Synthesis of small molecule agonists of neurotrophin

Abstract

The disclosure concerns a process for synthesizing a compound of formula F1: (F1) wherein: R1 is phenyl substituted with halogen or trifluoromethyl, and further optionally substituted with one or two substituents selected from the group consisting of halogen, (C1-C6)alkyl, (C1-C6)alkoxy, and halo(C1-C6)alkyl; or alternatively R1 is pyrrolidin-1-yl; R2 is 2-oxo-pyrrolidin-1-ylmethyl or sulfamoylphenyl; and R3 is chosen from propyl, 1-methylethyl, butyl, 2-methylpropyl, pentyl, 1 -methyl-butyl, 2- methylbutyl, hexyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, and 1- methylpentyl.

Description

DescriptionTitle: SYNTHESIS OF SMALL MOLECULE AGONISTS OF NEUROTROPHINTechnical Field

[0001] This disclosure pertains to the field of therapeutics for neurological, psychiatric disorders, and ageing. In particular, this disclosure relates to a synthesis route of small molecule agonists of neurotrophin (Nerve Growth Factor (NGF) or Brain-Derived Neurotrophic Factor (BDNF)), more specifically small molecules of formula Fl:Background Art

[0002] A synthesis route for compounds of formula F1 is known. For instance, Masip et al. (Med. Chem. 13 (2005)1929 (doi: / j.bmc.2005.01 .024) discloses a solid phase synthesis using positional scanning format and submonomer strategy. This synthesis route comprises 7 steps before a final step of cleavage to recover the targeted molecule from the solid support (Rink amide resin), as shown below:

[0003] The first step of this synthesis route is the deprotection of the amine function of the solid support. The six following steps are a repetition of a sequence of two steps, namely an acylation immediately followed by an amination. Therefore, in this synthesis route, molecules are grown sequentially by using appropriate primary amines regarding the targeted molecule.

[0004] Although this synthesis step may be satisfactory in certain conditions, it would be beneficial to propose a synthesis route without using a solid support, in particular which would be more suitable for large-scale synthesis for industrial manufacturing.Summary

[0005] It is proposed a process for synthesizing a compound of formula F1 :wherein:R1 is phenyl substituted with halogen or trifluoromethyl, and further optionally substituted with one or two substituents selected from the group consisting of halogen, (Ci-Ce)alkyl, (Ci-Ce) alkoxy, and halo(Ci-Ce)alkyl; or alternatively R1 is py rrolidin-1 -yl;R2is 2-oxo-pyrrolidin-1-ylmethyl or sulfamoylphenyl; andR3is selected from the group consisting of propyl, 1 -methylethyl, butyl, 2-methylpropyl, pentyl, 1 - methyl-butyl, 2- methylbutyl, hexyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, and 1- methylpentyl; comprising the steps of:(S1) synthesizing a compound of formula F2:wherein R4 is hydrogen atom, or a protecting group selected from the group consisting of Boc, Fmoc and formyl, wherein R5is -CN, -C(O)NH2, -C(O)NHCH2Ph or -C(O)OR6, Re being -CH3, -CH2CH3;jPr; -‘Bu, -H, or -Benzyl,(52) if R4 is a protecting group, removing said protecting group,(53) amidifying Rs.Brief Description of DrawingsFig. 1 to Fig. 29

[0006] Figures 1 to figure 29 are NMR spectra of molecules synthesized in examples 1 to 29.Detailed description of the disclosure

[0007] As mentioned above, the disclosure concerns a process for synthesizing a compound of formula F1 :wherein:Ri is phenyl substituted with halogen or trifluoromethyl, and further optionally substituted with one or two substituents selected from the group consisting of halogen, (Ci-Ce)alkyl, (Ci-Ce) alkoxy, and halo(Ci-Ce)alkyl; or alternatively Ri is py rrolidin-1 -yl;R2 is 2-oxo-pyrrolidin-1-ylmethyl or sulfamoylphenyl; andRs is selected from the group consisting of propyl, 1 -methylethyl, butyl, 2-methylpropyl, pentyl, 1 - methyl-butyl, 2- methylbutyl, hexyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, and 1- methylpentyl; comprising the steps of:(S1) synthesizing a compound of formula F2:F2 wherein R4 is hydrogen atom, or a protecting group selected from the group consisting of Boc, Fmoc and formyl, and R5is -CN, -C(O)NHCH2Ph or -C(O)OR6, Re being -CH3, -CH2CH3;jPr; -‘Bu, -H, or - Benzyl, preferably wherein R4 is hydrogen atom, or a protecting group selected from the group consisting of Boc, Fmoc and formyl, and R5 is -CN, -C(O)NHCH2Ph or -C(O)ORe, Re being -CH2CH3; 'Pr; -‘Bu, or -Benzyl; or R4 is a protecting group selected from the group consisting of Boc and Fmoc, and R5is -CN, -C(O)NH2, -C(O)NHCH2Ph or -C(O)OR6, Re being -CH3, -CH2CH3;jPr; -‘Bu, -H, or - Benzyl,(52) if R4 is a protecting group, removing said protecting group,(53) amidifying R5.

[0008] In some embodiments R4 is hydrogen atom, or a protecting group selected from the group consisting of Boc, Fmoc and formyl, and R5 is -CN, -C(O)NHCH2Ph or -C(O)ORe, Re being -CH2CH3;'Pr; -‘Bu, or -Benzyl; or wherein R4 is a protecting group selected from the group consisting of Boc and Fmoc, and R5is -CN, -C(O)NH2, -C(O)NHCH2Ph or -C(O)OR6, Re being -CH3, -CH2CH3;jPr; - ‘Bu, -H, or -Benzyl; more preferably R4 is a protecting group selected from the group consisting of Boc and Fmoc, and R5is -CN, -C(O)NHCH2Ph or -C(O)OR6, Re being -CH3, -CH2CH3;jPr; -‘Bu, -H, or -Benzyl. In some embodiments R4 is hydrogen atom, or a protecting group selected from the group consisting of benzyl, Boc, Fmoc and formyl, and Rs is -CN, -C(O)NHCH2Ph or -C(O)ORe, Re being - CH2CH3; 'Pr; -‘Bu, or -Benzyl; or wherein R4 is a protecting group selected from the group consisting of benzyl, Boc and Fmoc, and Rs is -CN, -C(O)NHCH2Ph or -C(O)ORe, Re being -CH3, -CH2CH3; 'Pr; -‘Bu, -H, or -Benzyl.

[0009] The term “amidifying” refers to a reaction in which an amide group -C(O)NH2is obtained. For instance, by reaction of a group -CN, or of a protected amide -C(O)NHCH2Ph, or of a carboxylic acid -C(O)OH, to obtain an amide -C(O)NH2. Thus, the method comprises a step (S3) of transforming group Rs into an amide group -C(O)NH2when required; wherein step (S3) may be:(S3-a) transforming a group -CN into an amide group -C(O)NH2;(S3-b) deprotecting a group -C(O)NHCH2Ph to obtain an amide group -C(O)NH2;(S3-c) transforming an ester group -C(O)ORe, Re being -CH3, -CH2CH3; 'Pr; -‘Bu or -Benzyl, into an amide group -C(O)NH2;(S3-d) transforming an acid group -C(O)OH into an amide group -C(O)NH2.

[0010] In some embodiments, R4 is hydrogen atom, or a protecting group selected from the group consisting of benzyl, Boc, Fmoc and formyl.

[0011] In some embodiments, R4 is hydrogen atom, or a protecting group selected from the group consisting of Boc, Fmoc and formyl.

[0012] In some embodiments, R4 is hydrogen atom, or a protecting group selected from the group consisting of Boc and Fmoc.

[0013] In some embodiments, R4 is hydrogen atom, or a protecting group selected from the group consisting of benzyl, Boc and Fmoc.

[0014] In some embodiments, Rs is -CN, -C(O)NHCH2Ph or -C(O)ORe, Re being -CH2CH3; 'Pr; -‘Bu, or -Benzyl.

[0015] In some embodiments, R4 is hydrogen atom, or a protecting group selected from the group consisting of Boc and Fmoc; and Rs is -CN, -C(O)NHCH2Ph or -C(O)ORe, Re being -CH3, -CH2CH3; 'Pr; -‘Bu, -H, or -Benzyl.

[0016] In some embodiments, R4 is hydrogen atom, or a protecting group selected from the group consisting of benzyl, Boc and Fmoc; and Rs is -CN, -C(O)NHCH2Ph or -C(O)ORe, Re being -CH3, - CH2CH3; 'Pr; -‘Bu, -H, or -Benzyl.

[0017] In some embodiments, R4 is hydrogen atom, or a protecting group selected from the group consisting of Boc, Fmoc and formyl; and R5 is -CN, -C(O)NHCH2Ph or -C(O)ORe, Re being -CH2CH3; 'Pr; -‘Bu, or -Benzyl.

[0018] In some embodiments, R4 is hydrogen atom, or a protecting group selected from the group consisting of benzyl, Boc, Fmoc and formyl; and R5 is -CN, -C(O)NHCH2Ph or -C(O)ORe, Re being - CH2CH3; 'Pr; -‘Bu, or -Benzyl.

[0019] In some preferred embodiments R4 and R5 are selected from one or more of the following groups consisting of:R4 is Boc and R5 is -C(O)ORe, being Re H; or R4 is H and R5 is -C(O)ORe, being Re 'Pr;R4 is formyl and R5 is -C(O)ORe, being Re benzyl;R4 is H and R5 is -C(O)ORe, being Re -CH3;R4 is Boc and R5 is -C(O)ORe, being Re benzyl;R4 is H and R5 is -C(O)ORe, being Re 'Pr;R4 is formyl and R5 is -CN; or R4 is H and R5 is -C(O)ORe, being Re -CH3;R4 is Boc and R5 is -CN; or R4 is H and R5 is -CN;R4 is Boc and R5 is -C(O)ORe, being Re -CH3;R4 is H and R5 is -C(O)ORe, being Re -CH3;R4 is formyl and R5 is -C(O)ORe, being Re benzyl;R4 is benzyl and R5 is -C(O)NHCH2Ph; andR4 is formyl and R5 is -C(O)ORe, being Re -CH2CH3; or R4 is H and R5 is -C(O)ORe, being Re -CH2CH3

[0020] For the processes and steps described herein, the halogen may be selected from the group consisting of F, Cl, Br and I.

[0021] In some embodiments the compound of formula F2 is selected from the group consisting of a compound of formula F2a and a compound of formula F2b:F2a wherein R4 is hydrogen atom, or a protecting group selected from the group consisting of benzyl, Boc, Fmoc and formyl; preferably R4 is hydrogen atom, or a protecting group selected from the group consisting of Boc, Fmoc and formylwherein R5 is -CN, -C(0)NHCH2Ph or -C(O)ORe, Re being, -CH2CH3; 'Pr; -‘Bu, or -Benzyl,F2b wherein R4 is hydrogen atom, or a protecting group selected in the group consisting of benzyl, Boc and Fmoc, preferably R4 is hydrogen atom, or a protecting group selected in the group consisting of Boc and Fmoc; wherein R5 is -CN, -C(O)NHCH2Ph or -C(O)ORe, Re being -CH3, -CH2CH3; 'Pr; -‘Bu, -H, or -Benzyl.The step S 1

[0022] Step S1 may be implemented in several ways.

