Abstract:
The present invention provides a method for treating diseases caused by and/or associated with an altered protein kinase activity which comprises administering to a mammal in need thereof an effective amount of a pyrrolo-pyrazole or pyrazolo-azepine. The invention also provides specific pyrrolo-pyrazoles and pyrazolo-azepines, useful intermediates, a library comprising at least two of them, a process for their preparation and the pharmaceutical compositions containing them, which are useful in the treatment of diseases caused by and/or associated with an altered protein kinase activity such as cancer, cell proliferative disorders, viral infections, autoimmune diseases and neurodegenerative disorders.

Description:
BACKGROUND OF THE INVENTION  
       [0001]     1. Field of the Invention  
         [0002]     The present invention relates to bicyclo-pyrazole derivatives active as kinase inhibitors and, more in particular, it relates to pyrrolo-pyrazole and pyrazolo-azepine derivatives, to a process for their preparation, to pharmaceutical compositions comprising them and to their use as therapeutic agents, particularly in the treatment of diseases linked to deregulated protein kinases.  
         [0003]     2. Discussion of the Background  
         [0004]     The malfunctioning of protein kinases (PKs) is the hallmark of numerous diseases.  
         [0005]     A large share of the oncogenes and proto-oncogenes involved in human cancers code for PKs. The enhanced activities of PKs are also implicated in many non-malignant diseases such as benign prostate hyperplasia, familial adenomatosis, polyposis, neuro-fibromatosis, psoriasis, vascular smooth cell proliferation associated with atherosclerosis, pulmonary fibrosis, arthritis glomerulonephritis and post-surgical stenosis and restenosis.  
         [0006]     PKs are also implicated in inflammatory conditions and in the multiplication of viruses and parasites. PKs may also play a major role in the pathogenesis and development of neurodegenerative disorders.  
         [0007]     For a general reference to PKs malfunctioning or deregulation see, for instance, Current Opinion in Chemical Biology 1999, 3, 459465.  
         [0008]     Some pyrrolo-pyrazole or pyrazolo-azepine derivative are known in the art. Few pyrazolo-azepine derivatives were studied (CAS 55:27362i, Yamamoto, H. et al, Bull. Chem. Soc. Jap., 44(1), 153-8, 1971 and Moriya, T. et al; Bull. Chem. Soc. Jap., 41(1), 230-1, 1968). Some pyrrolo-pyrazole derivatives were disclosed in Elguero, J. et al; Bull. Soc. Chim. Fr.(4), 1497-9 1971 and the antibacterial activity of some other pyrrolo-pyrazole derivatives was shown in WO01/042242 and JP06073056.  
       SUMMARY OF THE INVENTION  
       [0009]     The present inventors have now discovered that some pyrrolo-pyrazoles and pyrazolo-azepines are endowed with multiple protein kinase inhibiting activity and are thus useful in therapy in the treatment of diseases caused by and/or associated with deregulated protein kinases.  
         [0010]     As such, it is an object of the invention to provide compounds, which are useful as therapeutic agents against a host of diseases caused by a deregulated protein kinase activity.  
         [0011]     It is another object to provide compounds endowed with multiple protein kinase inhibiting activity.  
         [0012]     More specifically, the pyrrolo-pyrazoles and pyrazolo-azepines of this invention are useful in the treatment of a variety of cancers including, but not limited to: carcinoma such as bladder, breast, colon, kidney, liver, lung, including small cell lung cancer, esophagus, gall-bladder, ovary, pancreas, stomach, cervix, thyroid, prostate, and skin, including squamous cell carcinoma; hematopoietic tumors of lymphoid lineage, including leukemia, acute lymphocitic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell-lymphoma, Hodgkin&#39;s lymphoma, non-Hodgkin&#39;s lymphoma, hairy cell lymphoma and Burkett&#39;s lymphoma; hematopoietic tumors of myeloid lineage, including acute and chronic myelogenous leukemias, myelodysplastic syndrome and promyelocytic leukemia; tumors of mesenchymal origin, including fibrosarcoma and rhabdomyosarcoma; tumors of the central and peripheral nervous system, including astrocytoma, neuroblastoma, glioma and schwannomas; other tumors, including melanoma, seminoma, teratocarcinoma, osteosarcoma, xeroderma pigmentosum, keratocanthoma, thyroid follicular cancer and Kaposi&#39;s sarcoma.  
         [0013]     Due to the key role of PKs in the regulation of cellular proliferation, these pyrrolo-pyrazoles and pyrazolo-azepines are also useful in the treatment of a variety of cell proliferative disorders such as, for instance, benign prostate hyperplasia, familial adenomatosis, polyposis, neuro-fibromatosis, psoriasis, vascular smooth cell proliferation associated with atherosclerosis, pulmonary fibrosis, arthritis glomerulonephritis and post-surgical stenosis and restenosis.  
         [0014]     The compounds of the invention can be useful in the treatment of Alzheimer&#39;s disease, as suggested by the fact that cdk5 is involved in the phosphorylation of tau protein (J. Biochem., 117, 741-749, 1995).  
         [0015]     The compounds of this invention, as modulators of apoptosis, may also be useful in the treatment of cancer, viral infections, prevention of AIDS development in HIV-infected individuals, autoimmune diseases and neurodegenerative disorders.  
         [0016]     The compounds of this invention may be useful in inhibiting tumor angiogenesis and metastasis.  
         [0017]     The compounds of the invention are useful as cyclin dependent kinase (cdk) inhibitors and also as inhibitors of other protein kinases such as, for instance, protein kinase C in different isoforms, Met, PAK-4, PAK-5, ZC-1, STLK-2, DDR-2, Aurora 1, Aurora 2, Bub-1, PLK, Chk1, Chk2, HER2, raf1, MEK1; MAPK, EGF-R, PDGF-R, FGF-R, IGF-R, VEGF-R, P13K, weel kinase, Src, Abl, Akt, ILK, MK-2, IKK-2, Cdc7, Nek, and thus be effective in the treatment of diseases associated with other protein kinases.  
         [0018]     Accordingly, the present invention provides a method for treating diseases caused by and/or associated with an altered protein kinase activity which comprises administering to a mammal in need thereof an effective amount of a pyrrolo-pyrazole or pyrazolo-azepine derivative represented by formula (I):  
                         
 
 wherein R represents hydrogen or halogen atom, or an optionally substituted group selected from aryl C 2 -C 6  alkenyl, (heterocyclyl) C 2 -C 6  alkenyl, aryl C 2 -C 6  alkynyl, or (heterocyclyl) C 2 -C 6  alkynyl group, —R′, —COR′, —COOR′, —CN, —CONR′R″, —OR′, —S(O) q R′, —SO 2 NR′R″, —B(OR′″) 2 , —SnR″″, wherein R′ and R″, the same or different, independently represent hydrogen atom or an optionally further substituted straight or branched C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, saturated or unsaturated C 3 -C 6  cycloalkyl, aryl, heterocyclyl, aryl C 1 -C 6  alkyl or (heterocyclyl)C 1 -C 6  alkyl; R′″ represents hydrogen, 
 
         [0019]     C 1 -C 6  alkyl, or R′″, together with the two oxygen and the boron atoms, forms a saturated or unsaturated C 5 -C 8  (hetero)cycloalkyl, optionally benzocondensed or substituted, and R″″ represents C 1 -C 6  alkyl;  
         [0020]     R 1  represents hydrogen atom or an optionally substituted group selected from —R′, —CH 2 R′, —COR′, —COOR′, —CONR′R″, —C(═NH)NHR′, —S(O) q R′, or —SO 2 NR′R″, wherein R′ and R″ are as defined above;  
         [0021]     R 2  represents hydrogen atom, —COR′, —COOR′, —CONR′R″, —S(O) q R′, —SO 2 NR′R″, C 1 -C 6  alkyl or (heterocyclyl)C 1 -C 6  alkyl group, wherein R′ and R″ are as defined above; R a , R b , R c  and R d , being the same or different, independently represent hydrogen atom, an optionally further substituted straight or branched C 1 - 6  alkyl, aryl, heterocyclyl, aryl C 1 -C 6  alkyl, (heterocyclyl)C 1 -C 6  alkyl or —CH 2 OR′ group, wherein R′ is as above defined, or R a  and R b  and/or R c  and R d , taken together with the carbon atom to which they are bonded, form an optionally substituted, saturated or unsaturated, C 3 -C 6  cycloalkyl group; q is 0, 1 or 2; m and n, each independently, represents 0, 1 or 2, provided that m+n is 0 or equal to 2; or a pharmaceutically acceptable salt thereof.  
         [0022]     In a preferred embodiment of the method described above, the disease caused by and/or associated with an altered protein kinase activity is selected from the group consisting of cancer, cell proliferative disorders, Alzheimer&#39;s disease, viral infections, auto-immune diseases and neurodegenerative disorders.  
         [0023]     Specific types of cancer that may be treated according to the invention 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, teratocarcinoma, osteosarcoma, xeroderoma pigmentosum, keratoxanthoma, thyroid follicular cancer and Kaposi&#39;s sarcoma.  
         [0024]     In another preferred embodiment of the method described above, the cell proliferative disorder is selected from the group consisting of benign prostate hyperplasia, familial adenomatosis polyposis, neuro-fibromatosis, psoriasis, vascular smooth cell proliferation associated with atherosclerosis, pulmonary fibrosis, arthritis glomerulonephritis and post-surgical stenosis and restenosis. In addition, the method object of the present invention, provides tumor angiogenesis and metastasis inhibition. The present invention also provides a pyrrolo-pyrazole or pyrazolo-azepine derivative represented by formula (I):  
                         
 
         [0025]     wherein R represents hydrogen or halogen atom, or an optionally substituted group selected from aryl C 2 -C 6  alkenyl, (heterocyclyl) C 2 -C 6  alkenyl, aryl C 2 -C 6  alkynyl, or (heterocyclyl) C 2 -C 6  alkynyl group, —R′, —COR′, —COOR′, —CN, —CONR′R″, —OR′, —S(O) q R′, —SO 2 NR′R″, —B(OR′″) 2 , —SnR″″, wherein R′ and R″, the same or different, independently represent hydrogen atom or an optionally further substituted straight or branched C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, saturated or unsaturated C 3 -C 6  cycloalkyl, aryl, heterocyclyl, aryl C 1 -C 6  alkyl or (heterocyclyl)C 1 -C 6  alkyl; R′″ represents hydrogen, C 1 -C 6  alkyl, or R′″, together with the two oxygen and the boron atoms, forms a saturated or unsaturated C 5 -C 8  (hetero)cycloalkyl, optionally benzocondensed or substituted, and R″″ represents C 1 -C 6  alkyl;  
         [0026]     R 1  represents hydrogen atom or an optionally substituted group selected from —R′, —CH 2 R′, —COR′, —COOR′, —CONR′R″, C(═NH)NHR′, —S(O) q R′, or —SO 2 NR′R″, wherein R′ and R″ are as defined above;  
         [0027]     R 2  represents hydrogen atom, —COR′, —COOR′, —CONR′R″, —S(O) q R′, —SO 2 NR′R″, C 1 -C 6  alkyl or (heterocyclyl)C 1 -C 6  alkyl group, wherein R′ and R″ are as defined above;  
         [0028]     R a , R b , R c  and R d , being the same or different, independently represent hydrogen atom, an optionally further substituted straight or branched C 1 -C 6  alkyl, aryl, heterocyclyl, aryl C 1 -C 6  alkyl, (heterocyclyl)C 1 -C 6  alkyl or —CH 2 OR′ group, wherein R′ is as above defined, or R a  and R b  and/or R c  and R d , taken together with the carbon atom to which they are bonded, form an optionally substituted, saturated or unsaturated, C 3 -C 6  cycloalkyl group; q is 0, 1 or 2; m and n, each independently, represents 0, 1 or 2, provided that m+n is 0 or equal to 2; with the following further provisos: 
        when m and n are both 1, R is hydrogen atom or hydroxy group and R a , R b , R c  and R d  are all hydrogen atoms, then R 1  is not hydrogen atom, acetyl, benzyl or ethoxycarbonyl group;     when m is 2 and n is 0, R, R a , R b , R c  and R d  are all hydrogen atoms, then R 1  is not hydrogen atom or ethoxycarbonyl group;     when m and n are both 0, R, R a , R b , R c  and R d  are all hydrogen atoms, then R 1  is not hydrogen atom, phenyl-oxazolidinone, quinoline, pyridobenzoxazine or naphthyridine group;        
 
         [0032]     when m and n are both 0, R is propyl, R a , R b , R c  and R d  are all hydrogen atoms, then R 1  is not phenyl-oxazolidinone group and 
        when m and n are both 0, R is hydroxy, methyl or ethyl group and R a , R b , R c  and R d  are all hydrogen atoms, then R 1  is not a methoxycarbonyl group;        
 
         [0034]     or a pharmaceutically acceptable salt thereof.  
         [0035]     The pyrrolo-pyrazole and pyrazolo-azepine derivatives of formula (I), object of the invention, are obtainable through a synthetic process comprising well known reactions carried out according to conventional techniques, as well as through an extremely versatile solid-phase and/or combinatorial process, being all comprised within the scope of the invention.  
         [0036]     The present invention also provides a pharmaceutical composition comprising the pyrrolo-pyrazole or pyrazolo-azepine derivatives of formula (I) and at least one pharmaceutically acceptable excipient, carrier or diluent.  
         [0037]     A more complete appreciation of the invention and many of the attendant advantages thereof will be readily obtained as the same becomes better understood by reference to the following detailed description. 
     
