MULLER SEBASTIAN (FR)
CAÑEQUE TATIANA (FR)
COLOMBEAU LUDOVIC (FR)
THOIDINGJAM LEISHEMBA KHUMAN (FR)
CÔTÉ FRANCINE (FR)
INST NAT SANTE RECH MED (FR)
CENTRE NAT RECH SCIENT (FR)
UNIV PARIS CITE (FR)
ROUSSY INST GUSTAVE (FR)
PARIS SCIENCES ET LETTRES (FR)
FONDATION IMAGINE – INST DES MALADIES GENETIQUES (FR)
ASSIST PUBLIQUE HOPITAUX PARIS APHP (FR)
| WO2007081755A2 | 2007-07-19 | |||
| WO2022120475A1 | 2022-06-16 | |||
| WO2011047156A1 | 2011-04-21 |
| US20100052674W | 2010-10-14 |
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| CLAIMS 1. Compound of general formula (I) for use in preventing or treating metalloptosis associated disorders, or a pharmaceutically acceptable salt and/or solvate thereof, wherein formula (I) is: wherein R1, R2, R3 and R4 are independently selected in the group consisting of H, -OH, -C(O)OR9-, -S(O)2R10-, - C(O)R9-, -S(O)R10-, -NR1:LR12-, optionally substituted (C1-C24)alkyl, optionally substituted (C2-C24)alkenyl, optionally substituted (C2-C24)alkynyl, optionally substituted (C3-C10)cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl and optionally substituted heteroaryl, provided that at least one of R1, R2 and R3 is not H; or R1 and R4 are independently selected in the group consisting of H, -OH, -C(O)OR9-, -S(O)2R10-, -C(O)R9-, -S(O)R10-, -NR1:LR12-, optionally substituted (C1-C24)alkyl, optionally substituted (C2-C24)alkenyl, optionally substituted (C2-C24)alkynyl, optionally substituted (C3- C10)cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl and optionally substituted heteroaryl, and R2 and R3 form together with the nitrogen atom to which they bound an optionally substituted heterocycloalkyl; X is selected in the group consisting of (C1-C12)alkyl, -O-(C1-C12)alkyl-, -C(O)-, -C(O)-(C1-C12)alkyl-, -NH- C(O)-(C1-C12)alkyl-, -S-(C1-C12)alkyl-,-S(O)-(C1-C12)alkyl-, and -S(O)2-(C1-C12)alkyl-,; the (C1-C12)alkyl groups being optionally substituted and/or optionally interrupted by an heteroatom; Y°, Y1, Y2 and Y3 are independently absent or selected from -NH-, -O-, -S-, -S(O)-, -S(O)2-, -C(O)- , -C(O)O-,-OC(O)-, -NHC(O)-, -C(O)NH-; -C(O)NR14-,(C1-C24)alkyl, -(C1-C24)alkyl-NH-, -(C1-C24)alkyl-O-, -(C1- C24)alkyl-S-, (C1-C24)alkyl-NR13-, -(C1-C24)alkyl- S(O)-, -(C1-C24)alkyl-S(O)2-,-(C1-C24)alkyl-C(O)-, -(C1- C24)alkyl-C(O)O-,-(C1-C24)alkyl-OC(O)-, -(C1-C24)alkyl-NHC(O)-, -(C1-C24)alkyl-C(O)NH-, -(C1-C24)alkyl- C(O)NR14-, -NH-C(O)-NH-, -NH-S(O)-NH-, -NH-S(O2)-NH-, -S-C(O)-NH-, -O-C(O)-NH-, -O-S(O)-NH-, -O- S(O2)-NH-, -S-CH2-C(O)-NH-, -S-CH2-S(O)-NH-, -S-CH2-S(O2)-NH-, -S(O)-CH2-C(O)-NH-, -S(O2)-CH2-C(O)- NH-, -O-CH2-C(O)-NH-, -O-CH2-S(O)-NH-, -O-CH2-S(O2)-NH-, -NH-CH2-C(O)-NH-, -NH-CH2-S(O)-NH-, -NH- CH2-S(O2)-NH-, -O-(CH2)2-NH-C(O)-, -O-(CH2)2-N(CH3)-C(O)-, -O-(CH2)2-NH-S(O)-, -O-(CH2)2-N(CH3)-S(O)- , -O-(CH2)2-NH-S(O2)-, -O-(CH2)2-N(CH3)-S(O2)-, -S-(CH2)2-NH-C(O)-, -S-(CH2)2-N(CH3)-C(O)-, -S-(CH2)2-NH- S(O)-, -S-(CH2)2-N(CH3)-S(O)-, -S-(CH2)2-NH-S(O2)-, -S-(CH2)2-N(CH3)-S(O2)-, -NH-(CH2)2-NH-C(O)-, -NH- (CH2)2-N(CH3)-C(O)-, -NH-(CH2)2-NH-S(O)-, -NH-(CH2)2-N(CH3)-S(O)-, -NH-(CH2)2-NH-S(O2)-, -NH-(CH2)2- N(CH3)-S(O2)-, -O-CH2-CH(CH2-OH)-NH-C(O)-, -O-CH2-CH(CH2-OCH3)-NH-C(O)-, -O-CH2-CH(CH3)-NH- C(O)-, -O-CH(CH3)-CH2-NH-C(O)-, -O-CH2-CH(CH2-OH)-NH-S(O)-, -O-CH2-CH(CH2-OCH3)-NH-S(O)-, -O- CH2-CH(CH3)-NH-S(O)-, -O-CH(CH3)-CH2-NH-S(O)-, -O-CH2-CH(CH2-OH)-NH-S(O2)-, -O-CH2-CH(CH2- OCH3)-NH-S(O2)-, -O-CH2-CH(CH3)-NH-S(O2)-, -O-CH(CH3)-CH2-NH-S(O2)-, -S-CH2-CH(CH2-OH)-NH-C(O)-, -S-CH2-CH(CH2-OCH3)-NH-C(O)-, -S-CH2-CH(CH3)-NH-C(O)-, -S-CH(CH3)-CH2-NH-C(O)-, -S-CH2-CH(CH2- OH)-NH-S(O)-, -S-CH2-CH(CH2-OCH3)-NH-S(O)-, -S-CH2-CH(CH3)-NH-S(O)-, -S-CH(CH3)-CH2-NH-S(O)-, -S- CH2-CH(CH2-OH)-NH-S(O2)-, -S-CH2-CH(CH2-OCH3)-NH-S(O2)-, -S-CH2-CH(CH3)-NH-S(O2)-, -S-CH(CH3)- CH2-NH-S(O2)-, -NH-CH2-CH(CH2-OH)-NH-C(O)-, -NH-CH2-CH(CH2-OCH3)-NH-C(O)-, -NH-CH2-CH(CH3)- NH-C(O)-, -NH-CH(CH3)-CH2-NH-C(O)-, -NH-CH2-CH(CH2-OH)-NH-S(O)-, -NH-CH2-CH(CH2-OCH3)-NH- S(O)-, -NH-CH2-CH(CH3)-NH-S(O)-, -NH-CH(CH3)-CH2-NH-S(O)-, -NH-CH2-CH(CH2-OH)-NH-S(O2)-, -NH- CH2-CH(CH2-OCH3)-NH-S(O2)-, -NH-CH2-CH(CH3)-NH-S(O2)-, -NH-CH(CH3)-CH2-NH-S(O2)-, -O-(CH2)2-NH-, -S-(CH2)2-NH-, and -NH-(CH2)2-NH-; the (C1-C24)alkyl groups being optionally substituted.; and R5, R6, R7 and R8 are independently selected in the group consisting of H, halogen, optionally substituted (C1-C24)alkyl, optionally substituted (C2-C24)alkenyl, optionally substituted (C2-C24)alkynyl, optionally substituted (C3-C10)cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl and optionally substituted heteroaryl; and R9 to R14 are independently selected in the group consisting of optionally substituted (C1-C12)alkyl, optionally substituted (C2-C12)alkenyl, optionally substituted (C2-C12)alkynyl, optionally substituted aryl. 2. The compound for use according to claim 1, wherein the metalloptosis associated disorders are disorders associated to ferroptosis and/or cuproptosis. 3. The compound for use according to claim 1, wherein the metalloptosis associated disorders are selected among Hemorrhagic stroke; Ischemic Heart Injury; Ischemic Renal Injury; Ischaemia- reperfusion injury (IRI); Neurodegenerative diseases selected from Huntington Disease, Dementia, and amyotrophic lateral sclerosis (ALS); aging related diseases or disorders; sepsis; ishemia-reperfusion; and Diabetes. 4. Compound of general formula (I): or a pharmaceutically acceptable salt and/or solvate thereof, wherein R1, R2, R3 and R4 are independently selected in the group consisting of H, OH, -C(O)OR9-, -S(O)2R10-, - C(O)R9-, -S(O)R10-, -NR1:LR12-, optionally substituted (C1-C24)alkyl, optionally substituted (C2-C24)alkenyl, optionally substituted (C2-C24)alkynyl, optionally substituted (C3-C10)cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl and optionally substituted heteroaryl, provided that at least one of R2 and R3 is not H; or R1 and R4 are independently selected in the group consisting of H, OH, -C(O)OR9-, -S(O)2R10-, -C(O)R9-, -S(O)R10-, -NR1:LR12-, optionally substituted (C1-C24)alkyl, optionally substituted (C2-C24)alkenyl, optionally substituted (C2-C24)alkynyl, optionally substituted (C3- C10)cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl and optionally substituted heteroaryl, and R2 and R3 with the nitrogen atom to which they are bound form together a nitrogen-heterocycloalkyl optionally substituted with at least one substituent selected in the group consisting of halogen; CN; NO2; (C1-C6)alkyl; (C1-C6)haloalkyl; (C1-C6)haloalkoxy, (C1-C6jhalothioalkoxy, optionally substituted aryl (in particular optionally substituted with one or two (C1-C6)alkyl or NO2); heteroaryl; oxo; NRaRb; CORC; CO2Rd; CONReRf; ORg; SRh; SO2R1; SO2NRj Rk; NR'CORm; RnNR°Rp; NRq SO2Rr; wherein Ra to Rr are, independently of one another, H, (C1-C6)alkyl, (C1-C6)haloalkyl, aryl, (C1-C6)alkyl- aryl, heteroaryl or (C1-C6Jalkyl-heteroaryl; in particular consisting of halogen, CN, NO2, (C1-C6)alkyl, (C1- C6jhaloalkyl, oxo, NRaRb, CORc, C(O)ORd, CONReRf, and ORg, wherein Ra to Rg are, independently of one another, H or (C1-C6)alkyl; X is selected in the group consisting of (C1-C12)alkyl, -O-(C1-C12)alkyl-, -C(O)-, -C(O)-(C1-C12)alkyl-, -NH- C(O)-(C1-C12)alkyl-, -S-(C1-C12)alkyl-,-S(O)-(C1-C12)alkyl-, and -S(O)2-(C1-C12)alkyl-; the (C1-C12)alkyl groups being optionally substituted and/or optionally interrupted by an heteroatom; Y°, Y1, Y2 and Y3 are independently absent or selected from -NH-, -O-, -S-, -S(O)-, -S(O)2-, -C(O)-, -C(O)O- ,-OC(O)-, -NHC(O)-, -C(O)NH-; -C(O)NR14-, -(C1-C24)alkyl-NH-, -(C1-C24)alkyl-O-, -(C1-C24)alkyl-S-, (C1- C24)alkyl-NR13-, -(C1-C24)alkyl- S(O)-, -(C1-C24)alkyl-S(O)2-,-(C1-C24)alkyl-C(O)-, -(C1-C24)alkyl-C(O)O-,-(C1- C24)alkyl-OC(O)-, -(C1-C24)alkyl-NHC(O)-, -(C1-C24)alkyl-C(O)NH-, -(C1-C24)alkyl-C(O)NR14-, (C1-C24)alkyl, - NH-C(O)-NH-, -NH-S(O)-NH-, -NH-S(O2)-NH-, -S-C(O)-NH-, -O-C(O)-NH-, -O-S(O)-NH-, -O-S(O2)-NH-, -S- CH2-C(O)-NH-, -S-CH2-S(O)-NH-, -S-CH2-S(O2)-NH-, -S(O)-CH2-C(O)-NH-, -S(O2)-CH2-C(O)-NH-, -O-CH2- C(O)-NH-, -O-CH2-S(O)-NH-, -O-CH2-S(O2)-NH-, -NH-CH2-C(O)-NH-, -NH-CH2-S(O)-NH-, -NH-CH2-S(O2)- NH-, -O-(CH2)2-NH-C(O)-, -O-(CH2)2-N(CH3)-C(O)-, -O-(CH2)2-NH-S(O)-, -O-(CH2)2-N(CH3)-S(O)-, -O-(CH2)2- NH-S(O2)-, -O-(CH2)2-N(CH3)-S(O2)-, -S-(CH2)2-NH-C(O)-, -S-(CH2)2-N(CH3)-C(O)-, -S-(CH2)2-NH-S(O)-, -S- (CH2)2-N(CH3)-S(O)-, -S-(CH2)2-NH-S(O2)-, -S-(CH2)2-N(CH3)-S(O2)-, -NH-(CH2)2-NH-C(O)-, -NH-(CH2)2- N(CH3)-C(O)-, -NH-(CH2)2-NH-S(O)-, -NH-(CH2)2-N(CH3)-S(O)-, -NH-(CH2)2-NH-S(O2)-, -NH-(CH2)2-N(CH3)- S(O2)-, -O-CH2-CH(CH2-OH)-NH-C(O)-, -O-CH2-CH(CH2-OCH3)-NH-C(O)-, -O-CH2-CH(CH3)-NH-C(O)-, -O- CH(CH3)-CH2-NH-C(O)-, -O-CH2-CH(CH2-OH)-NH-S(O)-, -O-CH2-CH(CH2-OCH3)-NH-S(O)-, -O-CH2- CH(CH3)-NH-S(O)-, -O-CH(CH3)-CH2-NH-S(O)-, -O-CH2-CH(CH2-OH)-NH-S(O2)-, -O-CH2-CH(CH2-OCH3)- NH-S(O2)-, -O-CH2-CH(CH3)-NH-S(O2)-, -O-CH(CH3)-CH2-NH-S(O2)-, -S-CH2-CH(CH2-OH)-NH-C(O)-, -S-CH2- CH(CH2-OCH3)-NH-C(O)-, -S-CH2-CH(CH3)-NH-C(O)-, -S-CH(CH3)-CH2-NH-C(O)-, -S-CH2-CH(CH2-OH)-NH- S(O)-, -S-CH2-CH(CH2-OCH3)-NH-S(O)-, -S-CH2-CH(CH3)-NH-S(O)-, -S-CH(CH3)-CH2-NH-S(O)-, -S-CH2- CH(CH2-OH)-NH-S(O2)-, -S-CH2-CH(CH2-OCH3)-NH-S(O2)-, -S-CH2-CH(CH3)-NH-S(O2)-, -S-CH(CH3)-CH2- NH-S(O2)-, -NH-CH2-CH(CH2-OH)-NH-C(O)-, -NH-CH2-CH(CH2-OCH3)-NH-C(O)-, -NH-CH2-CH(CH3)-NH- C(O)-, -NH-CH(CH3)-CH2-NH-C(O)-, -NH-CH2-CH(CH2-OH)-NH-S(O)-, -NH-CH2-CH(CH2-OCH3)-NH-S(O)-, - NH-CH2-CH(CH3)-NH-S(O)-, -NH-CH(CH3)-CH2-NH-S(O)-, -NH-CH2-CH(CH2-OH)-NH-S(O2)-, -NH-CH2- CH(CH2-OCH3)-NH-S(O2)-, -NH-CH2-CH(CH3)-NH-S(O2)-, -NH-CH(CH3)-CH2-NH-S(O2)-, -O-(CH2)2-NH-, -S- (CH2)2-NH-, and -NH-(CH2)2-NH-; the (C1-C24)alkyl groups being optionally substituted.; and R5, R6, R7 and R8 are independently selected in the group consisting of H, halogen, optionally substituted (C1-C24)alkyl, optionally substituted (C2-C24)alkenyl, optionally substituted (C2-C24)alkynyl, optionally substituted (C3-C10)cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl and optionally substituted heteroaryl; and R9 to R14 are independently selected in the group consisting of optionally substituted (C1-C12)alkyl, optionally substituted (C2-C12)alkenyl, optionally substituted (C2-C12)alkynyl, optionally substituted aryl; provided that when R5, R6, R7 and R8 are H, Y° is -O-, and Y1, Y2 and Y3 are absent, then R1, R2 and R3 are not an optionally substituted (C2-C24)alkynyl . 5. A compound according to claim 4 or a pharmaceutically acceptable salt and/or solvate thereof, for use as a drug. 6. A pharmaceutical composition comprising a compound according to claim 4 or a pharmaceutically acceptable salt and/or solvate thereof, and at least one pharmaceutically acceptable excipient. 7. A compound for use according to claim 5 or a pharmaceutical composition according to claim 6, for use in preventing or treating iron- and/or copper-associated disorders, in particular iron and/or copper overload-associated disorders; or metal-dependent cell death associated disorders. 8. The compound or the pharmaceutical composition for use according to claim 7 , wherein the iron- and/or copper-associated disorders are selected among HFE-related hematochromatosis; non HFE- related hematochromatosis; congenital atransferrinenemia; iron-loading associated anemias such as thalassemia, myelodysplasia and hematopoietic stem-cell transplantation-associated disorders; chronic liver diseases; chronic inflammation linked to cancer; autoimmune or inflammatory diseases; neurodegeneration with brain iron accumulation-associated diseases such as Wilson's Disease; and polygenic neurodegenerative-associated diseases such as Parkinson's Disease and Alzheimer Disease. 9. The compound or the pharmaceutical composition for use according to claim 7, wherein the metal- dependent cell death associated disorders are metalloptosis associated disorders, in particular disorders associated to ferroptosis and/or cuproptosis; preferably selected among Hemorrhagic stroke; Ischemic Heart Injury; Ischemic Renal Injury; Ischaemia-reperfusion injury (IRI); Neurodegenerative diseases selected from Huntington Disease, Dementia, amyotrophic lateral and sclerosis (ALS); aging related diseases or disorders; sepsis; ishemia-reperfusion; and Diabetes. 10. The compound for use according to any one of claims 1 to 3, 5 and 7 to 9 or the compound according to claim 4, wherein X is a (C1-C12)al kyl optionally substituted and/or optionally interrupted by an heteroatom, preferably a (C1-C6)alkyl optionally substituted and/or optionally interrupted by an heteroatom, more preferably X is an ethyl. 11. The compound for use according to any one of claims 1 to 3, 5 and 7 to 10 or the compound according to any one of claims 4 and 10, wherein R5, R6, R7 and R8 are independently selected in the group consisting of H, halogen, optionally substituted (C1-C24)alkyl, optionally substituted (C2- C24)alkenyl, optionally substituted (C2-C24)alkynyl, preferably H, halogen, haloalkyl, or (C1-C24)al kyl. 12. The compound for use according to any one of claims 1 to 3, 5 and 7 to 11 or the compound according to any one of claims 4 and 10 to 11, wherein R4 is H. 13. The compound for use according to any one of claims 1 to 3, 5 and 7 to 12 or the compound according to any one of claims 4 and 10 to 12, wherein R1 is H. 14. The compound for use according to any one of claims 1 to 3, 5 and 7 to 13 or the compound according to any one of claims 4 and 10 to 13, wherein R2 and R3 are independently selected in the group consisting of H, -C(O)OR9-, -S(O)2R10-, optionally substituted (C1-C12)alkyl, optionally substituted (C2-C12)alkenyl, optionally substituted (C2-C12)alkynyl, optionally substituted (C3-C12)cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl and optionally substituted heteroaryl, provided that at least one of R2 and R3 is not H; or R2 and R3 with the nitrogen atom to which they are bound form together an optionally substituted nitrogen-heterocycloalkyl comprising 3 to 10 ring atoms; R9 to R12 being as defined in claims 1 or 4. 15. The compound for use according to any one of claims 1 to 3, 5 and 7 to 14 or the compound according to any one of claims 4 and 10 to 14, wherein Y^Y1, Y2 and Y3 are independently absent or - selected from the group consisting of NH-, -O-, -S-, -S(O)-, -S(O)2-, -C(O)-, -C(O)O-,-OC(O)-, -NHC(O)-, - C(O)NH-, -C(O)NR14-, (C1-C24)alkyl, -(C1-C24)alkyl-NH-, -(C1-C24)alkyl-O-, -(C1-C24)alkyl-S-, (C1-C24)alkyl- NR13-, -(C1-C24)alkyl- S(O)-, -(C1-C24)alkyl-S(O)2-,-(C1-C24)alkyl-C(O)-, -(C1-C24)alkyl-C(O)O-,-(C1-C24)alkyl- OC(O)-, -(C1-C24)alkyl-NHC(O)-, -(C1-C24)alkyl-C(O)NH-, -(C1-C24)alkyl-C(O)NR14-; the (C1-C24)alkyl groups being optionally substituted; and R13 and R14 being as defined in claim 1 or 4. 16. The compound for use according to any one of claims 1 to 3, 5 and 7 to 15 or the compound according to any one of claims 4 and 10 to 14, wherein Y^Y1, Y2 and Y3 are independently absent or - O-; -NH-, -S- or optionally substituted (C1-C24)alkyl; preferably Y^Y1, Y2 and Y3 are independently absent or -O-; more preferably Y° is -O- and Y1, Y2 and Y3 are independently absent or -O-. 17. The compound for use according to any one of claims 1 to 3, wherein said compound is selected from compounds recited in Table 1, or a pharmaceutically acceptable salt and/or solvate thereof. 18. The compound according to any one of claims 4 and the compound for use according to any one of claims 5 and 7-16, wherein said compound is selected from compounds (001) to (064) of Table 1; in particular selected from compounds (002), (003), (004), (008), (009), (010), (012), (013), (014), (015), (016), (017), (018), (019), (020), (022), (023), (024), (025), (026), (028), (029), (036), (039), (040), (043), (045), (049), (051), (052), (054), (057), (058), (059), (061), (063), and (064) of Table 1; particular selected from compounds (003) to (007), (013), (014), (021), (029) and (031) to (038) of Table 1; or a pharmaceutically acceptable salt and/or solvate thereof. |
Field of the invention
The present invention is in the field of medicine. The present invention relates to new serotonin analogues and their use as drugs, in particular for preventing and/or treating metalloptosis associated disorders.
Background of the invention
Beyond classical apoptosis, several forms of regulated cell death (RCD) have been identified. These RCD subroutines differ in the initiating stimuli, intermediate activation events, and end effectors. Various metals can induce regulated cell death, i.e. metalloptosis, through different subroutines. Metal ions are essential micronutrients, but either insufficient or excessive abundance of metals can trigger cell death. Metalloptosis includes in particular ferroptosis and cuproptosis that are dependent on iron and copper respectively.
Ferroptosis is a type of programmed cell death dependent on iron and characterized by the accumulation of lipid peroxides, and is genetically and biochemically distinct from other forms of regulated cell death such as apoptosis. Ferroptosis is initiated by the failure of the glutathione- dependent antioxidant defenses, resulting in unchecked lipid peroxidation and eventual cell death. The research field of ferroptosis has seen exponential growth over the past few years, since the term was coined in 2012. This unique modality of cell death, driven by iron-dependent phospholipid peroxidation, is regulated by multiple cellular metabolic pathways, including redox homeostasis, iron handling, mitochondrial activity and metabolism of amino acids, lipids and sugars, in addition to various signalling pathways relevant to disease (Xuejun Jiang et al., Nature Reviews Molecular Cell Biology vol. 22, 266-282 (25.01.2021)). Numerous organ injuries and degenerative pathologies are driven by ferroptosis. Recent studies have shown that ferroptosis is closely related to the pathophysiological processes of many diseases, such as tumors, nervous system diseases, ischemia- reperfusion injury, kidney injury, and blood diseases (Jie Li et al., Cell Death & Disease vol. 11, 88 (03.02.2020)).
A recent study showed that intracellular copper (Cu) induces a novel form of RCD that is different from oxidative stress-related cell death (e.g., apoptosis, ferroptosis, and necroptosis) and has been termed "cuproptosis" (Tsvetkov, P. et al. Science 375, 1254-1261 (2022)). In contrast, mitochondrial stress, especially the aggregation of lipoylated mitochondrial enzymes and the loss of Fe-S cluster proteins, ignites cuproptosis. There is thus a need to find new compounds activating or blocking the metalloptosis pathways to alleviate the progression of the disease, which provides a promising therapeutic strategy for many diseases.
Summary of the invention
The inventors discovered and developed serotonin analogues capable of activating or blocking the metalloptosis pathways, and thus preventing and/or treating diseases associated to metalloptosis. The inventors also discovered that these serotonin analogues are effective for preventing or treating iron- and/or copper-associated disorders.
Accordingly, the invention relates to a compound of general formula (I) for use in preventing or treating metalloptosis associated disorders, or a pharmaceutically acceptable salt and/or solvate thereof, wherein formula (I) is: wherein
R 1 , R 2 , R 3 and R 4 are independently selected in the group consisting of H, -OH, -C(O)OR 9 -, -S(O) 2 R 10 -, - C(O)R 9 -, -S(O)R 10 -, -NR 1:L R 12 -, optionally substituted (C 1 -C 24 )alkyl, optionally substituted (C 2 -C 24 )alkenyl, optionally substituted (C 2 -C 24 )alkynyl, optionally substituted (C 3 -C 10 )cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl and optionally substituted heteroaryl, provided that at least one of R 1 , R 2 and R 3 is not H; or
R 1 and R 4 are independently selected in the group consisting of H, -OH, -C(O)OR 9 -, -S(O) 2 R 10 -, -C(O)R 9 -, -S(O)R 10 -, -NR 1:L R 12 -, optionally substituted (C 1 -C 24 )alkyl, optionally substituted (C 2 -C 24 )alkenyl, optionally substituted (C 2 -C 24 )alkynyl, optionally substituted (C 3 -C 10 )cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl and optionally substituted heteroaryl, and R 2 and R 3 form together with the nitrogen atom to which they bound an optionally substituted heterocycloalkyl; X is selected in the group consisting of (C 1 -C 12 )alkyl, -O-(C 1 -C 12 )alkyl-, -C(O)-, -C(O)-(C 1 -C 12 )alkyl-, -NH- C(O)-(C 1 -C 12 )alkyl-, -S-(C 1 -C 12 )alkyl-,-S(O)-(C 1 -C 12 )alkyl-, and -S(O) 2 -(C 1 -C 12 )alkyl-,; the (C 1 -C 12 )alkyl groups being optionally substituted and/or optionally interrupted by an heteroatom;
Y°, Y 1 , Y 2 and Y 3 are independently absent or selected from -NH-, -O-, -S-, -S(O)-, -S(O) 2 -, -C(O)- , -C(O)O-,-OC(O)-, -NHC(O)-, -C(O)NH-; <(O)NR 14 -,(C 1 -C 24 )alkyl, -(C 1 -C 24 )alkyl-NH-, -(C 1 -C 24 )alkyl-O-, -(C 1 - C 24 )alkyl-S-, (C 1 -C 24 )alkyl-NR 13 -, -(C 1 -C 24 )alkyl- S(O)-, -(C 1 -C 24 )alkyl-S(O) 2 -,-(C 1 -C 24 )alkyl-C(O)-, -(C 1 - C 24 )alkyl-C(O)O-,-(C 1 -C 24 )alkyl-OC(O)-, -(C 1 -C 24 )alkyl-NHC(O)-, -(C 1 -C 24 )alkyl-C(O)NH-, -(C 1 -C 24 )alkyl- C(O)NR 14 -, -NH-C(O)-NH-, -NH-S(O)-NH-, -NH-S(O 2 )-NH-, -S-C(O)-NH-, -O-C(O)-NH-, -O-S(O)-NH-, -O- S(O 2 )-NH-, -S-CH 2 -C(O)-NH-, -S-CH 2 -S(O)-NH-, -S-CH 2 -S(O 2 )-NH-, -S(O)-CH 2 -C(O)-NH-, -S(O 2 )-CH 2 -C(O)- NH-, -O-CH 2 -C(O)-NH-, -O-CH 2 -S(O)-NH-, -O-CH 2 -S(O 2 )-NH-, -NH-CH 2 -C(O)-NH-, -NH-CH 2 -S(O)-NH-, -NH-CH 2 -S(O 2 )-NH-, -O-(CH 2 ) 2 -NH-C(O)-, -O-(CH 2 ) 2 -N(CH 3 )-C(O)-, -O-(CH 2 ) 2 -NH-S(O)-, -O-(CH 2 ) 2 -N(CH 3 )-S(O)- , -O-(CH 2 ) 2 -NH-S(O 2 )-, -O-(CH 2 ) 2 -N(CH3)-S(O 2 )-, -S-(CH 2 ) 2 -NH-C(O)-, -S-(CH 2 ) 2 -N(CH 3 )-C(O)-, -S-(CH 2 ) 2 -NH- S(O)-, -S-(CH 2 ) 2 -N(CH 3 )-S(O)-, -S-(CH 2 ) 2 -NH-S(O 2 )-, -S-(CH 2 ) 2 -N(CH 3 )-S(O 2 )-, -NH-(CH 2 ) 2 -NH-C(O)-, -NH- (CH 2 ) 2 -N(CH 3 )-C(O)-, -NH-(CH 2 ) 2 -NH-S(O)-, -NH-(CH 2 ) 2 -N(CH 3 )-S(O)-, -NH-(CH 2 ) 2 -NH-S(O 2 )-, -NH-(CH 2 ) 2 - N(CH 3 )-S(O 2 )-, -O-CH 2 -CH(CH 2 -OH)-NH-C(O)-, -O-CH 2 -CH(CH 2 -OCH 3 )-NH-C(O)- 7 -O-CH 2 -CH(CH 3 )-NH- C(O)-, -O-CH(CH 3 )-CH 2 -NH-C(O)-, -O-CH 2 -CH(CH 2 -OH)-NH-S(O)-, -O-CH 2 -CH(CH 2 -OCH 3 )-NH-S(O)- 7 -O- CH 2 -CH(CH 3 )-NH-S(O)-, -O-CH(CH 3 )-CH 2 -NH-S(O)-, -O-CH 2 -CH(CH 2 -OH)-NH-S(O 2 )-, -O-CH 2 -CH(CH 2 -
OCH 3 )-NH-S(O 2 )-, -O-CH 2 -CH(CH 3 )-NH-S(O 2 )- 7 -O-CH(CH 3 )-CH 2 -NH-S(O 2 )- 7 -S-CH 2 -CH(CH 2 -OH)-NH-C(O)-, -S-CH 2 -CH(CH 2 -OCH 3 )-NH-C(O)- 7 -S-CH 2 -CH(CH 3 )-NH-C(O)-, -S-CH(CH 3 )-CH 2 -NH-C(O)-, -S-CH 2 -CH(CH 2 - OH)-NH-S(O)-, -S-CH 2 -CH(CH 2 -OCH 3 )-NH-S(O)- 7 -S-CH 2 -CH(CH 3 )-NH-S(O)-, -S-CH(CH 3 )-CH 2 -NH-S(O)-, -S- CH 2 -CH(CH 2 -OH)-NH-S(O 2 )-, -S-CH 2 -CH(CH 2 -OCH 3 )-NH-S(O 2 )- 7 -S-CH 2 -CH(CH 3 )-NH-S(O 2 )- 7 -S-CH(CH 3 )- CH 2 -NH-S(O 2 )-, -NH-CH 2 -CH(CH 2 -OH)-NH-C(O)- 7 -NH-CH 2 -CH(CH 2 -OCH 3 )-NH-C(O)- 7 -NH-CH 2 -CH(CH 3 )- NH-C(O)-, -NH-CH(CH 3 )-CH 2 -NH-C(O)- 7 -NH-CH 2 -CH(CH 2 -OH)-NH-S(O)- 7 -NH-CH 2 -CH(CH 2 -OCH 3 )-NH- S(O)-, -NH-CH 2 -CH(CH 3 )-NH-S(O)- 7 -NH-CH(CH 3 )-CH 2 -NH-S(O)- 7 -NH-CH 2 -CH(CH 2 -OH)-NH-S(O 2 )- 7 -NH- CH 2 -CH(CH 2 -OCH 3 )-NH-S(O 2 )-, -NH-CH 2 -CH(CH 3 )-NH-S(O 2 )- 7 -NH-CH(CH 3 )-CH 2 -NH-S(O 2 )- 7 -O-(CH 2 ) 2 -NH-, -S-(CH 2 ) 2 -NH-, and -NH-(CH 2 ) 2 -NH-; the (C 1 -C 24 )alkyl groups being optionally substituted.; and
R 5 , R 6 , R 7 and R 8 are independently selected in the group consisting of H, halogen, optionally substituted (C 1 -C 24 )alkyl, optionally substituted (C 2 -C 24 )alkenyl, optionally substituted (C 2 -C 24 )alkynyl, optionally substituted (C 3 -C 10 )cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl and optionally substituted heteroaryl; and
R 9 to R 14 are independently selected in the group consisting of optionally substituted (C 1 -C 12 )alkyl, optionally substituted (C 2 -C 12 )alkenyl, optionally substituted (C 2 -C 12 )alkynyl, optionally substituted aryl. Preferably, R 9 is selected in the group consisting of optionally substituted (C 1 -C 12 )alkyl, optionally substituted (C 2 -C 12 )alkenyl, optionally substituted (C 2 -C 12 )alkynyl, and aryl optionally substituted with a (C 1 -C 6 )alkyl; and R 10 to R 14 are independently selected in the group consisting of optionally substituted (C 1 -C 12 )alkyl, optionally substituted (C 2 -C 12 )alkenyl, optionally substituted (C 2 -C 12 )alkynyl, optionally substituted aryl.
In a particular aspect, the metalloptosis associated disorders are disorders associated to ferroptosis and/or cuproptosis.
In a particular aspect, the metalloptosis associated disorders are selected among Hemorrhagic stroke; Ischemic Heart Injury; Ischemic Renal Injury; Ischaemia-reperfusion injury (IRI); Neurodegenerative diseases selected from Huntington Disease, Dementia, and amyotrophic lateral sclerosis (ALS); aging related diseases or disorders; sepsis; ishemia-reperfusion; and Diabetes.
The invention also relates to a compound of general formula (I): or a pharmaceutically acceptable salt and/or solvate thereof, wherein
R 1 , R 2 , R 3 and R 4 are independently selected in the group consisting of H, OH, -C(O)OR 9 -, -S(O) 2 R 10 -, - C(O)R 9 -, -S(O)R 10 -, -NR 1:L R 12 -, optionally substituted (C 1 -C 24 )alkyl, optionally substituted (C 2 -C 24 )alkenyl, optionally substituted (C 2 -C 24 )alkynyl, optionally substituted (C 3 -C 10 jcycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl and optionally substituted heteroaryl, provided that at least one of R 2 and R 3 is not H;
R 1 and R 4 are independently selected in the group consisting of H, OH, -C(O)OR 9 -, -S(O) 2 R 10 -, -C(O)R 9 -, -S(O)R 10 -, -NR 1:L R 12 -, optionally substituted (C 1 -C 24 )alkyl, optionally substituted (C 2 -C 24 )alkenyl, optionally substituted (C 2 -C 24 )alkynyl, optionally substituted (C 3 -C 10 jcycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl and optionally substituted heteroaryl, and R 2 and R 3 with the nitrogen atom to which they are bound form together a nitrogen-heterocycloalkyl optionally substituted with at least one substituent selected in the group consisting of halogen; CN; NO 2 ; (C 1 -C 6 )alkyl; (C 1 -C 6 )haloalkyl; (C 1 -C 6 )haloalkoxy, (C 1 -C 6 )halothioalkoxy, optionally substituted aryl (in particular optionally substituted with one or two (C 1 -C 6 )alkyl or NO 2 ); heteroaryl; oxo; NR a R b ; COR C ; CO 2 R d ; CONR e R f ; OR g ; SR h ; SO 2 R 1 ; SO 2 NR j R k ; NR'COR m ; R n NR°R p ; NR q SO 2 R r ; wherein R a to R r are, independently of one another, H, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, aryl, (C 1 -C 6 )alkyl-aryl, heteroaryl or (C 1 - C 6 )alkyl-heteroaryl; in particular consisting of halogen, CN, NO 2 , (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, oxo, NR a R b , COR c , C(O)OR d , CONR e Rf, and OR g , wherein R a to R g are, independently of one another, H or (C 1 - C 6 )alkyl;
X is selected in the group consisting of (C 1 -C 12 )alkyl, -O-(C 1 -C 12 )alkyl-, -C(O)-, -C(O)-(C 1 -C 12 )alkyl-, -NH- C(O)-(C 1 -C 12 )alkyl-, -S-(C 1 -C 12 )alkyl-,-S(O)-(C 1 -C 12 )alkyl-, and -S(O) 2 -(C 1 -C 12 )alkyl-; the (C 1 -C 12 )alkyl groups being optionally substituted and/or optionally interrupted by an heteroatom;
Y°, Y 1 , Y 2 and Y 3 are independently absent or selected from -NH-, -O-, -S-, -S(O)-, -S(O) 2 -, -C(O)-, -C(O)O- ,-OC(O)-, -NHC(O)-, -C(O)NH-; -C(O)NR 14 - -(C 1 -C 24 )alkyl-NH-, -(C 1 -C 24 )alkyl-O-, -(C 1 -C 24 )alkyl-S-, (C 1 - C 24 )alkyl-NR 13 -, -(C 1 -C 24 )alkyl- S(O)-, -(C 1 -C 24 )alkyl-S(O) 2 -,-(C 1 -C 24 )alkyl-C(O)-, -(C 1 -C 24 )alkyl-C(O)O-,-(C 1 - C 24 )alkyl-OC(O)-, -(C 1 -C 24 )alkyl-NHC(O)-, -(C 1 -C 24 )alkyl-C(O)NH-, -(C 1 -C 24 )alkyl-C(O)NR 14 -, (C 1 -C 24 )alkyl, - NH-C(O)-NH-, -NH-S(O)-NH-, -NH-S(O 2 )-NH-, -S-C(O)-NH-, -O-C(O)-NH-, -O-S(O)-NH-, -O-S(O 2 )-NH-, -S- CH 2 -C(O)-NH-, -S-CH 2 -S(O)-NH-, -S-CH 2 -S(O 2 )-NH-, -S(O)-CH 2 -C(O)-NH-, -S(O 2 )-CH 2 -C(O)-NH-, -O-CH 2 - C(O)-NH-, -O-CH 2 -S(O)-NH-, -O-CH 2 -S(O 2 )-NH-, -NH-CH 2 -C(O)-NH-, -NH-CH 2 -S(O)-NH-, -NH-CH 2 -S(O 2 )- NH-, -O-(CH 2 ) 2 -NH-C(O)-, -O-(CH 2 ) 2 -N(CH 3 )-C(O)-, -O-(CH 2 ) 2 -NH-S(O)-, -O-(CH 2 ) 2 -N(CH 3 )-S(O)-, -O-(CH 2 ) 2 - NH-S(O 2 )-, -O-(CH 2 ) 2 -N(CH 3 )-S(O 2 )-, -S-(CH 2 ) 2 -NH-C(O)-, -S-(CH 2 ) 2 -N(CH 3 )-C(O)-, -S-(CH 2 ) 2 -NH-S(O)-, -S- (CH 2 ) 2 -N(CH 3 )-S(O)-, -S-(CH 2 ) 2 -NH-S(O 2 )-, -S-(CH 2 ) 2 -N(CH 3 )-S(O 2 )-, -NH-(CH 2 ) 2 -NH-C(O)-, -NH-(CH 2 ) 2 - N(CH 3 )-C(O)-, -NH-(CH 2 ) 2 -NH-S(O)-, -NH-(CH 2 ) 2 -N(CH 3 )-S(O)-, -NH-(CH 2 ) 2 -NH-S(O 2 )-, -NH-(CH 2 ) 2 -N(CH 3 )- S(O 2 )-, -O-CH 2 -CH(CH 2 -OH)-NH-C(O)-, -O-CH 2 -CH(CH 2 -OCH 3 )-NH-C(O)-, -O-CH 2 -CH(CH 3 )-NH-C(O)-, -O- CH(CH 3 )-CH 2 -NH-C(O)-, -O-CH 2 -CH(CH 2 -OH)-NH-S(O)-, -O-CH 2 -CH(CH 2 -OCH 3 )-NH-S(O)-, -O-CH 2 -
CH(CH 3 )-NH-S(O)-, -O-CH(CH 3 )-CH 2 -NH-S(O)-, -O-CH 2 -CH(CH 2 -OH)-NH-S(O 2 )-, -O-CH 2 -CH(CH 2 -OCH 3 )- NH-S(O 2 )-, -O-CH 2 -CH(CH 3 )-NH-S(O 2 )-, -O-CH(CH 3 )-CH 2 -NH-S(O 2 )-, -S-CH 2 -CH(CH 2 -OH)-NH-C(O)-, -S-CH 2 - CH(CH 2 -OCH 3 )-NH-C(O)-, -S-CH 2 -CH(CH 3 )-NH-C(O)-, -S-CH(CH 3 )-CH 2 -NH-C(O)-, -S-CH 2 -CH(CH 2 -OH)-NH- S(O)-, -S-CH 2 -CH(CH 2 -OCH 3 )-NH-S(O)-, -S-CH 2 -CH(CH 3 )-NH-S(O)-, -S-CH(CH 3 )-CH 2 -NH-S(O)-, -S-CH 2 - CH(CH 2 -OH)-NH-S(O 2 )-, -S-CH 2 -CH(CH 2 -OCH 3 )-NH-S(O 2 )-, -S-CH 2 -CH(CH 3 )-NH-S(O 2 )-, -S-CH(CH 3 )-CH 2 - NH-S(O 2 )-, -NH-CH 2 -CH(CH 2 -OH)-NH-C(O)-, -NH-CH 2 -CH(CH 2 -OCH 3 )-NH-C(O)-, -NH-CH 2 -CH(CH 3 )-NH- C(O)-, -NH-CH(CH 3 )-CH 2 -NH-C(O)-, -NH-CH 2 -CH(CH 2 -OH)-NH-S(O)-, -NH-CH 2 -CH(CH 2 -OCH 3 )-NH-S(O)-, - NH-CH 2 -CH(CH 3 )-NH-S(O)-, -NH-CH(CH 3 )-CH 2 -NH-S(O)-, -NH-CH 2 -CH(CH 2 -OH)-NH-S(O 2 )-, -NH-CH 2 - CH(CH 2 -OCH 3 )-NH-S(O 2 )-, -NH-CH 2 -CH(CH 3 )-NH-S(O 2 )-, -NH-CH(CH 3 )-CH 2 -NH-S(O 2 )-, -O-(CH 2 ) 2 -NH-, -S- (CH 2 ) 2 -NH-, and -NH-(CH 2 ) 2 -NH-; the (C 1 -C 24 )alkyl groups being optionally substituted.; and
R 5 , R 6 , R 7 and R 8 are independently selected in the group consisting of H, halogen, optionally substituted (C 1 -C 24 )alkyl, optionally substituted (C 2 -C 24 )alkenyl, optionally substituted (C 2 -C 24 )alkynyl, optionally substituted (C 3 -C 10 )cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl and optionally substituted heteroaryl; and R 9 to R 14 are independently selected in the group consisting of optionally substituted (C 1 -C 12 )alkyl, optionally substituted (C 2 -C 12 )alkenyl, optionally substituted (C 2 -C 12 )alkynyl, optionally substituted aryl; provided that when R 5 , R 6 , R 7 and R 8 are H, Y° is -O-, and Y 1 , Y 2 and Y 3 are absent, then R 1 , R 2 and R 3 are not an optionally substituted (C 2 -C 24 )alkynyl .
