MXPA99007603A - Antitromboti agents - Google Patents

Abstract

The compounds of the formula (I) are antithrombotic agents, which have utility in a variety of therapeutic areas including the prevention and / or treatment of deep vein thrombosis (DVT) after surgery, major medical disease, paralysis, malignant disease , trauma of prolonged immobilization, application of plaster in the lower extremities, or fractures of the lower extremities or the pelvis, recurrent DVT, DVT during pregnancy when there is a previous history of it, reocclusion after thrombotic therapy, chronic arterial obstruction; peripheral vascular disease, acute myocardial infarction, unstable angina, atrial fibrillation, thrombotic apoplexy, transient ischemic attacks, disseminated intravascular coagulation, coagulation in extracorporeal circuits, occlusion of arteriovenous shunts and blood vessel grafts (including coronary artery bypass grafts) ) and restenosis and occlusion after s of angioplast

Description

ANTITROMBOTIC AGENTS The present invention relates to a series of indole, indazole and benzimidazole derivatives, which are antithrombotic agents, which have utility in a variety of therapeutic areas including the prevention and / or treatment of deep vein thrombosis (DVT) after surgery, major medical illness, paralysis, malignant disease, prolonged immobilization trauma, application of plaster on the lower extremities, or fractures of the lower extremities or pelvis, recurrent DVT; DVT during pregnancy when there is a previous history of it; reocclusion after thrombolytic therapy; chronic arterial obstruction; peripheral vascular disease; acute myocardial infarction; unstable angina; atrial fibrillation; thrombotic stroke; transient ischemic attacks; disseminated intravascular coagulation; coagulation in extracorporeal circuits; occlusion of arteriovenous shunts and blood vessel grafts (including coronary artery bypass grafts); and restenosis and occlusion after angioplasty. They also have utility as adjuncts to thrombolytic therapy. The compounds of the invention are potent selective inhibitors of thrombin, which is the final serine protease enzyme in the coagulation cascade. The main function of thrombin is the breakdown of fibrinogen to produce fibrin, which forms insoluble linear polymers which, in turn, are cross-linked by factor XI I, which is itself activated by thrombin. In addition, thrombin regulates its own production by activating factors V and VIII earlier in the cascade. It also has important actions at the cellular level, where it acts on specific receptors to cause platelet aggregation, activation of endothelial cells and proliferation of the fibroblast. Thus, thrombin has a central regulatory role in hemostasis and thrombus formation. Clearly then, potent, selective and orally bioavailable thrombin inhibitors represent an attractive target for convenient therapeutic control of thrombosis. In addition, thrombin strongly induces the retraction of neurites and, therefore, a thrombin inhibitor is of potential therapeutic utility in the treatment of acute and chronic neurodegenerative disorders. In addition, the compounds described herein have a potential value in the treatment of inflammatory disorders and healing, and in wound healing. Due to their potential as substrate mimics, arginine derivatives have been investigated as thrombin inhibitors, and this work led to the discovery of argatroban (see Cardiovascular Drug Rev., 1991, 9, 247). In turn, other research groups have sought to express the role of basic arginine in alternative structures; for example, WO-A-95/13274 discloses amidinophenylalanine and amidinopyridyl alanine derivatives as antithrombotic agents. Other variations on the subject of arginine mimicry among thrombin inhibitors are represented, inter alia, by the heterocyclic guanidinyl and amidinyl substituted compounds described in EP-A-0623595. In general, however, the compounds containing the arginine, amidine or guanidine basic function have poor oral bioavailability and are poorly selective, since they inhibit trypsin as well as thrombin. In the PCT patent, reference WO 96/18644, Corvas Int Ine, and in WO 98/16547, COR Therapeutics Ine, thrombin inhibitors containing a matrix of 3-amino-2-pyridone acetamide have been described. . Compounds of the types described in WO 96/18644 and WO 98/16547 contain a guanidino function such as an arginine mimic and are likely irreversible thrombin inhibitors by virtue of the presence of an aldehyde or an activated carbonyl fragment. In the PCT patents, references WO 97/40024, WO 97/01338, WO 97/30708, WO 98/09987, WO 99/11267 of Merck and in Bioorg Med Chem Letters. 1997, 7, p1497; 1998, 8, p1719, 1998, 8, p817, thrombin inhibitors have been described which contain a fragment of 3-amino-2-pyridone or pyrazinone acetamide and an arginine mimic which is not a guanidine or amidine. We have now found a class of non-basic bicyclic, or weakly basic, heterocyclic arginine mimics that are highly potent, selective, reversible inhibitors of thrombin, with good oral bioavailability. Accordingly, the present invention provides a compound of formula (I): wherein: R 1 is hydrogen, C 1 -C 4 alkyl, C 1 -C 4 perfluoroalkyl, C 1 -C 4 alkyl, fluoro, or chloro; R2 is hydrogen, CH3, or CF3; R3 is hydrogen, C1-C4 alkyl, C1-C4 perfluoroalkyl, C1-C4 alkyl, fluoro, or chloro; R 4 is hydrogen or C | -C alkyl; R 5 is hydrogen or C 1 -C 4 alkyl; R6 is hydrogen, fluoro or chloro; C 1 -C 4 alkyl, C 3 -C 6 carbocyclic (for example, cyclopropyl), carbocyclic (C 3 -C 6) alkyl (C 1 -C 4) alkyl and carbocyclic can be optionally substituted by C 1 -C 4 alkyl or fluoro (for example, C1-C4 perfluoroalkyl) and wherein the carbocycle contains zero, one or more double bonds; or R5 and R6 together form a chain that forms a bridge containing 2 or 3 carbon atoms; And it is hydrogen, chloro fluoro, bromo, methyl or CF3; W and X are independently CH, CF, CCL or N; V is C or N; BA- is any one of the following fragments: BC (R8) (R9) - B-CH2-C (R8) (R9) - BC (R8) (R9) -CH2-B-CH2-C (R8) (R9) ) -CH2- BC (R8) (R9) -CH2-CH2- in which: R j8 ° and. , R n99 are independently hydrogen, - (CH2) mN (R10) (R11), -CH2O- (CH2) 2N (R10) (R11), or R8 and R9 together form a 4 to 6 member ring containing an atom of nitrogen present as N (R12); and m is 0, 1 and 2 (preferably, m = 1) except when A represents -C (R8) (R9) -, when m is 1 or 2; R10 and R11 are independently selected from hydrogen or C | -C4 alkyl optionally containing an oxygen atom in the chain or at the end of the chain; or R10 and R11, together with the nitrogen atom to which they are attached, form a 4 to 6 membered saturated heterocyclic ring which, when the ring is six members, may optionally contain an oxygen atom or a nitrogen atom present as N (R12); R12 is hydrogen or C4 alkyl optionally containing an oxygen atom in the chain or at the end of the chain, B is phenyl or a 5-6 membered saturated heterocyclic aromatic ring containing up to two heteroatoms independently selected from oxygen, sulfur and nitrogen; R7 (when B is phenyl or an aromatic heterocycle) is one or more of hydrogen, Ci-Cß alkyl, perfluoroalkyl, Ci-Cβ, C Cß alkyl, C perf perf perfluoroalkyl, fluoro, chloro or any one of the following fragments: (CH 2) ) pO- (CH2) 2N (R10) (R11) wherein R10 and R11 are as defined above, and p wherein Q, together with the C atom to which it is attached, is a 5-6 membered heterocyclic (preferably saturated) ring containing a nitrogen atom, said heterocyclic ring being optionally substituted by C1-C4 alkyl, and q is 1 or 2; - (CH2), r -C (R13) (R14) - (CH2) S -N (R15) (R16) in which rys are independently 0, 1 or 2, R13 and R14 are independently hydrogen or C1-C4 alkyl optionally containing an oxygen atom in the chain or at the end of the chain, or R13 and R14 together with the carbon atom to which they are linked form a saturated carbocyclic ring of 4 to 6 members; R15 and R16 are independently selected from hydrogen or CrC4 alkyl optionally containing an oxygen atom in the chain or at the end of the chain, or R15 and R16 together with the nitrogen atom to which they are attached form a saturated heterocyclic ring of 4. to 6 members; or one of R13 or R14, and one of R15 or R16, together with the carbon and nitrogen atoms to which they are bound, form a 4 to 6-membered saturated heterocyclic ring, in which case the other radical R13 or R14 is hydrogen or C1-C4 alkyl, and the other radical of R15 or R16 is hydrogen or C1-C4 alkyl optionally containing an oxygen atom in the chain or at the end of the chain; or wherein R7-B represents any one of the following bicyclic fragments in which R12 is as defined above with the proviso that R7, R8 and R9 can not all be hydrogen, and only one of R7, R8 and R9 contains a nitrogen atom or, when R8 and R9 together form a ring, said ring contains only one nitrogen atom with the condition that one of R8 and R9 may be the following fragment containing two nitrogen atoms: (the above condition does not apply to the subject of the following paragraph) or, B is a saturated or partially saturated heterocyclic ring of 4 to 7 members containing one or two heteroatoms of which at least one is a nitrogen and the other is independently selected from oxygen, sulfur and nitrogen; and wherein R7 (when B is a saturated or partially saturated heterocycle) is one or more of C?-C6 alkyl, C3-C6 carbocyclic, carbocyclic (C3-C6) (C1-C4) alkyl, containing said carbocyclic zero, one or more double bonds, wherein said alkyl and carbocyclic optionally contain a heteroatom selected from oxygen, sulfur and nitrogen (ie, for alkyl, the heteroatoms will be in the chain or at the end of the chain) and are also optionally substituted by one or more fluoro, or CC alkyl optionally containing an oxygen atom in the alkyl chain or at the end of the chain; and pharmaceutically acceptable salts thereof. Thus, according to the invention, the basic center (containing nitrogen) can be located at various positions in formula 1, with the proviso that each compound of the invention should contain a single basic center with a pKa (defined as the log of the corresponding ionization constant of the corresponding conjugate acid) greater than 6 (such as 6.5) In the above definition, unless otherwise indicated, alkyl and alkoxy groups having three or more carbon atoms may be straight chain or branched chain.

Here C 1 -C 4 alkyl, or fragment containing C 1 -C 4 alkyl, means methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl and tere-butyl; and C 1-6 alkyl further includes the various linear and branched pentyl and hexyl fragments (although C 1-4 is preferred). C3-Cβ cycloalkyl (used hereafter) means cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Here C1-C4 alkyl optionally containing an oxygen atom in the chain or at the end of the chain includes residues of the formula - (CH2) tO- (CH2) u-CH3 wherein t is 1 to 5, and u is 0 to 4, and in d-C4 alkyl of the same definition, t is 1, 2 or 3, and u is 0, 1 or 2. The following independently represent preferred subclasses of the compounds of the formula I. R1 is hydrogen or methyl (more preferably hydrogen); R2 is hydrogen or methyl; R3 is hydrogen or methyl (more preferably hydrogen); R4 is hydrogen; R5 is hydrogen; R6 is Ci-Cβ alkyl (eg, methyl), C3-C6 carbocyclic optionally substituted by fluoro, or R5 and R6 together form a bridging chain containing 2 or 3 carbon atoms; And it is hydrogen, chlorine or bromine; V is C; W is CH or N; X is CH or N; R10 and R11 independently represent hydrogen, C1-C4 alkyl optionally containing an oxygen atom in the chain, or R10 and R11, together with the nitrogen atom to which they are attached form a 5-6 membered heterocyclic ring which, when the ring is six members, may optionally contain an oxygen atom or a nitrogen atom present as N (R12); R 12 is hydrogen or C 1 -C 4 alkyl optionally containing an oxygen atom in the chain or at the end of the chain; B is phenyl or a saturated six-membered heterocyclic aromatic ring containing a nitrogen atom, said phenyl or heterocyclic ring being capable of being substituted by fluoro, chloro, C 1 -C 4 alkyl or C 1 O 4 alkyl. Also, in a preferred subclass of the compounds of formula (I), BA represents B-CH2-C (R8) (R9), - (CH2) mN (R10) (R11), -CH20- (CH2) 2N (R10) ) (R11), wherein R8 and R9 are independently hydrogen, or R8 and R9 together form a 4 to 6 member ring containing N (R12), m is 0, 1 and 2, and R10 and R11 are as define before. More preferably, B is preferably phenyl when B-A represents B-CH2- (R8) (R9). When C * is chiral in B-CH2-C * (R8) (R9), then the S-enantiomer is preferred.

It is a preferred subclass of compounds, B is phenyl and R7 is - (CH2) r -C (R13) (R14) - (CH2) SN (R15) (R16) wherein r, s and R13 to R16 are as defined here before. When B is phenyl, R 7 is preferably connected in the 3-position of the phenyl ring (in relation to the connection to the remainder "A" in the 1-position). In another preferred subclass of compounds B is a saturated or partially saturated 4- to 7-membered heterocyclic ring containing one or two heteroatoms, at least one of which is a nitrogen and the other is selected from oxygen, sulfur and nitrogen; and R7 is R17 which is substituted on the nitrogen of the heterocyclic ring and is selected from one or more of C1-C4 alkyl, carbocyclic C3-C6) carbocyclic (C3-C6) alkyl (C1-C4), said carbocyclic zero, one or further double bonds, wherein said alkyl and carbocyclic optionally contain a heteroatom selected from oxygen, sulfur and nitrogen and are further optionally substituted by one or more fluoro atoms, or C1-C4 alkyl optionally containing an oxygen in the chain of I rent at the end of the chain. More preferably, the saturated or partially saturated heterocycle is further optionally substituted by R18 which is independently selected from one or more of C1-C4 alkyl, C1-C4 perfluoroalkyl, wherein said alkyl optionally contains an oxygen atom in the chain or at the end of the chain. Even more preferably, the heterocyclic ring is a 5-6 membered saturated heterocyclic ring, and B-A is B-C (R8) (R9), wherein R8 and R9 are as defined hereinbefore. Also preferably the heterocyclic ring is connected in position 2 (ie, adjacent to the nitrogen) to the remainder "A". Preferably, the C3-C6 carbocyclic and carbocyclic (C3-Cβ) C 1 -C 4 alkyl moiety of R 17 is an optionally substituted C 3 -C 6 cycloalkyl (such as cyclopentyl), or (C 3 -C 6) cycloalkyl alkyl (C | -C ) such as cyclopropylmethyl). More preferably R17 is cyclopropylmethyl. More particularly, the preferred radicals of R7-B-A are: wherein R10 and R11 are as defined in which R10 and R11 are defined above and R7 is as defined above; hydrogen, C 1 -C 4 alkyl, C 1 -C 4 perfluoroalkyl, C 1 -C 4 alkyl, perfluoro-C 1 -C 4 alkyl, fluoro or chloro; wherein R15 and R16 are as in which R13 to R16 are defined above: as defined above; wherein R13 to R16 are as defined in which R15 is hydrogen or defined above; CI-C4 alkyl optionally containing oxygen in the chain or at the end of the chain; wherein R15 is hydrogen or wherein R10 and R11 are such as C1-C4 alkyl optionally containing oxygen as defined above, and v is 0 or 1; chain or at the end of the chain; those that R17 and R18 in i, j, k are as defined here before. Below are examples of radicals (a) to (k) radical radical (b) (the S anantiomer being preferred for fragments (a) and (b) radical (c) radical (d) radical (e) radical (f) radical (g) radical (h) radical (i) radical (j) radical (k) The preferred compounds according to the invention are as follows: (R, S) -2- [3 - [(2-amino-1-benzylethyl) amino] -6-methyl-2-oxo-1 (2H) -pyridinyl] -N- (1 H -indole-5- ilmethyl) acetamide; 2- [3- (3 - [(dimethylamino) methyl] phenethylamino) -6-methyl-2-oxo-1 (2 H) -pyrazinyl] -N- (1 H -indol-5-ylmethyl) acetamide; 2- [3-chloro-5- (3 - [(dimethylamino) methyl] phenethylamino) -2-methyl-6-oxo-1 (6H) -pyrazinyl] -N- (1 H -indol-5-ylmethyl) acetamide; 2- [3 - [(1 S) -1-benzyl-2- (dimethylamino) ethyl] amino-6-methyl-2-oxo-1 (2H) -pyrazinyl] -N- (1 H -indole-5- ilmethyl) acetamide; 2- [3 - [(1S) -1-Benzyl-2- (dimethylamino) ethyl] amino-5-chloro-6-methyl-2-oxo-1 (2H) -pyrazinyl] -N- (1 H-indole -5-ylmethyl) acetamide; 2- [3-. { [(2R, S) -3- (dimethylamino) -2-phenylpropyl] amino} -6-methyl-2-oxo-1 (2H) -pyrazinyl] -N- (1 H -indol-5-ylmethyl) acetamide; N- [(3-methyl-1H-indol-5-yl) methyl] -2- [6-methyl-3 - ([3 - [(methylamino) methyl] phenethyl] amino) -2-oxo-1 (2H ) -pyrazinyl] acetamide; 2- [3-. { [(1 S) 1 -benzyl-2- (dimethylamino) ethyl] amino} -6-methyl-2-oxo-1 - (2H) -pyrazinyl] -N- [(6-methyl-1 H -indazol-5-ylmethyl] acetamide; 2- [3- { [3- (3 -zetidinyl) phenethyl] amino.} - 6-methyl-2-oxo-1 (2H) -pyrazinyl] -N- [(3-methyl-1 H -indol-5-yl) methyl] acetamide; N- [ (3-methyl-1 H-indol-5-yl) methyl] -2- [6-methyl-3 { [3- (1-methyl-3 azetidinyl) phenethyl] amino} -2 -oxo-1 (2H) -pyrazinyl] acetamide; 2- [3 - [(3- {[[(2-methoxyethyl) amino] methyl} phenethyl] amino] -6-methyl-2-oxo; -1 (2H) -pyrazinyl] -N- [(3-methyl-1 H -indol-5-yl) methyl] acetamide; 2- [3- ( { [(2R) 1 - (cylpropylmethyl) pipOlidinyl] methyl.}. Amino) -6-methyl-2-oxo-1 (2H) -pyrazinyl] -N- [(3- methyl-1 H-indol-5-yl) methyl] acetamide; 2- [3- ( { [(2R) -1-cyclopentylpyrrolidinyl] methyl.}. Amino) -6-methyl-2-oxo-1 (2H) -pyrazinyl] -N- [(3-methyl-1 H-indol-5-yl) methyl] acetamide; N- f [(3-methyl-1 H -indol-5-yl) methyl] -2- [6-methyl-2-oxo-3- ( { [(2R) -1-tetrahydro-2H-pyran -4-ylpyrrolidinyl] methyl.} Amino) -1 (2H) -pyrazinyl] acetamide; N- [(3-methyl-1 H-indol-5-yl) methyl] -2- [6-methyl-3 - [( { (2R) -1 - [(1-methylcyclopropyl) methyl] pyrrolidinyl} methyl) amino] -2-oxo-1- (2H) -pyrazinyl] acetamide; 2- [3- ( { [(2R) -1- (2-methoxyethyl) pyrrolidinyl] methyl.} Amino) -6-methyl-2-oxo-1 (2H) -pyrazinyl] -N- [( 3-methyl-1 H-indol-5-yl) methyl] acetamide; N- [(3-methyl-1 H-indol-5-yl) methyl] -2- [6-methyl-3- ( { [(2R) -1-Neopentylpyrrolidinyl] methyl} amino) -2 -oxo-1- (2H) -pyrazinyl] acetamide; 2- [3- ( { [(2R) -1-Isobutylpyrrolidinyl] methyl.}. Amino) -6-methyl-2-oxo-1 (2H) -pyrazinyl] -N- [(3-methyl-1 H-indol-5-yl) methyl] acetamide; 2- [3- ( { [(2R) -1- (2-methoxyethyl) pyrrolidinyl] methyl.} Amino) -6-methyl-2-oxo-1 (2H) -pyrazinyl] -N- [( 3-methyl-1 H-indol-5-yl) methyl] acetamide; 2- [3- ( { [(2R) -1-Cyclopentylpyrrolidinyl] methyl.}. Amino) -6-methyl-2-oxo-1 (2H) -pyrazinyl] -N- [(3-methyl-1 H-indol-5-yl) methyl] acetamide; 2- [3- ( { [(2R) -1 - (cyclopropylmethyl) piperidinyl] methyl.}. Amino) -6-methyl-2-oxo-1 (2H) -pyrazinyl] -N- [(3- methyl-1 H-indol-5-yl) methyl] acetamide; and pharmaceutically acceptable salts thereof.

Preferably the compounds of the invention are selected from: 2- [3- (3- [(dimethylamino) methyl] phenethylamino) -6-methyl-2-oxo-1 (2H) -pyrazinyl] -N- (1 H-indole -5-ylmethyl) acetamide; 2- [3- [(1S) -1-benzyl-2- (dimethylamino) ethyl] amino-6-methyl-2-oxo-1 (2H) -pyrazinyl] -N- (1 H -indol-5-ylmethyl) acetamide; N- [(3-methyl-1 H -indol-5-yl) methyl] -2- [6-methyl-3 - ([3 - [(methylamino) methyl] phenethyl] amino) -2-oxo-1- (2H) -pyrazinyl] acetamide; 2- [3- [(3- { [2-methoxyethyl) amino] methyl} phenethyl) amino] -6-methyl-2-oxo-1 (2H) -pyrazinyl] -N - [(3-methyl-1 H -indol-5-yl) methyl] acetamide; 2- [3- ( { [(2S) -1- (cyclopropylmethyl) pyrrolidinyl] methyl} amino) -6-methi-2-oxo-1 (2H) -pyrazinyl] -N- [(3-methyl-1 H-indol-5-yl) methyl] acetamide; 2- [3- ( { [(2R) -1-cyclopentyl-pyrrolidinyl] methyl.}. Amino) -6-methyl-2-oxo-1 (2H) -pyrazinyl] -N- [(3-methyl) -1H-indol-5-yl) methyl) acetamide; 2- [3- ( { [(2R) -1-Isobutylpyrrolidinyl] methyl.}. Amino) -6-methi-2-oxo-1 (2H) -pyrazinyl] -N - [(3-methyl) -1 - / - indol-5-yl) methyl] acetamide; and pharmaceutically acceptable salts thereof. It will be appreciated that many compounds of formula (I) contain one or more asymmetric centers and, therefore, will exist in the form of optical isomers. The present invention also includes within its scope all enantiomers and mixtures thereof, including racemic mixtures thereof. In addition, all possible diastereomeric forms (individual diastereomers and mixtures thereof) of the compounds of formula (I) are included within the scope of the invention. Thus, for example, when R8 and R9 are different, then the C * of the following fragments: BC * (R8) (R9) -, B-CH2-C * (R8) (R9) -, BC * ( R8) (R9) -CH2-, B-CH2-C * (R8) (R9) - CH2-, BC * (R8) (R9) - CH2- CH2-, and B-CH2- CH2- C * (R8) ) (R9) -, will form an asymmetric center. It has been found that, in the compounds containing the fragment B-C * (R8) (R9) -, the S-enantiomer is substantially more active than the R-enantiomer. In radicals (a) and (b), the S-enantiomer is preferred; in radicals (i) and (j), the R-enantiomer (wherein the chiral carbon is indicated by an asterisk) is preferred; while in the radical (k), the S-enantiomer is preferred. A further aspect of the invention provides compounds of formula (loe): in which: R1 is hydrogen, C1-C4 alkyl, C1-C4 perfluoroalkyl, or alkyl C1-C4, fluoro or chloro; R2 is hydrogen, CH3 or CF3; R3 is hydrogen, C1-C4 alkyl, C1-C4 perfluoroalkyl, C1-C4alkyl, fluoro or chloro; R 4 is hydrogen or C 1 -C 4 alkyl; R5 is hydrogen or C1-C4 alkyl; R6 is hydrogen, cyclopropyl, C1-C4 alkyl, C4 perfluoroalkyl, fluoro or chloro; or R5 and R6 together form a chain that forms a bridge containing 2 or 3 carbon atoms; And it is hydrogen, chlorine, fluoro, bromo, methyl or CF3; W and X are independently CH, CF, CCI or N; BA- is any one of the following fragments: BC (R8) (R9) - B-CH2- (R8) (R9) - BC (R8) (R9) - CH2- B-CH2- (R8) (R9) - CH2- BC (R8) (R9) - CH2- CH2- B-CH2- CH2-C (R8) (R9) - in which: R8 and R9 are independently hydrogen, - (CH2) mN (R10) (R11) , -CH2O- (CH2) 2N (R10) (R11), or R8 and R9 together form a ring of 4 to 6 members containing a nitrogen atom present as N (R12); and m is 0, 1 and 2 (preferably, m = 1) except when A represents -C (R8) (R9) -, when m is 1 or 2; R10 and R1 are independently selected from hydrogen or C1-C4 alkyl optionally containing an oxygen atom in the chain or at the end of the chain; or R10 and R11, together with the nitrogen atom to which they are linked, form a 4 to 6 membered saturated heterocyclic ring which, when the ring is six members, may optionally contain an oxygen atom or a nitrogen atom present as N (R12); R 12 is hydrogen or C 1 -C 4 alkyl optionally containing an oxygen atom in the chain or at the end of the chain; B is phenyl or a 5- or 6-membered heterocyclic aromatic ring containing up to two heteroatoms independently selected from oxygen, sulfur and nitrogen; R7 is one or more of hydrogen, C1-C4 alkyl, perfluoroalkyl Cr C4, C1-C4alkyl, perfluoro- C1-C4alkyl, fluoro, chloro, or any one of the following fragments: -O- (CH2) 2N (R10 ) (R11) wherein R10 and R11 are as defined above, - (CH2) rC (R13) (R14) - (CH2) sN (R15) (R16) wherein rys are independently 0, 1 or 2, and R13 and R14 are independently hydrogen or C1-C4 alkyl, or R13 and R14 together with the carbon atom to which they are linked form a saturated carbocyclic ring of 4 to 6 members; R15 and R16 are independently selected from hydrogen or C1-C4 alkyl optionally containing an oxygen atom in the chain or at the end of the chain, or together R15 and R16, together with the nitrogen atom to which they are bound, form a 4 to 6 membered saturated heterocyclic ring; or one of R13 or R14, and one of R15 or R16, together with the carbon and nitrogen atoms to which they are bound, form a saturated heterocyclic ring of 4 to 6 members, in which case the other radical of R13 or R14 is hydrogen or C 1 -C 4 alkyl, and the other radical of R 15 or R 16 is hydrogen or C 1 -C 4 alkyl optionally containing an oxygen atom in the chain or at the end of the chain; or wherein R7-B represents any one of the following bicyclic fragments in which R12 is as defined above with the proviso that R7, R8 and R9 can not all be hydrogen, and only one of R7, R8 and R9 contains a nitrogen atom or, when R8 and R9 together form a ring, said ring contains only one nitrogen atom with the ^ R12 condition that one of R8 and R9 may be the following fragment containing two nitrogen atom: and pharmaceutically acceptable salts thereof. Another aspect of the present invention provides processes for the preparation of compounds of the general formula (I), their pharmaceutically acceptable salts and acceptable solvates of any kind, as illustrated below. It will be appreciated by persons skilled in the art that, within the various methods described, the order of the synthetic steps employed may be varied and will depend, among others, on factors such as the nature of other functional groups present on a particular substrate, the availability of key intermediates, and the strategy of the protective group (if any) to adopt. Clearly, such factors will also influence the choice of reagent to be used in said synthetic steps. It will also be appreciated that various standard transformations, within certain compounds of formula (I), will provide other compounds of formula (I); examples are reductive alkylations, of N-unsubstituted and N-monosubstituted amines, with an appropriate aldehyde or ketone, and dealkylation of N-methylamines by treatment with oc-chloroethyl chloroformate, followed by methanolysis. In addition, those skilled in the art will be informed of the variations and alternatives to those methods described hereinafter in the Examples and Preparations section, which will allow obtaining the compounds defined by the formula (I).

Accordingly, in a further aspect of the present invention there are provided processes for preparing the compounds of general formula (I) and (loe), and pharmaceutically acceptable salts thereof, which comprise: (a) coupling an acid of formula (II) ) with a heterocyclic amine of formula (III) (b) coupling a heterocycle of formula (XII) (X I I) wherein Z is a suitable leaving group, such as halogen, with an amine of formula (V) R7-B-A-NH2 (V); or (c) coupling a heterocycle of formula (1c) with a carbonyl of formula (XXXVII) R -BA? -C (0) -Rβ (XXXVII) wherein A-, is C (R8) (R9), CH2C (R8) (R9) or C (R8) ( R9) CH2 in the presence of a reducing agent; and optionally converting to a pharmaceutically acceptable salt.

General Method A The compounds of the general formula (la) (Scheme I) can be prepared by coupling the acid (II) with the appropriate heterocyclic amine (H1) (Scheme 1). The coupling can be performed using conventional amide linkage forming techniques, in particular any one of various amino acid coupling variations. For example, the acid (II) can be activated using a carbodiimide such as 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, optionally in the presence of 1-hydroxybenzotriazole hydrate, or a catalyst such as 4-dimethylaminopyridine. Such couplings can be carried out in a suitable solvent such as dichloromethane or N, N-dimethylacetamide, optionally in the presence of a tertiary amine such as N-methylmorpholine or N, N-diisopropylamine at 0 ° C. The compounds of the general formula (II) can be prepared from compounds of the general formula (IV) by hydrolysis or hydrogenation of the carboxylic acid ester and dechlorination of the pyrazinone ring (in which R17 is an aryl radical or a radical alkyl susceptible to hydrolysis to form the corresponding carboxylic acid). This conversion can be carried out in a single step when the ester of the carboxylic acid is removed by catalytic nitrogenation (for example, R17 = benzyl). For example, a compound of the general formula (II) can be obtained from a compound of the general formula (IV), wherein R17 = benzyl, by treatment with a catalytic amount of Pearlmans catalyst under a hydrogen atmosphere (preferably 413.64 kPa) in a suitable solvent such as methanol, at room temperature for 2 to 24 hours. Alternatively, a compound of the general formula (IV) can be subjected to hydrolysis of the ester according to the abundant methods currently available. For example, treatment with lithium hydroxide or sodium hydroxide in a mixture of methanol, THF and water, at room temperature. The subsequent reduction of the chloro substituent of the pyrazinone can be carried out by treatment with a suitable active metal catalyst under a hydrogen atmosphere, for example: Pearlmans catalyst under a hydrogen atmosphere as described above, or by hydrogenation methodology by transfer, for example: treatment with ammonium formate in methanol, ethanol or isopropanol in the presence of a catalytic amount of palladium on carbon catalyst. The compounds of the general formula (IV) can be prepared by treating compounds of the general formula (VI) with a primary amine (V) in a solvent such as ethyl acetate or THF at reflux for 6 to 24 hours in the presence of a suitable tertiary amine base, for example triethylamine or N, N-diisopropylethylamine. The compounds of the general formula (VI) can be prepared from a suitable glycine ester derivative (VIII) according to the Hoomaert method (J. Het Chem. 1983, 20, 919).

SCHEME 1 - ^ -NH2 Et3N R7 'Ethyl acetate (V) The compounds of the general formula (III) can be prepared by reduction of compounds of the general formula (IX) (Scheme 2). Such reduction can be done with a variety of reagents; for example, lithium aluminum hydride or hydrogen on Raney Nickel catalyst. Preferred conditions involve the use of Raney Níquiel with methanol as solvent containing 20% ammonia. The reaction is carried out at a temperature of up to 50 ° C in an autoclave charged with hydrogen at a pressure of up to 5 MPa. The compounds of the general formula (IX), in which W = CH, V = C and R1 = R2 = R3 = R4 = H, are commercially available, while the compounds of the general formula (IX) in which W = N, V = C or N, R1 = R2 = R4 = H and R3 = Me, can be prepared from the precursor (X) according to the HD method Porter and W.D. Peterson, (Org Synthesis, Coll Vol lll p660). The compounds of the general formula (IX), in which W = CH, V = C, R2 = CH3 and R1 = R3 = R4 = H, can be prepared from commercially available 5-cyano-1 H-indole by formylation at position 3 according to the method of P.N. James and H.R. Snyder, (Sinthesis, Coll Vol IV p539), followed by simultaneous reduction of the formyl and cyano groups using a suitable reducing agent such as lithium aluminum hydride in an aprotic solvent, for example tetrahydrofuran or diethyl ester.

SCHEME 2 General Method B An alternative method of preparing compounds of the general formula (la) (Scheme 3) involves the dechlorination of compounds of the general formula (XI) by reduction. Typically this process can be carried out by treatment with a suitable active metal catalyst under a hydrogen atmosphere, for example, Pearlmans catalyst under a hydrogen atmosphere as described above (General Method A); or by transfer hydrogenation methodology, for example: treatment with ammonium formate in methanol, ethanol or isopropanol in the presence of a catalytic amount of palladium on carbon catalyst (General Method A).

In Scheme 3, Y has been indicated as chlorine according to a preferred embodiment, but it will be appreciated that the reaction scheme is applicable to other components of Y and, therefore, as a general principle, and may be indicated generally in the Scheme 3. Further, the leaving group of chlorine (in position 3) in scheme 3, as a general principle, may be indicated as a "leaving group" (formula XII), such as a halogen. The compounds of the general formula (XI) can be prepared by treating the compounds of the general formula (XI IA) with a primary amine of the general formula (V), according to the conditions described above in General Method A. The compounds of the general formula (XI IA) can be prepared from the carboxylic acid (XIII) and a suitable amine of the general formula (III), according to the general methods described above (General Method A). The compound (XIII) can be prepared from a compound of the general formula (VI), according to the abundant methods for the hydrolysis of a carboxylic acid ester (General Method A).

SCHEME 3 The amines of the general formula (V) can be prepared from a variety of precursors. Preferred routes include preparation from the corresponding nitrile, as illustrated by the formula (XIV) (scheme 4). The preparation of the amines (Va) from the nitriles (XIV) can be achieved by reduction of the appropriate nitriles using Raney nickel under a hydrogen atmosphere. The compounds of the general formula (XVI) can be prepared from compounds of the general formula (XV) by palladium-catalyzed functionalization of the halo-substituent, preferably a bromo-substituent (shown for convenience). For example, treatment of the compound (XV) with a palladium catalyst (palladium acetate or tri (triphenylphosphine) palladium) in the presence of sodium formate under an atmosphere of carbon monoxide gives the compound (XIV), wherein R7 = CHO. Subsequent treatment with a primary or secondary amine in the presence of a suitable reducing agent (e.g., sodium triacetoxyborohydride) in a protic solvent system (e.g., acetic acid, methanol) yields a compound of the general formula (XIV), wherein R7 = CH2NR-? 5R? 6. Alternatively, the reaction can be carried out under conventional catalytic hydrogenation conditions. This synthetic methodology allows the preparation of preferred compounds of type (d). In a related methodology, palladium-catalyzed cross-coupling of (XV) with the kincate derived from N-Boc-3-iodoazetidine, by direct analogy to the S. Billote procedure (Synlett, 1998, p379), gives a compound of the general formula (XIV) wherein R7 = N-BOC-azetidin-3-yl. Deprotection of nitrogen, using standard methodology such as protonolysis, using trifluoroacetic acid or hydrogen chloride and, if required, subsequent reductive alkylation with an appropriate aldehyde or ketone, allows the preparation of preferred compounds of type (g). In the case of an aldehyde or ketone precursor, the reaction can be carried out in the presence of a suitable reducing agent (for example, sodium triacetoxyborohydride) in a protic solvent system (for example, acetic acid, methanol). Alternatively, the reaction can be carried out using conventional catalytic hydrogenation conditions. The intermediate (XV) can be transmetalated with an appropriate organolithium, such as butyl lithium, and can be reacted in situ with an N-substituted 2-pyrrolidone, and the resulting intermediate (XV), with R7 = a fragment of 2. N-substituted hydroxypyrrolidin-2-yl can be directly reduced using, for example, platinum oxide under a hydrogen atmosphere, by direct analogy with the synthetic methodology of H. Malmberg, M. Nilisson and C. Ullenius, (Acta Chemica Scandlnavia, B, 35, 1981, p625), to allow the preparation of the intermediate (Va), with R7 = a fragment of N-substituted pyrrolidin-2-yl. This synthetic methodology allows the preparation of preferred compounds of type (g).

SCHEME 4 (XV) (Xiv) (Va) The amines of the general formula (Vb) can be prepared from a variety of precursors. Preferred routes include preparation from amino acid derivatives (XVI) (Scheme 5) and from nitrile derivatives (XIV). The preparation from amino acid derivatives (XVI), in which P is a suitable protecting group for an amine (preferably, BOC), can be carried out by reduction of the amide bond using lithium aluminum hydride, borane or borohydride. lithium in the presence of trimethylsilyl chloride in an aprotic solvent such as diethyl ether or tetrahydrofuran. The subsequent removal of the nitrogen protecting group can be carried out using trifluoroacetic acid in dichloromethane, or dichloromethane saturated with HCl. The amides of the general formula (XVI) can be prepared by coupling the appropriate amine HNR10R11 with the commercially available amino acid derivatives (XVII). The coupling can be carried out using conventional amide bond formation techniques, in particular any one of several variations of amino acid couplings described under General Method A. This synthetic methodology allows the preparation of preferred compounds of type (a).

SCHEME 5 XVII) (XVI) (Vb) The amines of the general formula (Vc) (Scheme 6) can be prepared by treatment of the compounds of the general formula (XVIII), wherein P is a suitable nitrogen protecting group (preferably, BOC) with, for example, bromoacetonitrile and a suitable base in an aprotic polar solvent such as tetrahydrofuran, followed by reduction of the nitrile and removal of the nitrogen protecting group using, for example, ether saturated with HCl or trifluoroacetic acid in dichloromethane. The compounds of the general formula (XVIII) are commercially available. This synthetic methodology allows the preparation of preferred compounds of type (b).

SCHEME 6 The amides of the general formula (Vd) (Scheme 7) can be prepared from the means of the general formula (XIX) by reduction according to the methods described above. The compounds of the general formula (XIX) can be prepared from compounds of the general formula (XX) by reacting compounds of the general formula (XX) with sodium cyanide in a suitable solvent, for example, tetrahydrofuran or acetonitrile.

The compounds of the general formula (XX) can be prepared from compounds of the general formula (XXI) by bromination using, for example, N-bromosuccinimide, as explained by L. Horner and EH Winkelmann in Angewandte Chemie 1959, 71, 349. Intermediates (XXI) can be prepared from compounds of the general formula (XXII) by nucleophilic attack on the carbon atom of the cyano group, according to the Ciganeck method (J. Org. Chem. 1992, 57, 4521) or the Calderwood method, (Tetrahedron Letters, 1997, 38, 1241). This synthetic methodology allows the preparation of preferred compounds of type (b).

