WO2009130232A1

WO2009130232A1 - Pyrazolo [1, 5 -a] pyrazine derivatives as antagonists of v1b receptors

Info

Publication number: WO2009130232A1
Application number: PCT/EP2009/054780
Authority: WO
Inventors: Romano Di Fabio; Gabriella Gentile; Alfonso Pozzan; Luca Tarsi; Silvia Terreni; Federica Tonelli
Original assignee: Glaxo Group Ltd
Current assignee: Glaxo Group Ltd
Priority date: 2008-04-24
Filing date: 2009-04-22
Publication date: 2009-10-29
Anticipated expiration: 2010-10-24

Abstract

The present invention relates to novel compounds of formula (I) or salts thereof: wherein R is -X-[CH₂]_nCR₄R₅-Y; or a group G; G is one of the groups selected form the list consisting of G1, G2, G3, G4, G5, G6, G7, G8, G9, G10, G11 and G12, and the rest of the variables are as specified in the claims, processes for their preparation, intermediates used in these processes, pharmaceutical compositions containing them and their use in therapy, as antagonists of V1b receptors, e.g. to treat depression and anxiety.

Description

PYRAZOLO [1 , 5 -A] PYRAZINE DERIVATIVES AS ANTAGONISTS OF VlB RECEPTORS

The present invention relates to novel compounds, processes for their preparation, intermediates used in these processes, pharmaceutical compositions containing them and their use in therapy, as V1 b receptor antagonists.

Evidence has accumulated during the last two decades indicating that Arginine Vasopressin (AVP) plays a major role in the regulation of the hypothalamic-pituitary- adrenal (HPA) axis. In particular, the release of the adrenocorticotropin hormone (ACTH) secretion from the pituitary gland is mediated by the V1 b receptor subtype (Antoni, 1993, Front Neuroendocrinol, 14:76-122). In rodents and in humans, AVP is a weak stimulus in physiological conditions but it participates in the adaptation of the hypothalamic-pituitary- adrenal (HPA) axis during stress through its ability to potentiate the stimulatory effect of corticotrophin releasing factor (CRF) (Rivier and Vale, Nature, 1983, 305, 325-327). An increased HPA axis activity is found in 40-70% of patients with major depression (Heuser et al., 1996, Am J Psychiatry, 153:93-99). AVP synergies with CRF in maintaining this overdrive and plays a major role in prolonged stressful states (Aguilera & Rabadan-Diehl, 2000, Regul Pept, 96, 23-29).

An emerging body of preclinical and clinical evidence demonstrates that CRF is the physiological mediator of ACTH release under acute stressful conditions whereas AVP represents the dynamic mediator of ACTH release and strongly potentiates CRH-induced ACTH release. This situation may be altered in disease states where a dysregulation or hyperactivation of the hypothalamic-pituitary-adrenal (HPA) axis is observed. In these cases, the primary control of ACTH release may be shifted from CRH to AVP (Volpi et al., 2004, Ann N Y Acad Sci, 1018:293-3014).

This suggests that the blockade of V1 b receptors could be exploited as a possible therapeutic strategy for the treatment of diseases that are characterized by an excessive Cortisol secretion, such as major depression (Scott & Dinan, 1998, Life Sci, 62:1985-1998) and stress-related disorders (Griebel et al. 2003, Curr Drug Targets CNS Neurol Disord, 2:191-200). Furthermore, abnormally elevated HPA activity may results in an over secretion of ACTH causing hypercortislaemia which predisposes to a metabolic syndrome characterised by insulin resistance, hyperinsulinemia, impaired glucose tolerance, dyslipideamia, obesity (in particular abdominal obesity) and non-insulin-dependent diabetes mellitus (NIDDM).

AVP effects are mediated via 7-transmembrane G-protein coupled receptor subtypes: Vi a (mainly distributed in vascular wall, liver, kidney, platelet), V1 b or V3 (mainly distributed in anterior pituitary) and V2 (almost exclusively found in the kidney). Activation of Via and V1 b receptors stimulates phosphatidylinositol (IP) hydrolysis and mobilises calcium; V2 receptors are positively coupled to adenylyl cyclase. The human V1 b receptor has a pharmacological profile clearly distinct from that of the human Vi a and V2 receptors and activates several signalling pathways via different G proteins of the Gq, Gi and Gs families (Thibonnier et al., 1998, Adv Exp Med Biol, 449:251-276).

V1 b mRNA is expressed in 90% of corticotrope cells and immunohistochemical localisation reveals significant expression of V1 b receptors in other brain area such as hippocampus, frontal, piriform and cingulate cortex, caudate putamen, medial habenula, central amygdala, hypothalamus and cerebellum in rats (Hernando et al., 2001 , Endocrinology, 142:1659-1668). Recent tissue localisation studies indicate that the V1 b receptor mRNA is not only present in anterior pituitary gland in human and rat, but also in other tissues, such as the adrenal medulla, pancreas, kidney, thymus, heart, lung and uterus (Lolait et al., 1995, Proc Natl Acad Sci U S A, 92:6783-6787).

Studies with V1 b receptor knock out mice revealed not only changes in HPA axis regulation (Lolait et al., 2007, Endocrinology 148:849-856) as expected, but also profound modification of social behavior (Wersinger et al., 2002, MoI Psychiatry 7:975-984) and insulin release from the pancreas (Oshikawa et al., 2004, MoI Pharmacol 65:623-629).

Taken together, these data strongly suggest that selective V1 b receptor ligands could bring beneficial effects to different patient populations. The synthetic V1 b receptor antagonist SSR149415 (Serradeil Le-GaI et al., 2002, J Pharmacol Exp Ther, 300:1 122-

1130) has been widely utilised in preclinical models and data obtained to date consistently support the potential therapeutic benefits that may derive from the blockade of V1 b receptors in stress-related disorders (Griebel et al, 2002, Proc Natl Acad Sci U S A, 99:

6370-6375).

Thus, the object of the present invention is to provide novel compounds which are V1 b antagonists.

The present invention provides compounds of formula (I) or pharmaceutically acceptable salt or solvate thereof:

wherein

R is -X-[CH₂]nCR₄R5-Y; or a group G;

R₁ is H or C1-C4 alkyl; R₂ is aryl, heteroaryl or C3-C7 cycloalkyl, which may be substituted with one or more: halogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, CN;

R₃ is -CH₂-C(=O)-NH-R₆; X is -CR₇R₈-, -0-,-NR₉-, -S-;

Y is-NRioRn

R₄ is H orC1-C4 alkyl;

R₅ is H orC1-C4alkyl;

R₆ is C1-C6 alkyl, C3-C6 cycloalkyl; C3-C6 cycloalkyl-(C1-C2 alkyl); which may be substituted by one or more halogen,

C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy;

R₇ is H orC1-C4alkyl;

R₈ is H orC1-C4 alkyl; R₉ is H orC1-C4alkyl;

R₁₀ is H or C1-C4 alkyl, or together with R₁₁ forms a 4-8 saturated or unsaturated heterocycle ring which may comprise a further heteroatom selected from O, S and - NR₁₂; such heterocycle may be substituted by one or more halogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-

C4 haloalkoxy;

R₁₁ is H orC1-C4 alkyl;

R₁₂ is H, C1-C6 alkyl, C3-C7 cycloalkyl; C3-C6 cycloalkyl-(C1-

C2 alkyl); which may be substituted by one or more halogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy;

G is one of the groups selected from the list consisting of G1,

G2, G3, G4, G5, G6, G7,G8, G9, G10, G11 and G12:

*—

G1 G2 G3

G4 G5

G6 G7 G8

G9 G10 G11 G12

R 13 is H or C1-C4 alkyl, or together with R₁₄ forms a 4-8 saturated or unsaturated heterocycle ring which may comprise a further heteroatom selected from O, S and - NR₂₄; such heterocycle may be substituted by one or more halogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1- C4 haloalkoxy; and may assume different meanings; R₁₄, R 16 is H, C1-C6 alkyl, C3-C7 cycloalkyl; C3-C6 cycloalkyl-(C1- C2 alkyl); which may be substituted by one or more halogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy; and may assume different meanings;

R- 1IS5,> R ^f^17 correspond to H or C1-C4 alkyl and may assume different meanings;

R 18 is H or C1-C4 alkyl, or together with R₁₇ forms a 4-8 saturated or unsaturated heterocycle ring which may comprise a further heteroatom selected from O, S and - NR₂₅; such heterocycle may be substituted by one or more halogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1- C4 haloalkoxy;

RiQ, R?n, R?i , R??, R?3, R ^:24: R₂₅ is H, C1-C6 alkyl, C3-C7 cycloalkyl; C3-C6 cycloalkyl-

(C1-C2 alkyl); which may be substituted by one or more halogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1- C4 haloalkoxy; and may assume different meanings;

R26> R27> R28> R29 is H, C1-C6 alkyl, C3-C7 cycloalkyl; C3-C6 cycloalkyl-(C1- C2 alkyl); which may be substituted by one or more halogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy; correspond to 1 or 2 and may assume different meanings; m, m m , m , m^lv, rrf correspond to 0, 1 or 2 and may assume different meanings; n is 1 , 2 or 3; q is 1 , 2 or 3; p, p', p", p'" correspond to 0, 1 , 2 or 3 and may assume different meanings.

The person skilled in the art would understand that for compounds of formula (I) the asterisk sign ^* is used in G groups to indicate the point of attachment of the group itself to the rest of the molecule.

The compounds of the present invention may be in the form of and/or may be administered as a pharmaceutically acceptable salt. For a review on suitable salts see Berge et al, J. Pharm. ScL, 1977, 66, 1-19.

Typically, a pharmaceutically acceptable salt may be readily prepared by using a desired acid or base as appropriate. The salt may precipitate from solution and be collected by filtration or may be recovered by evaporation of the solvent.

Suitable pharmaceutically acceptable addition salts are formed from acids which form non-toxic salts and examples are hydrochloride, hydrobromide, hydroiodide, sulphate, bisulphate, nitrate, phosphate, hydrogen phosphate, acetate, maleate, malate, fumarate, lactate, tartrate, citrate, formate, gluconate, succinate, pyruvate, oxalate, oxaloacetate, trifluoroacetate, saccharate, benzoate, methanesulphonate, ethanesulphonate, benzenesulphonate, p-toluenesulphonate and isethionate.

Pharmaceutically acceptable base salts include ammonium salts, alkali metal salts such as those of sodium and potassium, alkaline earth metal salts such as those of calcium and magnesium and salts with organic bases, including salts of primary, secondary and tertiary amines, such as isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexyl amine and N-methyl-D-glucamine.

Pharmaceutically acceptable salts may also be prepared from other salts, including other pharmaceutically acceptable salts, of the compound of formula (I) using conventional methods.

Those skilled in the art of organic chemistry will appreciate that many organic compounds can form complexes with solvents in which they are reacted or from which they are precipitated or crystallized. These complexes are known as "solvates". For example, a complex with water is known as a "hydrate". Solvates of the compound of the invention are within the scope of the invention.

In addition, prodrugs are also included within the context of this invention. As used herein, the term "prodrug" means a compound which is converted within the body, e.g. by hydrolysis in the blood, into its active form that has medical effects. Pharmaceutically acceptable prodrugs are described in T. Higuchi and V. Stella, Prodrugs as Novel Delivery Systems, Vol. 14 of the A.C.S. Symposium Series, Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, and in D. Fleisher, S. Ramon and H. Barbra "Improved oral drug delivery: solubility limitations overcome by the use of prodrugs", Advanced Drug Delivery Reviews (1996) 19(2) 115-130, each of which are incorporated herein by reference.

The term prodrug also encompasses any covalently bonded carriers that release a compound of structure (I) in vivo when such a prodrug is administered to a patient. Prodrugs are generally prepared by modifying functional groups in a way such that the modification is cleaved, either by routine manipulation or in vivo, yielding the parent compound. Prodrugs include, for example, compounds of this invention wherein amine groups are bonded to any group that, when administered to a patient, cleaves to form the amine groups. Thus, representative examples of prodrugs include (but are not limited to) acetate, formate and benzoate derivatives of amine functional groups of the compounds of structure (I).

With regard to stereoisomers, the compounds of formula (I) may have one or more asymmetric carbon atoms and may occur as racemates, racemic mixtures or diastereoisomeric mixtures and as individual enantiomers or diastereomers. All such isomeric forms are included within the present invention, including mixtures thereof.

When a specific enantiomer of a compound of formula (I) is required, this may be obtained for example by resolution of a corresponding enantiomeric mixture of a compound of formula (I) using conventional methods, such as H. P. L. C. of the corresponding racemate using a suitable chiral support or by fractional crystallisation of the diastereoisomeric salts formed by reaction of the corresponding racemate with a suitable optically active acid or base, as appropriate.

Or a specific enantiomer may also be prepared from a corresponding optically pure intermediate. Separation of diastereoisomers or cis and trans isomers or syn and anti isomers may be achieved by conventional techniques, e.g. by fractional crystallisation, chromatography or

H. P. L. C. of a stereoisomeric mixture.

Furthermore, some of the crystalline forms of the compounds of structure (I) may exist as polymorphs, which are included in the scope of the present invention.

The term C1-C6 alkyl as used herein as a group or a part of the group refers to a linear or branched alkyl group containing from 1 to 6 carbon atoms; examples of such groups include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert butyl, pentyl or hexyl. The term C1-C4 alkyl as used herein as a group or a part of the group refers to a linear or branched alkyl group containing from 1 to 4 carbon atoms; examples of such groups include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert butyl.

The term C3-C7 cycloalkyl group means a saturated monocyclic hydrocarbon ring of 3 to 7 carbon atom such as, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl.

The term C3-C6 cycloalkyl group means a saturated monocyclic hydrocarbon ring of 3 to 6 carbon atom such as, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.

The term C4-C7 cycloalkyl group means a saturated monocyclic hydrocarbon ring of 4 to 7 carbon atom such as, for example, cyclobutyl, cyclopentyl, cyclohexyl; cycloheptyl.

The term 'C3-6cycloalkylC1-2alkyr as used herein means an alkyl having one or two carbon atoms wherein one hydrogen atom is replaced with a C3-C6 cycloalkyl group as above defined, for example methylcyclopropane.

The term halogen refers to a fluorine, chlorine, bromine or iodine atom.

The term halo C1-C4 alkyl means an alkyl group having one to 4 carbon atoms and wherein at least one hydrogen atom is replaced with halogen such as for example a trifluoromethyl group and the like.

The term C1-C4 alkoxy group may be a linear or a branched chain alkoxy group, for example methoxy, ethoxy, propoxy, prop-2-oxy, butoxy, but-2-oxy or methylprop-2-oxy and the like.

The term halo C1-C4 alkoxy group may be a C1-C4 alkoxy group as defined before substituted with at least one halogen, preferably fluorine, such as OCHF₂, or OCF₃.

The term aryl means an aromatic carbocyclic moiety of 6 to 12 members. Representative aryl include (but are not limited to): phenyl, biphenyl or naphthyl.

The term heteroaryl means an aromatic heterocycle ring of 5 to 10 members and having at least one heteroatom selected from nitrogen, oxygen and sulfur, and containing at least 1 carbon atom, including both mono-and bicyclic ring systems.

Representative heteroaryls include (but are not limited to): furyl, benzofuranyl, thiophenyl, benzothiophenyl, pyrrolyl, indolyl, isoindolyl, azaindolyl, pyridyl, quinolinyl, isoquinolinyl, oxazolyl, isooxazolyl, benzoxazolyl, pyrazolyl, imidazolyl, benzimidazolyl, thiazolyl, benzothiazolyl, isothiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, cinnolinyl, phthalazinyl, triazolyl, tetrazolyl, quinazolinyl, benzodioxolyl, benzothiadiazolyl, benzooxadiazolyl, imidazo[1 ,2-a]pyrazinyl, isothiazolyl, thiadiazolyl, [1 ,2,4]thiazol[1 ,5- 9]pyridinyl.

Representative 5-6 membered heteroaryls include (but are not limited to): furyl, thiophenyl, pyrrolyl, indolyl, pyridyl, oxazolyl, isooxazolyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, triazolyl, tetrazolyl, isothiazolyl, thiadiazolyl.

The 4-8 saturated or unsaturated heterocycle ring means a 4-8 mono-, bicyclic heterocycle ring which is either saturated, or unsaturated and one to four carbon atoms may be replaced by an heteroatom as defined above. Thus, the term include (but are not limited to): azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, hydantoinyl, hexahydro-1 H-azepinyl and octahydroazocinyl.

In one embodiment, R is -X-[CH₂]_nCR₄R₅-Y or a group G. In another embodiment, R is -X- [CH₂]_HCR₄R₅-Y. In a further embodiment, R is a group G.

In one embodiment, R₁ ,_s H or C1-C4 alkyl (for example methyl). In another embodiment, R₁ is H. In a further embodiment, R_{1 ιs} C1-C4 alkyl (for example methyl).

In one embodiment, R₂ is aryl, heteroaryl or C3-C7 cycloalkyl, which may be substituted with one or more: halogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, -CN. In another embodiment, R₂ is aryl which may be substituted with one or more: halogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, -CN. In a further embodiment, R₂ is a phenyl ring which may be substituted with one or more: halogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy. In a still further embodiment, R₂ is a phenyl ring which m- or m, p- substituted with one or two: halogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy

In one embodiment, R₃ is -CH₂-C(=O)-NH-R₆

In one embodiment, X is -CR₇R₈-, -O-, -NR₉- or -S-. In another embodiment, X is -CR₇R₈- , -O- or -NR₉-. In a further embodiment, X is -CR₇R₈- or -O-. In a still further embodiment, X is -CR₇R₈-. In another embodiment, X is -O-.

In one embodiment, Y 1S-NR₁₀R₁₁

In one embodiment, R₄ is H or C1-C4 alkyl. In another embodiment, R₄ is H.

In one embodiment, R₅ is H or C1-C4 alkyl. In another embodiment, R₅ is H. In one embodiment, R₆ is C1-C6 alkyl, C3-C6 cycloalkyl; C3-C6 cycloalkyl-(C1-C2 alkyl); which may be substituted by one or more halogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy. In another embodiment, R₆ is C1-C6 alkyl, C3-C6 cycloalkyl or C3-C6 cycloalkyl-(C1-C2 alkyl). In a further embodiment, R₆ is C1-C6 alkyl. In a still further embodiment, R₆ is /-propyl or f-butyl.

In one embodiment, R₇ is H or C1-C4 alkyl. In another embodiment, R₇ is H.

In one embodiment, R₈ is H or C1-C4 alkyl. In another embodiment, R₈ is H.

In one embodiment, Rg is H or C1-C4 alkyl.

In one embodiment, R₁₀ is H or C1-C4 alkyl or together with R₁₁ forms a 4-8 saturated or unsaturated heterocycle ring which may comprise a further heteroatom selected from O, S and -NR₁₂; such heterocycle may be substituted by one or more halogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy. In another embodiment, R_1O iS C1-C4 alkyl or together with R₁₁ forms a 4-8 saturated or unsaturated heterocycle ring which may comprise a further heteroatom selected from O, S and -NR₁₂; such heterocycle may be substituted by one or more halogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy. In a still further embodiment, R₁₀ together with R₁₁ forms a 5-7 saturated heterocycle ring which may comprise a further heteroatom selected from O, S and -NR₁₂; such heterocycle may be substituted by one or more halogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy.

In one embodiment, R₁₁ is H or C1-C4 alkyl.

In one embodiment, R₁₂ is H or C1-C6 alkyl ( for example methyl).

In one embodiment, G is a group G1 , G2, G3, G4, G5, G6, G7 or G8. In another embodiment, G is a group G1 , G2, G3, G4, G6, G7 or G8. In a further embodiment, G is a group G1 ,G3, G4 or G6. In a still further embodiment, G is a group G4 or G6. In another embodiment, G is a group G3.

In one embodiment, n is 1 , 2 or 3. In another embodiment, n is 2.

In one embodiment, R is -X-[CH₂]_nCR₄R₅-Y or a group G; R₁ is H or C1-C4 alkyl (for example methyl); R₂ is a phenyl ring which may be substituted with one or more: halogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy; X is -CR₇R₈- or -O-; R₆ is C1-C6 alkyl, C3-C6 cycloalkyl; C3-C6 cycloalkyl-(C1-C2 alkyl); which may be substituted by one or more halogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy; Rg is H or C1-C4 alkyl; R₁₀ is C1-C4 alkyl or together with R₁₁ forms a 4-8 saturated or unsaturated heterocycle ring which may comprise a further heteroatom selected from O, S and -NR₁₂; such heterocycle may be substituted by one or more halogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy; R₁₁ is H or C1-C4 alkyl; R₁₂ is H or C1- C6 alkyl ( for example methyl); n is 1 , 2 or 3.

In one embodiment, example compounds of the invention include:

2-[6-(3-chlorophenyl)-4-oxo-2-{[3-(1-piperidinyl)propyl]oxy}pyrazolo[1 ,5-a]pyrazin-5(4H)- yl]-N-(1 -methylethyl)acetamide;

N-(1-methylethyl)-2-[4-oxo-2-{[3-(1-piperidinyl)propyl]oxy}-6-[3-

(trifluoromethyl)phenyl]pyrazolo[1 ,5-a]pyrazin-5(4H)-yl]acetamide; 2-[6-(3-chlorophenyl)-4-oxo-2-{[2-(1-piperidinyl)ethyl]oxy}pyrazolo[1 ,5-a]pyrazin-5(4H)-yl]-

N-(1 -methylethyl)acetamide;

2-[6-(3-chlorophenyl)-2-{[3-(4-morpholinyl)propyl]oxy}-4-oxopyrazolo[1 ,5-a]pyrazin-5(4H)- yl]-N-(1 ,1-dimethylethyl)acetamide;

2-[6-(3-chlorophenyl)-2-{[3-(4-morpholinyl)propyl]oxy}-4-oxopyrazolo[1 ,5-a]pyrazin-5(4H)- yl]-N-(1-methylethyl)acetamide;

2-[6-(3-chlorophenyl)-4-oxo-2-{[4-(1-piperidinyl)butyl]oxy}pyrazolo[1 ,5-a]pyrazin-5(4H)-yl]-

N-(1 -methylethyl)acetamide;

2-[6-(3-chloro-4-fluorophenyl)-4-oxo-2-{[3-(1-piperidinyl)propyl]oxy}pyrazolo[1 ,5-a]pyrazin-

5(4H)-yl]-N-(1-methylethyl)acetamide; 2-[6-[2-fluoro-5-(trifluoromethyl)phenyl]-4-oxo-2-{[3-(1-piperidinyl)propyl]oxy}pyrazolo[1 ,5- a]pyrazin-5(4H)-yl]-N-(1-methylethyl)acetamide;

N-(1 ,1-dimethylethyl)-2-[4-oxo-2-{[3-(1-piperidinyl)propyl]oxy}-6-[3-

(trifluoromethyl)phenyl]pyrazolo[1 ,5-a]pyrazin-5(4H)-yl]acetamide;

2-[6-[4-fluoro-3-(trifluoromethyl)phenyl]-4-oxo-2-{[3-(1-piperidinyl)propyl]oxy}pyrazolo[1 ,5- a]pyrazin-5(4H)-yl]-N-(1-methylethyl)acetamide;

N-(1 ,1-dimethylethyl)-2-[6-[4-fluoro-3-(trifluoromethyl)phenyl]-4-oxo-2-{[3-(1- piperidinyl)propyl]oxy}pyrazolo[1 ,5-a]pyrazin-5(4H)-yl]acetamide;

2-[6-(3-chloro-2-fluorophenyl)-4-oxo-2-{[3-(1-piperidinyl)propyl]oxy}pyrazolo[1 ,5-a]pyrazin-

5(4H)-yl]-N-(1-methylethyl)acetamide; 2-[6-[3,5-bis(trif luoromethyl)phenyl]-4-oxo-2-{[3-(1 -piperidinyl)propyl]oxy}pyrazolo[1 ,5- a]pyrazin-5(4H)-yl]-N-(1-methylethyl)acetamide;

2-[6-[4-fluoro-3-(trifluoromethyl)phenyl]-4-oxo-2-[4-(1-pyrrolidinyl)-1- piperidinyl]pyrazolo[1 ,5-a]pyrazin-5(4H)-yl]-N-(1-methylethyl)acetamide;

Λ/-(1-methylethyl)-2-[6-(6-methyl-2-pyridinyl)-4-oxo-2-{[3-(1- piperidinyl)propyl]oxy}pyrazolo[1 ,5-a]pyrazin-5(4H)-yl]acetamide;

2-[2-[(1-cyclopentyl-4-piperidinyl)oxy]-6-[4-fluoro-3-(trifluoromethyl)phenyl]-4- oxopyrazolo[1 ,5-a]pyrazin-5(4H)-yl]-N-(1-methylethyl)acetamide; or a pharmaceutically acceptable salt or solvate thereof.

In another embodiment, example compounds of the present invention include:

2-[6-(3-chlorophenyl)-4-oxo-2-{[3-(1-piperidinyl)propyl]oxy}pyrazolo[1 ,5-a]pyrazin-5(4H)- yl]-N-(1 -methylethyl)acetamide; N-(1 ,1-dimethylethyl)-2-[6-(3-methylphenyl)-4-oxo-2-{[3-(1- piperidinyl)propyl]oxy}pyrazolo[1 ,5-a]pyrazin-5(4H)-yl]acetamide;

2-[6-(3-chlorophenyl)-4-oxo-2-{[3-(1-piperidinyl)propyl]oxy}pyrazolo[1 ,5-a]pyrazin-5(4H)- yl]-N-(1 ,1-dimethylethyl)acetamide; N-(1-methylethyl)-2-[4-oxo-2-{[3-(1-piperidinyl)propyl]oxy}-6-[3-

(trifluoromethyl)phenyl]pyrazolo[1 ,5-a]pyrazin-5(4H)-yl]acetamide;

N-(1-methylethyl)-2-[4-oxo-2-{[3-(1-piperidinyl)propyl]oxy}-6-{3-

[(trifluoromethyl)oxy]phenyl}pyrazolo[1 ,5-a]pyrazin-5(4H)-yl]acetamide;

N-(1-methylethyl)-2-[6-[3-(methyloxy)phenyl]-4-oxo-2-{[3-(1- piperidinyl)propyl]oxy}pyrazolo[1 ,5-a]pyrazin-5(4H)-yl]acetamide;

2-[6-(3-chlorophenyl)-4-oxo-2-{[2-(1-piperidinyl)ethyl]oxy}pyrazolo[1 ,5-a]pyrazin-5(4H)-yl]-

N-(1 -methylethyl)acetamide;

2-[6-(3-chlorophenyl)-2-{[3-(4-morpholinyl)propyl]oxy}-4-oxopyrazolo[1 ,5-a]pyrazin-5(4H)- yl]-N-(1 ,1-dimethylethyl)acetamide; 2-[6-(3-chlorophenyl)-2-{[3-(4-morpholinyl)propyl]oxy}-4-oxopyrazolo[1 ,5-a]pyrazin-5(4H)- yl]-N-(1 -methylethyl)acetamide;

N-(1 -methylethyl)acetamide;

2-[6-(3-chloro-4-fluorophenyl)-4-oxo-2-{[3-(1-piperidinyl)propyl]oxy}pyrazolo[1 ,5-a]pyrazin- 5(4H)-yl]-N-(1 -methylethyl)acetamide; or a pharmaceutically acceptable salt or solvate thereof.