    
     DETAILED DESCRIPTION OF THE INVENTION  
       [0038]     The compounds of formula (I), object of the present invention, may have asymmetric carbon atoms and may therefore exist either as racemic admixtures or as individual optical isomers. Accordingly, all the possible isomers and their admixtures and of both the metabolites and the pharmaceutically acceptable bio-precursors (otherwise referred to as pro-drugs) of the compounds of formula (I), as well as any therapeutic method of treatment comprising them, are also within the scope of the present invention.  
         [0039]     As it will be readily appreciated, depending on the values of m and n, the ring condensed to the pyrazole may consist of 5 or 7 atoms; as to the pyrazole ring, two isomers are possible and therefore the R 2  substituent may be on one of the two nitrogens. Accordingly, in the present invention and unless otherwise indicated, the general formula I comprises the compounds of formula IA, IB, IC, ID, IE and IF:  
                         
 
         [0040]     wherein R, R 1 , R 2 , R a , R b , R c  and R d  are as defined above.  
         [0041]     As used herein, unless otherwise specified, with the term straight or branched C 1 -C 6  alkyl , we intend a group such as, for instance, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, neopentyl, n-hexyl, isohexyl, and the like.  
         [0042]     With the term aryl we intend an aromatic carbocycle such as, for instance, phenyl, biphenyl, 1-naphthyl, 2-naphthyl, and the like. Clearly, aryl groups may also refer to aromatic carbocyclic further fused or linked to non aromatic heterocyclic rings, typically 5 to 7 membered heterocycles.  
         [0043]     With the term heterocyclyl, hence encompassing aromatic heterocycles, we further intend a saturated or partially unsaturated 5 to 7 membered carbocycle wherein one or more carbon atoms are replaced by heteroatoms such as nitrogen, oxygen and sulphur, for instance, 1,3-dioxolane, pyran, thiophene, furan, pyrrole, imidazole, pyrazole, thiazole, isothiazole, oxazole, isoxazole, pyridine, pyrazine, pyrimidine, pyridazine, pyrrolidine, pyrroline, imidazolidine, imidazoline, piperidine, piperazine, morpholine, tetrahydrofurane, tetrahydropyran, tetrahydrothiopyran, imidazolidine, pyrazolidine, pyrazoline, piperidine, azabicyclononane and the like.  
         [0044]     Also the heterocycles may be optionally fused and, unless otherwise indicated, we intend any of the above defined heterocycles further condensed, through any one of the available bonds, with 5- or 6-membered, saturated or unsaturated heterocyclyl ring, or to a C 3 -C 6  cycloalkyl ring, or to a benzene or naphthalene ring such as, for instance, quinoline, isoquinoline, chroman, chromene, thionaphthalene, indoline, and the like.  
         [0045]     With the term C 2 -C 6  alkenyl, we intend a straight or branched alkenyl group such as vinyl, allyl, crotyl, 2-methyl-1-propenyl, 1-methyl-1-propenyl, butenyl, pentenyl. The C 2 -C 6  alkynyl group is a straight or branched alkynyl group such as ethynyl, propargyl, 1-propynyl, 1-butynyl, 2-butynyl.  
         [0046]     With the term saturated or unsaturated C 3 -C 6  cycloalkyl group we intend, for instance, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl cyclohexenyl, and the like. Unless otherwise specified, saturated or unsaturated cycloalkyl groups can be further condensed with 1 or 2 benzene rings are, for instance, 1,2,3,4tetrahydro-naphthalene-2-yl, fluorene-9-yl, and the like.  
         [0047]     The term “C 5 -C 8  (hetero)cycloalkyl” as used herein refers to a 5- to 8-membered, substituted or unsubstituted, saturated or unsaturated heterocyclyl ring, containing at least one boro and two oxygen atoms, any ring carbon may be oxidized as a carbonyl, and wherein said ring may be optionally fused to a second 5- or 6-membered, saturated or unsaturated heterocyclyl ring, or to a C 3 -C 7  cycloalkyl ring, or to a benzene or naphthalene ring.  
         [0048]     The term “aryl C 1 -C 6  alkyl” refer to a straight or branched chain alkyl moiety having from 1 to 6 carbon atoms substituted with at least one aryl group as defined above, such as, for instance, benzyl, phenylethyl, benzhydryl, benzyloxy and the like. The “aryl C 2 -C 6  alkenyl group” is an alkenyl group of 2 to 6 carbon atoms linked to a monocyclic or bicyclic aromatic hydrocarbon group of 6 to 10 carbon atoms. Examples of aryl alkenyl groups are styryl, 2-phenyl-1-propenyl, 3-phenyl-2-butenyl, 2-naphthylethenyl.  
         [0049]     The “aryl C 2 -C 6  alkynyl group” is an alkynyl group of 2 to 6 carbon atoms linked to a monocyclic or bicyclic aromatic hydrocarbon group of 6 to 10 carbon atoms. Examples of aryl alkynyl groups are 2-phenylethynyl, 2-naphthylethynyl.  
         [0050]     The (heterocyclyl) C 1 -C 6  alkyl group is an alkyl group of 1 to 6 carbon atoms linked to a heterocyclyl group. The (heterocyclyl) C 2 -C 6  alkenyl group is an alkenyl group of 2 to 6 carbon atoms linked to a heterocyclic group. The (heterocyclyl) C 2 -C 6  alkynyl group is an alkynyl group of 2 to 6 carbon atoms linked to a heterocyclic group.  
         [0051]     From all of the above, it is clear to the skilled man that any of the groups or substituents being defined, for instance, as arylalkyl, alkoxy, cycloalkoxy, aryloxy, arylalkyloxy and the like, have to be construed from the names of the groups from which they originate.  
         [0052]     As an example, unless specifically noted otherwise, any arylalkyloxy group has to be intended as an alkyloxy wherein the alkyl moiety is substituted by at least one aryl, both aryl and alkyl being as above defined.  
         [0053]     With the term halogen atom, we intend fluoro, bromo, chloro or iodo atom.  
         [0054]     The term “optionally substituted” means that the group may be substituted or unsubstituted; the substituents which may be present in the alkyl, cycloalkyl, aryl, arylalkyl, arylalkenyl, arylalkyl, alkoxy, aryloxy, cycloalkoxy, alkenyl, alkynyl or heterocyclyl groups in any of the above definitions include the following:  
         [0055]     halo (i.e., fluoro, bromo, chloro or iodo);  
         [0056]     hydroxy,  
         [0057]     oxo (i.e.,═O);  
         [0058]     nitro;  
         [0059]     azido;  
         [0060]     mercapto (i.e., —SH), and acetyl or phenylacetyl esters thereof (i.e., —SCOCH 3  and —SCOCH 2 C 6 H 5 );  
         [0061]     amino (i.e., —NH2 or —NHR I  or —NR I R II , wherein R I  and R II , which are the same or different, are straight or branched C 1 -C 6  alkyl, phenyl, biphenyl (i.e., —C 6 H 4 —G 6 H 5 ), or benzyl groups, optionally substituted by hydroxy, methoxy, methyl, amino, methylamino, dimethylamino, chloro or fluoro; or R I  and R II  taken together with the nitrogen atom to which they are attached form a heterocyclic ring such as morpholino, pyrrolidino, piperidino, pyperazino or N-methylpyperazino;  
         [0062]     guanidino, i.e., —NHC(═NH)NH 2 ;  
         [0063]     formyl (i.e. —CHO);  
         [0064]     cyano;  
         [0065]     carboxy (i.e. —COOH), or esters thereof (i.e., —COOR I ), or amides thereof (i.e., —CONH 2 , —CONHR I  or —CONHR I R II ), wherein R I  and R II  are as defined above, and including morpholino-amides, pyrrolidino-amides, and carboxymethylamides —CONHCH 2 COOH;  
         [0066]     sulfo (i.e., —SO 3 H);  
         [0067]     acyl, i.e., —C(O)R I , wherein R I  is as defined above, including monofluoroacetyl, difluoroacetyl, trifluoroacetyl;  
         [0068]     carbamoyloxy (i.e., —OCONH 2 ) and N-methylcarbamoyloxy,  
         [0069]     acyloxy, i.e., —OC(O)R I  wherein R I  is as defined above, or formyloxy,  
         [0070]     acylamino, i.e., —NHC(O)R I , or —NHC(O)OR I , wherein R I  is as defined above or is a group —(CH 2 ) t COOH where t is 1, 2 or3;  
         [0071]     ureido, i.e., —NH(CO)NH 2 , —NH(CO)NHR I , —NH(CO)NR I R II , wherein R I  and R II  are as defined above, including —NH(CO)-(4morpholino), —NH(CO)—(1-pyrrolidino), —NH(CO)—(1-piperazino), —NH(CO)-(4-methyl-1-piperazino);  
         [0072]     sulfonamido, i.e., —NHSO 2 R I  wherein R I  is as defined above;  
         [0073]     a group —(CH 2 ) t COOH, and esters and amides thereof, i.e., —(CH 2 ) t COOR I  and —(CH 2 ) t CONH 2 , —(CH 2 ) t CONHR I , —CH 2 ) t CONR I  R II , wherein t, R I  and R II  are as defined above;  
         [0074]     a group —NH(SO 2 )NH 2 , —NH(SO 2 )NHR I , —NH(SO 2 )NR I R II , wherein R I  and R II  are as defined above, including —NH(SO 2 )-(4morpholino), —NH(SO 2 )(1-pyrrolidino), —NH(SO 2 )(1-piperazino), —NH(SO 2 )-(4methyl-1-piperazino);  
         [0075]     a group —OC(O)OR I , wherein R I  is as defined above;  
         [0076]     a group —OR I , wherein R I  is as defined above, including —OCH 2 COOH;  
         [0077]     a group —O—CH 2 —O—, methylendioxy or —O—CH 2 — CH 2 —O—, ethylendioxy,  
         [0078]     a group —SR I , wherein R I  is as defined above, including —SCH 2 COOH;  
         [0079]     a group —S(O)R I , wherein R I  is as defined above;  
         [0080]     a group —S(O 2 )R I , wherein R I  is as defined above;  
         [0081]     a group —SO 2 NH 2 , —SO 2 NHR I , or —SO 2 NR I R II , wherein R I  and R II  are as defined above;  
         [0082]     C 1 -C 6  alkyl or C 2 -C 6  alkenyl;  
         [0083]     C 3 -C 7  cycloalkyl;  
         [0084]     substituted methyl selected from chloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, aminomethyl, N,N-dimethylaminoethyl, azidomethyl, cyanomethyl, carboxymethyl, sulfomethyl, carbamoylmethyl, carbamoyloxymethyl, hydroxymethyl, methoxycarbonylmethyl, ethoxycarbonylmethyl, tert-butoxycarbonylmethyl and guanidinomethyl.  
         [0085]     When present, carboxy, hydroxy, mercapto and amino groups may be either free or in a protected form. Protected forms of said groups are any of those generally known in the art.  
         [0086]     Preferably, carboxy groups are protected as esters thereof, in particular methyl, ethyl, tert-butyl, benzyl, and 4nitrobenzyl esters. Preferably, hydroxy groups are protected as silyl-ethers, ethers or esters thereof, in particular trimethyl silyl, tert-butyldiphenyl silyl, triethyl silyl, triisopropyl silyl or tert-butyldimethylsilyl ethers, methoxymethyl ethers, tetrahydropyranyl ethers, benzyl ethers, acetates or benzoates. Preferably, mercapto groups are protected as thioethers or thioesters, in particular tert-butyl thioethers, thioacetates or thiobenzoates. Preferably, amino groups are protected as carbamates, e.g. tert-butoxycarbonyl derivatives, or as amides, e.g. acetamides and benzamides.  
         [0087]     Furthermore, hydrates, solvates of compounds of formula (I), and physiologically hydrolyzable derivatives (i.e., prodrugs) of compounds of formula (I) are included within the scope of the present invention.  
         [0088]     Pharmaceutically acceptable salts of the compounds of formula (I) are the acid addition salts with inorganic or organic, e.g. nitric, hydrochloric, hydrobromic, sulphuric, perchloric, phosphoric, acetic, trifluoroacetic, propionic, glycolic, lactic, oxalic, malonic, malic, maleic, tartaric, citric, benzoic, cinnamic, mandelic, methanesulphonic, isethionic and salicylic acid, as well as the salts with inorganic or organic bases, e.g. alkali or alkaline-earth metals, especially sodium, potassium, calcium or magnesium hydroxides, carbonates or bicarbonates, acyclic or cyclic amines, preferably methylamine, ethylamine, diethylamine, triethylamine or piperidine.  
         [0089]     Preferred compounds of formula (I) are the compounds wherein R is H, I, Br, Cl, F, aryl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, —B(OR′″) 2 , —COR′, —CONR′R″, —CN, SO 2 R′, OR′, SR′, and R 1  is H, C 1 -C 6  alkyl, aryl, —COR′, —CONR′R″, —COOR′, —SO 2 R′, or —SO 2 NR′R″, and R 2  is H, —COOR′, —COR′, —CONR′R″, C 1 -C 6  alkyl, —SO 2 R′, or —SO 2 NR′R″, (heterocyclyl) C 1 -C 6  alkyl group , wherein R′ and R″, the same or different, are selected from hydrogen or optionally substituted straight or branched C 1 -C 6  alkyl, aryl or aryl C 1 -C 6  alkyl groups;  
         [0090]     R a , R b , R c  and R d , the same or different, are selected from hydrogen or straight or branched C 1 -C 3  alkyl or, taken together with the carbon atom to which they are bonded form a C 3 -C 6  cycloalkyl group.  
         [0091]     Other preferred compounds of formula (I) are the compounds wherein R is selected from aryl, heterocyclyl, —COR′, —CONR′R″, wherein R′ and R″, the same or different, are selected from hydrogen or optionally substituted straight or branched C 1 -C 6  alkyl, aryl or aryl C 1 -C 6  alkyl groups.  
         [0092]     Other preferred compounds of formula (I) are the compounds wherein R 1  is selected from H, C 1 -C 6  alkyl, aryl, —COR′, —CONR′R″, COOR′, —SO 2 R′ or —SO 2 NR′R″, wherein R′ and R″, the same or different, are selected from hydrogen or optionally substituted straight or branched C 1 -C 6  alkyl, aryl or aryl C 1 -C 6  alkyl groups.  
         [0093]     Another preferred class of compounds of formula (I) are the compounds wherein R 2  is H, —COOR′, —CONR′R″, C 1 -C 6  alkyl, wherein R′ and R″, the same or different, are selected from hydrogen or optionally substituted straight or branched C 1 -C 6  alkyl, aryl or aryl C 1 -C 6  alkyl groups.  
         [0094]     As formerly indicated, it is a further object of the invention a process for preparing the compounds of formula (I) and pharmaceutically acceptable salts thereof  
       General Reaction Scheme  
       [0095]    
       