Preferably, Y 1 , Y 2 and Y 3 are independently absent or selected in the following list and Y° is selected in the following list; the list being: -NH-, -O-, -S-, -S(O)-, -S(O) 2 -, -C(O)-, -C(O)O-,-OC(O)-, - NHC(O)-, -C(O)NH-; -C(O)NR 14 - -(C 1 -C 24 )alkyl-NH-, -(C 1 -C 24 )alkyl-O-, -(C 1 -C 24 )alkyl-S-, (C 1 -C 24 )alkyl-NR 13 -, -(C 1 -C 24 )alkyl- S(O)-, -(C 1 -C 24 )alkyl-S(O) 2 -,-(C 1 -C 24 )alkyl-C(O)-, -(C 1 -C 24 )alkyl-C(O)O-,-(C 1 -C 24 )alkyl-OC(O)-, -(C 1 -C 24 )alkyl-NHC(O)-, -(C 1 -C 24 )alkyl-C(O)NH-, -(C 1 -C 24 )alkyl-C(O)NR 14 -, (C 1 -C 24 )alkyl, -NH-C(O)-NH-, - NH-S(O)-NH-, -NH-S(O 2 )-NH-, -S-C(O)-NH-, -O-C(O)-NH-, -O-S(O)-NH-, -O-S(O 2 )-NH-, -S-CH 2 -C(O)-NH-, - S-CH 2 -S(O)-NH-, -S-CH 2 -S(O 2 )-NH-, -S(O)-CH 2 -C(O)-NH-, -S(O 2 )-CH 2 -C(O)-NH-, -O-CH 2 -C(O)-NH-, -O-CH 2 - S(O)-NH-, -O-CH 2 -S(O 2 )-NH-, -NH-CH 2 -C(O)-NH-, -NH-CH 2 -S(O)-NH-, -NH-CH 2 -S(O 2 )-NH-, -O-(CH 2 ) 2 -NH- C(O)-, -O-(CH 2 ) 2 -N(CH 3 )-C(O)-, -O-(CH 2 ) 2 -NH-S(O)-, -O-(CH 2 ) 2 -N(CH 3 )-S(O)-, -O-(CH 2 ) 2 -NH-S(O 2 )-, -O- (CH 2 ) 2 -N(CH 3 )-S(O 2 )-, -S-(CH 2 ) 2 -NH-C(O)-, -S-(CH 2 ) 2 -N(CH 3 )-C(O)-, -S-(CH 2 ) 2 -NH-S(O)-, -S-(CH 2 ) 2 -N(CH 3 )- S(O)-, -S-(CH 2 ) 2 -NH-S(O 2 )-, -S-(CH 2 ) 2 -N(CH 3 )-S(O 2 )-, -NH-(CH 2 ) 2 -NH-C(O)-, -NH-(CH 2 ) 2 -N(CH 3 )-C(O)-, -NH- (CH 2 ) 2 -NH-S(O)-, -NH-(CH 2 ) 2 -N(CH 3 )-S(O)-, -NH-(CH 2 ) 2 -NH-S(O 2 )-, -NH-(CH 2 ) 2 -N(CH 3 )-S(O 2 )-, -O-CH 2 - CH(CH 2 -OH)-NH-C(O)-, -O-CH 2 -CH(CH 2 -OCH 3 )-NH-C(O)-, -O-CH 2 -CH(CH 3 )-NH-C(O)-, -O-CH(CH 3 )-CH 2 - NH-C(O)-, -O-CH 2 -CH(CH 2 -OH)-NH-S(O)-, -O-CH 2 -CH(CH 2 -OCH 3 )-NH-S(O)-, -O-CH 2 -CH(CH 3 )-NH-S(O)-, - O-CH(CH 3 )-CH 2 -NH-S(O)-, -O-CH 2 -CH(CH 2 -OH)-NH-S(O 2 )-, -O-CH 2 -CH(CH 2 -OCH 3 )-NH-S(O 2 )-, -O-CH 2 - CH(CH 3 )-NH-S(O 2 )-, -O-CH(CH 3 )-CH 2 -NH-S(O 2 )-, -S-CH 2 -CH(CH 2 -OH)-NH-C(O)-, -S-CH 2 -CH(CH 2 -OCH 3 )- NH-C(O)-, -S-CH 2 -CH(CH 3 )-NH-C(O)-, -S-CH(CH 3 )-CH 2 -NH-C(O)-, -S-CH 2 -CH(CH 2 -OH)-NH-S(O)-, -S-CH 2 - CH(CH 2 -OCH 3 )-NH-S(O)-, -S-CH 2 -CH(CH 3 )-NH-S(O)-, -S-CH(CH 3 )-CH 2 -NH-S(O)-, -S-CH 2 -CH(CH 2 -OH)-NH- S(O 2 )-, -S-CH 2 -CH(CH 2 -OCH 3 )-NH-S(O 2 )-, -S-CH 2 -CH(CH 3 )-NH-S(O 2 )-, -S-CH(CH 3 )-CH 2 -NH-S(O 2 )-, -NH-CH 2 - CH(CH 2 -OH)-NH-C(O)-, -NH-CH 2 -CH(CH 2 -OCH 3 )-NH-C(O)-, -NH-CH 2 -CH(CH 3 )-NH-C(O)-, -NH-CH(CH 3 )- CH 2 -NH-C(O)-, -NH-CH 2 -CH(CH 2 -OH)-NH-S(O)-, -NH-CH 2 -CH(CH 2 -OCH 3 )-NH-S(O)-, -NH-CH 2 -CH(CH 3 )-NH- S(O)-, -NH-CH(CH 3 )-CH 2 -NH-S(O)-, -NH-CH 2 -CH(CH 2 -OH)-NH-S(O 2 )-, -NH-CH 2 -CH(CH 2 -OCH 3 )-NH-S(O 2 )-, - NH-CH 2 -CH(CH 3 )-NH-S(O 2 )-, -NH-CH(CH 3 )-CH 2 -NH-S(O 2 )-, -O-(CH 2 ) 2 -NH-, -S-(CH 2 ) 2 -NH-, and -NH-(CH 2 ) 2 - NH-; the (C 1 -C 24 )alkyl groups being optionally substituted
Preferably, R 9 is selected in the group consisting of optionally substituted (C 1 -C 12 )alkyl, optionally substituted (C 2 -C 12 )alkenyl, optionally substituted (C 2 -C 12 )alkynyl, and aryl optionally substituted with a (C 1 -C 6 )alkyl; and
R 10 to R 14 are independently selected in the group consisting of optionally substituted (C 1 - C 12 )alkyl, optionally substituted (C 2 -C 12 )alkenyl, optionally substituted (C 2 -C 12 )alkynyl, optionally substituted aryl. The invention also relates to a compound as defined above, or a pharmaceutically acceptable salt and/or solvate thereof, for use as a drug.
The invention also relates to a pharmaceutical composition comprising a compound as defined above or a pharmaceutically acceptable salt and/or solvate thereof, and at least one pharmaceutically acceptable excipient.
The invention also relates to a compound for use as defined above or a pharmaceutical composition as defined above, for use in preventing or treating iron- and/or copper-associated disorders, in particular iron and/or copper overload-associated disorders; or metal-dependent cell death associated disorders.
In a particular aspect, the iron- and/or copper-associated disorders are selected among HFE- related hematochromatosis; non HFE-related hematochromatosis; congenital atransferrinenemia; iron-loading associated anemias such as thalassemia, myelodysplasia and hematopoietic stem-cell transplantation-associated disorders; chronic liver diseases; chronic inflammation linked to cancer; autoimmune or inflammatory diseases; neurodegeneration with brain iron accumulation-associated diseases such as Wilson's Disease; and polygenic neurodegenerative-associated diseases such as Parkinson's Disease and Alzheimer Disease.
In a particular aspect, the metal-dependent cell death associated disorders are metalloptosis associated disorders, in particular disorders associated to ferroptosis and/or cuproptosis; preferably selected among Hemorrhagic stroke; Ischemic Heart Injury; Ischemic Renal Injury; Ischaemia- reperfusion injury (IRI); Neurodegenerative diseases selected from Huntington Disease, Dementia, amyotrophic lateral and sclerosis (ALS); aging related diseases or disorders; sepsis; ishemia- reperfusion; and Diabetes.
In a particular aspect, in the compounds of the invention, X is a (C 1 -C 12 )alkyl optionally substituted and/or optionally interrupted by an heteroatom, preferably a (C 1 -C 6 )alkyl optionally substituted and/or optionally interrupted by an heteroatom, more preferably X is an ethyl.
In a particular aspect, in the compounds of the invention, R 5 , R 6 , R 7 and R 8 are independently selected in the group consisting of H, halogen, optionally substituted (C 1 -C 24 )alkyl, optionally substituted (C 2 -C 24 )alkenyl, optionally substituted (C 2 -C 24 )alkynyl, preferably H, halogen, haloalkyl, or (C 1 -C 24 )alkyl.
In a particular aspect, in the compounds of the invention, R 4 is H.
In a particular aspect, in the compounds of the invention, R 1 is H.
In a particular aspect, in the compounds of the invention, R 2 and R 3 are independently selected in the group consisting of H, -C(O)OR 9 -, -S(O) 2 R 10 -, optionally substituted (C 1 -C 12 )alkyl, optionally substituted (C 2 -C 12 )alkenyl, optionally substituted (C 2 -C 12 )alkynyl, optionally substituted (C 3 - C 12 )cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl and optionally substituted heteroaryl, provided that at least one of R 2 and R 3 is not H; or R 2 and R 3 with the nitrogen atom to which they are bound form together an optionally substituted nitrogen-heterocycloalkyl comprising 3 to 10 ring atoms; R 9 to R 12 being as defined above.
In a particular aspect, in the compounds of the invention, Y^Y 1 , Y 2 and Y 3 are independently absent or -selected from the group consisting of NH-, -O-, -S-, -S(O)-, -S(O) 2 -, -C(O)-, -C(O)O-,-OC(O)-, - NHC(O)-, -C(O)NH-, -C(O)NR 14 -, (C 1 -C 24 )alkyl, -(C 1 -C 24 )alkyl-NH-, -(C 1 -C 24 )alkyl-O-, -(C 1 -C 24 )alkyl-S-, (C 1 - C 24 )alkyl-NR 13 -, -(C 1 -C 24 )alkyl- S(O)-, -(C 1 -C 24 )alkyl-S(O) 2 -,-(C 1 -C 24 )alkyl-C(O)-, -(C 1 -C 24 )alkyl-C(O)O-,-(C 1 - C 24 )alkyl-OC(O)-, -(C 1 -C 24 )alkyl-NHC(O)-, -(C 1 -C 24 )alkyl-C(O)NH-, -(C 1 -C 24 )alkyl-C(O)NR 14 -; the (C 1 - C 24 )al kyl groups being optionally substituted; and R 13 and R 14 being as defined above.
In a particular aspect, in the compounds of the invention, Y°, Y 1 , Y 2 and Y 3 are independently absent or -O-; -NH-, -S- or optionally substituted (C 1 -C 24 )alkyl; preferably Y^Y 1 , Y 2 and Y 3 are independently absent or -O-; more preferably Y° is -O- and Y 1 , Y 2 and Y 3 are independently absent or - O-.
In a particular aspect, the compound for use according to the invention is selected from compounds (001) to (064) and (Al) to (A4) of Table 1, or a pharmaceutically acceptable salt and/or solvate thereof.
In a particular aspect, the compound for use according to the invention is selected from compounds (001) to (038) and (Al) to (A4) of Table 1, or a pharmaceutically acceptable salt and/or solvate thereof.
In a particular aspect, the compound according to the invention is selected from compounds (001) to (064) of Table 1; preferably selected from compounds (002), (003), (004), (008), (009), (010), (012), (013), (014), (015), (016), (017), (018), (019), (020), (022), (023), (024), (025), (026), (028), (029), (036), (039), (040), (043), (045), (049), (051), (052), (054), (057), (058), (059), (061), (063), and (064) of Table 1; more preferably selected from compounds (003) to (007), (013), (014), (021), (022), (029) and (031) to (038) of Table 1; or a pharmaceutically acceptable salt and/or solvate thereof.
In a particular aspect, the compound according to the invention is selected from compounds (001) to (038) of Table 1; preferably selected from compounds (003) to (007), (013), (014), (021), (029) and (031) to (038) of Table 1; or a pharmaceutically acceptable salt and/or solvate thereof.
Brief description of the figures
Figure 1: Complexation studies of Serotonin, A3 and metals: Serotonin and A3 form differently colored solutions in the presence of FeCI3 and CuSO4, indicative of complex formation. Figure 2: NMR of Serotonin and derivatives with metals: Complexation studies of serotonin and derivatives show that these molecules interact with Fe2+, Fe3+ and Cu2+. Molecular structure of serotonin (Figure 2A), 1 H NMR Spectrum 7.8 mM serotonin (HCI form), D 2 O, 25°C (Figure 2B), 7.8 mM serotonin (HCI form), D 2 O, Fe(NO 3 ) 3 , 25°C (Figure 2C), 7.8 mM serotonin (HCI form), D 2 O, FeCI 2 , 25°C (Figure 2D); Molecular structure of derivatives A3 (Figure 2E), 1 H NMR spectrum, 25mM A3, MeOD, 25°C (Figure 2F), 25mM A3, MeOD, Fe(NO 3 ) 3 , 25°C (Figure 2G), 25mM A3, MeOD, FeCI2, 25°C (Figure 2H); Molecular structure of derivatives A3 (Figure 21), 1 H NMR spectrum 6.4mM A3, MeOD, 37°C (Figure 2J), 6.4mM A3, MeOD, Fe(NO3)3 , 37°C (Figure 2K), 6.4mM A3, MeOD, FeCI2 , 37°C (Figure 2L); 1 H NMR spectrum, 6.4mM A3, D 2 O, 37°C (Figure 2M), 6.4mM A3, D 2 O, Fe(NO 3 ) 3 , 37°C (Figure 2N), 7.7mM A3 (basic form), D2O, CuSO4 , 37°C (Figure 20); Molecular structure of derivatives A3 (Figure 2P), 1 H NMR spectrum, 20.2mM A3, MeOD, 37°C (Figure 2Q), 20.2mM A3, MeOD, FeCI 3 , 37°C (Figure 2R); Molecular structure of derivatives LT265B (Figure 2S), 1 H NMR spectrum, 7.8mM LT265B, D 2 O, 37°C (Figure 2T), 7.8mM LT265B, D 2 O, FeCI 3 , 37°C (Figure 2U); Molecular structure of derivatives LT262A (Figure 2V), 1 H NMR spectrum, 6mM LT262A, D 2 O, 37°C (Figure 2W), 6mM LT262A, D 2 O, FeCI 3 , 37°C (Figure 2X); Molecular structure of derivatives LC336(Figure 2Y), 1 H NMR spectrum, 15.3mM LC336, D 2 0, 37°C (Figure 2Z), 15.3mM LC336, D 2 O, FeCI 3 , 37°C (Figure 2AA), Molecular structure of derivatives LC357(Figure 2AB), 1 H NMR spectrum, 6.2mM LC357, D 2 0, 37°C (Figure 2AC), 6.2mM LC357, D 2 O, FeCI 3 , 37°C (Figure 2AD).
Figure 3: Serotonin analog localizes in lysosomes: HMLER cells were treated with 1 μM A3 for 3h and with LysoTracker for 45 mins. Cells were then washed, fixed and permeabilized. Subsequently, using Alexa-488-N 3 and click chemistry, A3 was visualized and found to localize in lysosomes.
Figure 4: Serotonin analogs increase lysosomal iron content: a) Serotonin analogs used in this figure (Fig. 4a). b) Flow cytometry analysis of RhoNox-M fluorescence in BELA cells treated with respective molecules (10 μM) for 24 h. RhoNox-M is a lysosome-specific probe for Fe 2+ (Fig. 4b).
Figure 5: Serotonin analogs increase total cellular iron and copper content: a) Inductively coupled plasma mass spectrometry (ICP-MS) analysis of total cellular iron in HMLER cells treated with 100 nM A3 (Fig. 5a). b) ICP-MS analysis of total cellular copper in HMLER cells treated with 100 nM A3 (Fig. 5b).
Figure 6: Serotonin analogs decrease lipid peroxidation caused by ferroptosis inducers: a) Cells treated with a ferroptosis inducer and co-treated with A3 or Liproxstatin-1 (Fig. 6a). A3 reduces lipid peroxidation caused by a ferroptosis inducer, b) A3 rescues cell death caused by a ferroptosis inducer (Fig. 6b).
Figure 7: Serotonin analogs rescue cell death caused by the ferroptosis inducer RSL3: Quantification of flow cytometry profiles of Annexin/propidium iodide of cells treated with various concentrations of RSL3 and co-treated with A3 or Liproxstatiin-1, showing that A3 protects against RSL3-induced ferroptosis (Fig. 7b).
Figure 8: Normalised mean fluorescence intensity fold change of BODIPY-C11 obtained from flow cytometry analysis of PDAC cells co-treated with ferroptosis inducer RSL3 (200nM) and serotonin derivatives (10μM).
Figure 9: a. Diagram of click labelling of cells; PDAC cells were treated with 10 μM A3 for 3h and (b,h) with LysoTracker for 45 mins. Cells were then washed, fixed and permeabilized. Subsequently, using Alexa-488-N3 and click chemistry, A3 was labelled and the corresponding antibodies for cell organelles were labelled for c-g. A3 was found to localize in lysosomes and not on other cell organelles.
Figure 10: a. Quantification of flow cytometry profiles of Annexin/propidium iodide of cells treated with various concentrations of RSL3 and co-treated with A3, A0 or Liproxstatiin-1. A3 protects against RSL3-induced ferroptosis. b. Cyclic voltammetry curve of FeCI 3 and after addition of compounds as indicated.
Detailed description of the invention
Definitions
For the purpose of the invention, the term "pharmaceutically acceptable" is intended to mean what is useful to the preparation of a pharmaceutical composition, and what is generally safe and non- toxic, for a pharmaceutical use.
The term "pharmaceutically acceptable salt" is intended to mean, in the framework of the present invention, a salt of a compound which is pharmaceutically acceptable, as defined above, and which possesses the pharmacological activity of the corresponding compound.
The pharmaceutically acceptable salts comprise:
(1) acid addition salts formed with inorganic acids such as hydrochloric, hydrobromic, sulfuric, nitric and phosphoric acid and the like; or formed with organic acids such as acetic, benzenesulfonic, fumaric, glucoheptonic, gluconic, glutamic, glycolic, hydroxynaphtoic, 2-hydroxyethanesulfonic, lactic, maleic, malic, mandelic, methanesulfonic, muconic, 2-naphtalenesulfonic, propionic, succinic, dibenzoyl-L- tartaric, tartaric, p-toluenesulfonic, trimethylacetic, and trifluoroacetic acid and the like, and
(2) salts formed when an acid proton present in the compound is either replaced by a metal ion, such as an alkali metal ion, an alkaline-earth metal ion, or an aluminium ion; or coordinated with an organic or inorganic base. Acceptable organic bases comprise diethanolamine, ethanolamine. N- methylglucamine, triethanolamine, tromethamine and the like. Acceptable inorganic bases comprise aluminium hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate and sodium hydroxide.
The "stereoisomers" are isomeric compounds that have the same molecular formula and sequence of bonded atoms, but differ in the 3D-dimensional orientations of their atoms in space. The stereoisomers include enantiomers, diastereoisomers, Cis-trans and E-Z isomers, conformers, and anomers. In a specific aspect of the disclosure, the stereoisomers include diastereoisomers and enantiomers.
The "tautomers" are isomeric compounds that differ only in the position of the protons and the electrons.
The "solvates" of the present disclosure include conventional solvates such as those formed during the last step of the preparation of the compounds of the invention due to the presence of solvents. It can be for example an hydrate or an alcoholate such as an ethanolate.
The term "halogen" or "halo", as used in the invention, refers to a fluorine, bromine, chlorine or iodine atom.
The term "C x -C y " in which x and y are integers, as used in the present disclosure, means that the corresponding hydrocarbon chain comprises from x to y carbon atoms. If, for example, the term C1-C3 is used, it means that the corresponding hydrocarbon chain may comprise from 1 to 3 carbon atoms, especially 1, 2 or 3 carbon atoms. If, for example, the term C 1 -C 6 is used, it means that the corresponding hydrocarbon chain may comprise from 1 to 6 carbon atoms, especially 1, 2, 3, 4, 5 or 6 carbon atoms. The term "C 0 " thus means that no hydrocarbon chain is present but only a single bond.
The term "alkyl", as used in the invention, refers to a monovalent linear or branched saturated hydrocarbon chain. For example, the term "(C 1 -C 3 )alkyl" more specifically means methyl, ethyl, n- propyl, or isopropyl. The term "(C 1 -C 6 )alkyl" more specifically means methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, pentyl or linear or branched hexyl.
The term « heteroalkyl » refers to an alkyl as defined herein, wherein the aliphatic carbon chain comprises at one or both of its two ends (in particular, the end attached to the remainder of the molecule), and/or is interrupted by at least one heteroatom such as O, N or S. Examples of heteroalkyl are in particular alkoxy (-O-alkyl), alkylthio (-S-alkyl), and alkylamino (-NH(alkyl) or -N(al kyl) 2 )- A « C 1 -C 6 heteroalkyl » refers to a heteroalkyl having 1 to 6 carbon atoms and at least one heteroatom such as O, N or S. Examples of heteroalkyl (or C 1 -C 6 heteroalkyl) include, but are not limited to, methoxy, ethoxy, propyloxy, isopropyloxy, butyloxy, isobutyloxy, tert-butyloxy, pentyloxy, hexyloxy, methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, tert-butylthio, pentylthio, hexylthio, methylamino, ethylamino, propylamino, isopropylamino, butylamino, isobutylamino, tert-butylamino, pentylamino, or hexylamino.
The term "alkoxy" or "alkyloxy", as used in the invention, refers to an alkyl group as defined above bound to the molecule via an oxygen atom. (C 1 -C 6 )alkoxy includes methoxy, ethoxy, propyloxy, and isopropyloxy. (C 1 -C 6 )alkoxy includes methoxy, ethoxy, propyloxy, isopropyloxy, butyloxy, isobutyloxy, tert-butyloxy, pentyloxy and hexyloxy. In a particular embodiment, the "alkoxy" or "alkyloxy" is a methoxy.
The term "haloalkyl" refers to an alkyl as defined herein substituted with at least one halogen, for example one, two or three halogens. A " (C 1 -C 6 )haloalkyl" refers to a haloalkyl having 1 to 6 carbon atoms and at least one halogen such as one fluorine, chlorine, bromine, or iodine atom. The haloalkyl includes a fluoromethyl (-CH 2 F), a difluoromethyl (-CHF 2 ), or a trifluoromethyl (-CF3).
The term "alkenyl", as used in the invention, refers to a straight or branched monovalent unsaturated hydrocarbon chain comprising at least one double bond including, but not limited to, ethenyl, propenyl, butenyl, pentenyl, hexenyl and the like.
The term "alkynyl", as used in the invention, refers to a straight or branched monovalent unsaturated hydrocarbon chain comprising at least one triple bond including, but not limited to, ethynyl, propynyl, butynyl, pentynyl, hexynyl and the like. Preferably, an alkynyl group as used in the present disclosure comprises one triple bond.
In particular, the term (Co-C 6 )alkyl-ethynyl, as used in the present disclosure, refers to an alkynyl as defined above comprising one terminal triple bond; i.e. a (C 0 -C 6 )alkyl terminally substituted by an ethynyl.
The term "cycloalkyl" corresponds to a saturated or unsaturated mono-, bi- or tri-cyclic alkyl group comprising between 3 and 20 atoms of carbons. It also includes fused, bridged, or spiro- connected cycloalkyl groups. The term "cycloalkyl" includes for instance cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, preferably cyclopropyl. The term "spirocycloalkyl" includes for instance a spirocyclopentyl. In a particular aspect, the term "cycloalkyl" corresponds to a saturated monocycloalkyl group comprising between 3 and 7 atoms of carbons. In a particular aspect, the cycloalkyl group is cyclohexyl.
The term "heterocycloalkyl" corresponds to a saturated or unsaturated cycloalkyl group as above defined further comprising at least one heteroatom such as nitrogen, oxygen, or sulphur atom. It also includes fused, bridged, or spiro-connected heterocycloalkyl groups. Representative heterocycloalkyl groups include, but are not limited to 3-dioxolane, benzo [1,3] dioxolyl, pyrazolinyl, pyranyl, thiomorpholinyl, pyrazolidinyl, piperidyl, piperazinyl, 1,4-dioxanyl, imidazolinyl, pyrrolinyl, pyrrolidinyl, piperidinyl, imidazolidinyl, morpholinyl, 1,4-dithianyl, pyrrolidinyl, oxozolinyl, oxazolidinyl, isoxazolinyl, isoxazolidinyl, thiazolinyl, thiazolidinyl, isothiazolinyl, isothiazolidinyl, dihydropyranyl, tetrahydro-2H-pyranyl, tetrahydrofuranyl, and tetrahydrothiophenyl. The term "heterocycloalkyl" may also refer to a 5-10 membered bridged heterocyclyl such as 7-oxabicyclo[2,2,l]heptanyl.
The term "aryl" corresponds to a mono- or bi-cyclic aromatic hydrocarbons having from 6 to 12 carbon atoms. For instance, the term "aryl" includes phenyl, biphenyl, or naphthyl. In a particular embodiment, the aryl is a phenyl.
The term "heteroaryl" as used herein corresponds to an aromatic, mono- or poly-cyclic group comprising between 5 and 14 atoms, including at least one heteroatom such as nitrogen, oxygen or sulphur atom. Examples of such mono- and poly-cyclic heteroaryl group may be: pyridinyl, thiazolyl, thiophenyl, furanyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, benzofuranyl, thianaphthalenyl, indolyl, indolinyl, quinolinyl, isoquinolinyl, benzimidazolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, triazinyl, thianthrenyl, isobenzofuranyl, chromenyl, xanthenyl, phenoxanthinyl, isothiazolyl, isoxazolyl, pyrazinyl, pyridazinyl, indolizinyl, isoindolyl, indazolyl, purinyl, quinolizinyl, phtalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, pteridinyl, carbazolyl, p- carbolinyl, phenanthridinyl, acridinyl, pyrimidinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, furazanyl, phenoxazinyl, isochromanyl, chromanyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, indolinyl, isoindolinyl, oxazolidinyl, benzotriazolyl, benzisoxazolyl, oxindolyl, benzoxazolinyl, benzothienyl, benzothiazolyl, isatinyl, dihydropyridyl, pyrimidinyl, s-triazinyl, oxazolyl, or thiofuranyl. In a particular embodiment, the heteroaryl group is a thiophenyl, a pyridinyl, a pyrazinyl, or a thiazolyl.
The term "(C 1 -C 6 )alkyl-aryl", as used herein, refers to a (C 1 -C 6 )alkyl group as defined above substituted with an aryl group as defined above. In particular, it can be a benzyl group.
The term "(C 1 -C 6 )alkyl-heterocycle", as used herein, refers to a (C 1 -C 6 )alkyl group as defined above substituted with a heterocycle group as defined above. In particular, a "(C 1 -C 6 )alkyl-heteroaryl" refers to a (C 1 -C 6 )al kyl group as defined above substituted with a heteroaryl group as defined above.
The expression "substituted by at least" or "substituted by" means that the group is substituted by one or several substituents of the list. For instance, the expression "a C 1 -C 6 alkyl substituted by at least one halogen" or "a C 1 -C 6 alkyl substituted by a halogen" may include a fluoromethyl (-CH 2 F), a difluoromethyl (-CHF 2 ), or a trifluoromethyl (-CF3).
The expression "optionally substituted" means that the group is not substituted or is substituted by one or several substituents of the list.
In the context of the invention, the substituents can be selected in the group consisting of halogen; CN; NO 2 ; (C 1 -C 6 )alkyl; (C 1 -C 6 )haloalkyl; (C 1 -C 6 )haloalkoxy, (C 1 -C 6 )halothioalkoxy, optionally substituted aryl (in particular optionally substituted with one or two (C 1 -C 6 )alkyl or NO 2 ); heteroaryl; oxo; NR a R b ; COR C ; CO 2 R d ; CONR e R f ; OR g ; SR h ; SO 2 R 1 ; SO 2 NR j R k ; NR'COR m ; R n NR°R p ; NR q SO 2 R r ; wherein R a to R r are, independently of one another, H, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, aryl, (C 1 -C 6 )alkyl-aryl, heteroaryl or (C 1 -C 6 )alkyl-heteroaryl.
By "-CO-" or "-C(O)-", it refers to an oxo group. By "-SO-" or "-S(O)-", it refers to a sulfinyl group.
By "-SO 2 -" or "-S(O 2 )-", it refers to a sulfonyl group.
As used herein, the terms "subject", "individual" or "patient" are interchangeable and refer to an animal, preferably to a mammal, even more preferably to a human, including adult and child. However, the term "subject" can also refer to non-human animals, in particular mammals such as dogs, cats, horses, cows, pigs, sheep and non-human primates, among others.
Within the context of the present disclosure, the term treatment denotes curative, symptomatic, and preventive treatment. Pharmaceutical compositions, kits, products and combined preparations of the invention can be used in humans with a disease or disorder. The pharmaceutical compositions, kits, products and combined preparations of the invention will not necessarily cure the patient but will delay or slow the progression or prevent further progression of the disease or disorder, and/or ameliorating thereby the patients' condition. In treating the disease or disorder, the pharmaceutical composition of the invention is administered in a therapeutically effective amount.
Whenever within this whole specification "treatment of a disease or disorder" or the like is mentioned with reference to the pharmaceutical composition of the invention, there is meant: a) a method for treating a disease or disorder, said method comprising administering a therapeutically effective amount of a compound of the invention or of a pharmaceutical composition comprising said compound to a subject in need of such treatment; b) the use of a compound of the invention or of a pharmaceutical composition comprising said compound for the treatment of a disease or disorder; c) the use of a compound of the invention or of a pharmaceutical composition comprising said compound for the manufacture of a medicament for the treatment of a disease or disorder; and/or d) a compound of the invention or of a pharmaceutical composition comprising said compound for use in the treatment a disease or disorder.
As used herein, the term "therapeutic effect" refers to an effect induced by an active ingredient, or a pharmaceutical composition according to the invention, capable to prevent or to delay the appearance or development of a disease or disorder, or to cure or to attenuate the effects of a disease or disorder.
By "therapeutically effective amount" or "active amount" or "effective amount", it is meant the quantity of the pharmaceutical composition of the invention which prevents, removes or reduces the deleterious effects of a disease or disorder in mammals, including humans, alone or in combination with the other active ingredients of the pharmaceutical composition, kit, product or combined preparation. It is understood that the administered dose may be lower for each compound in the composition to the "therapeutic effective amount" define for each compound used alone or in combination with other treatments than the combination described here. The "therapeutic effective amount" of the composition will be adapted by those skilled in the art according to the patient, the pathology, the mode of administration, etc.
As used herein, the term "pharmaceutically acceptable excipient" refers to any ingredient except active ingredients which are present in a pharmaceutical composition. Its addition may be aimed to confer a particular consistency or other physical or gustative properties to the final product. A pharmaceutically acceptable excipient must be devoid of any interaction, in particular chemical, with the active ingredients.
In the context of the invention, the ranges of values expressed by "from X to XX" or "between
X and XX" comprise the upper and lower limits.
