 Preferably, X is methyl, ethyl or n-propyl, more preferably ethyl.

[0042] According to a preferred embodiment, R 4 , H, C 1 -C 24 Alkyl, C 2 -C 24 Alkenyl, C 2 -C 24 Alkynyl, C 3 -C 7cycloalkyl and aryl, wherein the alkyl, alkenyl, alkynyl, aryl or cycloalkyl is selected from the group consisting of one or more halogens, C 1 -C 6 Alkyl, aryl, oxo, NH 2 , CO 2 Optionally substituted with H or OH. In particular, R 4 , H, C 1 -C 12 is selected from the group consisting of alkyl and aryl. Preferably, R 4 is H.

[0043] In certain embodiments, R 3 is H, 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 7 It is selected in the group consisting of cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl and optionally substituted heteroaryl.

[0044] In a preferred embodiment, R 1 , R 2 and optionally R 3 are independently H, C 1 -C 24 Alkyl, C 2 -C 24 Alkenyl, C 2 -C 24 Alkynyl, C 3 -C 7 cycloalkyl and aryl, wherein the alkyl, alkenyl, alkynyl, aryl or cycloalkyl is selected from the group consisting of one or more halogens, C 1 -C 6 Alkyl, aryl, oxo, NH 2 , CO 2 Optionally substituted with H or OH, provided that R 1 , R 2and R 3 At least one of R is not H. 1 , R 2 and optionally R 3 are independently H, C 1 -C 12 Alkyl, C 2 -C 12 Alkenyl and C 2 -C 12 alkynyl, wherein the alkyl, alkenyl or alkynyl is selected from the group consisting of one or more halogen, C 1 -C 6 Alkyl, aryl, oxo, NH 2 , CO 2 Optionally substituted with H or OH, provided that R 1 , R 2 and R 3 At least one of R is not H. 1 , R 2 and R 3 are independently H, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl and C 2 -C 6 In particular, R 1 , R 2 and R 3 are independently H and C 2 -C 6 alkynyl.

[0045] According to a particular embodiment, R 1 , R 2 and optionally R 3 is as defined above, where R 1 , R 2 and R 3 At least one of the groups is optionally substituted C 2 -C 12 Alkynyl, preferably one or more halogens, C 1 -C 6 Alkyl, aryl, oxo, NH2, CO 2 C optionally substituted with H or OH2 -C 12 More preferably, R 1 , R 2 and R 3 At least one of the following is C 2 -C 6 It is alkynyl.

[0046] Preferably, R 1 , R 2 and / or R 3 When is alkynyl it is preferably an ethynyl, propynyl or butynyl, especially a propynyl group.

[0047] In certain embodiments, X is CH 2 CH 2 - and R 4 is H and R 1 and R 2 are independently H, C 1 -C 24 Alkyl, C 2 -C 24 Alkenyl, C 2 -C 24 Alkynyl, C 3 -C 7 cycloalkyl and aryl, wherein the alkyl, alkenyl, alkynyl, aryl or cycloalkyl is selected from the group consisting of one or more halogens, C 1 -C 6 Alkyl, aryl, oxo, NH 2 , CO 2 is optionally substituted with H or OH; Preferably, R 1 and R 2 are independently H, optionally substituted C 1 -C 12 Alkyl, C 3 -C 7 Cycloalkyl and propynyl, etc. 2 -C 6 alkynyl.

[0048] In another particular embodiment, X is -CH 2 CH2 - and R 1 and R 4 is H and R 2 is H or C such as propynyl 2 -C 4 Alkynyl, advantageously H.

[0049] In certain embodiments, R 1 and R 2 are independently H, C 1 -C 24 Alkyl, C 2 -C 24 Alkenyl, C 2 -C 24 Alkynyl, C 3 -C 7 cycloalkyl and aryl, wherein the alkyl, alkenyl, alkynyl, aryl or cycloalkyl is selected from the group consisting of one or more halogens, C 1 -C 6 Alkyl, aryl, oxo, NH 2 , CO 2 Optionally substituted with H or OH, provided that R 1 , R 2 and R 3 At least one of R is not H. 1 and R 2 are independently H, C 1 -C 12 Alkyl, C 2 -C 12 Alkenyl and C 2 -C 12 alkynyl, wherein the alkyl, alkenyl or alkynyl is selected from the group consisting of one or more halogen, C 1 -C 6 Alkyl, aryl, oxo, NH 2 , CO 2 Optionally substituted with H or OH. Preferably, R 1 and R 2 are independently H, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl and C 2 -C 6In particular, R 1 and R 2 are independently H and C 2 -C 6 alkynyl. 1 and R 2 is especially H.

[0050] Advantageously, R 3 is an arbitrarily 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 Cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl and optionally substituted heteroaryl, optionally substituted -C(O)OC 1 -C 24 Alkyl, optionally substituted -C(O)OC 2 -C 24 Alkenyl, optionally substituted -C(O)OC 2 -C 24 Alkynyl, -C(O)O-optionally substituted aryl and optionally substituted -C(O)O-heteroaryl, optionally substituted -S(O) 2 -C 1 -C 24 Alkyl, optionally substituted -S(O) 2 -C 2 -C 24 Alkenyl, optionally substituted -S(O) 2 -C 2 -C 24 Alkynyl, -S(O) 2 -optionally substituted aryl and optionally substituted -S(O) 2 -heteroaryl.

[0051] In certain embodiments, R 3 is an arbitrarily substituted C 1 -C 12Alkyl, optionally substituted C 2 -C 12 Alkenyl, optionally substituted C 2 -C 6 Alkynyl, optionally substituted C 3 -C 10 Cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl and optionally substituted heteroaryl, optionally substituted -C(O)OC 1 -C 12 Alkyl, optionally substituted -C(O)OC 2 -C 12 Alkenyl, optionally substituted -C(O)OC 2 -C 6 Alkynyl, -C(O)O-optionally substituted aryl and optionally substituted -C(O)O-heteroaryl, optionally substituted -S(O) 2 -C 1 -C 12 Alkyl, optionally substituted -S(O) 2 -optionally substituted aryl and optionally substituted -S(O) 2 -heteroaryl.

[0052] R 3 may in particular be selected from the group consisting of: Aryl, cycloalkenyl, heteroaryl or NHR a C optionally substituted with 1 -C 12 Alkyl and aryl are 1 to 3, preferably 1 or 2, C 1 -C 4 Alkyl, halogen or -NO 2 and the heteroaryl is optionally substituted with 1 to 3, preferably 1 or 2, C 1 -C 4 optionally substituted with alkyl, halogen or -OH; In the formula, R a H is C 1 -C 6 Alkyl, C 1 -C 6 haloalkyl or aryl, preferably Or H or C 1 -C 6 Alkyl, C 1 -C 6 The alkyl group is optionally substituted with aryl or heteroaryl, the heteroaryl being optionally substituted with -OH; C 2 -C 12 Alkenyl, C 2 -C 6 Alkynyl, preferably C 2 -C 4 Alkynyl, especially propynyl C 3 -C 10 Cycloalkyl, Heterocycloalkyls, especially 1,3-benzodioxoles 1 to 3, preferably 1 or 2 C 1 -C 4 Alkyl, halogen or -NO 2 Aryl optionally substituted with 1 to 3, preferably 1 or 2 C 1 -C 4 Heteroaryl optionally substituted with alkyl and halogen -C(O)OC optionally substituted with aryl, cycloalkenyl or heteroaryl 1 -C 12 Alkyl, or aryl, cycloalkenyl, or heteroaryl, where the heteroaryl or aryl has 1 to 3, preferably 1 or 2, C 1 -C 4 Alkyl, halogen or -NO 2 is optionally replaced by -C(O)OC 2 -C 12 Alkenyl, -C(O)OC 2 -C 6 Alkynyl, 1 to 3, preferably 1 or 2 C 1 -C 4 Alkyl, halogen or -NO 2 optionally substituted with -C(O)O-optionally substituted aryl 1 to 3, preferably 1 or 2 C 1 -C 4 Alkyl, halogen or -NO 2 -C(O)O-heteroaryl optionally substituted with S(O) optionally substituted with aryl, cycloalkenyl or heteroaryl 2 -C 1 -C 12 Alkyl, or aryl, cycloalkenyl, or heteroaryl, where the heteroaryl or aryl has 1 to 3, preferably 1 or 2, C 1 -C 4 Alkyl, halogen or -NO 2 is optionally replaced by 1 to 3, preferably 1 or 2 C 1 -C 4 Alkyl, halogen or -NO 2 -S(O) optionally substituted with 2 -optionally substituted aryl, and 1 to 3, preferably 1 or 2 C 1 -C 4 Alkyl, halogen or -NO 2 -S(O) optionally substituted with 2 -Heteroaryl.

[0053] More specifically, R 3 may be selected from the group consisting of: Aryl, cycloalkenyl or heteroaryl or NHR a C optionally substituted with 1 -C 12 Alkyl and aryl are 1 to 3, preferably 1 or 2, C 1 -C 4 Alkyl, halogen or -NO 2 and the heteroaryl is optionally substituted with 1 to 3, preferably 1 or 2, C 1 -C 4 optionally substituted with alkyl, halogen or -OH; In the formula, R a H is C 1 -C 6Alkyl, C 1 -C 6 Haloalkyl or aryl, preferably H or C 1 -C 6 Alkyl, C 1 -C 6 The alkyl group is optionally substituted with an aryl or heteroaryl group, and the heteroaryl group is optionally substituted with -OH; C 2 -C 12 Alkenyl, C 2 -C 6 Alkynyl, preferably C 2 -C 4 Alkynyl, especially propynyl C 3 -C 10 Cycloalkyl, Heterocycloalkyls, especially 1,3-benzodioxoles -C(O)OC optionally substituted with aryl or heteroaryl 1 -C 12 Alkyl, aryl or heteroaryl, wherein the heteroaryl or aryl has 1 to 3, preferably 1 or 2, C 1 -C 4 Alkyl, halogen or -NO 2 is optionally replaced by -C(O)OC 2 -C 12 Alkenyl, -C(O)OC 2 -C 6 Alkynyl, S(O) optionally substituted with aryl, cycloalkenyl or heteroaryl 2 -C 1 -C 12 Alkyl, or aryl, cycloalkenyl, or heteroaryl, where the heteroaryl or aryl has 1 to 3, preferably 1 or 2, C 1 -C 4 Alkyl, halogen or -NO 2 is optionally replaced by 1 to 3, preferably 1 or 2 C1 -C 4 Alkyl, halogen or -NO 2 -S(O) optionally substituted with 2 -optionally substituted aryl, and 1 to 3, preferably 1 or 2 C 1 -C 4 Alkyl, halogen or -NO 2 -S(O) optionally substituted with 2 -Heteroaryl.

[0054] According to a particular embodiment, R 1 and R 2 are independently H, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl and C 2 -C 6 alkynyl; R 3 is C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl and C 2 -C 6 alkynyl, advantageously R 1 , R 2 and R 3 At least one of the groups is optionally substituted C 2 -C 12 It is alkynyl.

