EP2195320A1

EP2195320A1 - Pyrazolo-pyrazines derivatives used as g protein inhibitors

Info

Publication number: EP2195320A1
Application number: EP08858869A
Authority: EP
Inventors: Olivier Lavergne; Laëtitia BREHU; Grégoire Prevost
Original assignee: Ipsen Pharma SAS
Current assignee: Ipsen Pharma SAS
Priority date: 2007-09-27
Filing date: 2008-09-25
Publication date: 2010-06-16
Also published as: KR20100080541A; US20100222332A1; AU2008334535A1; JP2010540503A; CA2700599A1; CN101801975A; WO2009074743A1; RU2010116421A; FR2921658A1

Abstract

The invention relates to pyrazolo-pyrazines derivatives of the general formula (I) in which the radicals Z, R1, R2, R3 and R4 represent various variable groups, X is a sulphur atom or a selenium atom, and n is an integer equal to 1 or 2. These compounds are inhibitors of G proteins. They are of particular interest for treating diseases in which the heterotrimeric G protein is involved. The invention also relates to pharmaceutical compositions containing said products, and to the use thereof for preparing a drug.

Description

DERIVATIVES OF PYRAZOLO-PYRAZINES AS INHIBITORS OF

PROTEINS G

The present invention relates to pyrazolo-pyrazine derivatives. These compounds are inhibitors of G proteins. They are therefore particularly interesting for treating pathologies that result from the involvement of the heterotrimeric G protein. The invention also relates to pharmaceutical compositions containing said products and their use for the preparation of a medicament.

G proteins are in fact the structural association of three distinct subunits called α, β and γ, but function as dissociable entities consisting of α subunits on one side and β / γ dimers on the other. .

G-proteins participate in the transmission of signals from the outside of the cell through their interactions with receptors with seven transmembrane domains inward through different effectors including adenylate cyclase, phospholipase C or ion channels. The adenylate cyclase enzyme generates cyclic AMP (cAMP) (see Gilman, A.G. Biosci.Rep 15, 65-97 (1995)). Thus, it is known that, in order to activate the adenylate cyclase, it is necessary for the G proteins to be transiently in a heterotrimeric form, in which the monomer constituted by an α subunit is associated with the dimer constituted by the β subunits and γ. It is only in this situation that the signal from outside the cell can activate the α subunit of a G protein, which after dissociation can modulate the adenylate cyclase and modulate the production of cAMP.

It is also known that β / γ dimers can directly activate effectors leading to the activation of kinases regulated by extracellular signals (ERKs) or MAP kinases. A direct link between the β / γ subunits and the src or src like kinases has been demonstrated (see Gutkind, J.S. J.Biol.Chem.273, 1839-1842 (1998)).

On the other hand, bacterial toxins such as Vibrio cholera and Bortella pertussis, peptides such as mastoparan and suramin have been shown to directly modulate the activity of G proteins (see Freissmuth, M., Boehm, S., Beindl, W. Mol., Pharmacol., 49, 602-611 (1996), Boehm, S., Huck, S., Motejlek, A., et al., Journal of Negrochemistry 66, 1019-1026 (1996), Cachera, TG. , Rigual, R., Rocher, A. & Gonzalez, C.E.J.Neυrosci, 8, 2320-2327 (1996), Danilenko, M., Worland, P., Carlson, B., Sausville, EA & Sharoni , Y. Biochem.Biophys.Res.CommUn 196, 1296- 1302 (1993); Beindl, W., Mitterauer, T., Hohenegger, M., Ijzerman, AP, Nanoff, C. & Freissmuth, M. Mol. Pharmacol. 50, 415-423 (1996)).

For example, cholera toxin subunit modifies oc _s G protein by adding an ADP-ribose from NAD to a specific arginine acceptor site. This completely blocks the activity of GTPase, causing persistent stimulation of its effector following adenylate cyclase and leading to overproduction of cAMP.

The adverse effects of an abnormal level of cAMP are also known and include the following biological functions or disorders: smell, taste, light perception, neurotransmission, neurodegeneration, functioning of the endocrine and exocrine glands, autocrine regulation and paracrine, blood pressure, embryogenesis, benign cell proliferation, oncogenesis, viral infection and immunological functions, diabetes, obesity and pain.

The Applicant has just discovered that certain pyrazolo-pyrazine derivatives, namely the compounds of general formula (I) as defined below, can be used to treat or prevent pathologies that result from the involvement of the heterotrimeric G protein. .

The subject of the invention is therefore compounds of general formula

in racemic form, enantiomers or diastereoisomers or any combination of these forms and in which

Z represents a hydrogen atom or a radical of general formula

R ¹ and R ² represent, independently, a hydrogen atom, an aryl or heteroaryl radical, the aryl and heteroaryl radicals being optionally substituted by one or more idenic or different substituents chosen from: halo, hydroxy, alkyl, haloalkyl, alkoxy, haloalkoxy, aryl, aryloxy, -NRR ¹ , -C (O) -NRR ¹ , -NR _N -C (O) R ¹ , -SO ₂ -R, -SiRR ¹ R "or a heterocycloalkyl, or a radical of formula

or R ¹ and R ² together with the carbon atoms to which they are attached form a cycloalkyl or heterocycloalkyl radical;

R ³ represents a radical (CrCβ) alkyl or a cycloalkylalkyl, aryl or arylalkyl radical, the aryl group of the aryl and arylalkyl radicals being optionally substituted by one or more idenic or different substituents chosen from: halo, hydroxy, alkyl, haloalkyl, alkoxy, haloalkoxy, aryl, aryloxy, -NRR ¹ , -C (O) -NRR ", -NR _N -C (O) R", -SO ₂ -R, -SiRR ¹ R "or a heterocycloalkyl;

R _N represents a hydrogen atom or an alkyl radical;

R, R ¹ and R "represent, independently, an alkyl or aryl radical;

R ⁴ represents a hydrogen atom or a radical of formula -CO-OR ⁵ ;

R ⁵ represents an alkyl or arylalkyl radical;

n represents the integer 1 or 2;

X represents a sulfur atom or a selenium atom; or a pharmaceutically acceptable salt thereof.

In the definitions given above, the expression halo (halo) represents the fluoro, chloro, bromo or iodo radical, preferably fluoro, chloro or bromo.

By alkyl, when not more precise is meant a linear or branched alkyl radical of 1 to 6 carbon atoms, for example the methyl, ethyl, propyl, isopropyl, butyl, isobutyl or sec-butyl radicals. and tert-butyl, pentyl, neopentyl, isopentyl, hexyl, isohexyl. The term (C _r C ₈ ) alkyl denotes an alkyl radical having from 1 to 8 carbon atoms, linear or branched, such radicals containing from 1 to 6 carbon atoms as defined above but also the linear or branched radicals containing 7 or 8 carbon atoms, for example heptyl, octyl, 1,1,2,2-tetramethylpropyl, 1,1,3,3-tetramethylbutyl. By C4-C8 alkyl means an alkyl radical as defined above and containing from 4 to 8 carbon atoms. Haloalkyl means an alkyl radical of which at least one of the hydrogen atoms (and possibly all) is replaced by a halo radical such as trifluoromethyl, dichloroethyl.

The term alkoxy denotes radicals in which the alkyl radical is as defined above such as, for example, methoxy, ethoxy, propyloxy or isopropyloxy radicals, but also linear, secondary or tertiary butoxy, pentyloxy radicals. By haloalkoxy is meant an alkoxy radical in which at least one of the hydrogen atoms (and possibly all) is replaced by a halo radical such as trifluoromethoxy, dichloroethoxy.

The term cycloalkyl (or ring) refers to a saturated carbon monocyclic system comprising from 3 to 7 carbon atoms, and preferably cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl rings. The term cycloalkylalkyl preferably refers to radicals in which the cycloalkyl and alkyl radicals are as defined above such as for example cyclohexyl-methyl, cyclohexyl-ethyl, cyclopropyl-methyl.

The expression heterocycloalkyl (or heterocycle) denotes a fused monocyclic or bicyclic saturated system comprising from 2 to 6 carbon atoms and at least one heteroatom. This radical can contain several identical or different heteroatoms. Preferably, the heteroatoms are selected from oxygen, sulfur or nitrogen. As examples of heterocycloalkyl, mention may be made of pyrrolidine, imidazolidine, pyrrazolidine, isothiazolidine, thiazolidine, isoxazolidine, oxazolidine, piperidine, piperazine, azepane (azacycloheptane), azacyclooctane, diazepane, morpholine, decahydroisoquinoline (or decahydroquinoline), tetrahydrofuran or tetrahydrothiophene.

The term "aryl" represents an aromatic radical consisting of one ring or from 2 to 3 fused rings, for example the phenyl, naphthyl or fluorenyl radical. The term aralkyl (arylalkyl) preferably refers to radicals in which the aryl and alkyl radicals are as defined above such as, for example, benzyl, homobenzyl or phenethyl. The term arylalkoxy preferably denotes radicals in which the aryl and alkoxy radicals are as defined above such as, for example, benzyloxy or phenylethoxy. The term heteroaryl refers to an aromatic radical, consisting of one ring or 2 to 3 fused rings, with at least one ring containing one or more identical or different heteroatoms selected from sulfur, nitrogen or oxygen. As an example of a heteroaryl radical, mention may be made of the pyrrolyl, imidazolyl, pyrazolyl, isothiazolyl, thiazolyl, isoxazolyl, oxazolyl, triazolyl, thiadiazolyl, pyridyl, pyrazinyl, pyrimidyl, quinolyl, isoquinolyl, quinoxalinyl, indolyl, benzoxadiazoyl, carbazolyl, purinyl or triazinyl radicals. pyrrazolo-pyrimidyl but also thienyl, benzothienyl, furyl, benzofuryl or pyranyl, and preferably thienyl, furanyl, pyrrolyl, pyrazolyl, triazolyl, imidazolyl, thiazolyl, oxazolyl and pyridyl.

In the present application, the symbol -> corresponds to the point of attachment of the radical.

The subject of the present invention is also compounds of general formula I as defined above, or one of its diastereoisomers, as well as one of its pharmaceutically acceptable salts in which

R1 or R2 independently represents a hydrogen atom, an aryl radical or a heteroaryl radical, optionally substituted 1 to 3 times (and preferably 1 to 2 times) by a halogen atom, by an alkyl radical or by an alkoxy radical; ;

it being understood that R ¹ and R ² taken together may also form a ring or heterocycle;

R ³ represents a C1-C8 alkyl radical or a cycloalkylalkyl radical or an aryl or arylalkyl radical;

R ⁴ represents a hydrogen atom or a -CO-OR ⁵ radical with R ⁵ being either a linear or branched alkyl radical or a methylfluorene or benzyl radical;

n represents the integer 1 or 2;

X represents a sulfur atom or a selenium atom;

Z represents a hydrogen atom or a radical of general formula below

When it is stated that a radical is optionally substituted from 1 to 3 times, it is preferably optionally substituted 1 to 2 times and more preferably optionally substituted once. The invention preferably relates to compounds of formula I as defined above and characterized in that Z represents a hydrogen atom; or a pharmaceutically acceptable salt thereof.

Also preferably, the invention relates to compounds of formula I as defined above and characterized in that Z represents a radical of general formula

or a pharmaceutically acceptable salt thereof.

Also preferably, the invention relates to compounds of formula I as defined above and characterized in that X represents a sulfur atom; or a pharmaceutically acceptable salt thereof.

Preferably also, the invention relates to compounds of formula I as defined above and characterized in that X represents a selenium atom; or a pharmaceutically acceptable salt thereof.

Also preferably, the invention relates to compounds of formula I as defined above and characterized in that R ² represents a hydrogen atom; or a pharmaceutically acceptable salt thereof.

Preferably also, the invention relates to compounds of formula I as defined above and characterized in that R ⁴ represents a hydrogen atom or a radical of formula -CO-OR ⁵ and R ⁵ represents an alkyl radical; or a pharmaceutically acceptable salt thereof.

Preferably, the compound according to the invention of general formula (I) has a radical R ⁴ which represents a hydrogen atom.

Also preferably, the invention relates to compounds of formula I as defined above and characterized in that n is 1; or a pharmaceutically acceptable salt thereof.

Preferably also, the invention relates to compounds of formula I as defined above and characterized in that R ¹ represents an aryl or heteroaryl radical, the aryl radical being optionally substituted with one or more identical or different substituents chosen from halo. and alkoxy,

or a radical of formula

or a pharmaceutically acceptable salt thereof.

Preferably, the invention relates to compounds of general formula (I) characterized in that R ¹ represents a carbocyclic aryl radical or a heteroaryl radical, optionally substituted 1 to 3 times (and preferably 1 to 2 times) by a hydrogen atom. halogen, with an alkyl radical or with an alkoxy radical.

Also preferably, the invention relates to compounds of formula I as defined above and characterized in that R ³ represents a C 4 -C 8 alkyl, arylalkyl or cycloalkylalkyl radical; or a pharmaceutically acceptable salt thereof.

Also preferably, the invention relates to compounds of formula I as defined above and characterized in that R ² and R ⁴ represent a hydrogen atom; or a pharmaceutically acceptable salt thereof.

Preferably also, the invention relates to compounds of formula I as defined above and characterized in that R ³ represents a cycloalkylalkyl or arylalkyl radical; or a pharmaceutically acceptable salt thereof. Preferably also, the invention relates to compounds of formula I as defined above and characterized in that R ¹ represents an aryl or heteroaryl radical, the aryl radical being optionally substituted by one or more haloidentic or different substituents; or a pharmaceutically acceptable salt thereof.

Preferably also, the invention relates to compounds of formula I as defined above and characterized in that R ¹ represents a heteroaryl radical; or a pharmaceutically acceptable salt thereof.

Preferably also, the invention relates to compounds of formula I as defined above and characterized in that they comprise at least one of the following characteristics:

the cycloalkyl radical of the cycloalkyl and cycloalkylalkyl groups is the hexyl radical;

the aryl radical of the aryl and arylalkyl groups is the phenyl radical; and

the heteroaryl is chosen from the following radicals; furyl, thienyl, pyridinyl; or a pharmaceutically acceptable salt thereof.

In particular, the invention relates to a compound of general formula (I) or a salt thereof and selected from the following compounds:

tert-butyl {(1 R) -1 - [({(2-O) -2 - [(tert-butoxycarbonyl) amino] -3 - [(4 H) -4- (cyclohexylmethyl) -2-phenyl-6,7- dihydropyrazolo [1,5-a] pyrazin-5 (4 H) -yl] -3-oxopropyl) dithio) methyl] -2 - [(4 H) -4- (cyclohexylmethyl) -2-phenyl) -6 7-dihydropyrazolo [1,5-a] pyrazin-5 (4H) -yl] -2-oxoethyl} carbamate;

tert-butyl {(1 R) -1 - [({(2 ") - 2 - [(tert-butoxycarbonyl) amino] -3-oxo-3 - [(4 H] -2-phenyl] 4- (2-phenylethyl) -6,7-dihydropyrazolo [1,5-a] pyrazin-5 (4H) -yl] propyl} dithio) methyl] -2-oxo-2 - [(4f) S) -2 phenyl-4- (2-phenylethyl) -6,7-dihydropyrazolo [1,5-a] pyrazin-5 (4W) -yl] ethyl] carbamate;

tert-butyl {(1 f) -1 - [({(2 H) -2 - [(tert-butoxycarbonyl) amino] -3-oxo-3 - [(4 H, S) -4- (2-phenylethyl) -2 pyridin-4-yl-6,7-dihydropyrazolo [1,5-a] pyrazin-5 (4H) -yl] propyl} dithio) methyl] -2-oxo-2 - [(4fIS) -4- (2 phenylethyl) -2-pyridin-4-yl-6,7-dihydropyrazolo [1,5-a] pyrazin-5 (4H) -yl] ethyl} carbamate; tert-butyl {(1 H) -1 - [({(2 H) -2 - [(tert-butoxycarbonyl) amino] -3-oxo-3 - [(4 H) -4- (2-phenylethyl) 2-pyridin-3-yl-6,7-dihydropyrazolo [1,5-a] pyrazin-5 (4 H) -yl] propyl} dithio) methyl] -2-oxo-2 - [(4f? S) -4- (2-phenylethyl) -2-pyridin-3-yl-6,7-dihydropyrazolo [1,5-a] pyrazin-5 (4H) -yl] ethyl} carbamate;

tert-butyl {(1 R) -2 - [(4RS) -2- (1,3-benzodioxol-5-yl) -4- (2-phenylethyl) -6,7-dihydropyrazolo [1,5-a] ] pyrazin-5 (4H) -yl] -1 - [({(2f) -3 - [(4f) S) -2- (1,3-benzodioxol-5-yl) -4- (2-phenylethyl) -6 7-dihydropyrazolo [1,5-a] pyrazin-5 (4H) -yl] -2 - [(tert-butoxycarbonyl) amino] -3-oxopropyl} dithio) methyl] -2-oxoethyl} carbamate;

tert-butyl {(1 R) -1 - [({(2 R) -2 - [(tert-butoxycarbonyl) amino] -3-oxo-3 - [(4H) -4- (2-phenylethyl) 2- (3,4,5-trimethoxyphenyl) -6,7-dihydropyrazolo [1,5-a] pyrazin-5 (4H) -yl] propyl} dithio) methyl] -2-oxo-2 - [(4fIs) -4- (2-phenylethyl) -2- (3,4,5-trimethoxyphenyl) -6,7-dihydropyrazolo [1,5-a] pyrazin-5 (4H) -yl] ethyl} carbamate;

tert-butyl {(1 f) -1 - [({(2f) -2 - [(tert-butoxycarbonyl) amino] -3-oxo-3 - [(4f-S) -4- (2-phenylethyl)} 2- (2-Thienyl) -6,7-dihydropyrazolo [1,5-a] pyrazin-5 (4 H) -yl] propyl} dithio) methyl] -2-oxo-2 - [(4fIS)) 4- (2-phenylethyl) -2- (2-thienyl) -6 ₎ -7-dihydropyrazolo [1,5-a] pyrazin-5 (4H) -yl] ethyl} carbamate;

tert-butyl {(1 H) -1 - [({(2H) -2 - [(tert-butoxycarbonyl) amino] -3 - [(4f-S) -2- (2-furyl) -4- ( 2- (phenylethyl) -6,7-dihydropyrazolo [1,5-a] pyrazin-5 (4H) -yl] -3-oxopropyl} dithio) methyl] -2- [(4f) S) -2- (2-furyl) 4- (2-phenylethyl) -6,7-dihydropyrazolo [1,5-a] pyrazin-5 (4H) -yl] -2-oxoethyl] carbamate;

tert-butyl {(1 R) -1 - [({(2 R) -2 - [(tert-butoxycarbonyl) amino] -3-oxo-3 - [(4H) -4-pentyl-2- phenyl-6,7-dihydropyrazolo [1,5-a] pyrazin-5 (4H) -yl] propyl} dithio) methyl] -2-oxo-2 - [(4H) -4-pentyl-2-phenyl-6 7-dihydropyrazolo [1,5-a] pyrazin-5 (4H) -yl] ethyl] carbamate;

tert-butyl {(1 R) -1 - [({(2 H) -2 - [(tert-butoxycarbonyl) amino] -3 - [(4 H) -4-butyl-2-phenyl-6,7-dihydropyrazolo} [1,5-a] pyrazin-5 (4H) -yl] -3-oxopropyl} dithio) methyl] -2 - [(4H) -4-butyl-2-phenyl-6,7-dihydropyrazolo [1,5] -a] pyrazin-5 (4H) -yl] -2-oxoethyl} carbamate;

tert-butyl {(1H) -1 - [({(2H) -2 - [(tert-butoxycarbonyl) amino] -3 - [(4H) -2- (2,4-dichlorophenyl) -4- ( 2-phenylethyl) -6,7-dihydropyrazolo [1,5-a] pyrazin-5 (4H) -yl] -3-oxopropyl} dithio) methyl] -2 - [(4f S) -2- (2, 4-dichlorophenyl) -4- (2-phenylethyl) -6,7-dihydropyrazolo [1,5-a] pyrazin-5 (4A) -yl] -2-oxoethyl} carbamate; - (2 fl) -3 - ({(2 fl) -2-amino-3 - [(4 H) -4- (cyclohexylmethyl) -2-phenyl-6,7-dihydropyrazolo [1,5-a] pyrazin-5 ( 4H) -yl] -3-oxopropyl} dithio) -1 - [(4fîS) -4-