Compounds for use
As mentioned, the invention relates to a compound of the following general formula (I), or a pharmaceutically acceptable salt, stereoisomer, tautomer or solvate thereof, for use for preventing and/or treating metalloptosis associated disorders, or a pharmaceutically acceptable salt and/or solvate thereof, wherein formula (I) is: wherein
R 1 , R 2 , R 3 and R 4 are independently selected in the group consisting of H, OH, -C(O)OR 9 -, -S(O) 2 R 10 -, - C(O)R 9 -, -S(O)R 10 -, -NR 1:L R 12 -, optionally substituted (C 1 -C 24 )alkyl, optionally substituted (C 2 -C 24 )alkenyl, optionally substituted (C 2 -C 24 )alkynyl, optionally substituted (C 3 -C 10 )cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl and optionally substituted heteroaryl, provided that at least one of R 1 , R 2 and R 3 is not H; or
R 1 and R 4 are independently selected in the group consisting of H, OH, -C(O)OR 9 -, -S(O) 2 R 10 -,-C(O)R 9 -, - S(O)R 10 -, -NR 1:L R 12 -, optionally substituted (C 1 -C 24 )alkyl, optionally substituted (C 2 -C 24 )alkenyl, optionally substituted (C 2 -C 24 )alkynyl, optionally substituted (C 3 -C 10 )cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl and optionally substituted heteroaryl, and R 2 and R 3 form together with the nitrogen atom to which they bound an optionally substituted heterocycloalkyl;
X is selected in the group consisting of (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 )alkyl-, -S-(C 1 -C 12 )alkyl-,-S(O)-(C 1 -C 12 )alkyl-,-S(O) 2 -(C 1 -C 12 )alkyl-; the (C 1 -C 12 )alkyl groups being optionally substituted and/or optionally interrupted by an heteroatom;
Y°, Y 1 , Y 2 and Y 3 are independently absent or selected from -NH-, -O-, -S-, -S(O)-, -S(O) 2 -, -C(O)-, -C(O)O- ,-OC(O)-, -NHC(O)-, -C(O)NH-; -C(O)NR 14 - -(C 1 -C 24 )alkyl-NH-, -(C 1 -C 24 )alkyl-O-, -(C 1 -C 24 )alkyl-S-, (C 1 - C 24 )alkyl-NR 13 -, -(C 1 -C 24 )alkyl- S(O)-, -(C 1 -C 24 )alkyl-S(O) 2 -,-(C 1 -C 24 )alkyl-C(O)-, -(C 1 -C 24 )alkyl-C(O)O-,-(C 1 - C 24 )alkyl-OC(O)-, -(C 1 -C 24 )alkyl-NHC(O)-, -(C 1 -C 24 )alkyl-C(O)NH-, -(C 1 -C 24 )alkyl-C(O)NR 14 -, (C 1 -C 24 )alkyl, - NH-C(O)-NH-, -NH-S(O)-NH-, -NH-S(O 2 )-NH-, -S-C(O)-NH-, -O-C(O)-NH-, -O-S(O)-NH-, -O-S(O 2 )-NH-, -S- CH 2 -C(O)-NH-, -S-CH 2 -S(O)-NH-, -S-CH 2 -S(O 2 )-NH-, -S(O)-CH 2 -C(O)-NH-, -S(O 2 )-CH 2 -C(O)-NH-, -O-CH 2 - C(O)-NH-, -O-CH 2 -S(O)-NH-, -O-CH 2 -S(O 2 )-NH-, -NH-CH 2 -C(O)-NH-, -NH-CH 2 -S(O)-NH-, -NH-CH 2 -S(O 2 )- NH-, -O-(CH 2 ) 2 -NH-C(O)-, -O-(CH 2 ) 2 -N(CH 3 )-C(O)-, -O-(CH 2 ) 2 -NH-S(O)-, -O-(CH 2 ) 2 -N(CH 3 )-S(O)-, -O-(CH 2 ) 2 - NH-S(O 2 )-, -O-(CH 2 ) 2 -N(CH 3 )-S(O 2 )-, -S-(CH 2 ) 2 -NH-C(O)-, -S-(CH 2 ) 2 -N(CH 3 )-C(O)-, -S-(CH 2 ) 2 -NH-S(O)-, -S- (CH 2 ) 2 -N(CH 3 )-S(O)-, -S-(CH 2 ) 2 -NH-S(O 2 )-, -S-(CH 2 ) 2 -N(CH 3 )-S(O 2 )-, -NH-(CH 2 ) 2 -NH-C(O)-, -NH-(CH 2 ) 2 - N(CH 3 )-C(O)-, -NH-(CH 2 ) 2 -NH-S(O)-, -NH-(CH 2 ) 2 -N(CH 3 )-S(O)-, -NH-(CH 2 ) 2 -NH-S(O 2 )-, -NH-(CH 2 ) 2 -N(CH 3 )- S(O 2 )-, -O-CH 2 -CH(CH 2 -OH)-NH-C(O)-, -O-CH 2 -CH(CH 2 -OCH 3 )-NH-C(O)-, -O-CH 2 -CH(CH 3 )-NH-C(O)-, -O- CH(CH 3 )-CH 2 -NH-C(O)-, -O-CH 2 -CH(CH 2 -OH)-NH-S(O)-, -O-CH 2 -CH(CH 2 -OCH 3 )-NH-S(O)-, -O-CH 2 -
CH(CH 3 )-NH-S(O)-, -O-CH(CH 3 )-CH 2 -NH-S(O)-, -O-CH 2 -CH(CH 2 -OH)-NH-S(O 2 )-, -O-CH 2 -CH(CH 2 -OCH 3 )- NH-S(O 2 )-, -O-CH 2 -CH(CH 3 )-NH-S(O 2 )-, -O-CH(CH 3 )-CH 2 -NH-S(O 2 )-, -S-CH 2 -CH(CH 2 -OH)-NH-C(O)-, -S-CH 2 - CH(CH 2 -OCH 3 )-NH-C(O)-, -S-CH 2 -CH(CH 3 )-NH-C(O)-, -S-CH(CH 3 )-CH 2 -NH-C(O)-, -S-CH 2 -CH(CH 2 -OH)-NH- S(O)-, -S-CH 2 -CH(CH 2 -OCH 3 )-NH-S(O)-, -S-CH 2 -CH(CH 3 )-NH-S(O)-, -S-CH(CH 3 )-CH 2 -NH-S(O)-, -S-CH 2 - CH(CH 2 -OH)-NH-S(O 2 )-, -S-CH 2 -CH(CH 2 -OCH 3 )-NH-S(O 2 )-, -S-CH 2 -CH(CH 3 )-NH-S(O 2 )-, -S-CH(CH 3 )-CH 2 - NH-S(O 2 )-, -NH-CH 2 -CH(CH 2 -OH)-NH-C(O)-, -NH-CH 2 -CH(CH 2 -OCH 3 )-NH-C(O)-, -NH-CH 2 -CH(CH 3 )-NH- C(O)-, -NH-CH(CH 3 )-CH 2 -NH-C(O)-, -NH-CH 2 -CH(CH 2 -OH)-NH-S(O)-, -NH-CH 2 -CH(CH 2 -OCH 3 )-NH-S(O)-, - NH-CH 2 -CH(CH 3 )-NH-S(O)-, -NH-CH(CH 3 )-CH 2 -NH-S(O)-, -NH-CH 2 -CH(CH 2 -OH)-NH-S(O 2 )-, -NH-CH 2 - CH(CH 2 -OCH 3 )-NH-S(O 2 )-, -NH-CH 2 -CH(CH 3 )-NH-S(O 2 )-, -NH-CH(CH 3 )-CH 2 -NH-S(O 2 )-, -O-(CH 2 ) 2 -NH-, -S- (CH 2 ) 2 -NH-, and -NH-(CH 2 ) 2 -NH-; the (C 1 -C 24 )alkyl groups being optionally substituted.; and
R 5 , R 6 , R 7 and R 8 are independently selected in the group consisting of H, halogen, optionally substituted (C 1 -C 24 )alkyl, optionally substituted (C 2 -C 24 )alkenyl, optionally substituted (C 2 -C 24 )alkynyl, optionally substituted (C 3 -C 10 )cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl and optionally substituted heteroaryl; and
R 9 to R 14 are independently selected in the group consisting of optionally substituted (C 1 -C 12 )alkyl, optionally substituted (C 2 -C 12 )alkenyl, optionally substituted (C 2 -C 12 )alkynyl, optionally substituted aryl. In particular, R 9 is selected in the group consisting of optionally substituted (C 1 -C 12 )alkyl, optionally substituted (C 2 -C 12 )alkenyl, optionally substituted (C 2 -C 12 )alkynyl, and aryl optionally substituted with a (C 1 -C 6 )alkyl; and
R 10 to R 14 are independently selected in the group consisting of optionally substituted (C 1 -C 12 )alkyl, optionally substituted (C 2 -C 12 )alkenyl, optionally substituted (C 2 -C 12 )alkynyl, and optionally substituted aryl.
The invention also relates to the use of a compound of general formula (I) as defined above, especially one of those as disclosed in Table 1, or a pharmaceutically acceptable salt and/or solvate thereof, or a pharmaceutical composition comprising it, for the manufacture of a medicament for preventing and/or treating metalloptosis associated disorders.
The invention further relates to a method for preventing and/or treating metalloptosis associated disorders in a subject in need thereof, comprising administering a therapeutically effective amount of a compound of general formula (I) as defined above, especially one of those as disclosed in Table 1, or a pharmaceutically acceptable salt and/or solvate thereof, or a pharmaceutical composition comprising it, to said subject.
In a specific embodiment, the metalloptosis associated disorders are disorders associated to ferroptosis and/or cuproptosis. Advantageously, the metalloptosis associated disorders are selected among Hemorrhagic stroke; Ischemic Heart Injury; Ischemic Renal Injury; Ischaemia-reperfusion injury (IRI) such as IRI occurring during organ transplantation ((liver, lung, heart, kidneys, pancreas, intestine); Neurodegenerative diseases selected from Huntington Disease, Dementia, and amyotrophic lateral sclerosis (ALS); aging related diseases or disorders; sepsis; ishemia-reperfusion; and Diabetes. In particular, the use of the compound according to the invention is specifically disclosed below in the specification.
In the context of the invention, the compound of general formula (I) as defined above, or a pharmaceutically acceptable salt and/or solvate thereof, can also be used for preventing and/or treating iron- and/or copper-associated disorders. The invention can also relate to the use of a compound of general formula (I) as defined above, or a pharmaceutically acceptable salt and/or solvate thereof, or a pharmaceutical composition comprising it, for the manufacture of a medicine for use for preventing and/or treating iron- and/or copper-associated disorders. The invention can also relates to a method for preventing and/or treating iron- and/or copper-associated disorders in a subject in need thereof, comprising administering a therapeutically effective amount of a compound of general formula (I) as defined above, or a pharmaceutically acceptable salt and/or solvate thereof, or a pharmaceutical composition comprising it to said subject. In this context, the iron- and/or copper-associated disorders can be selected among HFE- related hematochromatosis; non HFE-related hematochromatosis; congenital atransferrinenemia; iron-loading associated anemias such as thalassemia, myelodysplasia and hematopoietic stem-cell transplantation-associated disorders; chronic liver diseases; chronic inflammation linked to cancer; autoimmune or inflammatory diseases; neurodegeneration with brain copper- or iron accumulation- associated diseases such as Wilson's Disease; and polygenic neurodegenerative-associated diseases such as Parkinson's Disease and Alzheimer Disease.
In particular, the iron-associated disorders can be selected among HFE-related hematochromatosis; non HFE-related hematochromatosis; congenital atransferrinenemia; iron- loading associated anemias such as thalassemia, myelodysplasia and hematopoietic stem-cell transplantation-associated disorders; chronic liver diseases; chronic inflammation linked to cancer; autoimmune or inflammatory diseases; neurodegeneration with brain iron accumulation-associated diseases such as Wilson's Disease; and polygenic neurodegenerative-associated diseases such as Parkinson's Disease and Alzheimer Disease.
In particular, the copper-associated disorders can be selected among HFE-related hematochromatosis; non HFE-related hematochromatosis; congenital atransferrinenemia; iron- loading associated anemias such as thalassemia, myelodysplasia and hematopoietic stem-cell transplantation-associated disorders; chronic liver diseases; chronic inflammation linked to cancer; autoimmune or inflammatory diseases; neurodegeneration with brain copper accumulation- associated diseases such as Wilson's Disease; and polygenic neurodegenerative-associated diseases such as Parkinson's Disease and Alzheimer Disease.
In the compound of general formula (I), X is selected in the group consisting of (C 1 -C 12 )alkyl, - O-(C 1 -C 12 )alkyl-, -C(O)-, -C(O)-(C 1 -C 12 )alkyl-, -NH-C(O)-(C 1 -C 12 )alkyl-, -S-(C 1 -C 12 )alkyl-,-S(O)-(C 1 -C 12 )alkyl-, and -S(O) 2 -(C 1 -C 12 )alkyl-; the (C 1 -C 12 )alkyl groups being optionally substituted and/or optionally interrupted by an heteroatom. Preferably X is selected in the group consisting of (C 1 -C 12 )alkyl, -O-(C 1 - C 12 )alkyl-, -C(O)-, -C(O)-(C 1 -C 12 )alkyl-, -NH-C(O)-(C 1 -C 12 )alkyl-; the (C 1 -C 12 )alkyl groups being optionally substituted and/or optionally interrupted by an heteroatom. Preferably, X is selected in the group consisting of (C 1 -C 6 )alkyl, -O-(C 1 -C 6 )alkyl-, -C(O)-, -C(O)-(C 1 -C 6 )alkyl- and -NH-C(O)-(C 1 -C 6 )alkyl-; the (C 1 - C 6 )alkyl groups being optionally substituted and/or optionally interrupted by an heteroatom;. More preferably, X is selected in the group consisting of (C 1 -C 3 )alkyl, -O-(C 1 -C 3 )alkyl-, -C(O)-(C 1 -C 3 )alkyl- and - NH-C(O)-(C 1 -C 3 )alkyl-; the (C 1 -C 3 )alkyl groups being optionally substituted and/or optionally interrupted by an heteroatom;.
In a specific embodiment, X is a (C 1 -C 6 )alkyl. Preferably X is a methyl, an ethyl or a n-propyl, more preferably an ethyl. In the compound of general formula (I), Y°, Y 1 , Y 2 and Y 3 are independently absent or selected from -NH-, -O-, -S-, -S(O)-, -S(O) 2 -, -C(O)-, -C(O)O-,-OC(O)-, -NHC(O)-, -C(O)NH-; -C(O)NR 14 - -(C 1 -C 24 )alkyl- NH-, -(C 1 -C 24 )alkyl-O-, -(C 1 -C 24 )alkyl-S-, (C 1 -C 24 )alkyl-NR 13 -, -(C 1 -C 24 )alkyl- S(O)-, -(C 1 -C 24 )alkyl-S(O) 2 -,-(C 1 - C 24 )alkyl-C(O)-, -(C 1 -C 24 )alkyl-C(O)O-,-(C 1 -C 24 )alkyl-OC(O)-, -(C 1 -C 24 )alkyl-NHC(O)-, -(C 1 -C 24 )alkyl-C(O)NH- , -(C 1 -C 24 )alkyl-C(O)NR 14 -, optionally substituted (C 1 -C 24 )alkyl, -NH-C(O)-NH-, -NH-S(O)-NH-, -NH-S(O 2 )- NH-, -S-C(O)-NH-, -O-C(O)-NH-, -O-S(O)-NH-, -O-S(O 2 )-NH-, -S-CH 2 -C(O)-NH-, -S-CH 2 -S(O)-NH-, -S-CH 2 - S(O 2 )-NH-, -S(O)-CH 2 -C(O)-NH-, -S(O 2 )-CH 2 -C(O)-NH-, -O-CH 2 -C(O)-NH-, -O-CH 2 -S(O)-NH-, -O-CH 2 -S(O 2 )- NH-, -NH-CH 2 -C(O)-NH-, -NH-CH 2 -S(O)-NH-, -NH-CH 2 -S(O 2 )-NH-, -O-(CH 2 ) 2 -NH-C(O)-, -O-(CH 2 ) 2 -N(CH 3 )- C(O)-, -O-(CH 2 ) 2 -NH-S(O)-, -O-(CH 2 ) 2 -N(CH 3 )-S(O)-, -O-(CH 2 ) 2 -NH-S(O 2 )-, -O-(CH 2 ) 2 -N(CH 3 )-S(O 2 )-, -S- (CH 2 ) 2 -NH-C(O)-, -S-(CH 2 ) 2 -N(CH 3 )-C(O)-, -S-(CH 2 ) 2 -NH-S(O)-, -S-(CH 2 ) 2 -N(CH 3 )-S(O)-, -S-(CH 2 ) 2 -NH-S(O 2 )- , -S-(CH 2 ) 2 -N(CH 3 )-S(O 2 )-, -NH-(CH 2 ) 2 -NH-C(O)-, -NH-(CH 2 ) 2 -N(CH 3 )-C(O)-, -NH-(CH 2 ) 2 -NH-S(O)-, -NH- (CH 2 ) 2 -N(CH 3 )-S(O)-, -NH-(CH 2 ) 2 -NH-S(O 2 )-, -NH-(CH 2 ) 2 -N(CH 3 )-S(O 2 )-, -O-CH 2 -CH(CH 2 -OH)-NH-C(O)-, -O- CH 2 -CH(CH 2 -OCH 3 )-NH-C(O)-, -O-CH 2 -CH(CH 3 )-NH-C(O)-, -O-CH(CH 3 )-CH 2 -NH-C(O)-, -O-CH 2 -CH(CH 2 - OH)-NH-S(O)-, -O-CH 2 -CH(CH 2 -OCH 3 )-NH-S(O)-, -O-CH 2 -CH(CH 3 )-NH-S(O)-, -O-CH(CH 3 )-CH 2 -NH-S(O)-, - O-CH 2 -CH(CH 2 -OH)-NH-S(O 2 )-, -O-CH 2 -CH(CH 2 -OCH 3 )-NH-S(O 2 )-, -O-CH 2 -CH(CH 3 )-NH-S(O 2 )-, -O-
CH(CH 3 )-CH 2 -NH-S(O 2 )-, -S-CH 2 -CH(CH 2 -OH)-NH-C(O)-, -S-CH 2 -CH(CH 2 -OCH 3 )-NH-C(O)-, -S-CH 2 -CH(CH 3 )- NH-C(O)-, -S-CH(CH 3 )-CH 2 -NH-C(O)-, -S-CH 2 -CH(CH 2 -OH)-NH-S(O)-, -S-CH 2 -CH(CH 2 -OCH 3 )-NH-S(O)- 7 -S- CH 2 -CH(CH 3 )-NH-S(O)- 7 -S-CH(CH 3 )-CH 2 -NH-S(O)- 7 -S-CH 2 -CH(CH 2 -OH)-NH-S(O 2 )- 7 -S-CH 2 -CH(CH 2 -OCH 3 )- NH-S(O 2 )-, -S-CH 2 -CH(CH 3 )-NH-S(O 2 )- 7 -S-CH(CH 3 )-CH 2 -NH-S(O 2 )- 7 -NH-CH 2 -CH(CH 2 -OH)-NH-C(O)- 7 -NH- CH 2 -CH(CH 2 -OCH 3 )-NH-C(O)- 7 -NH-CH 2 -CH(CH 3 )-NH-C(O)- 7 -NH-CH(CH 3 )-CH 2 -NH-C(O)- 7 -NH-CH 2 - CH(CH 2 -OH)-NH-S(O)- 7 -NH-CH 2 -CH(CH 2 -OCH 3 )-NH-S(O)- 7 -NH-CH 2 -CH(CH 3 )-NH-S(O)- 7 -NH-CH(CH 3 )- CH 2 -NH-S(O)-, -NH-CH 2 -CH(CH 2 -OH)-NH-S(O 2 )- 7 -NH-CH 2 -CH(CH 2 -OCH 3 )-NH-S(O 2 )- 7 -NH-CH 2 -CH(CH 3 )- NH-S(O 2 )-, -NH-CH(CH 3 )-CH 2 -NH-S(O 2 )- 7 -O-(CH 2 ) 2 -NH-, -S-(CH 2 ) 2 -NH-, and -NH-(CH 2 ) 2 -NH-; the (C 1 - C 24 )al kyl groups being optionally substituted.
In a specific embodiment, in the compound of general formula (I), Y°, Y 1 , Y 2 and Y 3 are independently absent or selected from -NH-, -O-, -S-, -S(O)-, -S(O) 2 -, -C(O)-, -C(O)O-,-OC(O)-, -NHC(O)- , -C(O)NH-; -C(O)NR 14 - -(C 1 -C 24 )alkyl-NH-, -(C 1 -C 24 )alkyl-O-, -(C 1 -C 24 )alkyl-S-, (C 1 -C 24 )alkyl-NR 13 -, -(C 1 - C 24 )al kyl- S(O)-, -(C 1 -C 24 )alkyl-S(O) 2 -,-(C 1 -C 24 )alkyl-C(O)-, -(C 1 -C 24 )alkyl-C(O)O-,-(C 1 -C 24 )alkyl-OC(O)-, -(C 1 - C 24 )alkyl-NHC(O)-, -(C 1 -C 24 )alkyl-C(O)NH-, -(C 1 -C 24 )alkyl-C(O)NR 14 -, optionally substituted (C 1 -C 24 )alkyl, - NH-C(O)-NH-, -NH-S(O)-NH-, -NH-S(O 2 )-NH-, -S-C(O)-NH-, -O-C(O)-NH-, -O-S(O)-NH-, -O-S(O 2 )-NH-, -O- (CH 2 ) 2 -NH-, -S-(CH 2 ) 2 -NH-, and -NH-(CH 2 ) 2 -NH-; the (C 1 -C 24 )alkyl groups being optionally substituted.
In a particular embodiment, in the compound of general formula (I), Y°, Y 1 , Y 2 and Y 3 are independently absent or selected from -NH-, -O-, -S-, -S(O)-, -S(O) 2 -, -C(O)-, -C(O)O-,-OC(O)-, -NHC(O)- , -C(O)NH-; -C(O)NR 14 - -(C 1 -C 24 )alkyl-NH-, -(C 1 -C 24 )alkyl-O-, -(C 1 -C 24 )alkyl-S-, (C 1 -C 24 )alkyl-NR 13 -, -(C 1 - C 24 )al kyl- S(O)-, -(C 1 -C 24 )alkyl-S(O) 2 -,-(C 1 -C 24 )alkyl-C(O)-, -(C 1 -C 24 )alkyl-C(O)O-,-(C 1 -C 24 )alkyl-OC(O)-, -(C 1 - C 24 )alkyl-NHC(O)-, -(C 1 -C 24 )alkyl-C(O)NH-, -(C 1 -C 24 )alkyl-C(O)NR 14 -, and optionally substituted (C 4 - C 24 )alkyl; the (C 1 -C 24 )alkyl groups being optionally substituted. In particular, Y°, Y 1 , Y 2 and Y 3 are independently absent or selected from -NH-, -O-, -S-, -S(O)-, -S(O) 2 -, -C(O)-, -C(O)O-,-OC(O)-, -NHC(O)- , -C(O)NH-; -C(O)NR 14 - -(C 1 -C 12 )alkyl-NH-, -(C 1 -C 12 )alkyl-O-, -(C 1 -C 12 )alkyl-S-, (C 1 -C 12 )alkyl-NR 13 -, -(C 1 - C 12 )alkyl- S(O)-, -(C 1 -C 12 )alkyl-S(O) 2 -,-(C 1 -C 12 )alkyl-C(O)-, -(C 1 -C 12 )alkyl-C(O)O-,-(C 1 -C 12 )alkyl-OC(O)-, -(C 1 - C 12 )alkyl-NHC(O)-, -(C 1 -C 12 )alkyl-C(O)NH-, -(C 1 -C 12 )alkyl-C(O)NR 14 -, and optionally substituted (C 4 - C 12 )al kyl; the (C 1 -C 12 )alkyl groups being optionally substituted. More particularly, Y°, Y 1 , Y 2 and Y 3 are independently absent or selected from -NH-, -O-,-S-, -S(O)-, -S(O) 2 -, -C(O)-, -C(O)O-,-OC(O)-, -NHC(O)-, -C(O)NH-; -C(O)NR 14 - -(C 1 -C 6 )alkyl-NH-, -(C 1 -C 6 )alkyl-O-, -(C 1 -C 6 )alkyl-S-, (C 1 -C 6 )alkyl-NR 13 -, -(C 1 -C 6 )alkyl- S(O)-, -(C 1 -C 6 )alkyl-S(O) 2 -,-(C 1 -C 6 )alkyl-C(O)-, -(C 1 -C 6 )alkyl-C(O)O-,-(C 1 -C 6 )alkyl-OC(O)-, -(C 1 -C 6 )alkyl- NHC(O)-, -(C 1 -C6)alkyl-C(O)NH-, -(C 1 -C6)alkyl-C(O)NR 14 -, and optionally substituted (C 1 -C 6 )alkyl; the (C 4 - C 6 )alkyl groups being optionally substituted. Preferably, Y°, Y 1 , Y 2 and Y 3 are independently absent or selected from -O-, and optionally substituted (C 1 -C 6 )alkyl.
In a specific embodiment, Y°, Y 1 , Y 2 and Y 3 are independently absent or -O-. Preferably Y° is -O- and, Y 1 , Y 2 and Y 3 are independently absent or -O-, preferably absent.
In a specific embodiment, in the compound of general formula (I), X is a (C 1 -C 6 )alkyl, Y° is -O-, and Y 1 , Y 2 and Y 3 are independently absent or -O-.
In a particular embodiment, X is a methyl, an ethyl or a n-propyl, Y° is -O-, and Y 1 , Y 2 and Y 3 are independently absent or -O-. Preferably, X is a methyl, an ethyl or a n-propyl, Y° is -O-, and Y 1 , Y 2 and Y 3 are absent. More preferably, X is an ethyl, Y° is -O-, and Y 1 , Y 2 and Y 3 are absent.
In the compound of general formula (I), R 5 , R 6 , R 7 and R 8 independently selected in the group consisting of H, halogen, optionally substituted (C 1 -C 24 )alkyl, optionally substituted (C 2 -C 24 )alkenyl, optionally substituted (C 2 -C 24 )alkynyl, optionally substituted (C 3 -C 10 )cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl and optionally substituted heteroaryl.
In a specific embodiment, R 5 , R 6 , R 7 and R 8 are independently selected in the group consisting of H, halogen, optionally substituted (C 1 -C 24 )alkyl, optionally substituted (C 2 -C 24 )alkenyl, optionally substituted (C 2 -C 24 )alkynyl. In particular, R 5 , R 6 , R 7 and R 8 are independently selected in the group consisting of H, halogen, optionally substituted (C 1 -C 12 )alkyl, optionally substituted (C 2 -C 12 )alkenyl, optionally substituted (C 2 -C 12 )alkynyl. More particularly, R 5 , R 6 , R 7 and R 8 are independently selected in the group consisting of H, halogen, optionally substituted (C 1 -C 6 )alkyl, optionally substituted (C 2 - C 6 )alkenyl, optionally substituted (C 2 -C 6 )alkynyl. Preferably R 5 , R 6 , R 7 and R 8 are independently selected in the group consisting of H, halogen, haloalkyl, or (C 1 -C 24 )alkyl. More preferably R 5 , R 6 , R 7 and R 8 are independently selected in the group consisting of H, halogen, haloalkyl such as CF 3 , or (C 1 -C 6 )alkyl.
In a specific embodiment, three of R 5 , R 6 , R 7 and R 8 are H, and the last one is as defined above.
In another specific embodiment, two of R 5 , R 6 , R 7 and R 8 are H, and two are as defined above.
In another specific embodiment, three of R 5 , R 6 , R 7 and R 8 are H, and one is as defined above.
In another specific embodiment, R 5 , R 6 , R 7 and R 8 are H.
In another specific embodiment, R 5 , R 6 , R 7 and R 8 are as defined above but not H.
In a particular embodiment, one or two of R 5 , R 6 , R 7 and R 8 are selected in the group consisting of H, halogen, haloalkyl such as CF 3 , or (C 1 -C 6 )alkyl, and the others are H.
In a specific embodiment, Y° is -O-, and Y 1 , Y 2 and Y 3 are absent, and: three of R 5 , R 6 , R 7 and R 8 are H, and the last one is as defined above; or two of R 5 , R 6 , R 7 and R 8 are H, and two are as defined above; or three of R 5 , R 6 , R 7 and R 8 are H, and one is as defined above; or
- R 5 , R 6 , R 7 and R 8 are H; or
R 5 , R 6 , R 7 and R 8 are as defined above but not H.
In a particular embodiment, Y° is -O-, and Y 1 , Y 2 and Y 3 are absent, one or two of R 5 , R 6 , R 7 and R 8 are selected in the group consisting of H, halogen, haloalkyl such as CF 3 , or (C 1 -C 6 )alkyl, and the others are H.
In one embodiment of the compound of general formula (I), R 1 , R 2 , R 3 and R 4 are independently selected in the group consisting of H, OH, -C(O)OR 9 -, -S(O) 2 R 10 -, -C(O)R 9 -, -S(O)R 10 -, -NR 1:L R 12 -, optionally substituted (C 1 -C 24 )alkyl, optionally substituted (C 2 -C 24 )alkenyl, optionally substituted (C 2 -C 24 )alkynyl, optionally substituted (C 3 -C 10 )cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted (C 1 -C 6 )alkyl-aryl, and optionally substituted heteroaryl, provided that at least one of R 1 , R 2 and R 3 is not H.
In a particular embodiment of the compound of general formula (I), R 1 , R 2 , R 3 and R 4 are independently selected in the group consisting of H, OH, -C(O)OR 9 -, -S(O) 2 R 10 -, 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 (C 1 -C 6 )alkyl-aryl, and optionally substituted heteroaryl, provided that at least one of R 1 , R 2 and R 3 is not H. In this definition, "optionally substituted" preferably means non-substituted or substituted with at least one, for example 1, 2 or 3, substituent(s) which may be selected in the group consisting of halogen; CN; NO 2 ; (C 1 -C 6 )alkyl; (C 1 -C 6 )haloalkyl; (C 1 -C 6 )haloalkoxy, (C 1 -C 6 )halothioalkoxy, optionally substituted aryl (in particular optionally substituted with one or two (C 1 -C 6 )alkyl or NO 2 ); heteroaryl; halogeno-heteroaryl, in particular halogeno-furanyl; oxo; NR a R b ; COR C ; CO 2 R d ; CONR e R f ; OR g ; SR h ; SO 2 R'; SO 2 NR j R k ; NR'COR m ; R n NR°R p ; NR q SO 2 R r ; wherein R a to R r are, independently of one another, H, (C 1 - C 6 )alkyl, (C 1 -C 6 )haloalkyl, aryl, (C 1 -C 6 )alkyl-aryl, heteroaryl or (C 1 -C 6 )alkyl-heteroaryl; in particular consisting of halogen; CN; NO 2 ; (C 1 -C 6 )alkyl; (C 1 -C 6 )haloalkyl; aryl optionally substituted with one or two (C 1 -C 6 )alkyl or NO 2 ; heteroaryl; oxo; NR a R b ; COR C ; CO 2 R d ; CONR e R f ; and OR g ; wherein R a to R g are, independently of one another, H, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, aryl, (C 1 -C 6 )alkyl-aryl, heteroaryl or (C 1 - C 6 jalkyl-heteroaryl.
In a specific embodiment, R 1 is preferably selected in the group consisting of H, (C 1 -C 24 )alkyl, (C 2 -C 24 )alkenyl, (C 2 -C 24 )alkynyl, (C 3 -C 12 )cycloalkyl and aryl; said alkyl, alkenyl, alkynyl, aryl or cycloalkyl group being optionally substituted with one or more halogens, (C 1 -C 6 )alkyl, aryl, oxo, -NH2, -CO 2 H or - OH. In particular, R 1 is selected in the group consisting of H, (C 1 -C 12 )alkyl, (C 2 -C 12 )alkenyl, (C 2 -C 12 )alkynyl and aryl. Preferably, R 1 is H.
In a specific embodiment, R 4 is preferably selected in the group consisting of H, (C 1 -C 24 )alkyl, (C 2 -C 24 )alkenyl, (C 2 -C 24 )alkynyl, (C 3 -C 12 )cycloalkyl and aryl; said alkyl, alkenyl, alkynyl, aryl or cycloalkyl group being optionally substituted with one or more halogens, (C 1 -C 6 )alkyl, aryl, oxo, -NH 2 , -CO 2 H or - OH. In particular, R 4 is selected in the group consisting of H, (C 1 -C 12 )alkyl and aryl. Preferably, R 4 is H.
In a specific embodiment, R 2 and R 3 are independently selected in the group consisting of H, OH, -C(O)OR 9 -, -S(O) 2 R 10 -, optionally substituted (C 1 -C 12 )alkyl, optionally substituted (C 2 -C 12 )alkenyl, optionally substituted (C 2 -C 12 )alkynyl, optionally substituted (C 3 -C 12 )cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl and optionally substituted heteroaryl, provided that at least one of R 1 , R 2 and R 3 is not H, preferably at least one of R 2 and R 3 is not H; or R 2 and R 3 form together with the nitrogen atom to which they bound an optionally substituted heterocycloalkyl. In this definition, "optionally substituted" preferably means non-substituted or substituted with at least one, for example 1, 2 or 3, substituent(s) which may be preferably a halogen; CN; NO 2 ; (C 1 -C 6 )alkyl; (C 1 - C 6 jhaloalkyl; (C 1 -C 6 )haloalkoxy, (C 1 -C 6 )halothioalkoxy, optionally substituted aryl (in particular optionally substituted with one or two (C 1 -C 6 )alkyl or NO 2 ; heteroaryl; halogeno-heteroaryl in particular halogeno-furanyl; oxo; NR a R b ; COR C ; CO 2 R d ; CONR e R f ; OR g ; SR h ; SO 2 R 1 ; SO 2 NR j R k ; NR'COR m ; R n NR°R p ; NR q SO 2 R r ; wherein R a to R r are, independently of one another, H, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, aryl, (C 1 -C 6 )alkyl-aryl, heteroaryl or (C 1 -C 6 )alkyl-heteroaryl; in particular a (C 1 -C 6 )alkyl; halogen; CN; NO 2 ; (C 1 -C 6 )haloalkyl; phenyl optionally substituted with one or two (C 1 -C 6 )alkyl or NO 2 ; heteroaryl optionally substituted with -OH; oxo; NR a R b ; (C 1 -C 12 )alkyl-NR a R b ; COR C ; CO 2 R d ; CONR e R f ; and OR g ; wherein R a to R g are, independently of one another, H, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, aryl, (C 1 -C 6 )alkyl- aryl, heteroaryl or (C 1 -C 6 )alkyl-heteroaryl.
In the compound of general formula (I), when one or more of R 1 , R 2 , R 3 and R 4 is -C(O)OR 9 -, - S(O) 2 R 10 -, -C(O)R 9 -, -S(O)R 10 -, or -NR 11 R 12 -, preferably -C(O)OR 9 - or -S(O) 2 R 10 -, R 9 to R 12 are independently selected in the group consisting of optionally substituted (C 1 -C 12 )alkyl, optionally substituted (C 2 -C 12 )alkenyl, optionally substituted (C 2 -C 12 )alkynyl, and optionally substituted aryl.
In the compound of general formula (I), when one or more of R 1 , R 2 , R 3 and R 4 is -C(O)OR 9 -, - S(O) 2 R 10 -, -C(O)R 9 -, -S(O)R 10 -, or -NR 1:L R 12 -, preferably -C(O)OR 9 - or -S(O) 2 R 10 -, R 9 is selected in the group consisting of optionally substituted (C 1 -C 12 )alkyl, optionally substituted (C 2 -C 12 )alkenyl, optionally substituted (C 2 -C 12 )alkynyl, and aryl optionally substituted with a (C 1 -C 6 )alkyl; and R 10 to R 12 are independently selected in the group consisting of optionally substituted (C 1 -C 12 )alkyl, optionally substituted (C 2 -C 12 )alkenyl, optionally substituted (C 2 -C 12 )alkynyl, and optionally substituted aryl.
In this definition, "optionally substituted" preferably means non-substituted or substituted with at least one, for example 1, 2 or 3, substituent(s) which may be preferably (C 1 -C 6 )alkyl.
In a specific embodiment, R 9 to R 12 are independently selected in the group consisting of optionally substituted (C 1 -C 6 )alkyl, optionally substituted (C 2 -C 6 )alkenyl, optionally substituted (C 2 - C 6 )alkynyl, and optionally substituted aryl.
In particular, R 9 is selected in the group consisting of optionally substituted (C 1 -C 6 )alkyl, optionally substituted (C 2 -C 6 )alkenyl, optionally substituted (C 2 -C 6 )alkynyl, and aryl optionally substituted with a (C 1 -C 6 )alkyl such as methyl; and R 10 to R 12 are independently selected in the group consisting of optionally substituted (C 1 -C 6 )alkyl, optionally substituted (C 2 -C 6 )alkenyl, optionally substituted (C 2 -C 6 )alkynyl, and optionally substituted aryl.
Preferably, R 9 to R 12 are independently selected in the group consisting of (C 1 -C 6 )alkyl, (C 2 - C 6 )alkenyl, (C 2 -C 6 )alkynyl, aryl or aryl substituted with a (C 1 -C 6 )alkyl such as methyl.
In another embodiment of the compound of general formula (I), R 1 and R 4 are independently selected in the group consisting of H, OH, -C(O)OR 9 -, -S(O) 2 R 10 -, 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 and optionally substituted heteroaryl; and R 2 and R 3 form together with the nitrogen atom to which they bound an optionally substituted heterocycloalkyl.
In a specific embodiment, the optionally substituted heterocycloalkyl formed by R 2 and R 3 with the nitrogen atom to which they are bound form together is preferably an optionally substituted nitrogen- heterocycloalkyl comprising 3 to 10 ring atoms; preferably an optionally substituted nitrogen- heterocycloalkyl comprising one nitrogen atom and 3 to 10 ring atoms. In particular, the nitrogen- heterocycloalkyl is non substituted or substituted with one or more substituents selected in the list consisting of a halogen; CN; NO 2 ; (C 1 -C 6 )alkyl; (C 1 -C 6 )haloalkyl; (C 1 -C 6 )haloalkoxy, (C 1 -C 6 jhalothioalkoxy, optionally substituted aryl (in particular optionally substituted with one or two (C 1 -C 6 )alkyl or NO 2 ); heteroaryl; oxo; NR a R b ; COR C ; CO 2 R d ; CONR e R f ; OR g ; SR h ; SO^; SO 2 NR j R k ; NR'COR m ; R n NR°R p ; NR q SO 2 R r ; wherein R a to R r are, independently of one another, H, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, aryl, (C 1 -C 6 )alkyl- aryl, heteroaryl or (C 1 -C 6 )alkyl-heteroaryl; in particular consisting of halogen, (C 1 -C 6 )alkyl, aryl, oxo, - NH 2 , -CO 2 H or -OH.
In a specific embodiment, when R 2 and R 3 form together with the nitrogen atom to which they bound an optionally substituted heterocycloalkyl, R 4 is preferably selected in the group consisting of H, (C 1 -C 24 )alkyl, (C 2 -C 24 )alkenyl, (C 2 -C 24 )alkynyl, (C 3 -C 12 )cycloalkyl and aryl; said alkyl, alkenyl, alkynyl, aryl or cycloalkyl group being optionally substituted with one or more halogens, (C 1 -C 6 )alkyl, aryl, oxo, -NH 2 , -CO 2 H or -OH; in particular, R 4 is selected in the group consisting of H, (C 1 -C 12 )alkyl and aryl; preferably, R 4 is H.
In a specific embodiment, when R 2 and R 3 form together with the nitrogen atom to which they bound an optionally substituted heterocycloalkyl, R 1 is preferably selected in the group consisting of H, (C 1 -C 24 )alkyl, (C 2 -C 24 )alkenyl, (C 2 -C 24 )alkynyl, (C 3 -C 12 )cycloalkyl and aryl; said alkyl, alkenyl, alkynyl, aryl or cycloalkyl group being optionally substituted with one or more halogens, (C 1 -C 6 )alkyl, aryl, oxo, -NH 2 , -CO 2 H or -OH; in particular, R 1 is selected in the group consisting of H, (C 1 -C 12 )alkyl, (C 2 -C 12 )alkenyl, (C 2 -C 12 )alkynyl and aryl; preferably, R 1 is H.
In a specific embodiment, when R 2 and R 3 form together with the nitrogen atom to which they bound an optionally substituted heterocycloalkyl:
R 4 is preferably selected in the group consisting of H, (C 1 -C 24 )alkyl, (C 2 -C 24 )alkenyl, (C 2 - C 24 )alkynyl, (C 3 -C 12 )cycloalkyl and aryl; said alkyl, alkenyl, alkynyl, aryl or cycloalkyl group being optionally substituted with one or more halogens, (C 1 -C 6 )alkyl, aryl, oxo, -NH 2 , -CO 2 H or -OH; and
R 1 is preferably selected in the group consisting of H, (C 1 -C 24 )alkyl, (C 2 -C 24 )alkenyl, (C 2 - C 24 )alkynyl, (C 3 -C 12 )cycloalkyl and aryl; said alkyl, alkenyl, alkynyl, aryl or cycloalkyl group being optionally substituted with one or more halogens, (C 1 -C 6 )alkyl, aryl, oxo, -NH 2 , -CO 2 H or -OH.
In a specific embodiment, when R 2 and R 3 form together with the nitrogen atom to which they bound an optionally substituted heterocycloalkyl:
R 4 is preferably selected in the group consisting of H, (C 1 -C 12 )alkyl and aryl; and R 1 is preferably selected in the group consisting of H, (C 1 -C 12 )alkyl, (C 2 -C 12 )alkenyl, (C 2 - C 12 )alkynyl and aryl.
In a specific embodiment, when R 2 and R 3 form together with the nitrogen atom to which they bound an optionally substituted heterocycloalkyl:
R 4 is preferably H; and
R 1 is preferably selected in the group consisting of H, (C 1 -C 12 )alkyl, (C 2 -C 12 )alkenyl, (C 2 - C 12 )alkynyl and aryl; more preferably, R 1 is H.
In a specific embodiment,
X is a methyl, an ethyl or a n-propyl; and/or Y° is-O-; and/or Y 1 , Y 2 and Y 3 are independently absent or -O-; and
R 2 and R 3 form together with the nitrogen atom to which they bound an optionally substituted nitrogen-heterocycloalkyl comprising 3 to 10 ring atoms; and
R 4 is preferably selected in the group consisting of H, (C 1 -C 24 )alkyl, (C 2 -C 24 )alkenyl, (C 2 - C 24 )alkynyl, (C 3 -C 12 )cycloalkyl and aryl; said alkyl, alkenyl, alkynyl, aryl or cycloalkyl group being optionally substituted with one or more halogens, (C 1 -C 6 )alkyl, aryl, oxo, -NH 2 , -CO 2 H or -OH; and/or R 1 is preferably selected in the group consisting of H, (C 1 -C 24 )alkyl, (C 2 - C 24 )alkenyl, (C 2 -C 24 )alkynyl, (C 3 -C 12 )cycloalkyl and aryl; said alkyl, alkenyl, alkynyl, aryl or cycloalkyl group being optionally substituted with one or more halogens, (C 1 -C 6 )alkyl, aryl, oxo, -NH 2 , -CO 2 H or -OH.