[0055] According to a preferred embodiment, the present invention relates to the following compounds of formula (I):

[0056] [ka]

[0057] According to another embodiment, the compound of formula (I) is:

[0058] [ka]

[0059] [ka]

[0060] Pharmaceutical Compositions The present invention also relates to a pharmaceutical composition comprising at least one compound of formula (I) or a pharma- ceutically acceptable salt and / or solvate thereof and at least one pharma- ceutically acceptable excipient.

[0061] In contrast to serotonin, the compounds of the present invention do not bind the serotonin receptors responsible for the vasoconstrictor and vasodilator properties, and therefore the compounds of formula (I) are injectable.

[0062] Thus, the pharmaceutical compositions of the present invention can be administered orally or parenterally (e.g., subcutaneously, intramuscularly, intravenously, ) administration, preferably intravenous administration. The active ingredient can be mixed with a conventional pharmaceutical carrier and administered in unitary forms for administration to animals, preferably mammals, including humans.

[0063] For oral administration, the pharmaceutical composition may be in solid or liquid (solution or suspension) form.

[0064] The solid composition can be in the form of tablets, gelatin capsules, powders, granules, etc. In tablets, the active ingredient can be mixed with pharmaceutical vehicle(s) such as gelatin, starch, lactose, magnesium stearate, talc, gum arabic, etc., before compression. The tablets may be further coated, inter alia, with sucrose or other suitable materials, or may be treated so that they have extended or delayed activity. In powders or granules, the active ingredient can be mixed or granulated with dispersing agents, wetting agents or suspending agents and flavoring or sweetening agents. In gelatin capsules, the active ingredient can be introduced into soft or hard gelatin capsules in the form of powders or granules as mentioned above, or in the form of liquid compositions as mentioned below.

[0065] The liquid compositions can contain the active ingredient in a solvent such as water, together with a sweetener, a taste enhancer or a suitable colorant. The liquid compositions can also be obtained by suspending or dissolving the powder or granules as described above in a liquid such as water, juice, milk, etc., which can be, for example, a syrup or elixir.

[0066] For parenteral administration, the composition can be in the form of an aqueous suspension or solution, which may contain a suspending agent and / or a wetting agent. The composition is advantageously sterile. It can be in the form of an isotonic solution (especially compared to blood).

[0067] The compounds of the present invention can be used in pharmaceutical compositions in doses ranging from 0.01 mg to 1,000 mg per day, and can be administered in a single dose per day or in several doses throughout the day, for example in equal amounts twice a day. The daily dosage is preferably 5 mg to 500 mg, more preferably 10 mg to 200 mg. However, it may be necessary to use doses outside these ranges, and this can be recognized by those skilled in the art.

[0068] The pharmaceutical composition of the present invention may further comprise an additional therapeutic agent that is particularly useful in the treatment of iron-related disorders such as anemia. Preferably, the therapeutic agent is selected in the group consisting of erythropoietin stimulating agents (ESAs) that activate the erythropoietin receptor and stimulate the bone marrow to make more red blood cells, e.g. recombinant erythropoietin drugs such as luspatercept.

[0069] treatment The compounds of formula (I) or their pharma- ceutically acceptable salts and / or solvates, or pharmaceutical compositions according to the invention are useful as medicaments, especially in the prevention and / or treatment of iron-related disorders.

[0070] The present invention therefore relates to a compound of formula (I) for use as a medicament, in particular for use in the prevention and / or treatment of iron-related disorders. The present invention also relates to a pharmaceutical composition according to the invention for use as a medicament, in particular for use in the prevention and / or treatment of iron-related disorders.

[0071] The present invention also relates to the use of a compound of formula (I) according to the present invention or a pharma- ceutically acceptable salt and / or solvate thereof, or a pharmaceutical composition according to the present invention, for preventing and / or treating iron-related disorders.

[0072] The present invention also relates to a method for preventing and / or treating an iron-related disorder, comprising administering to a patient in need thereof an effective amount of a compound of formula (I) according to the present invention or a pharma- ceutically acceptable salt and / or solvate thereof, or a pharmaceutical composition according to the present invention.

[0073] According to a preferred embodiment, the iron overload related disorder is an iron overload related disorder selected from among HFE-associated hematochromatosis, non-HFE-associated hematochromatosis, congenital atransferrinemia, iron overload related anemia, chronic liver disease, chronic inflammation associated with cancer, autoimmune or inflammatory diseases, neurodegeneration with brain iron accumulation related diseases and polygenic neurodegeneration related diseases, among others.

[0074] HFE-associated hematochromatosis may be due to, inter alia, C282Y homozygosity or C282 / H63D heterozygosity. Non-HFE-associated hematochromatosis may include, for example, juvenile hemochromatosis type 2A or type 2B, or may be due to mutant transferrin receptor 2 or mutant ferroportin 1 genes.

[0075] Neurodegeneration associated with brain iron accumulation-related disorders includes aceruloplasminemia, neuroferritinopathy, pantothenate kinase-associated neurodegeneration, Wilson's disease, and beta propeller protein-associated neurodegeneration (BPAN).

[0076] Polygenic neurodegenerative disorders include Parkinson's disease and Alzheimer's disease. In particular, iron overload-related disorders are thalassemia, myelodysplasia, aplastic anemia, Blackfan-Diamond anemia, congenital hematopoietic anemia, chronic hematopoietic anemia, especially sickle cell disease, hematopoietic stem cell transplant-related disorders, and iron-loading-related anemias such as chronic liver disease, including viral hepatitis, alcoholic hepatitis, steatohepatitis (NASH), and metabolic iron overload syndrome.

[0077] In certain embodiments, the iron-loading associated anemia is thalassemia, myelodysplasia or hematopoietic stem cell transplantation associated disorder.

[0078] Process for the preparation of compounds of formula (I) The compounds of the present invention may be prepared according to any method known to those skilled in the art. In particular, they may be prepared by the following methods:

[0079] The process for preparing the compounds of formula (I) according to the present invention comprises the steps of: (i) reacting serotonin chloride with a base; (ii) R 1 , R 2 and / or R 3 If is different from H, the resulting serotonin is R 1 radical precursor, R 2 Group Precursor and / or R 3 The method includes reacting the compound with a radical precursor.

[0080] R n The group precursor (n is 1, 2 or 3) in the context of the present invention reacts with deprotonated serotonin to form an R n is understood as a compound into which a group can be inserted to obtain a compound of formula (I).

[0081] In the first embodiment, in particular, R 1 , and / or R 2 , and / or R 3When is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, or optionally substituted cycloalkyl, the method of preparing compounds of formula (I) may be described as "nucleophilic substitution".

[0082] Typically, the precursor is a halide, particularly a bromide or chloride, a mesylate, a tosylate, R attached to a leaving group such as a sulfonate ester such as a phosphate or triflate n Contains a group.

[0083] In step (i), serotonin chloride is typically dissolved in a solvent, especially tetrahydrofuran (THF), diethyl ether (Et 2 The compound is dissolved in a non-polar aprotic solvent, including, but not limited to, dimethyl ether (DME), dichloromethane, hexane, 1-4-dioxane, toluene, and chloroform, or a polar aprotic solvent, such as acetonitrile, pyridine, acetone, DMSO, or acetic anhydride.

[0084] According to a particular embodiment, the base is Na 2 CO 3 , K 2 CO 3 , NaOH, KOH, Ca(OH) 2 , Ba(OH) 2 , NaH, KH or LiOH, in particular NaH.

[0085] In step (ii), R 1 , R 2 or R 3 is H, serotonin is R 1 Group, R 2 Group or R 3 does not react with the corresponding precursor of the group.

[0086] The reaction typically involves the reaction of nitrogen (N 2 ) or argon (Ar) atmosphere.

[0087] Optionally, additional steps of protection / deprotection and / or functionalization well known to those skilled in the art may be carried out before step (i) to protect positions that should not react. For example, the primary amine of serotonin may be protected by an OR of the OH group. 1 The group may be protected to allow selective conversion to a group.

[0088] The compound obtained can be separated from the reaction medium by methods well known to those skilled in the art, for example by extraction, evaporation of the solvent or by precipitation or crystallization followed by filtration.

[0089] The compounds can also be purified, if necessary, by methods well known to those skilled in the art, such as recrystallization, distillation, chromatography on a column of silica gel, or high performance liquid chromatography (HPLC).

[0090] In a second embodiment, in particular, R 1 , and / or R 2 , and / or R 3 When is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, or optionally substituted cycloalkyl, the method of preparing compounds of formula (I) may also be described as a reductive amination sequence.

[0091] In this case, the Rn group is an aldehyde or ketone.

[0092] In step (i), serotonin chloride is typically dissolved in a solvent, particularly C 1 -C 6 It is dissolved in alcoholic solvents such as alcohol. 1 -C 6 "Alcohol" refers to a linear or branched monovalent saturated hydrocarbon chain containing x to y carbon atoms and substituted with at least one OH group. 1 -C 6 Examples of alcohols include, but are not limited to, methanol, ethanol, and isopropanol, and preferably, methanol.

[0093] According to a particular embodiment, the base has the formula N(C 1 -C 6 Alkyl) 3 Or N(C 1 -C 6 Alkyl) 2 (OC 1 -C 6 alkyl)amines, especially triethylamine.

[0094] In this embodiment, the method comprises providing a hydride reducing agent suitable for reducing the imine or imine aldehyde, such as NaBH 4 or NaBH 3 The method further comprises the step (ii) of adding to the amine, such as CN.

[0095] Optionally, additional steps of protection / deprotection and / or functionalization well known to those skilled in the art may be carried out before step (i) to protect positions that should not react. For example, the primary amine of serotonin may be protected by an OR of the OH group. 1 The group may be protected to allow selective conversion to a group.

[0096] In the third embodiment, in particular R 1 and / or R 2 and / or R 3 is optionally substituted -C(O)OC 1 -C 24 Alkyl, optionally substituted -C(O)OC 2 -C 24 Alkenyl, optionally substituted -C(O)OC 2 -C 24 When the Rn group is an optionally substituted aryl, an optionally substituted -C(O)O-heteroaryl, each Rn group is an optionally substituted C(O)O-alkynyl, -C(O)O-optionally substituted aryl, or optionally substituted -C(O)O-heteroaryl. 1 -C 24 Alkyl chloroformates, optionally substituted C 2 -C 24 Alkenyl chloroformates, optionally substituted C 2 -C 24Chloroformates such as alkynyl chloroformates, optionally substituted aryl chloroformates, and optionally substituted heteroaryl chloroformates.

[0097] The other features are as described in the first embodiment of the method.

[0098] In the third embodiment, in particular R 1 and / or R 2 and / or R 3 , optionally substituted -S(O) 2 -C 1 -C 24 Alkyl, optionally substituted -S(O) 2 -C 2 -C 24 Alkenyl, optionally substituted -S(O) 2 -C 2 -C 24 Alkynyl, -S(O) 2 -optionally substituted aryl and optionally substituted -S(O) 2 -heteroaryl, each R group is typically an optionally substituted C 1 -C 24 Alkyl sulfonyl chlorides, optionally substituted C 2 -C 24 Alkenylsulfonyl chlorides, optionally substituted C 2 -C 24 Alkynylsulfonyl chlorides, optionally substituted arylsulfonyl chlorides, and optionally substituted heteroarylsulfonyl chlorides.