(cyclohexylmethyl) -2-phenyl-6,7-dihydropyrazolo [1,5-a] pyrazin-5 (4W) -yl] -1-oxopropan-2-amine hydrochloride;

- (2 FQ-3 - ({(2 R) -2-amino-3-oxo-3 - [(4 H) -2-phenyl-4- (2-phenylethyl) -6,7-dihydropyrazolo [1 5-a] pyrazin-5 (4H) -yl] propyl} dithio) -1-oxo-1 - [(4f-S) -2-phenyl-4- (2-phenylethyl) -6,7-dihydropyrazolo [ 1,5-a] pyrazin-5 (4H) -yl] propan-2-amine hydrochloride;

- (2 fl) -3 - ({(2 R) -2-amino-3-oxo-3 - [(4SH) -4- (2-phenylethyl) -2-pyridin-4-yl ₎ -6-dihydropyrazolo [ 1, 5-a] pyrazin-5 (4H) -yl] propyl} dithio) -1-oxo-1 - [(4 H) -4- (2-phenylethyl) -2-pyridin-4-yl) -6,7 dihydropyrazolo [1,5-a] pyrazin-5 (4A) yl] propan-2-amine hydrochloride;

(2 fl) -3 - ({(2 fl) -2-amino-3-oxo-3 - [(4 H) -4- (2-phenylethyl) -2-pyridin-3-yl-6,7-dihydropyrazolo [ 1, 5-a] pyrazin-5 (4H) -yl] propyl} dithio) -1-oxo-1 - [(4H) -4- (2-phenylethyl) -2-pyridin-3-yl) 6,7-dihydropyrazolo [1,5-a] pyrazin-5 (4H) -yl] propan-2-amine hydrochloride;

- (2f) -3 - ({(2fl) -2-amino-3 - [(4fîS) -2- (1 _I 3-benzodioxol-5-yl) -4- (2-phenylethyl) -6,7 dihydropyrazolo [1,5-a] pyrazin-5 (4H) -yl] -3-oxopropyl} dithio) -1 - [(4H) -2- (1,3-benzodioxol-5-yl) -4- phenylethyl) -6,7-dihydropyrazolo [1,5-a] pyrazin-5 (4H) -yl] -1-oxopropan-2-amine hydrochloride;

- (2f) -3 - ({(2f)) - 2-amino-3-oxo-3 - [(4f S) -4- (2-phenylethyl) -2- (3,4,5-trimethoxyphenyl) -6 7-dihydropyrazolo [1,5-a] pyrazin-5 (4H) -yl] propyl} dithio) -1-oxo-1 - [(4 H) -4- (2-phenylethyl) -2- (3,4-dihydropyrazolo [1,5-a] pyrazin-5 (4H) -yl] propyl} 5-trimethoxyphenyl) -6,7-dihydropyrazolo [1,5-a] pyrazin-5 (4H) -yl] propan-2-amine hydrochloride;

(2 H) -3 - ({(2 R) -2-amino-3-oxo-3 - [(4 H) -4 - (2-phenylethyl) -2- (2-thienyl) -6,7-dihydropyrazolo [ 1, 5-a] pyrazin-5 (4H) -yl] propyl} dithio) -1-oxo-1 - [(4 H) -4- (2-phenylethyl) -2- (2-thienyl) -6,7 Dihydropyrazolo [1,5-a] pyrazin-5 (4H) -yl] propan-2-amine hydrochloride

- (2 R) -3 - ({(2 R) -2-amino-3 - [(4 H) -2- (2-furyl) -4- (2-phenylethyl) -6,7-dihydropyrazolo [1, 5-a] pyrazin-5 (4H) -yl] -3-oxopropyl} dithio) -1 - [(4H) -2- (2-furyl) -4- (2-phenylethyl) -6,7-dihydropyrazolo [ 1,5-a] pyrazin-5 (4H) -yl] -1-oxopropan-2-amine hydrochloride; - (2 fl) -3 - ({(2 R) -2-amino-3-oxo-3 - [(4 H) -4-pentyl-2-phenyl-6,7-dihydropyrazolo [1,5-a] pyrazin-5 (4H) -yl] propyl} dithio) -1-oxo-1 - [(4f-S) -4-pentyl-2-phenyl-6,7-dihydropyrazolo [1,5-a] pyrazin-5 (4H - /) - yl] propan-2-amine hydrochloride;

- (2f) -3 - ({(2ff) -2-amino-3 - [(4H) -4-butyl-2-phenyl-6,7-dihydropyrazolo [1,5-a] pyrazin-4H); N -yl-3-oxopropyl-dithio) -1- [(4H) -4-butyl-2-phenyl-6,7-dihydropyrazolo [1,5-a] pyrazin-5 (4H) -yl] -1- oxopropan-2-amine hydrochloride;

- (2 fl) -3 - ({(2 R) -2-amino-3 - [(4 H) -2- (2,4-dichlorophenyl) -4- (2-phenylethyl) -6 ₎ -7-dihydropyrazolo [1, 5-a] pyrazin-5 (4H) -yl] -3-oxopropyl} dithio) -1 - [(4H) -2- (2,4-dichlorophenyl) -4- (2-phenylethyl) -6) 7-dihydropyrazolo [1,5-a] pyrazin-5 (4W) -yl] -1-oxopropan-2-amine hydrochloride;

tert-butyl {(1 fl) -1 - [({(2 fl) -2 - [(tert-butoxycarbonyl) amino] -3 - [(4S) -4- (cyclohexylmethyl) -2-phenyl-6,7 Dihydropyrazolo [1,5-a] pyrazin-5 (4H) -yl] -3-oxopropyl} dithio) methyl] -2 - [(4S) -4- (cyclohexylmethyl) -2-phenyl-6,7-dihydropyrazolo] [1,5-a] pyrazin-5 (4H) -yl] -2-oxoethyl} carbamate;

- (2 fl) -3 - ({(2 fl) -2-amino-3 - [(4S) -4- (cyclohexylmethyl) -2-phenyl-6,7-dihydropyrazolo [1,5-a] pyrazin-5 ( 4H) -yl] -3-oxopropyl} dithio) -1 - [(4S) -4- (cyclohexylmethyl) -2-phenyl-6,7-dihydropyrazolo [1,5-a] pyrazin-5 (4H) -yl] 1-oxopropan-2-amine hydrochloride;

tert-butyl {(1H) -1- [({(2f) -2 - [(tert-butoxycarbonyl) amino] -3 - [(4H) -4- (cyclohexylmethyl) -2- phenyl-6,7-dihydropyrazolo [1,5-a] pyrazin-5 (4H) -yl] -3-oxopropyl} dithio) methyl] -2-

[(4 fl) -4- (cyclohexylmethyl) -2-phenyl-6,7-dihydropyrazolo [1,5-a] pyrazin-5 (4H) -yl] -2-oxoethyl] carbamate

- (1H) -3 - ({(2R)) - 2-amino-3 - [(4H) -4- (cyclohexylmethyl) -2-phenyl-6,7-dihydropyrazolo [1,5-a] pyrazine) (4H) -yl] -3-oxopropyl} dithio) -1 - [(4H) -4- (cyclohexylmethyl) -2-phenyl-6,7-dihydropyrazolo [1,5-a] pyrazin-5 (4H); -yl] -1-oxopropan-2-amine hydrochloride

tert-butyl {(1 R) -1 - [({(2 R) -2 - [(tert-butoxycarbonyl) amino] -3 - [(4 H) -4- (cyclohexylmethyl) -2-phenyl-7,8 4-dihydro-4H-pyrazolo [1,5-a] [1,4] diazepin-5 (6H) -yl] -3-oxopropyl} dithio) methyl] -2 - [(4f) S) -4- (cyclohexylmethyl) 2-phenyl-7,8-dihydro-4H-pyrazolo [1,5-a] [1,4] diazepin-5 (6W) -yl] -2-oxoethyl} carbamate

- {(1 R) -1 - [({(2 R) -2-amino-3 - [(4 H) -4- (cyclohexylmethyl) -2-phenyl-7,8-dihydro-4H-pyrazolo [1,5] -a] [1,4] diazepin-5 (6H) -yl] -3-oxopropyl} dithio) methyl] -2 - [(4ffS) -4- (cyclohexylmethyl) -2-phenyl-7,8-dihydro-4H-pyrazolo [1,5-a] [1,4] diazepin-5 (6H) -yl] -2-oxoethyljamine hydrochloride

- (2H) -2-amino-3 - [(4H) -2- (2-fluoryl) -4- (2-phenylethyl) -6,7-dihydropyrazolo [1,5-a] pyrazin-5 (4H); -yl] -3-oxopropane-1-thiol hydrochloride

tert-butyl {(1R) -Λ - [({(2f) -2 - [(tert-butoxycarbonyl) amino] -3 - [(4fIS) -4-

(cyclohexylmethyl) -2-phenyl-6,7-dihydropyrazolo [1,5-a] pyrazin-5 (4H) -yl] -3-oxopropyl} diselanyl) methyl] -2 - [(4H) S) -4 - (cyclohexylmethyl) -2-phenyl-6,7-dihydropyrazolo [1,5-a] pyrazin-5 (4H) -yl] -2-oxoethyl} carbamate

- {(1 R) -1 - [({(2 R) -2-amino-3 - [(4 S) -4 - (cyclohexylmethyl) -2-phenyl-6,7-dihydropyrazolo [1,5-a] pyrazine] 5 (4H) -yl] -3-oxopropyl-diselanyl) methyl] -2 - [(4f-S) -4- (cyclohexylmethyl) -2-phenyl-6,7-dihydropyrazolo [1,5-a] pyrazine) -5 (4H) -yl] -2-oxoethyl} amine hydrochloride;

(2 fl) -3 - ({(2H) -2-Amino-3-oxo-3 - [(4 H) -4- (2-phenylethyl) -2-pyridin-2-yl-6,7-dihydropyrazolo [ 1,5-a] pyrazin-5 (4H) -yl] propyl} dithio) -1-oxo-1 - [(4f-S) -4- (2-phenylethyl) -2-pyridin-2-yl) 7-dihydropyrazolo [1,5-a] pyrazin-5 (4H) -yl] propan-2-amine hydrochloride.

The invention relates more particularly to a compound of general formula (I) chosen from the following compounds:

- (2 fl) -3 - ({(2 fl) -2-amino-3 - [(4 H) -4- (cyclohexylmethyl) -2-phenyl-6,7-dihydropyrazolo [1,5-a] pyrazin-5 ( 4H) -yl] -3-oxopropyl} dithio) -1 - [(4H) -4- (cyclohexylmethyl) -2-phenyl-6,7-dihydropyrazolo [1,5-a] pyrazin-5 (4W); ) -yl] -1-oxopropan-2-amine hydrochloride;

- (2fl) -3 - ({(2fl) -2-amino-3-oxo-3 - [(4 ^/: IS) -2-phenyl-4- (2-phenylethyl) _-6) 7- dihydropyrazolo [1 5-a] pyrazin-5 (4H) -yl] propyl} dithio) -1-oxo-1 - [(4H) -2-phenyl-4- (2-phenylethyl) -6,7-dihydropyrazolo [1, 5-a] pyrazin-5 (4H) -yl] propan-2-amine hydrochloride;

- (2 R) -3 - ({(2 R) -2-amino-3-oxo-3 - [(4 H) -4 - (2-phenylethyl) -2- (2-thienyl) -6, 7-dihydropyrazolo [1,5-a] pyrazin-5 (4H) -yl] propyl} dithio) -1-oxo-1 - [(4H) -4- (2-phenylethyl) -2- -thienyl) -6,7-dihydropyrazolo [1,5-a] pyrazin-5 (4H) -yl] propan-2-amine hydrochloride;

- (2 fl) -3 - ({(2 fl) -2-amino-3 - [(4HS) -2- (2,4-dichlorophenyl) -4- (2-phenylethyl) -6,7-dihydropyrazolo [1, 5-a] pyrazin-5 (4H) -yl] -3-oxopropyl} dithio) -1 - [(4fîS) -2- (2 _l 4- dichlorophenyl) -4- (2-phenylethyl) -6,7-dihydropyrazolo [1,5-a] pyrazin-5 (4H) -yl] -1-oxopropan-2-amine hydrochloride;

tert-butyl {(1 R) -1 - [({(2 R) -2 - [(tert-butoxycarbonyl) amino] -3 - [(4H) -4- (cyclohexylmethyl) -2-phenyl-6, 7-Dihydropyrazolo [1,5-a] pyrazin-5 (4 H) -yl] -3-oxopropyl} dithio) methyl] -2 - [(4H) -4- (cyclohexylmethyl) -2-phenyl-6) 7-dihydropyrazolo [1,5-a] pyrazin-5 (4H) -yl] -2-oxoethyl] carbamate;

- (2 fl) -3 - ({(2 fl) -2-amino-3-oxo-3 - [(4-yl) -4- (2-phenylethyl) -2-pyridin-2-yl) -7,7-diol dihydropyrazolo [1,5-a] pyrazin-5 (4H) -yl] propyl} dithio) -1-oxo-1 - [(4 S) -4 - (2-phenylethyl) -2-pyridin-2-yl) 7-dihydropyrazolo [1,5-a] pyrazin-5 (4H) -yl] propan-2-amine hydrochloride.

The terminology used for the nomenclature of the above compounds is the English IUPAC terminology.

The compounds according to the present invention comprise asymmetric centers. Therefore, the compounds according to the present invention have several possible epimeric forms, i.e. the "Ff or" S "configurations of said asymmetric centers.The present invention includes all diastereomeric forms and combinations thereof, For simplicity, when no specific configuration is indicated in the structural formulas, it is to be understood that all diastereoisomeric forms and mixtures thereof are shown and described.

By salt of a compound is meant the addition salts of said compound with an organic or inorganic acid or, where appropriate, with a base, and in particular the pharmaceutically acceptable salts of said compound.

By pharmaceutically acceptable salt is meant in particular inorganic acid addition salts such as hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, diphosphate and nitrate or organic acids such as acetate, maleate, fumarate, tartrate, succinate, citrate. , lactate, methanesulfonate, p-toluenesulfonate, pamoate and stearate. Also within the scope of the present invention, when used, are salts formed from bases such as sodium or potassium hydroxide. For other examples of pharmaceutically acceptable salts, reference may be made to "Saline Selection for Basic Drugs", Int. J. Pharm.

(1986), 33, 201-217. According to the definitions of the variable groups R ⁴ and Z, the compounds of the present invention may be prepared according to the various procedures described below.

A- Preparation according to Reaction Scheme A:

The compounds of formula (I) according to the invention in which R ⁴ represents a radical of formula -CO-OR ⁵ may be prepared according to the following scheme A:

peptide coupling conditions

(I)

The compounds of general formula (I) in which R ⁴ represents a radical of formula -CO-OR ⁵ can be prepared under so-called peptide coupling conditions (Montalbetti et al., Tetrahedron 2005, 61, 10827), by reacting a carboxylic acid of general formula (VII) (c / -protected cystine or seleno-cystine / V-protected) in which R ⁵ is as defined above, with a compound of general formula (VI) at a temperature between 0 ⁰ C and 30 ^° C (preferably at room temperature) in an aprotic solvent such as for example DCM, DCE, THF or MeCN.

B- Preparation according to Reaction Scheme B

The compounds of formula (I) according to the invention in which R ⁴ represents a hydrogen atom may be prepared according to the following scheme B:

The compounds of general formula (I) in which R ⁴ represents a hydrogen atom, may be prepared by treating a compound of general formula (I) in which R ⁴ represents a radical of formula -CO-OR ⁵ , under conditions deprotection. These conditions are, for example, an acid treatment (TFA, HCl, HCOOH) for tert-butoxycarbonyl (Boc), a treatment with a secondary amine (piperidine) for the 9-fluorenylmethyloxycarbonyl (Fmoc) group, at a temperature between 0 ^° C. and 30 ^° C., and preferably at room temperature.

C- Preparation according to Reaction Scheme C:

reduction -

The compounds of general formula (I) in which Z represents hydrogen can be prepared by treating the corresponding compounds of general formula (I) in which Z does not represent the hydrogen atom, under reducing conditions. such as, for example, sodium borohydride or dithiothreitol in a protic solvent such as, for example, methanol or ethanol. Preparation of the compound of formula (VI)

(VI)

The compounds of formula (VI) can be obtained from the compound of formula (IV) either indirectly via synthesis of the intermediate compound (V) or directly.