SCHEME 7 (XXII) (XXI) (XX) (Vd) (XIX) The amines of the general formula (Ve) (Scheme 8) can be prepared by reduction of the commercially available nitrile (XXIII) using the method of F. Vogtñe et al. (Chem Ber, 1984, 117, 1487). One of the amines in the intermediate (XXIV) can be protected with a suitable protective P group (preferably, BOC) using the method of Adamczyk et al. (Org Prep Proc Int, 1998, 30 (3) 339) or the method of Krapcho et al. (Syn Comm, 1990, 20, 2559) to give compounds of the general structure (XXV). Reductive animation of unprotected primary amine of compounds of the formula (XXV), and subsequent removal of the protecting group P, gives compounds of the general formula (Ve). This synthetic methodology allows the preparation of preferred compounds of type (e).

SCHEME 8 (XXIII) (XXIV) The amines of the general formula (vf) (scheme 9) can be prepared from intermediates of the general formula (XXVI) by reduction of the nitrile group using, for example, Raney nickel in ethanol saturated with ammonia. The compounds of the general formula (XXVI) can be prepared from the compounds of the general formula (XXVII) by removal of the nitrogen-protecting group P and subsequent reductive amination. The compounds of the general formula (XXVII) can be prepared by alkylation of the phenol (XXVIII) (or hydroxymethylphenyl) with a suitable protected alcohol (XXIX) according to the method of O. Mitsonubu, (Synthesis, 1981, 1). Compound (XXVIII) is prepared from (XXX) commercially available by demethylation using, for example, a solution of boron tribromide in dichloromethane. This methodology is also applicable for compounds in which there is a methylene between benzene and oxygen, as shown in the accompanying examples 27 and 28. This synthetic methodology allows the preparation of preferred compounds of type (h).

SCHEME 9 ; xxx) (XXVIII) PNHV "OH (XXIX) (XXVI) (XXVII) R1 (Vf) The amines of the general formula (Vg) (scheme 10 and scheme 11) can be prepared according to the method described by J. Permattan et al (Tett.

Let, 1991, 32, p7183). For example, commercially available D-prolinamide (XXXI) can be treated with an aldehyde in the presence of a suitable reducing agent (for example, sodium triacetoxyhydrohydride) in an aprotic solvent system (for example, acetic acid or methanol), or alkylation with a suitable alkylating agent as described by J.

Permattam et al. (Tett.Let, 1991, 32, p7183) to give a compound of formula (XXXII). The subsequent reduction of the amide with a suitable reducing agent (e.g., lithium aluminum hydride) in a suitable aprotic solvent (e.g., diethyl ether or tetrahydrofuran), as described by J. Permattam et al. (Tett. Let, 1991, 32, p7183), gives a compound of the general formula Vg. This synthetic methodology allows the preparation of preferred compounds of type (i) and (j).

SCHEME 10 (XXXI) (XXXII) (Vg) Preferred compounds of type (k) can be prepared according to the general method described in scheme 11. The carboxylic acid (XXXII) can be prepared according to the method described by G. R. Brown et al. in J. Chem. Soc. Perkin Trans I, 1985, 2577. The subsequent formation of the primary amide (XXXIV) can be performed using a suitable carboxylic acid activating agent (e.g., oxalyl chloride) in a suitable solvent system (e.g., dichloromethane with dimethylformamide moieties) Reduction of (XXXIV) using a suitable reducing agent (e.g., lithium aluminum hydride) in an aprotic solvent (e.g., diethyl ether or tetrahydrofuran) provides compounds of the type ( k).

SCHEME 11 (XXXII) (XXXIV) (Vg) General Method C As a general principle, the pyridone derivatives of formula (I) - that is, formula (1b) in scheme 12 - can be formed by coupling the heterocycle of formula (1c) with a carbonyl of formula (XXXVII) in the presence of a reducing agent (see here above). The compounds of the general formula (Ib) can also be prepared by coupling the acid (XXXV) with the appropriate heterocyclic amine (III) (scheme 12). Coupling can be performed using conventional amide linkage forming techniques, in particular in any of several variations of amino acid couplings. For example, the acid (XXXV) can be activated using a carbodiimide such as 1-ethyl-3- (3-dimethylamino-1-propyl) carbodiimide, optionally in the presence of 1-hydroxybenzotriazole, or a catalyst such as 4-dimethylaminopyridine. Such couplings can be carried out in a suitable solvent such as dichloromethane, optionally in the presence of a tertiary amine such as N-methylmorpholine or N, N-diisopropylamine at 0 ° C. The compounds of the general formula (XXXV) can be prepared from compounds of the general formula (XXXVI), in which P is a suitable carboxylic acid protecting group (preferably, P is the tere-butyl group), by hydrolysis of the carboxylic acid ester using, for example if P = tere-butyl, trifluoroacetic acid in a suitable solvent such as dichloromethane, for example, at a temperature between 0 ° C and room temperature. The compounds of the general formula (XXXVI) can be prepared by the reaction of the amine (XXXVIII) with the desired carbonyl compound (XXXVII) in the presence of a suitable reducing agent. Preferred conditions involve the use of sodium triacetoxyborohydride in tetrahydrofuran and acetic acid. The compound (XXXVIII) can be prepared from the carbamate (XXXIX) by elimination of the carbamate protecting group using a suitable catalyst under a hydrogen atmosphere. Typical conditions involve the use of 10% palladium on charcoal at room temperature, in ethyl acetate under a hydrogen pressure of 13,789 kPa at 137,894 kPa. The compound (XXXIX) can be prepared by alkylation of the compound (XXXX) using a suitable protected haloacetic acid derivative (XXXXI), wherein P is the acid protecting group (preferably, P = tere-butyl) and a suitable base , for example, potassium carbonate, sodium carbonate, cesium carbonate, sodium hydride or potassium hydride, in a polar solvent such as acetone, THF, dimethylformamide or 2-butanone. Preferred conditions involve the use of potassium carbonate in 2-butanone at room temperature. The compound (XXXXI) is prepared from commercially available (XXXXII) following the procedure described, for a forthcoming compound, by D. J. Wolanin and C. A. Véale et al., (J. Med Chem 1994, 37, 3303).

SCHEME 12 XXI) [XXXVIII] (XXXIX) R7-kf "R8 THF, AoOH, v, |, NaBH (OAc) 3 (???) (XXXVI) (XXXV) The carbonyl compounds of the general formula (XXXVII) can be prepared by oxidation of alcohols of the general formula (XXXXIII), in which Ai is C- (R8) (R9), CH2C (R8) (R9) or C (R8) ) (R9) CH2 (scheme 13). Such oxidation can be performed by a variety of known agents to oxidize an alcohol, including Cr03 / H2S? 4 in acetone (Jones reagent), CrO 3Pyr2 (Collins reagent), MnO2 or the Swern or Dess-Martin methods. A preferred method is that of Swern which involves the use of dry DMSO and oxalyl chloride in dichloromethane as solvent at -60 ° C under nitrogen atmosphere.

SCHEME 13 (XXXXIII) (XXXVII) General Method D Compounds of the general formula (XXXVII) can also be prepared from compounds of the general formula (XXXVIII) by treatment with a suitable triflate of the general formula (XXXXIV) in the presence of a base; for example, pyridine, triethylamine or N-ethyldiisopropylamine, in a non-protic solvent such as dichloromethane, THF or diethyl ether (scheme 14). Preferred conditions for this reaction involve the use of N-ethyl-diisopropylamine as the base, in dichloromethane .

SCHEME 14 (XXXVII) The triflates of the general formula (XXXXIV) can be prepared from the alcohols of the general formula (XXXXV) by treatment with anhydro trifluoromethanesulfonic acid in the presence of a suitable base; for example, pyridine, triethylamine or N-ethyl-diisopropylamine, in a non-protic solvent such as dichloromethane, THF or diethyl ether. Preferred conditions include the use of trifluoromethanesulfonic anhydride in dichloromethane with pyridine as the solvent at 0 ° C to room temperature (scheme 15).

SCHEME 15 (XXXXV) (XXXXIV) (XXXXVI) (XXXXVII) (XXXXVHI) The preparation of compounds of the type of example 24 (ie in which the pyrrolidine is attached in the 3-position to the methylamino moiety), can be prepared according to scheme 16. The amines of the general formula (XXXXVIII) can be prepared according to the general method described in scheme 16. The mesylate (XXXXVI) can be prepared in a 2-step process from (3R) -pyrrolidinol, by adequate protection of the amine (preferably, Boc), following methods such as that described in "proctective groups in Organic synthesis", by TW Greene and PGM Wutz (1991), or "Protecting Groups" by PJ Kocienski (1994), followed by mesylation of intermediate alcohol. The alcohol is treated with methanesulfonyl chloride in the presence of a suitable base, such as triethylamine, in a non-protic solvent such as dichloromethane, between 0 ° C and room temperature. The amines of the general formula (XXXXVII) can be prepared by reacting compounds of the formula (XXXXVI) with potassium cyanide in a suitable high-boiling solvent, preferably DMSO, between room temperature and 100 ° C. The amines of general formula (XXXXVIII) can be obtained from the nitrile of formula (XXXXVII) by reduction using Raney® nickel in an alcoholic solvent (eg, methanol), under an atmosphere of hydrogen.

SCHEME 17 (Ll) (Lll) (XXXXXII) This synthetic methodology below allows the preparation of preferred compounds of the analogous type to Example 29. Parallel-catalyzed cross coupling of (XV) with vinyl-tributyltin, by analogy with the methods described in (Org React, 1997; 50) gave the vinyl acetonitrile, and subsequent vinyl amine (XXXXIX) employed a selective reducing agent (e.g., AICI3 / LiAIH) in a non-protic solvent (e.g., tetrahydrofuran) . The protection of the amine with a suitable protecting group (preferably CBz) following methods described in "Protective groups in organicsynthesis", by TW Greene and PGM Wutz (1991), or "Protecting Groups" by PJ Kocienski (1994), followed by asymmetric aminohydroxylation (AA), according to the method of O'Brien et al (J. Chem. Soc. Perk, Trans 1, 1998, 2519) provided the hydroxyamine of general formula (Ll). Subsequent methylation, using an alkylating agent (e.g., methyl iodide), under phase transfer conditions, using a catalyst such as benzyltriethylammonium chloride, provided the compound of general formula (Lll). Removal of the initial protective group from nitrogen can be achieved, for example, by hydrogenation in the presence of a palladium on carbon catalyst in methanol, at a pressure of typically 103,410 kPa. The compounds of formula (I) and the various intermediates and reagents required for the processes described hereinbefore, when neither available commercially nor subsequently described, can be obtained either by analogy with the reactions described in the sections of the examples and preparations. or by conventional synthetic procedures, according to the standard textbooks of organic chemistry or preceding literature, from readily accessible starting materials using the appropriate reagents and reaction conditions. The new intermediates described herein form a further aspect of the invention. When there is a keto / enol tautomerism, the keto and enol forms will be claimed separately and together (as a mixture). Suitable pharmaceutically and physiologically acceptable salts will be apparent to those skilled in the art, and include, for example, acid addition salts formed with inorganic acids, for example hydrochloric, hydrobromic, sulfuric, nitric or phosphoric acids.; and organic acids, for example, succinic, maleic, acetic, fumaric, citric, tartaric, benzoic, p-toluenesulfonic or naphthalenesulfonic acid. Other non-physiologically acceptable salts, for example, oxalates, can be used in the isolation, for example, of compounds of formula (I), and are included within the scope of the invention. The acid addition salts of the compounds of formula (I) can be prepared in a conventional manner. For example, a solution of the free base is treated with the appropriate acid, either neat or in a suitable solvent, and the resulting salt is isolated either by filtration or by evaporation under reduced pressure of the reaction solvent. The pharmaceutically acceptable base addition salts can be obtained in an analogous manner by treating a solution of a compound of formula (I) with the appropriate base. Both types of salts can be formed or interconverted using ion exchange resin techniques. The present invention also includes pharmaceutically acceptable solvates (including hydrates) and polymorphs of the compounds of the invention. It will further be appreciated that certain moieties known as "pro-moieties" may be placed, for example as described in "Design of Prodrugs" by H. Bundgaard, Elsevier, 1985 (whose description is incorporated herein by reference), on appropriate functionalities of the compounds of formula 1. Such prodrugs are included within the scope of the invention. The present invention also includes compounds labeled with radioisotopes, which are identical to those set forth in formula (I), but with the difference that one or more atoms are replaced by an atom having an atomic mass or mass number different from the mass Atomic or mass number usually found in nature. Examples of isotopes that can be incorporated into the compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as 2H, 3H, 13C, 14C, 15N, 180, 170, 31P, 35S , 18F and 36CI, respectively. The compounds of the present invention and the pharmaceutically acceptable salts of said compounds, or of those containing the aforementioned isotopes and / or other isotopes of other atoms, are within the scope of the invention. Certain radiolabelled compounds of the present invention, for example those in which radioactive isotopes such as 3H and 14C are incorporated, are useful in drug and / or substrate tissue distribution assays. Particularly preferred are tritiated isotopes, ie 3 H and carbon-14, ie 14 C, for their ease of preparation and detectability. In addition, substitution with heavier isotopes, such as deuterium, ie, 2H, can produce certain therapeutic advantages resulting from increased metabolic stability, for example, increased in vivo half-life, or reduced dose requirements, and therefore , in some circumstances they may be preferred. The compounds of formula I of this invention labeled with radioisotopes, and prodrugs thereof, can generally be prepared by carrying out the procedures described in the schemes and / or in the examples and preparations below, substituting a readily available reagent labeled with radioisotopes. by a reagent not labeled with radioisotopes. In therapy, the compounds of formula (I), their pharmaceutically acceptable salts, and pharmaceutically acceptable solvates of any entity, can be administered alone, but will generally be administered in a mixture with a pharmaceutically selected carrier in relation to the route of administration and practice. standard pharmaceutical that are intended. Preferably, they are administered orally in the form of tablets containing excipients such as starch or lactose, or in capsules or ovules, either alone or in a mixture with excipients, or in the form of elixirs, solutions or suspensions containing flavoring or coloring agents. They can also be injected parenterally, for example intravenously, intramuscularly or subcutaneously. For parenteral administration, they are best used in the form of a sterile aqueous solution which may contain other substances, for example, enough salts or glucose to make the solution isotonic with the blood. For buccal or sublingual administration, they can be administered in the form of tablets or tablets, which can be formulated in a conventional manner. for oral, parenteral, buccal and sublingual administration to human patients, the daily dose level of the compounds of formula (I), and their pharmaceutically acceptable salts and solvates, may contain from 1 to 1,000 mg (in single or divided doses) . Thus, the tablets or tablets may contain from 0.5 to 500 mg of active compound for single administration, or two or more at the same time, as appropriate. In any case, the doctor will determine the actual dose, which will be the most appropriate for an individual patient, and will vary with the age, weight and response of the particular patient. The above doses are examples of the middle case; Of course, there may be individual circumstances in which higher or lower doses are needed, and such doses are within the scope of this invention. The following formulation examples are illustrative only and are not intended to limit the scope of the invention. "Active ingredient" means a compound according to formula 1, or a pharmaceutically acceptable salt thereof.

Formulation 1: A tablet is prepared using the following ingredients: Quantity (mq / tablet) Active ingredient 250 Cellulose, microcrystalline 400 Silicon dioxide, pyrolysis 10 Stearic acid 5 Total 665 mq The compounds are mixed and compressed to form tablets weighing, each 665 mg. Formulation 2: An intravenous formulation can be prepared as follows: Active ingredient 100 mg Isotonic saline solution 1,000 ml Other aspects of the invention are as follows below. (i) a pharmaceutical composition, comprising a compound of formula (I), a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier. (I) a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use as a medicament. (iii) use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the curative or prophylactic treatment of deep vein thrombosis (DVT) after surgery, a major medical condition , paralysis, malignant disease, trauma of prolonged immobilization, application of plaster on the lower extremities, or fractures of the lower extremities or pelvis; Recurrent DVT; DTV during pregnancy when there is a previous history of it; reocclusion after thrombolytic therapy; chronic arterial obstruction; peripheral vascular disease; acute myocardial infarction; unstable angina; atrial fibrillation; thrombotic stroke; passenger ischemic attacks; disseminated vascular disease; coagulation in extracorporeal circuits; occlusion of arteriovenous shunts and blood vessel grafts (including coronary artery bypass grafts); restenosis and occlusion after angioplasty; neurodegenerative disorders; inflammatory disorders; or scarring. (iv) a method to treat a mammal (including a human), to cure or prevent deep vein thrombosis (DVT) after surgery, major medical illness, paralysis, malignant disease, prolonged immobilization trauma, application of plaster in the lower extremities, or fractures of the lower extremities or pelvis, recurrent DVT; DVT during pregnancy when there is a previous history of it; reocclusion after thrombolytic therapy; chronic arterial obstruction; peripheral vascular disease; acute myocardial infarction; unstable angina; atrial fibrillation; thrombotic stroke; passenger ischemic attacks; disseminated intravascular coagulation; coagulation in extracorporeal circuits; occlusion of arteriovenous shunts and blood vessel grafts (including coronary artery bypass grafts); restenosis and occlusion after angioplasty; neurodegenerative disorders; inflammatory disorders; or scarring; which comprises treating said mammal with an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof. It will be appreciated that all references here to treatment include curative, palliative and prophylactic treatment. The syntheses of the compounds of the invention, and of the intermediates for use therein, are illustrated by the following examples. The purity (Rf) of the compounds was routinely monitored by thin layer chromatography using Merck Kieselgel 60 F25 plates and the following solvent systems (SS): 1. isobutylmethyl ketone: glacial acetic acid: water, 2: 1: 1 (upper phase); 2. hexane: ethyl acetate, 1: 1; 3. hexane: ethyl acetate, 7: 3; 4. dichloromethane: methanol: ammonia accuse 0.880, 85: 15: 2; 5. dichloromethane: methanol: aqueous ammonia 0.880, 84: 14: 2; 6. hexane: ethyl acetate, 6: 4; 7. Dichloromethane: methanol: aqueous ammonia 0.880, 93: 7: 1; 8. dichloromethane: methanol, 90:10; 9. dichloromethane: methanol: aqueous ammonia 0.880, 93: 7: 2; 10. dichloromethane: methanol: aqueous ammonia 0.880, 90: 10: 1; 11. dichloromethane: methanol, 95: 5; 12. dichloromethane: methanol: aqueous ammonia 0.880, 193: 7: 1; 13. ethyl acetate: 14. hexane: ether, 1: 1; 15. hexane: ether, 1: 3; 16. dichloromethane: methanol: aqueous ammonia 0.880, 80: 20: 5; 17. chloroform: methanol, 95: 5; 18. hexane: ethyl acetate, 3: 7; 19. methanol: ethyl acetate: acetic acid aqueous glaciakammonia 0.880: water, 60: 12: 4: 4: 8. The 1H nuclear magnetic resonance (NMR) spectra were recorded using either a Varian Nova 300 spectrometer or a Varian nova 400, and in all cases were consistent with the proposed structures. The mass spectra were obtained with a Trio 1000 Fisons Instrument spectrometer, using thermospray ionization. Ambient temperature means 20-25 ° C.

EXAMPLE 1 IRS) -2-r3-r (2-amino-1-benzyl-ethylene-1-6-methyl-2-oxo-1 (2H) -pyridin-N- (1 H -indol-5-ylmethyl) acetamide PREPARATION 1 N- (2-Hydroxy-3-phenylpropyl) carbamate of (R.S) -benzyl 1-amino-3-phenyl-2-propanol (3.9 g, 25.79 mmol, prepared as described in J. Amer. Chem. Soc.1946, 203) was dissolved in CH2Cl2 (200 ml) and treated with triethylamine (0.35). ml, 2.58 mmol), followed by 1 - [(benzyloxy) carbonyl] oxydihydro-1H-pyrrole-2,5-dione (6.43 g, 25.79 mmol), and the resulting mixture was stirred at room temperature (72 h). The resulting mixture was washed with aq. Nitric acid. (1 N, 200 ml), brine aq. sat (2 x 200 ml) and dried over MgSO4. Removal of the drying agent by filtration, followed by evaporation of the solvent gave the desired product as a viscous transparent oil (5.18 g, 78%). 1 H NMR (CDCl 3) d 1.60 (m, 1 H), 2. 20 (broad s, 1 / 2H), 2.70 (m, 1 H), 2.80 (m, 3 / 2H), 3.20 (m, 1 / 2H), 3.45 (m, 1 / 2H), 3.95 (m, 1 H), 5.10 (broad s, 2H), 5.30 (m, 1 H), 7.19-7.35 (m, 10H).

LRMS (low resolution mass spectrum: m / z = 286.3 (M + 1).

PREPARATION 2 N- (2-Oxo-3-phenylpropyl) benzyl carbamate Dry DMSO (3.0 mL, 43.54 mmol) in CH2Cl2 was added dropwise to a solution of oxalyl chloride (1.73 mL, 19.91 mmol) in CH2Cl2 (35 mL) at -60 ° C under a nitrogen atmosphere. After stirring for 2 minutes at -60 ° C, a solution of (RS) -benzyl benzyl N- (2-hydroxy-3-phenylpropyl) carbamate (preparation 1) (5.18 g, 18.15 mmol) was added dropwise in CH2Cl2 (17 mL) for 10 min, followed by triethylamine (17.63 mL, 90.74 mmol). The resulting mixture was allowed to warm to room temperature, after which water (100 ml) was added. The aqueous mixture was extracted with CH2Cl2 (3 x 100 ml) and the combined organic extracts were washed with aq. Brine. sat (2x250 ml) and dried over MgSO 4. Filtration with elimination of the drying agent, followed by evaporation of the solvent, gave the crude product, which was purified by chromatography (Si02, eluting with hexane: ethyl acetate 40:60), giving the desired product (crystalline yellow solid, 4.41 g. , 86%). 1 H NMR (CDCl 3) d 3.72 (s, 2 H), 4.11 (d, 2 H), 5.09 (s, 2H), 5.45 (broad s, 1 H), 7.20-7.35 (m, 10H). LRMS m / z = 301.0 (M + 18) +.

PREPARATION 3 N- (6-methyl-2-oxo-1,2-dihydro-3-pyridinyl) benzyl carbamate A suspension of 6-methyl-2-oxo-2,3-dihydro-3-pyridinecarboxylic acid (20 g, 0.13 mol) in dioxane (400 ml) was treated with trielamine (22 ml, 0.15 mol) followed by diphenylphosphonic azide. (30.8 ml, 0.14 moles), and heated under reflux for 2 h. An additional portion of the diphenylphosphoryl azide (3 ml) and trielamine (2 ml) was added, and it was heated under reflux for an additional 1 h. The resulting mixture was then treated with benzyl alcohol (18.8 ml, 0.18 mol) and heated to reflux for 18 h. The resulting mixture was cooled, and evaporation of the solvent gave a crude solid which was triturated with water. The solid was collected by filtration, washed. with HCl (1 N, 300 ml), then water. The solid was triturated with diethyl ether, filtered, washed with diethyl ether, and dried to give the desired product (22 g, 65%). 1 H NMR (CDCl 3) d 1.20 (s, 1H), 2.30 (s, 3H), 5.20 (s, 2H), 6.05 (d, 1H), 7.40 (m, 5H), 7.70 (s, 1H), 8.00 (d, 1 H), LRMS m / z = 259.2 (M + 1) +.

PREPARATION 4 2-r3-r (Benzyloxy) carboninamino-6-methyl-2-oxo-1 (2H) -pyridininacetate tere-butyl A pasty suspension of benzyl N- (6-methyl-2-oxo-1,2-dihydro-3-pyridinyl) carbamate (preparation 3) (20 g, 78 mmol) in 2-butanone (500 ml) was treated with K2CO3 (53.9 g, 94 mmol) and then 2-butanone (100 ml). The resulting mixture was treated cautiously with tere-butyl 2-bromoacetate (15.2 mL, 94 mmol) and stirred at room temperature for 18 h. The solvent was evaporated and the crude material was partitioned between ethyl acetate and water. The aqueous layer was washed with ethyl acetate, the combined organic layers were washed with aq. Brine. sat and dried over Na2S? 4. Removal of the drying agent by filtration, followed by evaporation of the solvent gave the crude product which was purified by recrystallization from ethyl acetate: hexane to give the desired product (white solid, 15.1 g, 52%). 1 H NMR (CDCl 3) d 1.40 (s, 9H), 2.20 (s, 3H), 4.70 (s, 2H), 5.20 (s, 2H), 6.05 (d, 1H), 7.40 (m, 5H), 7.70 (broad s, 1 H), 7.90 (d, 1 H). LRMS m / z = 373.6 (M + 1) +.

PREPARATION 5 tere-butyl 2-r3-Amino-β-methyl-2-oxo-1 (2H) pyridinyl acetate 2- [3- (Beciloxy) carbonyl] amino-6-methyl-2-oxo-1 (2H) pyridinyl-5-tert-butyl ester (preparation 4) (5 g, 13 mmol) in ethyl acetate (70 ml) was dissolved. ), treated with Pd catalyst, 10% on carbon (400 mg) and stirred under a hydrogen atmosphere (13,698 kPa, room temperature, 3 h). The catalyst was removed by filtration, and the solvent was evaporated to dryness to give the desired product as a cream solid (3.08 g, 99%). H NMR (CDCl 3) d 1.40 (s, 9H), 2.20 (s, 3H), 4.00 (s, broad, 2H), 4.70 (s, 2H), 5.90 (d, 1 H), 6.45 (d, 1 H) . LRMS m / z = 293.5 (M + 1 f.

PREPARATION 6 2-r3-r (1-Benzyl-2-r (benzyloxy) carbonylaminoethyl) -amino-1-6-methyl-2-oxo-1- (2H) -pyridin-nacetate of (R.S) -tert-butyl Tere-butyl 2- [3-amino-6-methyl-2-oxo-1- (2H) -pyridinyl] acetate was dissolved (preparation 5) (0.476 g, 2.00 mmol) and N- [2-oxo-3 phenylpropyl) benzyl carbamate (preparation 2) (0.68 g, 2.4 mmol) in THF (10 ml) and acetic acid (0.132 g, 2.2 mmol). This mixture was treated with sodium triacetoxyborohydride (0.634 g, 3.0 mmol), and the resulting mixture was stirred (18 h, room temperature). An additional amount of benzyl N- (2-oxo-3-phenylpropyl) carbamate (0.46 g, 1.6 mmol) was added followed by sodium triacetoxyborohydride (0.634 g, 3.0 mmol), and the resulting mixture was stirred (room temperature, 18 h). The resulting mixture was diluted with CH2Cl2 (100 mL) and washed with aq. NaHCO3. sat (100 ml), brine ac. sat (100 ml) and MgSO 4 was dried. Removal of the drying agent by filtration, and evaporation of the solvent gave a pale yellow oil which was purified by chromatography (SiO 2, elution gradient hexane 100%, hexane: ethyl acetate 90:10, hexane: ethyl acetate 80:20; hexane: ethyl acetate 75:25). The desired product was isolated impure (pale yellow oil, 1.0 g). 1 H NMR (CDCl 3) d 1.45 (s, 9H), 2.15 (s, 3H), 2.70 (m, 1 H), 2.80 (m, 1 H), 3.15 (m, 1 H), 3. 40 (m, 1H), 3.65 (m, 1H), 4.70 (m, 2H), 5.10 (m, 3H), 5.90 (d, 1 H), 6.25 (d, 1 H), 7.10-7.40 (m, 11 H). LRMS m / z = 506.3 (M + 1).

PREPARATION 7 Acid (R, S) -2-r3-r (1-benzyl-2-r (benzyloxy) carbonip-aminoethyl) -amino] -6-methyl-2-oxo-1 (2H) -pyridinyl-1-acetic acid 2- [3 - [(1-Benzyl-2 - [(benzyloxy) -carbonyl-] aminoethyl) amino] -6-methyl-2-oxo-1 (2H) -pyridinyl] acetate was dissolved ( R, S) -tere-butyl (preparation 6) (1.0 g, 1.98 mmol) in CH2Cl2 (16 mL) and treated with TFA (8.0 mL). After stirring at room temperature for 5 h, the resulting mixture was evaporated to dryness and azeotropically distilled with CH2Cl2 (x3). Chromatography (SiO2, elution gradient CH2Cl2 100%, CH2Cl2: MeOH 95: 5, CH2Cl2: MeOH 90:10) gave the desired product (white powder, 0.358 g, 40%). 1 H NMR (d 6 DMSO) d 2.05 (s, 3 H), 2.75 (m, 1 H), 2.85 (m, 1 H), 2.90 (m, 1 H), 3.15 (m, 1 H), 3.50 (m, 1 H), 4.45 (s, width 2H), 4.95 (d, 1 H), 5.0 (s, 2H), 5.90 (d, 1 H), 6.25 (d, 1 H), 7.10-7.30 (m, 10H), 7.45 (t, width, 1 HOUR). LRMS m / z = 450.3 (M + 1) +. Found C 56.30, H, 4.87, N 7.24%; C25H27NSO5 requires C 56.42, H 5.33, N 7.50%.

PREPARATION 8 1 H-lndol-5-ylmethylamine A stirred solution of 1 H-indole-5-carbonitrile (4.0 g, 28.1 mmol) in THF (50 mL) was treated dropwise at 0 ° C with lithium aluminum hydride in THF (1M, 98 mL, 98 mmol. ). The resulting mixture was stirred, warmed to room temperature overnight. Sat. NaHCOs were added. ac. (60 ml) at 0 ° C, and the resulting mixture was filtered through a celite filtering agent 521, and washed with THF. Evaporation of the solvent gave the crude product which was purified by chromatography (SiO2, gradient elution with CH2Cl2: MeOH 95: 5; CH2Cl2: MeOH 90:10; CH2Cl2: MeOH: NH3 90: 10: 1) giving the desired product ( white powder, 12.9 g, 71%). 1H-NMR (CD3OD) d 4.10 (s, 2H), 6.50 (d, 1H), 7.15 (d, 1 H), 7.30 (d, 1 H), 7.40 (d, 1H), 7.60 (s, 1 H) . LRMS m / z = 147.2 (M + 1) +.

PREPARATION 9 N-2-f (1 -2-rf 1 H-indol-5-ylmethyl) amino-1-oxoethyl-6-methyl-2-oxo-1,2-oxo-1, 2- dihydro-3- pyridinyl) amino1-3-phenylpropylcarbamate of (RS) -benzyl Acid (R, S) -2- [3 - [(1-benzyl-2 - [(benzyloxy) -carbonyl] aminoethyl) amino] -6-methyl-2-oxo-1 (2H) - was stirred pyridinyl] acetic acid (preparation 7) (157 mg, 0.349 mmol), 1 H-indol-5-ylmethylamine (preparation 8) (50 mg, 0.349 mmol), HOBT (49 mg, 0.349 mmol), WSCDI HCI (75 mg, 0.391 mmole), N-methylmorpholine (145 mg, 1.40 mmole) and DMF (5.0 ml) at room temperature for 18 h. The reaction mixture was diluted with water (20 ml) and ethyl acetate (20 ml), and stirred manually in a separatory funnel. The organic layer was separated, washed with sat. Brine. ac. (20 ml), and dried over MgS? 4. Removal of the drying agent by filtration, followed by evaporation of the solvent, gave the crude product, which was purified by chromatography (S102, gradient elution hexane: ethyl acetate 50:50, ethyl acetate 100%), yielding the desired product (white foam, 0.153 g, 76%). 1 H NMR (CDCl 3) d 2.35 (s, 3 H), 2.78 (d, 2 H), 3.15 (m, 1 H), 3.35 (m, 1 H), 3.65 (m, 1 H), 4.50 (d, 2 H), 4.75 (quartet AB, 2H), 5.0 (s, width 1H), 5.05 (s, 2H), 5.95 (d, 1 H), 6.30 (d, 1 H), 6.50 (s, 1 H), 6.95 (s, width, 1 H), 7.0 (d, 1H) 7. 10-7.35 (m, 13H), 7.45 (s, 1 H) (s, width, 1 H). LRMS m / z = 578.4 (M + 1).

PREPARATION 10 (R, S) -2-r3-rf2-Amino-1-benzyl-ethyl) amino-1-6-methyl-2-oxo-1 (2H) -pyridinin-N- (1 H -indole-5- ilmetil) acetamide N-2 - [(1-2 - [(1 H -indol-5-ylmethyl) amino] -2-oxoethyl-6-methyl-2-oxo-1,2-dihydro-3-pyridinyl was dissolved. amino] -3-phenylpropylcarbamate from (R, S) -benzyl (preparation 9) (0.15 g, 0.259 mmole) in ethanol (10 ml), treated with 10% Pd on carbon catalyst (50 mg) and stirred under a hydrogen atmosphere (97.335 kPa, room temperature, 18 h). An additional 50 mg of 10% Pd on carbon was added, and stirring was continued under hydrogen (97.335 kPa) for 18 h. The catalyst was removed by filtration, the solvent was evaporated to dryness and the resulting crude product was purified by chromatography (SiO 2, gradient elution CH 2 Cl: MeOH 90:10, CH 2 Cl 2: MeOH: NH 3 90: 10: 0.5; CH 2 Cl 2: MeOH: NH3 90: 10: 1) giving recovered starting material, as the first fraction eluted (8 mg to 53%), and the desired product as the second eluted fraction (white solid, 28 mg, a 24%). 1H-NMR (CD3OD) d 2.25 (s, 3H), 2.75-2.90 (m, 3H), 3.00 (dd, 1 H), 3.75 (s, 1H), 4.50 (s, 2H), 4.75 (d, 1H), 4.90 (d, 1H), 6.10 (d, 1H), 6.40 (d, 1H), 6.45 (d, 1H), 7.05 (d, 1H), 7.10-7.30 (m, 6H), 7.35 (d, 1H), 7.50 (s, 1H). LRMS m / z = 444.2 (M + 1) +.

EXAMPLE 2 2-r3- (3- (dimethylamino) methymphenethylamino) -6-methyl-2-oxo-1 (2H) -pyrazin-N- (1 H -indol-5-ylmethyl) acetamide PREPARATION 11 3-methyl r (Methylamino) carboninbenzoate A slurry of methyl isophthalate (5.10 g, 0.028 mol) in CH2Cl2 (100 ml) was treated at room temperature with oxalyl chloride (6.0 ml) with oxalyl chloride (6.0 ml), followed by DMF (3 drops). The resulting mixture was stirred at room temperature, the solvent was removed by evaporation and the residue was distilled azeotropically with CH2Cl2. The resulting mixture was dissolved in THF (100 ml), cooled to 0 ° C and treated with a solution of methylamine (2M, 28 ml, 56 mmol) in THF. The mixture was allowed to warm to room temperature overnight, the solvent was removed by evaporation and the resulting mixture was partitioned between ethyl acetate (200 ml) and water (200 ml). The organic layer was separated and washed with aq. NaHCOs. sat., brine ac. sat., and dried over MgSO4. Removal of the drying agent by filtration, followed by evaporation of the solvent gave the crude product (white solid, 4.60 g, 79%). 1 H NMR (CDCl 3) d 3.00 (d, 3 H), 4.00 (s, 3 H), 6.30 (s, width, 1 H), 7.50 (t, 1 H), 8.00 (d, 1 H), 8.20 (d, 1 H), 8.40 (s, 1 H). LRMS m / z = 211.1 (M + 1) +.

PREPARATION 12 3-r (Methylamino) metinphenylmethanol A stirred solution of methyl 3 - [(methylamino) carbonyl] benzoate (preparation 11) (5.0 g) was treated dropwise., 20.7 mmole) in THF (120 ml) with a solution of lithium aluminum hydride (1M, 30 ml, 30 mmol) in THF. The resulting pasty suspension was stirred under reflux overnight, cooled and treated with water (1.1 ml), 15% NaOH (1.8 ml) and water (2.5 ml). The resulting gel was removed by filtration, the liquors were concentrated in vacuo and taken up in ethyl acetate (120 ml). The organic layer was washed with aq. Brine. sat (100 ml) and dried over MgSO. Removal of the drying agent by filtration, followed by evaporation of the solvent gave an oil which was purified by chromatography (SiO2, elution gradient CH2Cl2; CH2Cl2: MeOH 95: 5; CH2Cl2: MeOH 90:10; CH2CI2: MeOH: NH3 90: 10: 1; CH2Cl2: MeOH: NH3 85: 15: 1). The second material eluted was the correct product (2.9 g, 69%). 1 H NMR (CDCl 3) d 2.20 (s, 2 H), 2.40 (s, 3 H), 3. 70 (s, 2H), 4.60 (s, 2H), 7.20-7.40 (m, 4H). LRMS m / z = 152.4 (M + 1) +.

PREPARATION 13 N-r3- (Bromomethyl) benzyl-N-methyl-tert-butylcarbamate A milky suspension of 3 - [(methylamino) -methyl] phenylmethanol (preparation 12) (2.7 g, 17.9 mmol) in THF (60 ml) and water (60 ml) was treated with di-t-butyl pyrocarbonate (5.4 g). , 24.7 mmoles), and the mixture was stirred at room temperature overnight. The THF was evaporated and the aqueous residue was treated with ethyl acetate (250 ml). The organic layer was washed with aq. Brine. sat (100 ml) and dried over MgSO4. Removal of the drying agent by filtration, followed by evaporation of the solvent gave the crude product, which was purified by chromatography (S¡O2) eluting CH2Cl2: MeOH 95: 5) giving the intermediate N- [3- (hydroxymethyl) benzyl] -N-methylcarbamate tere-butyl (4.2 g) which was used directly in the next step. A stirred solution of tere-butyl N- [3- (hydroxymethyl) benzyl] -N-methylcarbamate (4.2 g, 16.7 mmol) in CH2Cl2 (150 mL) was treated at 0 ° C, with carbon tetrabromide (8.0 g, 24.1 mmoles) and triphenylphosphine (6.35 g, 24.21 mmoles). The resulting solution was warmed to room temperature and stirred for 4 days. The resulting mixture was evaporated to dryness and the residue was purified by chromatography (SiO2, gradient elution with 100% hexane, hexane: ethyl acetate 99: 1, hexane: ethyl acetate 95: 5) to give the desired product (3.32 g. , 60%). 1 H NMR (CDCl 3) d 1.50 (s, 9 H), 2.80 (s, broad, 3 H), 4.20 (s, 2 H), 4.30 (s, 2 H), 7.15 (m, 1 H), 7.25 (m, 1 H) ), 7.30 (m, 2H). LRMS m / z = 333.2 (M + 18) +.