[0023] In an embodiment, step (S1) comprises the following successive sub steps:(S1-1 a) reacting a compound of formula F3 with a compound of formula F4,F3 F4 wherein R7 being -CH3, -CH2CH3; 'Pr; -‘Bu, -H, or -Benzyl, resulting in a compound of formula F5F5 as illustrated by Scheme 1 :(S1-1 b) reacting F5 with a compound of formula F6F6 resulting in product F2, as illustrated by Scheme 2:

[0024] In some embodiments of steps S1-1 a and S1-1 b, R4is hydrogen atom, or a protecting group selected from the group consisting of benzyl, Boc and Fmoc; R7 is selected from the group consisting of -CH3, -CH2CH3; Pr; -‘Bu, -H, and -Benzyl; and R5is -CN, -C(O)NHCH2Ph or -C(O)OR6, Re being - CH3, -CH2CH3; Pr; -‘Bu, -H, or -Benzyl. In some embodiments of steps S1-1 a and S1-1 b, R4is hydrogen atom, or a protecting group selected from the group consisting of Boc and Fmoc; R7 is selected from the group consisting of -CH3, -CH2CH3; Pr; -‘Bu, -H, and -Benzyl; and R5 is -CN, - C(O)NHCH2Ph or -C(O)OR6, Re being -CH3, -CH2CH3;jPr; -‘Bu, -H, or -Benzyl.

[0025] In some embodiments of steps S1-1 a and S1-1 b, R4is hydrogen atom, or a protecting group selected from the group consisting of benzyl, Boc, Fmoc and formyl; R7 is selected from the group consisting of -CH3, -CH2CH3; Pr; -‘Bu, and -Benzyl; and R5 is -CN, -C(O)NHCH2Ph or -C(O)ORe, Re being -CH3, -CH2CH3; Pr; -‘Bu, -H or -Benzyl. . In some embodiments of steps S1-1 a and S1-1 b, R4is hydrogen atom, or a protecting group selected from the group consisting of Boc, Fmoc and formyl; R7 is selected from the group consisting of -CH3, -CH2CH3; Pr; -‘Bu, and -Benzyl; and R5 is -CN, - C(O)NHCH2Ph or -C(O)OR6, Re being -CH3, -CH2CH3;jPr; -‘Bu, -H or -Benzyl.

[0026] In some embodiments of steps S1-1 a and S1-1 b, R4is hydrogen atom, or a protecting group selected from the group consisting of benzyl, Boc, Fmoc and formyl; R7 is selected from the group consisting of -CH3, -CH2CH3; Pr; -‘Bu, -H, and -Benzyl; and R5 is -CN, -C(O)NHCH2Ph or -C(O)ORe, Re being -CH2CH3; Pr; -‘Bu or -Benzyl. In some embodiments of steps S1-1 a and S1-1 b, R4is hydrogen atom, or a protecting group selected from the group consisting of, Boc, Fmoc and formyl; R7 is selected from the group consisting of -CH3, -CH2CH3; Pr; -‘Bu, -H, and -Benzyl; and R5 is -CN, -C(O)NHCH2Ph or -C(O)OR6, Re being -CH2CH3;jPr; -‘Bu or -Benzyl.

[0027] In some embodiments of steps S1-1 a and S1-1 b, R4is hydrogen atom, or a protecting group selected from the group consisting of benzyl, Boc, Fmoc and formyl; R7 is selected from the group consisting of -CH3, -CH2CH3; Pr; -‘Bu, -H, and -Benzyl; and R5 is -CN, -C(O)NHCH2Ph or -C(O)ORe, Re being -CH2CH3; Pr; -‘Bu or -Benzyl. In some embodiments of steps S1-1 a and S1-1 b, R4is hydrogen atom, or a protecting group selected from the group consisting of Boc, Fmoc and formyl; R7 is selected from the group consisting of -CH3, -CH2CH3; Pr; -‘Bu, -H, and -Benzyl; and R5 is -CN, -C(O)NHCH2Ph or -C(O)OR6, Re being -CH2CH3;jPr; -‘Bu or -Benzyl.

[0028] In some preferred embodiments of step steps S1-1 a and S1 -1 b, R4, R7 and R5 are selected from one or more of the following groups consisting of:R4is Boc, R7 is -H and R5 is -C(O)ORe, Re being -H;R4is formyl, R7 is -H and R5 is -C(O)ORe, Re being benzyl;R4IS BOC, R7 IS -H and R5 is -C(O)OR6, Re being benzyl;R4 is formyl, R7 is -H and R5 is -CN; or R4 is Boc, R7 is -H and R5 is -CN;R4 is benzyl, R7 is -H and R5 is -C(O)NHCH2Ph; andR4 is formyl, R7 is -H and R5 is -CH2CH3.

[0029] In an embodiment, step S1-1 a may be carried out in conditions adequate for the formation of an amide group. Adequate conditions for step S1-1 a comprise, for example, the use of 1 ,1 ’- carbonyldiimidazole (CDI), or of an activated benzotriazole containing compound, such as BOP (benzotriazol-l-yloxytris(dimethylamino)phosphonium hexafluorophosphate) or HATU (Hexafluorophosphate Azabenzotriazole Tetramethyl Uronium), together with trialkyamines or DBU, in an aprotic polar solvent such as N-methyl-2-pyrrolidinone (NMP), dimethyl formamide (DMF), dimethyl sulfoxide (DMSO) or dichloromethane (DCM). For example, step S1-1 a may be carried out in the presence of BOP and triethanolamine (EtsN) in DCM; or in the presence of HATU and N, N- Diisopropylethylamine (DIPEA) in DCM or DMF; or in the presence of CDI and DBU in NMP or DMF. In one specific embodiment step S1-1 a may be carried out in N-methyl-2-pyrrolidinone (NMP) at room temperature, for instance 25°C, in presence of 1 .5 molar equivalent of 1 ,1 ’-carbonyldiimidazole (CDI) and 4 molar equivalent of 1 ,8-diazabicyclo[5.4.0]undec-7-ene (DBU); or in DMF in the presence of HATU and DIPEA heating at 25-50°C, for instance at 40°C; or in DMF in the presence of 1 .2 molar equivalents of CDI and 4 molar equivalents of DBU, at a temperature between 0°C and room temperature, for instance at 25°C.

[0030] In an embodiment, step S1-1 b may be carried out in conditions adequate for the formation of an amide group as those disclosed for step S1-1 a. For example, step S1-1 b may be carried out in dimethylsulfoxide (DMSO) at room temperature, for instance 25°C, in presence of 1.5 molar equivalent of 1 ,1 ’-carbonyldiimidazole (CDI) and 4 molar equivalent of 1 ,8-diazabicyclo[5.4.0]undec- 7-ene (DBU); or may be carried out in DCM, heating at 25-50°C, for instance at 40°C, in the presence of 1 molar equivalent of BOP and 1 molar equivalent of EtsN; or may be carried out in DCM, at room temperature, for instance at 25°C, in the presence of HATU and DIPEA; or in DMF in the presence of CDI and DBU.

[0031] Step (S1) may also comprise the following successive sub steps:(S1-1 aa) reacting a compound of formula F3 with a compound of formula F7:F3 F7 wherein Ra being -CH3, -CH2CH3; 'Pr; -‘Bu, -H, or -Benzyl, resulting in a compound of formula F8:as illustrated by Scheme 3:(S1-1ab) reacting F8 with a compound or formula F9,R3X3F9 wherein X is a halogen atom, resulting in a compound of formula F10,F10 as illustrated by Scheme 4:(S1-1ac) if Rs is different from H, and R? is H, hydrolyzing F10 resulting in a compound of formula F5, as illustrated by Scheme 5:

[0032] In some embodiments step (S1) further comprises:(S1-1c) reacting the compound of formula F5 with a compound of formula F11 :F5 F11 resulting in a compound of formula F31 ,(S1-1d) reacting the compound of formula F31 with a compound of formula F12:resulting in a compound of formula F2, as illustrated by Scheme 7:

[0033] X may be selected from the group consisting of F, Cl, Br and I.

[0034] In some embodiments R4 is Boc, Rs is -CH3, X is Br, R7 is H and R5 is COORe, being Re -CH3.

[0035] In some embodiments steps S1-1 aa and S1-1c may be carried out in conditions adequate for an amide bond formation, as those disclosed for step S1-1a.

[0036] For example, in an embodiment, step S1-1aa may be carried out in dichloromethane (DCM) at a temperature around between 30°C and 50°C, in presence of 1.5 molar equivalent of benzotriazole-1-yl-oxy-tris-(dimethylamino)-phosphonium hexafluorophosphate (BOP) and 2 molar equivalent of triethylamine.

[0037] For instance, in an embodiment, step S1-1c may be carried out in dichloromethane (DCM) at a temperature around between 30°C and 50°C, in presence of 1 molar equivalent of benzotriazole- 1-yl-oxy-tris-(dimethylamino)-phosphonium hexafluorophosphate (BOP) and 1 molar equivalent of triethylamine.

[0038] In some embodiments, step S1-1ab and S1-1d may be carried out in conditions adequate for alkylation of the secondary amide with an alkyl halide, i.e. conditions adequate for a nucleophilicsubstitution of the halide of compounds F9 or F12 with, respectively, the amine of compounds F8 and F31. For instance, step S1-1d may be carried out in the presence of a strong nucleophilic base such as LiHDMS.

[0039] In an embodiment, compound of formula F6 may be synthesized by reacting a compound of formula F1 1 with a compound of formula F12F11 F12 wherein X is a halogen atom, as illustrated by Scheme 8:Scheme 8F11 F12 F6

[0040] In some embodiments of the synthesis of compound F6, R5 is CN, -C(O)NHCH2Ph or - C(O)ORe, Re being -CH2CH3; 'Pr; -‘Bu or -Benzyl, and X is Br.

[0041] In some embodiments the compound F6 may be synthesized by reacting a compound of formula F11 with a compound of formula F12 in conditions adequate for alkylation of the primary amine with an alkyl halide, i.e. conditions adequate for a nucleophilic substitution of the halide F12. For instance, if R5 is CN, compound of formula F6 may be synthesized by reacting compound of formula F11 with compound of formula F12 in triethylamine and acetonitrile (ACN) at room temperature, for instance around 25°C.

[0042] For instance, if R5 is -C(O)OBn, compound of formula F6 may be synthesized by reacting compound of formula F11 with compound of formula F12 in N,N-diisopropylethylamine (DIPEA) and acetonitrile (ACN) at room temperature, for instance around 25°C.

[0043] For instance, if R5 is -C(O)NHCH2Ph, the compound of formula F6 may be synthesized by reacting compound of formula F11 with compound of formula F12 in N,N-diisopropylethylamine (DIPEA) and dichloromethane (DCM) at room temperature, for instance around 25°C.

[0044] In other embodiment, R5 is COORe, Re being -CH3, -CH2CH3; 'Pr; -‘Bu, -H, or -Benzyl, and the compound of formula F6 may be synthesized by reacting a compound of formula F1 1 with the corresponding glyoxylate of formula H(O)C-C(O)Re, in conditions adequate for a reductive amination. For example, if R5 is COORe, Re being -CH3, -CH2CH3; 'Pr; -‘Bu, -H, or -Benzyl, the compound of formula F6 may be synthesized by reacting compound of formula F1 1 with the corresponding glyoxylate of formula H(O)C-C(O)Re, in water, or in a mixture of water and acetonitrile with formic acid, and subsequently adding an acid.

[0045] In some embodiments, compound of formula F3 is synthesized by reacting a compound of formula F13 with a compound of formula F14F13 F14 wherein X is a halogen atom, and wherein Rg being -CH3, -CH2CH3; 'Pr; -‘Bu, -H, or -Benzyl, resulting in a compound of formula F15,F15 protecting the amine function of said compound of formula F15 with a protecting group selected from the group consisting of, Boc, Fmoc and formyl, resulting in a compound of formula F16F16 optionally hydrolyzing the ester group of the compound of F16, resulting in a compound of formula F3, as illustrated by Scheme 9:

[0046] The compounds of formula F13 and F14 may react in conditions adequate for alkylation of the primary amine with an alkyl halide. For instance, if R9 is Me, compound of formula F15 may be synthesized by reacting compound of formula F13 with compound of formula F14 in triethylamine and acetonitrile (ACN) at room temperature, for instance around 25°C.