The compounds of the general formula (V) can be prepared by treating a compound of the general formula (IV) under acidic conditions in order to remove the Boc protecting group and then by adding a base to neutralize the acidity and promote the condensation. of the free amine with the carbonyl radical carrying the radical R ³ . The deprotection is carried out for example in a mixture of TFA and DCM, or in formic acid, at a temperature of between 0 ^° C. and 30 ^° C., preferably at room temperature. Neutralization can be achieved, for example, by adding TEA to the reaction medium.

The compounds of general formula (VI) can be obtained by reducing to amine the imine function of the compounds of general formula (V). This reaction is generally carried out with sodium borohydride in MeOH or EtOH at a temperature of between 0 ^° C. and 30 ^° C. This reaction can also be carried out under asymmetric transfer hydrogenation conditions, in such a way that the compound ( Vl) is obtained with a strong enantiomeric excess. An example of such a transformation is described by Williams GD et al. Org. Lett. 2003, 5, 4227.

These same compounds of general formula (VI), both racemic as with a strong enantiomeric excess, can also be prepared from a compound of general formula (IV) by successively performing the deprotection steps. to release the amine, condensation and reduction function in the same reactor and without purifying the intermediate products.

The deprotection of the compound (IV) can be obtained by treatment with an acid such as, for example, trifluoroacetic acid or formic acid, without a solvent or in a solvent such as, for example, dichloromethane, THF or acetonitrile. , at a temperature between 0 ⁰ C and 50 ⁰ C and preferably at room temperature. The imine formation conditions (V) and the amine reduction (VI) are known to those skilled in the art as reductive amination and can be obtained in various ways such as for example cyanoborohydride. sodium in acetonitrile, sodium triacetoxyborohydride or, for cyclic imines such as the compounds of formula (V), sodium borohydride in methanol. When the reductive amination is made from a ketone as in the compounds of formula (V), there is formation of a chiral center and it is then interesting that the reduction of imine is made in favor of one of two possible epimers relating to this chiral center. Such a conversion of imines into amines can be obtained under so-called asymmetric transfer hydrogenation conditions. The hydrogen source is then preferably formic acid or a salt thereof such as, for example, sodium formate, the solvent may be formic acid in the presence of a base such as, for example, the triétylamine. The reaction is catalyzed by a ruthenium complex obtained by reaction between bis ((η ⁶ -p-cymene) dichlororuthenium) and a tosylated asymmetric diamine as a chiral auxiliary such as, for example, (1, f, 2fl). - / V- (p-toluenesulfonyl) -1,2-diphenylethylenediamine ((f1, fl) -TsDPEN). Examples of such catalysts employed for the asymmetric transfer hydrogenation of cyclic imines are described in Org Lett 2003, vol 5, pp. 4227-4230; Green Chem 2007, Vol 9, pp 23-25; Green Chem 2007, vol 9, pp 391-397; Chem Common 2007, pp 1825-1827.

Preparation of the Intermediate of Formula (IV)

The compounds of general formula (IV) can be prepared by reacting a compound of general formula (III) with an organometallic reagent of formula general R ³ M wherein R ³ is as defined above and M represents for example Li or Mg (MgBr or MgCl), these reagents may be of commercial origin or generated in situ according to methods known to man of the job. This reaction is carried out in an aprotic solvent such as, for example, THF, at a temperature of between -80 ^° C. and 0 ^° C. for organolithium compounds and between 0 ^° C. and 60 ^° C., and preferably at room temperature for organomagnesium.

Preparation of the Intermediate of Formula (IH)

The derivatives of general formula (III) can be prepared under so-called peptide coupling conditions (Montalbetti et al., Tetrahedron 2005, 61, 10827), by reacting the carboxylic acid (II) with Λ, O-dimethylhydroxylamine. , at a temperature between 0 ⁰ C and 100 ⁰ C (preferably at room temperature), in an inert solvent such as for example dichloromethane (DCM), THF or DMF. The intermediate thus obtained may then be alkylated with tert-butyl (2-chloroethyl) carbamate or tert-butyl (3-bromopropyl) carbamate in the presence of a base such as sodium carbonate or tert-butyl potassium. butoxide, optionally combined with a phase transfer agent such as tetrabutylammonium bromide, at a temperature between room temperature and 110 ⁰ C and in an aprotic solvent, such as, for example, at 60 ⁰ C in THF, at 80 ° C in MeCN or at 110 ° C in DMF.

The carboxylic acids (II) are generally commercial products or can be prepared by standard methods known to those skilled in the art.

The subject of the invention is also a process for preparing a compound of formula (I) as defined above, characterized in that a compound of formula (VI) is reacted

in which the radicals R ¹ , R ² and R ³ and n are as defined above, with a carboxylic acid of general formula (VII)

in which R ⁵ and X are as defined above, under so-called peptide coupling conditions, at a temperature of between 0 ^° C. and 30 ^° C., in an aprotic solvent, to obtain the compound of formula (I) in which Z is different from the hydrogen atom and R ⁴ represents the radical -CO-OR ⁵ ,

compound of formula (I) in which R ⁴ represents the -CO-OR ⁵ radical which may be deprotected, to obtain the compound of formula (I) in which Z is different from the hydrogen atom and R ⁴ represents hydrogen atom,

and finally the compound of formula (I) in which Z is different from the hydrogen atom, can be reduced to obtain the corresponding compound of formula (I) in which Z represents the hydrogen atom.

The subject of the invention is also a compound of general formula (VI)

in racemic, enantiomeric form or any combination of these forms, wherein the radicals R ¹ , R ² and R ³ and n are as defined above.

The subject of the invention is also a process for the preparation of a compound of formula (VI) as defined above, characterized in that the compound (IV) is subjected

in which the radicals R ₁ R and R and n are as defined above,

at acidic conditions to release the amine function and form, after neutralization, the compound (V)

in which the radicals R ¹ , R ² and R ³ and n are as defined above, then the imine function of the compound of general formula (V) thus formed is then subjected to reducing conditions to give the corresponding cyclic amine (Vl).

The present invention also relates to a compound of general formula (I) as defined above or a pharmaceutically acceptable salt of such a compound, for use as a therapeutically active substance.

The subject of the present invention is also a pharmaceutical composition comprising, as active principle, a compound of general formula (I) as defined above, or a pharmaceutically acceptable salt of such a compound, with at least one pharmaceutically acceptable excipient. acceptable.

The subject of the present invention is also, as a medicament, a compound of general formula (I) as defined above, or a pharmaceutically acceptable salt of such a compound.

The subject of the present invention is also the use of at least one compound of general formula (I) as defined above or a pharmaceutically acceptable salt thereof, for preparing a medicament intended to prevent or treat a disease or a disorder chosen from the following diseases or the following disorders: cancers, non-tumoral proliferative diseases, proliferative tumoral diseases, neurodegenerative diseases, parasitic diseases, viral infections, spontaneous alopecia, alopecia induced by exogenous products, radiation-induced alopecia, autoimmune diseases, rejection of grafts, inflammatory diseases, allergies or pain.

The subject of the present invention is preferably the use of at least one compound of general formula (I) as defined above or a pharmaceutically acceptable salt thereof, for preparing a medicament intended to treat or prevent cancers,

and very preferentially cancers of the colon, rectum, stomach, lungs, pancreas, kidney, testes, breast, uterus, ovary, prostate, skin, bone, spinal cord, neck, tongue, head as well as sarcomas, carcinomas, fibroadenomas, neuroblastomas, leukemias, melanomas.

The compound of general formula (I) or its salt used according to the invention or the combination according to the invention may be in the form of a solid, for example powders, granules, tablets, capsules, liposomes or suppositories. Suitable solid carriers may be, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methyl cellulose, carboxymethyl cellulose sodium, polyvinylpyrrolidine and wax.

The compound of general formula (I) or its salt used according to the invention or the combination according to the invention may also be in liquid form, for example solutions, emulsions, suspensions or syrups. Suitable liquid carriers may be, for example, water, organic solvents such as glycerol or glycols, as well as their mixtures, in varying proportions, in water.

The administration of a compound of general formula (I) or its salt used according to the invention or the combination according to the invention may be carried out topically, orally, parenterally, by intramuscular injection, subcutaneously.

The dose of a product according to the present invention, to be provided for the treatment of the diseases or disorders mentioned above, varies according to the mode of administration, the age and the body weight of the subject to be treated as well as the state of the latter, and it will ultimately be decided by the attending physician or veterinarian. Such a quantity determined by the attending physician or veterinarian is herein called "therapeutically effective amount".

As an indication, the envisaged administration dose for a drug according to the invention is between 0.1 mg and 10 g depending on the type of active compound used.

All technical and scientific terms used in this text have the meaning known to those skilled in the art. In addition, all patents (or patent applications) as well as other bibliographic references are incorporated by reference.

Experimental part

According to the preceding definitions of the variable groups R 1, R 2, R 3, R 4, R 5, X and Z, the compounds of the invention may be prepared according to the various procedures described above.

The examples below are presented to illustrate the above procedures and should in no way be construed as limiting the scope of the invention.

Example 1: tert-Butyl {(1 H) -1 - [({(2 H) -2 - [(tert-butoxycarbonyl) amino] -3 - [(4 H) -4- (cyclohexylmethyl) - 2-phenyl-6,7-dihydropyrazolo [1,5-a] pyrazin-5 (4H) -yl] -3-oxopropyl} dithio) methyl] -2 - [(4A? S) -4- (cyclohexylmethyl) - 2-phenyl-6,7-dihydropyrazolo [1,5-a] pyrazin-5 (4W) -yl] -2-oxoethyl} carbamate

1 a. / V-methoxy- / V-methyl-3-phenyl-1H-pyrazole-5-carboxamide

3- (phenyl) -1H-pyrazole-5-carboxylic acid (7.53 g, 40 mmol) in solution in DCM (20OmL) is reacted with Λ-O-dimethylhydroxylamine hydrochloride, (7.80 g). 80 mmol), triethylamine (22.3 mL, 160 mmol, 4 eq.) And 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (15.4 g, 80 mmol, 2 eq.). The reaction medium is stirred at room temperature until the starting material has disappeared (24 hours, TLC, eluent: DCM / MeOH = 90/10). The volatile compounds are then evaporated and the residue is purified on SiO ₂ (eluent: DCM / MeOH = 99/1) to obtain the compound of Example 1a (6.22 g, 67%) in the form of a beige powder. . ¹ H NMR (δ ppm, DMSO): 3.32 (s, 3H); 3.78 (s, 3H); 7.18 (s, 1H); 7.34 (s, 1H); 7.43 (s, 2H); 7.86 (s, 2H); 13.66 (s, 1H).

¹³ C NMR (δ ppm, DMSO): 32.47; 61.45; 104.94; 125.19; 127.67; 128.65; 133.06; 135.17; 151, 04; 158.63.

Experimental MH ⁺ = 232.21; M theoretical = 231.25 Melting point: 135-138X

1 b. tert-butyl [2- (5 - {[methoxy (methyl) amino] carbonyl} -3-phenyl-1H-pyrazol-1-yl) ethyl] carbamate

The compound of Example 1a (4.58 g, 19.8 mmol) in DMF (80 mL) is reacted with tert-butyl (2-chloroethyl) carbamate (4.27 g, 23.8 mmol, 1, 2 eq.) In the presence of sodium carbonate (3.01 g, 21.8 mmol, 1.1 eq.). The reaction medium is heated to

110 ⁰ C for 5 hours and 30 minutes (TLC, eluent: DCM / MeOH = 98/2). The DMF is then evaporated and the residue is dissolved in AcOEt. It is then washed twice with water. The organic phase is dried over sodium sulfate, then filtered and concentrated in vacuo. The residue is purified on SiO 2 (eluent: heptane / AcOEt

= 60/40) to obtain the compound of Example 1b (6.4 g, 86%) as a translucent oil.

¹ H NMR (δ ppm, DMSO): 1.31 (s, 9H); 3.31-3.35 (m, 2H); 3.30 (s, 3H); 3.69 (s, 3H); 4.43 (t, 2H); 6.84 (br, 1H); 7.14 (s, 1H); 7.31 (s, 1H); 7.41 (s, 2H); 7.83 (s, 2H). ¹³ C NMR (δ ppm, DMSO): 27.54; 28.10; 40.39; 50.63; 61, 26; 77.63; 105.57; 125.15; 127.76; 128.61; 132.56; 134.76; 148.78; 155.44; 159.51.

Experimental MH ⁺ = 375.26; M theoretical = 374.44

1 C. tert-butyl {2- [5- (cyclohexylacetyl) -3-phenyl-1H-pyrazol-1-yl] ethyl} carbamate

Magnesium (1.07 g, 44 mmol, 5.5 eq.) Is placed under an inert atmosphere in a flask (100 ml), then iodine (2 crystals), anhydrous THF (20 ml) are introduced and bromomethylcyclohexane (560 μL, 4 mmol, 0.5 eq.). The reaction medium is heated at 30 ^° C. for 5 minutes to initiate the formation of the magnesium, then the heating is stopped and stirring is continued for 30 minutes. Note the disappearance of the brown color related to iodine and effervescence on the surface of the metal accompanied by the development of a disorder in the solution. Bromomethylcyclohexane (5.02 mL, 36 mmol, 4.5 eq.) In solution in anhydrous THF (20 mL) was then added dropwise (for 10 minutes), and a rise in the temperature of the medium as well as the transformation of magnesium. Once the temperature of the reaction has returned to 22 ° C. and there is almost no more magnesium remaining (~ 1 hour), the compound of Example 1b (3 hours) is added dropwise (for 1 hour). g, 8 mmol) in solution in anhydrous THF (10 mL). The reaction medium is stirred for 6 hours, which gradually becomes yellow (TLC, eluent: DCM / MeOH = 98/2). Water is added carefully and the resulting mixture is partitioned between ethyl acetate (100 mL) and water (100 mL). The aqueous phase is extracted with ethyl acetate and the washed organic phases are concentrated under reduced pressure with a saturated solution of sodium chloride, dried over sodium sulfate and pooled. The residue is purified on SiO2 (eluent: heptane / AcOEt = 80/20) to give the compound of Example 1c (1.62 g, 49%) as a white solid.

¹ H NMR (δ ppm, DMSO): 0.97-1.72 (m, 10H); 1, 28 (s, 9H); 1.85-1.89 (m, 1H); 2.80 (d, 2H); 3.29 (q, 2H); 4.52 (t, 2H); 6.86 (br, 1H); 7.33 (t, 1H); 7.42 (t, 2H); 7.66 (s, 1H); 7.85 (s, 2H). ¹³ C NMR (δ ppm, DMSO): 25.82; 25.98; 28.29; 32.71; 34.28; 47.58; 51.53; 77.73; 109.56; 125.30; 128.08; 128.84; 132.52; 140.25; 148.93; 155.61; 191, 54.

Experimental MH ⁺ = 412.27; M theoretical = 411.54

1 d. 4- (cyclohexylmethyl) -2-phenyl-6,7-dihydropyrazolo [1,5-a] pyrazine

The compound of Example 1c (573 mg, 1.4 mmol) in solution in DCM (3 ml) was reacted with trifluoroacetic acid (3 ml) for 5 hours and then the reaction medium was concentrated under pressure. scaled down. The resulting yellow oil is dissolved in DCM (3 mL), triethylamine (3 mL) is added, and the reaction is stirred at room temperature for 17 hours (TLC, eluent: DCM / MeOH = 98/2). ). The volatile compounds are evaporated under reduced pressure and the residue is dissolved in DCM. The residue is washed with water and then with a saturated solution of sodium chloride. The organic phase is dried over sodium sulfate and then concentrated under reduced pressure. The compound of Example 1d (454 mg, 100%) is obtained as a yellow oil.

¹ H NMR (δ ppm, DMSO): 0.95-1.74 (m, 10H); 1.74-1.81 (m, 1H); 2.47-2.50 (m, 2H); 3.93 (t, 2H); 4.13 (t, 2H); 7.10 (s, 1H); 7.31 (t, 1H); 7.41 (t, 2H); 7.84 (s, 2H).

¹³ C NMR (δ ppm, DMSO): 26.69; 26.82; 33.57; 36.32; 43.74; 44.30; 48.40; 101, 71; 125.98; 128.62; 129.57; 133.65; 140.36; 159.29. Experimental MH ⁺ = 294.36; M theoretical = 293.41

1 e. (4 S) -4- (cyclohexylmethyl) -2-phenyl-4,5,6,7-tetrahydropyrazolo [1,5-a] pyrazine

The compound of Example 1d (408 mg, 1.4 mmol) in solution in MeOH (20 mL) is reacted with sodium borohydride (63 mg, 1.7 mmol, 1.2 eq. room temperature, for 30 minutes. Volatiles were evaporated (TLC, eluent: DCM / MeOH = 95: 5, developer: ninhydrin), and the residue was dissolved in DCM. The residue is washed with water and then with saturated sodium chloride solution. The organic phase is dried over sodium sulfate and then concentrated under reduced pressure. The product is purified on SiO 2 (eluent: DCM / MeOH = 98/2) to give the compound of Example 1e (372 mg, 91%).

A white solid; Melting point: 128-130 ⁰ C

Experimental MH ⁺ = 296.39; M theoretical = 295.43

¹ H NMR (δ ppm, DMSO): 0.89-1.85 (m, 13H); 2.44 (br, 1H); 3.00 (ddd, 1H); 3.27 (dt, 1H); 3.91 -4.00 (m, 3H); 6.46 (s, 1H); 7.25 (t, 1H); 7.36 (t, 2H); 7.75 (d, 2H).

¹³ C NMR (δ ppm, DMSO): 25.60; 25.89; 31, 83; 33.15; 33.93; 41, 65; 47.86; 50.06; 97.90; 125.26; 127.50; 128.88; 134.07; 144.56; 149.12.