PREPARATION 14 N-r3- (Cyanomethyl) (tert-butyl benzyl-N-methylcarbamate) N- [3- (bromomethyl) benzyl] -N-methylcarbamate of tere-butyl (preparation 13) (3.2 g, 10.18 mmol) was dissolved in acetonitrile (50 ml), and treated with sodium cyanide (1.23 g, 25.10 g. mmoles), followed by benzyltriethylammonium bromide (220 mg, 0.8 mmol), and the resulting mixture was stirred at room temperature for 4 days. The resulting pasty suspension was diluted with ethyl acetate (200 ml), washed with water, brine aq. sat and MgSO was dried. Removal of the drying agent by filtration, followed by evaporation of the solvent, gave a pale yellow solid which was purified by chromatography (SiO2, eluting with 100% CH2Cl2) to give the desired product with an impurity residue (3.0 g). 1 H NMR (CDCl 3) d 1.50 (s, 9 H), 2.80 (s, broad, 3 H), 3.75 (s, 2 H), 4.40 (s, 2 H), 7.20 (m, 3 H), 7.35 (t, 1 H) . LRMS m / z = 278.1 (M + 18) +.

PREPARATION 15 N-r3- (2-Aminoethyl) benzin-N-methylcarbamate tere-butyl N- [3- (Cyanomethyl) benzyl] -N-methylcarbamate of tere-butyl (preparation 14) (3 g, 11.5 mmol, slightly impure) was dissolved in ethanol saturated with NH3 (300 ml), treated with Raney® nickel (500 mg) and stirred under a hydrogen atmosphere (410.940 kPa, room temperature, 18 h). The catalyst was removed by filtration under nitrogen, the solvent was evaporated to dryness and the resulting crude product was purified by chromatography (SiO2, elution gradient CH2Cl2 100%; CH2Cl2: MeOH 95: 5; CH2Cl2: MeOH 90:10) giving the desired product (2.40 g, 78%). 1 H NMR (CDCl 3) d 1.20 (s, 2H) 1.50 (s, 9H), 2.70-2.90 (m, 5H), 3.00 (s, 2H), 4.20 (s, broad, 2H), 7.05 (s, broad, 3H), 7.25 (s, width, 1 H). LRMS m / z = 265.1 (M + 1) +.

PREPARATION 16 2-R (1-Cioanoethyl) amino] acetate hydrochloride (R.S) -benzyl A cooled solution of the free base of the glycine benzyl ester (12.9 g, 78.09 mmol from the HCl salt was treated by partition between ethyl acetate and brine, basified with sat. Na 2 CO 3 solution) in CH 2 Cl 2 (100 ml ) with 3Á molecular sieves, with a solution of acetaldehyde (4.36 ml, 78.09 mmoles) in CH2Cl2 (5 ml). After 3 min, the mixture was treated dropwise with a solution of TMSCN (10.40 ml, 78.09 mmol) with caution, and the temperature was maintained at 5 ° C. The resulting mixture was stirred at room temperature for 3 h, washed with water, the aqueous layer was extracted with CH2Cl2 (x2), the combined organic layers were dried over MgSO4, and the solvent was evaporated. The resulting pale yellow oil was taken up in ether (150 ml), treated with a solution of HCl in ether (1M, 78 ml) to precipitate a solid which was collected by filtration and dried to give the desired product (17.85 g, 89 %). 1 H NMR (CD 3 OD) d 1.70 (d, 3 H), 4.20 (s, 2 H), 4.70 (c, 1 H), 5.30 (s, 2 H), 7.40 (m, 5 H). LRMS m / z = 236.3 (M + 18) +.

PREPARATION 17 2-r3.5-Dichloro-2-methyl-6-oxo-1 (6H) -pyzinyl acetate benzyl A suspension of 2 - [(1-cyanoethyl) amino] benzyl acetate hydrochloride (preparation 16) (17.8 g, 69.88 mmol) in toluene (120 ml) was treated with oxalyl chloride (24.38 ml). Once the effervescence has ceased, the reaction was heated to 100 ° C (24 h). The reaction was cooled, the solvent was evaporated to dryness and the resulting crude product was purified by chromatography (SiO2, gradient elution with pentane: ethyl acetate 70:30; pentane: ethyl acetate 50:50; pentane: ethyl acetate 30:70, 100% ethyl acetate). Again chromatography (SiO2, eluting with 100% CH2Cl2) gave the desired product as an off-white solid (9.40 g, 41%). 1 H NMR (CD3OD) d 2.35 (S, 3H), 4.90 (s, 2H), 5.25 (s, 2H), 7.40 (m, 5H).

PREPARATION 18 2-f3-r (3-r (tert-Butyloxycarbonyl) (methyl) amino] -methyl-1-phenethyl) amino-5-chloro-6-methyl-2-oxo-1 (2H) -pyrazine benzyl acetate Thereafter, N- [3- (2-aminoethyl) benzyl] -N-methylcarbamate of tere-butyl (preparation 15) (0.5 g, 1.89 mmol), 2- [3,5-dichloro-), was stirred at reflux for 24 h. 2-methyl-6-oxo-1 (6H) -pirazinyl] benzyl acetate (preparation 17) (0.6 g, 1. 83 mmoles) and triethylamine (0.5 ml, 3.66 mmoles) in ethyl acetate (30 ml).

The resulting mixture was diluted with ethyl acetate (20 ml) and washed with water, brine aq. sat., dried over MgSO4. Removal of the drying agent by filtration, followed by evaporation of the solvent, gave a red oil, which was purified by chromatography (SiO 2, gradient elution with 100% CH 2 Cl 2; CH2Cl2: MeOH 99: 1; CH 2 Cl 2: MeOH 98: 2), giving the desired product (0.76 g, 75%). 1 H NMR (CDCl 3) d 1.45 (s, 9H), 2.20 (s, 3H), 2.80 (s, broad, 3H), 2.90 (t, 2H), 3.70 (m, 2H), 4.20 (s, width, 2H), 4.80 (s, 2H), 5.20 (s, 2H), 6.10 (m, width, 1 H), 7.10 (m, 3H), 7.25 (m, 1 H), 7.35 (m, 5H). LRMS m / z = 555.3 (M + 1) +. Found C 62.50, H, 6.34, N 9.98%; C29H35N4O5CI requires C 62. 75, H 6.36, N 10.09%.

PREPARATION 19 2-r3-Chloro-2-met8l-5- (3-rfdimethylamino) methymphenethyl-amino) -6-oxo-1 (6H) -pyrazinMenate benzyl It was dissolved 2- [3 - [(3 - [(tert-butyloxycarbonyl) (methyl) -amino] methyl] phenethyl) amino] -5-chloro-6-methyl-2-oxo-1 (2H) -pyrazinyl] acetate of benzyl (preparation 18) (0.7 g, 1.26 mmol) in CH2Cl2 (10 ml), and treated with TFA (1.0 ml). After stirring at room temperature for 3 h, the reaction mixture was evaporated to dryness, then dissolved in ethyl acetate (200 ml), washed with aq. NaHCOs. sat., brine ac. sat., dried over MgSO4. Removal of the drying agent by filtration, followed by evaporation of the solvent, gave a dark brown oil, which was purified by chromatography (SiO2; gradient elution with 100% CH2Cl2; CH2Cl2: MeOH 98: 2; CH2Cl2: MeOH 95: 5; CH 2 Cl 2: MeOH: NH 3 95: 5: 1), giving the desired product (0.38 g, 65%). 1 H NMR (CDCl 3) d 2.00 (s, broad, 1H), 2.20 (s, 3H), 2.45 (s, 3H), 2.90 (t, 2H), 3.70 (m, 2H), 3.75 (s, 2H), 4.80 (s, 2H), 5.20 (s, 2H), 6. 10 (m, width, 1 H), 7.10 (m, 1 H), 7.15 (m, 2H), 7.25 (m, 1H), 7.35 (m, 5H).

LRMS m / z = 455.0, 457.2 (M + 1) +.

PREPARATION 20 2-r3-Chloro-5- (3-r (d-methylammon) -methylenephenethylamine) -2-methyl-6-oxo-1 (6H) -pyrazininacetate benzyl A stirred solution of benzyl 2- [3-chloro-2-methyl-5- (3 - [(methylamino) methyl] phenethylamino) -6-oxo-1 (6H) -pyrazinyl] acetate was treated. (preparation 19) (0.38 g, 0.83 mmol) in CH CI2 (10 ml) with formaldehyde (0.31 ml). After stirring at room temperature for 45 min, the resulting cloudy mixture was treated with sodium triacetoxyborohydride (253 g, 1. 19 mmol) and stirred at room temperature for 2 additional days. The reaction mixture was diluted with CH2Cl2 (200 ml) and washed with aq. NaHCOs. sai, brine ac sai, dried over MgSO 4. Removal of the drying agent by filtration, followed by evaporation of the solvent, gave a crude solid, which was purified by chromatography (Si02; gradient elution with CH2CI2 100%; CH2Cl2: MeOH 95: 5; CH 2 Cl 2: MeOH 90:10), giving the desired product (0.30 g, 77%). 1 H NMR (CDCl 3) d 2.20 (s, 3 H), 2.25 (s, 6 H), 2.90 (t, 2H), 3.40 (s, 2H), 3.70 (m, 2H), 4.80 (s, 2H), 5.20 (s, 2H), 6.10 (m, width, 1 H), 7. 10-7.20 (m, 3H), 7.25 (m, 1 H), 7.35 (m, 5H). LRMS m / z = 469.2, 471.2 (M + 1) PREPARATION 21 Acid 2-r3- (3-r (dimethylamino) meth-phenethylamino) -6-methyl-2-OXO-K2H) -pyrazinyl acetic acid 2- [3-Chloro-5- (3 - [(dimethylamino) methyl] -phenethylamino) -2-methyl-6-oxo-1 (6H) -pyrazinyl] benzyl acetate (preparation 20) was dissolved (137 mg, 0.29 mmole) in methanol: water (10: 2, 20 ml), treated with the catalyst Pearlman (10 mg) and stirred under a hydrogen atmosphere (413,640 kPa, room temperature, 2.5 h). The catalyst was removed by filtration, followed by evaporation of the solvent and azeotropic distillation with CH 2 Cl 2 to give a crude yellow solid. To the crude mixture was added 1 H-indol-5-ylmethylamine (preparation 8) (43 mg, 0.29 mmol), HOBT (46 mg, 0.34 mmol), WSCDI-HCl (74 mg, 0.39 mmol), N-methylmorpholine (0.061 mg, 0.55 mmol) and DMF (5 ml), stirring at room temperature for 18 h. The reaction mixture was evaporated to dryness and distilled azeotropically with CH2Cl2. Water (2 ml) was added followed by aq Na2CO3. sat (a few drops), and the residue was treated with ethyl acetate and methanol. The organic layer was separated, and dried over MgSO4. Removal of the drying agent by filtration, followed by evaporation of the solvent, gave the crude product, which was purified by chromatography (SIO2; gradient of elution with CH2CI2 100%; CH2Cl2: MeOH 95: 5; CH 2 Cl 2: MeOH: NH 3 95: 5: 0.5), giving the desired product (10 mg, 7%). 1 H NMR (CDCl 3) d 2.10 (s, 3 H), 2.20 (s, 6 H), 2. 90 (t, 2H), 3.45 (s, 2H), 3.60 (t, 2H), 4.45 (s, 2H), 4.70 (s, 2H), 6.40 (m, width, 1 H), 6.70 (m, 1 H), 7.05 (m, 2H), 7.10-7.30 (m, 4H), 7.35 (m, 2H), 7.50 (m, 2H). LRMS m / z = 473.2 (M + 1) +.

EXAMPLE 3 2-r 3-Chloro-5- (3-r (dimethylamino) -methiphenethyl-amino) -2-methyl-6-oxo-1 (6H) -pyrazin-NH- (1H-indol-5- ilmetiDacetamida PREPARATION 22 2-R3-Chloro-5- (3-α- (d -methyl-amino) -methylphenethylamine) -2-methyl-6-oxo-1 (6H) -pyrazine-napthacic acid hydrochloride 2- [3-Chloro-5- (3 - [(dimethylamino) methyl] -phenethylamino) -2-methyl-6-oxo-1 (6H) -pyrazinyl] benzyl acetate (preparation 20) was dissolved (100 mg, 0.21 mmol) in ethanol (10 ml), treated with 10% Pd on carbon catalyst (20 mg), aq. (1M, 0.1 ml), and stirred under a hydrogen atmosphere (137,880 kPa, room temperature, 2 h). The catalyst was removed by filtration, the solvent was evaporated to dryness and the residue was distilled azeotropically with CH 2 Cl 2 to give the desired, slightly impure product (white solid, 85 mg). 1H-NMR (CD3OD) d 2.30 (s, 3H), 2.80 (s, 6H), 3.00 (t, 2H), 3.60 (t, 2H), 4.20 (s, 2H), 4.70 (s, 2H), 7.30 (m, 2H), 7.40 (m, 2H). LRMS m / z = 379.1 (M + 1) +.

PREPARATION 23 2- [3-Chloro-5- (3-r (dimethylamino) methyn-phenethylamino) -2-methyl-6-oxo-1 (6H) -pyrazinpN- (1H-indole -5-ylmethyl) acetamide The title compound was prepared by a method similar to Preparation 9 from 2- [3-chloro-5- (3 - [(dimethylamino) methyl] phenethylamine) -2-methylene-6-hydrochloride. -oxo-1 (6H) -pyrazinyl] -N- (1 H -indol-5-ylmethyl) acetic acid (preparation 22) (85 mg, 0.20 mmol) and 1 H-indol-5-ylmethylamine (preparation 8) (35 mg, 0.24 mmol), giving the title compound (100 mg, 0.19 mmol, 98%). 1H-NMR (CD3OD) d 2.20 (s, 3H), 2.70 (s, 6H), 3.00 (m, 2H), 3.60 (m, 2H), 4.20 (s, 2H), 4.50 (s, 2H), 4.80 ( m, 2H), 7.05 (m, 1H), 7.10-7.55 (m, 9H), 7.75 (m, 1H), 7.85 (m, 1 H). LRMS m / z = 507.3, 509.3 (M + 1)? EXAMPLE 4 2-r3-f (1 S) -1-Benzyl-2- (d-methylamino) etipamno-6-methyl-2-oxo-1 (2 H) - pyrazin-N- (1 H -indole-5-ylmethyl) acetamide PREPARATION 24 2-f3-r (1 S) -1-benzyl-2- (dimethylamino) ethynamino-5-chloro-6-methyl-2-oxo-1 (2H) -benzyl pyridinyl acetate The title compound was prepared by a method similar to Preparation 18 from N - [(2S) -2-amino-3-phenylpropyl] -N, N-dimethylamine (190 mg, 1.07 mmol, prepared as described in Chem. Pharm. Bull. 1970, 18, 1731-1736) and 2- [3,5-dichloro-2-methyl-6-oxo-1 (6H) -pyrazinyl] benzyl acetate (preparation 17) (361 mg, 1.10 mmol). The crude product was purified by chromatography (Si0, elution gradient hexane 100%, hexane: ethyl acetate 80:20, hexane: ethyl acetate 60:40, hexane: ethyl acetate 40:60, hexane: ethyl acetate : 80) giving the desired product (yellow solid, 260 mg, 50%). 1 H NMR (CDCl 3) d 2.20 (m, 9 H), 2.30 (m, 1 H), 2.20 (m, 1 H), 2. 85 (m, 1 H), 3.10 (m, 1 H), 4.25 (m, 1 H), 4.80 (s, 2H), 5.20 (s, 2H), 6.20 (m, 1 H), 7.20 (m, 5H), 7.35 (m, 5H). LRMS m / z = 469.2, 471.3 (M + 1) +.

PREPARATION 25 2-r3-IY1 S) -1-Benzyl-2- (dimethylamino) ethylammon-6-methyl-2-oxo-1 (2H) -pyrazinin-N- (1H-indole -5-ylmethyl) acetamide The title compound was prepared by a method similar to Example 2 from 2- [3 - [(1S) -1-benzyl-2- (diethylamino) ethyl] amino-5-chloro-6-methyl-2-oxo (2 H) -pyrazinyl] benzyl acetate (preparation 24) (240 mg, 0.51 mmol), which was treated with the Peariman catalyst (see example 2) to give a crude acid (168 mg, 95%). The crude acid (100 mg, 0.26 mmol) was coupled with 1 H-indol-5-ylmethylamine (preparation 8) (41 mg, 0.29 mmol) to give a crude mixture which was purified by chromatography (S102, eluting with 100% CH2Cl2; CH 2 Cl 2: MeOH 95: 5; CH 2 Cl 2 MeOH: NH 3 95: 5: 0.5) giving example 5 as the first eluted fraction (yellow foam, 8 mg, 6% from crude acid), and the desired product as the second fraction eluted (white foam, 86 mg, 70% from the crude acid). 1 H NMR (CDCl 3) d 2.20 (s, 6 H), 2.25 (m, 4 H), 2.40 (m, 1 H), 2.85 (m, 1 H), 3.00 (m, 1 H), 4.30 (m, 1 H) ), 4.50 (m, 2H), 4.55-4.70 (m, 2H), 6.00 (m, 1 H), 6.50 (s, 1 H), 6.70 (m, 2H), 7.10 (m, 1 H), 7.20 (m, 6H), 7.35 (m, 1 H), 7.50 (m, 1 H), 8.20 (s, width, 1 H). LRMS m / z = 473.4 (M + 1) +. Found C 63.45, H, 6.46, N 15.88%; C 27 H 32 N 6 O 2 O 6 CH 2 Cl 2 requires C 63.32, H 6.39, N 16.05%.

EXAMPLE 5 2-r3-K1 S) -1-Benzyl-2-fdimethalamine) ethylamino-5-chloro-6-methyl-2-oxo-1 (2H) -pyrazinyl- (1H-indole- 5-ylmethyl) acetamide 1 H NMR (CDCl 3) d 2.20 (s, 7H), 2.35 (s, 3H), 2.50 (m, 1H), 2.80 (m, 1H), 3.00 (m, 1H), 4.30 (m, 1H), 4.40- 4.60 (m, 3H), 4.65 (m, 1H), 6.30 (s, width, 1H), 6.50 (s, 1H), 6.80 (s, width, 1H), 7.05 (m, 1H), 7.15-7.40 ( m, 7H), 7.50 (s, 1H), 8.30 (s, broad, 1H). LRMS m / z = 507.4, 509.6 (M + 1) +.

EXAMPLE 6 2-r 3-r (2R, S) -3- (Dimethyiamino) -2-phenylpropin-amino > -6-methyl-2-oxo-1 (2H) -pyrazinin-N- (1H-indol-5-ylmethyl) acetamide PREPARATION 26 (2R, S) -3-r (Benzyloxy) carbon-amino-2-phenylpropanoate ethyl Ethyl (2R, S) -3-amino-2-phenylpropanoate (1.0 g, 5.18 mmol, prepared as described in J. Org. Chem. 1961, 4062), 1 - [(benzyloxy) carbonyl] oxidi was stirred. hydro-1 H-pyrrol-2,5-dione (1.55 g, 6.21 mmol) and triethylamine (1.08 mL, 7.77 mmol) in CH2Cl2 (20 mL), at room temperature for 65 h. The reaction mixture was washed with citric acid aq. (1 N), NaHC03 aq, brine ac. sat., and dried over MgSO 4. Removal of the drying agent by filtration, followed by evaporation of the solvent gave the crude product which was purified by chromatography (SiO2; eluting with CH 2 Cl 2: MeOH 98: 2) to give the desired, slightly impure product (colorless oil, 1.8 g). 1 H NMR (CDCl 3) d 1.20 (t, 3 H), 3.50 (d, 1 H), 3.60 (m, 1 H), 3. 65 (m, 1H), 3.90 (m, 1H), 4.15 (m, 2H), 5.10 (s, 2H), 7.20-7.40 (m, 10H).

LRMS m / z = 328.2 (M + 1) +.

PREPARATION 27 (2R, S) -N-F3- (Dimethylamino) -2-phenyl-propylcarbamate benzyl A solution of ethyl (2R, S) -3 - [(benzyloxy) carbonyl] amino-2-phenylpropanoate (preparation 26) (1.8 g, 5.50 mmol) in toluene (10 ml) was cooled to -75 ° C, and it was treated with a solution of DIBAL (1M, 11 ml, 11 mmol) in toluene, keeping the temperature below -65 ° C. The reaction mixture was stirred for 30 min, then quenched by the addition of methanol. Sodium potassium tartrate was added ac, and the mixture was warmed to room temperature, partitioned between ethyl acetate and water, the organic layers were separated and dried over MgSO4. Removal of the drying agent by filtration, followed by evaporation of the solvent, gave the crude product, which was purified by chromatography (SiO2, eluting with CH CI2: MeOH 98: 2) giving the intermediate N- (3-oxo-2- phenylpropyl) benzyl carbamate (colorless oil, 933 mg, 60%). Benzyl N- (3-oxo-2-phenylpropyl) carbamate was dissolved (930 mg, 3.28 mmol) and dimethylamine hydrochloride (321 g, 3.94 mmol) in CH2Cl2 (20 mL), and stirred for 1 h. This mixture was treated with sodium triacetoxyborohydride (1.04 g, 4.92 mmol), and the resulting mixture was stirred (2 h, room temperature). The resulting mixture was washed with aq. NaHCOs. sat., brine ac. sat., and dried over MgSO4. Removal of the drying agent by filtration, and evaporation of the solvent, gave the crude product which was purified by chromatography (SiO2; eluting with CH 2 Cl 2: MeOH 90:10) to give the desired product (colorless oil, 741 mg, 72%). H NMR (CDCl 3) d 2.20 (s, 6H), 2.40 (m, 1 H), 2.65 (m, 1 H), 3.00 (m, 1 H), 3.40 (m, 1 H), 3.55 (m, 1 H), 5.05 (s, 2H), 5.85 (s, width, 1 H), 7.15 (m, 2H), 7.25 (m, 2H), 7.30 (m, 6H). LRMS m / z = 313.3 (M + 1) +.

PREPARATION 28 N- (2R, S) - (3-Amino-2-phenylpropyl) -N, N-dimethylamine Benzyl (2R, S) -N- [3- (dimethylamino) -2-phenylpropyl] carbamate was dissolved (preparation 27) (740 mg, 2.61 mmol) in ethanol (20 ml), treated with 10% Pd catalyst. % on carbon (100 mg), and stirred under a hydrogen atmosphere (64.980 kPa, room temperature, 1 h). The catalyst was removed by filtration, and the solvent was evaporated to dryness to give the desired product (colorless oil, 350 mg, 75%). 1 H NMR (CDCl 3) d 2.20 (s, 6 H), 2.40 (m, 1 H), 2.60 (m, 1 H), 2.80 (m, 2 H), 3.10 (m, 1 H), 7.20-7.40 (m, 5H). LRMS m / z = 179.4 (M + 1) +.

PREPARATION 29 2-r3-Chloro-5- (rf2R, S) -3- (dimethylamino) -2-phenylpropin-amino > Benzyl -2-methyl-6-oxo-1- (6H) -pyrazine-benzene The title compound was prepared by a method similar to Preparation 18 from N- (2R, S) - (3-amino-2-phenylpropyl) -N, N-dimethylamine (preparation 28) (261 mg, 1.47 mmol ) and benzyl 2- [3,5-dichloro-2-methyl-6-oxo-1 (6H) -pyrazinyl-acetic acid (preparation 17) (400 mg, 1.22 mmol). The crude product was purified by chromatography (S ?02, eluting with CH 2 Cl 2: MeOH 95: 5) to give the desired product (off-white solid, 325 mg, 57%). 1 H NMR (CDCls) d 2.20 (s, 3 H), 2.30 (s, 6 H), 2.50 (m, 1 H), 2.80 (m, 1 H), 3.15 (m, 1 H), 3.70 (m, 2 H), 4.80 ( s, 2H), 5.20 (s, 2H), 7.20-7.40 (m, 10H), 7.55 (s, broad, 1H). LRMS m / z = 469.2, 471.2 (M + 1) +.

PREPARATION 30 2-r 3 -frf 2 R, S) -3- (Dimethylamino) -2-phenylpropin-amino > -6-methyl-2-oxo-1 (2H) -pyrazinyl-N- (1H-indol-5-ylmethyl) acetamide The title compound was prepared by a method similar to Example 2 from 2- [3-chloro-5 - [(2R, S) -3- (dimethylamino) -2-phenylpropyl] amino-2-methyl-6- oxo-1 (6H) -pyrazinyl] benzyl acetate (preparation 29) (320 mg, 0.68 mmol), which was treated with the Pearlman catalyst (see example 2) to give a crude acid (233 mg, 99%) . The crude acid (230 mg, 0.67 mmol) was coupled with 1H-indol-5-ylmethylamine (preparation 8) (149 mg, 0.80 mmol) to give a crude product which was purified by chromatography (S1O2, eluting with CH2Cl2: MeOH: NH3 90: 10: 1) giving the desired product (90 mg, 28%). 1 H NMR (d6-DMSO) d 2.00 (s, 3H), 2.15 (s, 6H), 2.35 (m, 1H), 2.60 (m, 1H), 3.20 (m, 1H), 3.40 (m, 1H), 3.60 (m, 1H), 4.30 (d, 2H), 4.60 (s, 2H), 6.40 (m, 1 H), 6.60 (m, 1 H), 6.75 (s, 1H), 7.00 (m, 1H) , 7.20-7.35 (m, 7H), 7.40 (s, 1 H), 8.60 (m, 1H). LRMS m / z = 473.5 (M + 1) +.

EXAMPLE 7 2-G3-IG (1S) -1-Benzyl-2- (dimethylamine) etipamino} -6-methyl-2-oxo-1 (2H) -pyrazinyl-1-N-r (6-methyl-1H-indazol-5-methyl-T | acetamide) PREPARATION 31 4-Amino-2,5-dimethylbenzonitrile 2,5-Dimethyl-4-nitrobenzonitrile (500 mg, 2.84 mmol, purchased from Salor) was dissolved in ethanol (20 ml), treated with 10% Pd-carbon catalyst (50 mg), and stirred under a hydrogen atmosphere (64.980 kPa, room temperature, 3 h). The catalyst was removed by filtration, and the solvent was evaporated to dryness. The resulting mixture was dissolved in CH2Cl2 and washed with HCl (2N, 4x15 ml), the aqueous layer was treated with NaHCO3, then extracted repeatedly with CH2Cl2. The solvent was evaporated from the organic layer to give the desired product (brown solid, 350 mg, 84%). 1 H NMR (CDCl 3) d 2.10 (s, 3 H), 2.30 (s, 3 H), 6.60 (s, 1 H), 7.20 (s, 1 H). LRMS M / z = 147.4 (M + 1) +. Found C 72.12, H, 6.86, N 18.53%; requires C 72.16, H 7.00, N 18.70%.

PREPARATION 32 6-Methyl-1H-indazole-5-carbonitrile A solution of 4-amino-2,5-dimethylbenzonitrile (preparation 31) (111 mg, 0.76 mmol) in acetic acid (5 ml) was treated with a solution of sodium nitrite (53 mg, 0.76 mmol) in water ( 1 ml). The resulting mixture was stirred at room temperature for 10 min, then allowed to stand for 48 h. The solvent was removed by evaporation and the residue was purified by chromatography (S102, eluting with hexane: ethyl acetate 50:50) to give the desired product (25 mg, 21%). 1 H NMR (CD3OD) d 2.60 (s, 3 H), 7.50 (s, 1 H), 8.15 (s, 1 H), 8.20 (s, 1 H). LRMS m / z = 158.1 (M + 1) +.

PREPARATION 33 (6-Methyl-1H-indazol-5-yl) methylamine A solution of 6-methyl-1 H-indazole-5-carbonitrile (preparation 32) (230 mg, 1.47 mmol) in THF (10 ml) was treated under nitrogen, with a solution of lithium aluminum hydride (1 N, 3.66 mL, 3.66 mmol) in THF at 0 ° C. The resulting mixture was stirred for 16 h, warming to room temperature, then treated with MeOH (12 ml), H20 (0.8 ml), NaOH (4N, 2 ml) and H0 (4 ml). The resulting precipitate was removed by filtration, washed with THF and purified by chromatography (S1O2, eluting with CH2Cl2: MeOH: NH3 90: 10: 1) to give the desired product (71 mg, 30%). 1 H NMR (CD3OD) d 2.40 (s, 3 H), 3.95 (s, 2 H), 7.35 (s, 1 H), 7.70 (s, 1 H), 7.95 (s, 1 H). LRMS m / z = 162.0 (M + 1) + PREPARATION 34 2-r 3 ~ f 1 (1 S) -1-Benzyl-2- (dimethylamino) etipamino} -β-methyl-2-oxo-1 (2H) -pyrazinop-N-r (6-methyl-1H-nitrazol-5-methylacetamide) The title compound was prepared by a method similar to Example 2 from 2- [3 - [(1S) -1-benzyl-2- (dimethylamino) ethyl] amino-5-chloro-6-methyl-2-oxo -1 (2H) -pyrazinyl] benzyl acetate (preparation 24) (240 mg, 0.51 mmol), which was treated with the Pearlman catalyst (see example 2) to give a crude acid (168 mg, 95%). The crude acid (48 mg, 0.13 mmol) was then coupled with (6-methyl-1 H-indazol-5-yl) methylamine (preparation 33) (22.4 mg, 0.14 mmol) to give a crude mixture which was purified by chromatography. (Si02, eluting with CH2Cl2: 90:10 MeOH; CH2Cl2: MeOH: NH3 90: 10: 0.2; CH2Cl2: MeOH: NH3 90: 10: 0.2) giving the desired product (yellow solid, 28 mg, 46% from crude acid). 1 H NMR (CDCl 3) d 2.15-2.40 (m, 14H), 2.80 (m, 1 H), 3.05 (m, 1 H), 4.20-4.65 (m, 4H), 4.80 (m, 1 H), 6.00- 6.30 (m, width, 1 H), 6.75 (s, 1 H), 7.10 (s, 1H), 7.15-7.30 (m, 6H), 7.50 (s, 1 H), 7.80 (s, width, 1H) LRMS m / z = 488.2 (M + 1) + EXAMPLE 8 Nr (3-Met.l-1H-indol-5-yl) met.n2-r6-methyl-3- (. {3-r (methyl) lamno) methylfnetol-amino) -2-oxo-1 (2H) -pyrazine-acetamide PREPARATION 35 3-Formyl-1 H-indole-5-carbonitrile Phosphoryl chloride (4.24 ml, 45.48 moles) was added dropwise to dimethylformamide (3.52 ml, 45.48 mmol) and stirred for 30 min at room temperature. A solution of 1 H-indole-5-carbonitrile (5.39 g, 37.9 mmol) in dimethylformamide (10 ml) was added dropwise. A solid precipitated, additional dimethylformamide (10 ml) was added to aid stirring, and the reaction mixture was then stirred at room temperature for 3 h. Water was added to quench the reaction mixture, which was then stirred for 18 h. Agitation was stopped and the reaction mixture was allowed to stand; after 24 h, a pink solid precipitated in the organic layer. The layers were separated and the organic layer was filtered, washed with water and dried to give the desired product (5.44 g, 84%). RNM 1H (DMSO) d 7. 60-7.80 (m, 2H), 8.20-8.30 (m, 2H), 10.00 (s, 1 H), 12.20-12.35 (s, width, H).

PREPARATION 36 (3-MetH-1H-indol-5-yl) methylamine The title compound was prepared by a method similar to Preparation 8 from 3-formyl-1 H-indole-5-carbonitrile (preparation 35) (5.44 g, 32 mmol) to give the desired product as a white solid (2.57). g, fifty%). 1 H NMR (CDCls) d 2.35 (s, 3 H), 4.00 (s, 2 H), 7.00 (s, 1 H), 7.15 (d, 1 H), 7. 35 (d, 1 H), 7.50 (s, 1 H), 7.80-8.00 (s, width, 1 H).

PREPARATION 37 2-R3-Chloro-2-methyl-5-r (3-frmethyl (2,2,2-trifluoroacetypamino-methyl) -phenethyl) amino-1-6-oxo-1 (6H) -pyrazine-benzyl acetate A solution of benzyl 2- [3-chloro-2-methyl-5- (3 - [(methylamino) methyl] phenethylamino) -6-oxo-1 (6H) -pyrazinyl] acetate (preparation 19) was treated (1.77 g, 3.90 mmol) in CH2Cl2 (75 ml) with pyridine (0.65 ml) and trifluoroacetic anhydride (1 ml). After stirring at room temperature for 24 h, the reaction mixture was evaporated to dryness and distilled azeotropically with dichloromethane (x3). The residue was dissolved in dichloromethane (400 ml), washed with water, brine aq. sat and dried over MgSO4. Removal of the drying agent by filtration, followed by evaporation of the solvent, gave a pale orange solid, which was recrystallized from boiling methanol to give the desired product. The mother liquors were concentrated under reduced pressure and purified by chromatography (SiO2, gradient elution with 100% pentane; pentane: ethyl acetate 3: 1) giving more product (1.47 g, 68%). H NMR (CDCl 3) d 2.20 (s, 3 H), 3.90 (m, 3 H), 3.05 (s, 2 H), 3.60-3.70 (m, 2 H), 4.60 (s, 2 H), 4.80 (s, 2 H), 5.20 (s, 2H), 6.05- 6.15 (m, 1 H), 7.00-7.15 (m, 2H), 7.15-7.25 (m, 1 H), 7.25-7.40 (m, 7H). LRMS m / z = 551.8 (M + 1) +.

PREPARATION 38 2,2,2-Trifluoro-N-methyl-N-r3- (2 r5-mThyl-4- (2-fí (3-methyl-1H-indol-5-yl) methylamino> -2- oxoethyl) -3-oxo-3,4-dihydro-2-pyrazininamino ethyl) - benzylacetamide 2- [3-Chloro-2-methyl-5 - [(3- {[[methyl (2,2,2, -trifluoroacetyl) amino] methyl} phenethyl) amino] -6-oxo-1 was dissolved. (6H) -pyrazinyl] benzyl acetate (preparation 37) (200 mg, 0.36 mmol) in methanol (80 ml), treated with Pearlman's catalyst (80 mg) and stirred under a hydrogen atmosphere (413,640 kPa, room temperature, 2.5 h). The catalyst was removed by filtration, followed by evaporation of the solvent and azeotropic distillation with CH 2 Cl 2 to give a crude solid. To the crude mixture was added (3-methyl-1H-indol-5-yl) methylamine (preparation 36) (60 mg, 0.37 mmol), HOBT (56 mg, 0.41 mmol), WSCDI HCl (91 mg). , 0.47 mmole), N-methylmorpholine (0.073 mg, 0.66 mmole) and DMF (10 ml), and stirred at room temperature for 18 h. The resulting mixture was evaporated to dryness and triturated with water. The brown solid was filtered, dried, then purified by chromatography (SiO2, elution gradient with ethyl acetate: hexane 1: 2, ethyl acetate: hexane 2: 1) to give the desired product (42 mg, 20%). . 1 H NMR (CD 3 OD) d 2.15 (s, 3 H), 2.30 (s, 3 H), 2.85-3.20 (m, 3 H), 3. 35 (s, 2H), 3.60 (m, 2H), 4.50 (s, 2H), 4.60-4.65 (m, 2H), 4.75 (s, 2H), 6.65 (s, 1 H), 6.95-7.50 (m, 8H). LRMS m / z = 596.5 (M + 1) +.

PREPARATION 39 N-r (3-Methyl-1 H -indole-5-yl) metin-2-r6-methyl-3-f. { 3- r (methylamino) metinfenethyl > amino) -2-oxo-1 (2H) -pyrazinin acetamide 2,2,2-trifluoro-N-methyl-N- [3- (2 { [5-methyl-4- (2- {[[3-methyl-1H-indol-5-yl] was dissolved. ) methyI] amino} -2-oxoethyl) -3-oxo-3,4-dihydro-2-pyrazinyl] amino.} ethyl) benzyl] acetamide (preparation 38) (40 mg, 0.07 mmol) in hot methanol (15 ml), and treated with an aqueous solution of Na 2 CO 3 (0.6 ml, 0.46 moles) followed by an additional portion of water (1.5 ml). The resulting cloudy mixture was stirred at room temperature for 18 h, then evaporated to dryness and dried. The resulting white solid was purified by chromatography (SIO2), gradient elution with 90:10 CH2Cl2: MeOH; CH 2 Cl 2: MeOH: NH 3 90: 10: 1), giving the desired product (34 mg, 100%). NMR 1H (CDCls) d 2.15 (s, 3H), 2.30 (s, 3H), 2.50 (s, 3H), 2.90 (t, 2H), 3.60 (t, 2H), 3. 90 (s, 2H), 4.50 (s, 2H), 4.75 (s, 2H), 6.70 (s, 1 H), 7.00 (s, 1 H), 7.05 (d, 1 H), 7. 20-7.40 (m, 5H), 7.45 (s, 1 H). LRMS m / z = 473.4 (M + 1) +.

EXAMPLE 9 2-r3- (r3- (3-A2etidinyl) phenethylamine> -6-methyl-2-oxo-1 (2H) -pyrazin-Nr (3-methyl-1H-indole-5 -yl) metipacetamide Examples 9 and 10 were prepared following the general methods outlined above, in particular those described for compounds of type (g), and more particularly according to example 8 RMN 1H (CD3OD, 300 MHz) d 2.18 (s, 3H), 2.28 (s, 3H), 3.05 (t, 2H), 3.78 (m, 2H), 4.17-4.40 (m, 5H), 4.54 (m, 2H), 4.80 (s, 2H), 6.58 (m, 1 H) ), 6.99 (m, 1H), 7.05 (d, 1H), 7.18-7.57 (m, 6H). LRMS m / z = 485 (M + 1) +.

EXAMPLE 10 Nr (3-MTethyl-1H-ynol-5-yl) met.p-2-r6-meth yl-3- (r3- (1-methy1-3-azetidin) - phenetinamino> 2-oxo-1 (2H) -pyrazinin-acetamide 1 H NMR (CD 3 OD, 300 MHz) d 2.14 (s, 3 H), 2.27 (s, 3 H), 2.39 (s, 3 H), 2.90 (t, 2 H), 3.20-3.38 (m, 3 H), 3.58 (t, 2H), 3.78 (m, 2H), 4.49 (s, 2H), 4.75 (s, 2H), 6.66 (s, 1 H), 6.98 (s, 1 H), 7.02 (d, 2H), 7.12 (m , 2H), 7.18-7.30 (m, 3H), 7.42 (s, 1 H). LRMS m / z = 499 (M + 1 f.