[0047] Then, the amine function of compound of formula F15 may be protected, for instance with a Boc group, by reacting compound of formula F15 with 1.05 molar equivalent of di-tert-butyl- dicarbonate, with 1.5 molar equivalent of triethylamine in dichloromethane (DCM) at room temperature, for instance around 25°C, resulting in compound of formula F16.

[0048] Compound of formula F16 may be hydrolyzed in an adequate solvent, such as methanol, at room temperature, for instance around 25°C, in the presence of a base, for example 3.0 molar equivalent of sodium hydroxide.

[0049] Alternatively, compound of formula F3 may be synthesized by protecting the primary amine of the compound of formula F13 with a protecting group selected in the group consisting of benzyl, Boc, Fmoc and formyl, preferably benzyl, to obtain a protected compound of formula F32; and subsequently reacting the protected compound of formula F32 with a compound of formula F14 to obtain a compound of formula F16; and optionally hydrolyzing the ester group of the compound od formula F16, resulting in a compound of formula F3, as illustrated by Scheme 10:

[0050] For instance, compound of formula F3 may be synthesized by protecting the compound of formula F13 with a benzyl group to obtain a protected compound of formula F13, wherein R4 is a benzyl group, for instance by reacting the compound of formula F13 with benzaldehyde and subsequent reduction, for example with NaBF , in methanol; reacting the protected compound of formula F13 with the compound of formula F14, for example in DMF in the presence of DIPEA to obtain the compound of formula F16, and optionally hydrolyzing the ester group of the compound of formula F16, for example in an adequate solvent, such as a mixture of methanol and THF (tetrahydrofurane), at room temperature, for instance around 25°C, in the presence of a base, for example lithium hydroxide.

[0051] Alternatively, when R4 is formyl, the compound of formula F3 may be synthesized by reacting the compound of formula F13 with glyoxylic acid in adequate conditions for a reductive amination, for example in water in the presence of formic acid, to obtain the compound of formula F3, as illustrated in Scheme 11 :R4O R4 = formylF13 Scheme 11F3

[0052] In some embodiments, when R7 is H, the compound of formula F4 may be synthesized in conditions adequate for conducting a reductive amination as disclosed in the present specification, by reacting a compound of formula F22:,R3H2NDF22 with formic acid and glyoxylic acid in adequate conditions, for example in water, or in a mixture of water and acetonitrile, subsequently adding an acid, to obtain the compound of formula F4:F4 as illustrated by Scheme 12a:Formic acidGlyoxylic acidH2N'R3- -F22 Scheme 12a F4

[0053] In other embodiments, the compound of formula F4 may be synthesized in conditions adequate for the alkylation of the primary amine with an halide as disclosed in the present specification, by reacting a compound of formula F22 with a compound of formula F14wherein R9 in the compound of formula F14 corresponds to R7 of the compound of formula F4 and is -CH3, -CH2CH3; 'Pr; -‘Bu, -H, or -Benzyl, as illustrated by Scheme 12b:F22 F14 Scheme 12b F4

[0054] In some embodiments the compound of formula F4 may be synthesized by reacting a compound of formula F22 with a compound of formula F14 in conditions adequate for alkylation of the primary amine with an alkyl halide as disclosed in the present specification, For example, the compound of formula F22 and the compound of formula F14 may react in a polar aprotic solvent, such as DCM, at room temperature, for instance at 25°C, in the presence of a trialkylamine, such as DIPEA.

[0055] In some embodiments X is Br. In some embodiments Rgis H or Me. In some embodiments of the synthesis of compound of formula F3, X is Br and R9 is -CH3

[0056] In another embodiment, step (S1) comprises the following successive sub steps:(S1-2a) reacting a compound of formula F17 with a compound of formula F3:,F17 F3 resulting in a compound of formula F2, as illustrated by Scheme 13:

[0057] In an embodiment, step S1-2a may be carried out in conditions adequate for an amide bond formation, as those disclosed for step S1-1a, for example step S1-2a may be carried out in dichloromethane (DCM) at a temperature around between 30°C and 50°C, in presence of between1 and 2, preferably around 1.5 molar equivalent of benzotriazole-l-yl-oxy-tris-(dimethylamino)- phosphonium hexafluorophosphate (BOP) and between 2 and 4 molar equivalent of triethylamine.

[0058] In another embodiment, step (S1) comprises the following successive sub steps:(S1-3a) reacting a compound of formula F17 with 2-chloroacetyl chloride, represented as a compound of formula F18:resulting in a compound of formula F19F19 reacting F19 with a compound of formula F13,F13resulting in a compound of formula F2, as illustrated by Scheme 14:Scheme 14

[0059] In an embodiment, step S1-3a may be carried out in conditions adequate for the alkylation of a secondary amine of the compound of formula F17 with an acyl halide such as the compound of formula F18, for instance step S1-3a may be carried out in dichloromethane (DCM) at a temperature around between 20°C and 50°C, in presence of triethylamine to obtain compound of formula F19. Then, the resulting alkyl halide of formula F19 may react in conditions adequate for the alkylation of a primary amine, such as the primary amine of the compound of formula F13, for example, the compound of formula F19 reacts with compound of formula F13, in acetonitrile at a temperature around between 20°C and 50°C, in presence of triethylamine.

[0060] In some embodiments, compound of formula F17 may be synthesized by reacting a compound of formula F6 with a compound of formula F20resulting in a compound of formula F33:wherein R? is a protecting group selected from the group consisting of BOC, FMOC, formyl and benzyl, and removing said protecting group, as illustrated by Scheme 15a:Scheme 15a

[0061] In some embodiments the compound of formula F17 may be synthesized reacting a compound of formula F6 with a compound of formula F20 in conditions adequate for an amide bond formation, as those disclosed for step S1-1 a. For instance, if R? is BOC, compound of formula F17 may be synthesized by reacting compound of formula F6 with compound of formula F20 indichloromethane (DCM) at a temperature around between 25°C and 50°C, in presence of between 1 and 2, preferably 1 .5, molar equivalent of benzotriazole-l-yl-oxy-tris-(dimethylamino)- phosphonium hexafluorophosphate (BOP) and between 2 and 3 molar equivalent of triethylamine. Then BOC may be removed, for instance in isopropanol at a temperature around between 20°C and 50°C in the presence of HCI.

[0062] Alternatively, compound of formula F17 may be synthesized by reacting a compound of formula F6 with 2-chloroacetyl chloride, represented by a compound of formula F18F6 F18 resulting in a compound of formula F21F21 reacting F21 with a compound of formula F22, 2 RH N33F22 as illustrated by Scheme 15b:Scheme 15b

[0063] In some embodiments the compound of formula F17 may be synthesized reacting a compound of formula F6 with a compound of formula F18 in conditions adequate for the alkylation of a secondary amine of the compound of formula F6 with an acyl halide such as the compound of formula F18. For instance, compound of formula F6 may react with compound of formula F18 in dichloromethane (DCM) at room temperature, for instance around 25°C, in presence of triethylamine to obtain compound of formula F21 . Then, the resulting alkyl halide of formula F21 may react in conditions adequate for the alkylation of a primary amine, such as the primary amine of the compound of formula F22, for example, the compound of formula F21 reacts with compound offormula F22, in acetonitrile at room temperature, for instance around 25°C in presence of triethylamine.Step (S2)

[0064] According to the process of the present disclosure, if R4 is a protecting group selected from the group consisting of Boc, Fmoc and formyl, a step S2 of removing said protecting group should be caried out. Step S2 may be carried out by any conventional way known to those skilled in the art.

[0065] For instance, if R4 is BOC, it may be removed, for instance in isopropanol at a temperature around between 20°C and 60°C in the presence of HCI, or in methanol at room temperature, for instance around 25°C in the presence of sulfuric acid.

[0066] For instance, if R4 is formyl, it may be removed, for example in methanol at a temperature around between 20°C and 50°C in the presence of sulfuric acid.Step (S3)

[0067] According to the process of the present disclosure, step S3 consists of amidifying R5. Thus, according to the present specification, the step (S3) of transforming group R5 into an amide group -C(O)NH2 may be:(S3-a) transforming a group -CN into an amide group -C(O)NH2;(S3-b) deprotecting a group -C(O)NHCH2Ph to obtain an amide group -C(O)NH2;(S3-c) transforming an ester group -C(O)ORe, Re being -CH3, -CH2CH3; 'Pr; -‘Bu or -Benzyl, into an amide group -C(O)NH2;(S3-d) transforming an acid group -C(O)OH into an amide group -C(O)NH2.

[0068] In an embodiment, R5 is a group -CN, or a group -C(OOH, or a group -C(O)ORe, Re being - CH3, -CH2CH3; 'Pr; -‘Bu or -Benzyl, and step S3 may be carried out in a polar protic solvent, such as an alcohol R-OH, wherein R is a C1-12 alkyl group, in the presence of ammonia. For instance, step (S3) may be carried out in methanol at a temperature around between 20°C and 60°C in the presence of ammonia. In another embodiment, R5 is a group -C(O)NHCH2Ph and step (S3) may be carried out by hydrogenation, for instance in methanol, the presence of hydrogen H2, with Pd / C as a catalyst in acid media; or in a non protic polar solvent such as trichloromethane in the presence of N- bromosuccinimide (NBS).The compound of formula F1

[0069] According to the present disclosure, compound of formula F1 is the following:wherein:Ri is phenyl substituted with halogen or trifluoromethyl, and further optionally substituted with one or two substituents selected from the group consisting of halogen, (Ci-Ce)alkyl, (Ci-Ce) alkoxy, and halo(Ci-Ce)alkyl; or alternatively Ri is py rrolidin-1 -yl;R2 is 2-oxo-pyrrolidin-1 -ylmethyl or sulfamoylphenyl; andRa is selected from the group consisting of propyl, 1 -methylethyl, butyl, 2-methylpropyl, pentyl, 1 - methyl-butyl, 2- methylbutyl, hexyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, and 1- methylpentyl.

[0070] When Ri is (Ci-Ce)alkyl, it may be methyl, ethyl, propyl, butyl, 2-methylpropyl, pentyl, 2 methylbutyl, 2,2-dimethylpropyl, hexyl, 2-methylpentyl, 3-methylpentyl, 2,2-dimethylbutyl, 2,3- dimethylbutyl, Ri being linked by any carbon.

[0071] When Ri is (Ci-Ce)alkoxy, it may be -O-R12, wherein R12 may be methyl, ethyl, propyl, butyl, 2-methylpropyl, pentyl, 2 methylbutyl, 2,2-dimethylpropyl, hexyl, 2-methylpentyl, 3-methylpentyl, 2,2- dimethylbutyl, 2,3-dimethylbutyl, R12 being linked by any carbon to the oxygen, and Ri being linked by the oxygen.

[0072] When Ri is halo(Ci-Ce)alkyl, it may be -X-R12, wherein X is a halogen atom, preferably selected from the group consisting of fluorine, chlorine and bromine, wherein R12 may be methyl, ethyl, propyl, butyl, 2-methylpropyl, pentyl, 2 methylbutyl, 2,2-dimethylpropyl, hexyl, 2-methylpentyl, 3-methylpentyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, R12 being linked by any carbon to the halogen atom, and Ri being linked by the halogen.

[0073] In a preferred embodiment, Ri is 2-fluorophenyl, R2 is 2-oxo-py rrolidin-1 -ylmethyl and R3 is 2-methylpropyl. Thus, in a preferred embodiment, compound of formula F1 is N-(carbamoylmethyl)-2-(2-{[2-(2-fluorophenyl)ethyl]amino}-N-(2-methylpropyl)acetamido)-N-[3-(2- oxopy rrolidin-1 yl)propyl]acetamide as represented by formula F34 below:Intermediate compounds

[0074] The process according to the disclosure involves several intermediate compounds. Among them, some are of particular interest.

[0075] As such, the disclosure also pertains to the following compounds of formula F23, F24, F25, F26, F27, F28, F29 and F30, as disclosed herein, and salts thereof.