In a specific embodiment,
X is a methyl, an ethyl or a n-propyl; and/or Y° is-O-; and/or Y 1 , Y 2 and Y 3 are independently absent or -O-; and
R 2 and R 3 form together with the nitrogen atom to which they bound an optionally substituted nitrogen-heterocycloalkyl comprising one nitrogen atom and 3 to 10 ring atoms; and
R 4 is preferably selected in the group consisting of H, (C 1 -C 12 )alkyl and aryl; and/or R 1 is preferably selected in the group consisting of H, (C 1 -C 12 )alkyl, (C 2 -C 12 )alkenyl, (C 2 - C 12 )alkynyl and aryl.
In a specific embodiment,
X is a methyl, an ethyl or a n-propyl; and/or Y° is-O-; and/or Y 1 , Y 2 and Y 3 are independently absent or -O-; and
R 2 and R 3 form together with the nitrogen atom to which they bound a nitrogen- heterocycloalkyl comprising one nitrogen atom and 3 to 10 ring atoms; and
R 4 is preferably H; and/or R 1 is preferably selected in the group consisting of H, (C 1 -C 12 )alkyl, (C 2 -C 12 )alkenyl, (C 2 -C 12 )alkynyl and aryl; more preferably, R 1 is H. In a specific embodiment, when R 2 and R 3 are independently selected in the group consisting of H, -C(O)OR 9 -, -S(O) 2 R 10 -, -C(O)R 9 -, -S(O)R 10 -, -NR 1:L R 12 -, optionally substituted (C 1 -C 12 )alkyl, optionally substituted (C 2 -C 12 )alkenyl, optionally substituted (C 2 -C 12 )alkynyl, optionally substituted (C 3 - C 12 )cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl and optionally substituted heteroaryl (R 9 to R 12 being as defined above), R 4 is preferably selected in the group consisting of H, (C 1 -C 24 )alkyl, (C 2 -C 24 )alkenyl, (C 2 -C 24 )alkynyl, (C 3 -C 12 )cycloalkyl and aryl; said alkyl, alkenyl, alkynyl, aryl or cycloalkyl group being optionally substituted with one or more halogens, (C 1 - C 6 )alkyl, aryl, oxo, -NH2, -CO 2 H or -OH; in particular, R 4 is selected in the group consisting of H, (C 1 - C 12 )al kyl and aryl; preferably, R 4 is H.
In a specific embodiment, when R 2 and R 3 are independently selected in the group consisting of H, - C(O)OR 9 -, -S(O) 2 R 10 -, optionally substituted (C 1 -C 12 )alkyl, optionally substituted (C 2 -C 12 )alkenyl, optionally substituted (C 2 -C 12 )alkynyl, optionally substituted (C 3 -C 12 )cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl and optionally substituted heteroaryl (R 9 and R 10 being as defined above), R 1 is preferably selected in the group consisting of H, (C 1 -C 24 )alkyl, (C 2 -C 24 )alkenyl, (C 2 - C 2 4)alkynyl, (C 3 -C 12 )cycloalkyl and aryl; said alkyl, alkenyl, alkynyl, aryl or cycloalkyl group being optionally substituted with one or more halogens, (C 1 -C 6 )alkyl, aryl, oxo, -NH 2 , -CO 2 H or -OH; provided that at least one of R 1 , R 2 and R 3 is not H, preferably at least one of R 2 and R 3 is not H; in particular, R 1 is selected in the group consisting of H, (C 1 -C 12 )alkyl, (C 2 -C 12 )alkenyl, (C 2 -C 12 )alkynyl and aryl; preferably, R 1 is H.
In a specific embodiment, when R 2 and R 3 are independently selected in the group consisting of H, -C(O)OR 9 -, -S(O) 2 R 10 -, optionally substituted (C 1 -C 12 )alkyl, optionally substituted (C 2 -C 12 )alkenyl, optionally substituted (C 2 -C 12 )alkynyl, optionally substituted (C 3 -C 12 )cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl and optionally substituted heteroaryl; and R 9 and R 10 are as defined above:
R 4 is preferably selected in the group consisting of H, (C 1 -C 24 )alkyl, (C 2 -C 24 )alkenyl, (C 2 - C 24 )alkynyl, (C 3 -C 12 )cycloalkyl and aryl; said alkyl, alkenyl, alkynyl, aryl or cycloalkyl group being optionally substituted with one or more halogens, (C 1 -C 6 )alkyl, aryl, oxo, -NH2, -CO 2 H or -OH; and/or
R 1 is preferably selected in the group consisting of H, (C 1 -C 24 )alkyl, (C 2 -C 24 )alkenyl, (C 2 - C 24 )alkynyl, (C 3 -C 12 )cycloalkyl and aryl; said alkyl, alkenyl, alkynyl, aryl or cycloalkyl group being optionally substituted with one or more halogens, (C 1 -C 6 )alkyl, aryl, oxo, -NH 2 , -CO 2 H or -OH; provided that at least one of R 1 , R 2 and R 3 is not H, preferably at least one of R 2 and R 3 is not H. T1
In a specific embodiment, when R 2 and R 3 are independently selected in the group consisting of H, -C(O)OR 9 -, -S(O) 2 R 10 -, optionally substituted (C 1 -C 12 )alkyl, optionally substituted (C 2 -C 12 )alkenyl, optionally substituted (C 2 -C 12 )alkynyl, optionally substituted (C 3 -C 12 )cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl and optionally substituted heteroaryl; and R 9 and R 10 are as defined above:
R 4 is preferably selected in the group consisting of H, (C 1 -C 12 )alkyl and aryl; and/or
R 1 is preferably selected in the group consisting of H, (C 1 -C 12 )alkyl, (C 2 -C 12 )alkenyl, (C 2 - C 12 )alkynyl and aryl; provided that at least one of R 1 , R 2 and R 3 is not H, preferably at least one of R 2 and R 3 is not H.
In a specific embodiment, when R 2 and R 3 are independently selected in the group consisting of H, -C(O)OR 9 -, -S(O) 2 R 10 -, optionally substituted (C 1 -C 12 )alkyl, optionally substituted (C 2 -C 12 )alkenyl, optionally substituted (C 2 -C 12 )alkynyl, optionally substituted (C 3 -C 12 )cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl and optionally substituted heteroaryl; and R 9 and R 10 are as defined above:
R 4 is preferably H; and/or
R 1 is preferably selected in the group consisting of H, (C 1 -C 12 )alkyl, (C 2 -C 12 )alkenyl, (C 2 - C 12 )alkynyl and aryl; more preferably, R 1 is H; provided that at least one of R 1 , R 2 and R 3 is not H, preferably at least one of R 2 and R 3 is not H.
In a specific embodiment,
X is a methyl, an ethyl or a n-propyl; and/or Y° is-O-; and/or Y 1 , Y 2 and Y 3 are independently absent or -O-; and
R 2 and R 3 are independently selected in the group consisting of H, -C(O)OR 9 -, -S(O) 2 R 10 -, optionally substituted (C 1 -C 12 )alkyl, optionally substituted (C 2 -C 12 )alkenyl, optionally substituted (C 2 -C 12 )alkynyl, optionally substituted (C 3 -C 12 )cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl and optionally substituted heteroaryl (R 9 and R 10 being as defined above); and
R 4 is preferably selected in the group consisting of H, (C 1 -C 24 )alkyl, (C 2 -C 24 )alkenyl, (C 2 - C 2 4)alkynyl, (C 3 -C 12 )cycloalkyl and aryl; said alkyl, alkenyl, alkynyl, aryl or cycloalkyl group being optionally substituted with one or more halogens, (C 1 -C 6 )alkyl, aryl, oxo, -NH 2 , -CO 2 H or -OH; and/or R 1 is preferably selected in the group consisting of H, (C 1 -C 24 )alkyl, (C 2 - C 2 4)alkenyl, (C 2 -C 24 )alkynyl, (C 3 -C 12 )cycloalkyl and aryl; said alkyl, alkenyl, alkynyl, aryl or cycloalkyl group being optionally substituted with one or more halogens, (C 1 -C 6 )alkyl, aryl, oxo, -NH 2 , -CO 2 H or -OH; provided that at least one of R 1 , R 2 and R 3 is not H, preferably at least one of R 2 and R 3 is not H. In a specific embodiment,
X is a methyl, an ethyl or a n-propyl; and/or Y° is -O-; and/or Y 1 , Y 2 and Y 3 are independently absent or -O-; and
R 2 and R 3 are independently selected in the group consisting of H, -C(O)OR 9 -, -S(O) 2 R 10 -, optionally substituted (C 1 -C 12 )alkyl, optionally substituted (C 2 -C 12 )alkenyl, optionally substituted (C 2 -C 12 )alkynyl, optionally substituted (C 3 -C 12 )cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl and optionally substituted heteroaryl (R 9 and R 10 being as defined above); and
R 4 is preferably selected in the group consisting of H, (C 1 -C 12 )alkyl and aryl; and/or R 1 is preferably selected in the group consisting of H, (C 1 -C 12 )alkyl, (C 2 -C 12 )alkenyl, (C 2 - C 12 )alkynyl and aryl; provided that at least one of R 1 , R 2 and R 3 is not H, preferably at least one of R 2 and R 3 is not H.
In a specific embodiment,
X is a methyl, an ethyl or a n-propyl; and/or Y° is-O-; and/or Y 1 , Y 2 and Y 3 are independently absent or -O-; and
R 2 and R 3 are independently selected in the group consisting of H, -C(O)OR 9 -, -S(O) 2 R 10 -, optionally substituted (C 1 -C 12 )alkyl, optionally substituted (C 2 -C 12 )alkenyl, optionally substituted (C 2 -C 12 )alkynyl, optionally substituted (C 3 -C 12 )cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl and optionally substituted heteroaryl (R 9 and R 10 being as defined above); and
R 4 is preferably H; and/or R 1 is preferably selected in the group consisting of H, (C 1 -C 12 )alkyl, (C 2 -C 12 )alkenyl, (C 2 -C 12 )alkynyl and aryl; more preferably, R 1 is H; provided that at least one of R 1 , R 2 and R 3 is not H, preferably at least one of R 2 and R 3 is not H.
In the context of the invention, the compound of formula (I) for use according to the invention is preferably selected from compounds (001) to (064) and (Al) to (A4) of Table 1 below, or a pharmaceutically acceptable salt and/or solvate thereof. Preferably, the compound of formula (I) for use according to the invention is preferably selected from compounds (Al), (A2), (A3), (A4), (002), (003), (004), (008), (009), (010), (012), (013), (014), (015), (016), (017), (018), (019), (020), (022), (023), (024), (025), (026), (028), (029), (036), (039), (040), (043), (045), (049), (051), (052), (054), (057), (058), (059), (061), (063), and (064) of Table 1. More preferably, the compound of formula (I) for use according to the invention is preferably selected from compounds (001) to (038) of Table 1, or a pharmaceutically acceptable salt and/or solvate thereof. More preferably, the compound of formula (I) for use according to the invention is preferably selected from compounds (003) to (007), (013), (014), (021), (031) and (034) to (038) of Table 1, or a pharmaceutically acceptable salt and/or solvate thereof.
In the context of the invention, the compound of formula (I) for use according to the invention is preferably selected from compounds (001) to (038) and (Al) to (A4) of Table 1 below, or a pharmaceutically acceptable salt and/or solvate thereof. Preferably, the compound of formula (I) for use according to the invention is preferably selected from compounds (001) to (038) of Table 1, or a pharmaceutically acceptable salt and/or solvate thereof. More preferably, the compound of formula (I) for use according to the invention is preferably selected from compounds (003) to (007), (013), (014), (021), (029) and (031) to (038) of Table 1, or a pharmaceutically acceptable salt and/or solvate thereof.
In a specific embodiment, in the compound of formula (I) for use according to the invention, when R 5 , R 6 , R 7 and R 8 are H, Y° is -O-, and Y 1 , Y 2 and Y 3 are absent, then R 1 , R 2 and R 3 are not an optionally substituted (C 2 -C 24 )alkynyl.
In a specific embodiment, the compound of formula (I) for use according to the invention is not a compound (Al), (A2), (A3) or (A4).
New compounds
The invention also relates to a compound of general formula (I), or a pharmaceutically acceptable salt, stereoisomer, tautomer or solvate thereof, or a pharmaceutically acceptable salt and/or solvate thereof, wherein
R 1 , R 2 , R 3 and R 4 are independently selected in the group consisting of H,-OH, -C(O)OR 9 -, -S(O) 2 R 10 -, - C(O)R 9 -, -S(O)R 10 -, -NR 1:L R 12 -, optionally substituted (C 1 -C 24 )alkyl, optionally substituted (C 2 -C 24 )alkenyl, optionally substituted (C 2 -C 24 )alkynyl, optionally substituted (C 3 -C 10 )cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl and optionally substituted heteroaryl, provided that at least one of R 2 and R 3 is not H; or
R 1 and R 4 are independently selected in the group consisting of H, OH, -C(O)OR 9 -, -S(O) 2 R 10 -, -C(O)R 9 -, - S(O)R 10 -, -NR 1:L R 12 -, optionally substituted (C 1 -C 24 )alkyl, optionally substituted (C 2 -C 24 )alkenyl, optionally substituted (C 2 -C 24 )alkynyl, optionally substituted (C 3 -C 10 )cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl and optionally substituted heteroaryl, and R 2 and R 3 with the nitrogen atom to which they are bound form together a nitrogen-heterocycloalkyl optionally substituted with at least one substituent selected in the group consisting of halogen; CN; NO 2 ; (C 1 - C 6 )alkyl; (C 1 -C 6 )haloalkyl; (C 1 -C 6 )haloalkoxy, (C 1 -C 6 jhalothioalkoxy, optionally substituted aryl (in particular optionally substituted with one or two (C 1 -C 6 )alkyl or NO 2 ); heteroaryl; oxo; NR a R b ; COR C ; CO 2 R d ; CONR e R f ; OR g ; SR h ; SO 2 R 1 ; SO 2 NR j R k ; NR'COR m ; R n NR°R p ; NR q SO 2 R r ; wherein R a to R r are, independently of one another, H, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, aryl, (C 1 -C 6 )alkyl-aryl, heteroaryl or (C 1 - C 6 jalkyl-heteroaryl; in particular consisting of halogen, CN, NO 2 , (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, oxo, NR a Rb, COR c , C(O)ORd, CONR e Rf, and OR g , wherein R a to R g are, independently of one another, H or (C 1 - C 6 )alkyl;
X is selected in the group consisting of (C 1 -C 12 )alkyl, -O-(C 1 -C 12 )alkyl-, -C(O)-, -C(O)-(C 1 -C 12 )alkyl-, -NH- C(O)-(C 1 -C 12 )alkyl-, -S-(C 1 -C 12 )alkyl-,-S(O)-(C 1 -C 12 )alkyl-, and -S(O) 2 -(C 1 -C 12 )alkyl-; the (C 1 -C 12 )alkyl groups being optionally substituted and/or optionally interrupted by an heteroatom;
Y°, Y 1 , Y 2 and Y 3 are independently absent or selected from -NH-, -O-, -S-, -S(O)-, -S(O) 2 -, -C(O)-, -C(O)O- ,-OC(O)-, -NHC(O)-, -C(O)NH-; -C(O)NR 14 - -(C 1 -C 24 )alkyl-NH-, -(C 1 -C 24 )alkyl-O-, -(C 1 -C 24 )alkyl-S-, (C 1 - C 24 )alkyl-NR 13 -, -(C 1 -C 24 )alkyl- S(O)-, -(C 1 -C 24 )alkyl-S(O) 2 -,-(C 1 -C 24 )alkyl-C(O)-, -(C 1 -C 24 )alkyl-C(O)O-,-(C 1 - C 24 )alkyl-OC(O)-, -(C 1 -C 24 )alkyl-NHC(O)-, -(C 1 -C 24 )alkyl-C(O)NH-, -(C 1 -C 24 )alkyl-C(O)NR 14 -, (C 1 -C 24 )alkyl, - NH-C(O)-NH-, -NH-S(O)-NH-, -NH-S(O 2 )-NH-, -S-C(O)-NH-, -O-C(O)-NH-, -O-S(O)-NH-, -O-S(O 2 )-NH-, -S- CH 2 -C(O)-NH-, -S-CH 2 -S(O)-NH-, -S-CH 2 -S(O 2 )-NH-, -S(O)-CH 2 -C(O)-NH-, -S(O 2 )-CH 2 -C(O)-NH-, -O-CH 2 - C(O)-NH-, -O-CH 2 -S(O)-NH-, -O-CH 2 -S(O 2 )-NH-, -NH-CH 2 -C(O)-NH-, -NH-CH 2 -S(O)-NH-, -NH-CH 2 -S(O 2 )- NH-, -O-(CH 2 ) 2 -NH-C(O)-, -O-(CH 2 ) 2 -N(CH 3 )-C(O)-, -O-(CH 2 ) 2 -NH-S(O)-, -O-(CH 2 ) 2 -N(CH 3 )-S(O)-, -O-(CH 2 ) 2 - NH-S(O 2 )-, -O-(CH 2 ) 2 -N(CH 3 )-S(O 2 )-, -S-(CH 2 ) 2 -NH-C(O)-, -S-(CH 2 ) 2 -N(CH 3 )-C(O)-, -S-(CH 2 ) 2 -NH-S(O)-, -S- (CH 2 ) 2 -N(CH 3 )-S(O)-, -S-(CH 2 ) 2 -NH-S(O 2 )-, -S-(CH 2 ) 2 -N(CH 3 )-S(O 2 )-, -NH-(CH 2 ) 2 -NH-C(O)-, -NH-(CH 2 ) 2 - N(CH 3 )-C(O)-, -NH-(CH 2 ) 2 -NH-S(O)-, -NH-(CH 2 ) 2 -N(CH 3 )-S(O)-, -NH-(CH 2 ) 2 -NH-S(O 2 )-, -NH-(CH 2 ) 2 -N(CH 3 )- S(O 2 )-, -O-CH 2 -CH(CH 2 -OH)-NH-C(O)-, -O-CH 2 -CH(CH 2 -OCH 3 )-NH-C(O)-, -O-CH 2 -CH(CH 3 )-NH-C(O)-, -O- CH(CH 3 )-CH 2 -NH-C(O)-, -O-CH 2 -CH(CH 2 -OH)-NH-S(O)-, -O-CH 2 -CH(CH 2 -OCH 3 )-NH-S(O)-, -0-CH 2 -
CH(CH 3 )-NH-S(O)-, -O-CH(CH 3 )-CH 2 -NH-S(O)-, -O-CH 2 -CH(CH 2 -OH)-NH-S(O 2 )-, -O-CH 2 -CH(CH 2 -OCH 3 )- NH-S(O 2 )-, -O-CH 2 -CH(CH 3 )-NH-S(O 2 )-, -O-CH(CH 3 )-CH 2 -NH-S(O 2 )-, -S-CH 2 -CH(CH 2 -OH)-NH-C(O)-, -S-CH 2 - CH(CH 2 -OCH 3 )-NH-C(O)-, -S-CH 2 -CH(CH 3 )-NH-C(O)-, -S-CH(CH 3 )-CH 2 -NH-C(O)-, -S-CH 2 -CH(CH 2 -OH)-NH- S(O)-, -S-CH 2 -CH(CH 2 -OCH 3 )-NH-S(O)-, -S-CH 2 -CH(CH 3 )-NH-S(O)-, -S-CH(CH 3 )-CH 2 -NH-S(O)-, -S-CH 2 - CH(CH 2 -OH)-NH-S(O 2 )-, -S-CH 2 -CH(CH 2 -OCH 3 )-NH-S(O 2 )-, -S-CH 2 -CH(CH 3 )-NH-S(O 2 )-, -S-CH(CH 3 )-CH 2 - NH-S(O 2 )-, -NH-CH 2 -CH(CH 2 -OH)-NH-C(O)-, -NH-CH 2 -CH(CH 2 -OCH 3 )-NH-C(O)-, -NH-CH 2 -CH(CH 3 )-NH- C(O)-, -NH-CH(CH 3 )-CH 2 -NH-C(O)-, -NH-CH 2 -CH(CH 2 -OH)-NH-S(O)-, -NH-CH 2 -CH(CH 2 -OCH 3 )-NH-S(O)-, - NH-CH 2 -CH(CH 3 )-NH-S(O)-, -NH-CH(CH 3 )-CH 2 -NH-S(O)-, -NH-CH 2 -CH(CH 2 -OH)-NH-S(O 2 )-, -NH-CH 2 - CH(CH 2 -OCH 3 )-NH-S(O 2 )-, -NH-CH 2 -CH(CH 3 )-NH-S(O 2 )-, -NH-CH(CH 3 )-CH 2 -NH-S(O 2 )-, -O-(CH 2 ) 2 -NH-, -S- (CH 2 ) 2 -NH-, and -NH-(CH 2 ) 2 -NH-; the (C 1 -C 24 )alkyl groups being optionally substituted; preferably Y° is not absent, and
R 5 , R 6 , R 7 and R 8 are independently selected in the group consisting of H, halogen, optionally substituted (C 1 -C 24 )alkyl, optionally substituted (C 2 -C 24 )alkenyl, optionally substituted (C 2 -C 24 )alkynyl, optionally substituted (C 3 -C 10 )cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl and optionally substituted heteroaryl; and
R 9 to R 14 are independently selected in the group consisting of optionally substituted (C 1 -C 12 )alkyl, optionally substituted (C 2 -C 12 )alkenyl, optionally substituted (C 2 -C 12 )alkynyl, optionally substituted aryl; provided that when R 5 , R 6 , R 7 and R 8 are H, Y° is -O-, and Y 1 , Y 2 and Y 3 are absent, then R 1 , R 2 and R 3 are not an optionally substituted (C 2 -C 24 )alkynyl .
In particular, R 9 is selected in the group consisting of optionally substituted (C 1 -C 12 )alkyl, optionally substituted (C 2 -C 12 )alkenyl, optionally substituted (C 2 -C 12 )alkynyl, and aryl optionally substituted with a (C 1 -C 6 )alkyl; and
R 10 to R 14 are independently selected in the group consisting of optionally substituted (C 1 -C 12 )alkyl, optionally substituted (C 2 -C 12 )alkenyl, optionally substituted (C 2 -C 12 )alkynyl, optionally substituted aryl.
In the compound of general formula (I), X is selected in the group consisting of (C 1 -C 12 )alkyl, - O-(C 1 -C 12 )alkyl-, -C(O)-, -C(O)-(C 1 -C 12 )alkyl-, -NH-C(O)-(C 1 -C 12 )alkyl-, -S-(C 1 -C 12 )alkyl-,-S(O)-(C 1 -C 12 )alkyl-, and -S(O) 2 -(C 1 -C 12 )alkyl-; the (C 1 -C 12 )alkyl groups being optionally substituted and/or optionally interrupted by an heteroatom. Preferably X is selected in the group consisting of (C 1 -C 12 )alkyl, -O-(C 1 - C 12 )alkyl-, -C(O)-, -C(O)-(C 1 -C 12 )alkyl-, -NH-C(O)-(C 1 -C 12 )alkyl-; the (C 1 -C 12 )alkyl groups being optionally substituted and/or optionally interrupted by an heteroatom.; the (C 1 -C 12 )alkyl groups being optionally substituted and/or optionally interrupted by an heteroatom. Preferably, X is selected in the group consisting of (C 1 -C 6 )alkyl, -O-(C 1 -C 6 )alkyl-, -C(O)-, -C(O)-(C 1 -C 6 )alkyl- and -NH-C(O)-(C 1 -C6)alkyl-; the (C 4 - C 6 )alkyl groups being optionally substituted and/or optionally interrupted by an heteroatom. More preferably, X is selected in the group consisting of (C 1 -C 3 )alkyl, -O-(C 1 -C 3 )alkyl-, -C(O)-(C 1 -C 3 )alkyl- and - NH-C(O)-(C 1 -C 3 )alkyl-; the (C 1 -C 3 )alkyl groups being optionally substituted and/or optionally interrupted by an heteroatom.
In a specific embodiment, X is a (C 1 -C 6 )alkyl. Preferably X is a methyl, an ethyl or a n-propyl, more preferably an ethyl. In the compound of general formula (I), Y°, Y 1 , Y 2 and Y 3 are independently absent or selected from -NH-, -O-, -S-, -S(O)-, -S(O) 2 -, -C(O)-, -C(O)O-,-OC(O)-, -NHC(O)-, -C(O)NH-; -C(O)NR 14 - -(C 1 -C 24 )alkyl- NH-, -(C 1 -C 24 )alkyl-O-, -(C 1 -C 24 )alkyl-S-, (C 1 -C 24 )alkyl-NR 13 -, -(C 1 -C 24 )alkyl- S(O)-, -(C 1 -C 24 )alkyl-S(O) 2 -,-(C 1 - C 24 )alkyl-C(O)-, -(C 1 -C 24 )alkyl-C(O)O-,-(C 1 -C 24 )alkyl-OC(O)-, -(C 1 -C 24 )alkyl-NHC(O)-, -(C 1 -C 24 )alkyl-C(O)NH- , -(C 1 -C 24 )alkyl-C(O)NR 14 -, optionally substituted (C 1 -C 24 )alkyl, -NH-C(O)-NH-, -NH-S(O)-NH-, -NH-S(O 2 )- NH-, -S-C(O)-NH-, -O-C(O)-NH-, -O-S(O)-NH-, -O-S(O 2 )-NH-, -S-CH 2 -C(O)-NH-, -S-CH 2 -S(O)-NH-, -S-CH 2 - S(O 2 )-NH-, -S(O)-CH 2 -C(O)-NH-, -S(O 2 )-CH 2 -C(O)-NH-, -O-CH 2 -C(O)-NH-, -O-CH 2 -S(O)-NH-, -O-CH 2 -S(O 2 )- NH-, -NH-CH 2 -C(O)-NH-, -NH-CH 2 -S(O)-NH-, -NH-CH 2 -S(O 2 )-NH-, -O-(CH 2 ) 2 -NH-C(O)-, -O-(CH 2 ) 2 -N(CH 3 )- C(O)-, -O-(CH 2 ) 2 -NH-S(O)-, -O-(CH 2 ) 2 -N(CH 3 )-S(O)-, -O-(CH 2 ) 2 -NH-S(O 2 )-, -O-(CH 2 ) 2 -N(CH 3 )-S(O 2 )-, -S- (CH 2 ) 2 -NH-C(O)-, -S-(CH 2 ) 2 -N(CH 3 )-C(O)-, -S-(CH 2 ) 2 -NH-S(O)-, -S-(CH 2 ) 2 -N(CH 3 )-S(O)-, -S-(CH 2 ) 2 -NH-S(O 2 )- , -S-(CH 2 ) 2 -N(CH 3 )-S(O 2 )-, -NH-(CH 2 ) 2 -NH-C(O)-, -NH-(CH 2 ) 2 -N(CH 3 )-C(O)-, -NH-(CH 2 ) 2 -NH-S(O)-, -NH- (CH 2 ) 2 -N(CH 3 )-S(O)-, -NH-(CH 2 ) 2 -NH-S(O 2 )-, -NH-(CH 2 ) 2 -N(CH 3 )-S(O 2 )-, -O-CH 2 -CH(CH 2 -OH)-NH-C(O)-, -O- CH 2 -CH(CH 2 -OCH 3 )-NH-C(O)-, -O-CH 2 -CH(CH 3 )-NH-C(O)-, -O-CH(CH 3 )-CH 2 -NH-C(O)-, -O-CH 2 -CH(CH 2 - OH)-NH-S(O)-, -O-CH 2 -CH(CH 2 -OCH 3 )-NH-S(O)-, -O-CH 2 -CH(CH 3 )-NH-S(O)-, -O-CH(CH 3 )-CH 2 -NH-S(O)-, - O-CH 2 -CH(CH 2 -OH)-NH-S(O 2 )-, -O-CH 2 -CH(CH 2 -OCH 3 )-NH-S(O 2 )-, -O-CH 2 -CH(CH 3 )-NH-S(O 2 )-, -O-
CH(CH 3 )-CH 2 -NH-S(O 2 )-, -S-CH 2 -CH(CH 2 -OH)-NH-C(O)-, -S-CH 2 -CH(CH 2 -OCH 3 )-NH-C(O)-, -S-CH 2 -CH(CH 3 )- NH-C(O)-, -S-CH(CH 3 )-CH 2 -NH-C(O)-, -S-CH 2 -CH(CH 2 -OH)-NH-S(O)-, -S-CH 2 -CH(CH 2 -OCH 3 )-NH-S(O)-, -S- CH 2 -CH(CH 3 )-NH-S(O)- 7 -S-CH(CH 3 )-CH 2 -NH-S(O)- 7 -S-CH 2 -CH(CH 2 -OH)-NH-S(O 2 )- 7 -S-CH 2 -CH(CH 2 -OCH 3 )- NH-S(O 2 )-, -S-CH 2 -CH(CH 3 )-NH-S(O 2 )- 7 -S-CH(CH 3 )-CH 2 -NH-S(O 2 )- 7 -NH-CH 2 -CH(CH 2 -OH)-NH-C(O)- 7 -NH- CH 2 -CH(CH 2 -OCH 3 )-NH-C(O)- 7 -NH-CH 2 -CH(CH 3 )-NH-C(O)- 7 -NH-CH(CH 3 )-CH 2 -NH-C(O)- 7 -NH-CH 2 - CH(CH 2 -OH)-NH-S(O)- 7 -NH-CH 2 -CH(CH 2 -OCH 3 )-NH-S(O)- 7 -NH-CH 2 -CH(CH 3 )-NH-S(O)- 7 -NH-CH(CH 3 )- CH 2 -NH-S(O)-, -NH-CH 2 -CH(CH 2 -OH)-NH-S(O 2 )- 7 -NH-CH 2 -CH(CH 2 -OCH 3 )-NH-S(O 2 )- 7 -NH-CH 2 -CH(CH 3 )- NH-S(O 2 )-, -NH-CH(CH 3 )-CH 2 -NH-S(O 2 )- 7 -O-(CH 2 ) 2 -NH-, -S-(CH 2 ) 2 -NH-, and -NH-(CH 2 ) 2 -NH-; the (C 1 - C 24 )al kyl groups being optionally substituted. In particular, Y° is not absent.
In a specific embodiment, in the compound of general formula (I), Y°, Y 1 , Y 2 and Y 3 are independently absent or selected from -NH-, -O-, -S-, -S(O)-, -S(O) 2 -, -C(O)-, -C(O)O-,-OC(O)-, -NHC(O)- , -C(O)NH-; -C(O)NR 14 - -(C 1 -C 24 )alkyl-NH-, -(C 1 -C 24 )alkyl-O-, -(C 1 -C 24 )alkyl-S-, (C 1 -C 24 )alkyl-NR 13 -, -(C 1 - C 24 )al kyl- S(O)-, -(C 1 -C 24 )alkyl-S(O) 2 -,-(C 1 -C 24 )alkyl-C(O)-, -(C 1 -C 24 )alkyl-C(O)O-,-(C 1 -C 24 )alkyl-OC(O)-, -(C 1 - C 24 )alkyl-NHC(O)-, -(C 1 -C 24 )alkyl-C(O)NH-, -(C 1 -C 24 )alkyl-C(O)NR 14 -, optionally substituted (C 1 -C 24 )alkyl, - NH-C(O)-NH-, -NH-S(O)-NH-, -NH-S(O 2 )-NH-, -S-C(O)-NH-, -O-C(O)-NH-, -O-S(O)-NH-, -O-S(O 2 )-NH-, -O- (CH 2 ) 2 -NH-, -S-(CH 2 ) 2 -NH-, and -NH-(CH 2 ) 2 -NH-; the (C 1 -C 24 )alkyl groups being optionally substituted. In particular, Y° is not absent.
In a particular embodiment, the compound of general formula (I), Y°, Y 1 , Y 2 and Y 3 are independently absent or selected from -NH-, -0-,-S-, -S(O)-, -S(O) 2 -, -C(O)-, -C(O)O-,-OC(O)-, -NHC(O)-, -C(O)NH-; -C(O)NR 14 - -(C 1 -C 24 )alkyl-NH-, -(C 1 -C 24 )alkyl-O-, -(C 1 -C 24 )alkyl-S-, (C 1 -C 24 )alkyl-NR 13 -, -(C 1 - C 24 )al kyl- S(O)-, -(C 1 -C 24 )alkyl-S(O) 2 -,-(C 1 -C 24 )alkyl-C(O)-, -(C 1 -C 24 )alkyl-C(O)O-,-(C 1 -C 24 )alkyl-OC(O)-, -(C 1 - C 24 )alkyl-NHC(O)-, -(C 1 -C 24 )alkyl-C(O)NH-, -(C 1 -C 24 )alkyl-C(O)NR 14 -, and optionally substituted (C 1 - C 24 )alkyl; the (C 1 -C 24 )alkyl groups being optionally substituted; and preferably, Y° is not absent. In particular, Y°, Y 1 , Y 2 and Y 3 are independently absent or selected from -NH-, -O-, -S-, -S(O)-, -S(O) 2 -, - C(O)-, -C(O)O-,-OC(O)-, -NHC(O)-, -C(O)NH-; -C(O)NR 14 - -(C 1 -C 12 )alkyl-NH-, -(C 1 -C 12 )alkyl-O-, -(C 1 - C 12 )alkyl-S-, (C 1 -C 12 )alkyl-NR 13 -, -(C 1 -C 12 )alkyl- S(O)-, -(C 1 -C 12 )alkyl-S(O) 2 -,-(C 1 -C 12 )alkyl-C(O)-, -(C 1 - C 12 )alkyl-C(O)O-,-(C 1 -C 12 )alkyl-OC(O)-, -(C 1 -C 12 )alkyl-NHC(O)-, -(C 1 -C 12 )alkyl-C(O)NH-, -(C 1 -C 12 )alkyl- C(O)NR 14 -, and optionally substituted (C 1 -C 12 )alkyl; the (C 1 -C 12 )alkyl groups being optionally substituted; and preferably, Y° is not absent. More particularly, Y°, Y 1 , Y 2 and Y 3 are independently absent or selected from -NH-, -O-, -S-, -S(O)-, -S(O) 2 -, -C(O)-, -C(O)O-,-OC(O)-, -NHC(O)-, -C(O)NH-; - C(O)NR 14 - -(C 1 -C 6 )alkyl-NH-, -(C 1 -C 6 )alkyl-O-, -(C 1 -C 6 )alkyl-S-, (C 1 -C 6 )alkyl-NR 13 -, -(C 1 -C 6 )alkyl- S(O)-, -(C 1 - C 6 )alkyl-S(O) 2 -,-(C 1 -C 6 )alkyl-C(O)-, -(C 1 -C 6 )alkyl-C(O)O-,-(C 1 -C 6 )alkyl-OC(O)-, -(C 1 -C 6 )alkyl-NHC(O)-, -(C 1 - C 6 )alkyl-C(O)NH-, -(C 1 -C6)alkyl-C(O)NR 14 -, and optionally substituted (C 1 -C 6 )alkyl; the (C 1 -C 6 )alkyl groups being optionally substituted; and preferably, Y° is not absent.. Preferably, Y°, Y 1 , Y 2 and Y 3 are independently absent or selected from -O-, and optionally substituted (C 1 -C 6 )alkyl; and preferably, Y° is not absent. In particular, Y° is not absent.
In a specific embodiment, Y°, Y 1 , Y 2 and Y 3 are independently absent or -O-. Preferably Y° is -O- and, Y 1 , Y 2 and Y 3 are independently absent or -O-, preferably absent.
In a specific embodiment, in the compound of general formula (I), X is a (C 1 -C 6 )alkyl, Y° is -O-, and Y 1 , Y 2 and Y 3 are independently absent or -O-.
In a particular embodiment, X is a methyl, an ethyl or a n-propyl, Y° is -O-, and Y 1 , Y 2 and Y 3 are independently absent or -O-. Preferably, X is a methyl, an ethyl or a n-propyl, Y° is -O-, and Y 1 , Y 2 and Y 3 are absent. More preferably, X is an ethyl, Y° is -O-, and Y 1 , Y 2 and Y 3 are absent.
In the compound of general formula (I), R 5 , R 6 , R 7 and R 8 independently selected in the group consisting of H, halogen, optionally substituted (C 1 -C 24 )alkyl, optionally substituted (C 2 -C 24 )alkenyl, optionally substituted (C 2 -C 24 )alkynyl, optionally substituted (C 3 -C 10 )cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl and optionally substituted heteroaryl. Preferably, at least one of R 5 , R 6 , R 7 and R 8 is not H.
In a specific embodiment, R 5 , R 6 , R 7 and R 8 are independently selected in the group consisting of H, halogen, optionally substituted (C 1 -C 24 )alkyl, optionally substituted (C 2 -C 24 )alkenyl, optionally substituted (C 2 -C 24 )alkynyl. In particular, R 5 , R 6 , R 7 and R 8 are independently selected in the group consisting of H, halogen, optionally substituted (C 1 -C 12 )alkyl, optionally substituted (C 2 -C 12 )alkenyl, optionally substituted (C 2 -C 12 )alkynyl. More particularly, R 5 , R 6 , R 7 and R 8 are independently selected in the group consisting of H, halogen, optionally substituted (C 1 -C 6 )alkyl, optionally substituted (C 2 - C 6 )alkenyl, optionally substituted (C 2 -C 6 )alkynyl. Preferably R 5 , R 6 , R 7 and R 8 are independently selected in the group consisting of H, halogen, haloalkyl, or (C 1 -C 24 )alkyl. More preferably R 5 , R 6 , R 7 and R 8 are independently selected in the group consisting of H, halogen, haloalkyl such as CF 3 , or (C 1 -C 6 )alkyl. Preferably, at least one of R 5 , R 6 , R 7 and R 8 is not H.
In a specific embodiment, three of R 5 , R 6 , R 7 and R 8 are H, and the last one is as defined above except H.
In another specific embodiment, two of R 5 , R 6 , R 7 and R 8 are H, and two are as defined above except H.
In another specific embodiment, three of R 5 , R 6 , R 7 and R 8 are H, and one is as defined above except H.
In another specific embodiment, R 5 , R 6 , R 7 and R 8 are H.
In another specific embodiment, R 5 , R 6 , R 7 and R 8 are as defined above but not H.
In a particular embodiment, one or two of R 5 , R 6 , R 7 and R 8 are selected in the group consisting of H, halogen, haloalkyl such as CF 3 , or (C 1 -C 6 )alkyl, and the others are H.
In a particular embodiment, one or two of R 5 , R 6 , R 7 and R 8 are selected in the group consisting of halogen, haloalkyl such as CF 3 , or (C 1 -C 6 )alkyl, and the others are H.
In a specific embodiment, Y° is -O-, and Y 1 , Y 2 and Y 3 are absent, and: three of R 5 , R 6 , R 7 and R 8 are H, and the last one is as defined above except H; or two of R 5 , R 6 , R 7 and R 8 are H, and two are as defined above except H; or three of R 5 , R 6 , R 7 and R 8 are H, and one is as defined above except H; or
- R 5 , R 6 , R 7 and R 8 are H; or
R 5 , R 6 , R 7 and R 8 are as defined above but not H.
In a particular embodiment, Y° is -O-, and Y 1 , Y 2 and Y 3 are absent, one or two of R 5 , R 6 , R 7 and R 8 are selected in the group consisting of H, halogen, haloalkyl such as CF 3 , or (C 1 -C 6 )alkyl, and the others are H.