EXAMPLE 11 2-r3-rf3-frf2-Methoxyethylamino-1-methyl-phenethylamine-1-6-methyl-2-oxo-1 (2H) -pyrazinin-N-r (3-methyl-1H-indol-5-yl) -methinacetamide PREPARATION 40 3- (Cyanomethyl) -N- (methoxymethyl) benzamide 2- (3-Bromophenyl) acetonitrile (40 g, 0.20 mol) was added to a solution of 2-methoxyethylamine (61.3 g, 0.81 mol), triphenylphosphine (8.0 g, 0.03 mol), palladium acetate (4.0 g, 0.01 mol). ) and triethylamine (62 g, 0.61 mol) in tetrahydrofuran (400 ml). The reaction mixture was heated to 100 ° C in a sealed vessel under carbon monoxide at 684.9 kPa for 18 h, after which the solvent was removed under reduced pressure. The crude product was purified by column chromatography on silica gel using an elution gradient of dichloromethane: pentane (90:10), changing to dichloromethane (100%), and then dichloromethane: methanol (98: 2) to give the compound of the title, 14.57 g (33%). 1 H NMR (300 MHz, DMSO) d [ppm] 3.26 (3 H, s), 3.41 (4 H, m), 4.09 (2 H, s), 7.65-7.43 (2 H, m), 7.78 (1 H, s), 8.55 (1 H, s), 8.55 (1 H, broad s) LRMS m / z = 219 (MH +).

PREPARATION 41 3- (2-Aminoetyl) -N- (2-methoxyethyl) benzamide Borane (1 N in tetrahydrofuran, 467 mL, 0.467 moles) was added dropwise to a solution of 3- (Cyanomethyl) -N- (methoxymethyl) benzamide (14.57 g, 0.067 moles) [see preparation 40] in tetrahydrofuran (30 ml) for 20 minutes. The reaction mixture was then stirred at room temperature for 18 h, and then heated to reflux for 2 h, after which the solvent was evaporated under reduced pressure and the residue acidified with hydrochloric acid (2N). The resulting mixture was heated to reflux for 10 minutes, after which it was basified with sodium hydroxide. The product was extracted with dichloromethane (3x30 ml), the combined organic layers were dried over MgSO4, and the solvent was evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel using an elution gradient of dichloromethane: methanol: ammonia 0.88 (95: 5: 0.5), changing to (92.5: 7.5: 0.25), changing to (90: 10: 1) giving the title compound, 6.15 g (44%). 1 H NMR (300 MHz, DMSO) d [ppm] 1.60 (2H, broad s), 2.62 (4H, m), 2.73 (2H, m), 3.22 (3H, s), 3.40 (2H, t), 3.65 ( 2H, s), 7.05 (1H, d), 7.10 (2H, d), 7.22 (1H, d). LRMS: m / z = 209 (MH +).

PREPARATION 42 2-r3-Chloro-5-r (3-fr (2-methoxy-ethylamino-methyl) -phenethyl) -amino-1-2-methyl-6-oxo-1- (6H) -pyrazine-benzyl acetate 2- [3,5-Dichloro-2-methyl-6-oxo-1 (6H) -pyrazinyl] benzyl acetate (400 mg, 1.22 mmol) [see Preparation 17] was added to a solution of 3- (2- aminoethyl) -N- (2-methoxyethyl) benzamide (260 mg, 1.25 mmol) [see preparation 41] and triethylamine (0.34 ml, 2.4 mmol) in ethyl acetate (5 ml). The reaction mixture was heated to reflux for 4 h, after which the mixture was cooled to room temperature and stirred for an additional 56 h, the mixture was partitioned between ethyl acetate (20 ml) and water (20 ml). The organic layer was washed with water (2x20 ml), brine (20 ml), and dried over MgSO 4, and the solvent was evaporated under reduced pressure. The crude product was purified by trituration with diethyl ether to give the title compound, 365 mg, (60%) 1 H NMR (300 MHz, DMSO) d [ppm] 2.20 (3H, s), 2.60 (2H, t), 2.80 (2H, t), 3.30 (3H, s), 3.38 (2H, t), 3.45 (2H , m), 3.70 (2H, s), 4.85 (2H, s), 5.20 (2H, s), 7.07-7.25 (4H, m), 7.35 (5H, m), 7.50 (1H, t). LRMS: m / z = 499 (M +).

PREPARATION 43 2-r 3-Chloro-5-α (3. {R (2-methoxyethyl) (2,2,2-trifluoroacetyl) aminolmethyl> phenol) -amino-2-methyl-6- benzyl oxo-1 (6H) -pyrazine Trifluoroacetic anhydride (0.17 ml, 0.766 mmol) was added to a solution of 2- [3-chloro-5 - [(3- {[[(2-methoxyethyl) amino] methyl} phenethyl) amino] -2- Benzyl methyl-6-oxo-1 (6H) -pyrazinyl] acetate (365 mg, 0.73 mmol) [see preparation 42] and pyridine (0.077 ml, 0.95 mmol) in dichloromethane (5 ml). The reaction mixture was stirred at room temperature for 18 h, after which the mixture was partitioned between dichloromethane (20 ml) and water (20 ml), the organic layer was washed with brine (20 ml) and dried over MgSO4. , and the solvent was evaporated under reduced pressure. The crude product was purified by recrystallization from methanol to give the title compound as a white solid, 260 mg, (60%). 1 H NMR (300 MHz, DMSO) d [ppm] 2.20 (3H, s), 2.88 (2H, c), 3.20 (3H, m), 3.40-3.55 (6H, m), 4.65 (2H, d), 4.86. (2H, s), 5.20 (2H, s), 7.03-7.40 (9H, m), 7.55 (1H, m). LRMS: m / z = 596 (MH +).

PREPARATION 44 Acid 2-r 3 -r 3 -yr (2-methoxymethin (2,2,2-trifluoroacetyl) amino] methyl) phenyl) -amino-1-6-methyl-2-oxo-1 (2H), pyrazinyl acetic acid 2- [3-Chloro-5 - [(3. {[[(2-methoxyethyl) - (2,2,2, -trifluoroacetyl) amino] methyl.}. Phenethyl) amino] -2-methyl- was dissolved. 6-Oxo-1 (6H) -pyrazinyl] benzyl acetate [see preparation 43] (260 mg, 0.437 mmol) in methanol (10 ml) and palladium hydroxide catalyst (30 mg) was added. The reaction mixture was hydrogenated at 410.940 kPa for 4 h. The catalyst was removed by filtration, and the solvent was evaporated under reduced pressure to give the title compound as an oil, 190 mg, (92%). LRMS: m / z = 471 (MH +).

PREPARATION 45 2,2,2-Trifluoro-N- (2-methoxyethyn-N-r3- (2-yl-methyl-4- (2-fr3-methyl-1H, indol-5-yl) methylamino-2-oxoethyl ) -3-oxo-3,4-dihydro-2-pyrazin-amino-ethiO-benzyl-acetamide Hydroxybenzotriazole hydrate (60 mg, 0.44 mmol) was added and WSCDI? CI (93 mg, 0.47 mmol) to a solution of 2- [3 - [(3- {[[(2-methoxymethyl) (2,2,2-trifluoroacetyl)) amino] methyl} phenethyl. ) amino] -6-methyl-2-oxo-1 (2H) -pyrazinyl] acetic acid (190 mg, 0.40 mmol) [see Preparation 44] in N, N-dimethylformamide (3.0 mL). N-methylmorpholine (123 mg, 1.2 mmol) was added, followed by (3-methyl-1 H -indol-5-yl) methylamine (72 mg, 0.45 mmol) [see preparation 36]. The reaction mixture was stirred at room temperature for 18 h, after which the mixture was partitioned between ethyl acetate (30 ml) and water (30 ml). The organic layer was washed with water (3x30 ml), brine (30 ml) and dried over MgSO, and the solvent was evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel using an elution gradient of dichloromethane: methanol: ammonia 0.88 (99: 1: 0.1), changing to (98: 2: 0.2) to give the title compound as an oil , 113 mg (53%). 1 H NMR (300 MHz, CDCl 3) d [ppm] 2.93 (3H, m), 3.45-3.70 (12H, m), 4.50 (2H, d), 4.67 (2H, s), 4.73 (3H, m), 5.90 (1 H, m), 6.60 (1 H, m), 6.78 (1 H, s), 6.95-7.30 (8 H, m), 7.41 (1 H, s), 7.92 (1 H, m). LRMS: m / z = 613 (MH +).

PREPARATION 46 2-r3-r (3-fr (2-Methoxyethylamino-1-methyl-phenethyl) amino-1-6-methyl-2-oxo-1 (2H) -pyrazinyl-1-Nr (3-methyl-1H-indole-5 -yl) methyl1acetamide 2,2,2-Trifluoro-N- (2-methoxyethyl) -N- [3- (2. {[5-methyl-4- (2-. {[[(3-methyl- 1 H-indol-5-yl) methyl] amino.} -2-oxoethyl) -3-oxo-3,4-dihydro-2-pyrazinyl] amino.} Ethyl) benzyl] acetamide (preparation 45) (110 mg, 0.18 mmoles) in methanol (15 ml), and a solution of sodium carbonate in water (1.5 ml, 0.765 m, 1.15 mmol) was added. The reaction mixture was stirred for 56 h, after which the reaction was heated to 50 ° C and sodium carbonate (1.5 mL, 1.15 mmol) was added. The mixture was heated for 18 h, and then partitioned between ethyl acetate and water, the organic layer was washed with brine, dried over MgSO 4, and the solvent was evaporated under reduced pressure. The crude product was triturated with diethyl ether: methanol (1: 1) to give the title compound, 23 mg (25%). 1 H NMR (400 MHz, CDCl 3) d [ppm] 2.08 (3 H, s), 2.21 (3 H, s), 2.60 (1 H, t), 2.81 (2 H, m), 3.20 (3 H, s), 3.30 ( 3H, m), 3.39 (1H, t), 3.50 (3H, m), 3.57 (1H, m), 4.35 (2H, d), 4.60 (2H, m), 6.64 (1H, s), 6.78 (1 H, t), 6.94-7.30 (7H, m), 8.60 (1 H, t), 10.21 (1 H, broad s). LRMS: m / z = 517 (MH +). Found C 65.55, H, 6.78, N 15.48; C 29 H 36 N 6 O 3 H 2 O requires C 65.15, H 7.16, N 15.72%.

EXAMPLE 12 2-r3- (p (2R) -1- (Cyclopropylmethylpyrrolidinin-methyl > amino) -6-methyl-2-oxo-1 (2H) -pyrazinip-N-IT3-methyl-1H-indole -S-Dimethyl acetamide PREPARATION 47 2-R3-Chloro-5- ( { R (2R) -1- (cyclopropylmethyl) -pyrrolidin-methyl-methyl} -amino) -2-methyl-6-oxo-1-hydroxy-3-hydroxy-benzyl ester The title compound was prepared by a method similar to preparation 42 from 2- [3,5-dichloro-2-methyl-6-oxo-1 (6H) -pyrazinyl] benzyl acetate [see preparation 17] and [(12R) -1- (cyclopropylmethyl) pyrrolidinyl] methylamine [see WO 9839295 A1], giving the product as an orange oil (100%). LRMS: m / z = 445 (MH +).

PREPARATION 48 Hydrochloride of 2-r3-OT2R) -1- (cyclopropylmethyl) pyrrolidinH] methyl} amino) -6-methyl-2-oxo-1 (2H) -pyrazinyl acetic acid The title compound was prepared by a method similar to Preparation 44 from 2- [3-chloro-5- ( { [2R) -1- (cyclopropylmethyl) pyrrolidinyl] methyl} amino) -2-methyl-6-oxo-1 (6H) -pyrazinyl] benzyl acetate [see Preparation 47] and palladium hydroxide, giving the product as an oil, 352 mg, (100%). 1 H NMR (300 MHz, CDCl 3) d [ppm] 7.40 (1 H, t), 6.65 (1 H, s), 4.66 (2 H, s), 3.75-3.00 (7H, m), 2.87 (1 H, m ), 2.08 (3H, s), 1.96-1.71 (4H, m), 1.10 (1 H, m), 0.58 (2H, d), 0.35 (2H, m). 1 H NMR (300 MHz, CDCl 3) d [ppm] 0.35 (2H, m), 0.58 (2H, d), 1. 10 (1H, m), 1.91-1.96 (4H, m), 2.08 (3H, s), 2.87 (1H, m), 3.00-3.75 (7H, m), 4. 66 (2H, s), 6.65 (1 H, s), 7.40 (1 H, t).

PREPARATION 49 2-r 3 - (r 2 R) -1- (Cyclopropylmethyl) pyrrolidinin-methyl > amino) -6-methyl-oxo-1 (2H) -pyrazin-N-r (3-methyl-1 H -indol-5-yl) methyl-1-acetamide The title compound was prepared by a method similar to Preparation 45 from 2- [3- ( { [(2R) -1- (cyclopropylmethyl) pyrrolidinyl] methyl} amino) hydrochloride. 6-methyl-2-oxo-1 (2H) -pyrazinyl] acetic acid [see preparation 48] and (3-methyl-1 H -indol-5-yl) methylamine (72 mg, 0.45 mmol) [see preparation 36] ] The crude product was purified by column chromatography on silica gel using dichloromethane: methanol: ammonia 0.88 (96: 3.5: 0.5) as the eluent, giving the title compound as a yellow solid, 245 mg (55%). 1 H NMR (300 MHz, MeOD) d [ppm] 0.27 (2H, d), 0.53 (1 H, t), 0. 94 (1 H, m), 1.70 (1 H, m), 1.75 (2H, t), 1.90-2.00 (1 H, m), 2.18 (4H, m), 2.20- 2.40 (5H, m), 2.80 (2H, m), 3.30 (3H, m), 3.45-3.40 (2H, m), 4.46 (4H, m), 4.73 (1H, s), 6.68 (1 H, s), 6.98 (1 H, s), 7.06 (1 H, m), 7.26 (1 H, m), 7.45 (1 H, d). LRMS = 463 (MH +). The hydrochloride salt of preparation product 49 was prepared by dissolving the product in methanol (5 ml) and adding hydrochloric acid (1 N, 0.53 ml, 0.53 mmol) to give the hydrochloride of (2R) -1- (cyclopropylmethyl) -2- ( { [5-methyl-4- (2-. {[[(3-methyl-1 H -indol-5-yl) methyl] amino.} -2-oxoethyl) -3-oxo -3,4-dihydro-2-pyrazinyl] amino.} Methyl) pyrrolidinium as a solid. 1 H NMR consistent with the free base.

EXAMPLE 13 2-r3- ( { R (2R) -1-C-cyclopentyl-pyrrolidinomethyl &amine) -6-methyl-2-oxo-1 (2H) -pyrazinin- Nr (3-methyl-1H-indol-5-p-metipacetamide) PREPARATION 50 (2R) -2- ( { F (4-ethylphenol) sulfonpoxy> methyl) -1-pyrrolidinecarboxylate tert -butyl 4-Methylbenzenesulfonyl chloride (8.83 g, 46.32 mmol) was added to a solution of tere-butyl (2R) -2- (hydroxymethyl) -1-pyrrolidinecarboxylate (5.48 g, 27.24 mmole) in pyridine (25 ml). The reaction mixture was stirred for 2.5 h, after which the reaction was diluted with ethyl acetate (100 ml) and washed with water (100 ml), saturated copper sulfate solution (100 ml), dried over MgSO 4, and the solvent was evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel using ethyl acetate: pentane (20:80) as the eluent, giving the title compound as a clear oil, 9.2 g (95%). LRMS: m / z = 356 (MH +). Found C 57.44, H, 7.09, N 3.94; C17H25NO5S requires C 57.22, H 7.15, N 3.79%.

PREPARATION 51 (2R) -2- (Azidomethyl) -1-pyrrolidine-tert-butyl carboxylate Sodium azide (2.52 g, 38.80 mmol) was added to a solution of (2R) -2- (. {[[(4-Methylphenyl) sulfonyl] oxy} methyl] -1-pyrrolidinecarboxylic acid tert-butyl ester. (9.20 g, 25.90 mmol) [see preparation 50] in dimethylsulfoxide (100 ml). The reaction mixture was heated at 80 ° C for 18 h, after which the cooled mixture was partitioned between diethyl ether (200 ml) and water (200 ml). The aqueous layer was washed with diethyl ether (200 ml). The combined organic layers were dried over MgSO 4, and the solvent was evaporated under reduced pressure to give the title compound as a clear oil, 5.74 g, (98%). 1 H NMR (400 MHz, CDCl 3) d [ppm] 1.48 (9H, s), 1.50 (1 H, s), 1.80-2.06 (4H, m), 3.35 (4H, m), 3.90 (1 H, m) . LRMS: m / z = 227 (MH +).

PREPARATION 52 (2R) -2- (Aminomethyl) -1-pyrrolidine-carboxylate tert -butyl % palladium on charcoal (750 mg) was added to a solution of tert-butyl (2R) -2- (azidomethyl) -1-pyrrolidinecarboxylate (preparation 51) (5.74 g, 25.39 mmol) in ethanol (100 ml). ). The reaction mixture was hydrogenated 102,735 kPa for 2.5 h, after which the catalyst was removed by filtration and the solvent was evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel using dichloromethane: methanol: ammonia 0.88 (90: 10: 0.5) as the eluent, giving the title compound and some starting material. The mixture was dissolved in ethanol (100 ml) and 10% palladium on charcoal (500 mg) was added, the mixture was hydrogenated at 204 kPa for 18 h, after which the catalyst was removed by filtration and the solvent was removed. evaporated under reduced pressure, giving the title compound as a clear oil, 4. 32 g, (85%). 1 H NMR (300 MHz, CDCl 3): d [ppm] 1.30 (2H, broad s), 1.45 (9H, s), 1.72-2.00 (4H, m), 2.65-2.90 (2H, m), 3.26-3.33 ( 2H, m), 3.75 (1 H, m). LRMS: m / z = 201 (MH +).

PREPARATION 53 (2R) -2-r ((4-r2- (Benzyloxy) -2-oxoetin-6-chloro-5-methyl-3-oxo-3,4-dihydro-2-pyrazinyl > amino) methylated 1-pyrrolidine-tert-butyl carboxylate The title compound was prepared by a method similar to Preparation 42 from 2- [3,5-dichloro-2-methyl-6-oxo-1 (6H) -pyrazinyl] benzyl acetate (preparation 17) and ( 2R) -2- (aminomethyl) -1-pyrrolidinecarboxylic acid tert-butyl [see preparation 52]. The crude product was purified by column chromatography on silica gel using an elution gradient of ethyl acetate: pentane (10: α?), Changing to (80:20), in increments of %, giving the title compound as a clear oil, (80%). 1 H NMR (300 MHz, CDCl 3): d [ppm] 1.43 (9H, s), 1.70-2.08 (4H, m), 2.18 (2H, s), 2.35 (1 H, s), 3.26-3.65 (4H, m), 4.00-4.20 (1 H, m), 4.80 (2H, s), 5.25 (2H, s), 7.26-7.40 (5H, m). LRMS: m / z = 491 (MH +).

PREPARATION 54 Acid 2-r3 - ((r (2R) -1- (tert-butyloxycarbonyl) pyrrolidininmethyl amino) -6-methyl-2-OXQ-1 (2H) -pyrazine-acetic acid The title compound was prepared by a method similar to Preparation 44 from (2R) -2 - [(. {4- [2- (benzyloxy) -2-oxoethyl] -6-chloro-5-methyl- 3-Oxo-3,4-dihydro-2-pyrazinyl.} Amino) methyl] -1-pyrrolidinyl carboxylate of tert-butyl [see preparation 53] and palladium hydroxide giving the product as a white foam, (68%). 1 H NMR (400 MHz, DMSO): d [ppm] 1.40 (9H, s), 1.68-1.86 (4H, m), 2.00 (2H, s), 3.06-3.25 (4H, m), 3.40 (1H, s wide), 3.95 (1H, m), 4.13- 4.30 (2H, m), 5.72 (2H, s), 6.48 (1 H, s). LRMS: m / z = 367 (MH +).

PREPARATION 55 (2R) -2- r5-Methyl-4- (2- rf3-methyl-1H-indol-5-methamino-amino-2-oxoethyl) -3-oxo-3,4-dihydro-2-pyrazinipamline > methyl) -1-pyrrolidinecarboxylate tert-butyl The title compound was prepared by a method similar to Preparation 45 from 2- [3- ( { [(2R) -1- (tert-Butyloxycarbonyl) pyrrolidinyl] methyl]. amino) -6-methyl-2-oxo-1 (2H) -pyrazinyl] acetic acid [see Preparation 54] and (3-methyl-1 H-indol-5-yl) methylamine (72 mg, 0.45 mmol) [see Preparation 36]. The crude product was purified by column chromatography on silica gel using an elution gradient of dichloromethane: methanol (100: 0), changing to (95: 5) in 1% increments. 1 H NMR indicated starting chlorine compound material. A mixture of this product was then stirred in 10% palladium on charcoal (39.6 mg) and ammonium formate (439.5 mg, 6.98 mmol) in dichloromethane (50 ml), at room temperature overnight. Additionally, 10% palladium on charcoal (49 mg) was added, and the mixture was heated to reflux for 48 h, after which the catalyst was removed by filtration, and the solvent was evaporated under reduced pressure. The residue was partitioned between ethyl acetate (100 ml) and water (100 ml). The organic layer was separated and dried over MgSO 4, and the solvent was evaporated under reduced pressure, giving the title compound as an off white solid, (44%). 1 H NMR (400 MHz, DMSO): d [ppm] 1.40 (9H, s), 1.70-1.86 (4H, m), 2.06 (2H, s), 2.21 (3H, s), 3.23 (4H, m), 3.43 (1 H, m), 4.35 (2 H, d), 4.63 (2 H, s), 6.59 (1 H, s), 6.98 (1 H, d), 7.07 (1 H, s), 7.25 (1 H , d), 7.35 (1 H, s), 8.60 (1 H, m), 10.65 (1 H, broad s). LRMS: m / z = 509 (MH +).

PREPARATION 56 N-r (3-Met l-1 H -indol-5-n-methyn-2-r6-methyl-2-oxo-3- (r (2R) -pyrrolidinylmethylamino]. -1 (2H) -pyrazinyl acetamide It was dissolved (2R) -2- ( { [5-methyl-4- (2. {[[(3-methyl-1 H -indol-5-yl) methyl] amino.} -2-oxoethyl 3-oxo-3,4-dihydro-2-pyrazinyl] amino.} Methyl) -1-pyrrolidinecarboxylic acid tert-butyl ester (1.08 mg, 2.14 mmol) [see preparation 55] in methanol (10 ml) and added hydrochloric acid (6N, 10 ml, 60 mmol). The reaction mixture was stirred for 18 h, after which the pH was adjusted to 10 with sodium hydroxide (1 N). The product was then extracted with dichloromethane (100 ml), followed by dichloromethane: methanol (90:10) (100 ml). The aqueous and organic layers were then concentrated under reduced pressure and the residue was triturated with isopropanol (3x100 ml) to give the title compound as an off-white solid, 629 mg (72%). 1 H NMR (400 MHz, DMSO): d [ppm] 1.58-1.85 (4H, m), 2.06 (2H, s), 2.21 (3H, s), 2.77-290 (2H, m), 3.15-3.40 (5H , m), 4.35 (2H, d), 4.61 (2H, s), 6.60 (1 H, s), 6.80 (1 H, m), 6.98 (1 H, d), 7.06 (1 H, s), 7.26 (1 H, d), 7.37 (1 H, s), 8.65 (1 H, m), 10.68 (1 H, s). LRMS: m / z = 409 (MH +).

PREPARATION 57 2-r3- ( { R (2R) -1-Cyclopentyl-pyrrolidininmethyl > amino) -6-methyl-2-oxo-1 (2H) -pyrazinyl-Nr (3-methyl-1H-indole- 5-l) methapacetamide N - [(3-Methyl-1 H -indol-5-yl) methyl] -2- (6-methyl-2-oxo-3. {[[(2R) -pyrrolidinylmethyl] amino] was stirred together. -1- (2H) -pyrazinyl] acetamide (52.3 mg, 0.129 mmol) [see preparation 56] and cyclopentanone (22 ml, 0.248 mmol) in N, N-dimethylformamide (2 ml) was added sodium triacetoxyborohydride ( 27.3 mg, 0.129 mmol) The reaction mixture was stirred for 18 h, after which the mixture was quenched with water and made basic.The product was then extracted with ethyl acetate (4x50 ml), the combined organic layers were dried with MgSO 4 and the solvent was evaporated under reduced pressure.The crude product was purified by column chromatography on silica gel using an elution gradient of dichloromethane: methanol (100: 0), changing to (90:10), and then dichloromethane: methanol: ammonia 0.88 (90: 10: 1), changing to (84: 14: 2) to give the title compound as a solid, 19.4 mg, (32%). 1 H NMR (300 MHz, CD3OD): d [ppm] 1.40-2.00 (12H, m), 2.11 (3H, s), 2.28 (3H, s), 2.55-2.65 (1 H, c), 3.00-3.17 (3H, m), 3.20-3.35 (1 H, m), 3.47-3.55 (1 H, 2xd), 4.46 (2H, s) ), 4.71 (2H, s), 6.65 (1 H, s), 6.98 (1 H, s), 7.03 (1 H, d), 7.25 (1 H, d), 7.41 (1 H, s). LRMS: m / z = 477 (MH +).

EXAMPLES 14-19 The compounds of the following tabulated examples with the general formula: were prepared using a method similar to preparation 57 from N - [(3-methyl-1H-indol-5-yl) methyl] -2- [6-methylene-2-oxo-3-. { [(2R) -pyrrolidium] amino]} -1 (2H) -pyrazinyl] acetamide [see Preparation 56] and the corresponding carbonyl compound. fifteen 10 fifteen PREPARATION 58 1 -Methylcyclopropanecarbaldehyde Molecular sieves of 4A and N-methylmorpholine N-oxide (9.916 g, 84.64 mmol) were added to a solution of 1-methylcyclopropanmethanol (4.86 g, 56.4 mmol) in dichloromethane (200 ml) under a nitrogen atmosphere. The reaction mixture was stirred at room temperature for 20 min, after which tetrahydrofuran-n-propylammonium perruthenate (VII) (0.992 g, 2.82 mmol) was added. The mixture was stirred for an additional 4 h, and then filtered through a plug of silica eluting with dichloromethane to give the crude product, which was fractionally distilled, to give the title compound (100%).

EXAMPLE 18 2-r3-r (2R) -1-lsobutylpyrrolidinipmethyl > amino) -6-methyl-2-oxo-1 (2H) -pyrazinip-N- (3-methyl-1H-indol-5-yl) metpapacetamide PREPARATION 59 (2R) -1-lsobutyl-2-pyrrolidinecarboxamide The title compound was prepared by a method similar to preparation 57 from R-prolinamide and 3-methylbutanal. The crude product was purified by column chromatography on silica gel using dichloromethane: methanol: ammonia 0.88 (96: 3.5: 0.5), as the eluent, giving the product as a white solid, (87%). 1 H NMR (400 MHz, CDCl 3): d [ppm] 0.88 (3H, d), 0.97 (3H, d), 1. 68-1.93 (4H, m), 2.12-2.35 (4H, m), 3.00 (1H, m), 3.17 (1H, m), 6.67 (1H, s wide), 7.37 (1 H, wide s). LRMS: m / z = 171 (MH +).

PREPARATION 60 r (2R) -1-lsobutylpyrrolidinipmetanamide Lithium aluminum hydride [disol. 1.0 mol in tetrahydrofuran] (11.52 ml, 11.52 mmol) to a solution of (2R) -1-isobutyl-2-pyrrolidinecarboxamide (1.3 g, 7.68 mmol) [see preparation 59] in tetrahydrofuran (5 ml) at 0 ° C. The reaction mixture was stirred for 10 min, and then heated to reflux for 6 h. Water (0.5 ml) was added to the cooled mixture, followed by sodium hydroxide (1.5 ml) and water (1.5 ml). Tetrahydrofuran (10 ml) was added, and the mixture was stirred at room temperature for 1 h. The aluminum salts were removed by filtration and washed well with diethyl ether. The filtrate was then evaporated under reduced pressure to give the title compound as a white solid, 705 mg, (58%). 1 H NMR (400 MHz, CDCl 3): d [ppm] 0.86 (3H, d), 0.92 (3H, d), 1. 78-1.86 (5H, m), 2.04-2.10 (2H, m), 2.26-2.38 (2H, m), 2.60 (1H, 2xd), 2.72 (1 H, m), 3.09 (1 H, m). LRMS m / z = 157 (MH +).

PREPARATION 61 2-r3-CHLORO-5- rf2R) -1-isobutylpyrrolidinmethyl > amino) -2-methyl-6-oxo-1 (6H) -pyzinyl acetate benzyl The title compound was prepared by a method similar to preparation 42 of benzyl 2- [3,5-dichloro-2-methyl-6-oxo-1- (6H) -pyrazinyl] acetate (preparation 170) and [( 2R) -1-isobutylpyrrolidinyl] methanamine [see preparation 60]. The crude product was purified by column chromatography on silica gel using ethyl acetate as the eluent, giving the product as a yellow oil, (94%). 1 H NMR (400 MHz, CDCl 3): d [ppm] 0.90 (6H, 2xd), 1.60 (1 H, m), 1.70 (3H, m), 1.85 (1 H, m), 2.08 (2H, m), 2.20 (3H, s), 2.30 (1 H, m), 2.62 (1 H, m), 3.12 (1 H, m), 3.27 (1H, m), 3.55 (1 H, m), 4.78 (2H, m), 5.20 (2H, s), 6. 66 (1 H, m), 7.32 (5H, m). LRMS m / z = 447 (MH +).

PREPARATION 62 2-r3 - ((r (2R) -1-isobutylpyrrolidinipmethyl) amino) -6-methyl-2-oxo-1 (2H) -pyrazinyl-1-acetic acid hydrochloride The title compound was prepared by a method similar to Preparation 44 from 2- [3-chloro-5- ( { [(-2R) -1-isobutylpyrrolidinyl] methyl.}. Amino-2-methyl- 6-Oxo-1 (6H) -pyrazinyl] benzyl acetate [see Preparation 61] and palladium hydroxide, giving the product as an oil, LRMS m / z = 323 (MH +).

PREPARATION 63 2-r3- (2R) -1-lsobutylpyrrolidininmethyl amino) -6-methyl-2-oxo-1 (2H) -pyrazinin-N-r (3-methyl-1H-indol-5-8l) methinacetamide The title compound was prepared by a method similar to Preparation 49 from 2- [3- ( { [(2R) -1-Isobutylpyrrolidinyl] methyl.} Amino) -6-methyl-2-hydrochloride. -oxo-1 (2H) -pyrazinyl] acetic acid [see Preparation 62] and (3-methyl-1 H -indol-5-yl) methylamine (72 mg, 0.45 mmol) [see preparation 36]. The crude product was purified by column chromatography on silica gel using dichloromethane: methanol: ammonia 0.88 (92: 7: 1) as the eluent, giving the product as a foam. This was dissolved in methanol (5 ml) and hydrochloric acid (1M, 0.58 ml, 0.58 mmol), yielding the product, (56%). 1 H NMR (400 MHz, CDCl 3): d [ppm] 0.95 (6H, 2xd), 1.72-2.10 (7H, m), 2.21 (3H, s), 2.86-3.20 (4H, m), 3.33-3.50 (4H, m), 4.35 (2H, d), 4.63 (2H, s), 6.60 (1H, s), 6.98 (1H, d), 7.06 (1 H, s), 7.25 (1 H, d), 7.35 (1 H, s), 7.42 (1H, sa), 8.68 (1 H, t), 8.80 (1 H, sa), 10.68 (1 H, sa).

EXAMPLE J9 AND 20 The compounds of the following tabulated examples with the general formula: They were prepared using a method similar to preparation 57 from N - [(3-methyl-1 H -indol-5-yl) methyl-2- [6-methyl-2-oxo-3-. { [(2S) pyrrolidinylmethyl] amino} -1 (2H) -pyrazinyl] acetamide [see preparation 67] and the corresponding carbonyl compound.

PREPARATION 64 (2S) -2-r 4-r2- (Benzyloxy) -2-oxoetin-6-chloro-5-methyl-3-oxo-3,4-dihydro-2-pyrazinyl) amino) metip-1 -Pyrrolidin-tert-butyl carboxylate The title compound was prepared by a method similar to preparation 42 of 2- [3,5-dichloro-2-methyl-6-oxo-1 (6H) -pyrazinyl] benzyl acetate (preparation 17) and (2S) -2- (aminomethyl) -1-tert-butyl pyrrolidinecarboxylate [JP 63183560 A2], giving the product as a colorless oil, (100%). 1 H NMR (400 MHz, DMSO): d [ppm] 1.38 (9H, s), 1.68-1.86 (4H, m), 2.19 (3H, s), 3.20 -3.30 (3H, m), 4.01 (1H, m), 4.86 (2H, s), 5.19 (2H, s), 7.35 (5H, m), 7.45-7.60 (1H, m). LRMS m / z = 491 (M +).

PREPARATION 65 Acid 2-r3- (fí (2S) -1- (tert-butoxycarbonyl) pyrrolidininmethyl amino) -5-chloro-6-methyl-2-oxo-1 (2H) -pyrazine-acetic acid The title compound was prepared by a method similar to preparation 44 from (2S) -2 - [(. {4- [2- (benzyloxy) -2-oxoethyl] -6-chloro-5-methyl- 3-Oxo-3,4-dihydro-2-pyrazinyl.] Amino) methyl] -1-pyrrolidinecarboxylic acid tert-butyl ester (see preparation 64) and palladium hydroxide. The title compound was purified by column chromatography on silica gel using an elution gradient of dichloromethane: methanol: ammonia 0.88 (90: 10: 0.5) changing up to (80: 20: 3), giving the product as a colorless oil (44%) 1 H NMR (400 MHz, DMSO): d [ppm] 1.40 (9H, s), 1.68-1.86 (4H, m), 2.00 (3H, s), 3.05-3.27 (3H, m), 3.41 (1H, sa), 3.99 (1 H, m), 4.30 (2H, m), 6.50 (1 H, s), 6.61-6.80 (1 H, m). LRMS m / z = 367 (MH +).

PREPARATION 66 (2S) -2- (ir6-Chloro-5-methyl-4- (2-methyl-1H-indole-5-inmetinamino> 2-oxoethyl) -3-oxo-3,4-dihydro-2 -p¡raz¡n¡llam¡no) metl) -1-pirriolidincarboxylate The title compound was prepared by a method similar to Preparation 45 from 2- [3- (. {[[(2S) -1- (tert-butoxycarbonyl) pyrrolidinyl] methyl} amino) -6- methyl-2-oxo-1 (2H) -pyrazinyl] acetic acid [see Preparation 65) and (3-methyl-1H-indol-5-yl) methylamine (72 mg, 0.45 mmol) [see Preparation 36], giving the product as a colorless oil (89%). 1 H NMR (400 MHz, DMSO): d [ppm] 1.39 (9H, s), 1.66-1.87 (4H, m), 2.05 (3H, s), 2.21 (3H, s), 3.13-3.30 (4h, m) ), 3.40 (1 h, sa), 4.00 (1 h, m), 3.37 (2 H, d), 4.61 (2 H, s), 6.58 (1 H, s), 6.97 (1 H, d), 7.07 (1 h , s), 7.25 (1 h, d), 7.45 (1 h, s), 8.60 (1 H, t). LRMS m / z = 509 (MH +).

PREPARATION 67 N-r (3-Methyl-1H-indol-5-methyl-2-r6-methyl-2-oxo-3-. {R (2S) pyrrolidinylmethylamino] -1- (2H) -pyrazinyl acetamide The title compound was prepared by a method similar to Preparation 56 from (2S) -2- ( { [6-chloro-5-methyl-4- (2-. {[[(3-methyl- 1H-indol-5-yl) methyl] amino.} -2-oxoethyl) -3-oxo-3,4-dihydro-2-prazrazinyl] amino.} Methyl) -1- pyrrolidinecarboxylate tert -butyl [see preparation 66] and hydrochloric acid 6N, giving the product as a white solid, (60%). 1 H NMR (400 MHz, DMSO): d [ppm] 1.35 (1 H, m), 1.53-1.78 (3 H, m), 2.05 (3 H, s), 2.22 (3 H, s), 2.75 (2 H, m) , 3.08-3.32 (4h, m), 4.34 (2H, d), 4.61 (2H, s), 6.60 (1h, s), 6.66 (1h, m), 6.98 (1H, d), 7.06 (1H , s), 7.27 (1h, d), 7.39 (1H, s), 8.61 (1H t), 10.63 (1h, sa). LRMS m / z = 409 (MH +).

EXAMPLE 21 2-r3- ( { R2R) -1- (Cyclopropylmethyl) piperidinyl-1-methyl) -amino) -6-methyl-2-oxo-1 (2H) -pirazinip-Nr (3-methyl-1H- indole-S-iDmethylacetamide PREPARATION 68 (2R) -2 -Piperidinecarboxamide (2R) -2- (methoxycarbonyl) piperidine chloride (2.6 g, 14.5 mmol) was dissolved in ammonia (0.88 M, 30 mL). The reaction mixture was heated to 60 ° C for 1.5 h. The mixture was partitioned between ethyl acetate (100 ml) and sodium hydroxide (1N, 100 ml, 100 mmol), the aqueous was washed with ethyl acetate (3x100 ml). The combined organic layers were dried over sodium sulfate and the solvent was evaporated under reduced pressure. The aqueous layer was acidified with hydrochloric acid and evaporated to dryness under reduced pressure.

The resulting white solid was triturated with dichloromethane: methanol (9: 1), the remaining solid was removed by filtration and the filtrate was evaporated under reduced pressure to give the title compound as a white solid. 1.14 g, (61%). LRMS m / z = 129 (MH +).

PREPARATION 69 (2R) -1- (Cyclopropylmethyl) -2-piperidinecarboxamide The title compound was prepared by a method similar to preparation 57 from (2R) -2-piperidinecarboxamide [see preparation 68] and cyclopropylcarboxaldehyde. The crude compound was purified by column chromatography on silica gel using dichloromethane: methanol: ammonia 0.88 (92: 7: 1) as the eluent giving the product as a white solid, (44%). 1 H NMR (300 MHz, CDCl 3): d [ppm] 0.00-0.20 (2h, m), 0.40-0.61 (2H, m), 0.79-0.93 (1 H, m), 1.18-1.38 (1 H, m) , 1.40-1.80 (5H, m), 1.87-2.14 (3H, m), 2.56 (1 H, 2xd), 2.71 (1 H, 2xd), 3.30 (1 H, m), 5.29 (1 H, sa) 6.64 (1H, sa). LRMS m / z = 183 (MH +).