1 f. tert-butyl {(1 R) A - [({(2f)) - 2 - [(Fert-butoxycarbonyl) amino] -3 - [(4 H) -4- (cyclohexylmethyl) -2-phenyl-6,7- dihydropyrazolo [1,5-a] pyrazin-5 (4H) -yl] -3-oxopropyl} dithio) methyl] -2 - [(4H) -4- (cyclohexylmethyl) -2-phenyl-6,7 dihydropyrazolo [1,5-a] pyrazin-5 (4W) -yl] -2-oxoethyl} carbamate

The compound of Example 1e (484 mg, 2.2 mmol, 2.1 eq.) And N, N'-di-Boc-L-cystine (463 mg, 1.05 mmol, 1mg) were dissolved. eq.) in anhydrous THF (15 ml). The medium is cooled to a temperature between 0 and 5 ° C; then diisopropylethylamine (1.23 ml, 7 mmol, 6.7 eq.) and O- (7-azobenzotriazol-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) were added. 798 mg, 2.1 mmol, 2eq.) In solution in anhydrous acetonitrile (8 ml). The reaction medium is stirred at room temperature for 18 hours (TLC, eluent: DCM / MeOH = 90/10) and the volatile compounds are evaporated. The residue is dissolved in DCM and washed with water and then twice with saturated sodium chloride solution. The dried organic phase is dried over sodium sulfate, then filtered and the volatile compounds are evaporated under reduced pressure. The residue obtained is purified on silica column (eluent: DCM / MeOH = 95/5) to obtain 647 mg (73%) of the compound of Example 1f (mixture of 3 diastereoisomers) as a white solid.

Melting point: 129-132 ° C

[M + 2H] ²⁺ experimental = 498.43; M theoretical = 995.59

¹ H NMR (δ ppm, DMSO): 1.25-1.37 (m, 18H); 0.70-1.75 (m, 26H); 2.8-3.1 (m, 4H); 3.5-4.5 (m, 10H); 5.80 (m, 2H); 6.31-6.37 (m, 2H); 7.16-7.20 (m, 2H); 7.23-7.29 (m, 4H); 7.60-7.65 (m, 4H).

Example 2: Fert-butyl {(1 fl) -1 - [({(2 fl) -2 - [(f) t-butoxycarbonyl) amino] -3-oxo-3 - [(4 F) -2-phenyl-4 (2-phenylethyl) -6,7-dihydropyrazolo [1,5-a] pyrazin-5 (4H) -yl] propyl} dithio) methyl] -2-oxo-2 - [(4S) -2) phenyl-4- (2-phenylethyl) -6,7-dihydropyrazolo [1,5-a] pyrazin-5 (4H) -yl] ethyl} carbamate

2a. (4 / 7S) -2-phenyl-4- (2-phenylethyl) -4,5,6,7-tetrahydro-pyrazolo [1,5-a] pyrazine

The compound below is synthesized according to a method analogous to that described in Example 1e.

Yellow oil - experimental MH ⁺ = 304.14; M theoretical = 303.41

¹ H NMR (δ ppm, DMSO): 1.88-1.91 (m, 1H); 2.13-2.14 (m, 1H); 2.67 (br, 1H); 2.74-2.81 (m, 2H); 3.03 (ddd, 1H); 3.28-3.31 (m, 1H); 3.89 (dd, 1H); 3.97-4.03 (m, 2H); 6.55 (s, 1H); 7.16-7.19 (m, 1H); 7.23-7.31 (m, 5H); 7.36 (t, 2H); 7.76 (d, 2H).

¹³ C NMR (δ ppm, DMSO): 31.58; 36.63; 41, 91; 47.72; 52.09; 97.97; 125.08; 125.89; 127.34; 128.47; 128.52; 128.69; 133.86, 142.19; 143.53; 149.03. 2b. N-Butyl {(1 R) -1 - [({(2 R) -2 - [(tert-butoxycarbonyl) amino] -3-oxo-3 - [(4H) -2-phenyl-4 (2-phenylethyl) -6,7-dihydropyrazolo [1,5-a] pyrazin-5 (4W) -yl] propyl} dithio) methyl] -2-oxo-2 - [(4f-S) -2- phenyl-4- (2-phenylethyl) -6,7-dihydropyrazolo [1,5-a] pyrazin-5 (4H) -yl] ethyl} carbamate

The compound of Example 2 is synthesized according to a method analogous to that described in Example 1f.

White solid- Melting point: 123-127 ° C

[M + 2H] ²⁺ experimental = 506.39; M theoretical = 1011, 32

¹ H NMR (δ ppm, DMSO): 1.25-1.37 (m, 18H); 2.06-2.11 (m, 4H); 2.64-2.70 (m, 4H); 2.93-3.17 (m, 4H); 3.44-4.84 (m, 10H); 5.72 (m, 2H); 6.64 (m, 2H) 7.14-7.28 (m, 12H) 7.35-7.40 (m, 4H); 7.55-7.58 (m, 2H); 7.74-7.76 (m, 4H).

Example 3: tert-butyl {(1 H) -1 - [({(2 H) -2 - [(tert-butoxycarbonyl) amino] -3-oxo-3 - [(4 H) -4 (2-phenylethyl) -2-pyridin-4-yl-6,7-dihydropyrazolo [1,5-a] pyrazin-5 (4H) -yl] propyl} dithio) methyl] -2-oxo-2- [ (4S) -4- (2-phenylethyl) -2-pyridin-4-yl-6,7-dihydropyrazolo [1,5-a] pyrazin-5 (4W) -yl] ethyl} carbamate

3a. (4S) -4- (2-phenylethyl) -2-pyridin-4-yl-4,5,6,7-tetrahydropyrazolo [1,5-ajpyrazine]

Pale yellow powder - Melting point: 134-136 ° C Experimental MH ⁺ = 305.34; M theoretical = 304.39

¹ H NMR (δ ppm, DMSO): 1.89-1.91 (m, 1H); 2.13-2.15 (m, 1H); 2.74-2.81 (m, 3H); 3.04 (ddd, 1H); 3.32-3.34 (m, 1H); 3.90 (dd, 1H); 4.01-4.07 (m, 2H); 6.76 (s, 1H); 7.16-7.20 (m, 1H); 7.26-7.32 (m, 4H); 7.71 (d, 2H); 8.54 (d, 2H).

¹³ C NMR (δ ppm, DMSO): 31.59; 36.67; 41, 86; 48.03; 52.12; 99.40; 119.56; 125.99; 128.58; 140.84; 142.19; 144.18; 146.72; 150.26.

3b. teit-butyl {(1 R) -1 - [({(2Λ) -2 - [(tert-butoxycarbonyl) amino] -3-oxo-3 - [(4S) -4- (2-phenylethyl) - 2-pyridin-4-yl-6,7-dihydropyrazolo [1,5-a] pyrazin-5 (4W) -yl] propyl} dithio) methyl] -2-oxo-2 - [(4 / 7S) -4 (2-phenylethyl) -2-pyridin-4-yl-6,7-dihydropyrazolo [1,5-a] pyrazin-5 (4H) -yl] ethyl} carbamate

The compound of Example 3 is synthesized according to a method analogous to that described in Example 1f.

White solid - Melting point: 149-152 ° C

[M + 2H] ²⁺ experimental = 507.43; M theoretical = 1013.3

¹ H NMR (δ ppm, DMSO): 1.23-1.36 (m, 18H); 2.07-2.11 (m, 4H); 2.62-2.96 (m, 4H); 3.10-4.84 (m, 14H); 5.72 (m, 2H); 6.89 (m, 2H); 7.13-7.27 (m, 10H); 7.57-7.59 (m, 2H); 7.79-7.83 (m, 4H); 8.59-8.61 (m, 4H).

Example 4: tert-Butyl {(1H) -1 - [({(2H) -2 - [(tert-butoxycarbonyl) amino] -3-oxo-3- [(4H) S) -4 (2-phenylethyl) -2-pyridin-3-yl-6,7-dihydropyrazolo [1,5-a] pyrazin-5 (4W) -yl] propyl} dithio) methyl] -2-oxo-2- [ (4S) -4- (2-phenylethyl) -2-pyridin-3-yl-6,7-dihydropyrazolo [1,5-a] pyrazin-5 (4M) -yl] ethyl} carbamate

4a. (4 S) -4- (2-phenylethyl) -2-pyridin-3-yl-4,5,6,7-tetrahydropyrazolo [1,5-ajpyrazine

Yellow powder - Melting point: 92-94 ° C

Experimental MH ⁺ = 305.30; M theoretical = 304.39

¹ H NMR (δ ppm, DMSO): 1.89-1.91 (m, 1H); 2.13-2.14 (m, 1H); 2.69 (br, 1H); 2.74-2.82 (m, 2H); 3.04 (ddd, 1H); 3.29-3.33 (m, 1H); 3.90 (dd, 1H); 4.00-4.06 (m, 2H); 6.69 (s, 1H); 7.16-7.20 (m, 1H); 7.26-7.32 (m, 4H); 7.39 (dd, 1H); 8.11 (dt, 1H); 8.46 (dd, 1H); 8.97 (d, 1H).

¹³ C NMR (δ ppm, DMSO): 31.55; 36.64; 41, 84; 47.84; 52.07; 98.48; 123.90; 125.91; 128.52; 129.50; 132.18; 142.15; 143.87; 146.35; 146.42; 148.39.

4b. tert-butyl {(1 Λ) -1 - [({(2 fl) -2 - [(tert-butoxycarbonyl) amino] -3-oxo-3 - [(4f-S) -4- (2-phenylethyl) - 2-pyridin-3-yl-6,7-dihydropyrazolo [1,5-a] pyrazin-5 (4rt) -yl] propyl} dithio) methyl] -2-oxo-2 - [(4H) -sulphonyl] -2-oxo-2 - [(4H)) - 4- (2-phenylethyl) -2-pyridin-3-yl-6,7-dihydropyrazolo [1,5-a] pyrazin-5 (4H) -yl] ethyl} carbamate

The compound of Example 4 is synthesized according to a method analogous to that described in Example 1f.

White solid - Melting point: 115-130 ⁰ C

[M + 2H] ²⁺ experimental = 507.43; M theoretical = 1013.3

¹ H NMR (δ ppm, DMSO): 1.35 (m, 18H); 2.06-2.11 (m, 4H); 2.64-2.68 (m, 4H); 2.82-3.23 (m, 4H); 3.88-4.90 (m, 10H); 5.72 (m, 2H); 6.78 (m, 2H); 7.14-7.27 (m, 10H); 7.40-7.43 (m, 2H); 7.60-7.61 (m, 2H); 7.79-7.83 (m, 4H); 8.09-8.12 (m, 2H); 8.48-8.49 (m, 2H); 8.97 (s, 2H).

Example 5: tert-butyl {(1H) -2 - [(4H) -2- (1,3-benzodioxol-5-yl) -4- (2-phenylethyl) -6,7-dihydropyrazolo} [1, 5-a] pyrazin-5 (4H) -yl] -1 - [({(2f) -3 - [(4 S) -2- (1,3-benzodioxol-5-yl) -4- ( 2-phenylethyl) -6,7-dihydropyrazolo [1,5-a] pyrazin 5 (4W) -yl] -2 - [(tert-butoxycarbonyl) amino] -3-oxopropyl} dithio) methyl] -2-oxoethyl} carbamate

5a. (4S) -2- (1,3-benzodioxol-5-yl) -4- (2-phenylethyl) -4,5,6,7-tetrahydropyrazolo [1,5-a] pyrazine

Yellow oil - experimental MH ⁺ = 348.18; M theoretical = 347.42

¹ H NMR (δ ppm, DMSO): 1.86-1.91 (m, 1H); 2.09-2.14 (m, 1H); 2.63 (br, 1H); 2.71-2.80 (m, 2H); 3.00 (ddd, 1H); 3.26-3.30 (m, 1H); 3.85 (dd, 1H); 3.93-4.01 (m, 2H); 6.00 (s, 2H); 6.47 (s, 1H); 6.89 (d, 1H); 7.19 (m, 1H); 7.24-7.31 (m, 6H).

¹³ C NMR (δ ppm, DMSO): 31.56; 36.64; 41, 91; 47.63; 52.06; 97.67; 101, 03; 105.51; 108.53; 118.63; 125.88; 128.26; 128.47; 142.20; 143.44; 146.63; 147.70; 148.87.

5b. tert-butyl {(1 R) -2 - [(4S) -2- (1,3-benzodioxol-5-yl) -4- (2-phenylethyl) -6,7-dihydropyrazolo [1,5] -a] pyrazin-5 (4H) -yl] -1 - [({(2f) -3 - [(4H) -2- (1,3-benzodioxol-5-yl) -4- phenylethyl) -6,7-dihydropyrazolo [1,5-a] pyrazin-5 (4W) -yl] -2 - [(tert-butoxycarbonyl) amino] -3-oxopropyl} dithio) methyl] -2- oxoethyl} carbamate

The compound of Example 5 is synthesized according to a method analogous to that described in Example 1f. Yellow paste - [M + 2H] ²⁺ experimental = 550.30; M theoretical = 1099.34

¹ H NMR (δ ppm, DMSO): 1.35 (m, 18H); 2.06-2.11 (m, 4H); 2.63-2.66 (m, 4H); 2.81-3.13 (m, 4H); 3.82-4.84 (m, 10H); 5.66-5.71 (m, 2H); 6.01-6.02 (m, 4H); 6.56 (m, 2H); 6.89-6.92 (m, 2H); 7.15-7.28 (m, 14H); 7.55-7.61 (m, 2H).

¹³ C NMR (δ ppm, DMSO): 28.27; 31, 40; 32.49; 51, 42, 55.05; 99.98; 101, 13; 105, 58; 108.60, 118.85; 125.95; 127.70; 128.40; 141, 48; 141, 64; 146.91; 147.76; 149.83.

Example 6: tert-butyl {(1 H) -1 - [({(2 fl) -2 - [(tert-butoxycarbonyl) amino] -3-oxo-3 - [(4 H) S) -4- 2-phenylethyl) -2- (3,4,5-trimethoxyphenyl) -6,7-dihydropyrazolo [1,5-a] pyrazin-5 (4H) -yl] propyl} dithio) methyl] -2-oxo-2 - [(4S) -4- (2-phenylethyl) -2- (3,4,5-trimethoxyphenyl) -6,7-dihydropyrazolo [1,5-a] pyrazin-5 (4H) -yl] ethyl} carbamate

6a. (4 S) -4- (2-phenylethyl) -2- (3,4,5-trimethoxyphenyl) -4,5,6,7-tetrahydro pyrazolo [1,5-a] pyrazine

Yellow oil - experimental MH ⁺ = 394.22; M theoretical = 393.48

¹ H NMR (δ ppm, DMSO): 1.86-1.91 (m, 1H); 2.11-2.16 (m, 1H); 2.67 (br, 1H); 2.72-2.82 (m, 2H); 3.03 (ddd, 1H); 3.29-3.32 (m, 1H); 3.67 (br, 3H); 3.83 (br, 6H); 3.87 (dd, 1H); 3.96-4.03 (m, 2H); 6.57 (s, 1H); 7.04 (br, 2H); 7.16-7.20 (m, 1H); 7.26-7.31 (m, 4H).

¹³ C NMR (δ ppm, DMSO): 31.48; 36.61; 47.52; 51.95; 54.94; 55.82; 60.04; 98.02; 102.12; 125.77; 128.35; 128.40; 129.44; 136.77; 142.06; 143.35; 148.89; 153.05.

6b. tert-butyl {(1 R) -1 - [({(2 R) -2 - [(tert-butoxycarbonyl) amino] -3-oxo-3 - [(4 H) -4- (2-phenylethyl) -2- (3,4,5-trimethoxyphenyl) -6,7-dihydropyrazolo [1,5-a] pyrazin-5 (4H) -yl] propyl} dithio) methyl] -2-oxo-2 - [(4S) ) -4- (2-phenylethyl) -2- (3,4,5-trimethoxyphenyl) -6,7-dihydropyrazolo [1,5-a] pyrazin-5 (4H) -yl] ethyl} carbamate

The compound of Example 6 is synthesized according to a method analogous to that described in Example 1f.

White solid - Melting point: 130-136 ⁰ C

[M + 2H] ²⁺ experimental = 596.30; M theoretical = 1191, 47

¹ H NMR (δ ppm, DMSO): 1.28-1.37 (m, 18H); 2.07-2.11 (m, 4H); 2.63-2.69 (m, 4H); 2.61-3.21 (m, 4H); 3.66-3.84 (m, 18H); 3.99-4.83 (m, 10H); 5.71-5.74 (m, 2H); 6.65-6.67 (m, 2H); 7.00-7.25 (m, 4H); 7.14-7.25 (m, 10H); 7.55-7.57 (m, 2H).

¹³ C NMR (δ ppm, DMSO): 28.07; 31.63; 32.04; 36.11; 47.33; 48.63; 49.91; 51.45, 55.85; 60.00; 78.62; 99.56; 102.36; 125.75; 128.33; 128.92; 137.13; 140.28; 141.47; 149.76; 153.05; 155.40; 169.59.

Example 7: tert-butyl {(1H) -1- [({(2f) -2 - [(tert-butoxycarbonyl) amino] -3-oxo-3 - [(4H, s) -4- (2-phenylethyl) -2- (2-thienyl) -6,7-dihydropyrazolo [1,5-a] pyrazin-5 (4H) -yl] propyl} dithio) methyl] -2-oxo-2 - [(4HS) -4) (2-phenylethyl) -2- (2-thienyl) -6,7-dihydropyrazolo [1,5-a] pyrazin-5 (4H) -yl] ethyl} carbamate

7a. (4 / 7S) -4- (2-phenylethyl) -2- (2-thienyl) -4,5,6,7-tetrahydropyrazolo [1,5-a] pyrazine

Colorless oil - experimental MH ⁺ = 310.26; M theoretical = 309.43

¹ H NMR (δ ppm, DMSO): 1.82-1.91 (m, 1H); 2.07-2.16 (m, 1H); 2.67 (br, 1H); 2.72-2.77 (m, 2H); 3.00 (ddd, 1H); 3.27-3.33 (m, 1H); 3.85 (d, 1H); 3.92-3.99 (m, 2H); 6.45 (s, 1H); 7.04 (dd, 1H); 7.17-7.20 (m, 1H); 7.25-7.29 (m, 4H); 7.32 (dd, 1H); 7.39 (dd, 1H).

¹³ C NMR (δ ppm, DMSO): 31.53; 36.56; 41, 81; 47.60; 52.01; 97.87; 123.49; 124.57; 125.89; 127.70; 128.47; 137.19; 142.14; 143.59; 144.73.

7b. tert-butyl {(1 R) -Λ - [({(2 R) -2 - [(tert-butoxycarbonyl) amino] -3-oxo-3 - [(4 H) -4- (2-phenylethyl) - 2- (2-thienyl) -6,7-dihydropyrazolo [1,5-a] pyrazin-5 (4H) -yl] propyl} dithio) methyl] -2-oxo-2 - [(4H) -sub.b 4- (2-phenylethyl) -2- (2-thienyl) -6,7-dihydro-pyrazolo [1,5-a] pyrazin-5 (4H) -yl] ethyl} carbamate

The compound of Example 7 is synthesized according to a method analogous to that described in Example 1f.