                 
         
             
             
         
       
     
         [0096]     In particular, the present invention provides a process which comprises:  
         [0097]     a) submitting a compound of formula (II)  
                         
 
         [0098]     wherein R 1  is as defined above but not hydrogen, and R a , R b , R c , R d , R 2 , m and n are as defined above, to diazotation and subsequent appropriate quenching, thus obtaining a compound of formula (I)  
                         
 
         [0099]     wherein R 1  is as defined above but not hydrogen; R a , R b , R c , R d , R 2 , m and n are as defined above, and R is hydrogen, iodine, bromine, chlorine or fluorine atom or a CN group;  
         [0100]     b1) converting a thus obtained compound of formula (I) wherein R is L Br, Cl into another compound of formula (I) wherein R is an optionally substituted aryl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, —SR′, —OR′ or —COR′ wherein R′ is as defined above;  
         [0101]     b2) converting a compound of formula (I) wherein R is hydrogen into another compound of formula (I) wherein R is —B(OR′″) 2 , —SnR″″, —COOR′, —COR′, C 1 -C 6  alkyl or iodine, wherein R′, R′″ and R″″ are as defined above;  
         [0102]     c) converting a compound of formula (I) wherein R is —B(OR′″) 2  or —SnR″″ as above defined into another compound of formula (I) wherein R is an optionally substituted aryl C 2 -C 6  alkenyl, C 2 -C 6  alkynyl;  
         [0103]     d) optionally converting a compound of formula (I) into another different compound of formula (I), and, if desired, converting a compound of formula (I) into a pharmaceutically acceptable salt thereof or converting a salt into the free compound (I).  
         [0104]     The above process can be carried out according to well known methods. It is clear to the person skilled in the art that if a compound of formula (I), prepared according to the above process, is obtained as an admixture of isomers, their separation into the single isomers of formula (I), carried out according to conventional techniques, is still within the scope of the present invention.  
         [0105]     Likewise, the salification of a compound of formula (I) or the conversion of its salt into the free compound (I) carried out according to well-known procedures in the art, are still within the scope of the invention.  
         [0106]     According to a preferred aspect of the process of the invention avoiding the unwanted by-products formation, a compound of formula (I), obtained according to step a above, could be first supported onto a suitable solid support, such as resin and then, after the reactions as per steps b1, b2, c and d above described, reconverted into a compound of formula (I).  
                         
 
         [0107]     It is therefore a further object of the invention a process for preparing a compound of formula (I) as defined above, which process comprises:  
         [0108]     either  
         [0109]     b1a) converting a compound of formula (I) into another compound of formula (I) wherein R has the above reported meanings resulting from step b1 and R 1 , R a , R b , R c , R d , m and n are as defined above analogously to step b1 above described and  
         [0110]     Pa) reacting the resultant compound of formula (I) wherein R, R a , R b , R c , R d , m and n are as defined above, R 1  is as described above but not hydrogen and R 2  is hydrogen, with a suitable solid support so as to obtain a compound of formula (III)  
                         
 
         [0111]     wherein R, R a , R b , R c , R d , m and n are as defined above, R 1  is as defined above but not hydrogen, and Q is a solid support, or  
         [0112]     P) reacting a compound of formula (I) wherein R, R a , R b , R c , R d , m and n are as defined above, R 1  is as defined above but not hydrogen and R 2  is hydrogen, with a suitable solid support so as to obtain a compound of formula (III) as defined above and  
         [0113]     B) then, analogously to steps b1, b2, c and d above described, optionally converting a thus obtained compound of formula (III) into another compound of formula (III) wherein R has the above reported meanings for steps b1, b2, c and d and R 1 , R a , R b , R c , R d , m and n are as defined above;  
         [0114]     D) cleaving the resultant compound of formula (III) so as to eliminate the solid support and to obtain the desired compound of formula (I);  
         [0115]     E) optionally converting a compound of formula (I) into another different compound of formula (I),  
         [0116]     and, if desired, converting a compound of formula (I) into a pharmaceutically acceptable salt thereof or converting a salt into the free compound (I) as described above.  
         [0117]     It is a further object of the present invention to provide useful intermediates of formula III  
                         
 
         [0118]     wherein R, R 1  R a , R b , R c , R d , m and n are as defined above, and Q is a solid support, more preferably a residue derived from a resin selected from the group consisting of isocyanate polystyrenic resin, 2-chloro-trityl chloride resin, trityl chloride resin, p-nitrophenyl carbonate Wang resin and the bromo-4-methoxyphenyl)methyl polystyrene. A process for the preparation of a compound of formula (III) as defined above is also provided, which process comprises:  
         [0119]     either  
         [0120]     b1a) converting a compound of formula (I) into another compound of formula (I) wherein R has the above reported meanings resulting from step b1 and R 1 , R a , R b , R c , R d , m and n are as defined above, analogously to step b1 above described and  
         [0121]     Pa) reacting the resultant compound of formula (I) wherein R, R a , R b , R c , R d , m and n are as defined above, R 1  is as defined above but not hydrogen and R 2  is hydrogen, with a suitable solid support so as to obtain a compound of formula (III)  
                         