PREPARATION 70 IY2R) -1- (Cyclopropylmethylpiperidinipmethylamine) The title compound was prepared by a method similar to preparation 60 from (2R) -1 (cyclopropylmethyl) -2-piperidinecarboxamide [see preparation 69] and lithium aluminum hydride. The crude product was purified by column chromatography on silica gel using dichloromethane: methanol: ammonia 0.88 (90: 10: 0.1) as the eluent giving the product as a yellow oil, (71%).

PREPARATION 71 2-r3-chloro-5- ( { R (2R) -1-fc-chloropropylmethyl) piperidininmethyl) amino) -2-metin-6-oxo-1 (6H) -piperazine-benzyl acetate The title compound was prepared by a method similar to Preparation 42 from 2- [3,5-dichloro-2-methyl-6-oxo-1 (6H) -pyrazinyl] benzyl acetate (preparation 17) and [ (2R) -1 (chloropropylmethyl) piperidinyl] methylamine [see preparation 70]. The crude product was purified by column chromatography on silica gel using dichloromethane: methanol (95: 5), giving the product as a yellow oil, (87%). 1 H NMR (300 MHz, CDCl 3): d [ppm] 0.10 (2 H, m 9, 0.45 (2 H, m), 0.92 (1 H, m 9, 1.20-1.79 (5 H, m), 2.20-2.31 (5 H, m) , 2.57 (2H, m), 3.17 (1 H, m) 3.46 (2H, m), 4.80 (2H, s), 5.21 (2H, s), 6.63 (1H, m), 7.18 (1H, d) ), 7.39 (5H, m). LRMS m / z = 459 (MH +).

PREPARATION 72 i Acid 2-r3-chloro-5- ( {T (2R) -1 - (cyclopropylmethyl) priperidinylmethyl) amino-2-methyl-6-oxo-1 (6H) -pyrazinyl lalace The title compound was prepared by a method similar to preparation 44 from 2- [3-chloro-5- ( { [(2R) -1- (cyclopropylmethyl) piperidnol] meth l.}. amino) -2-methyl-6-oxo-1 (6H) -pyrazinyl] benzyl acetate [see preparation 71] and palladium hydroxide, giving the product as a yellow foam, (100%). LRMS m / z = 369 (MH +).

PREPARATION 73 2-r3-Chloro-5- (p (2R) -1- (cyclopropylmethyl) piperidin-methyl-amino) -2-methyl-6-oxo-1 (6H) -piperazinip-Nr (3- methyl-1H-indol-5-yl) methylpacetamide The title compound was prepared by a method similar to Preparation 45 from 2- [3-chloro-5- ( { [(2R) -1- (cyclopropylmethyl) piperidinyl] methyl} amino) - 2-methyl-6-oxo-1 (6H) -pyrazinyl] acetic acid [see Preparation 72] and (3-methyl-1 H -indole-5-yl) methylamine (preparation 36) giving the product as a white solid, (14%) LRMS m / z = 511 (MH +).

PREPARATION 74 2-r 3 - (r (2R) -1- (Cyclopropylmethyl) piperidinin-methyl > amino-6-methyl-2-oxo-1 (2H) -pyrazinin-N - [(3-methyl-1 H- indole-5-yl) methyl1acetamide The title compound was prepared by a method similar to Preparation 44 from 2- [3-cyoro-5- ( { [(2R) -1- (cyclopropylmethyl) piperidinyl] methyl.} Amino) -2 methyl-6-oxo-1 (6H) -pyrazinyl] -N - [(3-methyl-1 H -indol-5-yl) methyl] acetamide [see preparation 73] and palladium hydroxide. The crude product was purified by column chromatography on silica gel using dichloromethane: methanol: ammonia 0.88 (90: 10: 1) as eluent, giving the product as a white solid, (36%). NMR? (400 MHz, CD3OD): d [ppm] 0.15 (2H, m), 0.53 (2H, m), 0.96 (1H, m), 1.32-1.88 (6H, m), 2.15 (3H, s), 2.29 ( 3H, s), 2.40 (2H, s), 2.70 (3H, m), 3.20 (1H, m), 3.30 (3H, m), 3.33 (1H, m), 3.39-3.57 (2H, m), 4.48 (2H, s), 4.75 (2H, s), 6.65 (1H, s), 6.98 (1H, s), 7.06 (1H, d), 7.27 (1H, d), 7.43 (1H, s).

LRMS m / z = 477 (MH +).

EXAMPLE 22 -r3 - ((r (2S) -1- (Cyclopropylmethyl) pyrrolidinin-methyl) amino) -6-methyl-2-oxo-1 (2H) -p¡raz¡n¡pNr (3-methyl-1 H-indol-5-yl) methylpacetamide PREPARATION 75 2-r3-Chloro-5- ( { R (2S) -1- (cyclopropylmethyl) pyrrolidinimethylamino) -2-methyl-6-oxo-1 (6H) -pyrazinol acetate of benzyl A mixture of benzyl 2- [3,5-dichloro-2-methyl-6-oxo-1 (6H) -pyrazinyl] acetate (preparation 17) (400 mg, 1.22 mmol) and [(2S) -1- ( cyclopropylmethyl) pyrrolidinyl] methalamine (WO 87.07271) 190 mg, 1.22 mmol) and triethylamine (0.51 ml, 3.67 mmol) in ethyl acetate (20 ml) was heated under reflux for 18 hours. The cooled mixture was partitioned between water and ethyl acetate, the phases were separated, and the organic layer was dried over MgSO 4 and concentrated under reduced pressure. The residual orange oil was purified by column chromatography on silica gel using dichloromethane: methanol: ammonia 0.88 (96: 3.5: 0.5) as eluent, giving the desired product as a yellow oil, (476 mg, 88%). NMR (CDCls, 300 MHz): d 0.15 (m, 2H), 0.48 (m, 2H), 0.92 (m, 1H), 1.58-1.94 (m, 5H), 2.03 (m, 1 H), 2.23 (s) , 3H), 2.70 (m, 2H), 3.30 (m, 2H), 3.60 (m, 1 H), 4.80 (s, 2H), 5.22 (s, 2H), 6.62 (s, width, 1 H), 7.38 (m, 5H).

PREPARATION 76 2-r5- (ir2S) -1- (c-Chloropropylmethyl) pyrrolidininmethyl> 2-hydrochloride > ammonium) -2-methyl-6-oxo-1- (6H) -pyrazinyl lalacetic A mixture of 2- [3-chloro-5- ( { [(2S) -1- (cyclopropyl-methyl) pyrrolidinyl] methyl.} Amino) -2-methyl-6-oxo-1 (6H) - pyrazinyl] benzyl acetate (preparation 75) (470 mg, 1.06 mmol) and palladium hydroxide (230 mg) in methanol (20 ml) was hydrogenated at room temperature and 389.88 kPa for 3 h. The reaction mixture was filtered through Arbocel®, washed with ethanol, and the combined filtrate was evaporated under reduced pressure, giving the title compound as a yellow foam, (388 mg, 100%). 1 H NMR (d6-DMSO, 300 MHz) d: 0.38 (m, 2H), 0.60 (m, 2H), 0.97 (m, 1H), 1.77-1.99 (m, 4H), 2.07 (s, 3H), 2.96 (m, 1H), 3.06-3.76 (m, 6H), 4.66 (s, 2H), 6.64 (s, 1H), 7.40 (t, width, 1H), 10.05 (s, width, 1H).

PREPARATION 77 2-r3- ([[(2S) -1- (Cyclopropylmethylpyrrolidininmethyl) -amino) -6-methyl-2-oxo-1 (2 H) -pyrazinyl-1-N-r (3-methyl-1 H -indol-5-yl) methyl-1-acetamide A mixture of 2- [5- ( { [(2S) -1- (cyclopropylmethyl) pyrrolidinyl] methyl} -amino) -2-methyl-6-oxo-1 (6H) hydrochloride. ) -pyrazinyl] -acetic acid (preparation 76) (380 mg, 1.07 mmol), (3-methyl-1 H-indol-5-yl) methylamine (preparation 36) (171 mg, 1.07 mmol) ), HOBT (216 mg, 1.60 mmol), WSCDI.HCI (255 mg, 1.33 mmol) and N-methylmorpholine (0.38 mL, 3.46 mmol) in N, N-dimethylformamide (4 mL), it was stirred at room temperature for 24 h under a nitrogen atmosphere. The reaction mixture was evaporated under reduced pressure and the residue was purified by column chromatography on silica gel using dichloromethane: methanol: ammonia 0.88 (96: 3, 5: 0.5) as eluent. This product was further purified using a Biotage ™ cartridge (KP-Sil ™ 60 A silica gel) and dichloromethane: methanol: 0.88 ammonia (96: 3, 5: 0.5) as eluent to give the title compound as a white solid. (145 mg, 29%).

NMR? (CDCls, 300 MHz) d: 0.10 (m, 2H), 0.48 (m, 2H), 0.88 (m, 1H), 1.58-1.90 (m, 5H), 2.00 (m, 1H), 2.22 (s, 3H), 2.30 (s, 3H), 2.60-2.80 (m, 2H), 3.25 (m, 2H), 3.52 (m, 1H), 4.52 (d, 2H), 4.62 (s, 2H), 6.37 (s, width, 1H), 6.69 (m, 2H), 6.98 (s, 1H), 7.02 (d, 1H), 7.24 (m, 1H), 7.40 (s, 1H), 8.10 (s, 1H). LMRS: m / z = 463 (M + 1) + EXAMPLE 23 2-r 3 - (rt (3R) -1- (Cyclopropylmethyl) pyrrolidinmethyl > -amino) -6-methyl-2-oxo-1 (2H) -pyrazin-p-N-r (3-methyl-1H-indol-5-yl) methyl-1-acetamide PREPARATION 78 (3S) -3-r-Methylsulfonyl) oxy-1-pyrrolidinecarboxylic acid tert-butyl ester Triethylamine (8.7 ml, 62.4 mmol) was added to a solution of (3R) -3-pyrrolidinol (5.16 g, 41.7 mmol) in dichloromethane (30 ml), and the solution was stirred for 10 min. Di- tert -butyl dicarbonate (9.11 g, 41.7 mmol) was added and the reaction was stirred at room temperature for 20 h. The reaction mixture was concentrated under reduced pressure and the residue was partitioned between water and ethyl acetate, and the layers were separated. The organic phase was washed with 1 N citric acid, water and brine, then dried over MgSO 4, and evaporated under reduced pressure to give a pale yellow oil, 7.14 g.

This intermediate alcohol was dissolved in dichloromethane (100 ml, triethylamine (6.4 ml, 45.9 mmol) was added and the solution was cooled in an ice bath, methanesulfonyl chloride (3.25 ml, 41%) was slowly added. 9 mmol), and the reaction was stirred for 2 h. The reaction mixture was washed with 1 N citric acid, saturated NaHC 3 solution, brine, then Na 2 SO 4 was dried and evaporated under reduced pressure to give the title compound as one oil, (9.36 g, 85%).

NMR? (CDCl 3, 300 MHZ) d: 1.40 (s, 9H), 2.03-2.28 (m, 2H), 2.99 (s, 3H), 3.36-3.60 (m, 4H), 5.18 (m, 1 H).

LMRS: m / z = 283 (M + 18) + PREPARATION 79 (3R) -3-Cyano-1-pyrrolidinecarboxylate tert -butyl Potassium cyanide (5.80 g, 89 mmol) was added to a solution of tert-butyl (3S) -3 - [(methylsulfonyl) oxy] -1-pyrrolidinecarboxylate (preparation 78) (9.35 g, 35.3 mmol) in dimethyl sulfoxide (100 ml), and the reaction was stirred at room temperature for 18 h, and then at 100 ° C for a further 24 h. The cooled mixture was poured into water and extracted well with ethyl acetate. The combined organic extracts were washed with brine, dried over MgSO 4 and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using ethyl acetate: pentane (20:80) as eluent to give the title compound as an oil, (4.28 g, 62%).

NMR (CDCl 3, 300 MHz) d: 1.46 (s, 9H), 2.21 (m, 2H), 3.10 (m, 1 H), 3.39-3.78 (m, 4H).

LMRS: m / z = 214 (M + 18) + PREPARATION 80 (3R) -3-Aminomethyl-1-pyrrolidinecarboxylic acid tert-butyl ester A mixture of tert-butyl (3R) -3-cyano-1-pyrrolidinecarboxylate (preparation 79) (1.60 g, 8.13 mmol) and Nickel Raney® (1 g) in 0.88 ammonia (20 ml) and ethanol ( 150 ml), was hydrogenated at 389.88 kPa at room temperature for 8 h. The mixture was filtered through Arbocel®, and the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel using an elution gradient of dichloromethane: methanol: ammonia 0.88 (100: 0: 0 to 90: 10: 1) yielding the desired product as an oil, (1.59) g, 98%). 1 H NMR (CDCl 3, 300 MHz) d: 1.39 (s, 2 H), 1.48 (s, 9 H), 1.59 (m, 1 H), 2.00 (m, 1 H), 2.22 (m, 1 H), 2.74 (m, 2 H), 3.00 (m, 1 H), 3.30 (m, 1 H), 3.38-3.59 (m, 2H ).

LMRS: m / z = 201 (M + 1) + PREPARATION 81 (3R) -3-rf (4-r2-Benzyloxy) -2-oxoetyl-6-chloro-5-methyl-3-oxo-3,4-dihydro-2-pyrazinyl} amino) tert-butyl methyH-1-pyrrolidin-carboxylate A mixture of benzyl 2- [3,5-dichloro-2-methyl-6-oxo-1 (6H) -pyrazinyl] acetate (preparation 17) (647 mg, 1.98 mmol), (3R) -3- tert-butyl aminomethyl-1-pyrrolidinecarboxylate (preparation 80), 398 mg, 1.98 mmol) and triethylamine (830 ml, 5.95 mmol) in ethyl acetate (25 ml) was heated under reflux for 18 h. The cooled mixture was washed consecutively with water, 1N citric acid solution, brine, then dried over MgSO > and evaporated under reduced pressure to give the desired compound as a gum, (952 mg, 98%). 1 H NMR (CDCls, 300 MHz) d: 1.44 (s, 9H), 1.66 (m, 1 H), 2.01 (m, 1H), 2.21 (s, 3H), 2.56 (m, 1 H), 3.28-3.59 (m, 5H), 4.80 (s, 2H), 5.22 (s, 2H), 6. 15 (t, width, 1 H), 7.39 (m, 5H).

PREPARATION 82 Acid 2-r3- ( { R (3R) -1-tert-butoxycarbonyl) pyrrolidinylmethyl} amino) -6-methyl-2-OXQ-1 (2H) -pyrazinyl-1-acetic acid A mixture of (3R) -3 - [( { 4- [2- (benzyloxy) -2-oxoethyl] -6-chloro-5-methyl-3-oxo-3,4-dihydro-2- pyrazinyl.} amino) methyl] -1-pyrrolidinecarboxylic acid (preparation 81) (922.3 mg, 1.89 mmol), ammonium formate (1.19 g, 18.9 mmol) and palladium on charcoal 10% (166.8 mg) in methanol (50 ml) was stirred at room temperature under nitrogen atmosphere for 20 h. The mixture was filtered through Arbocerl®, and the filtrate was evaporated under reduced pressure. The residue was triturated with a 10% solution of dichloromethane: methanol, and the resulting solid was removed by filtration. The filtrate was evaporated under reduced pressure to give the title compound as a white, slightly impure solid, 703 mg.

NMR ^ (de-DMSO, 300 MHz) d: 1.39 (s, 9H), 1.58 (m, 1 H), 1.83 (m, 1 H), 2.00 (s, 3H), 2.97 (m, 1 H), 3.10-3.38 (m, 6H), 4.19 (s, 2H), 6.46 (s, 1 H).

LMRS: m / z = 367 (M + 1) + PREPARATION 83 (3R) -3-r ((5-Met.l-4-f2-fr (3-methyl-1H-indol-5-ynmethin-aminol-2-oxoetin-3-oxo-3, 4-dihydro -2-pyrazinillamno) tert-butyl methyp-1-pyrrolidinecarboxylate A mixture of 2- [3- ( { [(3R) -1-tert-butoxycarbonyl) pyrrolidinyl] methyl} amino) -6-methyl-2-oxo-1 (2H) -pyrazinyl] acetic acid (preparation 82) (698.2 mg, 1.91 mmol), 3-methyl-1 H-indol-5-yl) methylamine ( Preparation 36) (306.1 mg, 1.91 mmol), HOBT (291.2 mg, 1.90 mmol), WSCDl.HCl (367.2 mg, 1.92 mmol) and N-methylmorpholine (4.2 ml, 3.82 mmol) in N, N-dimethylformamide (30 ml) was stirred at room temperature for 66 h. The reaction was diluted with water, and this mixture was extracted with ethyl acetate. The combined organic extracts were washed with 1N citric acid, saturated aqueous NaHCO3, and brine, then dried over MgSO4, and evaporated under reduced pressure to give the title compound as an off-white solid, (402 mg, 42%) . 1 H NMR (d 6 -DMSO, 300 MHz) d: 1.39 (s, 9 H), 1.58 (m, 1 H), 1.83 (m, 1 H), 2.04 (s, 3 H), 2.73 (s, 2 H), 2.86 (s, 2H), 2.98 (m, 1 H), 3.14-3.34 (m, 4H), 4.38 (d, 2H), 4.62 (s, 2H), 6.60 (s, 1 H), 6.99 (m , 2H), 7.06 (s, 1H), 7.24 (d, 1 H), 7.37 (s, 1 H), 8.61 (m, 1 H), 10.65 (s, 1 H).

LMRS: m / z = 531 (M + 23) +.

PREPARATION 84 N-R (3-Methyl-1 H -indol-5-yl) methyl-2-r6-methyl-2-oxo-3-y (3R) -pyrrolidinylmethylaminol-l (2H) -pyrazinyl) acetamide It was dissolved (3R) -3 - [(. {5-methyl-4- (2. {[[(3-methyl-1 H -indol-5-yl) methyl] amino.} -2-oxoethyl ] -3-oxo-3,4-dihydro-2-pyrazinyl.] Amino) methyl] -1-pyrrolidinecarboxylic acid tert-butyl ester (Preparation 83) (400 mg, 0.79 mmol) in a methanol solution (50 mg). ml) and 6H hydrochloric acid (50 ml), and the reaction was stirred at room temperature for 1 1/2 h. The reaction was neutralized using a NaOH solution, the mixture was extracted with dichloromethane, and the combined organic extracts were evaporated. under reduced pressure The residue was purified by column chromatography on silica gel using an elution gradient of dichloromethane: methanol: ammonia 0.88 (100: 0: 0 to 95: 5: 0 to 90: 10: 1), giving the title compound.

The remaining aqueous solution was evaporated under reduced pressure, the residue was triturated with i-propanol, and the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel using an elution gradient of dichloromethane: methanol: ammonia 0.88 (90: 10: 1 to 84: 14: 2 to 80:20) to give more of the desired product as a white solid. vitreous appearance, (126 mg, 39% in total). 1 H NMR (CD 3 OD, 300 MHz) d: 1.66-1.80 (m, 1 H), 2.04-2.18 (m, 4 H), 2.30 (s, 3 H), 2.66 (m, 1 H), 2.96 (m, 1 H) ), 3.15 (m, 1 H), 3.25 (m, 3H), 3.40 (m, 2H), 4.50 (s, 2H), 4.77 (s, 2H), 6.66 (s, 1 H), 6.99 (s, 1 H), 7.04 (d, 1 H), 7.28 (d, 1 H), 7.43 (s, 1 H).

LMRS: m / z = 409 (M + 1) + PREPARATION 85 2-r3- ( { F (3R) -1- (Cylcopropylmethyl) pyrrolidininmethyl} .amino) -6-methyl-2-oxo-1 (2H) -pyrazinylNr (3-methyl-1H -indol-5-yl) methinacetamide A mixture of N - [(3-methyl-1 H -indol-5-yl) methyl-2- [6-methylene-2-oxo-3-. { [(3R) -pyrrolidylmethyl] amino} -1 (2H) -pyrazinyl] acetamide (preparation 84) (66.8 mg, 0.16 mmol), cyclopropanecarboxaldehyde (0.12 mL, 1.60 mmol) and sodium triacetoxyborohydride (35 mg, 0.165 mmol) in N, N-dimethylformamide (5 ml) was stirred at room temperature for 72 h. The reaction was diluted with water, basified and then extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over MgSO 4 and evaporated under reduced pressure. The residue was purified by chromatography on silica gel using an elution gradient of dichloromethane: methanol: ammonia 0.88 (90: 10: 0.1 to 90: 10: 1), yielding the title compound, (36 mg, 48% ). 1 H-NMR (de-DMSO, 300 MHz) d: 0.07 (m, 2 H), 0.42 (m, 2 H), 0.82 (m, 1 H), 1.42 (m, 1 H), 1.82 (m, 1 H), 2.04 (s) , 3H), 2.22 (s, 3H), 2.36-2.63 (m, 5H), 3.20 (m, 2H), 4.38 (d, 2H), 4.61 (s, 2H), 6.60 (s, 1H), 6.94 ( m, 1H), 6.99 (d, 1H), 7.07 (s, 1H), 7.23 (d, 1H), 7.38 (s, 1H), 8.60 (s, 1H), 10.64 (s, 1H). LMRS: m / z = 463 (M + 1) +.

EXAMPLE 24 2-r3-. { 2-r (2R, 4R) -1- (Cyclopropylmethyl-methyl-piperidinylmethyl) -amino) -6-methyl-2-oxo-1 (2H) -pirazinip-N - [( 3-methyl-1H-indol-5-yl) methyl] acetamide PREPARATION 86 (2R, 4R) -1-Benzyl-4-methyl-2-piperidinecarboxamide HCl gas was bubbled through a solution of (2R, 4R) -4-methyl-2-piperidinecarboxylic acid (Biochem. Biophys. Res. Comm. 1981, 440) (42 g, 29.0 mmol) in methanol (120 ml) for 15 minutes, and the resulting solution was stirred at room temperature overnight. The reaction was concentrated under reduced pressure and azeotropically distilled with dichloromethane to give a pale yellow oil. A solution of this intermediate methyl ester (5.6 g, 29 mmol) in 0.88 ammonium solution (100 ml) was stirred for 2 h at 50 ° C, followed by an additional 18 h at room temperature. The reaction mixture was concentrated under reduced pressure, the residue azeotropically distilled with toluene, and then dichloromethane, giving a white solid. Benzyl bromide (3.5 ml, 29.0 mol) was added to a solution of the intermediate carboxamide and triethylamine (8.1 ml, 58.0 mmol) in dichloromethane (100 ml), and the reaction was stirred at room temperature for 4 days. The mixture was diluted with dichloromethane (100 ml), then washed with water, brine, dried over MgSO 4, and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel using an elution gradient of dichloromethane: methanol (100: 0 to 95: 5) giving the desired product as a viscous oil, (3.5 g, 52%) . 1 H-NMR (CDCls, 300 MHz) d: 0.97 (d, 3 H), 1.29-1.50 (m, 3 H), 2.04 (m, 1 H), 2.63 (m, 1 H), 2.84 (m, 1 H) ), 3.22 (t, 1 H), 3.68 (d, 1 H), 3.89 (d, 1 H), 5.88 (s, wide, 1 H), 7.17 (s, 1 H), 7.30 (m, 5H) .

LMRS: m / z = 233 (M + 1) + PREPARATION 87 K2R, 4R) -1-Benzyl-4-methylpiperidinylmethylamine Lithium aluminum hydride (9.2 ml, 1M in tetrahydrofuran, 9.2 mmol) was added to a solution of (2R, 4R) -1-benzyl-4-methyl-2-piperidinecarboxamide (preparation 86) (3 5 g, 15.0 mmol) in tetrahydrofuran (60 ml), and the reaction was heated under reflux overnight. The reaction was cooled in an ice bath, and water (0.4 ml), 15% NaOH solution (0.4 ml), and water (1.2 ml) were added consecutively, and the resulting precipitate was filtered . The filtrate was concentrated under reduced pressure, redissolved in dichloromethane and washed with brine, dried over S ?4Na2 and evaporated under reduced pressure. The crude product was purified by silica gel column chromatography using an elution gradient of dichloromethane: methanol: ammonia 0.88 (100: 0: 0 to 85: 15: 1) to give the title compound as a yellow oil, (650 mg , twenty%). 1 H NMR (CDCls, 300 MHz) d: 0.88 (d, 3H), 1.19-1.54 (m, 3H), 1. 63 (m, 1 H), 2.14 (s, width, 2H), 2.46-2.75 (m, 4H), 2.94 (m, 1 H), 3.77 (d, 2H), 7.17-7.37 (m, 5H).

LMRS: m / z = 219 (M + 1) + PREPARATION 88 2-r3- ( { F (2R, 4R) -1-benzyl-4-methylpiperidininmethyl) amino) -5-chloro-6-methyl-2-oxo-1 (2H) -pyrazinyl] benzyl acetate A mixture of 2- [3- ( { [(2R, 4R) -1-benzyl-4-methylpiperidinyl] methyl.}. Amino) -5-chloro-6-methyl-2-oxo-1 (2H) -pyrazinyl] benzyl acetate (preparation 87) (650 mg, 2.98 mmol), 2- [3,5-dichloro-2-methyl-6-oxo-1 (6H) -pyrazinyl] benzyl acetate (preparation 17) ) (970 mg, 3.0 mmol) and triethylamine (0.42 ml, 3.0 mmol) in ethyl acetate (50 ml), was heated under reflux for 24 h. The cooled reaction was diluted with ethyl acetate, washed with water, brine, then dried over MgSO4, and evaporated under reduced pressure. The residual orange oil was purified by column chromatography on silica gel using an elution gradient of ethyl acetate: pentane (0: 100 to 28:72) to give the title compound as an orange oil, (1.2 g). , 80%). 1 H-NMR (CDCls, 300 MHz) d: 0.95 (d, 3 H), 1.22-1.56 (m, 5 H), 1.79 (m, 1 H), 2.20 (s, 3 H), 2.60 (m, 1 H), 2.78 ( m, 1H), 2.98 (m, 1 H), 3.41-3.60 (m, 2H), 3.80 (d, 1, 5H), 4.82 (d, 1, 5H), 5.22 (s, 2H), 6.61 (m , 1 H), 7-19-7.42 (m, 10H).

PREPARATION 89 2- [3 - ((r (2R, 4R) -4-methylpiperidinylmethyl] amino] -5-chloro-6-methyl-2-oxo-1 (2H) -pyrazine benzyl acetate H3C 7-Chloroethyl chloroformate (0.28 ml, 2.57 mmol) was added to an ice-cooled solution of 2- [3- ( { [(2R, 4R) -1-benzyl-4- methylpiperidinyl] methyl.} amino) -5-chloro-6-methyl-2-oxo-1 (2H) -pyrazinyl] benzyl acetate (preparation 88) (1.2 g, 2.36 mmol) and 1,8-bis (dimethylamino) naphthalene (100 mg) in dichloromethane (15 ml), and the reaction was stirred at room temperature overnight. Additional 1-chloroethyl chloroformate (0.30 ml, 2.75 mmol) and 1,8-bis (dimethylamin) naphthalene (700 mg) was added and the reaction was stirred for additional 4 hours. The solution was diluted with dichloromethane (200 ml), washed with 0.5 M citric acid solution (6x50 ml), water and then brine, dried MgSO 4, and evaporated under reduced pressure. The residue was dissolved in methanol (80 ml), and the solution was heated under reflux for 1 1/2 h, concentrated under reduced pressure and azeotropically distilled with dichloromethane giving the desired product as a brown, slightly impure foam, 1.1 g.

LMRS: m / z = 419 (M + 1) + PREPARATION 90 2-r3- ( { [(2R, 4R) -4-methyl-1- (2, 2, 2, -trifluoroacetyl) piperidonylmethyl}. Amino) -5-chloro-6-methyl- Benzyl 2-oxo-1 (2H) -pyrazinyl-1-acetate Pyridine (0.39 ml, 4.58 mmol) followed by trifluoroacetic anhydride (0.42 ml, 3.0 mmol) was added to a solution of 2- [3- ( { [(2R, 4R) -4 methyl-4-methyl-2-oxo-1 (2H) -pyrazinyl] benzyl acetate (preparation 89) (1.0 g, 2.3 mmol) in dichloromethane (30 ml), and the reaction was stirred at room temperature for 1 h. The solution was concentrated under reduced pressure and the residual oil was purified by column chromatography on silica gel using an elution gradient of ethyl acetate: pentane (0: 100 to 34:66) to give the title compound, (910 mg, 77%). 1 H-NMR (Consists of rotamers) (CDCl 3, 300 MHz) d: 0.97 (d, 3 H), 1.10-1.40 (m, 3 H), 1.78 (m, 2 H), 1.99 (m, 1 H), 2.21 (d, 3 H) ), 3.03 (m, 1 / 3H), 3.40 (m, 2 / 3H), 3.53-3.91 (m, 4H), 4.77-4.98 (m, 3H), 5.21 (s, 2H), 6.16 (m, 1 / 3H), 6.26 (m, 2 / 3H), 7.38 (m, 10H). LMRS: m / z = 516 (M + 1) + PREPARATION 91 Acid 2-G3- (IG (2R, 4R) -4-methyl-1- (2,2,2, -trifluoroacetyl) piperidinipmethyl) amino) -6-methyl-2-oxo-1 (2H) - pyrazinyl acetic Palladium on 10% charcoal (200 mg) followed by ammonium formate (1.1 g, 17.4 mmol) was added to a solution of 2- [3- ( { [(2R, 4R) -4-methyl-1 - (2,2,2, -trifluoroacetyl) pyrimidinyl] methyl} amino) -5-chloro-6-methyl-2-oxo-1- (2H) -pyrazinyl] benzyl acetate (preparation 90) ) (900 mg, 1.74 mmol) in methanol (20 ml), and the reaction was stirred at room temperature overnight. Palladium on additional charcoal (50 mg) was added and the reaction was stirred for an additional 24 h. The mixture was filtered through Whatman® fiber and the filtrate was concentrated under reduced pressure. The residue was suspended in a methanol solution: dichloromethane (10:90), the resulting precipitate was filtered, and the filtrate was evaporated under reduced pressure to give the title compound as a white solid (600 mg, 92%). LMRS: m / z = 391 (M + 1) + PREPARATION 92 Nr (3-methyl-1 H -indole-5-metin-2-r6-methyl-3-f 2 -K2R. 4R) -4-methyl-1 - (2,2,2-trifluoroacetyl) piperidinyl-1ethyl} -2-oxo-1 (2H) -pyrazinyl-1-acetamide A mixture of 2- [3- ( { [(2R, 4R) -4-methyl-1 - (2,2,2, -trifluoroacetyl) piperidinyl] methyl} amino) -6-methyl -2-oxo-1 (2H) -p -razinyl] acetic acid (preparation 91) (600 mg, 1.60 mmol), (3-methyl-1 H-indol-5-yl) methylamine (preparation 36) (256 mg, 1.60 mmol), HOBT (256 mg, 1.90 mmol), WSCDI, HCl (364 mg, 1.90 mmol) and N-methyl morpholine (3.5 mL, 3.18 mmol) in N, N-dimethyl formamide (5 mL), was stirred at Room temperature all night. The solution was diluted with water (50 ml), and the resulting precipitate was filtered and dried in vacuo. The solid was purified by column chromatography on silica gel using an elution gradient of pentane: ethyl acetate (100: 0 to 14:66) to give the title compound, (360 mg, 42%). 1 H NMR (Consistent with rotamers) (CDCl 3, 300 MHz) d: 0.97 (d, 3 H), 1.06-1.38 (m, 3 H), 1.78 (m, 2 H), 1.99 (m, 1 H), 2.22 (d, 3H), 2.30 (s, 3H), 3.00 (m, 1 / 3H), 3.30 (m, 2 / 3H), 3.50-3.88 (m, 3H), 4.23 (m, 1 / 3H), 4.39-4.72 ( m, 3H), 4.94 (m, 2 / 3H), 5.90 (m, 1 / 3H), 6.00 (t, width, 2 / 3H), 6.70 (m, 2H), 6.98 (s, 1 H), 7.03 (d, 1 H), 7.26 (m, 1 H), 7.40 (s, 1 H), 7.97 (s, width, 1 H). LMRS: m / z = 543 (M + 2) + PREPARATION 93 Nr (3-methyl-1 H-indol-5-n-met-p-2-r6-methyl-3- 2-r (2R, 4R) -4-methylpiperidinyl-1-ethyl} -2-oxo- 1 (2H) -pyrazinyl-1-acetamide A mixture of N - [(3-methyl-1 H -indol-5-yl) methyl] -2- [6-methyl-3-. { 2 - [(2R, 4R) -4-methyl-1- (2,2,2-trifluoroacetyl) pperidyl] etl} -2-oxo-1 (2H) -pyrazinyl] acetamide (preparation 92) (360 mg, 0.68 mmol) and an aqueous solution of C03Na2 (6 mL, 0.76 M, 4.6 mmol) in methanol (50 mL) and water (10 ml) was stirred at room temperature for 3 days, followed by an additional 3 hours, heating under reflux. The solution was concentrated under reduced pressure and extracted with a solution of dichloromethane: methanol (90:10) (3x100 ml), and the combined organic extracts were evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel using an elution gradient of dichloromethane: methanol: ammonia 0.88 (100: 0: 0 to 90: 10: 1) to give the title compound, (300 mg, 100% ). 1 H NMR (CDCb, 300 MHz) d: 1.06 (d, 3H), 1.44 (m, 1 H), 1.60 (m, 1H), 1.75-1.95 (m, 2H), 2.03 (m, 1 H), 2.18 (s, 3H), 2.30 (s, 3H), 3.08 (m, 1 H), 3. 20 (m, 1 H), 3.55 (m, 2H), 3.70 (m, 1 H), 4.50 (s, 2H), 4.78 (s, 2H), 6.70 (s, 1 H), 6.99 (s, 1 H), 7.04 (d, 1 H), 7.27 (d, 1 H), 7.42 (s, 1 H). LMRS: m / z = 473 (M + 1) + PREPARATION 94 2-r3-f2-lT2R. 4R) -1 - (Cyclopropylmethyl) -4-methylpiperidinyl-methyl-amino) -6-methyl-2-oxo-1 (2H) -pyrazinin-Nr (3-methyl-1H-indol-5-yl) ) methinacetamide The title compound was obtained as a white solid, (56%) from N - [(3-methyl-1 H -indol-5-yl) methyl] -2- [6-methyl-3-. { 2 - [(2R, 4R) -4-methyl-piperidinyl] ethyl} -2-oxo-1 (2H) -pirazin] acetamide (preparation 93) and cyclopropanecarboxaldehyde, following the procedure described in Preparation 85. 1 H NMR (CH30D, 300 MHz) d: 0.18 (M, 2H), 0.54 (m 2 H), 0.94 (m, 4H), 1.22-1.42 (m, 2H), 1.52-1.66 (m, 2H), 1.78 (m, 1H), 2.15 (s, 3H), 2.30 (s, 3H), 2.42 (m, 1H), 2.70 (m, 2H), 2.82 (m, 1H), 3.20 (m, 1H), 3.48 (m, 2H), 4. 48 (s, 2H), 4.75 (s, 2H), 6.64 (s, 1H), 6.99 (s, 1H), 7.04 (d, 1H), 7.26 (d, 1H), 7. 42 (s, 1H). LMRS: m / z = 513 (M + 23) +.

