OA13015A - Substituted pyrrolo-pyrazole derivatives as kinaseinhibitors. - Google Patents

Description

0130 15

TITLE OF THE INVENTION

SÜBSTITUTED PYRROLO-PYRAZOLE DERIVATIVES AS KINASEINBŒBITORS

BACKGROUND OF THE INVENTION

Field of tbe Invention:

The présent invention relates to pyrrolo-pyrazole dérivatives, to a process for theirpréparation, to pharmaceutical compositions comprising them, and to their use astherapeutic agents, partieularly in the treatment of cancer and cell prolifération disorders.Discussion of the Background

Several cytotoxic drugs such as, e.g., fluorouracil (5-FU), doxorubicin and camptothecins,damage DNA or affect cellular metabolic pathways and thus cause, in many cases, anindirect block of the cell cycle. Therefore, by producing an irréversible damage to bothnormal and tumor cells, these agents resuit in a significant toxicity and side-effects.

In this respect, compounds capable of functioning as highly spécifie antitumor agents byselectively leading to tumor cell arrest and apoptosis, with comparable efScacy butreduced toxicity than the currently available drugs, are désirable.

It is well known that progression through the cell cycle is govemed by a sériés ofcheckpoint Controls, otherwise referred to as restriction points, which are regulated by afamily of enzymes known as the Cyclin-dependent kinases (Cdk). In tum, the Cdksthemselves are regulated at many levels such as, for instance, binding to cyclins.

The coordinated activation and inactivation of different Cdk/Cyclin complexes isnecessary for normal progression through the cell cycle. Both the critical Gl-S and G2-Mtransitions are controlled by the activation of different Cdk/Cyclin activities. In Gl, bothCdk4/Cyclin D and Cdk2/Cyclin E are thought to médiate the onset of S-phase.Progression through S-phase requires the activity of Cdk2/Cyclin A whereas the activationof Cdc2/Cyclin A (Cdkl) and Cdc2/cyclin B are required for the onset of mitosis. For ageneral reference to cyclins and cyclin-dependent kinases see, for instance, Kevin R.Webster et al, in Exp. Opin. havest. Drugs, 1998, Vol. 7(6), 865-887. 2 Ο 130 1 5

Checkpoint Controls are defective in tumor cells due, in part, to disregulation of cdkactivity. For example, altered expression of cyclin E and cdks has been observed in tumOTcells, and délétion of the cdk inhibitor p27 KDP gene in mice has been shown to resuit in ahigher incidence of cancer. 5 Increasing evidence supports the idea that the cdks are rate-limiting enzymes in cell cycleprogression and, as such, represent molecular targets for therapeutic intervention. Inparticular, the direct inhibition of cdk/cyclin kinase activity should be helpfùl in restrictingthe unregulated prolifération of a tumor cell.

SUMMARY OF THE INVENTION 10 It is an object of the invention to provide compounds which are useful in treating cellproliférative disorders caused by and/or associated with an altered cell cycle dépendentkinase activity. It is another object to provide compounds which hâve cdk/cyclin kinaseinhibitoiy activity.

The présent inventors hâve now discovered that certain pyrazole compounds are endowed 15 with cdk/cyclin kinase inhibitory activity and are thus usefùl in therapy as antitumor agentsand lack, in terms of both toxicity and side effects, the aforementioned drawbacksassociated with currently available antitumor drugs.

More specifically, the pyrazole dérivatives of the invention are useful in the treatment of avariety of cancers including, but not limited to: carcinoma such as bladder, breast, colon, 20 kidney, liver, lung, including small cell lung cancer, esophagus, gall-bladder, ovary,pancréas, stomach, cervix, thyroid, prostate, and skin, including squamous cell carcinoma;hematopoietic tumors of lymphoid lineage including leukaemia, acute lymphociticleukaemia, acute lymphoblastic leukaemia, B-cell lymphoma, T-cell-lymphoma, Hodgkm'slymphoma, non-Hodgkin's lymphoma, hairy cell lymphoma and Burkett's lymphoma; 25 hematopoietic tumors of myeloid lineage, including acute and chronic myelogenousleukemias, myelodysplastic syndrome and promyelocytic leukaemia; tumors ofmesenchymal origin, including fibrosarcoma and rhabdomyosarcoma; tumors of thecentral and peripheral nervous System, including astrocytoma neuroblastoma, glioma andschwannomas; other tumors, including tnelanoma, seminoma, teratocarcinoma, 013015 osteosarcoma, xeroderma pigmentosum, keratoxanthoma, · thyroid follicular cancer andKaposi's sarcoma.

Due to the key rôle of cdks in the régulation of cellular prolifération, these pyrazoledérivatives are also useful in the treatment of a variety of cell proliférative disorders suchas, for example, benign prostate hypeiplasia, familial adenomatosis polyposis,neurofîbromatosis, psoriasis, vascular smooth cell prolifération associated withatherosclerosis, pulmonary fibrosis, arthritis, glomerulonephritis and post-surgieal stenosisand restenosis.

The compounds of the invention may be useful in treatment of Alzheimer's disease, assuggested by the fact that cdk5 is involved in the phosphorylation of tau protein (J.Biochem. 117, 741-749,1995).

The compounds of this invention, as modulatons of apoptosis, may also be useful in thetreatment of cancer, viral infections, prévention of AIDS development in HTV-infectedindividuals, autoimmune diseâses and neurodegenerative disorders.

The compounds of this invention may be useful in inhibiting tumor angiogenesis andmetastasis, as well as in the treatment of organ transplant rejection and host versus graftdisease.

The compounds of the invention may also act as inhibitor of other protein kinases, e.g.,protein kinase C in different isoforms, Met, PAK-4, PAK-5, ZC-1, STLK-2, DDR-2,Aurora 1, Aurora 2, Bub-1, PLK, Chkl, Chk2, HER2, rafl, MEK1, MAPK, EGF-R,PDGF-R, FGF-R, IGF-R, PI3K, weel kinase, Src, Abl, Akt, MAPK, ILK, MK-2, IKK-2,Cdc7, Nek, and thus be effective in the treatment of diseâses associated with other proteinkinases.

The compounds of the invention are also useful in the treatment and prévention ofradiotherapy-induced ot chemotherapy-induced alopecia.

Accordingly, the présent invention provides a method for treating cell proliférativedisorders caused by and/or associated with an altered cell cycle dépendent kinase activity,by administering to a mammal in need thereof an effective amount of a pyrazole dérivativerepresented by formula (la) or (Ib) 013015 4

wherein R is a group -CORa, -CONHRa or -CONRaRb wherein Ra and Rb are, each independently, 5 hydrogen or an optionally substituted group selected from straigbt or branched Ci-C6 alkyl,C3-C6 cycloalkyl, aiyl, arylalkyl, heterocyclyl or heterocyclylalkyl or; together with thenitrogen atom to which they aie bonded, Ra and Rb may form an optionally substituted 5 or6 membered heterocycle optionally containing one additional heteroatom or heteroatomicgroup selected among N, NH, O or S; 10 Ri is selected from the group consisting of: a) straight or branched C3-C4 alkyl; b) cycloalkyl, cycloalkyl-alkyl or alkyl-cycloalkyl wherein the cycloalkyl moietycomprises any C3-C6 cycloalkyl group and wherein the alkyl moiety comprises any straightor branched C1-C4 alkyl group: 15 c) 3-methylthienyl-2-yl; 2-thienyl; phenyl; 2,6-difluorophenyl; 4-(aminosulfonyl)phenyl; 4-(dimethylaminomethyl)phenyI; 4-(4-methylpiperazinyl)methyl-phenyl; d) a group of formula (lia) or (Hb): (Rc)n

20 wherein, in formula (lia), the cycle represents a 5 to 7 membered heterocyclic ring wherinX, directly linked to the rest of the molécule, represents a carbon or nitrogen atom; Y is a 013015 5 carbon, nitrogen, oxygen or sulfur atom or it is an NH group, provided that at least one of --X and Y is other than a carbon atom; Rc is, independently from each other and in any one of the free positions of the heterocyclic ring of formula (lia), a halogen atom or hydroxygroup or it is an optionally substituted group selected from straigbt or branched Ci-C6 5 alkyl, C3-C6 cycloalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, amino,aminocarbonyl, carboxy, oxo (=0), alkoxycarbonyl, alkylcarbonyl or arylcarbonyl; and nis 0 or an integer from 1 to 4; e) a group of formula (Ile) or (Hd): r

-Νχ -O R-d (Ile) (lld) 10 wherein Rd, R'd and Re represent, the same or different and independently from each other,a hydrogen atom or a straight or branched Cj-Cê alkyl optionally substituted by one ormore groupe selected from hydroxy (-OH), aminocarbonyl (-CONH2) ormethylaminocarbonyl (-CONHCH3); provided that in formula (la), when Ri is a group of formula (Ile) and one of Rd or R'd is a 15 hydrogen atom whilst the other of Rd or R'd is ethyl or n-butyl, then R is other than -CORawith Ra as 3-bromophènyl, benzyl, 4-tert-buiylphenyl, 4-tert-butylphenylmethyl, 4-fluorophenylmethyl, çyclopropyl or 2-naphthyhnethyl; or a pharmaceutically acceptable sait thereof.

In a preferred embodiment of the method described above, the cell proliférative disorder is 20 selected from the group consisting of cancer, Alzheimefs disease, viral infections, auto-immune diseases and neurodegenerative disorders.

Spécifie types of cancer that raay be treated include carcinoma, squamous cell carcinoma,hematopoietic tumors of myeloid or lymphoid lineage, tumors of mesenchymal origin,tumors of the central and peripheral nervous System, melanoma, seminoma, 25 teratocarcinoma, osteosarcoma, xerodeima pigmentosum, keratoxanthoma, thyroidfollicular cancer, and Kaposi's sarcoma. 013015 10

In another preferred embodiment of the method described above, the cell proliférativedisorder is selected from the group consisting of benign prostate hyperplasia, familialadenomatosis polyposis, neuro-fîbromatosis, psoriasis, vascular smooth cell proliférationassociated with atherosclerosis, pulmonary fibrosis, arthritis, glomerulonephritis and post-surgical stenosis and restenosis. In addition, the inventive method provides tumorangiogenesis and xnetastasis inhibition as well as treatment of organ transplant rejectionand host versus graft disease. The inventive method may also provide cell cycle inhibitionor cdk/cyclin dépendent inhibition.

In addition to the above, the method object of the présent invention provides treatment and prévention of radiotherapy-induced or chemotherapy-induced alopecia

The présent invention also provides a pyrazole dérivative represented by formula (la) or (Ib)

wherein 15 R is a group -CORa, -CONHR2 or -CONRaRb wherein Ra and Rb are, each independently,hydrogen or an optionally substituted group selected from straight or branched Cj-Ce alkyl,C3-C6 cycloalkyl, aryl, arylalkyl, heterocyclyl or heterocyclylalkyl or; together with thenitrogen atom to winch they are bonded, Ra and Rb may form an optionally substituted 5 or6 membered heterocycle optionally containing one additional heteroatom or heteroatomic 20 group selected among N, NH, O or S;

Ri is selected from the group consisting of:a) straight or branched C3-C4 alkyl; 013015 7 b) cycloalkyl, cycloalkyl-alkyl or alkyl-cycloalkyl wherein the cycloalkyl moietycomprises any C3-C6 cycloalkyl group and wherein the alkyl moiety comprises any straightor branched C1-C4 alkyl group: c) 3-methylthienyl-2-yl; 2-thienyI; phenyl; 2,6-difluorophenyl; 4-5 (aminosulfonyljphenyl; 4-(dimethylaminomethyl)phenyl; 4-(4-methylpiperazinyl)methyl- phenyl; d) a group of formula (lia) or (Ilb):

•N (Ha) ("b) wherein, in formula (lia), the cycle represents a 5 to 7 membered heterocyclic ring wherin 10 X, directly linked to the rest of the molécule, represents a carbon or nitrogen atom; Y is acarbon, nitrogen, oxygen or sulfur atom or it is an NH group, provided that at least one ofX and Y is other than a carbon atom; Rc is, independently from each other and in any oneof the free positions of the heterocyclic ring of formula (lia), a halogen atom or hydroxygroup or it is an optionally substituted group selected from straight or branched Ci-Ce 15 alkyl, C3-C6 cycloalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, amino,aminocarbonyl, carboxy, oxo (=0), alkoxycarbonyl, alkylcarbonyl or arylcarbonyl; and nis 0 or an integer from 1 to 4; e) a group of formula (Ile) or (Ild):

Rd R« / /

--O R'd (lie) (Ild) 20 wherein Rd, R'd and Re represent, the same or different and independently from each other,a hydrogen atom or a straight or branched Ci-Ci alkyl optionally substituted by one ormore groups selected from hydroxy (-OH), aminocarbonyl (-CONH2) ormethylaminocarbonyl (-CONHCH3); 013015 8 provided that in formula (la), when Ri is a group of formula (Ile) and one of Rd or R'd is ahydrogen atom whilst die other of Rd or R'd is ethyl or n-butyl, then R is other than -COR“with Ra as 3-bromophenyl, benzyl, 4-tert-butylphenyl, 4-tert-butylphenylmetliyl, 4-fluorophenylmethyl, cyclopropyl or 2-naphthylmethyl; or a pharmaceutically acceptable sait thereof.

The présent invention also includes methods for the synthesis of the pyrazole dérivativesrepresented by formulae (la) or (Tb) that, unless otherwise provided, may be convenientlygrouped and defined as compounds of formula (I). Pharmaceutical compositionscomprising the pyrazole dérivatives of formula (I) are also included in the présentinvention. A more complété appréciation of the invention and many of the attendant advantagesthereof will be readily obtained as the same becomes better understood by référencé to thefollowing detailed description. DETAILED DESCRIPTION OF THE INVENTIONSeveral heterocyclic compounds are known in the art as protein kinase inhibitors. As anexample, 2-carboxamido-pyrazoles and 2-ureido-pyrazoles, and dérivatives thereof, hâvebeen disclosed as protein kinase inhibitors in the international patent applications WO01/12189, WO 01/12188, WO 02/48114 and WO 02/70515, ail in the name of theapplicant itself.

Fused biçyclic compounds comprising pyrazole moieties and possessing kinase inhibitoryactivity hâve been also disclosed in WO 00/69846 and WO 02/12242 as well as in WO03/028720 (PCT/EP02/10534 claiming priority fiom US patent application No. 09/962162of September 26, 2001) and copending PCT/EP03/04862 (claiming priority &om USpatent application 60/381092 of May 17,2002), ail in the name of the applicant itself.

The compounds object of the présent invention fall within the scope of the general formulaof the aforementioned WO 02/12242, herewith incoiporated by référencé, but are notspecifically exemplified therein.

Unless otherwise specifîed, when referring to the compounds of formula (I) per se as wellas to any pharmaceutical composition thereof or to any therapeutic treatment comprisingthem, the présent invention includes ail of the hydrates, solvatés, complexes, métabolites 013015 and prodrugs of the compounds of this invention. Prodrugs aie any covalently bondedcompounds, which release the active parent drug according to formula (I) in vivo. A métabolite of a compound of formula (I) is any compound into which this samecompound of formula (I) is converted, in vivo, for instance upon administration to amammal in need thereof,

Typically, without however representing a limiting example, upon administration of acompound of formula (I), this same dérivative may be converted into a variety ofcompounds, for instance including more soluble dérivatives like hydroxylated dérivatives,which are easy to be excreted. Hence, depending upon the metabolic pathway thusoccurring, any of these hydroxylated dérivatives may be regarded as a métabolite of thecompounds of formula (I).

If a chiral center or another form of an isomeric center is présent in a compound of theprésent invention, ail forms of such isomer or isomers, including enantiomers anddiastereomers, are intended to be covered herein. Compounds containing a chiral centermay be used as a racemic mixture, an enantiomerically enriched mixture, or the racemicmixture may be separated using well-known techniques and an individual enantiomer maybe used alone. In cases in which compounds hâve unsaturated carbon-carbon doublebonds, both the cis (Z) and trans (E) isomers are within the scope of this invention. In caseswherein compounds may exist in tautomeric forms, such as keto-enol tautomers, eachtautomeric form is contemplated as being included within this invention whether existingin equilibrium or predominantly in one form.

In the présent description, unless otherwise specified, with the term straight or branchedCi~C6 alkyl, hence comprehensive of Ci-C4 alkyl, we intend any of the groups such as, forinstance, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, n-hexyl, and the like.

With the term C-i-Ce cycloalkyl we intend, unless otherwise provided, a cycloaliphatie ringsuch as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

The term aryl includes carbocyclic or heterocyclic hydrocarbons with fiom 1 to 2 ringmoieties, either ftised or linked to each other by single bonds, wherein at least one of therings is aromatic; if présent, any aromatic heterocyclic hydrocarbon also referred to as 013015 10 heteroaryl group, comprises a 5 to 6 membered ring with from 1 to 3 heteroatoms orheteroatomic groups selected among N, NH, O or S.

Examples of aryl groups according to the invention are, for instance, phenyl, biphenyl, a-or β-naphthyl, dihydronaphthyl, thienyl, benzothienyl, furyl, benzofuranyl, pyrrolyl, 5 imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridyl, pyrazinyl,pyrimidinyl, pyridazinyl, indolyl, isoindolyl, purinyl, quinolyl, isoquinolyl,dihydroquinolinyl, quinoxalinyl, benzodioxolyl, indanyl, indenyl, triazolyl, and the like.Unless otherwise specified, the term heterocycle or heterocyclyl includes 5 to 6 memberedsaturated, partly unsaturated or fully unsaturated heterocycles with from 1 to 3 heteroatoms 10 or heteroatomic groups selected among N, NH, O or S.

Apart from the fully unsaturated heterocycles, previously referred to as aromaticheterocycles and encompassed by the term aryl, examples of saturated or partlyunsaturated heterocycles according to the invention are, for instance, pyran, pyrrolidine,pyrroline, imidazoline, imidazolidine, pyrazolidine, pyrazoline, thiazoline, thiazolidine, 15 dihydrofuran, tetrahydrofaran, 1,3-dioxolane, piperidine, piperazine, morpholine and thelike.

When referring to the compounds of the invention wherein Ri is grouped under (b), Rjitself may represent a given cycloalkyl group, for instance cyclopropyl; a given cycloalkyl-alkyl group, for instance cyclopropylmethyl; or even a given alkyl-cycloalkyl group, for 20 instance methylcyclopropyl; ail of which hâve the following formulae: cycloalkyl cycloalkyl-alkyl alkyl-cycloalkyl

When referring to the compounds of the invention wherein Ri is a group of formula (Ha),the 5 to 7 membered heterocyclic ring is directly linked to the rest of the molécule throughthe X atom, as follows: 013015 11

Examples of these 5 to 7 membered heterocycles include any 5 to 6 membered heterocycleamong those already reported and, additionally, 7 membered heterocycles such as, forinstance, azepine, diazepine, oxazepine and the like.

Any Rc, if présent, is at any one of the free positions of the heterocyclic ring of formula(lia) by replacement of a hydrogen atom.

When referring to the componnds of the invention wherein Ri is a group of formula (Hc)or (Ild), ureido and carbamate dérivatives may be thus identified, having the foUowingsub-formulae: 2}

N ,R'd 10

6; 2}N

-RB 15 20

According to the présent invention and unless otherwise provided, any of the above Ra, Rband Rc groups may be optionally substituted, in any of their free positions, by one or moregroups, for instance 1 to 6 groups, independently selected from: halogen, nitro, oxo groups(=0), cyano, alkyl, polyfluorinated alkyl, polyfluorinated alkoxy, alkenyl, alkynyl,hydroxyalkyl, aryl, arylalkyl, heterocyclyl, cycloalkyl, hydroxy, alkoxy, aryloxy,heterocyclyloxy, methylenedioxy, alkylcarbonyloxy, arylcarbonyloxy, cycloalkenyloxy,alkylideneaminooxy, carboxy, alkoxycarbonyl, aryloxycarbonyl, cycloalkyloxycarbonyl,amino, ureido, alkylamino, dialkylamino, arylamino, diaiylamino, formylamino,alkylcarbonylamino, aiylcarbonylamino, heterocyclylcarbonylamino, alkoxycarbonylamino, alkoxyimino, alkylsulfonylamino, arylsulfonylamino, formyl, 013015 12 alkylcarbonyl, arylcarbonyl, cycloalkylcarbonyl, heterocyclylcarbonyl, aminocarbonyl,alkylaminocarbonyl, dialkylaminocarbonyl, alkylsulfonyl, arylsulfonyl, aminosulfonyl,alkylaminosulfonyl, dialkylaminosulfonyl, arylthio and alkylthio.

In this respect, with the terra halogen atom we intend a fluorine, chlorine, bromine oriodine atom.

With the tenn alkenyl or alkynyl we intend any of the aforementioned straight or branchedC2-C& alkyl groups further bearing a double or triple bond. Non limiting examples ofalkenyl or alkynyl groups of the invention are, for instance, vinyl, allyl, 1-propenyl,isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-pentenyl, 1-hexenyl, ethynyl, 2-propynyl, 4-pentynyl, and the like.

With the term polyfluorinated alkyl or alkoxy we intend any of the above straight orbranched Ci-Cé alkyl or- alkoxy groups which are substituted by more than one fluorineatom such as, for instance, trifluoromethyl, trifluoroethyl, 1,1,1,3,3,3-hexafluoropropyl,trifluoromethoxy and the like.

With the term alkoxy, aryloxy, heterocyclyloxy and derivativés thereof we intend any ofthe above alkyl, aryl or heterocyclyl groups linked to the rest of the molécule through aoxygen atom (-O-).

From ail of the above, it is clear to the skilled person that any group which name is acomposite name such as, for instance, cycloalkylalkyl, arylalkyl, heterocyclylalkyl, alkoxy,alkylthio, aryloxy, arylalkyloxy, alkylcarbonyloxy, arylalkyl, heterocyclylalkyl and thelike, hâve to be intended as conventionally construed by the parts fiom which they dérivé.As an example, a group such as heterocyclylalkyloxy is an alkoxy group, e.g. alkyloxy,wherein the alkyl moiety is further substituted by a heterocyclyl group, and wherein alkyland heterocyclyl are as above defïned.

Pharmaceutically acceptable salts of the compounds of formula (I) include the acidaddition salts with inorganic or organic acids, e.g., nitric, hydrochloric, hydrobromic,sulfuric, perchloric, phosphoric, acetic, trifluoroacetic, propionic, glycolic, lactic, oxalic,malonic, malic, maleic, tartàric, citric, benzoic, cinnamic, mandelic, methanesulphonic,isethionic and salicylic acid. Preferably, the acid addition sait of the compounds of theinvention is selected between the hydrochloride or mesylate sait. 13 G ΐ 30 1 5

Pharmaceutically acceptable salts of the compounds of formula (I) also include the saltswith inorganic or organic bases, e.g., alkali or alkaline-earth metals, especially sodium,potassium, calcium or magnésium hydroxides, carbonates or bicarbonates, acyclic or cyclicamines, preferably methylamine, ethylamine, diethylamine, triethylamine, piperidine and 5 the like. A first class of preferred compounds of formula (la) or (Ib) is represented by thedérivatives wherein R is a group -COR®, Ra is as above defined and Ri is tert-butyl.

Another class of preferred compounds of formula (la) or (Ib) is represented by thedérivatives wherein R is a group -CONHR®, R® is as above defined and Ri is tert-butyl. 10 Another class of preferred compounds of formula (la) or (Ib) is represented by thedérivatives wherein R is a group -CONR®Rb, R® and R6 are as above defined and Ri is tert-butyl.

Another class of preferred compounds of formula (la) or (Ib) is represented by thedérivatives wherein R is as above defined and Ri is a group of formula (lia) selected from:

wherein Rc has the above reported meanings.

Another class of preferred compounds of formula (la) or (Ib) is represented by thedérivatives wherein R is as above defined and Ri is a group of formula (lia) selected from:

20 wherein n and Rc hâve the above reported meanings.

Particularly preferred, within the above classes, are the compounds of formula (la) whereinR is a group -COR® with R® as 4-fluorophenyl or cyclobutyl, and Ri is as defined in thegeneral formula. 013015 14

Also particularly preferred are the compounds of formula (la) wherein R is as defined inthe general formula, and Ri is a group selected from tert-butyl, l-methyl-piperidyl-4-yl, 1-methyl-piperazinyl-4-yl, 2-(R,S)-tetrahydrofuranyl-2-yl, 2-(R)-tetrahydrofuranyl-2-yl or 2-(S)-tetrahydrofuranyl-2-yl. 5 For a general référencé to any spécifie compound of formula (I) of the invention,optionally in the form of a phannaceutically acceptable sait, see the experimental section.As formerly indicated, a further object of the présent invention is represented by theprocess for preparing the compounds of formula (I). - -

Therefore, the compounds of formula (I) and the phannaceutically acceptable salts may be 10 obtained by a process comprising: a) reacting a compound of formula (Ilia) or (IÏIb) H2N' (Ilia)

COOH H2N' (Mb)

'COOH with acrylonitrile so as to obtain the conresponding dérivative of formula (IVa) or (ÏVb)

COOH (IVa)

COOH (IVb) 15 b) protecting the amino group of the compound of formula (IVa) or (IVb) so as to obtainthe corresponding dérivative of formula (Va) or (Vb)

COOH (Va)

COOH (Vb) 20 wherein Q is a suitable amino protecting group; c) reacting the compound of formula (Va) or (Vb) with a suitable alkylating agent so as toobtain the corresponding ester dérivative of formula (Via) or (VIb) 013015 15

COOAlk (Via)

COOAlk (Vlb) wherein Alk stands for a suitable C1-C4 alkyl group; d) reacting the compound of formula (Via) or (Vlb) witb sodium hydride (NaH) so as toobtain the corresponding dérivative of formula (VHa) or (VHb)

e) reacting the compound of formula (Vlla) or (Vllb) with hydrazine hydrate so as toobtain the compound of formula (Villa) or (VlIIb)

10 f) reacting the compound of formula (Villa) or (VUIb) with ethyl chloroformate so as toobtain the dérivative of formula (Ka) or (Kb), eachone in any of the two regioisomericforms

and reacting the compounds of formula (Ka) or (Kb) according to any one of thealternative steps (g.l), (g.2) or (g.3) 013015 16 g.l) with a compound of formula (X)

RaCO-Z (X) wherein Ra is as above defined and Z is a halogen atom, so as to obtain the compound offormula (Xla) or (Xlb)

wherein R is a group -CORa; g.2) with a compound of formula (XII)

Ra-NCO (ΧΠ) wherein Ra is as above defined so as to obtain the compound of the formula (Xla) or (Xlb)10 wherein R is a group -CONHRa; or g.3) with a suitable amine of formula (XHI) in the presence of triphosgene or of a suitablechlorofonnate HNRaRb (XIH) wherein Ra and Rb are as above defined, so as to obtain the compound of formula (Xla) or15 (Xlb) wherein R is a group -CONRaRb; h) deprotecting the arnino group of the compound of formula (Xla) or (Xlb) preparedaccording to any one of steps from (g.l) to (g.3), so as to obtain the correspondingdérivative of formula (XlVa) or (XlVb)

013015 17 wherein R has the above reported meanings; and reacting the compound of formula (XlVa)or (XlVb) according to any one of the alternative steps (i.l), (i.2), (i.3) or (i.4)i. 1) with an acyl halide dérivative of formula (XV)

Ri-COZ (XV) wherein Ri is as set forth in formula (la) or (Ib) under groups (a), (b), (c), (Ha) with X as acarbon atom and (Rb), and Z is a halogen atom, so as to obtain a compound of formula(XVIa) or (XVIb)

wherein R and Ri are as above defined; 10 i.2) with a 5 to 7 membered heterocyclic compound of formula (XVII) or a suitable amine of formula (XVIII), in the presence of triphosgene (XVII) HN(Rd)R'd (XVIII) wherein X is NH and Y, R°, n, Rd and R"1 hâve tire above reported meanings, so as toobtain the corresponding compounds of formula (XVIa) or (XVIb) wherein R is as above 15 defined and Ri is either a group of formula (lia) with X as a nitrogen atom and R, Y, Rcand n as above defined, or of formula (Hc) wherein Rd and R'd are as above defined; 1.3) with a carboxylic acid of formula (XIX) in the presence of a suitable condensing agent

Ri-COOH (XIX) so as to obtain a compound of formula (XVIa) or ÇXVIb) wherein Rj is as set forth in20 formula (la) or (Ib) under groups (a), (b), (c) or it is a group of formula (Ha) with X as a carbon atom or of formula (Ilb), and R, Y, R° and n are as above defined; 1.4) with a compound of formula (XX)

Ri-COZ (XX) 013015

1S wherein Ri is a group of formula (Ild) and Z is a chlorine or bromine atom, so as to obtainthe a compound of formula (XVIa) or (XVIb) wherein R is as defined above and Ri is agroup of formula (Ild); and j) reacting the compound of formula (XVIa) or (XVIb) prepared according to any one ofsteps from (i.l) to (i.4) under basic conditions, so as to obtain the corresponding dérivativeof formula (la) or (Ib) wherein R and Ri are as above defined; and, optionally, k) converting them into other compounds of formula (la) or (Ib), respectively, and/or intopharmaceutically acceptable salts thereof.

The above process is an analogy process which can be carried out according to methodswell known in the art.

From ail of the above, it is clear to the person skilled in the art that if a compound offormula (la) or (Ib), prepared according to the above process, is obtained as a mixture ofisomers, their séparation into the single isomers of formula (la) or (Ib), carried outaccording to conventional techniques, is still within the scope of the présent invention.Likewise, the conversion into the free compound (la) or (Ib) of a corresponding saitthereof, according to well-known methods, is still within the scope of the invention.According to step (a) of the process, a compound of formula (Ilia) or (Hlb) is reacted withacrylonitrile in the presence of a suitable base, for instance sodium hydroxide. The reactionis preferably carried out in water at a température ranging from about -10°C to roomtempérature.

According to step (b) of the process, the amino group of the compound of formula (IVa) or(IVb) is protected according to conventional methods, for instance with tert-butoxycarbonyl anhydride (Boc2O) and in the presence of a suitable solvent such asacetonitrile or dichloromethane, so as to get the corresponding dérivative of formula (Va)or (Vb) wherein the amino protecting group Q just represents tert-butoxycarbonyl (boc).According to step (c) of the process, the carboxy group of the compound of formula (Va)or (Vb) is converted into the corresponding alkyl ester dérivative, for instance by operatingin the presence of a suitable alkyl halide, for instance methyl iodide.

The reaction is carried out in the presence of a suitable solvent such as dimethylformamideand under basic conditions, for instance by using sodium or potassium hydrogencarbonate. 013015 19

According to step (d) of the piocess, the compound of formula (Via) or (VIb) is convertedinto the corresponding cyclic dérivative of formula (VHa) or (Vllb) through reaction withsodium hydride. The réaction is carried out in the presence of a suitable solvent such asdioxane or tetrahydrofuran at refluxing température. —5 According to step (e) of the process, the compound of formula (VHa) or (VHb) is reactedwith hydrazine hydrate, preferably with an excess of hydrazine monohydrated, for instanceup to 10 équivalents, in the presence of a suitable solvent such as halogenatedhydrocarbons, lower alcohols or admixtures thereof. The reaction is preferably carried outin the presence of éthanol, by adding hydrazine to a solution of the compound of formula 10 (VHa) or (Vllb) and under stirring for a suitable time, for instance about 48 hours, at thetempérature ranging from about 20°C to about 70°C. Preferably, the above reaction iscarried out also in the presence of glacial acetic acid.

According to step (f) of the process, the compound of formula (Villa) or (VOTb) is reactedwith ethyl chloroformate so as to get the conesponding dérivative of formula (IXa) or 15 (IXb). The reaction is carried out according to well-known operative conditions, in thepresence of a suitable base, for instance diisopropylethylamine, and of a suitable solventsuch as tetrahydrofuran.

Clearly, the ethoxycarbonyl group may be bound to any one of the pyrazole nitrogen atomsof both compounds of formula (Villa) and (VlIIb) so as to give lise to the following 20 regioisomers of formula (IXa) or (IXb) 013015 20

In this respect, each couple of regioisomers of formula (EXa) or (IXb) may be convenientlyseparated according to well-known methods, for instance under chromatographieconditions, and each regioisomer so isolated subsequently worked out. In the alternative, 5 the mixture of regioisomers can be treated as such in the subséquent steps of the process,without providing any séparation.

In fact, as the ethoxycarbonyl group leading to two distinct regioisomers is finally removedat the end of the process, it is clear to the skilled person that both the above pathways canbe canied out for preparing the compounds of formula (la) or (Ib) of the invention. 10 Preferably, however, the process is carried out by first separating and isolating theregioisomers of formula (IXa) or (IXb) from their mixture, as reported in the workingexamples, and by subsequently reacting them to the desired compounds.

According to step (g.l) of the process, the compound of formula (EXa) or (IXb) is reactedwith a suitable dérivative of formula (X) wherein Z represents a halogen atom, preferably 15 chlorine or bromine.