[0076] One embodiment refers to the compound of formula F23F23 wherein R10 is -H or isobutyl, and salts thereof, preferably wherein R4 is hydrogen atom, or a protecting group selected from the group consisting of benzyl, Boc and Fmoc, or from the group consisting of Boc and Fmoc.

[0077] Another embodiment refers to the compound of formula F24F24 wherein R11 is -H or -CH2R5, wherein R5is -CN, -C(O)NH2, -C(O)NHCH2Ph or -C(O)OR6, Re being -CH3, -CH2CH3;jPr; -‘Bu, -H, or -Benzyl, preferably wherein Rs is -CN, -C(O)NHCH2Ph or -C(O)ORe, Re being -CH3, -CH2CH3; 'Pr; -‘Bu, -H, or -Benzyl; and salts thereof, preferably wherein R4 is hydrogen atom, or a protecting group selected from the group consisting of benzyl, Boc and Fmoc, or from the group consisting of Boc and Fmoc.

[0078] Another embodiment refers to the compound of formula F25F25 and salts thereof.

[0079] Another embodiment refers to the compound of formula F26F26 wherein Rs is -CN, -C(O)NH2, -C(O)NHCH2Ph or -C(O)OR6, Re being -CH3, -CH2CH3; Pr; -‘Bu, -H, or -Benzyl, preferably wherein Rs is -CN, -C(O)NHCH2Ph or -C(O)ORe, Re being -CH3, -CH2CH3; Pr; -‘Bu, -H, or -Benzyl, more preferably wherein Rs is -CN, -C(O)NHCH2Ph or -C(O)ORe, Re being - CH2CH3; Pr; -‘Bu, or -Benzyl; and salts thereof.

[0080] Another embodiment refers to the compound of formula F27F27 wherein Rs is -CN, -C(O)NH2, -C(O)NHCH2Ph or -C(O)OR6, Re being -CH3, -CH2CH3; Pr; -‘Bu, -H, or -Benzyl, preferably wherein Rs is -CN, -C(O)NHCH2Ph or -C(O)ORe, Re being -CH3, -CH2CH3; Pr; -‘Bu, -H, or -Benzyl; and salts thereof.

[0081] Another embodiment refers to the compound of formula F28F28 wherein Rs is -CN, -C(O)NH2, -C(O)NHCH2Ph or -C(O)OR6, Re being -CH3, -CH2CH3; Pr; -‘Bu, -H, or -Benzyl, preferably wherein Rs is -CN, -C(O)NHCH2Ph or -C(O)ORe, Re being -CH3, -CH2CH3; Pr; -‘Bu, -H, or -Benzyl; and wherein RI2is a hydrogen atom, BOC, FMOC, formyl, Bn or COCH2CI, and salts thereof.

[0082] Another embodiment refers to the compound of formula F29F29 wherein R5is -CN, -C(O)NH2, -C(O)NHCH2Ph or -C(O)OR6, Re being -CH3, -CH2CH3;jPr; -‘Bu, -H, or -Benzyl, preferably wherein Rs is -CN, -C(O)NHCH2Ph or -C(O)ORe, Re being -CH3, -CH2CH3; Pr; -‘Bu, -H, or -Benzyl, more preferably wherein Rs is -CN, -C(O)NHCH2Ph or -C(O)ORe, Re being - CH2CH3; Pr; -‘Bu, or -Benzyl; and salts thereof.

[0083] Another embodiment refers to the compound of formula F30F30 wherein Rs is -CN, -C(O)NH2, -C(O)NHCH2Ph or -C(O)OR6, Re being -CH3, -CH2CH3; Pr; -‘Bu, -H, or -Benzyl, preferably wherein Rs is -CN, -C(O)NHCH2Ph or -C(O)ORe, Re being -CH3, -CH2CH3; Pr; -‘Bu, -H, or -Benzyl; and salts thereof.

[0084] Another embodiment refers to the compound of formula F31and salts thereof, wherein R4 is hydrogen atom, or a protecting group selected from the group consisting of benzyl, Boc, Fmoc and formyl, or from the group consisting of Boc, Fmoc and formyl; R1 is phenyl substituted with halogen or trifluoromethyl, and further optionally substituted with one or two substituents selected from the group consisting of halogen, (Ci-Ce)alkyl, (Ci-Ce) alkoxy, and halo(Ci-Ce)alkyl; or alternatively R1 is pyrrolidin-1 -yl; R2is 2-oxo-pyrrolidin-1-ylmethyl orsulfamoylphenyl; and R3 is selected from the group consisting of propyl, 1-methylethyl, butyl, 2- methylpropyl, pentyl, 1 -methyl-butyl, 2- methylbutyl, hexyl, 4-methylpentyl, 3-methylpentyl, 2- methylpentyl, and 1 - methylpentyl.

[0085] Another embodiment refers to the compound of formula F33:and salts thereof, wherein R7 is a protecting group selected from the group consisting of BOC, FMOC, formyl and benzyl, preferably a BOC group; R5 is -CN, -C(O)NH2, -C(O)NHCH2Ph or -C(O)ORe, Re being -CH3, -CH2CH3; 'Pr; -‘Bu, -H, or -Benzyl, preferably wherein R5 is -CN, -C(O)NHCH2Ph or - C(O)ORe, Re being -CH3, -CH2CH3; 'Pr; -‘Bu, -H, or -Benzyl, even more preferably wherein R5 is -CN; and salts thereof; R3 is selected from the group consisting of propyl, 1-methylethyl, butyl, 2- methylpropyl, pentyl, 1 -methyl-butyl, 2- methylbutyl, hexyl, 4-methylpentyl, 3-methylpentyl, 2- methylpentyl, and 1 - methylpentyl; and R2 is 2-oxo-pyrrolidin-1-ylmethyl or sulfamoylphenyl.Pharmaceutical compositions

[0086] The disclosure also concerns pharmaceutical compositions comprising the compound of formula Fl obtained by the process described above, and optionally one or more pharmaceutically acceptable excipient(s).

[0087] In an embodiment, the pharmaceutical composition comprises less than 0.3% of each individual impurity.ExamplesMaterials and methods:

[0088] LC / MS analyses were recorded on a Waters UPLC Acquity system using the following parameters:Column: Acquity BEH C18 1.7 pm 2.1 *150mm;3 min runPhotodiode array detection from 210 to 400 nm, sum of absorbance at all wavelengths

[0089] MS Detection: Waters Acquity Qda (single quadrupole) detector with electrospray ionization (ESI) in positive and negative mode with scan range m / z 85-850Solvent system:Mobile phase A: Water / MeCN 95 / 5 + 0.1 % Formic AcidMobile phase B: MeCN + 0.1 % Formic AcidGradient:

[0090] 1H NMR and13C NMR were recorded on a Bruker Avance 400 MHz, 100 MHz. Chemical shifts are expressed in parts per million (ppm) downfield from residual solvent peaks, and coupling constants are reported in hertz (Hz).

[0091] Multiplicities of signals in1H NMR spectra are reported using the following abbreviations: br: broad, s = singlet, d = doublet, t = triplet, q = quartet, hep = heptet, dt = doublet of triplets, dq = doublet of quartets, td = triplet of doublets, tt = triplet of triplets, m = multiplet.

[0092] The following compounds, set forth in table below have been synthesized as reflected in examples 1 to 29 below:Example 1: Synthesis of a compound of formula F16:

[0093] In a 100 mL round bottom glass flask, 2-(2-fluorophenyl)ethan-1 -amine (7.00 g, 0.050 mol, 1.00 eq) was solubilized in acetronitrile(100 mL). Triethylamine was then added (15.4 mL, 0.111 mol, 2.20 eq), followed by methyl-2-bromoacetate (7.1 mL, 0.075 mol, 1 .50 eq). The reaction mixture was stirred for 2 hours at 25°C.

[0094] LCMS analysis after this time showed complete conversion. The reaction was quenched with addition of a saturated aqueous NH4CI solution and extracted with DCM. The organic layer was washed twice with NH4CI solution and concentrated till dryness to afford crude methyl (2- fluorophenethyl)glycinate which was used as such for the next step.

[0095] In a 500 mL round bottom flask, methyl (2-fluorophenethyl)glycinate (10.20 g, 0.036 mol, 1.000 eq) was solubilized in DCM (123 mL) and triethylamine was added (7.6 mL, 0.054 mol, 1.50 eq). Then, di-tert-butyl-dicarbonate was added portionwise, and reaction mixture was stirred for 16 hours at 25°C (orange solution).

[0096] LCMS analysis after this time showed complete conversion. The reaction mixture was hydrolyzed with water and phases were separated. The organic layer was washed twice with water then with 2M HCI three times. The organic layer was dried over Na2SO4, filtered, and evaporated to dryness to afford E1 as an orange oil (11.14 g, 0.035 mol, 69% yield over 2 steps).

[0097] MS (positive ESI, [M+H]+): 312.1 ,1H NMR (400 MHz, CDCI3) (figure 1) 5 7.19 (ddd, J = 12.4, 6.9, 3.8 Hz, 2H), 7.08 - 6.93 (m, 2H), 3.84 (d, J = 49.6 Hz, 2H), 3.71 (s, 3H), 3.49 (dt, J = 10.6, 7.4 Hz, 2H), 2.87 (dt, J = 14.1 , 7.5 Hz, 2H), 1 .40 (s, 9H).Example 2: Synthesis of a compound of formula F3:

[0098] In a 50 mL round bottom flask, methyl N-(tert-butoxycarbonyl)-N-(2-fluorophenethyl)glycinate E1 (9.80 g, 0.030 mol, 1.000 eq) was dissolved in MeOH (85 mL). Then, an aqueous solution of NaOH 30% (6.0 mL, 0.060 mol, 2.000 eq) was added and reaction mixture was stirred 2 hours at 25°C. LCMS analysis after this time showed complete conversion. The reaction mixture was quenched with water, and EtOAc was added. The organic layer was washed with aqueous saturatedNH4CI solution twice, and then with 1 M HCI. The organic phase was dried over Na2SO4, and concentrated till dryness to afford E2 as an orange oil .

[0099] MS (negative ESI, [M-H] ): 296.1 ,1H NMR (400 MHz, DMSO) (Figure 2) 5 7.37 - 7.18 (m, 2H), 7.11 (dtd, J = 8.6, 6.9, 1 .6 Hz, 2H), 3.76 (d, J = 22.1 Hz, 2H), 3.39 (q, J = 7.4 Hz, 2H), 2.80 (td, J = 7.0, 4.0 Hz, 2H), 1.27 (s, 9H).of formula F4:

[0100] In a 250 mL round bottom three-neck glass reactor was loaded isobutylamine (10.2 mL, 0.103 mol, 1 .000 eq) followed by water (30 mL). At 25°C, formic acid (5.4 mL, 0.144 mol, 1.400 eq) was slowly added (exothermic addition) keeping the internal temperature below 50°C.

[0101] This reaction mixture was stirred while going back to 35°C, and then glyoxylic acid monohydrate (28.3 g, 0.307 mol, 3.000 eq) solubilized in water (30 mL) was slowly added. The reaction temperature reached 45°C, turned yellow and a small degassing was observed. This solution was then heated at 50°C for 1 hour. After this time hydrochloric acid (37% aqueous solution, 13 mL, 0.151 mol, 1.470 eq) was added and the solution was stirred at 80°C for 16 hours.

[0102] The reaction mixture was then partially concentrated to a low volume in a rotary evaporator, and residual water was stripped by azeotroping several times with MeCN until an off-white solid was obtained. The solid was triturated with MeCN at 20°C for 30 minutes, filtered and dried in an oven at 45°C under vacuum to afford E3).