 
         [0122]     wherein R, R a , R b , R c , R d , m and n are as defined above, R 1  is as defined above but not hydrogen, and Q is a solid support, or  
         [0123]     P) reacting a compound of formula (I) wherein R, R a , R b , R c , R d , m and n are as defined above, R 1  is as described above but not hydrogen and R 2  is hydrogen, with a suitable solid support so as to obtain a compound of formula (III) as defined above and  
         [0124]     B) then, analogously to steps b1, b2, c and d above described, optionally converting a thus obtained compound of formula (III) into another compound of formula (III) wherein R has the above reported meanings for steps b1 to d and R 1 , R a , R b , R c , R d , m and n are as defined above.  
         [0125]     According to step a) of the process, a compound of formula (I) wherein R is hydrogen, I, Br, Cl, F, CN, and R 1  is as defined above but not hydrogen, and R a , R b , R c , R d , R 2 , m and n are as defined above, may be prepared by reacting a compound of formula (II), wherein R 1  is as defined above but not hydrogen, and R a , R b , R c , R d , R 2 , m and n are as defined above, with organic or inorganic nitrates such as sodium nitrate or isopentylnitrate, in the presence of a suitable hydrogen source, such as HPO 2 , thiophenol, sodium stannite, Bu 3 SnH, Et 3 SiH, or of a suitable halogenating or cyanating agent such as tetrabutylamonium iodide and/or iodine, tetrabutylamonium bromide and/or bromine, tetrabutylamonium chloride and/or chlorine, CuBr, CuCl, CuI, CuCN, sodium tetrafluoroborate, ammonium tetrafluoroborate, in aqueos acidic solution at various concentrations such as diluted chloridic acid or diluted citric acid, or in organic solvents such as tetrahydrofurane, 1,4-dioxan, dichloromethane, chloroform, toluene, acetonitrile, ethylacetate, acetone, dimethylformamide, ethanol, methanol water at a temperature ranging from about −78° C. to reflux, for a suitable time ranging from 5 min to 72 hours. More preferably, the step a) is carried out on compounds of the formula (II) wherein R 2  is not hydrogen atom.  
         [0126]     According to step b1) of the process, a compound of formula (I) wherein R is an optionally substituted aryl or C 2 -C 6  alkenyl group, and R 1 , R 2 , R a , R b , R c , R d , m and n are as defined above, can be obtained by reacting a compound of formula (I), wherein R is halogen atom, and R 1 , R 2 , R a , R b , R c , R d , m and n are as defined above, with a suitable aryl boronic acid or ester, alkenyl boronic acid or ester, arylstannane, in the presence of a suitable catalysing agent such as palladium(0)tetrakis, bis triphenylphosphine palladium(II) dichloride, bis tricyclohexylphosphine palladium(II) dichloride, bis tri-o-tolylphosphine palladium(II) dichloride, palladium(II) acetate, tris(dibenzylideneacetone)dipalladium(0), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), [1,1′-bis(diphenylphosphino)ferrocene]dichloronickel(II), 1,4-bis(diphenylphosphino)butane palladium(II), and of a suitable base such as sodium carbonate, cesium carbonate, potassium carbonate, potassium phosphate, triethylamine, sodium hydroxide, cesium fluoride, potassium tert-butylate, sodium ethylate, potassium acetate, in a suitable solvent, such as 1,4dioxan, tetrahydrofurane, DMF (N,N-dimethylformamide), dimethoxyethane, toluene, methanol, ethanol, water, N-methylpyrrolidone, and, when needed, adding a suitable ligand, such as tributylphosphine, triphenylphosphine, tri-o-tolylphosphine, tricyclohexyl, biphenyl(dicyclohexyl)phosphine, biphenyl(ditert-butyl)phosphine, diphenylphosphine ferrocene, and/or Cu(I) salts such as CuI, Cu(I)thiophene-2-carboxylate at a temperature ranging from room temperature to reflux, for a suitable time ranging from 15 minutes to 72 hours.  
         [0127]     According to step b1) of the process, a compound of formula (I) wherein R is an optionally substituted C 1 -C 6  alkynyl, and R 1 , R 2 , R a , R b , R c , R d , m and n are as defined above, can be obtained by reacting a compound of formula (I), wherein R is halogen, and R 1 , R 2 , R a , R b , R c , R d , m and n are as defined above, with a suitable alkyne under the condition of the Sonogashira&#39;s reaction, in the presence of a suitable catalysing agent such as bistriphenylphosine palladium(II) dichloride, palladium(0) tetrakis, palladium(II) acetate, tris(dibenzylideneacetone)dipalladium(0), and of a suitable Cu(I) salt, such as CuI, and in presence of a suitable base such as sodium carbonate, potassium carbonate, cesium carbonate, potassium phosphate, triethylamine, diisopropylamine, pyridine, in a suitable solvent, such as 1,4-dioxan, tetrahydrofurane, DMF, dimethoxyethane, toluene, ethanol, methanol, and, if needed, adding a suitable ligand such as triphenylphosphine, tri-o-tolylphosphine, tricyclohexyl, diphenylphosphineferrocene, at a temperature ranging from room temperature to reflux, for a suitable time ranging from 15 minutes to 72 hours.  
         [0128]     According to step b1) of the process, a compound of formula (I) wherein R is SR′, OR′, and R 1 , R 2 , R a , R b , R c , R d , R′, m and n are as defined above, can be obtained by reacting a compound of formula (I), wherein R is halogen, and R 1 , R 2 , R a , R b , R c , R d , m and n are as defined above, with a suitable alcohol or thiol R′OH or R′SH wherein R′ is as above defined, in the presence of a suitable base, such as potassium carbonate, sodium carbonate, cesium carbonate, potassium hydroxide, sodium hydroxide, sodium hydride, sodium methylate, sodium tert-butylate, diisopropylethylamine, pyridine, piperidine, N-methylmorpholine, dimethylaminopyridine, and, if needed, in the presence of catalysing agent, such as bis tricyclohexylphosphine palladium(II) dichloride, bis tri-o-tolylphosphine palladium(II) dichloride, palladium(II) acetate, tris(dibenzylideneacetone)dipalladium(0), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), and of a suitable ligand, such as, triphenylphosphine, tri-o-tolylphosphine, tricyclohexyl, diphenylphosphineferrocene, in a suitable solvent, such as dimethylformamide, NMP, dichloromethane, tetrahydrofurane, benzene, toluene, pyridine, dimethylsulfoxide at a temperature ranging from −20° C. to reflux, for a suitable time ranging from 15 minutes to 72 hours.  
         [0129]     According to step b1) of the process, a compound of formula (I) wherein R is —COR′, and R 1 , R 2 ; R a , R b , R c , R d , m and n are as defined above, can be obtained by reacting a compound of formula (I) wherein R is halogen and R 1 , R 2 , R a , R b , R c , R d , m and n are as defined above, with a suitable base, such as n-butyl lithium, LDA (lithium diisopropylamide), sec-butyl lithium, t-butyl lithium, lithium 2,2,6,6-tetramethylpiperidin amide, phenyl lithium, magnesium, isopropylmagnesium bromide in a suitable solvent, such as diethyl ether, tetrahydrofurane, 1,4dioxan, n-hexane, cyclohexane, pentane, toluene, DME (ethylene glycol dimethyl ether), dimethylsulfoxide in the presence of a base if needed, such as TMEDA (N,N,N′,N′-tetramethylethylenediamine), at a suitable temperature ranging from −78° C. to room temperature, for a time ranging from 15 minutes to 3 hours; the resulting lithium derivative can be quenched with a suitable electrophilic agent, such as, trialkylarylstannane/carbon monoxide, acid chlorides, acid fluorides, acid bromides, anhydrides, carbonates, halo carbonates, carbamates, DMF, and if needed, in the presence of a suitable catalysing agent, such as Pd(0)tetrakis, and of a suitable coordinating agent, such as ZnCl 2 , ZnBr 2 , CuCN.2LiCl, CuI CuBr, CuBr.SMe 2  at a suitable temperature ranging from about −78° C. to reflux, for a time ranging from 15 minutes to about 72 hours.  
         [0130]     According to step b2) of the process, a compound of formula (I) wherein R is iodine, B(OR′″) 2 , SnR″″, —COOR′, —COR′, C 1 -C 6  alkyl and R 1 , R 2 , R a , R b , R c , R d , R′, R′″, R″″, m and n are as defined above, can be obtained by reacting a compound of formula (I) wherein R is hydrogen and R 1 , R 2 , R a , R b , R c , R d , m and n are as defined above, with a suitable lithiating agent, such as n-butyl lithium, LDA, sec-butyl lithium, t-butyl lithium, lithium 2,2,6,6-tetramethylpiperidinamide, phenyl lithium, in a suitable solvent, such as diethyl ether, tetrahydrofurane, 1,4-dioxan, n-hexane, cyclohexane, toluene, DME, dimethylsulfoxide in the presence of a base if needed, such as TMEDA, at a suitable temperature ranging from −78° C. to room temperature, for a time ranging from 15 minutes to 3 hours; the resulting lithium derivative can be quenched with a suitable electrophilic agent, such as trialkyl boronic esters, trialkylstannyl chloride, acid chlorides, acid fluorides, acid bromides, anhydrides, carbonates, halo carbonates, DMF, iodine, aldehydes, ketones, alkyl halides, in the presence of a suitable coordinating agent, such as ZnCl 2 , ZnBr 2 , CuCN.2LiCl, CuI, CuBr, CuBr.SMe 2  when needed, at a suitable temperature ranging from about −78° C. to reflux, for a time ranging from 15 minutes to about 72 hours.  
         [0131]     According to step c) of the process, a compound of formula (I) wherein R is an optionally substituted aryl or C 1 -C 6  alkenyl group and R 1 , R 2 , R a , R b , R c , R d , m and n are as defined above, can be obtained by reacting a compound of formula (I) wherein R is B(OR′″) 2 , SnR″″, and R 1 , R 2 , R a , R b , R c , R d , R′″, R″″, m and n are as defined above, with a suitable aryl halide or halogeno olefine, in the presence of a suitable catalysing agent such as as palladium(0)tetrakis, bis triphenylphosphine palladium(II) dichloride, bis tricyclohexylphosphine palladium(II) dichloride, bis tri-o-tolylphosphine palladium(II) dichloride, palladium(II) acetate, tris(dibenzylideneacetone)dipalladium(0), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), [1,1′-bis(diphenylphosphino)ferrocene]dichloronickel(II), 1,4bis(diphenylphosphino)butane palladium(II), as sodium carbonate, cesium carbonate, potassium carbonate, potassium phosphate, triethylamine, sodium hydroxide, cesium fluoride, potassium tert-butylate, sodium ethylate, potassium acetate, in a suitable solvent, such as 1,4-dioxan, tetrahydrofurane, DMF, dimethoxyethane, toluene, methanol, ethanol, water, N-methylpyrrolidone and, if needed, adding a suitable ligand, such as tributylphosphine, triphenylphosphine, tri-o-tolylphosphine, tricyclohexyl, biphenyl(dicyclohexyl)phosphine, biphenyl(ditert-butyl)phosphine, diphenylphosphineferrocene, and/or a suitable Cu(I) salts, such as CuI, Cu(I)thiophene-2-carboxylate at a temperature ranging from room temperature to reflux, for a suitable time ranging from 15 minutes to 72 hours.  
         [0132]     According to step c) of the process, a compound of formula (I) wherein R is an optionally substituted C 2 -C 6  alkynyl, and R 1 , R 2 , R a , R b , R c , R d , m and n are as defined above, can be obtained by reacting a compound of formula (I) wherein R is B(OR′″) 2 , SnR″″, and R 1 , R 2 , R a , R b , R c , R d , R′″, R″″, m and n are as defined above, with a suitable 1-alkyl(aryl)thio-alkyne, 1-iodo(bromo)alkyne, or 1,1-dibromo-1-alkene, in the presence of a suitable catalysing agent such as as palladium(0)tetrakis, bis triphenylphosphine palladium(II) dichloride, bis tricyclohexylphosphine palladium(II) dichloride, bis tri-o-tolylphosphine palladium(II) dichloride, palladium(II) acetate, tris(dibenzylideneacetone)dipalladium(0), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), [1,1′-bis(diphenylphosphino)ferrocene]dichloronickel(E), 1,4-bis(diphenylphosphino)butane palladium(II) in a suitable solvent, such as 1,4-dioxan, tetrahydrofurane, DMF, dimethoxyethane, toluene, methanol, ethanol, water, N-methylpyrrolidone and, if needed, adding a suitable ligand, such as tributylphosphine, triphenylphosphine, tri-o-tolylphosphine, tricyclohexyl, biphenyl(dicyclohexyl)phosphine, biphenyl(ditert-butyl)phosphine, diphenylphosphineferrocene, and/or a suitable Cu(I) salts, such as CuI, Cu(I)thiophene-2-carboxylate at a temperature ranging from room temperature to reflux, for a suitable time ranging from 15 minutes to 72 hours.  
         [0133]     According to steps P and Pa of the process, a compound of formula (III) wherein R, R a , R b , R c , R d , m and n are as described above, R 1  is as described above but not hydrogen and Q is a solid support can be obtained by reacting a compound of formula (I) wherein R, R a , R b , R c , R d , m and n are as described above, R 1  is as described above but not hydrogen and R 2  is hydrogen (step P) or different from hydrogen (step Pa), with a suitable solid support such as a polymeric support like isocyanate polystyrenic resin, 2-chloro-trityl chloride resin, trityl chloride resin, p-nitrophenyl carbonate Wang resin, bromo-4-methoxyphenyl)methyl polystyrene or the like, which are all conventionally known in this field, in the presence, when needed, of a suitable base, such as diisopropylethylamine, triethylamine, 1,8-diazabiciclo[5.4.0]undec-7-ene or 2-tert-buytlimino-2-diethylamino-1,3-dimethylperhydro -1,3,2-diaza-phosphorine, in a suitable solvent such as dichloromethane, chloroform, tetrahydrofurane, dimethylformamide, dimethylacetamide, 1-methyl-2-pyrrolidinone, dimethylsulfoxide and the like, at a temperature ranging from room temperature to 50° C., for a suitable time ranging from 10 minutes to 90 hours.  
         [0134]     According to step b1 a) of the process, a compound of formula (I) may be converted into a different compound of formula (I) by steps analogous to the steps b1) herein described for the conversion of a compound of the formula (I) into a different compound of formula (I).  
         [0135]     According to step B of the process, a compound of formula (III) may be converted into a different compound of formula (III) by steps analogous to the steps b1), b2), c) and d) herein described for the conversion of a compound of the formula (I) into a different compound of formula (I).  
         [0136]     According to step D of the process, a compound of formula (I) wherein R, R a , R b , R c , R d , m and n are as described above, R 1  is as described above and R 2  is hydrogen, can be obtained by cleaving a compound (III) wherein R, R a , R b , R c , R d , m and n are as described above, R 1  is as described above and Q is a solid support, according to conventional hydrolytic methods in the presence of a suitable acid, such as hydrochloric acid, acetic acid, trifluoroacetic acid, hydrofluoric acid, or in the presence of a suitable base, such as sodium hydroxide, potassium hydroxide, sodium carbonate, sodium hydrogencarbonate, piperidine, or in the presence of other hydrolytic agents, such as tetrabutyl ammoniumfluoride, trimethyl silylchloride, in a suitable solvent such as dichloromethane, chloroform, methanol, ethanol, trifluoroethanol, dioxan, at a temperature ranging from room temperature to 70° C., for a suitable time ranging from 10 minutes to 90 hours. R 2  is According to step E of the process, a compound of formula (I) wherein R, R a , R b , R c , R d , m and n are as described above, R 1  is as described above and R 2  is hydrogen may be converted into another different compound of formula (I), the conversion being carried out in several ways, depending on the meanings of the substituents and the presence of other substituents in the molecule. For example, by this conversion a compound of formula (I) wherein R 2  is as defined above but not hydrogen may be obtained.  
         [0137]     According to step d) of the process, the conversion of a compound of formula (I) into another different compound of formula (I) may be carried out in several ways, depending on the meanings of the substituents and the presence of other substituents in the molecule. For example, a conversion can be a hydrolysis, a reductive amination, an arylation, an alkylation, an amination, a nucleophilic substitution, a catalytic reduction, an oxidation, a reduction, a condensation with an appropriate reagent or a combination of these reactions.  
         [0138]     As an example, the compounds of formula (I) or (III), wherein R 1  is —COO t Bu can be hydrolized to the corresponding compounds of formula (I) wherein R 1  is H, by treatment with a suitable acid, for instance trifluoroacetic or hydrochloric acid  
         [0139]     So far, any of the above compounds of formula (I) or (III) wherein R 1  is a hydrogen atom can be easily converted into the corresponding derivatives alkylated, acylated, sulfonated or arylated. The reactions are carried out according to conventional techniques, for instance by properly reacting the amino derivative (1) or (III) wherein R 1  is hydrogen with alkylating, acylating, sulfonylating or arylating agents and the like.  
         [0140]     In particular, a compound of formula (I) or (III) wherein R 1  is selected from R′ other than hydrogen, —COR′, —COOR′, —CONR′R″, —SO 2 R′, or —SO 2 NR′R″, wherein R′ and R″ have the above reported meanings; R, R 2  and R a , R b , R c , R d , m and n are as above defined, may be prepared by reacting a compound of formula (I) or a compound of formula (III), having R 1  equal to hydrogen, with a compound of formula (IV) 
 