In a further embodiment, example compounds of the present invention include:

2-[6-(3-chlorophenyl)-2-{[3-(4-morpholinyl)propyl]oxy}-4-oxopyrazolo[1 ,5-a]pyrazin-5(4H)- yl]-Λ/-(1-methylethyl)acetamide;

5(4H)-yl]-Λ/-(1-methylethyl)acetamide;

N-(1 ,1-dimethylethyl)-2-[4-oxo-2-{[3-(1-piperidinyl)propyl]oxy}-6-[3-

(trifluoromethyl)phenyl]pyrazolo[1 ,5-a]pyrazin-5(4H)-yl]acetamide; 2-[6-[4-fluoro-3-(trifluoromethyl)phenyl]-4-oxo-2-{[3-(1-piperidinyl)propyl]oxy}pyrazolo[1 ,5- a]pyrazin-5(4H)-yl]-N-(1-methylethyl)acetamide; or a pharmaceutically acceptable salt or solvate thereof.

In general, the compounds of formula (I) may be made according to the organic synthesis techniques known to those skilled in this field, as well as by the representative methods set forth in the Examples.

Compounds of formula (I), and salts or solvates thereof, may be prepared by the general methods outlined hereinafter. In the following description, the groups R, Ri, R₂, R3, R₄, R5, Re, R7, Rβ, Rθ, R-IO, R-11 , R-I2, Ri3, Ri4, Ri5, Ri6, Ri7, R-I8, R-I9, R20, R21 , R22, R23, R24, R25,

R₂₆, R₂₇, R₂₈, R₂₉, X, Y, G, G1 , G2, G3, G4, G5, G6, G7, G8, G9, G10, G1 1 , G12, I, I', m, m', m", m'", m^ιv, m^v, n, q, p, p', p", p'" have the meanings as previously defined for compounds of formula (I) unless otherwise stated.

Compounds of formula (Ia), which correspond to compounds of formula (I) as defined above wherein

may be obtained from compounds of formula (II), wherein n' = n-1 , according to Scheme 1, by hydrogenation procedure well described in the art, for example using Pd on charcoal as a catalyst and carrying out the reaction in protic solvents, such as ethanol, at atmospheric pressure and at RT.

Scheme 1

Compounds of formula (II) may be obtained, according to Scheme 2, from compounds of formula (III), wherein n' = n-1 and Lg is a suitable leaving group such as mesylate (OMs) or halogen (Cl, Br, I), by methods well known in the art, such as alkylation reactions of secondary amines, e.g. piperidine, using an inorganic base, e.g. K₂CO₃, and carrying out the reaction in aprotic solvents, such as MeCN, at temperature comprised between RT and 8O ⁰C.

Scheme 2

Compounds of formula (III), according to Scheme 3, may be obtained from the corresponding alcohol intermediates (IV), wherein n' = n-1 , by a variety of methods familiar to one skilled in the art. For example, wherein Lg = mesylate, mesyl chloride and

TEA in aprotic solvents, e.g. DCM, at temperature comprised between 0 ⁰C and RT can be used. Wherein Lg = halides, e.g. Br, compounds of formula (IV) may be reacted with carbon tetrabromide in the presence of triphenylphosphine and carrying out the reaction in aprotic solvents, such as DCM, at temperature comprised between 0 ⁰C and RT.

Scheme 3

Compounds of formula (IV) may be obtained starting from compounds of formula (V), according to Scheme 4, wherein Lg₁ is a group suitable for cross coupling reaction, such as an halogen (e.g. I, Br) or a triflate (OTf), by a cross-coupling procedure, such as Sonogashira reaction as reported in Journal of Organic Chemistry 2000, 65, 3274-83, using a suitable alkynyl alcohol of formula HCC[CH₂]_n CH₂OH (XXXIII) wherein n' = n-1.

Compounds of formula (Va), i.e. compounds of formula (V) wherein Lg₁ is an halogen (e.g. I), may be obtained, according to Scheme 5, from compounds of formula (Vl), wherein Lg₁ is an halogen (e.g. I), through alkylation procedures with suitable 2-halo-/V- (alkylacetamides) of formula (XXXIV), wherein Hal represents halogen. For example, suitable reaction conditions comprise using 2-chloro-Λ/-(1-methylethyl) acetamide and sodium hydride as a strong base and carrying out the reaction in aprotic solvents, e.g. DMF, at temperature comprised between RT and 80 ⁰C.

Scheme 5

Compounds of formula (Vl) may be obtained from compounds of formula (VII), wherein Lg₁ is an halogen (e.g. I), according to Scheme 6, by reaction with NH₄OAc in acetic acid at temperature between 80 and 110 ⁰C for several hours (24-48 h).

Scheme 6

Compounds of formula (Vila), i.e. compounds of formula (VII) wherein R₁ is hydrogen, may be obtained from compounds of formula (VIII), wherein Lg₁ is an halogen (e.g. I), according to Scheme 7, by alkylation reaction with a suitable 2-halo-1-arylketone (IX) using an inorganic base, e.g. Na₂CO₃, and carrying out the reaction in aprotic solvents, e.g. DMF, at temperature comprises between RT and 8O ⁰C.

Compounds of formula (VIII) may be obtained, according to Scheme 8, from the commercially available compound of formula (X) following procedures well reported in the art, for example using isoamyl nitrite in an aprotic solvent, e.g. diiodomethane, at a temperature between -10 and 9O ⁰C for some hours.

Compounds of formula (VIIb), i.e. compounds of formula (VII) wherein R₁ is not hydrogen, may be obtained, according to Scheme 9, from compounds of formula (Vila), as define above, by reaction with an alkylant agent, such as methyl iodide, in presence of an inorganic base, e.g. Cs₂CO₃, in aprotic solvents, such as DMF, at RT.

Scheme 9

Compounds of formula (Vb), i.e. compounds of formula (V) wherein Lg₁ is a triflate, may be obtained, according to Scheme 10, from compound of formula (XXXI) following procedures well reported in the art, for example using a triflic agent, e.g. 1 ,1 ,1 -trif luoro-N- phenyl-N-[(trifluoromethyl)sulfonyl]methanesulfonamide, a base, e.g. diisopropyl ethyl amine, in a aprotic solvent, e.g. DCM, at a temperarute comprises between RT and 40 ⁰C.

Scheme 10

Alternatively, compounds of formula (Ia), as defined above, and compounds of formula (Ib), which correspond to compounds of formula (I) as defined above wherein R is -CH(CH₃)-[CH₂]_nCH₂-Y, may be obtained from compounds of formula (Xl) and from compounds of formula (XII) respectively, wherein n' = n-1 , according to Scheme 11 , by standard hydrogenation procedure, for example using Pd on charcoal as a catalyst and carrying out the reaction in protic solvents, such as ethanol, at atmospheric pressure and at RT.

Scheme 11

Compounds of formula (Xl) and (XII) may be obtained respectively from compounds of formula (XIII) and from compounds of formula (XIV), wherein n' = n-1 and Lg is a suitable leaving group such as mesilate (OMs) or halogen (Cl, Br, I), according to Scheme 12, through standard alkylation reactions of secondary amines, such as piperidine, in the presence of an inorganic base, such as K₂CO₃, and carrying out the reaction in aprotic solvents, e.g. MeCN, at temperature comprised between RT and 8O ⁰C.

Scheme 12

Compounds of formula (XIII) and (XIV) may be obtained, according to Scheme 13, respectively from the corresponding alcohol intermediates (XV) and (XVI), wherein n' = n- 1 and Lg is a suitable leaving group, by a variety of methods familiar to one skilled in the art. For example, wherein Lg = -OMs, mesyl chloride and TEA in aprotic solvents, e.g. DCM, at temperature comprises between 0 ⁰C and RT can be used. Wherein Lg = halides, e.g. Br, compounds of formula (XV) and (XVI) may be reacted with carbon tetrabromide in presence of triphenylphosphine and carrying out the reaction in aprotic solvents, such as DCM, at temperature comprised between 0 ⁰C and RT.

Scheme 13

Compounds of formula (XV) and (XVI) may be obtained, according to Scheme 14, starting from compounds of formula (V), above define, through a Pd-catalyzed cross coupling methodology well known in the art, for example the Heck reaction, using the opportune alkenyl alcohols of formula (XXXV) wherein n'=n-1 , a catalyst, e.g. palladium (II) acetate, a phosphin, e.g. tris(2-methylphenyl)phosphane, a base, e.g. TEA, in an aprotic solvent, e.g. DMF, at a temperature between 50 and 100 ⁰C, for several hours.

(XVl)

Compounds of formula (Ic), which correspond to compounds of formula (I) as defined above wherein

R is -CH₂-[CH₂]_nCH(CH₃)-Y, may be obtained from compounds of formula (XVII), wherein n' = n-1 , according to Scheme 15, by hydrogenation procedure well described in the art, for example using Pd on charcoal as a catalyst and carrying out the reaction in protic solvents, such as ethanol at atmospheric pressure and at RT.

Scheme 15

(XVII) _(|c)

Compounds of formula (XVII) may be obtained, according to Scheme 16, from the corresponding aldehyde derivatives (XVIII), wherein n' = n-1 , by reductive amination procedure well described in the art, for example using a secondary amine, e.g. piperidine, using a reductive agent, e.g. NaBH₃CN, and carrying out the reaction in aprotic solvents, e.g. acetonitrile, at atmospheric pressure and at RT.

Scheme 16

Compounds of formula (XVIII) may be obtained from compounds of formula (V), as above define, according to Scheme 17, through a cross-coupling procedure, such as the Sonogashira reaction as reported in Jornal of Organic Chemistry 2000, 65, 3274-83, using a suitable alkynyl ketone of formula (XXXVI).

Scheme 17

Compounds of formula (Id), which correspond to compounds of formula (I) as defined above wherein

R is -O-[CH₂]_nCH₂-Y,

may be obtained, according to Scheme 18, starting from compounds of formula (XIX), wherein Lg is a suitable leaving group such as mesylate or halogen (e.g. Cl), by alkylation reaction of a secondary alkylamines, such as piperidine, in the presence of an inorganic base, e.g. K₂CO₃, and carrying out the reaction in aprotic solvents, e.g. MeCN, at temperature comprised between RT and 80⁰C.

(XIX)

( Id )

Compounds of formula (XIX) may be prepared, according to Scheme 19, from the corresponding alcohol intermediates (XX) by a variety of methods familiar to one skilled in the art. For example, wherein Lg = OMs, mesyl chloride and TEA, in aprotic solvents, e.g. DCM, at temperature comprises between 0 ⁰C and RT can be used. Wherein Lg = halides, e.g. Br, compounds of formula (XX) may be reacted with carbon tetrabromide in presence of triphenylphosphine and carrying out the reaction in aprotic solvents, such as DCM, at temperature comprised between 0 ⁰C and RT.

(XX) (XIX)

Compounds of formula (XX) may be prepared, according to Scheme 20, by hydrolysis reaction of compounds of formula (XXI). For example, suitable reaction conditions comprise using an inorganic base, such as LiOH, and carrying out the reaction in a mixture of aprotic and protic solvent, e.g. THF and water, at temperature comprises between RT and 60 ⁰C.

Scheme 20

(XXi) (XX) Compounds of formula (XXI) may be obtained, according to Scheme 21 , by reacting compounds of formula (XXII) with suitable 2-halo-Λ/-(alkylacetamides) of formula (XXXIV) as above define following alkylation procedures well reported in the art. For example, using 2-chloro-Λ/-(1-methylethyl) acetamide, sodium hydride as strong base and carrying out the reaction in aprotic solvents, e.g. DMF, at temperature comprised between RT and 80 ⁰C. Scheme 21

(XXXIV)

(XXI I) (XXI)

Compounds of formula (XXII) may be obtained, according to Scheme 22, from compounds of formula (XXIII), wherein Pg is a suitable oxygen protecting group such as tert-butyldimethylsilyl (TBDMS), by reaction with NH₄OAc in acetic acid at temperature between 80 and 1 10 ⁰C for several hours (24-48 h). This procedure involves the conversion of the -OPg group, wherein Pg is for example TBDMS, in alcohol and the consequent formation of its corresponding acetate derivative.

Compounds of formula (XXIII) may be obtained, according to Scheme 23, from compounds of formula (XXIV), wherein Pg is a suitable protecting group such as tert- butyldimethylsilyl (TBDMS), by alkylation reaction with a suitable 2-halo-1-arylketone (IX), such as 2-bromo-1-(3-chlorophenyl)ethanone, using an inorganic base, e.g. Na₂CO₃, and carrying out the reaction in aprotic solvents, e.g. DMF, at temperature comprises between RT and 80⁰C.

Scheme 23

( ⁽X^χX^xI^ιV^v)⁾

Compounds of formula (XXIV) may be obtained, according to Scheme 24, treating ethyl 5- oxo-2,5-dihydro-1 H-pyrazole-3-carboxylate (XXV) with a compound of formula HaI- [CH₂]_nCH₂OPg (XXXVII), wherein Hal is a halide and Pg a suitable alcohol protecting group, through procedures familiar to one skilled in the art. For example, wherein Pg is tert-butyldimethylsilyl (TBDMS), through alkylation reaction with a suitable halo-alkylsilyl derivative such as [(3-bromopropyl)oxy](1 ,1-dimethylethyl)dimethylsilane, using an inorganic base, e.g. Na₂CC>3, and carrying out the reaction in aprotic solvents, e.g. DMF, at temperature comprises between RT and 80⁰C.

Scheme 24

(XXXVII)

(XXV)

(XXIV)

Compound (XXV) may be obtained starting from the commercially available ethyl 4,4,4- trichloroacetoacetate (XXVI), according to Scheme 25, following procedures reported in literature, e.g. Synthesis (2003), (15), 2353-2357.

Scheme 25

(XXVI) (XXV)

Compounds of formula (XX), may be also obtained, according to Scheme 26, by reacting compounds of formula (XXVII) with the appropriate 2-halo-Λ/-alkylacetamide of formula (XXXIV) as above define by alkylation methodology well known in the art. For example using 2-chloro-Λ/-(1-methylethyl) acetamide and an inorganic base, such as K₂CO₃, carrying out the reaction in aprotic solvents, e.g. MeCN at temperature comprises between RT and 80 ⁰C.

Scheme 26

(XXXlV)

H

(XXVIl) (XX)

Compounds of formula (XXVII) may be obtained, according to Scheme 27, by hydrolysis reaction of compounds (XXII), for example using an inorganic base, such as LiOH, and carrying out the reaction in a mixture of aprotic and protic solvent, e.g. THF and water, at temperature comprises between RT and 60 ⁰C.

Scheme 27

H

^{(XXI I )} (XXVII)

Compounds of formula (Id), as define above, may be alternatively prepared, according to Scheme 28, starting from compounds of formula (XXVIII) by alkylation procedures well known in the art, using the appropriate 2-halo-Λ/-alkylacetamide of formula (XXXIV) as above define, e.g. 2-chloro-Λ/-(1-methylethyl), a base, e.g. potassium hydroxide, tetrabutylammonium bromide and carrying out the reaction in aprotic solvents, e.g. THF, at RT.

Scheme 28

Compounds of formula (XXVIII) may be prepared, according to Scheme 29, starting from compounds of formula (XXIX) by reaction with NH₄OAc in acetic acid at temperature between 80 and 110 ⁰C, for several hours (24-48 h).

Scheme 29

Compounds of formula (XXIX) may be obtained from compounds of formula (XXX), according to Scheme 30, by alkylation reaction with a suitable 2-halo-1-arylketone (IX) using an inorganic base, e.g. Na₂CO₃, and carrying out the reaction in aprotic solvents, e.g. DMF, at temperature comprises between O ⁰C and RT.

Scheme 30

Compounds of formula (XXX) may be obtained from compounds of formula (XXV), according to Scheme 31 , by reaction with a suitable halo-alkylamine compound of formula HaI[CH₂]_HCH₂NR₁₀Rn (XXXVIII) wherein Hal is halide, such as 1-(3- chloropropyl)piperidine, in presence of an inorganic base, e.g. K₂CO₃, and carrying out the reaction in aprotic solvents, such as MeCN, at temperature comprises between RT and 80 ⁰C.

Scheme 31

(XXXVI II)

(XXV) (XXX)

Compounds of formula (Id), as defined above, and compounds of formula (Ie), which correspond to compounds of formula (I) as defined above wherein

R is -O-[CH₂]_nCH₂-Y

R₁ is C1-C4 alkyl, may be obtained from compounds of formula (XXXI), according to Scheme 32, by reaction with a suitable halo-alkylamine compound of formula Hal[CH₂]_nCH₂NR₁₀Rn (XXXVIII), such as 1-(3-chloropropyl)piperidine, in presence of an inorganic base, e.g. K₂CO₃, and carrying out the reaction in aprotic solvents, such as MeCN, at temperature comprises between RT and 80 ⁰C.

Scheme 32

Compounds of formula (XXXI) may be obtained from compounds of formula (Va), as define above, according to Scheme 33, by in situ formation of the boronate derivatives using a boronate agent, e.g. 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi-1 ,3,2-dioxaborolane, an inorganic base, e.g. potassium acetate, and a catalyst, e.g. palladium (II) acetate, in an aprotic solvent , e.g. DMF, at temperature comprises between 50 and 100 ⁰C, followed by formation of the hydroxy derivatives using an oxidant agent, e.g. hydroperoxy(oxo)borane in a mixture of protic and aprotic solvents, e.g. water/THF, at RT.

Scheme 33

Compounds of formula (If), which correspond to compounds of formula (I) as defined above wherein

R is -O-[CH₂]_nCH(CH₃)-Y, may be obtained from compounds of formula (XXXII), according to Scheme 34, by reductive amination procedure well described in the art, for example using a secondary alkylamine, e.g. piperidine, using a reductive agent, e.g. NaBH₃CN, and carrying out the reaction in aprotic solvents, e.g. acetonitrile, at atmospheric pressure and at RT.

Scheme 34

(XXXII)

Compounds of formula (XXXII) may be obtained by usual alkylation methods well described in the art from compounds of formula (XXXI), according to Scheme 35, using halo-alkylketone of formula Hal[CH₂]_nCOCH₃ (XXXIX), such as 4-chloro-2-butanone, and carrying out the reaction in presence of an inorganic base, such as K₂CO₃, in aprotic solvents, e.g. DMF, at temperature comprises between RT and 8O ⁰C.

Scheme 35

Compounds of formula (Ig), which correspond to compounds of formula (I) as defined above wherein R is a group G among the following Gi-G₅ groups

G1 G2 G3

G4 G5 and compounds of formula (Ih), which correspond to compounds of formula (I) as defined above wherein

R is -NR₉-[CH₂]_nCH₂-Y, may be obtained, according to Scheme 36, starting from compounds of formula (V), wherein Lg₁ is as above define, by Cu-catalyzed cross coupling methodology well known in the art, for example using CuI as catalyst, a secondary alkylamine,e.g. N-methyl piperidine, and carrying out the reaction in presence of a ligand, e.g. LD-proline, and of an inorganic base, e.g. K₂CO₃, in aprotic solvents, e.g. DMSO, at temperature comprises between 80-100⁰C (18-48 h).

Scheme 36

G₅

Compounds of formula (Ii), which correspond to compounds of formula (I) as defined above wherein R is a group G among the following G₆-G₈ groups

G6 G7 G8 may be obtained from compounds of formula (XXXI), according to Scheme 37, through alkylation reaction with an appropriate halo-alkylcycloamine derivative, such as 3- (chloromethyl)-i -methylpiperidine hydrochloride,

using an inorganic base, i.e. K₂CO₃ or Cs₂CO₃, and carrying out the reaction in aprotic solvents, e.g. DMF or DMSO, at temperature comprises between RT and 8O ⁰C.

Compounds of formula (Ii) may be also obtained from compounds of formula (XXXI), according to Scheme 37, by Mitsunobu reaction with a suitable hydroxy-alkylcycloamine derivative, such as 4-hydroxymethyl-piridine hydrochloride,

using triphenylphosphine and diethyl azodicarboxylate and carrying out the reaction in aprotic solvents, e.g. THF, at temperature comprises between O ⁰C and RT.

Scheme 37

Compounds of formula (Im), which correspond to compounds of formula (I) as defined above wherein R is a group G among the following G₆-G₈ and G₉-Gi₂ groups

G6 G7 G8

and Ri is H may be obtained, according to Scheme 38, by compounds of formula (L), wherein G' corresponds to G6, G7, G8, G9, G10, G11 or G12 in which R_21, R₂₂₁R_23, R₂₆, R₂7, R₂8 or R₂₉are H, by reductive alkylation procedure well described in the art, for example using and aldehyde, e.g. formaldehyde, and a reductive agent, e.g. NaBH₃CN, carrying out the reaction in aprotic solvents, e.g. acetonitrile, at atmospheric pressure and at RT.

Scheme 38

0-) (Im) Compounds of formula (L) may be obtained, according to Scheme 39, by compounds of formula (Ll), wherein G" corresponds to G6, G7, G8, G9, G10, G11 or G12 in which R₂i, R₂₂, R₂3, R₂6, R₂7, R₂8 or R₂₉ are substituted with a nitrogen protecting group Pg₁. For example, wherein Pg₁ is a 1 ,1-dimethylethyl acetate (Boc) group its conversion in the corresponding amine, as well known in the art, may be carried out using trifluoroacetic acid in aprotic solvents, such as DCM, at RT.

(Ll) (L)

Compounds of formula (Ll) may be obtained, according to Scheme 40, by compounds of formula (LII), wherein -G" is as above defined, through alkylation procedures with a suitable 2-halo-Λ/-alkylacetamide of formula (XXXIV) as above defined, for example using 2-chloro-Λ/-(1-methylethyl) acetamide, sodium hydride as a strong base and carrying out the reaction in aprotic solvents, e.g. DMF, at temperature comprises between 0 and 70 ⁰C. An iodine derivative may be used to catalyse the reaction, such as sodium iodide.

Scheme 40

(LII) (Ll)

Compounds of formula (LII) may be prepared, according to Scheme 41 , by reaction of compounds of formula (LIII), wherein G' is as above defined, by procedure well know to one skill in the art. For example, wherein Pg₁ is a 1 ,1-dimethylethyl acetate (Boc) group, compound (LIII) may be obtained reacting compound (LII) with bis(1 ,1-dimethylethyl) dicarbonate (BoC₂O) carrying out the reaction in aprotic solvent, e.g. DCM, at RT.

(^Ll") (LII)

Compounds of formula (LIII) may be prepared, according to Scheme 42, by reaction of compounds of formula (LIV), wherein -G" is as above defined, with NH₄OAc in acetic acid at temperature comprises between 80 and 1 10 ⁰C for several hours (24-48 h).

Compounds of formula (LIV) may be obtained from compounds of formula (LV), according to Scheme 43, by by alkylation reaction with a suitable 2-halo-1-arylketone (IX) using an inorganic base, e.g. Na₂COs, snd carrying out the reaction in aprotic solvents, e.g. DMF, at temperature comprises between RT and 8O ⁰C.

Compounds of formula (LV), may be obtained from compounds of formula (XXV), according to Scheme 44, by Mitsunobu reaction with a suitable N-protecting group- hydroxy-alkylamine derivative of formula (LVI) (HO-C-Pg₁), such as N-Boc-4- hydroxypiperidine, using triphenylphosphine and di-tert-butyl azodicarboxylate and carrying out the reaction in aprotic solvents, e.g. THF, at temperature comprises between

O ⁰C and RT.

Compounds of formula (LVIa), i.e. compound of formula (LVI) as above define, wherein G' correspond to G12 in which R_2g is H, may be obtained, according to Scheme 45, from compounds of formula (LXXXI), wherein Pg₁ is a suitable N-protecting group, e.g. a 1 ,1- dimethylethyl acetate (Boc) group, by reduction, for example with diisobutyl aluminium hydride, in an aprotic solvent, e.g. toluene, at a temperature between -40 and -20 ⁰C.

(LXXXI) (LVIa)

Compounds of formula (LXXXI) may be obtained, according to Scheme 46, from compound of formula (LXXXII) by procedure well know to one skill in the art. For example, wherein Pg₁ is a 1 ,1-dimethylethyl acetate (Boc) group, compound (LXXXII) may be obtained reacting compound (LXXXI) with bis(1 ,1-dimethylethyl) dicarbonate (BoC₂O) carrying out the reaction in aprotic solvent, e.g. DCM, at RT. Compound of formula (LXXXI) may be prepared following the procedure reported in PCT Int. Appl. (2007) WO2007055093.

(LXXXIl) (LXXXI) Compounds of formula (LVIb), i.e. compound of formula (LVI) as above define, wherein G' correspond to G11 in which R₂₈ is H, may be obtained, according to Scheme 47, from compounds of formula (LXXXIII), wherein Pg₁ is a suitable N-protecting group, e.g. a 1 ,1- dimethylethyl acetate (Boc) group, by reduction, for example with diisobutyl aluminium hydride, in an aprotic solvent, e.g. toluene, at a temperature between -40 and -20 ⁰C.

Scheme 47

(LXXXIIi) (Lvib)

Compounds of formula (LXXXIII) may be obtained, according to Scheme 48, from compound of formula (LXXXIV) by procedure well know to one skill in the art. For example, wherein Pg₁ is a 1 ,1-dimethylethyl acetate (Boc) group, compound (LXXXIII) may be obtained reacting compound (LXXXIV) with bis(1 ,1-dimethylethyl) dicarbonate (BoC₂O) carrying out the reaction in aprotic solvent, e.g. DCM, at RT. Compound of formula (LXXXIV) is commercially available.

Scheme 48

(LXXXIII)

Compounds of formula (LVIc), i.e. compound of formula (LXXI) as above define, wherein G' correspond to G10 in which R₂₇ is H, may be obtained, according to Scheme 49, from compounds of formula (LXXXV), wherein Pg₁ is a suitable N-protecting group, e.g. a 1 ,1- dimethylethyl acetate (Boc) group, by reduction, for example, with lithium aluminium hydride in an aprotic solvent, e.g. THF, at a temperature between -40 and -20 ⁰C.

Compounds of formula (LXXXV) may be obtained, according to Scheme 50, from compound of formula (LXXXVI) by procedure well know to one skill in the art. For example, wherein Pg₁ is a 1 ,1-dimethylethyl acetate (Boc) group, compound (LXXXV) may be obtained reacting compound (LXXXVI) using bis(1 ,1-dimethylethyl) dicarbonate (BoC₂O) and carrying out the reaction in aprotic solvent, e.g. DCM, at RT. Compound of formula (LXXXVI) is commercially available.

(LXXXVI)

Compounds of formula (LVId), i.e. compound of formula (LVI) as above define, wherein G' correspond to G9 in which R₂₆ is H, may be obtained, according to Scheme 51 , from compounds of formula (LXXXVII), deprotecting the hydroxyl group with a procedure well know to one skilled in the art, such as using pyridine hydrofloride at RT. Scheme 51

Compounds of formula (LXXXVII), may be obtained, according to Scheme 52, from compounds of formula (LXXXVIII), wherein Pg₁ is a suitable N-protecting group, e.g. a tosyl (Tos) group, by cyclopropanation using, for example, diethyl zinc, diiodomethane and trifluoroacetyc acid in an aprotic solvent, e.g. DCM, at a temperature between 0 ⁰C and RT.

Scheme 52

Compounds of formula (LXXXVIII), may be obtained, according to Scheme 53, from compounds of formula (LXXXIX) by procedure well know to one skill in the art. For example, wherein Pg₁ is a tosyl (Tos) group, compound (LXXXVIII) may be obtained reacting compound (LXXXIX) sing tosyl chloride and a base, e.g. TEA, carrying out the reaction in aprotic solvent, e.g. DCM, at RT.

Scheme 53

(LXXXIX) (LXXXVIII)

Compounds of formula (LXXXIX), may be obtained, according to Scheme 54, from compounds of formula (XC), wherein Pg₂ is a suitable N-protecting group such as 1 ,1- dimethylethyl acetate (Boc) group, by procedure well know to one skill in the art, for example using trifluoroacetic acid in aprotic solvent, e.g. DCM, at RT.

