Pyrrolopyrazine compounds and their use in therapy

Abstract

The present invention relates to compounds of formula (I), wherein R1 to R11 are as defined in the description, to pharmaceutical compositions containing said compounds, and to the use of said compounds as medicaments, in particular for the treatment or prevention of cancers or fibrosis related diseases.

Description

[0001] Pyrrolopyrazine compounds and their use in therapy

[0002] Field of the invention

[0003] The present disclosure relates to compounds that modulate the YAP / TAZ-TEAD complex, to pharmaceutical compositions containing said compounds, and to the use of said compounds as medicaments, in particular for the treatment and / or prevention of cancers and / or fibrosis related diseases.

[0004] Background

[0005] The hippo signalling pathway has key roles in organ size control and tumor suppression. Signal transduction in the hippo signalling pathway involves a core kinase cascade, leading to YAP / TAZ phosphorylation. Physiological or pathological inactivation of the hippo signalling pathway leads to dephosphorylation and nuclear accumulation of YAP and / or TAZ. Nuclear YAP / TAZ binds to transcriptional enhanced associate domains (TEADs) to mediate target gene expression. The YAP / TAZ-TEAD complex regulates organ development and amplification of oncogenic factors in many cancers (e.g., sarcoma, lung cancer, thyroid cancer, skin cancer, ovarian cancer, colorectal cancer, prostate cancer, pancreatic cancer, esophageal cancer, liver cancer, breast cancer) and in fibrosis related diseases. There is a need to find inhibitors of the Hippo signalling pathway useful as medicaments.

[0006] The present invention provides new compounds that modulate the Hippo signalling pathway.

[0007] Summary of the invention

[0008] The present disclosure relates to a compound of formula (I) or a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, solvate, isotope substituent, polymorph, prodrug or metabolite thereof: wherein: Ri, R2, R3, R4, R5, Re, R7, Rs, R9, R10, R11, W, X and Y are as defined below.

[0009] The present disclosure also relates to a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, solvate, isotope substituent, polymorph, prodrug or metabolite thereof and one or more pharmaceutically acceptable excipients.

[0010] The present disclosure also relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof for use as a medicament.

[0011] The present disclosure also relates to a compound of formula (I) for use in the treatment and / or prevention of a cancer and / or fibrosis related diseases.

[0012] The present disclosure also relates to a method of treatment and / or prevention of a cancer and / or fibrosis related diseases, which comprises administering to a subject in need thereof an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, solvate, isotope substituent, polymorph, prodrug or metabolite thereof.

[0013] Description of the invention

[0014] In one aspect, the present disclosure relates to a compound of formula (I) or a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, solvate, isotope substituent, polymorph, prodrug or metabolite thereof: wherein:

[0015] X is C or N;

[0016] Y is C or N;

[0017] W is C or N;

[0018] R1 and R2are each independently H; a (Ci-C6)alkyl optionally substituted by a (C C4)alkoxy, CN, or CONRI2RI3; a (C2-C4)alkenyl; or R1 and R2are bound together to form a (C3-C6)cycloalkyl or a 5- to 7-membered heterocycle;

[0019] R3, R4and R5, when present, are each independently H, halogen or a (Ci-C4)alkoxy; R6is H; a (Ci-C6)alkyl optionally substituted with OH, COOH, CONH2, a (Ci-C4)alkoxy optionally substituted with OH or a (Ci-C4)alkoxy, or an aryl; an optionally substituted 5- or 6-membered heterocycle; a (C3-C6)cycloalkyl;

[0020] R7, R8, R9and R are each independently H; a (Ci-C6)alkyl optionally substituted with one or more substituents selected from OH, halogen, CF3and CN; halogen; CONRI2RI3; SO2(RI4); SO(RI4); CN; CF3; or CORI2;

[0021] R11 is H; a (Ci-C6)alkyl optionally substituted by a group selected from: OH, halogen, (C C4)alkoxy, CN, COOH, CONR12R13, COOR15, an optionally substituted phenyl, and an optionally substituted 5- or 6-membered heteroaryl; or -(CH2)mCORi6;

[0022] RI2and R are each independently H or a (Ci -C4)alkyl ;

[0023] RI4is a (Ci-C4)alkyl;

[0024] R15 is a (Ci-C4)alkyl;

[0025] RI6is a (Ci-C4)alkyl; m = 0, 1 or 2.

[0026] As used herein, the term “alkyl” means a linear or branched hydrocarbon moiety having the mentioned number of carbon atoms. In some embodiments, an alkyl comprises one to six carbon atoms (e.g., Ci-C6alkyl). In some embodiments, an alkyl comprises one to four carbon atoms (e.g., Ci-C4alkyl). In some embodiments, the alkyl group is selected from methyl, ethyl, propyl, 2-propyl, butyl, 2-methylpropyl, 2-butyl, tert-butyl, pentyl, 1 ,1 - dimethylpropyl, 2,2-dimethylpropyl, 3-methylbutyl, 1 -methylbutyl, 1 -ethylpropyl, 1 ,2- dimethylpropyl, 1 -methylethyl (isopropyl), 1 -butyl (n-butyl), 1 -methylpropyl (sec-butyl), pentyl or hexyl. The alkyl is attached to the rest of the molecule by a single bond. Unless stated otherwise specifically in the specification, an alkyl group is optionally substituted by one or more of the following substituents: halogen, -CN, -NO2, =0, =S, =NH, =NOH and cycloalkyl.

[0027] As used herein, the term “alkoxy” means a group -O-alkyl where alkyl is as defined above.

[0028] As used herein, the term “alkenyl” means a hydrocarbon moiety containing a carboncarbon double bond and having the mentioned number of carbon atoms, including ethenyl (aka vinyl), propenyl, 1 -butenyl or 2-butenyl.

[0029] As used herein, the term “cycloalkyl” means a 3- to 6-membered hydrocarbon cycle, which can be bridged, including cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

[0030] As used herein, the term “halogen” means F, Cl, Br or I, preferably F, Br or Cl.

[0031] As used herein, the term “5- or 6-membered heterocycle” means a saturated monocycle comprising from 1 to 3 heteroatoms, preferably 1 or 2 heteroatoms, chosen from nitrogen, oxygen and sulfur. Examples include the following groups: pyrrolidinyl, tetrahydrofuryl, tetrahydrothienyl, pyrrolidinyl, imidazolidinyl, thiazolidinyl, isoxazolidinyl, piperidinyl, piperazinyl, morpholinyl, or thiomorpholinyl.

[0032] As used herein, the term “5- to 7-membered heterocycle” means a saturated monocycle comprising from 1 to 3 heteroatoms, preferably 1 or 2 heteroatoms, chosen from nitrogen, oxygen and sulfur. Examples include the following groups: pyrrolidinyl, tetrahydrofuryl, tetrahydrothienyl, pyrrolidinyl, imidazolidinyl, thiazolidinyl, isoxazolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl or thiazepinyl.

[0033] As used herein, the term “5- or 6-membered heteroaryl” means an unsaturated or partially unsaturated monocycle comprising from 1 to 3 heteroatoms, preferably 1 or 2 heteroatoms, chosen from nitrogen, oxygen and sulfur. Examples include the following groups: pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, triazolyl, oxadiazolyl, furanyl, thienyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, tetrazolyl or dihydro(is)oxazolyl.

[0034] The “5- or 6-membered heterocycle” and the 5- or 6-membered heteroaryl” can optionally be substituted by one or more substituents selected from alkyl, alkoxy and halogen groups as defined above.

[0035] As used herein, the term "aryl" denotes an aromatic group comprising 5 to 16 atoms, in particular 5 or 6 atoms. Said aromatic group possibly comprising atoms other than carbon atoms, in particular N, O or S. An aryl group therefore also encompasses heteroaryl compounds. Phenyl, naphthyl, pyridyl and furanyl are examples of aryl groups encompassed herein. Said aryl groups may optionally be substituted with 1 or more substituents.

[0036] As used herein, the term "prodrug" is meant to indicate a compound that is converted under physiological conditions or by solvolysis to a biologically active compound described herein. Thus, the term "prodrug" refers to a precursor of a biologically active compound that is pharmaceutically acceptable. In some embodiments, a prodrug is inactive when administered to a subject, but is converted in vivo to an active compound, for example, by hydrolysis. The prodrug compound often offers advantages of solubility, tissue compatibility or delayed release in a mammalian organism. The term "prodrug" is also meant to include any covalently bonded carriers, which release the active compound in vivo when such prodrug is administered to a mammalian subject. In some embodiments, prodrugs of an active compound, as described herein, are prepared by modifying functional groups present in the active compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent active compound. As used herein, the term "solvate" refers to an aggregate of molecules comprising one or more compounds of the present disclosure and one or more solvent molecules. The solvent may be water, in which case the solvate may be a hydrate. Alternatively, the solvent may be an organic solvent. Thus, the compounds of the present disclosure may exist as hydrates, including monohydrate, dihydrate, hemihydrate, sesquihydrate, trihydrate, tetrahydrate, and the like, and as corresponding solvated forms. The disclosed compounds may be true solvates, while in other cases, the disclosed compounds may only remain in water or a mixture of water plus some solvent.

[0037] The compounds disclosed herein, or pharmaceutically acceptable salts thereof, may contain one or more chiral carbon atoms, and thus may yield enantiomers, diastereomers, and other stereoisomeric forms. Each chiral carbon atom may be defined as (R)-or (s)- based on stereochemistry. Unless stated otherwise, it is intended that all stereoisomeric forms of the compounds disclosed herein are contemplated by this disclosure. When the compounds described herein contain alkene double bonds, and unless specified otherwise, it is intended that this disclosure includes both E and Z geometric isomers (e.g., cis or trans). Likewise, all possible isomers, as well as their racemic and optically pure forms, and all tautomeric forms are also intended to be included. The term "geometric isomer" refers to E or Z geometric isomers (e.g., cis or trans) of an alkene double bond. The disclosure is intended to include all possible isomers, as well as racemates and optically pure forms thereof. The preparation of the compounds disclosed herein may select racemates, diastereomers or enantiomers as starting materials or intermediates. Optically active isomers may be prepared using chiral synthesizers or chiral reagents, or resolved using conventional techniques, such as crystallization and chiral chromatography.

[0038] Conventional techniques for preparing / separating individual isomers include chiral synthesis from suitable optically pure precursors or using chiral reagents / catalysts, separation of racemates / diastereoisomers (or racemates / diastereoisomers of salts or derivatives) using, for example, chiral high-performance liquid chromatography, chiral Supercritical Fluid chromatography (SFC) or recrystallization

[0039] As used herein, the term "stereoisomer" refers to a compound consisting of the same atom, bonded by the same bond, but having a different three-dimensional structure. The present disclosure will cover various stereoisomers and mixtures thereof.

[0040] As used herein, the term "tautomer" refers to a molecule wherein a proton shift from one atom of a molecule to another atom of the same molecule is possible. The compounds presented herein, in certain embodiments, exist as tautomers. In circumstances where tautomerization is possible, a chemical equilibrium of the tautomers will exist. The exact ratio of the tautomers depends on several factors, including physical state, temperature, solvent, and pH. All tautomeric forms of the compounds disclosed herein will also be included within the scope of the present disclosure.

[0041] The present disclosure also encompasses all suitable isotopic substitutions (or isotopic variations) of the compounds of the present disclosure, or pharmaceutically acceptable salts thereof. Isotopic variations of the compounds disclosed herein, or pharmaceutically acceptable salts thereof, are defined as those in which at least one atom is replaced by an atom having the same number of atoms but different in atomic mass from that found frequently in nature. Isotopes that may be incorporated into the compounds of the present disclosure and pharmaceutically acceptable salts thereof include, but are not limited to, isotopes of H, C, N, and O, such as2H,3H,11C,13C,14C,15N,17O,180,35S,18F,36CI, and125l. Isotopic variations of the compounds described herein, may be prepared by conventional techniques using suitable isotopic variations of suitable reagents.

[0042] As used herein, unless otherwise specified, wavy lines on each structural formula or group generally indicate where the structural formula or group is attached to other moieties in the compound.

[0043] As used herein, the terms "crystalline form" and "polymorph" are used interchangeably and refer to crystalline structures in which a compound (or a salt, enantiomer, diastereomer, tautomer, solvate, isotope substituent, polymorph, prodrug or metabolite) can crystallize in different crystal stacking arrangements (all having the same elemental composition). Different crystal forms generally have different X-ray diffraction patterns, infrared spectra, melting points, density hardness, crystal shape, optical and electrical properties, stability and solubility. Recrystallization solvents, crystallization rates, storage temperatures, or other factors may lead to dominance of one of the crystal forms. Polymorphs of compounds can be prepared by crystallization under different conditions.

[0044] As used herein, the term "metabolite" refers to derivatives that are also pharmacologically active resulting from the metabolic process of the parent pharmaceutical active ingredient in a subject, for example, such metabolites may result from oxidation, reduction, hydrolysis, amidation, deamidation, esterification, enzymatic cleavage, and the like of the administered compound or salt or prodrug.

[0045] In the context of the present disclosure, the various embodiments described herein can be combined.

[0046] In some embodiments, W is C and R3is H.

[0047] In some embodiments, X is C and R5is H.

[0048] In some embodiments, Y is C and R4is H. In some embodiments, Ri and R2are each independently H or a (Ci-C6)alkyl optionally substituted by a (Ci-C4)alkoxy or by CN, preferably the alkyl is a (Ci-C4)alkyl.

[0049] In some embodiments, R6is a (Ci-C6)alkyl, preferably a (Ci-C4)alkyl.

[0050] In some embodiments, R7, R9and R10are each H.

[0051] In some embodiments, R8is CN.

[0052] In some embodiments, Rn is H; a (Ci-C6)alkyl optionally substituted by a group selected from: OH, CN, CONR12R13 and a 5-membered heteroaryl; or -CH2CORI6; and RI2, R13 and RI6are as defined above.

[0053] In some embodiments, the compound of formula (I) is selected from:

[0054] 5-[(E)-[ethyl-(6-methylpyrrolo[1 ,2-a]pyrazin-1 -yl)hydrazono]methyl]-3,3-dimethyl-isoindolin-

[0055] 1-one;

[0056] 5-[(E)-[[6-(difluoromethyl)pyrrolo[1 ,2-a]pyrazin-1 -yl]-ethyl-hydrazono]methyl]-3,3-dimethyl- isoindolin-1 -one;

[0057] 5-[(E)-[ethyl-[6-(hydroxymethyl)pyrrolo[1 ,2-a]pyrazin-1 -yl]hydrazono]methyl]-3,3-dimethyl- isoindolin-1 -one;

[0058] 2-[1 -[[(E)-(3,3-dimethyl-1 -oxo-isoindolin-5-yl)methyleneamino]-ethyl-amino]pyrrolo[1 ,2- a]pyrazin-6-yl]acetonitrile;

[0059] 5-[(E)-[ethyl-(6-fluoropyrrolo[1 ,2-a]pyrazin-1-yl)hydrazono]methyl]-3,3-dimethyl-isoindolin-

[0060] 1-one;

[0061] 5-[(E)-[(6-chloropyrrolo[1 ,2-a]pyrazin-1-yl)-ethyl-hydrazono]methyl]-3,3-dimethyl- isoindolin-1 -one;

[0062] 1 -[[(E)-(3,3-dimethyl-1 -oxo-isoindolin-5-yl)methyleneamino]-ethyl-amino]pyrrolo[1 ,2- a]pyrazine-6-carboxamide;

[0063] 5-[(E)-[ethyl-(6-methylsulfonylpyrrolo[1 ,2-a]pyrazin-1 -yl)hydrazono]methyl]-3,3-dimethyl- isoindolin-1 -one;

[0064] 5-[(E)-[ethyl-(4-methylsulfinylpyrrolo[1 ,2-a]pyrazin-1-yl)hydrazono]methyl]-3,3-dimethyl- isoindolin-1 -one;

[0065] 2-[1 -[[(E)-(3,3-dimethyl-1 -oxo-isoindolin-5-yl)methyleneamino]-ethyl-amino]pyrrolo[1 ,2- a]pyrazin-4-yl]acetonitrile;

[0066] 1 -[[(E)-(3,3-dimethyl-1 -oxo-isoindolin-5-yl)methyleneamino]-ethyl-amino]-7-methyl- pyrrolo[1 ,2-a]pyrazine-6-carbonitrile;

[0067] 1 -[[(E)-(3,3-dimethyl-1 -oxo-isoindolin-5-yl)methyleneamino]-ethyl-amino]pyrrolo[1 ,2- a]pyrazine-6-carbonitrile;

[0068] 1 -[[(E)-(3,3-dimethyl-1 -oxo-isoindolin-5-yl)methyleneamino]-ethyl-amino]-4-methyl- pyrrolo[1 ,2-a]pyrazine-6-carbonitrile; 8-bromo-1 -[[(E)-(3,3-dimethyl-1 -oxo-isoindolin-5-yl)methyleneamino]-ethyl- amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile;

[0069] 8-chloro-1 -[[(E)-(3,3-dimethyl-1 -oxo-isoindolin-5-yl)methyleneamino]-ethyl- amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile;

[0070] 1 -[[(E)-(3,3-dimethyl-1 -oxo-isoindolin-5-yl)methyleneamino]-ethyl-amino]-8-fluoro- pyrrolo[1 ,2-a]pyrazine-6-carbonitrile;

[0071] 1 -[[(E)-(3,3-dimethyl-1 -oxo-isoindolin-5-yl)methyleneamino]-methyl-amino]pyrrolo[1 ,2- a]pyrazine-6-carbonitrile;

[0072] 1 -[[(E)-(3,3-dimethyl-1 -oxo-isoindolin-5-yl)methyleneamino]-isopropyl-amino]pyrrolo[1 ,2- a]pyrazine-6-carbonitrile;

[0073] 1 -[[(E)-(3,3-dimethyl-1 -oxo-isoindolin-5-yl)methyleneamino]-(2-hydroxyethyl) amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile;

[0074] 1 -[[(E)-(3,3-dimethyl-1 -oxo-isoindolin-5-yl)methyleneamino]-(3-hydroxypropyl) amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile;

[0075] 1 -[[(E)-(3,3-dimethyl-1 -oxo-isoindolin-5-yl)methyleneamino]-(4- hydroxybutyl)amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile;

[0076] 1 -[[(E)-(3,3-dimethyl-1 -oxo-isoindolin-5-yl)methyleneamino]-(2- methoxyethyl)amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile;

[0077] 1 -[[(E)-(3,3-dimethyl-1 -oxo-isoindolin-5-yl)methyleneamino]-(2-isopropoxyethyl) amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile;

[0078] 1 -[[(E)-(3,3-dimethyl-1 -oxo-isoindolin-5-yl)methyleneamino]-(3- methoxypropyl)amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile;

[0079] 1 -[[(E)-(3,3-dimethyl-1 -oxo-isoindolin-5-yl)methyleneamino]-tetrahydrofuran-3-yl- amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile;

[0080] 1 -[[(E)-(3,3-dimethyl-1 -oxo-isoindolin-5-yl)methyleneamino]-[2-(2- methoxyethoxy)ethyl]amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile;

[0081] 1 -[[(E)-(3,3-dimethyl-1 -oxo-isoindolin-5-yl)methyleneamino]-[2-(2- hydroxyethoxy)ethyl]amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile;

[0082] 5-[(6-cyanopyrrolo[1 ,2-a]pyrazin-1 -yl)-[(E)-(3,3-dimethyl-1 -oxo-isoindolin-5- yl)methyleneamino]amino]pentanoic acid;

[0083] 1 -[cyclopropyl-[(E)-(3,3-dimethyl-1 -oxo-isoindolin-5-yl)methyleneamino]amino]pyrrolo[1 ,2- a]pyrazine-6-carbonitrile;

[0084] 1 -[ethyl-[(E)-[6-(2-hydroxyethyl)-5,5-dimethyl-7-oxo-pyrrolo[3,4-b]pyridin-3- yl]methyleneamino]amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile;

[0085] 1 -[ethyl-[(E)-(2,3,3-trimethyl- 1 -oxo-isoindolin-5-yl)methyleneamino]amino]pyrrolo[1 ,2- a]pyrazine-6-carbonitrile; 1-[[(E)-(2-benzyl-3,3-dimethyl-1 -oxo-isoindolin-5-yl)methyleneamino]-ethyl- amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile;

[0086] 1-[ethyl-[(E)-[2-(3-hydroxypropyl)-3,3-dimethyl-1-oxo-isoindolin-5- yl]methyleneamino]amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile;

[0087] 1-[ethyl-[(E)-[2-(4-hydroxybutyl)-3,3-dimethyl-1-oxo-isoindolin-5- yl]methyleneamino]amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile;

[0088] 1-[ethyl-[(E)-[2-(2-isopropoxyethyl)-3,3-dimethyl-1 -oxo-isoindolin-5- yl]methyleneamino]amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile;

[0089] 1-[ethyl-[(E)-[2-(4-methoxybutyl)-3,3-dimethyl-1-oxo-isoindolin-5- yl]methyleneamino]amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile;

[0090] 1-[[(E)-[2-(cyanomethyl)-3,3-dimethyl-1 -oxo-isoindolin-5-yl]methyleneamino]-ethyl- amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile;

[0091] 1-[[(E)-[2-(2-cyanoethyl)-3,3-dimethyl-1 -oxo-isoindolin-5-yl]methyleneamino]-ethyl- amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile;

[0092] 1-[[(E)-(2-acetonyl-3,3-dimethyl-1 -oxo-isoindolin-5-yl)methyleneamino]-ethyl- amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile;

[0093] 4-[6-[(E)-[(6-cyanopyrrolo[1 ,2-a]pyrazin-1-yl)-ethyl-hydrazono]methyl]-1 ,1-dimethyl-3-oxo- isoindolin-2-yl]butanoic acid;

[0094] 4-[6-[(E)-[(6-cyanopyrrolo[1 ,2-a]pyrazin-1-yl)-ethyl-hydrazono]methyl]-1 ,1-dimethyl-3-oxo- isoindolin-2-yl]butan amide; isopropyl 2-[6-[(E)-[(6-cyanopyrrolo[1 ,2-a]pyrazin-1-yl)-ethyl-hydrazono]methyl]-1 ,1- dimethyl-3-oxo-isoindolin-2-yl]acetate;

[0095] 2-[6-[(E)-[(6-cyanopyrrolo[1 ,2-a]pyrazin-1-yl)-ethyl-hydrazono]methyl]-1 ,1-dimethyl-3-oxo- isoindolin-2-yl]acetamide;

[0096] 2-[6-[(E)-[(6-cyanopyrrolo[1 ,2-a]pyrazin-1-yl)-ethyl-hydrazono]methyl]-1 ,1-dimethyl-3-oxo- isoindolin-2-yl]-N-methyl-acetamide;

[0097] 3-[6-[(E)-[(6-cyanopyrrolo[1 ,2-a]pyrazin-1-yl)-ethyl-hydrazono]methyl]-1 ,1-dimethyl-3-oxo- isoindolin-2-yl]propanamide;

[0098] 1-[[(E)-[3,3-dimethyl-1-oxo-2-(2-pyridylmethyl)isoindolin-5-yl]methyleneamino]-ethyl- amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile;

[0099] 1-[[(E)-[3,3-dimethyl-2-(oxazol-2-ylmethyl)-1-oxo-isoindolin-5-yl]methyleneamino]-ethyl- amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile;

[0100] 1-[[(E)-[3,3-dimethyl-1-oxo-2-(thiazol-2-ylmethyl)isoindolin-5-yl]methyleneamino]-ethyl- amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile;

[0101] 1-[[(E)-[3,3-dimethyl-1-oxo-2-(thiazol-4-ylmethyl)isoindolin-5-yl]methyleneamino]-ethyl- amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile; 1 -[[(E)-[3,3-dimethyl-1 -oxo-2-(thiazol-5-ylmethyl)isoindolin-5-yl]methyleneamino]-ethyl- amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile;

[0102] 1 -[ethyl-[(E)-[2-( 1 H-imidazol-2-ylmethyl)-3,3-dimethyl-1 -oxo-isoindolin-5- yl]methyleneamino]amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile;

[0103] 1 -[[(E)-[3,3-dimethyl-1 -oxo-2-(1 H-tetrazol-5-ylmethyl)isoindolin-5-yl]methyleneamino]- ethyl-amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile;

[0104] 1 -[ethyl-[(E)-( 1 -oxoisoindolin-5-yl)methyleneamino]amino]pyrrolo[1 ,2-a]pyrazine-6- carbonitrile;

[0105] 1 -(1 -Ethyl-2-((3-methyl-1 -oxoisoindolin-5-yl)methylene)hydrazineyl)pyrrolo[1 ,2-a]pyrazine- 6-carbonitrile;

[0106] 1 -(2-((3,3-Diethyl- 1 -oxoisoindolin-5-yl)methylene)-1 -ethylhydrazineyl)pyrrolo[1 ,2- a]pyrazine-6-carbonitrile;

[0107] 1 -(2-((3- Allyl- 1 -oxoisoindolin-5-yl)methylene)-1 -ethylhydrazineyl)pyrrolo[1 ,2-a]pyrazine-6- carbonitrile;

[0108] 1 -[[(E)-[3,3-bis(methoxymethyl)-1 -oxo-isoindolin-5-yl]methyleneamino]-ethyl- amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile;

[0109] 1 -[[(E)-[3,3-bis(2-methoxyethyl)-1 -oxo-isoindolin-5-yl]methyleneamino]-ethyl- amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile;

[0110] 1 -[ethyl-[(E)-(3-ethyl- 1 -oxo-isoindolin-5-yl)methyleneamino]amino]pyrrolo[1 ,2-a]pyrazine- 6-carbonitrile;

[0111] 1 -[ethyl-[(E)-( 1 -oxo-3-propyl-isoindolin-5-yl)methyleneamino]amino]pyrrolo[1 ,2-a]pyrazine- 6-carbonitrile;

[0112] 1 -[ethyl-[(E)-(3-isopropyl-1 -oxo-isoindolin-5-yl)methyleneamino]amino]pyrrolo[1 ,2- a]pyrazine-6-carbonitrile;

[0113] 1 -[ethyl-[(E)-[3-(methoxymethyl)-1 -oxo-isoindolin-5-yl]methyleneamino]amino]pyrrolo[1 ,2- a]pyrazine-6-carbonitrile;

[0114] 1 -[[(E)-[3-(cyanomethyl)-1 -oxo-isoindolin-5-yl]methyleneamino]-ethyl-amino]pyrrolo[1 ,2- a]pyrazine-6-carbonitrile;

[0115] 1 -[ethyl-[(E)-(6-fluoro-3,3-dimethyl-1 -oxo-isoindolin-5- yl)methyleneamino]amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile;

[0116] 1 -[ethyl-[(E)-(4-fluoro-3,3-dimethyl-1 -oxo-isoindolin-5- yl)methyleneamino]amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile;

[0117] 1 -[ethyl-[(E)-(4-methoxy-3,3-dimethyl-1 -oxo-isoindolin-5- yl)methyleneamino]amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile;

[0118] 1 -[[(E)-(5,5-dimethyl-7-oxo-6H-pyrrolo[3,4-b]pyridin-3-yl)methyleneamino]-ethyl- amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile; 2-[6-[(E)-[(6-cyanopyrrolo[1 ,2-a]pyrazin-1 -yl)-ethyl-hydrazono]methyl]-7-methoxy-1 ,1 - dimethyl-3-oxo-isoindolin-2-yl]acetamide; and pharmaceutically acceptable salts thereof.

[0119] In some embodiments, the compound of formula (I) is selected from:

[0120] 1 -[[(E)-(3,3-dimethyl-1 -oxo-isoindolin-5-yl)methyleneamino]-ethyl-amino]pyrrolo[1 ,2- a]pyrazine-6-carbonitrile;

[0121] 1 -[ethyl-[(E)-[6-(2-hydroxyethyl)-5,5-dimethyl-7-oxo-pyrrolo[3,4-b]pyridin-3- yl]methyleneamino]amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile;

[0122] 1 -[ethyl-[(E)-(2,3,3-trimethyl- 1 -oxo-isoindolin-5-yl)methyleneamino]amino]pyrrolo[1 ,2- a]pyrazine-6-carbonitrile;

[0123] 1 -[ethyl-[(E)-[2-(3-hydroxypropyl)-3,3-dimethyl-1 -oxo-isoindolin-5-yl]methylene amino]amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile;

[0124] 1 -[[(E)-[2-(2-cyanoethyl)-3,3-dimethyl-1 -oxo-isoindolin-5-yl]methyleneamino]-ethyl- amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile;

[0125] 1 -[[(E)-(2-acetonyl-3,3-dimethyl-1 -oxo-isoindolin-5-yl)methyleneamino]-ethyl- amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile;

[0126] 2-[6-[(E)-[(6-cyanopyrrolo[1 ,2-a]pyrazin-1 -yl)-ethyl-hydrazono]methyl]-1 ,1 -dimethyl-3-oxo- isoindolin-2-yl]acetamide;

[0127] 2-[6-[(E)-[(6-cyanopyrrolo[1 ,2-a]pyrazin-1 -yl)-ethyl-hydrazono]methyl]-1 ,1 -dimethyl-3-oxo- isoindolin-2-yl]-N-methyl-acetamide;

[0128] 1 -[[(E)-[3,3-dimethyl-2-(oxazol-2-ylmethyl)-1 -oxo-isoindolin-5-yl]methylene amino]-ethyl- amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile;

[0129] 1 -[[(E)-[3,3-dimethyl-1 -oxo-2-(thiazol-2-ylmethyl)isoindolin-5-yl]methylene amino]-ethyl- amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile;

[0130] 1 -(1 -Ethyl-2-((3-methyl-1 -oxoisoindolin-5-yl)methylene)hydrazineyl)pyrrolo[1 ,2-a]pyrazine- 6-carbonitrile;

[0131] 1 -[[(E)-[3,3-bis(methoxymethyl)-1 -oxo-isoindolin-5-yl]methyleneamino]-ethyl- amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile ;

[0132] 1 -[[(E)-[3-(cyanomethyl)-1 -oxo-isoindolin-5-yl]methyleneamino]-ethyl-amino] pyrrolo[1 ,2- a]pyrazine-6-carbonitrile;

[0133] 1 -[ethyl-[(E)-(4-methoxy-3,3-dimethyl-1 -oxo-isoindolin-5-yl)methyleneamino] amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile;

[0134] 2-[6-[(E)-[(6-cyanopyrrolo[1 ,2-a]pyrazin-1 -yl)-ethyl-hydrazono]methyl]-7-methoxy-1 ,1 - dimethyl-3-oxo-isoindolin-2-yl]acetamide; and pharmaceutically acceptable salts, enantiomers, diastereomers, tautomers, solvates, isotope substituents, polymorphs, prodrugs or metabolites thereof. Pharmaceutically acceptable salts of the compounds of formula (I) can be formed from acids or bases which form non-toxic salts. Examples of pharmaceutically acceptable acids suitable as source of anions are those disclosed in the Handbook of Pharmaceutical Salts: Properties, Selection and Use (P. H. Stahl and C. G. Wermuth, Weinheim / Zurich:Wiley- VCH / VHCA, 2002).

[0135] The compounds of formula (I) can be administered in the form of a pharmaceutical composition. Accordingly, in one aspect, the present disclosure relates to a pharmaceutical composition comprising a compound of formula (I) or one of its pharmaceutically acceptable salts, enantiomer, diastereomer, tautomer, solvate, isotope substituent, polymorph, prodrug or metabolite thereof. In certain embodiments, the compound of formula (I) as described herein is substantially pure, in that it contains less than about 5%, or less than about 1%, or less than about 0.1%, of other organic small molecules, such as contaminating intermediates or by-products that are created, for example, in one or more of the steps of a synthesis method. Administration in vivo may be by any routes, including oral, parenteral, topical, buccal, parenteral (e.g. intramuscular, subcutaneous, intradermal, or intravenous), intranasal, sublingual, intratracheal, inhalation, ocular, vaginal and rectal routes. The most suitable form of administration in any given case will depend on the degree and severity of the condition being treated and on the nature of the particular compound being used. For example, disclosed compositions are formulated as a unit dose, and / or are formulated for oral or subcutaneous administration. Depending on the intended mode of in vivo administration, said composition may be in a solid dosage form, a semi-solid dosage form or a liquid dosage form, the list being not limitative. In some embodiments, the pharmaceutical composition is a solid dosage form. Exemplary solid dosage forms include tablets, capsules, stick-packs, dragees, sachets, lozenges, powders, pills, or granules. Preferred solid dosage forms include tablets, capsules and stick-packs, tablets being especially preferred.

[0136] In some embodiments, the pharmaceutical composition is a liquid dosage form. Exemplary liquid dosage forms include emulsions, microemulsions, solutions, suspensions, syrups and elixirs.

[0137] Advantageously, the compositions are administered in unit dosage forms suitable for single administration of precise dosage amounts.

[0138] The pharmaceutical compositions may also include, depending on the formulation desired, one or more pharmaceutically acceptable excipient(s). The choice of excipient(s) will to a large extent depend on factors such as the particular mode of administration, the effect of the excipient on solubility and stability, and the nature of the dosage form. The pharmaceutical compositions of the invention can be prepared by conventional methods, as described e.g. in Remington’s Pharmaceutical Sciences, 19thEdition (Mack Publishing Company, 1995), incorporated herein by reference. In some embodiments, the pharmaceutical compositions comprise a compound of formula (I) as defined above, or a pharmaceutically acceptable, enantiomer, diastereomer, tautomer, solvate, isotope substituent, polymorph, prodrug or metabolite thereof, and one or more pharmaceutically acceptable excipients.

[0139] In some embodiments, the pharmaceutical composition comprises from 0.01 mg to 1000 mg of compound of formula (I) or a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, solvate, isotope substituent, polymorph, prodrug or metabolite thereof.

[0140] In some embodiments, the pharmaceutical composition further comprises at least one other active pharmaceutical ingredient or its derivatives, prodrugs, solvates, tautomers or stereoisomers thereof as well as the pharmaceutically acceptable salts of each of the foregoing, including mixtures thereof in all ratios, wherein the at least one other active pharmaceutical ingredient is other than a compound of formula (I); preferably, at least one other active pharmaceutical ingredient is a compound that is useful in the treatment, prevention, suppression and / or amelioration of medicinal conditions or pathologies for which the compounds of the present invention are useful as well and which are listed elsewhere hereinbefore or hereinafter.

[0141] In some embodiments, the at least one other active pharmaceutical ingredient is selected from KRAS inhibitors, SHP2 inhibitors, EGFR inhibitors, PI3K inhibitors, MEK inhibitors, ERK inhibitors, MDM2 inhibitors, Raf inhibitors, CDK4 / 6 inhibitors, cMET inhibitors, chemotherapeutic agent, radiotherapeutic treatment, immunotherapy agent, immunotherapy drug based on oncolytic viruses and a combination thereof.

[0142] As used herein, the term “chemotherapeutic agent” includes, for example, alkylating agents such as nitrogen mustards, alkylsulfonates, nitrosoureas, triazines, ethylenimines and platinum derivatives; antimetabolites such as 5-fluorouracil (5-FU), 6-mercaptopurine (6-MP), cytarabine, capecitabine, fludarabine, gemcitabine, methotrexate, pemetrexed, pentostatin and thioguanine; anthracyclines, such as doxorubicin, daunorubicin, idarubicin and epirubicin; topoisomerase inhibitors, such as topotecan, irinotecan, etoposide and teniposide; mitotic spindle inhibitors, such as plant alkaloids and taxanes; and hormonal agents, such as corticosteroid hormones and sex hormones, the list of chemotherapeutic agent being not limitative.

[0143] Non-limiting examples of nitrogen mustards are chlorambucil, cyclophosphamide, ifosfamide, and melphalan. Non-limiting example of alkylsulfonates is busulfan. Non- limiting examples of nitrosoureas are streptozotocin, carmustine, and lomustine. Nonlimiting example of triazines is dacarbazine. Non-limiting examples of ethylenimines are thiotepa and altretamine. Non-limiting examples of platinum derivatives are cisplatin, carboplatin and oxaliplatin. Non-limiting examples of plant alkaloids are vinblastine, vincristine and vinorelbine. Non-limiting examples of taxanes are paclitaxel and docetaxel. Non-limiting examples of corticosteroid hormones are prednisone, methylprednisolone and dexamethasone. Non-limiting examples of sex hormones are tamoxifen and leuprolide.

[0144] As used herein, "radiotherapeutic treatment" may consist of gamma-radiation, X-ray radiation, electrons or photons, external radiotherapy or curitherapy. As used herein, the term "radiotherapeutic treatment”, is also intended to refer to any radiotherapeutic treatment known to one of skill in the art to be effective to treat or ameliorate cancer, without limitation. For instance, the radiotherapeutic treatment can be an agent such as those administered in brachytherapy or radionuclide therapy. Such methods can optionally further comprise the administration of one or more additional cancer therapies, such as, but not limited to, chemotherapies. For instance, the radiotherapeutic treatment can include radioligand therapy, such as for example but without limitations lutecium-177 (Lu177), vipivotide tetraxetan, andibritumomab tiuxetan.

[0145] Examples of immunotherapy agents include without limitations monoclonal antibodies, antibody-drug conjugates, bispecific antibodies, immunoconjugates, checkpoint modulators, cytokines and photoimmunotherapy.

[0146] Examples of immunotherapy drug based on oncolytic viruses include without limitations T- VEC (Imlygic®), and other oncolityc virus such as for example: adenovirus, herpes simplex virus, maraba virus, measles, newcastle disease virus, picornavirus, reovirus, vaccinia virus and vesicular stomatitis virus.

[0147] Such combination of two or more active pharmaceutical ingredients may be safer or more effective than either compound of formula (I) alone, or the combination is safer or more effective than it would be expected based on the additive properties of the individual drugs (at least one other active pharmaceutical ingredient and compound of formula (I)). Such at least one other active pharmaceutical ingredient may be administered, by a route and in an amount commonly used contemporaneously or sequentially with a compound of formula (I) of the invention. When a compound of formula (I) of the invention is used contemporaneously with at least one other active pharmaceutical ingredient, a combination product containing such at least one other active pharmaceutical ingredient and the compound of formula (I) of the invention - also referred to as “fixed dose combination” - is preferred. However, combination therapy also includes therapies in which the compound of formula (I) of the present invention and at least one other active pharmaceutical ingredient are administered on different overlapping schedules. It is contemplated that when used in combination with at least one other active pharmaceutical ingredient, the compound of formula (I) of the present invention or the at least one other active pharmaceutical ingredient or both may be used effectively in lower doses than when each is used alone. Accordingly, the pharmaceutical compositions of the present invention include those that contain at least one other active pharmaceutical ingredient, in addition to a compound of formula (I) of the invention. The compounds of formula (I) of the present invention - or any pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, solvate, isotope substituent, polymorph, prodrug or metabolite thereof - can be used as medicaments.

[0148] Consequently, in one aspect, the present disclosure relates to a medicament which comprises a compound according to the invention or a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, solvate, isotope substituent, polymorph, prodrug or metabolite thereof and at least one of the active pharmaceutical ingredients described above as combination partners, optionally together with one or more pharmaceutical acceptable excipients.

[0149] The compounds of formula (I) of the invention or pharmaceutically acceptable salts, enantiomers, diastereomers, tautomers, solvates, isotope substituents, polymorphs, prodrugs or metabolite thereof, and the additional active pharmaceutical ingredient to be combined therewith may both be present together in one formulation, for example a tablet or capsule, or separately in two identical or different formulations, for example as so- called kit-of-parts.

[0150] The compounds of formula (I) or pharmaceutically acceptable salts, enantiomers, diastereomers, tautomers, solvates, isotope substituents, polymorphs, prodrugs or metabolites thereof can be used in therapy.

[0151] In one aspect the present disclosure relates to a compound of formula (I) as defined above, or a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, solvate, isotope substituent, polymorph, prodrug or metabolite thereof, for use as a medicament.

[0152] In one aspect the present disclosure relates to a compound as defined above, or a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, solvate, isotope substituent, polymorph, prodrug or metabolite thereof, for use in the treatment or prevention of a cancer.

[0153] In one aspect, the present disclosure relates to the use of a compound as defined above, or a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, solvate, isotope substituent, polymorph, prodrug or metabolite thereof, in the manufacture of a medicament intended for the treatment or prevention of a cancer.

[0154] In one aspect, the present disclosure relates to a method of treating or preventing a cancer in a patient, comprising administering to the patient, a therapeutically effective amount of a compound of formula (I) as defined above, or a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, solvate, isotope substituent, polymorph, prodrug or metabolite thereof.

[0155] In one aspect, the present disclosure relates to a compound of formula (I) as defined above, or a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, solvate, isotope substituent, polymorph, prodrug or metabolite thereof for use in a method of treating or preventing cancer in a patient, the method comprising administering to the patient, a therapeutically effective amount of a compound of formula (I) as defined above, or a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, solvate, isotope substituent, polymorph, prodrug or metabolite thereof.

[0156] In one aspect, the present disclosure relates to a pharmaceutical composition comprising a compound of formula (I) as defined above, or a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, solvate, isotope substituent, polymorph, prodrug or metabolite thereof for use in therapy.

[0157] In one aspect, the present disclosure relates to a pharmaceutical composition comprising a compound of formula (I) as defined above, or a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, solvate, isotope substituent, polymorph, prodrug or metabolite thereof, for use as a medicament.

[0158] In one aspect, the present disclosure relates to a pharmaceutical composition comprising a compound of formula (I) as defined above, or a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, solvate, isotope substituent, polymorph, prodrug or metabolite thereof, for use in a method for the treatment or prevention of a cancer.

[0159] In one aspect, the present disclosure relates to the use of a pharmaceutical composition comprising a compound of formula (I) as defined above, or a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, solvate, isotope substituent, polymorph, prodrug or metabolite thereof, in the manufacture of a medicament intended for the treatment or prevention of a cancer.

[0160] In one aspect, the present disclosure relates to a method of treating or preventing a cancer in a patient, comprising administering to the patient a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) as defined above, or a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, solvate, isotope substituent, polymorph, prodrug or metabolite thereof. In one aspect, the present disclosure relates to a pharmaceutical composition comprising a compound of formula (I) as defined above, or a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, solvate, isotope substituent, polymorph, prodrug or metabolite thereof for use in a method of treating or preventing cancer in a patient, the method comprising administering to the patient a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) as defined above, or a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, solvate, isotope substituent, polymorph, prodrug or metabolite thereof.

[0161] In some embodiments, the pharmaceutical composition further comprises at least one other active pharmaceutical ingredient selected from KRAS inhibitors, SHP2 inhibitors, EGFR inhibitors, PI3K inhibitors, MEK inhibitors, ERK inhibitors, MDM2 inhibitors, Raf inhibitors, CDK4 / 6 inhibitors, cMET inhibitors, chemotherapeutic agent, radiotherapeutic treatment, immunotherapy agent, immunotherapy drug based on oncolytic viruses and a combination thereof.

[0162] In embodiments that involve administering to a patient a compound of formula (I) as defined above, or a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, solvate, isotope substituent, polymorph, prodrug or metabolite thereof, the expressions “effective amount”, "therapeutically effective amount", "amount effective to treat" or “pharmaceutically effective amount” denote the amount of compound of formula (I) as defined above, or a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, solvate, isotope substituent, polymorph, prodrug or metabolite thereof, which is needed to inhibit or reverse a disease condition (e.g., to treat cancer or fibrosis related diseases). Determining an effective amount specifically depends on such factors as toxicity and efficacy of the medicament. These factors will differ depending on other factors such as potency, relative bioavailability, patient body weight, severity of adverse side-effects and preferred mode of administration. Toxicity may be determined using methods well known in the art. Efficacy may be determined utilizing the same guidance. An effective amount, therefore, is an amount that is deemed by the clinician to be toxicologically tolerable, yet efficacious. This amount can be a fixed dose for all subjects being treated, or can vary depending upon the physical condition of the subject to be treated, a professional assessment of the medical situation, and other relevant factors.

[0163] As used herein, the term “treatment” or “treating” refers to any process, action, application, therapy, or the like, wherein the patient is under aid, in particular, medical, or veterinarian aid with the object of improving the patient's condition, in particular leading to a cure or a treatment which alleviates, improves and / or eliminates, reduces and / or stabilizes the symptoms of a disease or the suffering that it causes, either directly or indirectly.

[0164] As used herein, the term “prevent”, "prevention" or "prophylaxis" or "preventive treatment" or "prophylactic treatment" includes a treatment leading to the prevention of a disease as well as a treatment reducing and / or delaying the incidence of a disease or the risk of the disease occurring.

[0165] As used herein, “patient” or “subject” refers to a human individual or an animal different from a human. The patient is for example a human or an animal liable to have cancer and / or fibrosis related disease or suffering from such diseases. The patient is advantageously a human being. The patient may be a child (human patient aged 18 or under) or an adult (human patient over 18). In another embodiment, the subject is a nonhuman animal including, but are not limited to dog, cat, guinea pig, rabbit, rat, mouse, horse, cattle, bear, cow, ape, monkey, orangutan, and chimpanzee, and so on. In the context of the present disclosure the terms “patient” and “subject” are used interchangeably

[0166] In some embodiments, the cancer is a solid tumor. In some embodiments, the cancer is a liquid tumor. In some embodiments, the cancer is selected from: lip cancer, tongue cancer, oral cavity cancer, salivary gland cancer, tonsils cancer, mouth cancer, nasal cancer, oesophagus cancer, stomach cancer, small intestine cancer, colon cancer, rectum cancer, liver cancer, gallbladder cancer, bile ducts cancer, pancreas cancer, larynx cancer, lung cancer, bronchi cancer, trachea cancer, thymus cancer, cardiac cancer, thoracic cancer, pleural cancer, bone cancer, bone marrow cancer, mesothelioma, peripheral nerves cancer, peritoneum cancer, breast cancer, cervix cancer, uterus cancer, ovary cancer, placenta cancer, vaginal cancer, vulva cancer, penis cancer, prostate cancer, testicle cancer, kidney cancer, renal pelvis cancer, urinary bladder cancer, eye cancer, brain cancer, spinal cord cancer, cranial nerves cancer, neck cancer, thyroid cancer, adrenal gland cancer, muscle cancer, bladder cancer, soft tissues cancer (such as tendons, cartilage, fat) and any cancer related to blood cells or their progenitors.