In a particular embodiment, Y° is -O-, and Y 1 , Y 2 and Y 3 are absent, one or two of R 5 , R 6 , R 7 and R 8 are selected in the group consisting of halogen, haloalkyl such as CF 3 , or (C 1 -C 6 )alkyl, and the others are H. In the above embodiment, when R 5 , R 6 , R 7 and R 8 are H, and Y 1 , Y 2 and Y 3 are absent, R 1 , R 2 and R 3 are not an optionally substituted (Cj-Cj^alkynyl . The new compound of general formula (I) cannot be a compound (Al), (A2), (A3) or (A4).
In one embodiment of the compound of general formula (I), R 1 , R 2 , R 3 and R 4 are independently selected in the group consisting of H, OH, -C(O)OR 9 -, -S(O)zR 10 -, -C(O)R 9 -, -S(O)R 10 -, -NR 1:L R 12 -, optionally substituted (C 1 -C 24 )alkyl, optionally substituted (C 2 -C 24 )alkenyl, optionally substituted (C 2 -C 24 )alkynyl, optionally substituted (C 3 -C 10 )cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted (C 1 -C 6 )alkyl-aryl, and optionally substituted heteroaryl, provided that at least one of R 2 and R 3 is not H.
In one particular embodiment of the compound of general formula (I), R 1 , R 2 , R 3 and R 4 are independently selected in the group consisting of H, OH, -C(O)OR 9 -, -S(O) 2 R 10 -, 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 (C 1 -C 6 )alkyl-aryl, and optionally substituted heteroaryl, provided that at least one of R 2 and R 3 is not H.
In this definition, "optionally substituted" preferably means non-substituted or substituted with at least one, for example 1, 2 or 3, substituent(s) which may be selected in the group consisting of halogen; CN; NO 2 ; (C 1 -C 6 )alkyl; (C 1 -C 6 )haloalkyl; (C 1 -C 6 )haloalkoxy, (C 1 -C 6 jhalothioalkoxy, optionally substituted aryl (in particular optionally substituted with one or two (C 1 -C 6 )alkyl or NO 2 ); heteroaryl; halogeno-heteroaryl, in particular halogeno-furanyl; oxo; NR a R b ; COR C ; CC>2R d ; CONR e R f ; OR g ; SR h ; SO 2 R'; SC>2NR j R k ; NR'COR m ; R n NR°R p ; NR q S02R r ; wherein R a to R r are, independently of one another, H, (C 4 - C 6 )alkyl, (C 1 -C 6 )haloalkyl, aryl, (C 1 -C 6 )alkyl-aryl, heteroaryl or (C 1 -C 6 Jalkyl-heteroaryl; in particular consisting of halogen; CN; NO 2 ; (C 1 -C 6 )alkyl; (C 1 -C 6 )haloalkyl; aryl optionally substituted with one or two (C 1 -C 6 )alkyl or NO 2 ; heteroaryl; oxo; NR a R b ; COR C ; CC>2R d ; CONR e R f ; and OR g ; wherein R a to R g are, independently of one another, H, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, aryl, (C 1 -C 6 )alkyl-aryl, heteroaryl or (C 1 - C 6 )alkyl-heteroaryl.
In a specific embodiment, R 1 is preferably selected in the group consisting of H, (C 1 -C 24 )alkyl, (C 2 -C 24 )alkenyl, (C 2 -C 24 )alkynyl, (Ca-C 12 )cycloalkyl and aryl; said alkyl, alkenyl, alkynyl, aryl or cycloalkyl group being optionally substituted with one or more halogens, (C 1 -C 6 )alkyl, aryl, oxo, -NH2, -CO 2 H or - OH. In particular, R 1 is selected in the group consisting of H, (C 1 -C 12 )alkyl, (C 2 -C 12 )alkenyl, (C 2 -C 12 )alkynyl and aryl. Preferably, R 1 is H.
In a specific embodiment, R 4 is preferably selected in the group consisting of H, (C 1 -C 24 )alkyl, (C 2 -C 24 )alkenyl, (C 2 -C 24 )alkynyl, (Ca-C 12 )cycloalkyl and aryl; said alkyl, alkenyl, alkynyl, aryl or cycloalkyl group being optionally substituted with one or more halogens, (C 1 -C 6 )alkyl, aryl, oxo, -NH2, -CO 2 H or - OH. In particular, R 4 is selected in the group consisting of H, (C 1 -C 12 )alkyl and aryl. Preferably, R 4 is H.
In a specific embodiment, R 2 and R 3 are independently selected in the group consisting of H, OH, -C(O)OR 9 -, -S(O) 2 R 10 -, -C(O)R 9 -, -S(O)R 10 -, -NR 1:L R 12 -, optionally substituted (C 1 -C 12 )alkyl, optionally substituted (C 2 -C 12 )alkenyl, optionally substituted (C 2 -C 12 )alkynyl, optionally substituted (C 3 - C 12 )cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl and optionally substituted heteroaryl, provided that at least one of R 2 and R 3 is not H; or R 2 and R 3 form together with the nitrogen atom to which they bound an optionally substituted heterocycloalkyl. In this definition, "optionally substituted" preferably means non-substituted or substituted with at least one, for example 1, 2 or 3, substituent(s) which may be preferably halogen; CN; NO 2 ; (C 1 -C 6 )alkyl; (C 1 - C 6 jhaloalkyl; (C 1 -C 6 )haloalkoxy, (C 1 -C 6 )halothioalkoxy, optionally substituted aryl (in particular optionally substituted with one or two (C 1 -C 6 )alkyl or NO 2 ); heteroaryl; halogeno-heteroaryl, in particular halogeno-furanyl; oxo; NR a R b ; COR C ; CO 2 R d ; CONR e R f ; OR g ; SR h ; SO 2 R 1 ; SO 2 NR j R k ; NR'COR m ; R n NR°R p ; NR q SO 2 R r ; wherein R a to R r are, independently of one another, H, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, aryl, (C 1 -C 6 )alkyl-aryl, heteroaryl or (C 1 -C 6 )alkyl-heteroaryl; in particular (C 1 -C 6 )alkyl; halogen; CN; NO 2 ; (C 1 -C 6 )haloalkyl; phenyl optionally substituted with one or two (C 1 -C 6 )alkyl or NO 2 ; heteroaryl optionally substituted with -OH; oxo; NR a R b ; (C 1 -C 12 )alkyl-NR a R b ; COR C ; CO 2 R d ; CONR e R f ; and OR g ; wherein R a to R g are, independently of one another, H, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, aryl, (C 1 -C 6 )alkyl- aryl, heteroaryl or (C 1 -C 6 Jalkyl-heteroaryl.
In the compound of general formula (I), when one or more of R 1 , R 2 , R 3 and R 4 is -C(O)OR 9 -, - S(O) 2 R 10 -, -C(O)R 9 -, -S(O)R 10 -, or -NR 11 R 12 -, preferably -C(O)OR 9 - or -S(O) 2 R 10 -, R 9 to R 12 are independently selected in the group consisting of optionally substituted (C 1 -C 12 )alkyl, optionally substituted (C 2 -C 12 )alkenyl, optionally substituted (C 2 -C 12 )alkynyl, and optionally substituted aryl.
In the compound of general formula (I), when one or more of R 1 , R 2 , R 3 and R 4 is -C(O)OR 9 -, - S(O) 2 R 10 -, -C(O)R 9 -, -S(O)R 10 -, or -NR 1:L R 12 -, preferably -C(O)OR 9 - or -S(O) 2 R 10 -, R 9 is selected in the group consisting of optionally substituted (C 1 -C 12 )alkyl, optionally substituted (C 2 -C 12 )alkenyl, optionally substituted (C 2 -C 12 )alkynyl, and aryl optionally substituted with a (C 1 -C 6 )alkyl; and R 10 to R 12 are independently selected in the group consisting of optionally substituted (C 1 -C 12 )alkyl, optionally substituted (C 2 -C 12 )alkenyl, optionally substituted (C 2 -C 12 )alkynyl, and optionally substituted aryl.
In this definition, "optionally substituted" preferably means non-substituted or substituted with at least one, for example 1, 2 or 3, substituent(s) which may be preferably (C 1 -C 6 )alkyl.
In a specific embodiment, R 9 to R 12 are independently selected in the group consisting of optionally substituted (C 1 -C 6 )alkyl, optionally substituted (C 2 -C 6 )alkenyl, optionally substituted (C 2 - C 6 )alkynyl, and optionally substituted aryl. In particular, R 9 is selected in the group consisting of optionally substituted (C 1 -C 6 )alkyl, optionally substituted (C 2 -C 6 )alkenyl, optionally substituted (C 2 -C 6 )alkynyl, and aryl optionally substituted with a (C 1 -C 6 )alkyl such as methyl; and R 10 to R 12 are independently selected in the group consisting of optionally substituted (C 1 -C 6 )alkyl, optionally substituted (C 2 -C 6 )alkenyl, optionally substituted (C 2 -C 6 )alkynyl, and optionally substituted aryl.
Preferably, R 9 to R 12 are independently selected in the group consisting of (C 1 -C 6 )alkyl, (C 2 - C 6 )alkenyl, (C 2 -C 6 )alkynyl, aryl or aryl substituted with a (C 1 -C 6 )alkyl such as methyl.
In another embodiment of the compound of general formula (I), R 1 and R 4 are independently selected in the group consisting of H, OH, -C(O)OR 9 -, -S(O) 2 R 10 -, 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 and optionally substituted heteroaryl; and R 2 and R 3 form together with the nitrogen atom to which they bound an optionally substituted heterocycloalkyl.
In a specific embodiment, the optionally substituted heterocycloalkyl formed by R 2 and R 3 with the nitrogen atom to which they are bound form together is preferably an optionally substituted nitrogen-heterocycloalkyl comprising 3 to 10 ring atoms; preferably an optionally substituted nitrogen- heterocycloalkyl comprising one nitrogen atom and 3 to 10 ring atoms. In particular, the nitrogen- heterocycloalkyl is non substituted or substituted with one or more substituents selected in the list consisting of a halogen; CN; NO 2 ; (C 1 -C 6 )alkyl; (C 1 -C 6 )haloalkyl; (C 1 -C 6 )haloalkoxy, (C 1 -C 6 jhalothioalkoxy, optionally substituted aryl (in particular optionally substituted with one or two (C 1 -C 6 )alkyl or NO 2 ); heteroaryl; oxo; NR a R b ; COR C ; CO 2 R d ; CONR e R f ; OR g ; SR h ; SO 2 R 1 ; SO 2 NR j R k ; NR'COR m ; R n NR°R p ; NR q SO 2 R r ; wherein R a to R r are, independently of one another, H, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, aryl, (C 1 -C 6 )alkyl- aryl, heteroaryl or (C 1 -C 6 )alkyl-heteroaryl; in particular consisting of halogens, (C 1 -C 6 )alkyl, aryl, oxo, - NH 2 , -CO 2 H or -OH.
In a specific embodiment, when R 2 and R 3 form together with the nitrogen atom to which they bound an optionally substituted heterocycloalkyl, R 4 is preferably selected in the group consisting of H, (C 1 -C 24 )alkyl, (C 2 -C 24 )alkenyl, (C 2 -C 24 )alkynyl, (C 3 -C 12 )cycloalkyl and aryl; said alkyl, alkenyl, alkynyl, aryl or cycloalkyl group being optionally substituted with one or more halogens, (C 1 -C 6 )alkyl, aryl, oxo, -NH 2 , -CO 2 H or -OH; in particular, R 4 is selected in the group consisting of H, (C 1 -C 12 )alkyl and aryl; preferably, R 4 is H.
In a specific embodiment, when R 2 and R 3 form together with the nitrogen atom to which they bound an optionally substituted heterocycloalkyl, R 1 is preferably selected in the group consisting of H, (C 1 -C 24 )alkyl, (C 2 -C 24 )alkenyl, (C 2 -C 24 )alkynyl, (C 3 -C 12 )cycloalkyl and aryl; said alkyl, alkenyl, alkynyl, aryl or cycloalkyl group being optionally substituted with one or more halogens, (C 1 -C 6 )alkyl, aryl, oxo, -NH 2 , -CO 2 H or -OH; in particular, R 1 is selected in the group consisting of H, (C 1 -C 12 )alkyl, (C 2 -C 12 )alkenyl, (C 2 -C 12 )alkynyl and aryl; preferably, R 1 is H.
In a specific embodiment, when R 2 and R 3 form together with the nitrogen atom to which they bound an optionally substituted heterocycloalkyl:
R 4 is preferably selected in the group consisting of H, (C 1 -C 24 )alkyl, (C 2 -C 24 )alkenyl, (C 2 - C 24 )alkynyl, (C 3 -C 12 )cycloalkyl and aryl; said alkyl, alkenyl, alkynyl, aryl or cycloalkyl group being optionally substituted with one or more halogens, (C 1 -C 6 )alkyl, aryl, oxo, -NH 2 , -CO 2 H or -OH; and
R 1 is preferably selected in the group consisting of H, (C 1 -C 24 )alkyl, (C 2 -C 24 )alkenyl, (C 2 - C 24 )alkynyl, (C 3 -C 12 )cycloalkyl and aryl; said alkyl, alkenyl, alkynyl, aryl or cycloalkyl group being optionally substituted with one or more halogens, (C 1 -C 6 )alkyl, aryl, oxo, -NH 2 , -CO 2 H or -OH.
In a specific embodiment, when R 2 and R 3 form together with the nitrogen atom to which they bound an optionally substituted heterocycloalkyl:
R 4 is preferably selected in the group consisting of H, (C 1 -C 12 )alkyl and aryl; and
R 1 is preferably selected in the group consisting of H, (C 1 -C 12 )alkyl, (C 2 -C 12 )alkenyl, (C 2 - C 12 )alkynyl and aryl.
In a specific embodiment, when R 2 and R 3 form together with the nitrogen atom to which they bound an optionally substituted heterocycloalkyl:
R 4 is preferably H; and
R 1 is preferably selected in the group consisting of H, (C 1 -C 12 )alkyl, (C 2 -C 12 )alkenyl, (C 2 - C 12 )alkynyl and aryl; more preferably, R 1 is H.
In a specific embodiment,
X is a methyl, an ethyl or a n-propyl; and/or Y° is-O-; and/or Y 1 , Y 2 and Y 3 are independently absent or -O-; and
R 2 and R 3 form together with the nitrogen atom to which they bound an optionally substituted nitrogen-heterocycloalkyl comprising 3 to 10 ring atoms; and
R 4 is preferably selected in the group consisting of H, (C 1 -C 24 )alkyl, (C 2 -C 24 )alkenyl, (C 2 - C 24 )alkynyl, (C 3 -C 12 jcycloalkyl and aryl; said alkyl, alkenyl, alkynyl, aryl or cycloalkyl group being optionally substituted with one or more halogens, (C 1 -C 6 )alkyl, aryl, oxo, -NH 2 , -CO 2 H or -OH; and/or R 1 is preferably selected in the group consisting of H, (C 1 -C 24 )alkyl, (C 2 - C 24 )alkenyl, (C 2 -C 24 )alkynyl, (C 3 -C 12 )cycloalkyl and aryl; said alkyl, alkenyl, alkynyl, aryl or cycloalkyl group being optionally substituted with one or more halogens, (C 1 -C 6 )alkyl, aryl, oxo, -NH 2 , -CO 2 H or -OH.
In a specific embodiment,
X is a methyl, an ethyl or a n-propyl; and/or Y° is-O-; and/or Y 1 , Y 2 and Y 3 are independently absent or -O-; and
R 2 and R 3 form together with the nitrogen atom to which they bound an optionally substituted nitrogen-heterocycloalkyl comprising one nitrogen atom and 3 to 10 ring atoms; and
R 4 is preferably selected in the group consisting of H, (C 1 -C 12 )alkyl and aryl; and/or R 1 is preferably selected in the group consisting of H, (C 1 -C 12 )alkyl, (C 2 -C 12 )alkenyl, (C 2 - C 12 )alkynyl and aryl.
In a specific embodiment,
X is a methyl, an ethyl or a n-propyl; and/or Y° is-O-; and/or Y 1 , Y 2 and Y 3 are independently absent or -O-; and
R 2 and R 3 form together with the nitrogen atom to which they bound a nitrogen- heterocycloalkyl comprising one nitrogen atom and 3 to 10 ring atoms; and
R 4 is preferably H; and/or R 1 is preferably selected in the group consisting of H, (C 1 -C 12 )alkyl, (C 2 -C 12 )alkenyl, (C 2 -C 12 )alkynyl and aryl; more preferably, R 1 is H.
In a specific embodiment, when R 2 and R 3 are independently selected in the group consisting of H, -C(O)OR 9 -, -S(O) 2 R 10 -,-C(O)R 9 -, -S(O)R 10 -, -NR 1:L R 12 -, optionally substituted (C 1 -C 12 )alkyl, optionally substituted (C 2 -C 12 )alkenyl, optionally substituted (C 2 -C 12 )alkynyl, optionally substituted (C 3 - C 12 )cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl and optionally substituted heteroaryl (R 9 to R 12 being as defined above), R 4 is preferably selected in the group consisting of H, (C 1 -C 24 )alkyl, (C 2 -C 24 )alkenyl, (C 2 -C 24 )alkynyl, (C 3 -C 12 )cycloalkyl and aryl; said alkyl, alkenyl, alkynyl, aryl or cycloalkyl group being optionally substituted with one or more halogens, (C 1 - C 6 )alkyl, aryl, oxo, -NH 2 , -CO 2 H or -OH; in particular, R 4 is selected in the group consisting of H, (C 1 - C i2 )al kyl and aryl; preferably, R 4 is H.
In a specific embodiment, when R 2 and R 3 are independently selected in the group consisting of H, - C(O)OR 9 -, -S(O) 2 R 10 -, optionally substituted (C 1 -C 12 )alkyl, optionally substituted (C 2 -C 12 )alkenyl, optionally substituted (C 2 -C 12 )alkynyl, optionally substituted (C 3 -C 12 )cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl and optionally substituted heteroaryl (R 9 and R 10 being as defined above), R 1 is preferably selected in the group consisting of H, (C 1 -C 24 )alkyl, (C 2 -C 24 )alkenyl, (C 2 - C 24 )alkynyl, (C 3 -C 12 )cycloalkyl and aryl; said alkyl, alkenyl, alkynyl, aryl or cycloalkyl group being optionally substituted with one or more halogens, (C 1 -C 6 )alkyl, aryl, oxo, -NH 2 , -CO 2 H or -OH; provided that at least one of R 2 and R 3 is not H; in particular, R 1 is selected in the group consisting of H, (C 1 - C 12 )al kyl, (C 2 -C 12 )alkenyl, (Cj-C 12 Jalkynyl and aryl; preferably, R 1 is H.
In a specific embodiment, when R 2 and R 3 are independently selected in the group consisting of H, -C(O)OR 9 -, -S(O) 2 R 10 -, optionally substituted (C 1 -C 12 )alkyl, optionally substituted (C 2 -C 12 )alkenyl, optionally substituted (C 2 -C 12 )alkynyl, optionally substituted (C 3 -C 12 )cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl and optionally substituted heteroaryl; and R 9 and R 10 are as defined above:
R 4 is preferably selected in the group consisting of H, (C 1 -C 24 )alkyl, (C 2 -C 24 )alkenyl, (C 2 - C 24 )alkynyl, (C 3 -C 12 )cycloalkyl and aryl; said alkyl, alkenyl, alkynyl, aryl or cycloalkyl group being optionally substituted with one or more halogens, (C 1 -C 6 )alkyl, aryl, oxo, -NH2, -CO 2 H or -OH; and/or
R 1 is preferably selected in the group consisting of H, (C 1 -C 24 )alkyl, (C 2 -C 24 )alkenyl, (C 2 - C 2 4)alkynyl, (C 3 -C 12 )cycloalkyl and aryl; said alkyl, alkenyl, alkynyl, aryl or cycloalkyl group being optionally substituted with one or more halogens, (C 1 -C 6 )alkyl, aryl, oxo, -NH 2 , -CO 2 H or -OH; provided that at least one of R 2 and R 3 is not H.
In a specific embodiment, when R 2 and R 3 are independently selected in the group consisting of H, -C(O)OR 9 -, -S(O) 2 R 10 -, optionally substituted (C 1 -C 12 )alkyl, optionally substituted (C 2 -C 12 )alkenyl, optionally substituted (C 2 -C 12 )alkynyl, optionally substituted (C 3 -C 12 )cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl and optionally substituted heteroaryl; and R 9 and R 10 are as defined above:
R 4 is preferably selected in the group consisting of H, (C 1 -C 12 )alkyl and aryl; and/or
R 1 is preferably selected in the group consisting of H, (C 1 -C 12 )alkyl, (C 2 -C 12 )alkenyl, (C 2 - C 12 )alkynyl and aryl; provided that at least one of R 2 and R 3 is not H.
In a specific embodiment, when R 2 and R 3 are independently selected in the group consisting of H, -C(O)OR 9 -, -S(O) 2 R 10 -, optionally substituted (C 1 -C 12 )alkyl, optionally substituted (C 2 -C 12 )alkenyl, optionally substituted (C 2 -C 12 )alkynyl, optionally substituted (C 3 -C 12 )cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl and optionally substituted heteroaryl; and R 9 and R 10 are as defined above:
R 4 is preferably H; and/or
R 1 is preferably selected in the group consisting of H, (C 1 -C 12 )alkyl, (C 2 -C 12 )alkenyl, (C 2 - C 12 )alkynyl and aryl; more preferably, R 1 is H; provided that at least one of R 2 and R 3 is not H. In a specific embodiment,
X is a methyl, an ethyl or a n-propyl; and/or Y° is-O-; and/or Y 1 , Y 2 and Y 3 are independently absent or -O-; and
R 2 and R 3 are independently selected in the group consisting of H, -C(O)OR 9 -, -S(O) 2 R 10 -, optionally substituted (C 1 -C 12 )alkyl, optionally substituted (C 2 -C 12 )alkenyl, optionally substituted (C 2 -C 12 )alkynyl, optionally substituted (C 3 -C 12 )cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl and optionally substituted heteroaryl (R 9 and R 10 being as defined above); and
R 4 is preferably selected in the group consisting of H, (C 1 -C 24 )alkyl, (C 2 -C 24 )alkenyl, (C 2 - C 24 )alkynyl, (C 3 -C 12 )cycloalkyl and aryl; said alkyl, alkenyl, alkynyl, aryl or cycloalkyl group being optionally substituted with one or more halogens, (C 1 -C 6 )alkyl, aryl, oxo, -NH 2 , -CO 2 H or -OH; and/or R 1 is preferably selected in the group consisting of H, (C 1 -C 24 )alkyl, (C 2 - C 24 )alkenyl, (C 2 -C 24 )alkynyl, (C 3 -C 12 )cycloalkyl and aryl; said alkyl, alkenyl, alkynyl, aryl or cycloalkyl group being optionally substituted with one or more halogens, (C 1 -C 6 )alkyl, aryl, oxo, -NH 2 , -CO 2 H or -OH; provided that at least one of R 2 and R 3 is not H.
In a specific embodiment,
X is a methyl, an ethyl or a n-propyl; and/or Y° is-O-; and/or Y 1 , Y 2 and Y 3 are independently absent or -0-; and
R 2 and R 3 are independently selected in the group consisting of H, -C(O)OR 9 -, -S(O) 2 R 10 -, optionally substituted (C 1 -C 12 )alkyl, optionally substituted (C 2 -C 12 )alkenyl, optionally substituted (C 2 -C 12 )alkynyl, optionally substituted (C 3 -C 12 )cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl and optionally substituted heteroaryl (R 9 and R 10 being as defined above); and
R 4 is preferably selected in the group consisting of H, (C 1 -C 12 )alkyl and aryl; and/or R 1 is preferably selected in the group consisting of H, (C 1 -C 12 )alkyl, (C 2 -C 12 )alkenyl, (C 2 - C 12 )alkynyl and aryl; provided that at least one of R 2 and R 3 is not H.
In a specific embodiment,
X is a methyl, an ethyl or a n-propyl; and/or Y° is-O-; and/or Y 1 , Y 2 and Y 3 are independently absent or -0-; and R 2 and R 3 are independently selected in the group consisting of H, -C(O)OR 9 -, -S(O) 2 R 10 -, optionally substituted (C 1 -C 12 )alkyl, optionally substituted (C 2 -C 12 )alkenyl, optionally substituted (C 2 -C 12 )alkynyl, optionally substituted (C 3 -C 12 )cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl and optionally substituted heteroaryl (R 9 and R 10 being as defined above); and
R 4 is preferably H; and/or R 1 is preferably selected in the group consisting of H, (C 1 -C 12 )alkyl, (C 2 -C 12 )alkenyl, (C 2 -C 12 )alkynyl and aryl; more preferably, R 1 is H; provided that at least one of R 2 and R 3 is not H.
In the context of the invention, the new compound of formula (I) according to the invention is preferably selected from compounds (001) to (064) of Table 1 below, or a pharmaceutically acceptable salt and/or solvate thereof. Preferably, the new compound of formula (I) for use according to the invention is selected from compounds (002), (003), (004), (008), (009), (010), (012), (013), (014), (015), (016), (017), (018), (019), (020), (022), (023), (024), (025), (026), (028), (029), (036), (039), (040), (043), (045), (049), (051), (052), (054), (057), (058), (059), (061), (063), and (064) of Table 1. Preferably, the new compound of formula (I) for use according to the invention is preferably selected from compounds (003) to (007), (013), (014), (021), (029), (031) and (034) to (038) of Table 1, or a pharmaceutically acceptable salt and/or solvate thereof.
In the context of the invention, the new compound of formula (I) according to the invention is preferably selected from compounds (001) to (038) of Table 1 below, or a pharmaceutically acceptable salt and/or solvate thereof. Preferably, the new compound of formula (I) for use according to the invention is preferably selected from compounds (003) to (007), (013), (014), (021), (029), (031) to (038) of Table 1, or a pharmaceutically acceptable salt and/or solvate thereof.
The invention also relates to a pharmaceutical composition comprising a compound of general formula (I) as defined above, especially one selected from compounds (001) to (064) as disclosed in Table 1, or a pharmaceutically acceptable salt and/or solvate thereof.
The invention also relates to a pharmaceutical composition comprising a compound of general formula (I) as defined above, especially one selected from compounds (001) to (038) as disclosed in Table 1, or a pharmaceutically acceptable salt and/or solvate thereof.
The invention also relates to a compound of general formula (I) as defined above, especially one selected from compounds (001) to (064) as disclosed in Table 1, or a pharmaceutically acceptable salt and/or solvate thereof, or a pharmaceutical composition comprising it, for use as a drug. The invention also relates to a compound of general formula (I) as defined above, especially one selected from compounds (001) to (038) as disclosed in Table 1, or a pharmaceutically acceptable salt and/or solvate thereof, or a pharmaceutical composition comprising it, for use as a drug.
The invention also relates to the use of a compound of general formula (I) as defined above, especially one selected from compounds (001) to (064) as disclosed in Table 1, or a pharmaceutically acceptable salt and/or solvate thereof, or a pharmaceutical composition comprising it, for the manufacture of a medicament.
The invention also relates to the use of a compound of general formula (I) as defined above, especially one selected from compounds (001) to (038) as disclosed in Table 1, or a pharmaceutically acceptable salt and/or solvate thereof, or a pharmaceutical composition comprising it, for the manufacture of a medicament.
The invention further relates to a method for treating a disease or disorder in a subject in need thereof, comprising administering a therapeutically effective amount of a compound of general formula (I) as defined above, especially one selected from compounds (001) to (064) as disclosed in Table 1, or a pharmaceutically acceptable salt and/or solvate thereof, or a pharmaceutical composition comprising it, to said subject.
The invention further relates to a method for treating a disease or disorder in a subject in need thereof, comprising administering a therapeutically effective amount of a compound of general formula (I) as defined above, especially one selected from compounds (001) to (038) as disclosed in Table 1, or a pharmaceutically acceptable salt and/or solvate thereof, or a pharmaceutical composition comprising it,, to said subject.
The present invention also relates to a kit of parts and/or a combination comprising (i) a compound of general formula (I) according to the invention, especially one selected from compounds (001) to (064) as disclosed in Table 1, or a pharmaceutical acceptable salt thereof, and (ii) an additional active ingredient, for separate, sequential or simultaneous use.
The present invention also relates to a kit of parts and/or a combination comprising (i) a compound of general formula (I) according to the invention, especially one selected from compounds (001) to (038) as disclosed in Table 1, or a pharmaceutical acceptable salt thereof, and (ii) an additional active ingredient, for separate, sequential or simultaneous use.
The invention also relates to a compound of general formula (I) as defined above, especially one of those as disclosed in Table 1, or a pharmaceutically acceptable salt and/or solvate thereof, or a pharmaceutical composition comprising it, for use in preventing or treating iron- and/or copper- associated disorders, in particular iron and/or copper overload-associated disorders; or metal- dependent cell death associated disorders. The invention also relates to the use of a compound of general formula (I) as defined above, especially one of those as disclosed in Table 1, or a pharmaceutically acceptable salt and/or solvate thereof, or a pharmaceutical composition comprising it, for the manufacture of a medicament for preventing or treating iron- and/or copper-associated disorders, in particular iron and/or copper overload-associated disorders; or metal-dependent cell death associated disorders.
The invention further relates to a method for preventing or treating iron- and/or copper- associated disorders, in particular iron and/or copper overload-associated disorders; or metal- dependent cell death associated disorders in a subject in need thereof, comprising administering a therapeutically effective amount of a compound of general formula (I) as defined above, especially one of those as disclosed in Table 1, or a pharmaceutically acceptable salt and/or solvate thereof, or a pharmaceutical composition comprising it, to said subject.
In a specific embodiment, the metalloptosis associated disorders are disorders associated to ferroptosis and/or cuproptosis. Advantageously, the metalloptosis associated disorders are selected among Hemorrhagic stroke; Ischemic Heart Injury; Ischemic Renal Injury; Ischaemia-reperfusion injury (IRI) such as IRI occurring during organ transplantation ((liver, lung, heart, kidneys, pancreas, intestine); Neurodegenerative diseases selected from Huntington Disease, Dementia, and amyotrophic lateral sclerosis (ALS); aging related diseases or disorders; sepsis; ishemia-reperfusion; and Diabetes. In particular, the use of the compound according to the invention is specifically disclosed below in the specification.
In a specific embodiment, the iron- and/or copper-associated disorders are selected among HFE-related hematochromatosis; non HFE-related hematochromatosis; congenital atransferrinenemia; iron-loading associated anemias such as thalassemia, myelodysplasia and hematopoietic stem-cell transplantation-associated disorders; chronic liver diseases; chronic inflammation linked to cancer; autoimmune or inflammatory diseases; neurodegeneration with brain iron accumulation-associated diseases such as Wilson's Disease; and polygenic neurodegenerative- associated diseases such as Parkinson's Disease and Alzheimer Disease.
Therapeutic uses
As illustrated by examples, the inventors have demonstrated the therapeutic interest of the new compounds of the invention. Accordingly, the present invention relates to a pharmaceutical or veterinary composition comprising any new compound according to the present invention, or a pharmaceutically acceptable salt and/or solvate thereof. Preferably, the pharmaceutical or veterinary composition further comprises a pharmaceutically or veterinary acceptable carrier or excipient. The present invention relates to the use of any new compound according to the invention, or a pharmaceutically acceptable salt and/or solvate thereof, as a drug or as a medicine. The invention further relates to a method for treating a disease in a subject, wherein a therapeutically effective amount of any new compound according to the invention, or a pharmaceutically acceptable salt and/or solvate thereof, is administered to said subject in need thereof. The invention also relates to the use of any new compound according to the invention, or a pharmaceutically acceptable salt and/or solvate thereof, for the manufacture of a medicine. The invention also relates to a pharmaceutical composition comprising any new compound according to the invention or a pharmaceutically acceptable salt and/or solvate thereof, for use as a drug. The terms "any new compound according to the invention" or ""any new compound of general formula (I)" mean herein any compounds as defined in the section "New compounds” herein above. The terms "any compound according to the invention" or "any compound of general formula (I)" mean herein any compounds of general formula (I) as defined in the present specification, in particular in the sections "Compounds for use" and “New compounds" herein above.
The invention relates to any compounds of general formula (I) according to the invention, especially one of those as disclosed in Table 1, or a pharmaceutically acceptable salt and/or solvate thereof, or a pharmaceutical composition comprising it for use preventing and/or treating metalloptosis associated disorders. It further relates to the use of any compounds of general formula (I) according to the invention, especially one of those as disclosed in Table 1, or a pharmaceutically acceptable salt and/or solvate thereof, or a pharmaceutical composition comprising it for the manufacture of a medicine for use preventing and/or treating metalloptosis associated disorders. It also relates to a method for preventing and/or treating metalloptosis associated disorders in a subject in need thereof, comprising administering a therapeutically effective amount of any compounds of general formula (I) according to the invention, especially one of those as disclosed in Table 1, or a pharmaceutically acceptable salt and/or solvate thereof, or a pharmaceutical composition comprising it to said subject.
In the context if the invention, metalloptosis associated disorders are metal-dependent cell death associated disorders. In particular, metalloptosis associated disorders are disorders associated to ferroptosis and/or cuproptosis.
In the context of the invention, the metalloptosis associated disorders are selected among Hemorrhagic stroke; Ischemic Heart Injury; Ischemic Renal Injury; Ischaemia-reperfusion injury (IRI) such as IRI occurring during organ transplantation ((liver, lung, heart, kidneys, pancreas, intestine); Neurodegenerative diseases selected from Huntington Disease, Dementia, and amyotrophic lateral sclerosis (ALS); aging related diseases or disorders; sepsis; ishemia-reperfusion; and Diabetes. In another embodiment, the invention relates to any new compounds of general formula (I) according to the invention, or a pharmaceutically acceptable salt and/or solvate thereof, or a pharmaceutical composition comprising it for use for preventing and/or treating iron- and/or copper- associated disorders. It further relates to the use of any new compounds of general formula (I) according to the invention, or a pharmaceutically acceptable salt and/or solvate thereof, or a pharmaceutical composition comprising it for the manufacture of a medicine for use for preventing and/or treating iron- and/or copper-associated disorders. It also relates to a method for preventing and/or treating iron- and/or copper-associated disorders in a subject in need thereof, comprising administering a therapeutically effective amount of any new compounds of general formula (I) according to the invention, or a pharmaceutically acceptable salt and/or solvate thereof, or a pharmaceutical composition comprising it to said subject.
In the context of the invention, the iron- and/or copper-associated disorders are selected among HFE-related hematochromatosis; non HFE-related hematochromatosis; congenital atransferrinenemia; iron-loading associated anemias such as thalassemia, myelodysplasia and hematopoietic stem-cell transplantation-associated disorders; chronic liver diseases; chronic inflammation linked to cancer; autoimmune or inflammatory diseases; neurodegeneration with brain copper- or iron accumulation-associated diseases such as Wilson's Disease; and polygenic neurodegenerative-associated diseases such as Parkinson's Disease and Alzheimer Disease.
In particular, the iron-associated disorders are selected among HFE-related hematochromatosis; non HFE-related hematochromatosis; congenital atransferrinenemia; iron- loading associated anemias such as thalassemia, myelodysplasia and hematopoietic stem-cell transplantation-associated disorders; chronic liver diseases; chronic inflammation linked to cancer; autoimmune or inflammatory diseases; neurodegeneration with brain iron accumulation-associated diseases such as Wilson's Disease; and polygenic neurodegenerative-associated diseases such as Parkinson's Disease and Alzheimer Disease.
In particular, the copper-associated disorders are selected among HFE-related hematochromatosis; non HFE-related hematochromatosis; congenital atransferrinenemia; iron- loading associated anemias such as thalassemia, myelodysplasia and hematopoietic stem-cell transplantation-associated disorders; chronic liver diseases; chronic inflammation linked to cancer; autoimmune or inflammatory diseases; neurodegeneration with brain copper accumulation- associated diseases such as Wilson's Disease; and polygenic neurodegenerative-associated diseases such as Parkinson's Disease and Alzheimer Disease.
HFE-related hematochromatosis may notably be due to C282Y homozygosity or C282/H63D heterozygosity. Non HFE-related hematochromatosis include for example juvenile hemochromatosis type 2A or 2B, or may be due to Mutated transferrin receptor 2 or Mutated ferroportin 1 gene. Neurodegeneration with brain iron accumulation- associated diseases include aceruloplasminemia, neuroferritinopathy, pantothenate kinase-associated neurodegenration, Wilson's disease and Beta-propeller Protein-Associated Neurodegeneration (BPAN).
Polygenic neurodegenerative disorders include Parkinson's disease and Alzheimer's disease.
In particular, the iron overload-associated disorder is iron-loading related anemia, such as thalassemia, myelodysplasy, aplastic anemia, Blackfan diamond anemia, congenital dyserythopoietic anemia, chronic hemoytic anemia, in particular sickel cell disease, hematopoietic stem-cell transplantation- related disorder and chronic liver disease including viral hepatitis, alcoholic hepatitis, steatohepatitis (NASH), dysmetabolic iron overload syndrome.
Pharmaceutical compositions
The pharmaceutical compositions contemplated herein may include a pharmaceutically acceptable carrier in addition to the active ingredient(s). The term "pharmaceutically acceptable carrier" is meant to encompass any carrier (e.g., support, substance, solvent, etc.) which does not interfere with effectiveness of the biological activity of the active ingredient(s) and that is not toxic to the host to which it is administered. For example, for parental administration, the active compounds(s) may be formulated in a unit dosage form for injection in vehicles such as saline, dextrose solution, serum albumin and Ringer's solution.
The pharmaceutical composition can be formulated as solutions in pharmaceutically compatible solvents or as emulsions, suspensions or dispersions in suitable pharmaceutical solvents or vehicle, or as pills, tablets or capsules that contain solid vehicles in a way known in the art. Formulations of the present invention suitable for oral administration may be in the form of discrete units as capsules, sachets, tablets or lozenges, each containing a predetermined amount of the active ingredient; in the form of a powder or granules; in the form of a solution or a suspension in an aqueous liquid or non- aqueous liquid; or in the form of an oil-in-water emulsion or a water-in-oil emulsion. Formulations suitable for parental administration conveniently comprise a sterile oily or aqueous preparation of the active ingredient which is preferably isotonic with the blood of the recipient. Every such formulation can also contain other pharmaceutically compatible and nontoxic auxiliary agents, such as, e.g. stabilizers, antioxidants, binders, dyes, emulsifiers or flavoring substances. The formulations of the present invention comprise an active ingredient in association with a pharmaceutically acceptable carrier therefore and optionally other therapeutic ingredients. The carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulations and not deleterious to the recipient thereof. The pharmaceutical compositions are advantageously applied by injection or intravenous infusion of suitable sterile solutions or as oral dosage by the digestive tract. Methods for the safe and effective administration of most of these chemotherapeutic agents are known to those skilled in the art. In addition, their administration is described in the standard literature.
The pharmaceutical or veterinary composition as disclosed herein may further comprise an additional active ingredient or drug.
Further aspects and advantages of the present invention will be described in the following examples, which should be regarded as illustrative and not limiting.