Scheme 54

(LXXXVII) (LXXXVI)

Compounds of formula (XC) may be obtained, according to Scheme 55, from compounds of formula (XCI), wherein Pg₂ is a suitable N-protecting group such as 1 ,1-dimethylethyl acetate (Boc) group, by protection of the hydroxyl group using, for example, tert-butyl diisopropyl chloride and a base, e.g. imidazole, in aprotic solvent, e.g. DMF, at RT. Scheme 55

Compounds of formula (XCI), may be obtained, according to Scheme 56, from compounds of formula (XCII), wherein Pg₂ is a suitable N-protecting group such as 1 ,1- dimethylethyl acetate (Boc) group, by reduction, for example, using lithium boro hydride in an aprotic solvent, e.g. THF, at RT.

Scheme 56

Compounds of formula (XCII) may be obtained, according to Scheme 57, from compounds of formula (XCIII), wherein Pg₂ is a suitable N-protecting group such as 1 ,1- dimethylethyl acetate (Boc) group, by formation of the ester, for example, using a condensing reagent, e.g. o-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate (TBTU), MeOH and a base, e.g. diisopropil ethyl amine, in an aprotic solvent, e.g. DMF, at RT. Compound of formula (XCIII) is commercially available.

Scheme 57

In schemes 36,37 and 44, the several derivatives described to introduce R being a group G in the molecule may be commercially available, may be prepared according to procedures described in the literature available to the person skilled in the art or may be prepared through the procedures described in the experimental section.

Alternatively, compounds of formula (Id), as above defined, may be obtained according to Scheme 58, starting from compounds of formula (XCIV), by intramolecular condensation in an appropriate acidic media, e.g. polyphosphoric acid, in mixture of solvents, e.g. ethanol and toluene, at high temperature such as 90⁰C.

Scheme 58

Compounds of formula (XCIV) may be prepared, according to Scheme 59, starting from compounds of formula (XCV) by reaction with compounds of formula (XCVI), wherein R3 is as defined for compounds of formula (I), using a condensing reagent, e.g. o- (benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate (TBTU), and a base, e.g. diisopropil ethyl amine, in an aprotic solvent, e.g. DMF, at RT

Scheme 59

Compounds of formula (XCV) may be prepared, according to Scheme 60, starting from compounds of formula (XCVII), wherein AIk indicates a lower alkyl such as methyl, ethyl, propyl etc, by reaction with a base, eg lithium hydroxide hydrate in mixture of solvents such as ethanol and water at rt.

Scheme 60

Compounds of formula (XCVII) may be prepared, according to Scheme 61 , starting from compounds of formula (XCVIII), by reaction with a compound of formula (XCIX) or its HCI salt, wherein Lg is a suitable leaving group such as chloride, in the presence of a base, eg potassium carbonate, potassium iodide in an aprotic solvent such as acetone at reflux temperature.

Scheme 61

Compounds of formula (XCVIII) may be prepared, according to Scheme 62, starting from compounds of formula (XCX), where AIk is as above defined, by reaction with strong acids, e.g. polyphosphoric acid in a solvent such as toluene at high temperature such as 85°C.

Scheme 62

(XCX)

Compounds of formula (XCX) may be prepared, according to Scheme 63, starting from compounds of formula (XCXI), wherein Lg is a suitable leaving group such as bromine, by reaction with 1 ,1-dimethylethyl hydrazinecarboxylate, a base, e.g. diisopropil ethyl amine, in an aprotic solvent, e.g. DMF, at 5°C, followed by reaction of the obtained intermeditate with dialkyl 2-butynedioate of formula (XCXII), wherein alkyl group (AIk) is as above defined, in a protic solvent, e.g. ethanol at rt.

Scheme 63

(XCX)

In one embodiment, for the above mentioned process represented in schemes 58 to 63, R is X-[CH₂JnCR₄R₅-Y; X is oxygen; n is 2; R₄ and R₅ are hydrogen; R₁₀ and R₁₁ form a piperidine ring; R₁ is hydrogen; R₂ is 3-CF₃, 4-F phenyl and R₆ is /-propyl. Alternatively, compound of formula (XCVIII), where AIk is as above defined, may be prepared, according to Scheme 64, starting from compounds of formula (XCXI), by oxidation under appropriate conditions. Possible oxidation conditions involved the use of pure oxygen gas or air in basic conditions, in the presence of a catalytic amount of a metal salt such as iron (Il or III) chloride , potassium hexacyanoferrate , cobalt (Il or III ) chloride or Copper (I or II) chloride. In one embodiment, conditions involve the use of an acid medium ( for example H₂SO₄) and K₂S₂Os in acetonitrile at reflux temperature.

Scheme 64

)

(XCXI)

Those skilled in the art will appreciate that in the preparation of the compounds of the invention it may be necessary and/or desirable to protect one or more sensitive groups in the molecule to prevent undesirable side reactions. Suitable protecting groups for use according to the present invention are well known to those skilled in the art and may be used in a conventional manner. See, for example, "Protective groups in organic synthesis" by T. W. Greene and P. G. M. Wuts (John Wiley & sons 1991 ) or "Protecting Groups" by PJ. Kocienski (Georg Thieme Verlag 1994). Examples of suitable amino protecting groups include acyl type protecting groups (e.g. formyl, trifluoroacetyl, acetyl), aromatic urethane type protecting groups (e.g. benzyloxycarbonyl (Cbz) and substituted Cbz), aliphatic urethane protecting groups (e.g. 9-fluorenylmethoxycarbonyl (Fmoc), t- butyloxycarbonyl (Boc), isopropyloxycarbonyl, cyclohexyloxycarbonyl) and alkyl type protecting groups (e.g. benzyl, trityl, chlorotrityl).

The subject invention also includes isotopically-labelled compounds, which are identical to those recited in formula (I) and following, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the invention and pharmaceutically acceptable salts thereof include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulphur, fluorine, iodine, and chlorine, such as ²H, ³H, ¹¹C, ¹³C, ¹⁴C, ¹⁵N, ¹⁷O, ¹⁸0, ³¹P, ³²P, ³⁵S, ¹⁸F, ³⁶CI, ¹²³I and ¹²⁵I.

Compounds of the present invention that contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of the present invention. Isotopically- labelled compounds of the present invention, for example those into which radioactive isotopes such as ³H, ¹⁴C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i.e., ³H, and carbon-14, i.e., ¹⁴C, isotopes are particularly preferred for their ease of preparation and detectability. ¹¹C and ¹⁸F isotopes are particularly useful in PET (positron emission tomography), and ¹²⁵I isotopes are particularly useful in SPECT (single photon emission computerized tomography), all useful in brain imaging, lsotopically labelled compounds of formula I and following of this invention can generally be prepared by carrying out the procedures disclosed in the Schemes and/or in the Examples below, by substituting a readily available isotopically labelled reagent for a non-isotopically labelled reagent.

In a further aspect, the compounds of the present invention and their pharmaceutically acceptable salts and solvates may be useful in therapy. As such the compounds of the present invention may be useful for the manufacture of a medicament for the treatment or prevention of diseases influenced by modulation of the activity of the HPA axis. In particular the compounds may be useful for the manufacture of a medicament for the treatment of schizophrenia, anxiety, hot flushes, addiction, anorexia nervosa, stress- related disorders, sleep disorders, autistic spectrum disorders and Alzheimer's dementia. In one aspect the compounds may be useful for the manufacture of a medicament for the treatment of a metabolic syndrome characterised by insulin resistance, hyperinsulinemia, impaired glucose tolerance, dyslipideamia, obesity (in particular abdominal obesity) and non-insulin-dependent diabetes mellitus (NIDDM). In a further aspect, the compounds of the present invention may be useful for the manufacture of a medicament for the treatment or prevention of depression.

The present invention further includes a method for the treatment of a mammal, including a human, suffering from or liable to suffer from depression or any of the aforementioned disorders, which comprises administering an effective amount of a compound of the present invention or a pharmaceutically acceptable salt or solvate thereof.

Depression states in the treatment of which the compounds of the present invention and their pharmaceutically acceptable salts and solvates may be particularly useful are those classified as mood disorders in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition- Text Revised, American Psychiatric Association, Washington D. C. (2000), including mood episodes, depressive disorders, bipolar disorders and other mood disorders.

The term "depression" includes:

Depression and mood disorders including Major Depressive Episode, Manic Episode, Mixed Episode and Hypomanic Episode; Depressive Disorders including Major

Depressive Disorder, Dysthymic Disorder (300.4), Depressive Disorder Not Otherwise

Specified (31 1 ); Other Mood Disorders including Mood Disorder Due to a General Medical Condition (293.83) which includes the subtypes With Depressive Features, With Major Depressive-like Episode, With Manic Features and With Mixed Features), Substance- Induced Mood Disorder (including the subtypes With Depressive Features, With Manic Features and With Mixed Features) and Mood Disorder Not Otherwise Specified (296.90): Bipolar Disorders including Bipolar I Disorder, Bipolar Il Disorder (Recurrent Major Depressive Episodes with Hypomanic Episodes) (296.89), Cyclothymic Disorder (301.13) and Bipolar Disorder Not Otherwise Specified (296.80);

The term "anxiety disorders" includes:

Anxiety disorders including Panic Attack; Panic Disorder including Panic Disorder without Agoraphobia (300.01 ) and Panic Disorder with Agoraphobia (300.21 ); Agoraphobia; Agoraphobia Without History of Panic Disorder (300.22), Specific Phobia (300.29, formerly Simple Phobia) including the subtypes Animal Type, Natural Environment Type, Blood-lnjection-lnjury Type, Situational Type and Other Type), Social Phobia (Social Anxiety Disorder, 300.23), Obsessive-Compulsive Disorder (300.3), Posttraumatic Stress Disorder (309.81 ), Acute Stress Disorder (308.3), Generalized Anxiety Disorder (300.02), Anxiety Disorder Due to a General Medical Condition (293.84), Substance-Induced Anxiety Disorder, Separation Anxiety Disorder (309.21 ), Adjustment Disorders with Anxiety (309.24) and Anxiety Disorder Not Otherwise Specified (300.00).

In a further aspect therefore, the present invention provides a method of treating a condition for which inhibition of V1 b receptors is beneficial, which comprises administering to a mammal (e.g. human) in need thereof an effective amount of a compound of the present invention or a pharmaceutically acceptable salt or solvate thereof.

The invention also provides a a compound of the present invention or a pharmaceutically acceptable salt or solvate thereof for use in therapy.

The invention also provides a a compound of the present invention or a pharmaceutically acceptable salt or solvate thereof, for use in the treatment of a condition in a mammal (e.g. Human) for which inhibition of V1 b receptors is beneficial.

The invention also provides the use of a a compound of the present invention or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for the treatment of a condition in a mammal (e.g. human) for which inhibition of V1 b receptors is beneficial

In one embodiment, the above mentoned condition is depression.

"Treatment" includes prophylaxis, where this is appropriate for the relevant condition(s). For use in medicine, the compounds of the present invention, or a pharmaceutically acceptable salt or solvate thereof, are usually administered as a standard pharmaceutical composition. The present invention therefore provides in a further aspect a pharmaceutical composition comprising a compound of the invention, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier. The pharmaceutical composition can be for use in the treatment of any of the conditions described herein.

Compound of the invention, or a pharmaceutically acceptable salt or solvate thereof, may be administered by any convenient method, for example by oral, parenteral (e.g. intravenous), buccal, sublingual, nasal, rectal or transdermal administration and the pharmaceutical compositions adapted accordingly.

Compound of the invention, or a pharmaceutically acceptable salt or solvate thereof, which are active when given orally can be formulated as liquids or solids, for example syrups, suspensions or emulsions, tablets, capsules and lozenges.

A liquid formulation will generally consist of a suspension or solution of the compound or pharmaceutically acceptable salt in a suitable liquid carrier(s) for example an aqueous solvent such as water, ethanol or glycerine, or a non-aqueous solvent, such as polyethylene glycol or an oil. The formulation may also contain a suspending agent, preservative, flavouring or colouring agent.

A composition in the form of a tablet can be prepared using any suitable pharmaceutical carrier(s) routinely used for preparing solid formulations. Examples of such carriers include magnesium stearate, starch, lactose, sucrose and cellulose.

A composition in the form of a capsule can be prepared using routine encapsulation procedures. For example, pellets containing the active ingredient can be prepared using standard carriers and then filled into a hard gelatin capsule; alternatively, a dispersion or suspension can be prepared using any suitable pharmaceutical carrier(s), for example aqueous gums, celluloses, silicates or oils and the dispersion or suspension then filled into a soft gelatin capsule.

Typical parenteral compositions consist of a solution or suspension of the compound or pharmaceutically acceptable salt in a sterile aqueous carrier or parenterally acceptable oil, for example polyethylene glycol, polyvinyl pyrrolidone, lecithin, arachis oil or sesame oil. Alternatively, the solution can be lyophilised and then reconstituted with a suitable solvent just prior to administration. Compositions for nasal administration may conveniently be formulated as aerosols, drops, gels and powders. Aerosol formulations typically comprise a solution or fine suspension of the active substance in a pharmaceutically acceptable aqueous or non-aqueous solvent and are usually presented in single or multidose quantities in sterile form in a sealed container, which can take the form of a cartridge or refill for use with an atomising device. Alternatively the sealed container may be a unitary dispensing device such as a single dose nasal inhaler or an aerosol dispenser fitted with a metering valve which is intended for disposal once the contents of the container have been exhausted. Where the dosage form comprises an aerosol dispenser, it will contain a propellant which can be a compressed gas such as compressed air or an organic propellant such as a fluorochloro- hydrocarbon. The aerosol dosage forms can also take the form of a pump-atomiser.

Compositions suitable for buccal or sublingual administration include tablets, lozenges and pastilles, wherein the active ingredient is formulated with a carrier such as sugar and acacia, tragacanth, or gelatin and glycerin.

Compositions for rectal administration are conveniently in the form of suppositories containing a conventional suppository base such as cocoa butter.

Compositions suitable for transdermal administration include ointments, gels and patches.

In one embodiment, the composition is in unit dose form such as a tablet, capsule or ampoule.

A suitable daily dose for any of the above mentioned disorders will be in the range of 0.001 to 50 mg per kilogram body weight of the recipient (e.g. a human) per day, preferably in the range of 0.01 to 20 mg per kilogram body weight per day. The desired dose may be presented as multiple sub-doses administered at appropriate intervals throughout the day.

Each dosage unit for oral administration contains for example from 1 to 250 mg (and for parenteral administration contains for example from 0.1 to 25 mg) of a compound of the invention calculated as the free base.

The compounds of the invention, or a pharmaceutically acceptable salt or solvate thereof, will normally be administered in a daily dosage regimen (for an adult patient) of, for example, an oral dose of between 1 mg and 500 mg, for example between 10 mg and 400 mg, e.g. between 10 and 250 mg or an intravenous, subcutaneous, or intramuscular dose of between 0.1 mg and 100 mg, for example between 0.1 mg and 50 mg, e.g. between 1 and 25 mg of the compound of the formula (I) or a pharmaceutically acceptable salt thereof calculated as the free base, the compound being administered 1 to 4 times per day. Suitably the compounds will be administered for a period of continuous therapy, for example for a week or more.

The invention is further illustrated by the following non-limiting examples.

In the procedures that follow, after each starting material, reference to a Preparation or Example by number is typically provided. This is provided merely for assistance to the skilled chemist. The starting material may not necessarily have been prepared from the batch referred to.

Where reference is made to the use of a "similar" or "analogous" procedure, as will be appreciated by those skilled in the art, such a procedure may involve minor variation, for example reaction temperature, reagent/solvent amount, reaction time, work-up conditions or chromatographic purification conditions.

Compounds are named using ACD/Name PRO 6.02 chemical naming software (Advanced Chemistry Development Inc., Toronto, Ontario, M5H2L3, Canada).

All temperatures refer to ⁰C.

Proton Magnetic Resonance (NMR) spectra are typically recorded either on Varian instruments at 300, 400 or 500 MHz, or on a Bruker instrument at 300 and 400 MHz.

Chemical shifts are reported in ppm (d) using the residual solvent line as internal standard. Splitting patterns are designed as s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; b, broad. The NMR spectra were recorded at a temperature ranging from 25 to

9O⁰C. When more than one conformer was detected the chemical shifts for the most abundant one is reported.

Mass spectra (MS) are typically taken on a Agilent MSD 1 100 Mass Spectrometer, operating in ES (+) and ES (-) ionization mode, or on an ion-trap Finnigan MS LCQ, operating in ES (+) and ES (-) ionization mode, or on an Agilent LC/MSD 1100 Mass

Spectrometer, operating in ES (+) and ES (-) ionization mode coupled with HPLC instrument Agilent 1100 Series {LC/MS - ES (+):analysis performed on a Supelcosil ABZ

+Plus (33x4.6 mm, 3μm); mobile phase: 100% [water +0.1% HCO₂H] for 1 min, then from 100% [water +0.1% HCO₂H] to 5% [water +0.1% HCO₂H] and 95% [CH₃CN ] in 5 min, finally under these conditions for 2 min; T=40°C; flux= 1 mL/min; LC/MS - ES (-):analysis performed on a Supelcosil ABZ +Plus (33x4.6 mm, 3μm); mobile phase: 100% [water

+0.05% NH₃] for 1 min, then from 100% [water +0.05% NH₃ to 5% [water +0.05% NH₃] and 95% [CH₃CN ] in 5 min, finally under these conditions for 2 min; T=40°C; flux= 1 mL/min}, or on a quadrupole Mass Spectrometer on a Shimadzu lcms 2010 or Agilent

LC/MSD 1 100 Series , operating in ES (+) and ES (-) ionization mode {LC/MS - ES (+): analysis performed on YMC ODS (50x2.0 mm, 5um); mobile phase: from 90% [water +0.1% TFA] and 10% [CH₃CN+0.1% TFA] to 20% [water +0.1 % TFA] and 80% [CH₃CN +0.1% TFA] in 2.5 min, finally under these conditions for 0.5min; T=50°C; flux= 1.0 mL/min; LC/MS - ES (-): analysis performed on YMC ODS (50x2.0 mm, 5um); mobile phase: from 90% [water +0.1% TFA] and 10% [CH₃CN+0.1 % TFA] to 20% [water +0.1 % TFA] and 80% [CH₃CN +0.1% TFA] in 3 min, finally under these conditions for 2 min; T=50°C; flux= 1.0 mL/min}, or on Shimadzu 20AB HPLC with PDA detector {column: YMC ODS 50x4.6 mm, 5 cm; mobile phase: 90% [water +0.1% TFA] and 10% [CH₃CN+0.1% TFA] to 20% [water +0.1 % TFA] and 80% [CH₃CN +0.1% TFA] in 6 min, finally under these conditions for 2 min; T=40°C; flux= 3.0 mL/min}, or on a Agilent LC/MSD 1100 Mass Spectrometer, operating in ES (+) ionization mode coupled with HPLC instrument Agilent 1100 Series {LC/MS-ES (+): analysis performed on a Supelcosil ABZ+Plus (33x4.6 mm, 3 μm); mobile phase: from 10%[CH₃CN+0.05%TFA] to 90 %[CH₃CN+0.05%TFA] and 10% [water] in 2.2 min, under these conditions for 2.8 min. T= 45 ⁰C, flux = 0.9 mL/min}. In the mass spectra only one peak in the molecular ion cluster is reported.

Total ion current (TIC) and DAD UV chromatographic traces together with MS and UV spectra associated with the peaks were taken on a UPLC/MS Acquity™ system equipped with 2996 PDA detector and coupled to a Waters Micromass ZQ™ mass spectrometer operating in positive or negative electrospray ionisation mode [UPLC/MS - ES (+ or -): analyses were performed using an Acquity™ UPLC BEH C18 column (50 x 2.1 mm, 1.7 μm particle size). Mobile phase: solvent A - water + 0.1% HCO₂H / solvent B - CH₃CN + 0.06% HCO₂H. Gradient 1 : t = 0 min 3% B, t = 0.05 min 6% B, t = 0.57 min 70% B, t = 1.06 min 99% B, t = 1.449 min 99%, t = 1.45 min 3% B, stop time 1.5 min. or Gradient 2: t = 0 min 3% B, t = 1.06 min 99% B, t = 1.45 min 99% B, t = 1.46 min 3% B, stop time 1.5 min. Column T = 40 ⁰C. Flow rate = 1.0 mL/min. Mass range: ES (+): 100-1000 amu. ES (-): 100-800 amu. UV detection range: 210-350 nm. The usage of this methodology is indicated by "UPLC" in the analytic characterization of the described compounds.

Flash silica gel chromatography was carried out on silica gel 230-400 mesh (supplied by Merck AG Darmstadt, Germany) or on silica gel 300-400 mesh supplied by SCRC (Sinopharm Chemical Reagent Co., Ltd.). or over Varian Mega Be-Si pre-packed cartridges or over pre-packed Biotage silica cartridges.

In a number of preparations, purification was performed using either Biotage manual flash chromatography (Flash+) or automatic flash chromatography (Horizon or SP1 ) systems. All these instruments work with Biotage Silica cartridges.

SPE-SCX cartridges are ion exchange solid phase extraction columns supplied by Varian. The eluent used with SPE-SCX cartridges is methanol followed by 2N ammonia solution in methanol.

SPE-Si cartridges are silica solid phase extraction columns supplied by Varian. The following abbreviations are used in the text: dried refers to a solution dried over anhydrous sodium sulphate or by phase separator cartridge; BOC : te/f-butyloxycarbonyl; r.t. (RT) refers to room temperature; h = hour/hours; min = minute/minutes; Rt = retention time; DCM = dichloromethane; DMF = N,N'-dimethylformamide; DMSO = dimethylsulfoxide; MeOH = methanol; THF = tetrahydrofurane; EA, AcOEt or EtOAc = ethyl acetate; Cy = cyclohexane; Et₂O = diethyl ether; MeCN, ACN = acetonitrile; PE = petroleum ether; NH₃ = ammonia; Na₂SO₄ = sodium sulphate; MgSO₄ = magnesium sulphate; NaI = sodium iodide; DIPEA = diisopropylethylamine; TEA or Et₃N= triethylamine; NaOH = sodium hydroxide; KOH = potassium hydroxide; LiOH = lithium hydroxyde; NaH = sodium hydride; K₂CO₃ = potassium carbonate; Cs₂CO₃ = cesium carbonate; NaHCO₃ = sodium bicarbonate; TFA = trifluoroacetic acid; NH₄OAc = ammonium acetate; AcOH = acetic acid; HCI = hydrochloric acid; NaBH₃CN = sodium cyanoborohydride; Ac = acetyl; TBDMS = te/f-butyldimethylsilyl; TLC = Thin layer chromatography; SCX Cartridge = Strong Cation Exchange Cartridge; HPLC: = high performance liquid chromatography, FC = flash chromatography; MCX: mixed mode- cation exchange cartridge; NH column: secondary amine functionalised silica cartridge. oxo-2,5-dihydro-1H-pyrazole-3-carboxylate (P1)

To a stirring solution of hydrazine hydrochloride (2.24 g) in ethanol (200 mL) ethyl 4,4,4- trichloro-3-oxobutanoate (6.95 g, commercially available) was added and the mixture was heated at reflux for 54 h. After cooling, the solvent was evaporated under vacuum and the residue taken up with AcOEt and filtered. The filtrate was concentrated in vacuo and the crude was purified by flash chromatography (eluent DCM:[DCM\MeOH=9:1] with a gradient of DCM from 100% to 0%) to give the title compound (2.4 g) as a pale yellow solid.

¹H NMR (CDCI₃) δ: 6.23 (s, 1 H); 4.45 (q, 2H); 1.43 (t, 3H).

MS (m/z): 157 [MH]⁺.

Preparation 2: ethyl 3-[(3-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}propyl)oxy]-1H- pyrazole-5-carboxylate (P2)

OTBDMS

To a suspension of ethyl 5-oxo-2,5-dihydro-1 H-pyrazole-3-carboxylate (5.47 g, prepared with an analogous procedure to that described in Preparation 1 ) and Na₂CO₃ (4.46 g) in dry DMF (36 ml_), [(3-bromopropyl)oxy](1 ,1-dimethylethyl)dimethylsilane (8.52 ml.) was added drop wise and the mixture was stirred at 6O⁰C overnight. [(3-bromopropyl)oxy](1 ,1- dimethylethyl)dimethylsilane (0.8 mL) was added and the mixture was stirred for additional 4h. After cooling, the mixture was diluted with AcOEt, washed with chilly water and brine, dried, filtered and evaporated under reduced pressure. The crude was purified by flash chromatography on silica column eluting with Cy/AcOEt with a gradient of Cy from 100% to 80% to give the title compound as yellow oil (5.63 g).

¹H NMR (CDCI₃) δ: 10.53 (s, 1 H); 6.23 (s, 1 H); 4.38 (q, 2H); 4.27 (t, 2H); 3.79 (t, 2H); 2.0

(m, 2H); 1.39 (t, 3H); 0.9 (s, 9H); 0.05 (s, 6H).

MS (m/z): 328 [MH]⁺.

Preparation 3: ethyl 1 -[2-(3-chlorophenyl)-2-oxoethyl]-3-[(3-{[(1,1 - dimethylethyl)(dimethyl)silyl]oxy}propyl)oxy]-1H-pyrazole-5-carboxylate (P3)

OTBDMS

To a suspension of ethyl 3-[(3-{[(1 ,1-dimethylethyl)(dimethyl)silyl]oxy}propyl)oxy]-1 H- pyrazole-5-carboxylate (5.63 g, P2) and Na₂CO₃ (2.36 g) in dry DMF (20 mL), 2-bromo-1- (3-chlorophenyl)ethanone (5.20 g) was added and the mixture was stirred at 6O⁰C for 1.5h, then at RT overnight. The mixture was diluted with Et₂O and washed with water; the organic phase was dried (Na₂SO₄), filtered and evaporated under reduced pressure. The crude was purified by Si flash chromatography eluting with Cy/AcOEt with a gradient of Cy from 100% to 80% to give the title compound (2.77 g) as yellow oil.

¹H-NMR (CDCI₃) δ: 7.95 (s, 1 H); 7.85 (d, 1 H); 7.6 (d, 1 H); 7.46 (t, 1 H); 6.34 (s, 1 H); 5.82 (s, 2H); 4.25 (m, 4H); 3.79 (t, 2H); 1.98 (m, 2H); 1.32 (t, 3H); 0.91 (s, 9H); 0.06 (s, 6H). MS ( m/z): 481 [MH]⁺.

Preparation 4: 3-{[6-(3-chlorophenyl)-4-oxo-4,5-dihydropyrazolo[1,5-a]pyrazin-2- yl]oxy}propyl acetate (P4)

To a solution of ethyl 1-[2-(3-chlorophenyl)-2-oxoethyl]-3-[(3-{[(1 ,1- dimethylethyl)(dimethyl)silyl]oxy}propyl)oxy]-1 H-pyrazole-5-carboxylate (0.5 g, P3) in acetic acid (5 ml.) was added ammonium acetate (2.4 g) and the mixture was stirred at 100°C for 24h. After cooling the mixture was diluted with water and extracted with AcOEt. The organic phase was dried (Na₂SO₄), filtered and the solvent evaporated under vacuum. The residue was dissolved in AcOEt and washed three times with an aqueous sat. solution of NaHCθ3. The organic layers collected were dried, filtered and the solvent evaporated under vacuum to give the title compound (0.32 g) as pale yellow solid.

MS ( m/z): 362 [MH]⁺.