R 1 —X   (IV) 
 
         [0141]     wherein R 1  is as above defined but not hydrogen and X is a suitable leaving group, preferably fluorine, chlorine, bromine or iodine.  
         [0142]     The above reaction can be carried out according to conventional procedures well known in the art for acylating, sulfonylating, alkylating or arylating amino groups, for instance in the presence of a suitable base, such as potassium carbonate, triethylamine, N,N-diisopropylethylamine or pyridine, in a suitable solvent such as dimethylsulfoxide, toluene, dichloromethane, chloroform, diethyl ether, tetrahydrofurane, acetonitrile, or N,N-dimethylformamide, at a temperature ranging from about −10° C. to reflux and for a time varying from about 30 minutes to about 96 hours.  
         [0143]     A compound of formula (I) or (III) wherein R 1  is an aryl group, R, R 2  and R a , R b , R c , R d , m and n are as above defined, may be prepared by reacting a compound of formula (I) or a compound of formula (III), having R 1  equal to hydrogen with a compound of formula (V) 
 
R 1 —X   (V) 
 
         [0144]     wherein R 1  is an aryl group and X is as above defined. The above reaction can be carried out according to conventional procedures well known in the art for arylating amino groups, for instance in the presence of a suitable catalyst when needed, such as palladium(0)tetrakis, bistriphenylphosphinePalladium(II)chloride, bis tricyclohexylphosphine palladium(II) dichloride, bis tri-o-tolylphosphine palladium(II) dichloride, palladium(II) acetate, tris(dibenzylideneacetone)dipalladium(0), [1,1′-bis(diphenylphosphino) ferrocene]dichloropalladium(II), as sodium carbonate, cesium carbonate, potassium carbonate, potassium phosphate, triethylamine, sodium hydroxide, cesium fluoride, potassium tert-butylate, sodium tert-butylate, sodium ethylate, potassium acetate, in a suitable solvent, such as 1,4dioxan, tetrahydrofurane, DMF, dimethilsulfoxide, dimethoxyethane, toluene, methanol, ethanol, water, N-methylpyrrolidone and adding a suitable ligand, such as tributylphosphine, triphenylphosphine, tri-o-tolylphosphine, tricyclohexyl, biphenyl(dicyclohexyl)phosphine, biphenyl(ditert-butyl)phosphine, diphenylphosphineferrocene, BINAP [(2,2′-bis(diphenylphosphino)-1,1′-binaphthyl], and adding, when needed a phase transfer catalysing agent, such as 18-crown-6, at a temperature ranging from room temperature to reflux, for a suitable time ranging from 15 minutes to 72 hours.  
         [0145]     From the foregoing it is clear to the person skilled in the art that the preparation of the compounds of formula (I) or (III) having R 1  equal to —SO 2 NR′R″ can be actually performed as above described or, alternatively, by properly reacting a compound of formula (I) or (III) having R 1  equal to —SO 2 NHR′ with any suitable alkylating moiety, according to well known methodologies for preparing di-substituted sulfonamides.  
         [0146]     A compound of formula (I) or (III) wherein R 1  is a —CONHR′ group, R′ has the above reported meanings other than hydrogen, R, R 2 , and R a , R b , R c , R d , m and n are as above defined, may be prepared by reacting a compound of formula (I) or a compound of formula (III) having R 1  equal to hydrogen, with a compound of formula (VI) 
 
R′—NCO   (VI) 
 
         [0147]     wherein R′ is as above defined but not hydrogen, so as to obtain a corresponding compound of formula (I) or (III) which may be optionally further reacted with a compound of formula (VII) 
 
R″—X   (VII) 
 
         [0148]     wherein R″ is as above defined other than hydrogen and X is as above defined, so as to obtain a compound of formula (I) or (III) wherein R 1  is —CONR′R″, wherein R′ and R″ are as above defined but not hydrogen atom.  
         [0149]     The reaction between the above compounds (I) or (III) with a compound of formula (VII) can be carried out in the presence of a tertiary base, such as triethylamine, N,N-diisopropylethylamine or pyridine, in a suitable solvent, such as toluene, dichloromethane, chloroform, diethyl ether, tetrahydrofurane, acetonitrile, or N,N-dimethylformamide, at a temperature ranging from about −10° C. to reflux and for a time varying from about 30 minutes to about 72 hours.  
         [0150]     The optional subsequent conversion of a compound of formula (I) or (III) having R 1  equal to —CONHR′ into a corresponding derivative having R 1  equal to —CONR′R″ is carried out according to conventional methods used to prepare di-substituted ureido derivatives.  
         [0151]     A compound of formula (I) or (III) wherein R 1  is a —CONR′R″ group, R′ and R″ has the above reported meanings other than hydrogen, R, R 2  and R a , R b , R c , R d , m and n are as above defined, may be prepared by reacting a compound of formula (I) or a compound of formula (III) having R 1  equal to hydrogen with 4-nitrophenylchloroformate and subsequently with a compound of formula (VIII) 
 
R′R″NH   (VIII) 
 
         [0152]     wherein R′ and R″ are as defined above but not hydrogen.  
         [0153]     The reaction is carried out according to conventional methods used to prepare di-substituted ureido derivatives.  
         [0154]     Alternatively, a compound of formula (I) or a compound of formula (III), having R 1  equal to hydrogen may be reacted under reductive conditions with a compound of formula (IX) 
 
R′—CHO   (IX) 
 
         [0155]     wherein R′ is as defined above but not hydrogen, so as to obtain a corresponding compound of formula (I) or (III) wherein R 1  is a —CH 2 R′ group and R′ being as defined above but not hydrogen.  
         [0156]     The reaction is carried out in a suitable solvent such as, for instance, N,N-dimethylformamide, N,N-dimethylacetamide, chloroform, dichloromethane, tetrahydrofurane, or acetonitrile, optionally in the presence of acetic acid, ethanol or methanol as co-solvents, at a temperature ranging from about −10° C. to reflux and for a time varying from about 30 min to about 4 days.  
         [0157]     Conventional reducing agents in the reaction medium are, for instance, sodium boron hydride, sodium triacethoxy boron hydride, and the like.  
         [0158]     In a further example, any of the above compounds of formula (I) or of formula (III) wherein one or more of R a , R b , R b  and R d  is —CH 2 OH may be conveniently prepared by starting from a corresponding protected derivative having one or more of R a , R b , R b  and R d  as —CH 2 —O—Si(Me) 2 tBu or —CH 2 —O—Ph.  
         [0159]     The reaction is carried according to conventional techniques, for instance in a suitable solvent such as, for instance, N,N-dimethylformamide, chloroform, dichloromethane, tetrahydrofurane, methanol, ethanol or acetonitrile, at a temperature ranging from about −10° C. to reflux and for a time varying from about 30 min to about 72 hours with a suitable fluoride source, for instance tetrabutylamonium fluoride.  
         [0160]     Likewise, the above compounds of formula (I) or (III) having one or more R a , R b , R c  and R d  equal to —CH 2 OH can be reacted with a compound of formula (VII′) 
 
R′—X   (VII′) 
 
         [0161]     wherein R′ is as above defined but not hydrogen and X is as above defined, so as to obtain the corresponding compounds wherein one or more R a , R b , R c  and R d  are a —CH 2 OR′ group, wherein R′ is as defined above but not hydrogen.  
         [0162]     This latter reaction can be carried out in the presence of a base, such as sodium hydride, N,N-diisopropylethylamine or pyridine, in a suitable solvent, such as toluene, dichloromethane, chloroform, diethyl ether, tetrahydrofurane, acetonitrile, or N,N-dimethylformamide, at a temperature ranging from about −10° C. to reflux.  
         [0163]     In an analogous manner, a compound of the formula I wherein R 2  is hydrogen may be converted into another compound of the formula I wherein R 2  is as defined above but not hydrogen atom.  
         [0164]     The starting compound of formula (II) are known or can be prepared starting from known compounds using known methods of preparation, for example those described in WO02/12242. As it will be really appreciated by the man skilled in the art, when preparing the compounds of formula (I) object of the invention, optional functional groups within both the starting materials or the intermediates thereof, which could give rise to unwanted side reactions, need to be properly protected according to conventional techniques. Likewise, the conversion of these latter into the free deprotected compounds may be carried out according to known procedures.  
         [0165]     The above cited reagents of the process, i.e. arylboronic acids, arylboronic esters, alkenylboronic acids, alkenylboronic esters, triarylstannanes, acid chlorides, acid fluorides, acid bromides, anhydrides, carbonates, halo carbonates, alkynes, aryl halides, halogeno alkenes and the compounds of formula (IV), (V), (VI), (VII), (VII′), (VIII) and (IX) are known or can be prepared according to known methods.  
         [0166]     As it will be also really appreciated by the man skilled in the art, when preparing the compounds of formula (I) object of the invention, according to steps a)-c), each of the above cited reactants can be replaced by the corresponding polymer-supported reactant.  
         [0167]     In addition to the above, it is also clear to the skilled man that the compounds of formula (I) of the invention can be advantageously prepared by combining the above described reactions in a combinatorial fashion, for example according to solid-phase-synthesis (SPS) techniques, so as to get a combinatorial chemical library of compounds of formula (I).  
         [0168]     It is therefore a further object of the invention a library of two or more compounds of formula (I):  
                         