[0103] MS (positive ESI, [M+H]+): 132.2,1H NMR (400 MHz, D2O) (Figure 3) 5 3.97 (s, 2H), 2.99 (d, J = 7.3 Hz, 2H), 2.07 (dp, J = 13.8, 6.9 Hz, 1 H), 1 .03 (d, J = 6.7 Hz, 6H).Example 4: Synthesis of a compound of formula F5:

[0104] In a 50 mL round bottom flask, 3 (4.05 g, 0.013 mol, 1.00 eq) was dissolved in NMP (19 mL). At 25°C, CDI (3.08 g, 0.019 mol, 1 .50 eq) was added portionwise within 5 minutes, and the reaction was stirred 30 minutes. Then, 4 (4.25 g, 0.025 mol, 2.00 eq) was added, followed by DBU (7.6 mL, 0.051 mol, 4.00 eq). The reaction mixture was stirred at 25°C for 2 hours. The reaction mixture was quenched with EtOAc, and 2M HCI. Phases were separated and the aqueous layer was extracted twice with EtOAc. The combined organic layers were washed with 1 M aqueous HCI, dried over Na2SO4, filtered, and evaporated till dryness to afford E4.

[0105] MS (negative ESI, [M-H]-): 409.4,1H NMR (400 MHz, DMSO) (Figure 4) 5 12.43 (s, 1 H), 7.40 - 7.20 (m, 2H), 7.13 (tq, J = 7.2, 2.8 Hz, 2H), 4.16 - 3.76 (m, 4H), 3.33 (ddd, J = 14.1 , 11.2, 7.1 Hz, 2H), 3.09 (dd, J = 13.8, 7.4 Hz, 2H), t2.80 (dd, J = 9.5, 5.4 Hz, 2H), 1 .88 - 1 .71 (m, 1 H), 1 .52 - 1 .22 (m, 9H), 0.94 - 0.71 (m, 6H).Example 5: Synthesis of a compound of formula F6:

[0106] In a 500mL flask was introduced 1-(3-aminopropyl)-pyrrolidin-2-one (15.0g, .10 mol, 1.00 eq) followed with H2O (75.0 mL). Solution was stirred for 5min at 23°C before formic acid (5.8 mL, 0.15 mol, 1.40 eq) was added dropwise in 5 min leading to an exotherm. Internal temperature reached35°C. 10min later, at 23°C, glyoxylic acid (29.1 g, 0.32 mol, 3.00 eq) solution in water (37.5 mL) was added dropwise over 5min.

[0107] Solution was stirred at 23°C for 10min, then at 38°C for 2h and finally at 60°C for 4h30. Then a 37% HCI aqueous solution (12.8 mL, 0.15 mol, 1.50 eq) was added dropwise and the reaction mixture was stirred at 82°C for 16h. The Solution was cooled to 40°C and evaporated to dryness under reduced pressure. The residue was then co-evaporated several time with toluene to remove all traces of water. The residue was then dissolved in 30 mL of hot iPrOH and then allowed to cool to 23°C over 16 hours while the product crystallized. The solid was collected by filtration and dried under vacuum at 45°C for 16 hours before being triturated in MeCN (100.0 mL) at 50°C for 2h. The solid was collected by filtration rinsed once with ACN and dried under vacuum at 45°C overnight to afford E5 as a white solid.

[0108] MS (negative ESI, [M-H]-): 199.1 ,1H NMR (400 MHz, DMSO) (Figure 5) 5 13.77 (s, OH), 9.14 (s, 2H), 3.87 (s, 2H), 3.34 (t, J = 7.0 Hz, 2H), 3.23 (t, J = 6.7 Hz, 2H), 2.88 (d, J = 8.2 Hz, 2H), 2.33 - 2.15 (m, 2H), 1 .94 (qd, J = 8.1 , 6.6 Hz, 2H), 1 .84 (p, J = 6.9 Hz, 2H).Example 6: Synthesis of a compound of formula F2:

[0109] In a 100 mL round bottom flask, was E4 (1.00 g, 2.43 mmol, 1.00 eq) and DMSO (4 mL). To this solution was added CDI (594 mg, 3.65 mmol, 1.50 eq) portionwise and reaction mixture was stirred half an hour at 22°C. Then, E5 (976 mg, 4.87 mmol, 2.00 eq) was added and stirring was maintained for 10 minutes. DBU (1 .5 mL, 9.72 mmol, 4.00 eq) was finally added with small exotherm noticed, up to 26°C. The reaction mixture was heated near 40°C, and conditions were maintained for 22 hours. LCMS analysis after this time showed complete conversion. Solution was cooled down near 10°C and hydrolyzed with 6M aqueous HCI solution. The reaction mixture was diluted with water and extracted with DCM. The organic layer was then washed with a 0.5 M HCI solution and finally with water and brine. The organic layer was dried over Na2SO4, filtered and concentrated till dryness to afford E6 as an oil.

[0110] MS (negative ESI, [M-H]-): 591.3,1H NMR (400 MHz, DMSO) (Figure 6) 5 7.41 - 7.19 (m, 2H), 7.18 - 7.02 (m, 2H), 4.21 - 3.73 (m, 6H), 3.26 - 2.92 (m, 10H), 2.88 - 2.73 (m, 2H), 2.30 - 1 .55 (m, 7H), 1.59 - 1.10 (m, 9H), 1.03 - 0.57 (m, 6H).Example 7: Synthesis of a compound of formula F1 :

[0111] In a 25 mL round bottom flask, was charged E6 (240 mg, 0.324 mmol, 1.00 eq) followed by iPrOH (3.0 mL). Then a 5.5M HCI solution in iPrOH (236 pL, 1.296 mmol, 4.00 eq) was added and the reaction mixture was stirred at 40°C for 16 hours. LCMS analysis after this time showed complete Boc-cleavage and a mixture of isopropylester and carboxylic acid intermediates. The reaction mixture was concentrated till dryness under reduced pressure to afford an oily residue. This residue was dissolved in MeOH (1 .0 mL) and a 7M NH3 solution in MeOH was added (2.0mL). The solution was stirred at 50°C for 24h. The solution was evaporated to dryness under reduced pressure and the residue was purified by chromatography over SiO2 eluting with DCM / EtOH 98:2 to 90:10. Purestfractions were combined and evaporated to dryness to afford compound of formula F1 (E7) as a white solid.

[0112] MS (positive ESI, [M+H]+): 492.4,1H NMR (400 MHz, DMSO) (Figure 7) 5 7.70 - 6.88 (m, 7H), 4.37 - 3.68 (m, 4H), 3.46 - 2.99 (m, 10H), 2.79 - 2.63 (m, 4H), 2.41 - 2.11 (m, 2H), 2.05 - 1 .43 (m, 5H), 1.10 - 0.55 (m, 6H).Example 8: Synthesis of a compound of formula F6:

[0113] In a 250mL flask was introduced 1-(3-aminopropyl)pyrrolidin-2-one (7.00 g, 0.049 mol, 1.00 eq) followed by MeCN (105.0 mL). Benzyl 2-bromoacetate (12.50 g, 0.055 mol, 1 .1 1 eq) was added to the reaction mixture (exotherm) followed by DIPEA (25.7 mL, 0.148 mol, 3.00 eq). Precipitation was observed. The reaction mixture was stirred at 23°C for 15h. LCMS analysis after this time showed complete conversion with formation of mono and bis-alkylated compound in a 65 / 35 ratio. The reaction was quenched by addition of DCM (30 mL) and water (30 mL). Layers were separated and the aqueous phase was extracted DCM(2x30mL). Combined organic phases were washed with a saturated aqueous NaCI solution (2x15mL), dried over Na2SO4 and concentrated to dryness under reduced pressure to afford 12.9g of a yellowish oil. This residue was purified by chromatography over SiO2 eluting with DCM / EtOH 98:2 to 90:10. Purest fractions were combined and evaporated to dryness to afford E8 as a colorless oil.

[0114] MS (positive ESI, [M+H]+): 226.2,1H NMR (400 MHz, DMSO) (Figure 8) 5 7.42 - 7.29 (m, 5H), 5.12 (s, 2H), 3.37 (s, 2H), 3.29 (t, J = 7.0 Hz, 2H), 3.18 (t, J = 7.1 Hz, 2H), 2.47 (t, J = 7.0 Hz, 2H), 2.18 (t, J = 8.1 Hz, 2H), 1.95 - 1.83 (m, 2H), 1.55 (p, J = 7.0 Hz, 2H).Example 9: Synthesis of a compound of formula F10:

[0115] In a 2000mL four neck round bottom flask was introduced E24 (5.00 g, 0.022 mol, 1.00 eq) followed by NMP (25.0 mL). To this suspension was added portionwise CDI (5.40 g, 0.033 mol, 1 .50 eq) in 25min (and reaction mixture was stirred at 23°C for 1 h.

[0116] Then, E3 (7.4 g, 0.044 mol, 2.00 eq) was added portionwise and 5 min later DBU (13.3 mL, 0.088 mol, 4.00 eq) (exotherm observed but controlled with an ice bath). Internal temperature reached 28°C and the reaction mixture was stirred 10min at 23°C. and then 3h at 32°C. The reaction was quenched by the addition of 6M HCI (20.3 mL, 0.121 mol, 5.50 eq) under ice bath cooling. pH 1 was reached. The solution was diluted with 40mL of EtOAc and transferred into a separating funnel. Liquid liquid extraction was performed and aqueous layer was extracted once more with 40mL of EtOAc while organic layer was washed once more with 30mL 0.5M HCI aqueous solution. Organic layers were combined, washed twice with 30mL of water and evaporated to dryness under reduced pressure. The residue was then solubilized in 20 mL of iPrOH and then 50 mL of water were slowly added at 23°C. The solution was then stirred at 23°C for 24h while the product crystallizes. The solid was collected by filtration, washed with water and dried under vacuum at 45°C for 18h to afford E9 as a white solid.

[0117] MS (negative ESI, [M-H]-): 337.1 ,1H NMR (400 MHz, DMSO) (Figure 9) 5 13.26 - 12.06 (br, 1 H), 7.97 - 7.76 (m, 1 H), 7.39 - 7.21 (m, 2H), 7.15 (qdd, J = 7.5, 4.3, 2.2 Hz, 2H), 4.33 - 4.14 (m,2H), 4.02 (dd, J = 70.4, 4.5 Hz, 2H), 3.59 - 3.35 (m, 2H), 3.24 - 3.03 (m, 2H), 2.88 - 2.71 (m, 2H), 1 .98 - 1 .51 (m, 1 H), 1 .09 - 0.70 (m, 6H).Example 10: Synthesis of a compound of formula F2:

[0118] In a 50mL flask was introduced E8 (1.000 g, 0.003 mol, 1 .000 eq) followed by DCM (5.0 mL). To this solution was added E9 (1.716 g, 0.006 mol, 2.000 eq) and the temperature was raised to 40°C. BOP (1 .307 g, 0.003 mol, 1 .000 eq) was added followed by Et3N (0.41 1 mL, 0.003 mol, 1 .000 eq). The solution was stirred at 40°C for 2h.

[0119] LCMS analysis after this time showed complete conversion. The reaction was quenched by addition of DCM (20 mL) and water (20 mL). Layers were separated and the organic phase was washed with water (2x30 mL) and then with 1 N HCI (2x20 mL). The organic phase was then dried over Na2SO4 and concentrated to dryness under reduced pressure to afford 1 .54g of an orange oil.

[0120] This residue was purified by chromatography over SiO2 eluting with DCM / EtOH / EtsN (95 / 5 / 0.1). Purest fractions were combined and evaporated to dryness to afford E10 as a yellowish oil.