Preparation 5: 3-[(6-(3-chlorophenyl)-5-{2-[(1 -methylethyl)amino]-2-oxoethyl}-4-oxo- 4,5-dihydropyrazolo[1 ,5-a]pyrazin-2-yl)oxy]propyl acetate and 3-{[6-(3- chlorophenyl)-4-({2-[(1-methylethyl)amino]-2-oxoethyl}oxy)pyrazolo[1 ,5-a]pyrazin-2- yl]oxy}propyl acetate (P5 mixture)

To a solution of 3-{[6-(3-chlorophenyl)-4-oxo-4,5-dihydropyrazolo[1 ,5-a]pyrazin-2- yl]oxy}propyl acetate (0.1 g, P4) in dry DMF (2 ml.) at O⁰C, sodium hydride (0.012 g) was added and the mixture was stirred at RT for 30 min. The mixture was cooled down to O⁰C and 2-chloro-N-(1-methylethyl)acetamide (0.041 g, commercially available) and sodium iodide (0.041 g) were added, then the reaction was stirred at 7O⁰C for 6h. 2-chloro-N-(1- methylethyl)acetamide (8 mg) and NaI (8 mg) were added, and the mixture was stirred for additional 2h, then at RT o/n. After cooling the mixture was diluted with AcOEt and washed with chilly water and brine. The organic phase was dried, filtered and the solvent evaporated under vacuum. The crude was purified by Si FC eluting with Cy/AcOEt with a gradient of Cy from 100% to 50%, to give a 1 :1 mixture of the title compounds (44 mg) as white solid.

MS ( m/z): 461 [MH]⁺.

Preparation 6: 2-[6-(3-chlorophenyl)-2-[(3-hydroxypropyl)oxy]-4-oxopyrazolo[1 ,5- a]pyrazin-5(4H)-yl]-N-(1 -methylethyl)acetamide and 2-({6-(3-chlorophenyl)-2-[(3- hydroxy propyl )oxy]pyrazolo[1 ,5-a]pyrazin-4-yl}oxy)-Λ/-(1 -methylethyl)acetamide (P6 mixture)

To a solution of 3-[(6-(3-chlorophenyl)-5-{2-[(1-methylethyl)amino]-2-oxoethyl}-4-oxo-4,5- dihydropyrazolo[1 ,5-a]pyrazin-2-yl)oxy]propyl acetate and 3-{[6-(3-chlorophenyl)-4-({2-[(1- methylethyl)amino]-2-oxoethyl}oxy)pyrazolo[1 ,5-a]pyrazin-2-yl]oxy}propyl acetate (35 mg, P5 mixture) in tetrahydrofuran (2 ml.) lithium hydroxyde (0.5 ml_, 0.5 M solution in water) was added and the mixture was stirred at RT for 3h. Solvent was removed under reduced pressure, the residue was taken up with AcOEt and washed with water. The organic phase was dried, filtered and evaporated under vacuum to give the title compounds as mixture (30 mg).

MS ( m/z): 419 [MH]⁺.

Preparation 7: 2-[6-(3-chlorophenyl)-2-[(3-hydroxypropyl)oxy]-4-oxopyrazolo[1 ,5- a]pyrazin-5(4H)-yl]-Λ/-(1,1-dimethylethyl)acetamide (P7)

To a solution of 3-{[6-(3-chlorophenyl)-4-oxo-4,5-dihydropyrazolo[1 ,5-a]pyrazin-2- yl]oxy}propyl acetate (1.2 g, prepared with an analogous procedure to that described in P4) in dry DMF (30 ml.) at O⁰C, sodium hydride (0.16 g) was added and the mixture was stirred at RT for 30 min. The mixture was cooled down to O⁰C and 2-chloro-N-(1- methylethyl)acetamide (0.6 g, commercially available) and sodium iodide (0.5 g) were added, then the reaction was stirred at 7O⁰C for 7h. After cooling the mixture was diluted with AcOEt and washed with chilly water and brine. The organic phase was dried, filtered and the solvent evaporated under vacuum. The crude (2 g) was dissolved in THF (100 ml.) lithium hydroxyde (25 ml_, 0.5 M solution in water) was added and the mixture was stirred at RT for 3h. Solvent was removed under reduced pressure, the residue was taken up with AcOEt and washed with water. The organic phase was dried, filtered and evaporated under vacuum. The crude was purified by Si FC eluting with DCIWMeOH with a gradient of MeOH from 0% to 5%, to give the title compounds (0.388 g) as yellow pale solid. MS ( m/z): 433 [MH]⁺.

Preparation 8: ethyl 3-(3-(piperidin-1-yl)propoxy)-1H-pyrazole-5-carboxylate (P8)

To a suspension of ethyl 3-hydroxy-I H-pyrazole-S-carboxylate (4.5 g, prepared with an analogous procedure to that described in P1 ) and K₂CO₃ (7.97 g) in CH₃CN (100 ml) 1-(3- chloropropyl)piperidine HCI salt (5.71 g) and NaI (0.43 mg) were added and the mixture was stirred at 40-50 ⁰C for 7 h. The mixture was diluted with EA (500 ml) and washed with water (3X40 ml). The organic layer was dried over Na₂SO₄, filtered and evaporated under vacuum; the residue was purified by column on silica gel (elunt MeOH:CH₂CI₂ with a gradient of MeOH from 0% to 5%) to the title compound (give 4.2 g).

1H NMR (DMSO) δ: 13.05(1 H, s), 6.16(1 H, s), 4.25 (2H, q), 4.05 (2H, t), 2.30 (6H, m), 1.80 (2H, m), 1.44 (4H, m), 1.33 (2H, m), 1.27 (3H, t).

Preparation 9: ethyl 1 -(2-oxo-2-m-tolylethyl)-3-(3-(piperidin-1-yl)propoxy)-1H- pyrazole-5-carboxylate (P9)

To a solution of ethyl 3-(3-(piperidin-1-yl)propoxy)-1 H-pyrazole-5-carboxylate (1.1 g, P8) in CH₃CN (120 ml.) K₂CO₃ (0.54 g) was added, the mixture was stirred at room temperature for 30 min, then the mixture was cooled to 0 ⁰C and 2-bromo-1-m- tolylethanone (0.83 g, prepared with an analogous procedure to that described in Bioorg & Med Chem Letters, 17 (5), 1291-95; 2007) was added . The mixture was stirred at 0 ⁰C for 6h and then warmed to room temperature for 14h. The mixture was filtered and the pH of the filtrate was adjusted to 6-7 by adding the solution of AcOH. Then the solution was concentrated in vacuo to give the title compound (1.7 g). MS ( m/z): 414 [MH]⁺.

Preparation 10: 2-(3-(piperidin-1-yl)propoxy)-6-m-tolylpyrazolo[1,5-a]pyrazin-4(5H)-

To a solution of ethyl 1-(2-oxo-2-m-tolylethyl)-3-(3-(piperidin-1-yl)propoxy)-1 H-pyrazole-5- carboxylate (1.70 g, P9) in AcOH (10 ml) NH₄OAc (9.51 g) was added and the mixture was heated to 1 10 ⁰C for 16h. Then the mixture was cooled to room temperature and diluted with EA (200 ml). The mixture was washed with aqueous NH₃ H₂O (2X15 ml) and brine (5X20 ml). The organic layer was dried over Na₂SO₄ and evaporated. The crude was purified by preparative HPLC. The resulting solution was neutralized with NaHCO₃ and extracted with EA (2X20ml). The organic phase was dried, filtered and the solvent evaporated under vacuum to give the title compound (240 mg).

1H NMR (DMSO) δ: 7.85 (1 H, s), 7.54 (1 H, s), 7.48 (1 H, d), 7.33 (1 H, t), 7.23 (1 H, d), 6.41 (1 H, s), 4.22 (2H, t), 2.30-2.38 (9H, m), 1.88 (2H, m), 1.46 (4H, m), 1.41 (2H, m). Preparation 11 : ethyl 1-(2-oxo-2-(3-(trifluoromethyl)phenyl)ethyl)-3-(3-(piperidin-1- yl)propoxy)-1 H-pyrazole-5-carboxylate P(11 )

The title compound was prepared with an analogous procedure to that described in Preparation 9 in 1.8 g yield from ethyl 3-(3-(piperidin-1-yl)propoxy)-1 H-pyrazole-5- carboxylate (1.1 g, P8) and 2-bromo-1-(3-trifluoromethylphenyl)ethanone (1.04 g, prepared in analogy with the method described in JOC 45(24), 4989-90; 1980).

MS ( m/z): 468 [MH]⁺.

Preparation 12: 2-(3-(piperidin-1-yl)propoxy)-6-(3-

(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyrazin-4(5H)-one (P12)

The title compound was prepared with an analogous procedure to that described in Preparation 10 in 0.24 g yield from ethyl 1-(2-oxo-2-(3-(trifluoromethyl)phenyl)ethyl)-3-(3-

(piperidin-1-yl)propoxy)-1 H-pyrazole-5-carboxylate (1.8 g, P11 ).

1H NMR (DMSO-de) δ: 11.7(1 H, s), 8.1 1 (2H, m), 8.02 (1 H, d), 7.75 (1 H, d), 7.68 (1 H, t), 6.45 (1 H, s), 4.22(2H, t), 2.31-2.42 (6H, m), 1.85-1.91 (2H, m), 1.46 (4H, m), 1.36 (2H, m).

Preparation 13: ethyl 1-(2-oxo-2-(3-(trifluoromethoxy)phenyl)ethyl)-3-(3-(piperidin-1- yl)propoxy)-1 H-pyrazole-5-carboxylate (P13)

The title compound was prepared with an analogous procedure to that described in Preparation 9 in 1.8 g yield from ethyl 3-(3-(piperidin-1-yl)propoxy)-1 H-pyrazole-5- carboxylate (1.1 g, P8) and 2-bromo-1-(3-(trifluoromethoxy)phenyl)ethanone (1.04 g, prepared in analogy with the method described in J.Med.Chem. 50(1 ), 21-39; 2007).

MS ( m/z): 484 [MH]⁺.

Preparation 14: 2-(3-(piperidin-1-yl)propoxy)-6-(3-

(trifluoromethoxy)phenyl)Pyrazolo[1 ,5-a]pyrazin-4(5H)-one (P14)

The title compound was prepared with an analogous procedure to that described in Preparation 10 in 0.22 g yield from 1-(2-oxo-2-(3-(trifluoromethoxy)phenyl)ethyl)-3-(3-

(piperidin-1-yl)propoxy)-1 H-pyrazole-5-carboxylate (1.8 g, P13).

1 H NMR (DMSO) δ: 11.56 (1 H, b), 7.93 (1 H, s), 7.79-7.93 (2H, m), 7.43 (2H, d), 6.38 (1 H, s), 4.18 (2H, t), 2.28-2.45 (6H, m), 1.95(2H, m), 1.46 (4H, m), 1.35 (2H, m).

Preparation 15: ethyl 1-(2-(3-methoxyphenyl)-2-oxoethyl)-3-(3-(piperidin-1- yl)propoxy-1 H-pyrazole-5-carboxylate (P15)

The title compound was prepared with an analogous procedure to that described in Preparation 9 in 1.8 g yield from ethyl 3-(3-(piperidin-1-yl)propoxy)-1 H-pyrazole-5- carboxylate (1.1 g, P8) and 2-bromo-1-(3-methoxyphenyl)ethanone (0.9 g, commercially available).

MS ( m/z): 430 [MH]⁺.

Preparation 16: 6-(3-methoxyphenyl)-2-(3-(piperidin-1 -yl)propoxy)pyrazolo[1 ,5- a]pyrazin-4(5H)-one (P16)

The title compound was prepared with an analogous procedure to that described in Preparation 10 in 0.20 g yield from ethyl 1-(2-(3-methoxyphenyl)-2-oxoethyl)-3-(3- (piperidin-1-yl)propoxy)-1 H-pyrazole-5-carboxylate (1.8 g, P15).

1 H NMR (DMSO) δ : 1 1.49 (1 H, s) , 7.94 (1 H, s), 7. .25-7. 34 (3H, m), 6 .94 (1 H, dd), 6.39

(1 H , s), 4 ■ 19 (2H, t), 3.80 (3H, s), 2. .28-2.35 (6H, m), 1.85 (2H, m), 1.45 (4H , m), 1.36 (2H, m).

Preparation 17: ethyl 3-[(2-{[(1,1 -dimethylethyl)(dimethyl)silyl]oxy}ethyl)oxy]-1H- pyrazole-5-carboxylate (P17)

To a suspension of ethyl 5-oxo-2,5-dihydro-1 H-pyrazole-3-carboxylate (1.5 g, prepared with an analogous procedure to that described in Preparation 1 ) and Na₂CO₃ (1.22 g) in dry DMF (20 ml_), [(3-bromoethyl)oxy](1 ,1-dimethylethyl)dimethylsilane (1.11 ml.) was added drop wise and the mixture was stirred at 60 ⁰C overnight. The reaction mixture was cooled down to rt and filtered to remove the Na₂CO₃. The filtrate was diluted with DMF and Na₂CO₃ (1.22g) and [(3-bromoethyl)oxy](1 ,1-dimethylethyl)dimethylsilane (2.1 ml.) were added and the mixture was stirred at 60 ⁰C for additional 36h. After cooling, the mixture was diluted with Et₂O, washed with chilly water, dried, filtered and evaporated under reduced pressure. The crude was dissolved in DCM (15 ml.) and 2,6-lutidine (1.08 ml.) and [(3-bromoethyl)oxy](1 ,1-dimethylethyl)dimethylsilane (0.86 ml.) were added at 0 ⁰C and the mixture was stirred at rt for 1 h. The mixture was diluted in DCM, washed with NaHCO₃sat and then with HCI 0.25N. The organic layer was dried and the solvent evaporated under reduced pressure. The crude was purified by flash chromatography on silica column eluting with Cy/AcOEt with a gradient of Cy from 100% to 80% to give the title compound as colourless oil (0.63 g).

MS (m/z): 315 [MH]⁺.

Preparation 18: ethyl 1 -[2-(3-chlorophenyl)-2-oxoethyl]-3-[(2-{[(1,1- dimethylethyl)(dimethyl)silyl]oxy}ethyl)oxy]-1H-pyrazole-5-carboxylate (P18)

The title compound was prepared with an analogous procedure to that described in Preparation 9 in 0.57 g yield from ethyl 3-[(2-{[(1 ,1- dimethylethyl)(dimethyl)silyl]oxy}ethyl)oxy]-1 H-pyrazole-5-carboxylate (0.6 g, P17) and 2- bromo-1-(3-chlorophenyl)ethanone (0.6 g, commercially available).

MS ( m/z): 467 [MH]⁺. Preparation 19: 2-{[6-(3-chlorophenyl)-4-oxo-4,5-dihydropyrazolo[1 ,5-a]pyrazin-2- yl]oxy}ethyl acetate (P19)

The title compound was prepared with an analogous procedure to that described in Preparation 10 in 0.38 g yield from ethyl 1-[2-(3-chlorophenyl)-2-oxoethyl]-3-[(2-{[(1 ,1- dimethylethyl)(dimethyl)silyl]oxy}ethyl)oxy]-1 H-pyrazole-5-carboxylate (0.56 g, P18).

MS ( m/z): 348 [MH]⁺.

Preparation 20: 2-[6-(3-chlorophenyl)-2-[(2-hydroxyethyl)oxy]-4-oxopyrazolo[1 ,5- a]pyrazin-5(4H)-yl]-Λ/-(1 -methylethyl)acetamide and 2-({6-(3-chlorophenyl)-2-[(2- hydroxyethyl)oxy]pyrazolo[1 ,5-a]pyrazin-4-yl}oxy)-Λ/-(1 -methylethyl)acetamide (P20 mixture)

To a solution of 2-{[6-(3-chlorophenyl)-4-oxo-4,5-dihydropyrazolo[1 ,5-a]pyrazin-2- yl]oxy}ethyl acetate (0.38 g, P19) in dry DMF (5 ml.) under N₂ atmosphere at O⁰C, sodium hydride (0.052 g) was added and the mixture was warmed to RT and left stirring for 30 min. The mixture was cooled down to O⁰C and 2-chloro-N-(1-methylethyl)acetamide (0.178 g) and sodium iodide (0.164 g were added and the mixture was stirred at 7O⁰C for 6h. After cooling the mixture was diluted with AcOEt and washed with chilly water and brine. The organic phase was dried and evaporated under vacuum. The crude was dissolved in THF (40 ml.) and lithium hydroxide (0.5 M solution 10 ml.) was added and the mixture was stirred at RT overnight. The mixture was concentrated under reduced pressure, the residue taken up with DCM and washed with water. The organic phase was dried, filtered and evaporated under vacuum. The crude was tritured with Et₂O and filtered to give a mixture of the title compounds (0.25 g) that was used without further purification in the next step.

MS ( m/z): 405 [MH]⁺.

Preparation 21 : ethyl 3-[(4-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}butyl)oxy]-1H- pyrazole-5-carboxylate (P21)

The title compound was prepared with an analogous procedure to that described in Preparation 17 in 1.08 g yield from ethyl 5-oxo-2,5-dihydro-1 H-pyrazole-3-carboxylate (1.5 g, prepared in analogy with the method described in P1 ) and [(4-chlorobutyl)oxy](1 ,1- dimethylethyl)dimethylsilane (2.25 g).

MS (m/z): 343 [MH]⁺.

Preparation 22: ethyl 1 -[2-(3-chlorophenyl)-2-oxoethyl]-3-[(4-{[(1,1- dimethylethyl)(dimethyl)silyl]oxy}butyl)oxy]-1H-pyrazole-5-carboxylate (P22)

The title compound was prepared with an analogous procedure to that described in Preparation 9 in 0.72 g yield from ethyl 3-[(4-{[(1 ,1- dimethylethyl)(dimethyl)silyl]oxy}butyl)oxy]-1 H-pyrazole-5-carboxylate (1.08 g, P21 ) and 2- bromo-1-(3-chlorophenyl)ethanone (0.96 g, commercially available).

MS ( m/z): 495 [MH]⁺.

Preparation 23: 4-{[6-(3-chlorophenyl)-4-oxo-4,5-dihydropyrazolo[1 ,5-a]pyrazin-2- yl]oxy}butyl acetate (P23)

The title compound was prepared with an analogous procedure to that described in Preparation 10 in 0.48 g yield from ethyl 1-[2-(3-chlorophenyl)-2-oxoethyl]-3-[(4-{[(1 ,1- dimethylethyl)(dimethyl)silyl]oxy}butyl)oxy]-1 H-pyrazole-5-carboxylate (0.72 g, P22).

MS ( m/z): 376 [MH]⁺.

Preparation 24: 2-[6-(3-chlorophenyl)-2-[(4-hydroxybutyl)oxy]-4-oxopyrazolo[1 ,5- a]pyrazin-5(4H)-yl]-Λ/-(1 -methylethyl)acetamide and 2-({6-(3-chlorophenyl)-2-[(4- hydroxybutyl)oxy]pyrazolo[1 ,5-a]pyrazin-4-yl}oxy)-Λ/-(1 -methylethyl)acetamide (P24 mixture)

A solution of 4-{[6-(3-chlorophenyl)-4-oxo-4,5-dihydropyrazolo[1 ,5-a]pyrazin-2-yl]oxy}butyl acetate (0.25 g, P23) and potassium carbonate (0.18 g) in dry acetonitrile (6 ml.) 2-chloro- N-(1-methylethyl)acetamide (0.1 g) was added and the reaction was stirred at 8O⁰C on. After cooling the mixture was diluted with AcOEt and washed with chilly water and brine. The organic phase was dried, filtered and the solvent evaporated under vacuum. The crude was dissolved in THF (20 ml_), lithium hydroxyde (5 ml_, 0.5 M solution in water) was added and the mixture was stirred at RT for 2h. Solvent was removed under reduced pressure; the residue was taken up with AcOEt and washed with water. The organic phase was dried, filtered and evaporated under vacuum to give a mixture of the title compounds (0.21 g) that was used in next step without further purification.

MS ( m/z): 433 [MH]⁺.

Preparation 25: ethyl 1-[2-(3-chloro-4-fluorophenyl)-2-oxoethyl]-3-[(3-{[(1,1- dimethylethyl)(dimethyl)silyl]oxy}propyl)oxy]-1H-pyrazole-5-carboxylate (P25) -TBDMS

The title compound was prepared with an analogous procedure to that described in Preparation 9 in 1.17 g yield from ethyl 3-[(3-{[(1 ,1- dimethylethyl)(dimethyl)silyl]oxy}butyl)oxy]-1 H-pyrazole-5-carboxylate (1.68 g, prepared with an analogous procedure to that described in P2) and 2-bromo-1-(3-chloro-4- fluorophenyl)ethanone (1.6 g, prepared with an analogous procedure to that described in

J. Indian chem.. Soc. 70(6), 539-42; 1993).

MS ( m/z): 499 [MH]⁺.

Preparation 26: 3-{[6-(3-chloro-4-fluorophenyl)-4-oxo-4,5-dihydropyrazolo[1 ,5- a]pyrazin-2-yl]oxy}propyl acetate (P26)

The title compound was prepared with an analogous procedure to that described in Preparation 10 in 0.75 g yield from ethyl 1-[2-(3-chloro-4-fluorophenyl)-2-oxoethyl]-3-[(3- {[(1 ,1-dimethylethyl)(dimethyl)silyl]oxy}propyl)oxy]-1 H-pyrazole-5-carboxylate (1 g, P25). MS ( m/z): 379 [MH]⁺.

Preparation 27: 2-[6-(3-chloro-4-fluorophenyl)-2-[(3-hydroxypropyl)oxy]-4- oxopyrazolo[1 ,5-a]pyrazin-5(4H)-yl]-N-(1 -methylethyl)acetamide and 2-({6-(3-chloro- 4-fluorophenyl)-2-[(3-hydroxypropyl)oxy]pyrazolo[1,5-a]pyrazin-4-yl}oxy)-Λ/-(1 - methylethyl)acetamide (P27 mixture)

To a suspension of 3-{[6-(3-chloro-4-fluorophenyl)-4-oxo-4,5-dihydropyrazolo[1 ,5- a]pyrazin-2-yl]oxy}propyl acetate (0.25 g, P26) and potassium carbonate (0.18 g) in dry acetonitrile (7 ml.) 2-chloro-N-(1-methylethyl)acetamide (0.1 g) was added and the reaction was stirred at 8O⁰C for 24h. Then tetrabuthylammonium iodide (0.24 g) was added and the reaction mixture heated at 8O⁰C for additional 16h. After cooling the mixture was diluted with AcOEt and washed with chilly water and brine. The organic phase was dried, filtered and the solvent evaporated under vacuum. The crude was dissolved in THF (30 ml.) lithium hydroxyde (8 ml_, 0.5 M solution in water) was added and the mixture was stirred at RT for 3h. Solvent was removed under reduced pressure, the residue was taken up with AcOEt and washed with water. The organic phase was dried, filtered and evaporated under vacuum to give a mixture of the title compounds (0.18 g) that was used in next step without further purification.

MS ( m/z): 436 [MH]⁺.

Preparation 28: ethyl 3-[(3-{[(1,1 -dimethylethyl)(dimethyl)silyl]oxy}propyl)oxy]-1-{2- [2-fluoro-5-(trifluoromethyl)phenyl]-2-oxoethyl}-1H-pyrazole-5-carboxylate (P28)

O-TBDMS

The title compound was prepared with an analogous procedure to that described in Preparation 9 in 4 g yield from ethyl 3-[(3-{[(1 ,1- dimethylethyl)(dimethyl)silyl]oxy}butyl)oxy]-1 H-pyrazole-5-carboxylate (2.3 g, prepared with an analogous procedure to that described in P2) and 2-bromo-1-[2-fluoro-5- (trifluoromethyl)phenyl]ethanone (2.7 g, commercially available). MS ( m/z): 533 [MH]⁺.

Preparation 29: 3-({6-[2-fluoro-5-(trifluoromethyl)phenyl]-4-oxo-4,5- dihydropyrazolo[1 ,5-a]pyrazin-2-yl}oxy)propyl acetate (P29)

The title compound was prepared with an analogous procedure to that described in Preparation 10 in 1.2 g yield from ethyl 3-[(3-{[(1 ,1- dimethylethyl)(dimethyl)silyl]oxy}propyl)oxy]-1-{2-[2-fluoro-5-(trifluoromethyl)phenyl]-2- oxoethyl}-1 H-pyrazole-5-carboxylate (4 g, P28). MS ( m/z): 414 [MH]⁺.

Preparation 30: 2-[6-[2-fluoro-5-(trifluoromethyl)phenyl]-2-[(3-hydroxypropyl)oxy]-4- oxopyrazolo[1 ,5-a]pyrazin-5(4H)-yl]-Λ/-(1 -methylethyl)acetamide (P30)

The title compound was prepared with an analogous procedure to that described in

Preparation 24 and purified by preparative HPLC, in 86 mg yield from 3-({6-[2-fluoro-5-

(trifluoromethyl)phenyl]-4-oxo-4,5-dihydropyrazolo[1 ,5-a]pyrazin-2-yl}oxy)propyl acetate

(1.2 g, P29).

MS ( m/z): 471 [MH]⁺. Preparation 31 : ethyl 3-[(3-{[(1,1 -dimethylethyl)(dimethyl)silyl]oxy}propyl)oxy]-1-{2- oxo-2-[3-(trifluoromethyl)phenyl]ethyl}-1 H-pyrazole-5-carboxylate (P31 )

O-TBDMS

The title compound was prepared with an analogous procedure to that described in Preparation 9 in 7.5 g yield from ethyl 3-[(3-{[(1 ,1- dimethylethyl)(dimethyl)silyl]oxy}butyl)oxy]-1 H-pyrazole-5-carboxylate (2.85 g, prepared with an analogous procedure to that described in P2) and 2-bromo-1-[3- (trifluoromethyl)phenyl]ethanone (2.3 g, commercially available). MS ( m/z): 515 [MH]⁺.

Preparation 32: 3-({4-oxo-6-[3-(trifluoromethyl)phenyl]-4,5-dihydropyrazolo[1 ,5- a]pyrazin-2-yl}oxy)propyl acetate (P32)

The title compound was prepared with an analogous procedure to that described in Preparation 10 in 3.7 g yield from ethyl 3-[(3-{[(1 ,1- dimethylethyl)(dimethyl)silyl]oxy}propyl)oxy]-1-{2-oxo-2-[3-(trifluoromethyl)phenyl]ethyl}- 1 H-pyrazole-5-carboxylate (7.5 g, P31 ). MS ( m/z): 396 [MH]⁺. Preparation 33: Λ/-(1,1 -dimethylethyl)-2-[2-[(3-hydroxypropyl)oxy]-4-oxo-6-[3- (trifluoromethyl)phenyl]pyrazolo[1,5-a]pyrazin-5(4H)-yl]acetamide (P33)

Preparation 24 and purified by preparative HPLC, in 245 mg yield from 3-({4-oxo-6-[3-

(trifluoromethyl)phenyl]-4,5-dihydropyrazolo[1 ,5-a]pyrazin-2-yl}oxy)propyl acetate (3.6 g,

P32).

MS ( m/z): 467 [MH]⁺.

Preparation 34: ethyl 3-[(3-{[(1 J ^imethylethylHdimethylJsilylloxytøropyOoxyl-i-^- ^-fluoro-S-ttrifluoromethylJphenyl^-oxoethy^-IH-pyrazole-S-carboxylate (P34)

O-TBDMS

To a solution of ethyl 3-[(3-{[(1 ,1-dimethylethyl)(dimethyl)silyl]oxy}ethyl)oxy]-1 H-pyrazole- 5-carboxylate (3 g, prepared with an analogous procedure to that described in P2) and Na₂CO₃ (1.16 g) in DMF (20 ml.) 2-bromo-1-[4-fluoro-3-(trifluoromethyl)phenyl]ethanone (3.12 g, commercially available) was added . The mixture was stirred at 60⁰C for 8h. After cooling the mixture was diluted with Et₂O and washed with water and brine. The organic phase was separated from the aqueous phase, dried over Na₂SO₄ and the solvent evaporated under vacuum. The crude was purified by flash chromatography (eluent

AcOEt:Cy=2:8) to give of the title compound (2.5 g).