Examples
Table 1
Example 1: Synthesis of Compounds
1- General information
All solvents and chemicals were purchased from commercially available sources and used without further purification or purified according to Purification of Laboratory O 2 emicals (Armarego, W.L.F.; O 2 ai, C.L.L. 5 th Ed.). Solvents were dried under standard conditions. Reactions were monitored by thin layer chromatography (TLC) using pre-coated silica on aluminum plates from Merck (60F 254 ). TLC plates were visualized with UV-light and/or by treatment with ceric ammonium molybdate solution (CAM) and heating. Products were purified on column chromatography with Silica gel 60 from Macherey Nagel (0.036-0.071 mm; 215-400 mesh), a CombiFlash Rf+ Teledyne Isco system fitted with pre-packed silica gel columns (Interchim) or/and preparative HPLC Quaternary Gradient 2545 equipped with a Photodiode Array detector (Waters) fitted with a reverse phase column (XBridge Prep C18 5pm OBD, 30x150 mm). NMR spectroscopy was performed on Bruker spectrometers. Spectra were run in DMSO-d 6 or D 2 O or CD 3 OD, CD 2 CI 2 at 298 K. 1 H NMR were recorded at 400 or 500 MHz, and chemical shifts 6 are expressed in ppm using the residual non-deuterated solvent signal as internal standard and the coupling constants J are specified in Hz. The following abbreviations are used: s, singlet; brs, broad singlet; d, doublet; dd, doublet of doublets; dt, doublet of triplets; dq, doublet of quartets; ddd, doublet of doublet of doublets; dqd, doublet of quartet of doublets; t, triplet; td, triplet of doublets; tdd, triplet of doublet of doublets; q, quartet; m, multiplet. We only reported labile protons that could be clearly identified in the spectra. 13 C NMR were recorded at 101 or 126 MHz, and chemical shifts 6 are expressed in ppm using deuterated solvent signal as internal standard.
The purity of final compounds, determined to be >95% by UPLC MS, was recorded on a Waters Acquity H-class equipped with a Photodiode array detector and SO. Detector 2 with a reverse phase column (Aquity UPLC® BEH C18 1.7 pm, 2.1x50 mm).
"Classic System": ACN (+0.1% FA) and MilliQ. Water (+0.1% FA): isocratic at 5% of ACN (0.2 min), then linear gradient from 5% to 100% of ACN in 2.3 min, then isocratic at 100% of ACN (0.5 min).
2- Abbreviations
ACN, acetonitrile; AcOH, glacial acetic acid; aq., aqueous; Boc 2 O, di-tert-butyl dicarbonate; DCM, dichloromethane; equiv., equivalent(s); ESI, electrospray ionization; EtOAc, ethyl acetate; EtOH, ethanol; Et 2 O, diethyl ether; Et 3 N, trimethylamine; FA, formic acid; HPLC, high pressure liquid chromatography; HRMS, high resolution mass spectroscopy; K 2 CO 3 , potassium carbonate; MeOH, methanol; MgSO 4 , sulfate magnesium; MS, mass spectrometry; NaH, sodium hydride; NMR, nuclear magnetic resonance; RT, room temperature; THF, tetrahydrofuran; TLC, thin-layer chromatography; UPLC, ultra-high performance liquid chromatography; UV, ultraviolet.
3- Chemical Synthesis
3-1- Synthesis by nucleophilic substitution
3-1-1 Procedure for NH-monoalkylated compounds
In the dark and under inert atmosphere, serotonin hydrochloride (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 is stirred for 30 min, then alkyl bromide (0.6 equiv.) was added. The mixture was stirred for 3.5h, then was quenched with water. The resulting solution was extracted with DCM, dried on MgSO 4 and concentrated. The crude was purified by flash chromatography using DCM / MeOH (100/0 to 80/20) as eluent and by preparative HPLC to give the desired product after lyophilization. The obtained compound is the formic salt.
Yield: 44 mg, 21%. Isolated as a light grey powder, >95% pure by NMR and a single spot by TLC; Rr: 0.44 in DCM/MeOH, 90/10. Strain green with CAM. 1 H NMR (DMSO-d6, 500 MHz): δ ppm= 10.51 (1H, s); 7.12 (1H, d, J = 8.6 Hz); 7.04 (1H, d, J = 2.4 Hz); 6.82 (1H, d, J = 2.4 Hz); 6.60 (1H, dd, J = 2.3, J = 8.6 Hz); 3.52 (2H, d, J = 2.4 Hz); 3.21 (1H, t, J = 2.4 Hz); 2.92 (2H, m); 2.79 (2H, m). 13 C NMR (DMSO-d6, 126 MHz): δ ppm= 150.2; 130.8; 127.8; 123.2; 111.7; 111.3; 110.5; 102.2; 80.8; 75.2; 47.9; 36.7; 24.2. UPLC: R T : 0.8 to 1.0 (classic system). MS (ESI) m/z [M+H] + Calcd for CI 3 HI 5 N 2 O + 215.11; Found 215.22.
Yield: 28 mg, 12%. Isolated as a light grey powder, >95% pure by NMR and a single spot by TLC; Rr: 0.56 in DCM/MeOH, 80/20. Strain green with CAM;
'H NMR (CD 3 OD, 500 MHz): δ ppm = 8.51 (1H, s, FA); 7.19 (1H, d, J = 8.8 Hz); 7.11 (1H, s); 6.93 (1H, d, J = 2.1 Hz); 6.70 (1H, dd, J = 2.2, J = 8.8 Hz); 3.32-3.29 (2H, m); 3.18 (2H, t, J = 7.4 Hz); 3.09 (2H, t, J = 7.5 Hz); 2.62 (2H, dt, J = 2.7 Hz, J = 6.8 Hz); 2.52 (1H, t, J = 2.6 Hz).
13 C NMR (CD3OD, 126 MHz): δ ppm = 169.8 (FA); 151.5; 133.2; 128.8; 124.9; 113.0; 112.9; 109.3; 103.1;
79.4; 73.1; 49.7; 47.1; 23.4; 16.9.
UPLC: R T : 0.74 (classic system)
MS (ESI + ) m/z [M+H] + Calcd for CI 4 H 17 N 2 O + 229.13; Found 229.28.
LYS6 (LC344) (compound (002))
Yield: 43 mg, 19%. Isolated as a light grey powder, >95% pure by NMR and a single spot by TLC; Rf: 0.5 in DCM/MeOH/Et 3 N, 95/5/2. Strain green with CAM. 1 H NMR (CD 3 OD, 400 MHz): δ ppm= 7.16 (1H, d, J = 8.4 Hz); 7.00 (1H, s,); 6.92 (1H, d, J = 2.1 Hz); 6.67 (1H, dd, J = 2.3 Hz, J = 8.4 Hz); 5.21 (1H, m); 3.23 (2H, d, J = 7.2 Hz); 2.89 (4H, s); 1.71 (3H, brs); 1.62 (3H, brs). 13 C NMR (CD3OD, 101 MHz): δ ppm= 151.2; 136.8; 133.2; 129.3; 124.3; 122.3; 112.7; 112.5; 112.4; 103.5; 50.0; 47.4; 26.0; 25.9; 17.9. UPLC: R T : 1.45 (classic system)
MS (ESI + ) m/z [M+H] + Calcd for CI 5 H 2 IN 2 O + 245.16; Found 245.17.
Yield: 24 mg, 10%. Isolated as a light grey powder, >95% pure by NMR and a single spot by TLC; Rf: 0.49 in DCM/MeOH/Et 3 N, 90/10/2. Strain green with CAM;
3 H NMR (CD3OD, 400 MHz): δ ppm = 7.16 (1H, dd, J = 0.5 Hz, J = 8.5 Hz); 7.08 (1H, s,); 6.85 (1H, dd, J = 0.5 Hz, J = 2.3 Hz); 6.67 (1H, dd, J = 2.4 Hz, J = 8.7 Hz); 5.29 (2H, m); 3.72 (4H, d, J = 7.5 Hz); 3.27 (2H, m); 3.08 (2H, m); 1.81 (6H, brs); 1.72 (6H, d, J = 0.9 Hz).
13 C NMR (CD3OD, 101 MHz): δ ppm = 151.6; 145.3 (2C); 133.2; 128.8; 125.0 (2C); 114.3; 113.1; 112.9;
109.2; 103.2; 53.3; 51.9 (2C); 26.2 (2C); 22.0; 18.5 (2C).
UPLC: R T : 1.81 (classic system)
MS (ESI + ) m/z [M+H] + Calcd for C 20 H 29 N 2 O + 313.22; Found 313.04.
LYS7 (LC330) (=compound (003))
Yield: 124 mg, 37%. Isolated as a orange powder, >95% pure by NMR and a single spot by TLC; Rf: 0.48 in DCM/MeOH, 90/10. Strain green with CAM;
3 H NMR (DMSO-d6, 400 MHz):δ ppm= 10.43 (1H, brs); 8.68 (1H, t, J = 2.2 Hz); 8.60 (2H, d, J = 2.1 Hz); 8.51 (1H, s); 7.08 (1H, d, J = 8.5 Hz); 7.01 (1H, d, J = 2.5 Hz); 6.74 (1H, d, J = 2.2 Hz); 6.55 (1H, dd, J = 2.3 Hz, J = 8.6 Hz); 3.98 (2H, s); 2.77 (4H, m).
13 C NMR (DMSO-d6, 101 MHz): δ ppm= 150.5; 148.4 (2C); 146.9; 131.3; 128.5 (2C); 128.3; 123.5; 117.2;
112.0; 111.8; 111.6; 102.6; 51.7; 49.6; 26.2.
UPLC: R T : 1.48 (classic system)
MS (ESI + ) m/z [M+H] + Calcd for CI 7 HI 7 N 4 O 5 + 357.11; Found 357.13.
3-1-2-Procedure for polyalkylated compounds
In the dark and under inert atmosphere, serotonin hydrochloride (500 mg, 2.35 mmol, 1 equiv.) was dissolved in THF (25 mL). NaH (188 mg, 2 equiv.) was added to the mixture. The mixture is stirred for 30 min, and then propargyl bromide (524 pL, 2 equiv.) was added. The mixture was stirred for 4h, then was quenched with water. The resulting solution was extracted with DCM, dried on MgSO 4 and concentrated. The crude was purified by flash chromatography using DCM / MeOH (99/1 to 80/20) as eluent. 3 fractions were obtained and purified by preparative HPLC to give 3 products after lyophilization.
Al (LYS1) (NMR-SD095A1):
Yield: 5.5 mg, 0.8 %. Isolated as a light grey powder, >95% pure by NMR and a single spot by TLC; Rf: 0.71 in DCM/MeOH, 95/5. Strain green with CAM, 3 H NMR (CD 3 OD, 500 MHz): δ ppm= 7.23 (1H, d, J = 8.8 Hz); 7.16 (1H, d, J = 2.3 Hz); 7.06 (lH,s); 6.80 (1H, dd, J = 2.3 Hz, J = 8.8 Hz); 4.72 (2H, d, J = 2.4 Hz); 3.56 (4H, d, J = 2.5 Hz); 2.90 (4H, m); 2.89 (1H, t, J = 2.4 Hz); 2.69 (2H, t, J = 2.5 Hz). 13 C NMR (CD3OD, 126 MHz): δ ppm= 152.9; 133.9; 128.9; 124.2; 113.3 (2C); 112.9; 103.6; 80.7; 79.0 (2C); 76.2; 75.1 (2C); 57.8; 54.7; 42.8 (2C); 24.2. UPLC: R T : 1.88 (classic system). MS (ESI + ) m/z [M+H] + Calcd for C 1 gHigN 2 O + 291.14; Found 291.18.
Yield: 29 mg, 6%. Isolated as a light grey powder, >95% pure by NMR and a single spot by TLC; Rf: 0.14 in DCM/MeOH, 95/5. Strain green with CAM. 1 H NMR (DMSO-d6, 500 MHz): δ ppm= 10.51 (1H, s); 7.12 (1H, d, J = 8.6 Hz); 7.04 (1H, d, J = 2.4 Hz); 6.82 (1H, d, J = 2.4 Hz); 6.60 (1H, dd, J = 2.3, J = 8.6 Hz); 3.52 (2H, d, J = 2.4 Hz); 3.21 (1H, t, J = 2.4 Hz); 2.92 (2H, m); 2.79 (2H, m). 13 C NMR (DMSO-d6, 126 MHz): δ ppm= 150.2; 130.8; 127.8; 123.2; 111.7; 111.3; 110.5; 102.2; 80.8; 75.2; 47.9; 36.7; 24.2. UPLC: R T : 0.8 to 1.0 (classic system). MS (ESI + ) m/z [M+H-HCOOH] + Calcd for CI 3 HI 5 N 2 O + 215.11; Found 215.22.
A4 (LYS4) (NMR-SD095A4):
Yield: 57 mg, 10%. Isolated as a light grey powder, >95% pure by NMR and a single spot by TLC; Rf: 0.43 in DCM/MeOH, 95/5. Strain green with CAM. 3 H NMR (CD3OD, 500 MHz): δ ppm= 7.15 (1H, d, J = 8.3 Hz); 6.99 (1H, s); 6.95 (1H, d, J = 2.3 Hz); 6.67 (1H, dd, J =2.3 Hz, J = 8.6 Hz); 3.55 (4H, d, J = 2.5 Hz); 2.90- 2.85 (4H, m); 2.70 (2H, t, J = 2.5 Hz). 13 C NMR (CD3OD, 126 MHz): δ ppm= 151.0; 133.1; 129.3; 1234.1; 112.7; 112.5; 112.4; 103.6; 78.7 (2C); 75.3 (2C); 54.7; 42.8 (2C); 24.2. UPLC: R T : 1.42 (classic system). MS (ESI + ) m/z [M+H] + Calcd for CI 6 HI 7 N 2 O + 253.13; Found 253.15.
Yield: 67 mg, 9 %. Isolated as a light grey powder, >95% pure by NMR and a single spot by TLC; Rf: 0.68 in DCM/MeOH, 98/2. Strain green with CAM;
3 H NMR (CD 2 CI 2 , 500 MHz): δ ppm= 7.29 (1H, d, J = 8.8 Hz); 7.16 (1H, d, J = 2.5 Hz); 7.06 (lH,s); 6.92 (1H, dd, J = 2.4 Hz, J = 8.8 Hz); 4.82 (2H, d, J = 2.4 Hz); 4.74 (2H, d, J = 2.5 Hz); 3.52 (4H, d, J = 2.5 Hz); 2.90-2.85 (4H, m); 2.56 (1H, t, J = 2.5 Hz); 2.44 (1H, t, J = 2.5 Hz); 2.30 (2H, t, J = 2.5 Hz).
13 C NMR (CD 2 CI 2 , 126 MHz): δ ppm= 151.9; 131.9; 128.7; 125.9; 113.3; 112.5; 110.2; 103.4; 79.3; 78.9
(2C); 78.1; 74.8; 72.9; 72.7 (2C); 56.8; 53.3; 42.1 (2C); 35.8; 23.4.
UPLC: R T : 2.02 (classic system)
MS (ESI + ) m/z [M+H] + Calcd for C 22 H 2 IN 2 O + 329.16; Found 329.20. 3-1-3-Procedure for O-alkylated compounds
In the dark, serotonin hydrochloride (500 mg, 2.35 mmol, 1 equiv.) was dissolved in water (9 mL). K 2 CO 3 (665 mg, 4.81 mmol, 2.1 equiv.) and BOC 2 O (538 mg, 2.46 mmol, 1.05 equiv.) were added to the solution. The solution was stirred overnight, and then extracted with DCM. The organic phase was washed with aq. HCI 5% and brine, then dried on MgSO4 and concentrated. The crude was purified by flash chromatography using DCM / MeOH (100/0 to 90/10) as eluent to give the desired product (485 mg), which was engaged in the next step.
In the dark and under inert atmosphere, the product of the previous step (138 mg, 0.5 mmol, 1 equiv.) was dissolved in dry acetonitrile (4 mL). K 2 CO3 (138 mg, 2 equiv.) and propargyl bromide (59 pL, 1.06 equiv.) were added to the solution. The mixture was stirred and heated at reflux overnight, cooled down to r.t. then filtered with acetonitrile and concentrated. The crude was purified by flash chromatography using cyclohexane / EtOAC (90/10 to 0/100) as eluent to give LC466.
The product was then dissolved in CH2CI2/TFA, 4/1 (4 mL) and stirred for 2 h until the product was predominant in UPLC analysis. The mixture was then concentrated, and the crude was directly purified by preparative HPLC to give the desired product after lyophilization.
Yield: 39 mg, 17%. Isolated as a light grey powder, >95% pure by NMR and a single spot by TLC; Rf: 0.68 in DCM/MeOH/Et 3 N, 90/10/2. Strain green with CAM. 1 H NMR (D 2 O, 500 MHz): δ ppm= 8.45 (1H, s, (FA)); 7.47 (1H, d, J = 8.7 Hz); 7.31 (1H, s); 7.29 (1H, d, J = 2.5 Hz); 7.00 (1H, dd, J = 8.9 Hz, J = 2.4 Hz); 4.84 (2H, d, J = 2.4 Hz); 3.32 (2H, t, J = 7.1 Hz); 3.14 (2H, t, J = 7.1 Hz); 2.95 (1H, t, J = 2.4 Hz). UPLC: R T : 1.57 (classic system). MS (ESI + ) m/z [M+H] + Calcd for C 1 3Hi 5 N 2 O + 215.11; Found 215.23.
3-1-4-Procedure for carbamate esters
In the dark and under inert atmosphere, serotonin hydrochloride (75 mg, 0.315 mmol, 1 equiv.) was dissolved in DCM/H20, 1/2 (1/4 mL). Na2CC>3 (36 mg, 0.740 mmol, 2.1 equiv.) was added to the mixture. The mixture is stirred for 30 min, and then alkylchloroformate (1 equiv.) was added. The mixture was stirred for 18 h, then was quenched with water. The resulting solution was extracted with DCM, dried on MgSO 4 and concentrated. The crude was purified by flash chromatography using heptane / EtOAc (100/0 to 50/50) as eluent and then purified by preparative HPLC.
Yield: 39 mg, 17%. Isolated as a light grey powder, >95% pure by NMR and a single spot by TLC; Rf: 0.68 in DCM/MeOH/Et 3 N, 90/10/2. Strain green with CAM. 1 H NMR (CD 3 OD, 500 MHz): δ ppm = 7.15 (1H, d, J = 8.7 Hz); 6.98 (1H, s,); 6.95 (1H, d, J = 2.2 Hz); 6.67 (1H, dd, J = 2.2 Hz, J = 8.7 Hz); 4.63 (2H, d, J = 2.2 Hz); 3.36 (2H, t, J = 7.4 Hz); 2.85 (2H, t, J = 7.4 Hz); 2.83 (1H, t, J = 2.4 Hz). 13 C NMR (CD3OD, 126 MHz): δ ppm = 157.9; 151.0; 133.0; 129.3; 124.2; 112.6; 112.3 (2C); 103.5; 79.5; 75.6; 53.0; 42.6; 26.7. UPLC: R T : 1.83 (classic system). MS (ESI + ) m/z [M+H] + Calcd for CI 4 HI 5 N 2 O + 259.10; Found 259.24 L
3-1-5-Procedure for sulfonamides:
In the dark, serotonin hydrochloride (200 mg, 0.94 mmol) was dissolved in DCM (9 mL). Triethylamine (210 pL, 1.5 mmol, 1.6 equiv.) was added to the mixture. The mixture is stirred for 30 min, and then methanesulfonyl chloride (43 pL, 0.56 mmol, 0.6 equiv.) was added slowly. The mixture was stirred for 18 h, then was quenched with water. The resulting solution was extracted with DCM, dried on MgSO 4 and concentrated. The crude was purified by flash chromatography using n-Hexane / EtOAc (20/80 to 0/100) as eluent to afford a white solid.
LYS9 (= Compound (041))
Yield: 15 mg, 7%. Isolated as a pale yellow oil, >95% pure by NMR and a single spot by TLC; Rf: 0.23 in n-Hex/EtOAc, 10/90. Strain green with CAM;
3 H NMR (CD 3 OD, 500 MHz): δ ppm = 7.54 (1H, d, J = 2.2 Hz); 7.39 (1H, d, J = 8.7 Hz); 7.25 (1H, s,); 7.07 (1H, dd, J = 2.3 Hz, J = 8.6 Hz); 3.36 (2H, t, J = 7.2 Hz); 3.18 (3H, s); 2.99 (2H, t, J = 7.2 Hz); 2.81 (3H, s).
13 C NMR (CD3OD, 126 MHz): δ ppm = 144.3; 136.6; 128.9; 126.2; 116.8; 113.7; 113.1; 112.5; 44.9; 39.9;
36.9; 27.3.
UPLC: R T : 1.45 (classic system)
MS (ESI + ) m/z [M+H] + Calcd for CI 2 HI 7 N 2 O 5 S 2 + 333.05; Found 333.18.
3-1-6- Procedure for NH-alkylated tryptamine derivatives
In the dark and under inert atmosphere, tryptamin (160 mg, 1 mmol, 1 equiv.) was dissolved in DMF (10 mL). K 2 CO3 (138 mg, 1 equiv.) was added to the mixture. The mixture is stirred for 5 min, then alkyl bromide (0.6 equiv.) was added. The mixture was stirred for 4h, then was quenched with water. The resulting solution was extracted with DCM, dried on MgSO 4 and concentrated. The crude was purified by flash chromatography using DCM / MeOH (100/0 to 80/20) as eluent and by preparative HPLC to give the desired product after lyophilization. The obtained compound is the formic salt.
Yield: 25 mg, 13%. Isolated as a white powder, >95% pure by NMR and a single spot by TLC; Rf: 0.26 in DCM/MeOH, 95/5. Strain green with CAM; 3 H NMR (CD 3 OD, 500 MHz): δ ppm= 8.51 (1H, s, FA); 7.58 (1H, td, J = 0.9 Hz, J = 7.9 Hz); 7.38 (1H, td, J = 0.8 Hz, J = 8.1 Hz); 7.17 (1H, brs); 7.13 (1H, dt, J = 0.9 Hz, J = 7.9 Hz); 7.05 (1H, dt, J = 0.9 Hz, J = 8.1 Hz); 3.87 (2H, d, J = 2.5 Hz); 3.36 (2H, t, J = 7.5 Hz); 3.15 (2H, t, J = 7.4 Hz); 3.13 (1H, t, J = 2.5 Hz).
13 C NMR (CD 3 OD, 126 MHz): δ ppm= 169.7 (FA); 138.3; 128.1; 124.2; 122.7; 120.0; 118.9; 112.5; 110.3; 78.4; 75.6; 48.4; 37.4; 23.5.
UPLC: R T : 1.45 (classic system)
MS (ESI + ) m/z [M+H] + Calcd for CI 3 HI 5 N 2 + 199.12; Found 199.23.
Yield: 160 mg, 67%. Isolated as a white powder, >95% pure by NMR and a single spot by TLC; Rf: 0.63 in DCM/MeOH, 95/5. Strain green with CAM;
3 H NMR (CD 2 CI 2 , 500 MHz): δ ppm= 8.11 (1H, brs); 8.09 (1H, s, FA); 7.61 (1H, dd, J = 0.9 Hz, J = 7.8 Hz);
7.36 (1H, td, J = 0.9 Hz, J = 8.2 Hz); 7.16 (1H, dt, J = 1.0 Hz, J = 7.9 Hz); 7.08 (2H, m); 3.53 (4H, d, J = 2.5 Hz); 2.94 (2H, m); 2.89 (2H, m); 2.29 (2H, t, J = 2.5 Hz).
13 C NMR (CD 2 CI 2 , 126 MHz): δ ppm= 136.7; 127.9; 122.2; 122.1; 119.5; 119.1; 114.2; 111.5; 79.2 (2C);
73.2 (2C); 53.8; 42.4 (2C); 23.8.
UPLC: R T : 1.68 (classic system)
MS (ESI + ) m/z [M+H] + Calcd for CI 6 HI 7 N 2 + 237.13; Found 237.19.
3-2-Synthesis by reductive amination
3-2-1-Procedure from ketone (singly substituted analogs) [compounds 1 to 7]: In the dark and under inert atmosphere, serotonin hydrochloride (213 mg, 1 mmol) was dissolved in dry MeOH (10 mL). Et 3 N (153 pL, 1.1 equiv.) was added to the mixture. The mixture was stirred for 30 min at RT, and then the corresponding ketone (1.1 eq.) was added. The mixture was stirred overnight, and after that time NaBH 3 CN (1.1 equiv.) was added. The reaction mixture was stirred further at RT for additional 60 minutes. Next, the solvent was evaporated under reduced pressure. The crude was taken in a mixture of Et 2 O/water, 1/1 (10/10 mL), the resulting solution was alkal inized with NaOH [2M] until to obtain pH=10, then extracted with Et 2 O (2 x 20 mL), then with DCM (1 x 20 mL).The organic phases were dried over MgSO 4 and concentrated. The crude was purified by flash chromatography using DCM/MeOH/Et 3 N (100/0/2 to 80/20/2) as eluent.
Yield: 39 mg, 17%. Isolated as a light grey powder, >95% pure by NMR and a single spot by TLC; Rf: 0.68 in DCM/MeOH/Et 3 N, 90/10/2. Strain green with CAM. 1 H NMR (CD 3 OD, 400 MHz): δ ppm= 7.16 (1H, d, J = 8 Hz); 7.00 (1H, s,); 6.91 (1H, d, J = 4 Hz); 6.67 (1H, dd, J = 4 Hz, J = 8 Hz); 3.33 (1H, m); 2.84 (4H, m); 2.20 (2H, m); 1.72 (4H, m). 13 C NMR (CD 3 OD, 101 MHz): δ ppm= 151.2; 133.2; 129.2; 124.3; 112.7; 112.5; 112.4; 103.4; 54.6; 47.7; 30.8 (2C); 26.1;15.6. UPLC: R T : 1.21 (classic system). MS (ESI + ) m/z [M+H] + Calcd for CI 4 HI 9 N 2 O + 231.14; Found 231.17.
Yield: 138 mg, 48%. Isolated as a light grey powder, >95% pure by NMR and a single spot by TLC; Rf: 0.62 in DCM/MeOH/Et 3 N, 98/2/2. Strain green with CAM; 3 H NMR (CD3OD, 400 MHz): δ ppm = 8.54 (1H, s, FA)7.20 (1H, dd, J = 0.5 Hz, J = 8.6 Hz); 7.11 (1H, s,);
6.88 (1H, dd, J = 0.5 Hz, J = 2.3 Hz); 6.71 (1H, dd, J = 2.3 Hz, J = 8.6 Hz); 3.88 (2H, quint, J = 8.5 Hz); 3.19 (2H, m); 3.03 (2H, m); 2.33 (8H, m); 1.86 (4H, m).
13 C NMR (CD3OD, 101 MHz): δ ppm = 169.9 (FA); 151.6; 133.1; 128.7; 124.9; 113.1; 112.8; 109.6; 102.8;
58.2 (2C); 50.2; 28.9 (4C); 20.4;15.7 (2C).
UPLC: R T : 1.49 (classic system)
MS (ESI + ) m/z [M+H] + Calcd for CI 8 H 25 N 2 O + 285.18 Found 285.34.
Yield: 195 mg, 80%. Isolated as a light grey powder, >95% pure by NMR and a single spot by TLC; Rf: 0.51 in DCM/MeOH/Et 3 N, 95/5/2. Strain green with CAM. 3 H NMR (CD3OD, 400 MHz): δ ppm= 7.16 (1H, d, J = 8 Hz); 7.01 (1H, s,); 6.92 (1H, d, J = 4 Hz); 6.67 (1H, dd, J = 4 Hz, J = 8 Hz); 3.11 (1H, m); 2.90 (4H, s); 1.90 (2H, m); 1.66 (2H, m); 1.54 (2H, m); 1.36 (2H, m). 13 C NMR (CD3OD, 101 MHz): δ ppm= 151.2; 133.2; 129.3; 124.3; 112.7; 112.5 (2C); 103.5; 60.7; 49.6; 33.2 (2C); 26.1; 25.0 (2C). UPLC: R T : 1.34 (classic system). MS (ESI + ) m/z [M+H] + Calcd for CI 5 H 2 IN 2 O + 245.16; Found 245.10.
Yield: 253 mg, 98%. Isolated as a light grey powder, >95% pure by NMR and a single spot by TLC; Rf: 0.53 in DCM/MeOH/Et 3 N, 95/5/2. Strain green with CAM. 1 H NMR (CD 3 OD, 400 MHz): δ ppm= 7.16 (1H, d, J = 8 Hz); 7.01 (1H, s,); 6.93 (1H, d, J = 4 Hz); 6.67 (1H, dd, J = 4 Hz, J = 8 Hz); 2.90 (4H, m); 2.50 (1H, m); 1.90 (2H, m); 1.73 (2H, m); 1.63 (1H, m); 1.21 (5H, m). 13 C NMR (CD3OD, 101 MHz): δ ppm= 151.2; 133.2; 129.3; 124.3; 112.8; 112.5; 112.4; 103.5; 57.9; 47.6; 33.5 (2C); 27.1; 26.1 (3C). UPLC: R T :
1.46 (classic system). MS (ESI + ) m/z [M+H] + Calcd for CI 6 H 23 N 2 O + 259.17; Found 259.24.
Yield: 120 mg, 44%. Isolated as a light grey powder, >95% pure by NMR and a single spot by TLC; Rf: 0.43 in DCM/MeOH/Et 3 N, 95/5/2. Strain green with CM A. 1 H NMR (CD 3 OD, 400 MHz): δ ppm= 7.17 (1H, d, J = 8,6 Hz); 7.02 (1H, s,); 6.93 (1H, d, J = 2.5 Hz); 6.67 (1H, dd, J = 2.4 Hz, J = 8.6 Hz); 2.91 (4H, m); 2.71 (1H, m); 1.89-1.80 (2H, m); 1.71-1.32 (10H, m).
13 C NMR (CD3OD, 101 MHz): δ ppm= 151.2; 133.2; 129.2; 124.4; 112.8; 112.5; 112.2; 103.4; 60.2; 48.0;
34.8 (2C); 29.1 (2C); 25.8; 25.5 (2C).
UPLC: R T : 1.57 (classic system)
MS (ESI + ) m/z [M+H] + Calcd for CI 7 H 25 N 2 O + 273.19; Found 273.30.
Yield: 212 mg, 74%. Isolated as a light grey powder, >95% pure by NMR and a single spot by TLC; Rf: 0.6 in DCM/MeOH/Et 3 N, 90/10/2. Strain green with CMA;
3 H NMR (CD3OD, 400 MHz): δ ppm= 7.17 (1H, d, J = 8 Hz); 7.02 (1H, s,); 6.93 (1H, d, J = 4 Hz); 6.67 (1H, dd, J = 4 Hz, J = 8 Hz); 2.94 (4H, m); 2.78 (1H, m); 1.73 (4H, m); 1.48 (10H, m).
13 C NMR (CD3OD, 101 MHz): δ ppm= 151.2; 133.2; 129.2; 124.4; 112.8; 112.6; 112.1; 103.4; 59.1; 47.9;
32.9 (2C); 27.9 (2C); 26.9; 25.8; 25.3 (2C).
UPLC: R T : 1.66 (classic system) MS (ESI + ) m/z [M+H] + Calcd for CI 8 H 27 N 2 O + 287.20; Found 287.30.
Yield: 300 mg, 97%. Isolated as a a light grey powder, >95% pure by NMR and a single spot by TLC; Rf: 0.53 in DCM/MeOH/Et 3 N, 95/5/2. Strain green with CMA;
3 H NMR (CD 3 OD, 400 MHz): δ ppm= 7.17 (1H, d, J = 8.6 Hz); 7.04 (1H, s,); 6.94 (1H, d, J = 2.3 Hz); 6.67 (1H, dd, J = 2.4 Hz, J = 8.6 Hz); 2.93 (4H, m); 2.79 (1H, brs); 1.91-1.83 (4H, m); 1.80 (1H, m); 1.74-1.68 (4H, m); 1.65-1.56 (3H, m); 1.47-1.41 (2H, m).
13 C NMR (CD3OD, 101 MHz): δ ppm= 151.2; 133.2; 129.3; 124.4; 112.8; 112.5 (2C); 103.5; 62.4; 47.4;
38.8; 38.7 (2C); 32.4 (2C); 31.9 (2C); 29.1; 28.6; 26.0.
UPLC: R T : 1.62 (classic system)
MS (ESI + ) m/z [M+H] + Calcd for C 20 H 27 N 2 O + 311.21; Found 311.30.
Yield: 70 mg, 32%. Isolated as a white amorphous solid, >95% pure by NMR and a single spot by TLC; R f : 0.29 in DCM/MeOH/Et 3 N, 90/10/2. Strain green with CMA;
3 H NMR (CD3OD, 400 MHz): δ ppm= 7.18 (1H, d, J = 8.6 Hz); 7.04 (1H, s,); 6.93 (1H, d, J = 2.3 Hz); 6.68 (1H, dd, J = 2.3 Hz, J = 8.6 Hz); 3.05-2.91 (5H, m); 1.14 (6H, d, J = 6.5 Hz).
13 C NMR (CD3OD, 101 MHz): δ ppm= 151.3; 133.2; 129.2; 124.5; 112.8; 112.6; 111.6; 103.3; 50.3; 47.7;
25.4; 21.4 (2C).
UPLC: R T : 1.13 (classic system)
MS (ESI + ) m/z [M+H] + Calcd for CI 3 HI 9 N 2 O + 219.14; Found 219.21.
Yield: 57 mg, 23%. Isolated as a white amorphous solid, >95% pure by NMR and a single spot by TLC; R f : 0.63 in DCM/MeOH/Et 3 N, 90/10/2. Strain green with CMA;
3 H NMR (CD 3 OD, 400 MHz): δ ppm= 7.18 (1H, d, J = 8.6 Hz); 7.07 (1H, s,); 6.94 (1H, d, J = 2.4 Hz); 6.69 (1H, dd, J = 2.3 Hz, J = 8.7 Hz); 3.06 (2H, m); 2.99 (2H, m); 2.68 (1H, quint., J = 6.2 Hz); 1.56 (4H, m); 0.87 (6H, t, J = 7.5 Hz).
13 C NMR (CD3OD, 101 MHz): δ ppm= 151.4; 133.2; 129.1; 124.7; 112.9; 112.7; 111.1; 103.3; 61.6; 47.3;
24.9 (3C); 9.8 (2C).
UPLC: R T : 1.40 (classic system)
MS (ESI + ) m/z [M+H] + Calcd for CI 5 H 23 N 2 O + 247.17; Found 247.20.
Yield: 115 mg, 44%. Isolated as a white amorphous solid, >95% pure by NMR and a single spot by TLC; R f : 0.8 in DCM/MeOH/Et 3 N, 90/10/2. Strain green with CMA;
3 H NMR (CD3OD, 400 MHz): δ ppm = 7.17 (1H, dd, J = 0.5 Hz, J = 8.6 Hz); 7.05 (1H, s,); 6.93 (1H, dd, J = 0.5 Hz, J = 2.3 Hz); 6.68 (1H, dd, J = 2.3 Hz, J = 8.6 Hz); 3.08-2.85 (5H, m); 1.53 (1H, m); 1.36 (1H, m); 1.24 (1H, m); 1;12 (3H, m); 0.88 (6H, dd, J = 3.6 Hz, J = 6.6 Hz).
13 C NMR (CD3OD, 101 MHz): δ ppm = 151.3; 133.2; 129.1; 124.6; 112.9; 112.6; 111.4; 103.3; 52.9; 47.3;
45.8; 25.9; 25.3; 23.4; 22.3; 18.8.
UPLC: R T : 1.58 (classic system) MS (ESI + ) m/z [M+H] + Calcd for CI 5 H 23 N 2 O + 261.19; Found 261.27. g
Yield: 131 mg, 35%. Isolated as a white amorphous solid, >95% pure by NMR and a single spot by TLC; Rf: 0.33 in DCM/MeOH, 90/10. Strain green with CMA;
3 H NMR (CD 3 OD, 400 MHz): δ ppm= 7.21-7.10 (7H, m); 7.01 (4H, m); 6.84 (1H, d, J = 2.4 Hz); 7.07 (1H, s,); 6.94 (1H, d, J = 2.4 Hz); 6.67 (1H, dd, J = 2.4 Hz, J = 8.6 Hz); 6.62 (1H, s); 3.04 (1H, p, J = 6.9 Hz); 2.92 (2H, t, J = 6.6 Hz); 2.78 (1H, t, J = 6.6 Hz); 2.72 (2H, dd, J = 6.9 Hz, J = 13.8 Hz); 2.61 (2H, dd, J = 6.6 Hz, J = 13.8 Hz).
13 C NMR (CD3OD, 101 MHz): δ ppm= 151.1; 139.7 (2C); 133.2; 130.5 (4C); 129.6 (4C); 128.9; 127.5 (2C); 124.5; 112.8; 112.5; 111.3; 103.4; 62.5; 47.6; 40.8 (2C); 25.5.
UPLC: R T : 1.91 (classic system)
MS (ESI + ) m/z [M+H] + Calcd for C 25 H 27 N 2 O + 371.20; Found 371.27.
Yield: 187 mg, 63%. Isolated as a white amorphous solid, >95% pure by NMR and a single spot by TLC;
Rf: 0.6 in DCM/MeOH, 90/10. Strain green with CMA; 3 H NMR (CD3OD, 400 MHz): δ ppm = 7.18-7.12 (4H, m); 7.01 (2H, dd, J = 2.0 Hz, J = 7.8 Hz); 6.90 (1H, d, J = 0.5 Hz, J = 2.3 Hz); 6.82 (1H, s,); 6.68 (1H, dd, J = 2.3 Hz, J = 8.6 Hz); 3.0.3-2.81 (5H, m); 2.69 (1H, J = 7.1 Hz, J = 12.9 Hz); 2.59 (1H, J = 7.1 Hz, J = 12.9 Hz); 1.06 (3H, d, J = 6.5 Hz).
13 C NMR (CD3OD, 101 MHz): δ ppm = 151.1; 139.7; 133.2; 130.1 (2C); 129.5 (2C); 129.1; 127.4; 124.4;
112.8; 112.5; 111.8; 103.4; 55.8; 47.6; 43.5; 25.7; 19.4.
UPLC: R T : 1.62 (classic system)
MS (ESI + ) m/z [M+H] + Calcd for CI 5 H 23 N 2 O + 295.17; Found 295.28.
Yield: 273 mg, 95%. Isolated as a white amorphous solid, >95% pure by NMR and a single spot by TLC; R f : 0.12 in DCM/MeOH/Et 3 N, 95/5/2. Strain green with CMA;
3 H NMR (CD 3 OD, 400 MHz): δ ppm = 7.19 (1H, d, J = 0.4 Hz, J = 8.6 Hz); 7.08 (1H, s,); 6.94 (1H, d, J = 0.5 Hz, J = 2.2 Hz); 6.70 (1H, dd, J = 2.3 Hz, J = 8.7 Hz); 5.06 (1H, m); 3.14-2.91 (5H, m); 1.98 (2H, m); 1.66 (3H, J = 0.7 Hz); 1.65-1.60 (1H, m); 1.56 (3H, s); 1.46-1.36 (1H, m); 1.18 (3H, d, J = 6.5 Hz).
13 C NMR (CD3OD, 101 MHz): δ ppm = 151.4; 133.5; 133.2; 129.1; 124.7; 124.2; 112.9; 112.7; 110.9;
103.3; 54.6; 47.1; 35.8; 25.8; 25.1; 24.9; 18.0; 17.7.