Light yellow solid - Melting point: 105-112 ° C

Experimental [M + 2H] ²⁺ = 512.46; M theoretical = 1023.38

¹ H NMR (δ ppm, DMSO): 1.26-1.42 (m, 18H); 2.13-2.15 (m, 4H); 2.67-2.73 (m, 4H); 2.91-3.24 (m, 4H); 3.88-4.85 (m, 10H); 5.76-5.78 (m, 2H); 6.60-6.62 (m, 2H); 7.11-7.14 (m, 2H); 7.21-7.32 (m, 10H); 7.42 (s, 2H); 7.50 (s, 2H) 7.65-7.67 (m, 2H).

Example 8: tert-butyl {(1 fl) -1 - [({(2ff) -2 - [(tert-butoxycarbonyl) amino] -3 - [(4H) -s- 2- (2-furyl) - 4- (2-phenylethyl) -6,7-dihydropyrazolo [1,5-a] pyrazin-5 (4H) -yl] -3-oxopropyl} dithio) methyl] -2 - [(4f-S) -2- (2-Furyl) -4- (2-phenylethyl) -6,7-dihydro-pyrazolo [1,5-a] pyrazin-5 (4H) -yl] -2-oxoethyl} carbamate

8a. (4S) -2- (2-furyl) -4- (2-phenylethyl) -4,5,6,7-tetrahydropyrazolo [1,5-a] pyrazine

Yellow oil - experimental MH ⁺ = 294.23; M theoretical = 293.37

¹ H NMR (δ ppm, DMSO): 1.80-1.84 (m, 1H); 2.04-2.08 (m, 1H); 2.57 (br, 1H); 2.63 - 2.73 (m, 2H); 2.95 (ddd, 1H); 3.20-3.24 (m, 1H); 3.81 (dd, 1H); 3.88-3.94 (m, 2H); 6.28 (s, 1H); 6.45 (dd, 1H); 6.55 (dd, 1H); 7.09-7.24 (m, 5H); 7.57 (dd, 1H).

¹³ C NMR (δ ppm, DMSO): 31.29; 36.26; 41, 59; 47.53; 51, 79; 97.62; 104.97; 111, 38; 125.68; 128.29; 128.81; 141, 69; 141, 92; 142.94; 149.13.

8b. tert-butyl {(1 R) A - [({(2/7) -2 - [(tert-butoxycarbonyl) amino] -3 - [(4f) -2- (2-furyl) -4- (2- phenylethyl) -6,7-dihydropyrazolo [1,5-a] pyrazin-5 (4W) -yl] -3-oxopropyl} dithio) methyl] -2 - [(4f S) -2- (2-furyl) -4) (2-phenylethyl) -6,7-dihydropyrazolo [1,5-a] pyrazin-5 (4 W) -yl] -2-oxoethyl} carbamate

The compound of Example 8 is synthesized according to a method analogous to that described in Example 1f.

Yellow oil - [M + 2H] ²⁺ experimental = 496.37; M theoretical = 991, 24

¹ H NMR (δ ppm, DMSO): 1.29-1.36 (m, 18H); 2.03-2.19 (m, 4H); 2.61-2.73 (m, 4H); 2.89-3.21 (m, 4H); 3.79-4.81 (m, 1OH); 5.51-5.71 (m, 2H); 6.40-6.47 (m, 2H); 6.50 (s, 2H); 6.63 (s, 2H); 7.11-7.28 (m, 1OH); 7.51-7.58 (m, 2H); 7.62 (s, 2H). ¹³ C NMR (δ ppm, DMSO): 28.06; 31.38; 31.65; 38.20; 47.33; 48.37; 48.58; 49.95; 78.61; 99.50; 105, 36; 111.44; 125.75; 128.18; 141.39; 139.88; 142.19; 148.64; 155,39; 164.55.

Example 9: tert-Butyl {(1 R) -1 - [({(2 R) -2 - [(tert-butoxycarbonyl) amino] -3-oxo-3 - [(4 S) -4-pentyl-2-phenyl 6,6-dihydropyrazolo [1,5-a] pyrazin-5 (4H) -yl] propyl} dithio) methyl] -2-oxo-2 - [(4H, 7S) -4-pentyl-2-phenyl) 6,7-Dihydropyrazolo [1,5-a] pyrazin-5 (4H) -yl] ethyl} carbamate

9a. (4fîS) -4-pentyl-2-phenyl-4,5,6,7-tetrahydro-pyrazolo [1,5-a] pyrazine

Yellow oil - experimental MH ⁺ = 270.22; M theoretical = 269.40

¹ H NMR (δ ppm, DMSO): 0.88 (t, 3H); 1.30-1.34 (m, 4H); 1.44-1.46 (m, 2H); 1.57-1.60 (m, 1H); 1.81-1.82 (m, 1H); 2.54 (br, 1H); 3.01 (ddd, 1H); 3.27 (dt, 1H); 3.85 (dd, 1H); 3.94-4.04 (m, 2H); 6.48 (s, 1H); 7.25 (tt, 1H); 7.36 (t, 2H); 7.75 (dd, 2H).

¹³ C NMR (δ ppm, DMSO): 13.91; 22.04; 24.89; 31.31; 34.56; 41.77; 47.52; 52.33; 97.63; 124.87; 127.11; 128.48; 133.69; 143.67; 148.76.

9b. tert-butyl {(1 R) A - [({(2f) -2 - [(Fert-butoxycarbonyl) amino] -3-oxo-3 - [(4H) -4-pentyl-2-phenyl- 6,7-Dihydropyrazolo [1,5-a] pyrazin-5 (4A7) -yl] propyl} dithio) methyl] -2-oxo-2 - [(4H, 7S) -4-pentyl-2-phenyl-6) 7-dihydropyrazolo [1,5-a] pyrazin-5 (4H) -yl] ethyl} carbamate The compound of Example 9 is synthesized according to a method analogous to that described in Example 1f.

Yellow solid - Melting point: 94-100 ⁰ C

[M + 2H] ²⁺ experimental = 472.35; M theoretical = 943.28

¹ H NMR (δ ppm, DMSO): 0.81-0.88 (m, 6H); 1, 24-1, 40 (m, 30H); 1.76 (m, 4H); 2.90-3.10 (m, 4H); 3.78-4.89 (m, 10H); 5.59-5.64 (m, 2H); 6.57-6.61 (m, 2H); 7.25-7.30 (m, 2H); 7.35-7.40 (m, 4H); 7.48-7.55 (m, 2H); 7.71-7.76 (m, 2H).

¹³ C NMR (δ ppm, DMSO): 13.80; 21, 91; 27.30; 27.52; 28.06; 31, 20; 33.78; 45.33, 47.20; 48.32; 78.52; 99.50; 124.84; 127.40; 128.56; 133.17; 140.65; 149.74; 155.29; 164.43.

Example 10: tert-butyl {(1H) -1 - [({(2H) -2 - [(tert-butoxycarbonyl) amino] -3 - [(4H) -4-butyl-2-phenyl 6,6-dihydropyrazolo [1,5-a] pyrazin-5 (4H) -yl] -3-oxopropyl} dithio) methyl] -2 - [(4H) -4-butyl-2-phenyl) 6,7-Dihydropyrazolo [1,5-a] pyrazin-5 (4H) -yl] -2-oxoethyl} carbamate

10a. (4S) -4-Butyl-2-phenyl-4,5,6,7-tetrahydropyrazolo [1,5-a] pyrazine

Yellow oil - experimental MH ⁺ = 256.24; M theoretical = 255.36 ¹ H NMR (δ ppm, DMSO): 0.90 (t, 3H); 1.32-1.46 (m, 4H); 1.58-1.60 (m, 1H); 1.81-185 (m, 1H); 2.54 (br, 1H); 3.01 (ddd, 1H); 3.26 (dt, 1H); 3.85 (dd, 1H); 3.94-4.04 (m, 2H); 6.48 (s, 1H); 7.25 (tt, 1H); 7.36 (t, 2H); 7.75 (dd, 2H).

¹³ C NMR (δ ppm, DMSO): 13.93; 22.18; 27.45; 34.29; 41.77; 47.52; 52.30; 97.64; 124.87; 127.11; 128.48; 133.69; 143.67; 148.77.

10b. tert-butyl {(1/7) -1 - [({(2H) -2 - [(tert-butoxycarbonyl) amino] -3 - [(4H) -4-butyl-2-phenyl-6,7-dihydropyrazolo [1,5-a] pyrazin-5 (4H) -yl] -3-oxopropyl} dithio) methyl] -2- [(4f) S) -4-butyl-2-phenyl-6,7-dihydropyrazolo [1] 5-a] pyrazin-5 (4H) -yl] -2-oxoethyl} carbamate

The compound of Example 10 is synthesized according to a method analogous to that described in Example 1f.

White solid - Melting point: 95-102 ⁰ C

[M + 2H] ²⁺ experimental = 458.36; M theoretical = 915.23

¹ H NMR (δ ppm, DMSO): 0.83-0.93 (m, 6H); 1.24-1.40 (m, 26H); 1.70 (m, 4H); 2.90-3.13 (m, 4H); 3.78-4.28 (m, 10H); 5.60-5.64 (m, 2H); 6.57-6.61 (m, 2H); 7.27-7.30 (m, 2H); 7.35-7.40 (m, 4H); 7.49-7.55 (m, 2H); 7.73-7.76 (m, 2H).

¹³ C NMR (δ ppm, DMSO): 13.78; 21.91; 27.52; 28.06; 31.20; 33.78; 45.22, 47.33; 48.31; 49.64; 78.71; 99.50; 124.84; 127.41; 128.56; 133.17; 140.58; 149.74; 155.14; 164.43. Example 11: tert-Butyl {(1 H) -NH- [1H] -N-butoxycarbonylamino] -N- [1H] -N- [1- (dichlorophenyl) -1H-phenylethyl] -4-dihydropyrazolothiazol-5 (4H) -yl ] -3-oxopropyl} dithio) methyl] -2 - [(4 H) -2- (2,4-dichlorophenyl) -4- (2-phenylethyl) -6,7-dihydropyrazolo [1,5-a] pyrazine) 5 (4H) -yl] -2-oxoethyl} carbamate

11a. (4 R) -2- (2,4-dichlorophenyl) -4- (2-phenylethyl) -4,5,6,7-tetrahydropyrazolo [1,5-a] pyrazine

The compound below is synthesized according to a method analogous to that described in Example 1 e.

Experimental MH ⁺ = 372.13; M theoretical = 372.30

11 b. tert-butyl {(1 / T) - 1 - [({(2/7) -2 - [(tert-butoxycarbonyl) amino] -3 - [(4H, 7S) -2- (2,4-dichlorophenyl) 4- (2-phenylethyl) -6,7-dihydropyrazolo [1,5-a] pyrazin-5 (4W) -yl] -3-oxopropyl} dithio) methyl] -2 - [(4H)) - 2- (2,4-dichlorophenyl) -4- (2-phenylethyl) -6,7-dihydropyrazolo [1,5-a] pyrazin-5 (4H) -yl] -2-oxoethyl} carbamate

The compound of Example 11 is synthesized according to a method analogous to that described in Example 1f. Yellow solid

[M + 2H] ²⁺ experimental = 575.33; M theoretical = 1149.10

Example 12: (2 R) -3 - ({(2 fl) -2-Amino-3 - [(4 H) -4- (cyclohexylmethyl) -2-phenyl-6,7-dihydropyrazolo [1.5] a] pyrazin-5 (4H) -yl] -3-oxopropyl} dithio) -1 - [(4H) -4- (cyclohexylmethyl) -2-phenyl-6,7-dihydropyrazolo [1,5-de] a] pyrazin-5 (4H) -yl] -1-oxopropan-2-amine hydrochloride

The compound of Example 1 (230 mg, 0.23 mmol) was dissolved in a mixture of ethyl acetate (5 mL) and ethanol (5 mL). HCl (2Λ in Et ₂ O, 2.9 mL, 5.8 mmol, 25 eq) is added and the reaction medium is heated at 60 ^° C. for 2 hours and 30 minutes (TLC eluent: DCM / MeOH = 95 ^° C.). / 5, developer: ninhydrin), then let The reaction is cooled to room temperature. The precipitate is collected by filtration, washed twice with Et ₂ O and dried under vacuum at 70 ^° C. 129 mg (60%) of the compound of Example 12 is obtained.

Light yellow solid

Melting point: 218 ° C (dec)

[M + 2H] ²⁺ experimental = 398.40; M theoretical = 795.13

¹ H NMR (δ ppm, DMSO): 0.88-1.85 (m, 26H); 3.19-3.58 (m, 4H); 4.22-4.99 (m, 10H); 5.01-5.19 (m, 2H); 5.57-5.68 (m, 2H); 6.55 (s, 2H); 7.26-7.30 (m, 2H); 7.36-7.38 (m, 4H); 7.73-7.77 (m, 4H).

Example 13: (2f) -3 - ({(2f) -2-Amino-3-oxo-3 - [(4H) -2-phenyl-4- (2-phenylethyl) -6,7-dihydropyrazolo [1, 5-a] pyrazin-5 (4H) -yl] propyl} dithio) -1-oxo-1 - [(4H) -2-phenyl-4- (2-phenylethyl) -6,7 Dihydropyrazolo [1,5-a] pyrazin-5 (4W) -yl] propan-2-amine hydrochloride

The above compound is synthesized according to a method analogous to that described in Example 12.

Yellow solid - Melting point: 208 ⁰ C (dec)

[M + 2H] ²⁺ experimental = 406.41; M theoretical = 811, 09

¹ H NMR (δ ppm, DMSO): 2.08-2.14 (m, 4H); 2.66-2.75 (m, 4H); 3.25-3.42 (m, 4H); 4.23-4.86 (m, 10H); 5.60-5.63 (m, 2H); 6.67 (s, 2H); 7.14-7.30 (m, 12H); 7.34-7.40 (m, 4H); 7.73-7.81 (m, 4H); 8.60-8.80 (m, 6H).

¹³ C NMR (δ ppm, DMSO): 32.41; 36.73; 48.16; 49.68; 50.38; 125.93; 126.71; 128.46; 129.16; 129.52; 134.02; 140.47; 142.24; 150.77; 167.15.

Example 14: (2 R) -3 - ({(2 R) -2-amino-3-oxo-3 - [(4H) -4- (2-phenylethyl) -2-pyridin-4 -yl-6,7-dihydropyrazolo [1,5-a] pyrazin-5 (4A) -yl] propyl} dithio) -1-oxo-1 - [(4 / 7S) -4- (2-phenylethyl) -2-pyridin-4-yl-6,7-dihydropyrazolo [1,5-a] pyrazin-5 (4H) -yl] propan-2-amine hydrochloride

White solid - Melting point: 227 ° C (dec)

[M + 2H] ²⁺ experimental = 407.40; M theoretical = 813.07

¹ H NMR (δ ppm, DMSO): 2.12 (m, 4H); 2.73-2.77 (m, 4H); 3.26-5.82 (m, 14H); 5.61-5.89 (m, 2H); 6.67 (s, 2H); 7.18-7.42 (m, 12H); 8.24-8.32 (m, 4H); 8.78-8.88 (m, 10H).

¹³ C NMR (δ ppm, DMSO): 34.11; 36.07; 44.91; 48.48; 49.04; 52.06; 104.48; 122.06; 126.57; 126.72; 139.80; 141.67; 142.79; 145.56; 148.01; 166.88.

Example 15: (2f) -3 - ({(2f) -2-amino-3-oxo-3 - [(4H) -4- (2-phenylethyl) -2-pyridin-3-yl) -6 7-Dihydropyrazolo [1,5-a] pyrazin-5 (4H) -yl] propyl} dithio) -1-oxo-1 - [[4RS) -A- (2-phenylethyl) -2-pyridin-3- Yl-6,7-dihydropyrazolo [1,5-a] pyrazin-5 (4H) -yl] propan-2-amine hydrochloride

Light yellow solid - Melting point: 223 ⁰ C (dec)

[M + 2H] ²⁺ experimental = 407.44; M theoretical = 813.07 ¹ H NMR (δ ppm, DMSO): 2.09-2.12 (m, 4H); 2.71-2.77 (m, 4H); 3.20-3.57 (m, 4H); 3.58-5.09 (m, 10H); 5.60-5.68 (m, 2H); 6.99-7.07 (s, 2H); 7.17-7.29 (m, 10H); 7.97-7.99 (m, 2H); 8.73-8.90 (m, 10H); 9.21-9.24 (m, 2H).

Example 16: (2/7) -3 - ({(2/7) -2-amino-3 - [(4H, 7S) -2- (1,3-benzodioxol-5-yl) -4- phenylethyl) -6,7-dihydropyrazolo [1,5-a] pyrazin-5 (4H) -yl] -3-oxopropyl} dithio) -1 - [(4H) -2- (1,3-benzodioxol) -5 -yl) -4- (2-phenylethyl) -6,7-dihydropyrazolo [1,5-a] pyrazin-5 (4W) -yl] -1-oxopropan-2-amine hydrochloride

Beige solid - Melting point: 221 ⁰ C (dec)

[M + 2H] ²⁺ experimental = 450.17; M theoretical = 899.11

¹ H NMR (δ ppm, DMSO): 2.08-2.11 (m, 4H); 2.65-2.77 (m, 4H); 3.21-3.52 (m, 4H); 3.89-4.83 (m, 10H); 5.50-5.74 (m, 2H); 6.53-6.64 (s, 2H); 6.88-6.93 (m, 2H); 7.16-7.33 (m, 14H); 8.66-8.86 (m, 6H).

¹³ C NMR (δ ppm, DMSO): 31.60; 35.78; 47.18; 48.54; 48.67; 49.45; 99.27; 100.97; 105.39; 108.42; 118.69; 125.87; 127.45; 128.23; 139.55; 141, 36; 146.74; 147.58; 149.69; 166.29.