[0121] MS (positive ESI, [M+H]+): 611.5,1H NMR (400 MHz, DMSO) (Figure 10) 5 8.05 - 7.72 (m, 1 H), 7.55 - 7.22 (m, 7H), 7.16 - 6.98 (m, 2H), 5.38 - 4.92 (m, 2H), 4.56 - 3.88 (m, 6H), 3.60 - 2.62 (m, 12H), 2.26 - 2.10 (m, 2H), 1.97 - 1 .67 (m, 4H), 1.68 - 1 .51 (m, 1 H), 0.93 - 0.74 (m, 6H).Example 11: Synthesis of a compound of formula F1 :

[0122] In a 25mL flask was introduced CBU-043-001 (0.500 g, 0.001 mol, 1 .000 eq) followed by MeOH (3.0 mL) and cone. H2SO4 (0.218 mL, 0.004 mol, 5.000 eq). The solution was stirred at 50°C for 16h.

[0123] LCMS analysis after this time showed complete conversion. The reaction was quenched by addition of DCM (10 mL) and a 2.5M K3PO4 aqueous solution (2.6 mL). Layers were separated and the organic phase was washed with water (2x10 mL) and then with 1 N HCI (2x10 mL). The organic phase was then dried over Na2SO4 and concentrated to dryness under reduced pressure to afford a yellow oil.

[0124] This residue was dissolved in MeOH (0.5 mL) and a 7M NH3 solution in MeOH was added (1.5 mL). The solution was stirred at 50°C for 24h.

[0125] LCMS analysis after this time showed complete conversion into compound of formula F1 . The solution was evaporated to dryness under reduced pressure and the residue was diluted in EtOAc (5 mL) and warmed to 50°C. The solution was stirred at 50°C for 1 h and allowed to cool to 23°C for 24h while the product crystallized. The solid was collected by filtration, washed with DIE (5 mL) and dried under vacuum at 45°C for 24h to afford compound of formula F1 (E7).

[0126] MS (positive ESI, [M+H]+): 492.4,1H NMR (400 MHz, DMSO) (Figure 11) 5 7.70 - 6.88 (m, 7H), 4.37 - 3.68 (m, 4H), 3.46 - 2.99 (m, 10H), 2.79 - 2.63 (m, 4H), 2.41 - 2.11 (m, 2H), 2.05 - 1 .43 (m, 5H), 1.10 - 0.55 (m, 6H).of formula F2:

[0127] In a 25 mL sealed glass vial, E4 (595 mg, 1 .36 mmol, 1 .00 eq), 8 (1.01 g, 2.73 mmol, 2.00 eq) and BOP (723 mg, 1 .63 mmol, 1.20 eq) were dissolved in DCM (5.0 mL). Then, TEA (474 pL, 3.41 mmol, 2.50 eq) was added and the reaction mixture was stirred at 40°C for 16 hours. LCMS analysis after this time showed complete conversion. The reaction mixture was hydrolyzed with water and diluted with DCM. Organic layer was then washed 7 times with saturated aqueous NH4CI solution, and 3 times with HCI 1 M. The organic layer was then concentrated till dryness and the residue was purified by chromatography over SiO2 eluting with DCM / MeOH / Et3N (100 / 0 / 0.1 to 95 / 5 / 0.1). Purest fractions were combined and evaporated to dryness to afford E12 as a clear oil.

[0128] MS (positive ESI, [M+H]+): 683.7, 1 H NMR (400 MHz, DMSO) (Figure 12) 5 7.73 - 7.18 (m, 7H), 7.18 - 6.91 (m, 2H), 5.36 - 4.88 (m, 2H), 4.58 - 3.61 (m, 6H), 3.50 - 2.94 (m, 10H), 2.78 (dq, J = 19.8, 7.2 Hz, 2H), 2.19 (ddt, J = 15.7, 11.6, 5.1 Hz, 2H), 1.98 - 1.68 (m, 4H), 1.68 - 1.54 (m, 1 H), 1 .45 - 1 .13 (m, 9H), 1.10 - 0.49 (m, 6H).of formula F1 :

[0129] In a 4 mL sealed glass vial, was charged E12 (35.0 mg, 0.051 mmol, 1.00 eq) followed by iPrOH (350 pL). At 25°C, 5.5 M HCI solution in iPrOH (28.0 pL, 0.154 mmol, 3.00 eq), and the reaction was warmed to 50°C for 6h. LCMS analysis after this time showed complete hydrolysis of the Boc group. The reaction mixture was evaporated under reduced pressure and the residue was then dissolved in MeOH (500 pL). Then, Ammonia 7N in solution in MeOH (44.0 pL, 1.99 mmol, 40.00 eq) was added and the reaction mixture was stirred at 50°C for 5 days. The reaction mixture was then evaporated to dryness under reduced pressure and the residue was purified by preparative TLC, eluting with DCM / MeOH 90:10 to afford compound of formula F1 (E7) as a white solid.

[0130] MS (positive ESI, [M+H]+): 492.4,1H NMR (400 MHz, DMSO) (Figure 13) 5 7.70 - 6.88 (m, 7H), 4.37 - 3.68 (m, 4H), 3.46 - 2.99 (m, 10H), 2.79 - 2.63 (m, 4H), 2.41 - 2.11 (m, 2H), 2.05 - 1 .43 (m, 5H), 1.10 - 0.55 (m, 6H).Example 14: Synthesis of a compound of formula F6:

[0131] In a 500mL round bottom flask was introduced 1-(3-aminopropyl)pyrrolidin-2-one (10.0g, 0.070 mol, 1.00 eq) followed by MeCN (360 mL). To this solution was added bromoacetonitrile (8.6 g, 0.07mol, 1.01 eq) (slight exotherm) followed by DIPEA (37.1 mL, 0.21 mol, 3.03 eq). The solution was stirred for 18h.

[0132] LCMS analysis after this time showed full conversion with formation of both mono and bisalkylated product. The solution was quenched by addition of water (50 mL) and DCM (150 mL). Layers were separated and the aqueous phase was extracted DCM (3x50 mL DCM). Combined organic phases were washed with a saturated aqueous NaCI solution (2x30 mL), dried over Na2SO4 and concentrated to dryness under reduced pressure to afford 8.5g of a yellowish oil. This residue was purified by chromatography over SiO2 eluting with DCM / EtOH / Et3N (97 / 3 / 0.1). Purest fractions were combined and evaporated to dryness to afford E14 as a colorless oil.

[0133] MS (positive ESI, [M+H]+): 182.2,1H NMR (400 MHz, DMSO) (Figure 14) 5 3.60 (s, 2H), 3.38 - 3.29 (m, 2H), 3.20 (t, J = 7.1 Hz, 2H), 2.54 - 2.49 (m, 3H), 2.21 (dd, J = 8.7, 7.5 Hz, 2H), 1.98 - 1 .86 (m, 2H), 1 .59 (p, J = 7.0 Hz, 2H).Example 15: Synthesis of a compound of formula F2:

[0134] In a 100mL round bottom flask was introduced E9 (0.750g, 0.002mol, 1.00 eq) followed by DCM (360mL). To this solution was added triethylamine (0.300mL, 0.002mol, 1.00 eq) followed by E14 (0.603g, 0.003mol, 1.50 eq). Finally, BOP (1.5g, 0.003 mol, 1.50 eq) was added to the solution followed by triethylamine (0.300 mL, 0.002 mol, 1 .00 eq). The solution was stirred at 40°C for 2h.

[0135] LCMS analysis after this time showed full conversion with. The solution was quenched by addition of water (10mL) and DCM (10mL). Layers were separated and the organic phase was washed with water (4x20mL) then with 1 N aqueous HCI (2x20mL) and finally with a saturated aqueous NaCI solution (1x20mL). The organic phase was dried over Na2SO4 and concentrated to dryness under reduced pressure to afford a yellowish oil. This residue was purified by thin layer chromatography over SiO2 eluting with DCM / EtOH / Et3N (93 / 7 / 0.1). Purest fractions were combined and evaporated to dryness to afford E15 as a colorless oil.

[0136] MS (positive ESI, [M+H]+): 502.4,1H NMR (400 MHz, DMSO) (Figure 15) 5 8.35 - 7.73 (m, 1 H), 7.45 - 6.68 (m, 4H), 5.04 - 3.84 (m, 6H), 3.60 - 2.98 (m, 10H), 2.89 - 2.72 (m, 2H), 2.24 (q, J = 8.8 Hz, 2H), 2.01 - 1.77 (m, 5H), 0.99 - 0.73 (m, 6H).Example 16: Synthesis of a compound of formula F1 :

[0137] In a 25mL round bottom flask was introduced E15 (0.50 g, 0.001 mol, 1.00 eq) followed by MeOH (3.0 mL) and cone. H2SO4 (0.22 mL, 0.004 mol, 5.00 eq). The solution was stirred at 50°C for 16h.

[0138] LCMS analysis after this time showed complete conversion into the corresponding methyl ester. The reaction was diluted with DCM (10 mL) and a 2.5M K3PO4 aqueous solution (2.6 mL) was added. Layers were separated and the organic phase was washed with water (2x10 mL) and then with 1 N HCI (2x10 mL). The organic phase was then dried over Na2SO4 and concentrated to dryness under reduced pressure to afford yellow oil.

[0139] This residue was dissolved in MeOH (0.5 mL) and a 7M NH3 solution in MeOH was added (1.5 mL). The solution was stirred at 50°C for 24h in a sealed tube.

[0140] LCMS analysis after this time showed complete conversion into compound of formula F1 (E7). The solution was evaporated to dryness under reduced pressure and the residue was diluted in EtOAc (5 mL) and warmed to 50°C. The solution was stirred at 50°C for 1 h and allowed to cool to 23°C for 24h while the product crystallized. The solid was collected by filtration, washed with DIE (5 mL) and dried under vacuum at 45°C for 24h to afford compound of formula F1 (E7).

[0141] MS (positive ESI, [M+H]+): 492.4,1H NMR (400 MHz, DMSO) (figure 16) 5 7.70 - 6.88 (m, 7H), 4.37 - 3.68 (m, 4H), 3.46 - 2.99 (m, 10H), 2.79 - 2.63 (m, 4H), 2.41 - 2.11 (m, 2H), 2.05 - 1 .43 (m, 5H), 1.10 - 0.55 (m, 6H).of formula F2:

[0142] In a 25mL round bottom flask were introduced E4 (1.00 g, 0.002 mol, 1.00 eq) and E14 (0.83 g, 0.005mol, 2.00 eq) followed by DCM (8.4 mL). To this solution was added triethylamine (0.79 mL, 0.006 mol, 2.50 eq) and BOP (1.52 g, 0.003 mol, 1 .50 eq) and the reaction was stirred at 50°C for 16h.

[0143] LCMS analysis after this time showed full conversion. The reaction was quenched by addition of water (10.0mL) and DCM (10.0mL). Layers were separated and the organic phase was washed once with water (10.0mL), then with a NH4CI saturated aqueous solution (3x1 OmL). The organic phase was washed with water (10.OmL), dried on Na2SO4 and evaporated to dryness under reduced pressure to afford a yellowish oil which was purified by chromatography on SiO2 using DCM / EtOH (96 / 4) as eluant. Purest fractions were combined and evaporated to dryness to afford E17 as a colorless oil.

[0144] MS (positive ESI, [M+H]+): 574.4,1H NMR (400 MHz, DMSO) (figure 17) 5 7.47 - 6.98 (m, 4H), 4.73 - 3.72 (m, 6H), 3.53 - 2.94 (m, 10H), 2.91 - 2.67 (m, 2H), 2.29 - 2.18 (m, 2H), 2.06 - 1 .69 (m, 5H), 1.45 - 1.16 (m, 9H), 0.94 - 0.75 (m, 6H)Example 18: Synthesis of a compound of formula F2:

[0145] In a 20mL round bottom flask was introduced E17 (0.50 g, 0.001 mol, 1.00 eq) followed by iPrOH (1 .OmL) and 5.5N HCI in iPrOH (0.50 mL, 0.003 mol, 4.50 eq). The reaction mixture was stirred at 23°C for 20h.