MS ( m/z): 533 [MH]⁺.

Preparation 35: 3-({6-[4-fluoro-3-(trifluoromethyl)phenyl]-4-oxo-4,5- dihydropyrazolo[1 ,5-a]pyrazin-2-yl}oxy)propyl acetate (P35)

The title compound was prepared with an analogous procedure to that described in Preparation 10 in 0.97 g yield from ethyl 3-[(3-{[(1 ,1- dimethylethyl)(dimethyl)silyl]oxy}propyl)oxy]-1-{2-[4-fluoro-3-(trifluoromethyl)phenyl]-2- oxoethyl}-1 H-pyrazole-5-carboxylate (2.3 g, P34). MS ( m/z): 414 [MH]⁺.

Preparation 36: 2-[6-[4-fluoro-3-(trifluoromethyl)phenyl]-2-[(3-hydroxypropyl)oxy]-4- oxopyrazolo[1 ,5-a]pyrazin-5(4H)-yl]-N-(1 -methylethyl)acetamide and 2-({6-[4-fluoro- 3-(trifluoromethyl)phenyl]-2-[(3-hydroxypropyl)oxy]pyrazolo[1,5-a]pyrazin-4-yl}oxy)- Λ/-(1-methylethyl)acetamide (P36 mixture)

To a solution of 3-({6-[4-fluoro-3-(trifluoromethyl)phenyl]-4-oxo-4,5-dihydropyrazolo[1 ,5- a]pyrazin-2-yl}oxy)propyl acetate (0.5 g, P35) in dry DMF (5 ml.) under N₂ atmosphere at O⁰C, lithium hydride (0.011 g) was added and the mixture was warmed to RT and left stirring for 30 min. The mixture was cooled down to O⁰C and 2-chloro-N-(1- methylethyl)acetamide (0.197 g) and sodium iodide (0.091 g) were added and the mixture was stirred at 6O⁰C for 6h. Then one more portion of lithium hydride (0.01 g) and 2-chloro- N-(1-methylethyl)acetamide (0.164 g) were added and the mixture stirred at 6O⁰C overnight. After cooling the mixture was diluted with AcOEt and washed with chilly water and brine. The organic phase was dried and evaporated under vacuum. The crude was dissolved in THF (40 ml.) and lithium hydroxide (0.5 M solution 10 ml.) was added and the mixture was stirred at RT overnight. The mixture was concentrated under reduced pressure, the residue taken up with DCM and washed with water. The milky suspension that resulted was filtered and the organic phase of the filtrate was separated from the aqueous phase, dried over Na₂SO₄ and the solvent evaporated under vacuum to give a mixture of the title compounds (0.36 g) that was used without further purification in the next step.

MS ( ro/z): 471 [MH]⁺.

Preparation 37: Λ/-(1,1-dimethylethyl)-2-[6-[4-fluoro-3-(trifluoromethyl)phenyl]-2-[(3- hydroxypropyl)oxy]-4-oxopyrazolo[1,5-a]pyrazin-5(4H)-yl]acetamide (P37)

To a solution of 3-(6-(4-fluoro-3-(trifluoromethyl)phenyl)-4-oxo-4,5- dihydropyrazolo[1 ,5-a]pyrazin-2-yloxy)propyl acetate (1.6 g, prepared with an analogous procedure to that described in P35) in CH3CN (25ml_) were added K₂CO₃ (1.076 g) and N-tert-butyl-2-chloroacetamide (0.637 g). The mixture was stirred at 80 ⁰C overnight. Solvent was removed in vacuo and the residue was partitioned between EA (200 ml.) and water (300 ml_). The organic layer was dried with Na₂SO₄, filtered and the solvent was removed in vacuo to give a crude compound (2.17g) that was dissolved in THF (30 ml.) and LiOH (8M, 3 ml.) was added. The mixture was stirred at room temperature overnight. Solvent was removed in vacuo; the residue was partitioned between EA (100 ml.) and water (50 ml_). The organic layer was dried with Na₂SO₄, filtered and the solvent was removed in vacuo to give the title compound as crude product (1.536 g) that was used directly in next step.

MS ( m/z): 485 [MH]⁺.

Preparation 38: 2-bromo-1-(3-chloro-2-fluorophenyl)ethanone (P38)

To a solution of 1-(3-chloro-2-fluoro-phenyl)-ethanone (8.5 g, commercially available) in

1 ,4-dioxane (50 ml.) Br₂ (7.79 g) was added and the mixture was stirred at RT for overnight. Water was added to the mixture and the compound extracted with EA (30 ml. X 3). The organic phase was dried, filtered and the solvent evaporated under vacuum. The crude was purified by column to give the title compound (10.2 g).

¹H NMR (CDCI₃) δ: 4.44 (2H, s), 7.15-7.20 (1 H, m), 7.62-7.66 (1 H, t), 7.79-7.85 (1 H, t).

Preparation 39: 6-(3-Chloro-2-fluoro-phenyl)-2-(3-piperidin-1 -yl-propoxy)-5H- pyrazolo[1 ,5-a]pyrazin-4-one (P39)

To a solution of 5-(3-Piperidin-1-yl-propoxy)-2H-pyrazole-3-carboxylic acid ethyl ester (2.0 g, prepared with an analogous procedure to that described in P8) in DMF (15 ml.) was added K₂CO3 (0.98 g). The mixture was stirred at RT for 15min. Then 2-bromo-1-(3- chloro-2-fluoro-phenyl)-ethanone (2.68 g, P38) was added. The mixture was stirred at RT for overnight. The mixture was worked-up and the crude used in next step without any purification. The crude was dissolved in AcOH (15 ml.) NH₄OAc (10.2 g) was added and the mixture was heated at reflux for overnight. The mixture was neutralized with 1 N NaOH, extracted with EA (50 ml. X 3), concentrated and purified by column to give the title compound (250 mg).

¹H NMR (DMSO) δ: 1.35-1.49 (2H, m), 1.52-1.65 (4H, m), 2.00 (2H, m), 2.8-2.92 (6H, m), 4.21-4.24 (2H, t), 6.46 (1 H, s), 7.30-7.32 (1 H, t), 7.53 (1 H, t), 7.66 (1 H, t), 7.74 (1 H, s).

Preparation 40: 6-(3,5-bis-trifluoromethyl-phenyl)-2-(3-piperidin-1 -yl-propoxy)-5H- pyrazolo[1 ,5-a]pyrazin-4-one (P40)

The title compound was prepared with an analogous procedure to that described in Preparation 39 in 0.22 g yield from 5-(3-piperidin-1-yl-propoxy)-2H-pyrazole-3-carboxylic acid ethyl ester (2.0 g, P8) and 1-(3,5-bis-trifluoromethyl-phenyl)-2-bromo-ethanone (3.57 g, commercially available).

¹H NMR (DMSO) δ: 1.51-1.55 (3H, m), 1.68-1.72 (5H, m), 2.36-2.40 (2H, m), 2.90-2.94 (2H, m), 4.33-4.37 (2H, m), 5.82 (1 H, s), 6.58 (1 H, s), 8.43-8.46 (1 H, s), 8.52 (2H, s).

Preparation 41 : ethyl 3-iodo-1H-pyrazole-5-carboxylate (P41)

To a suspension of ethyl 3-amino-1 H-pyrazole-5-carboxylate (1 g) in diiodomethane (30 m) at -1O⁰C under N₂ atm., isoamyl nitrite (7.81 ml) was slowly added over 20 min. The mixture was stirred at RT for 1 h, then heated at 9O⁰C and stirred at that temperature for 1 h. After cooling, the mixture was diluted with AcOEt and washed with Na₂S₂O₄ and HCI 1 M. The organic phases collected were dried and evaporated under vacum. The crude was purified by chromatography on Si eluting with Cy/AcOEt (gradient from 0 to 30% of

AcOEt ) to give the title compound (0.75 g) as yellow solid.

MS ( m/z): 266 [MH]⁺.

Preparation 42: ethyl 1 -{2-[4-fluoro-3-(trifluoromethyl)phenyl]-2-oxoethyl}-3-iodo-1H- pyrazole-5-carboxylate (P42)

To a suspension of ethyl 3-iodo-I H-pyrazole-S-carboxylate (750 mg, P41 ) and sodium carbonate (359 mg) in dry DMF (7 ml.) under N₂ atmosphere, 2-bromo-1-[4-fluoro-3- (trifluoromethyl)phenyl]ethanone (964 mg) was adedd and the mixture was stirred at RT for 3h. The reaction mixture was diluted with Et₂O and washed with water. The organic phase was dried, evaporated under vacum and the crude was purified by Si flash chromatography (eluting with Cy/ AcOEt 9:1 ) to give the title compound (0.85 g).

MS ( m/z): 471 [MH]⁺.

Preparation 43: 6-[4-fluoro-3-(trifluoromethyl)phenyl]-2-iodopyrazolo[1,5-a]pyrazin-

To a stirring solution of ethyl 1-{2-[4-fluoro-3-(trifluoromethyl)phenyl]-2-oxoethyl}-3-iodo- 1 H-pyrazole-5-carboxylate (0.85 g, P42) in acetic acid (10 ml_), ammonium acetate (2.090 g) was added. The mixture was warmed to 100°C and stirred for 8h. Other 5 eq of ammonium acetate were added and the mixture was stirred overnight. After cooling, the mixture was diluted with AcOEt and washed with a saturated solution of NaHCO₃. The organic phase was dried over Na₂SO₄ and evaporated under reduced pressure. The crude was tritured with Et₂O and filtered to give the title compound (0.48 g) as white solid. MS ( m/z): 424 [MH]⁺.

Preparation 44: 2-[6-[4-fluoro-3-(trifluoromethyl)phenyl]-2-iodo-4-oxopyrazolo[1 ,5- a]pyrazin-5(4H)-yl]-Λ/-(1 -methylethyl)acetamide and 2-[6-[4-fluoro-3- (trifluoromethyl)phenyl]-2-iodo-4-oxopyrazolo[1 ,5-a]pyrazin-5(4H)-yl]-Λ/-(1- methylethyl)acetamide (P44 mixture)

To a stirring solution of 6-[4-fluoro-3-(trifluoromethyl)phenyl]-2-iodopyrazolo[1 ,5-a]pyrazin- 4(5H)-one (0.48 g, P43) in a mixture of 1 ,2-Dimethoxyethane (DME) (10 ml.) and DMF (2.5 ml.) at O⁰C under N₂ flux, sodium hydride (0.054 g) was added and the mixture was stirred at RT for 20 min. The mixture was cooled down again to O⁰C and lithium bromide (0.197 g) was added. After stirring at O⁰C for 10 min, the mixture was allowed to reach RT and 2-chloro-N-(1-methylethyl)acetamide (0.185 g) and sodium iodide (0.085 g) were added; the mixture was warmed to 6O⁰C and stirred at that temperature for 14h. Others 0.2 eq of NaH and of 2-chloro-N-(1-methylethyl)acetamide were added and the mixture was stirred for additional 6h. The mixture was concentrated in vacuo, and the residue diluted with AcOEt and washed with ice and brine. The organic phase was dried and evaporated. The residue was tritured with Et₂O, affording a mixture of the title compounds

(0.53 g).

MS ( m/z): 523 [MH]⁺.

Preparation 45: ethyl 3-[(3-{[(1 J ^imethylethylHdimethylJsilylloxytøropyOoxyl-i-^- fθ-methyl^-pyridinylJ^-oxoethyll-IH-pyrazole-S-carboxylate (P45)

OTBDMS

To a solution of ethyl 3-[(3-{[(1 ,1-dimethylethyl)(dimethyl)silyl]oxy}propyl)oxy]-1 H-pyrazole- 5-carboxylate (3.9 g, P2) in MeCN (70 ml.) 2-bromo-1-(6-methylpyridin-2-yl)ethanone (3.16 g, prepared with an analogous procedure to that described in Journal of Medicinal & Pharmaceutical Chemistry 3, 561-6, 1961 ) and K₂CO₃ (2.2 g), were added. The mixture was stirred at RT for one day, then the solvent was removed under reduce pressure. The mixture was diluted with EA and washed with water. The organic phase was dried, filtered and evaporated under reduced pressure to get a crude product (6.5 g), which was combined with another batch of crude material (6.0 g) produced with a procedure similar to that described above. This material was purified by flash chromatography eluting with

(PE:EA=10:1 ) to get desired compound (4.6g).

MS ( m/z): 463 [MH]⁺.

Preparation 46: 3-{[6-(6-methyl-2-pyridinyl)-4-oxo-4,5-dihydropyrazolo[1 ,5-a]pyrazin- 2-yl]oxy}propyl acetate (P46)

The title compound was prepared with an analogous procedure to that described in Preparation 4 in 600 mg yield from ethyl 3-[(3-{[(1 ,1- dimethylethyl)(dimethyl)silyl]oxy}propyl)oxy]-1-[2-(6-methyl-2-pyridinyl)-2-oxoethyl]-1 H- pyrazole-5-carboxylate (2.3 g, P45).

MS ( m/z): 343 [MH]⁺.

Preparation 47: 3-{[5-{2-[(1 -methylethyl)amino]-2-oxoethyl}-6-(6-methyl-2-pyridinyl)- 4-oxo-4,5-dihydropyrazolo[1,5-a]pyrazin-2-yl]oxy}propyl acetate and 3-{[4-({2-[(1- methylethyl)amino]-2-oxoethyl}oxy)-6-(6-methyl-2-pyridinyl)pyrazolo[1 ,5-a]pyrazin- 2-yl]oxy}propyl acetate (P47, mixture)

To a solution of 3-{[6-(6-methyl-2-pyridinyl)-4-oxo-4,5-dihydropyrazolo[1 ,5-a]pyrazin-2- yl]oxy}propyl acetate (P46, 500 mg) in MeCN (10 ml_), 2-chloro-N-isopropylacetamide (270 mg) and K₂CO₃ (490 mg) were added. The reaction mixture was heated to reflux overnight, then the solvent was removed under reduce pressure, water and DCM were added into it, extracted for three times, combined organic layers and dried with Na₂SO₄, then concentrated under reduced pressure to get title compounds in mixture (610 mg) as a crude product.

MS ( m/z): 442 [MH]⁺.

Preparation 48: 2-[2-[(3-hydroxypropyl)oxy]-6-(6-methyl-2-pyridinyl)-4- oxopyrazolo[1 ,5-a]pyrazin-5(4H)-yl]-Λ/-(1 -methylethyl)acetamide and 2-{[2-[(3- hydroxypropyl)oxy]-6-(6-methyl-2-pyridinyl)pyrazolo[1 ,5-a]pyrazin-4-yl]oxy}-Λ/-(1- methylethyl)acetamide (P48, mixture)

To a solution of 3-(5-(2-(isopropylamino)-2-oxoethyl)-6-(6-methylpyridin-2-yl)-4-oxo-4,5- dihydropyrazolo[1 ,5-a]pyrazin-2-yloxy)propyl acetate (P47, 600 mg) in THF (10 ml.) was added a solution of LiOH (420 mg, 10 mmol) in water (1 ml_). The mixture was stirred at room temperature overnight. Then the mixture was filtered, filtrate was concentrated under reduce pressure to get a crude product (350 mg), which was dissolved in DCM, then cooled down to 0 ⁰C. A solid appeared and was filtered off, and the filtrate was evaporated to get 230 mg title compound crude as yellow solid.

MS ( m/z): 400 [MH]⁺.

Preparation 49: 3-{[5-{2-[(1-methylethyl)amino]-2-oxoethyl}-6-(6-methyl-2-pyridinyl)- 4-oxo-4,5-dihydropyrazolo[1,5-a]pyrazin-2-yl]oxy}propyl methanesulfonate and 3- {[4-({2-[(1-methylethyl)amino]-2-oxoethyl}oxy)-6-(6-methyl-2-pyridinyl)pyrazolo[1,5- a]pyrazin-2-yl]oxy}propyl methanesulfonate (P49, mixture)

To a solution of 2-(2-(3-hydroxypropoxy)-6-(6-methylpyridin-2-yl)-4-oxopyrazolo[1 ,5- a]pyrazin-5(4H)-yl)-N-isopropylacetamide (230 mg, P48) in DCM (20 ml_), Et₃N (1 18 mg) and methanesulfonyl chloride (100 mg), were added. The mixture was stirred at RT overnight, then DCM was removed under reduce pressure to get the product as a yellow amorphous crude (478 mg).

MS ( m/z): 478 [MH]⁺.

Preparation 50: 2-(2-{[(1,1-dimethylethyl)oxo]carbonyl}-1 -{2-[4-fluoro-3- (trifluoromethyl)phenyl]-2-oxoethyl}hydrazino)-2-butenedioate) E, Z mixture (P50)

In a 4L round bottomed flask, 1 ,1-dimethylethyl hydrazinecarboxylate (45g, 334 mmol) was dissolved in dry DMF (1 L) followed by slow addition of DIPEA (0.059 L, 334 mmol); the system was cooled down until intrenal temperature was 5⁰C, then a solution of 2- bromo-1-[4-fluoro-3-(trifluoromethyl)phenyl]ethanone (105 g, 350 mmol) in dry DMF (0.100 L) was added dropwise. After 2 hours at O⁰C, the mixture was poured in to 2 L of water and extracted with diethyl ether (2x1 L); combined organics were washed with water (2x0.5L), dried on sodium sulphate and evaporated under reduced pressure (bath set at 25⁰C) to obtain 140.6 g of 1 ,1-dimethylethyl 2-{2-[4-fluoro-3-(trifluoromethyl)phenyl]-2- oxoethyl}hydrazinecarboxylate (140.6 g, 264 mmol, 79 % yield) as crude material (pale yellow solid) used quickly without further purifications in the next step. Crude material (1 ,1-dimethylethyl 2-{2-[4-fluoro-3-(trifluoromethyl)phenyl]-2- oxoethyl}hydrazinecarboxylate (140.6 g, 264 mmol) was quickly dissolved in absolute Ethanol (1.4 L), then diethyl 2-butynedioate (68 mL, 427 mmol) was added dropwise at rt. After 3 hours the solvent was removed under reduced pressure and the crude material (216 g) was purified on silica gel column eluted with cyclohexane/ethyl acetate 8:2 to obtain a first batch of pure product as major diastereomer (E): diethyl (2E)-(2-{[(1 ,1- dimethylethyl)oxy]carbonyl}-1-{2-[4-fluoro-3-(trifluoromethyl)phenyl]-2-oxoethyl}hydrazino)- 2-butenedioate (107.5 g, 212 mmol, 81 % yield) as yellow solid. Mix fractions of E, Z isomers obtained from the first purification were purified as above described to obtain a second batch as mixture of E/Z diastereomers of diethyl 2-(2-{[(1 ,1- dimethylethyl)oxy]carbonyl}-1-{2-[4-fluoro-3-(trifluoromethyl)phenyl]-2-oxoethyl}hydrazino)- 2-butenedioate (31.1 g, 61.4 mmol, 23.29 % yield) as yellow oil. Batches above described were combined together to get title material as mixture (138.6) of E, Z isomers and processed together in next step

¹H NMR of main E isomer (400 MHz, CDCI₃): δ 8.36-8.13 (m, 2 H) 7.39 (t, 1 H) 4.92 (s, 1 H) 4.81 (S, 2 H) 4.37 (q, 2 H) 4.13 (q, 2 H) 1.48 (S, 9H) 1.36-1.21 (m, 6 H). 1H NMR of E/Z mixture (400 MHz, CDCI₃): δ 8.35-8.13 (m, 2 H) 7.42-7.30 (m, 1 H) 4.92 (s, 1 H) 4.82 (s, 2 H) 4.40-4.08 (m, 4 H) 1.48-1.43 (s, 9H) 1.37-1.21 (m, 6 H).

Preparation 51 : 2-{2-[4-fluoro-3-(trifluoromethyl)phenyl]-20oxoethyl}-5-oxo-2,5- dihydro-1H-pyrazole-3-carboxylate (P51)

A three necked round bottomed flask, equipped with a mechanic stirrer, was charged with poly phosphoric acid (267 ml_, 262 mmol) and, under Argon, the system was heated to 85⁰C (external temperature); at this temperature a yellow solution of diethyl 2-(2-{[(1 ,1- dimethylethyl)oxy]carbonyl}-1-{2-[4-fluoro-3-(trifluoromethyl)phenyl]-2-oxoethyl}hydrazino)- 2-butenedioate (132.6 g, 262 mmol, P50) in dry Toluene (530 ml.) was added under vigorous agitation. After one hour approximately (disappearence of starting material), the mixture was cooled down, taken up with ethyl acetate (2.5 L) and water (1.5 L) and left stirring about 1 hour until poly phosphoric acid was completely dissolved. Phases were separated and the aqueous one was extracted with ethyl acetate 2 x 1 L; combined organic layer was washed with water 3 x 1.5L, with brine 1 x 2 L, dried on sodium sulphate, filtered and evaporated to dryness to afford 130 g of crude material which was triturated at O⁰C with 350 ml of a mixture cyclohexane/ethyl acetate 8:2 for about 1 hour to obtain, after cool wash and removal of the solvent, title compound (36.6 g, 102 mmol, 38.8

% yield) as white solid.

¹H NMR (400 MHz, CDCI₃): δ 8.24 (m, 2 H) 7.38 (t, 1 H) 6.28 (s, 1 H) 5.79 (s, 2 H) 4.28 (q, 2 H) 1.34 (t, 3 H). UPLC/MS (m/z): 361 [MH]⁺ ; rt 0.7 min. Preparation 52: ethyl 1 -{2-[4-fluoro-3-(trifluoromethyl)phenyl]-2-oxoethyl}-3-{[3-(1- piperidinyl)propyl]oxy}-1 H-pyrazole-5-carboxylate (P52)

Under argon atmosphere, a suspension of ethyl 2-{2-[4-fluoro-3-(trifluoromethyl)phenyl]-2- oxoethyl}-5-oxo-2,5-dihydro-1 H-pyrazole-3-carboxylate (54.2 g, 150 mmol, P51 ) in Acetone (915 ml) was added dropwise (over 1 hour) to a suspension of 1-(3- chloropropyl)piperidine hydrochloride (59.6 g, 301 mmol), potassium carbonate (62.4 g, 451 mmol) and potassium iodide (74.9 g, 451 mmol) in Acetone (339 ml) previously heated at reflux; the reaction mixture was reacted at gentle reflux (65⁰C of external temperature) for 15 hours after which it was cooled down to rt and taken up with ethyl acetate (1.5 L) and water (2 L). The aqueous phase was extracted with ethyl acetate (2 x 700 mL) and the combined organics were washed with brine (800 mL), dried on sodium sulphate, filtered and evaporated to dryness. 60 g of crude material were purified using a Biotage Amino Silica KP-NH column eluted with cycloexane/ethyl acetate from 9:1 to 1 :1 to obtain title compound (41.3 g, 85 mmol, 56.5 % yield) as yellow oil.

¹H NMR (400 MHz, CDCI₃): δ 8.23 (m, 2 H) 7.37 (t, 1 H) 6.35 (s, 1 H) 5.83 (s, 2 H) 4.27 (q, 2 H) 4.18 (t, 2H) 2.43 (m, 6H) 1.98 (m, 2H) 1.60 (m, 4H) 1.45 (m, 2H) 1.33 (t, 3 H). UPLC/MS (m/z): 486 [MH]⁺ ; rt 0.63 min.

Preparation 53: lithium 1 -{2-[4-fluoro-3-(trifluoromethyl)phenyl]-2-oxoethyl}-3-{[3-(1- piperidinyl)propyl]oxy}-1 H-pyrazole-5-carboxylate (P53)

To a solution of ethyl 1-{2-[4-fluoro-3-(trifluoromethyl)phenyl]-2-oxoethyl}-3-{[3-(1- piperidinyl)propyl]oxy}-1 H-pyrazole-5-carboxylate (41.3 g, 85 mmol, P52) in Ethanol (495 mL), a solution of lithium hydroxide hydrate (3.57 g, 85 mmol) in water (248 mL) was added and the resulting orange solution was stirred at rt under Argon until disappearance of starting ester (about 50 min, checked by UPLC). Solvent was evaporated in vacuo (water bath set at 35⁰C) and water was eliminated through several cycles of dilution with absolute ethanol/evaporation at reduced pressure to obtain title compound (38.6 g, 83 mmol, 98 % yield) as pale yellow solid.

¹H NMR (400 MHz, DMSO): δ 8.38-8.21 (m, 2 H) 7.69 (t, 1 H) 5.92 (s, 2 H) 5.80 (s, 1 H)

3.99 (t, 2H) 2.31 (m, 6H) 1.78 (m, 2H) 1.53-1.31 (m, 2H).

UPLC/MS (m/z): 458 [MH]⁺ ; rt 0.54 min.

Preparation 54: 1,1 -dimethylethyl {2-[(1-methylethyl)amino]-2-oxoethyl}carbamate

In a 4 L round flask N-{[(1 ,1-dimethylethyl)oxy]carbonyl}glycine (159 g, 908 mmol) was suspended in Dichloromethane (1.6 L), followed by addition, in one portion, of 1 -Ethyl-3- (3-dimethylaminopropyl)carbodiimide hydrochloride (226 g, 1 180 mmol). The resulting solution was cooled down in an ice bath and, at 2⁰C (internal temperature), isopropylamine (100 ml, 1 162 mmol) was added dropwise (the addition was slowly exothermic at the beginning) and the resulting mixture was stirred overnight at room temperature. The mixture was diluted with 500 ml. of DCM, washed with 2 L of sub saturated NaHCO3 solution, with 2 L of HCI 0.2 N solution, with 1 L of brine, dried on sodium sulphate, filtered and evaporated to dryness to obtain 162 g of crude material. This crude was purified on silica gel column eluted with cyclohexane/ethyl acetate from 70:30 to 0:100 to obtain title compound (85.4 g, 395 mmol, 43.5 % yield) as white solid. 1H NMR (400 MHz, CDCI₃): δ 5.94 (s, 1 H) 5.19 (s, 1 H) 4.10 (m, 1 H) 3.74 (d, 2H) 1.48 (s, 9H) 1.18 (d, 6 H).

Preparation 55: /^-(i-methylethyljglycinamide hydrochloride (P55)

HCI 4M solution in 1 ,4-dioxane (839 ml, 3356 mmol) was added to 1 ,1-dimethylethyl {2- [(1-methylethyl)amino]-2-oxoethyl}carbamate (85.4 g, 395 mmol, P54) at O⁰C and the resulting pale yellow solution was stirred at room temperature 1.5 hours then solvent was evaporated under reduced pressure and the wet solid obtained was dried in vacuum over week-end to give title compound (60.8 g, 398 mmol, 101 % yield) as crystalline white off solid.