[0167] In one aspect the present disclosure relates to a compound of formula (I) as defined above, or a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, solvate, isotope substituent, polymorph, prodrug or metabolite thereof, for use in a method for the treatment or prevention of fibrosis related diseases.

[0168] In one aspect, the present disclosure relates to the use of a compound of formula (I) as defined above, or a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, solvate, isotope substituent, polymorph, prodrug or metabolite thereof, in the manufacture of a medicament intended for the treatment or prevention of fibrosis related diseases.

[0169] In one aspect, the present disclosure relates to a method of treating or preventing a fibrosis related disease in a patient, comprising administering to the patient an effective amount of a compound of formula (I) as defined above, or a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, solvate, isotope substituent, polymorph, prodrug or metabolite thereof.

[0170] In one aspect the present disclosure relates to a pharmaceutical composition comprising a compound of formula (I) as defined above, or a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, solvate, isotope substituent, polymorph, prodrug or metabolite thereof, for use in a method for the treatment or prevention of a fibrosis related disease.

[0171] In one aspect, the present disclosure relates to the use of a pharmaceutical composition comprising a compound of formula (I) as defined above, or a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, solvate, isotope substituent, polymorph, prodrug or metabolite thereof, in the manufacture of a medicament intended for the treatment or prevention of a fibrosis related disease.

[0172] In one aspect, the present disclosure relates to a method of treating or preventing a fibrosis related disease in a patient, comprising administering to the patient a pharmaceutical composition comprising an effective amount of a compound of formula (I) as defined above, or a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, solvate, isotope substituent, polymorph, prodrug or metabolite thereof.

[0173] In some embodiments, fibrosis related diseases include, without limitations, skin fibrosis (such as for example hypertrophic scar or systemic sclerosis), heart fibrosis (such as for example cardiac fibrosis, hypertrophic cardiomyopathy, valvular diseases), bone marrow fibrosis (such as for example myelofibrosis, myelodysplatic syndrome), liver fibrosis (such as for example non-alcoholic steatohepatitis, cirrhosis, portal hypertension), retroperitoneum fibrosis, gut fibrosis (such as for example intestinal fibrosis, Inflammatory bowel disease, enteropathies), joint fibrosis (such as for example arthrofibrosis), brain fibrosis (such as glial scar), nervous system fibrosis, eye fibrosis (such as for example subretinal fibrosis, epiretinal fibrosis, vision loss), lung fibrosis (such as for example idiopathic pulmonary fibrosis, cystic fibrosis, pulmonary hypertension, emphysema), mediastinum fibrosis, pancreas fibrosis (such as for example pancreatic fibrosis, cystic fibrosis, chronic pancreatitis, duct obstruction) and kidney fibrosis (such as for example renal fibrosis, cystic fibrosis, nephrogenic systemic fibrosis, chronic kidney disease). In some embodiments, the doses of the composition comprising at least one compound of formula (I) as described herein differ, depending upon the patient's (e.g., human) condition, that is, stage of the disease, general health status, age, and other factors that a person skilled in the medical art will use to determine dose. In some instances, pharmaceutical compositions are administered in a manner appropriate to the disease to be treated as determined by skilled practitioner. An appropriate dose and a suitable duration and frequency of administration will be determined by such factors as the condition of the patient, the type and severity of the patient's disease, the particular form of the active ingredient, and the method of administration. In general, an appropriate dose and treatment regimen provides the composition(s) in an amount sufficient to provide therapeutic and / or prophylactic benefit (e.g., an improved clinical outcome, such as more frequent complete or partial remissions, or longer disease-free and / or overall survival, or a lessening of symptom severity) Optimal doses are generally determined using experimental models and / or clinical trials. In some embodiments, the optimal dose depends upon the body mass, weight, or blood volume of the patient and on the activity of the compound of formula (I) - or pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, solvate, isotope substituent, polymorph, prodrug or metabolite thereof.

[0174] The compounds of the invention can be prepared using the synthetic reactions illustrated in schemes I, II, III. Starting materials are commercially available or can be prepared by procedures described herein (schemes IV, V VI), by literature procedures, or by procedures well known to those skilled in the art of organic chemistry.

[0175] In scheme I, step a, an aldehyde (commercially available or prepared following scheme IV) in solution in alcohol or THF is reacted with hydrazine (commercially available or prepared following schemes V, VI) in the presence or not of an organic or mineral base (such as e.g. sodium acetate, triethylamine, sodium hydrogencarbonate, potassium carbonate ) (for example, Kurian et al., Bioorg. Med. Chem. Lett., 2014, 24(17), 41764180; Loghmani-Khouzani et al., J. Chem. Res. Syn., 2001 , (2), 80-81 ). In step b, the hydrazono derivative (obtained in step a) and a halogeno heterocycle (commercially available or prepared ones) can react together using or not an organic or mineral base (for example, Haffner et al., Bioorg. Med. Chem. Lett., 2010, 20(23), 6989-92; Haffner et al., Bioorg. Med. Chem. Lett., 2010, 20(23), 6983-88).

[0176] Scheme I

[0177] In scheme II, step a, aromatic substitution of a halogeno heterocycle (commercially available or prepared) with hydrazine (commercially available or prepared following schemes V, VI) may be done in similar conditions as described in scheme I step b. In step b, the heterocycle-hydrazine derivatives obtained in step a are reacted with an aldehyde (commercially available or prepared following schemes IV) under similar conditions as described in scheme I, step a.

[0178] Scheme II In scheme III, N-alkylation of lactames (prepared using transformations described in schemes I or II) may be done in THF or DMF, by formation of the anion using NaH, □HMDS, or KHMDS as base followed by addition of commercially available halogeno- derivatives.

[0179] Scheme III

[0180] Scheme IV described the preparation of aldehyde synthons. In step a, the protection of commercially available, or synthesized bromo-isoindolone is done either by a Boc or a PMB group using a classical method described in “Protective groups in organic chemistry” (T. W. Greene, Wiley, third edition). In step b, mono or di-alkylation can be performed with the corresponding halogeno-derivative in THF or DMF, using either NaH, NaHMDS or □HMDS as base. In the step d, cleavage of the Boc protecting group is done in acidic medium (such as HCI / Dioxane or TFA) and cleavage of the PMB protecting group is done using ceric ammonium nitrate in a mixture of acetonitrile and water (see “Protective groups in organic chemistry” - T. W. Greene, Wiley, third edition). The formation of the aldehyde can be done either by direct formylation of the bromo derivative or in two steps via an allyl group. In step d, formylation is performed, first by lithiation of the bromoderivative in THF with butyl-lithium followed by addition of DMF (as formylating agent). In step e, Stille reaction is done using classical conditions in dioxane with tributyl(vinyl)tin in the presence of a Pd catalyst. In step f, oxidation is done with RuCI3and NalO4. The final aldehyde can also be obtained by, first the formation of the formyl group starting from the compound obtained in step b, using the same conditions (e and f) as described above, followed by cleavage of the protecting group using the same conditions as described above (c) Scheme IV

[0181] Non-commercially available hydrazines can be obtained either using scheme V or scheme VI. In scheme V, step a, alkylation of bi-protected hydrazine is performed in acetonitrile with the corresponding halogeno-derivative using potassium carbonate as base and in the presence of an ammonium salt (such as butyl-triethyl ammonium chloride....). In step b, the phthaloyl group is cleaved with methylhydrazine in THF. In step c, BOC deprotection is done in acidic medium (like HCI / dioxane, TFA...).

[0182] Scheme V

[0183] In scheme VI, the desired alkyl-hydrazine is obtained by direct alkylation of hydrazine with the corresponding halogeno-derivative in propanol using a large excess of hydrazine. Scheme VI LI H2N-N H2- - H2N-N

[0184] R6

[0185] The present disclosure is illustrated by the following examples.

[0186] EXPERIMENTAL PROCEDURES

[0187] ABBREVIATIONS

[0188] AcOEt = ethyl acetate ; AcOH = Acetic acid; AIBN = Azobisisobutyronitrile; aq. = Aqueous; aq. sat. = Aqueous saturated; Boc = t-Butoxycarbonyl; Boc20 = Di-tert-butyl- dicarbonate; br = broad; BSA = Bovine serum albumin; BTEAC Benzyltriethylammoniumchloride; n-BuLi = n-Butyllithium ; CCI4= Tetrachloromethane; CDCI3= Chloroform deutered; CHCI3= chloroform; CsF = Cesium fluoride; CV : column volume; d = Doublet; DBll = 1 ,8-Diazabicyclo[5.4.0]undec-7-ene; DCE = 1 ,2- Dichlororethane; DCM = 1 ,2-Dichloromethane; DNPH = 2,4-Dinitrophenylhydrazine; dd = Doublet of doublets; DIPEA = Diisopropylethylamine; DMAP = 4-Dimethylaminopyridine; DMF = N,N-Dimethylformamide; DMSO = Dimethyl-sulfoxide; Edll = 5-Ethynyl-2’- deoxyuridine; eq = Equivalent(s); Etl = lodoethane; EtOAc = Ethyl acetate; Et2O = Ethylether; EtOH = Ethanol; Et3SiH = Triethylsilane; g = Gram(s); h = Hour(s); HATLI = O-(7- azabenzotriazol-1 -yl)-N,N,N’,N’-tetramethyluronium hexafluorophosphate; HCI Hydrochloric acid; Hz = Hertz; HOAt = 1-hydroxy-7-azabenzotriazole; HCOOH = formic acid; KCN = Potassium cyanide; K2CO3= Potassium carbonate; LC / MS = Liquid chromatography / mass spectrometry; LiHMDS = Lithium bis(trimethylsilyl)amide; m = Multiplet; MeCN = Acetonitrile; Mel = lodomethane; MeOH = Methanol; mg = Milligram; MgSO4= Magnesium sulfate; min = Minute(s); mmol = Millimole; mp = Melting point; MW = Microwave; N = Normal; NaCI = Sodium chloride; NaH = Sodium hydride; NaHCO3= Sodium bicarbonate; NaBH4= Sodium borohydride; Na2CO3= Sodium carbonate; NalO4= Sodium periodate; NaOH = Sodium hydroxide; Na2SO4= Sodium sulfate; Na2S2O3= Sodium thiosulfate; Na2S2O5= sodium metabisulfite; NBS = N-bromosuccinimide; NCS = N-Chlorosuccinimide; NH3= Ammonia; NH4CI = Ammonium chloride; NMR = Nuclear magnetic resonance; Patm: atmospheric pressure; PBS = Phosphate buffered saline; Pd / C = Palladium on carbon; Pd(dppf)CI2= Dichloro[1 ,T- bis(diphenylphosphino)ferrocene]palladium (II); Pd(PPh3)4

[0189] Tetrakis(triphenylphosphlne)palladium(0); PFA = Paraformaldehyde; POCI3= phosphoryl chloride; ppm = Parts per million; q = Quadruplet; quant = Quantitative; quint = Quintuplet; Rt = Retention time; rt = Room temperature; s = singlet; sept = septuplet; sext = sextuplet; t = triplet; TBAF = Tetrabutylammonium fluoride; td = triplet of doublets; TEA = Triethylamine; TFA = Trifluoroacetic acid; THF = Tetrahydrofuran; LIPLC = Ultra Performance Liquid Chromatography.

[0190] Analytical and semi-preparative Methods

[0191] Example 1 : 5-[(E)-[ethyl-(6-methylpyrrolo[1 ,2-a]pyrazin-1-yl)hydrazono]methyl]-3,3- dimethyl-isoindolin-1 -one

[0192] Step a: 5-bromo-2-[(4-methoxyphenyl)methyl]isoindolin-1 -one

[0193] Reaction was partitioned among 3 dry reactors of 1 L. Under Argon tertbutyl ammonium iodide (6.27 g; 16.98 mmol; 0.20 eq.) was suspended in THF (900.00 mL) (dry, Acroseal). NaH (60% in oil) (3.73 g; 93.38 mmol; 1.10 eq.) was added to give a white suspension. 5- Bromo-2,3-dihydro-1 H-isoindol-1-one (18.00 g; 84.89 mmol; 1.00 eq.) was added at rt. Then the mixture was stirred at rt for 1 h30, and 4-methoxybenzyl chloride 98% (12.72 mL; 93.38 mmol; 1.10 eq.) was added. The mixture was stirred at rt for 3 days, giving a beige cloudy mixture. The 3 mixtures were mixed and quenched with 450 mL of aq. sat. NH4CI solution. This solution was extracted three times with EtOAc. The combined organic layers were dried over MgSO4, filtered and concentrated in vacuum to give 34 g of beige paste. Crude product was purified by flash chromatography (Column Biotage SNAP 750g, 200 mL / min, Eluent DCM / acetone 100 / 0 over 2 CV, then gradient to 95 / 5 in 20 CV and finally isocratic over 5CV, solid deposit). Collected fractions were evaporated to give 5-bromo-2- [(4-methoxyphenyl)methyl]isoindolin-1 -one (16.67 g; 59.12 %) as a pale-yellow powder.1H NMR (400 MHz, DMSO-cfc) 6 ppm 7.81 (d, J=0.88 Hz, 1 H), 7.68 (m, 1 H), 7.65 (m, 1 H), 7.21 (m, 2 H), 6.91 (m, 2 H), 4.64 (s, 2 H), 4.32 (s, 2 H), 3.73 (s, 3 H).

[0194] Step b: 5-bromo-2-[(4-methoxyphenyl)methyl]-3,3-dimethyl-isoindolin-1 -one

[0195] In a dry 2 L three-necked round bottomed flask under argon, 5-bromo-2-[(4- methoxyphenyl)methyl]isoindolin-1 -one (19.67 g; 60 mmol; 1.00 eq.) was dissolved in THF (491.75 mL) (Dry, Acroseal). NaH (60% in oil) (11.84 g; 0.30 mol; 5.00 eq.) was added and mixture was stirred for 30 min at rt to give a brown cloudy mixture. Mel (22.12 mL; 0.36 mol; 6.00 eq.) was added, then the mixture was stirred at 70°C for 5h30 (Dry- Syn temperature). The reaction was cooled to rt overnight. The mixture was poured slowly in 750 mL of aq. sat. NH4CI solution and extracted three times with EtOAc. The combined organic layers were dried over MgSO4, filtered and concentrated under vacuum to give 25g of an orange oil. Crude product was purified by flash chromatography (Column Biotage SNAP 750 g, 200 mL / min, cyclohexane-EtOAc 100-0 / 2 CV, then gradient 100 / 0 to 80 / 20 over 10 CV and then isocratic 80 / 20 during 10 CV, solid deposit). Collected fractions were evaporated. Batch evaporated was dissolved in DCM and washed with saturated Na2S2O3, then dried over MgSO4, filtered and evaporated to give 5-bromo-2-[(4- methoxyphenyl)methyl]-3,3-dimethyl-isoindolin-1 -one (14.82 g; 69.48 %) as a yellow foam.1H NMR (400 MHz, DMSO-Gfc) 5 ppm 7.99 (m, 1 H), 7.67 (d, J=1.54 Hz, 1 H), 7.64 (m, 1 H), 7.30 (m, 2 H), 6.86 (m, 2 H), 4.60 (s, 2 H), 3.72 (s, 3 H), 1 .35 (s, 6 H).

[0196] Step c: 5-bromo-3,3-dimethyl-isoindolin-1 -one

[0197] In a 1 L three-necked round-bottomed flask, under nitrogen, 5-bromo-2-[(4- methoxyphenyl)methyl]-3,3-dimethyl-isoindolin-1 -one (14.82 g; 41.14 mmol; 1.00 eq.) was dissolved in MeCN (207.48 mL) and water (103.74 mL). The solution was cooled to 0°C, and ceric ammonium nitrate (67.66 g; 123.42 mmol; 3.00 eq.) was added portion-wise. The reaction mixture was stirred at 0°C for 20 min, then ice bath was removed and the resulting orange mixture was stirred at rt for 22h. The reaction mixture was dissolved in water and extracted twice with EtOAc. Combined organic layers were dried over MgSO4, filtered and concentrated in vacuum to give 17.6g of orange oil. Crude product was purified by flash chromatography (Column biotage SNAP 750g, 200 mL / min, Eluent Dichloromethane / Acetone 100 / 0 to 75 / 25 in 15 CV, then isocratic, Solid deposit). Collected fractions were evaporated to give 5-bromo-3,3-dimethyl-isoindolin-1 -one (7.13 g; 72.19 %) as a beige powder.1H NMR (400 MHz, DMSO-c / 6) 5 ppm 8.73 (s, 1 H), 7.95 (d, J=1.76 Hz, 1 H), 7.63 (m, 1 H), 7.53 (d, J=7.92 Hz, 1 H), 1.44 (s, 6 H).

[0198] Step d: 3,3-dimethyl-1 -oxo-isoindoline-5-carbaldehyde In a dry 1 L three-necked round-bottomed flask, under argon, 5-bromo-3,3-dimethyl- isoindolin-1 -one (7.13 g; 0.03 mol; 1.00 eq.) was dissolved in dry THF (356.50 mL) and

[0199] N,N,N',N' tetramethylethylene diamine (2.24 mL; 0.01 mol; 0.50 eq.) was added. The reaction mixture was cooled to -70°C. Then n-BuLi 1 ,6M in hexane (55.68 mL; 1 .60 mol / L;

[0200] O.09 mol; 3.00 eq.) was added dropwise over 30 min keeping the temperature below - 68°C. Stirring was momentary stopped during the addition, due to the formation of a thick beige precipitate. The reaction was stirred 45 min at - 70°C. Then DMF (9.19 mL; 0.12 mol; 4.00 eq.) was added dropwise to the lithiated species and the reaction mixture was stirred 1 h30 at -70°C to give a beige suspension. Bath was removed, and the reaction mixture was quenched by addition of 120 mL of aq. sat. NH4CI. The mixture was extracted twice with EtOAc, and combined organic layers were dried over MgSO4, filtered and concentrated under vacuum to give 8.8g of a beige paste. Crude product was purified by flash chromatography (Column biotage SFAR 200g, 150 mL / min, Eluent cyclohexane / EtOAc 70 / 30 to 0 / 100 in 70 min). Collected fractions were evaporated to give 3,3- dimethyl-1 -oxo-isoindoline-5-carbaldehyde (2.74 g; 48.76 %) as white powder.1H NMR (500 MHz, DMSO-cfc) 5 ppm 10.12 (s, 1 H), 8.95 (s, 1 H), 8.18 (d, J=2.06 Hz, 1 H), 8.00 (dd, J=7.70, 1.38 Hz, 1 H), 7.81 (d, J=8.12 Hz, 1 H), 1.49 (s, 6 H)

[0201] Step e: 5-[(E)-(ethylhydrazono)methyl]-3,3-dimethyl-isoindolin-1 -one

[0202] In a 100 ml round bottom flask with a condenser, under nitrogen, 3,3-dimethyl-1 -oxo- isoindoline-5-carbaldehyde (1.50 g; 7.93 mmol; 1.00 eq.) and ethylhydrazine dihydrochloride (1.05 g; 7.89 mmol; 1.00 eq.) were dissolved in propan-2-ol (30.00 mL). The mixture was stirred at 50°C (Dry-Syn temperature) for 20h to give a yellow solution. The mixture was evaporated. The residue was taken in DCM and evaporated. This operation was repeated two times to give 5-[(E)-(ethylhydrazono)methyl]-3,3-dimethyl- isoindolin-1 -one (2.30 g; 99.69 %) as a yellow powder.1H NMR (400 MHz, DMSO-c / 6) 5 ppm 8.65 (s, 1 H), 8.02 (m, 1 H), 7.83 (s, 1 H), 7.66 (m, 1 H), 7.59 (m, 1 H), 3.23 (q, J=7.1 Hz, 2 H),1.45 (s, 6 H), 1.21 (t, J=7.2 Hz, 3 H).

[0203] Step f: 6-bromo-1-chloro-pyrrolo[1 ,2-a]pyrazine

[0204] In a round bottom flask, 1-chloropyrrolo[1 ,2-a]pyrazine (3.00 g; 19.66 mmol; 1.00 eq.) was suspended in MeCN (180.00 mL). NBS (3.67 g; 20.64 mmol; 1.05 eq.) was added portionwise. The mixture was stirred 30 min. The reaction mixture was concentrated under vacuum. The residue was purified by chromatography (Biotage Isolera with Cartridge Biotage 100g; flow rate =80ml / min; UV=235 / 245nm. Sample adsorbed on silica, gradient: cyclohexane / EtOAc: 1 CV 5% EtOAc, 12CV 5% to 30% EtOAc, 3CV 30% EtOAc). The desired fractions were collected and concentrated under vacuum to give 6-bromo-1- chloro-pyrrolo[1 ,2-a]pyrazine (3.90 g; 83.98 %) as a white solid.1H NMR (400 MHz, DMSO-GO 6 ppm 7.07 (dd, J=4.40, 1.10 Hz, 1 H) 7.19 (d, J=4.29 Hz, 1 H) 7.53 (d, J=4.84 Hz, 1 H) 8.18 (dd, J=4.90, 1.05 Hz, 1 H).

[0205] Step g: 5-[(E)-[(6-bromopyrrolo[1 ,2-a]pyrazin-1 -yl)-ethyl-hydrazono]methyl]-3,3-dimethyl- isoindolin-1 -one

[0206] In a 10ml round bottom flask, 6-bromo-1 -chloro-pyrrolo[1 ,2-a]pyrazine (405.79 mg; 1.72 mmol; 1.00 eq.) and 5-[(E)-(ethylhydrazono)methyl]-3,3-dimethyl-isoindolin-1 -one (500.00 mg; 1.72 mmol; 1.00 eq.) were suspended in propan-2-ol (13.80 mL). The reaction mixture was stirred at 65°C for 8 hours (+ overnight at rt) (an insoluble pale-yellow suspension was obtained). The precipitate was filtered and washed with isopropanol and Et2O. The solid was dried under vacuum to give 5-[(E)-[(6-bromopyrrolo[1 ,2-a]pyrazin-1 - yl)-ethyl-hydrazono]methyl]-3,3-dimethyl-isoindolin-1 -one (665.00 mg; 80.61 %) as a yellow solid.1H NMR (400 MHz, DMSO-c / 6) 5 ppm 8.69 (s, 1 H), 8.21 (s, 1 H), 7.91 (s, 1 H), 7.80 (m, 1 H), 7.74 (m, 1 H), 7.70 (d, J=8 Hz, 1 H), 7.58 (m, 1 H), 7.39 (d, J=4 Hz, 1 H), 7.04 (d, J=4 Hz, 1 H), 4.48 q, J=8 Hz, 2 H), 1 .24 (t, J=8 Hz, 3 H).

[0207] Step h: 5-[(E)-[ethyl-(6-methylpyrrolo[1 ,2-a]pyrazin-1 -yl)hydrazono]methyl]-3,3-dimethyl- isoindolin-1 -one

[0208] In a 2-5mL MW tube, 5-[(E)-[(6-bromopyrrolo[1 ,2-a]pyrazin-1 -yl)-ethyl-hydrazono]methyl]- 3,3-dimethyl-isoindolin-1 -one (195.00 mg; 457.41 pmol; 1.00 eq.), PdCI2(dppf) dichloromethane complex (18.68 mg; 22.87 pmol; 0.05 eq.) and trimethylboroxine (95.49 pL; 686.12 pmol; 1.50 eq.) were dissolved in ethylene glycol dimethyl ether (1 950.00 pL; 18 759.78 pmol; 10.00 V). K2CO3(94.82 mg; 686.12 pmol; 1.50 eq.) and water (780.00 pL) were added in the reaction mixture. The reaction mixture was heated at 120°C for 15 min (incomplete reaction). PdCI2(dppf) dichloromethane complex (18.68 mg; 22.87 pmol; 0.05 eq.) and trimethylboroxine (95.49 pL; 686.12 pmol; 1.50 eq.) were added in the reaction mixture. The reaction mixture was heated at 120°C for 15 min. The reaction mixture was diluted with AcOEt and NaHCO3 / water. Then, aqueous layers were extracted three times with AcOEt. The combined organic layers were washed with brine, dried on MgSO4and concentrated under vacuum. The crude residue was purified chromatography (Column: X BRIDGE C18, 30 x 100mm 5pm (WATERS) Flow rate : 42 ml / min, TC : 45°C Mobile phase : H2O + 0.1% NH3 / MeCN +0.1% NH3) to give 5-[(E)-[ethyl-(6- methylpyrrolo[1 ,2-a]pyrazin-1 -yl)hydrazono]methyl]-3,3-dimethyl-isoindolin-1 -one (32.00 mg; 19.10 %) as a yellow powder.1H NMR (500 MHz, DMSO-d6) 5 ppm 8.68 (s, 1 H), 8.13 (s, 1 H), 7.90 (s, 1 H), 7.88 (dd, J=7.98, 1.10 Hz, 1 H), 7.70 (d, J=7.98 Hz, 1 H), 7.62 (d, J=4.68 Hz, 1 H), 7.42 (d, J=3.85 Hz, 1 H), 7.26 (d, J=4.68 Hz, 1 H), 6.64 (d, J=4.13 Hz, 1 H), 4.46 (q, J=6.88 Hz, 2 H), 2.46 (s, 3 H), 1.49 (s, 6 H), 1.22 (t, J=6.88 Hz, 3 H). mp : 184-194°C. Example 2: 5-[(E)-[[6-(difluoromethyl)pyrrolo[1 ,2-a]pyrazin-1-yl]-ethyl- hydrazono]methyl]-3,3-dimethyl-isoindolin-1-one

[0209] Step a: 1 -chloropyrrolo[1 ,2-a]pyrazine

[0210] 2H-pyrrolo[1 ,2-a]pyrazin-1 -one (5.88 g, 43.8 mmol, 1.0 eq.) was dissolved in POCI3(41.0 mL) and the resulting mixture was stirred at rt overnight. The progress of the reaction was monitored by TLC (CHCI3-MeOH=20:1 ) and LCMS analyses. After completion the reaction mixture was slowly added to sat. aq. Na2CO3solution under stirring and ice cooling (pH=7) and the precipitated solid was filtered. The solid was washed with water and dried to obtain the crude product 1 -chloropyrrolo[1 ,2-a]pyrazine (5.46 g, 81% yield) as a brown solid (used without further purification).

[0211] Step b: 1 -chloropyrrolo[1 ,2-a]pyrazine-6-carbaldehyde

[0212] Dry DMF (13.9 mL, 179.0 mmol, 5.0 eq.) was added to an ice-cooled solution of POCI3(33.5 mL, 358.0 mmol, 10.0 eq.), and the mixture was stirred until it became homogeneous. It was allowed to warm to rt and 1 -chloropyrrolo[1 ,2-a]pyrazine (5.46 g, 35.8 mmol, 1 .0 eq.) was added portion wise. Then the vial was sealed and heated at 90 °C for 3 h. The progress of the reaction was monitored by TLC (n-heptane-EtOAc=3:1 (2 runs) + DNPH) and LCMS analyses. After completion the reaction was cooled to rt and diluted with CHCI3and cold-water ice, stirred for 10 min under cooling, then the layers were separated. The aqueous layer was washed with CHCI3(4 times). The organic layer was extracted with sat. Na2CO3(until pH 7) and brine. The combined organic layers were dried and concentrated to obtain the crude 1 -chloropyrrolo[1 ,2-a]pyrazine-6-carbaldehyde (8, 4.6 g, 71% yield) as a pale brown solid.1H NMR (400 MHz, DMSO-c / 6) 5 ppm 9.91 (s, 1 H), 9.03 (d, J=8 Hz, 1 H), 7.87 (d, J=4 Hz, 1 H), 7.69 (d, J=4 Hz, 1 H), 6.90 (m, 1 H).

[0213] Step c: 1 -chloro-6-(difluoromethyl)pyrrolo[1 ,2-a]pyrazine

[0214] In a 12ml Q-tube, 1 -chloropyrrolo[1 ,2-a]pyrazine-6-carbaldehyde (250.00 mg; 1.34 mmol; 1.00 eq.) was suspended in [bis(2-methoxyethyl)amino]sulfur trifluoride (3.96 mL; 10.74 mmol; 8.00 eq.) and heated at 65°C for 2h30. The reaction mixture was quenched with an aqueous saturated solution of NH4CI and extracted three times with EtOAc. Combined organic layers were dried over MgSO4, filtered and evaporated under vacuum. The crude residue was purified by chromatography (Biotage isolera; column 10G Star HC Duo, 45ml / min gradient: Cyclohexane / EtOAc: 2CV 5% EtOAc, 12CV 5% to 45% EtOAc, 3CV 45 to 60% EtOAc, 1 CV 60% EtOAc) to give 1 -chloro-6-(difluoromethyl)pyrrolo[1 ,2- a]pyrazine (185.00 mg; 63.24 %) as a white solid.1H NMR (400 MHz, DMSO-c / 6) 5 ppm 8.40 (m, 1 H), 7.47 (t, J=57 Hz, 1 H), 7.55 (m, 1 H), 7.32 (m, 1 H), 7.01 (m, 1 H).

[0215] Step d: 5-[(E)-[[6-(difluoromethyl)pyrrolo[1 ,2-a]pyrazin-1 -yl]-ethyl-hydrazono]methyl]-3,3- dimethyl-isoindolin- 1 -one The compound was prepared using the same procedure as detailed in example 1 step g starting from 5-[(E)-(ethylhydrazono)methyl]-3,3-dimethyl-isoindolin-1-one (58.00 mg; 0.22 mmol; 1.00 eq.) and 1-chloro-6-(difluoromethyl)pyrrolo[1 ,2-a]pyrazine (47.19 mg; 0.22 mmol; 1.00 eq.) giving 5-[(E)-[[6-(difluoromethyl)pyrrolo[1 ,2-a]pyrazin-1 -yl]-ethyl- hydrazono]methyl]-3,3-dimethyl-isoindolin-1 -one (12 mg; 14.8 %) as a yellow powder.1H NMR (500 MHz, DMSO-Gfc) 6 ppm 9.89 (s, 1 H), 8.98 (d, J=4.68 Hz, 1 H), 8.71 (s, 1 H), 8.26 (s, 1 H), 7.93 (s, 1 H), 7.90 (dd, J=7.84, 1.24 Hz, 1 H), 7.66 - 7.73 (m, 3 H), 7.59 (d, J=4.68 Hz, 1 H), 4.49 (q, J=6.79 Hz, 2 H), 1.50 (s, 6 H), 1.25 (t, J=7.01 Hz, 3 H).

[0216] Example 3: 5-[(E)-[ethyl-[6-(hydroxymethyl)pyrrolo[1 ,2-a]pyrazin-1 - yl]hydrazono]methyl]-3,3-dimethyl-isoindolin-1-one

[0217] In a 20 ml round bottom flask, cooled to 0°C, 5-[(E)-[[6-(difluoromethyl)pyrrolo[1 ,2- a]pyrazin-1 -yl]-ethyl-hydrazono]methyl]-3,3-dimethyl-isoindolin-1 -one (18.00 mg; 0.05 mmol; 1.00 eq.) was suspended in anhydrous THF (360.00 pL). Sodium borohydride (1.88 mg; 0.05 mmol; 1.10 eq.) was added, the solution was stirred to 0°C for 2 hours (incomplete reaction). An excess of NaBH4(1.88 mg; 0.05 mmol; 1.10 eq.) was added at 0°C and the stirring was continued 20 hours at rt. The reaction was quenched with NH4CI and extracted twice with DCM. Organic layer was washed with brine, then dried on MgSO4 and concentrated under vacuum. The crude was purified by flash chromatography (Column Biotage Star duo 5g, 25 mL / min - hp= 240nm gradient: DCM / mixture B (CH2CI2 / MeOH=90 / 10) : 1CV 10% mixture B, 3CV 10% to 30% mixture B, 10CV 30% to 70% mixture B, 3CV 70% to 100%mixture B, 1CV 100%mixture B). Collected fractions were concentrated and then lyophilized to give 5-[(E)-[ethyl-[6-(hydroxymethyl)pyrrolo[1 ,2- a]pyrazin-1 -yl]hydrazono]methyl]-3,3-dimethyl-isoindolin-1 -one (5.00 mg; 29.25 %) as a beige solid.1H NMR (500 MHz, DMSO-Gfc) 5 ppm 8.68 (s, 1 H), 8.15 (s, 1 H), 7.85 - 7.92 (m, 2 H), 7.77 (d, J=4.68 Hz, 1 H), 7.70 (d, J=7.98 Hz, 1 H), 7.41 (d, J=4.13 Hz, 1 H), 7.27 (d, J=4.68 Hz, 1 H), 6.76 (d, J=4.13 Hz, 1 H), 5.21 (t, J=5.50 Hz, 1 H), 4.75 (d, J=5.50 Hz, 2 H), 4.47 (q, J=6.88 Hz, 2 H), 1.49 (s, 6 H), 1.15 - 1.30 (m, 3 H).

[0218] Example 4: 2-[1 -[[(E)-(3,3-dimethyl-1 -oxo-isoindolin-5-yl)methyleneamino]-ethyl- amino]pyrrolo[1,2-a]pyrazin-6-yl]acetonitrile

[0219] Step a: 2-(1-chloropyrrolo[1 ,2-a]pyrazin-6-yl)acetonitrile

[0220] A 25mL three-neck round-bottomed flask, under nitrogen, equipped with thermometer and charged with 1 -chloropyrrolo[1 ,2-a]pyrazine (100.00 mg; 0.66 mmol; 1.00 eq.), iodoacetonitrile (71.36 pL; 0.98 mmol; 1.50 eq.), iron sulfate (II), 7 H2O (91.10 mg; 0.33 mmol; 0.50 eq.) in DMSO (2.00 mL). Hydrogen peroxide (185.77 pL; 50.00 %w / w; 3.28 mmol; 5.00 eq.) was added dropwise with a syringe, over 30mn, maintaining the temperature between 20°C and 30°C (25°C the best) with a cold-water bath. At the end of addition, the reaction mixture was stirred at 20°C-25°C during 1 hour. The reaction mixture was cooled to 0°C and quenched with water and EtOAc, then the organic layer was re-extracted twice with EtOAc. Combined organic layers were washed with sat.Na2S2O5, then brine. The crude product was purified by chromatography (Cartridge Biotage Star 5g HC duo ; flow rate =25ml / min ; collect all / 230 / 245nm, gradient: Cyclohexane / EtOAc: 1 CV 20% EtOAc:, 5CV 20% to 40%EtOAc:, 10CV 40% to 60%EtOAc:, 8CV, 60% to 100% EtOAc, 1 CV 100% EtOAc) to give 2-(1 -chloropyrrolo[1 ,2- a]pyrazin-6-yl)acetonitrile (80.00 mg; 31.85 %) as a beige solid.1H NMR (400 MHz, DMSO-c / 6) 5 ppm 8.24 (d, J=8 Hz, 1 H), 7.51 (d, J=8 Hz, 1 H), 7.02 (m, 1 H), 6.95 (m, 1 H), 4.50 (s, 2 H).

[0221] Step b: 2-[1 -[[(E)-(3,3-dimethyl-1 -oxo-isoindolin-5-yl)methyleneamino]-ethyl- amino]pyrrolo[1 ,2-a]pyrazin-6-yl]acetonitrile

[0222] The compound was prepared using the same procedure as detailed in example 1 step g starting from 5-[(E)-(ethylhydrazono)methyl]-3,3-dimethyl-isoindolin-1 -one (46.58 mg; 0.16 mmol; 1.00 eq.) and 2-(1 -chloropyrrolo[1 ,2-a]pyrazin-6-yl)acetonitrile (30.00 mg; 0.16 mmol; 1.00 eq.) giving 2-[1 -[[(E)-(3,3-dimethyl-1 -oxo-isoindolin-5-yl)methyleneamino]- ethyl-amino]pyrrolo[1 ,2-a]pyrazin-6-yl]acetonitrile (15 mg; 25 %) as a pale yellow powder.1H NMR (500 MHz, DMSO-Gfc) 5 ppm 8.69 (s, 1 H), 8.18 (s, 1 H), 7.91 (s, 1 H), 7.88 (d, J=7.98 Hz, 1 H), 7.75 (d, J=4.68 Hz, 1 H), 7.70 (d, J=7.70 Hz, 1 H), 7.49 (d, J=4.13 Hz, 1 H), 7.37 (d, J=4.95 Hz, 1 H), 6.86 (d, J=4.13 Hz, 1 H), 4.41 - 4.50 (m, 4 H), 1.50 (s, 6 H), 1.23 (t, J=6.88 Hz, 3 H).

[0223] Example 5: 5-[(E)-[ethyl-(6-fluoropyrrolo[1 ,2-a]pyrazin-1-yl)hydrazono]methyl]-3,3- dimethyl-isoindolin-1 -one

[0224] Step a: 1 -chloro-6-fluoro-pyrrolo[1 ,2-a]pyrazine

[0225] In a 20 mL round bottom flask, 1 -chloropyrrolo[1 ,2-a]pyrazine (60.00 mg; 0.39 mmol; 1.00 eq.) was suspended in MeCN (3.90 mL) and cooled to 0°C. 1 -chloromethyl-4-fluoro-1 ,4- diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (153.24 mg; 0.43 mmol; 1.10 eq.) was added. Then the reaction mixture was stirred for 1 hour from 0°C to rt, and then 2 hours again at rt, under nitrogen. The reaction was diluted with EtOAc and washed with water, then brine. The aqueous layer was re-extracted with EtOAc and then the combined organic layers were dried on MgSO4and evaporated. The residue was purified by chromatography (Cartridge Biotage Star HC Duo 5g ; flow rate =25ml / min ; UV=235 / 215nm, Sample adsorbed on silica, gradient: cyclohexane / EtOAc: 1 CV 5% EtOAc, 12CV 5% to 20% EtOAc, 5CV 20% to 50% EtOAc,.3CV 50% to 80% EtOAc) to give 1 -chloro-6-fluoro-pyrrolo[1 ,2-a]pyrazine (20.00 mg; 29.82 %) as a white solid.1H NMR (400 MHz, DMSO-cfc) 6 ppm 8.15 (m, 1 H), 7.38 (m, 1 H), 6.90 (m, 1 H), 6.74 (m, 1 H).

[0226] Step b: 5-[(E)-[ethyl-(6-fluoropyrrolo[1 ,2-a]pyrazin-1 -yl)hydrazono]methyl]-3,3-dimethyl- isoindolin-1 -one

[0227] The compound was prepared using the same procedure as detailed in example 1 step g starting from 5-[(E)-(ethylhydrazono)methyl]-3,3-dimethyl-isoindolin-1 -one (30.71 mg; 105.53 pmol; 1.00 eq.) and 1 -chloro-6-fluoro-pyrrolo[1 ,2-a]pyrazine (18.00 mg; 105.53 pmol; 1.00 eq.) giving 5-[(E)-[ethyl-(6-fluoropyrrolo[1 ,2-a]pyrazin-1 -yl)hydrazono]methyl]- 3,3-dimethyl-isoindolin-1 -one (17 mg; 44 %) as a pale yellow powder.1H NMR (400 MHz, DMSO-Gfc) 5 ppm 8.68 (s, 1 H), 8.19 (s, 1 H), 7.83 - 7.94 (m, 2 H), 7.70 (d, J=8.14 Hz, 1 H), 7.63 (d, J=4.62 Hz, 1 H), 7.37 (t, J=5.24 Hz, 1 H), 7.27 (d, J=4.84 Hz, 1 H), 6.51 (dd, J=4.40, 3.52 Hz, 1 H), 4.46 (q, J=7.04 Hz, 2 H), 1 .49 (s, 6 H), 1 .22 (t, J=6.93 Hz, 3 H).

[0228] Example 6: 5-[(E)-[(6-chloropyrrolo[1 ,2-a]pyrazin-1-yl)-ethyl-hydrazono]methyl]-3,3- dimethyl-isoindolin-1 -one

[0229] Step a: 1 ,6-dichloropyrrolo[1 ,2-a]pyrazine

[0230] In a round bottom flask, 1 -chloropyrrolo[1 ,2-a]pyrazine (0.50 g; 3.28 mmol; 1.00 eq.) was suspended in MeCN (30.00 mL). NCS (0.46 g; 3.44 mmol; 1.05 eq.) was added dropwise. The reaction mixture was stirred overnight at room temperature and at 55°C for 3 hours. The reaction mixture was concentrated under vacuum. The residue was purified by chromatography (Biotage Isolera with Cartridge Biotage 25g ; flow rate =40ml / min ; UV=235 / 245nm gradient: cyclohexane / EtOAc: 1 CV 5% EtOAc, 15CV 5% to 30% EtOAc, 3CV 30% EtOAc) to give 1 ,6-dichloropyrrolo[1 ,2-a]pyrazine (0.16 g; 26.11 %).1H NMR (400 MHz, DMSO-Gfc) 5 ppm 8.18 (m, 1 H), 7.53 (m, 1 H), 7.19 (d, J=4.40 Hz, 1 H), 7.07 (dd, J=4.35, 1.05 Hz, 1 H).

[0231] Step b: 5-[(E)-[(6-chloropyrrolo[1 ,2-a]pyrazin-1 -yl)-ethyl-hydrazono]methyl]-3,3-dimethyl- isoindolin-1 -one

[0232] The compound was prepared using the same procedure as detailed in example 1 step g starting from 5-[(E)-(ethylhydrazono)methyl]-3,3-dimethyl-isoindolin-1 -one (38.90 mg; 0.13 mmol; 1.00 eq.) and 1 ,6-dichloropyrrolo[1 ,2-a]pyrazine (25.00 mg; 0.13 mmol; 1.00 eq.) giving 5-[(E)-[(6-chloropyrrolo[1 ,2-a]pyrazin-1 -yl)-ethyl-hydrazono]methyl]-3,3-dimethyl- isoindolin-1 -one (13 mg; 22.2 %) as a pale yellow powder.1H NMR (500 MHz, DMSO-c / 6) 5 ppm 8.71 (s, 1 H), 8.20 (s, 1 H), 7.91 (s, 1 H), 7.89 (d, J=7.98 Hz, 1 H), 7.74 (d, J=4.68 Hz, 1 H), 7.71 (d, J=7.98 Hz, 1 H), 7.54 (d, J=4.13 Hz, 1 H), 7.40 (d, J=4.68 Hz, 1 H), 6.96 (d, J=4.40 Hz, 1 H), 4.48 (q, J=6.88 Hz, 2 H), 1.50 (s, 6 H), 1.23 (t, J=6.88 Hz, 3 H). mp : 108°C. Example 7: 1-[[(E)-(3,3-dimethyl-1-oxo-isoindolin-5-yl)methyleneamino]-ethyl- amino]pyrrolo[1 ,2-a]pyrazine-6-carboxamide

[0233] Step a: 1-chloropyrrolo[1 ,2-a]pyrazine-6-carboxylic acid

[0234] In a dry 50 mL three-necked round-bottomed flask, under argon, 1 ,6-dichloropyrrolo[1 ,2- a]pyrazine (130.00 mg; 561.61 pmol; 1.00 eq.) was dissolved in dry THF (5.20 mL) and cooled to -78°C. n-BuLi 1.6M in hexane (421.21 pL; 1.60 mol / L; 673.93 pmol; 1.20 eq.) was added dropwise and the reaction was stirred 45 min at - 78°C (yellow mixture). Carbon dioxide (1.24 g; 28.08 mmol; 50.00 eq.) (dry ice, Pre- dried on MgSO4) was then added to the lithiated species and the reaction mixture was stirred 20mn at -20°C (orange mixture). The reaction mixture was quenched at 0°C by addition of 10 mL of aqueous HCI 0.1 M and 10 mL of DCM. After 15min of stirring, the organic layer was separated and aqueous layer was extracted twice with DCM. The combined organic layers were washed with brine, and dried over MgSO4, filtered and concentrated under vacuum. The residue was purified by chromatography (Cartridge Biotage Star HC duo 10g; flow rate =45ml / min, UV=230 / 245nm, gradient: CH2CI2 / mixture B(CH2CI2 / MeOH=90 / 10): 2CV 30% mixture B, 1 CV 30% to 50% mixture B, 12CV 50% to 80% mixture B, 2CV 80% to 100% mixture B, 1 CV to100% mixture B) to give 1-chloropyrrolo[1 ,2-a]pyrazine-6-carboxylic acid (85.00 mg; 56.97 %) as a yellow solid.1H NMR (400 MHz, DMSO-c / 6) 5 ppm 9.15 (m, 1 H), 7.69 (d, J=4 Hz, 1 H), 7.57 (d, J=4 Hz, 1 H), 7.03 (m, 1 H).

[0235] Step b: 1 -[[(E)-(3,3-dimethyl-1 -oxo-isoindolin-5-yl)methyleneamino]-ethyl- amino]pyrrolo[1 ,2-a]pyrazine-6-carboxylic acid

[0236] The compound was prepared using the same procedure as detailed in example 1 step g starting from 5-[(E)-(ethylhydrazono)methyl]-3,3-dimethyl-isoindolin-1 -one (64.52 mg; 228.90 pmol; 1.00 eq.) and 1-chloropyrrolo[1 ,2-a]pyrazine-6-carboxylic acid (45.00 mg; 228.90 pmol; 1.00 eq.) giving 1-[[(E)-(3,3-dimethyl-1-oxo-isoindolin-5-yl)methyleneamino]- ethyl-amino]pyrrolo [1 ,2-a]pyrazine-6-carboxylic acid (44 mg; 49.1 %) as a pale yellow powder. The compound was used without further purification.