Typically, the compound of formula (IXa) or (IXb) is dissolved in a suitable solvent suchas dichloromethane, dimethylformamide, tetrahydrofuran, dioxane or the like, and asuitable base such as triethylamine, diisopropylethylamine, sodium carbonate or the like is 013015 21 added. The compound of formula (X) is then added and the mixture stirred for a time ofabout 2 to about 15 hours, at a température ranging from about 20°C to about 80°C. A suitable catalyst such as dimethylamino-pyridine may be optionally used.

According to step (g.2) of the process, the compound of formula (Ka) or (Kb) is reactedwith an isocyanate dérivative of formula (XII), by operating substantially as set forth instep (g.l) of the process, except that the base may not be required.

According to step (g.3) of the process, the compound of formula (IXa) or (IXb) is reactedwith an amine of formula (XIII) in the presence of triphosgene or of a suitablechloroformate, for instance 4-nitrophenyl chloroformate, so as to get the correspondingureido dérivative. The reaction is carried out in tetrahydrofuran (THF) or in a suitablehalogenated hydrocarbon, preferably dichloromethane (DCM), and in the presence of asuitable amine such as diisopropylethylamine or triethylamine at a température rangingfrom about -70°C to room température.

According to step (h) of the process, the protected amino group in formula (Xla) or (Xlb)is deprotected under well-known operative conditions, for instance under acidic conditionsin the presence of trifluoroacetic or hydrochloric acid.

The compound of formula (Xla) or (Xlb) is thus suspended in a suitable solvent such asdichloromethane or dioxane, and treated with a concentrated solution of the selected acid.Altematively, commercially available solutions of gaseous hydrogen chloride dissolved indioxane (4 M HCl) may be advantageously employed. The mixture is then stirred for atime of about 2 hours to about 15 hours at a température ranging from about 20°C to about40°C.

According to any one of steps (i.l), (i.2), (i.3) or (i.4) of the process, the. compound offormula (XTVa) or (XTVb) is frirther reacted with a suitable dérivative so as to obtain thecorresponding carboxamido, ureido or carbamate dérivative of formula (XVIa) or (XVIb).Step (i.l) is carried out with an acyl halide, preferably chloride, of formula (XV) in asuitable solvent such as dichloromethane and under basic conditions, for instance in thepresence of a suitable amine such as diisopropylethylamine.

The reaction allows to obtain carboxamido dérivatives of formula (XVIa) or (XVIb)wherein Ri is as defined in formula (I) under groups from (a) to (c), (lia) with X as a 013015 22 carbon atom and (Ilb); from the above, it is clear to the skilled per son that the atom of theRi group which is directly linked to the carbonyl moiety of formula (XYIa) or (XVIb) is acarbon atom.

Step (i.2) is carried out with a heterocyclic dérivative of formula (XVII) or of an amine of 5 formula (XVffl), in the presence of triphosgene, substantially as described under step (g.3)of the process.

In this respect, step (i.2) allows to obtain ureido dérivatives of formula (XVIa) or (XVIb)wherein R) is a group of formula (Ha) with X as a nitrogen atom or of formula (Ile) andwherein Y, Rc, n, Rd and R'dare as above defined. 10 Likewise, the condensation of step (i.3) is carried out with a carboxylic acid dérivative offormula (XIX), in the presence of a suitable condensing agent such as, for instance,dicyclohexylcarbodiimide (DCC), l-ethyl-3-(3'-dimethylaminopropyl)carbodiimide (EDC)or O-benzotriazolyl tetramethylisouronium tetrafluoroborate (TBTU), and by operatingaccording to well-known methods for preparing carboxamido dérivatives. 15 According to step (i.4) of the process, the eompound of formula (XlVa) or (XlVb) isreacted with a suitable dérivative of formula (XX) wherein Ri is a group of formula (Ild)and Re is as set forth in formula (la) or (Ib), so as to obtain the corresponding carbamatedérivatives of formula (XVIa) or (XVIb).

In this respect, the eompound of formula (XlVa) or (XlVb) is dissolved in a suitable 20 solvent such as dichloromethane, dimethylformamide, tetrahydrofuran, dioxane or the like,and a suitable base such as triethylamine, diisopropylethylamine, sodium carbonate or thelike is added therein. The eompound of general formula (XX) is then added and themixture stiired for a time of about 2 hours to about 15 hours, at a température ranging fromabout 20°C to about 80°C. According to a preferred embodiment, a suitable catalyst such 25 as dimethylamino pyridine may be optionally used.

According to step (j) of the process, the eompound of formula (XVIa) or (XVIb) beingobtained in any one of steps from (i.l) to (i.4) is reacted with a suitable base, for instancetriéthylamine, and in the presence of a suitable solvent such as methanol or éthanol so as toobtain the desired eompound of formula (la) or (Ib). 013015 23

Finally, as per step (k) of the process, these latter compounds (la) or (Ib) may be optionallyconverted into phamiaceutically acceptable salts as fonnerly reported and by workingaccording to conventional methods or, altematively, may converted into additionalcompounds of formula (la) or (Ib).

Just as a non limiting example, compounds of formula (la) or (Ib) bearing a carboxyesterfonction may be converted into a variety of dérivatives according to methods well knownin the art to convert carboxyester groups into carboxamides, N-substituted carboxamides,Ν,Ν-disubstituted carboxamides, carboxylic acids, and the like.

The operative conditions are those widely known in the art and may comprise, for instancein tlie conversion of a carboxyester group into a carboxamide group, the reaction withammonia or ammonium hydroride in the presence of a suitable solvent such as a loweralcohol, dimethylfoimamide or mixtures thereof; preferably the reaction is canied out withammonium hydroride in a methanol/dimethylformamide mixture, at a température rangingfiom about 50°C to about 100°C.

Analogous operative conditions apply in the préparation of N-substituted or Ν,Ν-disubstituted carboxamides wherein a suitable primary or secondary amine is used in placeof ammonia or ammonium hydroxide.

Likewise, carboxyester groups may be converted into carboxylic acid dérivatives throughbasic or acidic hydrolysis conditions, widely known in the art.

As an additional example, compounds of formula (la) or (Ib) bearing an amino fonctionmay be easily converted into the coiresponding carboxamido or ureido dérivatives.

From ail of the above it is clear to the skilled person that according to step (k) of theprocess, any compound of formula (la) or (Ib) bearing a fonctional group whieh can befurther derivitized to another fonctional group, by working according to methods wellknown in the art thus leading to other compounds of formula (la) or (Ib), has to beintended as comprised within the scope of the présent invention.

According to any variant of the process for preparing the compounds of formula (I), thestarting material and any other reactant is known or easily prepared according to knownmethods. 013015 24

As an example, whilst the starting materials of formula (Ilia) or (HTb) are commerciallyavailable, the compounds of formula (X), (XII), (ΧΙΠ), (XV), (XVH), (XVIII), (XEX) and(XX) are known or can be easily prepared according to known methods.

The intermediate compounds of formula (Vlla) or (VHb) of the process

(Vllb) 10 15 20 25 wherein Q represents a suitable nitrogen protecting group, for instance tert-butoxycarbonyl(boc), are novel and, hence, respresent a further object of the invention.

As it will be readily appreciated, if the compounds of formula (I) prepared according to theprocess described above are obtained as an admixture of isomers, their séparation into thesingle isomers of formula (I), according to conventional techniques, is within the scope ofthe présent invention. Conventional techniques for racemate resolution include, forinstance, partitioned crystallization of diastereoisomeric sait dérivatives or préparativechiral HPLC.

In addition, it is clear from the above that a given compound of formula (la) or (Ib) may beprepared either by starting from the mixture of the regioisomers of formula (Ka) or (Rb)or, altematively, from each one of the two regioisomers themselves.

When preparing the compounds of formula (I) according to any one of the aforementionedprocess variants, optional fonctional groups within the starting materials or theintermediates thereof and which could give lise to unwanted side reactions, need to beproperly protected according to conventional techniques. Likewise, the conversion of these'latter into the free deprotected compounds may be carried out according to knownprocedures.

In addition, the compounds of formula (I) of the invention may be also prepared accordingto combinatorial chemistry techniques widely known in the art, by accomplishing theaforementioned reactions between the several intermediates in a serial manner and byworkingunder solid-phase-synthesis (SPS) conditions. 013015 25

As an example, the compounds of formula (Xla) or (Xlb) which are prepared according toany one of steps (g.l), (g.2) or (g.3) can be supported onto a suitable polymeric resin. Moreparticularly, the ethoxycarbonyl group in formula (Xla) or (Xlb) may be removed underbasic conditions, for instance in the presence of triethylamine or diisopropylamine, and the 5 résultant compound anchored to the above supporting resin, through the pyrazole nitrogenatom itself

10 15

The supported intermediate thus obtained may be then reacted according to step (h) andany one of steps (i.l), (i.2), (i.3) or (i.4) of the process, so as to obtain the correspondingcompound of formula (la) or (Ib) of the invention still supported on the polymeric resin.Subséquent resin cleavage, for instance under basic or acidic conditions according toknown methods, allows to obtain the desired compounds of formula (la) or (Ib).

Clearly, by performing the above reactions of the process in a serial manner, that is byfollowing a combinatorial approach for instance as set forfh above, several compounds offormula (la) and (Ib) may be thus prepared and collected.

Therefore, it is a further object of the présent invention a lihrary of two or morecompounds of formula (la)

wherein 013015 26 R is a group -COR\ -CONHR8 or -CONRaRb wherein Ra and Rb are, each independently,hydrogen or an optionally substituted group selected from straight or branched Ci-Cé alkyl,C3-C6 cycloalkyl, aryl, arylalkyl, heterocyclyl or heterocyclylalkyl or; together with thenitrogen atom to which they are bonded, R8 and Rb may fonn an optionally substituted 5 or 5 6 membered heterocycle optionally containing one additional heteroatom or heteroatomic group selected among N, NH. O or S;

Ri is selected from the group consisting of: a) straight or branched C3-C4 alkyl; b) cycloalkyl, cycloalkyl-alkyl or alkyl-cycloalkyl wherein the cycloalkyl moiety 10 comprises any C3-C6 cycloalkyl group and wherein the alkyl moiety comprises any straight or branched C1-C4 alkyl group: c) 3-methylthienyl-2-yl; 2-thienyl; phenyl; 2,6-difluorophenyl; 4-(aminosulfonyl)phenyl; 4-(dimethylaminomethyl)phenyl; 4-(4-methylpiperazinyl)methyl-phenyl; 15 d) a group of formula (lia) or (Ilb): /(R°)n

N (Ha) (Ilb) wherein, in formula (Ha), the cycle represents a 5 to 7 membered heterocyclic ring wherinX, directly linked to the rest of the molécule, represents a carbon or nitrogen atom; Y is acarbon, nitrogen, oxygen or sulfur atom or it is an NH group, provided that at least one of 20 X and Y is other tban a carbon atom; Rc is, independently from each other and in any oneof the free positions of the heterocyclic ring of formula (Ha), a halogen atom or hydroxygroup or it is an optionally substituted group selected from straight or branched Ci-Cgalkyl, C3-C0 cycloalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, amino,aminocarbonyl, carboxy, oxo (=0), alkoxycarbonyl, alkylcarbonyl or arylcarbonyl; and n 25 is 0 or an integer from 1 to 4; e) a group of formula (Ile) or (Ild): 013015 10 27

Rd \.d (Ile)

Re / (Hd) wherein Rd, R'd and Re represent, the same or different and independently from each other,a hydrogen atom or a straight or branched Ci-Ci alkyl optionally substituted by one ormore groupe selected from hydroxy (-OH), aminocarbonyl (-CONH2) ormethylaminocarbonyl (-CONHCH3); provided that in formula (la), when Rj is a group of formula (Ile) and one of Rd or R'd is ahydrogen atom whilst the other of Rd or R,d is ethyl or n-butyl, then R is other than -CORawith Ra as 3-bromophenyl, benzyl, 4-tert-butylphenyl, 4-tert-butylphenylmethyl, 4-fluorophenylmethyl, cyclopropyl or 2-naphthylmethyI; or a phaimaceutically acceptable sait thereof.

Likewise, it is a further object of the présent invention a library of two or more compoundsof formula (Ib)

15 20 wherein’ R is a group -COR3, -CONHR3 or -CONRaRb wherein Ra and Rb are, each independently,hydrogen or an optionally substituted group selected from straight or branched CrC6 alkyl,C3-C6 cycloalkyl, aryl, aiylalkyl, heterocyclyl or heterocyclylalkyl or; togetber with thenitrogen atom to which they are bonded, Ra and Rb may form an optionally substituted 5 or6 membered heterocycle optionally containing one additional heteroatom or heteroatomicgroup selected among N, NU, O or S;

Ri is selected from the group consisting of: a) straight or branched C3-C4 alkyl; 013015 28 b) cycloalkyl, cycloalkyl-alkyl or alkyl-cycloalkyl wherein the cycloalkyl moietycomprises any C3-C6 cycloalkyl group and wherein the alkyl moiety comprises any straightor branched C1-C4 alkyl group: c) 3-methylthienyl-2-yl; 2-thienyl; phenyl; 2,6-difluorophenyl; 4-5 (aminosulfonyl)phenyl; 4-(dimethylaminomethyl)phenyl; 4-(4-methylpiperazinyl)methyl- phenyl; d) a group of formula (Ha) or (Ilb): /(RC>n

•N (Ha) (Ilb) wherein,in formula (Ha), the cycle représente a 5 to 7 membered heterocyclic ring wherin 10 X, directly linked to the rest of the molécule, represents a carbon or nitrogen atom; Y is acarbon, nitrogen, oxygen or sulfur atom or it is an NH group, provided that at least one ofX and Y is other than a carbon atom; Rc is, independently from each other and in any oneof the free positions of the heterocyclic ring of formula (lia), a halogen atom or hydroxygroup or it is an optionally substituted group selected from straight or branched Ci-Ce 15 alkyl, C3-C6 cycloalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, amino,aminocarbonyl, carboxy, oxo (=0), alkoxycarbonyl, alkylcarbonyl or arylcarbonyl; and nis 0 or an integer from 1 to 4; e) a group of formula (Ile) or (Ild):

Rd R® / /

—N —O R’d (Ne) (Ild) 20 wherein R4, R'd and Re represent, the same or different and independently from each other,a hydrogen atom or a straight or branched C1-C0 alkyl optionally substituted by one ormore groups selected from hydroxy (-OH), aminocarbonyl (-CONH2) ormethylaminocarbonyl (-CONHCH3); or a pharmaceutically acceptable sait thereof. 013015 29

For a general reference to the above libraries of compounds of formula (I) see theexperimental section.

From ail of the above, it is clear to the skilled person that once a library of pyrrolo-pyrazole dérivatives is thus prepared, for instance consisting of a few hundreds or even afew thousands of compounds of formula (la) or (1b), the said library can be veryadvantageously used for screening towards given kinases, as fonnerly reported.

See, for a general reference to libraries of compounds and uses thereof as tools forscreening biological activities, J. Med. Chem. 1999, 42, 2373-2382; and Bioorg. Med.Chem. Lett. 10 (2000), 223-226.

PHARMACOLOGY

The compounds of formula (I) are active as protein kinase inhibitors and are thereforeuseful, for instance, to restrict the unregulated prolifération of tumor cells.

In therapy, they may be used in the treatment of various tumors, such as those fonnerlyreported, as well as in the treatment of other cell proliférative disorders such as psoriasis,vascular smooth cell prolifération associated with atherosclerosis and post-surgical stenosisand restenosis and in the treatment of Alzheimer’s disease.

The inhibiting activity of putative Cdi/Cyclin inhibitors and the potency of selectedcompounds was determined through a method of assay based on the use of the SPAtechnology (Amersham Pharmacia Biotech).

The assay consists of the transfer of radioactivity labelled phosphate moiety by the kinaseto a biotinylated substrate. The resulting 33P-labelled biotinylated product is allowed tobind to streptavidin-coated SPA beads (biotin capacity 130 pmol/mg), and light emittedwas measured in a scintillation counter.

Inhibition assay of Cdk2/Cyclin A activitv

Kinase reaction: 4 μΜ in house biotinylated histone H1 (Sigma # H-5505) substrate, 10uM ATP (0.1 microCi Ρ33γ-ΑΤΡ), 4.2 ng Cdk2/Cyclin A complex, inhibitor in a finalvolume of 30 μΐ buffer (TRIS HCl 10 mM pH 7.5, MgCl2 10 mM, DTT 7.5 mM + 0.2mg/ml BSA) were added to each well of a 96 U bottom. After 30 min at r.t. incubation,reaction was stopped by 100 pl PBS + 32 mM EDTA + 0.1% Triton X-100 + 500 μΜATP, containing 1 mg SPA beads. Then a volume of 110 μΐ is transferred to Optiplate. 013015 30

After 20 min. incubation for substrate capture, 100 μΐ 5M CsCl were added to allowstarification of beads to the top of the plate and let stand 4 hours before radioactivitycounting in the Top-Count instrument IC50 détermination: inhibitors were tested at different concentrations ranging from5 0.0015 to 10 μΜ. Experimental data were analyzed by the computer program GrapEPad

Prizm using the four parameter logistic équation:y = bottom+(top-bottom)/(l+l 0A((logIC50-x)* slope)) where x is the logarithm of the inhibitor concentration, y is the response; y starts at bottomand goes to top with a sigmoid shape. 10 Ki calculation:

Experimental method: Reaction was carried out in buffer (10 mM Tris, pH 7.5, 10 mMMgCl2, 0.2 mg/ml BSA, 7.5 mM DTT) containing 3.7 nM enzyme, histone and ATP(constant ratio of cold/labeled ATP 1/3000). Reaction was stopped with EDTA and thesubstrate captured on phosphomembrane (Multiscreen 96 well plates from Millipoie). 15 After extensive washing, the multiscreen plates are read on a top counter. Control (timezéro) for each ATP and histone concentrations was measured.

Experimental design: Reaction velocities are measured at different four ATP, substrate(histone) and inhibitor concentrations. An 80-point concentration matrix was designedaround the respective ATP and substrate Km values, and the inhibitor IC50 values (0.3, 1, 20 3, 9 fold the Km or IC50 values). A preliminary time course experiment in the absence of inhibitor and at the different ATP and substrate concentrations allow the sélection of asingle endpoint time (10 min) in the linear range of the reaction for the Ki déterminationexperiment.

Kinetic parameter estimâtes: Kinetic parameters were estimated by simultaneous 25 nonlinear least-square régression using [Eq.l] (compétitive inhibitor respect to ATP,random mechanism) using the complété data set (80 points):

Vm»A ·Β K a Π a·Ka*Kb +a·Κα·B + a· Kb* A + A·B+a·—·Ι·(ΚΙ>·\—}Ki β [Eq.l] 013015 31 where A=[ATP], B=[Substrate], I=[inhibitor], Vm= maximum velocity, Ka, Kb, Ki thedissociation constants of ATP, substrate and inhibitor respectively. a and β thecooperativity factor between substrate and ATP binding and substrate and inhibitor bindingrespectively. 5 In addition the selected compounds hâve been characteiized on a panel of ser/threo kinases strictly related to cell cycle (Cdk2/Cyclin E, Cdkl/cyclin Bl, Cdk5/p25, Cdk4/Cyclin Dl), — and also for specificity on MAPK, PKA, EGFR, IGF 1 -R, Aurora-2 and Akt.

Inhibition assav of Cdlr2/Cyclin E activity

Kinase reaction: 10 μΜ in house biotinylated histone H1 (Sigma # H-5505) substrate, 30 10 μΜ ATP (0.3 microCi P33y-ATP), 4 ng GST-Cdk2/Cyclin E complex, inhibitor in a finalvolume of 30 μΐ bufîer (TRIS HCl 10 mM pH 7.5, MgCl2 10 mM, DTT 7.5 mM + 0.2mg/ml BSA) were added to each well of a 96 U bottom. After 60 min at r.t. incubation,reaction was stopped by 100 μΐ PBS + 32 mM EDTA + 0.1% Triton X-100 + 500 μΜATP, containing 1 mg SPA beads. Then a volume of 110 μΐ is transfeired to Optiplate. 15 After 20 min. incubation for substrate capture, 100 μΐ 5M CsCl were added to allowstarification of beads to the top of the plate and let stand 4 hours hefore radioactivitycounting in the Top-Count instrument IC50 détermination: see aboveInhibition assav of Cdkl/CycIin Bl actjyitv 20 Kinase reaction: 4 μΜ in house biotinylated histone H1 (Sigma # H-5505) substrate, 20μΜ ATP (0.2 microCi Ρ33γ-ΑΤΡ), 3 ng Cdkl/Cyclin B complex, inhibitor in a finalvolume of 30 μΐ buffer (TRIS HCl 10 mM pH 7.5, MgCl2 10 mM, DTT 7.5 mM + 0.2mg/ml BSA) were added to each well of a 96 U bottom. After 20 min at r.t. incubation,reaction was stopped by 100 μΐ PBS + 32 mM EDTA + 0.1% Triton X-100 + 500 μΜ 25 ATP, containing 1 mg SPA beads. Then a volume of 110 μΐ is transferred to Optiplate.

After 20 min. incubation for substrate capture, 100μ1 5M CsCl were added to allowstarification of beads to the top of the Optiplate and let stand 4 hours before radioactivitycounting in the Top-Count instrument. IC50 détermination: see above 013015 32

Inhibition assay of Cdk5/p25 activltv

The inhibition assay of Cdk5/p25 activity was perfoimed according to the followingprotocol.

Kinase reaction: 10 μΜ biotinylated histone H1 (Sigma # H-5505) substrate, 30 μΜ ATP 5 (0.3 microCi Ρ33γ-ΑΤΡ), 15 ng CDK5/p25 complex, inhibitor in a final volume of 30 μΐ buffer (TRIS HCl 10 mM pH 7.5, MgCl2 10 mM, DTT 7.5 mM + 0.2 mg/ml BSA) wereadded to each well of a 96 U bottom. After 30 min at r.t. incubation, reaction was stoppedby 100 μΐ PBS + 32 mM EDTA + 0.1% Triton X-100 + 500 μΜ ATP, containing 1 mgSPA beads. Then a volume of 110 μΐ is transfeired to Optiplate. 10 After 20 min. incubation for substrate capture, ΙΟΟμΙ 5M CsCl were added to allowstarification of beads to the top of the plate and let stand 4 hours before radioactivitycounting in the Top-Count instrument. IC50 détermination: see aboveInhibition assay of Cdk4/Cyclin DI activity 15 Kinase reaction: 0,4 uM μΜ mouse GST-Rb (769-921) (# sc-4112 from Santa Cruz)substrate, 10 μΜ ATP (0.5 pCi Ρ^γ-ΑΤΡ), 100 ng of baculovirus expressed GST-Cdk4/Cyclin Dl, suitable concentrations of inhibitor in a final volume of 50 μΐ buffer(TRIS HCl 10 mMpH 7.5, MgCl2 10 mM, 7.5 mM DTT+ 0.2mg/ml BSA) were added toeach well of a 96 U bottom well plate. After 40 min at 37 °C incubation, reaction was 20 stopped by 20 μΐ EDTA 120 mM.

Capture: 60 μΐ were transferred ftom each well to MultiScreen plate, to allow substratebinding to phosphocellulose filter. Plates were then washed 3 rimes with 150 μΐ/well PBSCa44-/Mg44" ftee and filtered by MultiScTeen filtration System. Détection: filters were allowed to dry at 37°C, then 100 μΐ/well scintillant were added and 25 33P labeled Rb fragment was detected by radioactivity counting in the Top-Count instrument. IC50 détermination: see aboveInhibition assay of MAPK activity 013015 33

Kinase reaction: 10 μΜ in house biotinylated MBP (Sigma # M-1891) substrate, 15 μΜATP (0.15 microCi Ρ33γ-ΑΤΡ), 30 ng GST-MAPK (Upstate Biothecnology # 14-173),inhibitor in a final volume of 30 μΐ buffer (TRIS HCl 10 mM pH 7.5, MgCl2 10 mM, DTT 7.5 mM + 0.2 mg/ml BSA) were added to each well of a 96 U bottom. After 30 min at r.t.incubation, reaction was stopped by 100 μΐ PBS + 32 mM EDTA + 0.1% Triton X-100 +500 μΜ ATP, containing 1 mg SPA beads. Then a volume of 110 μΐ is transferred toOptiplate.

After 20 min, incubation for substrate capture, 100μ1 5M CsCl were added to allowstarification of beads to the top of the Optiplate and let stand 4 hours before radioactivitycounting in the Top-Count instrument. IC50 détermination: see above

Inhibition assav of PKA activitv

Kinase reaction: 10 μΜ in house biotinylated histone H1 (Sigma # H-5505) substrate, 10μΜ ATP (0.2 microM Ρ33γ-ΑΤΡ), 0.45 U PKA (Sigma # 2645), inhibitor in a final volumeof 30 μΐ buffer (TRIS HCl 10 mM pH 7.5, MgCl2 10 mM, DTT 7.5 mM + 0.2 mg/ml BSA)were added to each well of a 96 U bottom. After 90 min at r.t. incubation, reaction wasstopped by 100 μΐ PBS + 32 mM EDTA + 0.1% Triton X-100 + 500 μΜ ATP, containing1 mg SPA beads. Then a volume of 110 μΐ is transferred to Optiplate.

After 20 min. incubation for substrate capture, 100 μΐ 5M CsCl were added to allowstarification of beads to the top of the Optiplate and let stand 4 hours before radioactivitycounting in the Top-Count instrument. 1C50 détermination: see above

Inhibition assav of EGFR activity

Kinase réaction: 10 μΜ in house biotinylated MBP (Sigma # M-1891) substrate, 2 μΜATP (0.04 microCi Ρ33γ-ΑΤΡ), 36 ng insect cell expressed GST-EGFR, inhibitor in a finalvolume of 30 μΐ buffer (Hepes 50 mM pH 7.5, MgCl2 3 mM, MnCl2 3 mM, DTT 1 mM,NaVOj 3μΜ + 0.2 mg/ml BSA) were added to each well of a 96 U bottom. After 20 min atr.t. incubation, reaction was stopped by 100 μΐ PBS +32 mM EDTA + 0.1% Triton X-100 013015 34 + 500 μΜ ΑΤΡ, containing 1 mg SPA beads. Then a volume of 110 μΐ is transferred toOptiplate.

After 20 min. incubation for substrate capture, ΙΟΟμΙ 5M CsCl were added to allowstatifîcation of beads to the top of the Optiplate and let stand 4 hours before radioactivity 5 coun tin g in the Top-Count instrument. IC50 détermination: see aboveInhibition assay of IGF1-R activity

The inhibition assay of IGF1-R activity was performed according to the followingprotocol. 10 Kinase reaction: 10 μΜ biotinylated MBP (Sigma cat. # M-1891) substrate, 0-20 μΜinhibitor, 6 μΜ ΑΤΡ, 1 microCi 33P-ATP, and 22.5 ng GST-IGF1-R (pre-incubated for 30min at room température with cold 60 μΜ cold ATP) in a final volume of 30 μΐ buffer (50mM HEPES pH 7.9, 3 mM MnCl2, 1 mM DTT, 3 μΜ NaVO3) were added to each well ofa 96 U bottom well plate. After incubation for 35 min at room température, the reaction 15 was stopped by addition of 100 μΐ PBS buffer containing 32 mM EDTA, 500 μΜ coldATP, 0.1% Triton X100 and lOmg/ml streptavidin coated SPA beads. After 20 minincubation, 110 pL of suspension were withdrawn and transferred into 96-wellOPTIPLATEs containing 100 μΐ of 5M CsCl. After 4 hours, the plates were read for 2 minin a Packard TOP-Count radioactivity reader.

20 Inhibition assay of Aurora-2 activitY

Kinase reaction: 8 μΜ biotinylated peptide (4 repeats of LRRWSLG), 10 μΜ ATP (0.5uCi Ρ33γ-ΑΤΡ), 15 ng Aurora2, inhibitor in a final volume of 30 μΐ buffer (HEPES 50 mMpH 7.0, MgCL· 10 mM, 1 mM DTT, 0.2 mg/ml BSA, 3μΜ orthovanadate) were added toeach well of a 96 U bottom well plate. After 30 minutes at room température incubation, 25 reaction was stopped and biotinylated peptide captured by adding 100 μΐ of beadsuspension.

Stratification: 100 μΐ of CsC12 5 M were added to each well and let stand 4 hour beforeradioactivity was counted in the Top-Count instrument. IC50 détermination: see above 013015 35

Inhibition assay of Ctlc7/dbf4 activity

The inhibition assay of Cdc7/dbf4 activity was performed according to the followingprotocol.

The Biotin-MCM2 substrate is trans-phosphoiylated by the Cdc7/Dbf4 complex in the 5 presence of ATP traced with γ33-ΑΤΡ. The phosphorylated Biotin-MCM2 substrate is thencaptured by Streptavidin-coated SPA beads and the extent of phosphorylation evaluated byβ counting.

The inhibition assay of Cdc7/dbf4 activity was performed in 96 wells plate according tothe following protocol. 10 To each well of the plate weré added: - 10 μΐ substrate (biotinylated MCM2, 6 μΜ final concentration) - 10 μΐ enzyme (Cdc7/Dbf4,12.5 nM final concentration) - 10 μΐ test compound (12 increasing concentrations in the nM to μΜ range to generate adose-response curve)

15 - 10 μΐ of a mixture of cold ATP (10μΜ final concentration) and radioactive ATP (1/2500 molar ratio with cold ATP) was then used to start the reaction which wasallowed to take place at 37°C.

Substrate, enzyme and ATP were diluted in 50 mM HEPES pH 7.9 containing 15 mMMgCb, 2 mM DTT, 3 μΜ NaVC>3, 2mM glycérophosphate and 0.2mg/ml BSA. The 20 solvent for test compounds also contained 10% DMSO.

After incubation for 20 minutes, the réaction was stopped by adding to each well 100 μΐ ofPBS pH 7.4 containing 50 mM EDTA, 1 mM cold ATP, 0.1% Triton XI00 and 10 mg/mlstreptavidin coated SPA beads.

After 15 minutes of incubation at room température to allow the biotinylated MCM2- 25 streptavidin SPA beads interaction to occur, beads were trapped in a 96 wells filter plate(UnifilterR GF/B™) using a Packard Cell Harvester (Filtermate), washed with distilledwater and then counted using a Top Count (Packard).

Counts were blank-subtracted and then the experimental data (each point in triplicate) wereanalyzed for IC50 détermination using a ηοη-linear régression analysis (Sigma Plot). 013015 36

Given the above inhibition assays, the compounds of formula (I) of the invention resultedto possess a remarkable cdk inhibitory activity. See, as an example, the followingexperimental data (IC50) of two représentative, compounds of the invention of formula (la)and (Ib) being tested against Cdk2/Cyclin A: 5 Compound 1 : N-[5-(2,2-dimethylpropanoyl)-6,6-dimethyl-l ,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl]-4-fluorobenzamide (IC50 0.030 μΜ); and

Compound2; N-[5-(2,2-dimethylpropanoyl)-l,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-6-spirocyclopropan-3-yl]-4-fluorobenzamide (IC50 0.025 μΜ).

Suiprisingly, the said inhibitory activity resulted to be markedly superior that that of a very10 close compound of the prior art WO 02/12242, herewith referred to as Referencecompound (see compound 1143, bottom of page 76; and example 19, compound bridgingpages 242-3 of WO 02/12242), used for comparative purposes and tested against

Cdk2/Cyclin A, as formerly reported:

Reference Compound: N-[5-acetyl-6,6-dimethyl-4,6-dihydropyrrolo[3,4-c]pyrazol-3-yl]-15 (3-bromo)benzamide (IC501.7 μΜ)

Br

20

Compound 1 Compound 2 Reference compound S 0 far, the novel compounds of the invention are unexpectedly endowed with a cdkinhibitory activity significantly higher than that of the structurally closest prior artcompounds of WO 02/12242 and are thus particularly advantageous, in therapy, againstproliférative disorders associated with an altered cell cycle dépendent kinase activity.

The compounds of the présent invention can be administered either as single agents or,altematively, in combination with known anticancer treatments such as radiation therapyor chemotherapy regimen in combination with cytostatic or cytotoxic agents, antibiotic- 013015 37 type agents, alkylating agents, antimetabolite agents, hormonal agents, immunologicalagents, interferon-type agents, cyclooxygenase inhibitors (e.g. COX-2 inhibitors),matrixmetalloprotease inhibitors, telomerase inhibitors, tyrosine kinase inhibitors, anti-growth factor receptor agents, anti-HER agents, anti-EGFR agents, anti-angiogenesisagents (e.g. angiogenesis inhibitors), famesyl transferase inhibitors, ras-raf signaltransduction pathway inhibitors, cell cycle inhibitors, other cdks inhibitors, tubulin bindingagents, topoisomerase I inhibitors, topoisomerase II inhibitors, and the Iike.

If formulated as a fixed dose, such combination products employ the compounds of thisinvention within the dosage range described below and the other pharmaceutically activeagent within the approved dosage range.

Compounds of formula (1) may be used sequentially with known anticancer agents when acombination formulation is inappropriate.