¹H NMR (400 MHz, DMSO): δ 8.33 (d, 1 H) 8.09 (s, 3H) 3.88 (m, 1 H) 3.48 (s, 2H) 1.09 (d, 6 H). Preparation 56: 1 -{2-[4-fluoro-3-(trifluoromethyl)phenyl]-2-oxoethyl}-N-{2-[(1 ■ methylethyl)amino]-2-oxoethyl}-3-{[3-(1-piperidinyl)propyl]oxy}-1 H-pyrazole-5- carboxamide (P56)

In a round flask lithium 1-{2-[4-fluoro-3-(trifluoromethyl)phenyl]-2-oxoethyl}-3-{[3-(1- piperidinyl)propyl]oxy}-1 H-pyrazole-5-carboxylate (38.6 g, 83 mmol, P53) was dissolved in N,NDimethylformamide (390 ml_); DIPEA (58.2 mL, 333 mmol) and O-(Benzotriazol-i-yl)- N,N,N',N'-tetramethyluronium tetrafluoroborate (37.4 g, 1 17 mmol) were added; formation of complex was carried on for about 45 min, then N1-(1-methylethyl)glycinamide hydrochloride (22.89 g, 150 mmol, P55) was added portion wise. Check after overnight reaction showed disappearance of starting acid; the mixture was diluted with ethyl acetate (0.9 L) and water (0.3 L); the aqueous phase was extracted with ethyl acetate (2 x 0.4 L); combined organics were washed with iced water (8 x 100 mL) and washed with brine (0.7 L), dried on sodium sulphate, filtered and evaporated to dryness to obtain a crude material (yellow oil) which was charged on a Biotage Amino Silica KP-NH column and eluted with cyclohexane/ethyl acetate/methanol 70:25:5 to afford title compound (43.5 g, 78 mmol, 94

% yield) as yellow oil.

UPLC/MS (m/z): 556 [MH]⁺ ; rt 0.56 min.

Preparation 57: 1,1-dimethylethyl 4-({5-[(ethyloxy)carbonyl]-1 H-pyrazol-3-yl}oxy)-1- piperidinecarboxylate (P57)

To a stirred solution of ethyl 5-oxo-2,5-dihydro-1 H-pyrazole-3-carboxylate (0.6 g, 3.84 mmol, which may be prepared as described in Synthesis 2003, 15, 2353-2357), 1 ,1- dimethylethyl 4-hydroxy-1-piperidinecarboxylate (1.160 g, 5.76 mmol) and TPP (1.774 g, 6.76 mmol) in THF (8.4 ml), at 0 ⁰C and under a nitrogen atmosphere, a solution of bis(1 ,1-dimethylethyl) (E)- 1 ,2-diazenedicarboxylate (DBAD) (1.59 g, 6.92 mmol) in THF (2.4 ml) was added. After 5 min the ice-bath was removed and the reaction mixture was stirred at RT. After 2h additional amount of 1 ,1-dimethylethyl 4-hydroxy-i-piperidinecarboxylate (150 mg), TPP (160 mg) and DBAD (140 mg) were added and the reaction mixture was stirred overnight. The reaction mixture was concentrated under vacuum and the residue was purified by FC on silica (eluting with Cy/EA from 1/0 to 7/3) to give 0.32 g of the title product .

MS(m/z): 340.12 [MH]⁺.

Following the above procedure, starting from ethyl 5-oxo-2,5-dihydro-1 H-pyrazole-3- carboxylate (0.8 g, 5.12 mmol) and 1 ,1-dimethylethyl 4-hydroxy-1-piperidinecarboxylate (1.65 g, 8.20 mmol) a further amount of the title compound (0.49 g) was prepared.

MS(m/z): 340.12 [MH]⁺.

Preparation 57 bis: 2-bromo-1-[4-fluoro-3-(trifluoromethyl)phenyl]ethanone (P57bis)

To a vigorously stirred refluxing solution of Cub (15.17 g, 67.9 mmol) in EA (40 ml), a solution of 1-[4-fluoro-3-(trifluoromethyl)phenyl]ethanone (7 g, 34.0 mmol) in dry chloroform (50 ml) was added one pot, then the reaction mixture was refluxed for 6h. The mixture was cooled down to RT, filtered over a pad of celite and evaporated. The residue was partitioned between EA and saturated NaHCO₃ aqueous solution, then organic phase was washed with brine, dried over Na₂SO₄ and concentrated under reduced pressure. The crude product was purified by FC on silica (eluting with Cy/EA from 10/0 to 8/2) to give 6.95 g of the title compound.

NMR (¹H, CDCI3): δ ppm 8.15 - 8.30 (m, 2 H), 7.30 - 7.39 (m, 1 H), 4.45 (s, 2 H).

Preparation 58: 1,1-dimethylethyl 4-[(5-[(ethyloxy)carbonyl]-1 -{2-[4-fluoro-3-

(trifluoromethyl)phenyl]-2-oxoethyl}-1H-pyrazol-3-yl)oxy]-1-piperidinecarboxylate

(P58)

To a stirred solution of 1 ,1-dimethylethyl 4-({5-[(ethyloxy)carbonyl]-1 H-pyrazol-3-yl}oxy)-1- piperidinecarboxylate (P58, 0.81 g, 2.387 mmol) in DMF (8 ml_), at RT, 2-bromo-1-[4- fluoro-3-(trifluoromethyl)phenyl]ethanone (P57bis, 0.75 g, 2.63 mmol) and sodium carbonate (0.55 g, 5.19 mmol) were subsequently added and the reaction mixture was stirred overnight. Ether and cold water were added, the organic phase was washed with water, brine, dried over Na2SO4 and the solvent removed under reduced pressure. The residue was purified by FC on silica (eluting with Cy/EA from 1/0 to 7/3) to give 0.69 g of the title compound as a white foam.

NMR (¹H, CDCI3): δ ppm 8.11 - 8.31 (m, 2 H) 7.37 (t, 1 H), 6.33 (s, 1 H), 5.83 (s, 2 H), 4.68 (dt, 1 H), 4.27 (q, 2 H), 3.64 - 3.81 (m, 2 H), 3.20 - 3.37 (m, 2 H), 1.88 - 2.08 (m, 2 H), 1.68 - 1.86 (m, 2 H), 1.42 - 1.53 (m, 9 H), 1.32 (t, 3 H). MS(m/z): 544.16 [MH]⁺.

Preparation 59: 1 ,1-dimethylethyl 4-({6-[4-fluoro-3-(trifluoromethyl)phenyl]-4-oxo- 4,5-dihydropyrazolo[1 ,5-a]pyrazin-2-yl}oxy)-1 -piperidinecarboxylate (P59)

A mixture of 1 ,1-dimethylethyl 4-[(5-[(ethyloxy)carbonyl]-1-{2-[4-fluoro-3- (trifluoromethyl)phenyl]-2-oxoethyl}-1 H-pyrazol-3-yl)oxy]-1 -piperidinecarboxylate (P58, 0.69 g, 1.303 mmol), ammonium acetate (2.01 g, 26.1 mmol) and acetic acid (1 1 ml) in a sealed vial, was warmed at 130 ⁰C and stirred for 24 h. The reaction mixture was concentrated under vacuum, the residue was diluted with water and extracted with ether. The organic phase was washed with water, brine, dried over Na2SO4 and the solvent removed under reduced pressure to give 154 mg of a crude material mostly containing the title product. The aqueous phase was passed through a MCX cartridge (1g), eluting subsequently with water, methanol and 2N NH3/MeOH to give 230 mg of a crude material mostly containing the free base of the title product. This material was dissolved in DCM (10 ml), BOC-anhydride (0.160 ml, 0.687 mmol) was added and the reaction mixture was stirred for 2h. The reaction mixture was concentrated under reduced pressure, the residue was jointed with the previous crude material (154 mg) and was purified by FC on silica

(eluting with Cy/EA from 1/0 to 1/1 ) to give 46 mg of the title product as a white foam.

MS(ro/z): 497.13 [MH]⁺.

Preparation 60: 1,1 -dimethylethyl 4-[(6-[4-fluoro-3-(trifluoromethyl)phenyl]-5-{2-[(1- methylethyl)amino]-2-oxoethyl}-4-oxo-4,5-dihydropyrazolo[1,5-a]pyrazin-2-yl)oxy]-1- piperidinecarboxylate (P60)

To a stirred solution of 1 ,1-dimethylethyl 4-({6-[4-fluoro-3-(trifluoromethyl)phenyl]-4-oxo- 4,5-dihydropyrazolo[1 ,5-a]pyrazin-2-yl}oxy)-1-piperidinecarboxylate (P59, 46 mg, 0.093 mmol) in DME (0.8 ml) and DMF (0.2 ml), at RT and under a nitrogen atmosphere, sodium hydride (6 mg, 0.150 mmol) was added portionwise. After 5 min, LiBr (20 mg, 0.230 mmol) (fine powdered and dried) and NaI (3 mg, 0.020 mmol) were subsequently added followed after 5 min by 2-chloro-N-(1-methylethyl)acetamide (21 mg, 0.155 mmol). The reaction mixture was warmed to 65 ⁰C and stirred for 6h. The reaction mixture was allowed to reach RT and concentrated under reduced pressure in order to remove the DME. The residue was taken-up with EA and cold water. The organic phase was washed with cold water, brine, dried over Na2SO4 and the solvent evaporated under vacuum. The crude product was purified by FC on silica (eluting with Cy/EA from 8/2 to 3/7) to give 18 mg of the title compound.

MS(ro/z): 596.20 [MH]⁺.

Example 1 : 2-[6-(3-chlorophenyl)-4-oxo-2-{[3-(1 -piperidinyl)propyl]oxy}pyrazolo[1,5- a]pyrazin-5(4H)-yl]-N-(1 -methylethyl)acetamide (E1 )

To a suspension of a mixture of 2-[6-(3-chlorophenyl)-2-[(3-hydroxypropyl)oxy]-4- oxopyrazolo[1 ,5-a]pyrazin-5(4H)-yl]-N-(1-methylethyl)acetamide and 2-({6-(3- chlorophenyl)-2-[(3-hydroxypropyl)oxy]pyrazolo[1 ,5-a]pyrazin-4-yl}oxy)-N-(1- methylethyl)acetamide (30mg, P6 mixture) in dry chloroform (2 ml_), TEA (8.98 μl) and dimethylaminopyridine (0.22 mg) were added. The mixture was cooled to 0⁰C, then methansulfonyl chloride (4.19 μl_) was added and the mixture was stirred at RT for 3h. Methansulfonyl chloride (5 μl_) and TEA (9 μl_) were added and stirring was continued for 2h. Methansulfonyl chloride (5 μl_) and TEA (9 μl_) were added and stirring was continued overnight. The mixture was diluted with DCM and washed with water. The organic phase was dried, filtered and evaporated under reduced pressure. The resulting crude (33 mg) was dissolved in dry DMF (1 ml_), potassium carbonate (45 mg) and piperidine (0.023 ml.) were added and the mixture was stirred at 65⁰C for 2h, then at RT overnight. The mixture was heated at 65°C for additional 7h. After cooling the mixture was diluted with AcOEt and washed with chilly water and brine. The organic phase was dried over Na₂SO₄, filtered and evaporated under vacuum. The crude was purified by SCX cartridge (NH₃ 2M in MeOH as eluent) and by flash chromatography on NH column eluting with Cy/AcOEt (from

0% to 100% of EtOAc) to give the title compound (2 mg)

¹H-NMR (acetone-de) δ: 7.62-7.61 (m, 1 H); 7.58-7.52 (m, 3H); 7.36 (s, 1 H); 7.11 (broad s, 1 H); 6.37 (s, 1 H); 4.41 (s, 2H); 4.31 (t, 2H); 3.99-3.90 (m, 1 H); 2.47-2.35 (m, 6H); 2.00- 1.93 (m, 2H); 1.58-1.53 (m, 4H); 1.45-1.41 (m, 2H); 1.08 (s, 3H); 1.06 (s, 3H). MS (ro/z): 486 [MH]⁺.

Example 2: 2-[6-(3-chlorophenyl)-4-oxo-2-{[3-(1 -piperidinyl)propyl]oxy}pyrazolo[1,5- a]pyrazin-5(4H)-yl]-N-(1 -methylethyl)acetamide hydrochloride (E2)

2-[6-(3-chlorophenyl)-4-oxo-2-{[3-(1-piperidinyl)propyl]oxy}pyrazolo[1 ,5-a]pyrazin-5(4H)- yl]-N-(1-methylethyl)acetamide (2 mg, E1 ) was dissolved in dry DCM (0.5 mL) and hydrogen chloride (1 M solution in Et₂O) (4.5 μl_) was added. The solvent was evaporated and the residue thus obtained triturated with dry diethyl ether. Then diethyl ether was removed and the resultant solid dried under vacuum to provide the title compound (2 mg) as a white solid.

¹H-NMR (acetone-d₆) δ: 12.57 (broad s, 1 H); 7.63-7.49 (m, 4H); 7.36 (s, 1 H); 7.15 (d, 1 H); 6.38 (s, 1 H); 4.44-4.35 (m, 4H); 4.00-3.87 (m, 1 H); 3.57-3.48 (m, 2H); 3.27-3.16 (m, 2H); 2.98-2.89 (m, 2H); 2.51-2.40 (m, 2H); 2.26-2.1 1 (m, 2H); 1.87-1.76 (m, 3H); 1.56- 1.42 (m, 1 H); 1.06 (d, 6H) . MS (m/z): 486 [MH]⁺.

Example 3: N-(1,1-dimethylethyl)-2-[6-(3-methylphenyl)-4-oxo-2-{[3-(1- piperidinyl)propyl]oxy}pyrazolo[1 ,5-a]pyrazin-5(4H)-yl]acetamide (E3)

To a solution of 6-(3-methylphenyl)-2-{[3-(1-piperidinyl)propyl]oxy}pyrazolo[1 ,5-a]pyrazin- 4(5H)-one (240 mg, P10), tetrabutylammonium bromide (63 mg) and potassium hydroxide (51 mg) in THF (6 mL) at 0 ⁰C sodium iodide (108 mg, 0.720 mmol) and a solution of 2- chloro-N-(1 ,1-dimethylethyl)acetamide (108 mg, 0.720 mmol) in THF (1 mL) were added. The resultant mixture was stirred at room temperature for 24 h under nitrogen. Then tetrabutylammonium bromide (13 mg), potassium hydroxide (11 mgl), sodium iodide (30 mg) and 2-chloro-N-(1 ,1-dimethylethyl)acetamide (29 mg) were added and the solution was allowed to stir for further 22 h. The mixture was diluted with DCM and washed with water and brine. The organic phase was dried over anhydrous Na₂SO₄, filtered and evaporated under vacuum. The crude foam obtained was purified by SCX 5g cartridge and afterwards by flash column chromatography on silica gel with a gradient of DCIWMeQH (from 0% to 10% of MeOH) as eluent to give the title compound (55 mg). 1H NMR (400 MHz, CDCI₃): δ 7.40-7.22 (m, 4H), 7.19 (s, 1 H), 6.43 (s, 1 H), 5.58 (s, 1 H), 4.32 (s, 2H), 4.27 (t, 2H), 2.56-2.35 (m, 9H), 2.08-1.98 (m, 2H), 1.66-1.56 (m, 4H), 1.51- 1.39 (m, 2H), 1.33 (s, 9H). MS (m/z): 480 [MH]⁺

Example 4: N-(1 ,1 -dimethylethyl)-2-[6-(3-methylphenyl)-4-oxo-2-{[3-(1 - piperidinyl)propyl]oxy}pyrazolo[1 ,5-a]pyrazin-5(4H)-yl]acetamide hydrochloride (E4)

N-(1 ,1-dimethylethyl)-2-[6-(3-methylphenyl)-4-oxo-2-{[3-(1- piperidinyl)propyl]oxy}pyrazolo[1 ,5-a]pyrazin-5(4H)-yl]acetamide (55 mg, E3) was dissolved in dry DCM (2 ml.) and hydrogen chloride (1.25 M solution in MeOH) (92 μl_) was added. The solvent was evaporated and the residue thus obtained triturated with dry diethyl ether. Then diethyl ether was removed and the resultant solid dried under vacuum to provide the title compound (53 mg) as a white solid.

¹H NMR (400 MHz, DMSO-d₆): δ 9.47 (br s, 1 H), 7.61-7.54 (m, 1 H), 7.49-7.46 (m, 1 H), 7.42-7.19 (m, 4H), 6.55-6.49 (m, 1 H), 4.32 (t, 2H), 4.25 (s, 2H), 3.57-3.42 (m, 2H), 3.17 (br s, 2H), 2.90 (br s, 2H), 2.36-2.31 (m, 3H), 2.17 (br s, 2H), 1.90-1.59 (m, 5H), 1.41 (br s, 1 H), 1.22-1.15 (m, 9H). MS (m/z): 480 [MH]⁺

Example 5: 2-[6-(3-chlorophenyl)-4-oxo-2-{[3-(1 -piperidinyl)propyl]oxy}pyrazolo[1 ,5- a]pyrazin-5(4H)-yl]-Λ/-(1,1-dimethylethyl)acetamide (E5)

The title compound was prepared with an analogous procedure to that described in Example 1 in 42 mg yield as a white solid from 2-[6-(3-chlorophenyl)-2-[(3- hydroxypropyl)oxy]-4-oxopyrazolo[1 ,5-a]pyrazin-5(4H)-yl]-N-(1 ,1-dimethylethyl)acetamide

ClOO mg, P7).

¹H-NMR (400 MHz, CDCI₃) δ: 7.50-7.46 (m, 2H); 7.44-7.38 (m, 2H); 7.19 (s, 1 H); 6.45 (s, 1 H); 5.55 (broad s, 1 H); 4.41-4.29 (m, 4H); 2.73-2.50 (m, 4H); 2.20-2.10 (m, 2H); 1.78- 1.65 (m, 4H); 1.34 (s, 9H). MS (ro/z): 500 [MH]⁺.

Example 6: 2-[6-(3-chlorophenyl)-4-oxo-2-{[3-(1 -piperidinyl)propyl]oxy}pyrazolo[1 ,5- a]pyrazin-5(4H)-yl]-Λ/-(1,1-dimethylethyl)acetamide hydrochloride (E6)

The title compound was prepared with an analogous procedure to that described in Example 2 in 45 mg yield as white solid from 2-[6-(3-chlorophenyl)-4-oxo-2-{[3-(1- piperidinyl)propyl]oxy}pyrazolo[1 ,5-a]pyrazin-5(4H)-yl]-N-(1 ,1-dimethylethyl)acetamide (42 mg, E5).

¹H-NMR (400 MHz, DMSO-d₆) δ: 9.56 (br. s., 1 H) 7.57 - 7.68 (m, 3 H) 7.49 - 7.56 (m, 2

H) 7.43 (dt, 1 H) 6.50 - 6.57 (m, 1 H) 4.24 - 4.35 (m, 4 H) 3.51 (br. s., 2 H) 3.20 (br. s., 2

H) 2.89 (br. s., 2 H) 2.19 (br. s., 2 H) 1.61 - 1.87 (m, 5 H) 1.40 (br. s., 1 H) 1.15 - 1.21 (m,

9 H).

MS (m/z): 500 [MH]⁺ Example 7: N-(1 -methylethyl)-2-[4-oxo-2-{[3-(1 -piperidinyl)propyl]oxy}-6-[3- (trifluoromethyl)phenyl]pyrazolo[1,5-a]pyrazin-5(4H)-yl]acetamide (E7)

The title compound was prepared with an analogous procedure to that described in Example 3 in 32 mg yield as a white solid from 2-{[3-(1-piperidinyl)propyl]oxy}-6-[3- (trifluoromethyl)phenyl]pyrazolo[1 ,5-a]pyrazin-4(5H)-one (240 mg, P12) and 2-chloro-N-(1- methylethyl)acetamide (85 mg, commercially available).

¹H NMR (400 MHz, CDCI₃): δ 7.80-7.73 (m, 3H), 7.66-7.59 (m, 1 H), 7.23 (s, 1 H), 6.47 (s, 1 H), 5.69 (d, 1 H), 4.32 (s, 2H), 4.29 (t, 2H), 4.10-4.00 (m, 1 H), 2.55-2.36 (m, 6H), 2.08- 1.96 (m, 2H), 1.65-1.56 (m, 4H), 1.51-1.40 (m, 2H), 1.15 (d, 6H). MS (m/z): 520 [MH]⁺

Example 8: N-(1 -methylethyl)-2-[4-oxo-2-{[3-(1-piperidinyl)propyl]oxy}-6-[3- (trifluoromethyl)phenyl]pyrazolo[1,5-a]pyrazin-5(4H)-yl]acetamide hydrochloride (E8)

The title compound was prepared with an analogous procedure to that described in Example 4 in 27 mg yield from N-(1-methylethyl)-2-[4-oxo-2-{[3-(1-piperidinyl)propyl]oxy}-

6-[3-(trifluoromethyl)phenyl]pyrazolo[1 ,5-a]pyrazin-5(4H)-yl]acetamide (32 mg, E7).

¹H NMR (400 MHz, DMSO-d₆): δ 9.60 (br. s., 1 H) 7.82 - 7.94 (m, 2 H) 7.70 - 7.82 (m, 3 H) 7.64 - 7.68 (m, 1 H) 6.51 - 6.59 (m, 1 H) 4.17 - 4.39 (m, 4 H) 3.65 - 3.81 (m, 1 H) 3.46 (br. s., 2 H) 3.15 (br. s., 2 H) 2.88 (br. s., 2 H) 2.17 (br. s., 2 H) 1.56 - 1.88 (m, 5 H) 1.41

(br. s., 1 H) 0.95 (d, 6 H).

MS (m/z): 520 [MH]⁺

Example 9: N-(1 -methylethyl)-2-[4-oxo-2-{[3-(1 -piperidinyl)propyl]oxy}-6-{3- [(trifluoromethyl)oxy]phenyl}pyrazolo[1 ,5-a]pyrazin-5(4H)-yl]acetamide (E9)

The title compound was prepared with an analogous procedure to that described in Example 3 in 15 mg yield as a white solid from 2-{[3-(1-piperidinyl)propyl]oxy}-6-{3- [(trifluoromethyl)oxy]phenyl}pyrazolo[1 ,5-a]pyrazin-4(5H)-one (220 mg, P14) and 2-chloro-

N-(1-methylethyl)acetamide (75 mg, commercially available).

¹H NMR (400 MHz, CDCI₃): δ 7.60-7.53 (m, 2H), 7.36-7.29 (m, 2H), 7.20 (s, 1 H), 6.46 (s, 1 H), 5.71 (d, 1 H), 4.33 (s, 2H), 4.29 (t, 2H), 4.10-4.00 (m, 1 H), 2.57-2.36 (m, 6H), 2.09- 1.99 (m, 2H), 1.67-1.57 (m, 4H), 1.51-1.40 (m, 2H), 1.16 (d, 6H). MS (m/z): 536 [MH]⁺

Example 10: N-(1 -methylethyl)-2-[4-oxo-2-{[3-(1 -piperidinyl)propyl]oxy}-6-{3- [(trifluoromethyl)oxy]phenyl}pyrazolo[1 ,5-a]pyrazin-5(4H)-yl]acetamide hydrochloride (E10)

The title compound was prepared with an analogous procedure to that described in Example 4 in 12 mg yield as a white solid from N-(1-methylethyl)-2-[4-oxo-2-{[3-(1- piperidinyl)propyl]oxy}-6-{3-[(trifluoromethyl)oxy]phenyl}pyrazolo[1 ,5-a]pyrazin-5(4H)- yljacetamide (15 mg, E9).

¹H NMR (400 MHz, DMSO-d₆): δ 9.39 (br. s., 1 H) 7.82 (d, 1 H) 7.54 - 7.64 (m, 3 H) 7.46 - 7.52 (m, 2 H) 6.51 - 6.57 (m, 1 H) 4.23 - 4.37 (m, 4 H) 3.65 - 3.80 (m, 1 H) 3.47 (br. s., 2 H) 3.18 (br. s., 2 H) 2.89 (br. s., 2 H) 2.17 (br. s., 2 H) 1.57 - 1.88 (m, 5 H) 1.39 (br. s., 1 H) 0.94 (d, 6 H). MS (m/z): 536 [MH]⁺

Example 11 : N-(1 -methylethyl)-2-[6-[3-(methyloxy)phenyl]-4-oxo-2-{[3-(1 - piperidinyl)propyl]oxy}pyrazolo[1 ,5-a]pyrazin-5(4H)-yl]acetamide (E11)

The title compound was prepared with an analogous procedure to that described in Example 3 in 28 mg yield as a white solid from 6-[3-(methyloxy)phenyl]-2-{[3-(1- piperidinyl)propyl]oxy}pyrazolo[1 ,5-a]pyrazin-4(5H)-one (200 mg, P16).

¹H NMR (400 MHz, CDCI₃): δ 7.37 (t, 1 H), 7.23 (s, 1 H), 7.07-6.98 (m, 3H), 6.44 (s, 1 H), 5.71 (d, 1 H), 4.37 (s, 2H), 4.28 (t, 2H), 4.12-4.01 (m, 1 H), 3.84 (s, 3H), 2.55-2.34 (m, 6H), 2.08-1.98 (m, 2H), 1.66-1.56 (m, 4H), 1.50-1.40 (m, 2H), 1.15 (d, 6H). MS (m/z): 482 [MH]⁺

Example 12: N-(1-methylethyl)-2-[6-[3-(methyloxy)phenyl]-4-oxo-2-{[3-(1 - piperidinyl)propyl]oxy}pyrazolo[1 ,5-a]pyrazin-5(4H)-yl]acetamide hydrochloride (E12)

The title compound was prepared with an analogous procedure to that described in Example 2 in 25 mg yield as a white solid from N-(1-methylethyl)-2-[6-[3- (methyloxy)phenyl]-4-oxo-2-{[3-(1-piperidinyl)propyl]oxy}pyrazolo[1 ,5-a]pyrazin-5(4H)- yljacetamide (28 mg, E11 ).

¹H NMR (400 MHz, DMSO-d₆): δ 9.50 (br. s., 1 H) 7.85 (d, 1 H) 7.53 (s, 1 H) 7.40 (t, 1 H) 6.81 - 7.15 (m, 3 H) 6.50 (m, 1 H) 4.10 - 4.57 (m, 4 H) 3.69 - 3.88 (m, 4 H) 2.62-3.67 (m, 6 H) 1.93-2.27 (br. s., 2 H) 1.18 - 1.89 (m, 6 H) 0.96 (d, 6 H). MS (m/z): 482 [MH]⁺

Example 13: 2-[6-(3-chlorophenyl)-4-oxo-2-{[2-(1-piperidinyl)ethyl]oxy}pyrazolo[1,5- a]pyrazin-5(4H)-yl]-N-(1 -methylethyl)acetamide (E13)

The title compound was prepared with an analogous procedure to that described in Example 1 in 18 mg yield as a white solid from a mixture of 2-[6-(3-chlorophenyl)-2-[(2- hydroxyethyl)oxy]-4-oxopyrazolo[1 ,5-a]pyrazin-5(4H)-yl]-N-(1-methylethyl)acetamide and 2-({6-(3-chlorophenyl)-2-[(2-hydroxyethyl)oxy]pyrazolo[1 ,5-a]pyrazin-4-yl}oxy)-N-(1- methylethyl)acetamide (250 mg, P20 mixture).

¹H-NMR (400 MHZ, CD₃OD) δ: 7.42-7.57 (m, 5H); 6.47 (s, 1 H); 4.42-4.46 (m, 4H); 3.89- 3.95 (m, 1 H); 2.84 (t, 2H); 2.59 (m, 4H); 1.62-1.70 (m, 4H); 1.49-1.55 (m, 2H); 1.1 1 (s, 3H); 1.09 (s, 3H). MS (m/z): 472 [MH]⁺. Example 14: 2-[6-(3-chlorophenyl)-4-oxo-2-{[2-(1-piperidinyl)ethyl]oxy}pyrazolo[1,5- a]pyrazin-5(4H)-yl]-N-(1-methylethyl)acetamide hydrochloride (E14)

The title compound was prepared with an analogous procedure to that described in Example 2 in 18.5 mg yield as a white solid from 2-[6-(3-chlorophenyl)-4-oxo-2-{[2-(1- piperidinyl)ethyl]oxy}pyrazolo[1 ,5-a]pyrazin-5(4H)-yl]-N-(1 -methylethyl)acetamide (18 mg,

E13).