EXAMPLE 25 2-r3- ( { R (3R) -4- (Cyclopropylmethyl) morpholinipmethyl > amino) -6-methyl-2-oxo-1 (2H) -pyrazinin-Nr (3-methyl-1 H- indol-5-iDmetipacetamide PREPARATION 95 r (3R) -4-Benzylmorpholinylmethylamine Oxalyl chloride (4 mL, 45.8 mmol) is carefully added to a suspension of 4-benzyl- (2R) -5-oxo-2-morpholinecarboxylic acid (J. Chem. Soc. Perk., 1985; 2577) (7.3 g, 31 mmol) in dichloromethane (90 ml), followed by N, N-dimethylformamide (3 drops), and the reaction was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure, azeotropically distilled with dichloromethane (3x), and the resulting oil was dried under vacuum. Gaseous ammonia was bubbled through an ice-cooled solution of this intermediate acid chloride in ether (50 ml), during minutes, and the resulting solution was stirred at room temperature during 72 h. The reaction mixture was evaporated under reduced pressure to give a tan solid, 8.6 g. Lithium aluminum hydride (35.8 ml, 1 M in tetrahydrofuran, 35.8 mmol) was carefully added to a suspension of this amide in tetrahydrofuran (100 ml), and the resulting mixture was stirred at room temperature for 30 minutes, and then heated under reflux for 24 h. Additional lithium aluminum hydride (25 ml, 1M in tetrahydrofuran, 25 mmol) was added, and the reaction was heated under reflux for a further 48 h. The mixture was then cooled, in an ice bath, and treated sequentially, with stirring, with water (2.7 ml), 15% NaOH solution (2.7 ml), and water (8 ml), and the resulting precipitate filter. The filtrate was concentrated under reduced pressure and the residual gum was purified by column chromatography on silica gel using an elution gradient of dichloromethane: methanol: ammonia 0.88 (100: 0: 0 to 85: 15: 1) to give the title compound. titer, (4.2 g, 65%) LRMS: m / z = 207 (M + 1) + PREPARATION 96 2-r3 - ((r 3R) -4-benzylmorpholonolmetol> amino) -5- benzyl-6-methyl-2-oxo-1 (2H) -pyrazinyl acetate A solution of [(3R) -4-benzylmorpholinyl] methylamine (preparation 95) (4.2 g, 20.4 mmol), benzyl 2- [3,5-dichloro-2-methyl-6-oxo-1 (6H) -pyrazinyl-acetic acid ester (Preparation 17) (1g, 3.06 mmol), and triethylamine (0.7 mL, 5.0 mmol) in ethyl acetate (25 mL) was heated under reflux for 18 h. The cooled reaction mixture was diluted with ethyl acetate, washed with water, then with brine, dried over MgSO 4, and concentrated under reduced pressure. The residual brown oil was purified by column chromatography on silica gel using an elution gradient of ethyl acetate: pentane (0: 100 to 100: 0) to give the title compound as a white solid, (500 mg, 32% ). LRMS: m / z = 515 (M + 18) + PREPARATION 97 2-r3- (irf3R) -Morfolininmethyl} amino) -5-chloro-6-methyl-2-oxo-1 (2H) - benzyl pyrazinyl acetate 1,8-bis (dimethylamino) naphthalene (250 mg, 1.17 mmol) was added to a solution of 2- [3- ( { [(3R) -4-benzylmorpholinyl] methyl.} Amino) -5 -chloro-6-methyl-2-oxo-1 (2H) -pyrazinyl] benzyl acetate (preparation 96) (570 mg, 1.1 mmol) in dichloromethane (15 ml), followed by 1-chloroethyl chloroformate (120 ml, 1.1 mmol), and the reaction was stirred at room temperature for 18 h. Additional 1, 8-bis (dimethylamino) naphthalene (250 mg, 1.16 mmol) and 1-chloroethyl chloroformate (120 ml, 1.1 mmol) were added, and the reaction was stirred for an additional 4 days at room temperature and under reflux during the final 24 hours. The solution was diluted with dichloromethane (200 ml), and washed with 0.5N citric acid (5x), brine, then dried over MgSO4, and concentrated under reduced pressure. The crude brown solid was heated under reflux in methanol (30 ml), overnight, the cooled mixture was filtered, the filtrate was concentrated under reduced pressure and azeotropically distilled with dichloromethane yielding the desired product as a brown foam, weakly impure 520 mg. LRMS: m / z = 406 (M) + PREPARATION 98 2-f3-Chloro-2-methyl-6-oxo-5 - ((f (3R) -4- (2.2.2-trifluoroacetyl) morpholinyl-1-methyl-amino) -1 (6H) -pyrazinyl-benzyl acetate Pyridine (31 ml, 0.38 mmol) followed by trifluoroacetic anhydride (44 ml, 0.31 mmol) was added to an ice-cooled solution of 2- [3- ( { [(3R) -morpholinyl] methyl.} Amino) -5-chloro-6-methyl-2-oxo-1 (2H) -pyrazinyl] benzyl acetate (preparation 97) (120 mg, 0.29 mmol) in dichloromethane (7 ml), and the reaction was stirred at 0 ° C for 10 min, and then at room temperature for an additional 2 h. The reaction was quenched with water, the layers were separated, and the organic phase was dried over MgSO 4, and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using ethyl acetate: pentane (30:70) as eluent to give the title compound as a yellow solid, (83 mg, 56%). 1 H-NMR (CDCl 3, 300 MHz) d: 2.20 (s, 3 H), 3.40-4.20 (m, 9 H), 4. 80 (s, 2H), 5.21 (s, 2H), 6.20 (m, 1 H), 7.36 (m, 5H). MS: m / z = 502 (M) + PREPARATION 99 2-R 3-Chloro-2-methyl-6-oxo-5- (и (3 R) -4- (2,2,2-trifluoroacetyl) morpholinylmethyl} amino) -1- (6H) - prazinin-Nr (3-methyl-1H-indol-5-yl) methylacetamide A mixture of 2- [3-chloro-2-methyl-6-oxo-5- ( { [(3R) -4- (2,2,2-trifluoroacetyl) morpholinyl] methyl} amino) -1 (6H) -pyrazinyl] benzyl acetate (preparation 98) (300 mg, 0.60 mmol), and hydroxyl of palladium (80 mg) in methanol (4 ml), was hydrogenated at room temperature and 97.47 kPa for 18 hours. h. The reaction mixture was filtered through Whatman® fiber, and the filter element was washed well with ethyl acetate. The combined filtrate was evaporated under reduced pressure to give a pale yellow solid, 180 mg. (3-Methyl-1H-indol-5-yl) methylamine (preparation 36) (76 mg, 0.48 mmol), HOBT (64 mg, 0.48 mmol), WSCDI, HCl (91 mg, 0.48 mmol) and N are added. -methylmorpholine (79 mg, 0.71 mmol) to a solution of the intermediate acid in N, N-dimethylformamide (4 ml), and the reaction was stirred at room temperature for 72 hours. The reaction mixture was purified directly by column chromatography on silica gel using dichloromethane: methanol (90:10) as eluent to give the title compound as an off-white solid, (162 mg, 52%) 1 H-NMR (CDCl 3, 400 MHz) d: 2.30 (s, 3 H), 2.38 (s, 2 H), 2.40 ( s, 1H), 3.50 (m, 1 H), 3.50 (m, 1H), 3.62 (m, 2H), 3.75 (m, 1 H), 3.92-4.26 (m, 4H), 4.42-4.59 (m, 3H), 4.65 (m, 2H), 6.25 (m, 1 H), 6.55 (m, 1 / 3H), 6.65 (m, 2 / 3H), 6.98 (s, 1H), 7.02 (m, 1H), 7.27 (m, 1 H), 7.40 (s, 1 H), 7.99 (s, 1 H). LMRS: m / z = 555 (M + 1) + PREPARATION 100 2-r3-chloro-2-methyl-5 - ((r (3R) -morpholinylmethamino) -6-oxo-1- (6H) -pyrazin-NNr (3-methylene) 1H-indol-5-yl) methyl-1-acetamide A mixture of 2- [3-chloro-2-methyl-6-oxo-5- ( { [(3R) -4- (2,2,2-trifluoroacetyl) morpholinyl] methyl] amino) -1- (6H) -pyrazinyl] -N - [(3-methyl-1 H -indol-5-yl) methyl] acetamide (preparation 99) (162 mg, 0.31 mmol) and Na3CO3 (600 mg, 5.56 mmol) in water (8 ml), and methanol (6 ml), was stirred at 40 ° C for 18 hours. The cooled reaction was concentrated under reduced pressure to remove the methanol, and the remaining aqueous solution was extracted with ethyl acetate. The combined organic extracts were dried over MgSO 4, and evaporated under reduced pressure to give the title compound, (140 mg, slightly impure). 1 H NMR (CDCl 3, 400 MHz) d: 2.30 (s, 3 H), 2.39 (s, 2 H), 2.90 (m, 2 H), 3.08 (m, 1 H), 3.30 (m, 2 H), 3.49 (m, 1 H), 3.60-4.0 (m, 3H), 4.54 (d, 2H), 4.62 (s, 2H), 6.34 (m, 1 H), 6.54 (m, 1 H), 6.98 (s, 1H), 7.03 (d, 1 H), 7.28 (d, 1 H), 7.40 (s, 1 H), 7.96 (s, 1 H). LMRS: m / z = 459, 461 (M + 1) + PREPARATION 101 2-r 3 -chloro-5 - ((r (3R) -cyclopropylmethyl) morpholinophenyl) .amino) -2-methyl-6-oxo-1- (6H) -pyrazinin-Nr (3- methyl-1 H-indol-5-i-methylmethacemide A mixture of 2- [3-chloro-2-methyl-6-oxo-5- ( { [(3R) -4-morpholinyl] methyl} amino) -1- (6H) -pyrazine] -N - [(3-methyl-1 H -indole-5-yl) methyl] acetamide (preparation 100) (140 mg, 0.33 mmol), cyclopropane-carboxaldehyde (26 mL, 0.35 mmol) and sodium triacetoxyborohydride (105 mg, 0.49 mmol ) in tetrahydrofuran (4 ml) was stirred at room temperature under a nitrogen atmosphere for 16 hours. The solution was partitioned between water and ethyl acetate, the layers were separated, and the organic phase was dried over MgSO 4, and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel using an elution gradient of dichloromethane: methanol (95: 5 to 90:10) to give the title compound, (121 mg, 72%). NMR? (CDCls, 400 MHz) d: 0.10 (m, 2H), 0.45 (m, 2H), 0.86 (m, 1 H), 2.19 (m, 1H), 2.30 (s, 3H), 2.40 (s, 3H) , 2.48 (m, 1H), 2.60-2.75 (m, 2H), 3.02 (m, 1 H), 3.42 (m, 3H), 3.62 (m, 1H), 3.74 (m, 1 H), 3.80 (m , 1 H), 4.56 (s, 2H), 4.66 (s, 2H), 6.48 (m, 1 H), 6.56 (m, 1 H), 6.98 (s, 1 H), 7.05 (d, 1 H) , 7.30 (d, 1 H), 7.42 (s, 1 H), 7.92 (s, 1 H). LMRS: m / z = 513,515 (M + 1) + PREPARATION 102 2-r 3 - ( { R (3R) -4- (cyclopropylmethyl) morpholiniphenyl) .amino) -6-methyl-2-oxo-1- (2H) -pyrazinylNr (3-methyl-1H -indol-5-μl) methinacetamide A mixture of 2- [3-chloro-5- ( { [(3R) -4-cyclopropylmethyl) morpholinyl] -methyl} amino) -2-methyl-6-oxo-1- (6H) -pirazin] N - [(3-methyl-1 H -indol-5-yl) methyl] -acetamide (preparation 101) ( 120 mg, 0.23 mmol), ammonium formate (44 mg, 0.7 mmol) and 10% palladium on charcoal (catalytic) in methanol (5 ml) was stirred at room temperature under a nitrogen atmosphere for 64 hours. The reaction mixture was filtered through a Whatman® filter, washed with ethyl acetate. The combined filtrate was evaporated under reduced pressure and the residue was purified by column chromatography on silica gel using dichloromethane: methanol: ammonia 0.88 (90: 10: 0.5) as eluent to obtain the title compound as a white solid, (15 mg , 14%). NMR (CDCls, 400 MHz) d: 0.12 (m, 2H), 0.50 (m, 2H), 0.86 (m, 1 H), 2.18 (m, 1 H), 2.24 (s, 3H), 2.30 (s, 3H), 2.46 (m, 1 H), 2.65 (m, 2H), 3.02 (m, 1 H), 3.40 (m, 2H), 3.46-3.83 (m, 4H), 4.55 (m, 2H), 4.64 (s, 2H), 6.35 (s, width, 1 H), 6.60 (s, width, 1 H), 6.72 (s, 1 H), 6.98 (s, 1 H), 7.04 (d, 1H), 7.18 (m, 1H), 7.60 (s, 1H), 7.92 (s, width, 1 H). LMRS: m / z = 478 (M + 1) + EXAMPLE 26 2-r 3 - (3-r (2-Aminoethoxy) -methin-phenethylamino) -6-methylene-2-oxo-1- (2H) -pyrazinopyr (3-methyl-1H-indol-5-yl) metipacetamide PREPARATION 103 2-. { r3- (Bromomethyl) benzopoly} tert-butyl ethylcarbamate Sodium hydride was added portionwise to an ice-cooled solution of tert-butyl 2-hydroxyethylcarbamate (500 mg, 3.10 mmol), and 1,3-bis (bromomethyl) benzene (8.2 g, 31.0 mmol) in tetrahydrofuran (15 g). ml), and the reaction was stirred at 0 ° C for one hour under nitrogen atmosphere, then allowed to warm to room temperature. A saturated solution of ammonium chloride (10 ml) was added, and the mixture was partitioned between water and ethyl acetate, and the layers were separated. Then the organic phase was dried over MgSO 4, and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel eluting ethyl acetate: pentane (15:85 to 75:25) to give the title compound as a colorless oil, (796 mg, 74%). 1 H-NMR (CDCl 3, 400 MHz) d: 1.42 (s, 9 H), 3.38 (m, 2 H), 3.56 (t, 2 H), 4.50 (2x, 4 H), 4.88 (s, broad, 1 H), 7.38 ( m, 4H). LMRS: m / z = 362 (M + 18) + PREPARATION 104 2- (r3- (Cyanomethyl) benzyloxy} tert-butyl ethyl carbamate Sodium cyanide (284 mg, 5.78 mmol) and benzyl triethylammonium bromide (63 mg, 0.23 mmol) were added to a solution of 2-. { [3- (bromomethyl) benzyl] oxy} tert-butyl ethylcarbamate (Preparation 103) (798 mg, 2.31 mmol) in acetonitrile (5 mL), and the reaction was stirred at room temperature for 4 days. The mixture was partitioned between water and ethyl acetate and the layers were separated. The organic phase was left over MgSO 4, and evaporated under reduced pressure to give the title compound as an oil, (654 mg, 97%). NMR (CDCls, 400 MHz) d: 1.42 (s, 9H), 3.37 (t, 2H), 3.78 (s, 2H), 4.54 (s, 2H), 4.86 (s, broad, 1 H), 7.26 (m , 3H), 7.37 (m, 1 H). LMRS: m / z = 291 (M + 1 PREPARATION 105 2- (r3- (2-Aminoethyl) benzyloxy> tert-butyl ethyl carbamate Raney® nickel (170 mg) is added to a solution of 2-. { [3- (cyanomethyl) benzyl] oxy} ethyl ferba-butyl ethylcarbamate (preparation 104) (654 mg, 2.26 mmol) in an ethanolic ammonium solution (15 ml), and the mixture was hydrogenated at 389.88 kPa and room temperature for 24 hours. The reaction mixture was filtered through Arbocel®, and the filtrate was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using dichloromethane: methanol: 0.88 ammonia to give the title compound, (536 mg, 80%). 1 H NMR (CDCl 3, 300 MHz) d 1.25 (s, broad, 9H), 1.43 (s, 9H), 2. 78 (t, 2H), 2.98 (t, 2H), 3.36 (m, 2H), 3.57 (t, 2H), 4.50 (s, 2H), 4.88 (s, width, 1H), 7.18 (m, 2H) , 7.28 (m, 2H).

PREPARATION 106 2-r 3 -fr 3 - (2-tert-butoxycarbonyl) aminoethoxy > methylphenolyl-5-chloro-6-methyl-2-oxo-1 (2H) -pyrazine benzyl acetate A mixture of 2-. { [3- (2-aminoethyl) benzyl] oxy} ferric butyl ethylcarbamate (preparation 105) (270 mg, 0.92 mmol), 2- [3,5-dichloro-2-methyl-6-oxo-1 (6) -pyrazinyl] benzyl acetate (preparation 17) (300 mg, 0.92 mmol) and triethylamine (140 ml, 1.01 mmoles) in ethyl acetate was heated under reflux overnight. The cooled suspension was diluted with ethyl acetate, then washed with hydrochloric acid (2N), NaHC 3 solution, brine, then dried over MgSO 4 and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel using acetate: pentane (40:60) as eluent, and triturated with ether, giving the title compound as a white solid, (243 mg, 45%). Re-purification of the filtered ether by column chromatography on silica gel provided additional desired product (176 mg, 33%). 1 H NMR (CDCl 3, 300 MHz) d 1.42 (s, 9H); 2.20 (s 3H), 2.95 (t, 2H), 3.36 (m, 2H), 3.56 (t, 2H), 3.68 (m, 2H), 4.50 (s, 2H), 4.80 (s, 2H), 4.99 (m, 1 H), 5.21 (s, 2H), 6.12 (s, width, 1 H), 7.19 (m, 3H), 7.23-7.40 (m, 6H). LMRS: m / z = 607 (M + 23) + PREPARATION 107 Acid 2-r3-fr3- (2-tert-butoxycarbonyl) amino] ethoxy} methyl) fenetpamine > -6- methyl-2-oxo-1 (2H) -pyrazine-acetic acid Ammonium formate (425 mg, 6.74 mmol) and 10% palladium on charcoal (200 mg) were added to a solution of 2- [3-. { [3- (2-Ierc-butoxycarbonyl) amino] -ethoxy} methyl) phenethyl] amino} -5-chloro-6-methyl-2-oxo-1 (2H) -pyzinyl-benzyl acetate (preparation 106) (392 mg, 0.67 mmol) in acetonitrile (10 ml), and the reaction was stirred at room temperature overnight . The reaction mixture was filtered through Whatman® fiber, and the filtrate was concentrated under reduced pressure. The residue was suspended in dichloromethane, basified using a NaOH solution, and reacted to pH 4, using 1 N hydrochloric acid. This solution was extracted with ethyl acetate and the combined organic extracts were dried over MgSO and evaporated under pressure reduced by giving the title compound as a white foam, (180 mg, 58%). 1 H NMR (d6, 400 MHz) d 1.37 (s.9H), 2.02 (s, 3H), 2.82 (t, 2H), 3.10 (t, 2H), 3.40 (t, 2H), 3.46 (m, 2H) , 4.42 (m, 4H), 6.60 (s, 1H), 6.74 (t, width, 1 H), 6.80 (t, width, 1 H), 7.15 (m, 3H), 7.24 (m, 1 H). LMRS: m / z = 461 (M + 1) + PREPARATION 108 2-r3- r3- (2ir5-Methyl-4- (2- 3-methyl-1H-8ndol-5-inmetinamino-2-oxoetin-3-oxo-3,4-dihydro-2-p) razinyl-amino) ethyl) benzyloxy} ethylcarbamate A mixture of 2- [3-. { [3- (2-tert-butoxycarbonyl) -amino] ethoxy} methyI) phenethyl] amino} -6-methyl-2-oxo-1 (2H) -pyrazinyl] acetic acid (preparation 107) (174 mg, 0.38 mmol), (3-methyl-1H-indol-5-yl) methylamine (preparation 36) (67 mg 0.42 mmol), HOBT (77 mg, 0.57 mmol), WSCDl.HCl (91 mg, 0.47 mmol) and N-methylmorpholine (124 mL, 1.13 mmol) in N, N-dimethylformamide (5 mL) was stirred at room temperature. environment for 20 h. The reaction mixture was partitioned between ethyl acetate and water and the phases were separated. The organic layer was dried over MgSO 4 and evaporated under reduced pressure to give the title compound as a white solid (220 mg, 96%). NMR? (de-DMSO, 300 MHz) d 1.37 (s, 9H), 2.05 (s, 3H), 2.22 (s, 3H), 2.82 (t, 2H), 3.10 (m, 2H), 3.39 (t, 2H) , 3.46 (m, 2H), 4.36 (d, 2H), 4.41 (s, 2H), 4.61 (s, 2H), 6.62 (s, 1 H), 6.81 (m, 2H), 6.98 (d, 1 H) ), 7.08 (s, 1 H), 7.15 (m, 3H), 7.23 (m, 2H), 7.37 (s, 1 H), 8.62 (t, width 1 H), 10.68 (s, 1 H). LMRS. M / z = 603 (M + 1) + PREPARATION 109 2-r3- ( {3-f (2-Aminoethoxy) metinphenethyl amino) -6-methyl-2-oxo-1 (2H) -pyrazin-Nr (3-methyl-1H-indole-5 -yl) methyl-1-acetamide Hydrochloric acid (10 mL, 6 N, 60.0 mmol) was added to a solution of 2-. { [3- (2 { [5-methyl-4- (2-. {[[(3-methyl-1 H -indol-5-yl) methyl] amino.} -2-oxoethyl) -3- oxo-3,4-dihydro-2-pyrazinyl] amino} ethyl) benzyl] oxy} tert-butyl carbamate (preparation 108) (220 mg, 0.36 mmol) in methane (10 ml), and the reaction was stirred for one hour at room temperature. The mixture was basified using a solution of NaOH (1 N), and the mixture was extracted with ethyl acetate (2x), and dichloromethane (1x). The combined organic extracts were dried over MgSO4 and evaporated under reduced pressure.

The crude product was purified by column chromatography on silica gel using dichloromethane: methanol: ammonia 0.88 (90: 10: 1) to give the title compound as a white solid, (100 mg, 55%). NMR? (d6-DMSO, 400 MHz) d 2.05 (s, 3H), 2.21 (s, 3H), 2.72 (t, 2H), 2.82 (t, 2H), 3.40 (t, 2H), 3.48 (m, 2H) , 4.38 (d, 2H), 4.43 (s, 2H), 4.61 (s, 2H), 6.62 (s, 1 H), 6.79 (t, width, 1 H), 6.98 (d, 1 H), 7.06 ( s, 1 H), 7.15 (m, 3H), 7.24 (m, 2H), 7.37 (s, 1 H), 8.60 (t, width, 1 H), 10.65 (s, 1 H). LMRS. m / z = 503 (M + 1) + EXAMPLE 27 Nr (3-Met l-1 H-indol-5-n-methyl-2-r 6 -methyl-3-f 3 (r 2 - (methylamino) ethoxymethyl) pheneppamino-2-oxo-1 (2H -pirazinipacetamide PREPARATION 110 Metir2- (. {3-rbromometinbenzyl oxy) et-carbamate tert-butyl The title compound was obtained (85%) from 2-hydroxyethyl (methyl) carbamate (Synth Commun. 23; 17; 1993; 2443) and 1,3-bis (bromomethyl) benzene following the procedure described in the preparation. 103 1 H NMR (CDCl 3, 300 MHz) d 1.43 (s, 9 H), 2.95 (s, 3 H), 3.42 (s, broad, 2 H), 3.60 (s, broad, 2 H), 4.50 (2x s, 4 H), 7.25 ( m, 1 H), 7.35 (m, 3H).

PREPARATION 111 Metitryl- (. {3-rcynemethylbenzyl) tert-butyl oxoethylcarbamate The title compound was obtained (94%) as an oil from methyl [2- (. {3- [bromomethyl] benzyl}, ox) ethyl] carbamate, ferric-butyl (preparation 110), following the procedure described in 104. NMR? (CDCI3, 300 MHz) d 1.41 (s, 9H), 2.95 (s, 3H), 3.42 (s, broad, 2H), 3.60 (s, wide, 2H), 3.77 (s, 2H), 4.54 (s, 2H), 7.25 (m, 3H), 7.36 (m, 1 H). LMRS: m / z = 305 (M + 1) + PREPARATION 112 Methyl r2- (3- [2- (methylamino) et phenyl) xi) tert-butyl ethylcarbamate The title compound was obtained as an oil (99%) from methyl [2- (. {3- [cyanomethyl] benzyl} oxy) ethyl] tert-butyl carbamate (preparation 111), following the procedure described at 105. NMR (CDCI3, 400 MHz) d 1.26 (s, broad, 2H), 1.43 (s, 9H), 2.77 (t, 2H), 2.94 (s, 3H), 2.98 (t, 2H), 3.42 (s, width, 2H), 3.60 (s, width, 2H), 4.50 (s, 2H), 7.14 (d, 1 H), 7.18 (m, 2H), 7.28 (m, 1 H). LMRS: m / z = 309 (M + 1) + PREPARATION 113 2-r 3 -fr 3 - (2-r (ferric butoxycarbonyl) (methyl) amino] ethoxy) methyl) phenethylene} - 5-chloro-6-methyl-2-oxo-1 (2H) -pyridine benzyl acetate The title compound was obtained as a white crystalline solid (64%) from methyl [2- (. {3- [2- (methylamino) ethyl] benzyl} oxy) tert-butyl ethyl carbamate preparation 112) and 2- [3,5-dichloro-2-methyl-6-oxo-1 (6H) -pipercinyl-benzyl acetate (preparation 17), following the procedure described in Preparation 106. NMR? (CDCls, 300 MHz) d 1.42 (s, 9H), 2.21 (s, 3H), 2.95 (m, 5H), 3.42 (s, width, 2H), 3.60 (s, width, 2H), 3.68 (m, 2H), 4.50 (s, 2H), 4.80 (s, 2H), 5.21 (s, 2H), 6.10 (t, width, 1 H), 7.17 (d, 1 H), 7.20 (m, 2H), 7.26 (m, 1 H), 7.36 (m, 5H).

PREPARATION 114 2-r 3 -f- (2-r (fer- t -butoxycarbonD- (methyl) aminoxyethoxy} .methiphenetipamino} -6-methyl-2-oxo-1 (2H) -pyrazinyl acetic acid Ammonium formate (368 mg, 5.83 mmol) followed by palladium on 10% charcoal was added to a solution of 2-. { 3-. { [3-. { (2 - [(tert-butoxycarbonyl) (methyl) -amino] ethoxy] .methyl) phenethyl] amino} -5-chloro-6-methyl-2-oxo-1 (2H) -pyrazinyl} Benzyl acetate (Preparation 113) (350 mg, 0.58 mmol) in methanol (10 mL), and the reaction was stirred at room temperature overnight. The reaction mixture was filtered through Whatman® fiber, and the filtrate was concentrated under reduced pressure. The residue was triturated with dichloromethane, the resulting suspension was filtered again through Whatman® fiber then through celite, and this filtrate was evaporated under reduced pressure. The residual solid was dissolved in dichloromethane, the solution was washed with water, brine, then dried over MgSO 4 and evaporated under reduced pressure to give the desired product as a gum, (213 mg, 79%). 1 H-NMR (de-DMSO, 300 MHz) d 1.36 (s, 9 H), 1.98 (s, 3 H), 2.03 (s, 3H), 2.82 (m, 2H), 3.30 (t, 2H), 3.48 (m, 4H), 4.43 (s, 2H), 4.52 (s, 2H), 6.60 (s, 1 H), 6.78 (t, width, 1 H), 7.15 (m, 3H), 7.24 (m, 1 H). LMRS: m / z (M) + PREPARATION 115 Methyl (2-r 3 -fr 3 - (2 { R 5 -methyl-4- (2-fí (3-methyl-1 H -indol-5-yl) methylamino) -2-oxoet l) -3-oxo-3,4-dihydro-2-pyrazinyl > amino benzinoxy) ethylcarbamate tert -butyl The title compound was obtained as a white solid (97%) from 2- acid. { 3-. { [3- (2-tert-butoxycarbonyl) (methyl) amino] ethoxy} methyl) phenethyl] amino} -6-methyl-2-oxo-1 (2H) pyrazinyl] acetic acid (Preparation 114), and (3-methyl-1 H-indol-5-yl) methylamine (preparation 36), following a procedure similar to that described in Preparation 108. 1 H-NMR (d-400 MHz) d 1.37 (s, 9 H), 2.04 (s, 3 H), 2.21 (s, 3 H), 2. 80 (m, 5H), 3.35 (t, 2H), 3.48 (m, 4H), 4.38 (d, 2H), 4.43 (s, 2H), 4.62 (s, 2H), 6. 61 (s, 1H), 6.79 (t, width, 1 H), 6.98 (d, 1 H), 7.06 (s, 1 H), 7.15 (m, 3H), 7.24 (m, 2H), 7.37 (s, 1 H), 8.80 (t, width 1 H), 10.64 (s, 1 H). LMRS: m / z (M + 1) + PREPARATION 116 Nl (3-Methyl-1 H -indole-5-immethin-2-r6-methyl-3-r (3- { R 2 - (methylamino) ethoxymethyl) phenethyl) amino 1-2-oxo-1 (2H -pirazinyl acetamide The title compound was obtained as a cream colored solid, from methyl (2- [3-. {[3- (2 { [5-methyl-4- (2- { [(3 -methyl-1H-indol-5-yl) methyl] amino.} -2-oxoethyl) -3-oxo-3,4-dihydro-2-pyrazinyl] amino.} ethyl) benzyl] oxy. ethyl) tert-butyl carbamate (preparation 115), following a procedure similar to that described in preparation 109. 1 H-NMR (de-DMSO, 300 MHz) d 2.05 (s, 3 H), 2.20 (s, 3 H), 2.24, 3 H), 2.61 (t, 2 H), 2.82 (t, 2 H), 3.45 (m, 2 H) , 4.38 (d, 2H), 4.42 (s, 2H), 4.61, 2H), 6.62 (s, 1H), 6.78 (t, width, 1H), 6.98 (d, 1H), 7.05 (s, 1H), 7.14 (m, H), 7.22 (m, 2H), 7.38 (s, 1H), 8.80 (t, width, 1H), 10.64 (s, 1H).

EXAMPLE 28 2-r3- ( {3-r (IR / S) -1-Amino-2-methoxyethyphenethyl amino) -6-methy1-2-oxo-1 (2H) -pyrazineNr ( 3-methyl-1 H-indol-5-yl) methyl-1-acetamide PREPARATION 117 3-Vinylphenylethylamine A mixture of 3-bromophenylacetonitrile (3.31 ml, 25.5 mmol), vinyl tributyl tin (16.17 g, 51.0 mmol), bis (triphenylphosphine) palladium chloride (II) (1.48 g, 1.28 mmoles) and lithium chloride 83.24 g, 76.5 mmoles) in tetrahydrofuran (500 ml), heated under reflux for 6 hours, and stirred for an additional 18 hours at room temperature. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in ethyl acetate and washed with a solution of NaHCO3 (2x), then with brine, dried over MgSO and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel using ethyl acetate: hexane (16:84) as eluent to give a yellow oil. A solution of aluminum chloride (1.44 g, 10.8 mmol) in tetrahydrofuran (25 ml) was added cautiously to lithium aluminum hydride. (1.23 g, 32.4 mmol) in tetrahydrofuran (25 ml), and the mixture was stirred at room temperature for 10 min. A solution of the intermediate acetonitrile in tetrahydrofuran (50 ml) was then added and the reaction was stirred at room temperature for 3 hours. The reaction was quenched by the addition of hydrochloric acid, then basified using an aqueous solution of NaOH. The mixture was extracted with ethyl acetate, the combined organic extracts were dried over MgSO 4 and evaporated under reduced pressure. The crude product was redissolved in ethyl acetate, extracted with citric acid, and these aqueous extracts were rebasified using an aqueous solution of NaHCO3. This was then reextracted with ethyl acetate, and the combined extracts were evaporated under reduced pressure to give the title compound as a yellow solid, (1.79 g, 47%). NMR (CDCls, 300 MHz) d 1.18 (s, broad, 2H), 2.75 (t, 2H), 2. 97 (t, 2H), 5.22 (d, 1H), 5.76 (d, 1 H), 6.70 (dd, 1 H), 7.07 (m, 1 H), 7.22 (m, 3H).

PREPARATION 118 3-Benzyl vinylphenethyl carbamate a mixture of 3-vinylphenethylamine (preparation 117) (1.78 g, 12.1 mmol), N- (benzyloxy) succinimide (3.62 g, 14.52 mmol) and triethylamine (2.53 mL, 18.15 mmol) in dichloromethane (60 mL) was stirred at room temperature under nitrogen atmosphere all night. The reaction mixture was washed with a solution of citric acid, saturated aqueous NaHCO3, brine, then dried over MgSO4, and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel using dichloromethane as the eluent to give the desired product as a colorless oil, (1.43 g, 41%). 1 H NMR (CDCls, 300 MHz) d 2.80 (t, 2 H), 3.44 (t, 2 H), 4.96 (s, broad, 1 H), 5.12 (s, 2 H), 5.24 (d, 1 H), 5.78 ( d, 1 H), 6.70 (dd, 1 H), 7.08 (m, 1H), 7.20-7.41 (m, 8H).

PREPARATION 119 3-f (1 R / SM-r (ferc-Butoxycarbonyl) aminol-2-hydroxy-ethyl.}. Benzyl phenethylcarbamate A solution of NaOH (1.22 g, 30.5 mmol) in water (70 ml) was added, followed by hypochlorous acid, tert-butyl ester (3.5 ml, 30.5 mmol) to a solution of tert-butylcarbamate (3.57 g, 30.5 mmol). ) in n-propanol (75 ml), in a glass topaz bottle. This solution was stirred at room temperature for 5 min, then cooled in an ice bath. Solutions of (DHQ) 2PHAL (480 mg, 0.6 mmol) in n-propanol (40 ml), and benzyl 3-vinylphenethyl carbamate (preparation 118) (2.81 g, 10 mmol) in n-propanol (70 ml), followed by potassium osmiate dihydrate (184 mg, 0.5 mmole) in water (5 ml) and then the reaction was stirred at 0 ° C for 4 hours, and at room temperature for an additional 18 h. A saturated solution of sodium dithionite (100 ml) was added, the phases were separated, and the aqueous layer was extracted with ethyl acetate (2 × 100 ml). The combined organic extracts were dried over MgSO 4 and evaporated under reduced pressure. The brown residual oil was purified by column chromatography on silica gel twice, using an elution gradient of ethyl acetate: pentane (25:75 to 50:50) to give the desired product as a colorless oil, (603 mg, fifteen%). 1 H NMR (CDCl 3, 300 MHz) d 1.42 (s, 9 H), 2.52 (s, broad, 1H), 2. 80 (t, 2H), 3.46 (m, 2H), 3.80 (m, 2H), 4.74 (s, width, 1H), 4.84 (s, width, 1H), 5.07 (s, 2H), 5.32 (d, 1H), 7.11 (m, 3H), 7.30 (m, 6H).

PREPARATION 120 3- (IR / S) -1-r (Forç-Butoxycarbonyl) amino 1-2-methoxy-ethyl > benzyl phenethylcarbamate A mixture of methyl iodide (98 ml, 1.57 mmol), 3-. { (1 R / S) -1 - [(tert-butoxycarbonyl) amino] -2-hydroxy-ethyl} benzyl phenethylcarbamate, (Preparation 119) (590 mg, 1.4 mmol), benzyltriethylammonium chloride (325 mg, 1. 4 mmol) and a solution of NaOH (185 ml, 10 M, 1.85 mmol) in dichloromethane (10 ml) was stirred at room temperature for 3 days. The reaction mixture was partitioned between dichloromethane and water, the phases were separated, and the organic layer was dried over MgSO 4 and evaporated under reduced pressure. The residual oil was purified by column chromatography on silica gel, using an elution gradient of ethyl acetate: pentane (0: 100 to 50:50) to give the desired product as a colorless oil, (289 mg, 47%). 1 H NMR (CD 3 OD, 300 MHz) d: 1.40 (s, 9 H), 2.78 (t, 2 H), 3.32 (m, 5H), 3.50 (d, 2H), 4.75 (m, 1 H), 4.80 (s, 2H), 5.05 (s, 2H), 7.00-7.36 (m, 9H).

PREPARATION 121 (1 R / S) -1 - [3- (2-Aminoethyl) phenin-2-methoxyethylcarbamate tert -butyl A mixture of 3-. { (1 R / S) -1 - [(tert-butoxycarbonyl) -amino] -2-methoxyethyl} Benzyl phenethylcarbamate, (preparation 120) (289 mg, 0.68 mmol) and 10% charcoal on palladium (30 mg) in methanol (10 ml) was hydrogenated at 97.47 kPa and room temperature for 16 h. The reaction mixture was filtered through Arbocel®, and the filtrate was evaporated under reduced pressure to give the title compound, (196 mg, 98%).

NMR? (CD3OD, 300 MNz) d: 1.41 (s, 9H), 2.78 (t, 2H), 2.88 (t, 2H), 3.52 (d, 2H), 4.72-4.80 (m, 5H), 7.11 (d, 1H), 7.18 (m, 2H), 7.24 (m, 1H). LRMS: m / z = 295 (M + 1) + PREPARATION 122 2-r3-r (3-l (1R / S) -1-r (tert-Butoxycarbonyl) amino-2-methoxyethyl} -phenethyl) amino-1-5-chloro-6-methyl-2-oxo-1 - (2H) -pyzinyl-1-benzyl acetate A mixture of tert-butyl (1 R / S) -1- [3- (2-aminoethyl) phenyl] -2-methoxyethylcarbamate (preparation 121) (196 mg, 0.67 mmol), 2- [3,5-dichloro -2-methyl-6-oxo-1 (6H) -pyrazinyl] benzyl acetate (preparation 17) (182 mg, 0.56 mmol) and triethylamine (368 mL, 2.78 mmol) in ethyl acetate (5 mL) was heated under reflux for 18 h. The cooled mixture was washed with brine (15 ml), dried over MgSO 4 and evaporated under reduced pressure. The residual oil was purified by column chromatography on silica gel using an elution gradient of dichloromethane: methanol (100: 0 to 99: 1) to give the title compound as a colorless oil, (284 mg, 76%). 1 H NMR (CDCls, 300 MHz) d: 1.40 (s, 9H), 2.20 (s, 3H), 2.90 (t, 2H), 3.35 (s, 3H), 3.52-3.70 (m, 4H), 4.80 (m, 3H), 5.22 (m, 3H), 6.15 (t, width, 1 H), 7.17 (m, 3H), 7.24 (m, 1 H) 7.37 (m, 5H).

LRMS: m / z = 585 (M + 1) + PREPARATION 123 Acid 2-r3-r (3 - ((IR / SH -r (ferc-butoxycarbonylamino1-2-methoxyethyl) phenethyl) amino1-6-methyl-2-oxo-1 (2H) -pyrazinipaeacetic acid A mixture of 2- [3 - [(3- {(IR / S) -1 - [(tert-butoxycarbonyl) amino] -2-methoxyethyl} phenethyl) amino] -5-chloro-6-methyl -2-oxo-1 (2H) -piraz¡n¡l-} Benzyl acetate (preparation 122) (248 mg, 0.42 mmol), ammonium formate (265 mg, 4. 2 mmol) and palladium on 10% charcoal (100 mg) in methanol (10 ml) was heated under reflux for 25 h. The cooled reaction was filtered through Arbocel®, and NaOH (420 mL, 10 M, 4.2 mmol) was added to the filtrate. The mixture was evaporated under reduced pressure, triturated and filtered with a dichloromethane: methanol (91: 9) solution (3x), and the combined filtrates were evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel using a dichloromethane: methanol gradient. (100: up to 93: 7) giving the title compound as an oil (35 mg, 18%). 1 H NMR (CD 3 OD, 300 MHz) d: 1.40 (s, 9 H), 2.18 (s, 3 H), 2.90 (m, 2 H), 3.35 (s, 3 H), 3.55 (m, 4 H), 4.60 (s, 2 H) ), 4.80 (m, 1 H), 6.66 (s, 1 H), 7.17 (m, 2H), 7.24 (m, 2H).

LRMS: m / z = 483 (M + 1) PREPARATION 124 (IR / S) -2-Methoxy-1-r3- (2- (r5-methyl-4- (2-ir (3-methyl-1H-indol-5-inmetinamino > -2-oxoethyl) - 3-Oxo-3,4-dydro-2-pyrazin-amino-ethyl-tert-butyl-ethyl-phenethylcarbamate A mixture of 2- [3 - [(3- {(1 R / S) -1) - [(tert-butoxycarbonyl) amino] -2-methoxyethyl}. phenethyl) amino] -6-methyl-2-oxo-1 (2H) -pyrazinyl] acetic acid (preparation 123) (35 mg, 0.076 mmol, ) (3-methyl-1 H-indol-5-yl) methylamine (preparation 36) (13 mg, 0.08 mmol), HOBT (11 mg, 0.08 mmol), WSCDl.HCl (16 mg, 0.08 mmol) and N -methylmorpholine (16 ml, 0.15 mmol) in N, N-dimethylformamide (2 ml), was stirred at room temperature for 18 h, additional (3-methyl-1H-indol-5-yl) methylamine (preparation 36) was added. (8 mg, 0.38 mmol), and stirred continuously for an additional 72 h at room temperature The reaction mixture was poured into water (10 ml), and the resulting precipitate was filtered and dried to give the desired product, (26 mg , 57%). NMR? (CDsOD, 300 MHz) d: 1.41 (s, 9H), 2.1 6 (s, 3H), 2.29 (s, 3H), 2.94 (t, 2H), (s, 3H), 3.50 (d, 2H), 3.59 (t, 2H), 4.48 (s, 2H) 4.76 (s) , 2H), 4.82 (m, 1 H), 6.66 (s, 1 H), 6.98 (s, 1 H), 7.05 (d, 1 H), 7.16 (d, 2H), 7.22 (m, 3H), 7.42 (s, 1 H). LRMS: m / z = 625 (m + 23) + PREPARATION 125 2-f3-r (3-p R / SH -mino1-2-methoxypheptypethyl amino) -6-methy1) -2-oxo-1 (2H) -pyrazinyl > -N-r (3-methyl-1H-indol-5-yl) methinacetamide A solution of (1R / S) -2-methoxy-1- [3- (2 { [5-methyl-4- (2. {[[(3-methyl-1H-indol-5-yl ) methyl] amino.} -2-oxoethyl) -3-oxo-3,4-dihydro-2-pyrazinyl] amino.} ethyl) phenyl} Tert-butyl ethyl carmabate (Preparation 124) (26 mg, 0.043 mmol) in hydrochloric acid (2 mL, 6 N, 12 mmol) and methanol (2 mL) was stirred under nitrogen atmosphere for 3 h. The reaction mixture was basified to pH 10 using 1N NaOH solution, extracted with dichloromethane (4x10 ml), and ethyl acetate (3x10 ml). The combined organic extracts were dried over MgSO, and evaporated under reduced pressure to give the title compound as a white solid, (13 mg, 60%). Both R and S isomers are present although their relative proportions have not been determined.