The compounds of formula (I) of the présent invention, suitable for administration to amammal, e.g., to humans, can be administered by the usual routes and the dosage leveldépends upon the âge, weight, conditions of the patient and administration route.

For example, a suitable dosage adopted for oral administration of a compound of formula(I) may range from about 10 to about 500 mg per dose, from 1 to 5 times daily. Thecompounds of the invention can be administered in a variety of dosage forms, e.g., orally,in the form tablets, capsules, sugar or film coated tablets, liquid solutions or suspensions;rectally in the form suppositoires; parenterally, e.g., intramuscularly, or throughintravenous and/or intrathecal and/or intraspinal injection or infusion.

The présent invention also includes phannaceutical compositions comprising a compoundof formula (I) or a pharmaceutically acceptable sait thereof in association with apharmaceutically acceptable excipient, which may be a carrier or a diluent.

The pharmaceutical compositions containing the compounds of the invention are usuallyprepared following conventional methods and are administered in a suitablepharmaceutical form. For example, the solid oral forms may contain, together with theactive compound, diluents, e.g., lactose, dextrose saccharose, sucrose, cellulose, cornstarch or potato starch; lubricants, e.g., silica, talc, stearic acid, magnésium or calciumstéarate, and/or polyethylene glycols; binding agents, e.g., starches, arabic gum, gélatine 013015 38 methylcellulose, carboxymethylcellulose or polyvinyl pyrrolidone; disintegrating agents,e.g., starch, alginic acid, alginates or sodium starch glycolate; effervescing mixtures;dyestuffs; sweeteners; wetting agents such as lecithin, polysorbates, laurylsulphates; and,in general, non-toxic and pharmacologically inactive substances used in pharmaceutical 5 formulations. These pharmaceutical préparations may be manufactured in known manner,for example, by means of mixing, granulating, tabletting, sugar-coating, or film-coatingprocesses.

The liquid dispersions for oral administration may be, e.g., syrups, émulsions andsuspensions. As an example, the syrups may contain, as carrier, saccharose or saccharose 10 with glycérine and/or mannitol and sorbitol.

The suspensions and the émulsions may contain, as examples of carriers, natural gum,agar, sodium alginate, pectin, methylcellulose, carboxymethylcellulose, or polyvinylalcohol. The suspension or solutions for intramuscular injections may contain, togetherwith the active compound, a pharmaceutically acceptable carrier, e.g., stérile water, olive 15 oil, ethyl oleate, glycols, e.g., propylene glycol and, if desired, a suitable amount oflidocaine hydrochloride.

The solutions for intravenous injections or infusions may contain, as a carrier, stérile wateror preferably they may be in the form of stérile, aqueous, isotonie, saline solutions or theymay contain propylene glycol as a carrier. 20 The suppositoires may contain, together with the active compound, a phannaceuticallyacceptable carrier, e.g., cocoa butter, polyethylene glycol, a polyoxyethylene sorbitan fattyacid ester surfactant or lecithin.

With the aim of better illustrating the présent invention, withoutposing any limitation to it,the following examples are now given. 25 . General methods

Before taking into considération the synthetic préparation of the spécifie compounds offormula (I) of the invention, for instance as reported in the following examples, attentionshould be given to the fact that some compounds are herewith listed and indicatedaccording to their Chemical name whilst others, most of them, hâve been conveniently and 013015 39 unambiguously identified througb a coding System, together with their ’H-NMR data (seefollowing tables IH, IV and V) and HPLC/Mass data (see following table VI).

Each code, in particular, identifies a single spécifie compound of formula (la) or (Ib) andconsists of three units À-M-B. 5 A represents any substituent R [see formula (la) or (Ib)] and is attached to the rest of tbemolécule through the -NH-group; each spécifie A group is represented and consecutivelynumbered in the following table I.

Likewise, B represents any substituent R; [see formula (la) or (Ib)] and is attached to therest of the molécule through the carbonyl (CO) group; each spécifie B group is represented

10 and consecutively numbered in the following table IL M refers to the central core of the divalent moiety which is substituted by groups A and B;in particular, M may vary from Ml or M2 as per the formulae below, each identifying thecentral core of a compound having formula (la) or (Ib), respectively:

15 For ease of reference, ail of the A and B groups of tables I and Π hâve been identified withthe proper Chemical formula also indicating the point of attachaient with the rest of themolécule M.

Therefore, just as an example, the compound A06-M1-B01 of table ΙΠ represents thecompound of formula (la) having the central Ml core, being substituted by the group A06 20 and by the group B01, in the positions indicated by the arrows; likewise, the compoundA04-M2-BQ8 of table V represents the compound of formula (Ib) having the central M2core, being substituted by die group A04 and by the group B08, in the positions indicatedby the arrows: 013015 40

Table I

AOl F" 0 AO2 Fï O a A03 A04 F 1 O II F. τΓτ A 'M If S F-' F^ y AO5 0 || A06 0 II F. rv A 'M (I y AM V F ca y AO7 0 AO8 0 r Ά P 'M J A09 0 II A1O 0 £ y M 0 A M 013015 41

Ail 0 eA A12 ÀÂ, A13 A14 Λ A15 Al 6 •^x/" A17 0 Al 8 0 Çj/SxiT^fz^M A19 </ A20 p. A21 0 fA A22 0 A23 0 ΑΑΑ A24 U H A25 O U H A26 0 _ U ^"ïl M H 013015 42

A27 Αχ, H Α28 0 |ΑΛμ A29 A Α30 χ· A31 όΧ Α32 ,.9'Χ· A33 τνΧ Α34 0 Ό,χ· A35 ο xA Α36 ^.Χ· A37 Λ.Χ" A Α38 X /0 A39 .χ· νη2 Α40 0 jum nqA A41 χΛ* Α42 CN 0 X 013015 43 A43 ά "Μ Α44 ΥΥ 0 α A45 1 Α46 Ύ ο σ 'Μ ό A47 Π 0 Α48 π Π 9 Μ Λ 'Μ υ A49 ο Α50 0 II ο Λ Μ 0 A51 ο ο Λ Μ Α52 X 0 / 'Μ A53 0 Α54 0 Y Λ Μ h Μ J |Ι A55 Ίι 0 <5^ II -

Table Π 073015 44 BO1 Y B02 B03 Y B04 “'fl B05 B06 k/NH B07 B08 “Y B09 MO B10 O Bll ΎΧ B12 Ό, OH B13 Ms °ϊ OH B14 Ύ) B15 Mn 0—/ B16 Ό, nh2 013015 45 B17 Ό, ô Β18 <ΛΟ B19 “Ό Β20 “Ο B21 mJ/\| Β22 B23 Ν S ΟΗ Β24 Μ-Μ-^ν°Η V ΟΗ B25 Μ'κ,^/0Η Ν 1 Β26 μ.ν^,οη Η B27 Μ,. Η Β28 Μ. Ν Η B29 Μ 0<ik'NH2 Β30 Μ. Ν > ΆΗ B31 “Ό ΌΗ Β32 ,ί 013015 46

B33 "(TOH B34 y/*· B35 OH B36 B37 U B38 k k^NH B39 M-p %h2 B40 O v< Ιθχχ^ΟΗ B41 9A.0H Φ F B42 k/N^N OH V B43 M'O^ B44 B45 'V B46 Μ O HN^Â J ÏH HO 013015 47

B47 "O, B48 û N 1 B49 NH A B50 B51 B52 “Ό B53 B54 “Π B55 Ι^ΛγΝΗ2 O

Example 1 N-(2-cyanoethyl)-2-methylalanine 50 g (0.48 mol) of 2-methylalanine were added to a cooled solution (water/ice) of NaOH5 (19.6 g) in water (100 ml). Once the solution had tumed clear, 34 ml (0.50 mol) of — acrylonitrile were dropped on cooîing. The mixture was left ovemight. After 18 hours, 28 ml of acetic acid were added on cooling (water/ice); a white solid precipitated; 200 ml of 95% éthanol were dropped in the flask, stirring was continued for 1 hour, then the mixturewas allowed to stand in a fridge for 2-3 hours. After filtration, the solid was collected and 10 dried in an oven at 80°C. The filtrâtes were evaporated and taken up with éthanol (160 ml). 013015 48

On cooling a further amount of product was obtained, which was filtered and dried. 72 g ofthe title compound were obtained from the fîrst filtration. Total yield: 95%. ESI MS: m/z 157 (MH+); Ή NMR (400 MHz, DMSO-d6): δ 7.47 (s, 1H), 2.70 (t, 2H), 2.48 (t, 2H), 1.18 (s, 6H).

By working in an analogons manner the following compound was prepared: l-[(2-Cyanoethyl)amino]cyclopropanecarboxylic acid

El MS: m/z 154 (M), 136 (M-H2O), 114 (M-CH2CN), 68 (100%, cyclopi=C=O); Ή NMR (400 MHz, DMSO-d<): δ 7.47 (s, 1H), 2.86 (t, 2H, J = 6h Hz), 2.48 (t, 2H, J = 6.6 Hz), 1.09 (dd, 2H, J = 6.9 Hz, J = 4.1 Hz), 0.86 (dd, 2H, J = 6.9 Hz, J = 4.1 Hz).

Example 2 N-(Zcr/-butoxycarbonyl)-N-(2-cyanoethyl)-2-methylalanine 44.5 g (0.285 mol) of N-(2-cyanoethyl)-2-methylalanine and 51.7 g oftétraméthylammonium hydroxide pentahydrate were dissolved in acetonitrile (2 1) at 40°Cand when a clear solution was obtained, 112 g of Boc20 were added. The mixture was leftfor 24 hours at 40° C. The day after, further 20 g of Boc2O were added while maintainingthe température of 40°C. Every 8-12 hours 20 g of Boc2O were added up to a total of 192g. After 4 days the solvent was evaporated, the residue taken up with water (1000 ml) andwashed twice with ethyl ether (500 ml). The aqueous fraction was brought to pH 3-4 withcitric acid and extracted with ethyl acetate, washed with water (200 ml) and concentrated.52 g of the title compound were obtained. (yield: 72%). ESI MS: m/z 274 (M+NH4); Ή NMR (400 MHz, DMSO-d6): δ 3.52 (t, 2H, J = 6.8 Hz)), 2.68 (t, 2H, J = 6.8 Hz), 1.18-1.38 (m, 15H).

By working in an analogous manner the following compound was prepared: l-[(Zer/-Butoxycaibonyl)(2-cyanoethyl)amino]cyclopropanecarboxylic acidESI MS: m/z 272 (Μ+ΝΉ4), 255(MH+); *H NMR (400 MHz, DMSO-dg): δ 12.55 (bs, 1H), 3.33 (m, 2H), 2.71 (m, 2H), 0.97-1.63(m, 13H).

Example j

MethyïN-(ter/-butoxycarbonyI)-N-(2-cyanoethyl)-2-niethylaIaninate 013015 49 62 g (0.23 mol) of N-(Ze/t-butoxycarbonyl)-N-(2-cyanoethyl)-2-mstbylalanine weredissolved in 350 ml of DMF and 50 g of KHCO3 were added. Few minutes after, 30 ml ofmethyl iodide (Mel) were dropped and the mixture was stiired at room température for 6hours. Then a further 15 ml of Mel were added. The mixture was left at room températureovemight. After dilution with 1.5 1 of water, the solution was extracted with ethyl acetate(3 times). The organic phases were washed with a small amount of water, dried oversodium sulfate, evaporated and dried at the mechanical pump. 60.5 g (97%) of methyl N-(Ze?r-butoxycarbonyl)-N-(2-cyanoethyl)-2-methylalaninate were thus obtained. ESI MS: m/z 288 (M+HH4); ’H NMR (400 MHz, DMSO-di): δ 3.55 (m, 5H), 2.70 (t, 2H, J = 6.7 Hz)), 1.40 (s, 6H), 1.36 (s, 9H).

By working in an analogous manner the following compound was prepared:

Methyl l-[(ferf-butoxycarbonyl)(2-cyanoethyl)aminojcyclopropanecarboxylateESI MS: m/z 286 (M+NH4); ’H NMR (400 MHz, DMSO-de): δ 3.61 (s, 3H), 3.42 (t, 2H, J = 6.7 Hz), 2.71 (m, 2H),1.07-1.62 (m, 13H).

Example 4

ZerZ-Butyl 4-cyano-3-hydroxy-2,2-dimethyl-2,5-dihydro-lH-pyrrole-l-carboxylate45 g of methyl N-(ferZ-butoxycarbonyl)-N-(2-cyanoethyl)-2-methylalaninate weredissolved in dioxane (240 ml) under nitrogen and 7.9 g of sodium hydride were added. Themixture was refluxed for 6 hours (120 °C internai température), and then left to standovemight at room température (TLC: CH^Ch/EtOH 90/10). The solvent was evaporated,water was added (1000 ml) and the mixture was brought to pH 3-4 with citric acid. Theaqueous layer was extracted 4 times with ethyl acetate, the extracts washed with a Iimitedamount of water and evaporated. Then the residue was taken up with hexane, evaporatedand crystallized from hexane. 33.1 g of ierf-butyl 4-cyano-3-hydroxy-2,2-dimethyl-2,5-dihydro-lH-pyrrole-l-carboxylate were thus obtained (yield: 85%). ESIMS: m/z 237 (M-H-); ’H MMR (400 MHz, DMSO-φ,): δ 4.06-4.10 (2s, 2H, conformers), 1.48 (s, 6H), 1.47 (s,9H). 013015 50

By working in an analogous manner the following compound was prepared: /erZ-Butj'l 6-cyano-7-oxo-4-azaspiro[2.4]heptane-4-carboxylateESI MS: m/z 235 (M-H-); ’HNMR (400 MHz, DMSO-dfi): δ 4.63 (t, lH,J = 9.8Hz), 4.24 (t, 1H, J = 10.2 Hz), 3.74 5 (t, 1H, J = 10.2 Hz), 1.67-2.16 (m, 2H), 1.34-1.41 (s, 9H), 0.93-1.20 (m, 2H).

Example 5 /erf-Butyl 3-amino-6,6-dimethy]-2,6-dihydropyiTolo[3,4-c]pyrazole-5(4H)-carboxylate32 g of Zeri-Butyl 4-cyano-3-hydroxy-2,2-dimethyl-2,5-dihydro-lH-pyrrole-l-carboxylate(0.134 mol) were added to 430 ml of absolute éthanol. To this solution, 9 ml (0.18 mol) of 10 hydrazine hydrate were added, followed by 12 ml of glacial AcOH (1.5 eq); The mixturewas stirred at 60 °C for 48 hours, the éthanol was removed, the residue was taken up with400 ml of sodium hydrogencarbonate solution, and extracted several times with ethylacetate up to total extraction of the desired product. The organic phases were dried andevaporated. After purification by flash chromatography (eluent: CHCb/EtOH 97/3) and 15 trituration with a mixture of hexane/ethyl acetate 9/1,25 g of title compoud were obtained .

Total yield 30.5 g (yield: 88%) ESI MS: m/z 253 (MH+); [HNMR (400 MHz, DMSO-de): δ 4.06-4.10 (2s, 2H, conformers), 1.48 (2s, 6H,confonners), 1.47 (2s, 9H, conformers). 20 By working in an analogous manner the following compound was prepared: iert-Butyl-3-amino-2,6-dihydropyrrolo(3,4-c]pyrazole-6-spirocyclopropane-5(4H)- carboxylate ESI MS: m/z 251 (MH+); 1HNMR(400MHz, DMSO-d6): δ 11.12 (bs, 1H), 5.13 (bs,2H), 4.16-4.33 (m, 2H), 1.57- 25 1.91 (m, 2H), 1.38 (s, 9H), 0.65-0.83 (m, 2H).

Example 6 5-/ert-Butyl 2-ethyl 3-amino-6,6-dimethylpyrrolo[3,4-c]pyrazole-2,5(4H,6H)-dicarboxylate and 5-terf-butyl 1-ethyl 3-amino-6,6-dimethyl-4,6-dihydropyi-rolo[3,4- c]pyrazole-l,5-dicarboxylate 013015 51 15 g of ferf-Butyl 3-amino-6,6-dimethyl-2,6-dihydropynolo[3,4-c]pyrazole-5(4H)-carboxylate (59.4 mmol) were dissolved in anhydrous THF (150 ml) and treated, at 0°Cunder Ar atmosphère, first with N,N-diisopropyIethylamine (50 ml) and then with ClCO,Et(4.65 ml, 1 eq.) dropwise. 90 minutes later, the solvent was diluted with EtOAc (1 1),washed with water and then with brine, dried over sodium sulfate and evaporated. Thecrude product was purifîed by flash chromatography (hexane/EtOAc 2/8) to afford 7.3 g of5-terf-butyl 2-ethyl 3-amino-6,6-dimethylpyrrolo[3,4-c]pyrazole-2,5(4H,6H)-dicarboxylateas the major compound in 38% yield, together with 5.7 g of 5-fert-butyl 1-ethyl 3-amino- 6,6-dimethyl-4,6-dihydropyrrolo[3,4-c]pyrazole-l,5-dicarboxylate in 30% yield.5-Zert-Butyl 2-ethyl 3-amino-6,6-dimethylpyvrolo[3,4-c]pyrazole-2,5(4H,6H)-dicarboxylate ESI MS: m/z 325 (MH+); ’H NMR (400 MHz, DMSO-ds): δ 4.35 (q, 2H), 4.10 (2s, 2H, conformers), 1.50-1.51 (m,6H), 1.41-1.43 (2s, 9H, conformers), 1.29 (t, 3H). 5-Zert-Butyl 1-ethyl 3-amino-6,6-dimethyl-4,6-dihydropyrrolo[3,4-c]pyrazole-l,5- dicarboxylate ESI MS: m/z 325 (MH+); ’H NMR (400 MHz, DMSO-d6): δ 4.28 (q, 2H, J = 7.1 Hz), 4.09-4.14 (2s, 2H,conformers), 1.66-1.67 (m, 6H), 1.41-1.44 (2s, 9H conformers), 1.27 (t, 3H, J = 7.1 Hz).

By working in an analogous manner the following compounds were prepared: 5-fert-Butyl 2-ethyl 3-amino-pyrrolo[3,4-cjpyrazole-6-spirocyclopropane-2,5(4H,6H)-dicarboxylate ESI MS: m/z 323 (MH+); ’H NMR (400 MHz, DMSO-d0): δ 4.30 (q, 2H, J = 7.1 Hz), 4.27 (bs, 2H), 1.65-2.01 (m,2H), 1.38 (s, 9H) 1.27 (t, 3H, J = 7.1 Hz), 0.82-0.96 (m, 2H). 5-fert-B utyl 1-ethyl 3-amino-4,6-dïhydropyrralo [3,4-c]pyrazole-6-spirocyclopropane-1,5-dicarboxylate ESI MS: m/z 323 (MH+); ’H NMR (400 MHz, DMSO-d6): δ 4.26 (bs, 2H), 4.21 (q, 2H, J = 7.0 Hz), 1.36-1.97 (m,13H), 1.23 (t, 3H, J = 7.0Hz). 013015 52

Example 7 5-fert-Butyl 1-ethyl 3-((4-Quorobenzoyl)amino]-6,6-dimethyl-4,6-dihydropyrrolo[3,4-c]pyrazole-l,5-dicarboxylate 5-terf-Butyl 1 -ethyl 3-amino-6,6-dimethyl-4,6-dihydropyrrolo[3,4-c]pyrazole-1,5-dicarboxylate (2.0 g, 6.16 mmol) was dissolved in THF (40 ml), treated first with N,N-diisopropylethylamine (5.4 ml, 30.80 mmol) and then, at 0°C, with 4-fluorobenzoylchloride (800 μΐ, 6.77 mmol) dissolved in THF (8 ml) dropwise. The reaction mixture wasstirred at room température for 5 hours, concentrated and dissolved in DCM, washed withsaturated sodium hydrogencarbonate aqueous solution and with brine. The organic phasewas dried over sodium sulfate, evaporated and purified by flash chromatography (eluent:hexane/EtOAc 80/20) to afford 2.5 g of the title compound in 90% yield. ESI MS:m/z447(MH+); ’H NMR (400 MHz, DMSO-di): δ 11.47 (s, 1H), 8.04-8.17 (m, 2H), 7.25-7.37 (m, 2H),4.44-4.47 (2s, 2H, confonners), 4.43 (q, 2H, J = 7.1 Hz), 1.73-1.75 (2s, 6H, confonners),1.43-1.46 (2s, 9H, conformers), 1.33 (t, 3H, J = 7.1 Hz).

By working in an analogous manner the following compounds were prepared. 5-tert-Butyl 2-ethyl 3-[(4-fluorobenzoyl)amino]-6,6-dimethylpyrrolo[3,4-c]pyrazole-2,5(4H,6H)-dicarboxylate ESI MS: m/z 447 (MH+); *H NMR (400 MHz, DMSO-d6): δ 10.78 (s, 1H), 7.95-7.99 (m, 2H), 7.40-7.47 (m, 2H),4.51-4.49 (2s, 2H, confonners), 4.43 (q, 2H, J = 7.1 Hz), 1.59-1.60 (2s, 6H), 1.43-1.46 (2s,9H, confonners), 1.34 (t, 3H, J = 7.1 Hz). 5-ierf-Butyl 2-ethyl 3-[(4-fluorobenzoyl)amino]-pyrrolo[3,4-c]pyiazole-6- spirocycIopropane-2,5(4H,6H)-dicarboxylate ESI MS: m/z 445 (MH+); ^NMR (400 MHz, DMSO-d6): δ 10.81 (s, 1H), 7.95-8.06 (m, 2H), 7.39-7.49 (m, 2H),4.67 (bs, 2H), 4.41 (q, 2H, J = 7.1 Hz), 1.80-2.10 (m, 2H), 1.41 (s, 9H), 1.32 (t, 3H, J = 7.1Hz), 0.93-1.06 (m,2H).

Example 8 5-ferZ-Butyl 1-ethyl 3-({[(3-fluorophenyl)amino]carbonyl}amino)-6,6- 013015 53 dimethyl-4,6-dlhydropyrrolo[3,4-c]pyrazole-l,5-dicarboxylate 5-ZerZ-Butyl 1-ethyl 3-amino-6,6-dimethyl-4,6-dihydropyrrolo[3,4-c]pyrazole-1,5- dicarboxylate (3.0 g, 9.24 mmol) was dissolved in anhydrous THF (50 ml), treated at roomtempérature with 3-fluorophenyl-isocyanate (1.4 g, 10.21 mmol, 1.1 eq) and stirredovemight. The following day the reaction mixture was evaporated, taken up with DCMand washed with brine. The organic phase was dried over sodium sulfate and evaporated todryness. Purification by flash chromatography (CHîClz/MeOH 90/10) afforded 3.05 g(yield 71 %) of the title compound. ESI MS: m/z 462 (MH+); 'HNMR (400 MHz, DMSO-dg): δ 9.74 (s, 1H), 9.05 (s, 1H), 7.44 (m, 1H), 7.33 (m, 1H),7.16 (m, 1H), 6.84 (m, 1H), 4.43 (m, 4H), 1.76 (2s, 6H), 1.48 (2s, 9H, confoimers), 1.36 (t,3H,J=7.1Hz).

Example 9 5-tert-Butyl 1-ethyl 3-[(piperidine-l-carbonyl)-amino]-6,6-dimethyl-4,6-dihydropyrrolo[3,4-c]pyrazole-l,5-dicarhoxylate

To a solution of triphosgene (550 mg, 1.85 mmol, 0.4 eq) in tetrahydrofuran (50 ml) wasadded, at -40°C, a solution of 5-Zert-butyl 1-ethyl 3-amino?6,6-dimethyl-4,6-dihydropyrrolo[3,4-c]pyTazole-l,5-dicarboxylate (1.5 g, 4.62 mmol) in tetrahydrofuran (50ml) and Ν,Ν-diisopropylethylamine (1.8 ml, 2.2 eq). After 3 hours, a solution of piperidine(690 μΐ, 1.5 eq) and N,N-düsopropylethylamine (1.2 ml, 1.5 eq) in tetrahydrofuran (25 ml)was added. The reaction was allowed to reach room température in 2 hours (TLC:EtOAc/hexane 90/10). After évaporation of the solvent the solid was dissolved in DCMand the solution was washed with brine, the organic phase was dried over sodium sulfateand concentrated. The solid was purified by flash chromatography (eluent: EtOAc/hexane50/50). The solid was treated with diisopropylether and filtered to afford 1.45 g of the titlecompound in 72% yield. ESI MS: m/z 436 (MH+); 'HNMR (400 MHz, DMSO-d«): δ 9.36 (s, 1H),4.46 (m, 4H), 3.40 (m, 4H), 1.76 (2s, 6H),1.54 (m, 6H), 1.44 (2s, 9H, conformera), 1.36 (t, 3H, J = 7.1 Hz).

Example 10 013015 54

Ethyl 3-((4-fluorobenzoyl)amino]-6,6-dimethyl-5,6-dihydropyrrolo[3,4-c]pyrazole-l(4ÏÏ)-carboxylate hydrochloride 5-terf-ButyI 1-ethyl 3-[(4-fluorobenzoyl)amino]-6,6-dimethyl-4,6-dihydropyrrolo[3,4-c]pyrazole-l,5-dicarboxylate (2.5 g, 5.59 mmol) was dissolved in dioxane (50 ml) andtreated vdth HCl 4M in dioxane (28 ml, 20 eq). After 2 hours at 40°C (TLC:CHjCla/MeOH 90/10) the reaction mixture was concentrated and the residue was treatedwith diethyl ether, filtered to afford the title compound (2.09 g) as a solid in 98% yield. ESI MS: m/z 347 (MH+); 4ί NMR (400 MHz, DMSO-dc): δ 11.28 (s, 1H), 8.06-8.11 (m, 2H), 7.28-7.34 (m, 2H), 4.40 (q, 2H, J = 7.1 Hz), 3.92 (s, 2H), 1.42 (s, 6H), 1.33 (t, 3H, J = 7.1 Hz).

By working in an analogous manner the following compounds were prepared:

Ethyl 3-|(4-fluorobenzoyl)ammo]-6,6-diinethy]-5,6-dihydropyr«Olo[3,4-c)pyrazole-2(4H)-carboxylate hydrochlorideESI MS: m/z 347 (MH+); ’HNMR (400 MHz, DMSO-dô): δ 10.92 (s, 1H), 9.89 (s, 1H), 8.02 (m, 2H), 7.49 (m, 2H),4.61 (s,2H),4.51 (q,2H, J = 7.1 Hz), 1.69(s,6H), 1.39 (t, 3H, J = 7.1 Hz).

Ethyl 3-[(4-fluorobenzoyl)amino]-5,6-dihydropyrrolo[3,4-c]pyrazole-6- spirocyclopropane-2(4H)-carboxylate hydrochloride ESI MS: m/z 345 (MH+); ’HNMR (400 MHz, DMSO-ds): δ 10.87 (bs, 1H), 10.00 (bs, 2H), 7.93-8.04 (m, 2H), 7.39-7.53 (m, 2H), 4.69 (bs, 2H), 4.41 (q, 2H, J = 7.1 Hz), 1.68 (dd, 2H, J = 8.6 Hz, J = 6.1 Hz), 1.41 (dd, 2H, J = 8.6 Hz, J = 6.1 Hz), 1.33 (t, 3H, J = 7.1 Hz).

Example 11

Ethyl5-(2,2-dimethylpropanoyl)-3-[(4-fluorobenzoyl)amino)-6,6-dimethyl-5,6- dihydropyrrolo[3,4-c]pyrazole-l(4H)-carboïylate

Ethyl 3-[(4-fluorobenzoyl)amino]-6,6-dimethyl-5,6-dihydropynolo[3,4-c]pyrazole-l(4H)-carboxylate hydrochloride (2.0 g, 5.77 mmol) in dichloromethane (70 ml) was treated, at0°C, with N,N-diisopropylethyIamine (1.6 ml, 9.2 mmol, 1.6 eq) and with pivaloylchloride (780 pL, 6.3 mmol, 1.1 eq). Qradually, the reaction was brought to roomtempérature and stirred ovemight (TLC: CH^Cb/EtOAc 90/10). The solution was washed 013015 55 with saturated sodium hydrogencarbonate aqueous solution and brine. The organic phasewas dried over sodium sulfate, evaporated and purified by flash chromatography (eluent:CH2Cl2/EtOAc 90/10) to afford 2.03 g of the title compound in 82% yield. ESI MS: m/z 431 (MH+); 5 ^NMR (400 MHz, DMSO-d;): δ 11.51 (s, 1H), 8.05-8.14 (m, 2H), 7.23-7.37 (m, 2H), 4.90 (s, 2H), 4.42 (q, 2H, J = 7.1 Hz), 1.80 (s, 6H), 1.33 (t, 3H, J = 7.1 Hz), 1.22 (s, 9H).

By working in an analogous manner the following compound was prepared:

Ethyl 5-(2,2-dimethylpropanoyl)-3-[(4-fluorobenzoyl)amino]-5,6-dihydropyrrolo[3,4-c]pyrazole-6-spirocyclopropane-2(4H)-carboxylate 10 ESI MS: m/z 429 (MH+); ‘HNMR (400 MHz, DMSO-de): δ 10.81 (bs, 1H), 7.96-8.04 (m, 2H), 7.38-7.48 (m, 2H), 5.10 (bs, 2H), 4.42 (q, 2H, J = 7.1 Hz), 2.33 (dd, 2H, J = 6.8 Hz, J = 4.2 Hz), 1.32 (t, 3H, J= 7.1 Hz), 1.22 (s, 9H), 0.90 (dd, 2H, J = 6.8 Hz, J = 4.2 Hz).

Example 12 15 N-[5-(2,2-dimethylpropanoyl)-6,6-dimethyl-l,4,5,6-tetrahydropyiTolo[3,4-c]pyrazol- 3-yl]-4-fluorobenzamide

Ethyl 5-(2,2-dimethylpropanoyl)-3-[(4-fluorobenzoyl)amino]-6,6-dimethyl-5,6- dihydropyirolo[3,4-c]pyrazole-l(4H)-carboxylate (2.0 g, 4.64 mmol) was dissolved inmethanol (60 ml), treated with TEA (6.45 ml, 46.4 mmol, 10 eq) and stiired ovemight at 20 room température. (TEC: CILCE/MeOH 95/5). After évaporation, the solid was treatedwith diethyl ether/hexane and filtered to afford 1.43 g of the title compound in 86% yield.ESI MS: m/z 359 (MH+); ’HNMR (400 MHz, DMSO-d6): δ 12.41 (bs, 1H), 10.91 (bs, 1H), 7.98-8.11 (m, 2H), 7.20-7.44 (m, 2H), 4.66-4.92 (bs, 2H), 1.64 (s, 6H), 1.21 (s, 9H). 25 By working in an analogous manner the following compounds were prepared:N-[5-(2,2-dimethylpropanoyl)-2,4,5,6-tefrahydropyrrolo{3,4-c]pyrazoI-6-spirocyclopropan-3-yl]-4-fluorobenzamide ESI MS: m/z 357 (MH+); 013015 56 ^NMR (400 MHz, DMSO-de): δ 11.59-12.47 (bs, 1H), 10.94 (bs, 1H), 8.02-8.11 (m, 2H), 7.27-7.37 (m, 2H), 4.99 (s, 2H), 2.25 (dd, 2H, J = 6.5 Hz, J = 4.4 Hz), 1.20 (s, 9H),0.79 (dd, 2H, J = 6.5 Hz, J = 4.4 Hz). N-{6,6-dimethyl-5-[(2R)-tetrahydrofuran-2-ylcarbonyl]-l,4,5,6- 5 tetrahydropyrrolo[3,4-c]pyrazol-3-yl}-4-fluorobenzamideESI MS: m/z 373 (MH+); ]H NMR (400 MHz, DMSO-dé): δ 12.49 (bs, JH), 10.96 (bs, 1H), 8.09 (m, 2H), 7.34 (m,2H), 4.86 (m, 2H), 4.56 (t, 1H), 3.83 (m, 2H) 2.02 (m, 2H), 1.86 (m, 2H), 1.68 (s, 6H).aD +27.7 (c=0.50, MeOH) 10 N-{6,6-dimethyl-5-[(2S)-tetrahydrofuran-2-ylcarbonyl]-l,4,5,6-tetrahydropyrrolo[3,4- c]pyrazol-3-yl}-4-fluorobenzamideESI MS: m/z 373 (MH+); ^NMR (400 MHz, DMSO-de): δ 12.49 (bs, 1H), 10.96 (bs, 1H), 8.09 (m, 2H), 7.34 (m,2H), 4.86 (m, 2H), 4.56 (t, 1H), 3.83 (m, 2H) 2.02 (m, 2H), 1.86 (m, 2H), 1.68 (s, 6H). 15 aD-25.9 (c=0.76, MeOH)

Example 13 4-(l-Methyl-piperidin-4-yloxy)-benzoic acid methyl ester

To a solution of l-methyl-piperidin-4-oI (6.8 g. 59 mmoles), PPI13 (triphenylphosphine,

15.5 g, 59 mmoles) and 4-hydroxy-benzoic acid methyl ester (6 g, 39 mmoles) in THF 20 (150 ml) at 0°C, diethyl azodicarboxylate (9.5 ml, 59 mmoles) in THF (30 ml) was slowly added. The reaction mixture was allowed to warm to room température over a period of 24hours. It was then evaporated and the residue redissolved in 5% aqueous citric acid (700ml). The solution was washed with ethyl acetate (3 x 250 ml), made alkaline withconcentrated NH4OH ( pH ~ 8) and then extracted with dichloromethane (3 x 250 ml). The 25 combined dichloromethane extracts were washed with brine, dried and evaporated to givean oil which was purified by flash chromatography on silica gel using dichloromethane-MeOH (90 : 10) as eluent, to give the title compound as a yellow oil (7.4 g, 75%). ESI MS: m/z 250 (MH+); 013015 57 1H NMR (400 MHz, DMSO-D6) δ ppm 1.7 (m, 2 H) 2.0 (m, 2 H) 2.2 (τη, 5 H) 2.7 (m, 2FI) 3.8 (s, 3 H) 4.5 (m, 1 H) 7.1 (d, 7=9.0 Hz, 2 H) 7.9 (d, >9.0 Hz, 2 H).