[0237] Step c: 1 -[[(E)-(3,3-dimethyl-1 -oxo-isoindolin-5-yl)methyleneamino]-ethyl- amino]pyrrolo[1 ,2-a]pyrazine-6-carboxamide

[0238] 1 -[[(E)-(3,3-dimethyl-1 -oxo-isoindolin-5-yl)methyleneamino]-ethyl-amino]pyrrolo [1 ,2- a]pyrazi-ne-6-carboxylic acid (41.00 mg; 104.75 pmol; 1.00 eq.) was suspended into DMF (410.00 pL), with NMM (13.82 pL; 125.70 pmol; 1.20 eq.) and HATU (47.79 mg; 125.70 pmol; 1.20 eq.). The mixture was stirred 20 minutes at rt. NH4CI (28.02 mg; 523.73 pmol; 5.00 eq.) and NMM (57.58 pL; 523.73 pmol; 5.00 eq.) were added and the reaction mixture was stirred at rt for 3 hours. The reaction mixture was diluted with DCM and washed with water, then brine. The organic layer was dried on MgSO4and evaporated. The residue was purified by chromatography (LCMS semi-preparative (method B) solubilized with 600pl MeCN + 400pL MeOH). The solid obtained was diluted with water (400.00 pL) and NaHCO3(5.00 mg; 59.52 pmol; 0.57 eq.) was added, the heterogeneous suspension was stirred for 1 hour at rt. Then water (1.00 mL) was added and suspension was centrifuged; the aqueous layer was removed : this operation was made twice. The solid was freeze-dried with 2 mL of water into Genevac to give 1 -[[(E)-(3,3-dimethyl-1-oxo- isoindolin-5-yl)methyleneamino]-ethyl-amino]pyrrolo[1 ,2-a]pyrazine-6-carboxamide (9.00 mg; 22.01 %) as a yellow solid.1H NMR (500 MHz, DMSO-c / 6) 5 ppm 9.12 (dd, J=4.68, 0.55 Hz, 1 H), 8.70 (s, 1 H), 8.19 (s, 1 H), 7.92 (s, 1 H), 7.85 - 7.90 (m, 2 H), 7.71 (d, J=7.98 Hz, 1 H), 7.58 (d, J=4.40 Hz, 1 H), 7.51 (d, J=4.76 Hz, 1 H), 7.42 (d, J=4.68 Hz, 1 H), 7.31 (br s, 1 H), 4.47 (q, J=6.88 Hz, 2 H), 1 .50 (s, 6 H), 1 .24 (t, J=6.88 Hz, 3 H).

[0239] Example 8: 5-[(E)-[ethyl-(6-methylsulfonylpyrrolo[1 ,2-a]pyrazin-1- yl)hydrazono]methyl]-3,3-dimethyl-isoindolin-1-one

[0240] Step a: 1-chloro-6-methylsulfanyl-pyrrolo[1 ,2-a]pyrazine and 1-chloro-4-methylsulfanyl- pyrrolo[1 ,2-a]pyrazine

[0241] In a dry 25 mL three-necked round-bottomed flask, under argon, 6-bromo-1 -chloro- pyrrolo[1 ,2-a]pyrazine (250.00 mg; 1.06 mmol; 1.00 eq.) was dissolved in dry THF (9.80 mL) and cooled to -78°C. n-BuLi 1.6m in hexane (793.82 pL; 1.60 mol / L; 1.27 mmol; 1.20 eq.) was added dropwise and the reaction was stirred 45min at - 78°C (orange mixture). Methyl disulfide (112.55 pL; 1.27 mmol; 1.20 eq.) was added slowly at -78°C to the lithiated species and then the reaction mixture was stirred for 4.5 hours at -20°C with an Ice-bath saturated with NaCI (30g forl OOg ice) (orange mixture). The reaction mixture was quenched at 0°C by addition of 5 mL of HCI 0.1 M and 10 mL of EtOAc. After 15 min of stirring, the organic layer was separated and the aqueous layer was extracted twice with EtOAc. The combined organic layers were washed with brine, and dried over MgSO4, filtered and concentrated under vacuum. The residue was purified by chromatography (Cartridge Biotage Star HC duo 10g ; flow rate = 50ml / min ; UV=248 / 254nm, gradient: Cyclohexane / mixture B (Cyclohexane / EtOAc=90 / 10): 2CV 20% mixture B, 15CV 20% to 50% mixture B, 5CV 50% to 100% mixture B, 1CV to100% mixture B) to give a mixture of 1 -chloro-6-methylsulfanyl-pyrrolo[1 ,2-a]pyrazine and 1 -chloro-4-methylsulfanyl- pyrrolo[1 ,2-a]pyrazine (130.00 mg; 18.55 %) as a pale yellow solid which is used in the next step without further purification.

[0242] Step b: 5-[(E)-[ethyl-(6-methylsulfanylpyrrolo[1 ,2-a]pyrazin-1 -yl)hydrazono]methyl]-3,3- dimethyl-isoindolin- 1 -one and 5-[(E)-[ethyl-(4-methylsulfanylpyrrolo[1 ,2-a]pyrazin-1 - yl)hydrazono]methyl]-3,3-dimethyl-isoindolin-1-one The compound was prepared using the same procedure as detailed in example 1 step g starting from 5-[(E)-(ethylhydrazono)methyl]-3,3-dimethyl-isoindolin-1 -one (192.53 mg; 654.34 pmol; 1.00 eq.) and a mixture of 1 -chloro-6-methylsulfanyl-pyrrolo[1 ,2-a]pyrazine and 1 -chloro-4-methylsulfanyl-pyrrolo[1 ,2-a]pyrazine (130.00 mg; 654.34 pmol; 1.00 eq.) giving 5-[(E)-[ethyl-(6-methylsulfanylpyrrolo[1 ,2-a]pyrazin-1 -yl)hydrazono]methyl]-3,3- dimethyl-isoindolin-1 -one (45 mg; 16.8 %) as a yellow powder1H NMR (500 MHz, DMSO- d6) 6 ppm 8.69 (s, 1 H), 8.18 (s, 1 H), 7.97 (d, J=4.81 Hz, 1 H), 7.91 (s, 1 H), 7.88 (d, J=7.81 Hz, 1 H), 7.70 (d, J=7.84 Hz, 1 H), 7.51 (d, J=4.26 Hz, 1 H), 7.40 (d, J=4.68 Hz, 1 H), 7.04 (d, J=4.26 Hz, 1 H), 4.47 (q, J=7.02 Hz, 2 H), 2.34 (s, 3 H), 1.49 (s, 6 H), 1.23 (t, J=7.01 Hz, 3 H). and 5-[(E)-[ethyl-(4-methylsulfanylpyrrolo[1 ,2-a]pyrazin-1 - yl)hydrazono]methyl]-3,3-dimethyl-isoindolin-1 -one (95 mg, 36 %) as a yellow powder1H NMR (500 MHz, DMSO-cfc) 5 ppm 8.70 (s, 1 H), 8.20 (s, 1 H), 7.89 (m, 3 H), 7.71 (d, J=7.84 Hz, 1 H), 7.63 (dd, J=4.13, 1.51 Hz, 1 H), 7.46 (s, 1 H), 6.95 (dd, J=4.06, 2.68 Hz, 1 H), 4.47 (q, J=7.01 Hz, 2 H), 3.31 (m, 1 H), 2.45 (s, 3 H), 1.50 (s, 6 H), 1.23 (t, J=6.95 Hz, 3 H)

[0243] Step c: 5-[(E)-[ethyl-(6-methylsulfonylpyrrolo[1 ,2-a]pyrazin-1 -yl)hydrazono]methyl]-3,3- dimethyl-isoindolin- 1 -one

[0244] 5-[(E)-[ethyl-(6-methylsulfanylpyrrolo[1 ,2-a]pyrazin-1 -yl)hydrazono]methyl]-3,3-dimethyl- isoindolin-1 -one (45.00 mg; 114.36 pmol; 1.00 eq.) was dissolved in AcOH (540.00 pL). Hydrogen peroxide (63.53 pL; 2 287.14 pmol; 20.00 eq.) (solution 30% aq) was added slowly. The reaction mixture was stirred for 20 hours at rt (yellow suspension). The brown suspension was diluted with DCM and evaporated. The residue was purified by chromatography (Column: Kinetex C18,30 x 150mm 5pm (phenomenex; 330mg, Flowrate: 42 ml / min, Mobile phase: H2O with 0.1 % HCOOH / MeCN + 0.1 % HCOOH, gradient B / 12min) to give 5-[(E)-[ethyl-(6-methylsulfonylpyrrolo[1 ,2-a]pyrazin-1 - yl)hydrazono]methyl]-3,3-dimethyl-isoindolin-1 -one (3.5 mg; 6.9 %) as a yellow solid. 1 H NMR (500 MHz, DMSO-d6) 5 ppm 8.71 (s, 1 H), 8.26 (s, 1 H), 8.24 (d, J=4.68 Hz, 1 H), 7.92 (s, 1 H), 7.88 (dd, J=7.84, 1.24 Hz, 1 H), 7.71 (d, J=7.98 Hz, 1 H), 7.60 (d, J=4.90 Hz, 1 H), 7.58 (d, J=4.68 Hz, 1 H), 7.44 (d, J=4.40 Hz, 1 H), 4.49 (q, J=7.06 Hz, 2 H), 3.36 (s, 3 H), 1 .50 (s, 6 H), 1 .24 (t, J=7.02 Hz, 3 H)

[0245] Example 9: 5-[(E)-[ethyl-(4-methylsulfinylpyrrolo[1 ,2-a]pyrazin-1- yl)hydrazono]methyl]-3,3-dimethyl-isoindolin-1-one

[0246] 5-[(E)-[ethyl-(4-methylsulfanylpyrrolo[1 ,2-a]pyrazin-1 -yl)hydrazono]methyl]-3,3-dimethyl- isoindolin-1 -one (50.00 mg; 127.06 pmol; 1.00 eq.) was dissolved in AcOH (600.00 pL). Hydrogen peroxide (70.59 pL; 2 541.26 pmol; 20.00 eq.) (solution 30% aq) was added slowly. The reaction mixture was stirred for 24 hours at rt (yellow suspension). The orange solution was diluted with DCM and evaporated. The residue was purified by chromatography (method B) to give 5-[(E)-[ethyl-(4-methylsulfinylpyrrolo[1 ,2-a]pyrazin-1 - yl)hydrazono]methyl]-3,3-dimethyl-isoindolin-1 -one (30.00 mg; 55.06 %) as a yellow solid.1H NMR (500 MHz, DMSO-cfc) 5 ppm 8.73 (s, 1 H), 8.31 (s, 1 H), 8.15 (dd, J=2.61 , 1.24 Hz, 1 H), 7.96 (s, 1 H), 7.93 (dd, J=7.98, 1.10 Hz, 1 H), 7.73 (d, J=7.70 Hz, 1 H), 7.70 (dd, J=4.13, 1.38 Hz, 1 H), 7.67 (s, 1 H), 7.01 (dd, J=4.26, 2.61 Hz, 1 H), 4.48 - 4.55 (m, 2 H), 3.10 (s, 3 H), 1.50 (s, 6 H), 1.25 (t, J=6.88 Hz, 3 H). mp ; 1 18-148°C.

[0247] Example 10: 2-[1 -[[(E)-(3,3-dimethyl-1 -oxo-isoindolin-5-yl)methyleneamino]-ethyl- amino]pyrrolo[1 ,2-a]pyrazin-4-yl]acetonitrile

[0248] Step a: 1 -chloropyrrolo[1 ,2-a]pyrazine-4-carbaldehyde

[0249] Under argon, in a three-necked round bottomed flask, dried with a heat gun under vacuum and purged under argon, 1 -chloropyrrolo[1 ,2-a]pyrazine (2.50 g; 0.02 mol; 1.00 eq.) in suspension in dry THF (75.00 mL) was stirred at -78°C. n-BuLi 1.6M in hexane (12.29 mL; 1.60 mol / L; 0.02 mol; 1.20 eq.) was added dropwise (add during 50 minutes, T° max = - 70°C) and the reaction mixture was stirred at -78°C for 45 min. DMF (1.52 mL; 0.02 mol; 1.20 eq.) was slowly added at -78°C, the reaction mixture was stirred at -78°C for 1 hour. The reaction mixture was quenched with a saturated solution of NH4CI then allowed to warm to rt, extracted twice with EtOAc, the organic layer was dried over MgSO4, filtered and concentrated to give 3.082 g of an orange solid. The crude was purified by chromatography over silica gel (column: 120 g of silica, flow rate mL / min, eluent: 3CV of 100% cyclohexane then 10CV gradient from 100% cyclohexane to 70% cyclohexane - 30% EtOAc) to give 1 -chloropyrrolo[1 ,2-a]pyrazine-4-carbaldehyde (2.06 g; 69.48 %) as a yellow solid.1H NMR (400 MHz, DMSO-c / 6) 5 ppm 9.99 (s, 1 H), 8.90 (dd, J=2.59, 1.27 Hz, 1 H), 8.34 (s, 1 H), 7.28 (dd, J=4.35, 1.27 Hz, 1 H), 7.23 (dd, J=4.35, 2.59 Hz, 1 H).

[0250] Step b: (1 -chloropyrrolo[1 ,2-a]pyrazin-4-yl)methanol

[0251] Under N2at -78°C, to a solution of 1 -chloropyrrolo[1 ,2-a]pyrazine-4-carbaldehyde (1.58 g; 0.01 mol; 1 .00 eq.) in THF (31 .60 mL) (heterogenous) was added very slowly and portionwise NaBH4(364.10 mg; 0.01 mol; 1 .10 eq.). The reaction mixture was stirred to -78°C for 5 min. The reaction was quenched with brine and extracted with DCM twice. The organic layer was dried over MgSO4, filtered and concentrated to give 1 .641 g of a pale-yellow solid. The crude was purified by chromatography over silica gel (dry loading, column: 100g of silica, flow rate 150 mL / min, eluent: 3CV of 100% cyclohexane then 12CV gradient from 100% cyclohexane to 70% cyclohexane - 30% EtOAc, 3CV isocratic then 8CV gradient up to 50% cyclohexane - 50% EtOAc) to give 1 -chloropyrrolo[1 ,2-a]pyrazin- 4-yl)methanol (1.34 g; 84 %) as a off white solid.1H NMR (400 MHz, DMSO-c / 6) 5 ppm 7.86 (dd, J=2.64, 1.32 Hz, 1 H), 7.39 (s, 1 H), 7.04 (m, 1 H), 6.97 (d, J=4.24 Hz, 1 H), 5.64 (m, 1 H), 4.76 (d, J=5.28 Hz, 2 H).

[0252] Step c: 1 -chloro-4-(chloromethyl)pyrrolo[1 ,2-a]pyrazine

[0253] Under N2, 1 -chloropyrrolo[1 ,2-a]pyrazin-4-yl)methanol (600.00 mg; 3.28 mmol; 1.00 eq.) was dissolved in DCM (24.00 mL). The reaction mixture was cooled down at 0°C. Methanesulfonyl chloride (0.51 mL; 6.57 mmol; 2.00 eq.) and TEA (1.14 mL; 8.21 mmol; 2.50 eq.) were added. The reaction mixture was stirred at 0°C for 15 min then rt overnight. The reaction mixture was quenched with NH4CI and extracted with DCM twice. The organic layer was washed with water then brine, dried over MgSO4, filtered and concentrated to give 1 -chloro-4-(chloromethyl)pyrrolo[1 ,2-a]pyrazine (653.00 mg; 95.88 %) as a yellow solid.1H NMR (400 MHz, DMSO-c / 6) 5 ppm 7.96 (dd, J=2.64, 1.32 Hz, 1 H), 7.62 (s, 1 H), 7.10 (dd, J=15.68, 1.93 Hz, 1 H), 7.10 (m, 1 H), 5.24 (s, 2 H).

[0254] Step d: 2-(1 -chloropyrrolo[1 ,2-a]pyrazin-4-yl)acetonitrile

[0255] Under N2, 1 -chloro-4-(chloromethyl)pyrrolo[1 ,2-a]pyrazine (360.00 mg; 1.79 mmol; 1.00 eq.) was dissolved in dry DMF (6.98 mL). The reaction mixture was cooled at 0°C. KCN (124.41 mg; 1.97 mmol; 1 .10 eq.) was added. The reaction mixture was stirred at 0°C and allowed to warm up at rt overnight. The reaction mixture was diluted in NH4CI and extracted with EtOAc (twice). The organic layer was washed with brine. The organic layer was dried over MgSO4, filtered and concentrated. The crude was purified by chromatography over silica gel (dry loading, column: 10g of silica, flow rate 40mL / min, eluent: 3CV of 100% cyclohexane then 12CV gradient from 100% cyclohexane to 50% cyclohexane - 50% EtOAc) to give 2-(1 -chloropyrrolo[1 ,2-a]pyrazin-4-yl)acetonitrile (179.00 mg; 20.98 %) as a brown oil used without further purification.

[0256] Step e: 2-[1 -[[(E)-(3,3-dimethyl-1 -oxo-isoindolin-5-yl)methyleneamino]-ethyl- amino]pyrrolo[1 ,2-a]pyrazin-4-yl]acetonitrile

[0257] The compound was prepared using the same procedure as detailed in example 1 step g starting from 5-[(E)-(ethylhydrazono)methyl]-3,3-dimethyl-isoindolin-1 -one (156.14 mg; 1.33 mmol; 1.50 eq.) and 2-(1 -chloropyrrolo[1 ,2-a]pyrazin-4-yl)acetonitrile (170.00 mg; 0.88 mmol; 1.00 eq) giving 2-[1 -[[(E)-(3,3-dimethyl-1 -oxo-isoindolin-5-yl)methyleneamino]- ethyl-amino]pyrrolo[1 ,2-a]pyrazin-4-yl]acetonitrile (33 mg; 24.2 %) as a yellow powder.1H NMR (500 MHz, DMSO-c / 6) 5 ppm 8.69 (s, 1 H), 8.19 (s, 1 H), 7.92 (s, 1 H), 7.90 (dd,

[0258] J=7.84, 1.24 Hz, 1 H), 7.71 (d, J=7.70 Hz, 1 H), 7.68 (dd, J=2.75, 1.38 Hz, 1 H), 7.62 (dd,

[0259] J=4.13, 1.38 Hz, 1 H), 7.31 (s, 1 H), 6.99 (dd, J=4.13, 2.75 Hz, 1 H), 4.47 (q, J=6.88 Hz, 2

[0260] H), 4.38 (s, 2 H), 1 .50 (s, 6 H), 1 .23 (t, J=6.88 Hz, 3 H).

[0261] Example 11 : 1 -[[(E)-(3,3-dimethyl-1 -oxo-isoindolin-5-yl)methyleneamino]-ethyl- amino]-7-methyl-pyrrolo[1 ,2-a]pyrazine-6-carbonitrile Step a: 1-methoxy-7-methyl-pyrrolo[1 ,2-a]pyrazine

[0262] In a microreactor, under Argon, 2-methoxy-3-methylpyrazine (1 410.00 pL; 12.04 mmol; 1.00 eq.) and bromoacetone (1 042.08 pL; 12.40 mmol; 1.03 eq.) were added. The reaction mixture was heated at 60°C for the night. The reaction mixture was cooled down at rt and DCM (44.84 mL) was added. DBU (2 698.08 pL; 18.06 mmol; 1.50 eq.) was added and the reaction mixture was heated at 70°C for 1 h. The reaction mixture was cooled down at rt and water was added in the reaction mixture. The aqueous layers were extracted three times with DCM. The organic combined layers were dried on MgSO4and concentrated under vacuum. The residue was purified by chromatography (Cartridge Biotage Star 50g / 60pm silica Cyclohexane / AcOEt : 100-0% : 1 CV (column volume)100- 0% to 90-10% : 10 CV 90-10% : 8 CV, Flow rate 100ml / min) to give 1-methoxy-7-methyl- pyrrolo[1 ,2-a]pyrazine (1.49 g; 74.78 %) as a yellow oil.1H NMR (400 MHz, DMSO-c / 6) 5 ppm 7.82 (dd, J=4.79, 0.94 Hz, 1 H), 7.45 (d, J=2.42 Hz, 1 H), 7.01 (d, J=4.73 Hz, 1 H), 6.51 (d, J=1.43 Hz, 1 H), 3.94 (s, 3 H), 2.24 (t, J=0.66 Hz, 3 H).

[0263] Step b: 7-methyl-2H-pyrrolo[1 ,2-a]pyrazin-1 -one

[0264] In a 250mL round bottomed flask under Argon, 1-methoxy-7-methyl-pyrrolo[1 ,2-a]pyrazine (1.49 g; 9.00 mmol; 1.00 eq.) and HCI (43.81 mL; 524.55 mmol; 30.00 V) were added. The reaction mixture was heated at 110°C for 4h. The reaction mixture was cooled down to rt and was concentrated under vacuum. A mixture of ice / water and DCM were added in the reaction mixture. NaHCO3was added to obtain basic pH. The aqueous layers were extracted three times with DCM. The organic combined layers were dried on MgSO4and concentrated under vacuum. The crude was purified by chromatography (Cartridge Biotage Star 25g / 60pm silica, DCM / (DCM / MeOH:90 / 10) : 100-0% : 1 CV (column volume) 100-0% to 68-32% : 10 CV 68-32% : 22 CV 68-32% to 50-50% : 5 CV 50-50% : 5 CV, Flow rate 80ml / min° to give 7-methyl-2H-pyrrolo[1 ,2-a]pyrazin-1-one (869.00 mg;

[0265] 65.15 %).1H NMR (400 MHz, DMSO-cfc) 5 ppm 10.30 (br s, 1 H), 7.21 (d, J=5.20 Hz, 2 H), 7.20 (s, 2 H), 6.66 (dd, J=1.98, 0.99 Hz, 1 H), 6.48 (d, J=5.72 Hz, 1 H), 2.15 (t, J=0.72 Hz, 3 H).

[0266] Step c: 1-chloro-7-methyl-pyrrolo[1 ,2-a]pyrazine

[0267] In a Q-tube, 7-methyl-2H-pyrrolo[1 ,2-a]pyrazin-1 -one (869.00 mg; 5.87 mmol; 1.00 eq.) and POCI3(26.07 mL; 276.29 mmol; 30.00 V) were added. The reaction mixture was heated at 110°C for 2h20. The reaction mixture was cooled down to rt and was concentrated under vacuum. Water and DCM were added and the aqueous layers were extracted three times with DCM. The organic combined layers were dried on MgSO4and concentrated under vacuum to give 1 -chloro-7-methyl-pyrrolo[1 ,2-a]pyrazine (909.00 mg;

[0268] 91.16 %).1H NMR (400 MHz, DMSO-c / 6) 5 ppm 8.24 (dd, J=4.73, 0.99 Hz, 1 H), 7.72 (d, J=2.31 Hz, 1 H), 7.28 (d, J=4.62 Hz, 1 H), 6.71 (d, J=1.32 Hz, 1 H), 2.30 (t, J=0.72 Hz, 3 H).

[0269] Step d: 1 -chloro-7-methyl-pyrrolo[1 ,2-a]pyrazine-6-carbonitrile

[0270] Under Argon, 1 -chloro-7-methyl-pyrrolo[1 ,2-a]pyrazine (50.00 mg; 0.29 mmol; 1.00 eq.) was dissolved in MeCN (686.00 pL) and cooled to 0 °C. Chlorosulfonylisocyanate (102.40 pL; 1.18 mmol; 4.00 eq.) was slowly added dropwise during 3 minutes (keeping the internal temperature below 5 °C). The reaction mixture was stirred at 0°C for 30min. Then, anhydrous DMF (181.99 pL) was added (slightly exothermic at the start) and the reaction solution became clear. The reaction mixture was stirred 15min at 0 °C. The reaction mixture was quenched on ice (gas evolution) and the yellow precipitate was filtered and washed with water. The solid was dried under vacuum to give 1 -chloro-7-methyl- pyrrolo[1 ,2-a]pyrazine-6-carbonitrile (45.00 mg; 77.45 %).1H NMR (400 MHz, DMSO-c / 6) 5 ppm 8.46 (dd, J=4.68, 0.94 Hz, 1 H), 7.66 (d, J=4.62 Hz, 1 H), 6.94 (s, 1 H), 2.44 (d, J=0.66 Hz, 3 H).

[0271] Step e: 1 -[[(E)-(3,3-dimethyl-1 -oxo-isoindolin-5-yl)methyleneamino]-ethyl-amino]-7-methyl- pyrrolo[1 ,2-a]pyrazine-6-carbonitrile

[0272] The compound was prepared using the same procedure as detailed in example 1 step g starting from 5-[(E)-(ethylhydrazono)methyl]-3,3-dimethyl-isoindolin-1 -one (76.24 mg; 0.27 mmol; 1.20 eq.) and 1 -chloro-7-methyl-pyrrolo[1 ,2-a]pyrazine-6-carbonitrile (45.00 mg; 0.23 mmol; 1.00 eq.) giving 1 -[[(E)-(3,3-dimethyl-1 -oxo-isoindolin-5-yl)methyleneamino]- ethyl-amino]-7-methyl-pyrrolo[1 ,2-a]pyrazine-6-carbonitrile (29 mg; 32.3 %) as a yellow powder.1H NMR (500 MHz, DMSO-Gfc) 5 ppm 8.71 (s, 1 H), 8.24 (s, 1 H), 7.94 - 7.96 (m, 2 H), 7.83 (dd, J=7.98, 1.10 Hz, 1 H), 7.72 (d, J=7.70 Hz, 1 H), 7.52 (d, J=4.40 Hz, 1 H), 7.36 (s, 1 H), 4.46 (q, J=6.88 Hz, 2 H), 2.41 (s, 3 H), 1.51 (s, 6 H), 1.22 (t, J=6.88 Hz, 3 H).

[0273] Example 12: 1 -[[(E)-(3,3-dimethyl-1 -oxo-isoindolin-5-yl)methyleneamino]-ethyl- amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile

[0274] Step a: (6E)-1 -chloropyrrolo[1 ,2-a]pyrazine-6-carbaldehyde oxime 1 -chloropyrrolo[1 ,2-a]pyrazine-6-carbaldehyde (10 g, 59.5 mmol, 1.0 eq.) was added to mixture of EtOH (1 18 mL), water (57 mL) and hydroxylamine hydrochloride (5.3 g, 77.3 mmol, 1 .3 eq.) and heated at 65°C until the mixture became homogeneous. When the mixture reached homogeneity, it was ice cooled and the precipitate was filtered off, washed with water, and dried, to give first crystals. Then the mother liquor was diluted with water (3x volume to the mother liquor) and the precipitated second crystals were filtered, washed with water and dried. The first and second crystals were merged and used in the next step without further purification (7.7 g, 66% yield). Step b: 1 -chloropyrrolo[1 ,2-a]pyrazine-6-carbonitrile (6E)-1 -chloropyrrolo[1 ,2-a]pyrazine-6-carbaldehyde oxime (8.3 g, 42 mmol, 1.0 eq.) was added to stirred POCI3(33.7 mL, 361 mmol, 8.5 eq.), and heated at 80-85 °C until the mixture became homogeneous (-10-15 min). The mixture was cooled, poured into water containing ice, and stirred for 30 min. The precipitate was filtered off, washed with sat. NaHCO3solution, water, and dried. The crude product was dissolved in DCM and active C (10% based on the amount of the crude product) and silica gel (the same amount as the amount of crude product) were added. The mixture was stirred at rt for 30-60 min and then active C / silica gel were filtered through a short pad of Celite®, washed with DCM and the filtrate was concentrated to provide 1 -chloropyrrolo[1 ,2-a]pyrazine-6-carbonitrile.1H NMR (400 MHz, DMSO-cfc) 5 ppm 8.54 (dd, J=4.68, 0.94 Hz, 1 H), 7.76 (d, J=4.62 Hz, 1 H), 7.72 (d, J=4.62 Hz, 1 H), 7.08 (dd, J=4.68, 0.94 Hz, 1 H).

[0275] Step c: 1 -[amino(ethyl)amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile 1 -chloropyrrolo[1 ,2-a]pyrazine-6-carbonitrile (2.63 g, 14.81 mmol, 1.0 eq.) was dissolved in dry EtOH (74.0 mL) then ethylhydrazine dihydrochloride (2.95 g, 22.21 mmol, 1.5 eq.) and TEA (8.21 mL, 59.24 mmol, 4.0 eq.) were added. The resulting mixture was stirred at 80 °C for 3-4 h. The progress of the reaction was monitored by TLC (n-heptane:EtOAc = 1 :1 ) and LCMS analyses. After completion the solvent was evaporated, and water was added to the residue. The precipitated solid was filtered, washed with 5% Na2CO3solution, water, n-heptane and dried to obtain 1 -[amino(ethyl)amino]pyrrolo[1 ,2- a]pyrazine-6-carbonitrile (1 1 , 2.3 g, 77% yield) as a yellow solid.1H NMR (400 MHz, DMSO-Gfc) 5 ppm 7.64 (dd, J=4.51 , 0.88 Hz, 1 H), 7.57 (dd, J=4.62, 0.88 Hz, 1 H), 7.34 (d, J=4.51 Hz, 1 H), 7.30 (d, J=4.62 Hz, 1 H), 4.97 (s, 2 H), 3.79 (q, J=7.04 Hz, 2 H), 1.18 (t, J=7.10 Hz, 3 H).

[0276] Step d: 1 -[[(E)-(3,3-dimethyl-1 -oxo-isoindolin-5-yl)methyleneamino]-ethyl- amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile 1 -[amino(ethyl)amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile (2.3 g, 1 1.4 mmol, 1.0 eq.) and 3,3-dimethyl-1 -oxo-isoindoline-5-carbaldehyde (2.4 g, 1 1.4 mmol, 1.0 eq.) were suspended in dry 1 ,4-dioxane (34.0 mL) and few drops of AcOH were added. The resulting mixture was stirred at 80 °C for 3-4 h. The progress of the reaction was monitored by TLC (CHCI3-MeOH=20:1 (2 runs)) and LCMS analyses. After completion sat. aq. NaHCO3solution was added and stirred at rt for 1 -2 h. The precipitated solid was filtered, washed with water, Et2O and dried to obtain 1 -[[(E)-(3,3-dimethyl-1 -oxo-isoindolin- 5-yl)methyleneamino]-ethyl-amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile (2.88 g 67% yield).1H NMR (500 MHz, DMSO-cfc) 5 ppm 8.72 (s, 1 H), 8.27 (s, 1 H), 8.03 (dd, J=4.54, 0.55 Hz, 1 H), 7.92 (s, 1 H), 7.89 (dd, J=7.84, 1.24 Hz, 1 H), 7.72 (d, J=7.84 Hz, 1 H), 7.62 (d, J=4.54 Hz, 1 H), 7.59 (d, J=4.54 Hz, 1 H), 7.53 (d, J=4.83 Hz, 1 H), 4.48 (q, J=6.83 Hz, 2 H), 1 .50 (s, 6 H), 1 .24 (t, J=6.95 Hz, 3 H).

[0277] Example 13: 1 -[[(E)-(3,3-dimethyl-1 -oxo-isoindolin-5-yl)methyleneamino]-ethyl- amino]-4-methyl-pyrrolo[1 ,2-a]pyrazine-6-carbonitrile

[0278] Step a: 1 -chloro-4-methyl-pyrrolo[1 ,2-a]pyrazine-6-carbonitrile

[0279] Under Argon, in a three-necked round bottomed flask, dried with a heat gun under vacuum and purged under argon, 1 -chloropyrrolo[1 ,2-a]pyrazine-6-carbonitrile (130.00 mg; 732.02 pmol; 1.00 eq.) in suspension in dry THF (3.90 mL) was stirred at -78°C. n- BuLi 1.6M in hexane (549.02 pL; 1.60 mol / L; 878.43 pmol; 1.20 eq.) was added dropwise and the reaction mixture was stirred at -78°C for 30 min. (brown mixture). A cold solution of Mel (911.40 pL; 10.00 %w / w; 1.46 mmol; 2.00 eq.) in THF (C=10%mol) was slowly added at -78°C, (dark brown solution). The reaction mixture was stirred at -78°C for 20 min. The reaction mixture was cooled with an ice bath at 0°C, and quenched with a solution of sat.NH4CI and EtOAc. After 15 min of stirring at 0°C, the mixture was extracted twice with EtOAc. The organic layer was dried over MgSO4and concentrated. The residue was purified by chromatography (Cartridge Biotage Star HC Duo 5g ; flow rate =25ml / min ; UV=254 / 245nm, Sample adsorbed on silica, gradient: cyclohexan / EtOac: 3CV 5% EtOAc, 15CV 5% to 20% EtOAc, 5CV 20% to 40% EtOAc, 3CV 40% to 60% EtOAc, 1 CV 60% EtOAc) to give 1 -chloro-4-methyl-pyrrolo[1 ,2-a]pyrazine-6-carbonitrile (66.00 mg; 40.94 %) as a beige solid.1H NMR (400 MHz, DMSO-c / 6) 5 ppm 7.80 (d, J=4.62 Hz, 1 H), 7.54 (d, J=0.99 Hz, 1 H), 7.08 (d, J=4.73 Hz, 1 H), 2.85 (d, J=1.10 Hz, 3 H).

[0280] Step b: 1 -[amino(ethyl)amino]-4-methyl-pyrrolo[1 ,2-a]pyrazine-6-carbonitrile

[0281] The compound was prepared using the same procedure as detailed in example 12 step c starting from ethylhydrazine dihydrochloride (133.29 mg; 1 002.00 pmol; 3.00 eq.) and 1 - chloro-4-methyl-pyrrolo[1 ,2-a]pyrazine-6-carbonitrile (64.00 mg; 334.00 pmol; 1.00 eq.) giving 1 -[amino(ethyl)amino]-4-methyl-pyrrolo[1 ,2-a]pyrazine-6-carbonitrile (50 mg; 69.5 %) as a beige powder.1H NMR (400 MHz, DMSO-c / 6) 5 ppm 7.67 (d, J=4.62 Hz, 1 H), 7.40 (d, J=4.62 Hz, 1 H), 7.05 (d, J=0.99 Hz, 1 H), 3.72 (q, J=7.08 Hz, 2 H), 2.66 (s, 3 H), 1.16 (t, J=7.10 Hz, 4 H).

[0282] Step c: 1 -[[(E)-(3,3-dimethyl-1 -oxo-isoindolin-5-yl)methyleneamino]-ethyl-amino]-4-methyl- pyrrolo[1 ,2-a]pyrazine-6-carbonitrile

[0283] The compound was prepared using the same procedure as detailed in example 12 step d starting from 3,3-dimethyl-1 -oxo-isoindoline-5-carbaldehyde (35.60 mg; 188.15 pmol; 0.90 eq.) and 1 -[amino(ethyl)amino]-4-methyl-pyrrolo[1 ,2-a]pyrazine-6-carbonitrile (45.00 mg; 209.05 pmol; 1.00 eq.) giving 1 -[[(E)-(3,3-dimethyl-1 -oxo-isoindolin-5-yl)methyleneamino]- ethyl-amino]-4-methyl-pyrrolo[1 ,2-a]pyrazine-6-carbonitrile (15 mg; 18.6 %) as a yellow powder.1H NMR (500 MHz, DMSO-cfc) 6 ppm 8.70 (s, 1 H), 8.20 (s, 1 H), 7.89 (s, 1 H), 7.86 (dd, J=7.70, 1.10 Hz, 1 H), 7.69 (d, J=7.70 Hz, 1 H), 7.66 (d, J=4.40 Hz, 1 H), 7.61 (d, J=4.68 Hz, 1 H), 7.35 (s, 1 H), 4.44 (q, J=6.88 Hz, 2 H), 2.79 (s, 3 H), 1.49 (s, 6 H), 1.22 (t, J=6.88 Hz, 3 H).

[0284] Example 14: 8-bromo-1 -[[(E)-(3,3-dimethyl-1 -oxo-isoindolin-5-yl)methyleneamino]- ethyl-amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile

[0285] Step a: 8-bromo-1 -chloro-pyrrolo[1 ,2-a]pyrazine-6-carbonitrile

[0286] In a 25ml round bottom flask, 1 -chloropyrrolo[1 ,2-a]pyrazine-6-carbonitrile (150.00 mg; 0.79 mmol; 1.00 eq.) was dissolved in DCM (5.90 mL). At RT, NBS (309.57 mg; 1.74 mmol; 2.20 eq.) was added and the reaction mixture was stirred at 45°C. Addition of NBS (154.78 mg; 0.87 mmol; 1 .10 eq.) was done twice (every 20 hours) keeping the reaction at 45°C. The reaction mixture was concentrated to dryness. The crude was purified by chromatography on silica gel. The solid obtained was triturated in 2ml cold MeCN, filtered and washed with cold CH3CN to give 8-bromo-1 -chloro-pyrrolo[1 ,2-a]pyrazine-6- carbonitrile (173.00 mg; 85.32 %) as a yellow solid.1H NMR (500 MHz, DMSO-c / 6) 5 ppm 8.57 (d, J=4.68 Hz, 1 H), 7.99 (s, 1 H), 7.73 (d, J=4.68 Hz, 1 H).

[0287] Step b: 1 -[amino(ethyl)amino]-8-bromo-pyrrolo[1 ,2-a]pyrazine-6-carbonitrile

[0288] The compound was prepared using the same procedure as detailed in example 12 step c starting from ethylhydrazine dihydrochloride (88.17 mg; 0.66 mmol; 2.00 eq.) and 8- bromo-1 -chloro-pyrrolo[1 ,2-a]pyrazine-6-carbonitrile (85.00 mg; 0.33 mmol; 1.00 eq.) giving 1 -[amino(ethyl)amino]-8-bromo-pyrrolo[1 ,2-a]pyrazine-6-carbonitrile (69 mg; 74.3 %) as an orange oil.1H NMR (500 MHz, DMSO-c / 6) 6 ppm 8.03 (d, J=4.68 Hz, 1 H), 7.74 (s, 1 H), 7.48 (d, J=4.54 Hz, 1 H), 4.59 (br s, 2 H), 3.36 (m, 2 H), 1 .22 (t, J=7.02 Hz, 5 H). Step c: 8-bromo-1 -[[(E)-(3,3-dimethyl-1 -oxo-isoindolin-5-yl)methyleneamino]-ethyl- amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile

[0289] The compound was prepared using the same procedure as detailed in example 12 step d starting from 3,3-dimethyl-1 -oxo-isoindoline-5-carbaldehyde (44.58 mg; 0.24 mmol; 1.00 eq.) and 1 -[amino(ethyl)amino]-8-bromo-pyrrolo[1 ,2-a]pyrazine-6-carbonitrile (66.00 mg; 0.24 mmol; 1.00 eq.) giving 8-bromo-1 -[[(E)-(3,3-dimethyl-1 -oxo-isoindolin-5- yl)methyleneamino]-ethyl-amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile (40 mg; 37.6 %) as an off white powder.1H NMR (500 MHz, DMSO-c / 6) 5 ppm 8.64 (s, 1 H), 8.18 (d, J=4.68 Hz, 1 H), 8.12 (s, 1 H), 7.86 (s, 1 H), 7.81 (s, 1 H), 7.73 (d, J=7.98 Hz, 1 H), 7.59 - 7.61 (m, 2 H), 4.32 (q, J=6.97 Hz, 2 H), 1 .44 (s, 6 H), 1 .30 (t, J=6.88 Hz, 3 H).

[0290] Example 15: 8-chloro-1 -[[(E)-(3,3-dimethyl-1 -oxo-isoindolin-5-yl)methyleneamino]- ethyl-amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile

[0291] Step a: 1 ,8-dichloropyrrolo[1 ,2-a]pyrazine-6-carbonitrile In a 1 mL round-bottomed flask, 1 -chloropyrrolo[1 ,2-a]pyrazine-6-carbonitrile (70.00 mg; 0.39 mmol; 1 .00 eq.) was dissolved in CHCI3(3.50 mL). At rt, N-chlorosuccinimide (210.54 mg; 1.58 mmol; 4.00 eq.) was added and the reaction mixture was stirred at 60°C for 4 hours. Addition of NCS (65.00 mg; 0.49 mmol; 1 .23 eq.) was done ten times every 2 hours while keeping the reaction at 60°C. The reaction mixture was diluted in EtOAc and washed with NaOH 1 M, the organic layer was washed with water. The organic layer was dried over MgSO4, filtered and concentrated under reduced pressure to give 1 ,8- dichloropyrrolo[1 ,2-a]pyrazine-6-carbonitrile (80.00 mg; 86.15 %).1H NMR (400 MHz, DMSO-Gfc) 5 ppm 8.53 (d, J=4.73 Hz, 1 H), 7.95 (s, 1 H), 7.73 (d, J=4.73 Hz, 1 H).

[0292] Step b: 1 -[amino(ethyl)amino]-8-chloro-pyrrolo[1 ,2-a]pyrazine-6-carbonitrile

[0293] The compound was prepared using the same procedure as detailed in example 12 step c starting from ethylhydrazine dihydrochloride (108.41 mg; 0.81 mmol; 4.00 eq.) and 1 ,8- dichloropyrrolo[1 ,2-a]pyrazine-6-carbonitrile (48.00 mg; 0.20 mmol; 1.00 eq.) giving 1 - [amino(ethyl)amino]-8-chloro-pyrrolo[1 ,2-a]pyrazine-6-carbonitrile (23 mg; 47.9 %) as an orange solid.1H NMR (400 MHz, DMSO-c / 6) 5 ppm 7.97 (d, J=4.73 Hz, 1 H), 7.67 (s, 1 H), 7.46 (d, J=4.73 Hz, 1 H), 4.62 (s, 2 H), 3.38 (q, J=7.04 Hz, 2 H), 1.23 (t, J=6.99 Hz, 4 H).

[0294] Step c: 8-chloro-1 -[[(E)-(3,3-dimethyl-1 -oxo-isoindolin-5-yl)methyleneamino]-ethyl- amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile

[0295] The compound was prepared using the same procedure as detailed in example 12 step d starting from 3,3-dimethyl-1 -oxo-isoindoline-5-carbaldehyde (23.28 mg; 0.12 mmol; 1.00 eq.) and 1 -[amino(ethyl)amino]-8-chloro-pyrrolo[1 ,2-a]pyrazine-6-carbonitrile (29.00 mg; 0.12 mmol; 1.00 eq.) giving 8-chloro-1 -[[(E)-(3,3-dimethyl-1 -oxo-isoindolin-5- yl)methyleneamino]-ethyl-amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile (32 mg; 60.2 %) as a yellow powder.1H NMR (500 MHz, DMSO-c / 6) 5 ppm 8.64 (s, 1 H), 8.13 - 8.15 (m, 2 H), 7.82 (s, 1 H), 7.80 (s, 1 H), 7.74 (dd, J=7.84, 0.96 Hz, 1 H), 7.59 - 7.61 (m, 2 H), 4.33 (q, J=6.60 Hz, 2 H), 1.44 (s, 6 H), 1.29 (t, J=6.88 Hz, 3 H). mp : 232-245°C.

[0296] Example 16: 1 -[[(E)-(3,3-dimethyl-1 -oxo-isoindolin-5-yl)methyleneamino]-ethyl- amino]-8-fluoro-pyrrolo[1 ,2-a]pyrazine-6-carbonitrile

[0297] Step a: 1 -chloro-8-fluoro-pyrrolo[1 ,2-a]pyrazine-6-carbonitrile

[0298] In a 5mL round-bottomed flask, with condenser, under Argon, to 1 -chloropyrrolo[1 ,2- a]pyrazine-6-carbonitrile (500.00 mg; 2.82 mmol; 1.00 eq.) in suspension in DMF (12.50 mL) were added 1 -chloromethyl-4-fluoro-1 ,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (1.99 g; 5.63 mmol; 2.00 eq.) and AcOH (322.66 pL; 5.63 mmol; 2.00 eq.). The reaction mixture was stirred at 50°C for 50h. The reaction mixture was quenched with water and extracted with EtOAc (3 times). The organic layer was washed with brine, then dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified via prep LC-MS (method B) to give 1 -chloro-8-fluoro-pyrrolo[1 ,2- a]pyrazine-6-carbonitrile (90.00 mg; 15.36 %) as a beige solid.1H NMR (400 MHz, DMSO-Gfc) 5 ppm 8.46 (dd, J=4.84, 1.87 Hz, 2 H), 7.79 (s, 2 H), 7.66 (d, J=4.73 Hz, 2 H).

[0299] Step b: 1 -[amino(ethyl)amino]-8-fluoro-pyrrolo[1 ,2-a]pyrazine-6-carbonitrile

[0300] The compound was prepared using the same procedure as detailed in example 12 step c starting from ethylhydrazine dihydrochloride (40.00 mg; 0.19 mmol; 1.00 eq.) and 1 - chloro-8-fluoro-pyrrolo[1 ,2-a]pyrazine-6-carbonitrile (102.29 mg; 0.77 mmol; 4.00 eq.) giving 1 -[amino(ethyl)amino]-8-fluoro-pyrrolo[1 ,2-a]pyrazine-6-carbonitrile (15 mg; 35.6 %) as a yellow solid which was used in the next step without further purification.

[0301] Step c: 1 -[[(E)-(3,3-dimethyl-1 -oxo-isoindolin-5-yl)methyleneamino]-ethyl-amino]-8-fluoro- pyrrolo[1 ,2-a]pyrazine-6-carbonitrile

[0302] The compound was prepared using the same procedure as detailed in example 12 step d starting from 3,3-dimethyl-1 -oxo-isoindoline-5-carbaldehyde (12.95 mg; 0.07 mmol; 1.00 eq.) and 1 -[amino(ethyl)amino]-8-fluoro-pyrrolo[1 ,2-a]pyrazine-6-carbonitrile (15.00 mg; 0.07 mmol; 1.00 eq.) giving 1 -[[(E)-(3,3-dimethyl-1 -oxo-isoindolin-5-yl)methyleneamino]- ethyl-amino]-8-fluoro-pyrrolo[1 ,2-a]pyrazine-6-carbonitrile (9.5 mg; 35.6 %) as a pale yellow powder.1H NMR (500 MHz, DMSO-c / 6) 5 ppm 8.67 (s, 1 H), 8.21 (s, 1 H), 7.98 (dd, J=4.68, 1.10 Hz, 1 H), 7.88 (s, 1 H), 7.80 (d, J=7.98 Hz, 1 H), 7.61 - 7.63 (m, 2 H), 7.50 (d, J=4.68 Hz, 1 H), 4.39 (q, J=6.88 Hz, 2 H), 1 .45 (s, 6 H), 1 .25 (t, J=6.88 Hz, 3 H).

[0303] Example 17: 1-[[(E)-(3,3-dimethyl-1-oxo-isoindolin-5-yl)methyleneamino]-methyl- amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile

[0304] Step a: 1 -[amino(methyl)amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile

[0305] The compound was prepared using the same procedure as detailed in example 12 step c starting from 1 -chloropyrrolo[1 ,2-a]pyrazine-6-carbonitrile (36.00 mg; 195.82 pmol; 1.00 eq.) and methyl hydrazine (36.00 mg; 195.82 pmol; 1.00 eq.) giving (40 mg; 87.3 %) as a pale-yellow solid.1H NMR (400 MHz, DMSO-c / 6) 5 ppm 7.66 (dd, J=4.62, 0.77 Hz, 1 H), 7.54 (dd, J=4.62, 0.88 Hz, 1 H), 7.35 (d, J=4.51 Hz, 1 H), 7.31 (d, J=4.62 Hz, 1 H), 5.05 (s, 2 H), 2.60 (s, 3 H).