 
         [0169]     wherein R, R 1 , R 2  R a , R b , R c , R d  m and n are as defined above, which can be obtained starting from one or more compound supported onto a solid support of the formula (III) as defined above.  
         [0000]     Pharmacology  
         [0170]     The compounds of formula (I) are active as protein kinase inhibitors and are therefore useful, for instance, to restrict the unregulated proliferation of tumor cells.  
         [0171]     In therapy, they may be used in the treatment of various tumors, such as those formerly reported, as well as in the treatment of other cell proliferative disorders such as psoriasis, vascular smooth cell proliferation associated with atherosclerosis and post-surgical stenosis and restenosis and in the treatment of Alzheimer&#39;s disease.  
         [0172]     The inhibiting activity of putative cdk/cyclin inhibitors and the potency of selected compounds is determined through a method of assay based on the use of the SPA technology (Amersham Pharmacia Biotech).  
         [0173]     The assay consists of the transfer of radioactivity labelled phosphate moiety by the kinase to a biotinylated substrate. The resulting 33P-labelled biotinylated product is allowed to bind to streptavidin-coated SPA beads (biotin capacity 130 pmol/mg), and light emitted was measured in a scintillation counter.  
         [0000]     Inhibition Assay of Cdk2/Cyclin A Activity  
         [0174]     Kinase reaction: 4 μM in house biotinylated histone H1 (Sigma #H-5505) substrate, 10 μM ATP (0.1 microCi P 33 γ-ATP), 1.1 nM Cyclin A/CDK2 complex, inhibitor in a final volume of 30 μl buffer (TRIS HCl 10 mM pH 7.5, MgCl 2  10 mM, DTT 7.5 mM+0.2 mg/ml BSA) were added to each well of a 96 U bottom. After incubation for 60 min at room temperature, the reaction was stopped by addition of 100 μl PBS buffer containing 32 mM EDTA, 500 μM cold ATP, 0.1% Triton X100 and 10 mg/ml streptavidin coated SPA beads. After 20 min incubation, 110 μL of suspension were withdrawn and transferred into 96-well OPTIPLATEs containing 100 μL of 5M CsCl. After 4 hours, the plates were read for 2 min in a Packard TOP-Count radioactivity reader.  
         [0175]     IC50 determination: inhibitors were tested at different concentrations ranging from 0.0015 to 10 μM. Experimental data were analyzed by the computer program GraphPad Prizm using the four parameter logistic equation: 
 
 y= bottom+(top-bottom)/(1+10ˆ((log IC50- x )*slope)) 
 
         [0176]     where x is the logarithm of the inhibitor concentration, y is the response; y starts at bottom and goes to top with a sigmoid shape.  
         [0000]     Ki Calculation:  
         [0177]     Experimental method: Reaction was carried out in buffer (10 mM Tris, pH 7.5, 10 mM MgCl 2 , 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 the substrate captured on phosphomembrane (Multiscreen 96 well plates from Millipore).  
         [0178]     After extensive washing, the multiscreen plates were read on a top counter. Control (time zero) for each ATP and histone concentrations was measured.  
         [0179]     Experimental design: Reaction velocities are measured at four ATP, substrate (histone) and inhibitor concentrations. An 80-point concentration matrix was designed around the respective ATP and substrate Km values, and the inhibitor IC50 values (0.3, 1, 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 allows the selection of a single endpoint time (10 min) in the linear range of the reaction for the Ki determination experiment.  
         [0180]     Kinetic parameter estimates: Kinetic parameters were estimated by simultaneous nonlinear least-square regression using [Eq.1] (competitive inhibitor respect to ATP, random mechanism) using the complete data set (80 points):  
             v   =       Vm   ·   A   ·   B               α   ·   Ka   ·   Kb     +     α   ·   Ka   ·   B     +     a   ·   Kb   ·                 A   +     A   ·   B     +     α   ·     Ka   Ki     ·   I   ·     (     Kb   +     B   β       )                         [     Eq   .           ⁢   1     ]             
 
         [0181]     where A=[ATP], B=[Substrate], I=[inhibitor], Vm=maximum velocity, Ka, Kb, Ki the dissociation constants of ATP, substrate and inhibitor respectively. α and β the cooperativity factor between substrate and ATP binding and substrate and inhibitor binding respectively.  
         [0182]     In addition the selected compounds are characterized on a panel of ser/thre kinases strictly related to cell cycle (cdk2/cyclin E, cdk1/cyclin B1, cdk5/p25, cdk4/cyclin D1), and also for specificity on MAPK, PKA, EGFR, IGF1-R, Aurora-2 and Cdc 7  
         [0000]     Inhibition Assay of Cdk2/Cyclin E Activity  
         [0183]     Kinase reaction: 10 μM in house biotinylated histone H1 (Sigma #H-5505) substrate, 30 μM ATP (0.3 microCi P 33 γ-ATP), 4 ng GST-Cyclin E/CDK2 complex, inhibitor in a final volume of 30 μl buffer (TRIS HCl 10 mM pH 7.5, MgCl 2  10 mM, DTT 7.5 mM+0.2 mg/ml BSA) were added to each well of a 96 U bottom. After incubation for 60 min at room temperature, the reaction was stopped by addition of 100 μl PBS buffer containing 32 mM EDTA, 500 μM cold ATP, 0.1% Triton X100 and 10 mg/ml streptavidin coated SPA beads. After 20 min incubation, 110 μL of suspension were withdrawn and transferred into 96well OPTIPLATEs containing 100 μl of 5M CsCl. After 4 hours, the plates were read for 2 min in a Packard TOP-Count radioactivity reader.  
         [0184]     IC50 determination: see above  
         [0000]     Inhibition Assay of Cdk1/Cyclin B1 Activity  
         [0185]     Kinase reaction: 4 μM in house biotinylated histone H1 (Sigma #H-5505) substrate, 20 μM ATP (0.2 microCi P 33 γ-ATP), 3 ng Cyclin B/CDK1 complex, inhibitor in a final volume of 30 μl buffer (TRIS HCl 10 mM pH 7.5, MgCl 2  10 mM, DTT 7.5 mM+0.2 mg/ml BSA) were added to each well of a 96 U bottom. After 20 min at r.t. incubation, reaction was stopped by 100 μl PBS+32 mM EDTA+0.1% Triton X-100+500 μM ATP, containing 1 mg SPA beads. Then a volume of 110 μl is transferred to Optiplate. After 20 min. incubation for substrate capture, 100 μl 5M CsCl were added to allow statification of beads to the top of the Optiplate and let stand 4 hours before radioactivity counting in the Top-Count instrument.  
         [0186]     IC50 determination: see above  
         [0000]     Inhibition Assay of Cdk5/p25 Activity  
         [0187]     The inhibition assay of cdk5/p25 activity is performed according to the following protocol.  
         [0188]     Kinase reaction: 10 μM biotinylated histone H1 (Sigma #H-5505) substrate, 30 μM ATP (0.3 microCi P33γ-ATP), 15 ng CDK5/p25 complex, inhibitor in a final volume of 30 μl buffer (TRIS HCl 10 mM pH 7.5, MgCl2 10 nM, DTT 7.5 mM+0.2 mg/ml BSA) were added to each well of a 96 U bottom. After incubation for 35 min at room temperature, the reaction was stopped by addition of 100 μl PBS buffer containing 32 mM EDTA, 500 μM cold ATP, 0.1% Triton X100 and 10 mg/ml streptavidin coated SPA beads. After 20 min incubation, 110 μL of suspension were withdrawn and transferred into 96-well OPTIPLATEs containing 100 μl of 5M CsCl. After 4 hours, the plates were read for 2 min in a Packard TOP-Count radioactivity reader.  
         [0189]     IC50 determination: see above  
         [0000]     Inhibition Assay of Cdk4/Cyclin D1 Activity  
         [0190]     Kinase reaction: 0,4 μM μM mouse GST-Rb (769-921) (#sc-4112 from Santa Cruz) substrate, 10 μM ATP (0.5 μCi P 33 γ-ATP), 100 ng of baculovirus expressed GST-cdk4/GST-Cyclin D1, suitable concentrations of inhibitor in a final volume of 50 μl buffer (TRIS HCl 10 mM pH 7.5, MgCl 2  10 mM, 7.5 mM DTT+0.2 mg/ml BSA) were added to each well of a 96 U bottom well plate. After 40 min at 37° C. incubation, reaction was stopped by 20 μl EDTA 120 mM.  
         [0191]     Capture: 60 μl were transferred from each well to MultiScreen plate, to allow substrate binding to phosphocellulose filter. Plates were then washed 3 times with 150 μl/well PBS Ca ++ /Mg ++  free and filtered by MultiScreen filtration system.  
         [0192]     Detection: filters were allowed to dry at 37° C., then 100 μl/well scintillant were added and  33 P labeled Rb fragment was detected by radioactivity counting in the Top-Count instrument.  
         [0193]     IC50 determination: see above  
         [0000]     Inhibition Assay of MAPK Activity  
         [0194]     Kinase reaction: 10 μM in house biotinylated MBP (Sigma #M-1891) substrate, 15 μM ATP (0.15 microCi P 33 γ-ATP), 30 ng GST-MAPK (Upstate Biothecnology #14-173), inhibitor in a final volume of 30 μl buffer (TRIS HCl 10 mM pH 7.5, MgCl 2  10 mM, DTT 7.5 mM+0.2 mg/ml BSA) were added to each well of a 96 U bottom. After incubation for 35 min at room temperature, the reaction was stopped by addition of 100 μl PBS buffer containing 32 mM EDTA, 500 μM cold ATP, 0.1% Triton X100 and 10 mg/ml streptavidin coated SPA beads. After 20 min incubation, 110 μL of suspension were withdrawn and transferred into 96-well OPTIPLATEs containing 100 μl of 5M CsCl. After 4 hours, the plates were read for 2 min in a Packard TOP-Count radioactivity reader.  
         [0195]     IC50 determination: see above  
         [0000]     Inhibition Assay of PKA Activity  
         [0196]     Kinase reaction: 10 μM in house biotinylated histone H1 (Sigma #H-5505) substrate, 10 μM ATP (0.2 microM P 3 γ-ATP), 0.45 U PKA (Sigma #2645), inhibitor in a final volume of 30 μl buffer (TRIS HCl 10 mM pH 7.5, MgCl 2  10 mM, DTT 7.5 mM+0.2 mg/ml BSA) were added to each well of a 96 U bottom. After incubation for 90 min at room temperature, the reaction was stopped by addition of 100 μl PBS buffer containing 32 mM EDTA, 500 μM cold ATP, 0.1% Triton X100 and 10 mg/ml streptavidin coated SPA beads. After 20 min incubation, 110 μL of suspension were withdrawn and transferred into 96-well OPTlPLATEs containing 100 μl of 5M CsCl. After 4 hours, the plates were read for 2 min in a Packard TOP-Count radioactivity reader.  
         [0197]     IC50 determination: see above  
         [0000]     Inhibition Assay of EGFR Activity  
         [0198]     Kinase reaction: 10 μM in house biotinylated MBP (Sigma #M-1891) substrate, 2 μM ATP (0.04 microCi P 33 γ-ATP), 36 ng insect cell expressed GST-EGFR, inhibitor in a final volume of 30 μl buffer (Hepes 50 mM pH 7.5, MgCl 2  3 mM, MnCl 2  3 mM, DTT 1 mM, NaVO 3  3 μM,+0.2 mg/ml BSA) were added to each well of a 96 U bottom. After incubation for 20 min at room temperature, the reaction was stopped by addition of 100 μl PBS buffer containing 32 mM EDTA, 500 μM cold ATP, 0.1% Triton X100 and 10 mg/ml streptavidin coated SPA beads. After 20 min incubation, 110 μL of suspension were withdrawn and transferred into 96-well OPTIPLATEs containing 100 μl of 5M CsCl. After 4 hours, the plates were read for 2 min in a Packard TOP-Count radioactivity reader.  
         [0199]     IC50 determination: see above  
         [0000]     Inhibition Assay of IGF1-R Activity  
         [0200]     The inhibition assay of IGF1-R activity is performed according to the following protocol.  
         [0201]     Enzyme activation: IGF1-R must be activated by auto-phosphorylation before starting the experiment. Just prior to the assay, a concentrated enzyme solution (694 nM) is incubated for half a hour at 28° C. in the presence of 100 μM ATP and then brought to the working dilution in the indicated buffer.  
         [0202]     Kinase reaction: 10 μM biotinylated IRS1 peptide (PRIMM) substrate, 0-20 μM inhibitor, 6 μM ATP, 1 microCi  33 P-ATP, and 6 nM GST-IGF1-R (pre-incubated for 30 min at room temperature with cold 60 μM cold ATP) in a final volume of 30 μl buffer (50 mM HEPES pH 7.9, 3 MM MnCl 2 , 1 mM DTT, 3 μl NaVO 3 ) were added to each well of a 96 U bottom well plate. After incubation for 35 min at room temperature, the reaction was stopped by addition of 100 μl PBS buffer containing 32 mM EDTA, 500 μM cold ATP, 0.1% Triton X100 and 10 mg/ml streptavidin coated SPA beads. After 20 min incubation, 110 μL of suspension were withdrawn and transferred into 96-well OPTIPLATEs containing 100 μl of 5M CsCl. After 4 hours, the plates were read for 2 min in a Packard TOP-Count radioactivity reader.  
         [0000]     Inhibition Assay of Aurora-2 Activity  
         [0203]     Kinase reaction: 8 μM biotinylated peptide (4 repeats of LRRWSLG), 10 μM ATP (0.5 uCi P 33 γ-ATP), 7.5 ng Aurora 2, inhibitor in a final volume of 30 μl buffer (HEPES 50 mM pH 7.0, MgCl 2  10 mM, 1 mM DTT, 0.2 mg/ml BSA, 3 μM orthovanadate) were added to each well of a 96 U bottom well plate. After 60 minutes at room temperature incubation, reaction was stopped and biotinylated peptide captured by adding 100 μl of bead suspension.  
         [0204]     Stratification: 100 μl of CsCl2 5 M were added to each well and let stand 4 hour before radioactivity was counted in the Top-Count instrument.  
         [0205]     IC50 determination: see above  
         [0000]     Inhibition Assay of Cdc7/dbf4 Activity  
         [0206]     The inhibition assay of Cdc7/dbf4 activity is performed according to the following protocol.  
         [0207]     The Biotin-MCM2 substrate is trans-phosphorylated by the Cdc7/Dbf4 complex in the presence of ATP traced with γ 33 -ATP. The phosphorylated Biotin-MCM2 substrate is then captured by Streptavidin-coated SPA beads and the extent of phosphorylation evaluated by β counting.  
         [0208]     The inhibition assay of Cdc7/dbf4 activity was performed in 96 wells plate according to the following protocol.  
         [0209]     To each well of the plate were added: 
        10 μl substrate (biotinylated MCM2, 6 μM final concentration)     10 μl enzyme (Cdc7/Dbf4, 17.9 nM final concentration)     10 μl test compound (12 increasing concentrations in the nM to μM range to generate a dose-response curve)     10 μl of a mixture of cold ATP (2 μM final concentration) and radioactive ATP (1/5000 molar ratio with cold ATP) was then used to start the reaction which was allowed to take place at 37° C.        
 