Example 14 4-(l-Methyl-pïperidin-4-yIoxy)-benzoic acid, hydrochloride 5 4-(l-Methyl-piperidin-4-yloxy)-benzoic acid methyl ester (7.3 g, 29 immoles) wasdissolved in 6N aq HCl (220 ml). After beating at 85°C for 6 houis, the solvent wasremoved in vacuo. The residue was taken up with water and evaporated twice and thentaken up with acetone two more times. The solid obtained was finally triturated in acetoneto give the hydrochloride sait as a white powder (6.4 g, 80% yield). 10 1HNMR (400 MHz, DMSO-D6) δ ppm 2.0 (m, 4 H) 2.8 (m, 3 H) 3.3 (m, 4 H) 4.7 (m, 1H) 7.1 (m, 2 H) 7.9 (m, 2 H) 9.9 (d, 7=20.4 Hz, 1 H) 12.6 (s, 1 H).

Example 15 4-(4-Hydroxy-piperidin-l-yl)benzoic acid ethyl ester A mixture of 4-fluoro-benzoic acid ethyl ester (1.68 g, 10 mmoles), piperidin-4-ol (1.12 g, 15 11 mmoles) and anhydrous potassium carbonate (1.38 g, 10 mmoles) in DMSO (10 ml) was heated at 120°C for 6 bours. After cooling, the mixture was poured into water and ice(500 ml) and extracted with ethyl acetate. The organic layer was washed with water andbrine, dried and evaporated. The residue was purified by flash chromatography on silicagel using hexane/EtOAc (10/30) as eluent to give the title compound as a white solid (1.6 20 g, 64%). ESI MS: m/z 250 (MH+); 1H NMR (400 MHz, DMSO-D6) δ ppm 1.3 (t, 7=7.1 Hz, 3 H) 1.4 (m, 2 H) 1.8 (m, 2 H)3.0 (m, 2 H) 3.7 (m, 2 H) 4.2 (q, >7.1 Hz, 2 H) 4.7 (d, 7=4.3 Hz, 1 H) 6.9 (m, 2 H) 7.7 (m,2H). 25 Example 16 4-(4-Eluoro-piperidin-l-yl)benzoic acid ethyl ester

To a solution of 4-(4-hydroxy-piperidin-l-yl)benzoic acid ethyl ester (1.25 g. 5 mmoles) indry dichloromethane (30 ml) at room température under an inert atmosphère, it was slowly --added DAST (0.97 g, 6 mmoles) in dichloromethane (5 ml). The reaction mixture was 30 stirred at room température for 1 hour and then quenched with aqueous NaHCOj. The 013015 58 organic layer was washed with brine, dried and evaporated. The residue was purified byflash chromatography on silica gel using hexane/EtOAc (70/30) as eluent to give the titlecompound as a white solid (0.7 g, 56%). ESI MS: m/z 252 (MH+); 5 1H NMR (400 MHz, DMSO-D6) δ ppm 1.3 (t, 7=7.1 Hz, 3 H) 1.8 (m, 2 H) 2.0 (m, 2 H) 3.3 (m, 2 H) 3.6 (m, 2 H) 4.2 (s, 2 H) 4.8 (s, 1 H) 7.0 (s, 2 H) 7.8 (s, 2 H).

Bxample 17 4-(4-Fluoro-piperidin-l-yl)benzoic acid A mixture of 4-(4-fluoro-piperidin-l-yl)benzoic acid ethyl ester (0.7 g, 2.7 immoles) in 10 éthanol (50 ml) and a solution of 2N sodium hydroxide (20 ml) was stirred at roomtempérature for 24 hours. The éthanol was then evaporated, the solution diluted with water(20 ml) and neutralized with 2N HCl. The acid separated as a white solid which waswashed with water and dried under vacuum (0.52 g, 82%). ESI MS: m/z 224 (MH+); 15 1H NMR (400 MHz, DMSO-D6) δ ppm 1.8 (m, 2 H) 2.0 (m, 2 H) 3.3 (m, 2 H) 3.5 (m, 2H) 5.0 (s, 1 H) 7.0 (s, 2 H) 7.8 (s, 2 H) 12.2 (s, 1 H).

By working as described in any previous example, that is by using any proper startingmaterial and any suitable reactant according to the process previously disclosed, additionalcompounds of formula (la) and (Ib) were also prepared, as reported in the following table 20 ΠΙ. For explanatory notes conceming the coding System identifying each spécifiecompound of formula (la) and (Ib) see the "general method" at the beginning of theexperimental section.

Table ΙΠ A02M1B01 *Η NMR (400 MHz, DMSO-dfy δ 12.45 (bs, 1H), 10.99 (s, 1H), 7.84 (m, 2H), 7.52 (m, 1H), 7.40 (m, 1H), 4.86 (s, 2H), 1.65 (s, 6H),1.21 (s, 9H). A03M1B01 *H NMR (400 MHz, DMSO-d6): δ 12.46 (bs, 1H), 11.01 (s, 1H), 8.05 (m, 1H), 7.88 (m, 1H), 7.54 (m, 1H), 4.86 (s, 2H), 1.65 (s, 6H),1.21 (s, 9H). 013015 59 AO4M1BO1 ’H NMR (400 MHz, DMSO-cU): δ 12.45 (bs, 1H), 10.89 (s, 1H), 7.7(m, 1H), 7.38 (m, 1H), 7.20 (s, 1H), 4.89 (s, 2H), 1.68 (s, 6H), 1.24(s,9H). AO5M1BO1 ’HNMR (400 MHz, DMSO-dg): δ 12.54 (bs, 1H), 11.07 (s, 1H), 7.76 (s, 2H), 7.51 (s, 1H), 4.89 (s, 2H), 1.68 (s, 6H), 1.25 (s, 9H). A06M1B01 ’H NMR (400 MHz, DMSO-de): δ 12.43 (bs, 1H), 10.98 (s, 1H), 7.98 (d, 2H, J = 8.0 Hz), 7.54 (d, 2H, J = 8.0 Hz), 4.86 (s, 2H), 1.65(s, 6H), 1.21 (s, 9H). A07M1B01 ’HNMR(400MHz, DMSO-dc): δ 12.47 (bs, 1H), 11.16 (s, 1H), 8.16 (d, 2H, J = 7.9 Hz), 7.85 (d, 2H, J = 7.9 Hz), 4.88 (s, 2H), 1,65 (s, 6H), 1.21 (s, 9H). AO8M1BO1 ’H NMR (400 MHz, DMSO-d6): δ 12.50 (bs, 1H), 11.17 (s, 1H), 9.13 (s, 1H,), 8.76 (m, 1H), 8.33 (m, 1H) 7.51 (m, 1H), 4.91 (s, 2H),1.69 (s, 6H), 1.25 (s, 9H). AO9M1BO1 ’H NMR (400 MHz, DMSO-cU): δ 12.54 (bs, 1H), 11.25 (s, 1H), 8.75 (d, 2H), 7.91 (d, 2H), 4.92 (s, 2H), 1.69 (s, 6H), 1.25 (s, 9H). A10M1B01 ‘H NMR (400 MHz, DMSO-de): δ 12.47 (bs, 1H), 11.00 (s, 1H), 8.12 (m, 1H), 7.86 (m, 1H), 7.12 (m, 1H), 4.86 (s, 2H), 1.68 (s, 6H), 1.25 (s, 9H). A11M1BO1 ’H NMR (400 MHz, DMSO-ds): δ 12.11 (bs, 1H), 10.77 (s, 1H), 8.45 (s, 1H), 7.69 (m, 2H), 4.89 (s, 2H), 1.6S (s, 6H), 1.25 (s, 9H). A12M1B01 ' ’HNMR (400 MHz, DMSO-d6): δ 12.22 (bs, 1H), 10.31 (s, 1H), 4.76 (s, 2H), 2.12 (m, 3H), 1.61 (s, 6H), 1.19 (s, 9H), 0.87 (d, 6H, J= 6.5 Hz). A13M1B01 ’H NMR (400 MHz, DMSO-dô): δ 12.21 (bs, 1H), 10.19 (bs, 1H), 4.80 (s, 2H), 3.28 (m, 1H), 2.25-1.70 (m, 6H), 1.60 (s, 6H), 1.20 (s,9H). A14M1BO1 ’HNMR (400 MHz, DMSO-de): δ 12.35 (bs, 1H), 10.38 (bs, 1H), 4.75 (s, 2H), 1.82 (m, 1H), 1.60 (s, 6H), 1.20 (s, 9H), 0.78 (m, 4H). 013015 60 A15M1B01 'HNMR (400 MHz, DMSO-dé): δ 12.3 (bs, 1H), 9.89 (s, 1H), 4.80(s, 2H), 1.64 (s, 6H), 1.23 (s, 9H), 1.21 (s, 9H). A16M1B01. Ή NMR (400 MHz, DMSO-d6): δ 12.35 (bs, 1H), 11.02 (s, 1H), 8.09 (d, 2H, J = 8.2 Hz), 7.47 (d, 2H, J= 8.2 Hz), 4.85 (s, 2H), 1.64 (s, 6H), 1.21 (s, 9H). A19M1B01 ’HNMR (400 MHz, DMSO-di): δ 12.48 (bs, 1H), 10.82 (s, 1H), 8.43 (m, 1H), 7.45 (m, 1H), 6.70 (m, 1H), 4.85 (s, 2H), 1.67 (s, 6H), 1.25 (s, 9H). A20M1B01 1HNMR(400MHz, DMSO-d6): δ 12.26 (bs, 1H), 10.38 (s, 1H), 4.80 (s, 2H), 3.04 (m, 2H), 2.52 (m, 3H), 1.64 (m, 10H), 1.23 (s, 9H). A22M1BO1 ’lî NMR (400 MHz, DMSO-d6): δ 12.43 (bs, 1H), 11.06 (s, 1 H),8.3-7.6 (m, 7H), 4.99 (s, 2H), 1.71 (m, 6H), 1.26 (s, 9H). A23M1B01 *H NMR (400 MHz, DMSO-d^): δ 12.48 (bs, 1H), 11.07 (s, 1H), 8.68 (s, 1H), 8.08 (m, 4H), 7.66 (m, 2H), 4.95 (s, 2H), 1.70 (m, 6H), 1.27 (s,9H). A24M1BO1 XH NMR (400 MHz, DMSO-de): δ 12.05 (bs, 1H), 8.87 (s, 1H), 7.19(m, 4H), 6.91(bs, 1H), 4.73 (s, 2H), 4.32 (d, 2H, J = 5.85 Hz), 2.30 (s, 3H), 1.63 (s, 6H), 1.22 (s, 9H). A25M1B01 JH NMR (400 MHz, DMSO-dc): δ 12.31-12.05 (2bs, 1H), 8.48 (s, 1H), 7.30 (m, 5H), 7.00 (bs, 1H), 4.73 (s, 2H), 4.33 (d, 2H, J = 5.85 Hz), 1.63 (s, 6H), 1.22 (s, 9H). A28M1B01 ‘H NMR (400 MHz, DMSO-d6): δ 12.07 (bs, 1H), 8.99 (s, 1H), 4.72(s, 2H), 3.40 (m, 4H), 1.63 (s, 6H), 1.5 (m, 6H), 1.22 (s, 9H). A29M1B01 *H NMR (400 MHz, DMSO-d^): δ 12.36 (bs, 1H), 10.08 (s, 1H), 4.82 (s, 2H>, 3.15 (bs, 2H), 2.32 (s, 6H), 1.65 (s, 6H), 1.23 (s, 9H). A02M2B01 ‘HNMR (400 MHz, DMSO-dfi): δ 12.29 (bs, 1H), 11.05 (s, 1H),7.9-7.35 (m, 3H), 5.03 (s, 2H), 2.29 (m, 2H), 1.24 (s, 9H), 0.84 (m, 2H). 013015 61 A04M2B01 ’HNMR (400 MHz, DMSO-dfi): δ 12.21 (bs, 1H), 10.90 (s, 1H), 7.79 (m, 1H), 7.40 (m, 1H), 7.21 (m, 1H), 5.03 (s, 2H), 2.29 (m, 2H), 1.24 (s, 9H), 0.S3 (m, 2H). A05M2B01 ’HNMR (400 MHz, DMSO-d6): δ 12.30 (bs, 1H), 11.17 (s, 1H), 7.77 (s, 2H), 7.51 (s, 1H), 5.04 (s, 2H), 2.29 (m, 2H), 1.24 (s, 9H), 0.84 (m, 2H). À06M2B01 lH NMR (400 MHz, DMSO-d6): δ 12.28 (bs, 1H), 11.04 (s, 1 H), 8.03 (d, 2H, J = 8.0 Hz), 7.61 (d, 2H, J = 8.0 Hz), 5.03 (s, 2H), 2.29 (m, 2H), 1.24 (s, 9H), 0.83 (m, 2H). A07M2B01 ’HNMR (400 MHz, DMSO-d6): δ 12.32 (bs, 1H), 11.22 (s, 1H), 8.21 (d, 2H, J = 7.9 Hz), 7.91 (d, 2H, J = 7.9 Hz), 5.05 (s, 2H), 2.29 (m, 2H), 1.24 (s, 9H), 0.84 (m, 2H). A10M2B01 ’HNMR (400 MHz, DMSO-d6): δ 12.23 (bs, 1H), 11.02 (s, 1H), 8.10 (m, 1H), 7.87 (m, 1H), 7.22 (m, 1H), 5.01 (s, 2H), 2.29 (m, 2H), 1.24 (s, 9H), 0.84 (m, 2H). A12M2B01 ’HNMR (400MHz, DMSO-di): δ 12.03 (bs, 1H), 10.36 (bs, 1H), 4.95 (s, 2H), 2.26 (m, 2H), 2.17 (m, 2H), 2.09 (m, 1H), 1.22 (s, 9H), 0.93 (m, 6H), 0.80 (m, 2H). A13M2BO1 ’HNMR (400MHz, DMSO-de): δ 12.05 (bs, 1H), 10.28 (bs, 1H), 4.96 (s, 2H), 3.32 (m, 1H), 2.25 (m, 8H), 1.23 (s, 9H), 0.78 (m, 2H). A14M2B01 ’H NMR (400 MHz, DMSO-de): δ 12.03 (bs, 1H), 10.72 (bs, 1H), 4.91 (s, 2H), 2.25 (m, 2H), 1.82 (m, 1H), 1.20 (s, 9H), 0.80 (m, 6H). A15M2B01 ’HNMR(400MHz,DMSO-de): δ 12.01 (bs, 1H), 9.92 (s, 1H), 4.94(s, 2H), 2.25 (m, 2H), 1.22 (s, 18H), 0.78 (m, 2H). A19M2B01 ’HNMR (400 MHz, DMSO-ds): δ 12.21 (bs, 1H), 10.82 (s, 1H), 7.92 (m, 1H), 7.49(m, 1H ), 6.69 (m, 1H), 5.01 (s, 2H), 2.29 (m, 2H), 1.24 (s, 9H), 0.83 (m,2H). A27M2B01 ’HNMR (400 MHz, DMSO-ds): δ 11.98 (bs, 1H), 9.02 (s, 2H), 7.45(m, 1H), 7.33 (m, 1H), 7.13 (m, 1H), 6.81 (m, 1H),4.96 (s, 2H), 013015 62 A28M2B01 2.27 (m, 2H), 1.23 (s, 9H), 0.81 (m, 2H). ’HNMR (400 MHz, DMSO-d0): δ 11.83 (bs, 1H), 9:03 (s, 1H), 4.87(s, 2H), 3.41 (m, 4H), 2.23 (m, 2H), 1.58 (m, 2H), 1.49 (m, 4H), 1.22 (s, 9H), 0.76 (m, 2H). A30M1B01 ’H NMR (400 MHz, DMSO-dé): δ ppm 1.2 (s, 9 H) 1.7 (s, 6 H) 4.9(s, 2 H) 7.4-8.1 (m, 5 H)· 11.2 (s, 1 H) 12.5 (s, 1 H) A31M1B01 ’H NMR (400 MHz, DMSO-d<j): δ ppm 1.2 (s, 9 H) 1.7 (s, 6 H) 1.7(m, 2 H) 2.0 (m, 2 H) 2.2 (s, 3 H) 2.3 (m, 2 H) 2.7 (m, 2 H) 4.5 (m, 1 H) 4.9 (s, 2 H) 7.0 (d, 7=7.9 Hz, 2 H) 8.0 (d, 7=7.9 Hz, 2 H) 10.7(s, 1 H) 12.4 (s, 1 H) A32M1B01.HC1 'H NMR (400 MHz, DMSO-cU): (mixture of two conformers) δppml.25(s, 18H) 1.68(s, 12H) 1.84(m,2H) 2.07 (m,4H) 2.29 (d, 7=14.0 Hz, 2 H) 2.80 (d, 7=5.0 Hz, 3 H) 2.82 (d, 7=5.0 Hz, 3 H) 3.11 (m, 2 H) 3.20 (m, 2 H) 3.40 (m, 2 H) 3.52 (d, 7=14.0 Hz, 2 H) 4.67 (m, 1 H) 4.87 (m, 1 H) 4.89 (s, 4 H) 7.21 (dd, 7=8.8,2.3 Hz, 1H) 7.25 (dd, 7=8.8,2.3 Hz, 1H) 7.45 (m, 2 H) 7.5-7.7 (m, 4 H) 9.90 (bs, 1 H) 9.97 (bs, 1 H) 10.93 (s, 2 H) 12-13(bs, 2 H). A33M1B01.2HC1 ’H NMR (400 MHz, DMSO-d6): δ ppm 1.3 (s, 9 H) 1.7 (s, 6 H) 2.8(s, 3 H) 3.4 (m, 10 H) 4.9 (s, 2 H) 7.6 (s, 2 H) 8.1 (d,7=7.9 Hz, 2 H) 10.4 (s, 1 H) 11.0 (s, 1 H) A34M1B01.HC1 ’HNMR (400 MHz, DMSO-d6): δ ppm 1.3 (s, 9 H) 1.7 (s, 6 H) 1.9(m, 4 H) 3.4 (m, 4 H) 4.9 (m, 1 H) 4.9 (s, 2 H) 7.0 (d, 7=9.1 Hz, 2 H) 7.9 (d, 7=9.0 Hz, 2 H) 10.6 (s, 1 H) A35M1BO1 ’H NMR (400 MHz, DMSO-ds): δ ppm 1.2 (s, 9 H) 1.6 (s, 6 H) 2.3(s, 3 H) 2.5 (m, 4 H) 3.1 (m, 2 H) 3.3 (m, 2 H) 4.8 (s, 2 H) 6.9 (d,7=8.2 Hz, 2 H) 7.9 (d, 7=8.4 Hz, 2 H) 10.5 (s, 1 H) 12.3 (s, 1 H) A36M1B01 Ή NMR (400 MHz, DMSO-d6): δ ppm 1.2 (s, 9 H) 1.6 (s, 6 H) 2.1(m, 2 H) 2.5 (t, 7=8.0 Hz, 2 H) 3.9 (t, 7=7.0 Hz, 2 H) 4.8 (s, 2 H) 7.8 013015 63 (d, 7-8.9 Hz, 2 H) 8.0 (d, 7=8.8 Hz, 2 H) 10.8 (s, 1 H) 12.4 (s, 1 H) A37M1BO1 'H NMR (400 MHz, DMSO-de): δ ppm 1.3 (s, 9 H) 1.7 (s, 6 H) 4.1 (m, 2 H) 4.5 (m, 2 H) 4.9 (s, 2 H) 7.7 (d, 7=8.2 Hz, 2 H) 8.1 (d, 7=7.8 Hz, 2 H) 10.9 (s, 1 H) 12.4 (s, 1 H) A38M1BO1 Ή NMR (400 MHz, DMSO-dé): δ ppm 1.3 (s, 9 H) 1.7 (s, 6 H) 3.8 (s, 3 H) 3.9 (s, 3 H) 4.9 (s, 2 H) 7.1 (d, 7=8.5 Hz, 1 H) 7.6 (d, 7=1.2 Hz, 1 H) 7.7 (dd, 7=8.5,2.0 Hz, 1 H) 10.8 (s, 1 H) 12.4 (s, 1 H) A38M2B01 ’HNMR (400 MHz, DMSO-d6): δ ppm 0.8 (m, 2 H) 1.2 (s, 9 H) 2.3(m, 2H) 3.8 (s, 3 H) 3.9 (s, 3 H) 5.0 (s, 2 H) 7.1 (m, 1 H) 7.6 (m, 1 H) 7.7 (m, 1 H) 10.8 (s, 1 H) 12.2 (s, 1 H) A39M1B01 JH NMR (400 MHz, DMSO-d«): δ ppm 1.3 (s, 9 H) 1.7 (s, 6 H) 4.9 (s, 2 H) 7.5 (s, 1 H) 8.0 (d, 7=7.3 Hz, 2 H) 8.05 (d, 7=7.3 Hz, 2 H) 8.11 (s, 1 H) 11.0 (s, 1 H) 12.5 (s, 1 H) A40M1B01 ’H NMR (400 MHz, DMSO-de): δ ppm 1.2 (s, 9 H) 1.6 (s, 3 H) 4.9 (s, 2 H) 8.0 (d, 7=8.4 Hz, 2 H) 8.1 (d, 7=8.5 Hz, 2 H) 11.2 (s, 1 H) 12.5 (s, 1 H) A41M1B01 !H NMR (400 MHz, DMSO-d6): δ ppm 1.2 (s, 9 H) 1.7 (s, 6 H) 4.9(s, 2 H) 7.7 (t, 7=7.6 Hz, 1 H) 8.1 (d, 7=7.6 Hz, 1 H) 8.3 (d, 7=7.9 Hz, 1 H) 8.4 (s, 1 H) 11.2 (s, 1 H) 12.5 (s, 1 H) A43M1B01 ‘H NMR (400 MHz, DMSO-d6): δ ppm 1.2 (s, 9 H) 1.7 (s, 6 H) 4.9 (s, 2 H) 7.3 (m, 2 H) 7.6 (m, 1 H) 7.7 (m, 1 H) 10.9 (s, 1 H) 12.4 (s,ÏH) A44M1BO1 *H NMR (400 MHz, DMSO-cU): δ ppm 1.25 (s, 9 H) 1.68 (s, 6 H) 3.85 (s, 3 H) 4.88 (s, 2 H) 7.03 (m, 2 H) 8.01 (d, 7=8.29 Hz, 2 H) 10.74 (s, 1 H) 12.40 (s, 1 H) A45M1B01 ‘HNMR (400 MHz, DMSO-d«): δ ppm 1.3 (s, 9 H) 1.7 (s, 6 H) 3.8(s, 3 H) 4.9 (s, 2 H) 7.2 (m, 1 H) 7.4 (m, 1 H) 7.6 (m, 2 H) 10.9 (s, 1H) 12.5 (s, 1 H) A46M1B01 Ή NMR (400 MHz, DMSO-di): δ ppm 1.3 (s, 9 H) 1.7 (s, 6 H) 4.0 013015 .64 A47M1BO1 (s, 3 H) 4.9 (s, 2 H) 7.1 (t, J=1A Hz, 1 H) 7.2 (d, 7=8.3 Hz, 1 H) 7.6 (t, 7=7.8 Hz, 1 H) 7.8 (dd, 7=7.7,1.7 Hz, 1 H) 10.3 (s, 1 H) 12.4 (s, 1 H) ’H NMR. (400 MHz, DMSO-d6): δ ppm 1.2 (s, 9 H) 1.6 (s, 6 H) 3.6(s, 2 H) 4.8 (s, 2 H) 7.25 (m, 1 H) 7.32 (m, 4 H) 10.7 (s, 1 H) 12.3 (s,lH) A48M1B01 ’H NMR (400 MHz, DMSO-d6): δ ppm 1.16 (s, 9 H) 1.60 (s, 6 H)3.78 (s, 2 H) 4.75 (s, 2 H) 7.47 (m, 3 H) 7.80 (s, 1 H) 7.86 (m, 3 H) 10.74 (s, 1 H) 12.30 (s, 1 H) A49M1BO1 ’H NMR (400 MHz, DMSO-d6): δ ppm 1.23 (s, 9 H) 1.67 (m, 14 H)2.79 (m, 1 H) 4.80 (s, 2 H) 10.37 (s, 1 H) 12.23 (s, 1 H) A50M1B01 ’H NMR (400 MHz, DMSO-d6): δ ppm 1.32 (m, 6 H) 1.23 (s, 9 H)1.74 (m, 4 H) 1.64 (s, 6 H) 2.36 (m, 1 H) 4.79 (s, 2 H) 10.30 (s, 1 H) 12.21 (s, 1 H) A51M1BO1 ’H NMR (400 MHz, DMSO-de): δ ppm 1.2 (s, 9 H) 1.6 (s,. 6 H) 2.0(m, 4 H) 3.9 (m, 2 H) 4.4 (dd, 7=8.2, 5.6 Hz, 1 H) 4.8 (s, 2 H) 10:1 (s, 1 H) 12.3 (s, 1 H) A52M1B01.HC1 ’H NMR (400 MHz, DMSO-de): δ ppm 1.2 (s, 9 H) 1.6 (s, 6 H) 1.9(m, 4 H) 2.6 (m, 1 H) 2.8 (m, 3 H) 3.0 (m, 2 H) 3.4 (m, 2 H) 4.8 (s, 2 H) 9.6 (s, 1 H) 10.6 (s, 1 H) 12.4 (s, 1 H) A53M1B01 ’H NMR (400 MHz, DMSO-di): δ ppm 1.2 (s, 9 H) 1.4 (m, 1 H) 1.5(m, 1H) 1.6 (s, 6 H) 1.7 (m, 2 H) 2.0 (s, 3 H) 2.6 (m, 2 H) 3.0 (t, 7=13.0 Hz, 1 H) 3.8 (d, 7=13.7 Hz, 1 H) 4.4 (d, 7=12.9 Hz, 1 H) 4.8(s, 2 Hj 10.4 (s, 1 H) 12.3 (s, 1 H) A54M1B01 ’H NMR (400 MHz, DMSO-d<): δ 12.52 (bs, 1H), 11.23 (s, 1H), 8.30 (m, 2H), 7.96 (m, 1H), 7.76 (m, 1H), 4.91 (bs, 2H), 1.69 (s, 6H), 1.25 (s, 9H). A01M1B02 ’H NMR (400 MHz, DMSO-de): δ ppm 1.65 (s, 6 H), 2.0 (m, 4 H) 3.79 (m, 2 H), 4.53 (t, 1 H), 4.83 (m, 2H), 7.3 (m, 2 H), 8.05 (m, 2 013015 65 HQ, 10.92 (s, 1 H), 12.45 (s, 1 H). A48M1B02 *H NMR (400 MHz, DMSO-dfi): δ ppm 1.59 (s, 3 H) 1.60 (s, 3 H) 1.86 (m, 4 H) 3.70 (m, 2 HQ 3.76 (s, 2 H) 4.44 (t, 7=6.52 Hz, 1 H) 4.55 (d, 7=12.44 Hz, 1 HQ 4.72 (d, 7=12.56 Hz, 1 H) 7.46 (m, 3 H) 7.78 (s, 1 H) 7.86 (m, 3 HQ 10.74 (s, 1 BQ 12.32 (s, 1 H) A03M1B14 *H NMR (400 MHz, DMSO-de): δ ppm 1.7 (s, 6 BQ 2.0 (m, 4 BQ 3.8 (m, 2 H) 4.6 (t, 7=6.6 Hz, 1 H) 4.7 (d, 7=12.4 Hz, 1 H) 4.9 (d, 7=12.4 Hz, 1 H) 7.6 (ddd, 7=10.5, 8.5, 8.4 Hz, 1 H) 7.9 (m, 1 H) 8.1(m, 1 HQ 11.1 (s, 1 H) 12.5 (s, 1 H) ccd+24.5 (c=l.08, MeOHQ A12M1B14 ‘H NMR (400 MHz, DMSO-d6): δ ppm 0.92 (d, 7=6.58 Hz, 6 HQ 1.65 (d, 7=2.44 Hz, 6 HQ 1.96 (m, 5 HQ 2.16 (d, 7=6.95 Hz, 2 H) 3.80 (m, 2 HQ 4.53 (dd, 7=6.95,6.10 Hz, 1 H) 4.68 (m, 2 HQ 10.37(s, 1 HQ 12.30<s, 1 HQ <xd +24.0 (c=1.00, MeOHQ A13M1B14 lH NMR (400 MHz, DMSO-de): δ ppm 1.64 (s, 6 HQ 1.97 (m, 10 HQ 3.25 (m, 1 HQ 3.80 (m, 2 HQ 4.55 (t, 7=6.58 Hz, 1 HQ 4.70 (m, 2 HQ 10.26 (s, 1 HQ 12.28 (s, 1 H) aD+24.7 (c=l.09, MeOHQ A32M1B14.HC1 Ή NMR (400 MHz, DMSO-d<Q: (mixture of two conformers) δppm 1.68 (s, 12 BQ 1.8-2.1 (m, 10 HQ 2.30 (d, 7=14.0 Hz, 2 HQ 2.80 (d, 7=5.0 Hz, 3 H) 2.83 (d, 7=5.0 Hz, 3 HQ 3.1-3.3 (m, 4 H) 3.45 (m, 2 HQ 3.52 (d, 7=14.0 Hz, 2 HQ 3.7-3.8 (m, 4 HQ 4.56 (dd, 7=7.0, 6.0 Hz, 2 H) 4.66 (m, 1 H) 4.71,4.88 (2 d, J=13 Hz, 4 H) 4.87 (m, 1HQ 7.21 (dd, 7=8.0,2.3 Hz, 1H) 7.26 (dd, 7=8.8,2.3 Hz, 1H) 7.46 (m, 2 H) 7.5-7.7 (m, 4 HQ 9.89 (bs, 2 H) 10.94 (s, 2 HQ 12-13 (bs, 2 HQ. an+17.4 (c=1.02, MeOH) A33M1B14.2HC1 *H NMR (400 MHz, DMSO-de): δ ppm 1.7 (s, 3 H) 1.7 (s, 3 HQ 2.0 013015 66 A31M1B14 (m, 4 H) 2.8 (s, 3 H) 3.7 (m, 10 H) 3.S (m, 2 H) 4.6 (dd, 7=7.3, 5.9Hz, 1 H) 4.7 (d, 7=12.4 Hz, 1 H) 4.9 (d, 7=12.4 Hz, 1 H) 7.6 (d, 7=7.3 Hz, 2 H) 8.0 (d, 7=8.2 Hz, 2 H) 10.3 (s, 1 H) 11.0 (s, 1 H) aD+14.7 (c=l .09, MeOH) lHNMR (400 MHz, DMSO-de): δ ppm 1.7 (s, 6 H) 2.1 (m, 8 H) 2.8(m, 3 H) 3.3 (m, 4 H) 3.8 (m, 2 H) 4.6 (dd, 7=7.2, 6.1 Hz, 1 H) 4.7 (m, 1 H) 4.7 (d, 7=12.6 Hz, 1 H) 4.9 (d, 7=12.6 Hz, 1 H) 7.1 (m, 2 H) 8.0 (m, 2 H) 9.9 (m, 1 H) 10.8 (s, 1 H) 12.2 (s, 1 H) an (as hydrochloride sait) +17.0 (c=l .08, MeOH) A01M2B14 JH NMR (400 MHz, DMSO-d6): δ 12.25 (bs, 1H), 10.98 (bs, 1H), 8.11 (m, 2H), 7.34 (m, 2H), 4.96 (m, 2H), 4.56 (t, 1H), 3.77 (m, 2H)2.24 (m, 2H), 2.03 (m, 2H), 1.87 (m, 2H), 0.93 (s, 2H). <xD+15.9 (c=l.06, MeOH) A12M1B21.HCO2H JH NMR (400 MHz, DMSO-d6): δ ppm 0.9 (d, 7=6.6 Hz, 6 H) 1.2(s, 3 H) 1.5 (m, 2 H) 1.7 (s, 6 H) 2.2 (m, 12 H) 4.7 (s, 2 H) 8.2 (s, 1 H) 10.4 (s, 1 H) 12.3 (s, 1 H) A01M1B21.HC1 JH NMR (400 MHz, DMSO-dô): (mixture of two confonners) δppm 1.29 (s, 3 H) 1.38 (s, 3 H) 1.65 (m,2H) 1.70 (s, 3 H) 1.73 (s, 3 H) 1.95 (d, 7=14.0 Hz, 2 H) 2.08 (m, 2 H) 2.46 (d, 7=14.0 Hz, 2 H) 2.74 (d, 7=5.0 Hz, 3 H) 2.79 (d, 7=5.0 Hz, 3 H) 2.87 (m, 2 H) 3.13 (m, 2 H) 3.3-3.5 (m, 4 H) 4.86 (s, 4 H) 7.35 (t, 7=8.9 Hz, 4 H) 8.09 (dd, 7=8.9, 5.5 Hz, 4H) 9.5 (bs, 1 H) 9.7 (bs, 1 H)11.01 (s, 1 H) 11.03 (s, 1 H) 12-13 (bs,2H). A01M1B22.HC1 lH NMR (400 MHz, DMSO-de): δ ppm 1.69 (s, 6 H) 2.16 (m, 6 H) 3.32 (m, 6 H) 4.89 (s, 2 H) 7.36 (t, 7=8.66 Hz, 2 H) 8.08 (dd, 7=9.02, 5.49 Hz, 2 H) 9.58 (s, 1 H) 11.01 (s, 1 H) 12.55<s, 1 H) A48M1B43 ‘HNMR (400 MHz, DMSO-d6): δ ppm 1.16 (t, 7=7.13 Hz, 3 H) 1.57 (s, 6 H) 3.76 (s, 2 H) 4.00 (q, 7=7.07 Hz, 2 H) 4.38 (s, 2 H) 7.48 (m, 3 H) 7.79 (s, 1 H) 7.87 (m, 3 H) 10.73 (s,lH) 12.32 (s, 1H) 013015 67

Example 18 N-{6,6-dimethyl-5-[(l-methylpiperidin-4-yl)carbonyl]-2,4,5,6-tetrahydropyrrolo[3,4- c]pyrazol-3-yl}-4-fluorobenzamide 5 Ethyl 3-[(4-fluorobenzoyl)amino]-6,6-dimethyl-5,6-dihydropyrrolo[3,4-c]pyrazole- 1(4H)-carboxylate hydrochloride (0.5 g, 1.3 mmol), in dichloromethane (25 ml), was treated withΝ,Ν-dusopropylethylamine (1.13 ml, 6.5 mmol, 5 eq) and TBTU (0.542 g, 1.69 mmol, 1.3eq), at room température for 1 bour, and then l-methyl-piperidine-4-carboxylic acidhydrochloride (0.29 g, 1.61 mmol, 1.2 eq) was added. The reaction was stirred ovemight

10 (TLC: CELCb/MeOH 90/10). The solution was washed with saturated sodiumhydrogencarbonate aqueous solution and brine, the organic phase was dried over sodiumsulfate and concentrated. The residue was dissolved in methanol (16 ml), treated with TEA _ (2 ml, 14.3 mmol, 11 eq) and stirred ovemight at room température. (TLC: CHîCh/MeOH/NKLiOH 90/10/1). After évaporation, the solid was purified by flash 15 chromatography (eluent: CHîCh/MeOH/NLLiOH 90/10/2). The solid was treated withdiisopropylether and filtered to afford 0.36 g of the title compound in 69% yield. ESI MS: m/z 400 (MH+); 'H NMR (400 MHz, DMSO-d6): δ 12.48 (bs, 1H), 10.97 (bs, 1H), 8.09 (m, 2H), 7.35 (m,2H), 4.75 (bs, 2H), 2.87 (m, 2H), 2.40 (m, 1H), 2.24 (s, 3H), 2.05 (m, 2H), 1.67 (m, 10H). 20 By working in an analogous manner the following compound was prepared: N-[5-[(l-niethylpiperidin-4-yl)carbonyl]-2,4,5,6-tefrahydropyrrolo[3,4-c]pyiazo]-6- spirocyclopropan-3-yl]-4-fluorobenzainide ESI MS: m/z398(MH+); ’H NMR (400 MHz, DMSO-dè): δ 12.20 (bs, 1H), 11.00 (s, 1H), 8.10 (m, 2H), 7.36 (m, 25 2H), 4.91 (s, 2H), 2.84 (m, 2H), 2.40 (m, 1H), 2.23 (m, 5H), 2.0 (m, 2H), 1.65 (m, 4H), 0.89 (m, 2H).