¹H-NMR (400 MHz, DMSO-d₆) δ: 9.75 (br. s., 1 H) 7.86 (d, 1 H) 7.62 - 7.67 (m, 1 H) 7.59 (dq, 1 H) 7.49 - 7.55 (m, 2 H) 7.42 (dt, 1 H) 6.59 - 6.65 (m, 1 H) 4.60 (br. s., 2 H) 4.28 (s, 2 H) 3.69 - 3.80 (m, 1 H) 3.45 - 3.59 (m, 4 H) 2.92 - 3.07 (m, 2 H) 1.61 - 1.89 (m, 5 H) 1.31 - 1.45 (m, 1 H) 0.98 (d, 6 H). MS (m/z): 472 [MH]⁺.

Example 15: 2-[6-(3-chlorophenyl)-2-{[3-(4-morpholinyl)propyl]oxy}-4- oxopyrazolo[1,5-a]pyrazin-5(4H)-yl]-Λ/-(1,1-dimethylethyl)acetamide (E15)

The title compound was prepared with an analogous procedure to that described in Example 1 in 30 mg yield as a white solid from 2-[6-(3-chlorophenyl)-2-[(3- hydroxypropyl)oxy]-4-oxopyrazolo[1 ,5-a]pyrazin-5(4H)-yl]-N-(1 ,1-dimethylethyl)acetamide (85 mg, P7).

¹H-NMR (400 MHz, CDCI 3) δ: 7. 50-7.46 (m, 2H); 7.43-7 .38 (m, 2H); 7.19 (s, 1 H); 6 .45 (s,

1 H); 5.57 (broad s , 1 H); 4. 27-4 .35 (m, 4H); 3.71-3.76 (m, 4H) ; 2.45-2.58 (m, 6H); 1. 97-

2.06 (m, 2H); 1.34 1 [s, 9H) MS (m/z): 502 [MH]⁺.

Example 16: 2-[6-(3-chlorophenyl)-2-{[3-(4-morpholinyl)propyl]oxy}-4- oxopyrazolo[1,5-a]pyrazin-5(4H)-yl]-Λ/-(1,1-dimethylethyl)acetamide hydrochloride (E16)

The title compound was prepared with an analogous procedure to that described in Example 2 in 32.5 mg yield as white solid from 2-[6-(3-chlorophenyl)-2-{[3-(4- morpholinyl)propyl]oxy}-4-oxopyrazolo[1 ,5-a]pyrazin-5(4H)-yl]-N-(1 ,1- dimethylethyl)acetamide (30 mg, E15).

¹H-NMR (400 MHz, DMSO-d₆) δ: 10.14 (br. s., 1 H) 7.57 - 7.63 (m, 3 H) 7.47 - 7.54 (m, 2 H) 7.41 (dt, 1 H) 6.50 - 6.56 (m, 1 H) 4.22 - 4.38 (m, 4 H) 3.93 - 4.06 (m, 2 H) 3.71 (t, 2 H) 3.48 (d, 2 H) 3.24 - 3.30 (m, 2 H) 3.01 - 3.17 (m, 2 H) 2.13 - 2.28 (m, 2 H) 1.13 - 1.21 (m, 9 H). MS (m/z): 502 [MH]⁺

Example 17: 2-[6-(3-chlorophenyl)-2-{[3-(4-morpholinyl)propyl]oxy}-4- oxopyrazolo[1 ,5-a]pyrazin-5(4H)-yl]-Λ/-(1 -methylethyl)acetamide (E17)

The title compound was prepared with an analogous procedure to that described in Example 1 in 30 mg yield as a white solid from 2-[6-(3-chlorophenyl)-2-[(3- hydroxypropyl)oxy]-4-oxopyrazolo[1 ,5-a]pyrazin-5(4H)-yl]-N-(1 ,1-dimethylethyl)acetamide (85 mg, prepared with an analogous procedure to that described for P6 mixture). ¹H-NMR (400 MHz, CDCI₃) δ: 7.52-7.46 (m, 2H); 7.45-7.39 (m, 2H); 7.21 (s, 1 H); 6.47 (s, 1 H); 5.61 (broad s, 1 H); 4.37-4.28 (m, 4H); 4.02-4.13 (m, 1 H); 3.72-3.77 (m, 4H); 2.45- 2.59 (m, 4H); 1.97-2.10 (m, 2H); 1.17 (s, 3H); 1.16 (s, 3H). MS (m/z): 488 [MH]⁺.

Example 18: 2-[6-(3-chlorophenyl)-2-{[3-(4-morpholinyl)propyl]oxy}-4- oxopyrazolo[1 ,5-a]pyrazin-5(4H)-yl]-Λ/-(1 -methylethyl)acetamide hydrochloride (E18)

The title compound was prepared with an analogous procedure to that described in Example 2 in 24 mg yield as white solid from 2-[6-(3-chlorophenyl)-2-{[3-(4- morpholinyl)propyl]oxy}-4-oxopyrazolo[1 ,5-a]pyrazin-5(4H)-yl]-N-(1-methylethyl)acetamide

(25 mg, E17).

¹H-NMR (500 MHz, DMSO-d₆) δ 10.16 (br. s., 1 H) 7.85 (d, 1 H) 7.56 - 7.63 (m, 2 H) 7.48 - 7.54 (m, 2 H) 7.42 (d, 1 H) 6.52 - 6.55 (m, 1 H) 4.23 - 4.35 (m, 4 H) 3.98 (d, 2 H) 3.64 - 3.80 (m, 3 H) 3.47 (d, 2 H) 3.24 - 3.29 (m, 2 H) 3.03 - 3.15 (m, 2 H) 2.19 (br. s., 2 H) 0.98 (d, 6 H). MS (m/z): 488 [MH]⁺

Example 19: 2-[6-(3-chlorophenyl)-4-oxo-2-{[4-(1 -piperidinyl)butyl]oxy}pyrazolo[1,5- a]pyrazin-5(4H)-yl]-Λ/-(1 -methylethyl)acetamide (E19)

The title compound was prepared with an analogous procedure to that described in Example 1 in 21 mg yield as a white solid from mixture of 2-[6-(3-chlorophenyl)-2-[(4- hydroxybutyl)oxy]-4-oxopyrazolo[1 ,5-a]pyrazin-5(4H)-yl]-N-(1-methylethyl)acetamide and 2-({6-(3-chlorophenyl)-2-[(4-hydroxybutyl)oxy]pyrazolo[1 ,5-a]pyrazin-4-yl}oxy)-N-(1- methylethyl)acetamide (210 mg, P24 mixture).

¹H-NMR (400 MHz CDCI₃) δ: 7.40-7.50 (m, 4H); 7.21 (s, 1 H); 6.45 (s, 1 H); 5.63 (m, 1 H); 4.35 (m, 2H); 4.24-4.28 (t, 2H); 4.03-4.10 (m, 1 H); 2.37-2.49 (m, 6H); 1.80-1.90 (m, 2H); 1.67-1.77 (m, 2H); 1.58-1.67 (m, 4H); 1.42-1.51 (m, 2H); 1.17 (s, 3H); 1.16 (s, 3H). MS (m/z): 500 [MH]⁺.

Example 20: 2-[6-(3-chlorophenyl)-4-oxo-2-{[4-(1 -piperidinyl)butyl]oxy}pyrazolo[1 ,5- a]pyrazin-5(4H)-yl]-Λ/-(1-methylethyl)acetamide hydrochloride (E20)

The title compound was prepared with an analogous procedure to that described in Example 2 in 22 mg yield as a white solid from 2-[6-(3-chlorophenyl)-4-oxo-2-{[4-(1- piperidinyl)butyl]oxy}pyrazolo[1 ,5-a]pyrazin-5(4H)-yl]-N-(1 -methylethyl)acetamide (21 mg,

E19).

¹H-NMR (500 MHz, DMSO-d₆) δ: 9.39 (br. s., 1 H) 7.85 (d, 1 H) 7.56 - 7.61 (m, 2 H) 7.48 - 7.54 (m, 2 H) 7.41 (d, 1 H) 6.50 - 6.54 (m, 1 H) 4.22 - 4.34 (m, 4 H) 3.69 - 3.81 (m, 1 H) 3.42 (br. s., 2 H) 3.07 (br. s., 2 H) 2.84 (br. s., 2 H) 1.59 - 1.88 (m, 9 H) 1.32 - 1.45 (m, 1 H) 0.98 (d, 6 H). MS (m/z): 500 [MH]⁺.

Example 21 : 2-[6-(3-chloro-4-fluorophenyl)-4-oxo-2-{[3-(1 - piperidinyl)propyl]oxy}pyrazolo[1 ,5-a]pyrazin-5(4H)-yl]-Λ/-(1-methylethyl)acetamide

(E21)

The title compound was prepared with an analogous procedure to that described in Example 1 in 30 mg yield as a white solid from 2-[6-(3-chlorophenyl)-2-[(3- hydroxypropyl)oxy]-4-oxopyrazolo[1 ,5-a]pyrazin-5(4H)-yl]-N-(1 ,1-dimethylethyl)acetamide

(85 mg, P27 mixture).

¹H-NMR (400 MHz, CDCI₃) δ: 7.58-7.60 (m, 1 H); 7.42-7.45 (m, 1 H); 7.26-7.22 (m, 1 H);

7.18(s, 1 H); 6.45 (s, 1 H); 5.69 (m, 1 H); 4.28-4.32 (m, 4H); 4.01-4.10 (m, 1 H); 2.45-2.70

(m, 4H); 2.05-2.15 (m, 2H); 1.65-1.70 (m, 4H); 1.45-1.55 (m, 2H); 1.11 (s, 3H); 1.09 (s,

3H).

MS (m/z): 488 [MH]⁺.

Example 22: 2-[6-(3-chloro-4-fluorophenyl)-4-oxo-2-{[3-(1 - piperidinyl)propyl]oxy}pyrazolo[1 ,5-a]pyrazin-5(4H)-yl]-Λ/-(1-methylethyl)acetamide hydrochloride (E22)

The title compound was prepared with an analogous procedure to that described in Example 2 in 29 mg yield as white solid from 2-[6-(3-chloro-4-fluorophenyl)-4-oxo-2-{[3- (1-piperidinyl)propyl]oxy}pyrazolo[1 ,5-a]pyrazin-5(4H)-yl]-N-(1-methylethyl)acetamide (28 mg, E21 ).

¹H-NMR (500 MHz, DMSO-d₆) δ 9.50 (br. s., 1 H) 7.82-7.88 (d, 1 H) 7.45 - 7.69 (m, 4 H) 6.50 (m, 1 H) 4.22 - 4.34 (m, 4 H) 3.69 - 3.81 (m, 1 H) 3.42 (br. s., 2 H) 3.07 (br. s., 2 H) 2.84 (br. s., 2 H) 3.12-3.25 (m, 2 H) 3.70-3.80 (m, 2 H) 2.81 - 2.94 (m, 2 H) 2.10 - 2.23 (m, 2 H) 1.59 - 1.88 (m, 5 H) 1.32 - 1.45 (m, 1 H) 0.98 (d, 6 H). MS (m/z): 488 [MH]⁺

Example 23: 2-[6-[2-fluoro-5-(trifluoromethyl)phenyl]-4-oxo-2-{[3-(1 ^■ piperidinyl)propyl]oxy}pyrazolo[1 ,5-a]pyrazin-5(4H)-yl]-Λ/-(1-methylethyl)acetamide (E23)

To a suspension of 2-[6-[2-fluoro-5-(trifluoromethyl)phenyl]-2-[(3-hydroxypropyl)oxy]-4- oxopyrazolo[1 ,5-a]pyrazin-5(4H)-yl]-N-(1-methylethyl)acetamide (70mg, P30) in dry chloroform (2 ml_), TEA (41 μl) was added. The mixture was cooled to 0⁰C, then methansulfonyl chloride (17 μl_) was added and the mixture was stirred at RT for 3o minutes. The mixture was diluted with DCM and washed with water. The organic phase was dried, filtered and evaporated under reduced pressure. The resulting crude was dissolved in dry DMF (2 ml_), potassium carbonate (78 mg) and piperidine (0.033 ml.) were added and the mixture was stirred at 6O⁰C for 4h, then at RT overnight. After cooling the mixture was diluted with AcOEt and washed with chilly water and brine. The organic phase was dried over Na₂SO₄, filtered and evaporated under vacuum. The crude was purified by flash chromatography on silica column eluting with DCM/MeOH (from 0% to 10% of MeOH) to give the title compound (22 mg) as white solid.

¹H-NMR (400 MHz, CDCI₃) δ 7.75 - 7.85 (m, 2 H) 7.30 - 7.39 (m, 1 H) 7.25 (s, 1 H) 6.49 (s, 1 H) 5.59 - 5.73 (m, 1 H) 4.61 - 4.83 (m, 1 H) 4.33 (t, 2 H) 3.86 - 4.12 (m, 2 H) 2.55 - 2.95 (m, 6 H) 2.14 - 2.32 (m, 2 H) 1.81 (br. s., 5 H) 1.25 - 1.30 (m, 1 H) 1.10 (br. s., 6 H). MS (m/z): 538 [MH]⁺.

Example 24: 2-[6-[2-fluoro-5-(trifluoromethyl)phenyl]-4-oxo-2-{[3-(1 - piperidinyl)propyl]oxy}pyrazolo[1 ,5-a]pyrazin-5(4H)-yl]-Λ/-(1-methylethyl)acetamide hydrochloride (E24)

The title compound was prepared with an analogous procedure to that described in Example 2 in 23.5 mg yield as white solid from 2-[6-[2-fluoro-5-(trifluoromethyl)phenyl]-4- oxo-2-{[3-(1-piperidinyl)propyl]oxy}pyrazolo[1 ,5-a]pyrazin-5(4H)-yl]-N-(1- methylethyQacetamide (22 mg, E23).

¹H-NMR (500 MHz, DMSO-d₆) δ 9.31 (br. s., 1 H) 7.84 - 8.03 (m, 1 H) 7.65 - 7.82 (m, 3 H) 7.59 (t, 1 H) 6.54 (s, 1 H) 4.68 (d, 1 H) 4.25 (t, 2 H) 3.84 (d, 1 H) 3.47 - 3.64 (m, 1 H) 3.30 - 3.50 (m, 2 H) 3.04 - 3.20 (m, 2 H) 2.71 - 2.98 (m, 2 H) 2.01 - 2.21 (m, 2 H) 1.46 - 1.87 (m, 5 H) 1.22 - 1.45 (m, 1 H) 0.67 - 0.97 (m, 6 H) . MS (m/z): 538 [MH]⁺

Example 25: Λ/-(1,1-dimethylethyl)-2-[4-oxo-2-{[3-(1 -piperidinyl)propyl]oxy}-6-[3- (trifluoromethyl)phenyl]pyrazolo[1,5-a]pyrazin-5(4H)-yl]acetamide (E25)

The title compound was prepared with an analogous procedure to that described in Example 1 in 70 mg yield as a white solid from N-(1 ,1-dimethylethyl)-2-[2-[(3- hydroxypropyl)oxy]-4-oxo-6-[3-(trifluoromethyl)phenyl]pyrazolo[1 ,5-a]pyrazin-5(4H)- yliacetamide (100 mg, P33).

¹H-NMR (400 MHz, CDCI 3) 5 7.69 - 7.82 (m, 3 H) 7.58 - 7.66 (m, 1 H) 7.21 (s, 1 H) 6 .47

(s, 1 H) 5.54 - 5.60 (m, 1 H) 4.23 - 4 .34 (m, 4 H) 2. 47 - 2 .56 (m, 2 H) 2.37 - 2.47 (m, 3 H)

1.95 - 2. 09 (m , 3 H) 1.56 - ^■ 1 . 63 (m, 4 H) 1.41 - ^■ 1 .52 (m, 2 H) 1.33 (s, 9 H). MS (m/z): 534 [MH]⁺.

Example 26: N-(1,1-dimethylethyl)-2-[4-oxo-2-{[3-(1 -piperidinyl)propyl]oxy}-6-[3- (trifluoromethyl)phenyl]pyrazolo[1,5-a]pyrazin-5(4H)-yl]acetamide hydrochloride (E26)

The title compound was prepared with an analogous procedure to that described in Example 4 in 74 mg yield as white solid from N-(1 ,1-dimethylethyl)-2-[4-oxo-2-{[3-(1- piperidinyl)propyl]oxy}-6-[3-(trifluoromethyl)phenyl]pyrazolo[1 ,5-a]pyrazin-5(4H)- yljacetamide (70 mg, E25).

¹H-NMR (500 MHz, DMSO-d₆) δ 9.31 (br. s., 1 H) 7.84 - 8.03 (m, 1 H) 7.65 - 7.82 (m, 3 H) 7.59 (t, 1 H) 6.54 (s, 1 H) 4.68 (d, 1 H) 4.25 (t, 2 H) 3.84 (d, 1 H) 3.47 - 3.64 (m, 1 H) 3.30 - 3.50 (m, 2 H) 3.04 - 3.20 (m, 2 H) 2.71 - 2.98 (m, 2 H) 2.01 - 2.21 (m, 2 H) 1.46 - 1.87 (m, 5 H) 1.22 - 1.45 (m, 1 H) 0.67 - 0.97 (m, 6 H). MS (m/z): 534 [MH]⁺

Example 27: 2-[6-[4-fluoro-3-(trifluoromethyl)phenyl]-4-oxo-2-{[3-(1 - piperidinyl)propyl]oxy}pyrazolo[1 ,5-a]pyrazin-5(4H)-yl]-N-(1-methylethyl)acetamide

(E27)

Method a) The title compound was prepared with an analogous procedure to that described in Example 23 in 48 mg yield as a white solid from a mixture of 2-[6-[4-fluoro-3- (trifluoromethyl)phenyl]-2-[(3-hydroxypropyl)oxy]-4-oxopyrazolo[1 ,5-a]pyrazin-5(4H)-yl]-N- (1 -methylethyl)acetamide and 2-({6-[4-fluoro-3-(trifluoromethyl)phenyl]-2-[(3- hydroxypropyl)oxy]pyrazolo[1 ,5-a]pyrazin-4-yl}oxy)-N-(1-methylethyl)acetamide (360 mg,

P36 mixture).

¹H-NMR (400 MHz, CDCI₃) δ 7.70 - 7.87 (m, 2 H) 7.30 - 7.37 (m, 1 H) 7.21 (d, 1 H) 6.47 (s, 1 H) 5.66 - 5.83 (m, 1 H) 4.18 - 4.38 (m, 4 H) 3.92 - 4.17 (m, 1 H) 2.32 - 2.56 (m, 6 H) 1.94 - 2.10 (m, 2 H) 1.56 - 1.65 (m, 4 H) 1.41 - 1.50 (m, 2 H) 1.16 (d, 6 H) MS (m/z): 538 [MH]⁺.

Method b)

A 1 L round bottomed flask, equipped with a mechanical stirring bar and a condenser, was charged with polyphosphoric acid (87 ml_, 78 mmol) and the system was heated to 9O⁰C. At this temperature a solution of 1-{2-[4-fluoro-3-(trifluoromethyl)phenyl]-2-oxoethyl}-N-{2- [(1-methylethyl)amino]-2-oxoethyl}-3-{[3-(1-piperidinyl)propyl]oxy}-1 H-pyrazole-5- carboxamide (43.5 g, 78 mmol, P56) in toluene (200 ml.) and absolute ethanol (100 ml.) was added slowly under vigorous agitation to obtain an homogeneous slurry. The mixture was left stirring for 5 hours. The slurry was cooled down to rt and diluted with EtOAc (1 L) and water (1 L). The biphasic system was basified until pH 8 with NaOH 2 M after which phases were separated and the aqueous one was back extracted with 1 L of EtOAc; combined organics were washed with brine, dried on sodium sulphate and evaporated to dryness to obtain about 58 g of crude material. This crude was triturated with 200 mL of diethyl ether at rt to obtain, after removal of solvent, 33.93 g material as yellow solid. A second trituration with 150 mL of diethyl ether furnished 33.7 g of material. This solid was dissolved in 1.3 L of ethyl acetate and washed with water (2 x 250 mL), with brine, dried on sodium sulphate, filtered and evaporated to drieness to obtain title compound (33.6 g,

62.5mmol, 80 % yield).

¹H NMR (400 MHz, DMSO): δ 7.86 (m, 3 H) 7.66 (m, 2 H) 6.51 (s, 1 H) 4.36-4.19 (m, 4 H) 3.72 (m, 1 H) 2.34 (m, 6H) 1.89 (m, 2H) 1.55-1.32 (m, 6H) 0.95 (d, 6H).

Method c)

Two batches of the title compound (E27, 3.8 g and 1.85 g, obtained with a similar procedure to that described in E27, method a)) were dissolved in DCM; the two solutions were gathered and evaporated. The residue was triturated with pentan, the latter was removed under reduced pressure to afford the title compound (5.6g, 10.42 mmol).

X Ray Powder Diffraction (XRPD) analysis was performed on the batch obtained with the methodology described in method c), on Panalytical X'Pert Pro, using x'celerator / type RTMS detector. The acquisition conditions were: radiation: Cu K(, generator tension: 40 kV, generator current: 4OmA, start angle: 2.0 °2(, end angle: 45.0 °2( step size: 0.0170 °2(depends on actual X'celerator used) time per step: 32.3024 sec (about 10 min) slow scan or 9.5 sec for fast scan. The sample was prepared on a low background sample holder.

It will be recognised that spectra and diffraction data will vary slightly according to various factors such as the temperature, concentration and instrumentation used. The skilled person will recognise that XRPD peak positions are affected by differences in sample height. The peak positions quoted herein are thus subject to a variation of +/- 0.15 degrees 2-theta.

Characteristic XRPD angles and d-spacing are reported in Table 1. Table 1

Method d)

2-[6-[4-fluoro-3-(trifluoromethyl)phenyl]-4-oxo-2-{[3-(1-piperidinyl)propyl]oxy}pyrazolo[1 ,5- a]pyrazin-5(4H)-yl]-N-(1-methylethyl)acetamide [E27, 50 mg, obtained as described in method c)] in methanol (0.2 ml) was stirred for 24 hours at 50⁰C. Methanol (0.2 ml) and tert-butyl methyl ether was added. Additional 2-[6-[4-fluoro-3-(trifluoromethyl)phenyl]-4- oxo-2-{[3-(1-piperidinyl)propyl]oxy}pyrazolo[1 ,5-a]pyrazin-5(4H)-yl]-N-(1- methylethyl)acetamide was added until saturation was achieved. The resulting slurry was cooled to 40⁰C, stirred for 3 days at 40°C, then cooled to 35°C and stirred for 24 hours at 35°C. The mixture was cooled to 0⁰C for 24 hours and the solid was collected by filtration.

X-Ray Powder Diffraction (XRPD) analysis was performed on the batch obtained with the methodology described in method d), on a Panalytical Cubix Pro, using an X'celerator RTMS (real time multi-strip) detector. The acquisition conditions were: radiation: Cu Ka, generator tension: 40 kV, generator current: 4OmA, start angle: 2.0 °2Θ, end angle: 40.0 °2Θ step size: 0.0201 °2Θdepends on actual X'celerator used) time per step: 19.050 sec. The sample was prepared on a low background sample holder.

Characteristic XRPD angles and d-spacing are recorded in Table 2. Table 2

Method e)

A slurry of 2-[6-[4-fluoro-3-(trifluoromethyl)phenyl]-4-oxo-2-{[3-(1- piperidinyl)propyl]oxy}pyrazolo[1 ,5-a]pyrazin-5(4H)-yl]-N-(1-methylethyl)acetamide [E27, 61 mg, obtained as described in method c)] in water (0.4 ml) was stirred at 45-50⁰C for 2 weeks. The solid was collected by filtration, washed with water, dried on the filter under vacuum for 2 hours. The solid was further dried under vacuum over phosphorus pentoxide at 70⁰C overnight.

Method f)

2-[6-[4-fluoro-3-(trifluoromethyl)phenyl]-4-oxo-2-{[3-(1-piperidinyl)propyl]oxy}pyrazolo[1 ,5- a]pyrazin-5(4H)-yl]-N-(1-methylethyl)acetamide [E27, 55 mg, obtained as described in method c)] was stirred as a slurry in water (1.5 ml) seeded with 2-[6-[4-fluoro-3- (trifluoromethyl)phenyl]-4-oxo-2-{[3-(1-piperidinyl)propyl]oxy}pyrazolo[1 ,5-a]pyrazin-5(4H)- yl]-N-(1-methylethyl)acetamide [obtained as described in method e)]. The mixture was stirred for 3 days at 45 - 50⁰C. The slurry was cooled to ambient temperature and the solid was collected by filtration and dried on the filter under vacuum for 1 hour.

Method g) A solution of 2-[6-[4-fluoro-3-(trifluoromethyl)phenyl]-4-oxo-2-{[3-(1- piperidinyl)propyl]oxy}pyrazolo[1 ,5-a]pyrazin-5(4H)-yl]-N-(1-methylethyl)acetamide [E27, 63 mg, obtained as described in method c)] in a mixture of acetone (1.0 ml) and water (0.6 ml) was heated at 45°C and seeded with 2-[6-[4-fluoro-3-(trifluoromethyl)phenyl]-4- oxo-2-{[3-(1-piperidinyl)propyl]oxy}pyrazolo[1 ,5-a]pyrazin-5(4H)-yl]-N-(1- methylethyl)acetamide [obtained as described in method f)]. The reaction mixture was temperature cycled for 24 hours between 45°C to 15°C. The solid was collected by filtration and washed with water then dried under vacuum for 2 hours at 50⁰C.

X-Ray Powder Diffraction (XRPD) analysis was performed on the batch obtained with the methodology described in method g), on a Panalytical Cubix Pro, using an X'celerator RTMS (real time multi-strip) detector. The acquisition conditions were: radiation: Cu Ka, generator tension: 40 kV, generator current: 4OmA, start angle: 2.0 °2Θ, end angle: 40.0 °2Θ step size: 0.0201 °2Θdepends on actual X'celerator used) time per step: 19.050 sec. The sample was prepared on a low background sample holder. It will be recognised that spectra and diffraction data will vary slightly according to various factors such as the temperature, concentration and instrumentation used. The skilled person will recognise that XRPD peak positions are affected by differences in sample height. The peak positions quoted herein are thus subject to a variation of +/- 0.15 degrees 2-theta. Characteristic XRPD angles and d-spacing are recorded in Table 3. Table 3

Method h)

A slurry of 2-[6-[4-fluoro-3-(trifluoromethyl)phenyl]-4-oxo-2-{[3-(1- piperidinyl)propyl]oxy}pyrazolo[1 ,5-a]pyrazin-5(4H)-yl]-N-(1-methylethyl)acetamide [E27, 51 mg, obtained as described in method c)] in a mixture of water (0.3 ml) and methanol (0.6 ml) was seeded with 2-[6-[4-fluoro-3-(trifluoromethyl)phenyl]-4-oxo-2-{[3-(1- piperidinyl)propyl]oxy}pyrazolo[1 ,5-a]pyrazin-5(4H)-yl]-N-(1-methylethyl)acetamide

[obtained as described in method e)]. The mixture was stirred at 45-50⁰C for 3 days. The slurry was cooled to ambient temperature and the solid was collected by filtration, then dried on the filter for 1 hour under vacuum. The solid was stirred as a slurry in water (0.5 ml) with additional amounts of 2-[6-[4-fluoro-3-(trifluoromethyl)phenyl]-4-oxo-2-{[3-(1- piperidinyl)propyl]oxy}pyrazolo[1 ,5-a]pyrazin-5(4H)-yl]-N-(1-methylethyl)acetamide [E27, 40 mg, obtained as described in method c)] for 1.5 hours at 100⁰C.