         [0214]     Substrate, enzyme and ATP were diluted in 50 mM HEPES pH 7.9 containing 15 mM MgCl 2 , 2 mM DTT, 3 μM NaVO 3 , 2 mM glycerophosphate and 0.2 mg/ml BSA. The solvent for test compounds also contained 10% DMSO.  
         [0215]     After incubation for 60 minutes, the reaction was stopped by adding to each well 100 μl of PBS pH 7.4 containing 50 mM EDTA, 1 mM cold ATP, 0.1% Triton X100 and 10 mg/ml streptavidin coated SPA beads.  
         [0216]     After 20 min incubation, 110 μL of suspension were withdrawn and transferred into 96-well OPTIPLATEs containing 100 μl of 5M CsCl. After 4 hours, the plates were read for 2 min in a Packard TOP-Count radioactivity reader.  
         [0217]     IC50 determination: see above.  
         [0218]     The compounds of formula (I) of the present invention, suitable for administration to a mammal, e.g. to humans, can be administered by the usual routes and the dosage level depends upon the age, weight, conditions of the patient and the administration route.  
         [0219]     For example, a suitable dosage adopted for oral administration of a compound of formula (I) may range from about 10 to about 500 mg pro dose, from 1 to 5 times daily.  
         [0220]     The compounds of the invention can be administered in a variety of dosage forms, e.g. orally, in the form of tablets, capsules, sugar or film coated tablets, liquid solutions or suspensions; rectally in the form of suppositories; parenterally, e.g. intramuscularly, or by intravenous and/or intrathecal and/or intraspinal injection or infusion.  
         [0221]     In addition, the compounds of the invention can be administered either as single agents or, alternatively, ill combination with known anticancer treatments such as radiation therapy or chemotherapy regimen in combination with cytostatic or cytotoxic agents, antibiotic-type agents, alkylating agents, antimetabolite agents, hormonal agents, immunological agents, interferon-type agents, cyclooxygenase inhibitors (e.g. COX-2 inhibitors), metallomatrixprotease inhibitors, telomerase inhibitors, tyrosine kinase inhibitors, anti-growth factor receptor agents, anti-HER agents, anti-EGFR agents, anti-angiogenesis agents, farnesyl transferase inhibitors, ras-raf signal transduction pathway inhibitors, cell cycle inhibitors, other cdks inhibitors, tubulin binding agents, topoisomerase I inhibitors, topoisomerase II inhibitors, and the like.  
         [0222]     As an example, the compounds of the invention can be administered in combination with one or more chemotherapeutic agents such as, for instance, exemestane, formestane, anastrozole, letrozole, fadrozole, taxane, taxane derivatives, encapsulated taxanes, CPT-11, camptothecin derivatives, anthracycline glycosides, e.g., doxorubicin, idarubicin, epirubicin, etoposide, navelbine, vinblastine, carboplatin, cisplatin, estramustine, celecoxib, tamoxifen, raloxifen, Sugen SU-5416, Sugen SU-6668, Herceptin, and the like, optionally within liposomal formulations thereof.  
         [0223]     If formulated as a fixed dose, such combination products employ the compounds of this invention within the dosage range described above and the other pharmaceutically active agent within the approved dosage range.  
         [0224]     Compounds of formula (I) may be used sequentially with known anticancer agents when a combination formulation is inappropriate.  
         [0225]     It is therefore a further object of the invention a product or kit comprising the compound of formula (I) of the invention and one or more chemotherapeutic agents for simultaneous, separate or sequential use in anticancer therapy or for the treatment of cell proliferative disorders.  
         [0226]     The present invention also includes pharmaceutical compositions comprising an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof in association with a pharmaceutically acceptable excipient, carrier or diluent.  
         [0227]     The pharmaceutical compositions containing the compounds of the invention are usually prepared following conventional methods and are administered in a pharmaceutically suitable form.  
         [0228]     For example, the solid oral forms may contain, together with the active compound, diluents, e.g. lactose, dextrose, saccharose, sucrose, cellulose, corn starch or potato starch; lubricants, e.g. silica, talc, stearic, magnesium or calcium stearate, and/or polyethylene glycols; binding agents, e.g. starches, arabic gum, gelatine, methylcellulose, carboxymethylcellulose or polyvinyl pyrrolidone; disaggregating agents, e.g. a starch, alginic, 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 formulations. Said pharmaceutical preparations may be manufactured in known manner, for example, by means of mixing, granulating, tabletting, sugar-coating, or film-coating processes.  
         [0229]     The liquid dispersions for oral administration may be. e.g. syrups, emulsions and suspensions.  
         [0230]     The syrups may contain as carrier, for example, saccharose or saccharose with glycerine and/or mannitol and/or sorbitol.  
         [0231]     The suspensions and the emulsions may contain as carrier, for example, a natural gum, agar, sodium alginate, pectin, methylcellulose, carboxymethylcellulose, or polyvinyl alcohol.  
         [0232]     The suspension or solutions for intramuscular injections may contain, together with the active compound, a pharmaceutically acceptable carrier, e.g. sterile water, olive oil, ethyl oleate, glycols, e.g. propylene glycol, and, if desired, a suitable amount of lidocaine hydrochloride. The solutions for intravenous injections or infusions may contain as carrier, for example, sterile water or preferably they may be in the form of sterile, aqueous, isotonic saline solutions or they may contain as a carrier propylene glycol.  
         [0233]     The suppositories may contain together with the active compound a pharmaceutically acceptable carrier, e.g. cocoa butter, polyethylene glycol, a polyoxyethylene sorbitan fatty ester surfactant or lecithin.  
         [0000]     General Methods  
         [0234]     The following examples illustrates the invention without limiting it.  
         [0000]     HPLC Conditions  
         [0235]     LCMS instrument comprising: 
        Hewlett Packard 1312A binary pump     Gilson 215 autosampler fitted with a 1 ml syringe     Polymer Labs PL1000 Evaporative Light Scattering Detector     Micromass ZMD mass spectrometer operating in Electrospray positive ionisation mode.        
 
         [0240]     The LC eluent is split and approximately 200 μl/min enters the mass spectrometer, 800 μl/min to the ELS. The instruments are currently controlled using Micromass MassLynx 3.5 software under Windows NT4.0  
         [0241]     HPLC Conditions  
                                                                   Mobile Phase:   Aqueous - Water + 0.1% Trifluoroacetic acid           Organic - Acetonitrile + 0.1% Trifluoroacetic acid            Gradient:   Time (mins)   % Aqueous   % Organic                   0.0   100   0           1.8   5   95           2.1   5   95           2.3   100   0           2.4   100   0                    Run time:   2.4 mins       Flow rate:   1 ml/min       Injection vol:   3 μl       Column temperature:   ambient (20° C.)       Column:   50 × 2.0 mm Hypersil C18 BDS; 5 μm       ELS Detector   Nebuliser Temperature 8° C.           Evaporation temperature 9° C.           Gas Flow  1.5 l/hr       MS Detector   m/z 150-800 @ 0.5 secs/scan, 0.1 second           interscan delay           Cone voltage 25 V, Source Temp. 140° C.           Drying Gas 350 l/hr                  
 
         [0242]     As formerly indicated, several compounds of formula (I) of the invention have been synthesized in parallel, according to combinatorial chemistry techniques.  
         [0243]     In this respect, some compounds thus prepared have been conveniently and unambiguously identified, as per the coding system of tables I-III, together with HPLC retention time and mass.  
         [0244]     Each code, which identifies a single specific compound of formula (I), consists of three units A-M-B.  
         [0245]     A represents any substituent R-[see formula (I)] and is directly attached to the rest of the pyrrolopyrazole moiety so as to get pyrrolopyrazole derivatives being substituted in position 3 (A-M-B); each A radical (substituent) is represented in the following table I.  
         [0246]     B represents any substituent R 1 -[see formula (I)] and is attached to the rest of the pyrrolopyrazole moiety through the nitrogen atom so as to get pyrrolopyrazole derivatives being substituted in position 5 (A-M-B); each B radical (substituent) is represented in the following table II.  
         [0247]     M refers to the central core of the divalent pyrrolopyrazole moiety and is substituted by groups A and B.  
         [0248]     For ease of reference, each A or B groups of tables I and II has been identified with the proper chemical formula also indicating the point of attachment with the rest of the molecule M.  
         [0249]     Just as an example, the compound A7-M-B30 of table III (see entry 133) represents a pyrrolopyrazole M being substituted in position 3 (direct bond) by the group A7 and in position 5 (through the —N— group) by the group B30.  
                             TABLE I                                                                             A group                Code   Fragment                       A1                                                     A2                                                     A3                                                     A4                                                     A5                                                     A6                                                     A7                                                     A8                                                     A9                                                     A10                                                     A11                                                     A12                                                     A13                                                     A14                                                     A15                                                     A16                                                     A17                                                     A18                                                     A19                                                     A20                                                     A21                                                     A22                                                     A23                                                     A24                                                     A25                                                     A26                                                     A27                                                     A28                                                     A29                                                     A30                                                    
 