By working in analogous manner and by using the proper starting material and any suitablereactant, as per the aforementioned process, additional compounds of formula (la) and (Ib)were also prepared, as reported in the following table IV 30 013015

Table IV 68 A01M1B03.HC1 ]H NMR (400 MHz, DMSO-di): δ 11.02 (s, 1H), 9.56 (bs, 1H), 8.11(m, 2H), 7.36 (m, 2H), 4.80 (bs, 2H), 3.43 (m, 2H), 3.07 (m, 2H) 2.75(d, 3H), 2.69 (m, 1H), 1.94 (m, 4H), 1.67 (m, 6H). A02M1B03.HC1 ’lINMR (400 MHz, DMSO-d6) δ ppm 1.68 (m, 6 H) 1.93 (m, 4 H)2.74 (m, 4 H) 3.07 (m, 2 H) 3.42 (m, 2 H) 4.81 (s, 2 H) 7.46 (m, 1 H) 7.59 (td, 7=7.96, 5.91 Hz, 1 H) 7.82 (ddd, 7=10.00,2.32,1.59 Hz, 1 H) 7.87 (dt, 7=7.90,1.11 Hz, 1 H) 9.49 (s, 1 H) 11.09 (s, 1 H) A03M1B03.HC1 *H NMR (400 MHz, DMSO-d6) δ ppm 1.69 (m, 6 H) 1.93 (m, 4 H)2.74 (m, 4 H) 3.02 (m, 2 H) 3.34 (m, 2 H) 4.79 (s, 2 H) 7.40 (m, 1 H)7.53 (m, 1 H) 7.60 (m, l.H) 9.48 (s, 1 H) 11.11 (s, 1 H) A04M1B03 *H NMR (400 MHz, DMSO-dé): δ 12.48 (bs, 1H), 10.93 (s, 1H), 7.75(m, 1H), 7.40 (m, 1H), 7.22 (m, 1H), 4.75 (bs, 2H), 2.85 (m, 2H), 2.38 (m, 1H), 2.21 (bs, 3H), 2.01 (m, 2H), 1.67 (m, 10H). A05M1B03.HC1 *H NMR (400 MHz, DMSO-dé): δ 12.6 (bs, 1H), 11.19 (s, 1H), 9.49(bs, 1H), 7.72 (m, 2H), 7.51 (m, 1H), 4.80 (bs, 2H), 3.46 (m, 2H), 3.06 (m, 2H), 2.76 (bd, 3H), 2.71 (m, 1H), 1.97 (m, 2H), 1.81 (m, 2H), 1.67 (s, 6H). A06M1B03.HC1 Ή NMR (400 MHz, DMSO-d6): δ 12.55 (bs, 1H), 11.06 (s, 1H), 9.66(bs, 1H), 8.02 (m, 2H), 7.63 (m, 2H), 4.81 (s, 2H), 3.4 (m, 2H), 3.01(m, 2H), 2.75 (bs, 3H), 2.68 (m, 1H), 1.95 (m, 2H), 1.84 (m, 2H), 1.67 (s, 6H). A07M1B03.HC1 ^NMR (400 MHz, DMSO-d6): δ 12.60 (bs, 1H), 11.25 (s, 1H), 9.50 (bs, 1H), 8.19 (d, 2H, J = 7.9 Hz), 7.92 (d, 2H, J = 7.9 Hz), 4.83 (s, 2H), 3.4 (m, 2H), 3.01 (m, 2H), 2.78 (bd, 3H), 2.75 (m, 1H), 1.9 (m, 2H), 1.8 (m, 2H), 1.67 (s, 6H). A09M1B03.2HC1 1H NMR (400 MHz, DMSO-d6) δ ppm 11.38 (s, 1H), 9.68 (s, 1H), 8.83 (d, 7=6.22 Hz, 2H), 7.98 (d, 7=6.22 Hz, 2H), 4.82 (s, 2H), 3.4(m, 2H), 3.07 (m, 2H), 2.75 (bd, 3H), 2.69 (m, 1H), 1.90 (m, 4H), 013015 69 1.69 (s, 6 H) A10M1B03.HC1 NMR (400 MHz, DMSO-dfi): δ 12.52 (bs, 1H), 11.07 (s, 1H), 9.50(bs, 1H), S.12 (m, 1H), 7.86 (m, 1H), 7.22 (m, 1H), 4.79 (bs, 2H), 3.42 (m, 2H), 3.08 (m, 2H), 2.76 (m, 4H), 1.94 (m, 2H), 1.82 (m, 2H), 1.67 (s, 6H). A11M1BO3.HC1 (400 MHz, DMSO-di): δ 12.41 (bs, 1H), 10.83 (s, 1H), 9.55 (s, 1H), 8.43 (dd, 7=2.80,1.46 Hz, 1H), 7.67 (dd, 7=5.12,1.46 Hz, 1H), 7.65 (dd, 7=5.12,2.80 Hz, 1H), 4.79 (s, 2H), 3.47 (m, 2H), 3.06(m, 2H), 2.74 (m, 4H), 1.88 (m, 4H), 1.68 (s, 6H). A12M1B03 *H NMR (400 MHz, DMSO-d6): δ 12.29 (bs, 1H), 10.40 (s, 1H), 4.65 (s, 2H), 2.86 (m, 2H), 2.35 (m, 1H), 2.22 (bs, 3H), 2.17 (d, 2H, J = 7.07 Hz), 2.02 (m, 3H), 1.64 (m, 10H), 0.92 (d, 6H, J = 6.6 Hz). A12M1BO3.HC1 'HNMR (400 MHz, DMSO-de): δ 12.29 (s, 1H), 10.41 (bs, 1H), 9.57(s, 1H), 4.71 (s, 2H), 3.46 (m, 2H), 3.07 (m, 2H), 2.75 (bd, 3H), 2.69(m, 1H), 2.17 (d, 2H, J = 6.95 Hz), 2.04 (m, 1H), 1.92 (m, 4H), 1.67(s, 6H), 0.92 (d, 6H, J = 6.7 Hz). A13M1BO3 ‘HNMR (400 MHz, DMSO-di): δ 12.29 (bs, 1H), 10.27 (s, 1H), 4.69 (s, 2H), 3.35 (m, 1H), 2.87 (m, 2H), 2.38 (m, 1H), 2.24 (bs, 3H), 2.20(m, 6H), 2.07 (m, 2H), 1.63 (m, 10H). A13M1BO3.HC1 ^NMR (400 MHz, DMSO-d6): δ 12.34 (bs, 1H), 10.30 (s, 1H), 9.48 (bs, 1H), 4.75 (s, 2H), 3:47 (m, 2H), 3.31 (m, 1H), 3.09 (m, 2H), 2.75 (bd, 3H), 2.70 (m, 1H), 2.23-1.76 (m, 10H), 1.64 (s, 6H). A13M1B03.CH3S03H ^NMR (400 MHz, DMSO-dtf): δ 12.33 (bs, 1H), 10.31 (s, 1H), 9.21 (bs, 1H), 4.75 (s, 2H), 3.44 (m, 2H), 3.24 (m, 1H), 3.09 (m, 2H), 2.78(bd, 3H), 2.72 (m, 1H), 2.35 (s, 3H), 2.23-1.72 (m, 10H), 1.64 (s, 6H). A14M1B03 'HNMR (400 MHz, DMSO-de): δ 12.30 (bs, 1H), 10.72 (s, 1H), 4.63 (s, 2H), 2.86 (m, 2H), 2.34 (m, 1H), 2.23 (bs, 3H), 2.04 (m, 2H), 1.83(m, 1H), 1.63 (m, 10H), 0.79 (m, 4H). A16M1B03 ‘HNMR (400MHz, DMSO-d6): δ 12.30 (bs, 1H), 11.10 (s, 1H), 8.13 013015 70 (d, 2H, J = 7.9 Hz), 7.51 (d, 2H, J = 7.9 Hz), 4.75 (s, 2H), 2.86 (m, 2H), 2.39 (m, 1H), 2.22 (s, 3H), 2.03 (m, 2H), 1.69 (m, 1OH). A17M1B03 *H NMR (400 MHz, DMSO-d«): δ 12.48 (bs, 1H), 10.98 (s, 1H), 7.79(m, 1H), 7.61 (m, 1H), 7.54 (m, 1H), 7.45 (m, 2H), 7.25 (m, 2H), 7.10(m, 2H), 4.72 (s, 2H), 2.82 (m, 2H), 2.34 (m, 1H), 2.19 (s, 3H), 1.96 (m, 2H), 1.66 (m, 10H). A19M1B03.HC1 *H NMR (400 MHz, DMSO-dfi): δ 10.87 (s, 1H), 9.55 (bs, 1H), 7.93(dd, J=1.71,0.85 Hz, ÏH), 7.44 (dd, JH.dS, 0.79 Hz, 1H), 6.70 (dd,7=3.48, 1.77 Hz, 1H), 4.77 (bs, 2H), 3.30 (m, 2H), 3.05 (m, 2H), 2.74(m, 4H), 1.93 (m, 2H), 1.84 (m, 2H), 1.67 (s, 6H). A21M1B03 . ΧΗ NMR (400 MHz, DMSO-di): δ 12.40 (bs, 1H), 11.00 (s, 1H), 8.65(d, 1H, J = 2.5 Hz), 8.16 (d, 2H, J = 8.3 Hz), 8.01 (d, 2H, J = 8.3 Hz), 7.83 (d, 1H, J = 1.6 Hz), 6.62 (dd, 1H, J = 2.5 Hz), 4.47 (s, 2H), 2.86(m, 2H), 2.38 (m, 1H), 2.22 (s, 3H), 2.03 (m, 2H), 1.69 (m, 10H). A22M1B03 jH NMR (400 MHz, DMSO-d6): δ 12.44 (bs, 1H), 11.12 (s, 1H), 8.25(m, 1H), 8.09 (m, 1H), 8.03 (m, 1H), 7.75 (m, 1H), 7.60 (m, 3H), 4.82 (bs, 2H), 2.84 (m, 2H), 2.38 (m, 1H), 2.19 (s, 313), 1.98 (m, 2H), 1.70 (m, 10H). A23M1B03 JHNMR (400 MHz, DMSO-cU): δ 12.51 (bs, 1H), 11.11 (s, 1H), S.67(bs, 1H), 8.07 (m, 4H), 7.66 (m, 2H), 4.80 (bs, 2H), 2.86 (m, 2H), 2.38 (m, 1H), 2.22 (s, 3H), 2.02 (m, 2H), 1.69 (m, 10H). A24M1B03 *H NMR (400 MHz, DMSO-dé): δ 12.11 (bs, 1H), 8.82 (s, 1H), 7.19 (m, 4H), 6.81 (m, 1H), 4.61 (s, 2H), 4.29 (d, 2H, J = 5.80 Hz), 2.85(m, 2H), 2.33 (m, 1H), 2.30 (s, 3H), 2.21 (s, 3H), 2.03 (m, 2H), 1.63 (m, 10H). A25M1B03 *H NMR (400 MHz, DMSO-dô): δ 12.08 (bs, 1H), 8.85 (s, 1H), 7.30 (m, 5H), 6.91 (bs, 1H), 4.61 (s, 2H), 4.32 (d, 2H, J = 5.90 Hz), 2.S6(m, 2H), 2.35 (m, 1H), 2.30 (s, 3H), 2.05 (m, 2H), 1.63 (m, 10H). A26M1B03 Ή NMR (400 MHz, DMSO-cU): δ 12.00 (bs, 1H), 8.67 (s, 1H), 6.45 013015 71 (bs, 1H), 4.59 (s, 2H), 3.06 (m, 2H), 2.83 (m, 2H), 2.34 (m, 1H), 2.19(s, 3H), 1.96 (m, 2H), 1.65 (m, 4H), 1.62 (s, 6H), 1.43 (m, 2H), 0.88(t, 3H). A27M1B03 ‘H NMR (400 MHz, DMSO-dg): δ 12.25 (bs, 1H), 9.05 (s, HT), 7.45 (m, 1H), 7.33 (m, 1H), 7.13 (m, 1H), 6.81 (m, 1H), 4.68 (s, 2H), 2.89(m, 2H), 2.40 (m, 1H), 2.26 (s, 3H), 2.1 (m, 2H), 1.65 (m, 10H). A28M1B03.HC1 ‘H NMR (400 MHz, DMSO-dé): δ 12.13 (bs, 1H), 9.05 (bs, 1H), 4.64 (s, 2H), 3.5-3.2 (m, 8H), 2.75 (m, 4H), 1.94 (m, 2H), 1.82 (m, 2H), 1.63 (m, 12H). A30M01B03 JH NMR (400 MHz, DMSO-d6): δ 12.48 (bs, 1H), 10.93 (bs, 1H), 8.0 (m, 2H), 7.61 (m, 1H), 7.51 (m, 2H), 4.76 (bs, 2H), 2.86 (m, 2H), 2.38 (m, 1H), 2.23 (bs, 3H), 2.03 (m, 2H), 1.67 (m, 10H). A01M1B04.HC1 *H NMR (400 MHz, DMSO-d<;): δ 1.24 (t, 7=7.32 Hz, 3 H) 1.69 (s, 6 H) 1.98 (m, 4 H) 2.78 (m, 1 H) 3.09 (dd, 7=7.32,5.00 Hz, 4 H) 3.50(d, 7=11.71 Hz, 2 H) 4.80 (s, 2 H) 7.36 (t, 7=8.78 Hz, 2 H) 8.09 (m, 2 H) 9.30 (s, 1 H) 11.01 (s, 1 H) 12.56 (s, 1 H). A03M1B04.HC1 }H NMR (400 MHz, DMSO-de): δ 1.24 (t, 7=7.32 Hz, 3 H) 1.69 (s, 6 H) 1.91 (m, 4 H) 2.77 (m, 1 H) 3.31 (m, 6 H) 4.80 (s, 2 H) 7.61 (m, 1 H) 7.91 (m, 1 H) 8.07 (m, 1 H) 9.24 (s, 1 H) 11.11 (s, 1 H) 12.59 (s, 1 H). A12M01B04.HC1 XH NMR (400 MHz, DMSO-d6): δ 0.92 (d, 7=6.58 Hz, 6 H) 1.24 (t, 7=7.26 Hz, 3 H) 1.65 (s, 6 H) 1.88 (m, 4 H) 2.06 (m, 1 H) 2.17 (d,7=7.07 Hz, 2 H) 2.70 (m, 1 H) 3.23 (m, 6 H) 4.72 (s, 2 H) 9.32 (s, 1 H) 10.41 (s, 1 H) 12.34 (s, 1 H). A13M01B04.HC1 ‘H NMR (400 MHz, DMSO-d«): δ 1.25 (t, 7=7.32 Hz, 3 H) 1.65 (s, 6 H) 2.03 (m, 10 H) 2.77 (m, 1 H) 3.28 (m, 7 H) 4.75 (s, 2 H) 9.31 (s, 1 H) 10.30 (s, 1 H) 12.35 (s, 1 H). A27M01B04.HCI Ή NMR (400 MHz, DMSO-oj: δ 1.24 (t, 7=7.32 Hz, 3 H) 1.66 (s, 6 H) 1.89 (m, 4 H) 2.75 (s, 1 H) 3.18 (m, 6 H) 4.73 (s, 2 H) 6.80 (m, 1 013015 72 AO1M1BO5 H) 7.08 (ddd,/=8.17,1.95,0.73 Hz, 1 H) 7.32 (td, >8.17,6.95 Hz, 1H) 7.52 (dt, /=11.89,2.35 Hz, 1 H) 9.10 (s, 1 H) 9.22 (s, 1 H) 9.27 (s, 1 H) 12.24 (s, 1 H) JH NMR (400 MHz, DMSO-d^): δ 12.48 (bs, 1H), 10.97 (s, 1H), 8.09(m, 2H), 7.35 (m, 2H), 4.75 (s, 2H), 3.00 (m, 2H), 2.44 (m, 1H), 2.24 (m, 2H), 1.8-1.5 (m, 5H), 1.67 (s, 6H), 0.38 (m, 4H). A03M1B05.HC1 Ή NMR (400 MHz, DMSO-d*): δ 0.82 (m, 2 H) 0.99 (s, 2 H) 1.68 (s, 6 H) 1.91 (m, 4 H) 2.79 (m, 1 H) 3.38 (m, 5 H) 4.81 (s, 2 H) 7.62 (m, 1 H) 7.92 (ddd,/=8.72,4.27, 1.40 Hz, 1 H) 8.08 (ddd, /=11.52,7.80, 2.13 Hz, 1 H) 9.14 (s, 1 H) 11.12 (s, 1 H) 12.57 (s, 1 H) A12M1BO5.HC1 *H NMR (400 MHz, DMSO-dé): δ 0.82 (m, 2 H) 0.93 (d, /=6.58 Hz, 6 H) 1.00 (s, 2 H) 1.65 (s, 6 H) 1.90 (m, 4 H) 2.06 (m, 1 H) 2.17 (d, /=7.07 Hz, 2 H) 2.76 (m, 1 H) 3.36 (m, 5 H) 4.73 (s, 2 H) 9.20 (s, 1 KÇ) 10.41 (s, 1 H) 12.35 (s, 1 H) A13M1B05.HC1 ‘H NMR (400 MHz, DMSO-dj: δ 0.82 (m, 2 H) 1.01 (s, 2 H) 1.65 (s, 6 H) 2.01 (m, 10 H) 2.78 (m, 1 H) 3.33 (m, 6 H) 4.77 (s, 2 HQ 9.23 (s, 1 H) 10.30 (s, 1 H) 12.25 (s, 1 H) A27M1B05.HC1 Ή NMR (400 MHz, DMSO-dg): δ 0.82 (q, /=6.87 Hz, 2 H) 1.00 (m, 2 H) 1.66 (s, 6 H) 1.88 (m, 4 H) 2.77 (m, 1 H) 3.40 (m, 5 H) 4.75 (s, 2 H) 6.81 (m, 1 H) 7.09 (ddd, /=8.11, 1.95, 0.79 Hz, 1 H) 7.32 (td,/=8.20, 7.01 Hz, 1 H) 7.52 (dt,/=11.77, 2.23 Hz, 1 H) 9.10 (s, 1 H)9.17 (m, 1 H) 9.21 (s, 1 H) 12.99 (s, 1 H) A01M1B06.HC1 Ή NMR (400 MHz, DMSO-d^: δ 1.68 (s, 6 H) 1.80 (m, 4 H) 2.81(m, 1 H) 3.01 (m, 2 H) 3.38 (m, 2 H) 4.78 (s, 2 H) 7.36 (t, >8.84 Hz, 2 H) 8.09 (dd, /=8.96, 5.43 Hz, 2 H) 8.35 (m, 1 H) 8.62 (d, /=9.88 Hz, 1 H) 11.00 (s, 1 H) 12.52 (s, 1 H) A03M1B06.HC1 !H NMR (400 MHz, DMSO-de): δ 1.68 (s, 6 H) 1.83 (m, 4 H) 2.80 (m, 1 H) 3.00 (m, 2 H) 3.37 (m, 2 H) 4.78 (s, 2 H) 7.61 (m, 1 H) 7.92(m, 1 H) 8.07 (ddd, /=11.49,7.83,2.13 Hz, 1 H) 8.45 (m, 2 H) 11.11 013015 73 (s, 1 H) 12.57 (s, 1 H) A04M1B07 te NMR (400 MHz, DMSO-de): δ ppm 1.81 (s, 6 H) 2.21 (s, 3 H) 4.51 (s, 2H) 6.96 (d, 7=4.88 Hz, 1 H) 7.16 (t, 7=7.68 Hz, 1 H) 7.35 (t,7=10.97 Hz, 1 H) 7.54 (d, 7=5.00 Hz, 1 H) 7.69 (m, 1 H) 10.88 (s, 1 H) 12.56 (s, 1 H) A12M1B07 te NMR (400 MHz, DMSO-de): δ 12.37 (bs, 1H), 10.35 (s, 1H), 7.54(d, 1H, J = 5.0 Hz), 6.96 (d, 1H, J = 5.0 Hz), 4.42 (s, 2H), 2.20 (s, 3H), 2.10 (d, 2H, J = 7.19 Hz), 1.98 (m, 1H), 1.77 (s, 3H), 0.87 (d, 6H, J = 6.47 Hz). A13M1BO7 ‘H NMR (400 MHz, DMSO-de): δ ppm 1.74 (m, 1 H) 1.77 (s, 6 H) 1.88 (m, 1 H) 2.02 (m, 2 H) 2.14 (m, 2 H) 2.20 (s, 3 H) 3.18 (m, 1 H) 4.44 (s, 2 H) 6.97 (d, 7=5.00 Hz, 1 H) 7.55 (d, 7=4.88 Hz, 1 H) 10.25 (s, 1 H) 12.36 (s, 1 H) A14M1B07 te NMR (400 MHz, DMSO-de): δ ppm 0.72 (m, 4 H) 1.77 (s, 7 H) 2.18 (s, 3 H) 4.39 (s, 2 H) 6.95 (d, 7=5.00 Hz, 1 H) 7.54 (d, 7=5.00 Hz, 1 H) 10.69 (s, 1 H) 12.37 (s, 1 H) A21M1B07 te NMR (400 MHz, DMSO-de): δ ppm 1.82 (s, 6 H) 2.23 (s, 3 H) 4.53 (s, 2 H) 6.61 (s, 1 H) 6.98 (d, 7=5.00 Hz, 1 H) 7.56 (d, 7=4.88 Hz, 1 H) 7.82 (s, 1 H) 7.96 (m, 2 H) 8.10 (d, 7=7.44 Hz, 2 H) 8.64 (d,7=2.44 Hz, 1 H) 10.98 (s, 1 H) 12.57 (s, 1 H) A23M1B07 te NMR (400 MHz, DMSO-de): δ ppm 1.83 (s, 6 H) 2.23 (s, 3 H) 4.57 (s, 2 H) 6.98 (d, 7=5.00 Hz, 1 H) 7.56 (d, 7=4.88 Hz, 1 H) 7.63(m, 2 H) 8.01 (m, 4 H) 8.63 (m, 1 H) 11.07 (s, 1 H) 12.58 (s, 1 H) A25M1B07 3H NMR (400 MHz, DMSO-de): δ ppm 1.76 (s, 6 H) 2.19 (s, 3 H) 4.26 (d, 7=5.85 Hz, 2 H) 4.36 (s, 2 H) 6.86 (s, 1 H) 6.95 (d, 7=4.88 Hz, 1 H) 7.22 (s, 3 H) 7.32 (m, 2 H) 7.53 (d, 7=4.88 Hz, 1 H) 8.82 (s,lH)12.14(s, 1H) A27MIB07 te NMR (400 MHz, DMSO-de): δ ppm 1.79 (s, 6 H) 2.21 (s, 3 H) 4.44 (s, 2 H) 6.78 (m, 1 H) 6.97 (d, 7=4.88 Hz, 1 H) 7.07 (m, 1 H) 013015 74 A30M1B07 7.29 (m, 1 H) 7.35 (m, 1 H) 7.55 (d,7=5.00 Hz, 1 H) 9.04 (s, 1 H) 12.32 (s, 1 H) JH NMR (400 MHz, DMSO-d6): δ ppm 1.81 (s, 6 H) 2.22 (s, 3 H) 4.52 (s, 2 H) 6.97 (d, 7=5.00 Hz, 1 H) 7.48 (m, 2 H) 7.56 (m, 1 H) 7.56 (d, 7=5.00 Hz, 1 H) 7.95 (d, 7=7.32 Hz, 2 H) 10.92 (s, 1 H) 12.55 (s,lH) A48M1B07 *H NMR (400 MHz, DMSO-d6): δ ppm 1.73 (s, 6 H) 2.13 (s, 3 H) 3.71 (s, 2 H) 4.35 (s, 2 H) 6.89 (d, 7=4.88 Hz, 1 H) 7.40 (dd, 7=8.47,1.65 Hz, 1 H) 7.47 (m, 3 H) 7.74 (s, 1 H) 7.84 (m, 3 H) 10.74 (s, 1 H)12.40 (s, 1 H) A53M1B07 ‘H NMR (400 MHz, DMSO-di): δ ppm 1.34 (m, 1 H) 1.50 (m, 1 H)1.72 (m, 2 H) 1.77 (s, 6 H) 1.98 (s, 3 H) 2.19 (s, 3 H) 2.55 (m, 2 H)3.00 (m, 1 H) 3.81 (d, 7=12.56 Hz, 1 H) 4.35 (d, 7=12.07 Hz, 1 H) 4.42 (s, 2 H) 6.96 (d, 7=5.00 Hz, 1 H) 7.54 (d, 7=4.88 Hz, 1 H) 10.45(s, 1 H) 12.40 (s, 1 H) A54M1B07 Ή NMR (400 MHz, DMSO-de): δ ppm 1.82 (s, 6 H) 2.22 (s, 3 H) 4.53 (s, 2 H) 6.97 (d, 7=5.00 Hz, 1 H) 7.56 (d, 7=5.00 Hz, 1 H) 7.72(m, 1 H) 7.91 (m, 1 H) 8.24 (m, 2 H) 11.24 (s, 1 H) 12.62 (s, 1 H) A31M01B19.HC1 !H NMR (400 MHz, DMSO-d6): δ 1.80 (s, 6 H) 2.07 (m, 4 H) 2.81(m, 3 H) 3.14 (m, 4 H) 4.75 (m, 1 H) 4.99 (s, 2 H) 7.33 (m, 2 H) 7.20 (dd, 7=4.94,3.84 Hz, 1 H) 7.63 (dd, 7=3.72, 0.79 Hz, 1 H) 7.80 (d, 7=5.00 Hz, 1 H) 8.02 (m, 2 H) 10.07 (m, 1 H) 10.86 (s, 1 H) 11.99 (s, 1H) A31M1B20.HC1 ’H NMR (400 MHz, DMSO-de): (mixture of two conformers) δ ppm 1.63 (m, 8 H) 1.67 (s, 12 H) 1.86 (m, 2 H) 2.10 (m, 4 H) 2.28 (d,7=14.0 Hz, 2 H) 2.68 (m, 2 H) 2.79 (d, 7=5.0 Hz, 3 H) 2.81(d, 7=5.0 Hz, 3 H) ) 3.1-3.3 (m, 4 H) 3.46 (m,2H) 3.52 (d, 7=14.0 Hz, 2 H) 3.90 (m, 8 H) 4.68 (m, 1 H) 4.76 (m, 4 H) 4.89 (m, 1 H) 7.11 (d, J=8.9 Hz, 2 H) 7.14 (d, J=8.9 Hz, 2 H) 8.01 (d,J=8.9Hz, 013015 75 2 H) 8.03 (d, >8.9 Hz, 2 H) 10.02 (bs,. 2 H) 10.81 (bs, 2 H) A33M1B20.HC1 *H NMR (400 MHz, DMSO-ds):5 ppm 1.65 (m, 4 H) 1.68 (s, 6 H) 2.70 (m, 1 H) 2.81 (s, 3 H) 2.9-3-8 (bs, 8 H) 3.90 (m, 4 H) 4.06 (bs,2H) 4.77 (s, 2 H) 7.62 (bs, 2 H) 8.07 (d, J=7.S Hz, 2 H) 10.60 (bs, 1 H) 11.01 (s, 1 H) A12M1B44 4l NMR (400 MHz, DMSO-ds): δ ppm 0.14 (m, 2 H) 0.46 (m, 2 H)0.91 (d, >6.58 Hz, 6 H) 1.01 (m, 1 H) 1.66 (s, 6 H) 2:05 (m, 1 H) 2.16 (d, /=7.07 Hz, 2 H) 2.24 (d, >6.58 Hz, 2 H) 4.54 (s, 2 H) 10.35(s, 1 H) 12.27 (s, 1 H) A13M1B44 ‘H NMR (400 MHz, DMSO-d6): δ ppm 0.15 (m, 2 H) 0.47 (m, 2 H) 1.01 (m, 1 H) 1.66 (s, 6 H) 1.80 (m, 1 H) 1.92 (m, 1 H) 2.08 (m, 2 H) 2.17 (m, 2 H) 2.26 (d, /=6.46 Hz, 2 H) 3.25 (m, 1 H) 4.58 (s, 2 H) 10.25 (s, 1 H) 12.26 (s, 1 H) A14M1B44 JH NMR (400 MHz, DMSO-d6): δ ppm 0.13 (m, 2 H) 0.44 (m, 2 H) 0.76 (m, 4 H) 0.98 (m, 1 H) 1.65 (s, 6 H) 1.81 (m, 1 H) 2.22 (d, >6.58 Hz, 2 H) 4.51 (s, 2 H) 10.69 (s, 1 H) 12.27 (s, 1 H) A25M1B44 ’H NMR (400 MHz, DMSO-ds): δ ppm 0.13 (m, 2 H) 0.45 (m, 2 H) 0.99 (m, 1 H) 1.65 (s, 6 H) 2.23 (d, >6.46 Hz, 2 H) 4.31 (d, >5.85 Hz, 2 H) 4.49 (s, 2 H) 6.89 (s, 1 H) 7.25 (m, 1 H) 7.28 (d, >7.07 Hz, 2 H) 7.34 (m, 2 H) 8.83 (s, 1 H) 12.04 (s, 1 H) A26M1B44 *H NMR (400 MHz, DMSO-d6): δ ppm 0.14 (m, 2 H) 0.47 (m, 2 H) 0.87 (t, >7.44 Hz, 3 H) 1.00 (m, 1 H) 1.43 (m, 2 H) 1.64 (s, 6 H) 2.23 (d, >6.58 Hz, 2 H) 3.04 (m, 2 H) 4.48 (s, 2 H) 6.43 (s, 1 H) 8.65(s, 1 H) 12.00 (s, 1 H) A30M1B44 4-1 NMR (400 MHz, DMSO-d6): δ ppm 0.16 (m, 2 H) 0.47 (m, 2 H) 1.02 (m, 1 H) 1.70 (s, 6 H) 2.28 (d, >6.58 Hz, 2 H) 4.65 (s, 2 H) 7.51 (m, 2 H) 7.59 (m, 1 H) 8.01 (d, >7.44 Hz, 2 H) 10.91 (s, 1 H) 12.46 (s, 1 H) A54M1B44 ‘HNMR (400 MHz, DMSO-d6): δ ppm 0.16 (m, 2 H) 0.47 (m, 2 H) 013015 76 A04M1B45 1.02 (m, 1 H) 1.70 (s, 6 H) 2.28 (d, >6.58 Hz, 2 H) 4.65 (s, 2 H) 7.78(m, 1 H) 7.98 (m, 1 H) 8.35 (m, 2 H) 1125 (s, 1 H) 12.53 (s, 1 H) ΤΗ NMR (400 MHz, DMSO-de): δ ppm 0.60 (m, 1 H) 0.97 (m, 1 H) 1.12 (d, >5.97 Hz, 3 H) 1.19 (m, 1 H) 1.51 (m, 1 H) 1.66 (s, 6 H) 4.86 (s, 2 H) 7.20 (m, 1 H) 7.40 (m, 1 H) 7.76 (m, 1 H) 10.89 (s, 1 H)12.48 (s, 1 H) A3OM1B45 ’H NMR (400 MHz, DMSO-d^): δ ppm 0.61 (m, 1 H) 0.96 (m, 1 H)1.13 (d, >5.85 Hz, 3 H) 1.20 (m, 1 H) 1.53 (m, 1 H) 1.67 (s, 6 H) 4.87 (s, 2 H) 7.51 (m, 2 H) 7.60 (m, 1 H) 8.02 (d, >7.07 Hz, 2 H) 10.92 (s, 1 H) 12.47 (s, 1 H) A54M1B45 Ή NMR (400 MHz, DMSO-d6): δ ppm 0.61 (m, 1 H) 0.96 (m, 1 H) I. 13 (d, >5.85 Hz, 3 H) 1.20 (m, 1 H) 1.53 (m, 1 H) 1.67 (s, 6 H) 4.88 (s, 2 H) 7.77 (m, 1 H) 7.96 (m, 1 H) 8.31 (d, 1 H) 8.39 (m, 1 H) II. 26 (s, 1 H) 12.54 (s, 1 H) A01M1B47 JH NMR (400 MHz, DMSO~d6): δ ppm 1.79 (s, 6 H) 2.23 (s, 6 H) 3.52 (s, 2 H) 4.43 (s, 2 H) 7.26 (t, >8.78 Hz, 2 H) 7.38 (m, 4 H) 7.95(dd, >8.84,5.55 Hz, 2 H) 10.90 (s, 1 H) 12.50 (s, 1 H) A48M1B47 Ή NMR (400 MHz, DMSO-d6): δ ppm 1.79 (s, 6 H) 2.14 (s, 6 H) 3.41 (s, 2 H) 3.67 (s, 2H), 4.33 (s, 2 H) 7.30 (m, 5 H) 7.45 (m, 2 H) 7.70 (m, 1 H) 7.80 (m, 3 H) 10.70 (s, 1 H) 12.37 (s, 1 H) A48M1B48 JH NMR (400 MHz, DMSO-de): δ ppm 1.76 (s, 6 H) 2.18 (s, 3 H) 2.35 (m, SH), 3.45 (s, 2 H) 3.68 (s, 2H), 4.34 (s, 2 H) 7.30 (m, 5 H) 7.47 (m, 2 H) 7.70 (m, 1 H) 7.81 (m, 3 H) 10.70 (s, 1 H) 12.37 (s, 1 H) A01M1B50 ‘H NMR (400 MHz, DMSO-d6): δ ppm 0.87 (t, >7.44 Hz, 3 H) 1.49 (m, 2 H) 1.68 (s, 6 H) 2.27 (t, >7.38 Hz, 2 H) 4.64 (s, 2 H) 7.30 (m, 2 H) 8.04 (m, 2 H) 10.92 (s, 1 H) 12.43 (s, 1 H) A04M1B50 Ή NMR (400 MHz, DMSO-d6): δ ppm 0.93 (t, >7.44 Hz, 3 H) 1.56 (m, 2 H) 1.68 (s, 6 H) 2.28 (t, >7.38 Hz, 2 H) 4.68 (s, 2 H) 7.22 (m, 1 013015 77 H) 7.40 (m, 1 H) 7.75 (m, 1 H) 10.88 (s, 1 H) 12.47 (s, 1 H) A13M1B50 Ή NMR (400 MHz, DMSO-dg): δ ppm 0.93 (t, 7=7.38 Hz, 3 H) 1.55(m, 2 H) 1.64 (s, 6 H) 1.80 (m, 1 H) 1.93 (m, 1 H) 2.07 (m, 2 H) 2.18(m, 2 H) 2.27 (t, 7=7.38 Hz, 2 H) 3.23 (m, 1 H) 4.61 (s, 2 H) 10.24 (s, 1 H) 12.27 (s, 1 H) A14M1B50 ‘H NMR (400 MHz, DMSO-dé): δ ppm 0.78 (d, 7=1.95 Hz, 4 H) 0.91 (t, 7=7.38 Hz, 3 H) 1.52 (m, 2 H) 1.64 (s, 6 H) 1.82 (m, 1 H) 2.24 (t,7=7.38 Hz, 2 H) 4.55 (s, 2 H) 10.70 (s, 1 il) 12.27 (s, 1 H) A3OM1B5O *H NMR (400 MHz, DMSO-dg): δ ppm 0.94 (t, 7=7.44 Hz, 3 H) 1.57 (m, 2 H) 1.69 (s, 6 H) 2.30 (t, 7=7.38 Hz, 2 H) 4.68 (s, 2 H) 7.52 (m, 2H) 7.60 (m, 1 H) 8.01 (d, 7=7.80 Hz, 2 H) 10.92 (s, 1 H) 12.46 (s, 1 H» A54M1B50 *H NMR (400 MHz, DMSO-d6): δ ppm 0.94 (t, 7=7.44 Hz, 3 H) 1.57(m, 2 H) 1.69 (s, 6 H) 2.29 (t, 7=7.38 Hz, 2 H) 4.70 (s, 2 H) 8.31 (m, 4 H) 11.25 (s, 1 H) 12.53 (s, 1 H) A04M1B51 JH NMR (400 MHz, DMSO-de): δ ppm 1.68 (s, 6 H) 2.03 (m, 2 H) 3.27 (m, 1 H) 3.73 (m, 3 H) 3.93 (t, 7=8.11 Hz, 1 H) 4.76 (m, 2 H) 7.21 (m, 1 H) 7.39 (m, 1 H) 7.74 (m, 1 H) 10.90 (s, 1 H) 12.49 (s, 1 H) A1-2M1B51 ‘H NMR (400 MHz, DMSO-d6): δ ppm 0.92 (d, 7=6.58 Hz, 6 H) 1.65 (s, 6 H) 2.03 (m, 3 H) 2.17 (d, 7=7.07 Hz, 2 H) 3.21 (m, 1 H) 3.73 (m, 3 H) 3.91 (t, 7=8.11 Hz, 1 H) 4.66 (m, 2 H) 10.38 (s, 1 H) 12.30 (s, 1 H) A13M1B51 H NMR (400 MHz, DMSO-di): δ ppm 1.65 (s, 6 H) 1.80 (m, 1 H) 1.96 (m, 3 H) 2.07 (m, 2 H) 2.19 (m, 2 H) 3.26 (m, 2 H) 3.74 (m, 3 H)3.92 (t, 7=8.11 Hz, 1 H) 4.70 (m, 2 H) 10.27 (s, 1 H) 12.29 (s, 1 H) A14M1B51 JH NMR (400 MHz, DMSO-de): δ ppm 0.78 (m, 4 H) 1.64 (s, 6 H) 1.83 (m, 1 H) 2.01 (m, 2 H) 3.20 (m, 1 H) 3.72 (m, 3 H) 3.90 (t, 7=8.05 Hz, 1 H) 4.64 (m, 2 H) 10.71 (s, 1 H) 12.29 (s, 1 H) 013015 78 A01M1B52 te NMR (400 MHz, DMSO-dfi): δ ppm 1.79 (s, 6 H) 4.43 (s, 2 H)7.2-7.95 (m, 9 H) 10.90 (s, 1 H) 12.50 (s, 1 H) A01M1B53 te NMR (400 MHz, DMSO-de): δ ppm 1.82 (s, 6 H) 4.43 (s, 2 H) 7.15 (m, H) 7.27 (m, H) 7.34 (m, H) 7.58 (m, H) 7.68 (m, H) 10.93 (s, 1 H) 12.62 (s, 1 H) A04M1B53 te NMR (400 MHz, DMSO-dé): δ ppm 1.82 (s, 6 H) 4.43 (s, 2 H) 7.15 (m, 1 H) 7.27 (m, 2 H) 7.34 (m, 1 H) 7.58 (m, 1 H) 7.68 (m, 1 H) 10.93 (s, 1 H) 12.62 (s, 1 H) A48M1B53 te NMR (400 MHz, DMSO-d6): δ ppm 1.73 (s, 6 H) 3.69 (s, 2 H) 4.27 (s, 2 H) 7.18 (m, 2 H) 7.38 (m, 1 H) 7.45 (m, 3 H) 7.71 (m, 1 H)7.80 (m, 3 H) 10.76 (s, 1 H) 12.45 (s, 1 H) A54M1B53 te NMR (400 MHz, DMSO-d6): δ ppm 1.83 (s, 6 H) 4.46 (s, 2 H) 7.28 (m, 2 H) 7.59 (m, 1 H) 7.71 (m, 1 H) 7.92 (m, 1 H) 8.21 (m, 1 H) 8.29 (m, 1 H) 11.26 (s, 1 H) 12.68 (s, 1 H) A01M1B54 ‘H NMR (400 MHz, DMSO-dfi): δ ppm 1.81 (s, 6 H) 4.43 (s, 2 H) 7.24 (m, 2 H) 7.42 (m, 2 H) 7.63 (d, 7=8.26 Hz, 2 H) 7.87 (d, 7=8.26Hz, 2 H) 7.95 (m, 2 H) 10.93 (s, 1 H) 12.62 (s, 1 H) A48M1B54 te NMR (400 MHz, DMSO-dfi): δ ppm 1.77 (s, 6 H) 3.69 (s, 2 H) 4.33 (s, 2 H) 7.32-7.89 (m, 13 H) 10.75 (s, 1 H) 12.41 (s, 1 H) A01M2B03 te NMR (400 MHz, DMSO-dfi): δ 12.20 (bs, 1H), 11.00 (s, 1H), 8.10(m, 2H), 7.36 (m, 2H), 4.91 (s, 2H), 2.84 (m, 2H), 2.4 (m, 1H), 2.23(m, 5H), 2.0 (m, 2H), 1.65 (m, 4H), 0.89 (m, 2H). A02M2B03 te NMR (400 MHz, DMSO-dfi): δ 12.28 (bs, 1H), 11.08 (s, 1H), 7.88 (m, 2H), 7,51 (m, 2H), 4.92 (s, 2H), 2.84 (m, 2H), 2.41 (m, 1H), 2.25(m, 5H), 2.05 (m, 2H), 1.68 (m, 4H), 0.91 (m, 2H). A04M2B03 te NMR (400 MHz, DMSO-d6): δ 12.24 (bs, 1H), 10.91(s, 1H), 7.75 (m, 1H), 7.41 (m, 1H), 7.22 (m, 1H), 4.91 (s, 2H), 2.79 (m, 2H), 2.34(m, 1H), 2.24 (m, 2H), 2.16 (s, 3H), 1.91 (m, 2H), 1.65 (m, 4H), 0.89(m, 2H). 013015 79 A05M2B03 !H NMR (400 MHz, DMSO-dô): δ 12.31 (bs, 1H), 11.16(s, 1H), 7.75(m, 2H), 7.51 (m, 1H), 4.91 (s, 2H), 2.79 (m, 2H), 2.35 (m, 1H), 2.25(m, 2H), 2.17 (s, 3H), 1.90 (m, 2H), 1.65 (m, 4H), 0.90 (m, 2H). A06M2B03 ^NMR (400 MHz, DMSO-cU): δ 12.45 (bs, 1H), 11.06 (s, 1H), 8.03 (m, 2H), 7.61 (m, 2H), 4.91 (s, 2H), 2.84 (m, 2H), 2.41 (m, 1H), 2.21 (m, 5H), 2.0 (m, 2H), 1.65 (m, 4H), 0.89 (m, 2H). A07M2B03 ^NMR (400 MHz, DMSO-d^): δ 12.30 (bs, 1H), 11.25 (s, 1H), 8.20(m, 2H), 7.92 (m, 2H), 4.94 (s, 2H), 2.95 (m, 2H), 2.45 (m, 1H), 2.27(m, 5H), 2.2 (m, 2H), 1.73 (m, 4H), 0.91 (m, 2H). A10M2B03 'H NMR (400 MHz, DMSO-d«): δ 12.25 (bs, 1H), 11.04 (s, 1H), 8.15 (m, 1H), 7.87 (m, IH), 7.22 (m, 1H), 4.89 (s, 2H), 2.82 (m, 2H), 2.37(m, 1H), 2.22 (m, 5H), 1.9 (m, 2H), 1.65 (m, 4H), 0.91 (m, 2H). A11M2B03 NMR (400 MHz, DMSO-ds): δ 12.22 (bs, 1H), 10.81 (s, 1H), 8.45(m, 1H), 7.69 (m, 2H), 4.90 (s, 2H), 2.82 (m, 2H), 2.37 (m, 1H), 2.24(m, 2H), 2.18 (m, 3H), 1.93 (m, 2H), 1.66 (m, 4H), 0.89 (m, 2H). A12M2B03 >H NMR (400 MHz, DMSO-ds): δ 12.06 (bs, 1H), 10.04 (s, ÏH), 4.82(s, 2H), 2.85 (m, 2H), 2.34 (m, 1H), 2.22 (m, 7H), 2.05 (m, 3H), 1.65(m, 4H), 0.93 (d, 6H, J = 6.58Hz), 0.85 (m, 2H). A13M2B03 *H NMR (400 MHz, DMSO-ds): δ 12.04 (bs, 1H), 10.08 (s, 1H), 4.85 (s, 2H), 3.25 (m, 1H), 2.85 (m, 2H), 2.39 (m, 1H), 2.25-1.75 (m, 13H), 1.67 (m, 4H), 0.85 (m, 2H). A19M2B03 JH NMR (400 MHz, DMSO-ds): δ 12.24 (bs, 1H), 10.84 (s, 1H), 7.94 (m, 1H), 7.51 (m, 1H), 6.70 (m, 1H), 4.88 (s, 2H), 2.85 (m, 2H), 2.40(m, 1H), 2.22 (m, 5H), 2.01 (m, 2H), 1.67 (m, 4H), 0.89 (m, 2H). A38M2B03 *H NMR (400 MHz, DMSO-d6): δ 12.21 (bs, 1H), 10.81 (s, 1H), 7.66 (m, 2H), 7.08 (m, 1H), 4.92 (s, 2H), 3.86 (s, 6H), 2.81 (m, 2H), 2.38(m, 1H), 2.25 (m, 2H), 2.18 (s, 3H), 1.94 (m, 2H), 1.66 (m, 4H), 0.90 (m, 2H). A01M2B04 ‘HNMR (400 MHz, DMSO-ds): δ 32.45 (bs, 3H), 11.00 (s, 1H), 8.10 013015 80 (m, 2H), 7.36 (m, 2H), 4.91 (s, 2H), 2.95 (m, 2H), 2.42 (m, 3H), 2.24(m, 2H), 1.95 (m, 2H), 1.7 (m, 4H), 1.02 (t, 3H), 0.89 (m, 2H). A02M2B04 lH NMR (400 MHz, DMSO-di): δ 12.27 (bs, 1H), 11.07 (s, 1H), 7.85(m, 2H), 7.68 (m, 1H), 7.45 (m, 1H), 4.91 (s, 2H), 2.90 (m, 2H), 2.34(m, 3H), 2.25 (m, 2H), 1.92 (m, 2H), 1.65 (m, 4H), 1.0 (t, 3H), 0.90 (m, 2H). A04M2B04 teNMR (400 MHz, DMSO-dé): δ 12.23 (bs, 1H), 10.91 (s, 1H), 7.78 (m, 1H), 7.41 (m, 1K), 7.22 (m, 1H), 4.91 (s, 2H), 2.91 (m, 2H), 2.35(m, 3H), 2.24 (m, 2H), 1.91 (m, 2H), 1.65 (m, 4H), 1.00 (t, 3H), 0.89 (m,2H). A05M2B04 te NMR (400 MHz, DMSO-ds): δ 12.31 (bs, 1H), 11.16(s, 1H), 7.75 (m, 2H), 7.54 (m, 1H), 4.92 (s, 2H), 2.92 (m, 2H), 2.35 (m, 3I-I), 2.25(m, 2H), 1.92 (m, 2H), 1.65 (m, 4H), 1.01 (t, 3H), 0.90 (m, 2H). A06M2B04 Ή NMR (400 MHz, DMSO-4): δ 12.25 (bs, 1H), 11.05 (s, 1H), 8.03 (m, 2H), 7.6 (m, 2H), 4.91 (s, 2H), 2.90 (m, 2H), 2.45-2.20 (m, 5H),1.85 (m, 2H), 1.67 (m, 4H), 1.02 (t, 3H), 0.89 (m, 2H). A07M2B04 te NMR (400 MHz, DMSO-d0): δ 12.31 (bs, 1H), 11.34 (s, 1H), 8.20 (m, 2H), 7.91 (m, 2H), 4.95 (s, 2H), 3.15-1.5 (m, 13H), 1.06 (t, 3H), 0.91 (m, 2H). A10M2B04 teNMR (400 MHz, DMSO-dJ: δ 12.25 (bs, 1H), 11.04 (s, 1H), 8.15 (m, 1H), 7.88 (m, 1H), 7.22 (m, 1H), 4.89 (s, 2H), 2.92 (m, 2H), 2.45-2.20 (m, 5H), 1.9 (m, 2H), 1.65 (m, 4H), 1.01 (t, 3H), 0.89 (m, 2H). A11M2B04 te NMR (400 MHz, DMSO-d^): δ 12.22 (bs, 1H), 10.81 (s, 1H), 8.46 (m, 1H), 7.69 (m, 2H), 4.90 (s, 2H), 2.92 (m, 2H), 2.34 (m, 3H), 2.25(m, 2H), 1.92 (m, 2H), 1.65 (m, 4H), 1.01 (t, 3H), 0.89 (m, 2H). A13M2BO4 te NMR (400 MHz, DMSO-di): δ 12.04 (bs, 1H), 10.27 (s, 1H), 4.86 (s, 2H), 2.89 (m, 2H), 2.45-1.75 (m, 14H), 1.65 (m, 4H), 1.00 (t, 3H),0.85 (m, 2H). A14M2BO4 teNMR (400 MHz, DMSO-c^): δ 12.05 (bs, 1H), 10.71 (s, 1H), 4.79 013015 81 (s, 2H), 2.88 (m, 2H), 2.31 (m, 3H), 2.21 (m, 2H), 1.89 (m, 3H), 1.62(m, 4H), 0.99 (t, 3H), 0.82 (m, 6H). A19M2B04 ]H NMR (400 MHz, DMSO-dg): δ 12.24 (bs, 1H), 10.84 (s, 1H), 7.94 (m, 1H), 7.51 (m, 1H), 6.71 (m, 1H), 4.88 (s, 2H), 2.97 (m, 2H), 2.40(m, 3H), 2.24 (m, 2H), 2.01 (m, 2H), 1.68 (m, 4H), 1.02 (t, 3H), 0.89(m, 2H). A38M2B04 *H NMR (400 MHz, DMSO-ds): δ 12.20 (bs, 1H), 10.81(s, 1H), 7.66 (m, 2H), 7.08 (m, 1H), 4.92 (s, 2H), 3.86 (s, 6H), 2.92 (m, 2H), 2.45-2.20 (m, 5H), 1.84 (m, 2H), 1.66 (m, 4H), 1.01 (t, 3H), 0.89 (m, 2ΒΓ). A01M2B05 *H NMR (400 MHz, DMSO-de): δ 12.25 (bs, 1H), 11.00 (s, 1H), 8.11 (m, 2H), 7.36 (m, 2H), 4.92 (s, 2H), 3.00 (m, 2H), 2.44 (m, 1H), 2.24(m, 4H), 1.6 (m, 5H), 0.89 (m, 2H), 0.38 (m, 4H). A06M2B05 NMR (400 MHz, DMSO-dg): δ 12.3 (bs, 1H), 11.06 (s, 1H), 8.05 (m, 2H), 7.6 (m, 2H), 4.92 (s, 2H), 3.00 (m, 2H), 2.44 (m, 1H), 2.24(m, 4H), 1.62 (m, 5H), 0.89 (m, 2H), 0.39 (m, 4H). A07M2B05 *H NMR (400 MHz, DMSO-d6): δ 12.3 (bs, 1H), 11.24 (s, 1H), 8.21 (m, 2H), 7.9 (m, 2H), 4.94 (s, 2H), 2.99 (m, 2H), 2.44 (m, 1H), 2.25(m, 4H), 1.59 (m, 5H), 0.89 (m, 2H), 0.37 (m, 4H). A01M2B06.HC1 *H NMR (400 MHz, DMSO-ds): δ 0.92 (m, 2H), 1.78 (m, 4 H) 2.24 (m, 2H), 2.81 (m, 1 H) 3.01 (m, 2 H) 3.38 (m, 2 H) 4.95 (s, 2 H) 7.37(t, 7=8.84 Hz, 2 H) 8.10 (dd, 7=8.96, 5.43 Hz, 2 H) 8.35 (m, 1 H) 8.65(d, 7=9.88 Hz, 1 H) 11.00 (s, 1 H) 12.52 (s, 1 H) A01M2B47 *H NMR (400 MHz, DMSO-d6): δ ppm 1.01 (m, 2 H) 2.18 (s, 6 H) 2.36 (m, 2 H) 3.46 (s, 2 H) 4.62 (s, 2 H) 7.28 (m, 2 H) 7.36 (m, 2 H) 7.41 (m, 2 H) 7.98 (m, 2 H) 10.93 (s, 1 H) 12.27 (s, 1 H) A48M2B53 *H NMR (400 MHz,DMSO-de): δ ppm 1.13 (m,2H)2.29 (m,2H) 3.72 (s, 2 H) 4.43 (s, 2 H) 7.18 (m, 2 H) 7.38 (m, 1 H) 7.45 (m, 3 H) 7.71 (m, 1 H) 7.80 (m, 3 H) 10.79 (s, 1 H) 12.23 (s, 1 H) 013015 82