[0146] LCMS analysis after this time showed full conversion. Water (5. OmL) and DCM(5.0mL) were added. Layers were separated, and the aqueous layer was extracted with DCM (5x30mL), Organic layers were combined then dried over Na2SO4 and evaporated to dryness to afford E18.HCI as a colorless oil.

[0147] MS (positive ESI, [M+H]+): 474.4,1H NMR (400 MHz, DMSO) (figure 18) 5 9.16 (br, 2H), 7.42 - 7.28 (m, 2H), 7.25 - 7.05 (m, 2H), 4.87 - 3.75 (m, 6H), 3.56 - 2.84 (m, 12H), 2.32 - 2.13 (m, 2H), 1 .99 - 1 .54 t(m, 5H), 0.88 (dd, J = 21 .1 , 6.6 Hz, 6H).Example 19: Synthesis of a compound of formula F1 :

[0148] In a 8mL glass vial was charged E18 (100 mg, 0.211 mmol, 1.00 eq) followed by MeOH (1 .OmL). Then a 7M NH3 solution in MeOH was added (0.50 mL) and the reaction mixture was stirred at 40°C for 72h. After this time, the reaction mixture was cooled to 23°C and evaporated to dryness under reduced pressure. The residue was purified by chromatography on SiO2 using DCM / MeOH (98 / 2) as eluant. Purest fractions were combined and evaporated to dryness to afford compound of formula F1 (E7) as a white solid.

[0149] MS (positive ESI, [M+H]+): 492.4,1H NMR (400 MHz, DMSO) (figure 19) 5 7.70 - 6.88 (m, 7H), 4.37 - 3.68 (m, 4H), 3.46 - 2.99 (m, 10H), 2.79 - 2.63 (m, 4H), 2.41 - 2.11 (m, 2H), 2.05 - 1 .43 (m, 5H), 1.10 - 0.55 (m, 6H).of formula F24:

[0150] In a 25mL round-bottom flask was introduced 5 (0.50 g, 0.001 mol, 1 .00 eq) followed by DCM (2.3mL). Then 1-(3-aminopropyl)pyrrolidine-2-one (0.33 g, 0.002 mol, 2.00 eq) was added, followed by BOP (0.72 g, 0.002 mol, 1.40 eq) and Et3N (0.32 mL, 0.002 mol, 2.00 eq). The reaction mixture was stirred at 40°C for 16h .

[0151] LCMS analysis after this time showed complete conversion. The reaction was quenched by addition of DCM (10 mL) and water (10 mL). Layers were separated and the aqueous phase was extracted DCM (2x1 OmL). Combined organic phases were washed with a saturated aqueous NaCI solution (2x15mL), dried over Na2SO4 and concentrated to dryness under reduced pressure. The residue was purified by chromatography over SiO2 eluting with DCM / EtOH 96:4. Purest fractions were combined and evaporated to dryness to afford E20 as a colorless oil.

[0152] MS (positive ESI, [M+H]+): 535.4,1H NMR (400 MHz, DMSO) (figure 20) 5 8.05 - 7.49 (m, 1 H), 7.24 - 7.12 (m, 2H), 7.11 - 6.99 (m, 2H), 4.22 - 3.56 (m, 4H), 3.33 - 2.89 (m, 10H), 2.78 - 2.67 (m, 2H), 2.16 - 2.07 (m, 2H), 1.89 - 1.69 (m, 3H), 1.61 - 1.40 (m, 2H), 1.26 - 1 .15 (m, 9H), 1.11 - 0.59 (m, 6H).Example 21: Synthesis of a compound of formula F1 :

[0153] In a 8mL vial was introduced E20 (100 mg, 0.131 mmol, 1.00 eq) followed by THF (330 pL). □ HMDS (0.131 mL of a 1 M solution in THF, 0.131 mmol, 1 .0 eq) was added dropwise and the reaction mixture was let stirred at 23°C for 15min before methyl-bromoacetate (0.05 mL, 0.524 mmol, 4.0 eq) addition. The reaction mixture was stirred at 23°C for 18h.

[0154] The reaction was quenched by addition of DCM (5 mL) and water (5 mL). Layers were separated and the organic layer was washed once with a saturated NH4CI aqueous solution then with brine, dried over Na2SO4 and evaporated until dryness under reduce pressure to afford a colorless oil (240 mg). This crude oil was placed in a 4mL round bottom flask followed by MeOH (600 pL) and H2SO4 (70 pL). The reaction mixture was stirred at 23°C for 18h. LCMS analysis after this time showed complete Boc deprotection. The reaction was diluted with DCM (3 mL) and quenched with a 2.5 N K3PO4 aqueous solution (1 mL). Phases were separated and the organic phase was washed with brine (5mL), dried over Na2SO4 and evaporated until dryness under reduced pressure. The residue was then dissolved in MeOH (500 pL). Ammonia 7N in solution in MeOH (100 pL) was added and the reaction mixture was stirred at 50°C for 5 days. The reaction mixture was then evaporated to dryness under reduced pressure and the residue was purified by preparative TLC, eluting with DCM / MeOH 90:10 to afford compound of formula F1 (E7) as a white solid.

[0155] MS (positive ESI, [M+H]+): 492.4,1H NMR (400 MHz, DMSO) (figure 21) 5 7.70 - 6.88 (m, 7H), 4.37 - 3.68 (m, 4H), 3.46 - 2.99 (m, 10H), 2.79 - 2.63 (m, 4H), 2.41 - 2.11 (m, 2H), 2.05 - 1 .43 (m, 5H), 1.10 - 0.55 (m, 6H).of formula F20:

[0156] In a 250 mL round bottom flask was added E3 (7.00 g, 0.042 mol, 1.00 eq) followed by EtOH (50 mL). At 25°C, TEA was added (7.0 mL, 0.050 mol, 1 .20 eq) followed by a solution of BOC2O (9.1 g, 0.042 mol, 1 .00 eq) solubilized in EtOH (20 mL). The reaction solution was then stirred at 25°C for 16 hours. The reaction mixture was then concentrated till dryness under reduced pressure and the residue diluted with DCM and water. Phases were separated and the organic phase was washed with 0.05M aqueous HCI and with water. The organic layer was dried over Na2SO4, filtered, and concentrated till dryness under reduced pressure. Residual EtOH was stripped by azeotroping several times with Toluene to afford E22 as a colorless oil.

[0157] 1H NMR (400 MHz, DMSO) (figure 22) 5 12.49 (s, 1 H), 3.80 (d, J = 10.1 Hz, 2H), 3.00 (d, J = 7.2 Hz, 2H), 1 .79 (dq, J = 13.9, 6.9 Hz, 1 H), 1.37 (d, J = 16.8 Hz, 9H), 0.83 (dd, J = 6.6, 4.7 Hz, 6H).of formula F28:

[0158] In a 250 mL round bottom single neck flask was charged E22 (4.00 g, 17.3 mmol, 1 .00 eq), E8.HBr (6.42 g, 17.3 mmol, 1.00 eq) followed by DCM (80 mL). At 25°C, Et3N (7.2 mL, 52 mmol, 3.00 eq) was added, followed by BOP (1 1.47 g, 26 mmol, 1.50 eq). The reaction mixture was then stirred at 40°C for 2 hours and then at 25°C for 16 hours. LCMS analysis showed almost complete conversion after this time.

[0159] The reaction mixture was then hydrolyzed with a 1 M aqueous NaHCOs solution. Phases were separated and the organic layer was washed with water and concentrated till dryness to afford an orange oil. The residue was solubilized in 2-MeTHF / Heptane 85:15. The organic layer was warmed to 55°C and washed with water twice. The organic layer was then concentrated till dryness and the residue was purified by column chromatography on SiO2 eluting with DCM / EtOAc first and then with DCM / MeOH. Purest fractions were combined and concentrated to afford E23 as a yellow liquid.

[0160] MS (positive ESI, [M+H]+): 504.5,1H NMR (400 MHz, DMSO) (figure F23) 5 7.52 - 7.12 (m, 5H), 5.38 - 4.96 (m, 2H), 4.60 - 3.73 (m, 4H), 3.57 - 3.07 (m, 6H), 3.05 - 2.75 (m, 2H), 2.31 - 2.1 1 (m, 2H), 1 .97 - 1 .53 (m, 5H), 1 .45 - 1 .25 (m, 9H), 0.90 - 0.71 (m, 6H).Example 24: Synthesis of a compound of formula F3:

[0161] In a 500 mL flask was introduced 2-(2-fluorophenyl)ethan-1 -amine (5.6 mL, 0.043 mol, 1.00 eq) followed with H2O (36.0 mL), IPA (9.0 mL) and formic acid (2.58 mL, 0.060 mol, 1 .40 eq). Formic acid addition led to an exotherm and internal temperature reached 33°C. After cooling at 25°C, was added dropwise in 15min a glyoxylic acid (11 .9 g, 0.130 mol, 3.00 eq) solution in H2O (18.0 mL) (no exotherm observed) and reaction was stirred at 50°C for 18 hours. The suspension was allowed to slowly come back at 23°C and was stirred for 1 h at 23°C. The solid was collected by filtration, washed with water and dried under vacuum at 45°C overnight to afford E24 as a white solid.

[0162] MS (positive ESI, [M+H]+): 226.2,1H NMR (400 MHz, DMSO) (figure 24) 5 12.77 (s, 1 H), 7.85 (s, 1 H), 7.42 - 7.20 (m, 3H), 7.23 - 6.96 (m, 3H), 3.98 (s, 2H), 3.54 (t, J = 7.0 Hz, 2H), 2.86 (t, J = 7.0 Hz, 2H).Example 25: Synthesis of a compound of formula F2:

[0163] In a 25 mL round bottom flask was charged E23 (310 mg, 0.616 mmol, 1.000 eq) followed by iPrOH (1 .5 mL). At 25°C, HCI 5.5 N solution in iPrOH (448 pL, 2.46 mmol, 4.000 eq) was added and the reaction solution was stirred at 50°C for 1 hour and then at 23°C for 16 hours. The reaction mixture was then concentrated to dryness under reduced pressure. The residue was suspended in DCM (5.0 mL) and E24 (57.6 mg, 0.256 mmol, 1 .000 eq) was added followed by BOP (169.6 mg, 0.384 mmol, 1.500 eq). The reaction mixture was heated at 40°C, and EtaN (142 pL, 1.023 mmol, 4.000 eq) was added. The reaction mixture was stirred at 40°C for 1 h. LCMS analysis showed complete conversion after this time. The reaction mixture was hydrolyzed with water, phases were separated, and the organic layer was washed with water, dried over Na2SO4 filtered and concentrated till dryness under reduced pressure. The residue was purified by chromatography over SiO2 eluting with DCM I EtOH 95:5 to afford E10 as a white solid.

[0164] MS (positive ESI, [M+H]+): 611.5,1H NMR (400 MHz, DMSO) (figure 25) 5 8.05 - 7.72 (m, 1 H), 7.55 - 7.22 (m, 7H), 7.16 - 6.98 (m, 2H), 5.38 - 4.92 (m, 2H), 4.56 - 3.88 (m, 6H), 3.60 - 2.62 (m, 12H), 2.26 - 2.10 (m, 2H), 1.97 - 1 .67 (m, 4H), 1.68 - 1 .51 (m, 1 H), 0.93 - 0.74 (m, 6H).Example 26: Synthesis of a compound of formula F28:

[0165] In a 25 mL round bottom flask, was loaded E14 (380 mg, 2.09 mmol, 1.00 eq) and E22 (485 mg, 2.09 mmol, 1 .00 eq) followed by DCM (3.8 mL) and BOP (1.39 g, 3.14 mmol, 1.50 eq). The reaction mixture was warmed to 40°C and Et3N (0.58 mL, 4.193 mmol, 2.00 eq) was added. The reaction mixture was then stirred at 40°C for 2 hours.