NMR? (CD3OD, 300 MHz) d: 2.13 (s, 3H), 2.26 (s, 3H), 2.90 (t, 2H), 3.35 (s, 3H), 3.41 (m, 1 H), 3.49 (m, 1 H) ), 3.58 (m, 2H), 4.06 (m, 1 H), 4.45 (s, 2H), 4.74 (s, 2H), 6.64 (s, 1 H), 6.98 (s, 1 H), 7.02 (d) , 1 H), 7.18 (m, 2H), 7.24 (m, 3H), 7.42 (s, 1H).

LRMS: m / z = 503 (M + 1) + EXAMPLE 29 2-r3CT2- (2-Aminoethoxy) phenethylamine) -6-methyl-2-oxo-1 - (2H) -pyrazinin-N-r (3-methyl-1H-indol-5-yl) methylacetamide hydrochloride PREPARATION 126 3-Hydroxyphenyl acetonitrile Boron tribromide (68 ml, 1 M in dichloromethane, 68 mmoles) is added dropwise to an ice-cooled solution of (3-methoxyphenyl) acetonitrile (5.0 g, 34 mmol) in dichloromethane (50 ml), and once that the addition was complete, the reaction was allowed to warm to room temperature and stirred overnight. The reaction was poured into an ice / water solution, the mixture was basified using NaHCO3 and extracted with dichloromethane. The combined organic extracts were dried over MgSO 4 and evaporated under reduced pressure to give the desired product as a brown oil, 84.13 g, 91%). 1 H-NMR (CDCl 3, 300 MHz) d: 3.72 (s, 3 H), 5.99-6.20 (s, broad, 1 H), 6.82 (m, 3 H), 7.22 (m, 1 H).

LRMS: m / z = 151 (M + 18) + PREPARATION 127 2-r2- (Cyanomethyl) phenoxyethyl tert-butylcarbamate Diethyl azodicarboxylate (6.2 ml, 39.4 mmol) was added dropwise to an ice-cooled solution of 3-hydroxyphenyl acetonitrile (preparation 126) (4.2 g, 31.5 mmol), triephenylphosphine (10.34 g, 39.4 mmol) and 2-hydroxyethyl carbamate. tert-butyl (5.4 mL, 34.9 mmol) in tetrahydrofuran (70 mL), and once the addition was complete, the reaction was stirred at room temperature overnight. The reaction was diluted with ethyl acetate (400 ml), washed with a 1 N NaOH solution, water, brine, then dried over MgSO 4 and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using ethyl acetate: pentane (30:70) as eluent to give the desired product as a yellow / green oil, which crystallized at rest, (5.88 g, 68%). 1 H-NMR (CDCls, 300 MHz) d: 1.44 (s, 9 H), 3.59 (m, 2 H), 3.68 (s, 2 H), 4.10 (t, 2 H), 5.08 (s, broad, 1 H), 6.86 ( d, 1 H), 6.98 (m, 1 H), 7.34 (m, 2H).

LRMS: = m / z = 299 (M + 23) + PREPARATION 128 2-r2- (Aminomethyl) phenoxy] ethylcarbamate tert-butyl The title compound was obtained as a pale yellow crystalline solid, (51%) from tert-butyl 2- [2- (cyanomethyl) phenoxy] ethylcarbamate (preparation 127), following the procedure described in Preparation 105. 1 H NMR (CDCl 3, 300 MHz) d: 1.43 (s, 9H), 1.54 (s, broad, 2H), 2. 80 (t, 2H), 2.98 (t, 2H), 3.58 (m, 2H), 4.02 (t, 2H), 5.28 (s, width, 1 H), 6.81 (d, 1 H), 6.92 (m, 1 H), 7.18 (m, 2H).

LRMS: m / z = 281 (M + 1) + PREPARATION 129 2-r3-f3- ( {2-rTerc-butoxycarbonyl) amino-1-ethoxy] -phenethyl-lamino-5-chloro-6-methyl-2-oxo-1 (2H) -pyrazine-benzyl acetate A mixture of 2- [3,5-dichloro-2-methyl-6-oxo-1 (6H) -pyrazinyl benzyl acetate (preparation 17) (300 mg, 0.92 mmol), 2- [2- (aminomethyl) phenoxy] ] tert-butyl ethylcarbamate (Preparation 128), (257 mg, 0.92 mmol) and triethylamine (140 mL, 1.0 mmol) in ethyl acetate (6 mL) was heated under reflux for 18 h. The cooled mixture was partitioned between ethyl acetate (80 ml) and hydrochloric acid (2N, 30 ml) and the phases were separated. The organic layer was washed consecutively with hydrochloric acid (2N), saturated NaHCO3 solution, brine, then dried over MgSO4 and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel using acetate: pentane (50:50) as eluent to give the title compound as an orange foam, (500 mg, 95%). NMR (CDCl 3, 300 MHz) d: 1.40 (s, 9 H), 2.20 (s, 3 H), 2.98 (t, 2 H), 3.60 (m, 4 H), 4.10 (t, 2 H), 4.80 (s, 2 H) , 5.21 (s, 2H), 5.68 (s, width, 1H), 6.57 (s, width, 1 H), 6.68-6.88 (m, 2H), 7.18 (m, 2H), 7.37 (m, 5H). LRMS: m / z = 571. 573 (M + 1) + PREPARATION 130 Acid 2-r3-fí3 - ((2-r (tert-butoxycarbonipamino-1-ethoxy) phenethyl) amino] -6-methyl-2-oxo-1 (2H) -pyrazin-3-acetic acid Palladium on 10% charcoal (125 mg) was added, followed by ammonium formate (553 mg, 8.77 mmol) to a solution of 2- [3-. { [3- ( {2 - [(tert-butoxycarbonyl) amino] ethoxy.])) Phenethyl] amino} -5-chloro-6-methyl-2-oxo-1 (2H) -pyrazinyl] benzyl acetate (preparation 129) (500 mg, 0.88 mmol) in methanol (10 ml), and the reaction was stirred at room temperature for one night. The reaction mixture was filtered through Whatman® fiber, and NaOH solution (8.77 ml, 1 Nm 8.77 mmol) was added to the filtrate and the solution was evaporated under reduced pressure, the residue was triturated with a 10% methanol solution: dichloromethane , the suspension was filtered, the filtrate was dried over MgSO 4 and evaporated under reduced pressure to give the title compound as a white solid (289 mg, 69%). NMR (d6-DMSO, 300 MHz) d: 1.37 (S, 9H), 2.01 (s, 3H), 2.80 (t, 2H), 3.35 (t, 2H), 3.41 (t, 2H), 3.94 (t, 2H), 4.19 (s, 2H), 6.55 (s, 1 H), 6.80- 6.92 (m, 2H) , 7.14 (m, 2H).

Preparation 131 2-r 2 - (2- (r 5-Methyl-4- (2-fr (3-methyl-1 H -indol-5-yl) methylamino> 2-oxoethyl) -3-oxo-3, 4- tert-butyl 4-dihydro-2-pyridomethyl-3-methyl-phenoxy] ethylcarbamate A mixture of 2- [3-. { [3- ( {2 - [(tert-butoxycarbonyl) amino] ethoxy.])) Phenethyl) amino] -6-methyl-2-oxo-1 (2H) -pyrazinyl] acetic acid (preparation 130) (268 mg , 0.60 mmol), and (3-methyl-1 H-indol-5-yl) methylamine (preparation 36) (106 mg, 0.66 mmol) was added to a solution of HOBT (122 mg, 0.90 mmol), WSCDl.HCl (144 mg, 0.75 mmol) and N-methylmorpholine (198 ml, 1.8 mmol) in N, N-dimethylformamide (5 ml), and the reaction was stirred at room temperature for 20 h. The mixture was poured into water (100 ml), with vigorous stirring, and the resulting precipitate was filtered. This solid was washed well with water, triturated with ether and dried under vacuum to give the title compound (315 mg, 89%). NMR (de-DMSO, 300 MHz) d: 1.37 (s, 9H), 2.04 (s, 3H), 2.22 (s, 3H), 2.82 (t, 2H), 3.37 (m, 2H), 3.43 (m, 2H), 3.95 (t, width, 2H), 4.37 (d, 2H), 4.62 (s, 2H), 6.61 (s, 1 H), 6.78 (t, width, 1 H), 6.83 (m, 1 H) ), 6.90 (d, 1 H), 6.98 (d, 1H), 7.04-7.19 (m, 4H), 7.24 (d, 1H), 7.38 (s, 1H), 8.60 (t, width, 1H), 10.66 (s, 1 H). LRMS: m / z = 589 (M + 1) + Preparation 132 2-r3fí2- (2-Aminoethoxy) phenenamnamino-6-methyl-2-oxo-1 (2H-pyrazinin-N-r (3-methyl-1H-indol-5-yl) methylacetamide hydrochloride Hydrochloric acid (10 mL, 6N, 60 mmol) was added to a solution of 2- [2- (2 { [5-methyl-4- (2-. {[[(3-methyl-1 H- indole-5-yl) methyl] amino.} -2-oxoethyl) -3-oxo-3,4-dihydro-2-pyrazinyl] amino.}, etiI) phenoxy] tert-butyl ethylcarbamate (preparation 131) ( 315 mg, 0.54 mmol) in methanol (10 ml), and the reaction was stirred at room temperature for 1 1/2 h. The reaction mixture was basified using NaOH (2N), and the resulting precipitate was filtered. This yellow solid was preabsorbed onto silica gel, and purified by column chromatography on silica gel using dichloromethane: methanol: 0.88 ammonia (92: 7: 1) as eluent, yielding a cream-colored solid, 169 mg. This was dissolved in a 10% solution of methanokydloromethane, hydrochloric acid (1 N, 1 equiv) was added, the solution was stirred for 5 min, then evaporated under reduced pressure. The product was triturated with a methanol: ether solution to give the title compound as a white solid (153 mg, 54%). NMR? (de-DMSO, 300 MHz) d: 2.05 (s, 3H), 2.22 (s, 3H), 2.88 (t, 2H), 3.32 (m, 2H), 3.42 (t, 2H), 4.18 (t, 2H) ), 4.38 (d, 2H), 4.62 (s, 2H), 6.63 (s, 1 H), 6.96 (m, 4H), 7.08 (s, 1 H), 7.19 (m, 2H) 7.23 (d, 1) H), 7.38 (s, 1 H), 8.17 (s, width, 3H), 8.66 (t, width, 1 H), 10.70 (s, 1 H). LRMS: m / z = 489 (M + 1) + Found: C, 59.78; H, 6.47; N, 15.54 C27H32O3; HCi; H2O requires C, 59.71; H, 6.51; N, 15.47%.

EXAMPLE 30 N-r (3-MetHl-1H-indol-5-yl) methan-2-r6-methyl-2-oxo-3-3-r (2R) pyrrolidinylmethoxy-1-phenethyl > amino) -1 (2H) -pyrazine-nacetamide PREPARATION 133 (2R) -2- (r3- (Cyanomethyl) phenoxylmethyl.} -1-pyrrolidinecarboxylic acid tert-butyl ester Diethyl azodicarboxylate (3.92 g, 22.5 mmol) was added dropwise to a solution of 3-hydroxyphenyl acetonitrile (3.0 g, 22.5 mmol), triphenylphosphine (5.90 g, 22.5 mmol) and Boc- (R) -proinol ( 4.53 g, 22.5 mmol) in tetrahydrofuran (30 ml), and the reaction was stirred at room temperature for 18 h. The mixture was evaporated under reduced pressure and the residue was partitioned between dichloromethane and water. The layers were separated, the organic phase was washed with water, dried over MgSO and concentrated under reduced pressure.

The crude product was purified by column chromatography on silica gel using an elution gradient of dichloromethane: pentane: methanol (80:20 to 100: 0: 0 to 95: 0: 5) to give the title compound, (2.69 g. , 38%). NMR (de-DMSO, 300 MHz) d: 1.39 (s, 9H), 1.77-2.00 (m, 4H), 3.24 (m, 2H), 3.88 (m, 1 H), 4.00 (m, 4H), 6.94 (m, 3H), 7.27 (m, 1 H). LRMS: m / z = 339 (m + 23) + PREPARATION 134 (2R) -2-fr3- (2-Aminoethyl) phenoxymethyl-1-pyrrolidinecarboxylic acid tert-butyl ester A mixture of (2R) -2-. { [3- (Cyanomethyl) phenoxy] methyl} -1- tert-butyl pyrrolidinecarboxylate (preparation 133) (2.70 g, 8.54 mmol), and Raney® nickel (400 mg) in saturated ethanolic ammonium solution (100 ml), was hydrogenated at 389.88 kPa and room temperature for 20 h. The reaction mixture was filtered through a glass microfiber filter, and the filtrate was evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel using an elution gradient of dichloromethane: methanol: ammonia 0.88 (95: 5: 0.5 to 90: 10: 1) to give the title compound, (1.54 g, 56% ). 1 H-NMR (d 6 -DMSO, 300 MHz) d: 1.38 (s, 9 H), 1.78 (m, 1 H), 1.90 (m, 3 H), 2.59 (t, 2 H), 2.75 (t, 2 H), 3.23 ( m, 2H), 3.81 (t, 1 H), 3.99 (m, 2H), 6.77 (m, 3H), 7.18 (m, 1 H).

LRMS: m / z = 321 (M + 1) + PREPARATION 135 (2R) -2-K3-r2-a4-r2-fBenzyloxy) -2-oxoetin-6-chloro-5-methyl-3-oxo-3,4-dihydro-2-pyrazinyl > amino) etiHfenoxi > methyl) -1-pyrrolidinecarboxylate tert-butyl Triethylamine (0.51 ml, 3.67 mmol) was added to a solution of (2R) -2-. { [3- (2-aminoethyl) phenoxy] methyl} -1-tert-butyl pyrrolidinecarboxylate (preparation 134) (588 mg, 1.84 mmol) and 2- [3,5-dichloro-2-methyl-6-oxo-1 (6H) -pyrazinyl] benzyl acetate (preparation 17) ) (60 mg, 1.83 mmol) in ethyl acetate (10 ml), and the reaction was heated under reflux for 6 h. The cooled mixture was partitioned between water and ethyl acetate, and the layers were separated. The organic phase was washed with water, then with brine, dried over MgSO, and evaporated under reduced pressure to give the title compound, (1.07 g, 94%). 1 H NMR (d6-DMSO, 300 MHz) d: 1.40 (s, 9H), 1.75-2.20 (m, 6H), 2.81 (t, 2H), 3.26 (m, 5H), 3.45 (m, 2H), 3.82 (m, 1 H), 4.88 (s, 2H), 5.20 (s, 2H), 6.80 (m, 3H), 7.18 (m, 1 H), 7.38 (m, 5H), 7.48 (m, 1 H) .

LRMS: m / z = 612 (M + 1) + PREPARATION 136 Acid 2-r3-r (3-fr (2R) -1- (tert-butoxycarbonyl) pyrrolidinyl] methoxy.) Phenethyl) amino] -6-methyl-2-oxo-1 ( 2H) - pyrazinyl acetic Palladium on 10% charcoal (125 mg) and ammonium formate (515 mg, 8.17 mmol) were added to a solution of (2R) -2- (. {3- [2- (. {4- [2 - (benzyloxy) -2-oxoethyl] -6-chloro-5-methyl-3-oxo-3,4-dihydro-2-pyrazinyl} - amino) ethyl] phenoxy] - methyl - 1 - tert-butyl pyrrolidinecarboxylate (preparation 135) (500 mg, 0.82 mmol) in methanol (10 ml), and the reaction was stirred at room temperature under nitrogen atmosphere for 18 h, followed by an additional 24 h, at 50 ° C. The cooled mixture was filtered through Whatman® fiber, and NaOH (327 mg, 8.17 mmol) in water was added to the filtrate.This solution was evaporated under reduced pressure and the residue was purified by column chromatography on silica gel using a gradient. elution dichloromethane: methanol: ammonia 0.88 (90: 10: 1 to 85: 15: 2) giving the desired product, (67 mg, 11%). 1 H NMR (de-DMSO, 300 MHz) d: 1.38 (s, 9H), 1.78 (m, 1 H), 1.91 (m, 3H), 2.01 (s, 2H), 2.80 (t, 2H), 3.33 (s, wide, 3H), 3.43 ( m, 2H), 3.82 (m, 1 H), 4.00 (m, 2H), 4.38 (s, 2H), 6.58 (s, 1 H), 6.63 (m, 1 H), 6.78 (m, 3H), 7.18 (m, 1 H). LRMS: m / z = 487 (M + 1) + PREPARATION 137 (2R) -2-fr3- (2-fr5-MetHl-4- (2-fr (3-methyl-1H-indol-5-yl) methyl-amyl> -2-oxoetyl) ) - 3-oxo-3,4-dihydro-2-pyrazinylamino) etl) phenoxy] methyl > -1- tert-butyl pyrrolidinecarboxylate A mixture of 2- [3 - [(3. {[[(2R) -1 - (tert-butoxycarbonyl) pyrrolidinyl] methoxy.} Phenethyl) amino] -6-methyl-2-oxo-1 (2H) acid ) -pyrazinyl] acetic acid (preparation 136) (65 mg, 0.13 mmol), (3-methyl-1 H -indol-5-yl) methylamine (preparation 36) (25 mg, 0.16 mmol), HOBT (20 mg, 0.15 mmol), WSCDI. HCl (31 mg, 0.16 mmol) and N-methylmorpholine (40 mg, 0.40 mmol) in N, N-dimethylformamide (2.5 ml), was stirred at room temperature for 20 h. The reaction mixture was partitioned between ethyl acetate and water and the phases were separated. The organic layer was washed with water, brine, then dried over MgSO 4 and evaporated under reduced pressure to give the title compound, (84 mg, 100%). 1 H-NMR (ds-DMSO, 400 MHz) d: 1.38 (s, 9 H), 1.78 (m, 1 H), 1.90 (m, 3 H), 2.02 (s, 3 H), 2.20 (s, 3 H), 2.80 ( t, 2H), 3.25 (m, 2H), 3.45 (m, 2H), 3.82 (m, 1 H), 4.00 (m, 2H), 4.38 (d, 2H), 4.60 (s, 2H), 6.61 ( s, 1 H), 6.78 (m, 3 H), 6.98 (d, 1 H), 7.05 (s, 1 H), 7.18 (m, 1 H), 7.24 (d, 1 H), 7.36 (s, 1 H), 7.96 (s, 1 H), 8.60 (m, 1 H), 10.64 (s, 1 H). LRMS: m / z = 629 (M + 1) + PREPARATION 138 Nr 3-Methyl-1H-indol-5-n-methyn-2-r6-methyl-2-r6-methyl-2-oxo-3 - ((3-r (2R) pyrrolidinylmethoxylphenethylamine-1 (2H) -pyrazin Nacetamide Hydrochloric acid (4 ml, 6 N, 24 mmol) was added dropwise to a solution of (2R) -2-. { [3- (2- { [5-methyl-4- (2- { [(3-methyl-1 H-indol-5-yl) methyl] amino.} -2-oxoethyl) -3 -oxo-3,4-dihydro-2-pyrazinyl] amino.} ethyl) phenoxy] methyl} -1-tert-butyl pyrrolidinecarboxylate (preparation 137) (84 mg, 0.13 mmol) in methanol (4 ml), and the reaction was stirred at room temperature for 2 1/2 h. The reaction mixture was basified to pH 9 using an NaOH solution, and the resulting precipitate was filtered. This solid was purified by column chromatography on silica gel using dichloromethane: methanol: 0.88 ammonia (90: 10: 0.5) as eluent to give the title compound, (30 mg, 41%). 1 H NMR (d6-DMSO, 300 MHz) d: 1.44 (m, 1 H), 1.66 (m, 2 H), 1.83 (m, 1 H), 2.05 (s, 3H), 2.22 (s, 3H), 2.80 (m, 4H), 3.39 (m, 1 H), 3.46 (m, 2H), 3. 80 (d, 2H), 4.38 (d, 2H), 4.60 (s, 2H), 6.62 (s, 1 H), 6.97 (m, 4H), 6.98 (d, 1 H), 7. 05 (s, 1 H), 7.18 (m, 1 H), 7.25 (d, 1 H), 7.37 (s, 1 H), 8.60 (m, 1 H), 10.66 (s, 1 H). LRMS: m / z = 529 (M + 1) + EXAMPLE 31 N- (1H-lndol-5-methyl] -2-r3- (p (2R) -1-isobutylpyrrolidin-n-methyl) -amino) -6-methyl-2-oxo-1 (2H) -pyrazinepatamide PREPARATION 139 N- (1 H-lndol-5-methyl) -2-r3- ( { R (2R) -1 -sobutylpyrrolidinylmethanol> -6- Methyl-2-oxo-1 (2H) -pyrazinepacetamide HOBT (24 mg, 0.18 mmol), WSCDl.HCl (29 mg, 0.15 mmol), N-methylmorpholine (39 mL, 0.36 mmol) and 1 H-indol-5-ylmethylamine (preparation 8) (19 mg, 0.13) were added. mmol) to a solution of 2- [3- ( { [2R) -1-isobutylpyrrolidinyl] methyl} amino) -6-methyl-2-oxo-1 (2H) -pyrazinyl] acetic acid (Preparation 62) (38 mg, 0.12 mmol) in N. N -dimethylformamide (2 mL), and the reaction was stirred at room temperature overnight. The mixture was evaporated under reduced pressure and the residue was purified by column chromatography on silica gel using dichloromethane: methanol: ammonia 0.88 (95: 5: 0.5) as eluent. The product was repurified using a Biotage ™ cartridge (silica gel KP-Sil ™ 60 A) and dichloromethane: methanol: ammonia 0.88 (95: 5: 0.5) as eluent to give the title compound, (16 mg, 30%. ). 1 H-NMR (CDCl 3, 400 MHz) d: 0.83 (d, 3 H), 0.90 (d, 3 H), 1.56-1.78 (m, 5 H), 1.82 (m, 1 H), 2.07 (m, 2 H), 2.24 ( s, 3H), 2.60 (m, 1 H), 3.16 (m, 1H), 3.21 (m, 1H), 3.52 (m, 1 H), 4.50 (d, 2H), 4.63 (s, 2H), 6.42 (m, 1 H), 6.50 (s, 1 H), 6.63 (s, width, 1 H), 6.70 (s, 1 H), 7.05 (d, 1 H), 7.20 (m, 1 H), 7.34 (d, 1 H), 7.49 (s, 1 H), 8.20 (s, width, 1 H). LRMS: m / z = 450 (M) + EXAMPLE 32 2-r3- (ir (2R) -1- (Cyclopropylmethyl) pyrrolidininmethyl amino) -6-methyl-2-oxo-1 (2H) -pyrazinip-N- (1H-indol-5-ylmethyl) acetamide PREPARATION 140 2-r3- ( { F (2R) -1- (Cyclopropylmethyl) pyrrolidinin-methyl > amino) -6-methyl-2-oxo-1 (2H) -pyrazin-N- (1H-indol-5-ylmethyl) acetamide The title compound was obtained as a partially crystallized oil (32%), from 2- [3- ( { [(2R) -1- (cyclopropylmethyl) pyrrolidinyl] methyl.} Amino) -6- metii-2-oxo-1 (2H) -pyrazinyl] acetic acid (preparation 48) and 1 H-indole-5-ylmethylamine (preparation 8), using the procedure described in Preparation 45. 1H-NMR (CD3OD, 300 MHz) d : 0.17 (m, 2H), 0.50 (m, 2H), 0.94 (m, 1 H), 1.62 (m, 1 H), 1.78 (m, 2H), 1.94 (m, 1 H), 2.08 (m, 4H), 2.32 (m, 1 H), 2.75 (m, 2H), 3.28 (m, 2H), 3.57 (m, 1 H), 4.44 (s, 2H), 4.70 (s, 2H), 6.40 (d , 1 H), 6.62 (s, 1 H), 7.03 (d, 1 H), 7.20 (d, 1 H), 7.34 (d, 1 H), 7.46 (s, 1 H).

EXAMPLE 33 2-r3-r (2R) -1- (C-cyclopentyl) pyrrolidinylmethyl > amino) -6-methy1-2-oxo-1 (2H) -pyrazinop-N- (1H-indol-5-ylmethyl) acetamide PREPARATION 142 (2R) -1-Cyclopentyl-2-pyrrolidinecarboxamide Cyclopentanone (388 ml, 4.38 mmol), acetic acid (251 ml, 4.38 mmol) and sodium triacetoxyborohydride (1.4 g, 6.6 mmol) were added consecutively to a solution of (2R) -pyrrolidinecarboxamide (500 mg, 4.38 mmol) in dichloromethane ( 10 ml), and the solution was stirred at room temperature for 4 hours. A saturated solution of NaHC 3 (100 mL) was added, and the mixture was extracted with ethyl acetate. The combined organic extracts were washed with water, brine, and then dried over MgSO4 and concentrated under reduced pressure. The residue was triturated with ether, giving the title compound as a white solid, (320 mg, 40%). 1 H-NMR (CDCl 3, 400 MHz) d: 1.39-1.81 (m, 10 H), 1.95 (m, 1 H), 2.10 (m, 1 H), 2.42 (m, 1 H), 2.86 (t, 1 H) , 3.17 (m, 2H), 5.36 (s, width, 1 H), 7.38 (s, width, 1H). LRMS: m / z = 183 (M + 1) + PREPARATION 143 r (2R) -1-Cyclopentyl-pyrrolidine] methylamine Lithium aluminum hydride was added dropwise (2.63 ml, 1M in tetrahydrofuran, 2.63 mmol) to a solution of (2R) -1-cyclopentyl-2-pyrrolidinecarboxamide (preparation 142) (320 mg, 1.76 mmol) in tetrahydrofuran. (5 ml), and once the addition was complete, the reaction was stirred at room temperature for 4 h. Water was added to complete the reaction, the mixture was diluted with ethyl acetate and dried over MgSO4. This mixture was filtered through Whatman® fiber, and the filtrate was evaporated under reduced pressure. The residue was purified by column chromatography using a Biotage ™ cartridge (silica gel KP-Sil ™ 60 A) and an elution gradient of dichloromethane: methanol: ammonia 0.88 (95: 5: 0.5 to 90: 10: 1) giving the desired product as a clear oil, (208 mg, 71%). 1 H-NMR (CDCl 3, 400 MHz) d: 1.19 (s, broad, 2H), 1.40-1.94 (m, 12H), 2.44 (dd, 1 H), 2.57-2.77 (m, 3H), 2.88 (m, 1 H), 3.00 (m, 1 H). LRMS: m / z = 169 (M + 1) + PREPARATION 144 2-r3-Chloro-5- ( { R (2R) -1- (cyclopentylpyrrolidinolmetol) amino) -2-methyl-6-oxo-1 (6H) -pyrazinoline benzyl ester 2- [3- was added, 5-dichloro-2-methyl-6-oxo-1 (6H) -pyrazinyl] benzyl acetate (preparation 17) (404 mg, 1.23 mmol) to a solution of [(2R) -1-cyclopentylpyrrolidinyl-methylamine (preparation 143) (208 mg, 1.23 mmol) in ethyl acetate (10 ml), followed by triethylamine (190 ml, 1.36 mmol) and the reaction was heated under reflux overnight, under a nitrogen atmosphere. The reaction mixture was diluted with ethyl acetate, washed with water, brine, then dried over MgSO 4 and concentrated under reduced pressure. The crude product was purified by chromatography using a cartridge Biotage ™ (silica gel KP-Sil ™ 60 A) and an elution gradient of dicoromethane: methanol: ammonia 0.88 (100: 0: 0 to 95: 5: 0.5) giving the desired product as a cream solid, (450 mg , 80%). H-NMR (CDCls, 400 MHz) d: 1.42-1.59 (m, 10H), 1.86 (m, 2H), 2.20 (s, 3H), 2.47 (m, 1H), 2.90 (m, 1 H), 2.90 ( m, 1 H), 2.98 (m, 1 H), 3.04 (m, 1 H), 3.22 (m, 1 H) 3.54 (m, 1 H), 4.80 (s, 2 H), 5.21 (s, 2 H) , 6.58 (s, broad, 1 H), 7.37 (m, 5H). LRMS: m / z = 458.460 (M + 1) + PREPARATION 145 2-r3- (IT (2R) -1-cyclopentyl-pyrrolidininmethyl-amino) -6-methyl-2-oxo-1 (2H) -pyrazinyl-acetic acid hydrochloride A mixture of 2- [3- ( { [(2R) -1-cyclopentyl pyrrolidinyl] methyl} amino) -6-methyl-2-oxo-1 (2H) -pyrazinyl] benzyl acetate (preparation 144) ) (450 mg, 0.98 mmol), and palladium hydroxide (200 mg) in methanol, was hydrogenated at 389.88 kPa at room temperature overnight. The mixture was filtered through Whatman® fiber and the filtrate was concentrated under reduced pressure. The residue was distilled azeotropically with dichloromethane several times to give the title compound as a green foam, (370 mg, 100%). 1 H-NMR (de-DMSO, 400 MHz) d: 1.50 (m, 2 H), 1.69 (m, 4 H), 1.82 (m, 2 H), 1.96 (m, 4 H), 2.06 (s, 3 H), 3.08 (m , 1 H), 3.20-3.62 (m, 4H), 3.78 (m, 1 H), 4.62 (s, 2H), 6.63 (s, 1 H), 7.36 (s, width, 1 H). LRMS: m / z = 335 (M + 1) + PREPARATION 146 2-r3-Ur (2R) -1-Cyclopentylpyrrolidinomethyl-amino) -6-methyl-2-oxo-1 (2H) -pyrazin-N- (1H-indol-5-ylmethyl) acetamide The title compound was prepared from 2- [3- (. {[[(2R) -1-cyclopentyl] -yrrolidol] methyl] -6-hydrochloride. methyl-2-oxo-1 (2H) -pyrazinyl] acetic acid (preparation 145) and 1 H-indol-5-ylmethylamine (preparation 8), following the procedure described in preparation 45. The crude product was purified by chromatography using a Biotage ™ cartridge (silica gel KP-Sil ™ 60 A) and dichloromethane: methanol: ammonia 0.88 (95: 5: 0.5) as eluent. The product was further purified using preparative tic and dichloromethane: methane: ammonia 0.88 (90: 10: 1) as eluent to give the title compound, (11 mg, 16%). NMR (CD3OD, 400 MHz) d: 1.50-1.62 (m, 4H), 1.65-1.82 (m, 5H), 1.83-2.00 (m, 3H), 2.18 (s, 3H), 2.60 (m, 1 H) , 3.00-3.17 (m, 3H), 3.26 (m, 1 H), 3.57 (m, 1 H), 4.50 (s, 2H), 4.78 (s, 2H), 6.43 (d, 1 H), 6.70 ( s, 1 H), 7.10 (d, 1 H), 7.24 (d, 1 H), 7.38 (d, 1 H), 7.54 (s, 1 H). LRMS: m / z = 463 (M + 1) + EXAMPLE 34 2-r3-r (2R) -1-Cyclohexylpyrrolidinylmethyl > amino) -6-methy1-2-oxo-1 (2H) -pyrazinyl-N- (1H-indol-5-ylmethyl) acetamide PREPARATION 147 (2R) -1-Cyclohexyl-2-pyrrolidinecarboxamide The title compound was obtained as a white solid (55%) from cyclohexanone and (2R) -pyrrolidinecarboxamide, following the procedure described in preparation 142.

NMR? (CDCb, 400 MHz) d: 1.02-1.25 (m, 6H), 1.77 (m, 5H), 1. 92 (m, 2H), 2.02 (m, 1 H), 2.36 (m, 1 H), 2.50 (m, 1H), 3.08 (t, 1 H), 3.24 (dd, 1 H), 5.38 (s, width, 1 H) 7.39 (s, width, 1 H).

PREPARATION 148 r (2R) -1-Cyclohexylpyrrolidininmethylamine Lithium aluminum hydride was added dropwise (7.3 ml, 1 M in tetrahydrofuran, 7.3 mmol) to a solution of (2R) -1-cyclohexyl-2-pyrrolidinecarboxamide (preparation 147) (950 mg, 4.85 mmol) in tetrahydrofuran (15 ml) and once the addition was complete, the reaction was heated under reflux for 20 h. The cooled mixture was quenched carefully with water, and extracted with ethyl acetate. The combined organic extracts were dried over MgSO 4 and evaporated under reduced pressure. The residue was suspended in dichloromethane, filtered through Whatman® fiber and the filtrate was evaporated under reduced pressure to give the desired product as an oil (894 mg, 96%). 1 H NMR (CDCls, 400 MHz) d: 1.03-1.54 (m, 8H), 1.54-1.90 (m, 8H), 2.40 (m, 1 H), 2.45-2.63 (m, 3H), 2.79 (m, 1 H), 2.94 (m, 1 H). LRMS: m / z 183 (M + 1) + PREPARATION 149 2-r3-Chloro-5 - ((r (2R) -1-cyclohexylpyrrolidininmethyl) amino) -2-methyl-6-oxo-1 (6H) -pyrazine-benzyl acetate The title compound was obtained as a pale brown solid (60%), from (2R) -1-cyclohexylpyrrolidinyl] methylamine (preparation 148) and 2- [3,5-dichloro-2-methyl-6-oxo-1 (6H) -pyrazinyl] benzyl acetate (preparation 17), following the procedure described in Preparation 144. 1 H-NMR (CDCl 3, 400 MHz) d: 1.07-1.34 (m, 6H), 1.58-1.83 (m, 7H), 1.92 (m, 1 H), 2.20 (s, 3H ), 2.43 (m, 1 H), 2.58 (m, 1 H), 2.98 (m, 1 H), 3.16 (m, 2 H), 3.48 (m, 1 H), 4.80 (s, 2 H), 5.21 ( s, 2H), 6.58 (s, broad, 1 H), 7.38 (m, 5H). LRMS: m / z = 473.475 (M + 1) + PREPARATION 150 2-r3- ((2R) -1-Cyclohexylpyrrolidinipmethyl) amino) -6-methyl-2-oxo-1 (2H) -pyrazine hydrochloride Nacetic The title compound was obtained (100%) from 2- [3-chloro-5- ( { [(2R) -1-cyclohexylpyrrolidinyl] methyl.} Amino) -2-methyl-6-oxo- 1 (6H) -pyrazinyl] benzyl acetate (preparation 149) following a procedure similar to that described in Preparation 145. NMR (de-DMSO, 400 MHz) d: 1.01-1.29 (m, 4H), 1.38 (m, 2H ), 1.58 (m, 1 H), 1.75-2.17 (m, 8H), 3.04-3.39 (m, 5H), 3.58 (m, 2H), 3.83 (m, 1 H), 4.62 (s, 2H), 6.62 (s, 1H), 7.38 (s, width, 1H).

PREPARATION 151 2-r3 - ((r (2R) -1- (Cyclohexin) pyrrolidininmethyl amino) -6-methyl-2-oxo-1 (2H) -pyrazinin-N- (1H-indol-5-ylmethyl) acetamide The title compound was obtained as a white powder after trituration with ether (40%), from 2- [3- ( { [(2R) -1- (cyclohexyl) hydrochloride] ) pyrrolidinyl] methyl} amino) -6-methyl-2-oxo-1 (2H) -p -razinyl] acetic acid (preparation 150) and 1 H-indol-5-ylmethylamine (preparation 8), following a procedure similar to that described in Preparation 139. NMR? (CD3OD, 400 MHz) d: 1.12-1.34 (m, 5H), 1.60-1.82 (m, 7H), 1.92 (m, 1 H), 1.98 (m, 1 H), 2.14 (s, 3H), 2.52 (m, 1 H), 2.61 (m, 1 H), 2.98 (m, 1H), 3.20 (m, 2H), 3.42 (m, 1 H), 4.44 (s, 2H), 4.75 (s, 2H) , 6.40 (d, 1 H), 6.64 (s, 1 H), 7.04 (d, 1 H), 7.20 (d, 1 H), 7.34 (d, 1 H), 7.48 (s, 1 H). LRMS: m / z = 476 (M + 1) + EXAMPLE 35 2-r 3 - (1 (2R) -1-Methylcyclopropyl > methyl) pyrrolidin-methyl-amino) -6-methyl-2-oxo-1 ( 2H) -pyrazinyl-1-N- (1 H -indol-5-ylmethyl) acetamidate PREPARATION 152 (2R) -1-f (1-methylcyclopropyl) methan-2-pyrrolidinecarboxamide (2R) -pyrrolidinecarboxamide (1.0 g, 8.73 mmol) was added to a solution of 1-methylcyclopropanecarbamide (preparation 58) (412 ml, 0. 04M, 17.6 mmol in dichloromethane) and the solution was stirred at room temperature for 30 min. To the reaction was added acetic acid (502 ml, 8.73 mmol) followed by sodium triacetoxyborohydride (2.8 g, 13.2 mmol) and the reaction was stirred at room temperature overnight. The mixture was concentrated under reduced pressure to a volume of 200 ml, then basified using a saturated solution of NaHCOs and the phases were separated.

The organic layer was dried over MgSO 4 and evaporated under reduced pressure.