Example 19 N-{6,6-dimethyl-5-[(4-methylpiperazin-l-yl)carbonyl]-2,4,5,6-tetrahydro pyrrolo[3,4-c]pyrazol-3-yl}-4-fluorobenzamide 5 To a solution of triphosgene (195 mg, 0.65 mmol, 0.56 eq) in DCM (15 ml) was added asolution of ethyl 3-[(4-fluorobenzoyl)amino]-656-dimethyl-5,6-dihydropynOlo[3,4-c]pyrazole-2(4H)-carboxylate hydrochloride (442 mg, 1.15 mmol) in DCM (30 ml)followed by N,N-diisopropylethylamine (760 μΐ, 4.31 mmol, 3.75 eq). Aller 3 hours, asolution of N-methylpiperazine (195 μΐ, 1.72 mmol, 1.5 eq) and diisopropylelhylamine 10 (300 μΐ, 1.72 mmol, 1.5 eq) in DCM (8 ml) was added. The reaction was stirred ovemight at room température (TLC: CTLClo/MeOH 90/10). The solution was washed with brine,the organic phase was dried over sodium sulfate and concentrated. The residue wasdissolved in methanol (16 ml), treated with TEA (1.6 ml, 11.5 mmol, 10 eq) and stirredovemight at room température. (TLC: ŒLCL/MeOH 90/10). Aller évaporation, the solid 15 was purified by flash chromatography (eluent: CHzCL/MeOH 90/10). The solid wastreated with diisopropylether and filtered to afford 0.294 g of the title compound in 64%yield. ESI MS: m/z 401 (MH+); 'HNMR (400 MHz, DMSO-d6): δ 12.39 (bs, 1H), 10.39 (s, 1H), 8.04 (m, 2H, Ai), 7.31 20 (m, 2H), 4.53 (bs, 2H), 3.04 (m, 4H), 2.40 (m, 4H), 2.22 (bs, 3H), 1.60 (bs, 6H).

By working in an analogous manner the following compounds were prepared: N-[5-[(4-methylpiperazin-l-yl)carbonyI]-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-6- spirocyclopropan-3-yl]-4-fluorobenzamide ESI MS: m/z 399 (MH+); 25 !H NMR. (400 MHz, DMSO-di): δ 12.19 (bs, 1H), 10.95 (s, 1H), 8.09 (m, 2H), 7.35 (m,2H), 4.70 (bs, 2H), 3.18 (m, 4H), 2.34 (m, 7H), 1.92 (m, 2H), 0.97 (m, 2H).

Example 20 013015 83 4-Chloro-N-[6,6-dimethyl-5-(4-pyrrolidin-l-ylmethyl-piperidine-l-carbonyl)-l,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylJ-benzamide, hydrochlorïdeA mixture of N-[5-(4-aminomethyl-piperidine-l-carbonyl)-6,6-dimethyl-2,4,5,6- tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-4-chloro-benzamide (310 mg, 0.7 mmoles), 1,4- 5 dibromobutane (92 μΐ, 0.7 mmoles) and NaHCCh (600 mg, 7 mmoles) in absolute éthanol(15 ml) was heated at 150°C for 15 minutes in a microwave oven. After cooling, thesolution was evaporated. The residue was taken up with dichloromethane/MeOH (90:10)and water, the suspension obtained filtered and the organic layer was evaporated todryness. The residue was purified by flash chromatography with 10 dichloromethane/MeOH/30% NTUOHaq (95/5/0.5). The product was obtained in 20%yield(71mg).

The compound was dissolved in methanol (3 ml), a solution of 4N HCl in dioxane (40 μΐ,0.16 mmoles) was added and then the solution was evaporated. The solid obtained wastriturated in ether to give the title hydrochlorïde sait as a white powder. 15 ESI MS: m/z485 (MH+); 1HNMR (400 MHz, DMSO-D6) δ ppm 1.24 (m, 2 H) 1.63 (s, 6 H) 1.92 (m, 7 H) 2.67 (t,7=11.83 Hz, 2 H) 3.01 (m, 2 H) 3.09 (t, 7=6.46 Hz, 2 H) 3.47 (m, 4 H) 4.56 (s, 2 H) 7.59(d, 7=8.54 Hz, 2 H) 8.01 (d, 7=8.66 Hz, 2 H) 9.49 (s, 1 H) 11.02 (s, 1 H) 12.50 (s, 1 H)

By working in analogous manner and by using the proper starting material and any suitable 20 reactant, as per the aforementioned process, additional compounds of formula (la) and (Ib)were also prepared, as reported in thê following table V.