Example 17: (2f) -3 - ({(2f) -2-amino-3-oxo-3 - [(4H) -4- (2-phenylethyl) -2- (3,4,5-d); trimethoxyphenyl) -6,7-dihydropyrazolo [1,5-a] pyrazin-5 (4H) -yl] propyl} dithio) -1-oxo-1 - [(4H, 7S) -4- (2-phenylethyl) - 2- (3,4,5-trimethoxyphenyl) -6,7-dihydropyrazolo [1,5-a] pyrazin-5 (4H) -yl] propan-2-amine hydrochloride

Light yellow solid - Melting point: 211 ⁰ C (dec)

[M + 2H] ²⁺ experimental = 496.38; M theoretical = 991, 25

¹ H NMR (δ ppm, DMSO): 2.1 (m, 4H); 2.65-2.74 (m, 4H); 3.20-3.41 (m, 4H); 3.70-3.71 (m, 6H); 3.75-3.80 (m, 12H); 3.93-5.78 (m, 12H); 6.64-6.75 (m, 2H); 6.96-7.03 (m, 4H); 7.15-7.25 (m, 1OH); 8.71-8.90 (m, 6H).

¹³ C NMR (δ ppm, DMSO): 31.59; 32.04; 35.99; 47.28; 48.63; 48.87; 49.53; 55.86; 60.05; 99.80; 102.42; 125.80; 128.25; 128.80; 137.16; 139.62; 141.43; 149.78; 153.06; 166.99.

Example 18: (2/7) -3 - ({(2ff) -2-amino-3-oxo-3 - [(4H) -4- (2-phenylethyl) -2- (2-thienyl) -6, 7-Dihydropyrazolo [1,5-a] pyrazin-5 (4H) -yl] propyl} dithio) -1-oxo-1 - [(4H) -4- (2-phenylethyl) -2- -thienyl) -6,7-dihydropyrazolo [1,5-a] pyrazin-5 (4W) -yl] propan-2-amine hydrochloride

Light yellow solid - Melting point: 218 ° C (dec)

[M + 2H] ²⁺ experimental = 412.36; M theoretical = 823.14 ¹ H NMR (δ ppm, DMSO): 2.04.2.07 (m, 4H); 2.59-2.69 (m, 4H); 3.18-3.49 (m, 4H); 3.81-4.89 (m, 10H); 5.51-5.73 (m, 2H); 6.51-6.52 (m, 2H); 7.00-7.02 (m, 2H); 7.11-7.23 (m, 10H); 7.30-7.33 (m, 2H); 7.37-7.39 (m, 2H); 8.61-8.65 (m, 6H).

Example 19: (2/7) -3 - ({(2f) -2-amino-3 - [(4H) -2- (2-furyl) -4- (2-phenylethyl) -6,7 dihydropyrazolo [1,5-a] pyrazin-5 (4W) -yl] -3-oxopropyl} dithio) -1 - [(4H) -2- (2-furyl) -4- (2-phenylethyl) -6- 7-Dihydropyrazolo [1,5-a] pyrazin-5 (4H) -yl] -1-oxopropan-2-amine hydrochloride

Light yellow solid - Melting point: 207 ⁰ C (dec)

[M + 2H] ²⁺ experimental = 396.37; M theoretical = 791, 01

¹ H NMR (δ ppm, DMSO): 1.96.2.21 (m, 4H); 2.62-2.71 (m, 4H); 3.23-3.58 (m, 4H); 3.92-4.93 (m, 10H); 5.61-5.76 (m, 2H); 6.40-6.53 (m, 4H); 6.67 (m, 2H); 7.11-7.28 (m, 10H); 7.67 (m, 2H); 8.69-8.92 (m, 6H).

¹³ C NMR (δ ppm, DMSO): 31.43; 31.87; 35.72; 47.30; 48.48; 48.63; 49.41; 99.44; 111, 52; 125.79; 128.22; 139.36; 141, 35; 142.29; 148.45; 166.29.

Example 20: (2f) -3 - ({(2f) -2-Amino-3-oxo-3 - [(4H) -4-pentyl-2-phenyl-6,7-dihydropyrazolo [1,5-a] pyrazin-5 (4H) -yl] propyl} dithio) -1-oxo-1 - [(4H, 7S) -4-pentyl-2-phenyl-6,7-dihydropyrazolo [1,5-a] pyrazin-5 (4ft) -yl] propan-2-amine hydrochloride

The above compound is synthesized according to a method analogous to that described in Example 12. Beige solid - Melting point: 199-204 ⁰ C (dec)

[M + 2H] ²⁺ experimental = 372.30; M theoretical = 743.06

¹ H NMR (δ ppm, DMSO): 0.78-0.87 (m, 6H); 1.25-1.38 (m, 12H); 1.75-1.83 (m, 4H); 3.19-3.43 (m, 4H); 3.84-4.39 (m, 10H); 5.44-5.67 (m, 2H); 6.56-6.65 (m, 2H); 7.26-7.30 (m, 2H); 7.34-7.39 (m, 4H); 7.73-7.77 (m, 4H); 8.63-8.80 (m, 6H).

¹³ C NMR (δ ppm, DMSO): 13.93; 21, 86; 24.88; 30.86; 31, 09; 33.84; 47.17; 48.50; 48.67; 99.51; 124.87; 127.52; 128.48; 133.10; 139.83; 148.76; 165.99.

Example 21: (2 R) -3 - ({(2 R) -2-amino-3 - [(4H) -4-butyl-2-phenyl-6,7-dihydro-pyrazolo [1, 5-a] pyrazin-5 (4W) -yl] -3-oxopropyl} dithio) -1 - [(4H) -4-butyl-2-phenyl-6,7-dihydropyrazolo [1,5-a] ] pyrazin-5 (4W) -yl] -1-oxopropan-2-amine hydrochloride

Beige solid - Melting point: 210-215 ^° C (dec)

[M + 2H] ²⁺ experimental = 358.28; M theoretical = 715.00

¹ H NMR (δ ppm, DMSO): 0.82-0.91 (m, 6H); 1.25-1.36 (m, 8H); 1.75-1.84 (m, 4H); 3.21-3.44 (m, 4H); 3.84-4.95 (m, 10H); 5.45-5.55 (m, 2H); 6.60-6.65 (m, 2H); 7.26-7.29 (m, 2H); 7.34-7.39 (m, 4H); 7.73-7.77 (m, 4H); 8.63-8.81 (m, 6H).

¹³ C NMR (δ ppm, DMSO): 13.83; 21, 97; 27.33; 27.39; 33.62; 47.15; 48.75; 49.48; 99.51; 124.99; 127.52; 128.59; 133.10; 139.78; 149.78; 165.98.

Example 22: (2/7) -3 - ({(2 ") - 2-amino-3 - [(4H) -2- (2,4-dichlorophenyl) -4- (2-phenylethyl) - 6,7-Dihydropyrazolo [1,5-a] pyrazin-5 (4H) -yl] -3-oxopropyl} dithio) -1- [(4F) -2- (2,4-dichlorophenyl) -4- phenylethyl) -6,7-dihydropyrazolo [1,5-a] pyrazin-5 (4W) -yl] -1-oxopropan-2-amine hydrochloride

Pale yellow solid - Melting point: 198-202 ⁰ C

Experimental MH ⁺ = 947.28; M theoretical = 948.87

¹ H NMR (δ ppm, DMSO): 2.09-2.15 (m, 4H); 2.66-2.76 (m, 4H); 3.27-3.42 (m, 4H); 3.98-4.42 (m, 10H); 6.66-6.73 (m, 2H); 7.16-7.28 (m, 10H); 7.43-7.45 (m, 2H); 7.66-7.69 (m, 2H); 7.76-7.79 (m, 2H); 8.60-8.79 (m, 6H).

¹³ C NMR (δ ppm, DMSO): 32.41; 36.56; 48.23; 49.72; 50.27; 104.29; 126.74; 128.41; 129.17; 130.55; 131, 68; 132.28; 132.63; 133.67; 139.93; 142.18; 147.29; 167.21.

Example 23: tert-butyl {(1 fl) -1 - [({(2 fl) -2 - [(f-butoxycarbonyl) amino] -3 - [(4S) -4 - (cyclohexylmethyl) -2-phenyl 6,7-dihydropyrazolo [1,5-a] pyrazin-5 (4H) -yl] -3-oxopropyl} dithio) methyl] -2 - [(4S) -4- (cyclohexylmethyl) -2-phenyl) -6 7-Dihydropyrazolo [1,5-a] pyrazin-5 (4H) -yl] -2-oxoethyl} carbamate

23a. (4S) -4- (cyclohexylmethyl) -2-phenyl-4,5,6,7-tetrahydropyrazolo [1,5-a] pyrazine

The compound of Example 1c (823 mg, 2.0 mmol) in solution in formic acid (7.4 ml, 196 mmol, 9 vol) is reacted under an inert atmosphere at room temperature for 27 hours ( TLC, eluent: DCM / MeOH = 98/2). The reaction medium is cooled to 0 ^° C. and trethylamine (10.9 ml, 75 mmol, 3.6 vol) is added dropwise and the temperature is allowed to return to ambient temperature. The hydrogen transfer catalyst is prepared by stirring under argon for 40 minutes at 28 ^° C. in anhydrous acetonitrile (4 ml) of bis ((η ⁶ -p-cymene) dichlororuthenium) (3 mg, 5 μmol). 25% eq), (1f, 2f) -TsDPEN (/ V- (4-toluenesulfonyl) -1,2-diphenylethylenediamine, 3.7 mg, 10 μmol, 0.50% eq) and a drop of _3N was added the catalyst solution to the reaction mixture which is stirred at 28 ° C for 20 hours (TLC, eluent: DCM / MeOH = 95/5). The reaction medium is basified (pH 9-10) by adding a saturated solution of sodium carbonate and extracted three times with DCM. The organic phase is dried over sodium sulfate, then filtered and concentrated in vacuo. The residue is purified on SiO ₂ (eluent: DCM / MeOH = 98/2) to obtain the compound of Example 23a (207 mg, 35%) and its formamide derivative (422 mg, 65%). The formamide derivative can be hydrolyzed to the compound of Example 23a by refluxing in ethanol in the presence of 10% hydrochloric acid without significant loss of enantiomeric purity.

A white solid; Melting point: 113 ° C

Experimental MH ⁺ = 296.25; M theoretical = 295.43

¹ H NMR (δ ppm, DMSO): 0.91-1.85 (m, 13H); 2.44 (s, 1H); 3.01 (ddd, 1H); 3.27 (dt, 1H); 3.91-4.00 (m, 3H); 6.45 (s, 1H); 7.25 (t, 1H); 7.36 (t, 2H); 7.75 (d, 2H).

¹³ C NMR (δ ppm, DMSO): 25.30; 25.56; 32.22; 33.54; 34.32; 42.05; 47.47; 49.66; 97.50; 124.86; 127.10; 128.48; 133.69; 144.17; 149.12.

23b. tert-butyl {(1/3) -1 - [({(2fr) -2 - [(tert-butoxycarbonyl) amino] -3 - [(4S) -4-

(cyclohexylmethyl) -2-phenyl-6,7-dihydropyrazolo [1,5-a] pyrazin-5 (4W) -yl] -3-oxopropyl} dithio) methyl] -2 - [(4S) -4- (cyclohexylmethyl) 2-phenyl-6,7-dihydro-pyrazolo [1,5-a] pyrazin-5 (4W) -yl] -2-oxoethyl} carbamate

The procedure is analogous to the preparation of compound 1f.

A white solid; Melting point: 106-108 ^° C.

[M + 2H] ²⁺ experimental = 498.35; M theoretical = 995.36 ¹ H NMR (δ ppm, DMSO): 1.24-1.40 (m, 18H); 0.85-1.93 (m, 26H); 2.79-3.07 (m, 4H); 3.41-4.77 (m, 10H); 5.73-5.75 (m, 2H); 6.52-6.55 (m, 2H) 7.24-7.28 (m, 2H) 7.45-7.48 (m, 2H); 7.71-7.77 (m, 4H).

¹³ C NMR (δ ppm, DMSO): 25.40; 26.05; 27.98; 32.51; 33.07; 33, 16; 41.68; 46.09; 47.34; 49.65; 97.50; 124.86; 127, 10; 128.48; 133.69; 144, 17; 149, 12.

Example 24: (2f) -3 - ({(2f) -2-amino-3 - [(4S) -4- (cyclohexylmethyl) -2-phenyl-6,7-dihydropyrazolo [1,5-a] pyrazine) 5 (4H) -yl] -3-oxopropyl} dithio) -1 - [(4S) -4- (cyclohexylmethyl) -2-phenyl-6,7-dihydropyrazolo [1,5-a] pyrazin-5 (4H) -yl] -1-oxopropan-2-amine hydrochloride

The procedure is analogous to the preparation of compound 12.

Pale yellow solid

Melting point: 214-219 ^° C.

[M + 2H] ²⁺ experimental = 398.40; M theoretical = 795.13

¹ H NMR (δ ppm, DMSO): 0.88-1.90 (m, 26H); 3.18-3.42 (m, 4H); 3.87-4.80 (m, 10H); 5.22-5.63 (m, 2H); 6.43-6.58 (m, 2H); 7.26-7.30 (m, 2H); 7.34-7.39 (m, 4H); 7.73-7.77 (m, 4H); 8.70-8.75 (m, 6H).

¹³ C NMR (δ ppm, DMSO): 25.35; 26.09; 32.52; 32.86; 38.08; 41, 37; 46.98; 47.19; 48.62; 99.41; 124.85; 127.53; 128.22; 133.08; 139.94; 149.83; 165.86.

Example 25: tert-Butyl {(1/7) -1 - [({(2ff) -2 - [(tert-butoxycarbonyl) amino] -3 - [(4 H) -4- (cyclohexylmethyl) -2-phenyl) 6,7-dihydropyrazolo [1,5-a] pyrazin-5 (4H) -yl] -3-oxopropyl} dithio) methyl] -2 - [(4H) -4- (cyclohexylmethyl) -2-phenyl-6, 7-dihydropyrazolo [1,5-a] pyrazin-5 (4W) -yl] -2-oxoethyl} carbamate

25a. (4/7) -4- (cyclohexylmethyl) -2-phenyl-4,5,6,7-tetrahydropyrazolo [1,5-a] pyrazine

The procedure is analogous to the preparation of Example 23a using (1S, 2S) -TsDPEN instead of (1/2, 2f) -ZDPEN. A white solid is obtained; Melting point: 117-118 ° C

Experimental MH ⁺ = 296.27; M theoretical = 295.43

¹ H NMR (δ ppm, DMSO): 0.88-1.88 (m, 13H); 2.45 (s, 1H); 3.03 (ddd, 1H); 3.26 (dt, 1H); 3.91-4.00 (m, 3H); 6.45 (s, 1H); 7.25 (t, 1H); 7.37 (t, 2H); 7.75 (d, 2H).

¹³ C NMR (δ ppm, DMSO): 25.60; 25.89; 26.16; 31, 83; 33.15; 33.93; 41, 65; 42.38; 47.47; 49.67; 97.50; 124.86; 127.10; 128.48; 133.69; 144.17; 148.72.

25b. tert-butyl {(1/7) -1 - [({(2 H) -2 - [(tert-butoxycarbonyl) amino] -3 - [(4 H) -4- (cyclohexylmethyl) -2-phenyl-6,7 Dihydropyrazolo [1,5-a] pyrazin-5 (4W) -yl] -3-oxopropyl} dithio) methyl] -2 - [(4H) -4- (cyclohexylmethyl) -2-phenyl-6,7-dihydro pyrazolo [1,5-a] pyrazin-5 (4H) -yl] -2-oxoethyl} carbamate

The procedure is analogous to the preparation of compound 1f.

A white solid; Melting point: 114-139 ° C

[M + 2H] ²⁺ experimental = 498.37; M theoretical = 995.36 ¹ H NMR (δ ppm, DMSO): 1.24-1.40 (m, 18H); 0.85-1.93 (m, 26H); 2.79-3.07 (m, 4H); 3.41-4.77 (m, 10H); 5.81-5.83 (m, 2H); 6.61-6.64 (m, 2H) 7.33-7.36 (m, 2H) 7.41-7.46 (m, 2H); 7.79-7.83 (m, 4H).

Example 26: (1 R) -3 - ({(2 R) -2-amino-3 - [(4H) -4- (cyclohexylmethyl) -2-phenyl-6,7-dihydropyrazolo [1,5-a] ] pyrazin-5 (4H) -yl] -3-oxopropyl} dithio) -1 - [(4Λ) -4- (cyclohexylmethyl) -2-phenyl-6,7-dihydropyrazolo [1,5-a] pyrazin-5 (4H) -yl] -1-oxopropan-2-amine hydrochloride

The procedure is analogous to the preparation of Example 12.

Solid yellow white - Melting point: 212-217 ° C

[M + 2H] ²⁺ experimental = 398.41; M theoretical = 795.13

¹ H NMR (δ ppm, DMSO): 0.91-1.97 (m, 26H); 3.33-3.57 (m, 4H); 3.86-4.98 (m, 10H); 5.83 (m, 2H); 6.54-6.61 (m, 2H); 7.20-7.40 (m, 6H); 7.73-7.77 (m, 4H); 8.70-8.75 (m, 6H).

¹³ C NMR (δ ppm, DMSO): 25.55; 25.78; 26.04; 32.16; 33.10; 33.34; 38.00; 41, 67; 46.37; 47.36; 48.37; 99.29; 125.02; 127.52; 128.60; 133.13; 140.40; 149.79; 166.78.

Example 27: tert-Butyl {(1 R) -1 - [({(2 R) -2 - [(tert-butoxycarbonyl) amino] -3 - [(4H) -4- (cyclohexylmethyl) - 2-phenyl-7,8-dihydro-4H-pyrazolo [1,5-a] [1,4] diazepin-5 (6H) -yl] -3-oxopropyl} dithio) methyl] -2 - [(4fIS)) 4- (cyclohexylmethyl) -2-phenyl-7,8-dihydro-4H-pyrazolo [1,5-a] [1,4] diazepin-5 (6H) -yl] -2-oxoethyl} carbamate

27a. tert-butyl [3- (5 - {[methoxy (methyl) amino] carbonyl} -3-phenyl-1H-pyrazol-1-yl) propyl] carbamate

The compound of Example 1a (2.65 g, 11.5 mmol) in DMF (50 ml) is reacted with tert-butyl (3-bromopropyl) carbamate (3.55 g, 14.9 g). mmol, 1, 3 eq.) in the presence of potassium carbonate (1.90 g, 13.7 mmol, 1.2 eq.). The reaction medium is heated at 110 ^° C. for 6 hours (TLC, eluent: heptane / AcOEt = 98/2). The DMF is then evaporated and the residue is dissolved in AcOEt. It is then washed twice with water. The organic phase is dried over sodium sulfate, then filtered and concentrated in vacuo. The residue is purified on SiO 2 (eluent: heptane / AcOEt

= 60/40) to obtain the compound of Example 27a (3.93 g, 72%) as a translucent oil.