[0099] Other features are as described in the first embodiment of the method. A preferred base is tri(C 1 -C 6 ) an alkylamine, such as triethylamine, and the preferred non-polar aprotic solvent is dichloromethane. [Brief description of the drawings]

[0100] [Figure 1-1]Erythropoiesis and iron overload in model 1 (HbbTh1 / th1 mice). Evolution from days 1 to 5 of the number of erythrocytes (A), the percentage of hemoglobin (B), the hematocrit content (C), the splenic iron content (D, left) and the bone marrow iron content (D, right) in HbbTh1 / th1 mice untreated or treated with either Derivative A1 or Derivative A3. [Figure 1-2] Erythropoiesis and iron overload in model 1 (HbbTh1 / th1 mice). Evolution from days 1 to 5 of the number of erythrocytes (A), the percentage of hemoglobin (B), the hematocrit content (C), the splenic iron content (D, left) and the bone marrow iron content (D, right) in HbbTh1 / th1 mice untreated or treated with either Derivative A1 or Derivative A3. [Figure 2-1] Erythropoiesis and iron overload in model 2 (Tph1 KO mice). Evolution from day 1 to day 5 of erythrocyte count (A), hemoglobin percentage (B), hematocrit content (C), heme content in erythrocytes (D), mean cell volume (MCV) (E), splenic iron content (F) and bone marrow iron content (G) in Tph1 KO mice either untreated or treated with either serotonin (5-HT), derivative A3 or derivative A4. [Figure 2-2] Erythropoiesis and iron overload in model 2 (Tph1 KO mice). Evolution from day 1 to day 5 of erythrocyte count (A), hemoglobin percentage (B), hematocrit content (C), heme content in erythrocytes (D), mean cell volume (MCV) (E), splenic iron content (F) and bone marrow iron content (G) in Tph1 KO mice either untreated or treated with either serotonin (5-HT), derivative A3 or derivative A4. [Figure 2-3] Erythropoiesis and iron overload in model 2 (Tph1 KO mice). Evolution from day 1 to day 5 of erythrocyte count (A), hemoglobin percentage (B), hematocrit content (C), heme content in erythrocytes (D), mean cell volume (MCV) (E), splenic iron content (F) and bone marrow iron content (G) in Tph1 KO mice either untreated or treated with either serotonin (5-HT), derivative A3 or derivative A4. [Diagram 3]Iron overload in model 3 (Hamp KO). Measurement of blood iron content (A) and transferrin saturation (%) (C) after 5 days in untreated or serotonin-treated Hamp KO mice. Measurement of iron content in liver (B) after 5 days in untreated or A3-derivative-treated Hamp KO mice. [Figure 4-1] FACS (fluorescence-activated single cell sorting) for model 1 (HbbTh1 / th1 mice). Results obtained on day 13 in HbbTh1 / th1 mice treated with A3 and in HbbTh1 / th1 mice treated with PBS. A: Representative flow cytometry analysis of bone marrow erythroblast subset distribution in HbbTh1 / Th1 mice + / - A3, B: Cumulative representation of bone marrow erythroblast differentiation in HbbTh1 / Th1 mice + / - A3 after 13 days of treatment, C: Subpopulations of bone marrow erythroblast differentiation in HbbTh1 / Th1 mice + / - A3 after 13 days of treatment. [Figure 4-2] FACS (fluorescence-activated single cell sorting) for model 1 (HbbTh1 / th1 mice). Results obtained on day 13 in HbbTh1 / th1 mice treated with A3 and in HbbTh1 / th1 mice treated with PBS. A: Representative flow cytometry analysis of bone marrow erythroblast subset distribution in HbbTh1 / Th1 mice + / - A3, B: Cumulative representation of bone marrow erythroblast differentiation in HbbTh1 / Th1 mice + / - A3 after 13 days of treatment, C: Subpopulations of bone marrow erythroblast differentiation in HbbTh1 / Th1 mice + / - A3 after 13 days of treatment. [Figure 5-1]Red blood cell (RBC) production and iron overload in model 1 (HbbTh1 / th1 mice). A: RBCs on day 13 in HbbTh1 / th1 mice treated with A3 and HbbTh1 / th1 mice treated with PBS at different cell differentiation stages. B: Total body iron content on day 13 in HbbTh1 / th1 mice treated with A3 and HbbTh1 / th1 mice treated with PBS. C: RBCs and total iron content in HbbTh1 / th1 mice treated with A3 and HbbTh1 / th1 mice treated with PBS. D: Ferritin levels on day 13 in HbbTh1 / th1 mice treated with A3 and HbbTh1 / th1 mice treated with PBS. [Figure 5-2] Red blood cell (RBC) production and iron overload in model 1 (HbbTh1 / th1 mice). A: RBCs on day 13 in HbbTh1 / th1 mice treated with A3 and HbbTh1 / th1 mice treated with PBS at different cell differentiation stages. B: Total body iron content on day 13 in HbbTh1 / th1 mice treated with A3 and HbbTh1 / th1 mice treated with PBS. C: RBCs and total iron content in HbbTh1 / th1 mice treated with A3 and HbbTh1 / th1 mice treated with PBS. D: Ferritin levels on day 13 in HbbTh1 / th1 mice treated with A3 and HbbTh1 / th1 mice treated with PBS. [Figure 6] Iron content in the body, plasma, duodenum, liver, spleen, bone marrow (BM), kidney and pancreas in Tph1 KO and wild-type mice. [Figure 7-1] A: Distribution of body iron content in Tph1 KO mice, wild-type mice, and A3-treated Tph1 KO mice on day 5. B: Distribution of body iron content in PBS-treated and A3-treated Tph1 KO mice on day 21. C: FACS results and ferritin levels in bone marrow (BM) in A3-treated and PBS-treated Tph1 KO mice on day 21. [Figure 7-2]A: Distribution of body iron content in Tph1 KO mice, wild-type mice, and A3-treated Tph1 KO mice on day 5. B: Distribution of body iron content in PBS-treated and A3-treated Tph1 KO mice on day 21. C: FACS results and ferritin levels in bone marrow (BM) in A3-treated and PBS-treated Tph1 KO mice on day 21. [Figure 8] A: 5-HT levels in β-thalassemia patients, B: iron levels in β-thalassemia patients. C: 5-HT levels in blood from 15 MDS patients vs. control individuals (n=14). D: FACS analysis in cells from β-thalassemia patients treated with A3. [Figure 9] A: Western blot analysis of skin fibroblasts from FA / BPAN patients treated with 100uM ferric ammonium citrate (FAC) or placebo + / - A3. B: Western blot analysis of skin fibroblasts from FA / BPAN patients treated with 100uM ferric ammonium citrate (FAC) or placebo + / - A3. [Figure 10] Western blot analysis of skin fibroblasts from BPAN patients treated with 100 uM ferric ammonium citrate (FAC) + / - 5A1, A3 or A4. [Figure 11] Western blot analysis of skin fibroblasts from FA / BPAN patients treated with 100 uM ferric ammonium citrate (FAC) or placebo + / - A3, B1 (=LYS12), B2 (=LYS29), B3 (=LYS9), or B4 (=LYS9a). EXAMPLES

[0101] 1.Synthesis Materials and Methods All solvents and chemicals were purchased from commercial sources and used without further purification or were collected by Purification of Laboratory Chemicals (Armarego, WLF; Chai, CLL5). thThe reaction was purified according to the procedure of the 1990s Ed. Solvents were dried under standard conditions. The reaction was run on precoated silica (60F) on aluminium plates from Merck. 254 Reactions were monitored by thin layer chromatography (TLC) using a 500 s counterscrew. TLC plates were visualized with UV light and / or by treatment with ceric ammonium molybdate solution (CAM) and heating. Products were purified by column chromatography with Macherey Nagel silica gel 60 (0.036-0.071 mm; 215-400 mesh), a CombiFlash Rf+Teledyne Isco system equipped with a prepacked silica gel column (Interchim), or / and a preparative HPLC Quaternary Gradient 2545 equipped with a photodiode array detector (Waters) equipped with a reversed-phase column (XBridge Prep C18 5 μm OBD, 30 × 150 mm).

[0102] NMR spectroscopy was performed on a Bruker spectrometer. Spectra were analyzed in DMSO-d 6 Or D 2 O or CD 3 The experiment was carried out at 298 K during OD. 1 H NMR was recorded at 400 or 500 MHz, chemical shifts δ are expressed in ppm using residual non-deuterated solvent signals as internal standard, and coupling constants J are specified in Hz. The following abbreviations are used: s, singlet; brs, broad singlet; d, doublet; dd, doublet of doublet; dt, triplet of triplet; dq, quartet of doublet; ddd, doublet of doublet of doublet; dqd, doublet of quartet of doublet; t, triplet; td, doublet of triplet; tdd, doublet of doublet of triplet; q, quartet; m, multiplet. We reported only labile protons that could be clearly identified in the spectra. 13 C NMR was recorded at 101 or 126 MHz and chemical shifts δ are expressed in ppm using the deuterated solvent signal as internal standard.

[0103] The purity of the final compounds, determined to be >95% by UPLC MS, was recorded on a Waters Acquity H class equipped with a photodiode array detector and an SQ detector 2 with a reversed phase column (Aquity UPLC® BEH C18 1.7 pm, 2.1×50 mm).

[0104] "Classical system": ACN (+0.1% FA) and MilliQ water (+0.1% FA): isocratic at 5% ACN (0.2 min), then a linear gradient from 5% to 100% ACN in 2.3 min, then isocratic at 100% ACN (0.5 min).

[0105] UPLC system: Column: Aquity UPLC® BEH C18 1.7 pm, 2.1×50 mm.

[0106] System: ACN (+0.1% FA) and MilliQ water (+0.1% FA): isocratic at 5% ACN (0.2 min), then a linear gradient from 5% to 100% ACN in 2.3 min, then isocratic at 100% ACN (0.5 min).

[0107] Abbreviation ACN, acetonitrile; AcOH, glacial acetic acid; aq., aqueous; Boc20, di-tert-butyl dicarbonate; DCM, dichloromethane; equiv., equivalent; ESI, electrospray ionization; EtOAc, ethyl acetate; EtOH, ethanol; Et20, diethyl ether; Et3N, trimethylamine; FA, formic acid; HPLC, high pressure 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, TLC, thin layer chromatography; UPLC, ultra performance liquid chromatography; UV, ultraviolet.

[0108] Synthesis and characterization Synthetic Procedure for A1, A3 and A4: Serotonin chloride (100 mg, 0.470 mmol, 1 equiv) was dissolved in THF (5 mL) under an inert atmosphere. NaH (36 mg, 0.893 mmol, 1.9 equiv) was added to the mixture. The mixture was stirred for 30 min, then propargyl bromide (57 μL, 0.517 mmol, 1.1 equiv) was added. The mixture was stirred for 3.5 h, 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 (99 / 1 to 80 / 20) as eluent. Four fractions were obtained and purified by preparative HPLC to give compounds A1, A3, and A4 after lyophilization.