Table V AO3M1BO8.HC1 ’HMMR (400 MHz, DMSO-dfi): δ 1.65 (d, 7=9.15 Hz, 6 H) 2.84 (d, 7=3.17Hz, 3 H) 3.06 (s, 4 H) 3.58 (s, 4 H) 4.62 (s, 2 H) 7.61 (m, 1 H) 7.91 (m, 1 H) 8.07 (m, 1 H) 9.98 (s, 1 H) 11.08 (s, 1 H) 12.61 (s, 1 H) A04M1B0S ’HNMR (400 MHz, DMSO-dé): δ 12.44 (bs, 1H), 10.85 (s, 1H), 7.74 (m, 1H), 7.18 (m, 1H), 7.20 (s, 1H), 4.59 (bs, 2H), 3.06 (m, 4H), 2.38 (m, 4H),2.22 (bs, 3H), 1.64(bs,6H). 013015 84 A06M1B08 NMR (400 MHz, DMSO-dé): δ 12.46 (bs, 1H), 10.99 (s, 1H), 8.01 (m, 2H), 7.59 (m, 2H), 4.59 (bs, 2H), 3.07 (m, 4H), 2.40 (m, 4H), 2.25 (bs, 3H), 1.64 (bs, 6H). A07M1B08 *H NMR (400 MHz, DMSO-d6): δ 12.49 (bs, 1H), 11.16 (s, 1H), 8.19 (d,2H, J = 7.80 Hz), 7.88 (d, 2H, J = 7.80 Hz), 4.60 (s, 2H), 3.06 (m, 4H), 2.38 (m, 4H), 2.22 (s, 3H), 1.64 (bs, 6H). A12M1BO8 ‘H NMR (400 MHz, DMSO-cU): δ 12.24 (bs, 1H), 10.32 (s, 1H), 4.47 (s,2H), 3.03 (m, 4H), 2.34 (m, 4H), 2.20 (s, 3H), 2.15 (d, 2H, J = 7.20 Hz), 2.05(m, 1H), 1.59 (s, 6H), 0.92 (d, 6H, J = 6.59 Hz). A13M1BO8 Ή NMR (400 MHz, DMSO-de): δ 12.23 (bs, 1H), 10.22 (s, 1H), 4.50 (bs,2H), 3.32 (m, 1H), 3.04 (m, 4H), 2.35 (m, 4H), 2.21 (s, 3H), 1.91-1.8 (m, 6H), 1.59 (bs, 6H). A14M1B08 ]H NMR (400 MHz, DMSO-cU): δ 12.23 (bs, 1H), 10.66 (s, 1H), 4.44 (bs,2H), 3.02 (m, 4H), 2.33 (m, 4H), 2.19 (s, 3H), 1.82 (m, 1H), 1.59 (bs, 6H),0.78 (m, 4H). A16M1B08 NMR (400 MHz, DMSO-dc): δ 12.46 (bs, 1H), 11.04 (s, 1H), 8.12 (m, 2H), 7.51 (m, 2H), 4.57 (bs, 2H), 3.06 (m, 4H), 2.36 (m, 4H), 2.20 (s, 3H),1.64(bs,6H). A17M1B08 ’H NMR (400 MHz, DMSO-cU δ 12.44 (bs, 1H), 10.94 (s, 1H), 7.78 (m,1H), 7.61 (bs, 1H), 7.51 (m, 1H), 7.45 (m, 2H), 7.20 (m, 2H), 7.09 (m, 2H),4.55 (bs, 2H), 3.06 (m, 4H), 2.40 (m, 4H), 2.24 (bs, 3H), 1.63 (bs, 6H). A18M1BO8 !H NMR (400 MHz, DMSO-d6): δ 12.44 (bs, 1H), 10.99 (s, 1H), 7.96 (m,2H), 7.47-7.33 (m, 7H), 4.55 (bs, 2H), 3.03 (m, 4H), 2.52 (m, 4H), 2.28 (bs,3H), 1.63 (bs, 6H). A21M1B08 ‘H NMR (400 MHz, DMSO-di): δ 12.44 (bs, 1H), 10.95 (bs, 2H), 8.66 (m, 1H), 8.14 (m, 2H), 8.00 (m, 2H), 7.83 (m, 1H), 6.82 (m, 1H), 4.59 (s, 2H),3.06 (m, 4H), 2.36 (m, 4H), 2.21 (s, 3H), 1.64 (bs, 6H). A22M1B08 Ή NMR (400 MHz, DMSO-dê): δ 12.41 (bs, 1H), 11.06 (bs, 1H), 8.50-7.60(m, 7H), 4.64 (s, 2H), 3.07 (m, 4H), 2.35 (m, 4H),2.18 (s, 3H),1.66 (bs, 6H). 013015 85 A23M1B08 Ή NMR (400 MHz, DMSO-d6): δ 12.45 (bs, 1H), 11.05 (bs, 1H), 8.66 (bs,1H), 7.07 (m, 4H), 7.65 (m, 2H), 4.62 (s, 2H), 3.07 (m, 4H), 2.37 (na, 4H), 2.21 (s, 3H), 1.65 (bs, 6H). A24M1B08 ‘H NMR (400 MHz, DMSO-d6): δ 12.02 (bs, 1H), 8.80 (s, 1H), 7.19 (m,4H), 6.90 (bs, 1H), 4.42 (s, 2H), 4.31 (d, 2H J = 5.73 Hz), 3.02 (m, 4H), 2.34(m, 4H), 2.30 (s, 3fi), 2.20 (s, 3H), 1.59 (s, 6H). A25M1B08 'H NMR (400 MHz, DMSO-d^): δ 12.02 (bs, 1H), 8.83 (s, 1H), 7.31 (m, 5H), 6.99 (bs, 1H), 4.42 (s, 2H), 4.33 (d, 2H J = 5.85 Hz), 3.02 (m, 4H), 2.34(m, 4H), 2.19 (s, 3H), 1.59 (s, 6H). A26M1B08 *H NMR (400 MHz, DMSO-d«): δ 12.00 (bs, 1H), 8.65 (s, 1H), 6.54 (m, 1H), 4.41 (s, 2H), 3.02 (m, 6H), 2.34 (m, 4H), 2.20 (s, 3H), 1.58 (s, 6H), 1.43 (m, 2H), 0.88 (t, 3H). A27M1B08 . ’H NMR (400 MHz, DMSO-d6): δ 12.22 (bs, 1H), 9.16 (s, 2H), 7.46 (m,1H), 7.33 (m, 1H), 7.13 (m, 1H), 6.80 (m, 1H), 6.99 (bs, 1H), 4.48 (s, 2H),3.05 (m, 4H), 2.35 (m, 4H), 2.20 (s, 3H), 1.61 (s, 6H). A01M1B09 *H NMR (400 MHz, DMSO-ds): δ 12.37 (bs, 1H), 10.88 (s, 1H), 8.04 (m, 2H), 7.31 (m, 2H), 4.51 (bs, 2H), 2.97 (m, 4H), 1.59 (bs, 6H), 1.50 (m, 6H). A06M1B09 ‘H NMR (400 MHz, DMSO-d6): δ 12.44 (bs, 1H), 10.98 (s, 1H), 8.01 (d,2H, J = 8.3 Hz), 7.58 (d, 2H, J = 8.3 Hz), 4.57 (bs, 2H), 3.00 (m, 4H), 1.63(bs, 6H), 1.54 (m, 6H). AO1M1B1O Ή NMR (400 MHz, DMSO-de): δ 12.41 (bs, 1H), 10.89 (s, 1H), 8.04 (m, 2H), 7.30 (m, 2H), 4.56 (bs, 2H), 3.59 (m, 4H), 3.01 (m, 4H), 1.61 (bs, 6H). A01M1B11 JH NMR (400 MHz, DMSO-de): δ 12.52 (bs, 1H), 10.91 (s, 1H), 8.07 (m, 2H), 7.35 (m, 2H), 4.54 (bs, 2H), 3.33 (m, 2H), 2.63 (m, 2H), 1.63 (m, 8H),1.49 (m, 1H), 1.15 (m, 2H), 0.94 (d, 3H, J = 6.5 Hz). A13M1B11 ’H NMR (400 MHz, DMSO-d0): δ 12.23 (bs, 1H), 10.19 (s, 1H), 4.50 (s, 2H), 3.33 (m, 3H), 2.62 (m, 2H), 2.4-1.4 (m, 15H), 1.15 (m, 2H), 0.95 (d,3H, J= 6.58 Hz). A14M1B11 % NMR (400 MHz, DMSO-ds): δ 12.23 (bs, 1H), 10.63 (s, 1H), 4.43 (s, 013015 86 2H), 3.33 (m, 2H), 2.61 (m, 2H), 1.9-1.4 (m, 1 OH), 1.11 (m, 2H), 0.95 (d,3H, J = 6.58 Hz), 0.77 (m, 4H). A14M1B12 JH NMR (400 MHz, DMSO-d6): δ 12.23 (bs, 1H), 10.64 (s, 1H), 4.43 (s,3H), 3.33 (m, 4H), 2.60 (m, 2H), 1.59 (m, 10H), 1.11 (m, 2H), 0.78 (m, 4H). A01M1B13 *H NMR (400 MHz, DMSO-d^): δ 12.42 (bs, 1H), 10.91 (s, 1H), 8.08 (m,2H), 7.33 (m, 2H), 4.56 (bs, 2H), 4.35 (bs, 1H), 3.46 (m, 4H), 2.65 (m, 2H), 1.75-1.05 (m, 13H). A02M2B08 ’HNMR (400 MHz, DMSO-ds): δ 12.00 (bs, 1H), 11.02 (s, 1H), 7.86 (m, 2H), 7.57 (na, 2H), 4.70 (bs, 2H), 3.14 (m, 4H), 2.40 (m, 4H), 2.25 (bs, 3H), 1.91 (m,2H), 0.97 (m,2H). A04M2B08 ’HNMR (400 MHz, DMSO-d6): δ 12.16 (bs, 1H), 10.84 (s, 1H), 7.76 (m, 3H), 4.69 (bs, 2H), 3.12 (m, 4H), 2.35 (m, 4H), 2.21 (bs, 3H), 1.90 (m, 2H), 0.97 (m, 2H). A06M2B08 ’HNMR (400 MHz, DMSO-d6): δ 12.20 (bs, 1H), 11.00 (s, 1H), 8.02 (m, 2H), 7.59 (m, 2H), 4.70 (bs, 2H), 3.15 (m, 4H), 2.51 (m, 4H), 2.29 (bs, 3H),1.92 (m, 2H), 0.89 (m,2H). A07M2B08 ’HNMR (400 MHz, DMSO-dg): δ 12.24 (bs, 1H), 11.17 (s, 1H), 8.19 (m, 2H), 7.89 (m, 2H), 4.72 (bs, 2H), 3.14 (m, 4H), 2.41 (m, 4H), 2.26 (bs, 3H),1.92 (m,2H), 0.98 (m,2H). A10M2B08 ’HNMR (400 MHz, DMSO-dg): δ 12.18 (bs, 1H), 10.98 (s, 1H), 8.11 (m, 1H), 7.87 (m, 1H), 7.21 (m, 1H), 4.66 (bs, 2H), 3.13 (m, 4H), 2.37 (m, 4H),2.23 (bs, 3H), 1.91 (m, 2H), 0.97 (m, 2H). A14M2B08 ’H NMR (400 MHz, DMSO-d6): δ 11.98 (bs, 1H), 10.66 (s, 1H), 4.56 (bs, 2H), 3.10 (m, 4H), 2.34 (m, 4H), 2.21 (bs, 3H), 1.87 (m, 2H), 1.86 (m, 1H),0.92 (m,2H), 0.82 (m,4H). A17M2B08 ’H NMR (400 MHz, DMSO-d^): δ 12.17 (bs, 1H), 10.95 (s, 1H), 7.79 (ni, 1H), 7.62 (bs, 1H), 7.51 (m, 1H), 7.45 (m, 2H), 7.27 (m, 1H), 7.20 (m, 1H),7.09 (m, 2H), 4.66 (bs, 2H), 3.12 (m, 4H), 2.35 (m, 4H), 2.21 (s, 3H), 1.90(m, 2H), 0.98 (m, 2Ή). 013015 87 A18M2B08 ’H NMR (400 MHz, DMSO-dê): δ 12.17 (bs, 1H), 11.00 (s, IB), 7.97 (bs, 1H), 7.94 (m, 1H), 7.42 (m, 7H), 4.67 (bs, 2H), 3.11 (m, 4H), 2.32 (m, 4H),2.20 (s, 3H), 1.90 (m, 2H), 0.98 (m, 2H). A19M2B08 Ή NMR (400 MHz, DMSO-dê): δ 12.17 (bs, 1H), 10.77 (s, 1H), 7.92 (bs, 1H), 7.49 (m, 1H), 6.69 (m, 1H), 4.66 (bs, 2H), 3.12 (m, 4H), 2.37 (m, 4H),2.23 (s, 3H), 1.90 (m, 2H), 0.96 (m, 2H). A01M2B09 ^NMR (400 MHz, DMSO-dê): δ 12.13 (bs, 1H), 10.93 (s, 1H), 8.09 (m, 2H), 7.36 (m, 2H), 4.65 (bs, 2H), 3.08 (m, 4H), 1.87 (m, 2H), 1.53 (m, 6H),0.96 (m, 2H). A01M2B10 Ή NMR (400 MHz, DMSO-dê): δ 12.10 (bs, 1H), 10.95 (s, 1H), 8.09 (m, 2H), 7.34 (m, 2H), 4.70 (bs, 2H), 3.62 (m, 4H), 3.12 (m, 4H), 1.93 (m, 2H), 0.96 (m,2II). AO1M2B11 'H NMR (400 MHz, DMSO-dÉ): δ 12.15 (bs, 1H), 10.93 (s, 1H), 8.09 (m, 2H), 7.36 (m, 2H), 4.65 (bs, 2H), 3.54 (m, 2H), 2.65 (m, 2B), 1.87 (m, 2H),1.61 (m, 2H), 1.50 (m, 1H), 1.12 (m, 2H), 0.94 (m, 5H). A01M2B12 XH NMR (400 MHz, DMSO-d6): δ 11.88 (bs, 1H), 10.93 (s, 1H), 8.08 (m, 2H), 7.36 (m, 2H), 4.66 (bs, 2H), 3.54 (m, 2H), 3.45 (m, 3H), 2.65 (m, 2H),1.87 (m, 2H), 1.66 (m, 2H), 1.50 (m, 1H), 1.12 (m, 2H), 0.94 (m, 2H). A01M2B13 NMR (400 MHz, DMSO-d6): δ 11.33 (bs, 1H), 10.93.(s, 1H), 8.08 (m, 2H), 7.36 (m, 2H), 4.65 (bs, 2H), 3.54 (m, 2H), 3.45 (m, 3H), 2.65 (m, 2H),1.87 (m, 2H), 1.66 (m, 2H), 1.50 (m, 1H), 1.40 (m, 2H), 1.12 (m, 2H), 0.95 (m, 2H). A48M1B08 ’HNMR (400MHz, DMSO-d6): δ 1.55 (s, 6H), 2.19 (s, 3H), 2.35 (m, 4H), 2.98 (m, 4H), 3.75 (s, 2H), 4.44 (s, 2H), 7.5 (m, 3H), 7.75 (s,.lH), .7.85 (m,3H), 10.7 (bs, 1H), 12.5 (bs, 1H). A30M1B08 ‘H NMR (400 MHz, DMSO-d6): δ 1.63 (s, 6H), 2.20 (s, 3H), 2.36 (m, 4H),3.06 (m, 4H), 4.57 (s, 2H), 7.51 (m, 2H), 7.60 (m, 1H), 7.99 (m, 2H), 10.89 (bs, 1H), 12.42 (bs, 1H). A38M2B08 JH NMR (400 MHz, DMSO-d6): δ 0.96 (m, 2H), 1.91 (bs, 2H), 2.23 (bs, 0î 301 5 88 3Η), 2.37 (bs, 4H), 3.13 (bs, 4H), 3.86 (s, 6H), 4.69 (s, 2H), 7.07 (s, 1H), 7.66 (bs, 2H), 10.76 (s, 1H), 12.14 (bs, 1H). Α54Μ1Β08 ’HNMR (400 MHz, DMSO-de): δ 1.64 (s, 6H), 2.20 (s, 3H), 2.36 (m, 4H),3.06 (m, 4H), 4.59 (bs, 2H), 7.77 (m, 1H), 7.96 (m, 1H), 8.3 (m, 1H), 8.36 (s,1H), 11.23 (s, 1H), 12.50 (bs, 1H). Α04Μ1Β12 ^NMR(400MHz,DMSO-de): δ 1.16 (m,2H), 1.4-1.75 (m, 9H), 2.62 (m,2H), 3.33 (m, 4H), 4.46 (t, 1H), 4.56 (bs, 2H), 7.2 (m, 2H), 7.75 (m, 1H), 10.84 (s, 1H), 12.43 (s, 1H). Α01Μ1Β12 lHNMR (400 MHz, DMSO-de): δ 1.17 (m, 2H), 1.51 (m, 1H), 1.63 (s, 6H),1.66 (m, 2H), 2.62 (m, 2H), 3.32 (m, 4H), 4.54 (bs, 2H), 7.35 (m, 2H), 8.07(m, 2H), 10.92 (s, 1H), 12.4 (bs, 1H). Α48Μ1Β13 ^NMR (400 MHz, DMSO-de): δ 12.25 (bs, 1H), 10.7 (s, 1H), 7.85 (m, 3H), 7.8 (s, 1H), 7.45 (m, 3H), 4.4 (bs, 2H), 4.3 (t, 1H), 3.75 (s, 2H), 3.44(m, 4H), 2.65 (m, 2H), 1.70 (m, 2H), 1.67 (s, 6H), 1.52 (m, 1H), 1.39 (m, 2H), 1.15 (m, 2H). Α30Μ1Β13 ’HNMR (400 MHz, DMSO-de): δ 7.99 (m, 2H), 7.59 (m, 1H), 7.51 (m, 2H), 4.56 (bs, 2H), 4.35 (t, 1H), 3.46 (m, 4H), 2.97 (m, 2H), 1.45-1.95 (m, 11H), 1.17 (m,2H). Α23Μ1Β13 Ή NMR (400 MHz, DMSO-de): δ 12.45 (bs, 1H), 11.02 (s, 1H), 8.67 (s, 1H), 8.07 (m, 4H), 7.65 (m, 2H), 4.61 (bs, 2H), 4.35 (t, 1H), 3.46 (m, 4H), 2.63 (m, 2H), 1.45-1.85 (m, 8H), 1.52 (m, 1H), 1.42 (m, 2H), 1.18 (m, 2H). Α14Μ1Β13 ^NMR (400 MHz, DMSO-de): δ 12.23 (bs, 1H), 10.64 (s, 1H), 4.42 (bs, 2H), 4.35 (t, 1H), 3.47 (m, 2H), 3.33 (m, 2H), 2.56 (m, 2H), 1.82 (m, 1H), 1.65 (m, 2H), 1.59 (s, 6H), 1.52 (m, 1H),1.4 (m, 2H), 1.12 (m, 2H), 0.78 (m,4H). Α04Μ1Β13 *HNMR (400 MHz, DMSO-de): δ 12.43 (bs, 1H), 10.84 (s, 1H), 7.76 (m, 1H), 7.38 (m, 1H), 7.2 (m, 1H), 4.56 (bs, 2H), 4.34 (t, 1H), 3.45 (m, 2H), 3.33 (m, 2H), 2.56 (m, 2H), 1.75-1.55 (m, 8H), 1.53 (m, 1H), 1.40 (m, 2H), 1.15 (m,2H). 013015 89 A16M1B13 ’HNMR (400 MHz, DMSO-dg): δ 12.45 (bs, 1H), 11.02 (s, 1H), 8.12 (m, 2H), 7.51 (m, 2H),4.56 (bs, 2H),4.35 (t, 1H), 3.48-3.20 (m, 4H), 2.61 (m,2H), 1.72-1.09 (xn, 13H). A22M1B13 ’HNMR (400 MHz, DMSO-dg): δ 12.40 (bs, 1H), 11.02 (s, 1H), 7.3-8.4 (m,7H), 4.65 (bs, 2H), 4.33 (t, 1H), 3.44 (m, 4H), 2.65 (m, 2EQ, 1.70 (m, 2H), 1.67 (s, 6H), 1.52 (m, 1H), 1.39 (m, 2H), 1.15 (m, 2H). A13M1B13 ’HNMR (400 MHz, DMSO-dg): δ 1.15 (m, 2 H) 1.40 (q, 7=6.54 Hz, 2 H) 1.51 (m, 1 H) 1.59 (s, 6 H) 1.68 (m, 2 H) 1.79 (m, 1 H) 1.91 (m, 1 H) 2.07(m, 2 H) 2.17 (m, 2 EQ 2.61 (t, 7=12.13 Hz, 2 H) 3.24 (m, 1 H) 3.39 (d,7=14.75 Hz, 2 H) 3.47 (m, 2 EQ 4.35 (m, 1 H) 4.49 (s, 2 H) 10.19 (s, 1 H) 12.22 (s, 1 H) A21M1B13 ’HNMR (400 MHz, DMSO-dg): δ 1.16 (m, 2 H) 1.40 (q, 7=6.71 Hz, 2 H) 1.55 (m, 1 H) 1.64 (s, 6 H) 1.69 (d, 7=12.80 Hz, 2 H) 2.62 (m, 2 H) 3.42 (d,7=11.83 Hz, 2 H) 3.47 (m, 2 EQ 4.35 (t, 7=5.12 Hz, 1 H) 4.58 (s, 2 BQ 6.62 (m, 1 H) 7.83 (d, 7=1.46 Hz, 1 H) 7.99 (d, 7=9.39 Hz, 2 H) 8.15 (d, 7=8.17 Hz, 2 H) 8.65 (d, 72.44 Hz, 1 H) 10.94 (s, 1 H) 12.43 (s, 1 H) A25M1B13 ’HNMR (400 MHz, DMSO-dg): δ 12.02 (bs, 1H), 8.82 (bs, 1H), 7.3 (m, 5H), 7.0 (bs, 1H), 4.40 (s, 2BQ, 4.33 (m, 3H), 3.45 (m, 2H), 3.33 (m, 2H), 2.59 (m, 2H), 1.66 (m, 2HQ, 1.57 (m, 7H), 1.40 (m, 2H), 1.13 (m, 2H). A27M1B13 ’HNMR (400 MHz, DMSO-dg): δ 12.20 (bs, 1H), 9.02 (bs, 1H), 7.45 (m, 1H), 7.31 (m, 1H), 7.12 (m, 1H), 6.81 (m, 1H), 4.47 (bs, 2EQ, 4.34 (t, 1H), 3.46 (m, 2H), 3.32 (m, 2ËQ, 2.62 (m, 2BQ, 1.66 (m, 2H), 1.58 (m, 7H), 1.40(m, 2H), 1.15 (m, 2H). A24M1B13 ’HNMR (400 MHz, DMSO-dg): δ 12.03 (bs, 1H), 8.79 (bs, 1H), 7.24 (m, 1H), 7.18 (m, 3EQ, 6.92 (bs, 1H), 4.39 (bs, 2H), 4.35 (t, 1H), 4.31 (m, 2H), 3.46 (m, 2H), 3.33 (m, 2H), 2.56 (m, 2H), 2.3 (s, 3H), 1.65 (m, 2H), 1.58 (m,7H), 1.40 (m, 2H), 1.13 (m, 2H). A26M1B13 ’HNMR (400 MHz, DMSO-dg): δ 11.99 (bs, 1HQ, 8.66 (bs, 1H), 6.56 (bs, 1H), 4.38 (bs, 2H), 4.35 (t, 1H), 3.46 (m, 2H), 3.32 (m, 2HQ, 3.05 (m, 2H), 013015 90 A12M1B13 2.56 (m, 2H), 1.66 (m, 21¾ 1.57 (m, 7H), 1.46 (m, 4H), 1.14 (m, 2H), 0.88 (t, 3H). ‘H NMR (400 MHz, DMSO-cU): δ ppm 0.92 (d, 7=6.46 Hz, 6 H) 1.12 (m, 2H) 1.39 (q, 7=6.58 Hz, 2 H) 1.54 (m, 1 H) 1.59 (s, 6 H) 1.67 (d, 7=14.51 Hz, 2 H) 2.06 (m, 1 H) 2.16 (d, 7=6.95 Hz, 2 H) 2.60 (m, 2 H) 3.38 (m, 2H) 3.46 (m, 2 H) 4.35 (t, 7=5.12 Hz, 1 H) 4.46 (s, 2 H) 10.30 (s, 1 H) 12.23 (s, 1 H) A54M1B13 NMR (400 MHz, DMSO-d6): δ ppm 1.15 (m, 2 H) 1.40 (q, 7=6.63 Hz, 2 H) 1.53 (m, 1 H) 1.64 (s, 6 H) 1.68 (d, 7=12.93 Hz, 2 H) 2.62 (t, 7=11.89 Hz, 2 H) 3.42 (d, 7=11.22 Hz, 2 H) 3.46 (m, 2 H) 4.35 (t, 7=4.88 Hz, 1 H) 4.57 (s, 2 H) 7.77 (t, 7=8.72 Hz, 1 H) 7.97 (d, 7=6.10 Hz, 1 H) 8.30 (d, 7=7.68 Hz, 1 H) 8.36 (s, 1 H) 11.21 (s, 1 H) 12.49 (s, 1 H) A01M1B27 Ή NMR (400 MHz, DMSO-d6): δ ppm 0.86 (t, 3 il), 1.27 (m, 2 H), 1.38 (m, 2 H), 1.61 (s, 6H), 3.0 (m, 2 H), 4.41 (m, 2 H), 5.98 (bs, 1H), 7.31 (m, 2 H),8.06 (m, 2 H), 10.86 (s, 1 H) 12.39 (s, 1 H). A01M2B27 XH NMR (400 MHz, DMSO-d6): δ ppm 0.78 (m, 2 H), 0.86 (t, 3 H), 1.27 (m, 2 H), 1.38 (m, 2 H>, 2.06 (m, 2 H), 3.0 (m, 2 H), 4.41 (m, 2 H), 5.98 (bs, 1 H), 7.31 (m, 2H), 8.05 (m, 2 H), 10.86 (s, 1 H) 12.38 (s, 1 H). AO1M1B2S ’H NMR (400 MHz, DMSO-d6): δ ppm 1.00 (t, 3 H), 1.62 (s, 6H), 3.04 (m, 2 H), 4.42 (m, 2 H), 6.01 (bs, 1H), 7.30 (m, 2 H), 8.07 (m, 2 H), 10.85 (s, 1 H) 12.38 (s, 1 H). A55M1B28 ’H NMR (400 MHz, DMSO-d6): δ ppm 1.00 (t, 3 H), 1.49 (d, 7=7.50 Hz, 3 H), 1.55 (s, 3 H), 1.58 (s, 3 H), 3.01 (m, 2 H), 4.04 (q, 1 H), 4.34 (m, 2 H),5.99 (bs, 1H), 7.48 (m, 3 H), 7.87 (m,.4 H), 10.61 (s, 1 H) 12.23 (s, 1 H). A01M2B28 ’H NMR (400 MHz, DMSO-d6): δ ppm 0.78 (m, 2 H), 0.99 (m, 3 H), 2.06 (m, 2 H), 2.98 (m, 2 H), 4.56 (m, 2 H), 6.14 (bs, 1 H), 7.33 (m, 2 H), 8.07(m, 2 H), 10.88 (s, 1 H) 12.09 (s, 1 H). A48M2B28 ‘H NMR (400 MHz, DMSO-d0): δ ppm 0.74 (m, 2 H), 0.96 (m, 3 H), 2.03 (m, 2 H), 2.96 (m, 2 H), 3.80 (s, 2 H), 4.45 (s, 2 H), 5.68 (bs, 1 H), 6.06 (bs, 1 H), 7.4-8.0 (m, 7 H), 10.70 (s, 1 H). 0130 1 5 91 A01M1B49 ’HNMR (400 MHz, DMSO-de): δρρηι 1.06 (d, 7=6.55 Hz, 6 H), 1.61 (s, 6 H), 3.78 (m, 1 H), 4.41 (m, 2 H), 5.66 (m, 1 H), 7.31 (m, 2 H), 8.06 (m, 2 H), 10.85 (s, 1 H) 12.39 (s, 1 H). A48M1B49 ’H NMR (400 MHz, DMSO-dç): δ ppm 1.01 (d, 7=6.5 Hz, 6 H), 1.56 (s, 6 H), 3.76 (m, 1 H), 4.29 (m, 2 H), 5.66 (m, 1H), 7.47 (m, 3 H), 7.78 (m, 1 H),7.85 (m, 3 H), 10.67 (s, 1 H) 12.24 (s, 1 H). A01M2B49 Ή NMR (400 MHz, DMSO-d«): δ ppm 0.81 (m, 2H), 1.09 (d, 7=6.64 Hz, 6 H), 2.09 (m, 2 H), 3.74 (m, 1 H), 4.60 (m, 2 H), 5.85 (m, 1 H), 7.36 (m, 2 H),8.10 (m, 2 H), 10.92 (s, 1 H) 11.76 (s, I H). AO1M1B55 Ή NMR (400 MHz, DMSO-d6): δ ppm 1.57 (m, 2 H), 1.63 (s, 6 H), 1.73 (m, 2 H), 2.25 (m, 1 H), 2.64 (m, 2 H), 3.43 (m, 2 H), 4.56 (m, 2 H), 6.75 (s, 1 H), 7.27 (s, 1 H), 7.34 (m, 2 H), 8.09 (m, 2 H), 10.92 (s, 1 H) 12.45 (s, 1 H). A01M2B55 ‘H NMR (400 MHz, DMSO-d6): δ ppm 0.96 (m, 2H), 1.55 (m, 2 H), 1.71(m, 2 H), 1.82 (m, 2 H), 2.34 (m, 1 H), 2.75 (m, 2 H), 3.48 (m, 2 H), 4.67 (m, 2 H), 6.75 (s, 1 H), 7.28 (s, 1 H), 7.35 (m, 2 H), 8.10 (m, 2 H), 10.98 (s, 1 H)12.19 (s, 1 H).

Example 21

Several compounds of the invention of formula (la) and (Ib), being prepared as formerly5 reported, were also characterised by means of HPLC/Mass techniques, hence through rétention time (r.t.) and Mass [M+H]+'

The operative conditions are reported below: HPLC/MS Method 1

The HPLC equipment consisted of a Waters 2790 HPLC System equipped with a 99610 Waters PDA detector and Micromass mod, ZQ single quadrupole mass spectrometer,equipped with an electrospray (ESI) ion source. Instrument control, data acquisition and data processing were provided by Millennium 4.0 and MassLynx 3.5 software. 013015 92 HPLC was carried out at 25°C at a flow rate of 1 ml/min using a RP18 Waters X Terra (4,6x 50 mm, 3.5 μπι) column. Mobile phase A was ammonium acetate 5 mM buffer (pH 5.5with acetic acid/acetonitrile 95:5), and Mobile phase B was HaO/acetonitrile (5:95); thegradient was from 10 to 90% B in 8 minutes then hold 90% B 2 minutes. The injection 5 volume was 10 μΐ.

The mass spectometer was operated in positive and in négative ion mode, the capillaryvoltage was set up at 2.5 KV; the source température was 120°C; cône was 10 V; fu.ll scan,mass range from 100 to 800 amu was set up. HPLC/MS Method 2 10 The HPLC equipment consisted of a Waters 2790 HPLC System equipped with a 996Waters PDA detector and Micromass mod. ZQ single quadrupole mass spectrometer,equipped with an electrospray (ESI) ion source. Instrument contrai, data acquisition anddata processing were providen by Millennium 4.0 and MassLynx 3.5 software. HPLC was carried out at 25°C at a flow rate of 1 ml/min using a RP18 Waters X Terra (4,6 15 x 50 mm, 3.5 pm) column. Mobile phase A was ammonium acetate 5 mM buffer (pH 5.5with acetic acid/acetonitrile 95:5), and Mobile phase B was H2O/acetonitrile (5:95); thegradient was from 10 to 90% B in 4 min then hold 90% B 1 minute. The injection volumewas 10 μΐ.

The mass spectometer was operated in positive and in négative ion mode, the capillary 20 voltage was set up at 2.5 KV; the source température was 120°C; cône was 10 V; full scan,mass range from 100 to 800 amu was set up. HPLC/MS Method 3

Mass spectra were recorded on a Finnigan LCQ ion trap mass spectrometer using theelectrospray (ESI) ionization technique with positive and négative ion détection. The mass 25 spectrometer was directly connected to a SSP4000 HPLC System (Thermo Séparation),equipped with an LcPal autosampler (CTC Analytics) and a UV 6000LP PDA detector(Thermo Séparation). Instrument control, data acquisition and processing were performedby using Xcalibur 1.2 software. HPLC analysis were carried out at room température at aflow rate of 1 ml/min using an RP Cl 8 Waters X-Terra column (4.6x 50mm; 3.5 pm). 013015 93

Mobile phase A was ammonium acetate 5 mM buffer (pH 5.5 with acetic acid): acetonitrile90:10, and Mobile phase B was ammonium acetate 5 mM buffer (pH 5.5 with acetic acid):acetonitrile 10:90; the gradient was from 0 to 100% B in 7 minutes then hold 100% B for 2minutes before requilibration. Total LC time is 12 minutes. The injection volume was1 ΟμΙ. UV Détection was performed between 215 and 400 nm.

Ions were generated trader the following conditions: ESI sprayer voltage 4.0 kV, heatedcapillary température 255°C, sheath gas nitrogen with a pressure of 5.0 Bar. A full scandétection mode (from 50 to 1000 amu) was used with an MS/MS analysis of the mostintense ion (normalized collision energy: 35%). UV Détection: 215-400 nm. HPLCZMS Method 4

The HPLC System used (Alliance 2790, with thermostated autosampler and divert valveLabPro, UV detector 2487 and satin interface, ZQ mass spectrometer with ESI interface) isaproduct of Waters Inc., Milford, Massachusetts. The chemiluminescent nitrogen detector(CLND) mod. 8060 is a product of ANTEK Instruments Inc., Houston, Texas. The liquidhandler Miniprep 75 is a product of Tecan Group Ltd., Maennedorf, Switzerland.

The chromatographie conditions used were as follows: The flow rate was set at 1 mL/min.Two mobile phases (mobile phase A: 0.1% foimic acid, mobile phase B: 0.1% fonnic acidin methanol) were employed to run in 10 min a linear gradient from 5 % B to 95 % B,which was maintained for 2 min, and followed by re-equilibration at 5% B for the next 3minutes. Run time was 15 min. Injection volume 10 pL, autosampler température 25°C,détection wavelength 220 nm.