[0306] Step b: 1 -[[(E)-(3,3-dimethyl-1 -oxo-isoindolin-5-yl)methyleneamino]-methyl- amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile

[0307] The compound was prepared using the same procedure as detailed in example 12 step d starting from 3,3-dimethyl-1 -oxo-isoindoline-5-carbaldehyde (37.05 mg; 195.82 pmol; 1.00 eq.) and 1 -[amino(methyl)amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile (36 mg; 195.82 pmol; 1.00 eq.) giving 1 -[[(E)-(3,3-dimethyl-1 -oxo-isoindolin-5-yl)methyleneamino]-methyl- amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile (44 mg; 66.7 %) as an off white powder.1H NMR (500 MHz, DMSO-d6) 5 ppm 8.72 (s, 1 H), 8.19 (s, 1 H), 8.03 (dd, J=4.68, 0.83 Hz, 1 H), 7.89 (s, 1 H), 7.88 (d, J=8.88 Hz, 1 H), 7.71 (d, J=7.98 Hz, 1 H), 7.63 (d, J=4.68 Hz, 1 H), 7.55 - 7.58 (m, 2 H), 3.76 (s, 3 H), 1 .49 (s, 6 H).

[0308] Example 18: 1-[[(E)-(3,3-dimethyl-1-oxo-isoindolin-5-yl)methyleneamino]-isopropyl- amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile

[0309] Step a: 1 -[amino(isopropyl)amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile

[0310] The compound was prepared using the same procedure as detailed in example 12 step c starting from 1 -chloropyrrolo[1 ,2-a]pyrazine-6-carbonitrile (80.00 mg; 0.43 mmol; 1.00 eq.) and isopropylhydrazine hydrochloride (57.15 mg; 0.52 mmol; 1.20 eq.) giving 1 - [amino(isopropyl)amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile (45 mg; 48.5 %) as a beige powder.1H NMR (400 MHz, DMSO-c / 6) 5 ppm 7.64 (dd, J=4.62, 0.88 Hz, 1 H), 7.59 (dd, J=4.51 , 0.88 Hz, 1 H), 7.35 (d, J=4.51 Hz, 1 H), 7.31 (d, J=4.51 Hz, 1 H), 5.00 (quin, J=6.68 Hz, 1 H), 4.64 (s, 2 H), 1.15 (d, J=6.71 Hz, 6 H)

[0311] Step b: 1 -[[(E)-(3,3-dimethyl-1 -oxo-isoindolin-5-yl)methyleneamino]-isopropyl- amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile

[0312] The compound was prepared using the same procedure as detailed in example 12 step d starting from 3,3-dimethyl-1 -oxo-isoindoline-5-carbaldehyde (43.00 mg; 0.23 mmol; 1.00 eq.) and 1 -[amino(isopropyl)amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile (48.92 mg; 0.23 mmol; 1.00 eq.) giving 1 -[[(E)-(3,3-dimethyl-1 -oxo-isoindolin-5-yl)methyleneamino]- isopropyl-amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile (56 mg; 63.8 %) as a yellow powder.1H NMR (500 MHz, DMSO-d6) 5 ppm 8.69 (s, 1 H), 8.35 (s, 1 H), 8.06 (d, J=4.68 Hz, 1 H), 7.90 (s, 1 H), 7.84 (d, J=7.98 Hz, 1 H), 7.67 (d, J=7.98 Hz, 1 H), 7.59 (t, J=5.23 Hz, 2 H), 7.27 (d, J=4.40 Hz, 1 H), 5.34 - 5.42 (m, 1 H), 1 .56 (d, J=6.88 Hz, 6 H), 1 .47 (s, 6 H). mp : 217-229°C.

[0313] Example 19: 1 -[[(E)-(3,3-dimethyl-1 -oxo-isoindolin-5-yl)methyleneamino]-(2- hydroxyethyl) amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile

[0314] Step a: 1 -[amino(2-hydroxyethyl)amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile

[0315] The compound was prepared using the same procedure as detailed in example 12 step c starting from 1 -chloropyrrolo[1 ,2-a]pyrazine-6-carbonitrile (80.0 mg, 0.45 mmol, 1.0 eq.) and 2-hydrazinylethanol (61.0 pL, 0.90 mmol, 2.0 eq.) giving 1 -[amino(2-hydroxyethyl) amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile (70 mg; 71.5 %) as a beige powder. ES+ MS m / z 218 [M+H]+.

[0316] Step b: 1 -[[(E)-(3,3-dimethyl-1 -oxo-isoindolin-5-yl)methyleneamino]-(2- hydroxyethyl)amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile

[0317] The compound was prepared using the same procedure as detailed in example 12 step d starting from 3,3-dimethyl-1 -oxo-isoindoline-5-carbaldehyde (67.0 mg, 0.35 mmol, 1.1 eq.) and 1 -[amino(2-hydroxyethyl)amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile (70.0 mg, 0.32 mmol, 1.0 eq.) giving 1 -[[(E)-(3,3-dimethyl-1 -oxo-isoindolin-5-yl)methyleneamino]-(2- hydroxyethyl)amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile (34.0 mg 27 %) as a brown solid.1H NMR (500 MHz, DMSO-cfc): 5 8.72 (s, 1 H), 8.38 (s, 1 H), 8.02 (d, J= 4.4 Hz, 1 H), 7.88 (s, 1 H), 7.85 (d, J= 8.0 Hz, 1 H), 7.7 (d, J= 7.8 Hz, 1 H), 7.61 (d, J= 4.4 Hz, 1 H), 7.54 (dd, J= 19.3 and 4.4 Hz, 2 H), 4.98 (t, J= 5.5 Hz, 1 H), 4.51 (t, J= 6.3 Hz, 2 H), 3.72 (q, J= 6.0 Hz, 2 H), 1 .49 (s, 6 H). Mp: 258-259 °C

[0318] Example 20: 1 -[[(E)-(3,3-dimethyl-1 -oxo-isoindolin-5-yl)methyleneamino]-(3- hydroxypropyl)amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile

[0319] Step a: 1 -[amino(3-hydroxypropyl)amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile

[0320] The compound was prepared using the same procedure as detailed in example 12 step c starting from 1 -chloropyrrolo[1 ,2-a]pyrazine-6-carbonitrile (200.00 mg; 1.07 mmol; 1.00 eq.) and hydrazinylpropan-1 -ol (290.49 mg; 3.22 mmol; 3.00 eq.) giving 1 -[amino(3- hydroxypropyl)amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile (201 mg; 80.9 %) as a paleyellow powder.1H NMR (400 MHz, DMSO-c / 6) 5 ppm 7.63 (dd, J=4.57, 0.83 Hz, 1 H), 7.58 (dd, J=4.62, 0.88 Hz, 1 H), 7.34 (d, J=4.62 Hz, 1 H), 7.29 (d, J=4.62 Hz, 1 H), 5.01 (s, 2 H), 4.58 (t, J=5.17 Hz, 1 H), 3.82 (m, 2 H), 3.47 (m, 2 H), 1.83 (m, 2 H).

[0321] Step b: 1 -[[(E)-(3,3-dimethyl-1 -oxo-isoindolin-5-yl)methyleneamino]-(3- hydroxypropyl)amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile

[0322] The compound was prepared using the same procedure as detailed in example 12 step d starting from 3,3-dimethyl-1 -oxo-isoindoline-5-carbaldehyde (200 mg; 0.86 mmol; 1 eq.) and 1 -[amino(3-hydroxypropyl)amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile (196.37 mg; 1.04 mmol; 1.20 eq.) giving 1 -[[(E)-(3,3-dimethyl-1 -oxo-isoindolin-5-yl)methyleneamino]- (3-hydroxypropyl)amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile (269 mg; 77.3 %) as a pale yellow powder.1H NMR (500 MHz, DMSO-c / 6) 5 ppm 8.72 (s, 1 H), 8.26 (s, 1 H), 8.00 - 8.05 (m, 1 H), 7.85 - 7.90 (m, 2 H), 7.71 (d, J=7.70 Hz, 1 H), 7.62 (d, J=4.40 Hz, 1 H), 7.58 (d, J=4.68 Hz, 1 H), 7.53 (d, J=4.88 Hz, 1 H), 4.69 (br s, 1 H), 4.48 (br t, J=7.43 Hz, 2 H), 3.56 (br t, J=5.91 Hz, 2 H), 1.78 - 1 .90 (m, 2 H), 1 .50 (s, 6 H). mp : 246-261 °C.

[0323] Example 21 : 1-[[(E)-(3,3-dimethyl-1-oxo-isoindolin-5-yl)methyleneamino]-(4- hydroxybutyl) amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile

[0324] Step a: 1 -[amino(4-hydroxybutyl)amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile

[0325] The compound was prepared using the same procedure as detailed in example 12 step c starting from 1 -chloropyrrolo[1 ,2-a]pyrazine-6-carbonitrile (80.00 mg; 0.43 mmol; 1.00 eq.) and 4-hydrazino-1 -butanol (142.23 mg; 1.30 mmol; 3.00 eq.) giving 1 -[amino(4- hydroxybutyl)amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile (68 mg; 57.0 %) as a pale-yellow powder.1H NMR (400 MHz, DMSO-d6) 5 ppm 7.63 (dd, J=4.57, 0.83 Hz, 1 H), 7.57 (dd, J=4.62, 0.88 Hz, 1 H), 7.34 (d, J=4.62 Hz, 1 H), 7.29 (d, J=4.62 Hz, 1 H), 4.96 (s, 2 H), 4.39 (t, J=5.12 Hz, 1 H), 3.77 (m, 2 H), 3.43 (td, J=6.46, 5.34 Hz, 2 H), 1.70 (m, 2 H), 1.43 (m, 2 H).

[0326] Step b: 1 -[[(E)-(3,3-dimethyl-1 -oxo-isoindolin-5-yl)methyleneamino]-(4-hydroxybutyl) amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile

[0327] The compound was prepared using the same procedure as detailed in example 12 step d starting from 3,3-dimethyl-1 -oxo-isoindoline-5-carbaldehyde (50.91 mg; 0.27 mmol; 1.00 eq.) and 1 -[amino(4-hydroxybutyl)amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile (66.00 mg; 0.27 mmol; 1.00 eq.) giving 1 -[[(E)-(3,3-dimethyl-1 -oxo-isoindolin-5-yl)methyleneamino]- (4-hydroxybutyl)amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile (70 mg; 62.5 %) as a yellow powder.1H NMR (500 MHz, DMSO-c / 6) 5 ppm 8.71 (s, 1 H), 8.24 (s, 1 H), 8.02 (dd, J=4.68, 0.83 Hz, 1 H), 7.90 (s, 1 H), 7.88 (d, J=7.66 Hz, 1 H), 7.71 (d, J=7.98 Hz, 1 H), 7.62 (d, J=4.68 Hz, 1 H), 7.58 (d, J=4.68 Hz, 1 H), 7.53 (d, J=4.31 Hz, 1 H), 4.49 (t, J=4.95 Hz, 1 H), 4.44 (br t, J=7.70 Hz, 2 H), 3.46 - 3.49 (m, 2 H), 1.68 - 1.74 (m, 2 H),

[0328] 1.51 - 1.58 (m, 2 H), 1.50 (s, 6 H).

[0329] Example 22: 1 -[[(E)-(3,3-dimethyl-1 -oxo-isoindolin-5-yl)methyleneamino]-(2- methoxyethyl)amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile

[0330] Step a: 1 -[amino(2-methoxyethyl)amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile

[0331] The compound was prepared using the same procedure as detailed in example 12 step c starting from 1 -chloropyrrolo[1 ,2-a]pyrazine-6-carbonitrile (50.0 mg, 0.28 mmol, 1.0 eq.) and (2-methoxyethyl)hydrazine dihydrochloride (76.0 mg, 0.85 mmol, 3.0 eq.) giving 1 - [amino(2-methoxyethyl)amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile (30 mg; 46 %) as a beige powder. ES+ MS m / z 232 [M+H]+.

[0332] Step b: 1 -[[(E)-(3,3-dimethyl-1 -oxo-isoindolin-5-yl)methyleneamino]-(2- methoxyethyl)amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile

[0333] The compound was prepared using the same procedure as detailed in example 12 step d starting from 3,3-dimethyl-1 -oxo-isoindoline-5-carbaldehyde (27.0 mg, 0.14 mmol, 1.1 eq.) and 1 -[amino(2-methoxyethyl)amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile (30.0 mg, 0.13 mmol, 1.0 eq.) giving 1 -[[(E)-(3,3-dimethyl-1 -oxo-isoindolin-5-yl)methyleneamino]-(2- methoxyethyl)amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile (24 mg; 46 %) as a green solid.1H NMR (500 MHz, DMSO-cfc): 5 8.72 (s, 1 H), 8.34 (s, 1 H), 8.02 (d, J= 4.5 Hz, 1 H), 7.89 (s, 1 H), 7.86 (d, J= 8.0 Hz, 1 H), 7.70 (d, J= 7.8 Hz, 1 H), 7.59 (dd, J= 22.2 4.5 Hz, 2 H),

[0334] 7.51 (d, J= 4.5 Hz, 1 H), 4.63 (t, J= 6.0 Hz, 2 H), 3.67 (t, J= 6.0 Hz, 2 H), 3.28 (s, 3 H), 1.49 (s, 3 H). mp: 228-229 °C.

[0335] Example 23: 1 -[[(E)-(3,3-dimethyl-1 -oxo-isoindolin-5-yl)methyleneamino]-(2- isopropoxyethyl) amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile

[0336] Step a: 1 -[amino(2-isopropoxyethyl)amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile The compound was prepared using the same procedure as detailed in example 12 step c starting from 1 -chloropyrrolo[1 ,2-a]pyrazine-6-carbonitrile (150.00 mg; 0.81 mmol; 1.00 eq.) and [2-(propan-2-yloxy)ethyl]hydrazine dihydrochloride (461.96 mg; 2.42 mmol; 3.00 eq.) giving 1 -[amino(2-isopropoxyethyl)amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile (155 mg; 65.5 %) as a yellow oil.1H NMR (400 MHz, DMSO-c / 6) 6 ppm 7.66 (dd, J=4.62, 0.88 Hz, 1 H), 7.57 (dd, J=4.51 , 0.88 Hz, 1 H), 7.35 (d, J=4.62 Hz, 1 H), 7.30 (d, J=4.62 Hz, 1 H), 5.02 (s, 2 H), 3.91 (m, 2 H), 3.69 (m, 2 H), 3.57 (quin, J=6.08 Hz, 1 H), 1 .07 (m, 6 H). Step b: 1 -[[(E)-(3,3-dimethyl-1 -oxo-isoindolin-5-yl)methyleneamino]-(2-isopropoxyethyl)- amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile

[0337] The compound was prepared using the same procedure as detailed in example 12 step d starting from 3,3-dimethyl-1 -oxo-isoindoline-5-carbaldehyde (1 19.43 mg; 0.63 mmol; 1.20 eq.) and 1 -[amino(2-isopropoxyethyl)amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile (155.00 mg; 0.53 mmol; 1.00 eq.) giving 1 -[[(E)-(3,3-dimethyl-1 -oxo-isoindolin-5- yl)methyleneamino]-(2-isopropoxyethyl)amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile (150 mg; 66.2 %) as an off white powder.1H NMR (500 MHz, DMSO-c / 6) 5 ppm 8.72 (s, 1 H), 8.39 (s, 1 H), 8.03 (d, J=4.68 Hz, 1 H), 7.88 (s, 1 H), 7.85 (d, J=7.98 Hz, 1 H), 7.71 (d, J=7.70 Hz, 1 H), 7.62 (d, J=4.40 Hz, 1 H), 7.58 (d, J=4.68 Hz, 1 H), 7.52 (d, J=4.40 Hz, 1 H), 4.59 (t, J=6.05 Hz, 2 H), 3.70 (t, J=6.33 Hz, 2 H), 3.57 - 3.64 (m, 1 H), 1.49 (s, 6 H), 1.06 (d, J=6.05 Hz, 6 H). mp : 195-206°C.

[0338] Example 24: 1 -[[(E)-(3,3-dimethyl-1 -oxo-isoindolin-5-yl)methyleneamino]-(3- methoxypropyl)amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile

[0339] Step a: 1 -[amino(3-methoxypropyl)amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile

[0340] The compound was prepared using the same procedure as detailed in example 12 step c starting from 1 -chloropyrrolo[1 ,2-a]pyrazine-6-carbonitrile (60.0 mg, 0.34 mmol, 1.0 eq.) and (3-methoxypropyl)hydrazine dihydrochloride (77.4 mg, 0.74 mmol, 2.2 eq.) giving 1 - [amino(3-methoxypropyl)amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile (82.8 mg; 99 %) as a beige powder. ES+ MS m / z 246 [M+H]+

[0341] Step b: 1 -[[(E)-(3,3-dimethyl-1 -oxo-isoindolin-5-yl)methyleneamino]-(3-methoxypropyl)- amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile

[0342] The compound was prepared using the same procedure as detailed in example 12 step d starting from 3,3-dimethyl-1 -oxo-isoindoline-5-carbaldehyde (70.0 mg, 0.37 mmol, 1.1 eq.) and 1 -[amino(3-methoxypropyl)amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile (98.0 mg, 0.34 mmol, 1.0 eq.) giving 1 -[[(E)-(3,3-dimethyl-1 -oxo-isoindolin-5-yl)methyleneamino]-(3- methoxypropyl)amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile (89.7 mg; 63 %) as a yellow powder.1H NMR (500 MHz, DMSO-cfc): 6 8.71 (s, 1 H), 8.22 (s, 1 H), 8.02 (d, J= 4.5 Hz, 1 H), 7.89 (s, 1 H), 7.86 (d, J= 8.0 Hz, 1 H), 7.70 (d, J= 7.8 Hz, 1 H), 7.62 (d, J= 4.5 Hz, 1 H), 7.58 (d, J= 4.5 Hz, 1 H), 7.51 (d, J= 4.6 Hz, 1 H), 4.47 (t, J= 7.4 Hz, 2H), 3.45 (t, J= 6.0 Hz, 2H), 3.26 (s, 3H), 1.91 (quint, J= 6.9 Hz, 2H), 1.49 (s, 6H). mp: 216-219 °C.

[0343] Example 25: 1 -[[(E)-(3,3-dimethyl-1 -oxo-isoindolin-5-yl)methyleneamino]- tetrahydrofuran-3-yl-amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile

[0344] Step a: 1 -[amino(tetrahydrofuran-3-yl)amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile

[0345] The compound was prepared using the same procedure as detailed in example 12 step c starting from 1 -chloropyrrolo[1 ,2-a]pyrazine-6-carbonitrile (80.00 mg; 0.45 mmol; 1.00 eq.) and (tetrahydro-3-furanyl)hydrazine hydrochloride (156.08 mg; 1.13 mmol; 2.50 eq.) giving 1 -[amino(tetrahydrofuran-3-yl)amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile (59 mg; 53.8 %) as a yellow powder.1H NMR (400 MHz, DMSO-c / 6) 5 ppm 7.73 (dd, J=4.62, 0.88 Hz, 1 H), 7.52 (dd, J=4.51 , 0.88 Hz, 1 H), 7.39 (d, J=4.51 Hz, 1 H), 7.33 (d, J=4.62 Hz, 1 H), 5.35 (m, 1 H), 4.03 (d, J=1.10 Hz, 1 H), 3.86 (m, 2 H), 3.68 (m, 1 H), 2.13 (m, 2 H).

[0346] Step b: 1 -[[(E)-(3,3-dimethyl-1 -oxo-isoindolin-5-yl)methyleneamino]-tetrahydrofuran-3-yl- amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile

[0347] The compound was prepared using the same procedure as detailed in example 12 step d starting from 3,3-dimethyl-1 -oxo-isoindoline-5-carbaldehyde (42.78 mg; 0.23 mmol; 1.00 eq.) and 1 -[amino(tetrahydrofuran-3-yl)amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile (55.00 mg; 0.23 mmol; 1.00 eq.) giving 1 -[[(E)-(3,3-dimethyl-1 -oxo-isoindolin-5- yl)methyleneamino]-tetrahydrofuran-3-yl-amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile (38 mg; 40.5 %) as a yellow powder.1H NMR (500 MHz, DMSO-c / 6) 5 ppm 8.71 (s, 1 H), 8.32 (s, 1 H), 8.10 (d, J=4.68 Hz, 1 H), 7.78 - 7.83 (m, 2 H), 7.68 (d, J=7.70 Hz, 1 H), 7.62 (br d, J=4.40 Hz, 1 H), 7.60 (br d, J=4.68 Hz, 1 H), 7.33 (br d, J=4.40 Hz, 1 H), 6.06 (br s, 1 H), 4.30 - 4.36 (m, 1 H), 4.12 (br dd, J=9.49, 4.81 Hz, 1 H), 3.95 (br t, J=9.35 Hz, 1 H), 3.75 (q, J=7.98 Hz, 1 H), 2.32 - 2.39 (m, 1 H), 2.19 - 2.26 (m, 1 H), 1.48 (br d, J=3.85 Hz, 6 H). mp : 250-260°C.

[0348] Example 26: 1 -[[(E)-(3,3-dimethyl-1 -oxo-isoindolin-5-yl)methyleneamino]-[2-(2- methoxyethoxy)ethyl]amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile

[0349] Step a: tert-butyl N-(1 ,3-dioxoisoindolin-2-yl)-N-[2-(2-methoxyethoxy)ethyl]carbamate

[0350] In a 250 ml round bottom flask with a condenser, under nitrogen, carbamic acid, n-(1 ,3- dihydro-1 ,3-dioxo-2h-isoindol-2-yl)-, 1 ,1 -dimethylethyl ester (500.00 mg; 1.91 mmol; 1.00 eq.) was dissolved in MeCN (50.00 mL) at rt. 1 -(2-bromoethoxy)-2-methoxyethane (510.00 pL; 3.79 mmol; 1.99 eq.), BTEAC (170.00 mg; 0.75 mmol; 0.39 eq.) and K2CO398% (790.00 mg; 5.72 mmol; 3.00 eq.) were added and the mixture was stirred at 60°C overnight (Dry-Syn temperature). The mixture was diluted in 100 mL of water, extracted one time with 100 mL and twice with 50 mL of EtOAc (+ solid NaCI to help decantation). The combined organic layers were dried over MgSO4, filtered and concentrated under vacuum. The crude was purified by chromatography (Cartridge Biotage Star 25 g 60 pm silica, cyclohexane-EtOAc 100-0 / 2 CV (column volume) 100-0 to 60-40 / 10 CV 60-40 / 5 CV flow rate 80 ml / min) to give tert-butyl N-(1 ,3-dioxoisoindolin-2-yl)-N-[2-(2- methoxyethoxy)ethyl]carbamate (625.00 mg; 89.97 %) as a colorless oil.1H NMR (400 MHz, DMSO-Gfc) 5 ppm 7.95 (m, 4 H), 3.72 (m, 2 H), 3.56 (m, 2 H), 3.40 (m, 2 H), 3.23 (m, 2 H), 3.05 (m, 3 H), 1 .46 (s, 3 H), 1 .25 (s, 6 H).

[0351] Step b: tert-butyl N-amino-N-[2-(2-methoxyethoxy)ethyl]carbamate

[0352] In a 10 ml round bottom flask under nitrogen, tert-butyl N-(1 ,3-dioxoisoindolin-2-yl)-N-[2- (2-methoxyethoxy)ethyl]carbamate (367.00 mg; 1.01 mmol; 1.00 eq.) was dissolved in THF (3.70 mL) and cooled to 0°C. Methyl hydrazine (96.00 pL; 1.80 mmol; 1.79 eq.) was added, then the ice bath was removed and the colorless limpid mixture was stirred at rt for 3h to give a white cloudy mixture. The mixture was stirred at rt 1 h more. The reaction was filtered and the solid was washed three times with Et2O. The filtrate was evaporated. The residue was purified by chromatography (Cartridge Biotage Star 25 g 60 pm silica, DCM- MeOH 100-0 / 2 CV (column volume) 100-0 to 95-5 / 20 CV 95-5 / 5 CV flow rate 80 ml / min) to give tert-butyl N-amino-N-[2-(2-methoxyethoxy)ethyl]carbamate (205.00 mg; 86.88 %) as a colorless oil.1H NMR (400 MHz, DMSO-c / 6) 5 ppm 4.39 (s, 2 H), 3.50 (m, 4 H), 3.40 (m, 4 H), 3.24 (s, 3 H), 1 .40 (s, 9 H).

[0353] Step c: 2-(2-methoxyethoxy)ethylhydrazine

[0354] In a 10 ml round bottom flask, N-amino-N-[2-(2-methoxyethoxy)ethyl]carbamate (202.00 mg; 0.86 mmol; 1.00 eq.) was dissolved in 1 ,4-dioxane (2.00 mL) and HCI 4.0M in 1 ,4- dioxane (2.00 mL; 4.00 mol / L; 8.00 mmol; 9.28 eq.) was added. The resulting colorless limpid mixture was stirred at rt overnight to give a white cloudy mixture. The mixture was evaporated to give 2-(2-methoxyethoxy)ethylhydrazine (161.00 mg; 90.17 %).1H NMR (400 MHz, DMSO-cfc) 5 ppm 3.56 (m, 2 H), 3.46 (m, 1 H), 3.24 (m, 1 H), 3.05 (t, J=5.39 Hz, 1 H).

[0355] Step d: 1 -[amino-[2-(2-methoxyethoxy)ethyl]amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile The compound was prepared using the same procedure as detailed in example 12 step c starting from 1 -chloropyrrolo[1 ,2-a]pyrazine-6-carbonitrile (67.00 mg; 0.38 mmol; 1.00 eq.) and 2-(2-methoxyethoxy)ethylhydrazine (156.00 mg; 0.75 mmol; 2.00 eq.) giving 1 - [amino-[2-(2-methoxyethoxy)ethyl]amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile (55 mg; 47.7 %) as a pale yellow oil.1H NMR (400 MHz, DMSO-c / 6) 5 ppm 7.66 (dd, J=4.62, 0.88 Hz, 1 H), 7.58 (dd, J=4.51 , 0.88 Hz, 1 H), 7.35 (d, J=4.62 Hz, 1 H), 7.30 (d, J=4.62 Hz, 1 H), 5.02 (s, 2 H), 3.95 (t, J=5.83 Hz, 2 H), 3.74 (t, J=5.83 Hz, 2 H), 3.54 (m, 3 H), 3.43 (m, 3 H), 3.21 (m, 3 H). Step e: 1 -[[(E)-(3,3-dimethyl-1 -oxo-isoindolin-5-yl)methyleneamino]-[2-(2-methoxyethoxy) ethyl]amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile

[0356] The compound was prepared using the same procedure as detailed in example 12 step d starting from 3,3-dimethyl-1 -oxo-isoindoline-5-carbaldehyde (39.00 mg; 0.21 mmol; 1.09 eq.) and 1 -[amino-[2-(2-methoxyethoxy)ethyl]amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile (52.00 mg; 0.19 mmol; 1.00 eq.) giving 1 -[[(E)-(3,3-dimethyl-1 -oxo-isoindolin-5- yl)methyleneamino]-[2-(2-methoxyethoxy)ethyl]amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile (39 mg; 46.2 %) as a pale yellow powder.1H NMR (500 MHz, DMSO-c / 6) 5 ppm 8.72 (s, 1 H), 8.38 (s, 1 H), 8.03 (d, J=4.40 Hz, 1 H), 7.87 (m, 2 H), 7.72 (d, J=7.70 Hz, 1 H), 7.62 (d, J=4.40 Hz, 1 H), 7.57 (d, J=4.40 Hz, 1 H), 7.52 (d, J=4.40 Hz, 1 H), 4.62 (t, J=5.91 Hz, 2 H), 3.75 (t, J=6.05 Hz, 2 H), 3.57 (dd, J=5.36, 3.71 Hz, 2 H), 3.42 (dd, J=5.50, 3.85 Hz, 2 H), 3.18 (s, 3 H), 1.50 (s, 6 H). mp: 186-192°C.

[0357] Example 27: 1-[[(E)-(3,3-dimethyl-1-oxo-isoindolin-5-yl)methyleneamino]-[2-(2- hydroxyethoxy)ethyl]amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile

[0358] Step a: 2-(2-hydrazinoethoxy)ethanol

[0359] In a 50 mL round bottom flask with a condenser, hydrazine monohydrate (2.50 mL; 51.54 mmol; 12.83 eq.) was dissolved in PrOH (6.50 mL) and stirred at rt. 2-(2-chloroethoxy)- ethanol 99% (424.00 pL; 4.02 mmol; 1.00 eq.) was added and the mixture was stirred at 60°C for 5h. The reaction mixture was concentrated and the residue was taken in HCI (20.00 mL; 4.00 mol / L; 80.00 mmol; 19.92 eq.) to give a white suspension. It was stirred at rt for 1 h30 and filtered. The solid was washed twice with dioxane and twice with Et2O, then dried at 40°C under vacuum for 1 h to give 2-(2-hydrazinoethoxy)ethanol (1.38 g; 99.66 %) used without further purification.1H NMR (400 MHz, DMSO-c / 6) 5 ppm 3.62 (m, 2 H), 3.48 (m, 4 H), 3.08 (m, 2 H).

[0360] Step b: 1 -[amino-[2-(2-hydroxyethoxy)ethyl]amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile

[0361] The compound was prepared using the same procedure as detailed in example 12 step c starting from 1 -chloropyrrolo[1 ,2-a]pyrazine-6-carbonitrile (104.00 mg; 0.59 mmol; 1.00 eq.) and 2-(2-hydrazinoethoxy)ethanol (81 1.00 mg; 2.35 mmol; 4.02 eq.) giving 1 -[amino- [2-(2-hydroxyethoxy)ethyl]amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile (57 mg; 22.3 %) as a yellow powder.1H NMR (400 MHz, DMSO-c / 6) 5 ppm 7.66 (m, 1 H), 7.58 (d, J=4.61 Hz, 1 H), 7.35 (d, J=5.15 Hz, 1 H), 7.29 (d, J=4.51 Hz, 1 H), 5.05 (s, 2 H), 4.63 (t, J=5.23 Hz, 1 H), 3.96 (t, J=5.67 Hz, 2 H), 3.74 (t, J=5.72 Hz, 2 H), 3.47 (m, 4 H).

[0362] Step c: 1 -[[(E)-(3,3-dimethyl-1 -oxo-isoindolin-5-yl)methyleneamino]-[2-(2-hydroxyethoxy) ethyl]amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile

[0363] The compound was prepared using the same procedure as detailed in example 12 step d starting from 3,3-dimethyl-1 -oxo-isoindoline-5-carbaldehyde (54.00 mg; 0.12 mmol; 1.00 eq.) and 1 -[amino-[2-(2-hydroxyethoxy)ethyl]amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile (26.00 mg; 0.14 mmol; 1.1 1 eq.) giving 1 -[[(E)-(3,3-dimethyl-1 -oxo-isoindolin-5- yl)methyleneamino]-[2-(2-hydroxyethoxy)ethyl]amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile (37 mg; 39 %) as a yellow powder.1H NMR (500 MHz, DMSO-c / 6) 6 ppm 8.72 (s, 1 H), 8.40 (s, 1 H), 8.04 (dd, J=4.68, 0.83 Hz, 1 H), 7.90 (s, 1 H), 7.87 (dd, J=7.98, 1.10 Hz, 1 H), 7.71 (d, J=7.70 Hz, 1 H), 7.62 (d, J=4.40 Hz, 1 H), 7.58 (d, J=4.68 Hz, 1 H), 7.52 (dd, J=4.40, 0.83 Hz, 1 H), 4.61 - 4.65 (m, 3 H), 3.75 (t, J=6.19 Hz, 2 H), 3.48 - 3.51 (m, 4 H), 1.50 (s, 6 H). mp : 219-230°C.

[0364] Example 28: 5-[(6-cyanopyrrolo[1 ,2-a]pyrazin-1-yl)-[(E)-(3,3-dimethyl-1-oxo- isoindolin-5-yl)methyleneamino]amino]pentanoic acid

[0365] Step a: tert-butyl 5-hydrazinopentanoate

[0366] The compound was prepared using the same procedure as detailed in example 27 step a starting from hydrazine monohydrate (3.74 mL; 35.00 %w / w; 42.17 mmol; 10.00 eq.) and 5-bromo-pentanoic acid tert-butyl ester (1.00 g; 4.22 mmol; 1.00 eq.) giving tert-butyl 5- hydrazinopentanoate (1.2 mg; quant.).1H NMR (400 MHz, DMSO-c / 6) 5 ppm 2.65 (t, J=6.93 Hz, 2 H), 2.18 (m, 2 H), 1.48 (m, 4 H), 1.39 (s, 9 H).

[0367] Step b: tert-butyl 5-[amino-(6-cyanopyrrolo[1 ,2-a]pyrazin-1 -yl)amino]pentanoate

[0368] The compound was prepared using the same procedure as detailed in example 12 step c starting from 1 -chloropyrrolo[1 ,2-a]pyrazine-6-carbonitrile (500.00 mg; 2.69 mmol; 1.00 eq.) and tert-butyl 5-hydrazinopentanoate (1.01 g; 5.37 mmol; 2.00 eq.) giving tert-butyl 5- [amino-(6-cyanopyrrolo[1 ,2-a]pyrazin-1 -yl)amino]pentanoate (737 mg; 55.8 %) as a white powder. The crude was used without further purification.

[0369] Step c: tert-butyl 5-[(6-cyanopyrrolo[1 ,2-a]pyrazin-1 -yl)-[(E)-(3,3-dimethyl-1 -oxo-isoindolin- 5-yl)methyleneamino]amino]pentanoate

[0370] The compound was prepared using the same procedure as detailed in example 12 step d starting from 3,3-dimethyl-1 -oxo-isoindoline-5-carbaldehyde (378.42 mg; 2.00 mmol; 1.00 eq.) and tert-butyl 5-[amino-(6-cyanopyrrolo[1 ,2-a]pyrazin-1 -yl)amino]pentanoate (938.00 mg; 2.00 mmol; 1.00 eq.) giving tert-butyl 5-[(6-cyanopyrrolo[1 ,2-a]pyrazin-1 -yl)-[(E)-(3,3- dimethyl-1 -oxo-isoindolin-5-yl)methyleneamino]amino]pentanoate (317 mg; 31.7 %) as a yellow powder.1H NMR (400 MHz, DMSO-c / 6) 5 ppm 8.71 (s, 1 H), 8.23 (s, 1 H), 8.02 (dd, J=4.62, 0.88 Hz, 1 H), 7.89 (s, 1 H), 7.89 (d, J=8.38 Hz, 2 H), 7.71 (d, J=7.94 Hz, 1 H), 7.57 (m, 3 H), 4.44 (br t, J=6.88 Hz, 2 H), 2.29 (t, J=7.04 Hz, 2 H), 1.64 (m, 4 H), 1.49 (s, 6 H), 1.36 (s, 9 H).

[0371] Step d: 5-[(6-cyanopyrrolo[1 ,2-a]pyrazin-1 -yl)-[(E)-(3,3-dimethyl-1 -oxo-isoindolin-5- yl)methyleneamino]amino]pentanoic acid In a 25 mL flask, tert-butyl 5-[(6-cyanopyrrolo[1 ,2-a]pyrazin-1 -yl)-[(E)-(3,3-dimethyl-1 -oxo- isoindolin-5-yl)methyleneamino]amino]pentanoate (317.00 mg; 0.63 mmol; 1.00 eq.) was dissolved in 1 ,4-dioxane (7.00 mL). HCI 4.0M in 1 ,4-dioxane (3.97 mL; 4.00 mol / L; 19.90 mmol; 25.00 eq.) was added and the reaction mixture was stirred at rt for 34 hours. The reaction mixture was concentrated to dryness, diluted with 1 ,4-dioxane (30 mL) and concentrated to dryness again to give 5-[(6-cyanopyrrolo[1 ,2-a]pyrazin-1 -yl)-[(E)-(3,3- dimethyl-1 -oxo-isoindolin-5-yl)methyleneamino]amino]pentanoic acid (300.00 mg; quant) as a white powder.1H NMR (500 MHz, DMSO-c / 6) 5 ppm 12.05 (br s, 1 H), 8.72 (s, 1 H), 8.23 (s, 1 H), 8.02 (dd, J=4.68, 0.55 Hz, 1 H), 7.90 (s, 1 H), 7.88 (d, J=7.82 Hz, 1 H), 7.71 (d, J=7.70 Hz, 1 H), 7.62 (d, J=4.40 Hz, 1 H), 7.58 (d, J=4.40 Hz, 1 H), 7.53 (d, J=4.73 Hz, 1 H), 4.44 (br t, J=7.15 Hz, 2 H), 2.32 (t, J=7.15 Hz, 2 H), 1.61 - 1.71 (m, 4 H), 1.50 (s, 6 H).

[0372] Example 29: 1 -[cyclopropyl-[(E)-(3,3-dimethyl-1 -oxo-isoindolin-5-yl)methylene- amino]amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile

[0373] In a 5 mL round bottom flask with a condenser, 3,3-dimethyl-1 -oxo-isoindoline-5- carbaldehyde (100.00 mg; 0.53 mmol; 1.00 eq.) and 1 -cyclopropylhydrazine hydrochloride (69.00 mg; 0.64 mmol; 1.20 eq.) were stirred in propan-2-ol (3.00 mL) at rt for 30 min. 1 - chloropyrrolo[1 ,2-a]pyrazine-6-carbonitrile (94.00 mg; 0.53 mmol; 1.00 eq.) was added and the mixture was stirred at 80°C overnight (oil bath temperature). The mixture was diluted in 20 mL of EtOAc and washed three times with 20 mL of aq. NaOH (1 N). The organic layer was dried over MgSO4, filtered and concentrated under vacuum The residue was purified by chromatography (Cartridge Biotage Star 10 g 20 pm silica, DCM-MeOH 100-0 / 2 CV (column volume) 100-0 to 95-5 / 20 CV 95-5 / 5 CV, flow rate 40 ml / min) to give 1 -[cyclopropyl-[(E)-(3,3-dimethyl-1 -oxo-isoindolin-5-yl)methyleneamino]amino]- pyrrolo[1 ,2-a]pyrazine-6-carbonitrile (75.00 mg; 36.91 %) as a yellow powder.1H NMR (500 MHz, DMSO-Gfc) 5 ppm 8.71 (s, 1 H), 8.57 (s, 1 H), 8.09 (dd, J=4.68, 0.83 Hz, 1 H), 7.91 (s, 1 H), 7.88 (dd, J=7.84, 1.24 Hz, 1 H), 7.68 (d, J=7.98 Hz, 1 H), 7.62 (dd, J=4.40, 3.58 Hz, 2 H), 7.37 (dd, J=4.54, 0.69 Hz, 1 H), 2.88 - 2.91 (m, 1 H), 1.49 (s, 6 H), 1.30 - 1 .34 (m, 2 H), 0.74 - 0.77 (m, 2 H). mp : 220-248°C.

[0374] Example 30: 1 -[ethyl-[(E)-[6-(2-hydroxyethyl)-5,5-dimethyl-7-oxo-pyrrolo[3,4- b]pyridin-3-yl]methyleneamino]amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile

[0375] Step a: 1 -[[(E)-[3,3-dimethyl-1 -oxo-2-(2-tetrahydropyran-2-yloxyethyl)isoindolin-5-yl] methyleneamino]-ethyl-amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile

[0376] In a 5 mL round-bottomed flask, under N2, 1 -[[(E)-(3,3-dimethyl-1 -oxo-isoindolin-5- yl)methyleneamino]-ethyl-amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile (60.00 mg; 0.16 mmol; 1.00 eq.) was dissolved in DMF (2.38 mL) (Dry, Acroseal) to give an yellow suspension. NaH (60% in oil) (14.05 mg; 0.35 mmol; 2.20 eq.) was added portion wise at rt and the mixture was stirred for 15 min at 50°C to give an orange mixture. 2-(2- bromoethoxy)tetrahydro-2h-pyran (53.06 pL; 0.35 mmol; 2.20 eq.) was added at 50°C, then the mixture was stirred at 50°C for 1 h. The mixture was hydrolyzed with NH4CI solution, mixed and extracted with EtOAc (3 times). The combined organic layers were washed with brine, dried over MgSO4and concentrated. The crude was triturated in Et2O, filtered, washed with Et2O and dried under vacuum at 50°C to give 1 -[[(E)-[3,3-dimethyl-1 - oxo-2-(2-tetrahydropyran-2-yloxyethyl)isoindolin-5-yl]methyleneamino]-ethyl- amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile (30.00 mg; 37.54 %).1H NMR (400 MHz, DMSO-cfc) 5 ppm 8.27 (s, 1 H), 8.03 (dd, J=4.57, 0.61 Hz, 1 H), 7.95 (s, 1 H), 7.90 (d, J=8.03 Hz, 1 H), 7.75 (d, J=7.92 Hz, 1 H), 7.58 (m, 3 H), 4.62 (m, 1 H), 4.48 (br d, J=7.37 Hz, 2 H), 3.85 (m, 1 H), 3.73 (m, 1 H), 3.62 (m, 2 H), 3.42 (br s, 1 H), 3.30 (m, 1 H), 1.62 (br d, J=14.75 Hz, 2 H), 1 .52 (s, 6 H), 1 .49 (m, 4 H), 1 .24 (t, J=6.93 Hz, 3 H).

[0377] Step b: 1 -[ethyl-[(E)-[2-(2-hydroxyethyl)-3,3-dimethyl-1 -oxo-isoindolin-5- yl]methyleneamino]amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile

[0378] In a 5 mL round-bottomed flask, 1 -[[(E)-[3,3-dimethyl-1 -oxo-2-(2-tetrahydropyran-2- yloxyethyl)isoindolin-5-yl]methyleneamino]-ethyl-amino]pyrrolo[1 ,2-a]pyrazine-6- carbonitrile (29.00 mg; 0.06 mmol; 1.00 eq.) was dissolved in THF (580.00 pL) to give a yellow solution. HCI (28.97 pL; 1.00 mol / L; 0.03 mmol; 0.50 eq.) was added and the mixture was stirred at rt. The mixture became heterogeneous (gummy). HCI (0.03 mL; 1.00 mol / L; 0.03 mmol; 0.50 eq.) and MeOH (100.00 pL) were added. The mixture stayed heterogeneous as a beige solid in suspension. The solvent was evaporated. A NaHCO3solution was added to the residue, which was extracted with DCM (twice). The combined organic layers were washed with brine, dried on MgSO4, filtered and evaporated to give 1 - [ethyl-[(E)-[2-(2-hydroxyethyl)-3,3-dimethyl-1 -oxo-isoindolin-5- yl]methyleneamino]amino]pyrrolo [1 ,2-a]pyrazine-6-carbonitrile (14.00 mg; 58.03 %) as a pale yellow powder.1H NMR (500 MHz, DMSO-c / 6) 5 ppm 8.27 (s, 1 H), 8.03 (d, J=4.68 Hz, 1 H), 7.95 (s, 1 H), 7.90 (d, J=8.80 Hz, 1 H), 7.75 (d, J=7.98 Hz, 1 H), 7.62 (d, J=4.68 Hz, 1 H), 7.58 (d, J=4.40 Hz, 1 H), 7.53 (d, J=4.40 Hz, 1 H), 4.84 (t, J=5.64 Hz, 1 H), 4.48 (q, J=6.79 Hz, 2 H), 3.63 (q, J=6.42 Hz, 2 H), 3.48 (t, J=6.74 Hz, 2 H), 1.50 (s, 6 H), 1.24 (t, J=7.02 Hz, 3 H).

[0379] Example 31 : 1-[ethyl-[(E)-(2,3,3-trimethyl-1-oxo-isoindolin-5- yl)methyleneamino]amino] pyrrolo[1 ,2-a]pyrazine-6-carbonitrile

[0380] The compound was prepared using the same procedure as detailed in example 30 step a starting from 1 -[[(E)-(3,3-dimethyl-1 -oxo-isoindolin-5-yl)methyleneamino]-ethyl- amino]pyrrolo[1 ,2-a] pyrazine-6-carbonitrile (60.00 mg; 0.16 mmol; 1.00 eq.) and Mel (22.00 pL; 0.35 mmol; 2.21 eq.) giving 1 -[ethyl-[(E)-(2,3,3-trimethyl-1 -oxo-isoindolin-5- yl)methyleneamino]amino]pyrrolo [1 ,2-a]pyrazine-6-carbonitrile (55 mg; 89.1 %) as a yellow powder.1H NMR (500 MHz, DMSO-c / 6) 6 ppm 8.27 (s, 1 H), 8.03 (dd, J=4.54, 0.69 Hz, 1 H), 7.98 (s, 1 H), 7.90 (dd, J=7.84, 1.24 Hz, 1 H), 7.76 (d, J=7.98 Hz, 1 H), 7.62 (d, J=4.40 Hz, 1 H), 7.58 (d, J=4.68 Hz, 1 H), 7.53 (d, J=4.47 Hz, 1 H), 4.48 (q, J=6.88 Hz, 2 H), 2.96 (s, 3 H), 1 .48 (s, 6 H), 1 .24 (t, J=7.02 Hz, 3 H).