[0109] Characterization: Derivative A1 (N-(prop-2-yn-1-yl)-N-(2-(5-(prop-2-yn-1-yloxy)-1H-indol-3-yl)ethyl)prop-2-yn-1-amine):

[0110] [ka]

[0111] UPLC:R T :1.88 1 HNMR(DMSO-d6,500MHz):10.65(1H,s);7.24(1H,d,J9.1Hz);7.11(2H,d,J18.3Hz);6.76(1H,dd,J8.7 5&1.75Hz);4.75(2H,d,J1.7Hz);3.50(1H,bt);3.46(4H,bd);3.17(2H,bs);2.76(4H,bd,J10.45Hz).

[0112] 13 C NMR (DMSO-d6,125MHz):151.3;132.3;127.8;123.9;112.4(2C);112.0;102.7;80.5;79.7(2C);78.1;76.0(2C);56.6;53.5;42.0(2C);23.4.

[0113] Derivative A3 (formate) (N-(2-(5-hydroxy-1H-indol-3-yl)ethyl)prop-2-yn-1-aminium formate):

[0114] [ka]

[0115] UPLC:R T :0.80-1.00 1 HNMR(DMSO-d6,500MHz):10.51(1H,s);8.31(1H,s(FA));7.13(1H,d,J8.55Hz);7.05(1H,s);6.82(1H,s);6 .60(1H,dd,J1.75&8.5Hz);3.50(1H,d,J1.65Hz);3.19(1H,s);2.91(2H,t,J7.15Hz);2.78(2H,t,J7.45Hz).

[0116] 13 C NMR (DMSO-d6, 125MHz): 164.6; 150.6; 131.3; 128.3; 123.6; 112.1; 111.7; 111.2; 102.7; 81.7; 75.3; 48.5; 37.3; 24.9.

[0117] Derivative A4 (3-(2-(di(prop-2-yn-1-yl)amino)ethyl)-1H-indol-5-ol):

[0118] [ka]

[0119] UPLC:R T :1.42 1 HNMR(DMSO-d6,500MHz):10.46(1H,s);8.58(1H,bs(OH));7.11(1H,d,J8.5Hz);7.04(1H,s); 6.82(1H,s);6.60(1H,dd,J1.1&8.4Hz);3.45(4H,bs);3.17(2H,bs);2.73(4H,bs). (+FA trace)

[0120] 13 C NMR (DMSO-d6, 125 MHz): 150.6; 131.2; 128.3; 123.4; 112.1; 111.7; 111.6; 102.7; 79.7 (2C); 76.1 (2C); 53.5; 42.0 (2C); 23.6. (+FA trace 163.9)

[0121] Synthesis of A2: Serotonin chloride (500 mg, 2.35 mmol, 1 equiv.) was dissolved in water (9 mL). 2 CO 3 (665 mg, 4.81 mmol, 2.1 equiv.) and BOC 2 0 (538 mg, 2.46 mmol, 1.05 equiv) was added to the solution. The solution was stirred overnight and then extracted with DCM. The organic phase was washed with HCl 5% and brine, then dried over MgSO4 and concentrated. The crude product was purified by flash chromatography using DCM / MeOH (100 / 0 to 90 / 10) as eluent to give the desired product (485 mg), which was used in the next step.

[0122] Under an inert atmosphere, the product from the previous step (485 mg, 1.75 mmol, 1 equiv.) was dissolved in dry acetonitrile (5 mL). 2 CO 3 (435 mg, 3.15 mmol, 1.8 equiv.) and propargyl bromide (235 μL, 2.1 mmol, 1.2 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 (90 / 10 to 0 / 100) as eluent.

[0123] The product was then dissolved in 1M HCl in EtOAc (10 mL) and stirred for 2 h until the product predominated in UPLC analysis. The mixture was then concentrated and the crude product was directly purified by preparative HPLC to give the desired product after lyophilization.

[0124] Compound A2 (formate) (2-(5-(prop-2-yn-1-yloxy)-1H-indol-3-yl)ethanaminium formate):

[0125] [ka]

[0126] UPLC:R T :1.57 1 HNMR(DMSO-d6,500MHz):10.82(1H,s);8.45(1H,s)7.26(1H,d,J8Hz);7.18(1H,d,J2.1Hz);7.13( 1H,d,J2.1Hz);6.78(1H,dd,J8.5&2.3Hz);4.77(2H,d,J1.8Hz);3.51(1H,t,J2.3Hz);2.94(4H,m)

[0127] 1- Synthesis by Nucleophilic Substitution 1-1- Procedure for NH-monoalkylated compounds In the dark and under an inert atmosphere, serotonin chloride (200 mg, 0.940 mmol, 1 equiv.) was dissolved in THF (10 mL). NaH (45 mg, 1.128 mmol, 1.2 equiv.) was added to the mixture. The mixture was stirred for 30 min, then alkyl bromide (0.6 equiv.) was added. The mixture was stirred for 3.5 h, then quenched with water. The resulting solution was extracted with DCM and MgSO 4 The crude product was purified by flash chromatography using DCM / MeOH (100 / 0 to 80 / 20) as eluent and by preparative HPLC to obtain the desired product after lyophilization. The compound obtained is the formate salt. A3(LYS3)

[0128] [ka]

[0129] 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. Strains that stain green with CAM; UPLC: RT: 0.8-1.0 (classical system); MS (ESI + ) m / z [M+H] + C 13 H 15 N 2 O + Calculated value: 215.11; measured value: 215.22.

[0130] LYS6

[0131] [ka]

[0132] Yield: 43 mg, 19%. Isolated as a light gray powder with purity >95% by NMR and a single spot by TLC; R f :DCM / MeOH / Et 3 N, 0.5 in 95 / 5 / 2. Strains staining green with CAM; 1 HNMR(CD 3 OD,400MHz):ppm=7.16(1H,d,J=8.4Hz);7.00(1H,s,);6.92(1H,d,J=2.1Hz);6.67( 1H,dd,J=2.3Hz,J=8.4Hz);5.21(1H,m);3.23(2H,d,J=7.2Hz);2.89(4H,s);1.71(3H,brs);1.62(3H,brs).

[0133] 13 C NMR (CD 3OD,101MHz):□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:RT:1.45 (classical system) MS(ESI + ) m / z [M+H] + C 15 H 21 N 2 O + Calculated value: 245.16; measured value: 245.17.

[0134] LYS7

[0135] [ka]

[0136] Yield: 124 mg, 37%. Isolated as an orange powder with purity >95% by NMR and a single spot by TLC; f : 0.48 in DCM / MeOH, 90 / 10. Strains that stain green with CAM; 1 HNMR(DMSO-d6,400MHz): □□ppm=10.43(1H,brs);8.68(1H,t,J=2.2Hz);8.60(2H,d,J=2.1Hz);8.51(1H,s);7.08(1H,d,J=8.5Hz); 7.01(1H,d,J=2.5Hz);6.74(1H,d,J=2.2Hz);6.55(1H,dd,J=2.3Hz,J=8.6Hz);3.98(2H,s);2.77(4H,m).

[0137] 13 C NMR (DMSO-d6,101MHz):□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.

[0138] UPLC:R T:1.48 (classical system)

[0139] MS(ESI + ) m / z [M+H] + C 17 H 17 N 4 O 5 + Calculated value: 357.11; measured value: 357.13.

[0140] 1-2- Procedure for polyalkylated compounds Serotonin chloride (500 mg, 2.35 mmol, 1 equiv.) was dissolved in THF (25 mL) in the dark and under an inert atmosphere. NaH (188 mg, 2 equiv.) was added to the mixture. The mixture was stirred for 30 min, then propargyl bromide (524 μL, 2 equiv.) was added. The mixture was stirred for 4 h, then quenched with water. The resulting solution The solution was extracted with DCM and MgSO 4 The crude product was purified by flash chromatography using DCM / MeOH (99 / 1 to 80 / 20) as eluent. Three fractions were obtained and purified by preparative HPLC to give three products after lyophilization.

[0141] A1(LYS1):

[0142] [ka]

[0143] Yield: 5.5 mg, 0.8%. Isolated as a light gray powder with purity >95% by NMR and a single spot by TLC; R f : 0.71 in DCM / MeOH, 95 / 5. Strains that stain green with CAM;

[0144] A3(LYS3):(Formate):

[0145] [ka]

[0146] 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 that stain green with CAM;

[0147] A4(LYS4)

[0148] [ka]

[0149] Yield: 57 mg, 10%. Isolated as a light grey powder with purity >95% by NMR and a single spot by TLC; Rf: 0.43 in DCM / MeOH, 95 / 5. Strain stains green with CAM;

[0150] Procedure for 1-3-O-alkylated compounds: Serotonin chloride (500 mg, 2.35 mmol, 1 equiv.) was dissolved in water (9 mL) in the dark. 2 CO 3 (665mg, 4.81mmol, 2.1equiv.) and B0C 2 KOH (538 mg, 2.46 mmol, 1.05 equiv.) was added to the solution. The solution was stirred overnight and then extracted with DCM. The organic phase was washed with aq. HCl 5% and brine, then dried over MgSO4 and concentrated. The crude product was purified by flash chromatography using DCM / MeOH (100 / 0 to 90 / 10) as eluent to give the desired product (485 mg), which was used in the next step. In the dark and under inert atmosphere, the product from the previous step (138 mg, 0.5 mmol, 1 equiv.) was dissolved in dry acetonitrile (4 mL). 2 CO 3(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 (90 / 10 to 0 / 100) as eluent.

[0151] The product was then separated into CH 2 CI 2 / TFA, 4 / 1 (4 mL) and stirred for 2 h until the product predominated in UPLC analysis. The mixture was then concentrated and the crude product was directly purified by preparative HPLC to give the desired product after lyophilization.

[0152] A2(LYS2)(Formate):

[0153] [ka]

[0154] Yield: 53 mg, 49%. Isolated as a light gray powder with purity >95% by NMR and a single spot by TLC; R f :DCM / MeOH / Et 3 N,90 / 10 / 2, 0 .38. Green stocks using CAM

[0155] Procedure for 1-4-Carbamate esters: Serotonin chloride (213 mg, 1 mmol) was dissolved in DCM / H 2 Dissolved in 1 / 2 (3.33 / 6.66 mL) of Na 2 CO 3 (223 mg, 2.1 mmol, 2.1 equiv.) was added to the mixture. The mixture was stirred for 30 min, then alkyl chloroformate (1 equiv.) was added. The mixture was stirred for 6 h, then quenched with water. The resulting solution was extracted with DCM and MgSO 4It was dried at 40° C. and concentrated. The crude product was purified by flash chromatography using DCM / MeOH (100 / 0 to 80 / 20) as eluent.

[0156] LYS8

[0157] [ka]

[0158] Yield: 217 mg, 84%. Isolated as a pale yellow oil, >95% pure by NMR, single spot by TLC; R f : 0.53 in DCM / MeOH, 98 / 2. Strains that stain green with CAM; 1 HNMR(CD 3 OD,400MHz):ppm=7.15(1H,d,J=8.6Hz);6.99(1H,s,);6.93(1H,d,J=2.1Hz);6.66(1 H,dd,J=2.3Hz,J=8.6Hz);4.64(2H,d,J=2.4Hz);3.36(2H,t,J=7.4Hz);2.85(3H,m).