[0166] LCMS analysis showed complete conversion after this time. The reaction mixture was hydrolyzed with a 1 N aqueous NaHCOs solution water and phases were separated. The organic layer was washed a 1 M HCI solution, then with water and evaporated to dryness under reduced pressure. The residue was purified by chromatography over SiO2 eluting with DCM / EtOAc 50:50 and then DCM / EtOH 95:5. Purest fractions were combined and evaporated to dryness under reduced pressure to afford E26 as a yellow oil.

[0167] MS (positive ESI, [M+H]+): 395.4,1H NMR (400 MHz, DMSO) (figure 26) 5 4.80 - 4.28 (m, 2H), 4.04 (d, J = 15.0 Hz, 2H), 3.51 - 3.10 (m, 6H), 3.06 - 2.81 (m, 2H), 2.23 (t, J = 8.0 Hz, 2H), 2.07 - 1 .61 (m, 5H), 1 .36 (d, J = 25.7 Hz, 9H), 0.85 (d, J = 2.9 Hz, 6H).of formula F27:

[0168] In a 100 mL round bottom flask, was loaded E14 (3.15 g, 17.38 mmol, 1.00 eq) followed by DCM (31.5 mL). At 25°C, EtaN (3.1 mL, 22.59 mmol, 1.30 eq) was added followed by chloroacetyl chloride (1 .4 mL, 17.38 mmol, 1 .000 eq). The reaction mixture was then stirred at 25°C for 1 hour.

[0169] LCMS analysis showed complete conversion after this time. The reaction mixture was hydrolyzed with water and phases were separated. The organic layer was washed with water and then concentrated in a rotary evaporator till dryness to afford E27 as an orange oil, which crystallizes overtime.

[0170] MS (positive ESI, [M+H]+): 258.3,1H NMR (400 MHz, DMSO) (figure 27) 5 4.98 - 4.08 (m, 4H), 3.58 - 3.27 (m, 4H), 3.21 (t, J = 6.8 Hz, 2H), 2.23 (t, J = 8.0 Hz, 2H), 1.93 (p, J = 7.4 Hz, 2H), 1.88 - 1.59 (m, 2H).Example 28: Synthesis of a compound of formula F2:

[0171] In a 8 mL glass vial was charged E26 (550.0 mg; 1.39 mmol; 1.00 eq) followed iPrOH (5.0 mL). At 25°C, 5-6N HCI in iPrOH (1.0 mL; 5.6 mmol; 4.00 eq) was added and reaction solution was heated up to 40°C for 16 hours.

[0172] LCMS analysis showed complete conversion after this time. The reaction mixture was evaporated to dryness under reduced pressure to afford a pale yellow oil (448 mg). The residue was solubilized in DCM (5.0 mL) and E24(343 mg, 1.522 mmol, 1.00 eq) and BOP (1.00 g, 2.283 mmol, 1 .50 eq) were added. This solution was then heated near 40°C, and EtaN (423 pL; 3.043 mmol; 2.000 eq) was added. The reaction mixture was stirred at 40°C for 1 h. LCMS analysis showed complete conversion after this time. The reaction mixture was concentrated till dryness, diluted with 2-MeTHF, and washed with a saturated aqueous NaHCOs solution. The organic layer was concentrated till dryness to afford an orange oily residue, which was purified by chromatography over SiO2 eluting with DCM I EtOAc 1 / 1 to afford E15 as a colorless oil.

[0173] MS (positive ESI, [M+H]+): 502.4,1H NMR (400 MHz, DMSO) (figure 28) 5 8.35 - 7.73 (m, 1 H), 7.45 - 6.68 (m, 4H), 5.04 - 3.84 (m, 6H), 3.60 - 2.98 (m, 10H), 2.89 - 2.72 (m, 2H), 2.24 (q, J = 8.8 Hz, 2H), 2.01 - 1.77 (m, 5H), 0.99 - 0.73 (m, 6H).Example 29: Synthesis of a compound of formula F2:

[0174] In a 100 mL round bottom flask was charged E27 (3.20 g; 12 mmol; 1.00 eq) followed by MeCN (25.0 mL). To this solution was then added EtaN (2.1 mL; 15 mmol; 1.20 eq) followed few minutes later by isobutylamine (1 .4 mL; 14 mmol; 1.10 eq). The reaction mixture was stirred at 23°C for 18 hours.

[0175] LCMS analysis showed complete conversion after this time. The reaction mixture was concentrated under reduced pressure to a low volume and diluted with 2-MeTHF and water. Phases were separated and the organic layer was washed with water. Aqueous layers were combined and extracted 3 times with DCM / EtOH 80:20. Organic layers (2-MeTHF and DCM / EtOH) were combined, dried over Na2SO4 and evaporated to dryness under reduced pressure to afford a brown oil (2.2 g).

[0176] 400mg of this crude compound were solubilized in DCM (5.0 mL). At 25°C, EtaN (420 pL; 3.020 mmol) was added, followed by Chloroacetyl chloride (110 pL; 1.379 mmol). This solution was stirred at 25°C for 30 minutes. LCMS analysis showed complete conversion after this time. The reaction mixture was hydrolyzed with water and phases were separated. The organic phase was dried over Na2SO4 and evaporated to dryness under reduced pressure to afford a brown oil (550 mg). This residue was solubilized in MeCN (2.5 mL). At 25°C, EtaN (155 pL; 1.1 12 mmol) was added, followed by a solution of 2-(2-fluorophenyl)ethan-1 -amine (97 pL ; 0.741 mmol) in MeCN (1.3 mL). The reaction mixture was then stirred at 25°C for 16 hours. LCMS analysis showed complete conversion after this time. The reaction mixture was then evaporated under reduced pressure tilldryness and the residue was diluted with 2-MeTHF and washed with an aqueous NaHCOs solution. The organic phase was dried over Na2SO4 and evaporated to dryness under reduced pressure to afford an oily orange residue which was purified by chromatography over SiO2 eluting with DCM / EtOH 9:1 to afford E18 as a colorless oil.

[0177] MS (positive ESI, [M+H]+): 474.4,1H NMR (400 MHz, DMSO) (figure 29) 6 7.38 - 7.18 (m, 2H), 7.18 - 7.07 (m, 2H), 4.92 - 4.02 (m, 4H), 3.56 - 2.96 (m, 11 H), 2.79 - 2.59 (m, 3H), 2.22 (t, J = 8.0 Hz, 2H), 2.05 - 1 .53 (m, 5H), 0.84 (dd, J = 23.9, 6.6 Hz, 6H).

Claims

Claims

1. A process for synthesizing a compound of formula F1 :wherein:R1 is phenyl substituted with halogen or trifluoromethyl, and further optionally substituted with one or two substituents selected from the group consisting of halogen, (Ci-Ce)alkyl, (Ci-Ce) alkoxy, and halo(Ci-Ce)alkyl; or alternatively R1 is py rrolidin-1 -yl;R2 is 2-oxo-pyrrolidin-1-ylmethyl or sulfamoylphenyl; andRa is selected from the group consisting of propyl, 1 -methylethyl, butyl, 2-methylpropyl, pentyl, 1 - methyl-butyl, 2- methylbutyl, hexyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, and 1- methylpentyl; comprising the steps of:(S1) synthesizing a compound of formula F2:F2 wherein R4 is hydrogen atom, or a protecting group selected from the group consisting of Boc, Fmoc and formyl, and R5is -CN, -C(O)NHCH2Ph or -C(O)OR6, Re being -CH3, -CH2CH3;jPr; -‘Bu, -H, or - Benzyl,(52) if R4 is a protecting group, removing said protecting group,(53) amidifying R5.

2. Process according to claim 1 , wherein step (S1) comprises the following successive sub steps:(S1-1 a) reacting a compound of formula F3 with a compound of formula F4:F3 F4wherein R7 being -CH3, -CH2CH3; 'Pr; -‘Bu, -H, or -Benzyl, resulting in a compound of formula F5F5(S1-1 b) reacting F5 with a compound of formula F6resulting in a compound of formula F2.

3. Process according to claim 1 , wherein step (S1) comprises the following successive sub steps:(S1-1 aa) reacting a compound of formula F3 with a compound of formula F7:wherein Rs being -CH3, -CH2CH3; 'Pr; -‘Bu, -H, or -Benzyl, resulting in a compound of formula F8(S1-1 ab) reacting F8 with a compound or formula F9,R3X3F9 wherein X is a halogen atom, resulting in a compound of formula F10(S1-1 ac) if Rs is different from H, and R7 is H, hydrolyzing F10 resulting in a compound of formula F5F5(S1-1 b) reacting F5 with a compound or formula F6F6.

4. Process according to any one of claims 2 and 3, wherein compound of formula F6 is synthesized by reacting a compound of formula F11 with a compound of formula F12F11 F12 wherein X is a halogen atom.

5. Process according to any one of claims 2 to 4, wherein compound of formula F3 is synthesized by reacting a compound of formula F13 with a compound of formula F14F13 F14 wherein X is a halogen atom, and wherein R9 being -CH3, -CH2CH3; 'Pr; -‘Bu, -H, or -Benzyl, resulting in a compound of formula F15,F15 protecting the amine function of said compound of formula F15 with a protecting group selected from the group consisting of, Boc, Fmoc and formyl, resulting in a compound of formula F16F16 optionally hydrolyzing the ester group of the compound of F16.

6. Process according to claim 1 , wherein step (S1) comprises the following successive sub steps:(S1-2a) reacting a compound of formula F17 with a compound of formula F3:

7. Process according to claim 1 , wherein step (S1) comprises the following successive sub steps:(S1-3a) reacting a compound of formula F17 with a compound of formula F18:F17 F18 resulting in a compound of formula F19F19 reacting F19 with a compound of formula F13:F13

8. Process according to anyone of claims 6 and 7, wherein compound of formula F17 is synthesized by reacting a compound of formula F6 with a compound of formula F20wherein R? is a protecting group selected from the group consisting of BOC, FMOC, formyl and benzyl, andremoving said protecting group.

9. Process according to anyone of claims 6 and 7, wherein compound of formula F17 is synthesized by reacting a compound of formula F6 with a compound of formula F18resulting in a compound of formula F21reacting F21 with a compound of formula F22F22

10. A Compound of formula F23:F23 and salts thereof, wherein R10 is -H or isobutyl; and R4 is hydrogen atom, or a protecting group selected from the group consisting of Boc and Fmoc.

11. A Compound of formula F24:F24 and salts thereof; whereinR11 is -H or -CH2R5;R5is -CN, -C(O)NHCH2Ph or -C(O)OR6, Re being -CH3, -CH2CH3; Pr; -‘Bu, -H, or -Benzyl;and R4 is hydrogen atom, or a protecting group selected from the group consisting of Boc and Fmoc.

12. A Compound of formula F25:F25 and salts thereof.

13. A Compound of formula F26:and salts thereof; wherein R5 is -CN, -C(O)NHCH2Ph or -C(O)ORe, Re being -CH2CH3; 'Pr; -‘Bu or - Benzyl.

14. A compound of formula F27:and salts thereof; wherein R5 is -CN, -C(O)NHCH2Ph or -C(O)ORe, Re being -CH3, -CH2CH3; 'Pr; - ‘Bu, -H, or -Benzyl.

15. A compound of formula F28:F28 and salts thereof; wherein R5 is -CN, -C(O)NHCH2Ph or -C(O)ORe, Re being -CH3, -CH2CH3; 'Pr; - ‘Bu, -H, or -Benzyl, and wherein R12 is a hydrogen atom, BOC, FMOC, formyl, Bn or COCH2CI.

16. A Compound of formula F29:F29 and salts thereof; wherein R5 is -CN, -C(O)NHCH2Ph or -C(O)ORe, Re being -CH2CH3; 'Pr; -‘Bu or - Benzyl.

17. A Compound of formula F30:F30 and salts thereof; wherein Re is -CN, -C(O)NHCH2Ph or -C(O)ORe, Re being -CH3, -CH2CH3; 'Pr; - ‘Bu, -H, or -Benzyl.

Images