[0381] Example 32: 1 -[[(E)-(2-benzyl-3,3-dimethyl-1 -oxo-isoindolin-5-yl)methyleneamino]- ethyl-amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile

[0382] The compound was prepared using the same procedure as detailed in example 30 step a starting from 1 -[[(E)-(3,3-dimethyl-1 -oxo-isoindolin-5-yl)methyleneamino]-ethyl- amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile (50.00 mg; 0.13 mmol; 1.00 eq.) and benzyl bromide (35.01 pL; 0.29 mmol; 2.20 eq.) giving 1 -[[(E)-(2-benzyl-3,3-dimethyl-1 -oxo- isoindolin-5-yl)methyleneamino]-ethyl-amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile (38 mg; 58.7 %) as a yellow powder.1H NMR (500 MHz, DMSO-c / 6) 5 ppm 8.27 (s, 1 H), 8.03 (d, J=4.68 Hz, 1 H), 7.96 (s, 1 H), 7.93 (d, J=7.83 Hz, 1 H), 7.83 (d, J=7.70 Hz, 1 H), 7.61 (d, J=4.40 Hz, 1 H), 7.58 (d, J=4.68 Hz, 1 H), 7.53 (d, J=4.40 Hz, 1 H), 7.37 - 7.40 (m, 2 H), 7.32 (t, J=7.19 Hz, 2 H), 7.22 - 7.26 (m, 1 H), 4.72 (s, 2 H), 4.48 (q, J=7.06 Hz, 2 H), 1 .41 (s, 6 H), 1.24 (t, J=7.02 Hz, 3 H). mp: 195-205°C.

[0383] Example 33: 1 -[ethyl-[(E)-[2-(3-hydroxypropyl)-3,3-dimethyl-1 -oxo-isoindolin-5- yl]methylene amino]amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile

[0384] Step a: 1 -[[(E)-[3,3-dimethyl-1 -oxo-2-(3-tetrahydropyran-2-yloxypropyl)isoindolin-5- yl]methyleneamino]-ethyl-amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile

[0385] The compound was prepared using the same procedure as detailed in example 30 step a starting from 1 -[[(E)-(3,3-dimethyl-1 -oxo-isoindolin-5-yl)methyleneamino]-ethyl- amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile (60.00 mg; 0.16 mmol; 1.00 eq.) and 2-(3- bromopropoxy)tetrahydro-2h-pyran (59.64 pL; 0.35 mmol; 2.20 eq.) giving 1 -[[(E)-[3,3- dimethyl-1 -oxo-2-(3-tetrahydropyran-2-yloxypropyl)isoindolin-5-yl]methyleneamino]-ethyl- amino]pyrrolo[1 ,2-a] pyrazine-6-carbonitrile (73 mg; 82.6 %) as a yellow powder.1H NMR (400 MHz, DMSO-d6) 5 ppm 8.27 (s, 1 H), 8.03 (dd, J=4.62, 0.88 Hz, 1 H), 7.95 (s, 1 H), 7.90 (dd, J=7.87, 1.16 Hz, 1 H), 7.74 (d, J=7.92 Hz, 1 H), 7.58 (m, 3 H), 4.48 (m, 2 H), 3.73 (m, 2 H), 3.45 (m, 6 H), 1.92 (m, 2 H), 1.72 (s, 1 H), 1.64 (br d, J=10.45 Hz, 2 H), 1 .52 (s, 6 H), 1 .49 (m, 4 H), 1 .24 (m, 3 H).

[0386] Step b: 1 -[ethyl-[(E)-[2-(3-hydroxypropyl)-3,3-dimethyl-1 -oxo-isoindolin-5-yl]methylene amino]amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile

[0387] The compound was prepared using the same procedure as detailed in example 30 step b starting from 1 -[[(E)-[3,3-dimethyl-1 -oxo-2-(3-tetrahydropyran-2-yloxypropyl)isoindolin-5- yl]methyleneamino]-ethyl-amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile (71.00 mg; 0.14 mmol; 1.00 eq.) giving 1 -[ethyl-[(E)-[2-(3-hydroxypropyl)-3,3-dimethyl-1 -oxo-isoindolin-5- yl]methyleneamino]amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile (38 mg; 62.1 %) as a yellow powder.1H NMR (500 MHz, DMSO-c / 6) 6 ppm 8.27 (s, 1 H), 8.03 (dd, J=4.40, 0.83 Hz, 1 H), 7.95 (s, 1 H), 7.90 (dd, J=7.84, 1.24 Hz, 1 H), 7.75 (d, J=7.98 Hz, 1 H), 7.63 (d, J=4.68 Hz, 1 H), 7.59 (d, J=4.40 Hz, 1 H), 7.53 (dd, J=4.40, 0.83 Hz, 1 H), 4.56 (t, J=5.23 Hz, 1 H), 4.48 (q, J=6.88 Hz, 2 H), 3.44 - 3.52 (m, 4 H), 1.77 - 1.84 (m, 2 H), 1.51 (s, 6 H), 1.24 (t, J=7.02 Hz, 3 H).

[0388] Example 34: 1 -[ethyl-[(E)-[2-(4-hydroxybutyl)-3,3-dimethyl-1 -oxo-isoindolin-5- yl]methyleneamino]amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile

[0389] Step a: 1 -[[(E)-[2-[4-[tert-butyl(dimethyl)silyl]oxybutyl]-3 ,3-dimethyl- 1 -oxo-isoindolin-5-yl] methyleneamino]-ethyl-amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile

[0390] The compound was prepared using the same procedure as detailed in example 30 step a starting from 1 -[[(E)-(3,3-dimethyl-1 -oxo-isoindolin-5-yl)methyleneamino]-ethyl- amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile (60.00 mg; 0.16 mmol; 1.00 eq.) and (4- bromobutoxy)(1 ,1 -dimethylethyl)dimethyl-silane (90.00 pL; 0.36 mmol; 2.26 eq.) giving 1 - [[(E)-[2-[4-[tert-butyl(dimethyl)silyl]oxybutyl]-3,3-dimethyl-1 -oxo-isoindolin-5- yl]methyleneamino]-ethyl-amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile (59 mg; 66.1 %) as a yellow powder.1H NMR (400 MHz, DMSO-c / 6) 5 ppm 8.22 (s, 1 H), 7.99 (dd, J=4.62, 0.88 Hz, 1 H), 7.90 (s, 1 H), 7.85 (dd, J=7.98, 1.27 Hz, 1 H), 7.70 (d, J=7.70 Hz, 1 H), 7.54 (m, 3 H), 4.44 (br d, J=7.15 Hz, 2 H), 3.60 (t, J=6.22 Hz, 2 H), 3.38 (m, 2 H), 1.64 (m, 2 H), 1 .48 (m, 2 H), 1 .47 (s, 6 H), 1 .20 (m, 3 H), 0.83 (m, 9 H), -0.01 (s, 6 H).

[0391] Step b: 1 -[ethyl-[(E)-[2-(4-hydroxybutyl)-3,3-dimethyl-1 -oxo-isoindolin-5- yl]methyleneamino] amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile

[0392] T o 1 -[[( E) -[2-[4-[tert-buty I (d i methy l)si ly l]oxybuty l]-3 ,3-di m ethy I- 1 -oxo-isoindolin-5- yl]methyleneamino]-ethyl-amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile (58.00 mg; 0.10 mmol; 1.00 eq.) was added a HCI solution, 4.0M in 1 ,4-dioxane (1.16 mL; 4.00 mol / L; 4.64 mmol; 20.00 V). The reaction mixture was stirred at rt for 10 min. The reaction mixture was concentrated under reduced pressure. A solution of saturated NaHCO3was added and the mixture extracted with DCM. The organic layer was washed with water, dried with MgSO4, filtered and concentrated under reduced pressure to give 1 -[ethyl-[(E)-[2-(4- hydroxybutyl)-3,3-dimethyl-1 -oxo-isoindolin-5-yl]methyleneamino]amino]pyrrolo[1 ,2- a]pyrazine-6-carbonitrile (40.00 mg; 86.69 %) as a yellow solid.1H NMR (500 MHz, DMSO-Gfc) 5 ppm 8.27 (s, 1 H), 8.03 (d, J=4.94 Hz, 1 H), 7.95 (s, 1 H), 7.90 (d, J=7.64 Hz, 1 H), 7.74 (d, J=7.98 Hz, 1 H), 7.62 (d, J=4.40 Hz, 1 H), 7.59 (d, J=4.68 Hz, 1 H), 7.54 (d, J=3.85 Hz, 1 H), 4.48 (q, J=6.88 Hz, 2 H) 4.42 (t, J=5.22 Hz, 1 H), 3.38 - 3.49 (m, 4 H), 1.62 - 1 .71 (m, 2 H), 1 .51 (s, 6 H), 1 .43 - 1 .50 (m, 2 H), 1 .24 (t, J=7.02 Hz, 3 H).

[0393] Example 35: 1 -[ethyl-[(E)-[2-(2-isopropoxyethyl)-3,3-dimethyl-1 -oxo-isoindolin-5- yl]methylene amino]amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile

[0394] The compound was prepared using the same procedure as detailed in example 30 step a starting from 1 -[[(E)-(3,3-dimethyl-1 -oxo-isoindolin-5-yl)methyleneamino]-ethyl- amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile (60.00 mg; 0.16 mmol; 1.00 eq.) and 2-(2- bromoethoxy)propane (47.00 pL; 0.35 mmol; 2.22 eq.) giving 1 -[ethyl-[(E)-[2-(2- isopropoxyethyl)-3,3-dimethyl-1 -oxo-isoindolin-5-yl]methyleneamino]amino]pyrrolo[1 ,2- a]pyrazine-6-carbonitrile (55 mg; 72.9 %) as a yellow powder.1H NMR (500 MHz, DMSO- d6) 5 ppm 8.27 (s, 1 H), 8.03 (d, J=4.85 Hz, 1 H), 7.95 (s, 1 H), 7.90 (dd, J=7.70, 1.10 Hz, 1 H), 7.75 (d, J=7.98 Hz, 1 H), 7.62 (d, J=4.40 Hz, 1 H), 7.59 (d, J=4.40 Hz, 1 H), 7.53 (d, J=4.87 Hz, 1 H), 4.48 (q, J=6.98 Hz, 2 H), 3.53 - 3.62 (m, 5 H), 1.51 (s, 6 H), 1.24 (t, J=7.01 Hz, 3 H), 1.09 (d, J=6.05 Hz, 6 H).

[0395] Example 36: 1 -[ethyl-[(E)-[2-(4-methoxybutyl)-3,3-dimethyl-1 -oxo-isoindolin-5- yl]methyleneamino]amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile

[0396] The compound was prepared using the same procedure as detailed in example 30 step a starting from 1 -[[(E)-(3,3-dimethyl-1 -oxo-isoindolin-5-yl)methyleneamino]-ethyl- amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile (60.00 mg; 0.16 mmol; 1.00 eq.) and 1 -bromo- 4-methoxybutane (44.96 pL; 0.35 mmol; 2.20 eq.) giving 1 -[ethyl-[(E)-[2-(4-methoxybutyl)- 3,3-dimethyl-1 -oxo-isoindolin-5-yl]methyleneamino]amino]pyrrolo[1 ,2-a]pyrazine-6- carbonitrile (43 mg; 58.7 %) as a yellow powder.1H NMR (500 MHz, DMSO-c / 6) 5 ppm 8.26 (s, 1 H), 8.03 (dd, J=4.68, 0.83 Hz, 1 H), 7.95 (s, 1 H), 7.90 (dd, J=7.98, 1.38 Hz, 1 H), 7.74 (d, J=7.98 Hz, 1 H), 7.62 (d, J=4.68 Hz, 1 H), 7.59 (d, J=4.68 Hz, 1 H), 7.54 (dd, J=4.68, 0.83 Hz, 1 H), 4.48 (q, J=6.88 Hz, 2 H), 3.37 - 3.44 (m, 4 H), 3.24 (s, 3 H), 1 .63 - 1 .71 (m, 2 H), 1.54 - 1 .60 (m, 2 H), 1 .51 (s, 6 H), 1 .22 - 1 .26 (m, 3 H).

[0397] Example 37: 1-[[(E)-[2-(cyanomethyl)-3,3-dimethyl-1-oxo-isoindolin-5- yl]methyleneamino]ethylamino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile

[0398] The compound was prepared using the same procedure as detailed in example 30 step a starting from 1 -[[(E)-(3,3-dimethyl-1 -oxo-isoindolin-5-yl)methyleneamino]-ethyl- amino]pyrrolo[1 ,2-a] pyrazine-6-carbonitrile (175.00 mg; 0.47 mmol; 1.00 eq.) and bromoacetonitrile (71.44 pL; 1.02 mmol; 2.20 eq.) giving 1 -[[(E)-[2-(cyanomethyl)-3,3- dimethyl-1 -oxo-isoindolin-5-yl]methyleneamino]-ethyl-amino]pyrrolo[1 ,2-a]pyrazine-6- carbonitrile (13 mg; 7 %) as a yellow powder.1H NMR (500 MHz, DMSO-c / 6) 5 ppm 8.27 (s, 1 H), 8.04 (d, J=4.68 Hz, 1 H), 8.01 (s, 1 H), 7.95 (dd, J=7.98, 1.10 Hz, 1 H), 7.84 (d, J=7.70 Hz, 1 H), 7.63 (d, J=4.68 Hz, 1 H), 7.59 (d, J=4.40 Hz, 1 H), 7.53 (d, J=4.68 Hz, 1 H), 4.69 (s, 2 H), 4.49 (q, J=6.79 Hz, 2 H), 1 .58 (s, 6 H), 1 .25 (t, J=7.02 Hz, 3 H).

[0399] Example 38: 1 -[[(E)-[2-(2-cyanoethyl)-3,3-dimethyl-1 -oxo-isoindolin-5- yl]methyleneamino]-ethyl-amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile

[0400] The compound was prepared using the same procedure as detailed in example 30 step a starting from 1 -[[(E)-(3,3-dimethyl-1 -oxo-isoindolin-5-yl)methyleneamino]-ethyl- amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile (50.00 mg; 0.13 mmol; 1.00 eq.) and 3-bromo propionitrile (97 pL; 1.16 mmol; 8.80 eq.) giving 1 -[[(E)-[2-(2-cyanoethyl)-3,3-dimethyl-1 - oxo-isoindolin-5-yl]methyleneamino]-ethyl-amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile (24 mg; 40.9 %) as a yellow powder.1H NMR (500 MHz, DMSO-c / 6) 5 ppm 8.27 (s, 1 H), 8.04 (dd, J=4.40, 0.83 Hz, 1 H), 7.97 (s, 1 H), 7.92 (dd, J=7.98, 1.10 Hz, 1 H), 7.78 (d, J=7.98 Hz, 1 H), 7.63 (d, J=4.40 Hz, 1 H), 7.59 (d, J=4.68 Hz, 1 H), 7.53 (dd, J=4.40, 0.83 Hz, 1 H), 4.49 (q, J=6.88 Hz, 2 H), 3.75 (t, J=7.02 Hz, 2 H), 2.95 (t, J=7.02 Hz, 2 H), 1.55 (s, 6 H), 1.24 (t, J=7.01 Hz, 3 H).

[0401] Example 39: 1 -[[(E)-(2-acetonyl-3,3-dimethyl-1 -oxo-isoindolin-5-yl)methyleneamino]- ethyl-amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile

[0402] The compound was prepared using the same procedure as detailed in example 30 step a starting from 1 -[[(E)-(3,3-dimethyl-1 -oxo-isoindolin-5-yl)methyleneamino]-ethyl- amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile (60.00 mg; 0.16 mmol; 1.00 eq.) and bromacetone (29.52 pL; 0.35 mmol; 2.20 eq.) giving 1 -[[(E)-(2-acetonyl-3,3-dimethyl-1 - oxo-isoindolin-5-yl)methyleneamino]-ethyl-amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile (33 mg; 48.3 %) as a pale yellow powder.1H NMR (500 MHz, DMSO-c / 6) 5 ppm 8.28 (s, 1 H), 8.03 (dd, J=4.68, 0.55 Hz, 1 H), 7.96 (s, 1 H), 7.92 (dd, J=7.98, 1.10 Hz, 1 H), 7.77 (d, J=7.98 Hz, 1 H), 7.63 (d, J=4.68 Hz, 1 H), 7.59 (d, J=4.40 Hz, 1 H), 7.53 (d, J=4.53 Hz, 1 H), 4.49 (q, J=6.88 Hz, 2 H), 4.38 (s, 2 H), 2.19 (s, 3 H), 1.43 (s, 6 H), 1.25 (t, J=4.53 Hz, 3 H).

[0403] Example 40: 4-[6-[(E)-[(6-cyanopyrrolo[1 ,2-a]pyrazin-1 -yl)-ethyl-hydrazono]methyl]- 1 ,1 -dimethyl-3-oxo-isoindolin-2-yl]butanoic acid

[0404] Step a: tert-butyl 4-[6-[(E)-[(6-cyanopyrrolo[1 ,2-a]pyrazin-1 -yl)-ethyl-hydrazono]methyl]- 1 , 1 -dimethyl-3-oxo-isoindolin-2-yl]butanoate

[0405] The compound was prepared using the same procedure as detailed in example 30 step a starting from 1 -[[(E)-(3,3-dimethyl-1 -oxo-isoindolin-5-yl)methyleneamino]-ethyl- amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile (200.00 mg; 0.52 mmol; 1.00 eq.) and t-Butyl 4-bromobutyrate (357.60 pL; 2.08 mmol; 4.00 eq.) giving tert-butyl 4-[6-[(E)-[(6- cyanopyrrolo[1 ,2-a]pyrazin-1 -yl)-ethyl-hydrazono]methyl]-1 ,1 -dimethyl-3-oxo-isoindolin-2- yl]butanoate (290 mg; quant.) as an orange powder.1H NMR (400 MHz, DMSO-c / 6) 5 ppm 8.27 (s, 1 H), 8.03 (dd, J=4.57, 0.94 Hz, 1 H), 7.90 (dd, J=7.98, 1.27 Hz, 1 H), 7.75 (d, J=7.81 Hz, 1 H), 7.62 (d, J=4.62 Hz, 1 H), 7.59 (d, J=4.62 Hz, 1 H), 7.53 (dd, J=4.51 , 0.88 Hz, 1 H), 4.47 (d, J=7.20 Hz, 2 H), 3.41 (dd, J=8.36, 6.82 Hz, 2 H), 2.31 (t, J=7.37 Hz, 2 H), 1.86 (m, 2 H), 1.51 (s, 9 H).

[0406] Step b: 4-[6-[(E)-[(6-cyanopyrrolo[1 ,2-a]pyrazin-1 -yl)-ethyl-hydrazono]methyl]-1 ,1 - dimethyl-3-oxo-isoindolin-2-yl]butanoic acid

[0407] In a 1 mL flask, under Argon, to tert-butyl 4-[6-[(E)-[(6-cyanopyrrolo[1 ,2-a]pyrazin-1 -yl)- ethyl-hydrazono]methyl]-1 ,1 -dimethyl-3-oxo-isoindolin-2-yl]butanoate (280.00 mg; 0.54 mmol; 1.00 eq.) was added HCI 4.0 M in 1 ,4-dioxane (5.44 mL; 4.00 mol / L; 21.76 mmol; 40.00 eq.). The reaction mixture was stirred at rt for 20h. The reaction mixture was concentrated under reduced pressure. The residue was purified by chromatography (Prep LC / MS) to give 4-[6-[(E)-[(6-cyanopyrrolo[1 ,2-a]pyrazin-1 -yl)-ethyl-hydrazono]methyl]-1 ,1 - dimethyl-3-oxo-isoindolin-2-yl]butanoic acid (17.00 mg; 6.75 %) as a yellow solid.1H NMR (400 MHz, DMSO-cfc) 5 ppm 12.04 (br s, 1 H), 8.27 (s, 1 H), 8.03 (dd, J=4.62, 0.88 Hz, 1 H), 7.95 (s, 1 H), 7.90 (dd, J=7.92, 1.32 Hz, 1 H), 7.75 (d, J=7.92 Hz, 1 H), 7.62 (d, J=4.62 Hz, 1 H), 7.58 (d, J=4.62 Hz, 1 H), 7.53 (dd, J=4.62, 0.88 Hz, 1 H), 4.49 (q, J=7.12 Hz, 2 H), 3.34 - 3.51 (m, 2 H), 2.32 (t, J=7.37 Hz, 2 H), 1.82 - 1.94 (m, 2 H), 1.52 (s, 6 H), 1.24 (t, J=7.04 Hz, 3 H).

[0408] Example 41 : 4-[6-[(E)-[(6-cyanopyrrolo[1 ,2-a]pyrazin-1-yl)-ethyl-hydrazono]methyl]- 1 ,1 -dimethyl-3-oxo-isoindolin-2-yl]butanamide

[0409] In a 10 mL round-bottomed flask, under N2, 4-[6-[(E)-[(6-cyanopyrrolo[1 ,2-a]pyrazin-1 -yl)- ethyl-hydrazono]methyl]-1 ,1 -dimethyl-3-oxo-isoindolin-2-yl]butanoic acid (50.00 mg; 0.1 1 mmol; 1.00 eq.) was dissolved in DCM (500.00 pL). HATU (53.90 mg; 0.14 mmol; 1.30 eq.) and NH3(89.94 pL; 35.00 %w / w; 1.09 mmol; 10.00 eq.) were added. The reaction mixture was stirred at rt over the weekend. The reaction mixture was quenched with water and extracted with EtOAc (3 times). The organic layer was dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by chromatography (Cartridge : Biotage Star Duo 5g, Flow rate : 18mL / min, Gradient : DCM / MeOH with 1 CV at 100% of DCM, 10CV from 0 to 10% of MeOH and 5CV at 10%) to give 4-[6-[(E)-[(6- cyanopyrrolo[1 ,2-a]pyrazin-1 -yl)-ethyl-hydrazono]methyl]-1 ,1 -dimethyl-3-oxo-isoindolin-2- yl]butanamide (17.00 mg; 32.54 %) as a pale yellow powder.1H NMR (500 MHz, DMSO- d6) 5 ppm 8.27 (s, 1 H), 8.03 (d, J=4.68 Hz, 1 H), 7.95 (s, 1 H), 7.90 (d, J=7.70 Hz, 1 H), 7.75 (d, J=7.70 Hz, 1 H), 7.63 (d, J=4.40 Hz, 1 H), 7.59 (d, J=4.68 Hz, 1 H), 7.54 (d, J=4.68 Hz, 1 H), 7.31 (br s, 1 H), 6.75 (br s, 1 H), 4.49 (q, J=6.60 Hz, 2 H), 3.36 - 3.45 (m, 2 H), 2.14 (t, J=7.43 Hz, 2 H), 1.85 (quin, J=7.63 Hz, 2 H), 1.52 (s, 6 H), 1.24 (t, J=6.88 Hz, 3 H). Example 42: isopropyl 2-[6-[(E)-[(6-cyanopyrrolo[1 ,2-a]pyrazin-1-yl)-ethyl- hydrazono]methyl]-1 ,1 -dimethyl-3-oxo-isoindolin-2-yl]acetate

[0410] The compound was prepared using the same procedure as detailed in example 30 step a starting from 1 -[[(E)-(3,3-dimethyl-1 -oxo-isoindolin-5-yl)methyleneamino]-ethyl- amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile (1 10.00 mg; 0.29 mmol; 1.00 eq.) and isopropyl 2-bromoacetate (1 16.57 mg; 0.64 mmol; 2.20 eq.) giving isopropyl 2-[6-[(E)-[(6- cyanopyrrolo[1 ,2-a]pyrazin-1 -yl)-ethyl-hydrazono]methyl]-1 ,1 -dimethyl-3-oxo-isoindolin-2- yl]acetate (42 mg; 29.9 %) as a pale yellow powder.1H NMR (500 MHz, DMSO-c / 6) 5 ppm 8.28 (s, 1 H), 8.03 (d, J=4.68 Hz, 1 H), 7.98 (s, 1 H), 7.92 (d, J=7.70 Hz, 1 H), 7.79 (d, J=7.98 Hz, 1 H), 7.63 (d, J=4.68 Hz, 1 H), 7.59 (d, J=4.40 Hz, 1 H), 7.54 (d, J=4.40 Hz, 1 H), 4.88 - 4.99 (m, 1 H), 4.49 (q, J=6.79 Hz, 2 H), 4.25 (s, 2 H), 1 .49 (s, 6 H), 1 .19 - 1 .27 (m, 9 H).

[0411] Example 43: 2-[6-[(E)-[(6-cyanopyrrolo[1 ,2-a]pyrazin-1-yl)-ethyl-hydrazono]methyl]- 1 ,1 -dimethyl-3-oxo-isoindolin-2-yl]acetamide

[0412] The compound was prepared using the same procedure as detailed in example 30 step a starting from 1 -[[(E)-(3,3-dimethyl-1 -oxo-isoindolin-5-yl)methyleneamino]-ethyl- amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile (50.00 mg; 0.13 mmol; 1.00 eq.) and 2- bromoacetamide (40.38 mg; 0.29 mmol; 2.20 eq.) giving 2-[6-[(E)-[(6-cyanopyrrolo[1 ,2- a]pyrazin-1 -yl)-ethyl-hydrazono]methyl]-1 ,1 -dimethyl-3-oxo-isoindolin-2-yl]acetamide (17 mg; 28.4 %) as a beige powder.1H NMR (500 MHz, DMSO-c / 6) 6 ppm 8.28 (s, 1 H), 8.04 (d, J=4.68 Hz, 1 H), 7.96 (s, 1 H), 7.92 (dd, J=7.98, 1.10 Hz, 1 H), 7.78 (d, J=7.70 Hz, 1 H), 7.63 (d, J=4.68 Hz, 1 H), 7.59 (d, J=4.40 Hz, 1 H), 7.54 (d, J=4.68 Hz, 1 H), 7.40 (br s, 1 H), 7.07 (br s, 1 H), 4.49 (q, J=6.60 Hz, 2 H), 4.01 (s, 2 H), 1.48 (s, 6 H), 1.25 (t, J=7.02 Hz, 3 H).

[0413] Example 44: 2-[6-[(E)-[(6-cyanopyrrolo[1 ,2-a]pyrazin-1 -yl)-ethyl-hydrazono]methyl]- 1 ,1 -dimethyl-3-oxo-isoindolin-2-yl]-N-methyl-acetamide

[0414] The compound was prepared using the same procedure as detailed in example 30 step a starting from 1 -[[(E)-(3,3-dimethyl-1 -oxo-isoindolin-5-yl)methyleneamino]-ethyl- amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile (60.0 mg, 0.16 mmol, 1.0 eq.) and 2-chloro- / V- methylacetamide (26.0 mg, 0.24 mmol, 1.5 eq.) giving 2-[6-[(E)-[(6-cyanopyrrolo[1 ,2- a]pyrazin-1 -yl)-ethyl-hydrazono]methyl]-1 ,1 -dimethyl-3-oxo-isoindolin-2-yl]-N-methyl- acetamide (28.0 mg; 39%) as a yellow powder.1H NMR (400 MHz DMSO-c / 6): 5 8.27 (s, 1 H), 8.03 (d, J= 4.6 Hz, 1 H), 7.96 (s, 1 H), 7.91 (d, J= 8.0 Hz, 1 H), 7.86 - 7.81 (m, 1 H), 7.77 (d, J= 8.0 Hz, 1 H), 7.60 (dd, J= 15.9, 4.6 Hz, 2H), 7.53 (d, J= 4.6 Hz, 1 H), 4.49 (q, J= 7.0 Hz, 2H), 4.03 (s, 2H), 2.61 (d, J= 4.5 Hz, 3H), 1 .24 (t, J= 7.0 Hz, 3H). mp.: 243-244°C. Example 45: 3-[6-[(E)-[(6-cyanopyrrolo[1 ,2-a]pyrazin-1 -yl)-ethyl-hydrazono]methyl]- 1 ,1 -dimethyl-3-oxo-isoindolin-2-yl]propanamide

[0415] The compound was prepared using the same procedure as detailed in example 30 step a starting from 1 -[[(E)-(3,3-dimethyl-1 -oxo-isoindolin-5-yl)methyleneamino]-ethyl- amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile (50.0 mg, 0.13 mmol, 1.0 eq.) and 3- bromopropionamide (1 , 69.4 mg, 0.45 mmol, 3.4 eq.) giving 3-[6-[(E)-[(6-cyanopyrrolo[1 ,2- a]pyrazin-1 -yl)-ethyl-hydrazono]methyl]-1 ,1 -dimethyl-3-oxo-isoindolin-2-yl]propanamide (21 mg; 35 %) as a yellow powder.1H NMR (400 MHz CDCI3): 5 7.92 (s, 1 H), 7.89-7.76 (m, 3H), 7.70 (s, 1 H), 7.53 (dd, J= 12.8 and 3.8 Hz, 2H), 7.34-7.28 (m, overlapping with CDCI3signal), 6.38 (br s, 1 H), 5.37 (br s, 1 H), 4.49 (q, J= 6.6 Hz, 2H), 3.8 (t, J= 6.7 Hz, 2H), 2.78 (t, J= 6.7 Hz, 2H), 1.56 (s, 6H), 1.33 (t, J= 6.6 Hz, 3H). mp.: decomposed 220- 230 °C.

[0416] Example 46: 1 -[[(E)-[3,3-dimethyl-1 -oxo-2-(2-pyridylmethyl)isoindolin-5- yl]methyleneamino]-ethyl-amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile

[0417] The compound was prepared using the same procedure as detailed in example 30 step a starting from 1 -[[(E)-(3,3-dimethyl-1 -oxo-isoindolin-5-yl)methyleneamino]-ethyl- amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile (70.00 mg; 0.19 mmol; 1.00 eq.) and 2-picolyl chloride hydrochloride (67.83 mg; 0.41 mmol; 2.20 eq.) giving 1 -[[(E)-[3,3-dimethyl-1 -oxo- 2-(2-pyridylmethyl)isoindolin-5-yl]methyleneamino]-ethyl-amino]pyrrolo[1 ,2-a]pyrazine-6- carbonitrile (60 mg; 68.9 %) as a yellow powder.1H NMR (500 MHz, DMSO-c / 6) 5 ppm 8.48 - 8.53 (m, 1 H), 8.28 (s, 1 H), 8.03 (dd, J=4.54, 0.69 Hz, 1 H), 7.98 (s, 1 H), 7.94 (dd, J=7.84, 1.24 Hz, 1 H), 7.82 (d, J=7.98 Hz, 1 H), 7.74 (td, J=7.70, 1.93 Hz, 1 H), 7.62 (d, J=4.40 Hz, 1 H), 7.59 (d, J=4.68 Hz, 1 H), 7.53 (dd, J=4.54, 0.69 Hz, 1 H), 7.34 (d, J=7.70 Hz, 1 H), 7.25 - 7.29 (m, 1 H), 4.79 (s, 2 H), 4.49 (q, J=6.88 Hz, 2 H), 1.44 (s, 6 H), 1.25 (t, J=7.01 Hz, 3 H). mp : 173-186°C.

[0418] Example 47: 1-[[(E)-[3,3-dimethyl-2-(oxazol-2-ylmethyl)-1-oxo-isoindolin-5- yl]methylene amino]-ethyl-amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile

[0419] The compound was prepared using the same procedure as detailed in example 30 step a starting from 1 -[[(E)-(3,3-dimethyl-1 -oxo-isoindolin-5-yl)methyleneamino]-ethyl- amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile (50.00 mg; 0.13 mmol; 1.00 eq.) and 2- chloromethyl-oxazole (46.91 mg; 0.40 mmol; 3.00 eq.) giving 1 -[[(E)-[3,3-dimethyl-2- (oxazol-2-ylmethyl)-1 -oxo-isoindolin-5-yl]methyleneamino]-ethyl-amino]pyrrolo[1 ,2- a]pyrazine-6-carbonitrile (23 mg; 30.1 %) as a yellow powder.1H NMR (500 MHz, DMSO- d6) 5 ppm 8.28 (s, 1 H), 8.06 (d, J=0.83 Hz, 1 H), 8.04 (dd, J=4.54, 0.69 Hz, 1 H), 7.98 (s, 1 H), 7.93 (dd, J=7.84, 1.24 Hz, 1 H), 7.80 (d, J=7.70 Hz, 1 H), 7.62 (d, J=4.68 Hz, 1 H), 7.59 (d, J=4.40 Hz, 1 H), 7.53 (dd, J=4.54, 0.69 Hz, 1 H), 7.18 (d, J=0.83 Hz, 1 H), 4.85 (s, 2 H), 4.49 (q, J=6.88 Hz, 2 H), 1 .47 (s, 6 H), 1 .25 (t, J=7.02 Hz, 3 H).

[0420] Example 48: 1 -[[(E)-[3,3-dimethyl-1 -oxo-2-(thiazol-2-ylmethyl)isoindolin-5- yl]methylene amino]-ethyl-amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile

[0421] The compound was prepared using the same procedure as detailed in example 30 step a starting from 1 -[[(E)-(3,3-dimethyl-1 -oxo-isoindolin-5-yl)methyleneamino]-ethyl- amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile (50.00 mg; 0.13 mmol; 1.00 eq.) and 2- (chloromethyl)thiazole hydrochloride (50.23 mg; 0.30 mmol; 2.20 eq.) giving 1 -[[(E)-[3,3- dimethyl-1 -oxo-2-(thiazol-2-ylmethyl)isoindolin-5-yl]methyleneamino]-ethyl- amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile (31 mg; 48.8 %) as a pale yellow powder.1H NMR (500 MHz, DMSO-c / 6) 5 ppm 8.28 (s, 1 H), 8.04 (dd, J=4.68, 0.83 Hz, 1 H), 7.98 (s, 1 H), 7.94 (dd, J=7.98, 1.10 Hz, 1 H), 7.83 (d, J=7.98 Hz, 1 H), 7.74 (d, J=3.03 Hz, 1 H), 7.66 (d, J=3.30 Hz, 1 H), 7.62 (d, J=4.40 Hz, 1 H), 7.59 (d, J=4.68 Hz, 1 H), 7.53 (dd, J=4.40, 0.83 Hz, 1 H), 5.01 (s, 2 H), 4.49 (q, J=6.88 Hz, 2 H), 1.50 (s, 6 H), 1.24 (t, J=7.02 Hz, 3 H).

[0422] Example 49: 1 -[[(E)-[3,3-dimethyl-1 -oxo-2-(thiazol-4-ylmethyl)isoindolin-5- yl]methylene amino]-ethyl-amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile

[0423] The compound was prepared using the same procedure as detailed in example 30 step a starting from 1 -[[(E)-(3,3-dimethyl-1 -oxo-isoindolin-5-yl)methyleneamino]-ethyl- amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile (70.00 mg; 0.19 mmol; 1.00 eq.) and 4- chloromethylthiazole (55.25 mg; 0.41 mmol; 2.20 eq.) giving 1 -[[(E)-[3,3-dimethyl-1 -oxo-2- (thiazol-4-ylmethyl)isoindolin-5-yl]methyleneamino]-ethyl-amino]pyrrolo[1 ,2-a]pyrazine-6- carbonitrile (40 mg; 41.2 %) as a brown powder.1H NMR (500 MHz, DMSO-c / 6) 5 ppm 9.05 (d, J=1 .93 Hz, 1 H), 8.28 (s, 1 H), 8.03 (d, J=4.68 Hz, 1 H), 7.97 (s, 1 H), 7.89 - 7.96 (m, 1 H), 7.80 (d, J=7.98 Hz, 1 H), 7.62 (d, J=4.68 Hz, 1 H), 7.59 (d, J=4.40 Hz, 1 H), 7.51 - 7.56 (m, 2 H), 4.83 (s, 2 H), 4.49 (q, J=7.06 Hz, 2 H), 1.46 (s, 6 H), 1.24 (t, J=6.88 Hz, 3 H). mp : 158-194°C.

[0424] Example 50: 1 -[[(E)-[3,3-dimethyl-1 -oxo-2-(thiazol-5-ylmethyl)isoindolin-5- yl]methylene amino]-ethyl-amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile

[0425] The compound was prepared using the same procedure as detailed in example 30 step a starting from 1 -[[(E)-(3,3-dimethyl-1 -oxo-isoindolin-5-yl)methyleneamino]-ethyl- amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile (70.00 mg; 0.18 mmol; 1.00 eq.) and 5- (chloromethyl)thiazole (48.72 mg; 0.36 mmol; 2.00 eq.) giving 1 -[[(E)-[3,3-dimethyl-1 -oxo- 2-(thiazol-5-ylmethyl)isoindolin-5-yl]methyleneamino]-ethyl-amino]pyrrolo[1 ,2-a]pyrazine- 6-carbonitrile (38 mg; 42.7 %) as a pale yellow powder.1H NMR (500 MHz, DMSO-c / 6) 5 ppm 8.98 (d, J=0.83 Hz, 1 H), 8.26 (s, 1 H), 8.03 (dd, J=4.68, 0.83 Hz, 1 H), 7.98 (s, 1 H), 7.95 (s, 1 H), 7.92 (dd, J=7.98, 1.10 Hz, 1 H), 7.81 (d, J=7.98 Hz, 1 H), 7.62 (d, J=4.68 Hz, 1 H), 7.58 (d, J=4.68 Hz, 1 H), 7.52 (dd, J=4.68, 0.83 Hz, 1 H), 4.95 (s, 2 H), 4.48 (q, J=6.60 Hz, 2 H), 1.49 (s, 6 H), 1.24 (t, J=7.02 Hz, 3 H). mp : 193-204°C.

[0426] Example 51 : 1-[ethyl-[(E)-[2-(1 H-imidazol-2-ylmethyl)-3,3-dimethyl-1-oxo-isoindolin- 5-yl] methyleneamino]amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile

[0427] The compound was prepared using the same procedure as detailed in example 30 step a starting from 1 -[[(E)-(3,3-dimethyl-1 -oxo-isoindolin-5-yl)methyleneamino]-ethyl- amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile (25.78 mg; 0.00 mol; 1.00 eq.) and tert-butyl 2- (chloromethyl)imidazole-l -carboxylate (15.00 mg; 0.00 mol; 1.00 eq.) giving 1 -[ethyl-[(E)- [2-(1 H-imidazol-2-ylmethyl)-3,3-dimethyl-1 -oxo-isoindolin-5- yl]methyleneamino]amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile (12 mg; 35.3 %) as a yellow powder.1H NMR (500 MHz, DMSO-c / 6) 5 ppm 11 .85 (br s, 1 H), 8.27 (s, 1 H), 8.03 (dd, J=4.68, 0.83 Hz, 1 H), 7.91 - 7.96 (m, 2 H), 7.81 (d, J=7.98 Hz, 1 H), 7.62 (d, J=4.40 Hz, 1 H), 7.59 (d, J=4.68 Hz, 1 H), 7.53 (dd, J=4.68, 0.83 Hz, 1 H), 7.01 (s, 1 H), 6.82 (s, 1 H), 4.72 (s, 2 H), 4.48 (q, J=6.88 Hz, 2 H), 1 .39 (s, 6 H), 1 .24 (t, J=7.02 Hz, 3 H).

[0428] Example 52: 1-[[(E)-[3,3-dimethyl-1-oxo-2-(1 H-tetrazol-5-ylmethyl)isoindolin-5- yl]methylene amino]-ethyl-amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile

[0429] The compound was prepared using the same procedure as detailed in example 30 step a starting from 1 -[[(E)-(3,3-dimethyl-1 -oxo-isoindolin-5-yl)methyleneamino]-ethyl- amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile (70.00 mg; 0.19 mmol; 1.00 eq.) and 5- chloromethyl-1 H-tetrazole (49.00 mg; 0.41 mmol; 2.20 eq.) giving 1 -[[(E)-[3,3-dimethyl-1 - oxo-2-(1 H-tetrazol-5-ylmethyl)isoindolin-5-yl]methyleneamino]-ethyl-amino]pyrrolo[1 ,2- a]pyrazine-6-carbonitrile (17 mg; 19.1 %) as a yellow powder.1H NMR (500 MHz, DMSO- d6) 6 ppm 8.28 (s, 1 H), 8.04 (dd, J=4.54, 0.69 Hz, 1 H), 7.99 (s, 1 H), 7.94 (dd, J=7.84, 1.24 Hz, 1 H), 7.82 (d, J=7.98 Hz, 1 H), 7.63 (d, J=4.40 Hz, 1 H), 7.59 (d, J=4.68 Hz, 1 H), 7.54 (dd, J=4.54, 0.69 Hz, 1 H), 5.03 (s, 2 H), 4.49 (q, J=6.69 Hz, 2 H), 1.50 (s, 6 H), 1.25 (t, J=7.01 Hz, 3 H).

[0430] Example 53: 1 -[ethyl-[(E)-(1 -oxoisoindolin-5-yl)methyleneamino]amino]pyrrolo[1 ,2- a]pyrazine -6-carbonitrile

[0431] Step a: 1 -oxoisoindoline-5-carbaldehyde

[0432] The compound was prepared using the same procedure as detailed in example 1 step d starting from 5-bromo-2,3-dihydro-1 H-isoindol-1 -one (300.00 mg; 1.41 mmol; 1.00 eq.) giving 1 -oxoisoindoline-5-carbaldehyde (65 mg; 28.5 %) as a white powder.1H NMR (400 MHz, DMSO-Gfc) 5 ppm 10.14 (s, 1 H), 8.11 (s, 1 H), 8.02 (d, J=7.51 Hz, 1 H), 7.87 (m, 1 H), 4.48 (s, 2 H). Step b: 1 -[ethyl-[(E)-( 1 -oxoisoindolin-5-yl)methyleneamino]amino]pyrrolo[1 ,2-a]pyrazine-6- carbonitrile

[0433] The compound was prepared using the same procedure as detailed in example 12 step d starting from 1 -oxoisoindoline-5-carbaldehyde (101.0 mg, 0.63 mmol, 2.5 eq.) and 1 - [amino(ethyl)amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile (50.0 mg, 0.25 mmol, 1.0 eq.) giving 1 -[ethyl-[(E)-( 1 -oxoisoindolin-5-yl)methyleneamino]amino]pyrrolo[1 ,2-a]pyrazine-6- carbonitrile (36.0 mg 42% %) as a brown solid.1H NMR (500 MHz, DMSO-c / 6) 5 8.61 (s, 1 H), 8.27 (s, 1 H), 8.02 (d, J= 2.5 Hz, 1 H), 7.93 (s, 1 H), 7.88 (d, J= 7.3 Hz, 1 H), 7.76 (d, J= 7.3 Hz, 1 H), 7.63-7.53 (m, 3H), 4.54-4.42 (m, 4H), 1 .23 (t, J= 6.7 Hz, 3H). mp > 300°C.

[0434] Example 54: 1 -(1 -Ethyl-2-((3-methyl-1 -oxoisoindolin-5-yl)methylene)- hydrazineyl)pyrrolo[1 ,2-a]pyrazine-6-carbonitrile

[0435] Step a: tert-Butyl 5-bromo-1 -oxoisoindoline-2-carboxylate

[0436] 5-Bromoisoindolin-1 -one (1 , 1.0 g, 4.71 mmol, 1.00 eq.) was dissolved in dry DCM (35.0 mL) then Boc20 (1.62 mL, 7.07 mmol, 1.5 eq.), TEA (719.0 pL, 5.18 mmol, 1.1 eq.) and DMAP (633.7 mg, 5.18 mmol, 1.1 eq.) were added. The resulting mixture was stirred at rt overnight. The progress of the reaction was monitored by TLC (n-heptane:EtOAc = 1 :1 ) and LCMS analyses. After completion the mixture was poured onto water and extracted with DCM. The organic phase was dried, filtered, and concentrated. The crude product was purified by column chromatography (eluent: 0-20% EtOAc in cyclohexane) to obtain tert-Butyl 5-bromo-1 -oxoisoindoline-2-carboxylate (1.36 g, 92% yield) as a white solid. ES+ MS m / z 334 [M+H+Na]+, UPLC-MS using Waters method

[0437] 5min_normal_A2B2_ELS_EVO (220 nm) 90% (AUC).

[0438] Step b: tert-Butyl 5-bromo-3-methyl-1 -oxoisoindoline-2-carboxylate tert-Butyl 5-bromo-1 -oxoisoindoline-2-carboxylate (1.0 g, 3.20 mmol, 1.0 eq.) was dissolved in dry THF (15.0 mL) and cooled to -20 °C. A solution of LiHMDS (1.0 M solution in THF, 4.8 mL, 4.8 mmol, 1.5 eq.) was added dropwise. After stirring at -20 °C for 1 h, Mel (3, 359.0 pL, 5.76 mmol, 1.8 eq.) was added and the resulting mixture was stirred at -20 °C for 3 h. The progress of the reaction was monitored by TLC (n- heptane:EtOAc = 3:2) and LCMS analyses. After completion the mixture was quenched with brine and extracted with EtOAc. The organic phase was dried and concentrated. The crude product was purified by column chromatography (eluent: 0-10% EtOAc in cyclohexane) to obtain tert-Butyl 5-bromo-3-methyl-1 -oxoisoindoline-2-carboxylate (379.0 mg 36% yield) as a beige solid. ES+ MS m / z 348 [M+H+Na]+, UPLC-MS using Waters method 5min_normal_A2B2_ELS_EVO (220 nm) 83% (AUC).

[0439] Step c: 5-Bromo-3-methylisoindolin-1 -one tert-Butyl 5-bromo-3-methyl-1 -oxoisoindoline-2-carboxylate (273.0 mg, 0.84 mmol, 1.00 eq.) was dissolved in dioxane (1.7 mL) and HCI / dioxane solution (1.7 mL) was added. The resulting mixture was stirred at rt for 2-3 h. The progress of the reaction was monitored by TLC (n-heptane:EtOAc : 3:2) and LCMS analyses. After completion the solvent was evaporated, and the residue was diluted with Et2O. The solvent was evaporated again, and the procedure was repeated three times to obtain 5-Bromo-3- methylisoindolin-1 -one (195.0 mg, quant.) as a pink solid. ES+ MS m / z 226 [M+H]+, UPLC-MS using Waters method 5min_normal_A2B2_ELS_EVO (220 nm) 96% (ALIC). Step d: 3-Methyl-1 -oxoisoindoline-5-carbaldehyde

[0440] The compound was prepared using the same procedure as detailed in example 1 step d starting from 5-Bromo-3-methylisoindolin-1 -one (95.0 mg, 0.86 mmol, 1.0 eq.) giving 3- Methyl-1 -oxoisoindoline-5-carbaldehyde (30.0 mg, 20%) as a mustard-yellow solid. ES+ MS m / z 176 [M+H]+, UPLC-MS using Waters method 5min_normal_A2B2_ELS_EVO (220 nm) 87% (AUC).