[0159] MS(ESI + ) m / z [M+H] + C 14 H 15 N 2 O + Calculated value: 259.10; measured value: 259.18.

[0160] Compounds LYS9 and LYS9a were obtained using the same protocol.

[0161] LYS9

[0162] [ka]

[0163] Yield: 217 mg, 84%. Purity >95% by NMR, single spot by TLC. Isolated as a pale yellow oil; f : 0.53 in DCM / MeOH, 98 / 2. Strains that stain green with CAM; 1 HNMR(CD 3 OD,400MHz):dppm=7.15(1H,d,J=8.6Hz);6.99(1H,s,);6.93(1H,d,J=2.1Hz);6.66( 1H,dd,J=2.3Hz,J=8.6Hz);4.64(2H,d,J=2.4Hz);3.36(2H,t,J=7.4Hz);2.85(3H,m).

[0164] 13 C NMR (CD 3 OD,101MHz):d ppm=158.0;151.1;133.1;129.4;124.2;112.6;112.3(2C);103.5;79.6;75.6;53.0;42.7;26.8.

[0165] UPLC:R T :1.74 (classical system) MS(ESP)m / z[M+H] + C 14 H 15 N 2 O + Calculated value: 259.10; measured value: 259.18.

[0166] LYS9a

[0167] [ka]

[0168] Yield: 485 mg, 74%. Isolated as a pale yellow powder with purity >95% by NMR and a single spot by TLC; f : 0.44 in DCM / MeOH, 90 / 10. Strains that stain green with CAM; 1 HNMR(CDCl 3,500MHz):6ppm=7.94(1H,brs);7.24(1H,d,J=8.6Hz);7.04(2H,m);6.81(1H,dd,J=2.3Hz, J=8.6Hz);5.04(1H,brs);4.67(1H,brs);3.46(2H,m);2.90(2H,t,J=6.7Hz);1.46(9H,s).

[0169] UPLC:R T :1.99 (classical system) MS(ESI + ) m / z [M+H] + C 15 H 21 N 2 O 3 + Calculated value: 277.15; measured value: 277.10.

[0170] Procedure for 1-5-sulfonamides: In the dark, serotonin chloride (200 mg, 0.94 mmol) was dissolved in DCM (9 mL). Triethylamine (210 μL, 1.5 mmol, 1.6 equiv.) was added to the mixture. The mixture was stirred for 30 min, then methanesulfonyl chloride (43 μL, 0.56 mmol, 0.6 equiv.) was added slowly. The mixture was stirred for 18 h, then quenched with water. The resulting solution was extracted with DCM and MgSO 4 The mixture was dried at 40° C. and concentrated. The crude was purified by flash chromatography using n-hexane / EtOAc (20 / 80 to 0 / 100) as eluent. Compound LYS11 was obtained as a white solid in 7% yield (15 mg).

[0171] LYS11

[0172] [ka]

[0173] 2- Synthesis by reductive amination. 2-1- Procedure from ketones (monosubstituted analogues):

[0174] [ka]

[0175] Serotonin chloride (213 mg, 1 mmol) was dissolved in dry MeOH (10 mL) in the dark and under an inert atmosphere. 3 N (153 μL, 1.1 equiv.) was added to the mixture. The mixture was stirred at RT for 30 min, then the corresponding ketone (1.1 equiv.) was added. The mixture was stirred overnight, then NaBH 3 CN (1.1 equiv.) was added. The reaction mixture was stirred at RT for another 60 min. The solvent was then evaporated under reduced pressure. The crude product was dissolved in Et 2 0 / water, 1 / 1 (10 / 10 mL), and the resulting solution was alkalized with NaOH [2 M] until pH = 10, then added with Et 2 The organic phase was extracted with O (2×20 mL) and then with DCM (1×20 mL). 4 The crude product was purified by elution with DCM / MeOH / Et 3 Purification was performed by flash chromatography using N (100 / 0 / 2 to 80 / 20 / 2).

[0176] LYS12

[0177] [ka]

[0178] Yield: 39 mg, 17%. Isolated as a light gray powder with purity >95% by NMR and a single spot by TLC; R f :DCM / MeOH / Et 3 N,90 / 10 / 2, 0 .68. Strains that stain green with CAM; 1 HNMR(CD 3OD,500MHz):ppm=8.55(1H,s,(FA));7.19(1H,d,J=8.7Hz);7.10(1H,s,);6.92(1H,d,J=2.1Hz);6.70(1H,dd,J=2.1Hz,J= 8.7Hz);3.73(1H,quint;,J=8.1Hz);3.14(2H,t,J=7.4Hz);3.04(2H,t,J=7.4Hz);2.30(2H,m);2.17(2H,m);1.89(2H,m).

[0179] UPLC:R T : 1.21 (classical system); MS (ESI + ) m / z [M+H] + C 14 H 19 N 2 O + Calculated value 231.14; measured value 231.17.

[0180] LYS13

[0181] [ka]

[0182] 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 / Et 3 N, 0.51 in 95 / 5 / 2. Strains staining green with CAM; 1 HNMR(CD 3 OD,500MHz):ppm=8.53(1H,s,(FA));7.19(1H,d,J=8.6Hz);7.11(1H,s,);6.93(1H,d,J=2.2Hz);6.70(1H,dd,J=2.1Hz,J= 8.7Hz);3.55(1H,quint.,J=7.2Hz);3.25(2H,t,J=7.5Hz);3.07(2H,t,J=7.5Hz);2.10(2H,m);1.80(2H,m);1.64(4H,m).

[0183] UPLC:RT : 1.34 (classical system); MS (ESI + ) m / z [M+H] + C 15 H 21 N 2 O + Calculated value: 245.16; measured value: 245.10.

[0184] LYS14

[0185] [ka]

[0186] Yield: 253 mg, 98%. Isolated as a light gray powder with purity >95% by NMR and a single spot by TLC; R f :DCM / MeOH / Et 3 N, 0.53 in 95 / 5 / 2. Strains staining green with CAM; 1 HNMR(CD 3 OD,400MHz):ppm=7.16(1H,d,J=8Hz);7.01(1H,s,);6.93(1H,d,J=4Hz);6.67(1H,dd,J=4 Hz,J=8Hz);2.90(4H,m);2.50(1H,m);1.90(2H,m);1.73(2H,m);1.63(1H,m);1.21(5H,m).

[0187] UPLC:R T : 1.46 (classical system); MS (ESI + ) m / z [M+H] + C 16 H 23 N 2 O + Calculated value: 259.17; measured value: 259.24.

[0188] LYS15

[0189] [ka]

[0190] Yield: 120 mg, 44%. Isolated as a light gray powder with purity >95% by NMR and a single spot by TLC; R f :DCM / MeOH / Et 3 N, 0.43 in 95 / 5 / 2. Strains staining green with CMA; 1 HNMR(CD 3 OD,400MHz):ppm=7.17(1H,d,J=8,6Hz);7.02(1H,s,);6.93(1H,d,J=2.5Hz);6.67(1H,d d,J=2.4Hz,J=8.6Hz);2.91(4H,m);2.71(1H,m);1.89-1.80(2H,m);1.71-1.32(10H,m).

[0191] UPLC:R T : 1.57 (classical system); MS (ESP) m / z [M+H] + C 17 H 25 N 2 O + Calculated value: 273.19; measured value: 273.30.

[0192] LYS16

[0193] [ka]

[0194] Yield: 212 mg, 74%. Purity >95% by NMR, single spot by TLC. Isolated as a light gray powder; f :DCM / MeOH / Et 3 N, 0.6 in 90 / 10 / 2. Strains staining green with CMA; 1 HNMR(CD 3 OD,400MHz):ppm=7.17(1H,d,J=8Hz);7.02(1H,s,);6.93(1H,d,J=4Hz);6.67 (1H,dd,J=4Hz,J=8Hz);2.94(4H,m);2.78(1H,m);1.73(4H,m);1.48(10H,m).

[0195] UPLC:R T : 1.66 (classical system); MS (ESI + ) m / z [M+H] + C 18 H 27 N 2 O + Calculated value: 287.20; measured value: 287.30.

[0196] LYS17

[0197] [ka]

[0198] Yield: 300 mg, 97%. Isolated as a light gray powder with purity >95% by NMR and a single spot by TLC; R f :DCM / MeOH / Et 3 N, 0.53 in 95 / 5 / 2. Strains staining green with CMA; 1 HNMR(CD 3 OD,500MHZ):ppm=8.57(1H,s,(FA));7.19(1H,d,J=8.6Hz);7.12(1H,s,);6.93(1H,d,J=2.2Hz);6.70(1H,dd,J=2.2Hz,J=8.6Hz);3.36(1H,br s);3.27(2H,t,J=6.7Hz);3.12(2H,t,J=6.7Hz);2.12(2H,brs);1.96(2H,brd,J=13.6Hz);1.89(4H,m);1.78(4H,m);1.71(2H,brd,J=13.6Hz).

[0199] UPLC:R T : 1.62 (classical system); MS (ESI + ) m / z [M+H] + C 20 H 27 N 2 O + Calculated value: 311.21; measured value: 311.30.

[0200] LYS19

[0201] [ka]

[0202] Yield: 70 mg, 32%. Isolated as a white amorphous solid, >95% pure by NMR, single spot by TLC; R f :DCM / MeOH / Et 3 N, 0.29 in 90 / 10 / 2. Strains staining green with CMA; 1 HNMR(CD 3 OD,400MHz):ppm=7.18(1H,d,J=8.6Hz);7.04(1H,s,);6.93(1H,d,J=2.3Hz) ;6.68(1H,dd,J=2.3Hz,J=8.6Hz);3.05-2.91(5H,m);1.14(6H,d,J=6.5Hz).

[0203] UPLC:RT:1.13 (classical system); MS (ESI + ) m / z [M+H] + C1 3 Hi9N2O + Calculated value: 219.14; measured value: 219.21.

[0204] LYS20

[0205] [ka]

[0206] Yield: 57 mg, 23%. Isolated as a white amorphous solid, >95% pure by NMR, single spot by TLC; R f :DCM / MeOH / Et 3 N, 0.63 in 90 / 10 / 2. Strains staining green with CMA; 1 HNMR(CD 3OD,500MHz):ppm=8.57(1H,s,(FA));7.19(1H,d,J=8.6Hz);7.11(1H,s,);6.94(1H,d,J=2.2Hz);6.71(1H,dd, J=2.2Hz,J=8.6Hz);3.24(2H,m);3.08(2H,m);3.04(1H,quint.,J=7.0Hz);1.71(4H,m);0.95(6H,t,J=7.4Hz).

[0207] UPLC:R T : 1.40 (classical system); MS (ESP) m / z [M+H] + C 15 H 23 N 2 O + Calculated value: 247.17; measured value: 247.20.