Experimental MH ⁺ = 389.28; M theoretical = 388.46

¹ H NMR (δ ppm, DMSO): 1.36 (s, 9H); 1, 87-1, 94 (tt, 2H); 2.91-2.97 (m, 2H); 3.30 (s, 3H); 3.68 (s, 3H); 4.35 (t, 2H); 6.81 (br, 1H); 7.13 (s, 1H); 7.31 (m, 1H); 7.41 (m, 2H); 7.83 (m, 2H).

¹³ C NMR (δ ppm, DMSO): 28.38; 30.74; 37.60; 49.04; 61, 52; 77.68; 105.36; 125.35; 127.96; 128.83; 132.71; 134.88; 148.89; 155.71; 159.98.

27b. tert-Butyl {3- [5- (cyclohexylacetyl) -3-phenyl-1H-pyrazol-1-yl] propyl} carbamate

The procedure is analogous to the preparation of Example 1c. A yellow oil is obtained. ¹ H NMR (δ ppm, DMSO): 0.85-1.89 (m, 11H); 1, 37 (s, 9H); 2.80 (d, 2H); 2.95 (m, 2H); 4.47 (t, 2H); 6.80 (br, 1H); 7.33 (m, 1H); 7.43 (m 2H); 7.66 (s, 1H); 7.85 (m, 2H).

¹³ C NMR (δ ppm, DMSO): 25.57; 25.76; 27.44; 28.19; 30.41; 32.50; 34.17; 37.37; 47.41; 49.52; 77.48; 109.28; 125.12; 127.92; 128.68; 132.20; 139, 77; 148.69; 155.49; 191.41.

Experimental MH ⁺ = 426.31; M theoretical = 425.57

27c. 4- (cyclohexylmethyl) -2-phenyl-7,8-dihydro-6W-pyrazolo [1,5-a] [1,4] diazepine

The procedure is analogous to the preparation of Example 1d. A yellow oil is obtained.

Experimental MH ⁺ = 308.27; M theoretical = 307.44

¹ H NMR (δ ppm, DMSO): 0.87-1.65 (m, 10H); 1.74-1.81 (m, 1H); 2.12-2.15 (m, 2H); 2.73-2.78 (m, 2H); 3.53-3.56 (m, 2H); 4.26 (t, 2H); 7.02 (s, 1H); 7.25 (m, 1H); 7.35 (m, 2H); 7.80 (m, 2H).

27d. (4S) -4- (cyclohexylmethyl) -2-phenyl-5,6,7,8-tetrahydro-4H-pyrazolo [1,5-a] [1,4] diazepine

The procedure is analogous to the preparation of Example 1e. A translucent oil is obtained. Experimental MH ⁺ = 310.31; M theoretical = 309.45

¹ H NMR (δ ppm, DMSO): 0.89-1.85 (m, 15H); 2.49 (br, 1H); 2.88-3.29 (ddd, 2H); 3.71-4.39 (m, 3H); 6.46 (s, 1H); 7.25 (t, 1H); 7.36 (t, 2H); 7.75 (d, 2H).

¹³ C NMR (δ ppm, DMSO): 25.73; 25.90; 26.18; 29.83; 32.13; 33.52; 33.68; 41, 02; 49.86; 50.60; 51, 98; 99.89; 124.77; 126.92; 128.46; 133.72; 147.07; 150.29.

27th. tert-butyl {(1/7) -1 - [({(2 H) -2 - [(Fert-butoxycarbonyl) amino] -3 - [(4 H) -4- (cyclohexylmethyl) -2-phenyl-7, 8-dihydro-4H-pyrazolo [1,5-a] [1,4] diazepin-5 (6H) -yl] -3-oxopropyl} dithio) methyl] -2 - [(4f S) -4- ( cyclohexylmethyl) -2-phenyl-7,8-dihydro-4W-pyrazolo [1,5-a] [1,4] diazepin-5 (6H) -yl] -2-oxoethyl} carbamate

The procedure is analogous to the preparation of Example 1f. A pale yellow solid is obtained

Melting point: 105-116 ° C

[M + 2H] ²⁺ experimental = 512.42; M theoretical = 1023.41

¹ H NMR (δ ppm, DMSO): 1.31-1.41 (m, 18H); 0.70-1.96 (m, 30H); 2.7-3.3 (m, 4H); 3.5-4.5 (m, 10H); 5.74 (m, 2H); 6.6 (m, 2H) 7.23-7.27 (m, 2H) 7.33-7.39 (m, 4H); 7.72-7.75 (m, 4H).

¹³ C NMR (δ ppm, DMSO): 25.49; 35.74; 26.01; 27.97; 28.08; 28.59; 31, 71; 32.92; 33.06; 33.41; 38.20; 50.07; 51, 13; 54.85; 78.54; 99.49; 124.80; 124.89; 127.20; 128.52; 133.14; 133.18; 144.01; 147.71; 154.88; 155.03.

Example 28: {(1 R) -1 - [({(2 R) -2-amino-3 - [(4H) -4- (cyclohexylmethyl) -2-phenyl-7,8-dihydro-4W- pyrazolo [1,5-a] [1,4] diazepin-5 (6W) -yl] -3-oxopropyl} dithio) methyl] -2 - [(4H) -4- (cyclohexylmethyl) -2- phenyl-7,8-dihydro-4H-pyrazolo [1,5-a] [1,4] diazepin-5 (6H) -yl] -2-oxoethyl} amine hydrochloride

The procedure is analogous to the preparation of Example 12.

Pale pink solid - Melting point: 198-208 ⁰ C

[M + 2H] ²⁺ experimental = 412.37; M theoretical = 823.18

¹ H NMR (δ ppm, DMSO): 0.89-2.2 (m, 30H); 3.18-3.42 (m, 4H); 3.87-4.80 (m, 10H); 5.9 (m, 2H); 6.63-6.68 (m, 2H); 7.23-7.27 (m, 2H); 7.34-7.38 (m, 4H); 7.71-7.76 (m, 4H); 8.56-8.74 (m, 6H).

¹³ C NMR (δ ppm, DMSO): 25.41; 25.62; 25.73; 26.04; 31.55; 32.12; 32.92; 33.13; 33.20; 37.93; 48.86; 51, 16; 99.49; 124.82; 127.32; 128.65; 133.09; 143.56; 147.80; 166.99.

Example 29: (2f) -2-Amino-3 - [(4S) -2- (2-furyl) -4- (2-phenylethyl) -6,7-dihydropyrazolo [1,5-a] pyrazine -5 (4H) -yl] -3-oxopropane-1-thiol hydrochloride

The compound of Example 19 (93.7 mg, 0.100 mmol) is dissolved in ethanol, dithiothreitol (23 mg, 0.150 mmol) is added and the reaction is heated at reflux for 5 hours under a vacuum. argon, then at room temperature for 12h. The reaction is cooled to 5 ° C., then TBME and then TEt ₂ O are added. The precipitate is collected on a fry and washed at ^{1 °} and _{2 °} , and then dried under vacuum, to obtain a beige solid (85 ° C.). mg, 90%).

[M + H] ⁺ experimental = 397.22; M theoretical = 396.51 ¹ H NMR (δ ppm, DMSO): 2.09-2.14 (m, 2H); 2.66-2.75 (m, 2H); 3.2-3.6 (m, 3H); 3.8-4.9 (m, 5H); 5.65-5.80 (m, 1H); 6.48-6.54 (m, 2H); 6.67 (m, 1H); 7.15-7.29 (m, 5H); 7.67 (m, 1H); 8.4-8.9 (m, 3H).

¹³ C NMR (δ ppm, DMSO): 24.65; 31, 45; 35.68; 38.07; 47.26; 48.76; 49.25; 51, 34; 105.55; 111.49; 125.81; 128.25; 139.38; 141, 02; 142.28; 148.45; 166.56.

Example 30: tert-butyl {(1 fl) -1 - [({(2 fl) -2 - [(tert-butoxycarbonyl) amino] -3 - [(4 H) -4- (cyclohexylmethyl) -2-phenyl 6,7-dihydropyrazolo [1,5-a] pyrazin-5 (4H) -yl] -3-oxopropyl) diselanyl) methyl] -2 - [(4SH) -4- (cyclohexylmethyl) -2-phenyl-6) 7-Dihydropyrazolo [1,5-a] pyrazin-5 (4f) -yl] -2-oxoethyl} carbamate

The procedure is analogous to the preparation of the compound 1f using Λ /, Λ / '- di - Boc - L - selenocystine. A pale yellow solid is obtained.

Melting point: 117-120 ^° C.

[M + H] ⁺ experimental monoisotopic = 1091, 47; M average isotopic = 1089.15

¹ H NMR (δ ppm, DMSO): 1.25-1.37 (m, 18H); 0.83-1.74 (m, 26H); 2.9-3.4 (m, 4H); 3.7-4.8 (m, 10H); 5.73 (m, 2H); 6.39-6.55 (m, 2H) 7.25-7.29 (m, 2H) 7.34-7.44 (m, 4H); 7.71-7.76 (m, 4H).

¹³ C NMR (δ ppm, DMSO): 25.40; 25.54; 25.68; 26.06; 31, 21; 32.55; 32.75; 32.97; 33.14; 38.89; 47.33; 124.85; 127.42; 128.59; 133.16; 140.82; 149.66; 154.67; 169.48.

EXAMPLE 31: {(1 R) -1 - [({(2 R) -2-amino-3 - [(4H) -4- (cyclohexylmethyl) -2-phenyl-6,7-dihydropyrazolo [1, 5-a] pyrazin-5 (4H) -yl] -3-oxopropyl-diselanyl) methyl] -2 - [(4H) -4- (cyclohexylmethyl) -2-phenyl-6,7-dihydropyrazolo [1] 5-a] pyrazin-5 (4rt) -yl] -2-oxoethyl} amine hydrochloride

The procedure is analogous to the preparation of Example 12.

Light yellow solid

Melting point: 217-220 ^° C (dec)

[M + H] ⁺ experimental monoisotopic = 891.4; M isotopic average = 888.92

¹ H NMR (δ ppm, DMSO): 0.88-1.84 (m, 26H); 3.41-3.46 (m, 4H); 3.87-4.78 (m, 10H); 5.60-5.63 (m, 2H); 6.56 (s, 2H); 7.26-7.30 (m, 2H); 7.35-7.39 (m, 4H); 7.75-7.78 (m, 4H); 8.63 (br, 6H).

¹³ C NMR (δ ppm, DMSO): 25.35; 26.07; 29.20; 32.48; 32.88; 32.93; 41, 35; 46.96; 49.86; 99.38; 125.04; 127.52; 128.57; 133.08; 139.91; 149.82; 166.07.

Exempt 32: (2f) -3 - ({(2/7) -2-amino-3-oxo-3 - [(4H) -4- (2-phenylethyl) -2-pyridin-2-yl 6,6-dihydropyrazolo [1,5-a] pyrazin-5 (4H) -yl] propyl} dithio) -1-oxo-1 - [(4RS) -A- (2-phenylethyl) -2-pyridin] 2-yl-6,7-dihydropyrazolo [1,5-a] pyrazin-5 (4H) -yl] propan-2-amine hydrochloride

The procedure is analogous to the preparation of Example 12.

White solid - Melting point: 232-234 ° C (dec)

[M + 2H] ²⁺ experimental = 407.51; M theoretical = 813.07

¹ H NMR (δ ppm, DMSO): 2.12 (m, 4H); 2.66-2.80 (m, 4H); 3.24-5.85 (m, 14H); 5.62-5.85 (m, 2H); 6.67 (s, 2H); 7.16-7.71 (m, 12H); 8.17-8.32 (m, 4H); 8.69-8.91 (m, 10H). ¹³ C NMR (δ ppm, DMSO): 31.02; 31, 17; 35.41; 37.70; 47.59; 48.35; 49.04; 102.50; 121.42; 124.17; 125.61; 127.95; 128.07; 140, 35; 140.89; 166, 74.

Pharmacological study of the products of the invention

Test Protocol: characterization of anti-proliferative activity:

By way of example, the effect of a treatment on three human cell lines DU 145, LNCaP and A2058 by the compounds of the examples described above will be studied. Cell lines DU 145 and LNCaP (human prostate cancer cells) and A2058 (human melanoma cancer cells) were purchased from American Tissue Culture Collection (Rockville, Maryland, USA). Cells placed in 80 μl of modified Dulbecco's Eagle medium (Gibco-Brl, Cergy-Pontoise, France) supplemented with 10% heat inactivated calf fetal serum (Gibco-Brl, Cergy-Pontoise, France), 50000 units / 1 penicillin and 50 mg / l streptomycin (Gibco-Brl, Cergy-Pontoise, France), and 2 mM glutamine (Gibco-Brl, Cergy-Pontoise, France) were inoculated on a 96-well plate at day 0. The cells were treated on day 1 for 96 hours with increasing concentrations of each of the test compounds up to 10 μM. At the end of this period, quantification of cell proliferation is evaluated by colorimetric assay based on cleavage of tetrazolium salt WST1 by mitochondrial dehydrogenases in viable cells leading to formazan formation (Boehringer Mannheim, Meylan, France). ). These tests are performed in duplicate with 8 determinations per concentration tested. For each test compound, the values included in the linear part of the sigmoid were retained for a linear regression analysis and used to estimate the Cl ₅₀ inhibitory concentration. The products are solubilized in dimethylsulfoxide (DMSO) 10 ^'2 M and used in culture with 0.1% DMSO final.

! _M desjests resu States:

a) The compounds of the following examples show, on the cell proliferation of the lines DU 145, an Cl ₅₀ less than or equal to:

20 μM: examples: 16; 21; 22;

15 μM: examples: 13; 17; 18; 19; 20; 24

10 μM: examples: 12 b) The compounds of the following examples show, on the cell proliferation of LNCaP lines, an Cl ₅₀ less than or equal to:

10 μM: examples: 3; 14; 15; 16; 17; 20

5 μM: examples: 18; 19; 21

1 μM: examples: 12; 13; 22; 24

c) The compounds of the following examples have on cell proliferation of A2058 lines an IC ₅₀ less than or equal to:

30 μM: examples: 14; 16

20 μM: examples: 15; 17; 18; 19

10 mM: examples: 12; 13; 20; 21; 22; 24.

Claims

1. Compound of general formula (I)

Z represents a hydrogen atom or a radical of general formula

R ³ represents a radical (C _r C ₈ ) alkyl or a cycloalkylalkyl, aryl or arylalkyl radical, the aryl group of the aryl and arylalkyl radicals being optionally substituted with one or more idenic or different substituents chosen from: halo, hydroxy, alkyl, haloalkyl alkoxy, haloalkoxy, aryl, aryloxy, -NRR ¹ , -C (O) -NRR ¹ , -NR _N -C (O) R ¹ , -SO ₂ -R, -SiRR ¹ R "or a heterocycloalkyl; R _N represents a hydrogen atom or an alkyl radical;

R, R ¹ and R "represent, independently, an alkyl or aryl radical;

R ⁴ represents a hydrogen atom or a radical of formula -CO-OR ⁵ ;

R ⁵ represents an alkyl or arylalkyl radical;

n represents the integer 1 or 2;

2. Compound according to claim 1 characterized in that Z represents a hydrogen atom; or a pharmaceutically acceptable salt thereof.

3. Compound according to claim 1 characterized in that Z represents a radical of general formula

or a pharmaceutically acceptable salt thereof.

4. Compound according to one of the preceding claims, characterized in that X represents a sulfur atom; or a pharmaceutically acceptable salt thereof.

5. Compound according to one of the preceding claims, characterized in that X represents a selenium atom; or a pharmaceutically acceptable salt thereof.

6. Compound according to one of the preceding claims, characterized in that R ² represents a hydrogen atom; or a pharmaceutically acceptable salt thereof.

7. Compound according to one of the preceding claims, characterized in that R ⁴ represents a hydrogen atom or a radical of formula -CO-OR ⁵ and R ⁵ represents an alkyl radical; or a pharmaceutically acceptable salt thereof.

8. Compound according to one of the preceding claims, characterized in that n is equal to 1; or a pharmaceutically acceptable salt thereof.

9. Compound according to one of the preceding claims, characterized in that R ¹ represents an aryl or heteroaryl radical, the aryl radical being optionally substituted with one or more idendic or different substituents chosen from halo and alkoxy,

or a radical of formula

or a pharmaceutically acceptable salt thereof.

10. Compound according to one of the preceding claims, characterized in that R ³ represents a C 4 -C 8 alkyl, arylalkyl or cycloalkylalkyl radical; or a pharmaceutically acceptable salt thereof.

11. Compound according to claim 1 characterized in that R ² and R ⁴ represent a hydrogen atom; or a pharmaceutically acceptable salt thereof.

12. Compound according to one of claims 1 and 11, characterized in that R ³ represents a cycloalkylalkyl or arylalkyl radical; or a pharmaceutically acceptable salt thereof.

13. Compound according to one of claims 1 and 11 to 12 characterized in that R ¹ represents an aryl or heteroaryl radical, the aryl radical being optionally substituted by one or more halo idendic or different substituents; or a pharmaceutically acceptable salt thereof.

14. Compound according to claim 13, characterized in that R ¹ represents a heteroaryl radical; or a pharmaceutically acceptable salt thereof.