As reported in the following table VI, some other compounds of formula (la) and (Ib) wereprepared, each identifïed through the aforementioned A-M-B coding System, and furthercharacterised through HPLC/Mass, according to the experimental conditions being abovereported. 013015 94

Table VI

Compound HPLC Method r.t. (min) [M+H]+ A01M1B09 3 4.60 386.0 A01M1B10 3 3.52 388.0 A01M1B11 1 5.55 400.5 A01M1B16 1 2.82 415.5 A01M1B18 1 3.06 455.5 A01M1B23 3 2.71 406.0 A01M1B24 3 5.05 434.0 A01M1B25 3 3.10 376.0 A01M1B26 3 2.80 362.1 A01M1B29 1 4.00 431.5 A01M1B30 1 3.39 402.4 AO1M1B31 1 2.60 431.5 A01M1B32 3 6.07 430.0 A01M1B33 3 3.67 416.0 A01M1B35 1 3.66 402.4 A01M1B36 1 2.70 401.5 A01M1B37 1 4.75 404.4 A01M1B38 1 2.76 401.5 A01M1B40 1 2.74 475.5 A01M1B41 3 4.75 510.1 A01M1B42 1 3.79 480.5 A01M1B46 3 2.68 419.0 A01M1B49 3 3.87 360.0 A02M1B11 2 2.35 400.5 A02M1B16 2 1.09 415.5 A02M1B18 2 1.16 455.5 A02M1B29 2 1.64 431.5 A02M1B30 2 1.36 402.4 A02M1B31 2 0.96 431.5 A02M1B35 2 1.48 402.4 A02M1B36 2 1.01 401.5 A02M1B37 2 1.96 404.4 A02M1B38 2 1.03 401.5 A02M1B40 2 1.01 475.5 A02M1B42 2 1.59 480.5 A04M1B09 1 5.02 404.4 A04M1B10 1 3.77 406.4 A04M1B11 1 5.57 418.5 A04M1B25 1 3.25 394.4 013015 95 A04M1B27 1 4.72 392.4 A04M1B28 1 3.68 364.4 A04M1B30 1 3.34 420.4 A04M1B33 1 3.88 434.5 A04M1B34 1 3.40 447.5 A04M1B41 1 5.25 528.5 A04M1B49 1 4.18 378.4 A05M1B11 1 6.03 418.5 A05M1B18 1 3.08 473.5 A05M1B29 1 4.30 449.5 A05M1B30 1 0.72 420.4 A05M1B31 1 2.66 449.5 A05M1B35 1 4.00 420.4 A05M1B36 1 2.83 419.4 A05M1B37 1 5.17 422.4 A05M1B38 1 2.79 419.4 A05M1B40 1 2.82 493.5 A05M1B42 1 4.07 498.5 A06M1B11 1 6.09 416.9 A06M1B16 1 3.17 431.9 A06M1B18 1 3.39 472.0 A06M1B29 1 4.42 447.9 A06M1B31 1 2.99 447.9 A06M1B36 1 3.04 417.9 A06M1B39 1 3.15 447.0 A06M1B40 1 3.08 492.0 AO6M1B42 1 4.17 497.0 A07M1B11 2 3.07 450.5 A07M1B16 2 1.78 465.5 ' A07M1B18 2 1.86 505.6 AO7M1B29 2 2.36 481.5 A07M1B30 2 2.11 452.4 A07M1B31 2 1.69 481.5 AO7M1B35 2 2.24 452.4 A07M1B36 2 1.72 451.5 A07M1B37 2 2.73 454.4 A07M1B38 2 1.71 451.5 A07M1B40 2 1.73 525.5 AO7M1B42 2 2.25 530.5 A1OM1B11 1 3.83 388.5 A10M1B16· 1 2.56' 403.5 A10M1B18 1 2.58 443.6 A10M1B29 1 3.76 419.5 013015 96 A1OM1B3O 1 3.13 390.5 A10M1B31 1 2.24 419.5 A10M1B37 1 4.45 392.5 A10M1B38 1 2.35 389.5 A10M1B40 1 2.34 463.6 A10M1B42 1 3.54 468.6 A12M1B09 1 4.43 348.5 A12M1B1O 1 3.18 350.4 A12M1B25 1 2.71 338.4 A12M1B28 1 3.08 308.4 A12M1B31 1 1.89 393.5 A12M1B33 1 3.40 378.5 A12M1B41 1 4.80 472.6 A12M1B49 i 3.56 322.4 A13M1B09 1 4.24 346.4 A13M1B10 1 2.98 348.4 A13M1B11 1 4.82 360.5 A13M1B25 1 2.52 336.4 A13M1B28 1 2.86 306.4 A13M1B30 1 2.66 362.4 A13M1B31 1 1.86 391.5 A13M1B33 1 3.22 376.5 A13M1B41 1 4.67 470.6 A13M1B49 1 3.37 320.4 A14M1B09 1 3.80 332.4 A14M1B1O 1 2.57 334.4 A14M1B11 4 8.32 346.2 A14M1B30 1 2.28 348.4 A14M1B31 1 1.39 377.5 A14M1B33 1 2.87 362.4 A14M1B34 1 2.41 375.4 A14M1B35 1 2.52 348.4 A14M1B41 1 4.30 456.5 A14M1B49 1 2.94 306.4 A16M1B09 1 5.93 452.4 À16M1B10 1 4.78 454.4 A16M1B11 1 6.43 466.5 A16M1B25 1 4.27 442.4 A16M1B28 1 4.73 412.4 A16M1B30 1 4.32 468.4 A16M1B31 1 3.37 497.5 A16M1B32 1 5.20 496.5 A16M1B33 1 4.82 482.5 013015 97 A16M1B34 1 4.34 495.5 A16M1B35 1 4.60 468.4 A16M1B49 1 5.15 426.4 A17M1B11 2 3.37 474.6 A17M1B16 2 2.29 489.6 A17M1B18 2 2.33 529.7 A17M1B29 2 2.60 505.6 A17M1B30 2 2.39 476.5 A17M1B31 2 2.08 505.6 A17M1B35 2 2.53 476.5 A17M1B36 2 2.08 475.6 A17M1B37 2 3.01 478.5 A21M1B09 1 4.92 434.5 A21M1B10 1 3.78 436.5 A21M1B25 1 3.33 424.5 A21M1B28 1 3.71 394.4 A21M1B31 1 2.66 479.6 A21M1B33 1 3.90 464.5 A21M1B49 1 4.13 408.5 A22M1B09 1 5.54 418.5 A22M1B10 1 4.65 420.5 A22M1B11 1 6.05 432,5 A22M1B25 1 3.81 408.5 A22M1B27 1 5.27 406.5 A22M1B28 1 4.33 378.4 A22M1B30 1 3.86 434.5 A22M1B31 1 2.92 463.6 A22M1B32 1 4.81 462.6 A22M1B33 1 4.40 448.5 A22M1B34 1 3.90 461.5 A22M1B35 1 4.46 434.5 A22M1B41 1 4.11 542.6 A22M1B49 1 4.77 392.5 A23M1B09 1 5.91 418.5 A23M1B10 1 4.67 420.5 A23M1B11 1 6.45 432.5 A23M1B25 1 4.16 408.5 A23M1B27 1 5.56 406.5 A23M1B28 1 4.62 378.4 A23M1B30 1 4.20 434.5 A23M1B31 1 3.21 463.6 - A23M1B32 1 5.13 462.6 A23M1B33 1 4.72 448.5 013015 98 A23M1B34 1 4.24 461.5 A23M1B35 1 4.49 434.5 A23M1B41 1 5.98 542.6 A23M1B49 1 5.05 392.5 A24M1B09 1 5.02 411.5 A24M1B10 1 3.91 413.5 A24M1B28 1 3.87 371.5 A24M1B31 1 2.73 456.6 A24M1B33 1 4.05 441.5 A24M1B49 1 4.28 385.5 A25M1B09 1 4.65 397.5 A25M1B10 1 3.53 399.5 A25M1B25 1 3.13 387.5 A25M1B28 1 3.48 357.4 A25M1B30 1 3.20 413.5 A25M1B31 1 2.26 442.5 A25M1B33 1 3.47 427.5 A25M1B41 1 4.94 521.6 A25M1B49 1 3.91 371.5 A26M1B09 1 3.87 349.4 A26M1B10 1 2.72 351.4 A26M1B28 1 2.62 309.4 A26M1B33 1 3.00 379.5 A26M1B49 1 3.06 323.4 A27M1B09 1 5.34 401.5 A27M1B1Ô 1 4.13 403.4 A27M1B25 1 3.65 391.4 A27M1B31 1 2.85 446.5 A27M1B33 1 4.22 431.5 A27M1B49 1 4.52 375.4 A30M1B09 1 4.78 368.5 A30M1B10 1 3.53 370.4 A30M1B11 1 5.33 382.5 A30M1B25 1 3.04 358.4 A30M1B27 1 4.45 356.4 A30M1B28 1 3.43 328.4 A30M1B30 1 3.13 384.4 A30M1B31 1 2.27 413.5 A30M1B33 1 3.69 398.5 A30M1B34 1 3.21 411.5 A30M1B35 1 3.38 384.4 A30M1B41 1 5.06 492.6 A30M1B49 1 3.91 342.4 013015 99 A48M1B09 3 5.30 432.1 A48M1B10 3 4.18 434.1 A48M1B23 3 3.38 452.1 A48M1B24 3 3.78 480.1 A48M1B25 3 3.83 422.1 A48M1B26 3 3.48 408.2 A48M1B30 3 4.00 448.2 A48M1B31 3 3.22 477.1 A48M1B32 3 4.28 476.3 A48M1B33 3 4.23 462.1 A48M1B40 3 3.33 521.3 A48M1B41 3 4.72 556.2 A48M1B46 3 3.43 465.1 A48M1B49 3 4.77 406.1 A53M1B09 1 3.10 417.5 A53M1B28 1 2.02 377.5 A53M1B49 1 2.37 391.5 A54M1BO9 1 5.87 436.4 A54M1B10 1 4.65 438.4 A54M1B11 4 9.71 450.1 A54M1B25 1 4.14 426.4 A54M1B28 1 4.60 396.4 A54M1B31 1 3.22 481.5 A54M1B33 1 4.70 466.5 A54M1B34 1 4.20 479.5 A54M1B35 1 4.46 452.4 A54M1B41 1 5.93 560.6 A54M1B49 1 5.05 410.4 AO1M2B11 2 2.75 398.5 A01M2B16 2 1.40 413.5 A01M2B18 2 1.50 453.5 AO1M2B29 2 2.08 429.5 A01M2B30 2 1.71 400.4 A01M2B31 2 1.27 429.5 A01M2B35 2 1.84 400.4 A01M2B36 2 1.31 399.2 A01M2B37 2 2.33 402.4 A01M2B38 2 1.34 399.4 A01M2B40 2 1.34 473.5 A01M2B42 2 1.93 478.5 A06M2B09 1 5.52 400.9 AO6M2B11 1 6.04 414.9 A06M2B16 1 2.95 429.9 013015 100 A06M2B18 1 3.16 470.0 A06M2B29 1 4.57 445.9 A06M2B30 1 3.82 416.9 A06M2B31 1 2.90 445.9 A06M2B35 1 4.08 416.9 A06M2B36 1 2.94 415.9 A06M2B37 1 5.20 418.9 A06M2B38 1 3.00 415.9 A06M2B40 1 3.03 490.0 A07M2B11 2 3.10 448.5 A07M2B16 2 1.80 463.5 A07M2B18 2 1.90 503.5 A07M2B29 2 2.46 479.5 A07M2B30 2 2.13 450.4 A07M2B31 2 1.71 479.5 A07M2B35 2 2.26 450.4 A07M2B36 2 1.74 449.4 A07M2B37 2 2.75 452.4 A07M2B38 2 1.78 449.4 A07M2B40 2 1.76 523.5 A07M2B42 2 2.29 528.5 A17M2B16 2 2.10 487.6 A17M2B18 2 2.17 527.6 A17M2B29 2 2.73 503.6 A17M2B30 2 2.40 474.5 A17M2B31 2 2.01 503.6 A17M2B35 2 2.55 474.5 A17M2B36 2 2.03 473.5 A17M2B37 2 3.05 476.5 A17M2B38 2 2.07 473.5 A17M2B40 2 2.04 547.6 A17M2B42 2 2.55 552.6

Claims (2)

1. 013015 101 CLAIMS 1) Use of a compound represented by formula (la) or(lb) R

   N À '3 R

   N Λ (la) (lb) wherein R is a group -CORa, -CONHRa or -CONRaRb wherein Ra and Rb are, each independently,hydrogen or an optionally substituted group selected from straight or branched Ci-Ce alkyl,C3-C6 cycloalkyl, aryl, arylalkyl, heterocyclyl or heterocyclylalkyl or; together wilh the nitrogen atom to which they are bonded, Ra and Rb may form an optionally substituted 5 or 6 membered heterocycle optionally containing one additional heteroatom or heteroatomicgroup selected among N, NH, O or S; Ri is selected from the group consisting of: a) straight or branched C3-C4 alkyl; b) . cycloalkyl, cycloalkyl-alkyl or alkyl-cycloalkyl wherein the cycloalkyl moietycomprises any C3-C6 cycloalkyl group and wherein the alkyl moiety comprises any straightor branched C1-C4 alkyl group: c) 3-methylthienyl-2-yl; 2-thienyl; phenyl; 2,6-difluorophenyl; 4-(aminosulfonyl)phenyl; 4-(dimethylaminomethyl)phenyl; 4-(4-methylpiperazmyl)methyl-phenyl; —— d) a group of formula (Ha) or (Db): 20

   N (Ha) (llb) 013015 102 wherein, in formula (lia), the cycle represents a 5 to 7 membered heterocyclic ring wherinX, directly linked to the rest of the molécule, represents a carbon or nitrogen atom; Y is acarbon, nitrogen, oxygen or sulfur atom or it is an NH group, provided that at least one ofX and Y is other tihan a carbon atom; R° is, independently from each other and in any oneof the free positions of the heterocyclic ring of formula (Ha), a halogen atom or hydroxygroup or it is an optionally substituted group selected from straight or branched Q-Cgalkyl, C3-C6 cycloalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, amino,aminocarbonyl, carboxy, oxo (=Ô), alkoxycarbonyl, alkylcarbonyl or arylcarbonyl; and nis 0 or an integer from 1 to 4; e) a group of formula (Ile) or (Ild): /Rd Λ ——oR’d (lie) (Ild) 5 wherein Rd, R'd and Re represent, the same or different and independently from each other,a hydrogen atom or a straight or branched Ci-Cg alkyl optionally substituted by one ormore groups selected from hydroxy (-OH), aminocarbonyl (-CONH2) ormethylaminocarbonyl (-CONHCH3); provided that in formula (la), when Ri is a group of formula (Hc) and one of Rd or R'd is a 10 hydrogen atom whilst the other of Rd or R’d is ethyl or n-butyl, then R is other than -CORawith Ra as 3-bromophenyl, benzyl, 4-tert-butylphenyl, 4-tert-butylphenylmethyl, 4-fluorophenylmethyl, cyclopropyl or 2-naphthylmethyl; or a pharmaceutically acceptable saltthereof, in the manufacture of a médicament for treating cellproliférative disorders caused by and/or associated with an altered cell cycle dépendent kinaseactivity. 2) The use according to ciaim 1 wherein the cell proliférative disorder is selected from the 15 group consisting of cancer, Alzheimer's disease, viral infections, auto-immune diseases andneurodegenerative disorders. 20 013015 103 3) The use according to claim 2 wherein the cancer is selected from the group consisting ofcarcinoma, squamous cell carcinoma, hematopoietic tumors of myeloid or lymphoid lineage,tumors of mesenchymal origin, tumors of the central and peripheral nervous System, meianoma,seminoma, teratocarcinoma, osteosarcoma, xeroderma pigmentosum, keratoxanthoma,thyroidfollicular cancer, and Kaposi's sarcoma. 4) The use according to claim 1 wherein the cell proliférative disorder is selected from thegroup consisting of benign prostate hyperplasia, familial adenomatosis polyposis, neuro-fibromatosis, psoriasis, vascularsmooth cell prolifération associated with atherosclerosis,pulmonary fibrosis, arthritis, glomerulonephritis and post-surgical stenosis and restenosis. 5) The use according to claim 1 which prûvidës tumor angiogenesis and metastasisinhibition. 10 6) The use according to claim 1 which provides organ transplant rejection and host versusgraftdisease treatments. 7) The use according to claim 1 which provides treatment o'r prévention of radiotherapy-induced or chemotherapy-induced alopecia. 15 8) The use according to claim 1 further comprising subjecting the mammal in need thereofto a radiation therapy or chemotherapy regimen in combination with at least one cytostatic orcytotoxic agent. — 9) The use according to claim 1 wherein the mammal in need thereof is a human. 20 10) Use of a compound as defined in claim 1 in the manufacture of an inhibitor of cyclindépendent kinase activity. 11) A compound represented by formula (la) or (Ib)

   013015 104 wherein R is a group -COR3, -CONHR3 or -CONRaRb wherein Ra and Rb are, each independently,hydrogen or an optionally substituted group selected from straight or branched Ci-C6 alkyl,C3-C6 cycloalkyl, aiyl, aiylalkyl, heterocyclyl or heterocyclylalkyl or; together with the 5 nitrogen atom to which they are bonded, R3 and Rb may form an optionally substituted 5 or6 membered heterocycle optionally containing one additional heteroatom or heteroatomicgroup selected among N, NH, O or S; Ri is selected from the group consisting of. · a) straight or branched C3-C4 alkyl; 10 b) cycloalkyl, cycloalkyl-alkyl or alkyl-cycloalkyl wherein the cycloalkyl moietycomprises any C3-C6 cycloalkyl group and wherein the alkyl moiety comprises any straightor branched C1-C4 alkyl group: c) 3-methylthienyl-2-yl; 2-thienyl; phenyl; 2,6-difluorophenyl; 4-(aminosulfonyl)phenyl; 4-(dimethylaminomethyl)phenyl; 4-(4-methyIpiperazinyl)methyl- 15 phenyl; d) a group of formula (Ha) or (Iïb): (Rc)n

   wherein, in formula (lia), the cycle represents a 5 to 7 membered heterocyclic ring wherinX, directly linked to the rest of the molécule, represents a carbon or nitrogen atom; Y is a 20 carbon, nitrogen, oxygen or suliur atom or it is an NH group, provided that at least one ofX and Y is other than a carbon atom; Rc is, independently from each other and in any oneof the free positions of the heterocyclic ring of formula (Ha), a halogen atom or hydroxygroup or it is an optionally substituted group selected from straight ot branched Cj-C6alkyl, C3-C6 cycloalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, amino, 25 aminocarbonyl, carboxy, oxo (=0), alkoxycarbonyl, alkylcarbonyl or aiylcarbonyl; and nis 0 or an integer from 1 to 4; . e) a group of formula (Ile) or (Ild): 013015 105 r r --O R'd (Ile) (lld) wherein Rd. R'd and Rc represent, thé same or different and. independently from each other,a hydrogen atom or a straight or branched Ci-Cô alkyl optionally substituted by one ormore groups selected from bydroxy (-OH), aminocarbonyl (-CONHz) or 5 methylaminocarbonyl (-CONHCH3); provided that in formula (la), when Ri is a gronp of formula (Hc) and one of Rd or R'd is ahydrogen atom whilst the other of Rd or R'd is ethyl or n-butyl, then R is other than -CORawith Ra as 3-bromophenyl, benzyl, 4-tert-butylphenyl, 4-tert-butylphenylmethyl, 4-fluorophenylmethyl, cyclopropyl or 2-naphthylmethyl; 10 or a pharmaceutically acceptable sait thereof. 12) A compound of formula (la) or (Ib) according to claim 11 wherein R is a group-CORa, Ra is as defined in claim 11 and Ri is tert-butyl. 13) A compound of formula (la) or (Ib) according to claim 11 wherein R is a group-CONHR3, R4 is as defined in claim lî and Ri is tert-butyl. 15 14) A compound of formula (la) or (Ib) according to claim 11 wherein R is a group -CONRaRb, Ra and Rb are as defined in claim 11 and Ri is tert-butyl. 15) A compound of formula (la) or (Ib) according to claim 11 wherein R is as defined inclaim 11 and Ri is a group of formula (Ha) selected from:

   20 wherein n and Rc are as defined in claim 11. 16) A compound of formula (la) or (Ib) according to claim 11 wherein R is as defined inclaim 11 and Rj is a group of formula (lia) selected from: 013015 106

   wherein Rc is as defined in claim 11. 17) A compound of formula (la) according to claim 11, wherein R is a group -COR1 withRa as 4-fluorophenyl or cyclobutyl, and Rj is as defined in claim 11. 5 18) A compound of formula (la) according to claim 11 wherein R is as defined in claim 11 and Ri is a group selected from tert-butyl, 1-methyl-piperidyl-4-yl, 1-methyl-piperazinyl-4-yl, 2-(R,S)-tetrahydrofuranyl-2-yl, 2-(R)-tetrahydrofuranyl-2-yl or 2-(S)-tetrahydrofùranyl-2-yl. 19) A compound of formula (la) or (Ib), according to claim 11, wherein any of R\ Rb and 10 Rc is a group, as defined in claim 11, optionally further substituted in one or more of their free positions, by groups independently selected from: halogen, nitro, oxo groups (=0),cyano, alkyl, polyfluorinated alkyl, polyfluorinated alkoxy, alkenyl, alkynyl, hydroxyalkyl,aiyl, aiylalkyl, heterocyclyl, cycloalkyl, hydroxy, alkoxy, aryloxy, heterocyclyloxy,methylenedioxy, alkylcarbonyloxy, aiylcarbonyloxy, cycloalkenyloxy, 15 alkylideneaminooxy, carboxy, alkoxycarbonyî, aryloxycarbonyl, cycloalkyloxycarbonyl,amino, ureido, alkylamino, dialkylamino, arylamino, diarylamino, formylamino,alkylcarbonylamino, arylcarbonylamino, heterocyclylcarbonylamino, alkoxycarbonylamino, alkoxyimino, alkylsulfonylamino, aiylsulfonylamino, formyl,alkylcaTbonyl, arylcarbonyl, cycloalkylcarbonyl, heterocyclylcarbonyl, aminocarbonyl, 20 aîkylaminocarbonyl, dialkylaminocarbonyl, alkylsulfonyl, arylsulfonyl, aminosulfonyl,alkylaminosulfonyl, dialkylaminosulfonyl, arylthio and alkylthio. 20) A compound of formula (la) or (Ib), optionally in the form of a pharmaceuticallyacceptable sait, selected from the group consisting of: N-{6,6-dimethyl-5-[(l-methylpiperidin-4-yl)carbonyl]-2,4,5,6-tetrahydropyrrolo[3,4- 25 c]pyrazol-3-yl}cyclobutanecarboxamide; N-[5-(2,2-dimethylpropanoyl)-6,6-dimethyl-l,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl]- 4-fluorobenzamide; 013015 107 N-[5-(2,2-dimethylpropanoyl)-2,4,5,6-tetrahydropynolo[3,4-c.]pyrazol-6- spirocyclopropan-3-yl]-4-fluorobenzamide; N-{6,6-dimethyl-5-[(2R)-tetrahydroiuran-2-ylcarbonyl]-I,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-4-fluorobenzamide; 5 N-{6,6-dimethyl-5-[(2S)-tetrahydrofuran-2-y]carbonyl]-l,4,5,6-tetrahydropyirolo[3,4-c]pyrazol-3-yl) -4-fluorobenzamide; N-(6,6-dimethyl-5-[(l-methylpiperi.din-4-yl)carbonyl]-2,4,5,6-tetrahydropyrrolo[3,4- c]pyrazol-3-yl)-4-fluorobenzamide; N-[5-[(l-methylpiperidin-4-yl)carbonyl)-2,4,5,6-tetrahydropyrrolo[3,4-c)pyrazol-6- 10 spirocyclopropan-3-yl]-4-fluorobenzamide; N-{ô,6-dimethyl-5-[(4-methylpiperazin-l-yI)carbonyl]-2,4,5,6-tetrahydro pynolo[3,4-c]pyrazol-3-yl}-4-fluorobenzamide; N-[5-[(4-methylpiperazin-l-yl)carbonyl]-2,4,5,6-tetrahydropyrrolo[3,4-c)pyrazol-6- spirocyclopropan-3-yl]-4-fluorobenzamide;
2. 4-Chloro-N-[6,6-dimethyl-5-(4-pyrrolidin-l-ylmethyl-piperidine- 1-carbonyl)-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-benzamide. 21) Any compound of formula (la) and (Ib), optionally in the fonn of a pharmaceuticallyacceptable sait, as specifically identified in tables ΙΠ, IV, V and VI of the experimentalsection. 20 22) The compound A13-M1-B03 of fonnula (la) wherein R is a group -CORa rvith Ra as cyclobutyl and Ri is a group of fonnula (lia) corresponding to l-methyI-piperidyl-4-yl,either as such or in the form of hydrochloride or mesylate sait 23) A process for preparing a compound of fonnula (la) or (Ib) as defïned in daim 11, ortbe pharmaceutically acceptable salts thereof, which process comprises: 25 a) reacting a compound of fonnula (Hla) or (Hlb) (lllb) H2N COOH h2n‘ COOH with acrylonitrile so as to obtain the corresponding dérivative of fonnula (TVa) or (IVb) 013015 108 .

   COOH (IVa)

   COOH (IVb) b) protecting the amino group of the compound of formula (IVa) or (IVb) so as to obtainthe corresponding dérivative of formula (Va) or (Vb)

   COOH

   COOH Q (Va) Q (Vb) wherein Q is a suitable amino protecting group; c) reacting the compound of formula (Va) or (Vb) with a suitable alkylating agent so as toobtain the corresponding ester dérivative of formula (Via) or (Vlb)

   COOAlk (Via)

   COOAlk (Vlb) .10 wherein Alk stands for a suitable C1-C4 alkyl group; d) reacting the compound of formula (Via) or (Vlb) with sodium hydride (NaH) so as toobtain the corresponding dérivative of formula (VHa) or (Vllb)

   (VI la)

   (Vllb) e) reacting the compound of formula (Vlla) or (Vllb) with hydrazine hydrate so as toobtain the compound of formula (Villa) or (VlUb) C . 013015 109

   30 reacting the compound of formula (Villa) or (VOTb) with ethyl chloroformate so as toobtain the dérivative of formula (Ka) or (IXb), each one in any of the two regioisomericfonns

   50 and reacting the compounds of formula (Ka) or (DCb) according to any one of thealternative steps (g. 1), (g.2) or (g.3)g. 1) with a compound of formula (X) RaCO-Z (X) wherein Ra is as defined in clairn 11 and Z is a halogen atom, so as to obtain the compoundof formula (Xla) or (Xïb)

   15 wherein R is a group -COR3; g.2) with a compound of formula (XII) RS-NCO (XH) 013015 110 wherein Ra is as defined in claim 11, so as to obtain the compound of the formula (Xla) or(Xlb) wherein R is a group -CONHRa; or g.3) with a suitable amine of formula (ΧΠ1) in the presence of triphosgene or of a suitablechloroformate 5 HNRaRb (XIH) wherein Ra and Rb are as defined in claim 11, so as to obtain the compound of formula(Xla) or (Xlb) wherein R is a group -CONRaRb; h) deprotecting the amino group of the compound of formula (Xla) or (Xlb) preparedaccording to any one of steps fiom (g.l) to (g.3), so as to obtain the corresponding 10 dérivative of formula (XTVa) or (XTVb)

   wherein R has the above reported meanings; and reacting the compound of formula (XTVa)or (XTVb) according to any one of the alternative steps (i.l), (i.2), (i.3) or (i.4)i. 1) with an acyl halide dérivative of formula (XV) 15 Ri-COZ (XV) wherein Ri is as set forth in claim 11 under groups (a), (b), (c), (lia) with X as a carbonatom and (Ilb), and Z is a halogen atom, so as to obtain a compound of formula (XVla) or

   013015 111 i.2) with a 5 to 7 membered heterocyclic compound of formula (XVII) or a suitable amineof formula (XVHI), in the presence of triphosgene

   HNÇR^R"1 (XVIII) 10 wherein X is MH and Y, Rc, n, Rd and R'd are as defîned in claim 11, so as to obtain thecoiresponding compounds of formula (XVIa) or (XVIb) wherein R is as above defîned andRi is either a group of formula (lia) with X as a nitrogen atom and R, Y, Rc and n as abovedefîned, or of formula (lie) wherein Rd and R'd are as above defîned; 1.3) with a carboxylic acid of formula (XIX) in the presence of a suitable condensing agent Ri-COOH (XIX) so as to obtain a compound of formula (XVIa) or (XVIb) wherein Ri is as set forth informula (la) or (1b) under groups (a), (b), (c) or it is a group of formula (lia) with X as acarbon atom or of formula (Ilb), and R, Y, Rc and n are as above defîned; 1.4) with a compound of formula (XX) . Ri-COZ (XX) 15 wherein Ri is a group of formula (Ild) and Z is a chlorine or bromine atom, so as to obtainthe a compound of formula (XVIa) or (XVIb) wherein R is as defîned above and Ri is agroup of formula (Tld); and j) reacting the compound of formula (XVIa) or (XVIb) prepared according to any one ofsteps from (i.l) to (i.4) under basic conditions, so as to obtain the corresponding dérivative 20 of formula (la) or (Ib) wherein R and Ri are as above defîned; and, optionally, k) converting them into other compounds of formula (la) or (Ib), respectively, and/or intopharmaceutically acceptable salts thereof. 24) The process of claim 23 wherein, in step (b), Q is tert-butoxycarbonyl (boc). 25) The process of claim 23 wherein, in step (c), Alk is methyl. 013015 112 26) The compounds of formula (Vïïa) or (VHb)

   CN (Vlla)

   :O (Vllb) CN wherein Q represents a suitable nitrogen protecting group such as tert-butoxycarbonyl(boc). 5 27) A libraTy of two ot more compounds of formula (la)

   wherein R is a group -COR3, -C0NHR3 or -CONRaRb wherein R3 and Rb are, each independently,hydrogen or an optionally substituted group selected from straight or branched Cj-Ce alkyl, 10 C3-Cé cycloalkyl, aryl, arylalkyl, heterocyclyl or heterocyclylalkyl or; together with thenitrogen atom to which they are bonded, Ra and Rb may form an optionally substituted 5 or6 membered heterocycle optionally containing one additional heteroatom or heteroatomicgroup selected among N, NH, O or S; Ri is selected from the group consisting of: 15 a) straight or branched C3-C4 alkyl; b) cycloalkyl, cycloalkyl-alkyl or alkyl-cycloalkyl wherein the cycloalkyl moietycomprises any C3-C.6 cycloalkyl group and wherein the alkyl moiety comprises any straightor branched C1-C4 alkyl group: c) 3-methylthienyl-2-yl; 2-thienyl; phenyl; 2,6-difluorophenyl; 4- 20 (aminosulfonyllphenyl; 4-(dimethylaminomethyl)phenyl; 4-(4-methylpiperazinyI)methyl- phenyl; AV 013015 113 d) a group of formula (lia) or (Ilb): •N (Ha) (Hb) wherein, in formula (Ha), the cycle représente a 5 to 7 membered heterocyclic ring wherinX, directly linked to the rest of the molécule, représente a carbon or nitrogen atom; Y is a 5 carbon, nitrogen, oxygen or sulfur atom or it is an NH group, provided that at least one ofX and Y is other fhan a carbon atom; Rc is, independently from eacb other and in any oneof the free positions of the heterocyclic ring of formula (Ha), a halogen atom or hydroxygroup or it is an optionally substituted group selected from straight or branched CrC6alkyl, C3-C6 cycloalkyl, aryl, aiylalfcyl, heterocyclyl, heterocyclylalkyl, amino, 10 aminocarbonyl, carboxy, oxo (=0), alkoxycarbonyl, alhylcarbonyl or arylcarbonyl; and nis 0 or an integer from 1 to 4; e) a group of formula (Ile) or (Ild):

   R-d (Ile) (Ild) wherein Rd, R'd and RB represent, the same or different and independently from each other, 15 a hydrogen atom or a straight or branched Cj-Cg alkyl optionally substituted by one ormore groups selected from hydroxy (-OH), aminocarbonyl (-CONH2) ormethylaminocarbonyl (-CONHCH3); provided that in formula (la), when Ri is a group of formula (Ile) and one of Rd or R'd is ahydrogen atom whilst the other of Rd or R'd is ethyl or n-butyl, then R is other than -CORa 20 with Ra as 3-bromophenyl, benzyl, 4-tert-butylphenyl, 4-tert-butylphenylmethyl, 4-fluorophenylmethyl, cyclopropyl or 2-naphthylmethyl;or a pharmaceutically acceptable sait thereof. 28) A library of rivo or more compounds of formula (Ib) 013015 114

   whcrcin R is a group -COR8, -C0NHR8 or -CONRaR° wherein Ra and Rb are, each independently,hydrogen or an optionally substituted group selected from straight or branched C1-C0 alkyl, 5 C3-C0 cycloalkyl, aryl, arylalkyl, heterocyclyl or heterocyclylalkyl or; together with the nitrogen atom to which Ihey are bonded, R8 and Rb roay form an optionally substituted 5 or6 ruembered heterocycle optionally containing one additional heteroatom or heteroatomicgroup selected among N, NH, O or S; Ri is selected from the group consisting of: 10 a) straight or branched C3-C4 alkyl; b) cycloalkyl, cycloalkyl-alkyl or alkyl-cycloalkyl wherein the cycloalkyl moietycomprises any C3-C6 cycloalkyl group and wherein the alkyl moiety comprises any straightor branched Cj-C4 alkyl group: ' c) 3-methylthienyl-2-yl; 2-thienyl; phenyl; 2,6-difluorophenyl; 4- 15 (aminosulfonyl)phenyl; 4-(dimethylaminomethyl)phenyl; 4-(4-methylpiperazinyl)methyl- phenyl; d) a group of formula (Ha) or (Ilb): .N (Ha) (Hb) wherein,in formula (Ha), the cycle represents a 5 to 7 membered heterocyclic ring wherin20 X, directly linked to the rest of the molécule, represents a carbon or nitrogen atom; Y is acarbon, nitrogen, oxygen or sulfur atom or it is an NH group, provided that at least one of 013015 115 X and Y is other than a carbon atom; Rc is, independently from each other and in any oneof the free positions of the heterocyclic ring of formula (lia), a halogen atom or hydroxygroup or it is an optionally substituted group selected from straight or branched Ci-Cgalkyl, C3-Q cycloalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, amino, 5 aminocarbonyl, carboxy, oxo (=0), alkoxycarbonyl, alkylcarbonyl or aiylcarbonyl; and n is 0 or an integer from 1 to 4; e) a group of formula (Ile) or (Ild): Rd R® / / --O R-d (Ile) (Ild) wherein Rd, R'd and R’ represent, the same or different and independently from each other, 10 a hydrogen atom or a straight or branched Cj-C-e alkyl optionally substituted by one ormore groups selected from hydroxy (-OH), aminocarbonyl (-CONH2) ormethylaminocarbonyl (-CONHCH3); or a pharmaceutically acceptable sait thereof. 29) A pharmaceutical composition comprising a therapeutically effective amount of a 15 compound of formula (la) or (Ib), as defined in claim 11, and at least one pharmaceutically acceptable excipient, carrier and/or diluent. 30) A pharmaceutical composition according to claim 29 further comprising one or morechemotherapeutic agents. 31) A product or kit comprising a compound of formula (la) or (Ib) as defined in claim 11 20 or a pharmaceutical composition thereof as defined in claim 29, and one or more chemotherapeutic agents, as a combined préparation for simultaneous,. separate orsequential use in anticancer therapy. 32) A compound of formula (la) or (Ib), as defined in claim 11, for use as a médicament. 33) Use of a compound of formula (la) or (Ib), as defined in claim 11, in the manufacture 25 of a médicament with antitumor activity.