[0208] LYS23

[0209] [ka]

[0210] Yield: 131 mg, 35%. Isolated as a white amorphous solid, >95% pure by NMR, single spot by TLC; R f : 0.33 in DCM / MeOH, 90 / 10. Strains that stain green with CMA; 1 HNMR(CD 3 OD,400MHz):ppm=7.21-7.10(7H,m);7.01(4H,m);6.84(1H,d,J=2.4Hz);7.07(1H,s,);6.94(1H,d,J=2.4Hz);6.67(1H,dd,J=2.4Hz,J=8.6Hz);6.6 2(1H,s);3.04(1H,p,J=6.9Hz);2.92(2H,t,J=6.6Hz);2.78(1H,t,J=6.6Hz);2.72(2H,dd,J=6.9Hz,J=13.8Hz);2.61(2H,dd,J=6.6Hz,J=13.8Hz).

[0211] UPLC:R T: 1.91 (classical system); MS (ESI + ) m / z [M+H] + C 25 H 27 N 2 O + Calculated value: 371.20; measured value: 371.27.

[0212] LYS25

[0213] [ka]

[0214] Yield: 131 mg, 35%. Isolated as a white amorphous solid with purity >95% by NMR and a single spot by TLC; Rf: 0.33 in DCM / MeOH, 90 / 10. Strain stains green with CMA; 1 HNMR(CD 3 OD,500MHz):ppm=8.54(2H,s,(FA));7.20(2H,d,J=8.6Hz);7.11(2H,s);6.92(2H,d,J=2.3Hz);6.71(2H ,dd,J=2.3Hz,J=8.6Hz);3.29-3.16(6H,m);3.07(4H,m);1.71(2H,m);1.48(2H,m);1.41-1.22(14H,m).

[0215] UPLC:R T : 1.48 (classical system), MS (ESI + ) m / z [M+H] + C 30 H 42 N 4 O 2 + Calculated value: 491.33; observed value: 491.49.

[0216] 2-2- Procedure from aldehydes (monosubstituted analogues):

[0217] [ka]

[0218] In the dark and under an inert atmosphere, serotonin chloride (213 mg, 1 mmol) was dissolved in dry MeOH (10 mL) and the corresponding aldehyde (1.1 equiv.) was added. The mixture was stirred for 3 h and then added with NaBH 3 CN (1.1 equiv.) was added. The reaction mixture was stirred at RT for another 30 min. The solvent was then evaporated under reduced pressure. The crude product was dissolved in Et 2 0 / water, 1 / 1 (10 / 10 mL), and the resulting solution was alkalized with NaOH [2 M] until pH = 10, then added with Et 2 The mixture was extracted with 2×20 mL of HO and then with DCM (1×20 mL). The organic phase was dried over MgSO4 and concentrated. The crude product was purified by elution with DCM / MeOH / Et 3 Purification was performed by flash chromatography using N (100 / 0 / 2 to 80 / 20 / 2).

[0219] LYS29

[0220] [ka]

[0221] Yield: 88 mg, 36%. Isolated as a white amorphous solid, >95% pure by NMR, single spot by TLC; R f :DCM / MeOH / Et 3 N, 0.31 in 2 / 2 / 98. Strains staining green with CMA; 1 HNMR(CD 3 OD,500MHz):ppm=8.58(1H,s,(FA));7.19(1H,d,J=8.7Hz);7.09(1H,s,);6.95(1H,d,J=2.2Hz);6.71(1H,dd,J=2.2Hz,J=8.7Hz); 3.21(2H,t,J=7.5Hz);3.07(2H,t,J=7.5Hz);2.94(2H,t,J=7.9Hz);1.65(2H,quint,J=7.8Hz);1.33(4H,m);0.92(3H,t,J=6.7Hz).

[0222] UPLC:R T : 1.45 (classical system); MS (ESP) m / z [M+H] + C 15 H 22 N 2 O + Calculated value 247.17; measured value 247.27.

[0223] LYS30

[0224] [ka]

[0225] Yield: 122 mg, 47%. Isolated as a white amorphous solid, >95% pure by NMR, single spot by TLC; R f :DCM / MeOH / Et 3 N, 0.16 in 2 / 2 / 98. Strains staining green with CMA; 1 HNMR(CD 3 OD,400MHz):ppm=7.16(1H,d,J=8.7Hz);7.01(1H,s,);6.92(1H,d,J=2.1Hz);6.67(1H,dd,J= 2.91(4H,s);2.62(2H,m);1.48(2H,m);1.26(6H,m);0.88(3H,t,J=6.5Hz).

[0226] UPLC:R T : 1.68 (classical system); MS (ESI + ) m / z [M+H] + C 16 H 25 N 2 O + Calculated value 261.19; measured value 261.19.

[0227] LYS26

[0228] [ka]

[0229] Yield: 10 mg, 4.5%. Isolated as a white amorphous solid, >95% pure by NMR, single spot by TLC; R f :DCM / MeOH / Et 3 N, 0.3 in 80 / 20 / 2. Strains staining green with CMA; 1 HNMR(CD 3 OD,400MHz):ppm=8.57(1H,s,(FA));7.21(1H,d,J=8.6Hz);7.13(1H,s);6.95(1H,d,J=2.3Hz);6. 72(1H,dd,J=8.6Hz,J=2.3Hz);3.28(2H,t,J=7.6Hz);3.10(2H,t,J=7.6Hz);2.99(2H,d,J=8.6Hz). 1.72(2H,d,J=7.5Hz);1.02(3H,t,J=7.4Hz). UPLC:R T : 0.9-1.12 (classical system); MS (ESI + ) m / z [M+H] + C 13 H 19 N 2 O + Calculated value: 219.14; measured value: 219.26.

[0230] LYS28

[0231] [ka]

[0232] Yield: 27.6 mg, 11.8%. Isolated as a white amorphous solid, >95% pure by NMR, single spot by TLC; R f :DCM / MeOH / Et 3 N, 0.5 in 90 / 10 / 2. Strains staining green with CMA; 1 HNMR(CD 3OD,500MHz):ppm=8.58(s,1H(FA));7.21(1H,dd,J=8.7Hz,J=2.7Hz);7.12(1H,s);6.96(1H,d,J=2.4Hz);6.72(1H,dd,J=8.6Hz,J=2.0Hz) ;3.27(2H,t,J=7.6Hz,);3.10(2H,t,J=7.6Hz);3.00(2H,t,J=8.2Hz);1.67(2H,p,J=7.9Hz);1.42(2H,h,J=7.4Hz);0.98(3H,t,J=7.4Hz).

[0233] UPLC:R T : 1.23 (classical system); MS (ESI + ) m / z [M+H] + C 14 H 21 N 2 O + Calculated value: 233.16; measured value: 233.20.

[0234] LYS31

[0235] [ka]

[0236] Yield: 71.8 mg, 26%. Isolated as a white amorphous solid, >95% pure by NMR, single spot by TLC; R f :DCM / MeOH / Et 3 N, 0.6 in 90 / 10 / 2. Strains staining green with CMA; 1 HNMR(CD 3 OD,500MHz):ppm=8.59(1H,s,(FA));7.21(1H,d,J=8.7Hz);7.12(1H,s);6.96(1H,d,J=2.5Hz);6.72(1H,dd,J=8. 7Hz,J=2.0Hz);3.26(2H,dd,J=6.5Hz,J=5.5Hz);3.09(2H,t,J=7.6Hz),2.98(2H,dd,J=6.6Hz,J=5.3Hz);1.73-1. 58(2H,m);1.44-1.25(8H,m);0.93(3H,t,J=7.6Hz).

[0237] UPLC:R T : 1.61 (classical system); MS (ESP) m / z [M+H] + C 17 H 27 N 2 O + Calculated value 275.20; measured value 275.28.

[0238] LYS32

[0239] [ka]

[0240] Yield: 69 mg, 24%. Isolated as a white amorphous solid, >95% pure by NMR, single spot by TLC; R f :DCM / MeOH / Et 3 N, 0.4 in 90 / 10 / 2. Strains staining green with CMA; 1 HNMR(CD 3 OD,500MHz):ppm=8.60(1H,d,J=2.3Hz,(FA));7.21(1H,d,J=8.6Hz);7.11(1H,s);6.97(1H,d,J=2.4Hz);6.73(1H,dd,J=8.6Hz,J= 2.3Hz);3.28-3.19(2H,m);3.08(2H,t,J=7.6Hz);3.04-2.88(2H,m);1.75-1.60(2H,m);1.43-1.23(10H,m);0.92(3H,t,J=6.7Hz).

[0241] UPLC:R T :1.85 (classical system) MS(ESI + ) m / z [M+H] + C 18 H 29 N 2 O + Calculated value 289.22; measured value 289.22.

[0242] LYS33

[0243] [ka]

[0244] Yield: 22 mg, 7%. Isolated as a white amorphous solid, >95% pure by NMR, single spot by TLC; R f :DCM / MeOH / Et 3 N, 0.7 in 80 / 20 / 2. Strains staining green with CMA; 1 HNMR(CD 3 OD,500MHz):ppm=8.59(1H,s,(FA));7.21(1H,d,J=8.6Hz);7.12(1H,s);6.96(1H,d,J=2.3Hz);6.72(1H,dd,J=8.6Hz,J=2.3Hz);3. 26(2H,t,J=7.6Hz);3.09(2H,t,J=7.6Hz);2.99(2H,t,J=7.1Hz);1.67(2H,p,J=7.4Hz);1.46-1.19(14H,m);0.92(3H,t,J=6.8Hz).

[0245] UPLC:R T :2.03 (Classical system)

[0246] MS(ESI + ) m / z [M+H] + C 20 H 33 N 2 O + Calculated value: 317.25; measured value: 317.03.

[0247] LYS34

[0248] [ka]

[0249] Yield: 77 mg, 22%. Isolated as a white amorphous solid, >95% pure by NMR, single spot by TLC; R f :DCM / MeOH / Et 3 N, 0.4 in 90 / 10 / 2. Strains staining green with CMA; 1 HNMR(CD 3 OD,500MHz):ppm=8.60(1H,s,(FA));7.21(1H,d,J=8.7Hz);7.12(1H,s);6.96(1H,d,J=2.2Hz);6.72(1H,dd,J=8.7Hz,J=2.3Hz);3. 25(2H,t,J=7.6Hz);3.09(2H,t,J=7.6Hz);2.97(2H,t,J=8.0Hz);1.67(2H,p,J=7.5Hz);1.47-1.21(18H,m);0.92(3H,t,J=6.9Hz).

[0250] UPLC:R T : 2.32 (classical system); MS (ESP) m / z [M+H] + C 22 H 37 N 2 O + Calculated value: 345.28; measured value: 345.16.

[0251] LYS35

[0252] [ka]

[0253] Yield: 93 mg, 35%. Isolated as a white amorphous solid, >95% pure by NMR, single spot by TLC; R f :DCM / MeOH / Et 3 N, 0.46 during 2 / 2 / 98.

[0254] 1 HNMR(CD 3OD,400MHz):ppm=7.31-7.21(5H,m);7.16(1H,d,J=8.6Hz);6.98(1H,s);6.90 (1H,d,J=2.4Hz);6.66(1H,dd,J=8.6Hz,J=2.4Hz);3.78(2H,s);2.91(4H,s).