X-Ray Powder Diffraction (XRPD) analysis was performed on the batch obtained with the methodology described in method h), on a Panalytical Cubix Pro, using an X'celerator RTMS (real time multi-strip) detector. The acquisition conditions were: radiation: Cu Ka, generator tension: 40 kV, generator current: 4OmA, start angle: 2.0 °2Θ, end angle: 40.0 °2Θ step size: 0.0201 °2Θdepends on actual X'celerator used) time per step: 19.050 sec. The sample was prepared on a low background sample holder. It will be recognised that spectra and diffraction data will vary slightly according to various factors such as the temperature, concentration and instrumentation used. The skilled person will recognise that XRPD peak positions are affected by differences in sample height. The peak positions quoted herein are thus subject to a variation of +/- 0.15 degrees 2-theta.

Characteristic XRPD angles and d-spacing are recorded in Table 4. Table 4

Method i)

A batch of 2-[6-[4-fluoro-3-(trifluoromethyl)phenyl]-4-oxo-2-{[3-(1- piperidinyl)propyl]oxy}pyrazolo[1 ,5-a]pyrazin-5(4H)-yl]-N-(1-methylethyl)acetamide [E27, obtained as described in method h)] was heated to 150⁰C for 30 minutes.

X-Ray Powder Diffraction (XRPD) analysis was performed on the batch obtained with the methodology described in method i), on a Panalytical Cubix Pro, using an X'celerator RTMS (real time multi-strip) detector. The acquisition conditions were: radiation: Cu Ka, generator tension: 40 kV, generator current: 4OmA, start angle: 2.0 °2Θ, end angle: 40.0 °2Θ step size: 0.0201 °2Θdepends on actual X'celerator used) time per step: 19.050 sec. The sample was prepared on a low background sample holder.

Characteristic XRPD angles and d-spacing are reported in Table 5. Table 5

Example 28: 2-[6-[4-fluoro-3-(trifluoromethyl)phenyl]-4-oxo-2-{[3-(1- piperidinyl)propyl]oxy}pyrazolo[1 ,5-a]pyrazin-5(4H)-yl]-Λ/-(1-methylethyl)acetamide hydrochloride (E28)

Method a)

The title compound was prepared with an analogous procedure to that described in Example 4 in 49 mg yield as white solid from 2-[6-[4-fluoro-3-(trifluoromethyl)phenyl]-4- oxo-2-{[3-(1-piperidinyl)propyl]oxy}pyrazolo[1 ,5-a]pyrazin-5(4H)-yl]-N-(1- methylethyl)acetamide (48 mg, E27).

¹H-NMR (500 MHz, DMSO-d₆) δ 9.43 (br. s., 1 H) 7.75 - 7.93 (m, 3 H) 7.58 - 7.72 (m, 2 H) 6.53 (s, 1 H) 4.16 - 4.38 (m, 4 H) 3.61 - 3.76 (m, 1 H) 3.38 - 3.53 (m, 2 H) 3.11 - 3.25 (m, 2 H) 2.79 - 2.94 (m, 2 H) 2.07 - 2.23 (m, 2 H) 1.73 - 1.86 (m, 2 H) 1.57 - 1.73 (m, 3 H) 1.28 - 1.44 (m, 1 H) 0.92 (d, 6 H). MS (m/z): 538 [MH]⁺

Method b) To a solution of 2-[6-[4-fluoro-3-(trifluoromethyl)phenyl]-4-oxo-2-{[3-(1- piperidinyl)propyl]oxy}pyrazolo[1 ,5-a]pyrazin-5(4H)-yl]-N-(1-methylethyl)acetamide (33.6 g, 62.5 mmol, E27) in Dichloromethane (235 ml)/Methanol (118 ml), HCI 1 M in Et20 (70 ml, 70.0 mmol) was added dropwise over 15 min. After about 15 min of stirring, the solvent was evaporated and the resulting solid residue (40 g) was triturated with 120 ml_ of diethyl ether for about 20 min, washed with diethyl ether and with pentane to obtain, after drying overnight at 4O⁰C, title compound (34.73 g, 60.5 mmol, 97 % yield) as off white solid.

¹H NMR (400 MHz , DMSO): δ ppm 9.74 (bs, 1 H) 7.87 (m, 3 H) 7.68 (m, 2 H) 6.56 (s, 1 H)

4.30 (m, 4 H) 3.71 (m, 1 H) 3.48 (m , 2H) 3.19 (m, 2H) 2.89 (m, 2H) 2.20 (m, 2H) 1 .75 (m,

5H) 1.38 (m, 1 H) O .94 (d, 6H).

Example 29: Λ/-(1,1-dimethylethyl)-2-[6-[4-fluoro-3-(trifluoromethyl)phenyl]-4-oxo-2- {[3-(1-piperidinyl)propyl]oxy}pyrazolo[1,5-a]pyrazin-5(4H)-yl]acetamide hydrochloride (E29)

To a solution of N-tert-butyl-2-(6-(4-fluoro-3-(trifluoromethyl)phenyl) -2-(3-hydroxypropoxy)-4-oxopyrazolo[1 ,5-a]pyrazin-5(4H)-yl)acetamide (1.436 g, P37) in DCM (30 ml.) triethylamine (0.646 g) and methanesulfonyl chloride (0.510 g) were added. The mixture was stirred at room temperature for 1 hour. Solvent was removed in vacuo to give a crude (1.67 g) that was dissolved in acetonitrile (30 ml.) and K₂CO₃ (616 mg) and piperidine (1.518 g) were added. The mixture was stirred at 80 ⁰C for 1.5 hours. Solvent was removed in vacuo. The residue was partitioned between EA (50 ml.) and water (20 ml_). The organic layer was washed with brine (20 ml_), dried with Na₂SO₄ and filtered. Solvent was removed in vacuo and the crude product was purified by preparative HPLC to give the title compound as free base (150mg). To a solution of this product in dichloromethane HCI in Ether (0.1 ml.) was added at 0 ⁰C and the mixture was stirred for 30min. The mixture was concentrated under reduced pressure to give the title compound (160 mg). 1H-NMR (400 MHz, DMSO-d₆) δ 0.70 (9H, s), 0.95 (2H, m), 1.25 (1 H, m), 1.36-1.38 (4H, m), 1.82 (2H, m), 2.42-2.47 (2H, m), 2.72-2.73 (2H, m), 3.00-3.03 (2H, m), 3.87-3.88 (4H, m), 6.11 (1 H, s), 7.22-7.26 (3H, m), 7.41-7.44 (2H, m), 9.92 (1 H, s) . MS (m/z): 552[MH]⁺

Example 30: 2-[6-(3-chloro-2-fluorophenyl)-4-oxo-2-{[3-(1 - piperidinyl)propyl]oxy}pyrazolo[1 ,5-a]pyrazin-5(4H)-yl]-N-(1-methylethyl)acetamide hydrochloride (E30)

To a solution of 6-(3-Chloro-2-fluoro-phenyl)-2-(3-piperidin-1-yl-propoxy)-5H-pyrazolo[1 ,5- a]pyrazin-4-one (220 mg, P39) in DMF (5 ml.) was added 2-chloro-N-isopropyl-acetamide (88.4 mg) and K₂CO3 (150.2 mg). The mixture was stirred at RT for 15 mins and then heated at 60 ⁰C for overnight. Water was added to the mixture and the product extracted with EA. The organic layer was washed with brine and water. The organic phase was dried, filtered and concentrated to get the crude that was purified by SI column, by preparative TLC and by preparative HPLC to give the title compound as free base (90 mg). To a solution of this product in dichloromethane HCI in Ether (0.1 mL) was added at 0 ⁰C and the mixture was stirred for 30min. The mixture was concentrated under reduced pressure to give the title compound (43 mg).

¹H-NMR (400 MHz, MeOD) δ 0.97-1.05 (6H, m), 1.51-1.54 (1 H, m), 1.80-1.87 (3H, m), 1.94-1.98 (2H, m), 2.27-2.32 (2H, m), 2.95-3.01 (2H, m), 3.30-3.34 (2H, m), 3.58-3.60 (2H, m), 3.78-3.81 (1 H, m), 4.08-4.12 (1 H, m), 4.38-4.41 (2H, m), 4.81 (1 H, s), 6.49 (1 H, s), 7.28-7.32 (1 H, m), 7.38-7.41 (1 H, m), 7.52 (1 H, s), 7.66-7.70 (1 H, m). MS (m/z): 504[MH]⁺

Example 31 : 2-[6-[3,5-bis(trifluoromethyl)phenyl]-4-oxo-2-{[3-(1 - piperidinyl)propyl]oxy}pyrazolo[1 ,5-a]pyrazin-5(4H)-yl]-Λ/-(1-methylethyl)acetamide hydrochloride (E31)

The title compound was prepared with an analogous procedure to that described in Example 30 in 8 mg yield from 6-(3,5-bis-trifluoromethyl-phenyl)-2-(3-piperidin-1-yl- propoxy)-5H-pyrazolo[1 ,5-a]pyrazin-4-one (230 mg, P40). 1H-NMR (400 MHz, MeOD) δ 1.02-1.04 (6H, d), 1.51-1.53 (1 H, m), 1.77-1.79 (3H, m), 1.94-1.96 (2H, m), 2.23-2.27 (2H, m), 2.91-2.95 (2H, m), 3.30-3.32 (2H, m), 3.56-3.58 (2H, m), 3.83-3.87 (2H, m), 6.47-6.48 (1 H, d), 7.54-7.55 (1 H, d), 8.13-8.14 (1 H, d). MS (m/z): 588[MH]⁺

Example 32: 2-[6-[4-fluoro-3-(trifluoromethyl)phenyl]-4-oxo-2-[4-(1-pyrrolidinyl)-1- piperidinyl]pyrazolo[1 ,5-a]pyrazin-5(4H)-yl]-Λ/-(1 -methylethyl)acetamide (E32)

A mixture of 2-[6-[4-fluoro-3-(trifluoromethyl)phenyl]-2-iodo-4-oxopyrazolo[1 ,5-a]pyrazin- 5(4H)-yl]-Λ/-(1-methylethyl)acetamide and 2-[6-[4-fluoro-3-(trifluoromethyl)phenyl]-2-iodo- 4-oxopyrazolo[1 ,5-a]pyrazin-5(4H)-yl]-Λ/-(1-methylethyl)acetamide (50 mg, P44 mixture), K₂CO₃ (40 mg), prolina (16 mg), copper iodide (27 mg) and 4-(1-pyrrolidinyl)piperidine (150 mg) was suspended in dry DMSO (2 ml.) and the mixture was shaken at 8O⁰C for 2Oh. After cooling, the mixture was diluted with AcOEt and washed with a saturated solution of NH₄CI. The organic phase was dried and evaporated under reduced pressure. The crude was purified by Si flash chromatography, eluting with DCM/MeOH = 9:1 , and by NH column eluting with Cy/ AcOEt (gradient from 100 to 0% of Cy) to give the title compound (6 mg) as white solid. ¹H-NMR (400 MHz, CDCI3-d₆) δ 7.81-7.75 (m, 2H); 7.36-7.30 (t, 1 H); 7.22 (s, 1 H); 6.44 (s, 1 H); 5.78 (b s, 1 H); 4.30 (b s, 2H); 4.10-4.01 (m, 1 H); 3.90-3.82 (m, 2H); 2.94-2.85 (m, 2H); 2.69-2.61 (m, 4H); 2.28-2.17 (m, 1 H); 2.05-1.97 (m, 2H); 1.87-1.80 (m, 4H); 1.75- 1.65 (m, 2H); 1.16 (d, 6H) . MS (m/z): 549[MH]⁺

Example 33: 2-[6-[4-fluoro-3-(trifluoromethyl)phenyl]-4-oxo-2-[4-(1 -pyrrolidinyl)-1 - piperidinyl]pyrazolo[1 ,5-a]pyrazin-5(4H)-yl]-Λ/-(1 -methylethyl)acetamide dihydrochloride (E33)

The title compound was prepared with an analogous procedure that described in Example 4 in 6.7 mg yield from 2-[6-[4-fluoro-3-(trifluoromethyl)phenyl]-4-oxo-2-[4-(1-pyrrolidinyl)-1- piperidinyl]pyrazolo[1 ,5-a]pyrazin-5(4H)-yl]-N-(1-methylethyl)acetamide (6 mg, E32).

¹H-NMR (500 MHz, DMSO-d₆) δ 10.01 (br. s., 2 H) 7.78 - 7.91 (m, 3 H) 7.66 (t, 1 H) 7.61 (s, 1 H) 6.62 (s, 1 H) 4.29 (br. s., 2 H) 3.91 - 4.02 (m, 2 H) 3.64 - 3.77 (m, 1 H) 3.47 - 3.59 (m, 2 H) 3.27 - 3.33 (m, 1 H) 2.99 - 3.15 (m, 2 H) 2.75 - 2.87 (m, 2 H) 2.05 - 2.14 (m, 2 H) 1.79 - 2.03 (m, 4 H) 1.63 - 1.77 (m, 2 H) 0.94 (d, 6 H). MS (m/z): 549[MH]⁺

Example 34: Λ/-(1-methylethyl)-2-[6-(6-methyl-2-pyridinyl)-4-oxo-2-{[3-(1- piperidinyl)propyl]oxy}pyrazolo[1 ,5-a]pyrazin-5(4H)-yl]acetamide hydrochloride (E34)

To a solution of 3-(5-(2-(isopropylamino)-2-oxoethyl)-6-(6-methylpyridin-2-yl)-4-oxo-4,5- dihydropyrazolo[1 ,5-a]pyrazin-2-yloxy)propyl methanesulfonate and 3-{[4-({2-[(1- methylethyl)amino]-2-oxoethyl}oxy)-6-(6-methyl-2-pyridinyl)pyrazolo[1 ,5-a]pyrazin-2- yl]oxy}propyl methanesulfonate (470 mg, P49, mixture) in MeCN (20 ml_), K₂CO₃ (209 mg) and piperidine (257 mg) were added. The reaction mixture was heated to reflux overnight, then cooled down to RT, organic solvent was removed under reduce pressure. The mixture was diluted with AcOEt and washed with water. The organic phase was dried over Na₂SO₄, filtered and evaporated under reduce pressure to get crude product. The crude product was purified by preparative T. L. C. eluting with (PE:EA=2:1 ) and trasformed into

HCI salt (title compound, 12 mg, E34)

¹H-NMR (400 MHz, CD₃OD) δ 8.35-8.50 (1 H, m), 7.80-8.05 (3H, m), 6.55 (1 H, m), 4.55 (2H, m), 4.40 (2H, m), 3.95 (1 H, m), 3.60 (2H, m), 3.34 (2H, m), 2.98 (2H, m), 2.80 (3H, m), 2.40 (2H, m), 1.70-2.00 (5H, m), 1.52 (1 H, m), 1.15 (6H, m). MS (m/z): 467 [MH]⁺

Example 35: 2-[2-[(1 -cyclopentyl^-piperidinylJoxyl-θ-^-fluoro-S-

(trifluoromethyl)phenyl]-4-oxopyrazolo[1,5-a]pyrazin-5(4H)-yl]-N-(1- methylethyl)acetamide (E35)

To a solution of 1 ,1-dimethylethyl 4-[(6-[4-fluoro-3-(trifluoromethyl)phenyl]-5-{2-[(1- methylethyl)amino]-2-oxoethyl}-4-oxo-4,5-dihydropyrazolo[1 ,5-a]pyrazin-2-yl)oxy]-1- piperidinecarboxylate (P60, 18 mg, 0.030 mmol) in DCM (0.1 ml_), TFA (30 μL, 0.389 mmol) was added and the reaction mixture was stirred for 1 h. The solution was concentrated under reduced pressure, the residues was taken up with DCM and passed through a SCX cartridge, eluting with MeOH and 2N NH3 in methanol. The organic phase was removed under reduced pressure to give 14 mg of the corresponding free base. This crude material was dissolved in DCE (0.4 ml_), cyclopentanone (6 μL, 0.067 mmol) was added at RT. After 10 min, acetic acid (2.1 μL, 0.037 mmol) was added, followed after 15 min by sodium triacetoxyborohydride (9.61 mg, 0.045 mmol). DCM was added, the organic phase was washed with saturated NaHCO3, brine, dried over Na2SO4 and the solvent removed under reduced pressure. The crude material so obtained was dissolved in methanol and passed through a SCX cartridge (eluting with MeOH and 2N NH3/MeOH) to give 10 mg of the title product as a white foam. NMR (¹H, CDCI3): δ 7.72 - 7.87 (m, 2 H), 7.32 (t, 1 H), 7.28 (s, 1 H), 6.45 (s, 1 H), 5.79 (d, 1 H), 4.62 (dt, 1 H), 4.29 (s, 2 H), 4.04 (dq, 1 H), 2.84 (m, 2 H), 2.47 - 2.62 (m, 1 H), 2.36 (m, 2 H), 2.06 - 2.28 (m, 2 H), 1.82 - 1.96 (m, 3 H), 1.63 - 1.80 (m, 3 H), 1.36 - 1.66 (m, 4 H), 1.08 - 1.22 (m, 6 H). MS(m/z): 564.23 [MH]⁺.

Example 36: 2-[2-[(1 -cyclopentyl^-piperidinylJoxyl-θ-^-fluoro-S-

(trifluoromethyl)phenyl]-4-oxopyrazolo[1,5-a]pyrazin-5(4H)-yl]-N-(1- methylethyl)acetamide hydrochloride (E36)

Xl

H^'

2-[2-[(1-cyclopentyl-4-piperidinyl)oxy]-6-[4-fluoro-3-(trifluoromethyl)phenyl]-4- oxopyrazolo[1 ,5-a]pyrazin-5(4H)-yl]-N-(1-methylethyl)acetamide (E35, 10 mg) was dissolved in DCM (0.2 ml) and hydrochloric acid (17 μl_, 0.017 mmol) (I M/ether) was added. The mixture was concentrated under vacuum, the solid was triturated twice with diethyl ether to give 10.5 mg of the title compound as a white solid.

NMR (¹H, METHANOL-c/₄): δ ppm 7.65 - 7.85 (m, 2 H), 7.31 - 7.49 (m, 2 H), 6.43 (s, 1 H), 4.50 (br. s., 1 H), 4.35 (br. s., 2 H), 3.69 - 3.86 (m, 1 H), 3.58 - 3.10 (m, 6 H), 1.50 - 2.39 (m, 12 H), 0.97 (d, 6 H). (Spectral lines very broad likely due to presence of protonation isomers) MS(m/z): 564.17 [MH]⁺.

In vitro profile

The in vitro assessment of the V1 b antagonist compounds used a functional assay system to determine the potency against the V1 b receptor.

The functional activity of the compounds of the invention for the V1 b receptor may be determined by the FLIPR/Ca²⁺ assay as described below. Such potency is typically calculated as an IC₅₀ value obtained in FLIPR experiments as the concentration of a compound necessary to decrease 50% of the calcium release following cells exposure to a concentration of AVP eliciting 80% response (i.e. EC80).

In the context of the present invention plC₅₀ values (corresponding to the antilogarithm of IC₅₀) are used instead of IC₅₀; plC₅₀ results are only estimated to be accurate to about 0.3- 0.5.

Functional activity at recombinant human V1 b receptor

The functional activity at the human V1 b (h-V1 b) receptor stably expressed in Chinese

Hamster Ovary (CHO) cells was assessed using FLIPR/Ca²⁺ methodology.

AVP is an endogenous agonist and can activate the receptor, thereupon causing an increase in the level of calcium in the cells sensed by Fluo4-AM and measured by FLIPR. Antagonist effects are monitored by the blockade or decrease in calcium release once cells co-expressing h-V1 b receptor are exposed to a concentration of AVP eliciting 80% response (i.e. EC80). A non-linear, 4 parameter logistic curve-fit of the data generated plC₅₀ value.

Cells are cultured in DMEM/F12 supplemented with 10% FBS, 2mM Glutamine and

200μg/mL G418. The day before a FLIPR experiment, cells are plated out into 384-well Poly-D-Lysine coated FLIPR plates at a density of 400'0OO cells/mL corrects to give 20'0OO cells per 50μL per well using medium without antibiotics. On the day of experiment, cells are washed with an assay buffer containing 2OmM HEPES/NaOH, 145mM NaCI, 5mM KCI, 1 mM MgCI₂, 2mM CaCI₂, 1g/L D-glucose and 2.5mM probenecid, pH 7.3 and loaded with 2μM Fluo-4 AM for 60 min at 37 ⁰C and 5% CO₂. The excess of dye solution is removed by washing cells with buffer. Compound solutions, prepared by serially diluting compounds in neat DMSO and then a final 1 :50 dilution step in assay buffer added with 0.05% pluronic acid, are added and incubated with the loaded cells for 10 min at 37 ⁰C and 5% CO₂. The final concentration of DMSO in the assay was kept constant at 0.4%.

Cells are then put in the FLIPR for the stimulus addition corresponding to a concentration of AVP eliciting 80% of the response. The response of cells to the agonist is fast and measured for 2min after AVP addition.

All the compounds of formula (I) are believed to bind the V1 b receptor.

Preferred examples show plC₅₀ comprised between 6 and 10 towards V1 b receptor.

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof:

wherein

R is -X-[CH₂]nCR₄R5-Y; or a group G;

R₃ is -CH₂-C(=O)-NH-R₆;

X is -CR₇R₈-, -0-, -NR₉-, -S-; Y is-NR₁₀Rn

R₄ is H or C1-C4 alkyl;

R₅ is H or C1-C4 alkyl;

R₆ is C1-C6 alkyl, C3-C6 cycloalkyl; C3-C6 cycloalkyl-(C1-C2 alkyl); which may be substituted by one or more halogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy;

R₇ is H or C1-C4 alkyl;

R₈ is H or C1-C4 alkyl;

R₉ is H or C1-C4 alkyl; R₁0 is H or C1-C4 alkyl, or together with R₁₁ forms a 4-8 saturated or unsaturated heterocycle ring which may comprise a further heteroatom selected from O, S and - NR₁₂; such heterocycle may be substituted by one or more halogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1- C4 haloalkoxy;

R₁₁ is H or C1-C4 alkyl;

R₁₂ is H, C1-C6 alkyl, C3-C7 cycloalkyl; C3-C6 cycloalkyl-(C1-

G is one of the groups selected from the list consisting of G1 ,

G2, G3, G4, G5, G6, G7,G8, G9, G10, G1 1 and G12:

G1 G2 G3

G4 G5

G6 G7 G8

G9 G10 G11 G12

R 13 is H or C1-C4 alkyl, or together with R₁₄ forms a 4-8 saturated or unsaturated heterocycle ring which may comprise a further heteroatom selected from O, S and - NR₂₄; such heterocycle may be substituted by one or more halogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1- C4 haloalkoxy; and may assume different meanings;

R-I4, R 16 is H, C1-C6 alkyl, C3-C7 cycloalkyl; C3-C6 cycloalkyl-(C1- C2 alkyl); which may be substituted by one or more halogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy; and may assume different meanings;

Ri 155,, R rV|7 correspond to H or C1-C4 alkyl and may assume different meanings;

Ri9> R20> R21 > R22> R23> R24> R25 is H, C1-C6 alkyl, C3-C7 cycloalkyl; C3-C6 cycloalkyl- (C1-C2 alkyl); which may be substituted by one or more halogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1- C4 haloalkoxy; and may assume different meanings;

R26, R27, R28, R29 is H, C1-C6 alkyl, C3-C7 cycloalkyl; C3-C6 cycloalkyl-(C1-

C2 alkyl); which may be substituted by one or more halogen,

5 C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy;

1, I' correspond to 1 or 2 and may assume different meanings; m, m', m", m"', m^ιv, m^v correspond to 0, 1 or 2 and may assume different meanings; n is 1 , 2 or 3; O q is 1 , 2 or 3; p, p', p", p'" correspond to 0, 1 , 2 or 3 and may assume different meanings.

2. A compound of formula (I) according to claim 1 , which is selected in the group5 consisting of:

N-(1-methylethyl)-2-[4-oxo-2-{[3-(1-piperidinyl)propyl]oxy}-6-[3-

(trifluoromethyl)phenyl]pyrazolo[1 ,5-a]pyrazin-5(4H)-yl]acetamide; 0 2-[6-(3-chlorophenyl)-4-oxo-2-{[2-(1-piperidinyl)ethyl]oxy}pyrazolo[1 ,5-a]pyrazin-5(4H)-yl]-

N-(1 -methylethyl)acetamide;

2-[6-(3-chlorophenyl)-2-{[3-(4-morpholinyl)propyl]oxy}-4-oxopyrazolo[1 ,5-a]pyrazin-5(4H)-5 yl]-N-(1 -methylethyl)acetamide;

N-(1 -methylethyl)acetamide;

5(4H)-yl]-N-(1-methylethyl)acetamide; 0 2-[6-[2-fluoro-5-(trifluoromethyl)phenyl]-4-oxo-2-{[3-(1-piperidinyl)propyl]oxy}pyrazolo[1 ,5- a]pyrazin-5(4H)-yl]-N-(1-methylethyl)acetamide;

N-(1 ,1-dimethylethyl)-2-[4-oxo-2-{[3-(1-piperidinyl)propyl]oxy}-6-[3-

(trifluoromethyl)phenyl]pyrazolo[1 ,5-a]pyrazin-5(4H)-yl]acetamide;

2-[6-[4-fluoro-3-(trifluoromethyl)phenyl]-4-oxo-2-{[3-(1-piperidinyl)propyl]oxy}pyrazolo[1 ,5-5 a]pyrazin-5(4H)-yl]-N-(1-methylethyl)acetamide;

5(4H)-yl]-N-(1-methylethyl)acetamide; 0 2-[6-[3,5-bis(trif luoromethyl)phenyl]-4-oxo-2-{[3-(1 -piperidinyl)propyl]oxy}pyrazolo[1 ,5- a]pyrazin-5(4H)-yl]-N-(1-methylethyl)acetamide; 2-[6-[4-fluoro-3-(trifluoromethyl)phenyl]-4-oxo-2-[4-(1-pyrrolidinyl)-1- piperidinyl]pyrazolo[1 ,5-a]pyrazin-5(4H)-yl]-N-(1-methylethyl)acetamide; Λ/-(1-methylethyl)-2-[6-(6-methyl-2-pyridinyl)-4-oxo-2-{[3-(1- piperidinyl)propyl]oxy}pyrazolo[1 ,5-a]pyrazin-5(4/-/)-yl]acetamide; 2-[2-[(1-cyclopentyl-4-piperidinyl)oxy]-6-[4-fluoro-3-(trifluoromethyl)phenyl]-4- oxopyrazolo[1 ,5-a]pyrazin-5(4H)-yl]-N-(1-methylethyl)acetamide; and pharmaceutically acceptable salts and solvates thereof.

3. A compound of formula (I) according to claim 1 or 2, or a pharmaceutically acceptable salt or solvate thereof, for use in therapy.

4. A compound of formula (I) according to claim 1 or 2, or a pharmaceutically acceptable salt or solvate thereof, for use in the treatment of depression.

5. A compound of formula (I) according to claim 1 or 2, or a pharmaceutically acceptable salt or solvate thereof, for use in the treatment of anxiety.

6. Use of a compound of formula (I) according to claim 1 or 2, or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for the treatment of depression.

7. Use of a compound of formula (I) according to claim 1 or 2, or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for the treatment of anxiety.

8. Method of treating depression comprising administering to a human in need thereof a compound of formula (I) according to claim 1 or 2, or a pharmaceutically acceptable salt or solvate thereof.

9. Method of treating anxiety comprising administering to a human in need therof a compound of formula (I) according to claim 1 or 2, or a pharmaceutically acceptable salt or solvate thereof.

10. A pharmaceutical composition comprising a compound of formula (I) according to claim 1 or 2, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.