[0441] Step e: 1 -(1 -Ethyl-2-((3-methyl-1 -oxoisoindolin-5-yl)methylene)hydrazineyl)pyrrolo[1 ,2- a]pyrazine-6-carbonitrile

[0442] The compound was prepared using the same procedure as detailed in example 12 step d starting from 3-Methyl-1-oxoisoindoline-5-carbaldehyde (30.0 mg, 0.15 mmol, 1.1 eq.) and 1-[amino(ethyl)amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile (27.0 mg, 0.13 mmol, 1.0 eq.) giving 1 -(1 -Ethyl-2-((3-methyl-1 -oxoisoindolin-5-yl)methylene)hydrazineyl)pyrrolo[1 ,2- a]pyrazine-6-carbonitrile (17.0 mg 35% yield) as a brown powder.1H NMR (400 MHz, DMSO-Gfc): 5 8.70 (s, 1 H), 8.27 (s, 1 H), 8.01 (d, J= 4.5 Hz, 1 H), 7.9 (s, 1 H), 7.88 (d, J= 6.5 Hz, 1 H), 7.72 (d, J= 7.8 Hz, 1 H), 7.60 (d, J= 4.5 Hz, 1 H), 7.57 (d, J= 4.5 Hz, 1 H), 7.53 (d, J= 4.5 Hz, 1 H), 4.71 (q, J= 6.7 Hz, 1 H), 4.48 (q, J= 7.0 Hz, 2H), 1.41 (d, J= 6.7 Hz, 3H), 1 .23 (t, J= 7.0 Hz, 3H). mp: 266-267 °C.

[0443] Example 55: 1 -(2-((3,3-Diethyl-1 -oxoisoindolin-5-yl)methylene)-1 - ethylhydrazineyl)pyrrolo [1 ,2-a]pyrazine-6-carbonitrile

[0444] Step a: 5-Bromo-3,3-diethyl-2-(4-methoxybenzyl)isoindolin-1 -one

[0445] The compound was prepared using the same procedure as detailed in example 1 step b starting from 5-bromo-2-[(4-methoxyphenyl)methyl]isoindolin-1-one (1.0 g, 3.0 mmol, 1.0 eq.) and Etl (722.0 pL, 9.0 mmol, 3.0 eq.) giving 5-Bromo-3,3-diethyl-2-(4- methoxybenzyl)isoindolin-1-one (880.0 mg, 80% yield) as a white solid. ES+ MS m / z 388 [M+H]+, UPLC-MS using Waters method 2min_strong_A2B2_EVO (220 nm) 99% (AUC). Step b: 5-Bromo-3,3-diethylisoindolin-1-one

[0446] The compound was prepared using the same procedure as detailed in example 1 step c starting from 5-Bromo-3,3-diethyl-2-(4-methoxybenzyl)isoindolin-1-one (880.0 mg, 2.26 mmol, 1.0 eq.) giving 5-Bromo-3,3-diethylisoindolin-1 -one (461.0 mg, 76% yield) as a yellow solid. ES+ MS m / z 268 [M+H]+, UPLC-MS using Waters method 2min_normal_A2B2_EVO (220 nm) 100% (AUC).

[0447] Step c: 3,3-Diethyl-1 -oxoisoindoline-5-carbaldehyde 5-Bromo-3,3-diethylisoindolin-1 -one (250.0 mg, 0.93 mmol, 1.0 eq.), Pd(dppf)CI2(17.0 mg, 0.023 mmol, 0.025 eq.) and Na2CO3(99.0 mg, 0.93 mmol, 1.0 eq.) were suspended in dry DMF (1.9 mL) then Et3SiH (297.0 pL, 1.86 mmol, 2.0 eq.) was added in an autoclave. The reactor was sealed and purged with CO several times then charged with 9- 10 bar CO and stirred at 80-90 °C overnight. The progress of the reaction was monitored by TLC (n-heptane:EtOAc = 1 :1 + DNPH) and LCMS analyses. After completion the reaction mixture was diluted with brine and EtOAc. The phases were separated, and the aqueous phase was extracted with EtOAc (2x). The organic phase was dried and concentrated to obtain the crude 3,3-Diethyl-1 -oxoisoindoline-5-carbaldehyde (400.0 mg, quant.) as a brown solid, which was used in the next step without further purification. ES+ MS m / z 218 [M+H]+, UPLC-MS using Waters method 2min_normal_A2B2_EVO (220 nm) 86% (AUC).

[0448] Step d: 1 -(2-((3 ,3-Diethyl- 1 -oxoisoindolin-5-yl)methylene)-1 -ethylhydrazineyl)pyrrolo[1 ,2- a]pyrazine-6-carbonitrile

[0449] The compound was prepared using the same procedure as detailed in example 12 step d starting from 3,3-Diethyl-1 -oxoisoindoline-5-carbaldehyde (54.0 mg (crude), 0.25 mmol, 1.4 eq.) and 1 -[amino(ethyl)amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile (53.0 mg, 0.18 mmol, 1.0 eq.) giving 1 -(2-((3,3-Diethyl-1 -oxoisoindolin-5-yl)methylene)-1 - ethylhydrazineyl)pyrrolo[1 ,2-a] pyrazine-6-carbonitrile (13 mg 18% yield) as a yellow solid.1H NMR (500 MHz, DMSO-c / 6): 5 8.46 (s, 1 H), 8.26 (s, 1 H), 8.02 (d, J= 4.5 Hz, 1 H), 7.87 (d, J= 7.9 Hz, 1 H), 7.80 (s, 1 H), 7.70 (d, J= 7.9 Hz, 1 H), 7.59 (dd, J= 10.6 and 4.5 Hz, 2 H), 7.51 (d, J= 4.5 Hz, 1 H), 4.47 (q, J= 7.0 Hz, 2 H), 1.86 (q, J= 7.4 Hz, 4 H), 1.24 (t, J= 7.0 Hz, 3 H), 0.60 (t, J= 7.4 Hz, 6 H). mp : 240 °C.

[0450] Example 56: 1-(2-((3-Allyl-1-oxoisoindolin-5-yl)methylene)-1- ethylhydrazineyl)pyrrolo[ 7,2-a]pyrazine-6-carbonitrile Step a: 3-Allyl-5-bromo-2-(4-methoxybenzyl)isoindolin-1 -one

[0451] The compound was prepared using the same procedure as detailed in example 1 step b starting from 5-bromo-2-[(4-methoxyphenyl)methyl]isoindolin-1 -one (1.5 g, 4.51 mmol, 1.00 eq.) and 1 ,3-dibrompropane (2, 1.37 mL, 13.54 mmol, 3.0 eq.) giving 3-Allyl-5- bromo-2-(4-methoxybenzyl)isoindolin-1 -one (584.0 mg, 35% yield) as a yellow oil. ES+ MS m / z 372 [M+H]+, UPLC-MS using Waters method 5min_normal_A2B2_ELS_EVO (220 nm) 89% (AUC). Step b: 3-Allyl-5-bromoisoindolin-1 -one

[0452] The compound was prepared using the same procedure as detailed in example 1 step c starting from 3-Allyl-5-bromo-2-(4-methoxybenzyl)isoindolin-1 -one (473.0 mg, 1.27 mmol, 1.0 eq.) giving 3-Allyl-5-bromoisoindolin-1 -one (198.0 mg 62% yield) as a pale yellow solid. ES+ MS m / z 252 [M+H]+, UPLC-MS using Waters method

[0453] 5min_normal_A2B2_ELS_EVO (220 nm) 100% (AUC).

[0454] Step c: 3-Allyl-1 -oxoisoindoline-5-carbaldehyde

[0455] 3-Allyl-5-bromoisoindolin-1 -one (198.0 mg, 0.785 mmol, 1.0 eq.), Pd(dppf)CI2(14.0 mg, 0.020 mmol, 0.025 eq.) and Na2CO3(83.0 mg, 0.785 mmol, 1.0 eq.) were suspended in dry DMF (1.6 mL) then Et3SiH (250.0 pL, 1.57 mmol, 2.0 eq.) was added in an autoclave. The reactor was sealed and purged with CO several times then charged with 8-9 bar CO and stirred at 90 °C overnight. The progress of the reaction was monitored by TLC (n- heptane:EtOAc = 1 :1 and EtOAc + DNPH) and LCMS analyses. After completion the reaction mixture was diluted with brine and EtOAc. The phases were separated, and the aqueous phase was extracted with EtOAc (2x). The organic phase was washed with sat. aq. NaHCO3solution and brine. The organic phase was dried and concentrated. The crude product was purified by column chromatography (eluent: 0-70% EtOAc in cyclohexane) to obtain 3-Allyl-1 -oxoisoindoline-5-carbaldehyde (5, DCOM31 -426_1 , 95.0 mg 60% yield) as a brown solid. ES+ MS m / z 202 [M+H]+, UPLC-MS using Waters method 5min_normal_A2B2_ELS_EVO (220 nm) 91% (AUC).1H NMR (500 MHz, DMSO- d6y. 6 10.12 (s, 1 H), 8.99 (s, 1 H), 8.13 (s, 1 H), 8.00 (d, J= 7.7 Hz, 1 H), 7.83 (d, J= 7.7 Hz, 1 H), 5.69-5.58 (m, 1 H), 5.07 (d, J= 17.0 Hz, 1 H), 5.02 (d, J= 10.3 Hz, 1 H), 4.78 (t, J= 5.6 Hz, 1 H), 2.69-2.60 (m, 1 H), 2.57-2.52 (m, 1 H).

[0456] Step d: 1 -(2-((3- Allyl- 1 -oxoisoindolin-5-yl)methylene)-1 -ethylhydrazineyl)pyrrolo[ 1,2- a]pyrazine-6-carbonitrile

[0457] The compound was prepared using the same procedure as detailed in example 12 step d starting from 3-Allyl-1 -oxoisoindoline-5-carbaldehyde (50.0 mg, 0.25 mmol, 1.0 eq.) and 1 - [amino(ethyl)amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile (73.6 mg, 0.25 mmol, 1.0 eq.) giving 1 -(2-((3- Allyl- 1 -oxoisoindolin-5-yl)methylene)-1 -ethylhydrazineyl)pyrrolo[ 1,2- a]pyrazine-6-carbonitrile (37.0 mg 38% yield) as a brown solid.1H NMR (500 MHz, DMSO-ck): 5 8.73 (s, 1 H), 8.26 (s, 1 H), 8.01 (d, J= 4.6 Hz, 1 H), 7.94 (s, 1 H), 7.86 (d, J= 7.9 Hz, 1 H), 7.73 (d, J= 7.8 Hz, 1 H), 7.60 (d, J= 4.5 Hz, 1 H), 7.57 (d, J= 4.5 Hz, 1 H), 7.53 (d, J= 4.5 Hz, 1 H), 5.79-5.69 (m, 1 H), 5.13 (d, J= 17.3 Hz, 1 H), 5.07 (d, J= 10.3 Hz, 1 H), 4.75 (t, J= 5.7 Hz, 1 H), 4.54-4.41 (m, 2H), 2.61 -2.52 (m, 2H), 1.23 (t, J= 7.0 Hz, 3H). mp : 252-254 °C. Example 57: 1-[[(E)-[3,3-bis(methoxymethyl)-1-oxo-isoindolin-5-yl]methyleneamino]- ethyl-amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile

[0458] Step a: 5-bromo-3,3-bis(methoxymethyl)-2-[(4-methoxyphenyl)methyl]isoindolin-1 -one

[0459] The compound was prepared using the same procedure as detailed in example 1 step b starting from 5-bromo-2-[(4-methoxyphenyl)methyl]isoindolin-1 -one (600.00 mg; 1.81 mmol; 1.00 eq.) and bromomethyl methyl ether (589.70 pL; 7.22 mmol; 4.00 eq.) giving 5- bromo-3,3-bis(methoxymethyl)-2-[(4-methoxyphenyl)methyl]isoindolin-1 -one (177.00 mg; 23.32 %) as a beige solid.1H NMR (400 MHz, DMSO-c / 6) 5 ppm 7.92 (d, <7=1.21 Hz, 1 H), 7.68 (dd, J=8.00, 1.70 Hz, 1 H), 7.60 (dd, J=8.00, 1.00 Hz, 1 H), 7.29 (m, 2 H), 6.86 (m, 2 H), 4.59 (s, 2 H), 3.72 (s, 3 H), 3.66 (d, J=10.20 Hz, 2 H), 3.58 (d, J=10.00 Hz, 2 H), 2.92 (s, 6 H).

[0460] Step b: 5-bromo-3,3-bis(methoxymethyl)isoindolin-1 -one

[0461] The compound was prepared using the same procedure as detailed in example 1 step c starting from 5-bromo-3,3-bis(methoxymethyl)-2-[(4-methoxyphenyl)methyl]isoindolin-1 - one (205.00 mg; 0.51 mmol; 1.00 eq.) giving 5-bromo-3,3-bis(methoxymethyl)isoindolin-1 - one (142.0 mg 93.4 %) as a pale-yellow solid.1H NMR (400 MHz, DMSO-c / 6) 5 ppm 8.79 (s, 1 H), 7.81 (s, 1 H), 7.67 (dd, J=7.98, 1.71 Hz, 1 H), 7.55 (dd, J=8.03, 0.55 Hz, 1 H), 5.75 (s, 1 H), 3.56 (m, 4 H), 3.23 (s, 6 H).

[0462] Step c: 3,3-bis(methoxymethyl)-5-vinyl-isoindolin-1 -one

[0463] In a 2-5 mL MW tube, 5-bromo-3,3-bis(methoxymethyl)isoindolin-1 -one (82.00 mg; 0.27 mmol; 1.00 eq.), Pd(PPh3)4 (6.31 mg; 0.01 mmol; 0.02 eq.), CsF (124.50 mg; 0.82 mmol; 3.00 eq.) and tributyl(vinyl)tin (1 19.22 pL; 0.41 mmol; 1 .50 eq.) were added and dissolved in dry 1 ,4-dioxane (1.23 mL) (adjusted to 1.7 mL) under Argon. The reaction mixture was stirred at 120°C for 1 h45. The reaction mixture was diluted with water and extracted with AcOEt (three times). The combined organic layers were washed with water, brine, dried over MgSO4, filtered and concentrated under reduced pressure; The residue was purified by chromatography (Column Biotage HC Star 5g 18mL / min, Eluent A cyclo eluent B: EtOAc gradient : 100 / 0 over 1 CV, then gradient to 20 / 80 on 10CV and 20 / 80(iso) 4CV) to give 3,3-bis(methoxymethyl)-5-vinyl-isoindolin-1 -one (53.00 mg; 66.68 %).1H NMR (400 MHz, DMSO-Gfc) 5 ppm 10.11 (s, 1 H), 8.67 (s, 1 H), 7.65 (s, 1 H), 7.57 (s, 2 H), 6.84 (dd, J=17.72, 1 1.00 Hz, 1 H), 5.95 (dd, J=17.61 , 0.66 Hz, 1 H), 5.38 (m, 1 H), 3.57 (m, 4 H), 3.24 (m, 6 H).

[0464] Step d: 3,3-bis(methoxymethyl)-1 -oxo-isoindoline-5-carbaldehyde

[0465] In a 5 mL round bottom flask, 3,3-bis(methoxymethyl)-5-vinyl-isoindolin-1 -one (53.00 mg; 0.18 mmol; 1.00 eq.) was dissolved in MeCN (1.13 mL) to give an homogeneous solution. RUCI3, H2O (182.18 pL; 0.04 mol / L; 0.01 mmol; 0.04 eq.) was added at 0°C to give a black solution. NalO4(77.93 mg; 0.36 mmol; 2.00 eq.) was dissolved in water (450.50 pL) and added to the mixture. The reaction mixture was stirred at 0°C for 10 min. The reaction mixture was quenched with sat. Na2S2O3. The reaction mixture was extracted with AcOEt (two times). The organic layer was dried with MgSO4, filtered and concentrated under reduce pressure. The crude product was purified by chromatography (Column Biotage HC Star 5g 18mL / min, Eluent A cyclo eluent B: EtOAc, gradient : 100 / 0 over 1 CV, then gradient to 0 / 100 on 8CV and 0 / 100 (iso) 10CV) to give 3,3-bis(methoxymethyl)-1 -oxo- isoindoline-5-carbaldehyde (28.00 mg; 61.66 %) as a beige solid.1H NMR (400 MHz, DMSO-cfc) 5 ppm 10.1 1 (s, 1 H), 9.01 (s, 1 H), 8.10 (d, J=2.09 Hz, 1 H), 8.03 (dd, J=7.70, 1.32 Hz, 1 H), 7.82 (d, J=7.70 Hz, 1 H), 3.61 (m, 4 H), 3.23 (s, 6 H).

[0466] Step e: 1 -[[(E)-[3,3-bis(methoxymethyl)-1 -oxo-isoindolin-5-yl]methyleneamino]-ethyl- amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile

[0467] The compound was prepared using the same procedure as detailed in example 12 step d starting from 3-Allyl-1 -oxoisoindoline-5-carbaldehyde (27.00 mg; 0.1 1 mmol; 1.00 eq.) and 1 -[amino(ethyl)amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile (23.95 mg; 0.1 1 mmol; 1.00 eq) giving 1 -[[(E)-[3,3-bis(methoxymethyl)-1 -oxo-isoindolin-5-yl]methyleneamino]-ethyl- amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile (31.0 mg, 64.9 %) as a yellow powder.1H NMR (500 MHz, DMSO-Gfc) 5 ppm 8.78 (s, 1 H), 8.27 (s, 1 H), 8.03 (d, J=4.68 Hz, 1 H), 7.98 (s, 1 H), 7.88 (dd, J=7.98, 1.10 Hz, 1 H), 7.72 (d, J=7.98 Hz, 1 H), 7.61 (d, J=4.40 Hz, 1 H), 7.59 (d, J=4.40 Hz, 1 H), 7.53 (d, J=4.68 Hz, 1 H), 4.48 (q, J=7.15 Hz, 2 H), 3.62 (d, J=9.63 Hz, 2 H), 3.56 (d, J=9.63 Hz, 2 H), 3.29 (s, 6 H), 1.23 (t, J=6.88 Hz, 3 H).

[0468] Example 58: 1-[[(E)-[3,3-bis(2-methoxyethyl)-1-oxo-isoindolin-5-yl]methyleneamino]- ethyl-amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile

[0469] Step a: 5-bromo-3,3-bis(2-methoxyethyl)-2-[(4-methoxyphenyl)methyl]isoindolin-1 -one

[0470] The compound was prepared using the same procedure as detailed in example 1 step b starting from 5-bromo-2-[(4-methoxyphenyl)methyl]isoindolin-1 -one (1.00 g; 3.01 mmol; 1.00 eq.) and 2-bromoethyl methyl ether (1.72 mL; 18.06 mmol; 6.00 eq.) giving 5-bromo- 3,3-bis(2-methoxyethyl)-2-[(4-methoxyphenyl)methyl]isoindolin-1 -one (880.00 mg; 54.2 %) as a yellow solid.1H NMR (400 MHz, DMSO-c / 6) 5 ppm 7.98 (m, 1 H), 7.66 (dd, J=8.00, 1.80 Hz, 1 H), 7.61 (dt, J=7.81 , 1.00 Hz, 1 H), 7.48 (m, 2 H), 6.87 (m, 2 H), 4.51 (s, 2 H), 3.72 (s, 3 H), 2.78 (s, 6 H), 2.45 (t, J=7.60 Hz, 4 H), 2.26 (t, J=7.30 Hz, 4 H).

[0471] Step b: 5-bromo-3,3-bis(2-methoxyethyl)isoindolin-1 -one

[0472] The compound was prepared using the same procedure as detailed in example 1 step c starting from 5-bromo-3,3-bis(2-methoxyethyl)-2-[(4-methoxyphenyl)methyl]isoindolin-1 - one (376.00 mg; 0.70 mmol; 1.00 eq.) giving 5-bromo-3,3-bis(2-methoxyethyl)isoindolin-1 - one (227.0 mg 99.4 %) as a brown solid.1H NMR (400 MHz, DMSO-c / 6) 5 ppm 8.55 (s, 1 H), 7.93 (m, 1 H), 7.63 (dd, J=8.03, 1.65 Hz, 1 H), 7.52 (d, J=8.03 Hz, 1 H), 3.12 (dt, J=9.66, 6.84 Hz, 2 H), 3.04 (s, 6 H), 2.91 (dt, J=9.68, 7.10 Hz, 2 H), 2.10 (t, J=7.10 Hz, 4 H).

[0473] Step c: 3,3-bis(2-methoxyethyl)-1 -oxo-isoindoline-5-carbaldehyde

[0474] The compound was prepared using the same procedure as detailed in example 1 step d starting from 5-bromo-3,3-bis(2-methoxyethyl)isoindolin-1 -one (207.00 mg; 0.63 mmol; 1.00 eq.) giving 3,3-bis(2-methoxyethyl)-1 -oxo-isoindoline-5-carbaldehyde (140 mg, 53.3%) as a brown solid.1H NMR (400 MHz, DMSO-c / 6) 5 ppm 10.12 (s, 1 H), 8.78 (s, 1 H), 8.16 (m, 1 H), 7.99 (dd, J=7.76, 1.27 Hz, 1 H), 7.80 (d, J=7.70 Hz, 1 H), 3.13 (m, 2 H), 3.01 (s, 6 H), 2.92 (m, 2 H), 2.14 (m, 4 H).

[0475] Step d: 1 -[[(E)-[3,3-bis(2-methoxyethyl)-1 -oxo-isoindolin-5-yl]methyleneamino]-ethyl- amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile

[0476] The compound was prepared using the same procedure as detailed in example 12 step d starting from 3,3-bis(2-methoxyethyl)-1 -oxo-isoindoline-5-carbaldehyde (138.00 mg; 0.36 mmol; 1.00 eq.) and 1 -[amino(ethyl)amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile (76.08 mg; 0.37 mmol; 1.02 eq.) giving 11 -[[(E)-[3,3-bis(2-methoxyethyl)-1 -oxo-isoindolin-5- yl]methyleneamino]-ethyl-amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile (30.0 mg, 17.8 %) as a yellow powder.1H NMR (500 MHz, DMSO-c / 6) 5 ppm 8.57 (s, 1 H), 8.27 (s, 1 H), 8.03 (dd, J=4.68, 0.55 Hz, 1 H), 7.88 - 7.91 (m, 2 H), 7.71 (d, J=8.53 Hz, 1 H), 7.59 (d, J=4.40 Hz, 2 H), 7.53 (d, J=4.55 Hz, 1 H), 4.49 (q, J=6.88 Hz, 2 H), 3.17 - 3.22 (m, 2 H), 3.07 (s, 6 H), 2.98 (ddd, J=9.28, 8.18, 6.46 Hz, 2 H), 2.09 - 2.19 (m, 4 H), 1.25 (t, J=7.02 Hz, 3 H).

[0477] Example 59: 1 -[ethyl- [(E)-(3-ethyl- 1 -oxo-isoindolin-5-yl)methyleneamino]- amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile

[0478] Step a: 5-bromo-3-ethyl-2-[(4-methoxyphenyl)methyl]isoindolin-1 -one

[0479] The compound was prepared using the same procedure as detailed in example 54 step b starting from 5-bromo-2-[(4-methoxyphenyl)methyl]isoindolin-1 -one (600.00 mg; 1.77 mmol; 1.00 eq.) and bromoethane (171.74 pL; 2.30 mmol; 1.30 eq.) giving 5-bromo-3- ethyl-2-[(4-methoxyphenyl)methyl]isoindolin-1 -one (395.00 mg; 57.25 %) as a colorless oil.1H NMR (400 MHz, DMSO-c / 6) 5 ppm 7.83 (d, J=1.65 Hz, 1 H), 7.69 (dd, J=8.03, 1.65 Hz, 1 H), 7.65 (d, J=8.36 Hz, 1 H), 7.23 (m, 2 H), 6.89 (m, 2 H), 4.98 (d, J=15.08 Hz, 1 H), 4.47 (t, J=3.85 Hz, 1 H), 4.19 (d, J=15.08 Hz, 1 H), 3.72 (s, 3 H), 2.02 (m, 2 H), 0.34 (t, J=7.32 Hz, 3 H).

[0480] Step b: 5-bromo-3-ethyl-isoindolin-1 -one

[0481] The compound was prepared using the same procedure as detailed in example 1 step c starting from 5-bromo-3-ethyl-2-[(4-methoxyphenyl)methyl]isoindolin-1 -one (340.00 mg; 0.94 mmol; 1.00 eq.) giving 5-bromo-3-ethyl-isoindolin-1 -one (237.0 mg 91.1 %) as a yellow solid.1H NMR (400 MHz, DMSO-c / 6) 5 ppm 8.78 (s, 1 H), 7.84 (m, 1 H), 7.66 (m, 1 H), 7.57 (d, J=8.03 Hz, 1 H), 5.75 (s, 1 H), 4.56 (dd, J=6.88, 4.35 Hz, 1 H), 1.95 (m, 1 H),

[0482] 1.58 (dt, J=14.03, 7.07 Hz, 1 H), 0.80 (t, J=7.37 Hz, 3 H)

[0483] Step c: 3-ethyl-1 -oxo-isoindoline-5-carbaldehyde

[0484] The compound was prepared using the same procedure as detailed in example 1 step d starting from 5-bromo-3,3-bis(2-methoxyethyl)isoindolin-1 -one (188.00 mg; 0.78 mmol; 1.00 eq.) giving 3-ethyl-1 -oxo-isoindoline-5-carbaldehyde (58 mg, 29.1 %) as a brown solid.1H NMR (400 MHz, DMSO-c / 6) 5 ppm 10.13 (s, 1 H), 9.01 (s, 1 H), 8.11 (t, J=1.32 Hz, 1 H), 8.01 (dd, J=7.76, 1.93 Hz, 1 H), 7.84 (d, J=7.81 Hz, 1 H), 4.67 (m, 1 H), 1.99 (m,

[0485] 1 H), 1.65 (dt, J=14.09, 7.04 Hz, 1 H), 0.83 (t, J=7.37 Hz, 3 H).

[0486] Step d: 1 -[ethyl-[(E)-(3-ethyl-1 -oxo-isoindolin-5-yl)methyleneamino]amino]pyrrolo[1 ,2- a]pyrazine-6-carbonitrile

[0487] The compound was prepared using the same procedure as detailed in example 12 step d starting from 3,3-bis(2-methoxyethyl)-1 -oxo-isoindoline-5-carbaldehyde (46.00 mg; 0.22 mmol; 1.00 eq.) and 1 -[amino(ethyl)amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile (45.43 mg; 0.22 mmol; 1.00 eq.) giving 1 -[ethyl-[(E)-(3-ethyl-1 -oxo-isoindolin-5- yl)methyleneamino]amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile (53.0 mg, 53.5 %) as a yellow powder.1H NMR (500 MHz, DMSO-c / 6) 5 ppm 8.76 (s, 1 H), 8.28 (s, 1 H), 8.03 (d, J=4.68 Hz, 1 H), 7.87 - 7.93 (m, 2 H), 7.74 (d, J=7.70 Hz, 1 H), 7.61 (d, J=4.40 Hz, 1 H),

[0488] 7.58 (d, J=4.40 Hz, 1 H), 7.54 (d, J=4.68 Hz, 1 H), 4.63 (t, J=5.78 Hz, 1 H), 4.43 - 4.54 (m,

[0489] 2 H), 1.88 - 1.98 (m, 1 H), 1.68 (quin, J=7.08 Hz, 1 H), 1.24 (t, J=7.02 Hz, 3 H), 0.89 (t, J=7.43 Hz, 3 H). mp: 250-255°C.

[0490] Example 60: 1-[ethyl-[(E)-(1-oxo-3-propyl-isoindolin-5- yl)methyleneamino]amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile

[0491] Step a: 5-bromo-2-[(4-methoxyphenyl)methyl]-3-propyl-isoindolin-1 -one

[0492] The compound was prepared using the same procedure as detailed in example 54 step b starting from 5-bromo-2-[(4-methoxyphenyl)methyl]isoindolin-1 -one (600.00 mg; 1.81 mmol; 1.00 eq.) and 1 -bromopropane (213.44 pL; 2.35 mmol; 1.30 eq.) giving 5-bromo-2- [(4-methoxyphenyl)methyl]-3-propyl-isoindolin-1 -one (324.00 mg; 47.9 %) as a yellow solid.1H NMR (400 MHz, DMSO-c / 6) 5 ppm 7.83 (d, J=1.65 Hz, 1 H), 7.68 (m, 1 H), 7.64 (m, 1 H), 7.24 (m, 2 H), 6.89 (m, 2 H), 4.94 (d, J=14.97 Hz, 1 H), 4.47 (t, J=4.02 Hz, 1 H), 4.26 (d, J=14.97 Hz, 1 H), 3.72 (s, 3 H), 1.94 (m, 2 H), 0.83 (m, 1 H), 0.69 (t, J=7.20 Hz, 3 H), 0.61 (m, 1 H).

[0493] Step b: 5-bromo-3-propyl-isoindolin-1 -one

[0494] The compound was prepared using the same procedure as detailed in example 1 step c starting from 5-bromo-2-[(4-methoxyphenyl)methyl]-3-propyl-isoindolin-1 -one (324.00 mg; 0.87 mmol; 1.00 eq.) giving 5-bromo-3-propyl-isoindolin-1 -one (200.0 mg 90.9 %) as a yellow solid.1H NMR (400 MHz, DMSO-c / 6) 5 ppm 8.81 (s, 1 H), 7.84 (s, 1 H), 7.65 (dd, J=8.03, 1.65 Hz, 1 H), 7.56 (d, J=8.03 Hz, 1 H), 4.58 (dd, J=7.76, 4.02 Hz, 1 H), 1.89 (m, 1 H), 1.48 (m, 1 H), 1.31 (m, 2 H), 0.88 (t, J=7.32 Hz, 3 H).

[0495] Step c: 1 -oxo-3-propyl-isoindoline-5-carbaldehyde

[0496] The compound was prepared using the same procedure as detailed in example 1 step d starting from 5-bromo-3,3-bis(2-methoxyethyl)isoindolin-1 -one (50.00 mg; 0.20 mmol; 1.00 eq.) giving 1 -oxo-3-propyl-isoindoline-5-carbaldehyde (40 mg, 61.1 %) as a colorless oil used without further purification.

[0497] Step d: 1 -[ethyl-[(E)-(1 -oxo-3-propyl-isoindolin-5-yl)methyleneamino]amino]pyrrolo[1 ,2- a]pyrazine-6-carbonitrile

[0498] The compound was prepared using the same procedure as detailed in example 12 step d starting from 1 -oxo-3-propyl-isoindoline-5-carbaldehyde (46.00 mg; 0.22 mmol; 1.00 eq.) and 1 -[amino(ethyl)amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile (45.43 mg; 0.22 mmol; 1.00 eq.) giving 1 -[ethyl-[(E)-( 1 -oxo-3-propyl-isoindolin-5-yl)methyleneamino]amino]pyrrolo[1 ,2- a]pyrazine-6-carbonitrile (13.0 mg, 41.6 %) as a yellow powder.1H NMR (500 MHz, DMSO-Gfc) 5 ppm 8.79 (s, 1 H), 8.28 (s, 1 H), 8.03 (d, J=4.40 Hz, 1 H), 7.92 (s, 1 H), 7.89 (d, J=7.70 Hz, 1 H), 7.74 (d, J=7.98 Hz, 1 H), 7.59 (dd, J=7.57, 4.54 Hz, 2 H), 7.54 (d, J=4.68 Hz, 1 H), 4.66 (t, J=6.05 Hz, 1 H), 4.44 - 4.54 (m, 2 H), 1.81 - 1 .90 (m, 1 H), 1 .54 - 1 .64 (m, 1 H), 1 .32 - 1 .49 (m, 2 H), 1 .24 (t, J=7.02 Hz, 3 H), 0.94 (t, J=7.43 Hz, 3 H).

[0499] Example 61 : 1-[ethyl-[(E)-(3-isopropyl-1-oxo-isoindolin-5- yl)methyleneamino]amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile

[0500] Step a: tert-butyl 5-bromo-3-isopropyl-1 -oxo-isoindoline-2-carboxylate

[0501] The compound was prepared using the same procedure as detailed in example 54 step b starting from tert-butyl 5-bromo-1 -oxo-isoindoline-2-carboxylate (800.00 mg; 2.56 mmol; 1.00 eq.) and 2-iodopropane (333.14 pL; 3.33 mmol; 1.30 eq.) giving tert-butyl 5-bromo-3- isopropyl-1 -oxo-isoindoline-2-carboxylate (175.00 mg; 19.3 %) as a yellow solid.1H NMR (400 MHz, DMSO-Gfc) 5 ppm 7.83 (d, J=1.65 Hz, 1 H), 7.77 (dt, J=8.25, 1.98 Hz, 1 H), 7.71 (d, J=8.14 Hz, 1 H), 5.09 (d, J=3.08 Hz, 1 H), 2.57 (m, 1 H), 1.51 (m, 9 H), 1.08 (d, J=7.04 Hz, 3 H), 0.44 (d, J=6.82 Hz, 3 H).

[0502] Step b: 5-bromo-3-isopropyl-isoindolin-1 -one

[0503] The compound was prepared using the same procedure as detailed in example 54 step c starting from tert-butyl 5-bromo-3-isopropyl-1 -oxo-isoindoline-2-carboxylate (180.00 mg; 0.51 mmol; 1.00 eq.) giving 5-bromo-3-isopropyl-isoindolin-1 -one (140 mg quant.) as a yellow solid.1H NMR (400 MHz, DMSO-c / 6) 5 ppm 8.75 (m, 1 H), 7.81 (m, 1 H), 7.66 (d, J=0.55 Hz, 1 H), 7.57 (d, J=8.03 Hz, 1 H), 4.53 (d, J=2.86 Hz, 1 H), 2.26 (dtd, J=13.73, 6.84, 6.84, 3.19 Hz, 1 H), 1.01 (d, J=6.93 Hz, 3 H), 0.53 (d, J=6.82 Hz, 3 H).

[0504] Step c: 3-isopropyl-1 -oxo-isoindoline-5-carbaldehyde

[0505] The compound was prepared using the same procedure as detailed in example 1 step d starting from 5-bromo-3-isopropyl-isoindolin-1 -one (200.00 mg; 0.79 mmol; 1.00 eq.) giving 3-isopropyl-1 -oxo-isoindoline-5-carbaldehyde (79 mg, 33.6 %) as a colorless oil used without further purification.1H NMR (400 MHz, DMSO-c / 6) 6 ppm 10.14 (s, 1 H), 8.97 (s, 1 H), 8.08 (m, 1 H), 8.01 (dd, J=7.76, 0.72 Hz, 1 H), 7.84 (d, J=7.70 Hz, 1 H), 4.64 (d, J=2.75 Hz, 1 H), 2.30 (m, 1 H), 1.01 (d, J=6.93 Hz, 3 H), 0.60 (d, J=6.82 Hz, 3 H).

[0506] Step d: 1 -[ethyl-[(E)-(3-isopropyl-1 -oxo-isoindolin-5-yl)methyleneamino]amino]pyrrolo[1 ,2- a]pyrazine-6-carbonitrile

[0507] The compound was prepared using the same procedure as detailed in example 12 step d starting from 3-isopropyl-1 -oxo-isoindoline-5-carbaldehyde (79.00 mg; 0.24 mmol; 1.00 eq.) and 1 -[amino(ethyl)amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile (33.52 mg; 0.16 mmol; 1.00 eq) giving 1 -[ethyl-[(E)-(3-isopropyl-1 -oxo-isoindolin-5-yl)methyleneamino]- amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile (47.0 mg, 74.5 %) as a yellow powder.1H NMR (500 MHz, DMSO-c / 6) 6 ppm 8.73 (s, 1 H), 8.29 (s, 1 H), 8.03 (dd, J=4.54, 0.69 Hz, 1 H), 7.92 (s, 1 H), 7.89 (d, J=7.98 Hz, 1 H), 7.74 (d, J=7.70 Hz, 1 H), 7.59 (dd, J=6.46, 4.54 Hz, 2 H), 7.54 (d, J=4.86 Hz, 1 H), 4.60 (d, J=3.30 Hz, 1 H), 4.44 - 4.52 (m, 2 H), 2.19 - 2.26 (m, 1 H), 1.24 (t, J=7.02 Hz, 3 H), 0.99 (d, J=6.88 Hz, 3 H), 0.73 (d, J=6.60 Hz, 3 H). mp : 221 -253°C.

[0508] Example 62: 1 -[ethyl-[(E)-[3-(methoxymethyl)-1 -oxo-isoindolin-5- yl]methyleneamino]amino] pyrrolo[1 ,2-a]pyrazine-6-carbonitrile

[0509] Step a: tert-butyl 5-bromo-3-(methoxymethyl)-1 -oxo-isoindoline-2-carboxylate

[0510] The compound was prepared using the same procedure as detailed in example 54 step b starting from tert-butyl 5-bromo-1 -oxo-isoindoline-2-carboxylate (600.00 mg; 1.92 mmol; 1.00 eq.) and bromomethyl methyl ether (188.26 pL; 2.31 mmol; 1.20 eq.) giving tert-butyl 5-bromo-3-(methoxymethyl)-1 -oxo-isoindoline-2-carboxylate (378 mg; 55.2 %) as a yellow solid.1H NMR (400 MHz, DMSO-c / 6) 5 ppm 7.95 (m, 1 H), 7.73 (dd, J=8.25, 1.87 Hz, 1 H), 7.67 (d, J=7.92 Hz, 1 H), 5.20 (m, 1 H), 3.98 (dd, J=10.45, 2.20 Hz, 1 H), 3.88 (dd, J=10.10, 4.20 Hz, 1 H), 3.16 (s, 3 H), 1.52 (s, 9 H).

[0511] Step b: 5-bromo-3-(methoxymethyl)isoindolin-1 -one

[0512] The compound was prepared using the same procedure as detailed in example 54 step c starting from tert-butyl 5-bromo-3-(methoxymethyl)-1 -oxo-isoindoline-2-carboxylate (378.00 mg; 1.06 mmol; 1.00 eq.) giving 5-bromo-3-(methoxymethyl)isoindolin-1 -one (296 mg; quant.) as a yellow solid.1H NMR (400 MHz, DMSO-c / 6) 6 ppm 8.79 (s, 1 H), 7.85 (d, 7.68 (ddd, J=8.03, 1.76, 0.55 Hz, 1 H), 7.58 (d, J=8.03 Hz, 1 H), 4.72 (t, 3.64 (dd, J=9.79, 4.84 Hz, 1 H), 3.52 (dd, J=9.79, 5.94 Hz, 1 H), 3.28 (s,

[0513] Step c: 3-(methoxymethyl)-1 -oxo-isoindoline-5-carbaldehyde

[0514] The compound was prepared using the same procedure as detailed in example 1 step d starting from 5-bromo-3-(methoxymethyl)isoindolin-1 -one (260.00 mg; 1.02 mmol; 1.00 eq.) giving 3-(methoxymethyl)-1 -oxo-isoindoline-5-carbaldehyde (29 mg, 8.2 %) as beige solid.1H NMR (400 MHz, DMSO-c / 6) 5 ppm 10.13 (s, 1 H), 8.13 (d, J=2.75 Hz, 1 H), 8.03 (dd, J=7.76, 1.93 Hz, 1 H), 7.85 (d, J=7.70 Hz, 1 H), 4.83 (t, J=5.56 Hz, 1 H), 4.71 (m, 1 H), 3.66 (m, 1 H), 3.59 (m, 1 H), 3.29 (s, 3 H).

[0515] Step d: 1 -[ethyl-[(E)-[3-(methoxymethyl)-1 -oxo-isoindolin-5-yl]methyleneamino]- amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile

[0516] The compound was prepared using the same procedure as detailed in example 12 step d starting from 3-(methoxymethyl)-1 -oxo-isoindoline-5-carbaldehyde (28.00 mg; 0.08 mmol; 1.00 eq.) and 1 -[amino(ethyl)amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile (16.53 mg; 0.08 mmol; 1.00 eq.) giving 1 -[ethyl-[(E)-[3-(methoxymethyl)-1 -oxo-isoindolin-5- yl]methyleneamino]amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile (16.0 mg, 50.1 %) as a yellow powder.1H NMR (500 MHz, DMSO-c / 6) 5 ppm 8.76 (s, 1 H), 8.28 (s, 1 H), 8.03 (dd, J=4.54, 0.69 Hz, 1 H), 7.99 (s, 1 H), 7.89 (d, J=7.98 Hz, 1 H), 7.75 (d, J=7.70 Hz, 1 H), 7.61 (d, J=4.54 Hz, 1 H), 7.58 (d, J=4.54 Hz, 1 H), 7.55 (dd, J=4.68, 0.83 Hz, 1 H), 4.80 (t, J=5.78 Hz, 1 H), 4.43 - 4.55 (m, 2 H), 3.55 - 3.63 (m, 2 H), 3.35 (s, 3 H), 1.23 (t, J=7.02 Hz, 3 H).

[0517] Example 63: 1 -[[(E)-[3-(cyanomethyl)-1 -oxo-isoindolin-5-yl]methyleneamino]-ethyl- amino] pyrrolo[1 ,2-a]pyrazine-6-carbonitrile

[0518] Step a: tert-butyl 5-bromo-3-(cyanomethyl)-1 -oxo-isoindoline-2-carboxylate

[0519] The compound was prepared using the same procedure as detailed in example 54 step b starting from tert-butyl 5-bromo-1 -oxo-isoindoline-2-carboxylate (800.00 mg; 2.56 mmol; 1.00 eq.) and bromoacetonitrile (268.09 pL; 3.84 mmol; 1.50 eq.) giving tert-butyl 5- bromo-3-(cyanomethyl)-1 -oxo-isoindoline-2-carboxylate (469 mg; 52.1 %) as a yellow solid.1H NMR (400 MHz, DMSO-c / 6) 5 ppm 8.09 (d, J=2.86 Hz, 1 H), 7.83 (ddd, J=8.14, 1.65, 0.55 Hz, 1 H), 7.76 (d, J=8.14 Hz, 1 H), 5.39 (dd, J=4.62, 3.19 Hz, 1 H), 3.58 (dd, J=17.39, 3.19 Hz, 1 H), 3.50 (dd, J=17.72, 4.84 Hz, 1 H), 1.54 (s, 9 H).

[0520] Step b: 2-(6-bromo-3-oxo-isoindolin-1 -yl)acetonitrile

[0521] The compound was prepared using the same procedure as detailed in example 54 step c starting from tert-butyl 5-bromo-3-(cyanomethyl)-1 -oxo-isoindoline-2-carboxylate (550.00 mg; 1.57 mmol; 1.00 eq.) giving 2-(6-bromo-3-oxo-isoindolin-1 -yl)acetonitrile (204 mg; 51.9 %) as a beige solid.1H NMR (400 MHz, DMSO-c / 6) 5 ppm 8.86 (s, 1 H), 8.01 (d, J=1.65 Hz, 1 H), 7.74 (ddd, J=8.14, 1.76, 0.55 Hz, 1 H), 7.63 (d, J=8.03 Hz, 1 H), 4.92 (t, J=4.51 Hz, 1 H), 3.31 (dd, J=16.95, 4.29 Hz, 1 H), 3.16 (dd, J=17.17, 4.84 Hz, 1 H).

[0522] Step c: 2-(3-oxo-6-vinyl-isoindolin-1 -yl)acetonitrile

[0523] The compound was prepared using the same procedure as detailed in example 57 step c starting from 2-(6-bromo-3-oxo-isoindolin-1 -yl)acetonitrile (80.00 mg; 0.31 mmol; 1.00 eq.) giving 2-(3-oxo-6-vinyl-isoindolin-1 -yl)acetonitrile (82 mg; 97.1 %) as a yellow oil.1H NMR (400 MHz, DMSO-cfc) 5 ppm 8.74 (m, 1 H), 7.82 (m, 1 H), 7.64 (m, 2 H), 6.87 (dd, J=17.61 , 1 1.00 Hz, 1 H), 5.99 (dd, J=17.66, 0.83 Hz, 1 H), 5.43 (dd, J=11 .00, 0.77 Hz, 1 H), 4.90 (t, J=4.46 Hz, 1 H), 3.31 (m, 1 H), 3.16 (m, 1 H).

[0524] Step d: 2-(6-formyl-3-oxo-isoindolin-1 -yl)acetonitrile

[0525] The compound was prepared using the same procedure as detailed in example 57 step d starting from 2-(3-oxo-6-vinyl-isoindolin-1 -yl)acetonitrile (75.00 mg; 0.38 mmol; 1.00 eq.) giving 2-(6-formyl-3-oxo-isoindolin-1 -yl)acetonitrile (33 mg; 40.2 %) as a white solid used without further purification.

[0526] Step e: 1 -[[(E)-[3-(cyanomethyl)-1 -oxo-isoindolin-5-yl]methyleneamino]-ethyl- amino]pyrrolo [1 ,2-a]pyrazine-6-carbonitrile

[0527] The compound was prepared using the same procedure as detailed in example 12 step d starting from 2-(6-formyl-3-oxo-isoindolin-1 -yl)acetonitrile (38.00 mg; 0.19 mol; 1.00 eq.) and 1 -[amino(ethyl)amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile (33.52 mg; 0.18 mol; 1.00 eq.) giving 1 -[[(E)-[3-(cyanomethyl)-1 -oxo-isoindolin-5-yl]methyleneamino]-ethyl- amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile (23.0 mg, 36.7 %) as a yellow powder.1H NMR (500 MHz, DMSO-Gfc) 5 ppm 8.83 (s, 1 H), 8.28 (s, 1 H), 8.06 (s, 1 H), 8.03 (d, J=4.40 Hz, 1 H), 7.95 (d, J=7.70 Hz, 1 H), 7.81 (d, J=7.98 Hz, 1 H), 7.57 - 7.59 (m, 3 H), 5.01 (t, J=4.95 Hz, 1 H), 4.50 (q, J=7.15 Hz, 2 H), 3.29 - 3.32 (m, 1 H), 3.14 (dd, J=17.06, 5.50 Hz, 1 H), 1.24 (t, J=7.02 Hz, 3 H).