[0255] UPLC:R T : 1.48 (classical system); MS (ESI + ) m / z [M+H] + C 17 H 19 N 2 O + Calculated value: 267.14; measured value: 267.21.

[0256] LYS36

[0257] [ka]

[0258] Yield: 154 mg, 49%. Isolated as a white amorphous solid, >95% pure by NMR, single spot by TLC; R f :DCM / MeOH, 95 / 5, 0.10.

[0259] 1 HNMR(CD 3 OD,400MHz):ppm=7.16(1H,d,J=8.8Hz);6.98(1H,s);6.89(1H,d,J=2.4Hz);6.98(1H,s);6.76(1H,brs );6.71(2H,brs);6.66(1H,dd,J=8.7Hz,J=2.4Hz);5.90(2H,s);3.68(2H,s);2.89(4H,brt,J=3.9Hz).

[0260] UPLC:RT:1.49 (classical system); MS (ESI + ) m / z [M+H] + C 18 H 19 N 2 O +Calculated value: 311.13; measured value: 311.23.

[0261] LYS37

[0262] [ka]

[0263] Yield: 31 mg, 12%. Isolated as a white amorphous solid, >95% pure by NMR, single spot by TLC; R f :DCM / MeOH / Et 3 N, 0.5 in 90 / 10 / 2. Strains staining green with CMA; 1 HNMR(CD 3 OD,500MHz):ppm=8.53(1H,s);7.63(1H,d,J=1.8Hz);7.21(1H,d,J=8.7Hz);7.11(1H,s);6.93(1H,d,J=2.3Hz);6.72(1H,dd,J= 8.7Hz,J=2.3Hz);6.61(1H,d,J=3.3Hz);6.50(1H,dd,J=3.3,1.8Hz);4.27(2H,s);3.27(2H,t,J=7.7Hz);3.09(2H,t,J=7.6Hz).

[0264] UPLC:R T : 1.22 (classical system); MS (ESI + ) m / z [M+H] + C 15 H 17 N 2 O + Calculated value 257.12; measured value 257.14.

[0265] LYS38

[0266] [ka]

[0267] Yield: 37.3 mg, 13%. Isolated as a white amorphous solid, >95% pure by NMR, single spot by TLC; R f :DCM / MeOH / Et 3 N, 0.4 in 90 / 10 / 2. Strains staining green with CMA; 1 HNMR(CD 3 OD,400MHz):ppm=8.41(1H,s);7.09(1H,d,J=8.6Hz);6.98(1H,s);6.81(1H,d,J=2.2Hz);6.60(1H,dd,J=8.7Hz,J =2.3Hz);6.48(1H,d,J=3.4Hz);6.22(1H,d,J=3.3Hz);4.06(2H,s),3.12(2H,t,J=7.6Hz);2.95(2H,t,J=7.5Hz).

[0268] UPLC:R T : 1.43 (classical system); MS (ESI + ) m / z [M+H] + C 15 H 16 N 2 O + Calculated value: 291.08; measured value: 291.10.

[0269] 2. Biological Results - In Vivo Studies In vivo studies were performed using three mouse models.

[0270] Model 1: Hbb Th1 / th1 Hbb th1 / th1 The mice carry a 3.7 kb homozygous spontaneous deletion that eliminates the hemoglobin subunit beta (HBB) gene and 2 kb of the 5' flanking region including the promoter. Based on genetic and hematological criteria, these mice constitute the first animal model of β-thalassemia. They exhibit intrasplenic iron overload, transfusion independence, ineffective erythropoiesis, hepatosplenomegaly, anemia, and abnormal red blood cell morphology (see Dussiot et al., Nature Medicine 2014;20(4),398-407).

[0271] Model 2: Tph1 KO This model is a peripheral serotonin-deficient mouse. It is a mouse model of low-risk myelodysplastic syndrome with ineffective erythropoiesis, mild anemia, iron overload (spleen), apoptosis of abnormal erythrocytes and proerythroblasts (see Cote et al., PNAS, 2003, 100(23), 13525-13530).

[0272] Model 3: Hepcidin KO Hepcidin, encoded by the HAMP gene, is a master regulator of iron homeostasis and its expression is tightly regulated by signals including iron levels, erythropoietic activity, hypoxia, and inflammation.

[0273] This is a mouse model of hemochromatosis. Hepcidin-deficient mice progressively develop multiorgan iron overload; plasma iron overcomes transferrin-binding capacity and non-transferrin-bound iron accumulates in various tissues, including the pancreas and heart (see Nicolas et al., PNAS 2001, 98(15), 8780-8785).

[0274] 2.1 Experimental approach A mouse model of Hbb with ineffective erythropoiesis and iron overload Th1 / Th1 Starting on day 0, mice were given intraperitoneal (Ip) injections of the A1 or A3 derivatives.

[0275] A mouse model of Tph1 KO with ineffective erythropoiesis and iron overload was given intraperitoneal (Ip) injections of A1, A3, A4 derivatives or serotonin starting from day 0.

[0276] A mouse model of iron overload without ineffective erythropoiesis (Hamp KO) was given intraperitoneal (Ip) injections of A3 derivatives or serotonin starting on day 0.

[0277] Control mice (wild-type, unaltered, healthy) and each type of model mouse that did not receive any injections were also evaluated.

[0278] In the first round of experiments, complete red blood cell counts (RBC) were achieved on days 1, 2 and 5.

[0279] On the fifth day, the animals were sacrificed and their organs were subjected to histological examination and iron determination in the organs.

[0280] In the second round of experiments, complete red blood cell (RBC) counts were achieved on days 2, 5, 10, 15, 20, 25 and 30. Four mice were subjected to toxicity testing, essentially flow cytometry analysis and FACS (fluorescence activated cytometry) on bone marrow and spleen. Mice were sacrificed on day 5 and every 5 days thereafter for single cell sorting), biochemical analysis, iron status (organs, serum and urine) and histology.

[0281] 2.2 Results Model 1 (Hbb Th1 / th1 Mice: Erythropoiesis and iron overload

[0282] First round of experiments Hbb administered either derivative A1 or derivative A3 Th1 / th1 The evolution of red blood cell count (RBC), hemoglobin percentage and hematocrit content in mice over several days is shown in FIG.

[0283] It is demonstrated that derivatives A1 and A3 improve hemoglobin (FIG. 1B), hematocrit content (FIG. 1C) and RBC count (FIG. 1A), thus correcting anemia in β-thalassemia mice.

[0284] Control mice and Hbb mice receiving A1 or A3 Th1 / th1 In mice, iron content in different organs (spleen, bone marrow) was measured on day 5 (after sacrifice) and the results are shown in Figure ID.

[0285] These results indicate that derivatives A1 and A3 inhibit Hbb Th1 / th1We show that it reduces iron overload in the spleen of mice, where iron is mobilized and transported to cells in the bone marrow where it is required for the synthesis of red blood cells.

[0286] Second round of experiments Hbb receiving derivative A3 Th1 / th1 The FACS analysis and RBC results obtained for the mice are reported in FIG. 4, in comparison with control mice treated with PBS (phosphate buffered saline).

[0287] Intraperitoneal injection of 20 mg / g of derivative A3 for 13 and 21 days, respectively, improved the condition of the mice compared to controls, which in contrast exhibited ineffective erythropoiesis (IE) characterized by anemia with expansion of immature erythroblasts, resulting in an unbalanced ratio of immature / mature erythroblasts as observed in humans.

[0288] Figure 4 shows FACS and red blood cell counts depending on the cell differentiation stage on day 13. BM = bone marrow, ns = not significant.

[0289] ProE and Ebaso are part of phases I-II of cell differentiation, EBaso and LBaso are part of phases Ill-IVa, and Poly and Ortho are part of phases IVb-V. The maturation stage is also called "acido".

[0290] A3 Treatment Hbb Th1 / th1 Flow cytometry analysis of bone marrow cells from mice revealed both a decrease in the percentage of Ter-119+CD71+FSC cells (Ill-IVa) and a concomitant increase in the percentage and absolute number of Ter-119+CD71-FSC cells (IVb-V) compared to PBS-treated mice.Therefore, it can be concluded that compound A3 corrects the pathological characteristics of β-thalassemia in this mouse model.

[0291] Figures 5a, 5b and 5c show that Hbb1 cells received derivative A3 compared to control mice treated with PBS. Th1 / th1The number of erythrocytes (5a) and the body iron content of the mice depending on their differentiation stage after 13 days (5b) and 21 days (5c), respectively, are shown. Urinary ferritin levels in HbbTh1 / Th1 mice treated with A3 are reported in Fig. 5d.

[0292] After 13 days of in vivo injection of Compound A3: β-thalassemia Hbb th1 / th1 Correction of bone marrow proliferation in mice is observed (see FIG. 5a).

[0293] Binding of iron by Compound A3 allows for the release of iron and its subsequent use in hemoglobin production, thereby countering iron overload and correcting anemia in a preclinical mouse model of thalassemia.

[0294] Addition of 5-HT derivatives restores the immature / mature erythroblast ratio (ratio IV / V). After 13 days of in vivo injection of compound A3, β-thalassemia Hbb th1 / th1 A reduction in iron overload in mice is observed (see FIG. 5b).

[0295] After 21 days of in vivo injection of compound A3, β-thalassemia Hbb th1 / th1 Reduction of iron overload in mice (see FIG. 5c): A decrease in the number of erythroid progenitors and an increase in the number of mature erythroid cells are observed. Treatment with compound A3 restores the immature / mature erythroblast ratio (Poly / Acido ratio), but a decrease in iron content is observed.

[0296] A significant increase in urinary ferritin levels is observed for A3-treated mice compared to control mice (see FIG. 5d). The data suggest that liberated iron is taken up into the ferritin storage compartment and removed from the body.

[0297] Cytospin analysis was performed to determine the presence of β-thalassemia Hbb th1 / th1 Correction of bone marrow proliferation in mice was confirmed.

[0298] From these studies, Hbb treated with PBS Th1 / Th1It can be concluded that in mice (control mice), an arrest of erythroid proliferation and maturation is observed along with a decrease in cell survival.

[0299] In contrast, Hbb treated with compound A3 Th1 / Th1 In mice, erythroid proliferation is restored and maturation arrest is halted, while cell survival is increased.

[0300] Thus, compound A3 acts as an iron shuttle.

[0301] Erythropoiesis and iron metabolism are closely related. Erythropoiesis is a finely tuned process by which red blood cells (RBCs) are produced in the bone marrow and depends on oxygen and iron availability for proper hemoglobin (Hb) synthesis. In β-thalassemia patients, the reduced life span of RBCs leads to increased proliferation and reduced differentiation of erythrocyte precursors (ineffective erythropoiesis) in the bone marrow and extramedullary erythropoiesis in the spleen. This ineffective erythropoiesis (IE) further contributes to anemia, causing iron overabsorption to meet the increased iron demand for Hb synthesis, resulting in organ iron overload. Thus, patients suffer from both complications of iron overload and chronic anemia. Therefore, in view of the above, the compounds of the present invention provide a promising innovative treatment for normalizing iron stores and restoring erythropoiesis in thalassemia patients.