UPLC: R T : 1.71 (classic system)
MS (ESI + ) m/z [M+H] + Calcd for CI 5 H 23 N 2 O + 287.20; Found 287.30. Yield: 36 mg, 16%. Isolated as a white amorphous solid, >95% pure by NMR and a single spot by TLC; R f : 0.32 in DCM/MeOH, 90/10 + 2% Et 3 N. Strain green with CMA;
3 H NMR (CD 3 OD, 500 MHz): δ ppm= 8.54 (2H, s, (FA)); 7.20 (2H, d, J = 8.6 Hz); 7.11 (2H, s); 6.92 (2H, d, J = 2.3 Hz); 6.71 (2H, dd, J = 2.3 Hz, J = 8.6 Hz); 3.29-3.16 (6H, m); 3.07 (4H, m); 1.71 (2H, m); 1.48 (2H, m); 1.41-1.22 (14H, m).
13 C NMR (CD3OD, 126 MHz): δ ppm= 170.1 (FA) (2C); 151.6 (2C); 133.2 (2C); 128.8 (2C); 124.9 (2C); 113.1 (2C); 112.9 (2C); 109.4 (2C); 103.1 (2C); 55.5 (2C); 46.1 (2C); 34.1 (2C); 30.2 (2C); 26.4 (2C); 23.7 (2C); 16.6 (2C).
UPLC: R T : 1.48 (classic system)
MS (ESI + ) m/z [M+H] + Calcd for C 30 H 42 N 4 O 2 491.33; Found 491.49.
3-2-2-Procedure from aldehyde (singly substituted analogs) [compound 8 to x]:
In the dark and under inert atmosphere, serotonin hydrochloride (213 mg, 1 mmol) was dissolved in MeOH dry (10 mL) and the corresponding aldehyde (1.1 equiv.) was added. The mixture was stirred for 3h, and after that time NaBH 3 CN (1.1 equiv.) was added. The reaction mixture was stirred further at RT for additional 30 minutes. Next, the solvent was evaporated under reduced pressure. The crude was taken in a mixture of Et 2 O/water, 1/1 (10/10 mL), the resulting solution was alkalinized with NaOH [2M] until to obtain pH=10, then extracted with Et 2 O (2 x 20 mL), then with DCM (1 x 20 mL).The organic phases were dried over MgSO 4 and concentrated. The crude was purified by flash chromatography using DCM/MeOH/Et 3 N (100/0/2 to 80/20/2) as eluent. Yield: 88 mg, 36%. Isolated as a white amorphous solid, >95% pure by NMR and a single spot by TLC; R f : 0.31 in DCM/MeOH/Et 3 N, 98/2/2. Strain green with CMA;
3 H NMR (CD 3 OD, 500 MHz): d ppm = 8.58 (1H, s, (FA)); 7.19 (1H, d, J = 8.7 Hz); 7.09 (1H, s,); 6.95 (1H, d, J = 2.2 Hz); 6.71 (1H, dd, J = 2.2 Hz, J = 8.7 Hz); 3.21 (2H, t, J = 7.5 Hz); 3.07 (2H, t, J = 7.5 Hz); 2.94 (2H, t, J = 7.9 Hz); 1.65 (2H, quint, J = 7.8 Hz); 1.33 (4H, m); 0.92 (3H, t, J = 6.7 Hz).
13 C NMR (CD3OD, 126 MHz): d ppm = 170.3; 151.5; 133.1; 128.9; 124.9; 113.0; 112.8; 109.4; 103.1;
49.0; 48.8; 29.7; 26.9; 23.4; 23.2; 14.1.
UPLC: R T : 1.45 (classic system)
MS (ESI + ) m/z [M+H] + Calcd for CI 5 H 22 N 2 O + 247.17; Found 247.27.
Yield: 122 mg, 47%. Isolated as a white amorphous solid, >95% pure by NMR and a single spot by TLC; R f : 0.16 in DCM/MeOH/Et 3 N, 98/2/2. Strain green with CMA;
3 H NMR (CD3OD, 400 MHz): δ ppm= 7.16 (1H, d, J = 8.7 Hz); 7.01 (1H, s,); 6.92 (1H, d, J = 2.1 Hz); 6.67 (1H, dd, J = 2.1 Hz, J = 8.7 Hz); 2.91 (4H, s); 2.62 (2H, m); 1.48 (2H, m); 1.26 (6H, m); 0.88 (3H, t, J = 6.5 Hz).
13 C NMR (CD3OD, 101 MHz): δ ppm= 151.2; 133.2; 129.3; 124.3; 112.8; 112.5; 112.2; 103.4; 50.6; 50.3;
32.8; 30.0; 27.9; 25.8; 23.6; 14.3.
UPLC: R T : 1.68 (classic system)
MS (ESI + ) m/z [M+H] + Calcd for CI 6 H 25 N 2 O 10 + 261.19; Found 261.19.
LYS26 Compound 10: (exp: LT266A) (=compound (022))
Yield: 10 mg, 4.5%. Isolated as a white amorphous solid, >95% pure by NMR and a single spot by TLC; R f : 0.3 in DCM/MeOH/Et 3 N, 80/20/2. Strain green with CMA;
3 H NMR (CD 3 OD, 400 MHz): δ ppm= 8.57 (1H, s, (FA)); 7.21 (1H, d, J = 8.6 Hz); 7.13 (1H, s); 6.95 (1H, d, J = 2.3 Hz); 6.72 (1H, dd, J = 8.6Hz, J =2.3 Hz); 3.28 (2H, t, J = 7.6 Hz); 3.10 (2H, t, J = 7.6 Hz); 2.99 (2H, d, J = 8.6 Hz). 1.72 (2H, d, J = 7.5 Hz); 1.02 (3H, t, J = 7.4 Hz).
13 C NMR (CD3OD, 126 MHz): δ ppm= 168.7 (FA); 150.2; 131.8; 127.5; 123.5; 111.6; 111.5; 108.0; 101.7;
49.0; 22.0; 19.2; 9.8.
UPLC: R T : 0.9 to 1.12 (classic system)
MS (ESI + ) m/z [M+H] + Calcd for CI 3 HI 9 N 2 O + 219.14; Found 219.26.
Yield: 27.6 mg, 11.8%. Isolated as a white amorphous solid, >95% pure by NMR and a single spot by TLC; R f : 0.5 in DCM/MeOH/Et 3 N, 90/10/2. Strain green with CMA;
3 H NMR (CD3OD, 500 MHz): δ ppm= 8.58 (s, 1H (FA)); 7.21 (1H, dd, J = 8.7 Hz, J =2.7 Hz); 7.12 (1H, s); 6.96 (1H, d, J = 2.4 Hz); 6.72 (1H, dd, J = 8.6 Hz, J =2.0 Hz); 3.27 (2H, t, J = 7.6 Hz,); 3.10 (2H, t, J = 7.6 Hz); 3.00 (2H, t, J = 8.2 Hz); 1.67 (2H, p, J = 7.9 Hz); 1.42 (2H, h, J = 7.4 Hz); 0.98 (3H, t, J = 7.4 Hz).
13 C NMR (CD3OD, 126 MHz): δ ppm= 168.9; 150.2; 131.8; 127.5; 123.5; 111.6; 111.5; 108.0; 101.7; 27.8;
22.1; 19.4; 12.5.
UPLC: R T : 1.23 (classic system) MS (ESI + ) m/z [M+H] + Calcd for CI 4 H 2 IN 2 O + 233.16; Found 233.20.
Yield: 71.8 mg, 26%. Isolated as a white amorphous solid, >95% pure by NMR and a single spot by TLC; R f : 0.6 in DCM/MeOH/Et 3 N, 90/10/2. Strain green with CMA;
3 H NMR (CD 3 OD, 500 MHz): δ ppm= 8.59 (1H, s, (FA)); 7.21 (1H, d, J = 8.7 Hz); 7.12 (1H, s); 6.96 (1H, d, J = 2.5 Hz); 6.72 (1H, dd, J = 8.7 Hz, J = 2.0 Hz); 3.26 (2H, dd, J = 6.5 Hz, J = 5.5 Hz); 3.09 (2H, t, J = 7.6 Hz), 2.98 (2H, dd, J = 6.6 Hz, J = 5.3 Hz); 1.73 - 1.58 (2H, m); 1.44 - 1.25 (8H, m); 0.93 (3H, t, J = 7.6 Hz). 1 3 C NMR (CD3OD, 126 MHz): δ ppm= 169.0, 150.2, 131.8, 127.5, 123.5, 111.6, 111.5, 108.1, 101.7, 31.3, 28.5, 26.2, 25.9, 22.2, 22.1, 13.0 ppm.
UPLC: R T : 1.61 (classic system)
MS (ESI + ) m/z [M+H] + Calcd for CI 7 H 27 N 2 O + 275.20; Found 275.28.
Yield: 69 mg, 24%. Isolated as a white amorphous solid, >95% pure by NMR and a single spot by TLC;
R f : 0.4 in DCM/MeOH/Et 3 N, 90/10/2. Strain green with CMA;
3 H NMR (CD3OD, 500 MHz): δ ppm= 8.60 (1H, d, J = 2.3 Hz, (FA)); 7.21 (1H, d, J = 8.6 Hz); 7.11 (1H, s);
6.97 (1H, d, J = 2.4 Hz); 6.73 (1H, dd, J = 8.6 Hz, J = 2.3 Hz); 3.28 - 3.19 (2H, m); 3.08 (2H, t, J = 7.6 Hz);
3.04 - 2.88 (2H, m); 1.75 - 1.60 (2H, m); 1.43 - 1.23 (10H, m); 0.92 (3H, t, J = 6.7 Hz). 13 C NMR (CD3OD, 126 MHz): δ ppm= 169.0; 150.2; 131.8; 127.5; 123.5; 111.6; 111.5; 108.1; 101.8; 31.5;
28.8 (2C); 26.2; 25.8; 22.3; 22.1; 13.0.
UPLC: R T : 1.85 (classic system)
MS (ESI + ) m/z [M+H] + Calcd for CI 8 H 29 N 2 O + 289.22; Found 289.22.
Yield: 22 mg, 7%. Isolated as a white amorphous solid, >95% pure by NMR and a single spot by TLC; Rr: 0.7 in DCM/MeOH/Et 3 N, 80/20/2. Strain green with CMA;
3 H NMR (CD3OD, 500 MHz): δ ppm= 8.59 (1H, s, (FA)); 7.21 (1H, d, J = 8.6 Hz); 7.12 (1H, s); 6.96 (1H, d, J = 2.3 Hz); 6.72 (1H, dd, J = 8.6 Hz, J = 2.3 Hz); 3.26 (2H, t, J = 7.6 Hz); 3.09 (2H, t, J = 7.6 Hz); 2.99 (2H, t, J = 7.1 Hz); 1.67 (2H, p, J = 7.4 Hz); 1.46 - 1.19 (14H, m); 0.92 (3H, t, J = 6.8 Hz).
13 C NMR (CD3OD, 126 MHz): δ ppm= 169.0; 150.2; 131.8; 127.5; 123.5; 111.6; 111.5; 108.1; 101.7; 31.6;
29.2; 29.1; 29.0; 28.8; 26.2; 25.9; 22.3; 22.1; 13.0.
UPLC: R T : 2.03 (classic system)
MS (ESI + ) m/z [M+H] + Calcd for C 20 H 33 N 2 O + 317.25; Found 317.03. Yield: 77 mg, 22%. Isolated as a white amorphous solid, >95% pure by NMR and a single spot by TLC; R f : 0.4 in DCM/MeOH/Et 3 N, 90/10/2. Strain green with CMA. 3 H NMR (CD3OD, 500 MHz): δ ppm= 8.60 (1H, s, (FA)); 7.21 (1H, d, J = 8.7 Hz); 7.12 (1H, s); 6.96 (1H, d, J = 2.2 Hz); 6.72 (1H, dd, J = 8.7 Hz, J = 2.3 Hz); 3.25 (2H, t, J = 7.6 Hz); 3.09 (2H, t, J = 7.6 Hz); 2.97 (2H, t, J = 8.0 Hz); 1.67 (2H, p, J = 7.5 Hz); 1.47 - 1.21 (18H, m); 0.92 (3H, t, J = 6.9 Hz). 13 C NMR (CD3OD, 126 MHz): δ ppm= 169.0; 150.2; 131.8; 127.5; 123.5; 111.6; 111.5; 108.1; 101.8; 31.7; 29.3 (2C); 29.2; 29.1; 29.1; 28.8; 26.2; 25.9; 22.3; 22.2; 13.1. UPLC: R T : 2.32 (classic system). MS (ESI + ) m/z [M+H] + Calcd for C 22 H 37 N 2 O + 345.28; Found 345.16.
Yield: 93 mg, 35%. Isolated as a white amorphous solid, >95% pure by NMR and a single spot by TLC; R f : 0.46 in DCM/MeOH/Et 3 N, 98/2/2. 1 H NMR (CD 3 OD, 400 MHz): δ ppm= 7.31-7.21 (5 H, m); 7.16 (1H, d, J = 8.6 Hz); 6.98 (1H, s); 6.90 (1H, d, J = 2.4 Hz); 6.66 (1H, dd, J = 8.6 Hz, J = 2.4 Hz); 3.78 (2H, s); 2.91 (4H, s). 13 C NMR (CD3OD, 101 MHz): δ ppm= 151.2; 139.9; 133.2; 129.6 (2C); 129.5 (2C); 129.3; 128.3; 124.3; 112.7; 112.5; 112.4; 103.5; 54.2; 50.1; 25.9. UPLC: R T : 1.48 (classic system). MS (ESI + ) m/z [M+H] + Calcd for CI 7 HI 9 N 2 O + 267.14; Found 267.21. Yield: 154 mg, 49%. Isolated as a white amorphous solid, >95% pure by NMR and a single spot by TLC; R f : 0.10 in DCM/MeOH, 95/5. 1 H NMR (CD 3 OD, 400 MHz): δ ppm= 7.16 (1H, d, J = 8.8 Hz); 6.98 (1H, s);
6.89 (1H, d, J = 2.4 Hz); 6.98 (1H, s); 6.76 (1H, brs); 6.71 (2H, brs); 6.66 (1H, dd, J = 8.7 Hz, J = 2.4 Hz);
5.90 (2H, s); 3.68 (2H, s); 2.89 (4H, brt, J = 3.9 Hz). 13 C NMR (CD3OD, 101 MHz): δ ppm= 151.1; 149.2; 148.3; 133.8; 133.2; 129.3; 124.3; 122.9; 112.7; 112.4 (2C); 109.8; 108.9; 103.5; 102.3; 53.9; 49.8; 25.9. UPLC: R T : 1.49 (classic system). MS (ESI + ) m/z [M+H] + Calcd for CI 8 HI 9 N 2 O + 311.13; Found 311.23.
Yield: 82 mg, 18%. Isolated as a white amorphous solid, >95% pure by NMR and a single spot by TLC; R f : 0.49 in DCM/MeOH, 95/5.
3 H NMR (CD3OD, 400 MHz): δ ppm = 7.12 (1H, d, J = 8.5 Hz); 6.88 (1H, s); 6.82 (2H, d, J = 1.6 Hz); 6.75 (3H, m); 6.70 (2H, m); 6.62 (1H, dd, J = 8.6 Hz, J = 2.3 Hz); 5.89 (4H, s); 3.53 (4H, s); 2.84 (2H, m); 2.70 (2H, s).
13 C NMR (CD3OD, 101 MHz): δ ppm = 150.8; 149.1 (2C); 148.0 (2C); 134.8 (2C); 133.1; 129.5; 123.9;
123.1 (2C); 113.7; 112.5; 112.1; 110.1 (2C); 108.7 (2C); 103.7; 102.1 (2C); 58.9 (2C); 54.9; 24.0.
UPLC: R T : 1.79 (classic system)
MS (ESI + ) m/z [M+H] + Calcd for C 26 H 25 N 2 O 5 + 445.17; Found 445.23. Yield: 31 mg, 12%. Isolated as a white amorphous solid, >95% pure by NMR and a single spot by TLC; R f : 0.5 in DCM/MeOH/Et 3 N, 90/10/2. Strain green with CMA. 3 H NMR (CD3OD, 500 MHz): δ ppm= 8.53 (1H, s); 7.63 (1H, d, J = 1.8 Hz); 7.21 (1H, d, J = 8.7 Hz); 7.11 (1H, s); 6.93 (1H, d, J = 2.3 Hz); 6.72 (1H, dd, J = 8.7 Hz, J = 2.3 Hz); 6.61 (1H, d, J = 3.3 Hz); 6.50 (1H, dd, J = 3.3, 1.8 Hz); 4.27 (2H, s); 3.27 (2H, t, J = 7.7 Hz); 3.09 (2H, t, J = 7.6 Hz). 13 C NMR (CD3OD, 126 MHz): δ ppm= 168.4; 150.2; 145.4; 144.3; 131.8; 127.4; 123.5; 112.0; 111.6; 111.5; 110.7; 108.0; 101.8; 47.0; 42.7; 22.0. UPLC: R T : 1.22 (classic system). MS (ESI + ) m/z [M+H] + Calcd for CI 5 HI 7 N 2 O + 257.12; Found 257.14.
Yield: 37.3 mg, 13%. Isolated as a white amorphous solid, >95% pure by NMR and a single spot by TLC; R f : 0.4 in DCM/MeOH/Et 3 N, 90/10/2. Strain green with CMA. 1 H NMR (CD 3 OD, 400 MHz): δ ppm= 8.41 (1H, s); 7.09 (1H, d, J = 8.6 Hz); 6.98 (1H, s); 6.81 (1H, d, J = 2.2 Hz); 6.60 (1H, dd, J = 8.7 Hz, J = 2.3 Hz); 6.48 (1H, d, J = 3.4 Hz); 6.22 (1H, d, J = 3.3 Hz); 4.06 (2H, s), 3.12 (2H, t, J = 7.6 Hz); 2.95 (2H, t, J = 7.5 Hz). 13 C NMR (CD3OD, 101 MHz): δ ppm= 150.1; 146.4; 137.4; 131.8; 127.5; 123.5; 114.0; 111.6; 111.4; 108.3; 107.4; 101.8; 47.3; 43.0; 22.3. UPLC: R T : 1.43 (classic system). MS (ESI + ) m/z [M+H] + Calcd for CI 5 HI 6 N 2 O + 291.08; Found 291.10.
3-3- N-cycloalkylation
Strategy : O-silylation then N-cycloalkylation A mixture of serotonin hydrochloride (1.0 g, 4.7 mmol), tert-butyl d im ethylsilyl chloride (TBDMSCI, 3.97 g, 5.6 equiv.) and imidazole (640 mg, 2 equiv.) in acetonitrile (47 mL) was stirred at room temperature for overnight under N2 and then was filtered. The solid residue was dissolved in 0.5 M NaOH aqueous solution (100 mL), and immediately extracted with CH 2 CI2 (3 x 30 mL). The combined CH 2 CI2 extracts were washed with deionized water (30 mL) and dried over Mg 2 SO4. Removing the solvent under reduced pressure afforded the desired compound LC423 as a greyish solid.
In the dark and under inert atmosphere, the product of the previous step LC423 (145 mg, 0.5 mmol, 1 equiv.) was dissolved in dry acetonitrile (4 mL). K2CC>3 (276 mg, 4 equiv.) and dibromoalkyl (1 equiv.) were added to the solution. The mixture was stirred and heated at reflux overnight, cooled down to r.t. then filtered with acetonitrile and concentrated. The crude was purified by flash chromatography using cyclohexane / EtOAC (90/10 to 0/100) as eluent to give the O-silylated-N-cycloalkylated derivatives.
The product was then dissolved in THF (C=0.1M) and 1.1 equivalent of TBAF (1 M in THF) was added. The mixture was stirred for 1 h until the O-deprotected product was predominant in UPLC analysis. The mixture was then concentrated and the crude was directly purified by preparative HPLC to give the desired product after lyophilization.
Yield: 1.29 g, 94%. Isolated as a light grey foam, >95% pure by NMR and a single spot by TLC; Rf: 0.15 in DCM/MeOH, 95/5 +2% Et 3 N. Strain green with CAM;
3 H NMR (CD 2 CI 2 , 400 MHz): δ ppm = 8.17 (1H, brs); 7.20 (1H, dd, J = 0.6 Hz, J = 8.5 Hz); 7.01 (1H, d, J = 2.1 Hz); 6.99 (1H, d, J = 2.3 Hz); 6.73 (1H, dd, J = 2.3 Hz, J = 8.5 Hz); 2.95 (2H, t, J = 7.0 Hz); 2.80 (2H, t, J = 6.8 Hz); 1.31 (2H, brs); 1.01 (9H, s); 0.19 (6H, s).
13 C NMR (CD 2 CI 2 , 101 MHz): δ ppm = 148.9; 132.1; 128.3; 122.9; 115.9; 113.5; 111.3; 108.3; 42.5; 29.7;
25.6 (3C); 18.1; -3.8 (2C).
UPLC: R T : 1.85 (classic system)
MS (ESI + ) m/z [M+H] + Calcd for C 16 H 28 OSP 291.18; Found 291.18.
Yield: 70 mg, 41%. Isolated as a light grey foam, >95% pure by NMR and a single spot by TLC; Rf: 0.67 in DCM/MeOH, 95/5 +2% Et 3 N. Strain green with CAM;
3 H NMR (CD 3 OD, 400 MHz): δ ppm = 7.19 (1H, dd, J = 0.5 Hz, J = 8.6 Hz); 7.04 (1H, s); 6.96 (1H, d, J = 2.1 Hz); 6.67 (1H, dd, J = 2.3 Hz, J = 8.6 Hz); 2.92 (4H, m); 2.78 (4H, m); 1.88 (4H, m); 1.02 (9H, s); 0.19 (6H, s).
13 C NMR (CD3OD, 101 MHz): δ ppm = 149.7; 133.9; 129.1; 124.2; 116.5; 112.6 (2C); 108.7; 58.1; 55.1 (2C); 26.3 (3C); 25.3; 24.1 (2C); 19.1; -4.2 (2C).
UPLC: R T : 2.05 (classic system)
MS (ESI + ) m/z [M+H] + Calcd for C 20 H 3 3N 2 OSi + 345.57; Found 345.21.
Yield: 35 mg, 76%. Isolated as a light grey foam, >95% pure by NMR and a single spot by TLC; Rf: 0.41 in DCM/MeOH, 95/5 +2% Et 3 N. Strain green with CAM;
3 H NMR (CD3OD, 500 MHz): δ ppm = 8.51 (1H, s, FA); 7.19 (1H, d, J = 8.5 Hz); 7.10 (1H, s); 6.96 (1H, brs);
6.70 (1H, brd, J = 8.4 Hz); 3.37 (2H, d, J = 7.5 Hz); 3.29 (4H, m); 3.08 (2H, t, J = 7.8 Hz); 2.01 (4H, brs).
13 C NMR (CD3OD, 101 MHz): δ ppm = 169.8 (FA); 151.6; 133.1; 128.8; 125.0; 113.1; 112.9; 109.2; 103.2;
56.5; 55.1 (2C); 23.9 (2C); 23.2.
UPLC: R T : 0.61 (classic system) MS (ESI + ) m/z [M+H] + Calcd for CI 4 HI 9 N 2 O + 231.14; Found 231.09.
Comment : LC432F2 is obtained directly deprotected after the alkylation reaction.
Yield: 65 mg, 53%. Isolated as a light grey foam, >95% pure by NMR and a single spot by TLC; Rf: 0.59 in DCM/MeOH, 95/5 +2% Et 3 N. Strain green with CAM;
3 H NMR (CD 3 OD, 400 MHz): δ ppm = 8.56 (1H, brs, FA); 7.18 (1H, d, J = 8.6 Hz); 7.09 (1H, s); 6.93 (1H, d, J = 2.1 Hz); 6.70 (1H, dd, J = 2.4 Hz, J = 8.5 Hz); 3.33-3.15 (6H, m); 3.12 (2H, m); 1.85 (4H, m); 1.67 (2H, brs).
13 C NMR (CD3OD, 101 MHz): δ ppm = 170.2 (FA); 151.6; 133.1; 128.8; 124.7; 113.0; 112.8; 109.5; 103.1;
58.6; 54.3 (2C); 24.4 (2C); 22.9; 22.6.
UPLC: R T : 1.15 (classic system)
MS (ESI + ) m/z [M+H] + Calcd for CI 5 H 2 IN 2 O + 244.16; Found 245.17.
3-4- N-dimer
In the dark and under inert atmosphere, LC423 (145 mg, 0.5 mmol) was dissolved in dry DMF (1 mL).
K 2 CO 3 (76 mg, 1.1 equiv.) and 1,10-dibromodecane (75 mg, 0.5 equiv.) were added to the solution. The mixture was stirred at 40°C overnight, cooled down to r.t. then concentrated to dryness. The crude was purified by flash chromatography using DCM / MeOH (100/0 to 90/10) + 2% Et 3 N as eluent, then by preparative HPLC to give the desired product LC439 after lyophilization.
LC439 was then dissolved in THF (C=0.1M) and 1.1 equivalent of TBAF (1 M in THF) was added. The mixture was stirred for 1 h until the O-deprotected product was predominant in UPLC analysis. The mixture was then concentrated and the crude was directly purified by preparative HPLC to give the desired product LC469 after lyophilization.
Yield: 34 mg, 9.5%. Isolated as a light grey foam, >95% pure by NMR and a single spot by TLC; Rf: 0.50 in DCM/MeOH, 90/10 +2% Et 3 N. Strain green with CAM;
3 H NMR (CD 3 OD, 500 MHz): δ ppm = 8.59 (2H, brs, FA); 7.25 (2H, d, J = 8.7 Hz); 7.16 (2H, s); 7.00 (2H, d, J = 2.0 Hz); 6.72 (2H, dd, J = 2.3 Hz, J = 8.7 Hz); 3.25 (4H, t, J = 7.5 Hz); 3.10 (4H, t, J = 7.5 Hz); 2.98
(4H, m); 1.67 (4H, m); 1.34 (12H, m); 1.03 (18H, s); 0.21 (12 H, s).
13 C NMR (CD3OD, 126 MHz): δ ppm = 168.9 (FA); 148.7 (2C); 132.6 (2C); 127.4 (2C); 123.7 (2C); 115.5
(2C); 111.5 (2C); 108.5 (2C); 107.1 (2C); 47.8 (2C); 47.5 (2C); 28.9 (2C); 28.8 (2C); 26.2 (2C); 25.9 (2C);
24.9 (6C); 22.1 (2C); 17;7 (2C); -5.6 (4C).
UPLC: R T : 2.43 (classic system)
MS (ESI + ) m/z [M+H] + Calcd for C 42 H 7 iN 4 O 2 Si 2 + 719.50; Found 719.62.
Yield: 18 mg, 78%. Isolated as a light grey foam, >95% pure by NMR;
3 H NMR (CD3OD, 400 MHz): δ ppm = 8.53 (2H, brs, FA); 7.19 (2H, d, J = 8.7 Hz); 7.10 (2H, s); 6.93 (2H, d, J = 2.2 Hz); 6.70 (2H, dd, J = 2.1 Hz, J = 8.7 Hz); 3.26 (4H, t, J = 7.5 Hz); 3.08 (4H, t, J = 7.5 Hz); 2.99 (4H, m); 1.66 (4H, m); 1.34 (12H, m). 13 C NMR (CD 3 OD, 101 MHz): δ ppm = 170.1 (FA); 1516 (2C); 133.2 (2C); 128.9 (2C); 124.9 (2C); 113.0 (2C); 112.8 (2C); 109.4 (2C); 103.1 (2C); 49.1 (2C); 48.9 (2C); 30.4 (2C); 30.2 (2C); 27.6 (2C); 27.2 (2C);
23.5 (2C).
UPLC: R T : 1.49 (classic system)
MS (ESI + ) m/z [M+H] + Calcd for C 42 H 7 iN 4 O 2 Si 2 + 491.33; Found 491.56.
3-5- pyrrole C-alkylation
3-5-1-Strategy 1 : N- et O-Acetyl
To a cold (0°C) solution of serotonin hydrochloride (2.5 g, 11.5 mmol) and triethylamine (8.25 mL, 5 equiv.) in CH 2 CI 2 (80 mL) was added slowly acetyl chloride (2.67 mL, 3.2 equiv.) over 10 min. After the addition was complete, the reaction mixture was allowed to warm at room temperature and stirred for 2 hours. The reaction was diluted with CH 2 CI 2 (20 mL) and washed with water (2 x 20 mL) and brine (30 mL), dried over MgSO 4 and the solvent was evaporated to afford the compound LC377 as a pale yellow foam.
To a mixture of diacetylated serotonin derivative LC377 (130mg, 0.50 mmol), norbornene (94 mg, 2.00 equiv), K 2 CO 3 (276 mg, 4.00 equiv), and PdCI 2 (8.9 mg, 10 mol %) was added 2.5 mL of DMF (containing 0.5 M H 2 O) and l-bromo-2-methylpropane (218 pL, 4.00 equiv). The resulting suspension was stirred at 60 °C for 24 h. After being cooled to room temperature, the reaction mixture was diluted with Et 2 O (30 mL) and washed with water (50 mL). The aqueous layer was then extracted with Et 2 O (2 x 50 mL), and the combined organic extracts were dried over MgSO 4 and concentrated. The crude product was purified by flash column chromatography on silica gel to afford the 2-alkylserotonin product LC385. Comment: desacetylation of the phenol occurs during the reaction. Yield: 3.06 g, 100%. Isolated as a light yellow foam, >95% pure by NMR and a single spot by TLC; Rf: 0.5 in DCM/MeOH, 95/5. Strain green with CAM;
3 H NMR (DMSO-c/6, 500 MHz): δ ppm = 10.91 (1H, s); 7.92 (1H, brt, J = 5.4 Hz); 7.35 (1H, d, J = 8.6 Hz);
7.22 (2H, dd, J = 2.4 Hz, J = 7.9 Hz); 6.81 (1H, dd, J = 2.2 Hz, J = 8.6 Hz); 3.30 (2H, dd, J = 6.0 Hz, J = 7.0 Hz); 2.79 (2H, t, J = 7.4 Hz); 2.26 (3H, s); 1.80 (3H, s).
13 C NMR (DMSO-c/6, 126 MHz): δ ppm = 169.9; 169.1; 143.3; 134.0; 127.4; 124.2; 115.3; 112.2; 111.7;
110.4; 54.9; 25.1; 22.7; 20.9.
UPLC: R T : 1.70 (classic system)
MS (ESI + ) m/z [M+H] + Calcd for CI 4 HI 7 N 2 O 3 + 261.12; Found 261.21.
Yield: 19 mg, 12%. Isolated as a light grey powder, >95% pure by NMR and a single spot by TLC; Rf: 0.64 in EtOAc/MeOH, 95/5. Strain green with CAM;
3 H NMR (CD 3 OD, 500 MHz): δ ppm = 7.06 (1H, d, J = 8.5 Hz); 6.87 (1H, d, J = 2.3 Hz); 6.58 (1H, dd, J = 2.3 Hz, J = 8.5 Hz); 3.34 (2H, t, J = 7.5 Hz); 2.81 (2H, t, J = 7.5 Hz); 2.55 (2H, d, J = 7.5 Hz); 1.99 (1H, quint;, J = 6.9 Hz); 1.91 (3H, s); 0.94 (6H, d, J = 6.7 Hz).
13 C NMR (CD3OD, 126 MHz): δ ppm = 173.2; 150.9; 137.9; 132.1; 130.5; 111.8; 111.1; 108.6; 103.2;
41.5; 36.3; 30.4; 25.4; 22.9 (2C); 22.7.
UPLC: R T : 1.87 (classic system)
MS (ESI + ) m/z [M+H] + Calcd for CI 6 H 23 N 2 O 2 + 275.17; Found 275.28.
3-5-2-Strategy2 : NH-Boc et O-TBDMS
In the dark, serotonin hydrochloride (500 mg, 2.35 mmol, 1 equiv.) was dissolved in water (9 mL). K 2 CO 3 (665 mg, 4.81 mmol, 2.1 equiv.) and BOC 2 O (538 mg, 2.46 mmol, 1.05 equiv.) were added to the solution. The solution was stirred overnight, and then extracted with DCM. The organic phase was washed with aq. HCI 5% and brine, then dried on MgSO4 and concentrated. The crude was purified by flash chromatography using DCM / MeOH (100/0 to 90/10) as eluent to give the desired product (485 mg), which was engaged in the next step.
In the dark and under inert atmosphere, the product of the previous step (553 mg, 2 mmol), tert- butyldimethylsilyl chloride (TBDMSCI, 1.69 g, 5.6 equiv.) and imidazole (272 mg, 2 equiv.) in acetonitrile (20 mL) was stirred at room temperature for overnight under N 2 and then was filtered. The solid residue was dissolved in 0.5 M NaOH aqueous solution (50 mL), and immediately extracted with CH 2 CI 2 (3 x 20 mL). The combined CH 2 CI 2 extracts were washed with deionized water (30 mL) and dried over Mg 2 SO 4 . The crude was purified by flash chromatography using n-Hex / EtOAc (100/0 to 50/50) as eluent to give the desired product LC429 as a white solid.
To a mixture of LC429 serotonin derivative (117 mg, 0.30 mmol), norbornene (56 mg, 2.00 equiv), K 2 CO 3 (166 mg, 4.00 equiv), and PdCI 2 (5.3 mg, 10 mol %) was added 2.1 mL of DMF (containing 0.5 M H 2 O) and bromoethane (90 μ.L, 4.00 equiv). The resulting suspension was stirred at 60 °C for 24 h. After being cooled to room temperature, the reaction mixture was diluted with Et 2 0 (30 mL) and washed with water (50 mL). The aqueous layer was then extracted with Et 2 0 (2 x 50 mL), and the combined organic extracts were dried over MgSO 4 and concentrated. The crude product was purified by flash column chromatography on silica gel using n-Hex / EtOAc (100/0 to 50/50) as eluent to give LC464.
SUBSTITUTE SHEET (RULE 26) LC464 was dissolved in THF (C=0.1M) and 1.1 equivalent of TBAF (1 M in THF) was added. The mixture was stirred for 1 h until the O-deprotected product was predominant in UPLC analysis. The mixture was then concentrated and the crude was directly purified by preparative HPLC to give the desired product LC468 after lyophilization.
LC468 was dissolved in CH 2 CI 2 /TFA, 4/1 (4 mL) and stirred for 2 h until the product was predominant in UPLC analysis. The mixture was then concentrated and the crude was directly purified by preparative HPLC to give the desired product LC470 after lyophilization.
Yield: 691 mg, 88%. Isolated as a light grey powder, >95% pure by NMR and a single spot by TLC; Rf: 0.56 in n-Hex/EtOAc, 60/40. Strain green with ninhydrin;
1 H NMR (CD 3 OD, 500 MHz): δ ppm = 7.17 (1H, d, J = 8.6 Hz); 7.02 (1H, s); 6.98 (1H, brd, J = 1.2 Hz); 6.66 (1H, dd, J = 2.3 Hz, J = 8.5 Hz); 3.29 (2H, t, J = 7.3 Hz); 2.83 (2H, t, J = 7.3 Hz); 1.43 (9H, s); l;02 (9H, s); 0.19 (6H, s).
13 C NMR (CD3OD, 126 MHz): δ ppm = 158.5; 149.7; 133.9; 129.4; 124.3; 116.4; 112.9; 112.5; 108.9;
79.9; 42.4; 28.8 (3C); 26.8; 26.3 (3C); 19.1; -4.2 (2C).
UPLC: R T : 3.04 (classic system)
MS (ESI + ) m/z [M+Na] + Calcd for C 2 iH3 4 N 2 O 3 SiNa + 413.21; Found 413.29.
Yield: 50 mg, 40%. Isolated as a light grey powder, >95% pure by NMR and a single spot by TLC; Rf: 0.65 in n-Hex/EtOAc, 70/30. Strain green with ninhydrin;
SUBSTITUTE SHEET (RULE 26) 1 H NMR (CD 3 OD, 500 MHz): δ ppm = 7.09 (1H, d, J = 8.4 Hz); 6.90 (1H, brs); 6.57 (1H, dd, J = 2.4 Hz, J = 8.6 Hz); 3.20 (2H, t, J = 7.0 Hz); 2.79 (2H, t, J = 7.2 Hz); 2.73 (2H, q, J = 7.7 Hz); 1.43 (9H, s); 1.28 (3H, t, J = 7.5 Hz); 1.01 (9H, s); 0.18 (6H, s).
13 C NMR (CD 3 OD, 126 MHz): δ ppm = 158.5; 149.6; 140.4; 132.9; 130.5; 115.2; 111.6; 108.5; 107.7; 79.8; 42.5; 28.8 (3C); 26.3 (3C); 25.7; 20.3; 19.1; 14.9; -4.2 (2C).
UPLC: R T : 3.18 (classic system)
MS (ESI + ) m/z [M+Na] + Calcd for C 23 H38N 2 O 3 SiNa + 441.23; Found 441.22.
Yield: 20 mg, 56%. Isolated as a light grey powder, >95% pure by NMR and a single spot by TLC; Rf: 0.38 in n-Hex/EtOAc, 60/40. Strain green with ninhydrin; 1H NMR (CD3OD, 400 MHz): δ ppm = 7.06 (1H, dd, J = 0.5 Hz, J = 8.5 Hz); 6.85 (1H, brd, J = 1.8 Hz); 6.57 (1H, dd, J = 2.3 Hz, J = 8.5 Hz); 3.20 (2H, t, J = 7.0 Hz); 2.77 (2H, t, J = 7.5 Hz); 2.72 (2H, q, J = 7.7 Hz); 1.43 (9H, s); 1.27 (3H, t, J = 7.5 Hz).
13 C NMR (CD3OD, 101 MHz): δ ppm = 158.5; 150.9; 140.2; 132.1; 130.6; 111.7; 111.0; 107.4; 103.3;
79.8; 42.3; 28.8 (3C); 25.8; 20.3; 14.9.
UPLC: R T : 2.17 (classic system)
MS (ESI + ) m/z [M+H] + Calcd for C 17 H 24 N 2 O 3 Na + 327.18; Found 327.46.
Yield: 10 mg, 77%. Isolated as a light grey powder, >95% pure by NMR;
SUBSTITUTE SHEET (RULE 26) 1 H NMR (CD 3 OD, 400 MHz): δ ppm = 7.11 (1H, dd, J = 0.5 Hz, J = 8.7 Hz); 6.84 (1H, d, J = 2.3 Hz); 6.62 (1H, dd, J = 2.4 Hz, J = 8.7 Hz); 3.10 (2H, m); 2.99 (2H, m); 2.75 (2H, q, J = 7.6 Hz); 1.29 (3H, t, J = 7.6 Hz). 1 3 C NMR (CD 3 OD, 101 MHz): δ ppm = 151.4; 140.9; 132.2; 130.0; 112.2; 111.5; 104.2; 102.8; 41.3; 23.5; 20.1; 14.8. UPLC: R T : 1.19 (classic system)
MS (ESI + ) m/z [M+H] + Calcd for CI 2 HI 7 N 2 O + 205.13; Found 188.13.
For the trifluoromethylation of indole, LC429 (195 mg, 0.5 mmol) and Togni reagent (342 mg, 1.3 equiv.) were added to a Schlenk tube. Under vacuum, DCM (5 mL) and TMSOTf (18 μL, 0.2 equiv.) were added and the mixture was stirred for 15 min. NaHCO3 aq. sat. (15 mL) was added to quench the reaction mixture, then extracted with CH 2 CI 2 (3 x 20 mL). The combined CH 2 CI 2 extracts were dried over
Mg 2 SC>4. The crude was purified by flash chromatography using n-Hex / EtOAc (100/0 to 50/50) as eluent to give the desired product LC471F1 and a side product LC471F2 as white solids.