[0528] Example 64: 1 -[ethyl- [(E)-(6-f luoro-3,3-dimethyl-1 -oxo-isoindolin-5-yl)methylene- amino]amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile

[0529] Step a: methyl 4-bromo-2-(bromomethyl)-5-fluoro-benzoate

[0530] In a 50 mL flask, to a solution of 4-bromo-5-fluoro-2-methylbenzoic acid methyl ester (1 .00 g; 4.05 mmol; 1.00 eq.) in DCE (15.00 mL) was added NBS (864.49 mg; 4.86 mmol; 1.20 eq.) and AIBN (132.93 mg; 0.81 mmol; 0.20 eq.). The mixture was stirred at 85°C overnight. NBS (144.08 mg; 0.81 mmol; 0.20 eq.) and AIBN (132.93 mg; 0.81 mmol; 0.20 eq.) were added in the mixture which was stirred at 85°C for 2 h. The mixture was cooled to rt and quenched with sat. aq. Na2S2O3, extracted with DCM (3 times), then the organic layer was washed with NaCI, dried over MgSO4, filtered and concentrated. The crude product was purified by Chromatography (Column: Kinetex C18,30 x 150mm 5pm (phenomenex; 330mg, Flowrate : 42 ml / min, Mobile phase: H2O with 0.1% HCOOH / MeCN + 0.1 % HCOOH, gradient B / 12min) to give methyl 4-bromo-2-(bromomethyl)-5- fluoro-benzoate (518.00 mg; 36.91 %).1H NMR (400 MHz, DMSO-c / 6) 5 ppm 8.06 (d, J=6.82 Hz, 1 H), 7.80 (d, J=9.24 Hz, 1 H), 4.98 (s, 2 H), 3.88 (s, 3 H).

[0531] Step b: 5-bromo-6-fluoro-2-[(4-methoxyphenyl)methyl]isoindolin-1 -one

[0532] In a 20 ml round bottom flask, methyl 4-bromo-2-(bromomethyl)-5-fluoro-benzoate (456.00 mg; 2.63 mmol; 1.00 eq.) was suspended in THF (5.14 mL). 4-methoxybenzylamine (343.61 pL; 5.26 mmol; 2.00 eq.) was added and the reaction mixture was stirred overnight at 80°C. The reaction mixture was concentrated. The crude was purified by chromatography (Column Star HC 25g, Flowrate 42mL / min, Eluent: Cyclohexane / AcOEt, gradient 0 to 50) to give: 5-bromo-6-fluoro-2-[(4-methoxyphenyl)methyl]isoindolin-1 -one (293.00 mg; 63.63 %).1H NMR (400 MHz, DMSO-c / 6) 5 ppm 7.95 (d, J=6.05 Hz, 1 H), 7.66 (d, J=7.59 Hz, 1 H), 7.22 (m, 2 H), 6.91 (m, 2 H), 4.64 (s, 2 H), 4.31 (s, 2 H), 3.73 (s, 3 H).

[0533] Step c: 5-bromo-6-fluoro-2-[(4-methoxyphenyl)methyl]-3,3-dimethyl-isoindolin-1 -one

[0534] The compound was prepared using the same procedure as detailed in example 1 step b starting from 5-bromo-6-fluoro-2-[(4-methoxyphenyl)methyl]isoindolin-1 -one (293.00 mg; 0.83 mmol; 1.00 eq.) giving 5-bromo-6-fluoro-2-[(4-methoxyphenyl)methyl]-3,3-dimethyl- isoindolin-1 -one (156.00 mg; 44.86 %) as a white powder.1H NMR (400 MHz, DMSO-c / 6) 5 ppm 8.17 (d, J=5.94 Hz, 1 H), 7.65 (d, J=7.59 Hz, 1 H), 7.30 (d, J=8.80 Hz, 2 H), 6.86 (d, J=8.80 Hz, 2 H), 4.60 (s, 2 H), 3.72 (s, 3 H), 1 .36 (s, 6 H).

[0535] Step d: 6-fluoro-2-[(4-methoxyphenyl)methyl]-3,3-dimethyl-5-vinyl-isoindolin-1 -one

[0536] In a 0.5-2 mL MW tube, 5-bromo-6-fluoro-2-[(4-methoxyphenyl)methyl]-3,3-dimethyl- isoindolin-1 -one (156.00 mg; 0.38 mmol; 1.00 eq.), Pd(PPh3)4(8.67 mg; 0.7 mmol; 0.02 eq.), CsF (171.04 mg; 1.12 mmol; 3.00 eq.) and tributyl(vinyl)tin (163.78 pL; 0.56 mmol; 1.50 eq.) were added and dissolved in dry 1 ,4-dioxane (2.13 mL) under Argon. The reaction mixture was stirred at 120°C for 2h. The reaction mixture was diluted with water and extracted with AcOEt (three times). The combined organic layers were washed with water, with brine, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by chromatography (Column Star HC 5g, Eluant: Cyclohexane / AcOEt ) to give 6-fluoro-2-[(4-methoxyphenyl)methyl]-3,3-dimethyl-5-vinyl- isoindolin-1 -one (52.00 mg; 38.32 %) as a white powder.1H NMR (400 MHz, DMSO-c / 6) 5 ppm 8.01 (d, J=6.49 Hz, 1 H), 7.47 (d, J=9.46 Hz, 1 H), 7.30 (d, J=8.80 Hz, 2 H), 6.93 (m, 1 H), 6.86 (d, J=8.80 Hz, 2 H), 6.11 (dd, J=17.72, 0.88 Hz, 1 H), 5.56 (m, 1 H), 4.61 (s, 2 H), 3.72 (s, 3 H), 1.37 (s, 6 H). Step e: 6-fluoro-2-[(4-methoxyphenyl)methyl]-3,3-dimethyl-1 -oxo-isoindoline-5- carbaldehyde

[0537] In a round bottomed-flask, 6-fluoro-2-[(4-methoxyphenyl)methyl]-3,3-dimethyl-5-vinyl- isoindolin-1 -one (52.00 mg; 0.14 mmol; 1.00 eq.), PIDA (138.98 mg; 0.43 mmol; 3.00 eq.), and RUCI3, hydrate (0.01 mL; 0.04 mol / L; 0.25 mmol; 2.00 eq.) were added to a solution of DCM (0.94 mL) and water (0.23 mL).The reaction mixture was stirred at rt overnight. The reaction mixture was diluted with water and extracted with DCM (three times). The combined organic layers were washed with water, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by chromatography (Column Star HC 5g, 18mL / min, cyclohexane / AcOEt) to give 6-fluoro-2-[(4- methoxyphenyl)methyl]-3,3-dimethyl-1 -oxo-isoindoline-5-carbaldehyde (20.00 mg; 35.68 %) as a white powder.1H NMR (400 MHz, DMSO-c / 6) 5 ppm 10.30 (s, 1 H), 8.16 (d, J=5.72 Hz, 1 H), 7.70 (d, J=9.35 Hz, 1 H), 7.32 (d, J=8.80 Hz, 2 H), 6.87 (d, J=8.80 Hz, 2 H), 4.65 (s, 2 H), 3.72 (s, 3 H), 1 .40 (s, 6 H).

[0538] Step f: 6-fluoro-3,3-dimethyl-1 -oxo-isoindoline-5-carbaldehyde

[0539] In a 12mL Q-tube™, 6-fluoro-2-[(4-methoxyphenyl)methyl]-3,3-dimethyl-1 -oxo-isoindoline- 5-carbaldehyde (20.00 mg; 0.06 mmol; 1.00 eq.) was dissolved in TFA (0.34 mL; 20.00 V). The reaction mixture was stirred at 95°C overnight. The reaction mixture was concentrated under reduced pressure. Sat. NaHCO3was added to the mixture which was then extracted with DCM (3 times). The organic layer was washed with NaCI, dried over MgSO4, filtered and evaporated under reduced pressure. The residue was purified by flash chromatography (Column Star HC 5g, 18mL / min, cyclohexane / AcOEt) to give 6- fluoro-3,3-dimethyl-1 -oxo-isoindoline-5-carbaldehyde (10.00 mg; 83.70 %).1H NMR (400 MHz, DMSO-Gfc) 5 ppm 10.29 (s, 1 H), 9.07 (m, 1 H), 8.12 (d, J=5.72 Hz, 1 H), 7.58 (d, J=9.35 Hz, 1 H), 1.48 (s, 7 H).

[0540] Step g: 1 -[ethyl-[(E)-(6-fluoro-3,3-dimethyl-1 -oxo-isoindolin-5-yl)methyleneamino]amino]- pyrrolo[1 ,2-a]pyrazine-6-carbonitrile

[0541] The compound was prepared using the same procedure as detailed in example 12 step d starting from 6-fluoro-3,3-dimethyl-1 -oxo-isoindoline-5-carbaldehyde (23.00 mg; 0.10 mmol; 1.00 eq.) and 1 -[amino(ethyl)amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile (20.74 mg; 0.10 mmol; 1.00 eq.) giving 1 -[ethyl-[(E)-(6-fluoro-3,3-dimethyl-1 -oxo-isoindolin-5- yl)methyleneamino]amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile (6.00 mg; 14.73 %) as an off-white powder.1H NMR (500 MHz, DMSO-c / 6) 5 ppm 8.88 (s, 1 H), 8.19 (s, 1 H), 8.06 (d, J=5.23 Hz, 1 H), 8.00 (d, J=6.05 Hz, 1 H), 7.60 - 7.62 (m, 2 H), 7.48 - 7.55 (m, 2 H), 4.51 (q, J=6.79 Hz, 2 H), 1.50 (s, 6 H), 1.23 (t, J=7.02 Hz, 3 H). Example 65: 1 -[ethyl- [(E)-(4-f luoro-3,3-dimethyl-1 -oxo-isoindolin-5-yl)methylene- amino]amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile

[0542] Step a: 5-bromo-4-fluoro-2-[(4-methoxyphenyl)methyl]isoindolin-1 -one

[0543] The compound was prepared using the same procedure as detailed in example 1 step a starting from 5-bromo-4-fluoro-isoindolin-1 -one (500.00 mg; 2.17 mmol; 1.00 eq.) giving 5- bromo-4-fluoro-2-[(4-methoxyphenyl)methyl]isoindolin-1 -one (332 mg; 41 %).1H NMR (500 MHz, DMSO-cfc) 6 ppm 7.84 (dd, J=7.91 , 6.12 Hz, 1 H), 7.51 (d, J=7.98 Hz, 1 H), 7.24 (d, J=8.67 Hz, 2 H), 6.91 (m, 2 H), 4.64 (s, 2 H), 4.47 (s, 2 H), 3.73 (s, 3 H) Step b: 5-bromo-4-fluoro-2-[(4-methoxyphenyl)methyl]-3,3-dimethyl-isoindolin-1 -one

[0544] The compound was prepared using the same procedure as detailed in example 1 step b starting from 5-bromo-4-fluoro-2-[(4-methoxyphenyl)methyl]isoindolin-1 -one (258.00 mg; 0.74 mmol; 1.00 eq.) giving 5-bromo-4-fluoro-2-[(4-methoxyphenyl)methyl]-3,3-dimethyl- isoindolin-1 -one (237.00 mg; 73.83 %).1H NMR (400 MHz, DMSO-c / 6) 5 ppm 7.86 (dd, J=7.98, 6.00 Hz, 1 H), 7.53 (d, J=7.92 Hz, 1 H), 7.31 (d, J=8.80 Hz, 2 H), 6.87 (d, J=8.69 Hz, 2 H), 4.63 (s, 2 H), 3.72 (m, 3 H), 1 .44 (s, 6 H)

[0545] Step c: 4-fluoro-2-[(4-methoxyphenyl)methyl]-3,3-dimethyl-5-vinyl-isoindolin-1 -one

[0546] The compound was prepared using the same procedure as detailed in example 64 step d starting from 5-bromo-4-fluoro-2-[(4-methoxyphenyl)methyl]-3,3-dimethyl-isoindolin-1 -one (176.00 mg; 0.47 mmol; 1.00 eq.) giving 4-fluoro-2-[(4-methoxyphenyl)methyl]-3,3- dimethyl-5-vinyl-isoindolin-1 -one (142.00 mg; 90.04 %).1H NMR (400 MHz, DMSO-c / 6) 6 ppm 7.80 (dd, J=7.65, 6.77 Hz, 1 H), 7.56 (d, J=7.37 Hz, 1 H), 7.31 (m, 2 H), 6.89 (m, 1 H), 6.87 (m, 2 H), 6.06 (dd, J=17.72, 0.88 Hz, 1 H), 5.56 (m, 1 H), 4.63 (s, 2 H), 3.72 (s, 3 H), 1.44 (m, 6 H).

[0547] Step d: 4-fluoro-2-[(4-methoxyphenyl)methyl]-3,3-dimethyl-1 -oxo-isoindoline-5- carbaldehyde

[0548] The compound was prepared using the same procedure as detailed in example 57 step d starting from 4-fluoro-2-[(4-methoxyphenyl)methyl]-3,3-dimethyl-5-vinyl-isoindolin-1 -one (142.00 mg; 0.42 mmol; 1.00 eq.) giving 4-fluoro-2-[(4-methoxyphenyl)methyl]-3,3- dimethyl-1 -oxo-isoindoline-5-carbaldehyde (48.00 mg; 35.00 %).1H NMR (400 MHz, DMSO-Gfc) 5 ppm 10.29 (s, 1 H), 7.99 (dd, J=7.65, 5.89 Hz, 1 H), 7.74 (d, J=7.59 Hz, 1 H), 7.33 (d, J=8.58 Hz, 2 H), 6.88 (m, 2 H), 4.67 (s, 2 H), 3.72 (s, 3 H), 1 .48 (s, 6 H).

[0549] Step e: 4-fluoro-3,3-dimethyl-1 -oxo-isoindoline-5-carbaldehyde

[0550] The compound was prepared using the same procedure as detailed in example 64 step f starting from 4-fluoro-2-[(4-methoxyphenyl)methyl]-3,3-dimethyl-1 -oxo-isoindoline-5- carbaldehyde (47.00 mg; 0.14 mmol; 1.00 eq.) giving 4-fluoro-3,3-dimethyl-1 -oxo- isoindoline-5-carbaldehyde (13.00 mg; 43.70 %).1H NMR (400 MHz, DMSO-c / 6) 6 ppm 10.29 (s, 1 H), 9.15 (s, 1 H), 7.96 (d, J=7.70 Hz, 1 H), 7.63 (m, 1 H), 1.56 (s, 6 H).

[0551] Step f : 1 -[ethyl-[(E)-(4-fluoro-3,3-dimethyl-1 -oxo-isoindolin-5-yl)methyleneamino]amino]- pyrrolo[1 ,2-a]pyrazine-6-carbonitrile

[0552] The compound was prepared using the same procedure as detailed in example 12 step d starting from 4-fluoro-3,3-dimethyl-1-oxo-isoindoline-5-carbaldehyde (13.00 mg; 0.06 mmol; 1.00 eq.) and 1-[amino(ethyl)amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile (12.88 mg; 0.06 mmol; 1.00 eq.) giving 1 -[ethyl-[(E)-(4-fluoro-3,3-dimethyl-1 -oxo-isoindolin-5- yl)methyleneamino]amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile (11.00 mg; 44.37 %) as a yellow powder.1H NMR (500 MHz, DMSO-c / 6) 5 ppm 8.93 (s, 1 H), 8.21 (s, 1 H), 8.06 (d, J=4.68 Hz, 1 H), 7.99 (t, J=6.98 Hz, 1 H), 7.56 - 7.64 (m, 3 H), 7.52 (d, J=4.68 Hz, 1 H), 4.51 (q, J=7.15 Hz, 2 H), 1.58 (s, 6 H), 1.23 (t, J=7.02 Hz, 3 H).

[0553] Example 66: 1 -[ethyl-[(E)-(4-methoxy-3,3-dimethyl-1 -oxo-isoindolin-5-yl)methylene- amino]amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile

[0554] Step a: 3-hydroxy-2-methyl-4-nitro-benzoic acid

[0555] In a 250 mL three-necked round bottomed flask under nitrogen, 2-methyl-3- hydroxybenzoic acid (5.00 g; 32.86 mmol; 1.00 eq.) was suspended in AcOH (40.00 mL) and cooled to 5°C with cold water. Nitric acid (4.86 mL; 70.00 %w / w; 75.58 mmol; 2.30 eq.) (aqueous solution) was added slowly at 0°C, and then the reaction mixture was stirred for 40 min at rt. (suspension yellow insoluble). The reaction mixture was poured onto 100 mL of water + ice and stirred for 15 min; the yellow precipitate was filtered and washed with cold water; dried under vacuum at rt for 24 hours. The filtrate was extracted twice with DCM; then the organic layer was washed with brine, dried on MgSO4and evaporated. The solids were mixed by dissolution in a mixture THF / DCM, dried on MgSO4and evaporated under vacuum to give 3-hydroxy-2-methyl-4-nitro-benzoic acid (3.65 g; 52.96 %) as a yellow solid.1H NMR (500 MHz, CHLOROFORM-cf) 5 ppm 11.08 (s, 1 H), 8.04 (d, J=9.08 Hz, 1 H), 7.51 (d, J=8.94 Hz, 1 H), 2.60 (s, 3 H)

[0556] Step b: methyl 3-methoxy-2-methyl-4-nitro-benzoate

[0557] In a 500 mL round bottomed flask under nitrogen, cooled to 0°C, 3-hydroxy-2-methyl-4- nitro-benzoic acid (3.62 g; 17.26 mmol; 1.00 eq.) and dimethyl sulfate (4.26 mL; 44.88 mmol; 2.60 eq.) were suspended in acetone (85.07 mL); K2CO398% (10.73 g; 77.67 mmol; 4.50 eq.) was added portionwise, and then the reaction mixture was stirred at rt overnight (red insoluble suspension). The reaction mixture was filtered and washed with acetone and DCM; the filtrate was concentrated under vacuum. The crude residue was purified by chromatography (Cartridge Biotage Star 50g HC duo ; flow rate =120ml / min ; gradient: Cyclohexan / EtOAc:3CV 30% EtOAc, 12CV 30% to 60%, 5CV 60% to 100%, 1 CV to 100% EtOAc) to give methyl 3-methoxy-2-methyl-4-nitro-benzoate (3.10 g; 79.75 %) as a pale-yellow solid.1H NMR (500 MHz, CHLOROFORM-d) 5 ppm 7.68 (d, J=9.08 Hz, 1 H), 7.61 (d, J=8.94 Hz, 1 H), 3.94 (s, 3 H), 3.91 (s, 3 H), 2.55 (s, 3 H).

[0558] Step c: methyl 2-(bromomethyl)-3-methoxy-4-nitro-benzoate

[0559] In a 50 mL round bottom flask, methyl 3-methoxy-2-methyl-4-nitro-benzoate (1.50 g; 6.66 mmol; 1.00 eq.) was suspended in MeCN (30.00 mL). NBS (1.42 g; 7.99 mmol; 1.20 eq.) and AIBN (546.89 mg; 3.33 mmol; 0.50 eq.) were added. The reaction mixture was stirred for 24 hours at 80°C (yellow solution). The reaction mixture was diluted with EtOAc and washed with a saturated solution of Na2S2O3and brine, dried on MgSO4and concentrated under reduced pressure. The residue was purified by chromatography (Biotage Isolera with Cartridge Biotage Star 25g HC duo ; flow rate =75ml / min gradient: Cyclohexane / EtOAc: 3CV 30% EtOAc, 12CV 30% to 60%, 5CV 60% to 100%, 1 CV to 100% EtOAc) to give methyl 2-(bromomethyl)-3-methoxy-4-nitro-benzoate (1.79 g; 53.02 %) as an amorphous solid.1H NMR (500 MHz, CHCI3-c / ) 5 ppm 7.79 (d, 1 H), 7.77 (d, 1 H), 5.04 (s, 2 H), 4.05 (s, 3 H), 3.99 (s, 3 H).

[0560] Step d: 4-methoxy-2-[(4-methoxyphenyl)methyl]-5-nitro-isoindolin-1 -one

[0561] In a 50 mL round bottom flask, methyl 2-(bromomethyl)-3-methoxy-4-nitro-benzoate (1 .80 g; 3.55 mmol; 1.0 eq.) was suspended in THF (16.20 mL). 4-methoxybenzylamine (556.80 pL; 4.26 mmol; 1.20 eq.) and DIPEA (1.76 mL; 10.65 mmol; 3.00 eq.) were added. The reaction mixture was stirred for 7 h at rt. The reaction mixture was concentrated under reduced pressure. The residue was purified by chromatography (Column Biotage 5g 25mL / min, Gradient : Cyclohexane / EtOAc : 2Cv to 20% EtOAc, 5 CV 20% to 40% EtOAc, 10CV 40% to 70% EtOAc, 2CV 70% EtOAc0to give 4-methoxy-2-[(4- methoxyphenyl)methyl]-5-nitro-isoindolin-1 -one (1.10 g; 94.34 %) as a pale yellow solid.1H NMR (500 MHz, DMSO-d6) 5 ppm 7.95 (d, J=8.12 Hz, 1 H), 7.51 (d, J=7.98 Hz, 1 H), 7.26 (m, 2 H), 6.92 (m, 2 H), 4.75 (s, 2 H), 4.67 (s, 2 H), 4.03 (s, 3 H), 3.73 (s, 3 H).

[0562] Step e: 5-amino-4-methoxy-2-[(4-methoxyphenyl)methyl]isoindolin-1 -one

[0563] To a solution of 4-methoxy-2-[(4-methoxyphenyl)methyl]-5-nitro-isoindolin-1 -one (1.20 g; 3.65 mmol; 1.00 eq.) in THF (3.60 mL) and MeOH (36.00 mL) purged under nitrogen, was added Pd / C (10% Pd) (388.96 mg; 0.37 mmol; 0.10 eq.). The reaction mixture was stirred at rt under hydrogen (Patm) for 3 h. The reaction mixture was filtered on Millipore™ filter and washed with THF and MeOH; then concentrated and dried under vacuum to give 5- amino-4-methoxy-2-[(4-methoxyphenyl)methyl]isoindolin-1 -one (1.05 g; 96.29 %) as a colorless oil.1H NMR (500 MHz, DMSO-d6) 5 ppm 7.20 (d, J=8.53 Hz, 2 H), 7.14 (d, J=8.12 Hz, 1 H), 6.90 (m, 2 H), 6.74 (d, J=7.98 Hz, 1 H), 5.48 (s, 2 H), 4.56 (s, 2 H), 4.32 (s, 2 H), 3.74 (s, 3 H), 3.73 (s, 3 H). Step f: 5-bromo-4-methoxy-2-[(4-methoxyphenyl)methyl]isoindolin-1 -one 5-amino-4-methoxy-2-[(4-methoxyphenyl)methyl]isoindolin-1 -one (750.00 mg; 2.51 mmol; 1.00 eq.) and copper(l) bromide (783.00 mg; 5.46 mmol; 2.17 eq.) were suspended in MeCN (15.00 mL). The reaction mixture was cooled with an ice bath and tert-butylnitrite (872.00 pL; 7.27 mmol; 2.89 eq.) was added dropwise. The reaction mixture was stirred at rt for 4h (dark mixture). The reaction mixture was cooled to 0°C and quenched by slow addition of 20 mL of HCI 1 N and extracted twice with DCM. The combined organic layers were washed with water, sat. NaHCO3and brine; dried over MgSO4, filtered and concentrated under vacuum. The brown residue was purified by chromatography (Cartridge Biotage 25g HC Duo - flow rate 50ml / min - gradient: Cyclohexane / EtOAc :1 CV, 10% EtOAc, 5CV 10% to 30% EtOAc, 12CV 30% to 60% EtOAc, 3CV 60% to 100%EtOAc, 3CV 100%EtOAc) to give 5-bromo-4-methoxy-2-[(4- methoxyphenyl)methyl]isoindolin-1 -one (510.00 mg; 56.01 %) as a pale-yellow oil.1H NMR (500 MHz, DMSO-c / 6) 5 ppm 7.73 (d, J=7.98 Hz, 1 H), 7.33 (d, J=7.84 Hz, 1 H), 7.24 (m, 2 H), 6.91 (m, 2 H), 4.64 (s, 2 H), 4.61 (s, 2 H), 3.94 (s, 3 H), 3.73 (s, 3 H).

[0564] Step g: 5-bromo-4-methoxy-2-[(4-methoxyphenyl)methyl]-3,3-dimethyl-isoindolin-1 -one The compound was prepared using the same procedure as detailed in example 1 step b starting from 5-bromo-4-methoxy-2-[(4-methoxyphenyl)methyl]isoindolin-1 -one (510.00 mg; 1.41 mmol; 1.00 eq.) giving 5-bromo-4-methoxy-2-[(4-methoxyphenyl)methyl]-3,3- dimethyl-isoindolin-1 -one (365.00 mg; 66.42 %) as a pale-yellow oil.1H NMR (500 MHz, DMSO-Gfc) 5 ppm 7.78 (d, J=7.98 Hz, 1 H), 7.43 (d, J=7.98 Hz, 1 H), 7.29 (d, J=8.53 Hz, 2 H), 6.86 (d, J=8.67 Hz, 2 H), 4.61 (s 2 H), 3.93 (s, 3 H), 3.72 (s, 3 H), 1 .43 (s, 6 H).

[0565] Step h: 5-bromo-4-methoxy-3,3-dimethyl-isoindolin-1 -one

[0566] The compound was prepared using the same procedure as detailed in example 1 step c starting from 5-bromo-4-methoxy-2-[(4-methoxyphenyl)methyl]-3,3-dimethyl-isoindolin-1 - one (293.00 mg; 750.76 pmol; 1.00 eq.) giving 5-bromo-4-methoxy-3,3-dimethyl- isoindolin-1 -one (176.00 mg; 82.45 %) as a pale-yellow solid.1H NMR (500 MHz, DMSO- d6) 5 ppm 8.77 (s, 1 H), 7.73 (d, J=7.84 Hz, 1 H), 7.32 (d, J=7.84 Hz, 1 H), 3.93 (s, 3 H), 1.51 (s, 6 H).

[0567] Step i: 4-methoxy-3,3-dimethyl-5-vinyl-isoindolin-1 -one

[0568] The compound was prepared using the same procedure as detailed in example 57 step c starting from 5-bromo-4-methoxy-3,3-dimethyl-isoindolin-1 -one (80.00 mg; 281.35 pmol; 1.00 eq.) giving 4-methoxy-3,3-dimethyl-5-vinyl-isoindolin-1 -one (42.00 mg; 64.59 %) as a pale-yellow solid.1H NMR (500 MHz, DMSO-c / 6) 5 ppm 8.64 (s, 1 H), 7.69 (d, J=7.84 Hz, 1 H), 7.36 (d, J=7.84 Hz, 1 H), 6.97 (dd, J=17.61 , 1 1.14 Hz, 1 H), 5.94 (m, 1 H), 5.48 (m, 1 H), 3.78 (s, 3 H), 1.51 (s, 6 H). Step j: 4-methoxy-3,3-dimethyl-1 -oxo-isoindoline-5-carbaldehyde

[0569] The compound was prepared using the same procedure as detailed in example 57 step d starting from 4-methoxy-3,3-dimethyl-5-vinyl-isoindolin-1 -one (41.00 mg; 177.39 pmol; 1.00 eq.) giving 4-methoxy-3,3-dimethyl-1 -oxo-isoindoline-5-carbaldehyde (30.00 mg; 46.25 %) as a pale-yellow oil.1H NMR (500 MHz, DMSO-c / 6) 5 ppm 10.31 (s, 1 H), 8.98 (s, 1 H), 7.90 (d, J=7.70 Hz, 1 H), 7.53 (d, J=7.70 Hz, 1 H), 4.00 (s, 3 H), 1.54 (s, 6 H).

[0570] Step k: 1 -[ethyl-[(E)-(4-methoxy-3,3-dimethyl-1 -oxo-isoindolin-5-yl)methyleneamino]- amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile

[0571] The compound was prepared using the same procedure as detailed in example 12 step d starting from 4-methoxy-3,3-dimethyl-1 -oxo-isoindoline-5-carbaldehyde (28.00 mg; 127.72 pmol; 1.00 eq.) and 1 -[amino(ethyl)amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile (26.49 mg; 127.72 pmol; 1.00 eq.) giving 1 -[ethyl-[(E)-(4-methoxy-3,3-dimethyl-1 -oxo-isoindolin-5- yl)methylene amino]amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile (12.00 mg; 21.39 %) as a yellow powder.1H NMR (500 MHz, DMSO-c / 6) 5 ppm 8.75 (s, 1 H), 8.19 (s, 1 H), 8.04 (dd, J=4.54, 0.69 Hz, 1 H), 7.95 (d, J=7.98 Hz, 1 H), 7.54 - 7.65 (m, 3 H), 7.51 (d, J=7.83 Hz, 1 H), 4.53 (q, J=6.88 Hz, 2 H), 3.91 (s, 3 H), 1 .57 (s, 6 H), 1 .26 (t, J=7.02 Hz, 3 H).

[0572] Example 67: 1-[[(E)-(5,5-dimethyl-7-oxo-6H-pyrrolo[3,4-b]pyridin-3-yl)methylene- amino]ethylamino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile

[0573] Step a: methyl 5-bromo-3-(bromomethyl)pyridine-2-carboxylate

[0574] In a 100 mL round bottomed flask, 5-bromo-2-(methoxycarbonyl)-3-methylpyridine (2.00 g; 8.69 mmol; 1.00 eq.) was dissolved in CCI4(20.00 mL). AIBN (142.76 mg; 0.87 mmol; 0.10 eq.) and NBS (3.09 g; 17.39 mmol; 2.00 eq.) were added. The reaction mixture was stirred at 80°C overnight. The reaction mixture was cooled to rt and filtered on Whatman™ and washed with DCM. The filtrate was evaporated to give 4.9 g of crude as a brown solid. The residue was solubilized in THF (40.00 mL) and cooled to 0°C. DIPEA (2.87 mL; 17.39 mmol; 2.00 eq.) and diethyl phosphite (2.22 mL; 17.39 mmol; 2.00 eq.) were added, the ice bath was removed and the mixture was stirred at rt for 60 min. The mixture was diluted in 100 mL of EtOAc and washed with 100 mL of water. The aqueous layer was again extracted twice with 50mL of EtOAc. The combined organic layers were dried over MgSO4, filtered and concentrated under vacuum to give 5.4 g of crude as a brown oil. The crude residue was purified by chromatography (Cartridge Biotage Star 100 g 60 pm silica, cyclohexane-EtOAc 100-0 / 4 CV, 100-0 to 70-30 / 15 CV, 70-30 / 6 CV, flow rate 100 mL / min) to give methyl 5-bromo-3-(bromomethyl)pyridine-2-carboxylate (2.27 g; 79.45 %) as a pale yellow solid.1H NMR (500 MHz, DMSO-c / 6) 5 ppm 8.77 (d, J=2.20 Hz, 1 H), 8.41 (d, J=2.20 Hz, 1 H), 4.91 (s, 2 H), 3.90 (s, 3 H)

[0575] Step b: 3-bromo-6-[(4-methoxyphenyl)methyl]-5H-pyrrolo[3,4-b]pyridin-7-one In a 50 mL round bottom flask, methyl 5-bromo-3-(bromomethyl)pyridine-2-carboxylate (2.27 g; 7.35 mmol; 1.00 eq.) was suspended in THF (27.24 mL). 4-methoxybenzylamine (1.92 mL; 14.69 mmol; 2.00 eq.) was added. The reaction mixture was stirred at 80°C overnight. The reaction mixture was concentrated. The crude residue was purified by chromatography (Cartridge Biotage Star 100g / 60 pm silica, Cyclohexane / AcOEt): isocratic 100 / 0 over 4 CV, 100 / 0 to 0 / 100 over 15 CV, isocratic 100 / 0 over 6CV, Flow rate 100 mL / min° to give 3-bromo-6-[(4-methoxyphenyl)methyl]-5H-pyrrolo[3,4-b]pyridin-7-one (1.1 1 g; 45.34 %) as white powder.1H NMR (400 MHz, DMSO-c / 6) 5 ppm 8.84 (d, J=2.20 Hz, 1 H), 8.31 (m, 1 H), 7.24 (m, 2 H), 6.92 (m, 2 H), 4.68 (s, 2 H), 4.34 (s, 2 H), 3.73 (s, 3 H).

[0576] Step c: 3-bromo-6-[(4-methoxyphenyl)methyl]-5,5-dimethyl-pyrrolo[3,4-b]pyridin-7-one

[0577] The compound was prepared using the same procedure as detailed in example 1 step b starting from 3-bromo-6-[(4-methoxyphenyl)methyl]-5H-pyrrolo[3,4-b]pyridin-7-one (555.00 mg; 1.67 mmol; 1.00 eq.) giving 3-bromo-6-[(4-methoxyphenyl)methyl]-5,5-dimethyl- pyrrolo[3,4-b]pyridin-7-one (242.00 mg; 40.22 %) as a brown solid.1H NMR (400 MHz, DMSO-Gfc) 5 ppm 8.84 (d, J=1.98 Hz, 1 H), 8.57 (d, J=2.09 Hz, 1 H), 7.32 (m, 2 H), 6.87 (m, 2 H), 4.65 (s, 2 H), 3.72 (s, 3 H), 1 .39 (s, 6 H).

[0578] Step d: 3-bromo-5,5-dimethyl-6H-pyrrolo[3,4-b]pyridin-7-one

[0579] The compound was prepared using the same procedure as detailed in example 1 step c starting from 3-bromo-6-[(4-methoxyphenyl)methyl]-5,5-dimethyl-pyrrolo[3,4-b]pyridin-7- one (239.00 mg; 0.66 mmol; 1.00 eq.) giving 3-bromo-5,5-dimethyl-6H-pyrrolo[3,4- b]pyridin-7-one (146.00 mg; 91.53 %) as a brown solid.1H NMR (400 MHz, DMSO-c / 6) 5 ppm 9.12 (s, 1 H), 8.80 (d, J=1.98 Hz, 1 H), 8.53 (d, J=1.98 Hz, 1 H), 1.47 (s, 6 H).

[0580] Step e: 5,5-dimethyl-3-vinyl-6H-pyrrolo[3,4-b]pyridin-7-one

[0581] The compound was prepared using the same procedure as detailed in example 57 step c starting from 3-bromo-5,5-dimethyl-6H-pyrrolo[3,4-b]pyridin-7-one (145.00 mg; 0.60 mmol; 1.00 eq.) giving 5,5-dimethyl-3-vinyl-6H-pyrrolo[3,4-b]pyridin-7-one (216.00 mg; 83.84 %) as a brown solid.1H NMR (400 MHz, DMSO-c / 6) 5 ppm 9.02 (s, 1 H), 8.74 (d, J=1.87 Hz, 1 H), 8.30 (d, J=1.98 Hz, 1 H), 6.88 (dd, J=17.66, 11.06 Hz, 1 H), 6.15 (dd, J=17.72, 0.77 Hz, 1 H), 5.53 (m, 1 H), 1.47 (s, 6 H).

[0582] Step f: 5,5-dimethyl-7-oxo-6H-pyrrolo[3,4-b]pyridine-3-carbaldehyde

[0583] The compound was prepared using the same procedure as detailed in example 57 step d starting from 5,5-dimethyl-3-vinyl-6H-pyrrolo[3,4-b]pyridin-7-one (100.00 mg; 0.48 mmol; 1.00 eq.) giving 5,5-dimethyl-7-oxo-6H-pyrrolo[3,4-b]pyridine-3-carbaldehyde (28.00 mg; 30.79 %) as a white powder.1H NMR (400 MHz, CHLOROFORM-c / ) 5 ppm 10.25 (s, 1 H), 9.24 (d, J=1 .76 Hz, 1 H), 8.28 (d, J=1 .76 Hz, 1 H), 7.57 (br s, 1 H), 1 .65 (s, 6 H). Step g: 1 -[[(E)-(5,5-dimethyl-7-oxo-6H-pyrrolo[3,4-b]pyridin-3-yl)methyleneamino]-ethyl- amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile

[0584] The compound was prepared using the same procedure as detailed in example 12 step d starting from 5,5-dimethyl-7-oxo-6H-pyrrolo[3,4-b]pyridine-3-carbaldehyde (23.00 mg; 0.12 mmol; 1.00 eq.) and 1 -[amino(ethyl)amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile (25.22 mg; 0.13 mmol; 1.04 eq.) giving 1 -[[(E)-(5,5-dimethyl-7-oxo-6H-pyrrolo[3,4- b]pyridin-3-yl)methyleneamino]-ethyl-amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile (36.00 mg; 78.85 %) as a yellow powder.1H NMR (500 MHz, DMSO-c / 6) 5 ppm 9.13 (s, 1 H), 9.09 (d, J=1 .65 Hz, 1 H), 8.32 (d, J=1 .65 Hz, 1 H), 8.29 (s, 1 H), 8.06 (dd, J=4.68, 0.83 Hz, 1 H), 7.63 (d, J=4.68 Hz, 1 H), 7.60 (d, J=4.40 Hz, 1 H), 7.50 (dd, J=4.68, 0.83 Hz, 1 H), 4.49 (q, J=6.88 Hz, 2 H), 1 .52 (s, 6 H), 1 .25 (t, J=7.02 Hz, 3 H).

[0585] Example 68: 2-[6-[(E)-[(6-cyanopyrrolo[1 ,2-a]pyrazin-1 -yl)-ethyl-hydrazono]methyl]- 7-methoxy-1 ,1 -dimethyl-3-oxo-isoindolin-2-yl]acetamide

[0586] The compound was prepared using the same procedure as detailed in example 30 step a starting from 1 -[ethyl-[(E)-(4-methoxy-3,3-dimethyl-1 -oxo-isoindolin-5-yl)methyleneamino]- amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile (55.0 mg, 0.137 mmol, 1.0 eq.) and 2- bromoacetamide (41.5 mg, 0.301 mmol, 2.2 eq.) giving 2-[6-[(E)-[(6-cyanopyrrolo[1 ,2- a]pyrazin-1 -yl)-ethyl-hydrazono]methyl]-7-methoxy-1 ,1 -dimethyl-3-oxo-isoindolin-2- yl]acetamide (18.0 mg 29 %) as a yellow solid.1H NMR (400 MHz CDCI3): 5 8.10 (s, 1 H), 8.03 (d, J = 7.9 Hz, 1 H), 7.82 (d, J = 4.6 Hz, 1 H), 7.71 (d, J = 7.9 Hz, 1 H), 7.60 (d, J = 4.6 Hz, 1 H), 7.52 (d, J = 4.6 Hz, 1 H), 7.28 (d, J = 4.5 Hz, 1 H), 6.78 (s, 1 H), 5.33 (s, 1 H), 4.53 (q, J = 7.0 Hz, 2H), 4.15 (s, 2H), 3.95 (s, 3H), 1.66 (s, 5H), 1.37 (t, J = 7.0 Hz, 3H). mp : 227-228 °C.

[0587] Inhibition of malignant mesothelioma tumor cell growth

[0588] The tumor cell growth inhibitory activity of the YAP / TAZ-TEAD interaction inhibitors was evaluated in NCI-H2052 mesothelioma cell line harboring a NF2 mutation. 10,000 cells / well were plated in a 96-well black plate with clear flat bottom TC-Treated Imaging plate (Falcon #353219) in regular medium (as suggested from ATCC for each cell line) with serum, which was replaced the day after with starvation medium containing 1 % serum. After one day growth in the starvation medium, cells were incubated with compounds. The starting concentration was 30 pM and serial dilutions in DMSO and medium were performed until 0.1 p M to achieve a final DMSO concentration of 0.5%. The cells were then allowed to grow for 3 days, and then, Edll (Invitrogen, Molecular Probe) was added in each well at a final concentration of 10 pM and the cells were returned to the incubator for an additional 24h. The starvation medium was removed and 100 pl of PFA 4% containing Hoechst dye was adding in each well to fix the cells. Plates were then incubated at rt for 15 min, washed twice with PBS and the cells were permeabilized by adding 100 pl per well of triton-100 containing 0.3% BSA. After 20 min cells were washed with PBS and Edll detection was performed according to the instructions of the manufacturer. Image acquisition was performed using the ImageXpress Micro and analysed using the MetaXpress software (Molecular Device). The results were expressed as a percent of inhibition (%) of the cell proliferation values obtained with 0.5 % DMSO treatment alone. The cellular response was determined by fitting the concentration response curves using a 3-parameter curve fit equation and determining the concentration that inhibited cell growth between 50% and 100%. The results are shown in Table 1 . Table 1 : NCI-H2052 antiproliferative activity

[0589]

[0590] Aspects of the present disclosure are further illustrated by reference to the following, nonlimiting embodiments.

[0591] 1. A compound of formula (I) or a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, solvate, isotope substituent, polymorph, prodrug or metabolite thereof: wherein:

[0592] X is C or N; Y is C or N;

[0593] W is C or N;

[0594] Ri and R2are each independently H; a (Ci-C6)alkyl optionally substituted by a (C C4)alkoxy, CN, CONR^R or a (C2-C4)alkenyl; or R1 and R2 are bound together to form a (C3-C6)cycloalkyl or a 5- to 7-membered heterocycle ;R3, R4and R5, when present, are each independently H, halogen or a (Ci-C4)alkoxy;

[0595] R6is H; a (Ci-C6)alkyl optionally substituted with OH, COOH, CONH2, a (Ci-C4)alkoxy optionally substituted with OH or a (Ci-C4)alkoxy, or an aryl; an optionally substituted 5- or 6-membered heterocycle; a (C3-C6)cycloalkyl; R7, R8, R9 and R are each independently H; a (Ci-C6)alkyl optionally substituted with one or more substituents selected from OH, halogen, CF3and CN; halogen; CONR12R13; SO2(RI4); SO(RI4); CN; CF3; COR12;

[0596] R11 is H; a (Ci-C6)alkyl optionally substituted by a group selected from: OH, halogen, (C1- C4)alkoxy, CN, COOH, CONRI2RI3, COOR15, an optionally substituted phenyl, and an optionally substituted 5- or 6-membered heteroaryl; or -(CH2)mCORi6;

[0597] RI2and RI3are each independently H or a (Ci -C4)alkyl ;

[0598] RI4is a (Ci-C4)alkyl;

[0599] R15 is a (Ci-C4)alkyl;

[0600] RI6is a (Ci-C4)alkyl; m = 0, 1 or 2.

[0601] 2. The compound of item 1 or a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, solvate, isotope substituent, polymorph, prodrug or metabolite thereof, wherein W is C and R3is H.

[0602] 3. The compound of item 1 or item 2, or a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, solvate, isotope substituent, polymorph, prodrug or metabolite thereof, wherein X is C and R5is H.

[0603] 4. The compound of any of items 1 to 3, or a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, solvate, isotope substituent, polymorph, prodrug or metabolite thereof, wherein Y is C and R4is H.

[0604] 5. The compound of any of items 1 to 4, or a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, solvate, isotope substituent, polymorph, prodrug or metabolite thereof, wherein R1 and R2are each independently H or a (Ci-C6)alkyl optionally substituted by a (Ci-C4)alkoxy or by CN, preferably the alkyl is a (Ci-C4)alkyl.

[0605] 6. The compound of any of items 1 to 5, or a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, solvate, isotope substituent, polymorph, prodrug or metabolite thereof, wherein R6is a (Ci-C6)alkyl, preferably a (Ci-C4)alkyl.

[0606] 7. The compound of any of items 1 to 6, or a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, solvate, isotope substituent, polymorph, prodrug or metabolite thereof, wherein R7, R9and R are each H.

[0607] 8. The compound of any of items 1 to 7, or a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, solvate, isotope substituent, polymorph, prodrug or metabolite thereof, wherein R8is CN.

[0608] 9. The compound of any of items 1 to 8, or a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, solvate, isotope substituent, polymorph, prodrug or metabolite thereof, wherein Rn is H; a (Ci-C6)alkyl optionally substituted by a group selected from: OH, CN, CONR12R13 and a 5-membered heteroaryl; or -CH2CORI6;

[0609] R12, R13, and RI6are as defined in claim 1 .