The crude product was purified by column chromatography using a Biotage ™ cartridge (silica gel KP-Sil ™ 60 A) with dichloromethane: methanol: ammonia 0.88 (95: 5: 0.5) as eluent to give the desired product (771 mg, 48%). 1 H-NMR (CDCl 3, 300 MHz) d: 0.22 (m, 2 H), 0.36 (m, 2 H), 1.13 (s, 3 H), 1.72-1.97 (m, 4 H), 2.07-2.28 (m, 2 H), 2.98 (m, 2H), 3.31 (m, 1 H), 5.38 (s, width, 1 H), 7.24 (s, width, 1 H). LRMS: m / z = 182 (M) + PREPARATION 153. { (2R) -1-rf 1 -methylcyclopropyl) methynpyrrolidinyl} methylamine The title compound was obtained as an oil (72%) from (2R) -1 - [(1-methylcyclopropyl) methyl] -2-pyrrolidinecarboxamide (preparation 152) following the procedure described in preparation 148. 1 H NMR (CDCls, 400 MHz) d: 0.19 (m, 2H), 0.32 (m, 2H), 1.06 (s, 3H), 1.26 (s, width, 2H), 1.52 (d, 1 H), 1.56-1.82 (m, 4H), 2.05 (dd, 1 H), 2.34 (m, 1 H), 2.60 (d, 1 H), 2.76 (dd, 1 H), 2.97 (d, 1 H), 3.23 (m, 1 H). LRMS: m / z = 168 (M) + PREPARATION 154 2-r3-Chloro-2-methyl-5-r ( { R (2R) -1-r (1-methylcyclopropyl) methan-2-pyrrolidinyl} methyl) amino-1-6-oxo- 1 (6H) -pyrazinyl-benzyl acetate The title compound was obtained as a yellow oil (81%), de. { (2R) -1 - [(1-methylcyclopropyl) methyl] -2-pyrrolidinyl} methylamine (preparation 153) and 2- [3,5-dichloro-2-methyl-6-oxo-1 (6H) -pyrazinyl] benzyl acetate (preparation 17), following a procedure similar to that described in preparation 144. NMR 1H (CDCls, 300 MHz) d: 0.20 (m, 2H), 0.34 (m, 2H), 1.11 (s, 3H), 1.56-1.90 (m, 5H), 2.11 (m, 1 H), 2.20 (s) , 3H), 2.61 (m, 1 H), 3.00 (d, 1 H), 3.30 (m, 2H), 3.60 (m, 1 H), 4.80 (s, 2H), 5.20 (s, 2H), 6.75 (m, 1 H), 7.38 (m, 5H).

LRMS: m / z = 459, 461 (M + 1) + PREPARATION 155 2-R 2 -methyl-5-R a (2 R) -1-r (1-methylcyclopropinmet M-2-pyrrolidinyl) methyl) amino 1 -6-oxo-1 (6H) -pyrazinyl-1-acetic acid hydrochloride The title compound was obtained as a yellow oil (100%) from 2- [3-chloro-2-methyl-5 - [( { [(2R) -1 - [(1-methylcyclopropyl) methyl]] -2-pyrrolidinyl.} Methyl) amino] -6-oxo-1 (6H) -pyrazinyl] benzyl acetate (preparation 154), following the procedure described in Preparation 145. 1H-NMR (d6-DMSO, 400 MHz) d: 0.39 (m, 2H), 0.50 (m, 1H), 0.59 (m, 1 H), 1.18 (s, 3H) , 1.70-1.97 (m, 3H), 2.02 (m, 4H), 2.78 (m, 1 H), 3.05 (m, 1 H), 3.20-3.65 (m, 5H), 4.65 (s, 2H), 6.62 (s, 1 H), 7.40 (s, width, 1 H). LRMS: m / z = 335 (m + 1) +.

PREPARATION 156 N- (1 H-lndol-5-ylmethyl) -2-r 6 -methyl-3-r ( { (2R) -1-y (1-methylcyclopropyl) methyl- 2- pyrrolidinyl > methyl) amino1-2-oxo-1 (2H) -pyrazinyl-1-acetamide The title compound was prepared from 2- [2-methyl-5 - [(. {(2R) -1 - [(1-methylcyclopropyl) methyl] -2-pyrrolidinyl} methyl] amino acid hydrochloride. ] -6-oxo-1 (6H) -pyrazinyl] acetic acid (preparation 155), using the procedure described in Preparation 139. The product was then purified by column chromatography on silica gel using hexane: i-propanol: ammonia 0.88 ( 75: 25: 2) as eluent, giving the title compound as a white foam (99 mg, 48%). 1 H NMR (CDCl 3, 400 MHz) d: 0.18 (m, 2 H), 0.30 (m, 2 H), 1.02 (s, 3H), 1.50-1.84 (m, 5H), 2.08 (m, 1H), 2.20 (s, 3H), 2.60 (s, width, 1 H), 2.99 (d, 1 H), 3.28 (m, 2H) , 3.54 (m, 1H), 4.52 (d, 2H), 4.62 (s, 2H), 6.45 (m, 2H), 6.61 s, width, 1H), 6.70 (s, 1H), 7.04 (d, 1H) , 7.20 (s, 1H), 7.34 (d, 1H), 7.48 (s, H), 8.18 (s, width, 1H). LRMS: m / z = 463 (M + 1) + EXAMPLE 36 N-f1H-lndol-5-methylmethyl) -2-r6-methyl-2-oxo-3-r (2R) -1-tetrahydro-2H-pyran-4-yl-2-pyrrolidinylmethyl > amino) -1 (2H) -pyrazinin acetamide PREPARATION 157 r (2R) -1-Tetrahydro-2H-pyran-4-yl-2-pyrrolidininmethylamine Tetrahydro-4H-pyran-4-one (291 ml, 3.15 mmole) and acetic acid (181 ml, 3.15 mmole) were added to a suspension of (2R) -pyrrolidinecarboxamide (360 mg, 3.15 mmole) in tetrahydrofuran (8 ml). , followed by sodium triacetoxyborohydride (1.0 g, 4.73 mmol), and the reaction was stirred at room temperature overnight. Water was added, the mixture was extracted with ethyl acetate, and the combined organic extracts were evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using dichloromethane: methanol (95: 5) as eluent to give a white solid. Lithium aluminum hydride (5 ml, 1 M in tetrahydrofuran, 5.0 mmol) was added to a solution of the intermediate amide in tetrahydrofuran (8 ml), and the reaction was heated to reflux overnight. The cooled reaction was quenched with water (1.5 mL), dried over MgSO4, filtered and the filter washed well with ethyl acetate. The combined filtrates were evaporated under reduced pressure to give the title compound as an oil (460 mg, 79%). NMR? (CDCls, 400 MHz) d: 1.39-1.84 (m, 9H), 2.50-2.73 (m, 3H), 2.81 (m, 1 H), 2.98 (m, 1 H), 3.38 (m, 2H), 4.00 (m, 2H). LRMS: m / z = 185 (M + 1) + PREPARATION 158 2-r3-Chloro-2-methyl-6-oxo-5- (fí (2R) -1-tetrahydro-2H-pyran-4-yl-2-pyrrolidinipmethyl) amino) -1 (6H) -pyrazinipacetate of benzyl A mixture of [(2R) -1-tetrahydro-2H-pyran-4-yl-2-pyrrolidinyl] -methylamine (preparation 157) (460 mg, 2.50 mmol), 2- [3,5-dichloro-2-methyl] 6-oxo-1 (6H) -pyrazinyl] benzyl acetate (preparation 17), and triethylamine (870 ml, 6.24 mmol) in ethyl acetate (8 ml) was heated under reflux for 18 h, then cooled. Water (1.5 ml) was added, the reaction mixture was dried over MgSO, and filtered through celite, washing the filter well with ethyl acetate. The combined filtrates were concentrated under reduced pressure and the residue was purified by column chromatography on silica gel using hexane: ethyl acetate (50:50) as eluent to give the desired product as a white solid (970 mg, 82%). 1 H-NMR (CDCls, 400 MHz) d: 1.55-1.94 (m, 8 H), 2.20 (s, 3 H), 2.58 (m, 1 H), 2.71 (m, 1 H), 3.00 (m, 1 H), 3.16 (m, 2H), 3.38 (m, 2H), 3.52 (m, 1H), 4.00 (m, 2H), 4.80 (s, 2H), 5.20 (s, 2H), 6.48 (s, 1 H), 7.37 (m, 5H). LRMS: m / z = 475 (M + 1f PREPARATION 159 2-R6-Methyl-2-oxo-3- (L (2R) -1-tetrahydro-2H-pyran-4-yl-2-pyrrolidinyl-1-methyl) -1-hydroxy-2-oxo-2-oxo-pyrazine co A mixture of 2- [3-chloro-2-methyl-6-oxo-5- ( { [(2R) -1-tetrahydro-2H-pyran-4-yl-2-pyrrolidinyl] methyl}. ) -1- (6H) -pyrazinyl] benzyl acetate (preparation 158) (970 mg, 2.04 mmol) and palladium hydroxide (80 mg) in ethanol (8 ml) was hydrogenated at 97.47 kPa at room temperature for 20 minutes. h. The reaction mixture was filtered through Whatman fiber, and the filtrate was evaporated under reduced pressure to give the desired compound (680 mg, 95%). LRMS: m / z = 351 (M + 1) + PREPARATION 160 N- (1 H-lndol-5-ylmethyl) -2-r 6 -methyl-2-oxo-3-r (2 R) -1-tetrahydro-2 H -pyran-4-yl-2-pyrrolidinylmethyl > amino) -1 (2H) -pyrazinin acetamide The title compound was obtained as a white powder (31%), from 2- [6-methyl-2-oxo-3- ( { [(2R) -1-tetrahydro-2H-pyran hydrochloride] 4-l-2-pyrrolidinyl] methyl.} Amin) -1 (2H) -p -razinyl] acetic acid (preparation 159) and 1 H-indol-5-ylmethylamine (preparation 8), using a procedure similar to that described in Preparation 45. 1 H NMR (CDCl 3, 400 MHz) d: 1.54-1.84 (m, 8H), 2.23 (s, 3 H), 2.57 (m, 1 H), 2.70 (m, 1 H), 2.99 (m, 1 H), 3.15 (m, 2H), 3.37 (m, 2H), 3.46 (m, 1 H), 3.99 (m, 2H), 4.52 (d, 2H), 4.63 (s, 2H), 6.27 (s, wide, 2H), 6.52 (s, 1 H), .59 (s, wide, 1 H), 6.73 (s, 1 H), 7.06 (d, 1 H), 7.20 (s, 1 H) ), 8.22 (s, width, H). LRMS: m / z = 478 (M) + EXAMPLE 37 2-5 5- ({í ((2R, 4R) -1-Cyclopentyl-4-methylpiperidin-methylene] -amino) -2-methyl-6-oxo- 1 (6H) -pyrazinyl-N- (1 H -indole-4-ylmethyl) acetamide PREPARATION 161 2-r3-Chloro-5-yl (2R, 4R) -1-cyclopentyl-4-methylpiperidininmethyl amine) -2-methyl-6-oxo-1 (6H) -pyrazine benzyl acetate A mixture of (2R, 4R) -4-methyl-2-piperidinecarboxamide (prepared as in preparation 86) (5.0 g, crude), cyclopentanone (3.1 ml, 35 mmol), sodium triacetoxyborohydride (9.5 g, 45.5 mmol) and Acetic acid (2 ml, 35 mmol) in tetrahydrofuran (30 ml) was stirred at room temperature overnight. The reaction mixture was evaporated under reduced pressure to give the crude carboxamide (6 g). This intermediate (3 g) was suspended in tetrahydrofuran (30 ml), lithium aluminum hydride (17 ml, 1 M in tetrahydrofuran, 17 mmol) was added, and the reaction was heated under reflux for 18 h. Water was added to the cooled reaction, the mixture was dried over MgSO, and filtered, washing well with ethyl acetate. The combined filtrates were concentrated under reduced pressure and the residue was redissolved in ethyl acetate (12 ml). Triethylamine (1.3 ml, 9 mmol) and benzyl 2- [3,5-dichloro-2-methyl-6-oxo-1 (6H) -pyrazinyl-acetic acid ester (preparation 17) (2.0 g, 6.11 mmol) were added and the reaction it was heated under reflux for 20 h. The cooled mixture was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel using ethyl acetate: pentane (5:95) as eluent to give the title compound as a white solid (850 mg, 12%) . NMR (CDCls, 400 MHz) d: 0.88 (d, 3H), 1.20-1.60 (m, 8H), 1.70 (m, 3H), 1.85 (m, 1 H), 1.97 (m, 1 H), 2.20 ( s, 3H), 2.61 (m, 1 H), 2.81 (m, 1 H), 3.17 (m, 2H), 3.42 (m, 1 H), 3.58 (m, 1 H), 4.80 (s, 2H) , 5.20 (s, 2H), 6.50 (s, width, 1H), 7.36 (m, 5H). LRMS: m / z = 487, 489 (M + 1) + PREPARATION 162 2-r 5 - (flT 2 R 4 R) -1-Cyclopentyl-4-methylpiperidinylmethyl > amino) -2-methyl-6-oxo-1 (6H) -pyrazinyl-1-N- (1 H -indol-4-ylmethyl) acetamide A mixture of 2- [3-chloro-5- ( { [(2R, 4R) -1-cyclopentyl-4-methylpiperidinyl] methyl.} Amino) -2-methyl-6-oxo-1 (6H) -pyrazinyl] benzyl acetate (preparation 161) (320 mg, 0.66 mmol) and palladium hydroxide (85 mg) in methanol (6 ml) was hydrogenated at 97.47 kPa and room temperature overnight. The incomplete reaction was filtered, the filtrate was evaporated under reduced pressure and the residue redissolved in methanol (8 ml). Palladium hydroxide (85 mg) was added and the reaction was hydrogenated at 194.94 kPa and room temperature overnight. The reaction mixture was filtered through Whatman® fiber, and the filtrate was evaporated under reduced pressure to give an oil, 200 mg-. A mixture of 1 H-indole-5-ylmethylamine (preparation 8) (85 mg, 0.56 mmole), HOBT (78 mg, 0.56 mmole), WSCDl.HCl (111 mg, 0.56 mmole) and N-methymorpholine (96 ml, 0.87 mmoles) was added to a solution of the intermediate acid in dichloromethane (6 ml), and the reaction was stirred at room temperature for 20 h. The reaction mixture was poured directly onto a silica column and purified using dichloromethane: methanol: ammonia 0.88 995: 5: 0.5) as eluent, giving the title compound as a white powder (22 mg, 8%). 1 H-NMR (CDCl 3, 400 MHz) d: 0.86 (d, 3 H), 1.20-1.99 (m, 13 H), 2.28 (s, 3 H), 2.60 (m, 1 H), 2.81 (m, 1 H), 3.16 (m, 2H), 3.40 (m, 1 H), 3.55 (m, 1 H), 4.50 (d, 2H), 4.63 (m, 2H), 6.42 (s, width, 1 H), 6.52 (m, 2H), 7.04 (d, 1 H), 7.20 (m, 1 H), 7.35 (d, 1 H), 7.50 (s, 1 H), 8.24 (s, width, 1 H).

EXAMPLE 38 N- (1 H-Benzimidazol-6-ylmetin-2-r3-fflT2R) -1-isobutylpyrrolidinyl] methyl} amino) -6-methyl-2-oxo-1 (2H) -pyrazinyl-1-acetamide H H PREPARATION 163 N- (1 H-Benzimidazol-6-ylmethin-2-r 3 -arf 2 R) -1-isobutyl-pyrrolidinimethyl > amino) -6-methyl-2-oxo-1 (2H) -pyrazinin acetamide HOBT (25 mg, 0.19 mmol), WSCDl.HCl (31 mg, 16 mmol), N-methylmorpholine (41 mL, 0.37 mmol) and 1 H-benzimidazol-6-ylmethylamine (21 mg, 0.14 mmol) were added. 2- [3- ( { [(2R) -1-Isobutylpyrrolidinyl] methyl} amino) -6-methyl-2-oxo-1 (2H) -pyrazinyl] acetic acid solution (preparation 62) (40 mg, 0.12 mmol) in NN-dimethylformamide (2 ml), and the reaction was stirred at room temperature overnight. The mixture was evaporated under reduced pressure and the residue was preadsorbed onto silica gel, and then purified by column chromatography on silica gel using dichloromethane: methanol: ammonia 0.88 (95: 5: 0.5) as eluent to give the title compound (6 mg, 10%). 1 H NMR (CDCls, 400 MHz) d: 0.82 (d, 3 H), 0.87 (d, 3 H), 1.52-1.84 (m, 5 H), 2.07 (m, 2 H), 2.22 (s, 3 H), 2.30 (m , 1 H), 2.60 (m, 1 H), 3.14 (m, 1 H), 3.20 (m, 1 H), 3.48 (m, 1 H), 4.53 (m, 2 H), 4.62-4.78 (m, 2H), 6.40 (s, broad, 1H), 6.74 (s, 1 H), 7.10 (m, 2H), 7.28-7.70 (m, 2H), 8.00 (s, 1 H). LRMS: m / z = 452 (M + 1) + EXAMPLE 39 N- (1 H-Benzimidazol-6-methylmeth-2-r3- (2R) -1-cyclopentylpyrrolidinH1methyl}. Amino) -6-methyl-2-oxo-1 (2H) -pyrazinyl ] acetamide PREPARATION 164 N- (1 H-Benzamdazol-6-ylmethyl) -2-r3-r (2R) -1-cyclopentylpyrrolidinylmethyl > amino) -6-methy1-2-oxo-1 (2H) -pyrazine-nacetamide H The title compound was obtained as a white foam (42%) from 2- [3- ( { [(2R) -1-Cyclopentyl-pyrrolidinyl] methyl.} Amino) -6-methyl hydrochloride. -2-oxo-1 (2H) -pyrazinyl] acetic acid (preparation 145) and 1H-benzamidazol-6-ylmethylamine following the procedure described in Preparation 163. 1 H-NMR (CDCls, 400 MHz) d: 1.40-1.92 ( m, 10H), 2.21 (s, 3H), 2.38 (m, 1 H), 2.50 (m, 1H), 2.92 (m, 1 H), 3.00 (m, 2H), 3.20 (m, 2H), 3.42 (m, 1 H9, 4.54 (d, 2H), 4.66 (s, 2H), 6.35 (s, width, 1 H), 6.69 (s, 1 H), 7.04-7.20 (m, 2H), 7.38-7.60 (m, 2H), 7.98 (s, 1 H) LRMS: m / z = 463 (M + 1) + Abbreviations: DIBAL Diisobutylaluminum hydride HOBT 1-hydroxybenzotriazolo hydrate LRMS Low resolution mass spectroscopy TFA Trifluoroacetic acid TMSCN Trimethylsilyl cyanide WSCDl.HCl 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride The biological activities of the compounds of the present invention were determined by the following test methods.

Chromogenic Assays The inhibition of thrombin, trypsin, plasmin or factor Xa is measured in chromogenic assays in 96-well plates. The percentage of inhibition and IC50 were calculated from triplicate samples of a dose-response curve of concentration 8. The Ki for each inhibitor was calculated from the Km of the substrate and from Cl50. All the trials were carried out in a total incubation of 200 ul of 50 mM HEPES and 150 mM NaCl at pH 8.0, and all dilutions of the compound were preincubated with enzyme at room temperature for 15 minutes before the substrate addition. After 30 minutes of incubation at 30 ° C, the D.O: was measured at 405 nM in a 96-well reader. Thrombin activity was measured using bovine thrombin and S2238 (HD-Phe-Pip-Arg-pNA), bovine pancreatic trypsin was tested with S2222 (Benz-lsoleu-Glu-Gly-Arg-pNA), the bovine plasma plasmin was assayed with Chromozym PL (Tosil-Gly-Pro-Lys-pNA) and bovine factor Xa was assayed in 50 mM Tris buffer, NaCl 150 mM, pH 7.5 with S2222.

Coagulation assays Thrombin time (TT) and partial activation time of thromboplastin (APTT) were measured using respectively Instrumentation Laboratories (IL) Test TT reagent and IL Test APTT (ellagic acid) reagent in an Automated Coagulation Laboratory (ACL) , according to the manufacturer's instructions.

In Vitro It was added to aliquots of 1 ml of combined plasma of rat (cipher), a 1/100 volume of a range of compound concentrations and the resulting mixtures of pre-incubated at room temperature for 15 minutes, after which the TT and APTT were measured.

Ex vivo The compounds were dosed to rats per os, intravenously or intraduodenally. Blood samples were taken pre and post dose in citrate solution and the plasma was prepared. TT and APTT were measured as in the in vitro tests. All specifically exemplified compounds exhibited in vitro measures of inhibitory activities against thrombin with Ki < 3 x 10"7 M and inhibitory potencies in vitro against trypsin with Ki> 1 x 10" 5 M.

Claims (31)

NOVELTY OF THE INVENTION CLAIMS

1. - A compound of formula 1: wherein: R 1 is C 1 -C 4 hydrogen, C 1 -C 6 perfluoroalkyl, C 1 -C 4 alkyl, fluoro, or chloro; R2 is hydrogen, CH3, or CF3; R3 is hydrogen, C1-C4 alkyl, C1-C4 perfluoroalkyl C1-C4 perfluoroalkyl, C1-C4alkyl, fluoro or chloro; R 4 is hydrogen or C 1 -C 4 alkyl; R5 is hydrogen or C1-C4 alkyl; R6 is hydrogen, fluoro or chloro; C 1 -C 4 alkyl, C 3 -C 6 carbocyclic, C 3 -C 6 carbocyclic) - (C 1 -C 4 alkyl) wherein the alkyl and carbocyclic may be optionally substituted by C 1 -C 4 alkyl or fluoro, and wherein the carbobocycle contains zero, one or more double bonds; or R5 and Rd together form a chain that forms a bridge containing 2 or 3 carbon atoms; And it is hydrogen, chlorine, fluoro, bromo, methyl or CF3; V is C or N; W and X are independently CH, CF, CCI or N; BA- is any one of the following fragments: BC (R8) (R9) - B-CH2-C (R8) (R9) - BC (R8) (R9) - CH2- B- CH2- (R8) (R9) CH2- BC (R8) (R9) -CH2-CH2-B-CH2-CH2-C (R8) (R9) - in which:

R8 and R9 are independently hydrogen, - (CH2) mN (R10) (R11), -CH20- (CH2) 2N (R10) (R11), or R8 and R9 together form a 4- to 6-membered ring containing N (R12) ); and m is 0, 1 and 2, except when A represents - (R8) (R9) -, when m is 1 or 2; R 10 and R 11 are independently chosen from hydrogen or C 1 -C 4 alkyl optionally containing an oxygen atom in the chain or chain end; or R10 and R11, together with the nitrogen atom to which they are bonded, form a 4 to 6 membered saturated heterocyclic ring which, when the ring is six members, may optionally contain an additional oxygen or nitrogen atom present as N (R12); R 12 is hydrogen or C 1 -C 4 alkyl optionally containing an oxygen atom in the chain or at the end of the chain; B is phenyl or a heterocyclic aromatic ring of 5 to 6 members independently selected from oxygen, sulfur and nitrogen; R7 (when B is phenyl or an aromatic heterocycle) is one or more of hydrogen, C-C6 alkyl, fluoro, chloro, or any one of the following fragments: (CH2) pO- (CH2) 2N (R10) ( R11) are as defined above, and p is 0 or 1; wherein Q, together with the C atom to which it is attached, is a 5- or 6-membered heterocyclic ring containing a nitrogen atom, said heterocyclic being optionally substituted by C 1 -C 4 alkyl, and q being 1 or 2; - (CH2) C (in which rys are independently = 0, 1 or 2, R13 and R14 are independently hydrogen or C1-C4 alkyl optionally containing an oxygen atom in the chain or at the end of the chain, or R13 and R14 together with the atom to which they are linked form a saturated carbocyclic ring of 4 to 6 members, R15 and R16 are independently selected from hydrogen or C1-C4 alkyl optionally containing an oxygen atom in the chain or at the end of the chain. chain, or R15 and R16, together with the nitrogen atom to which they are bound form a saturated heterocyclic ring of 4 to 6 members, or one of R13 or R14, and one of R15 or R16, together with the carbon and nitrogen atoms to which they are linked, they form a saturated heterocyclic ring of 4 to 6 members, in which case the other radical of R13 or R14 is hydrogen or C1-C4 alkyl, and the other radical R15 or R16 is hydrogen C1-C4 alkyl containing optionally an oxygen atom in the chain or in the end of the chain; or wherein R7-B represents the following bicyclic fragments in which R12 is as defined above with the proviso that R7, R8 and R9 can not all be hydrogen, and only one of R7, R8 and R9 contains a nitrogen atom or, when R8 and R9 together form a ring, said ring contains only one nitrogen atom with the condition that one of R > 8 or "R D9 can be the following fragment containing two nitrogen atoms: or, B is a saturated or partially saturated 4- to 7-membered heterocyclic ring containing one or two heteroatoms of which at least one is a nitrogen and the other is independently selected from oxygen, sulfur and nitrogen; and wherein R7 (when B is a saturated or partially saturated heterocycle) is one or more of C-Cß alkyl, carbocyclic CI-CT, carbocyclic (C3-C-β-alkyl) (C1-C4), said carbocyclic containing zero, one or more double bonds , wherein said alkyl and cycloalkyl optionally contain a heteroatom selected from oxygen, sulfur and nitrogen and are further optionally substituted by one or more fluoro, or C 1 -C 4 alkyl optionally containing an oxygen atom in the alkyl chain or in the end of the chain, and pharmaceutically acceptable salts thereof 2. A compound according to claim 1, wherein R1 is hydrogen or methyl

3. A compound according to claim 1 or 2, wherein R2 is hydrogen or methyl.

4. A compound according to any one of claims 1 to 3, wherein R is hydrogen or methyl.

5. A compound according to any one of the preceding claims, wherein R 4 is hydrogen.

6. A compound according to any one of the preceding claims, wherein R5 is hydrogen.

7. A compound according to any one of the preceding claims, wherein R6 is C6-C6 alkyl, C3-C6 carbocyclic, optionally substituted by fluoro, or R5 and R6 together form a bridge containing 2 or 3 carbon atoms.

8. A compound according to any one of the preceding claims, wherein Y is hydrogen, chlorine or bromine.

9. A compound according to any one of the preceding claims, wherein W is CH or N.

10. A compound according to any one of the preceding claims, wherein X is CH or N.

11. A compound according to any of the preceding claims, wherein BA- represents B-CH2-C (R8) (R9) wherein R8 and R9 are independently hydrogen, - (CH2) mN (R10) (R11), -CH2O- or R? 8 ° . and, R D9a together form a ring of 4 to 6 members containing N (R j12) \, and m is 0, 1 and 2, except when A represents -C (R j8) \ (/ DR9) \ -, when m is 1 or 2.

12. A compound according to claim 11, wherein, when C * is chiral, then BC * (R8) (R9) represents the S enantiomer.

13. A compound according to claim 11 or 12, wherein B is phenyl.

14. A compound according to any one of the preceding claims, wherein m is 1.

15. A compound according to any one of the preceding claims, wherein R10 and R11 independently represent hydrogen, Cisque alkyl optionally contains an oxygen atom In the chain, R10 and R11, together with the nitrogen atom to which they are bonded, form a 5- to 6-membered heterocyclic ring in which, when the ring is six members, it may optionally contain an oxygen or a nitrogen atom.

16. A compound according to any one of the preceding claims, wherein R12 is hydrogen or C1-C4 alkyl optionally containing an oxygen atom in the chain or at the end of the chain.

17. A compound according to any one of the preceding claims, wherein B is phenyl or a six-membered heterocyclic aromatic ring containing a nitrogen atom, said phenyl or heterocyclic ring being able to be substituted by fluoro, chloro, C1-C4 alkyl u C1-C4 O-alkyl.

18. A compound according to any one of the claims 1 to 13, wherein B is phenyl and R7 - (CH2) r (R13) (R14) - (CH2) sN (R15) (R16) wherein r, s and R13 to R16 are as defined in the claim 1.

19. A compound according to any one of the claims 1 to 10, wherein B is a saturated or partially saturated heterocyclic ring of 4 to 7 members containing one or two heteroatoms of which at least one is nitrogen and the other is independently selected from oxygen, sulfur and nitrogen; and R7 is R17 which is substituted on the nitrogen of the heterocyclic ring and is selected from one or more of C-? -C6 alkyl, C3-C6 carbocyclic, carbocyclic (C3-C6) (C1-C4) alkyl, said carbocyclic being zero , one or more double bonds, wherein said alkyl and carbocyclic optionally contain a heteroatom selected from oxygen, sulfur and nitrogen, and are further optionally substituted by one or more fluoro, or C1-C4 alkyl optionally containing an oxygen atom in the alkyl chain or at the end of the chain.

20. A compound according to claim 19, wherein the saturated or partially saturated heterocyclic ring is further optionally substituted by R18 which is independently selected from one or more of Ct-Cß alkyl and Ci-Cβ perfluoroalkyl, said alkyl optionally containing one atom of oxygen in the chain or at the end of the chain.

21. A compound according to claims 19 or 20, wherein R? It is cyclopropylmethyl.

22. A compound according to any one of claims 19 to 21, wherein the heterocyclic ring is a 5- or 6-membered saturated heterocyclic aryl.

23. A compound according to any of claims 19 to 22, wherein B-A is B-C (R8) (R9).

24. A compound according to any one of the preceding claims, wherein R7-B-A is selected from the following radicals: wherein R 10 and R 11 are as defined above and R 7 is hydrogen, C 1 -C alkyl, perfluoro-C 1 -C 4 alkyl, C 1 -C 4 -alkyl, perfluoro-C 1 -C 4 -alkyl, fluoro or chloro; wherein R10 and R11 are as defined in claim 1: wherein R15 and R16 are as defined in claim 1; wherein R13 to R16 are as defined in claim 1: wherein R13 to R16 are as defined in claim 1; in which R15 is hydrogen or C1-C4 alkyl optionally containing oxygen in the chain or at the end of the chain; wherein R15 is hydrogen or C1-C4 alkyl optionally containing oxygen in the chain or at the end of the chain; wherein R10 and R11 are as defined in claim 1, and v is 0 or 1; wherein R17 and R18 in (i), (j) and (k) are as defined in claims 19 to 21.

25. A compound according to claim 24, wherein radical (a) to (i) is selected from: 10 radical (b) H-, radical (c) radical (d) radical (e) radical (f)

26. A compound according to any one of the preceding claims, selected from the group comprising: (R, S) -2- [3 - [(2-amino-1-benzylethyl) amino] -6-methyl-2-oxo-1 ( 2H) -pyridinyl] -N- (1 H -indol-5-ylmethyl) acetamide; 2- [3- (3 - [(dimethylamino) methyl] phenylamino) -6-methyl-2-oxo-1 (2H) -pyrazinyl] -N- (1 H -indole-5-ylmethyl) acetamide; 2- [3-chloro-5- (3 - [(dimethylamino) methyI] phenylamino) -2-methyl-6-oxo-1 (6H) pyrazinyl] -N- (1 H -indol-5-ylmethyl) acetamide; 2- [3 - [(1 S) -1-benzyl-2- (dimethylamino) ethyl] amino-6-methyl-2-oxo-2 (2H) -pyrazinyl] -N- (1 H -indole-5- ilmethyl) acetamide; 2- [3 - [(1 S) -1-benzyl-2- (d -methylamino) ethyl] amino-5-chloro-6-methyl-2-oxo-1 (2H) -pyrazinyl] N- ( 1 H-indol-5-ylmethyl) acetamide; 2- [3. { [2R, S) -3- (dimethylamino) -2-phenylpropyl] amino} -6-methyl-2-oxo-1 (2H) -pyrazinyl] -N- (1 H -indol-5-ylmethyl) acetamide; N - [(3-methyl-1 H -indol-5-yl) methyl-2- [6-methyl-3 - ([3- (methylamino) methyl] phenethyl] amino) -2-oxo-1 (2H) -pirazinyl] -acetamide; 2- [3. { [(1 S) -1-benzyl-2- (dimethylamino) ethyl) amino} -6-methyl-2-oxo-1 (2H) -pyrazinyl] -N - [(6-methyl-1 H -indazol-5-ylmethyl] acetamide; 2- [3-. {[3- ( 3-azetidinyl) phenethyl] amino] -6-methylene-2-oxo-1 (2H) -pyrazinyl] -N - [(3-methyl-1 H -indol-5-yl) metii] acetamide; N- [(3-methyl-1 H-indol-5-yl) mephyl] -2- [6-methyl-3- { [3- (1-methyl-3-azetine) phenyl] amino] -2-oxo-1 (2H-pyrazinyl-acetamide; 2- [3 [(3- {[[(2-methoxyethyl) amino] methyl} phenethyl) amino] -6 - methyl-2-0X0-1 (2H) -pyrazinyl] -N - [(3-methyl-1 H -indol-5-yl) methyI] acetamide; 2- [3- ( { (2R) -1 - (Cyclopropylmethyl) pyrrolidinyl] methyl.} amino) -6-methyl-2-oxo-1 (2H) -pyrazinyl-N - [(3-methyl-1 H -indol-5-yl) methyl] acetamida; 2- [3- ( { [(2R) -1-Cyclopentylpyrrolidinyl] methyl.}. Amino-6-methyl-2-oxo-1 (2H) -pyrazinyl] -N - [(3-methyl) -1H-indol-5-yl) methyl] acetamide; N [(3-methyl-1 H -indol-5-yl) methyl] -2- [6-methyl-2-oxo-3- ( { [(2R) -1-tetrahydro-2H-pyran-4-ylpyrrolidinyl] methyl] amino] -1 (2H) -pyrazinyl] acetamide; N - [(3-methyl-1 H-indole-5- il) methyl] -2- [6-methyl-3 - [( { (2R) -1 - [(1-methylcyclopropyl) methyl] methyl] p rrol¡dinil} methyl) am¡no] -2-oxo-1 (2H) -pyrazinyl] acetamide..; 2- [3- ( { [(2R) -1- (2-methoxyethyl) pyrrolidinyl] methyl} amino) -6-methyl-2-OXO-1 (2H) -pyrazinyl] -N - [( 3-methyl-1 H-indol-5-yl) methyl] acetamide; N - [(3-methyl-1 H-indol-5-yl) methyl] -2- [6-methyl-3- ( { [(2R) -1-neopentylpyrrolidinyl] methyl.} Amino) -2- oxo-1 (2H) -pyrazinyl] -acetamide; 2- [3- ( { [(2R) -1-Isobutylpyrrolidinyl] methyl.}. Amino) -6-methyl-2-oxo-1 (2H) -pyrazinyl] -N - [(3-methyl-1 H-indol-5-yl) methyl] acetamide; 2- [3- ( { [(2R) -1- (2-methoxyethyl) pyrrolidinyl] methyl.}. Amino-6-methyl-2-oxo-1 (2H) -pyrazinyl] -N- [(3-methyl) -1H-indol-5-yl) methyl] acetamide; 2- [3- ( { [(2R) -1-cyclopentylpyrrolidinyl] methyl} amino) -6-methyl-2-oxo-1 (2H ) -pyrazinyl] -N - [(3-methyl-1H-indol-5-yl) methyl] acetamide; 2- [3- ( { [(2R) -1 - (cyclopropylmethyl) piperidinyl] methyl} amino) -6-methyl-2-oxo-1 (2H) -p -razinyl] -N- [3-methyl-1 H -indol-5-yl) methyl] acetamide; and pharmaceutically acceptable salts thereof.

27. A compound according to claim 26, selected from the group comprising: 2- [3- (3 - [(dimethylamino) methyl] phenethylammon) -6-methyl-2-oxo-1 (2H) pyrazinyl] -N- (1 H-indol-5-ylmethyl) acetamide; 2- [3 - [(1 S) -1-benzyl-2- (dimethylamino) ethyl] amino-6-methyl-2-oxo-1 (2H) -p -razin-N- (1 H-indole -5-ylmethyl) acetamide; N - [(3-methyl-1 H-indol-5-yl) methyl] 2- [6-meth] l - 3 - ([3 [(methylamino) methyl] phenethyl] amino) -2-oxo-1 ( 2H) -pyrazinyl] acetamide; 2 [3 - [(3- {[[(2-methoxyethyl) amino] methyl] phenethyl) amino] -6-methyl-2-oxo-1 (2H) -pyrazinyl] -N- [(3-methyl-1 H-indol-5-yl) methyl] acetamida; 2- [3- ( { [(2R) -1 - (c'clopropylmethyl) pyrrolidinyl] methyl} amino) -6-methyl-2-oxo-1 (2H) -pyrazinol ] -N- (3-methyl-1 H-inodol-5-yl) methyl] acetamide; 2- [3 ( { (2R) -1-Cyclopentylpyrrolidinyl] methyl.}. Amino) -6-methyl) -2-oxo-1 (2H) -pyrazinyl] -N - [(3-methyl) l-1 H-indol-5-yl) methyl] acetamide; 2- [3- ( { (2R) -1-isobutylpyrrolidinyl] methyl} amino) -6-methy1-2-oxo-l (2H) pyraziniI] -N- [3- methyl-1 H-indol-5-yl) methyl] acetamide; and pharmaceutically acceptable salts thereof.

28. A pharmaceutical composition, comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, according to any one of the preceding claims, together with a pharmaceutically acceptable carrier.

29. A compound of formula (I), or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 28, for use in medicine.

30. Use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 28, in the manufacture of a medicament for the treatment of prophylaxis of deep vein thrombosis (DVT) after surgery, major medical illness, paralysis, malignant disease, prolonged immobilization trauma, application of plaster on the lower extremities, or fractures of the lower extremities or pelvis; Recurrent DVT; DVT during pregnancy when there is a previous history of it, reocclusion after thrombolytic therapy; chronic arterial obstruction; peripheral vascular disease; acute myocardial infarction; unstable angina; atrial fibrillation; thrombotic stroke; passenger ischemic attacks; disseminated intravascular coagulation; coagulation in extracorporeal circuits; occlusion of arteriovenous shunts and blood vessel grafts (including coronary artery bypass grafts); restenosis and occlusion after angioplasty; neurodegenerative disorders; inflammatory disorders; or scarring.

31. A method to treat a mammal (including a human patient), to cure or prevent deep vein thrombosis (DVT) after surgery, major medical disease, paralysis, malignant disease, prolonged immobilization trauma, application of plaster in the lower extremities, or fractures of the lower extremities or the pelvis; Recurrent DVT; DVT during pregnancy when there is a previous history of it, reocclusion after thrombolytic therapy; chronic arterial obstruction; peripheral vascular disease; acute myocardial infarction; unstable angina; atrial fibrillation; thrombotic stroke; passenger ischemic attacks; disseminated vascular disease; coagulation in extracorporeal circuits; occlusion of arteriovenous shunts and blood vessel grafts (including coronary artery bypass grafts); restenosis and occlusion after angioplasty; neurodegenerative disorders; inflammatory disorders; or scarring; which comprises treating said mammal with an effective amount of a compound of the formula 81), or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 28.