SUBSTITUTE SHEET (RULE 26) LC471F1 was dissolved in THF (C=0.1M) and 1.1 equivalent of TBAF (1 M in THF) was added. The mixture was stirred for 1 h until the O-deprotected product was predominant in UPLC analysis. NH4CI aq. sat. (15 mL) was added and extracted with EtOAc (3 x 20 mL). The combined organic phases were dried with MgSCU. Removing the solvent under reduced pressure afforded the desired compound LC472 which is used for the next step without purification.
LC471F2 was dissolved in THF (C=0.1M) and 1.1 equivalent of TBAF (1 M in THF) was added. The mixture was stirred for 1 h until the O-deprotected product was predominant in UPLC analysis. NH4CI aq. sat. (15 mL) was added and extracted with EtOAc (3 x 20 mL). The combined organic phases were dried with MgSO4. Removing the solvent under reduced pressure afforded the desired compound LC473 which is used for the next step without purification.
LC472 was dissolved in CH 2 CI 2 /TFA, 4/1 (4 mL) and stirred for 2 h until the product was predominant in UPLC analysis. The mixture was then concentrated and the crude was directly purified by preparative HPLC to give the desired product LC474 after lyophilization.
LC473 was dissolved in CH 2 CI 2 /TFA, 4/1 (4 mL) and stirred for 2 h until the product was predominant in UPLC analysis. The mixture was then concentrated and the crude was directly purified by preparative HPLC to give the desired product LC475 after lyophilization.
Yield: 59 mg, 22%. Isolated as a light grey powder, >95% pure by NMR and a single spot by TLC; Rf: 0.64 in n-Hex/EtOAc, 80/20. Strain green with ninhydrin; 1H NMR (CD 3 OD, 400 MHz): δ ppm = 7.27 (1H, d, J = 8.2 Hz); 7.13 (1H, s); 6.84 (1H, dd, J = 2.3 Hz, J = 8.7 Hz); 3.26 (2H, t, J = 6.8 Hz); 2.98 (2H, t, J = 6.8 Hz); 1.44 (9H, s); 1.02 (9H, s); 0.21 (6H, s).
19 F NMR (CD3OD, 376 MHz): δ ppm = -59.38.
UPLC: R T : 3.21 (classic system)
MS (ESI + ) m/z [M+Na] + Calcd for C 22 H34F 3 N 2 O 3 SiNa + 481.22; Found 481.41.
SUBSTITUTE SHEET (RULE 26)
Yield: 90 mg, 39%. Isolated as a light grey powder, >95% pure by NMR and a single spot by TLC; Rf: 0.53 in n-Hex/EtOAc, 80/20. Strain green with ninhydrin; 1H NMR (CD3OD, 400 MHz): δ ppm = 7.55 (1H, d, J = 8.7 Hz); 6.96 (1H, d, J = 8.7 Hz); 3.21 (2H, t, J = 6.4 Hz); 3.05 (2H, t, J = 6.4 Hz); 1.42 (9H, s); 1.04 (9H, s); 0.26 (6H, s).
19 F NMR (CD3OD, 376 MHz): δ ppm = -52.95; -59.38.
UPLC: R T : 3.20 (classic system)
MS (ESI + ) m/z [M+Na] + Calcd for C 23 H 32 F 6 N 2 O 3 SiNa 4 - 549.21; Found 549.48.
Yield: 22 mg, 52%. Isolated as a light grey powder, >95% pure by NMR; 1H NMR (CD3OD, 500 MHz): δ ppm = 7.29 (1H, d, J = 8.6 Hz); 7.01 (1H, d, J = 2.2 Hz); 6.89 (1H, dd, J =
2.2 Hz, J = 8.7 Hz); 3.19 (2H, m); 3.14 (2H, m).
13 C NMR (CD3OD, 126 MHz): δ ppm = 152.8; 132.3; 128.7; 124.2 (d, J = 38.2 Hz); 123.5 (d, J = 268.2 Hz);
116.6; 114.1; 111.1; 103.5; 41.1; 23.2.
19 F NMR (CD3OD, 470 MHz): δ ppm = -59.4
UPLC: R T : 1.31 (classic system)
MS (ESI + ) m/z [M+H] + Calcd for C 1 iHi2F 3 N 2 O + 245.08; Found 245.24.
LC475
SUBSTITUTE SHEET (RULE 26)
Yield: 38 mg, 58%. Isolated as a light grey powder, >95% pure by NMR; 1H NMR (CD 3 OD, 500 MHz): δ ppm = 8.50 (1H, s, FA); 7.53 (1H, d, J = 8.8 Hz); 6.99 (1H, d, J = 8.8 Hz); 3.26 (2H, m); 3.06 (2H, m). 1 3 C NMR (CD3OD, 126 MHz): δ ppm = 168.2 (FA); 151.9; 131.2; 125.5 (d, J = 269.3 Hz) ; 125.3 (d, J = 39.4
Hz); 122.2; 121.9 (d, J = 268.2 Hz); 117.7; 116.3; 109.8; 104.8 (d, J = 31.2 Hz); 39.9; 22.9.
19 F NMR (CD3OD, 470 MHz): δ ppm = -53.5; -59.6.
UPLC: R T : 1.43 (classic system)
MS (ESI + ) m/z [M+H] + Calcd for CI 2 HI 0 F 6 N 2 O + 313.07; Found 313.16.
In the dark and under inert atmosphere, LC423 (145 mg, 0.5 mmol, 1 equiv.) was dissolved in dry acetonitrile (5 mL). K 2 CO 3 (83 mg, 1.2 equiv.) and propargyl bromide (56 μL, 1 equiv.) were added to the solution. The mixture was stirred and heated at reflux overnight, cooled down to r.t. then filtered
SUBSTITUTE SHEET (RULE 26) with acetonitrile and concentrated. The crude was purified by flash chromatography using DCM / MeOH (100/0 to 80/20) as eluent to give LC451.
For the trifluoromethylation of indole, LC451 (67 mg, 0.2 mmol) and Togni reagent (140 mg, 1.3 equiv.) were added to a Schlenk tube. Under vacuum, DCM (2 mL) and TMSOTf (7.4 μL, 0.2 equiv.) were added and the mixture was stirred for 15 min. NaHCO3 aq. sat. (15 mL) was added to quench the reaction mixture, then extracted with CH 2 CI 2 (3 x 20 mL). The combined CH 2 CI 2 extracts were dried over Mg 2 SC>4. The crude was purified by flash chromatography using n-Hex / EtOAc (100/0 to 50/50) as eluent to give the desired product LC456 as a white solid.
LC456 was dissolved in THF (C=0.1M) and 1.1 equivalent of TBAF (1 M in THF) was added. The mixture was stirred for 1 h until the O-deprotected product was predominant in UPLC analysis. The mixture was then concentrated and the crude was directly purified by preparative HPLC to give the desired product LC458 after lyophilization.
Yield: 67 mg, 41%. Isolated as a light grey powder, >95% pure by NMR and a single spot by TLC; Rf: 0.67 in DCM/MeOH, 90/10. Strain green with ninhydrin; 1H NMR (CD 3 OD, 400 MHz): δ ppm = 7.19 (1H, dd, J = 0.6 Hz, J = 8.6 Hz); 7.04 (1H, s); 6.98 (1H, dd, J = 0.6 Hz, J = 2.4 Hz); 6.67 (1H, dd, J = 2.3 Hz, J = 8.5 Hz); 3.41 (2H, d, J = 2.5 Hz); 2.97 (2H, m); 2.89 (2H, m); 2.56 (1H, t, J = 2.5 Hz); 1.01 (9H, s); 0.19 (6H, s).
13 C NMR (CD3OD, 101 MHz): δ ppm = 149.7; 134.0; 129.2; 124.4; 116.6; 112.9; 112.6; 108.9; 81.9; 73.2;
49.8; 38.3; 26.3 (3C); 26.0; 19.1; -4.2 (2C).
UPLC: R T : 2.10 (classic system)
MS (ESI + ) m/z [M+H] + Calcd for C 19 H 28 N 2 OSi + 329.20; Found 328.98.
LC456
SUBSTITUTE SHEET (RULE 26)
Yield: 19 mg, 23%. Isolated as a light grey powder, >95% pure by NMR and a single spot by TLC; Rf: 0.6 in n-Hex/EtOAc, 60/40. Strain green with ninhydrin; 1H NMR (CD 3 OD, 400 MHz): δ ppm = 7.30 (1H, d, J = 8.7 Hz); 7.09 (1H, d, J = 2.6 Hz); 6.86 (1H, dd, J = 2.4 Hz, J = 8.7 Hz); 3.59 (2H, d, J = 2.3 Hz); 3.08 (2H, m); 3.02 (2H, m); 2.76 (1H, t, J = 2.4 Hz); 1.02 (9H, s); 0.21 (6H, s).
UPLC: R T : 2.23 (classic system)
MS (ESI + ) m/z [M+H] + Calcd for C 20 H 28 F 3 N 2 OSi + 397.18; Found 397.40.
Yield: 7 mg, 63%. Isolated as a light grey powder, >95% pure by NMR; 1H NMR (CD3OD, 500 MHz): δ ppm = 8.41 (1H, s, FA); 7.28 (1H, d, J = 8.7 Hz); 7.01 (1H, d, J = 2.0 Hz);
6.88 (1H, dd, J = 2.0 Hz, J = 8.7 Hz); 3.82 (2H, d, J = 2.2 Hz); 3.18 (4H, m); 3.05 (1H, t, J = 2.1 Hz).
19 F NMR (CD3OD, 470 MHz): δ ppm = -59.41.
UPLC: R T : 1.45 (classic system)
MS (ESI + ) m/z [M+H] + Calcd for C 14 Hi 4 F 3 N 2 OSi + 283.10; Found 283.12.
3-8-Bromination
SUBSTITUTE SHEET (RULE 26) Strategy
To a cold solution (0°C) of diacetylated serotonin derivative LC377 (284 mg, 1.1 mmol) in AcOH (11 mL) was added dropwise bromide (67 μL, 1.2 equiv.) over 5 min. After the addition was complete, the reaction mixture was allowed to warm at room temperature and stirred for 5 hours. The reaction was poured in cold water (30 mL) and extracted with EtOAc (3 x 30 mL), dried over MgSO 4 and the solvent was evaporated under reduced pressure. The crude was directly purified by preparative HPLC to give the desired products LC380F2 and LC380F3 after lyophilization.
13 C NMR (CD 3 OD, 126 MHz): δ ppm = 171.9; 169.7; 141.9; 135.4; 125.7; 116.7; 112.8; 112.3; 110.2;
105.6; 40.5; 24.7; 21.3; 19.3. UPLC: R T : 1.96 (classic system)
MS (ESI + ) m/z [M+H] + Calcd for C 14 H 15 Br 2 O 3 + 419.05; Found 419.02.
LC380F3 (=Compound (052))
SUBSTITUTE SHEET (RULE 26)
Yield: 20 mg, 4.4%. Isolated as a light yellow foam, >95% pure by NMR and a single spot by TLC; Rf: 0.5 in DCM/MeOH, 95/5. Strain green with CAM; 1H NMR (CD 3 OD, 500 MHz): δ ppm = 7.55 (1H, s); 7.35 (1H, s); 3.38 (2H, t, J = 6.9 Hz); 2.88 (2H, t, J = 7.0 Hz); 2.35 (3H, s); 1.88 (3H, s).
13 C NMR (CD3OD, 126 MHz): δ ppm = 172.1; 169.9; 141.3; 134.9; 127.4; 114.2; 112.0; 111.6; 110.7;
109.1; 39.1; 24.1; 21.2; 19.3.
UPLC: R T : 2.01 (classic system)
MS (ESI + ) m/z [M+H] + Calcd for C 14 Hi 5 Br 2 N 2 O3 + 419.05; Found 419.02.
Yield: 4 mg, 0,7%. Isolated as a light yellow foam, >95% pure by NMR and a single spot by TLC; Rf: 0.5 in DCM/MeOH, 95/5. Strain green with CAM; 1H NMR (CD3OD, 500 MHz): Mixture of two isomers 6 ppm = 7.38 (1H, s); 7.19 (1H, s); 3.47 (2H, t, J = 7.0 Hz); 3.39 (2H, t, J = 6.8 Hz); 3.18 (2H, t, J = 6.7 Hz); 2.89 (2H, t, J = 6.7 Hz); 2.35 (6H, s); 1.91 (3H, s); 1.87 (3H, s).
13 C NMR (CD3OD, 126 MHz): Mixture of two isomers 6 ppm = 172.1; 171.9; 169.6; 169.3; 142.1; 142.0; 134.3; 134.1; 127.2; 126.2; 119.5; 114.4; 113.9; 113.5; 112.3; 112.0; 111.0; 110.7; 106.4; 105.4; 102.4; 40.3; 38.9; ; 24.9; 24.2; 21.3; 21.2; 19.3; 19.2.
UPLC: R T : 2.05 (classic system)
MS (ESI + ) m/z [M+H] + Calcd for C 14 Hi 4 Br 3 N 2 O 3 + 494.85; Found 494.72.
SUBSTITUTE SHEET (RULE 26)
The synthetic procedure is adapted from the patent WO 2011/047156 PCT/US2010/052674. A suspension of LC377 (260 mg, 1 mmol) and K 2 CO 3 (138 mg, 1 equiv.) in MeOH (3.2 mL) was stirred at 26°C for 2 hours. The reaction mixture was concentrated under reduced pressure and then the crude material was diluted in water (10 mL) and extracted with EtOAc (2 x 20 mL). The combined organic layers were washed with water (10 mL) and brine (10 mL), dried over MgSO4, and the solvent was evaporated under reduced pressure. The desired compound LC460 was obtained as a pale-yellow foam.
LC460 (117 mg, 0.54 mmol) was solubilized in a 30% NaOH solution (67 μL) and stirred at 26°C. Dimethyl sulfate (86 pL, 1.7 equiv.) was added drop by drop, and the reaction was stirred for 2 hours. The reaction mixture was acidified with 2N HCI to obtain pH = 2, then diluted with water (10 mL), and extracted with EtOAc (2 x 20 mL). The combined organic layers were washed with water (2 x 10 mL) and brine (10 mL). dried over MgSO4, and the solvent was removed to afford the crude Melatonin LC461. Melatonin was then purified by preparative HPLC to afford a light-yellow gum.
Yield: 139 mg, 61%. Isolated as a light yellow foam, >95% pure by NMR and a single spot by TLC; Rf: 0.2 in DCM/MeOH, 95/5. Strain green with CAM;
SUBSTITUTE SHEET (RULE 26) 1 H NMR (CD3OD, 400 MHz): δ ppm = 7.22 (1H, dd, J = 0.5 Hz, J = 8.5 Hz); 7.00 (1H, s); 6.92 (1H, dd, J = 0.5 Hz, J = 2.5 Hz); 6.65 (1H, dd, J = 2.3 Hz, J = 8.6 Hz); 3.43 (2H, t, J = 7.2 Hz); 2.86 (2H, dt, J = 0.6 Hz, J = 7.2 Hz); 1.91 (3H, s).
13 C NMR (CD3OD, 101 MHz): δ ppm = 173.3; 151.1; 133.1; 129.5; 124.2; 112.6; 112.5; 112.3; 103.5;
41.5; 26.3; 22.6.
UPLC: R T : 1.32 (classic system)
MS (ESI + ) m/z [M+H] + Calcd for C 12 H 15 N 2 O 2 + 2 219.11; Found 219.12.
Yield: 76 mg, 61%. Isolated as a light yellow foam, >95% pure by NMR and a single spot by TLC; Rf: 0.5 in DCM/MeOH, 95/5. Strain green with CAM; 1H NMR (CD 3 OD, 400 MHz): δ ppm = 7.21 (1H, dd, J = 0.4 Hz, J = 8.7 Hz); 7.05 (1H, d, J = 2.5 Hz); 7.03 (1H, s); 6.75 (1H, dd, J = 2.5 Hz, J = 8.7 Hz); 3.82 (3H, s); 3.45 (2H, t, J = 7.5 Hz); 2.90 (2H, dt, J = 0.5 Hz, 7 = 7.5 Hz); 1.91 (3H, s).
13 C NMR (CD3OD, 101 MHz): δ ppm = 173.3; 154.9; 133.4; 129.1; 124.1; 113.1; 112.9; 112.6; 101.3;
56.3; 41.5; 26.2; 22.6.
UPLC: R T : 1.68 (classic system)
MS (ESI + ) m/z [M+H] + Calcd for C 13 H 17 N 2 O 2 + 233.12; Found 233.12.
3-10- Phenylcarbamate
Strategy :
SUBSTITUTE SHEET (RULE 26)
In the dark, serotonin hydrochloride (500 mg, 2.35 mmol, 1 equiv.) was dissolved in water (9 mL). K2CO3 (665 mg, 4.81 mmol, 2.1 equiv.) and BOC2O (538 mg, 2.46 mmol, 1.05 equiv.) were added to the solution. The solution was stirred overnight, and then extracted with DCM. The organic phase was washed with aq. HCI 5% and brine, then dried on MgSO4 and concentrated. The crude was purified by flash chromatography using DCM / MeOH (100/0 to 90/10) as eluent to give the desired product (485 mg), which was engaged in the next step.
In the dark and under inert atmosphere, the product of the previous step (138 mg, 0.5 mmol, 1 equiv.) was dissolved in dry THF (4 mL). NMM (110μL, 2 equiv.) and propargylchloroformate (97 μL, 2 equiv.) were added to the solution. The mixture was stirred at room temperature for lh. The reactional mixture was then concentrated to dryness. The crude was purified by flash chromatography using n- Hex / EtOAC (100/0 to 50/50) as eluent to give LC483.
The product was then dissolved in CH 2 CI2/TFA, 4/1 (4 mL) and stirred for 2 h until the product was predominant in UPLC analysis. The mixture was then concentrated and the crude was directly purified by preparative HPLC to give the desired product LC487 after lyophilization.
Yield: 125 mg, 69 %. Isolated as a light grey powder, >95% pure by NMR and a single spot by TLC; Rf: 0.58 in n-Hex/EtOAc, 60/40. Strain green with CAM 1H NMR (CDCI2, 400 MHz): δ ppm = 8.34 (1H, s); 7.36 (2H, m); 7.10 (1H, d, J = 1.1 Hz); 6.98 (1H, dd, J = 2.3 Hz, J = 8.7 Hz); 4.84 (2H, d, J = 2.6 Hz); 4.65 (1H, brs); 3.39 (2H, q, J = 6.6 Hz); 2.90 (2H, t, J = 7.1 Hz); 2.65 (1H, t, J = 2.3 Hz); 1.41 (9H, s).
SUBSTITUTE SHEET (RULE 26) 13 C NMR (CDCI, 101 MHz): δ ppm = 156.2; 154.4; 145.1; 134.7; 128.1; 124.4; 115.9; 114.0; 112.0; 110.8;
79.2; 77.3; 76.1; 56.1; 41.2; 28.5 (3C); 26.1.
UPLC: R T : 2.36 (classic system)
MS (ESI + ) m/z [M+Na] + Calcd for C 19 H 2 3N 2 O 5 Na + 381.15; Found 381.29.
Yield: 75 mg, 87 %. Isolated as a light grey powder, >95% pure by NMR; 1H NMR (CD 3 OD, 500 MHz): δ ppm = 7.38 (2H, m); 7.24 (1H, s); 6.95 (1H, dd, J = 2.3 Hz, J = 8.6 Hz); 4.86 (2H, d, J = 2.6 Hz); 3.19 (2H, t, J = 7.0 Hz); 3.07 (3H, m).
13 C NMR (CD3OD, 126 MHz): δ ppm = 155.7; 145.9; 136.2; 128.3; 126.3; 116.2; 113.1; 110.8; 110.7;
78.1; 77.3; 56.7; 41.1; 24.3.
UPLC: R T : 1.41 (classic system)
MS (ESI + ) m/z [M+H] + Calcd for CI 4 HI 5 N 2 O 5 + 259.10; Found 259.10.
In the dark, serotonin hydrochloride (500 mg, 2.35 mmol, 1 equiv.) was dissolved in water (9 mL). K 2 CO3 (665 mg, 4.81 mmol, 2.1 equiv.) and Boc 2 O (538 mg, 2.46 mmol, 1.05 equiv.) were added to the solution. The solution was stirred overnight, and then extracted with DCM. The organic phase was washed with aq. HCI 5% and brine, then dried on MgSO4 and concentrated. The crude was purified by flash chromatography using DCM / MeOH (100/0 to 90/10) as eluent to give the desired product (quantitative yield). Then it was further purified by HPLC. 1H NMR (, CD2CI2, 500 MHz) 6 ppm=8.12 (s, 1H), 7.26 (dd, J = 8.6, 0.6 Hz, 1H), 7.05 (d, J = 2.3 Hz, 1H), 7.03 (d, J = 2.4 Hz, 1H), 6.79 (dd, J = 8.7, 2.4 Hz, 1H), 4.76 (s, 1H), 3.43 (d, J = 6.9 Hz, 2H), 2.89 (t, J = 7.0 Hz, 2H), 1.46 (s, 9H). 1 3 C NMR (, CD2CI2, 126 MHz) 6 ppm=155.98, 149.66, 131.58, 128.15, 123.21, 112.37, 111.74, 103.11, 78.95, 40.77, 28.13, 25.82.
SUBSTITUTE SHEET (RULE 26) MS (ESI + ) m/z [M+H] + Calcd for CI 5 H 2 IN 2 O 3 + 277.14; found 277.24
To solution of LT273 (200mg) in acetone anhydrous (8mL), K 2 C0 3 (300mg, 3eq) and Nal (109 mg, leq) were added and stirred at room temperature for 5 minutes. Then, CH 3 I was added to the reaction mixture and refluxed for 5 hours. The solution was concentrated in vacuo and purified by flash chromatography in EtOAc and cyclohexane gradient. It was then further purified by HPLC to obtain pure final product (80 mg, 38%). 1H NMR (MeOD, 500 MHz) 6 ppm=7.23 (d, J = 8.7 Hz, 1H), 7.08 (s, 1H), 7.03 (s, 1H), 6.76 (dt, J = 8.7, 1.9 Hz, 1H), 3.84 (s, 3H), 3.33 (t, J = 7.4 Hz, 2H), 2.88 (t, J = 7.4 Hz, 2H), 1.44 (s, 9H).
13 C NMR (MeOD, 126 MHz) 6 ppm=157.12, 153.54, 132.00, 127.74, 122.75, 111.84, 111.43, 111.14, 100.05, 78.50, 54.96, 41.04, 27.39, 25.53.
MS (ESI + ) m/z [M+H] + Calcd for CI 6 H 23 N 2 O 3 + 291.16; found 291.32
To diacetylated serotonin derivative LC337 (200 mg) in anhydrous DCM (4mL), 0.6 eq of N- bromosuccinimide (96 mg) was added and stirred at room temperature for 20 minutes. Then 0.1 eq of N-bromosuccinimide (15mg) was added further and left for another 20 minutes. The reaction solution was concentrated in vacuo and purified by flash chromatography in EtOAc and cyclohexane gradient and then finally by HPLC to obtain the final product (13 mg, 5%). 1H NMR (CD 3 CN, 500 MHz) 6 ppm=9.64 (s, 1H), 7.35 (dd, J = 8.7, 0.6 Hz, 1H), 7.28 - 7.19 (m, 1H), 6.89 (dd, J = 8.7, 2.2 Hz, 1H), 6.42 (s, 1H), 3.35 (td, J = 6.9, 6.1 Hz, 2H), 2.83 (t, J = 6.9 Hz, 2H), 2.28 (s, 3H), 1.81 (s, 3H).
13 C NMR (CD 3 CN, 126 MHz) 6 ppm=170.24, 169.65, 144.63, 134.15, 127.84, 116.35, 112.60, 111.15, 110.33, 109.92, 38.79, 24.73, 22.15, 20.28.
MS (ESI + ) m/z [M+H] + Calcd for C 14 Hi 6 BrN 2 O 3 + 339.03; found 339.21
SUBSTITUTE SHEET (RULE 26) Example 2: Biological activity
Materials and methods
Complexation studies
Calorimetric assessment of complex formation: To an aqueous solution of serotonin hydrochloride (3 equiv., C = 0.1 M) or A3 formic salt (3 equiv., C = 0.1 M) iron (III) chloride (1 equiv.) or copper(ll) sulfate (C = 0.1 M) was added. A color change characterized the formation of metal complexes.
For NMR experiments: NMR spectroscopy was performed on a 500 MHz Bruker spectrometer. Samples were dissolved in D 2 O or CD3OD, at 298 K or 310K. 1 H-NMR were recorded at 500 MHz and chemical shifts δ are expressed in ppm using the residual non-deuterated solvent signal as internal standard. Titration of the samples up to 0.3, 0.6 or 1 mol equivalent of iron or copper was performed, using conditions (solvent and temperature) as indicated in the figures. For some samples, trifluoroacetic acid (TFA) was added as indicated in the figures.
Cell culture
All cells were grown in an incubator equilibrated at 37°C with 5% CO 2 , grown to confluence and split with Trypsin/EDTA (Gibco, TRYPGIB01) once or twice a week according to confluence. HMLER cells (sex: female) naturally repressing E-cadherin, obtained from human mammary epithelial cells infected with a retrovirus carrying hTERT, SV40 and the oncogenic allele H-rasV12, and HMLER CD44 and TFRC ko clones were cultured in DMEM/F12 (Thermo Fisher Scientific, 31331093) supplemented with 10% FBS (v/v) (Thermo Fisher Scientific, 10270106), 10 μg/mL insulin (Sigma-Aldrich, 10516), 0.5 pg/mL hydrocortisone (Sigma-Aldrich, H0888) and 0.5 pg/mL puromycin (Life Technologies, A11138-02), unless stated otherwise. PDAC053T cells were grown in serum-free ductal medium: DMEM/F12 supplemented with 0.61g/500mL nicotinamide (Sigma-Aldrich, 3376), 2.50g/ 500mL glucose (Sigma- Aldrich, G6152), 1:200 ITS+ (Corning, 354352), 1:20 Nu-serum IV (Corning, 355104), 100 ng/ml cholera toxin, 1 μM dexamethasone (Sigma-Aldrich, D4902), 50 nM 3,3',5-triiodo-L-thyronine (Sigma-Aldrich, T6397) and 1 x PenStrep. BELA cells were cultured using published procedures (Nat. Comm, doi: 10.1038/ncommsl4750).
Fluorescence microscopy
Immunofluorescence. Cells were plated on cover slips 24 h prior to the experiment. Subsequently, cells were washed three times with lx PBS and fixed with 2% paraformaldehyde (w/v) in lx PBS for 12 min, and then washed three times with lx PBS. After fixation, cells were permeabilized with 0.1% Triton X- 100 (v/v) in lx PBS for 5 min and washed three times with lx PBS. Then, cells were blocked in 2% BSA, 0.2% Tween-20 (w/v) /lx PBS (blocking buffer) for 20 min at room temperature. Cells were incubated with the relevant antibody in blocking buffer for 1 h at room temperature and washed three times
SUBSTITUTE SHEET (RULE 26) with blocking buffer. Then, cells were incubated with secondary antibodies for 1 h. Finally, cover slips were washed three times with lx PBS and mounted using VECTASHIELD (Vector Laboratories) containing DAPI.
Fluorescence microscopy of clickable serotonin analog A3: Cells were plated on cover slips 24 h prior to the experiment. The cells were treated with 10 μM A3 for 3 h and LysoTracker Deep Red (Thermo Fisher Scientific L12492, 1:10000) according to the manufacturer's protocol. Subsequently, cells were washed three times with 1 x PBS and fixed with 2% paraformaldehyde (w/v) in lx PBS for 12 min, and then washed three times with 1 x PBS. After fixation, cells were permeabilized with 0.1% Triton X-100 (v/v) in 1 x PBS for 5 min and washed three times with 1 x PBS. Then, cells were blocked in 2% BSA, 0.2% Tween-20 (w/v) /I x PBS (blocking buffer) for 20 min at RT. The click reaction cocktail was prepared from Click-iT EdU Imaging Kits (ThermoFisher Scientific, C10337) according to the manufacturer's protocol. Briefly, 868 pL of 1 x Click-iT reaction buffer was mixed with 40 pL CuSCU solution, 2 pL Alexa Fluor azide and 90 pL reaction buffer additive (sodium ascorbate) to reach a final volume of 1 mL. Cover slips were incubated with 50 pL of the click reaction cocktail in the dark at RT for 30 minutes, then washed three times with 1 x PBS. Cover slips were mounted using VECTASHIELD containing DAPI and were sealed with nail varnish Express manucure (Maybelline, 16P201).
Flow cytometry
Bodipy-C11 (Thermo Fisher Scientific, D3861) were used according to the manufacturer's protocol. RhoNox-M (in-house) was added to live cells prior to flow cytometry analysis for 1 h at a concentration of 1 μM. For the Annexin/ PI assay (Thermo Fisher Scientific, V13245, manufacturer's protocol) BELA cells were treated with RSL3 in the presence or absence of 1 μM Liproxstatin-1 (Sigma-Aldrich, SML1414) or 10 μM A3 for 24 h. Cells were then washed twice with ice-cold 1 x PBS and suspended in incubation buffer prior to being analyzed by flow cytometry. The manufacturer's protocol was followed. For each condition, at least 10,000 cells were counted. Data were recorded on an Attune (Thermo Fisher Scientific) and processed using FlowJo (FLOWJO, LLC).
Inductively coupled plasma mass spectrometry
Glass vials equipped with Teflon septa were cleaned with nitric acid 65% (w/v) (VWR, Suprapur, 1.00441.0250), washed with ultrapure water (Sigma-Aldrich, 1012620500) and dried. Cells were plated 24 h prior to the experiments. Cells were harvested using trypsinization (TrypLE Express Enzyme, Life Technologies, 12605010) followed by two washes with lx PBS. Cells were then counted using an automated cell counter (Entek) and transferred in 100 pL lx PBS to the cleaned glass vials, and samples were lyophilized using a freeze dryer (CHRIST, 22080). Samples were subsequently mixed with nitric
SUBSTITUTE SHEET (RULE 26) acid 65% (w/v) overnight followed by heating at 80 °C for 2 h. Samples were diluted with ultrapure water (Sigma-Aldrich, 1012620500) to a final concentration of 0.475 N nitric acid and transferred to metal-free centrifuge vials (VWR, 89049-172) for subsequent ICP-MS analysis. 56 Fe concentrations were measured using an Agilent 7900 ICP-Q.MS in low-resolution mode. Sample introduction was achieved with a micro-nebulizer (MicroMist, 0.2 mL/min) through a Scott spray chamber. Isotopes were measured using a collision-reaction interface with helium gas (5 mL/min) to remove polyatomic interferences. Scandium and indium internal standards were injected after inline mixing with the samples to control the absence of signal drift and matrix effects. A mix of certified standards was measured at concentrations spanning those of the samples to convert count measurements to concentrations in the solution. Uncertainties on sample concentrations were calculated using algebraic propagation of ICP-MS blank and sample counts uncertainties. Values were normalized by dry weight and cell number.
Cell viability
Cell viability was evaluated by plating 4,000 cells/well in 96-well plates using CellTiter-Blue viability assay according to the manufacturer's protocol. Cells were treated as indicated in the figure. CellTiter- Blue reagent (Promega, G8081) was added after 72 h treatment and cells were incubated for 2 h before recording fluorescence intensities (E ex . 560 nm; E em . 590 nm) using a Perkin Elmer Wallac 1420 Victor2 Microplate Reader.
Results
Serotonin and A3 form readily complexes with Fe(ll), Fe(lll) and Cu(ll) as attested by colorimetric complexation studies in solution (Figure 1) and by NMR spectroscopy (Figure 2).
We treated cells with 1 μM of the serotonin analog A3 for 3 h and performed click chemistry using previously developed techniques by us. 1 - 2 Using a co-staining with LysoTracker, we found that these molecules accumulate in lysosomes (Figure 3).
Using a lysosomotropic probe that detects Fe(ll) specifically in lysosomes, called RhoNox-M, 3 we saw an increase of RhoNox-M fluorescence measured by flow cytometry of cells treated with the serotonin analogs A3, LT262A, LC357, LC336 or LT265B (Figures 4 a,b). This data shows an increase of lysosomal Fe(ll) upon treatment of cells with these compounds.
Treatment of cells with 100 nM A3 for 3h or 24h led to an increase of total intracellular iron and copper, measured by inductively coupled plasma mass spectrometry (Figures 5a, b).
SUBSTITUTE SHEET (RULE 26) A3 led to a reduction of lipid peroxidation (measured by BODIPY-C11 fluorescence) induced by a ferroptosis inducer (Figure 6a) and also to a rescue of cell viability due to toxicity caused by this ferroptosis inhibitor (Figure 6b).
The serotonin analog A3 rescued cell death induced by the ferroptosis inducer RSL-3, with Liproxstatin- 1 as a control in the same experiment (Figure 7).
Taken together, these results demonstrate that the serotonin analogs form complexes with iron and copper, accumulate in lysosomes and can sequester lysosomal iron and copper. This leads to an increase of total intracellular iron and copper. The complexation of these metals protects the cells from oxidative stress and protects them against ferroptosis and cuproptosis.
Example 3: Anti-ferroptotic activity
Method:
Pancreatic Ductal Adenocarcinoma (PDAC) cells were grown at 37°C and 5% CO 2 using medium prepared based on previously described (https://doi.Org/10.1053/i.gastro.2004.03.058).
Antibodies and reagents IF: Immunofluorescence
Annexin/PI kit (Thermo Fisher Scientific, V13245, manufacturer's protocol), BODIPY-C11 (Thermo Fisher Scientific, D3861, manufacturer's protocol), Cyt c (Cell Signaling, 12963S, IF 1:200), EEA1 (Enzo Life Science, ALX210-239, IF 1:200), LysoTracker (LysoTracker Deep Red, Thermo Fisher Scientific, L12492, 45 min on live cells before fixation), Rcasl (Cell Signaling, 12290, IF 1:200), PDIA3 (Sigma- Aldrich, AMAB90988, IF 1:200), RSL3 (Sigma-Aldrich, SML2234-5MG).
Anti-ferroptotic activity (Fig 8)
PDAC cells were seeded on 6 well plates at the density of 2xl0 5 cells/well. RSL3 (200nM) was added along with compounds (lOμM for screening) on the following day and after 23 hr, BODIPY (4μM) was added for 1 hr. The media was removed and the cells were washed with PBS twice before typsinization. The cells were harvested, pelleted, washed with PBS and finally PBS buffer containing 10% FBS and EDTA, was added for flow cytometry.
The results are shown in Figure 8 and this enabled us to establish a robust structure activity relationship on the serotonin scaffold.
SUBSTITUTE SHEET (RULE 26) Fluorescence microscopy (Fig 9)
Cells were plated on cover slips 24 h prior to the experiment. The cells were treated with 10 μM of compounds for 3 h and LysoTracker Deep Red (ThermoFisher Scientific L12492, 1:10000) according to the manufacturer's protocol. Subsequently, cells were washed three times with 1 x PBS and fixed with 2% paraformaldehyde (w/v) in lx PBS for 12 min, and then washed three times with 1 x PBS. After fixation, cells were permeabilized with 0.1% Triton X-100 (v/v) in 1 x PBS for 5 min and washed three times with 1 x PBS. Then, cells were blocked in 2% BSA, 0.2% Tween-20(w/v)/l x PBS (blocking buffer) for 20 min at RT. The click reaction cocktail was prepared from Click-iT EdU Imaging Kits (ThermoFisher Scientific, C10337) according to the manufacturer's protocol. Briefly, 868 pL of 1 x Click- iT reaction buffer was mixed with 40 pL CuSO4solution, 2 pL Alexa Fluor azide and 90 pL reaction buffer additive (sodium ascorbate) to reach a final volume of 1 mL. Cover slips were incubated with 50 pL of the click reaction cocktail in the dark at RT for 30 minutes, then washed three times with 1 x PBS. Further, cells were incubated with the relevant antibody in blocking buffer for 1 h at room temperature and washed three times with blocking buffer. Then, cells were incubated with secondary antibodies for 1 h. Finally, cover slips were washed three times with lx PBS and mounted using VECTASHIELD (Vector Laboratories) containing DAPI and were sealed with nail varnish Express manucure (Maybelline, 16P201). Fluorescence images were acquired using a Deltavision real-time microscope (Applied Precision). 100x/1.4NA objectives were used for 2D and 3D acquisitions that were deconvoluted with SoftWorx (Ratio conservative— 10 iterations, Applied Precision) and processed with ImageJ.
The results are shown in Figure 9 which reveals that A3 goes to lysosomes in cells and it doesn't colocalize with other cell organelles. Active compounds Al and A4 are also localized in lysosomes and inactive compound A0 doesn't go to lysosomes, indicating importance of lysosomes in targeting ferroptosis.
Cell Apoptosis assay with Annexin V & Propidium Iodide (PI) (FiglOa)
PDAC cells were seeded on 6 well plates at the density of 2xl0 5 cells/well. RSL3 (0.1, 0.5, 2, 10 μM) was added along with compounds (10μM) on the following day and after 24 h, the media was recovered and the cells were typsinated. The cells were harvested, pelleted along with the media recovered, washed with PBS, and 100 μL of lx annexin binding buffer containing annexin V and PI (according to the manufacturer's protocol Dead Cell Apoptosis Kits with Annexin V for Flow Cytometry (Invitrogen)). Finally, PBS buffer containing 10% FBS and ImM of EDTA, was added for flow cytometry.
SUBSTITUTE SHEET (RULE 26) Figure 10a. shows flow cytometry profiles of Annexin/propidium iodide of cells treated with various concentrations of RSL3 and co-treated with A3, AO or Liproxstatiin-1 and their quantification. A3 protects against RSL3-induced ferroptosis.
Cyclic voltammetry experiment (Fig 10b)
Cyclic voltammetry experiments were performed with a three-electrode cell under argon. Saturated Calomel Electrode (SCE) was used as reference, a steady Glassy Carbon (GC) electrode of diameter 3 mm was selected as working electrode and a Platinum wire as counter-electrode. All cyclic voltammograms were recorded at RT with a p-autolab III from Metrohm using Nova software with a scan rate of 2 V/s. MeCN was used as a degassed HPLC grade from Carlo Erba. Water was mQ. H2O. Stock solution of FeCI 3 (lOOmM) and Lip-1, A3, A0 and DFO (20mM) were prepared with 0.3 M nBu4NBF4 in MeCN. ImM FeCI 3 in 0.3 M nBu4NBF4 in MeCN (ImL) was used as working solution for recording and subsequently equivalents of compounds were added, stirred and recorded.
Figure 10b. shows cyclic voltammetry curve of FeCI 3 and after addition of compounds. This shows that A3 chelates/binds to Fe 3+ similar to the known Fe 3+ chelator-DFO, as opposed to inactive compound A0 which doesn't binds to Fe 3+ .
References
1 Caneque, T., Muller, S. & Rodriguez, R. Visualizing biologically active small molecules in cells using click chemistry. Nat. Rev. Chem. 2, 202-215 (2018).
2 Mai, T. T. et al. Salinomycin kills cancer stem cells by sequestering iron in lysosomes. Nat. Chem. 9, 1025-1033 (2017).
3 Niwa, M., Hirayama, T., Okuda, K. & Nagasawa, H. A new class of high-contrast Fe(ll) selective fluorescent probes based on spirocyclized scaffolds for visualization of intracellular labile iron delivered by transferrin. Org. Biomol. Chem. 12, 6590-6597 (2014).
SUBSTITUTE SHEET (RULE 26)