[0302] Model 2 (Tph1 KO mice): Erythropoiesis and iron overload First round of experiments The evolution over several days of red blood cell count, hemoglobin percentage, hematocrit content and mean cell volume (MCV) in Tph1 KO mice administered either derivative A3 or derivative A4 or serotonin is shown in FIG.

[0303] Derivatives A3 and A4, as well as serotonin, react with hemoglobin (Figure 2B), hematocrit, and It is demonstrated that injection of A3, A4 derivatives or serotonin improves heme content (Figure 2C) in red blood cells (Figure 2D) and RBC count (Figure 2A), thus ameliorating anemia in Tph1KO mice. In addition, A3 and A4 derivatives as well as serotonin reduce mean cell volume (MCV) (Figure 2E). MCV is a measure of the average volume (size) of red blood cells (RBCs) in a blood sample, and an increase in MCV is associated with macrocytic anemia. The results suggest that injection of A3, A4 derivatives or serotonin improves the anemic phenotype.

[0304] In addition, iron content in different organs (spleen, bone marrow) was measured on day 5 (after sacrifice) in control mice and Tph1 KO mice receiving A3 or A4 derivatives or serotonin. The results are shown in Figures 2F and 2G. Iron is mobilized from the spleen and transported to cells of the bone marrow where it is required for the synthesis of red blood cells.

[0305] Second round of experiments Intraperitoneal (IP) injections of 20 mg / g of derivative A3 for 5 and 21 days, respectively, improved the condition of the mice compared to controls, which in contrast displayed a bone marrow displacement syndrome-like phenotype.

[0306] The iron contents in the body, plasma, duodenum, liver, spleen, bone marrow, kidney and pancreas of Tph1 KO and wild-type mice (WT) are reported in Figure 6. Thus, under steady-state conditions, Tph1 KO mice exhibit iron overload in the spleen, intestine and kidney.

[0307] After 5 days of treatment, compound A3 corrects cellular iron misdistribution in Tph1 KO mice compared to untreated Tph1 KO mice (see FIG. 7a).

[0308] After intraperitoneal injection of 21 mg / kg, compound A3 corrected cellular iron misdistribution in Tph1 KO mice (see Figure 7b), corrected pathological hallmarks of ineffective erythropoiesis, and reduced iron overload (ferritin levels) in Tph1 KO mice compared to PBS-treated Tph1 KO mice (see Figure 7c).

[0309] In 5-HT deficient (Tph1 KO) mice treated with PBS, reduced erythroid proliferation is observed along with reduced cell survival.

[0310] In contrast, 5-HT-deficient mice treated with compound A3 have restored erythroid proliferation and increased cellular blood survival.

[0311] Compound A3 acts as an iron shuttle, thus offering a promising innovative treatment to normalize iron stores and restore erythropoiesis in patients with bone marrow displacement syndrome (MDS).

[0312] Model 3 (Hamp KO): Iron overload Iron content was measured in the blood and liver of Hamp KO and control mice on day 5 (after sacrifice) that received A3 or serotonin. The results are shown in Figure 3. Iron levels are decreased in the blood and liver of treated mice. Furthermore, transferrin saturation was also decreased, suggesting decreased iron uptake.

[0313] 3. Biological Results - In Vitro Studies 3.1 Preliminary results Increasing evidence from many investigators suggests that manipulation of the serotonergic system to coordinate iron homeostasis and erythropoiesis may counter the vicious cycle of ineffective erythropoiesis and iron overload seen, for example, in patients with myelodysplastic syndromes (MDS).

[0314] Analysis of Tph1 knockout mice (model 2) revealed a critical function for 5-HT in erythropoiesis: the mice display a macrocytic anemia phenotype due to ineffective erythropoiesis and reduced red blood cell (RBC) survival. Further investigation of 5-HT-deficient mice revealed that in the bone marrow (BM), 5-HT plays a cell-autonomous role in erythroblasts and downregulates CD36 +We have shown that 5-HT is required for normal proliferation of human umbilical cord blood cells. Our data show that the impaired erythropoiesis seen in MDS patients is associated with reduced 5-HT levels, providing evidence that a lack of 5-HT contributes to the emergence of the disease.

[0315] Furthermore, using an in vivo model of MDS-associated anemia (model 2-Tph1 KO mice), we showed that pharmacological modulation of 5-HT levels rescued the anemic phenotype (see above).

[0316] In vitro tests were performed on cells derived from the blood of B-thalassemia patients before transfusion.

[0317] Type B0 / B0 BE / B0 First, the mechanism of action of 5-HT derivatives seen in cells from mouse models was confirmed in human progenitor erythroid cells from thalassemia patients (see Figures 8a and 8b, Ctrl = control patient, B-Thal = thalassemia patient). More specifically, a significant decrease in 5-HT levels in blood from MDS patients (n = 15) is observed compared to control individuals (n = 14).

[0318] Furthermore, patients with the MDS phenotype, ring sideroblasts, i.e., refractory anemia with RARS, demonstrated reduced serum 5-HT levels, demonstrating a role for 5-HT in iron homeostasis (Figure 8c: significant reduction in blood 5-HT levels from 15 MDS patients vs. control individuals (n=14)).

[0319] Finally, in cells derived from β-thalassemia patients (n=3), compound A3 was demonstrated to increase differentiation of erythroid progenitor cells, as evidenced by a decrease in the immature / mature ratio (see FIG. 8d, FACS analysis in cells derived from β-thalassemia patients).

[0320] 3.2 In vitro models Further studies were performed on skin fibroblasts from patients with Friedreich's ataxia and beta-propeller protein-associated neurodegeneration (BPAN) to specifically evaluate the effect of compounds of the invention on iron accumulation in both the cytosol and mitochondria of the fibroblasts.

[0321] Cultured skin fibroblasts from patients with Friedreich's ataxia were used (reviewed in Petit et al., Blood. 2021;137(15):2090-2102 and Ingrassia set al., Front Genet 2017 Feb 17;8:18).

[0322] 3.3 Results Western blot analysis of skin fibroblasts from FA / BPAN patients treated with 100 uM ferric ammonium citrate (FAC) or placebo + / - A3 is shown in Figure 9a.

[0323] In conditions of iron overload (FAC 100uM), the addition of A3 reduced FTH expression (-40%). Western blot analysis of skin fibroblasts from FA / BPAN patients treated with 100uM ferric ammonium citrate (FAC) or placebo + / - A3 shows the results in Fig. 9b. Shows.

[0324] The experiment was performed twice with n=2 in BPAN / Friedreich's ataxia patients. In addition to A3, A1 and A4 were used to treat patient-derived fibroblasts (see FIG. 10).

[0325] Under conditions of iron overload (FAC 100uM), addition of A3 increased p62 expression (approximately 60%), suggesting an increase in autophagic flux.

[0326] A Western blot analysis of skin fibroblasts from FA / BPAN patients treated with 100 uM ferric ammonium citrate (FAC) or placebo + / - a derivative according to the invention is shown in FIG.

[0327] Compound B1 corresponds to the above-mentioned derivative LYS12.

[0328] Compound B2 corresponds to the above-mentioned derivative LYS29.

[0329] Compound B3 corresponds to the derivative LYS9 shown above.

[0330] Compound B4 corresponds to the above-mentioned derivative LYS9a.

[0331] 4. Conclusion The compounds of the invention, in particular compounds A1, A3 and A4, which have been tested in vivo, in vitro, in human cells and in animal models of thalassemia and MDS, have three important properties: Counteracts iron overload in organs. Mobilizes and redistributes iron. · Relieves anemia and enhances erythropoiesis by correcting the proportion of erythrocyte precursors.

Claims

1. Compounds of formula (I): 【Chemical 1】 or a pharmaceutically acceptable salt and / or solvate thereof, During the ceremony, R １ , R ２ and R ４ are independently H, 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 ７ cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; 、 R ３ is H, 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 Cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted —C(O)O—C １ -C ２４ Alkyl, optionally substituted —C(O)O—C ２ -C ２４ Alkenyl, optionally substituted —C(O)O—C ２ -C ２４ Alkynyl, —C(O)O-optionally substituted aryl, optionally substituted —C(O)O-heteroaryl, optionally substituted —S(O)2-C １ -C ２４ Alkyl, optionally substituted —S(O) ２ -C ２ -C ２４ Alkenyl, optionally substituted -S(O) ２ -C ２ -C ２４ Alkynyl, —S(O) ２ -optionally substituted aryl and optionally substituted -S(O) ２ -heteroaryl, with the proviso that R １ , R ２ and R ３ At least one of them is not H, X is C １ -C １２ Alkyl, O-C １ -C １２ Alkyl, C(O), C(O)-C １ -C １２ Alkyl and NH—C(O)—C １ -C １２ A compound selected from the group consisting of alkyl, or a pharmaceutically acceptable salt and / or solvate thereof.

2. X is C １ -C ６ 2. The compound of claim 1, wherein X is alkyl, preferably ethyl.

3. R ４ The compound of claim 1 , wherein is H.

4. R １ and R ２ However, independently, H, C １ -C １２ Alkyl, C ２ -C １２ Alkenyl and C ２ -C １２ alkynyl, wherein said alkyl, alkenyl or alkynyl is selected from the group consisting of one or more halogen, C １ -C ６ Alkyl, aryl, oxo, NH ２ , CO ２ 10. The compound of claim 1, optionally substituted with H or OH.

5. R ３ is H, 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 ７ is selected from the group consisting of cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl and optionally substituted heteroaryl, preferably H, C １ -C １２ Alkyl, C ２ -C １２ Alkenyl and C ２ -C １２ alkynyl, wherein said alkyl, alkenyl or alkynyl is selected from the group consisting of one or more halogen, C １ -C ６ Alkyl, aryl, oxo, NH ２ , CO ２ 10. The compound of claim 1, optionally substituted with H or OH.

6. R １ , R ２ and R ３ However, independently, H, C １ -C ６ Alkyl, C ２ -C ６ Alkenyl and C ２ -C ６ alkynyl, and advantageously R １ , R ２ and R ３ At least one of the following is optionally substituted C ２ -C １２ The compound of claim 1 which is alkynyl.

7. 10. The compound of claim 1, selected from the following compounds: 【Chemistry 2】 【Chemistry 3】 【Chemistry 4】 Preferably 【Chemistry 5】 A compound.

8. A pharmaceutical composition comprising a compound according to any one of claims 1 to 7.

9. The pharmaceutical composition of claim 8, further comprising at least one pharmaceutically acceptable excipient.

10. A pharmaceutical composition as described in claim 8 for use in the prevention or treatment of iron-related disorders, in particular iron overload-related disorders, such as HFE-associated hematochromatosis, non-HFE-associated hematochromatosis, congenital atransferrinemia, iron-loading-related anemia, chronic liver disease, chronic inflammation associated with cancer, autoimmune or inflammatory diseases, neurodegeneration and polygenic neurodegeneration-related diseases associated with brain iron accumulation-related diseases.

11. The pharmaceutical composition of claim 10, wherein the iron overload-related disorder is an iron overload-related anemia such as thalassemia, myelodysplasia, and hematopoietic stem cell transplantation-related disorders.

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