[0610] 10. The compound of item 1 , which is selected from:

[0611] 5-[(E)-[ethyl-(6-methylpyrrolo[1 ,2-a]pyrazin-1 -yl)hydrazono]methyl]-3,3-dimethyl-isoindolin-

[0612] 1-one;

[0613] 5-[(E)-[[6-(difluoromethyl)pyrrolo[1 ,2-a]pyrazin-1 -yl]-ethyl-hydrazono]methyl]-3,3-dimethyl- isoindolin-1 -one;

[0614] 5-[(E)-[ethyl-[6-(hydroxymethyl)pyrrolo[1 ,2-a]pyrazin-1 -yl]hydrazono]methyl]-3,3-dimethyl- isoindolin-1 -one;

[0615] 2-[1 -[[(E)-(3,3-dimethyl-1 -oxo-isoindolin-5-yl)methyleneamino]-ethyl-amino]pyrrolo[1 ,2- a]pyrazin-6-yl]acetonitrile;

[0616] 5-[(E)-[ethyl-(6-fluoropyrrolo[1 ,2-a]pyrazin-1-yl)hydrazono]methyl]-3,3-dimethyl-isoindolin-

[0617] 1-one;

[0618] 5-[(E)-[(6-chloropyrrolo[1 ,2-a]pyrazin-1-yl)-ethyl-hydrazono]methyl]-3,3-dimethyl- isoindolin-1 -one;

[0619] 1 -[[(E)-(3,3-dimethyl-1 -oxo-isoindolin-5-yl)methyleneamino]-ethyl-amino]pyrrolo[1 ,2- a]pyrazine-6-carboxamide;

[0620] 5-[(E)-[ethyl-(6-methylsulfonylpyrrolo[1 ,2-a]pyrazin-1 -yl)hydrazono]methyl]-3,3-dimethyl- isoindolin-1 -one;

[0621] 5-[(E)-[ethyl-(4-methylsulfinylpyrrolo[1 ,2-a]pyrazin-1-yl)hydrazono]methyl]-3,3-dimethyl- isoindolin-1 -one;

[0622] 2-[1 -[[(E)-(3,3-dimethyl-1 -oxo-isoindolin-5-yl)methyleneamino]-ethyl-amino]pyrrolo[1 ,2- a]pyrazin-4-yl]acetonitrile;

[0623] 1-[[(E)-(3,3-dimethyl-1 -oxo-isoindolin-5-yl)methyleneamino]-ethyl-amino]-7-methyl- pyrrolo[1 ,2-a]pyrazine-6-carbonitrile;

[0624] 1 -[[(E)-(3,3-dimethyl-1 -oxo-isoindolin-5-yl)methyleneamino]-ethyl-amino]pyrrolo[1 ,2- a]pyrazine-6-carbonitrile;

[0625] 1-[[(E)-(3,3-dimethyl-1 -oxo-isoindolin-5-yl)methyleneamino]-ethyl-amino]-4-methyl- pyrrolo[1 ,2-a]pyrazine-6-carbonitrile;

[0626] 8-bromo-1-[[(E)-(3,3-dimethyl-1-oxo-isoindolin-5-yl)methyleneamino]-ethyl- amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile;

[0627] 8-chloro-1-[[(E)-(3,3-dimethyl-1-oxo-isoindolin-5-yl)methyleneamino]-ethyl- amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile;

[0628] 1-[[(E)-(3,3-dimethyl-1 -oxo-isoindolin-5-yl)methyleneamino]-ethyl-amino]-8-fluoro- pyrrolo[1 ,2-a]pyrazine-6-carbonitrile; 1 -[[(E)-(3,3-dimethyl- 1 -oxo-isoindolin-5-yl)methyleneamino]-methyl-amino]pyrrolo[1 ,2- a]pyrazine-6-carbonitrile;

[0629] 1 -[[(E)-(3,3-dimethyl-1 -oxo-isoindolin-5-yl)methyleneamino]-isopropyl-amino]pyrrolo[1 ,2- a]pyrazine-6-carbonitrile;

[0630] 1 -[[(E)-(3,3-dimethyl-1 -oxo-isoindolin-5-yl)methyleneamino]-(2-hydroxyethyl)amino]- pyrrolo[1 ,2-a]pyrazine-6-carbonitrile;

[0631] 1 -[[(E)-(3,3-dimethyl-1 -oxo-isoindolin-5-yl)methyleneamino]-(3-hydroxypropyl)amino]- pyrrolo[1 ,2-a]pyrazine-6-carbonitrile;

[0632] 1 -[[(E)-(3,3-dimethyl-1 -oxo-isoindolin-5-yl)methyleneamino]-(4-hydroxybutyl)amino]- pyrrolo[1 ,2-a]pyrazine-6-carbonitrile;

[0633] 1 -[[(E)-(3,3-dimethyl-1 -oxo-isoindolin-5-yl)methyleneamino]-(2-methoxyethyl)amino]- pyrrolo[1 ,2-a]pyrazine-6-carbonitrile;

[0634] 1 -[[(E)-(3,3-dimethyl-1 -oxo-isoindolin-5-yl)methyleneamino]-(2-isopropoxyethyl)amino]- pyrrolo[1 ,2-a]pyrazine-6-carbonitrile;

[0635] 1 -[[(E)-(3,3-dimethyl-1 -oxo-isoindolin-5-yl)methyleneamino]-(3-methoxypropyl)amino]- pyrrolo[1 ,2-a]pyrazine-6-carbonitrile;

[0636] 1 -[[(E)-(3,3-dimethyl-1 -oxo-isoindolin-5-yl)methyleneamino]-tetrahydrofuran-3-yl- amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile;

[0637] 1 -[[(E)-(3,3-dimethyl-1 -oxo-isoindolin-5-yl)methyleneamino]-[2-(2-methoxyethoxy)ethyl]- amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile;

[0638] 1 -[[(E)-(3,3-dimethyl-1 -oxo-isoindolin-5-yl)methyleneamino]-[2-(2-hydroxyethoxy)ethyl]- amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile;

[0639] 5-[(6-cyanopyrrolo[1 ,2-a]pyrazin-1 -yl)-[(E)-(3,3-dimethyl-1 -oxo-isoindolin-5- yl)methyleneamino]amino]pentanoic acid;

[0640] 1 -[cyclopropyl-[(E)-(3,3-dimethyl-1 -oxo-isoindolin-5-yl)methyleneamino]amino]pyrrolo[1 ,2- a]pyrazine-6-carbonitrile;

[0641] 1 -[ethyl-[(E)-[6-(2-hydroxyethyl)-5,5-dimethyl-7-oxo-pyrrolo[3,4-b]pyridin-3- yl]methyleneamino]amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile;

[0642] 1 -[ethyl-[(E)-(2,3,3-trimethyl- 1 -oxo-isoindolin-5-yl)methyleneamino]amino]pyrrolo[1 ,2- a]pyrazine-6-carbonitrile;

[0643] 1 -[[(E)-(2-benzyl-3,3-dimethyl-1 -oxo-isoindolin-5-yl)methyleneamino]-ethyl- amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile;

[0644] 1 -[ethyl-[(E)-[2-(3-hydroxypropyl)-3,3-dimethyl-1 -oxo-isoindolin-5-yl]methyleneamino]- amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile;

[0645] 1 -[ethyl-[(E)-[2-(4-hydroxybutyl)-3,3-dimethyl-1 -oxo-isoindolin-5-yl]methyleneamino]- amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile; 1 -[ethyl-[(E)-[2-(2-isopropoxyethyl)-3,3-dimethyl-1 -oxo-isoindolin-5-yl]methyleneamino]- amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile;

[0646] 1 -[ethyl-[(E)-[2-(4-methoxybutyl)-3,3-dimethyl-1 -oxo-isoindolin-5-yl]methyleneamino]- amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile;

[0647] 1 -[[(E)-[2-(cyanomethyl)-3,3-dimethyl-1 -oxo-isoindolin-5-yl]methyleneamino]-ethyl- amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile;

[0648] 1 -[[(E)-[2-(2-cyanoethyl)-3,3-dimethyl-1 -oxo-isoindolin-5-yl]methyleneamino]-ethyl- amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile;

[0649] 1 -[[(E)-(2-acetonyl-3,3-dimethyl-1 -oxo-isoindolin-5-yl)methyleneamino]-ethyl- amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile;

[0650] 4-[6-[(E)-[(6-cyanopyrrolo[1 ,2-a]pyrazin-1 -yl)-ethyl-hydrazono]methyl]-1 ,1 -dimethyl-3-oxo- isoindolin-2-yl]butanoic acid;

[0651] 4-[6-[(E)-[(6-cyanopyrrolo[1 ,2-a]pyrazin-1 -yl)-ethyl-hydrazono]methyl]-1 ,1 -dimethyl-3-oxo- isoindolin-2-yl]butan amide;

[0652] Isopropyl 2-[6-[(E)-[(6-cyanopyrrolo[1 ,2-a]pyrazin-1 -yl)-ethyl-hydrazono]methyl]-1 ,1 - dimethyl-3-oxo-isoindolin-2-yl]acetate;

[0653] 2-[6-[(E)-[(6-cyanopyrrolo[1 ,2-a]pyrazin-1 -yl)-ethyl-hydrazono]methyl]-1 ,1 -dimethyl-3-oxo- isoindolin-2-yl]acetamide;

[0654] 2-[6-[(E)-[(6-cyanopyrrolo[1 ,2-a]pyrazin-1 -yl)-ethyl-hydrazono]methyl]-1 ,1 -dimethyl-3-oxo- isoindolin-2-yl]-N-methyl-acetamide;

[0655] 3-[6-[(E)-[(6-cyanopyrrolo[1 ,2-a]pyrazin-1 -yl)-ethyl-hydrazono]methyl]-1 ,1 -dimethyl-3-oxo- isoindolin-2-yl]propanamide;

[0656] 1 -[[(E)-[3,3-dimethyl-1 -oxo-2-(2-pyridylmethyl)isoindolin-5-yl]methyleneamino]-ethyl- amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile;

[0657] 1 -[[(E)-[3,3-dimethyl-2-(oxazol-2-ylmethyl)-1 -oxo-isoindolin-5-yl]methyleneamino]-ethyl- amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile;

[0658] 1 -[[(E)-[3,3-dimethyl-1 -oxo-2-(thiazol-2-ylmethyl)isoindolin-5-yl]methyleneamino]-ethyl- amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile;

[0659] 1 -[[(E)-[3,3-dimethyl-1 -oxo-2-(thiazol-4-ylmethyl)isoindolin-5-yl]methyleneamino]-ethyl- amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile;

[0660] 1 -[[(E)-[3,3-dimethyl-1 -oxo-2-(thiazol-5-ylmethyl)isoindolin-5-yl]methyleneamino]-ethyl- amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile;

[0661] 1 -[ethyl-[(E)-[2-( 1 H-imidazol-2-ylmethyl)-3,3-dimethyl-1 -oxo-isoindolin-5-yl]methylene- amino]amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile;

[0662] 1 -[[(E)-[3,3-dimethyl-1 -oxo-2-(1 H-tetrazol-5-ylmethyl)isoindolin-5-yl]methyleneamino]- ethyl-amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile; 1 -[ethyl-[(E)-( 1 -oxoisoindolin-5-yl)methyleneamino]amino]pyrrolo[1 ,2-a]pyrazine-6- carbonitrile;

[0663] 1 -(1 -Ethyl-2-((3-methyl-1 -oxoisoindolin-5-yl)methylene)hydrazineyl)pyrrolo[1 ,2-a]pyrazine- 6-carbonitrile

[0664] 1 -(2-((3,3-Diethyl- 1 -oxoisoindolin-5-yl)methylene)-1 -ethylhydrazineyl)pyrrolo[1 ,2- a]pyrazine-6-carbonitrile;

[0665] 1 -(2-((3- Allyl- 1 -oxoisoindolin-5-yl)methylene)-1 -ethylhydrazineyl)pyrrolo[ 7,2-a]pyrazine-6- carbonitrile;

[0666] 1 -[[(E)-[3,3-bis(methoxymethyl)-1 -oxo-isoindolin-5-yl]methyleneamino]-ethyl- amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile;

[0667] 1 -[[(E)-[3,3-bis(2-methoxyethyl)-1 -oxo-isoindolin-5-yl]methyleneamino]-ethyl- amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile;

[0668] 1 -[ethyl-[(E)-(3-ethyl- 1 -oxo-isoindolin-5-yl)methyleneamino]amino]pyrrolo[1 ,2-a]pyrazine- 6-carbonitrile;

[0669] 1 -[ethyl-[(E)-( 1 -oxo-3-propyl-isoindolin-5-yl)methyleneamino]amino]pyrrolo[1 ,2-a]pyrazine- 6-carbonitrile;

[0670] 1 -[ethyl-[(E)-(3-isopropyl-1 -oxo-isoindolin-5-yl)methyleneamino]amino]pyrrolo[1 ,2- a]pyrazine-6-carbonitrile;

[0671] 1 -[ethyl-[(E)-[3-(methoxymethyl)-1 -oxo-isoindolin-5-yl]methyleneamino]amino]pyrrolo[1 ,2- a]pyrazine-6-carbonitrile;

[0672] 1 -[[(E)-[3-(cyanomethyl)-1 -oxo-isoindolin-5-yl]methyleneamino]ethylamino]pyrrolo[1 ,2- a]pyrazine-6-carbonitrile;

[0673] 1 -[ethyl-[(E)-(6-fluoro-3,3-dimethyl-1 -oxo-isoindolin-5-yl)methyleneamino]amino] pyrrolo[1 ,2-a]pyrazine-6-carbonitrile ;

[0674] 1 -[ethyl-[(E)-(4-fluoro-3,3-dimethyl-1 -oxo-isoindolin-5-yl)methyleneamino]amino]- pyrrolo[1 ,2-a]pyrazine-6-carbonitrile;

[0675] 1 -[ethyl-[(E)-(4-methoxy-3,3-dimethyl-1 -oxo-isoindolin-5-yl)methyleneamino]amino]- pyrrolo[1 ,2-a]pyrazine-6-carbonitrile;

[0676] 1 -[[(E)-(5,5-dimethyl-7-oxo-6H-pyrrolo[3,4-b]pyridin-3-yl)methyleneamino]-ethyl- amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile;

[0677] 2-[6-[(E)-[(6-cyanopyrrolo[1 ,2-a]pyrazin-1 -yl)-ethyl-hydrazono]methyl]-7-methoxy-1 ,1 - dimethyl-3-oxo-isoindolin-2-yl]acetamide; and pharmaceutically acceptable salts, enantiomers, diastereomers, tautomers, solvates, isotope substituents, polymorphs, prodrugs or metabolites thereof.

[0678] 11 . The compound if item 10, which is selected from: 1 -[[(E)-(3,3-dimethyl- 1 -oxo-isoindolin-5-yl)methyleneamino]-ethyl-amino]pyrrolo[1 ,2- a]pyrazine-6-carbonitrile;

[0679] 1 -[ethyl-[(E)-[6-(2-hydroxyethyl)-5,5-dimethyl-7-oxo-pyrrolo[3,4-b]pyridin-3- yl]methyleneamino]amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile;

[0680] 1 -[ethyl-[(E)-(2,3,3-trimethyl- 1 -oxo-isoindolin-5-yl)methyleneamino]amino]pyrrolo[1 ,2- a]pyrazine-6-carbonitrile;

[0681] 1 -[ethyl-[(E)-[2-(3-hydroxypropyl)-3,3-dimethyl-1 -oxo-isoindolin-5-yl]methyleneamino]- amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile;

[0682] 1 -[[(E)-[2-(2-cyanoethyl)-3,3-dimethyl-1 -oxo-isoindolin-5-yl]methyleneamino]-ethyl- amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile;

[0683] 1 -[[(E)-(2-acetonyl-3,3-dimethyl-1 -oxo-isoindolin-5-yl)methyleneamino]-ethyl- amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile;

[0684] 2-[6-[(E)-[(6-cyanopyrrolo[1 ,2-a]pyrazin-1 -yl)-ethyl-hydrazono]methyl]-1 ,1 -dimethyl-3-oxo- isoindolin-2-yl]acetamide;

[0685] 2-[6-[(E)-[(6-cyanopyrrolo[1 ,2-a]pyrazin-1 -yl)-ethyl-hydrazono]methyl]-1 ,1 -dimethyl-3-oxo- isoindolin-2-yl]-N-methyl-acetamide;

[0686] 1 -[[(E)-[3,3-dimethyl-2-(oxazol-2-ylmethyl)-1 -oxo-isoindolin-5-yl]methyleneamino]-ethyl- amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile;

[0687] 1 -[[(E)-[3,3-dimethyl-1 -oxo-2-(thiazol-2-ylmethyl)isoindolin-5-yl]methyleneamino]-ethyl- amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile;

[0688] 1 -(1 -Ethyl-2-((3-methyl-1 -oxoisoindolin-5-yl)methylene)hydrazineyl)pyrrolo[1 ,2-a]pyrazine- 6-carbonitrile;

[0689] 1 -[[(E)-[3,3-bis(methoxymethyl)-1 -oxo-isoindolin-5-yl]methyleneamino]-ethylamino]- pyrrolo[1 ,2-a]pyrazine-6-carbonitrile;

[0690] 1 -[[(E)-[3-(cyanomethyl)-1 -oxo-isoindolin-5-yl]methyleneamino]-ethyl-amino]pyrrolo[1 ,2- a]pyrazine-6-carbonitrile;

[0691] 1 -[ethyl-[(E)-(4-methoxy-3,3-dimethyl-1 -oxo-isoindolin-5-yl)methyleneamino]amino]- pyrrolo[1 ,2-a]pyrazine-6-carbonitrile;

[0692] 2-[6-[(E)-[(6-cyanopyrrolo[1 ,2-a]pyrazin-1 -yl)-ethyl-hydrazono]methyl]-7-methoxy-1 ,1 - dimethyl-3-oxo-isoindolin-2-yl]acetamide; and pharmaceutically acceptable salts, enantiomers, diastereomers, tautomers, solvates, isotope substituents, polymorphs, prodrugs or metabolites thereof.

[0693] 12. A pharmaceutical composition comprising a compound according to any one of items 1 to 11 , or a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, solvate, isotope substituent, polymorph, prodrug or metabolite thereof, and at least one pharmaceutically acceptable excipient. 13. The pharmaceutical composition of item 12, which further comprises at least one other active pharmaceutical ingredient selected from KRAS inhibitors, SHP2 inhibitors, EGFR inhibitors, PI3K inhibitors, MEK inhibitors, ERK inhibitors, MDM2 inhibitors, Raf inhibitors, CDK4 / 6 inhibitors, cMET inhibitors, chemotherapeutic agent, radiotherapeutic treatment, immunotherapy agent, immunotherapy drug based on oncolytic viruses and combinations thereof.

[0694] 14. The pharmaceutical composition according to any one of items 12 to 13, for use in a method for the prevention or the treatment of a cancer.

[0695] 15. The pharmaceutical composition according to any one of items 12 to 13, for use in a method the prevention or the treatment of a fibrosis related disease.

[0696] 16. A compound according to any one of items 1 to 11 , or a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, solvate, isotope substituent, polymorph, prodrug or metabolite thereof, for use as a medicament.

[0697] 17. A compound according to any one of items 1 to 11 , or a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, solvate, isotope substituent, polymorph, prodrug or metabolite thereof, for use in a method for the treatment of a cancer.

[0698] 18. A compound according to any one of items 1 to 11 , or a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, solvate, isotope substituent, polymorph, prodrug or metabolite thereof, for use in a method for the prevention of a cancer.

[0699] 19. Use of a compound according to any one of items 1 to 11 , or a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, solvate, isotope substituent, polymorph, prodrug or metabolite thereof, in the manufacture of a medicament intended for the treatment of a cancer.

[0700] 20. Use of a compound according to any one of items 1 to 11 , or a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, solvate, isotope substituent, polymorph, prodrug or metabolite thereof, in the manufacture of a medicament intended for the prevention of a cancer.

[0701] 21. A method of treating a cancer in a patient, comprising administering to the patient an effective amount of a compound of formula (I) according to any one of items 1 to 11 , or a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, solvate, isotope substituent, polymorph, prodrug or metabolite thereof.

[0702] 22. A method of preventing a cancer in a patient, comprising administering to the patient an effective amount of a compound of formula (I) according to any one of items 1 to 11 , or a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, solvate, isotope substituent, polymorph, prodrug or metabolite thereof.

[0703] 23. The method according to item 21 or item 22, which further comprises administering to the patient at least one other active pharmaceutical ingredient selected from KRAS inhibitors, SHP2 inhibitors, EGFR inhibitors, PI3K inhibitors, MEK inhibitors, ERK inhibitors, MDM2 inhibitors, Raf inhibitors, CDK4 / 6 inhibitors, cMET inhibitors, chemotherapeutic agent, radiotherapeutic treatment, immunotherapy agent, immunotherapy drug based on oncolytic viruses and combinations thereof.

[0704] 24. The compound for use, use or method according to any one of items 16 to 23, wherein the cancer is selected from: lip cancer, tongue cancer, oral cavity cancer, salivary gland cancer, tonsils cancer, mouth cancer, nasal cancer, oesophagus cancer, stomach cancer, small intestine cancer, colon cancer, rectum cancer, liver cancer, gallbladder cancer, bile ducts cancer, pancreas cancer, larynx cancer, lung cancer, bronchi cancer, trachea cancer, thymus cancer, cardiac cancer, thoracic cancer, pleural cancer, bone cancer, bone marrow cancer, mesothelioma, peripheral nerves cancer, peritoneum cancer, breast cancer, cervix cancer, uterus cancer, ovary cancer, placenta cancer, vaginal cancer, vulva cancer, penis cancer, prostate cancer, testicle cancer, kidney cancer, renal pelvis cancer, urinary bladder cancer, eye cancer, brain cancer, spinal cord cancer, cranial nerves cancer, neck cancer, thyroid cancer, adrenal gland cancer, muscle cancer, bladder cancer, soft tissues cancer (such as tendons, cartilage, fat) and any cancer related to blood cells or their progenitors.

[0705] 25. A compound according to any one of items 1 to 11 , or a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, solvate, isotope substituent, polymorph, prodrug or metabolite thereof, for use in a method for the treatment of a fibrosis related disease.

[0706] 26. A compound according to any one of items 1 to 11 , or a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, solvate, isotope substituent, polymorph, prodrug or metabolite thereof, for use in a method for the prevention of a fibrosis related disease.

[0707] 27. Use of a compound according to any one of items 1 to 11 , or a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, solvate, isotope substituent, polymorph, prodrug or metabolite thereof, in the manufacture of a medicament intended for the treatment of a fibrosis related disease.

[0708] 28. Use of a compound according to any one of items 1 to 11 , or a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, solvate, isotope substituent, polymorph, prodrug or metabolite thereof, in the manufacture of a medicament intended for the prevention of a fibrosis related disease.

[0709] 29. A method of treating a fibrosis related disease in a patient, comprising administering to the patient an effective amount of a compound of formula (I) according to any one of items 1 to 11 , or a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, solvate, isotope substituent, polymorph, prodrug or metabolite thereof.

[0710] 30. A method of preventing a fibrosis related disease in a patient, comprising administering to the patient an effective amount of a compound of formula (I) according to any one of items 1 to 11 , or a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, solvate, isotope substituent, polymorph, prodrug or metabolite thereof.

[0711] 31 . The method according to item 29 or item 30, which further comprises administering to the patient at least one other active pharmaceutical ingredient selected from KRAS inhibitors, SHP2 inhibitors, EGFR inhibitors, PI3K inhibitors, MEK inhibitors, ERK inhibitors, MDM2 inhibitors, Raf inhibitors, CDK4 / 6 inhibitors, cMET inhibitors, chemotherapeutic agent, radiotherapeutic treatment, immunotherapy agent, immunotherapy drug based on oncolytic viruses and a combination thereof.

[0712] 32. The compound for use, use or method according to any one of items 25 to 31 , wherein the fibrosis related disease is selected from: skin fibrosis (such as for example hypertrophic scar or systemic sclerosis), heart fibrosis (such as for example cardiac fibrosis, hypertrophic cardiomyopathy, valvular diseases), bone marrow fibrosis (such as for example myelofibrosis, myelodysplatic syndrome), liver fibrosis (such as for example non-alcoholic steatohepatitis, cirrhosis, portal hypertension), retroperitoneum fibrosis, gut fibrosis (such as for example intestinal fibrosis, Inflammatory bowel disease, enteropathies), joint fibrosis (such as for example arthrofibrosis), brain fibrosis (such as glial scar), nervous system fibrosis, eye fibrosis (such as for example subretinal fibrosis, epiretinal fibrosis, vision loss), lung fibrosis (such as for example idiopathic pulmonary fibrosis, cystic fibrosis, pulmonary hypertension, emphysema), mediastinum fibrosis, pancreas fibrosis (such as for example pancreatic fibrosis, cystic fibrosis, chronic pancreatitis, duct obstruction) and kidney fibrosis (such as for example renal fibrosis, cystic fibrosis, nephrogenic systemic fibrosis, chronic kidney disease).

[0713] 33. A pharmaceutical composition according to any one of items 12 to 13, for use as a medicament.

[0714] 34. Use of a pharmaceutical composition according to any one of items 12 to 13, in the manufacture of a medicament intended for the treatment or prevention of a cancer.

[0715] 35. A method of treating or preventing a cancer in a patient, comprising administering to the patient a pharmaceutical composition according to any one of items 12 to 13, wherein the pharmaceutical composition comprises an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, solvate, isotope substituent, polymorph, prodrug or metabolite thereof.

[0716] 36. The pharmaceutical composition for use, use or method according to any one of items 12 to 14 or 33 to 35, wherein the cancer is selected from: lip cancer, tongue cancer, oral cavity cancer, salivary gland cancer, tonsils cancer, mouth cancer, nasal cancer, oesophagus cancer, stomach cancer, small intestine cancer, colon cancer, rectum cancer, liver cancer, gallbladder cancer, bile ducts cancer, pancreas cancer, larynx cancer, lung cancer, bronchi cancer, trachea cancer, thymus cancer, cardiac cancer, thoracic cancer, pleural cancer, bone cancer, bone marrow cancer, mesothelioma, peripheral nerves cancer, peritoneum cancer, breast cancer, cervix cancer, uterus cancer, ovary cancer, placenta cancer, vaginal cancer, vulva cancer, penis cancer, prostate cancer, testicle cancer, kidney cancer, renal pelvis cancer, urinary bladder cancer, eye cancer, brain cancer, spinal cord cancer, cranial nerves cancer, neck cancer, thyroid cancer, adrenal gland cancer, muscle cancer, bladder cancer, soft tissues cancer (such as tendons, cartilage, fat) and any cancer related to blood cells or their progenitors.

[0717] 37. The method according to item 35, which further comprises administering to the patient at least one other active pharmaceutical ingredient selected from KRAS inhibitors, SHP2 inhibitors, EGFR inhibitors, PI3K inhibitors, MEK inhibitors, ERK inhibitors, MDM2 inhibitors, Raf inhibitors, CDK4 / 6 inhibitors, cMET inhibitors, chemotherapeutic agent, radiotherapeutic treatment, immunotherapy agent, immunotherapy drug based on oncolytic viruses and combinations thereof.

[0718] 38. Use of a pharmaceutical composition according to any one of items 12 to 13, in the manufacture of a medicament intended for the treatment or prevention of a fibrosis related disease.

[0719] 39. A method of treating or preventing a fibrosis related disease in a patient, comprising administering to the patient a pharmaceutical composition according to any one of items 12 to 13, wherein the pharmaceutical composition comprises an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, solvate, isotope substituent, polymorph, prodrug or metabolite thereof.

[0720] 40. The method according to item 39, which further comprises administering to the patient at least one other active pharmaceutical ingredient selected from KRAS inhibitors, SHP2 inhibitors, EGFR inhibitors, PI3K inhibitors, MEK inhibitors, ERK inhibitors, MDM2 inhibitors, Raf inhibitors, CDK4 / 6 inhibitors, cMET inhibitors, chemotherapeutic agent, radiotherapeutic treatment, immunotherapy agent, immunotherapy drug based on oncolytic viruses and combinations thereof.

[0721] 41 . The pharmaceutical composition for use, use or method according to any one of items 12 to 13, 15, or 38 to 40, wherein the fibrosis related disease is selected from: skin fibrosis (such as for example hypertrophic scar or systemic sclerosis), heart fibrosis (such as for example cardiac fibrosis, hypertrophic cardiomyopathy, valvular diseases), bone marrow fibrosis (such as for example myelofibrosis, myelodysplatic syndrome), liver fibrosis (such as for example non-alcoholic steatohepatitis, cirrhosis, portal hypertension), retroperitoneum fibrosis, gut fibrosis (such as for example intestinal fibrosis, Inflammatory bowel disease, enteropathies), joint fibrosis (such as for example arthrofibrosis), brain fibrosis (such as glial scar), nervous system fibrosis, eye fibrosis (such as for example subretinal fibrosis, epiretinal fibrosis, vision loss), lung fibrosis (such as for example idiopathic pulmonary fibrosis, cystic fibrosis, pulmonary hypertension, emphysema), mediastinum fibrosis, pancreas fibrosis (such as for example pancreatic fibrosis, cystic fibrosis, chronic pancreatitis, duct obstruction) and kidney fibrosis (such as for example renal fibrosis, cystic fibrosis, nephrogenic systemic fibrosis, chronic kidney disease).

Claims

CLAIMS1. A compound of formula (I) or a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, solvate, isotope substituent, polymorph, prodrug or metabolite thereof:wherein:X is C or N;Y is C or N;W is C or N;Ri and R2are each independently H; a (Ci-C6)alkyl optionally substituted by a (C C4)alkoxy, CN, CONR12R13 or a (C2-C4)alkenyl ; or R1 and R2are bound together to form a (C3-C6)cycloalkyl or a 5- to 7-membered heterocycle;R3, R4and R5, when present, are each independently H, halogen or a (Ci-C4)alkoxy;R6is H; a (Ci-C6)alkyl optionally substituted with OH, COOH, CONH2, a (Ci-C4)alkoxy optionally substituted with OH or a (Ci-C4)alkoxy, or an aryl; an optionally substituted 5- or 6-membered heterocycle; a (C3-C6)cycloalkyl;R7, R8, R9and R are each independently H; a (Ci-C6)alkyl optionally substituted with one or more substituents selected from OH, halogen, CF3and CN; halogen; CONR12R13; SO2(R14); SO(R14); CN; CF3, or COR12;R11 is H; a (Ci-C6)alkyl optionally substituted by a group selected from: OH, (Ci-C4)alkoxy, CN, COOH, CONR12R13, COOR15, an optionally substituted phenyl, and an optionally substituted 5- or 6-membered heteroaryl; or -(CH2)mCORi6;RI2and RI3are each independently H or a (Ci -C4)alkyl ;RI4is a (Ci-C4)alkyl;R15 is a (Ci-C4)alkyl;RI6is a (Ci-C4)alkyl; m = 0, 1 or 2.

2. The compound of claim 1 or a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, solvate, isotope substituent, polymorph, prodrug or metabolite thereof, wherein W is C and R3is H.

3. The compound of claim 1 or claim 2, or a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, solvate, isotope substituent, polymorph, prodrug or metabolite thereof, wherein X is C and R5is H.

4. The compound of any of claims 1 to 3, or a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, solvate, isotope substituent, polymorph, prodrug or metabolite thereof, wherein Y is C and R4is H.

5. The compound of any of claims 1 to 4, or a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, solvate, isotope substituent, polymorph, prodrug or metabolite thereof, wherein Ri and R2are each independently H or a (Ci-C6)alkyl optionally substituted by a (Ci-C4)alkoxy or by CN, preferably the alkyl is a (Ci-C4)alkyl.

6. The compound of any of claims 1 to 5, or a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, solvate, isotope substituent, polymorph, prodrug or metabolite thereof, wherein R6is a (Ci-C6)alkyl, preferably a (Ci-C4)alkyl.

7. The compound of any of claims 1 to 6, or a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, solvate, isotope substituent, polymorph, prodrug or metabolite thereof, wherein R7, R9and R are each H.

8. The compound of any of claims 1 to 7, or a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, solvate, isotope substituent, polymorph, prodrug or metabolite thereof, wherein R8is CN.

9. The compound of any of claims 1 to 8, or a pharmaceutically acceptable salt enantiomer, diastereomer, tautomer, solvate, isotope substituent, polymorph, prodrug or metabolite thereof, wherein Rn is H; a (Ci-C6)alkyl optionally substituted by a group selected from: OH, CN, CONR12R13 and a 5-membered heteroaryl; or -CH2CORI6;R12, R13, and RI6are as defined in claim 1 .

10. The compound of claim 1 , which is selected from:5-[(E)-[ethyl-(6-methylpyrrolo[1 ,2-a]pyrazin-1 -yl)hydrazono]methyl]-3,3-dimethyl-isoindolin-1-one;5-[(E)-[[6-(difluoromethyl)pyrrolo[1 ,2-a]pyrazin-1 -yl]-ethyl-hydrazono]methyl]-3,3-dimethyl- isoindolin-1 -one;5-[(E)-[ethyl-[6-(hydroxymethyl)pyrrolo[1 ,2-a]pyrazin-1 -yl]hydrazono]methyl]-3,3-dimethyl- isoindolin-1 -one;2-[1 -[[(E)-(3,3-dimethyl-1 -oxo-isoindolin-5-yl)methyleneamino]-ethyl-amino]pyrrolo[1 ,2- a]pyrazin-6-yl]acetonitrile;5-[(E)-[ethyl-(6-fluoropyrrolo[1 ,2-a]pyrazin-1-yl)hydrazono]methyl]-3,3-dimethyl-isoindolin-1-one;5-[(E)-[(6-chloropyrrolo[1 ,2-a]pyrazin-1-yl)-ethyl-hydrazono]methyl]-3,3-dimethyl- isoindolin-1 -one;1 -[[(E)-(3,3-dimethyl-1 -oxo-isoindolin-5-yl)methyleneamino]-ethyl-amino]pyrrolo[1 ,2- a]pyrazine-6-carboxamide;5-[(E)-[ethyl-(6-methylsulfonylpyrrolo[1 ,2-a]pyrazin-1-yl)hydrazono]methyl]-3,3-dimethyl- isoindolin-1 -one;5-[(E)-[ethyl-(4-methylsulfinylpyrrolo[1 ,2-a]pyrazin-1-yl)hydrazono]methyl]-3,3-dimethyl- isoindolin-1 -one;2-[1 -[[(E)-(3,3-dimethyl-1 -oxo-isoindolin-5-yl)methyleneamino]-ethyl-amino]pyrrolo[1 ,2- a]pyrazin-4-yl]acetonitrile;1 -[[(E)-(3,3-dimethyl-1 -oxo-isoindolin-5-yl)methyleneamino]-ethyl-amino]-7-methyl- pyrrolo[1 ,2-a]pyrazine-6-carbonitrile;1 -[[(E)-(3,3-dimethyl-1 -oxo-isoindolin-5-yl)methyleneamino]-ethyl-amino]pyrrolo[1 ,2- a]pyrazine-6-carbonitrile;1 -[[(E)-(3,3-dimethyl-1 -oxo-isoindolin-5-yl)methyleneamino]-ethyl-amino]-4-methyl- pyrrolo[1 ,2-a]pyrazine-6-carbonitrile;8-bromo-1-[[(E)-(3,3-dimethyl-1-oxo-isoindolin-5-yl)methyleneamino]-ethyl- amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile;8-chloro-1-[[(E)-(3,3-dimethyl-1-oxo-isoindolin-5-yl)methyleneamino]-ethyl- amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile;1 -[[(E)-(3,3-dimethyl-1 -oxo-isoindolin-5-yl)methyleneamino]-ethyl-amino]-8-fluoro- pyrrolo[1 ,2-a]pyrazine-6-carbonitrile;1 -[[(E)-(3,3-dimethyl- 1 -oxo-isoindolin-5-yl)methyleneamino]-methyl-amino]pyrrolo[1 ,2- a]pyrazine-6-carbonitrile;1 -[[(E)-(3,3-dimethyl-1 -oxo-isoindolin-5-yl)methyleneamino]-isopropyl-amino]pyrrolo[1 ,2- a]pyrazine-6-carbonitrile;1 -[[(E)-(3,3-dimethyl-1 -oxo-isoindolin-5-yl)methyleneamino]-(2-hydroxyethyl)amino]- pyrrolo[1 ,2-a]pyrazine-6-carbonitrile;1 -[[(E)-(3,3-dimethyl-1 -oxo-isoindolin-5-yl)methyleneamino]-(3-hydroxypropyl)amino]- pyrrolo[1 ,2-a]pyrazine-6-carbonitrile;1 -[[(E)-(3,3-dimethyl-1 -oxo-isoindolin-5-yl)methyleneamino]-(4-hydroxybutyl)amino]- pyrrolo[1 ,2-a]pyrazine-6-carbonitrile;1 -[[(E)-(3,3-dimethyl-1 -oxo-isoindolin-5-yl)methyleneamino]-(2-methoxyethyl)amino]- pyrrolo[1 ,2-a]pyrazine-6-carbonitrile;1 -[[(E)-(3,3-dimethyl-1 -oxo-isoindolin-5-yl)methyleneamino]-(2-isopropoxyethyl)amino]- pyrrolo[1 ,2-a]pyrazine-6-carbonitrile;1 -[[(E)-(3,3-dimethyl-1 -oxo-isoindolin-5-yl)methyleneamino]-(3-methoxypropyl)amino]- pyrrolo[1 ,2-a]pyrazine-6-carbonitrile;1 -[[(E)-(3,3-dimethyl-1 -oxo-isoindolin-5-yl)methyleneamino]-tetrahydrofuran-3-yl- amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile;1 -[[(E)-(3,3-dimethyl-1 -oxo-isoindolin-5-yl)methyleneamino]-[2-(2-methoxyethoxy)ethyl]- amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile;1 -[[(E)-(3,3-dimethyl-1 -oxo-isoindolin-5-yl)methyleneamino]-[2-(2-hydroxyethoxy)ethyl]- amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile;5-[(6-cyanopyrrolo[1 ,2-a]pyrazin-1 -yl)-[(E)-(3,3-dimethyl-1 -oxo-isoindolin-5- yl)methyleneamino]amino]pentanoic acid;1 -[cyclopropyl-[(E)-(3,3-dimethyl-1 -oxo-isoindolin-5-yl)methyleneamino]amino]pyrrolo[1 ,2- a]pyrazine-6-carbonitrile;1 -[ethyl-[(E)-[6-(2-hydroxyethyl)-5,5-dimethyl-7-oxo-pyrrolo[3,4-b]pyridin-3- yl]methyleneamino]amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile;1 -[ethyl-[(E)-(2,3,3-trimethyl- 1 -oxo-isoindolin-5-yl)methyleneamino]amino]pyrrolo[1 ,2- a]pyrazine-6-carbonitrile;1 -[[(E)-(2-benzyl-3,3-dimethyl-1 -oxo-isoindolin-5-yl)methyleneamino]-ethyl- amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile;1 -[ethyl-[(E)-[2-(3-hydroxypropyl)-3,3-dimethyl-1 -oxo-isoindolin-5-yl]methyleneamino]- amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile;1 -[ethyl-[(E)-[2-(4-hydroxybutyl)-3,3-dimethyl-1 -oxo-isoindolin-5-yl]methyleneamino]- amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile;1 -[ethyl-[(E)-[2-(2-isopropoxyethyl)-3,3-dimethyl-1 -oxo-isoindolin-5-yl]methyleneamino]- amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile;1-[ethyl-[(E)-[2-(4-methoxybutyl)-3,3-dimethyl-1-oxo-isoindolin-5-yl]methyleneamino]- amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile;1-[[(E)-[2-(cyanomethyl)-3,3-dimethyl-1 -oxo-isoindolin-5-yl]methyleneamino]-ethyl- amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile;1 -[[(E)-[2-(2-cyanoethyl)-3,3-dimethyl-1 -oxo-isoindolin-5-yl]methyleneamino]-ethyl- amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile;1 -[[(E)-(2-acetonyl-3,3-dimethyl-1 -oxo-isoindolin-5-yl)methyleneamino]-ethyl- amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile;4-[6-[(E)-[(6-cyanopyrrolo[1 ,2-a]pyrazin-1-yl)-ethyl-hydrazono]methyl]-1 ,1-dimethyl-3-oxo- isoindolin-2-yl]butanoic acid;4-[6-[(E)-[(6-cyanopyrrolo[1 ,2-a]pyrazin-1-yl)-ethyl-hydrazono]methyl]-1 ,1-dimethyl-3-oxo- isoindolin-2-yl]butan amide; isopropyl 2-[6-[(E)-[(6-cyanopyrrolo[1 ,2-a]pyrazin-1-yl)-ethyl-hydrazono]methyl]-1 ,1- dimethyl-3-oxo-isoindolin-2-yl]acetate;2-[6-[(E)-[(6-cyanopyrrolo[1 ,2-a]pyrazin-1-yl)-ethyl-hydrazono]methyl]-1 ,1-dimethyl-3-oxo- isoindolin-2-yl]acetamide;2-[6-[(E)-[(6-cyanopyrrolo[1 ,2-a]pyrazin-1-yl)-ethyl-hydrazono]methyl]-1 ,1-dimethyl-3-oxo- isoindolin-2-yl]-N-methyl-acetamide;3-[6-[(E)-[(6-cyanopyrrolo[1 ,2-a]pyrazin-1-yl)-ethyl-hydrazono]methyl]-1 ,1-dimethyl-3-oxo- isoindolin-2-yl]propanamide;1 -[[(E)-[3,3-dimethyl-1-oxo-2-(2-pyridylmethyl)isoindolin-5-yl]methyleneamino]-ethyl- amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile;1 -[[(E)-[3,3-dimethyl-2-(oxazol-2-ylmethyl)-1-oxo-isoindolin-5-yl]methyleneamino]-ethyl- amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile;1 -[[(E)-[3,3-dimethyl-1-oxo-2-(thiazol-2-ylmethyl)isoindolin-5-yl]methyleneamino]-ethyl- amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile;1 -[[(E)-[3,3-dimethyl-1-oxo-2-(thiazol-4-ylmethyl)isoindolin-5-yl]methyleneamino]-ethyl- amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile;1 -[[(E)-[3,3-dimethyl-1-oxo-2-(thiazol-5-ylmethyl)isoindolin-5-yl]methyleneamino]-ethyl- amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile;1 -[ethyl-[(E)-[2-( 1 H-imidazol-2-ylmethyl)-3,3-dimethyl-1 -oxo-isoindolin-5-yl]methylene- amino]amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile;1 -[[(E)-[3,3-dimethyl-1 -oxo-2-(1 H-tetrazol-5-ylmethyl)isoindolin-5-yl]methyleneamino]- ethyl-amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile;1 -[ethyl-[(E)-( 1 -oxoisoindolin-5-yl)methyleneamino]amino]pyrrolo[1 ,2-a]pyrazine-6- carbonitrile;1 -(1 -Ethyl-2-((3-methyl-1 -oxoisoindolin-5-yl)methylene)hydrazineyl)pyrrolo[1 ,2-a]pyrazine- 6-carbonitrile1 -(2-((3,3-Diethyl- 1 -oxoisoindolin-5-yl)methylene)-1 -ethylhydrazineyl)pyrrolo[1 ,2- a]pyrazine-6-carbonitrile;1 -(2-((3- Allyl- 1 -oxoisoindolin-5-yl)methylene)-1 -ethylhydrazineyl)pyrrolo[ 1,2-a]pyrazine-6- carbonitrile;1 -[[(E)-[3,3-bis(methoxymethyl)-1 -oxo-isoindolin-5-yl]methyleneamino]-ethyl- amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile;1 -[[(E)-[3,3-bis(2-methoxyethyl)-1 -oxo-isoindolin-5-yl]methyleneamino]-ethyl- amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile;1 -[ethyl-[(E)-(3-ethyl- 1 -oxo-isoindolin-5-yl)methyleneamino]amino]pyrrolo[1 ,2-a]pyrazine- 6-carbonitrile;1 -[ethyl-[(E)-( 1 -oxo-3-propyl-isoindolin-5-yl)methyleneamino]amino]pyrrolo[1 ,2-a]pyrazine- 6-carbonitrile;1 -[ethyl-[(E)-(3-isopropyl-1 -oxo-isoindolin-5-yl)methyleneamino]amino]pyrrolo[1 ,2- a]pyrazine-6-carbonitrile;1 -[ethyl-[(E)-[3-(methoxymethyl)-1 -oxo-isoindolin-5-yl]methyleneamino]amino]pyrrolo[1 ,2- a]pyrazine-6-carbonitrile;1 -[[(E)-[3-(cyanomethyl)-1 -oxo-isoindolin-5-yl]methyleneamino]ethylamino]pyrrolo[1 ,2- a]pyrazine-6-carbonitrile;1 -[ethyl-[(E)-(6-fluoro-3,3-dimethyl-1 -oxo-isoindolin-5-yl)methyleneamino]amino] pyrrolo[1 ,2-a]pyrazine-6-carbonitrile ;1 -[ethyl-[(E)-(4-fluoro-3,3-dimethyl-1 -oxo-isoindolin-5-yl)methyleneamino]amino]- pyrrolo[1 ,2-a]pyrazine-6-carbonitrile;1 -[ethyl-[(E)-(4-methoxy-3,3-dimethyl-1 -oxo-isoindolin-5-yl)methyleneamino]amino]- pyrrolo[1 ,2-a]pyrazine-6-carbonitrile;1 -[[(E)-(5,5-dimethyl-7-oxo-6H-pyrrolo[3,4-b]pyridin-3-yl)methyleneamino]-ethyl- amino]pyrrolo[1 ,2-a]pyrazine-6-carbonitrile;2-[6-[(E)-[(6-cyanopyrrolo[1 ,2-a]pyrazin-1 -yl)-ethyl-hydrazono]methyl]-7-methoxy-1 ,1 - dimethyl-3-oxo-isoindolin-2-yl]acetamide; and pharmaceutically acceptable salts, enantiomers, diastereomers, tautomers, solvates, isotope substituents, polymorphs, prodrugs or metabolites thereof.11 . The compound or a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, solvate, isotope substituent, polymorph, prodrug or metabolite thereof according to any one of claims 1 to 10, for use as a medicament.

12. The compound or a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, solvate, isotope substituent, polymorph, prodrug or metabolite thereof according to any one of claims 1 to 10, for use in a method for the treatment or prevention of a cancer or of a fibrosis related disease.

13. The compound for use of claim 12, wherein the cancer is selected from : lip cancer, tongue cancer, oral cavity cancer, salivary gland cancer, tonsils cancer, mouth cancer, nasal cancer, oesophagus cancer, stomach cancer, small intestine cancer, colon cancer, rectum cancer, liver cancer, gallbladder cancer, bile ducts cancer, pancreas cancer, larynx cancer, lung cancer, bronchi cancer, trachea cancer, thymus cancer, cardiac cancer, thoracic cancer, pleural cancer, bone cancer, bone marrow cancer, mesothelioma, peripheral nerves cancer, peritoneum cancer, breast cancer, cervix cancer, uterus cancer, ovary cancer, placenta cancer, vaginal cancer, vulva cancer, penis cancer, prostate cancer, testicle cancer, kidney cancer, renal pelvis cancer, urinary bladder cancer, eye cancer, brain cancer, spinal cord cancer, cranial nerves cancer, neck cancer, thyroid cancer, adrenal gland cancer, muscle cancer, bladder cancer, soft tissues cancer (such as tendons, cartilage, fat) and any cancer related to blood cells or their progenitors.

14. The compound for use of claim 12, wherein the fibrosis related disease is selected from: skin fibrosis, heart fibrosis, bone marrow fibrosis, liver fibrosis, retroperitoneum fibrosis, gut fibrosis, joint fibrosis, brain fibrosis, nervous system fibrosis, eye fibrosis, lung fibrosis, mediastinum fibrosis, pancreas fibrosis and kidney fibrosis.

15. A pharmaceutical composition comprising a compound of formula (I) according to any one of claims 1 to 10, or a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, solvate, isotope substituent, polymorph, prodrug or metabolite thereof, and one or more pharmaceutically acceptable excipients.

16. The pharmaceutical composition of claim 15, which further comprises at least one other active pharmaceutical ingredient selected from KRAS inhibitors, SHP2 inhibitors, EGFR inhibitors, PI3K inhibitors, MEK inhibitors, ERK inhibitors, MDM2 inhibitors, Rafinhibitors, CDK4 / 6 inhibitors, cMET inhibitors, chemotherapeutic agent, radiotherapeutic treatment, immunotherapy agent, immunotherapy drug based on oncolytic viruses and combinations thereof.

17. The pharmaceutical composition of claim 15 or 16, for use in a method for the treatment or prevention of a cancer or of a fibrosis related disease.

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