15. Compound according to one of the preceding claims, characterized in that it comprises at least one of the following characteristics: the cycloalkyl radical of the cycloalkyl and cycloalkylalkyl groups is the hexyl radical;

the aryl radical of the aryl and arylalkyl groups is the phenyl radical, and

16. Compound according to one of claims 1 to 15 characterized in that it is chosen from the following compounds:

tert-butyl {(1f) -1 - [({(2f) -2 - [(tert-butoxycarbonyl) amino] -3 - [(4HS) -4- (cyclohexylmethyl) -2-phenyl-6, 7-Dihydropyrazolo [1,5-a] pyrazin-5 (4H) -yl] -3-oxopropyl} dithio) methyl] -2 - [(4H) -4-cyclohexylmethyl) -2-phenyl-6 7-dihydropyrazolo [1,5-a] pyrazin-5 (4A7) -yl] -2-oxoethyl} carbamate;

tert-butyl {(1H) -1- [({(2fl) -2 - [(tert-butoxycarbonyl) amino] -3-oxo-3 - [(4H) -2-phenyl-4- phenylethyl) -6,7-dihydropyrazolo [1,5-a] pyrazin-5 (4H) -yl] propyl} dithio) methyl] -2-oxo-2 - [(4f S) -2-phenyl-4- ( 2-phenylethyl) -6,7-dihydropyrazolo [1,5-a] pyrazin-5 (4H) -yl] ethyl} carbamate;

tert-butyl {(1f) -1 - [({(2f) -2 - [(tert-butoxycarbonyl) amino] -3-oxo-3 - [(4f) S) -4- (2-phenylethyl) 2-pyridin-4-yl-6,7-dihydropyrazolo [1,5-a] pyrazin-5 (4H) -yl] propyl} dithio) methyl] -2-oxo-2 - [(4f) S) 4- (2-phenylethyl) -2-pyridin-4-yl-6,7-dihydropyrazolo [1,5-a] pyrazin-5 (4H) -yl] ethyl} carbamate;

tert-butyl {(1H) -1 - [({(2H) -2 - [(tert-butoxycarbonyl) amino] -3-oxo-3 - [(4H) -4- (2-phenylethyl) -2 pyridin-3-yl-6,7-dihydropyrazolo [1,5-a] pyrazin-5 (4H) -yl] propyl} dithio) methyl] -2-oxo-2 - [(4 S) -4 - (2 phenylethyl) -2-pyridin-3-yl-6,7-dihydro-pyrazolo [1,5-a] pyrazin-5 (4A) -yl] ethyl} carbamate;

tert-butyl {(1 R) -2 - [(4S) -2- (1,3-benzodioxol-5-yl) -4- (2-phenylethyl) -6,7-dihydropyrazolo [1,5-a] ] pyrazin-5 (4H) -yl] -1 - [({(2f) -3 - [(4f) S) -2- (1,3-benzodioxol-5-yl) -4- (2-phenylethyl) -6 7-dihydropyrazolo [1,5-a] pyrazin-5 (4H) -yl] -2 - [(tert-butoxycarbonyl) amino] -3-oxopropyl} dithio) methyl] -2-oxoethyl} carbamate;

tert-butyl {(1 H) -1 - [({(2 fl) -2 - [(tert-butoxycarbonyl) amino] -3-oxo-3 - [(4 H) -4- (2-phenylethyl) -2} (3,4,5-trimethoxyphenyl) -6,7-dihydropyrazolo [1 ₎ 5-a] pyrazin-5 (4H) -yl] propyl} dithio) methyl] -2-oxo-2 - [(4fIS) - 4- (2-phenylethyl) -2- (3,4,5-trimethoxyphenyl) -6,7-dihydropyrazolo [1,5-a] pyrazin-5 (4H) -yl] ethyl} carbamate; tert-butyl {(1 R) -1 - [({(2 R)) - 2 - [(tert-butoxycarbonyl) amino] -3-oxo-3 - [(4 H, S) -4- (2-phenylethyl) ) -2- (2-thienyl) -6,7-dihydropyranothio [1,5-a] pyrazin-5 (4H) -yl] propyl} dithio) methyl] -2-oxo-2 - [(4S) -4- (2-phenylethyl) -2- (2-thienyl) -6 ₎ -7-dihydropyrazolo [1,5-a] pyrazin-5 (4H) -yl] ethyl} carbamate;

tert-butyl {(1 R) -1 - [({(2 R) -2 - [(tert-butoxycarbonyl) amino] -3 - [(4A) S - -2- (2-uryl) -4- (2-phenylethyl) -6,7-dihydropyrazolo [1,5-a] pyrazin-5 (4H) -yl] -3-oxopropyl} dithio) methyl] -2- [(4ffS) -2- (2-furyl) -4- (2-phenylethyl) -6,7-dihydropyrazolo [1,5-a] pyrazin-5 (4W) -yl] -2-oxoethyl] carbamate;

tert-butyl {(1 R) -1 - [({(2 R)) - 2 - [(tert-butoxycarbonyl) amino] -3-oxo-3 - [(4H) -4-pentyl-2- phenyl-6,7-dihydropyrazolo [1,5-a] pyrazin-5 (4H) -yl] propyl} dithio) methyl] -2-oxo-2-

[(4 S) -4-pentyl-2-phenyl-6,7-dihydropyrazolo [1,5-a] pyrazin-5 (4H) -yl] ethyl} carbamate;

tert-butyl {(1H) -1 - [({(2f)) - 2 - [(tert-butoxycarbonyl) amino] -3 - [(4H) -4-butyl-2-phenyl-6, 7-Dihydropyrazolo [1,5-a] pyrazin-5 (4H) -yl] -3-oxopropyl} dithio) methyl] -2 - [(4f-S) -4-butyl-2-phenyl-6,7- dihydropyrazolo [1,5-a] pyrazin-5 (4H) -yl] -2-oxoethyl} carbamate;

tert-butyl {(1/7) -1 - [({(2 R) -2 - [(tert-butoxycarbonyl) amino] -3 - [(4 S) -2- (2,4-dichlorophenyl) -4- (2-phenylethyl) -6,7-dihydropyrazolo [1,5-a] pyrazin-5 (4H) -yl] -3-oxopropyl} dithio) methyl] -2 - [(4f S) -2- (2,4 dichlorophenyl) -4- (2-phenylethyl) -6,7-dihydropyrazolo [1,5-a] pyrazin-5 (4H) -yl] -2-oxoethyl} carbamate;

- (2H) -3 - ({(2 R) -2-amino-3 - [(4 H) -4- (cyclohexylmethyl) -2-phenyl-6,7-dihydropyrazolo [1,5-a] pyrazin-5 ( 4H) -yl] -3-oxopropyl} dithio) -1 - [(4 ^/? S) -4- (cyclohexylmethyl) -2-phenyl; l-6,7-dihydropyrazolo [1, 5-a] pyrazin (4H) -yl] -1-oxopropan-2-amine hydrochloride;

- (2 fl) -3 - ({(2π) -2-amino-3-oxo-3 - [(4H) -2-phenyl-4- (2-phenylethyl) -6,7-dihydro pyrazolo [ 1,5-a] pyrazin-5 (4W) -yl] propyl) dithio) -1-oxo-1 - [(4H) -2-phenyl-4- (2-phenylethyl) -6,7-dihydropyrazolo [1] 5-a] pyrazin-5 (4H) -yl] propan-2-amine hydrochloride;

- (2 H) -3 - ({(2 fl) -2-amino-3-oxo-3 - [(4-yl) -4- (2-phenylethyl) -2-pyridin-4-yl) -6,7- dihydropyrazolo [1,5-a] pyrazin-5 (4H) -yl] propyl} dithio) -1-oxo-1 - [(4 H) -4- (2-phenylethyl) -2-pyridin-4-yl) 7-dihydropyrazolo [1,5-a] pyrazin-5 (4H) -yl] propan-2-amine hydrochloride; - (2 fl) -3 - ({(2 fl) -2-Amino-3-oxo-3 - [(4-yl) -4- (2-phenylethyl) -2-pyridin-3-yl) -7,7- dihydropyrazolo [1,5-a] pyrazin-5 (4W) -yl] propyl} dithio) -1-oxo-1 - [(4H) -4- (2-phenylethyl) -2-pyridin-3- N-6,7-dihydropyrazolo [1,5-a] pyrazin-5 (4 H) -yl) propan-2-amine hydrochloride;

- (2 fl) -3 - ({(2 fl) -2-amino-3 - [(4 H) -2- (1,3-benzodioxol-5-yl) -4- (2-phenylethyl) -6,7- dihydropyrazolo [1,5-a] pyrazin-5 (4H) -yl] -3-oxopropyl} dithio) -1 - [(4H) -2- (1,3-benzodioxol-5-yl) -4- phenylethyl) -6,7-dihydropyrazolo [1,5-a] pyrazin-5 (4H) -yl] -1-oxopropan-2-amine hydrochloride;

- (2 fl) -3 - ({(2 fl) -2-amino-3-oxo-3 - [(4 F) -4 - (2-phenylethyl) -2- (3,4,5-trimethoxyphenyl) -6, 7-Dihydropyrazolo [1,5-a] pyrazin-5 (4 H) -yl] propyl} dithio) -1-oxo-1 - [(4f-S) -4- (2-phenylethyl) -2- (3,4,5-trimethoxyphenyl) -6,7-dihydropyrazolo [1,5-a] pyrazin-5 (4H) -yl] propan-2-amine hydrochloride;

(2 fl) -3 - ({(2 R) -2-amino-3-oxo-3 - [(4 H) -4- (2-phenylethyl) -2- (2-thienyl) -6,7-dihydropyrazolo [ 1,5-a] pyrazin-5 (4H) -yl] propyl} dithio) -1-oxo-1 - [(4H) -4- (2-phenylethyl) -2- (2-thienyl) - 6,7-Dihydropyrazolo [1,5-a] pyrazin-5 (4H) -yl] propan-2-amine hydrochloride

- (2 fl) -3 - ({(2 H) -2-amino-3 - [(4 H) -2- (2-furyl) -4- (2-phenylethyl) -6,7-dihydropyrazolo [1,5-t]; a] pyrazin-5 (4H) -yl] -3-oxopropyl} dithio) -1 - [(4H) -2- (2-furyl) -4- (2-phenylethyl) -6,7-dihydropyrazolo [1, 5-a] pyrazin-5 (4H) -yl] -1-oxopropan-2-amine hydrochloride;

- (2 H) -3 - ({(2 R)) - 2-amino-3-oxo-3 - [(4 H) -4-pentyl-2-phenyl-6,7-dihydropyrazolo [1,5-a] pyrazine 5 (4A7) -yl] propyl) dithio) -1-oxo-1 - [(4 H) -4-pentyl-2-phenyl-6,7-dihydropyrazolo [1,5-a] pyrazin-5 (4W)) 2-amine hydrochloride;

- (2 fl) -3 - ({(2 fl) -2-amino-3 - [(4 S) -4-butyl-2-phenyl-6,7-dihydropyrazolo [1,5-a] pyrazin-4 (4H)) -yl] -3-oxopropyl} dithio) -1 - [(4f-S) -4-butyl-2-phenyl-6,7-dihydropyrazolo [1,5-a] pyrazin-5 (4H) -yl] - 1-oxopropan-2-amine hydrochloride;

- (2fl) -3 - ({(2fl) -2-amino-3 - [(4 ^/: S) -2- (2,4-dichlorophenyl) -4- (2-phenylethyl) _-6?) 7- dihydropyrazolo [1,5-a] pyrazin-5 (4A) -yl] -3-oxopropyl} dithio) -1 - [(4H) -2- (2,4-dichlorophenyl) -4- (2-phenylethyl) - 6,7-dihydropyrazolo [1,5-a] pyrazin-5 (4H) -yl] -1-oxopropan-2-amine hydrochloride;

tert-butyl {(1 R) -1 - [({(2 R)) - 2 - [(tert-butoxycarbonyl) amino] -3 - [(4S) -4- (cyclohexylmethyl) -2-phenyl-6, 7-Dihydropyrazolo [1,5-a] pyrazin-5 (4H) -yl] -3- oxopropyl (dithio) methyl] -2 - [(4S) -4- (cyclohexylmethyl) -2-phenyl-6,7-dihydropyrazolo [1,5-a] pyrazin-5 (4H) -yl] -2-oxoethyl} carbamate;

- (2 fl) -3 - ({(2 fl) -2-amino-3 - [(4S) -4- (cyclohexylmethyl) -2-phenyl-6,7-dihydropyrazolo [1,5-a] pyrazin-5 ( 4 - (-) - yl] -3-oxopropyl} dithio) -1 - [(4S) -4- (cyclohexylmethyl) -2-phenyl-6,7-dihydropyrazolo [1,5-a] pyrazin-5 (4H); ) -yl] -1-oxopropan-2-amine hydrochloride;

tert-butyl {(1 F9-1 - [({(2 F) -2 - [(tert-butoxycarbonyl) amino] -3 - [(4H) -4- (cyclohexylmethyl) -2-phenyl-6,7-dihydropyrazolo} [1,5-a] pyrazin-5 (4AY) -yl] -3-oxopropyl} dithio) methyl] -2 - [(4f) -4- (cyclohexylmethyl) -2-phenyl-6,7-dihydropyrazolo [1] , 5-a] pyrazin-5 (4H) -yl] -2-oxoethyl} carbamate

- (1 R) -3 - ({(2 F)) - 2-amino-3 - [(4 R) -4- (cyclohexyl-methyl) -2-phenyl-6,7-dihydropyrazolo [1,5-a] pyrazin 5 (4H) -yl] -3-oxopropyl} dithio) -1 - [(4 fl) -4- (cyclohexylmethyl) -2-phenyl-6,7-dihydropyrazolo [1,5-a] pyrazin-5 (4 (1H) -1-oxopropan-2-amine hydrochloride

tert-butyl {(1H) -1 - [({(2f) -2 - [(tert-butoxycarbonyl) amino] -3 - [(4fIS) -4-

(cyclohexylmethyl) -2-phenyl-7,8-dihydro-4H-pyrazolo [1,5-a] [1,4] diazepin-5 (6A) -yl] -3-oxopropyl} dithio) methyl] -2- [(4RS) -4- (cyclohexylmethyl) -2-phenyl-7,8-dihydro-4H-pyrazolo [1,5-a] [1,4] diazepin-5 (6H) -yl] -2-oxoethyl} carbamate

- {(1 R) - [({(2 R) -2-amino-3 - [(4 S) -4 - (cyclohexylmethyl) -2-phenyl-7,8-dihydro-4H-pyrazolo [1,5] a] [1, 4] diazepin-5 (6W) -yl] -3-oxopropyl} dithio) methyl] -2 - [(4f-S) -4-

(cyclohexylmethyl) -2-phenyl-7,8-dihydro-4H-pyrazolo [1,5-a] [1,4] diazepin-5 (6W) -yl] -2-oxoethyljamine hydrochloride

- (2 fl) -2-amino-3 - [(4f-S) -2- (2-furyl) -4- (2-phenylethyl) -6,7-dihydropyrazolo [1,5-a] pyrazin-5 ( 4H) -yl] -3-oxopropane-1-thiol hydrochloride

tert-butyl {(1 R) -1 - [({(2 R) -2 - [(tert-butoxycarbonyl) amino] -3 - [(4H, s) -4-

(cyclohexylmethyl) -2-phenyl-6,7-dihydropyrazolo [1, 5-a] pyrazin-5 (4H) -yl] -3-oxopropyl} diselanyl) methyl] -2 - [(4 ^/: fS) -4 - (cyclohexylmethyl) -2-phenyl-6,7-dihydropyrazolo [1,5-a] pyrazin-5 (4H) -yl] -2-oxoethyl} carbamate

- {(1 R) -1 - [({(2 R) -2-amino-3 - [(4 H) -4- (cyclohexylmethyl) -2-phenyl-6,7-dihydro-pyrazolo [1,5-a] pyrazin-5 (4H) -yl] -3-oxopropyl} diselanyl) methyl] -2 - [(4f S) -4?

(cyclohexylmethyl) -2-phenyl-6,7-dihydropyrazolo [1,5-a] pyrazin-5 (4H) -yl] -2-oxoethyl] amine hydrochloride; - (2H) -3 - ({(2 R) -2-amino-3-oxo-3 - [(4 H) -4- (2-phenylethyl) -2-pyridin-2-yl-6,7-dihydropyrazolo [ 1, 5-a] pyrazin-5 (4H) -yl] propyl} dithio) -1-oxo-1 - [(4HS) -4- (2-phenylethyl) -2-pyridin-2-yl) -6,7 dihydropyrazolo [1,5-a] pyrazin-5 (4H) -yl] propan-2-amine hydrochloride; or a pharmaceutically acceptable salt thereof.

17. Process for the preparation of a compound of formula (I) as defined in one of the preceding claims, characterized in that a compound of formula (VI) is reacted.

in which the radicals R ¹ , R ² and R ³ and n are as defined in claim 1, with a carboxylic acid of general formula (VII)

in which R ⁵ and X are as defined in claim 1, under so-called peptide coupling conditions, at a temperature of between 0 ^° C. and 30 ^° C., in an aprotic solvent, to obtain the compound of formula (I) in which Z is different from the hydrogen atom and R ⁴ represents the radical -CO-OR ⁵ ,

and finally the compound of formula (I) in which Z is different from the hydrogen atom which can be reduced to obtain the corresponding compound of formula

(I) wherein Z represents the hydrogen atom.

18. A pharmaceutical composition comprising, as active ingredient, a compound of formula (I) according to one of claims 1 to 16 or a pharmaceutically acceptable salt of such a compound, with at least one pharmaceutically acceptable excipient.

19. As a medicament, a compound of general formula (I) according to one of claims 1 to 16 or a pharmaceutically acceptable salt of such a compound.

20. Use of at least one compound of general formula (I) according to one of claims 1 to 16 or a pharmaceutically acceptable salt thereof, for preparing a medicament for treating or preventing a disease or a disorder. selected from the following diseases or disorders: cancers, non-tumorous proliferative diseases, neurodegenerative diseases, parasitic diseases, viral infections, spontaneous alopecia, alopecia induced by exogenous products, alopecia induced, autoimmune diseases, rejection of transplants, inflammatory diseases, allergies or pain.

21. Use according to claim 20, characterized in that the medicament is intended to treat or prevent cancers.

22. Use according to claim 21, characterized in that the cancers are chosen from cancers of the colon, rectum, stomach, lungs, pancreas, kidney, testes, breast, uterus, ovarian, prostate, skin, bones, spinal cord, neck, tongue, head as well as sarcomas, carcinomas, fibroadenomas, neuroblastomas, leukemias, melanomas .

23. Compound of general formula (VI)

in racemic, enantiomeric form or any combination thereof, wherein the radicals R ¹ , R ² and R ³ and n are as defined in claim 1.

24. Process for the preparation of a compound of formula (VI) as defined in claim 23, characterized in that the compound (IV) is subjected

in which the radicals R, R and R and n are as defined in claim 1,

in which the radicals R ¹ , R ² and R ³ and n are as defined in claim 1, then the imine function of the compound of general formula (V) thus formed is then subjected to reducing conditions to give the cyclic amine corresponding (Vl).