         [0250]    
       
         
               
             
               
               
               
             
           
               
                 TABLE II 
               
             
             
               
                   
               
               
                   
               
               
                 B groups 
               
             
          
           
               
                   
                 Code 
                 Fragment 
               
               
                   
                   
               
               
                   
                   
                   
               
               
                   
                 B1 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
                   
               
               
                   
                 B2 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
                   
               
               
                   
                 B3 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
                   
               
               
                   
                 B4 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
                   
               
               
                   
                 B5 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
                   
               
               
                   
                 B6 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
                   
               
               
                   
                 B7 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
                   
               
               
                   
                 B8 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
                   
               
               
                   
                 B9 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
                   
               
               
                   
                 B10 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
                   
               
               
                   
                 B11 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
                   
               
               
                   
                 B12 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
                   
               
               
                   
                 B13 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
                   
               
               
                   
                 B14 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
                   
               
               
                   
                 B15 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
                   
               
               
                   
                 B16 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
                   
               
               
                   
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       EXAMPLE 1  
       [0251]     Preparation of 5-tert-butyloxycarbonyl-1-ethoxycarbonyl-4,6-dihydropyrrolo[3,4-c]pyrazole (I, R a ═R b ═R c ═R d ═H, R═H, R 1 =t-Butyloxycarbonyl(BOC), R 2 =ethoxycarbonyl).  
         [0252]     A solution of 3-amino-5-tert-butyloxycarbonyl-1-ethoxycarbonyl-4,6-dihydropyrrolo[3,4-c]pyrazole (0.4 g, 1.35 mmol) in dry tetrahydrofurane (10 ml) was added drop wise to a solution of isoamylnitrite (0.32 ml, 2.36 mmol) in dry tetrahydrofurane (2 ml) maintained at reflux. The resulting solution was stirred at reflux for 4 hours, and then cooled to room temperature. After removal of the solvent under vacuum, the crude material was purified by flash chromatography on silica gel using n-hexane÷ethyl acetate 90÷10; 70÷30. The title compound was obtained as a light yellow oil (200 mg, y 53%).  
         [0253]      1 H-NMR(DMSO-d 6 ) δ ppm: 7.67(s, 1H); 4.54(m, 2H); 4.39(q,2H); 4.32(m, 2H); 1.43(s,9H); 1.31 (t,3H).  
         [0254]     Operating in an analogous way, the following compound was also obtained 5-tert-butyloxycarbonyl-2-ethoxycarbonyl-4,6-dihydropyrrolo[3,4-c]pyrazole  
         [0255]      1 H-NMR(DMSO-d 6 ) δ ppm: 8.05(s, 1H); 4.39(q,2H); 4.37(m, 4H); 1.43(s,9H); 1.31(t,3H).  
       EXAMPLE 2  
       [0256]     Preparation of 5-tert-butyloxycarbonyl-1(2)H-4,6-dihydropyrrolo[3,4-c]pyrazole (I, R a ═R b ═R c ═R d ═H, R 1 ═H, R 1 =t-Butyloxycarbonyl(BOC), R 2 ═H).  
         [0257]     5-tert-butyloxycarbonyl-1-ethoxycarbonyl-4,6-dihydropyrrolo[3,4-c]pyrazole (1.5 g, 5.3 mmol) was treated with a solution of 10% triethylamine in methanol (74 ml) at room temperature for about 20 hours. After removal of the solvents under vacuum, the crude material was dissolved with chloroform (30 ml) and washed with water (20 ml×2), brine (20 ml), dried over sodium sulphate, filtered and evaporated to dryness. The title compound was obtained as a beige powder (1.08 g, yield 97%).  
         [0258]      1 H-NMR (DMSO-d 6 ) δ ppm: 12.63(s,1H); 7.47(s, 1H); 4.31(m, 4H); 1.42(s,9H).  
         [0259]     Operating in an analogous way, the following compounds were obtained:  
         [0260]     3-iodo-5-t-butyloxycarbonyl-1(2)H-4,6-dihydropyrrolo[3,4-c]pyrazole (I, R a ═R b ═R c ═R d ═H, R═I, R 1 =t-butyloxycarbonyl, R 2 ═H).  
         [0261]      1 H-NMR (CDCl 3 ) δ ppm: 11.00 (1H, br. s), 4.60-4.26 (4H, m), 1.46 (9H, s)  
         [0262]     3-iodo-5-isopropylaminocarbonyl-1(2)H-4,6-dihydropyrrolo[3,4-c]pyrazole (I, R a ═R b ═R c ═R d ═H, R═I, R 1 =3-isopropylaminocarbonyl, R 2 ═H).  
         [0263]      1 H-NMR (DMSO-d 6 ) δ ppm: 13.03(s,1H); 5.63(s, 1H); 4.18(m, 4H); 3.78(m, 1H); 1.07(d, 6H).  
       EXAMPLE 3  
       [0264]     Preparation of 5-tert-butyloxycarbonyl-1-(2-trimethylsilanyl-ethyloxymethyl)-4,6-dihydropyrrolo[3,4-c]pyrazole and 5-tert-butyloxycarbonyl-2-(2-trimethylsilanyl-ethyloxymethyl)-4,6-dihydropyrrolo[3,4-c]pyrazole (I, R a ═R b ═R c ═R d ═H, R═H, R 1 ═t-Butyloxycarbonyl(BOC), R 2 =Trimethylsilanyl-ethoxymethyl (SEM)).  
         [0265]     A solution of 5-tert-butyloxycarbonyl-1(2)H-4,6-dihydropyrrolo[3,4-c]pyrazole (0.7 g, 3.35 mmol) in dry tetrahydrofurane (3 ml) was added dropwise to a suspension of 60% sodium hydride (0.147 g, 3.68 mmol) in dry tetrahydrofurane (2 ml), maintained at room temperature under an Argon atmosphere. After 1 hour, the mixture was cooled to 0° C. and added with a solution of trimethylsilylethyloxymethyl chloride (SEMCl, 0.651 ml, 3.68 mmol) in dry tetrahydrofurane (2 ml). The reaction mixture was then allowed to warm to room temperature and stirring was continued for about 20 hours. After addition of water (10 ml), the mixture was extracted with ethyl acetate (15 ml×4). The organic layers were combined, dried over sodium sulphate, filtered and evaporated to dryness under vacuum. The crude material was purified by flash chromatography on silica gel, using cyclohexane:ethyl acetate 80:20 as eluent to yield the title compound (yellow oil, 0.85 g, 75% yield) as a mixture of 1-SEM and 2-SEM regioisomers (30:70), which were used without being separated.  
         [0266]      1 H-NM (DMSO-d 6 ) δ ppm: 7.7(s,1H); 7.32(s,1H); 5.34(s,1H); 5.33(s,1H); 4.4(m, 4H); 4.29(m, 4H); 3.48(m,2×2H); 1.42(s,2×9H); 0.81(m,2×2H); −0.06(m, 2×9H).  
       EXAMPLE 4  
       [0267]     Preparation of 3-boronic acid-5-tert-butyloxycarbonyl-1-(2-Trimethylsilanyl-ethoxymethyl)-4,6-dihydropyrrolo[3,4-c]pyrazole and 3-boronic acid-5-tert-butyloxycarbonyl-2-(2-Trimethylsilanyl-ethoxymethyl)-4,6-dihydropyrrolo[3,4-c]pyrazole (I, R a ═R b ═R c ═R d ═H, R═B(OH) 2 , R 1 =t-Butyloxycarbonyl(BOC), R 2 =Trimethylsilanyl-ethoxymethyl (SEM)).  
         [0268]     n-Buthyllithium (1.6M in n-hexane, 0.75 ml, 1.2 mmol) was slowly added to a solution of the mixture of 5-tert-butyloxycarbonyl-1-(and 2)-(2-Trimethylsilanyl-ethoxymethyl)-4,6-dihydropyrrolo[3,4-c]pyrazole regioisomers (0.339 g, 1 mmol) in dry tetrahydrofurane (4 ml), maintained under stirring at −7° C., under an argon atmosphere.  
         [0269]     After 30 minutes, triisopropyl borate (1.15 ml, 5 mmol) was added dropwise, while keeping the temperature at −78° C. The reaction mixture was allowed to spontaneously warm to room temperature and stirring was continued for about 4.5 hours before quenching with 2N HCl to pH6; water (5 ml) was added and the mixture was extracted 15 with ethyl acetate (15 ml×4). The organic layers were combined, washed with brine, dried over sodium sulphate, filtered and dried under vacuum to yield the title compound (light orange oil which solidifies on standing, 350 mg) as a mixture of 1-SEM and 2-SEM regioisomers, which was used without any further purification.  
         [0270]      1 H-NMR (DMSO-d 6 ) δ ppm: 8.3(m,2H); 7.65(m,2H); 5.54(s,1H); 5.34(s,1H); 4.4-4.3(m, 2×4H); 3.6-3.4(m,2×2H); 1.43(s,2×9H); 0.6(m,2×2H); −0.06-−0.07(m, 2×9H).  
       EXAMPLE 5  
       [0271]     Preparation of 5-tert-butyloxycarbonyl-3-phenyl-1-(2-trimethylsilanyl-ethoxymethyl)-4,6-dihydropyrrolo[3,4-c]pyrazole (I, R a ═R b ═R c ═R d ═H, R=Ph, R 1 =t-Butyloxycarbonyl (BOC), R 2 =Trimethylsilanyl-ethoxymethyl (SEM)) .  
         [0272]     A mixture of 3-boronic acid-5-tert-butyloxycarbonyl-1-(2-Trimethylsilanyl-ethoxymethyl)-4,6-dihydropyrrolo[3,4-c]pyrazole (70%, 0.060 g, 0.16 mmol), iodobenzene (0.005 ml, 0.044 mmol), sodium carbonate (0.055 g, 0.52 mmol) and palladium(0)tetrakis (2 mg, 5%) in water (0.16 ml)-Dimethoxyethane (1 ml) was heated under an Argon atmosphere at 80° C. for about 6 hours. The mixture was diluted with ethyl acetate (5 ml), washed with water (3 ml), brine (3 ml), dried over sodium sulphate, filtered and evaporated to dryness. The crude material was purified by flash chromatography to yield the title compound as a light yellow solid (20 mg).  
       EXAMPLE 6  
       [0273]     Preparation of 1-ethoxycarbonyl-5-(3-methylbutanoyl)-3-iodo-4,6-dihydropyrrolo[3,4-c]pyrazole (I, R a ═R b ═R c ═R d ═H, R=Iodo, R 1 =3-methylbutanoyl, R 2 =1-ethoxycarbonyl).  
         [0274]     A solution of 5-tert-butyloxycarbonyl-1-ethoxycarbonyl-3-iodo-4,6-dihydropyrrolo[3,4-c]pyrazole (0.7 g, 1.72 mmol) in dichloromethane (40 ml) was treated with trifluoroacetic acid (9 ml) at room temperature for about 4 hours. After removal of the solvents, the crude salt was dissolved with dry tetrahydrofurane (40 ml) and added with diisopropyl ethyl amine (1.47 ml, 8.6 mmol) and isovaleroyl chloride (0.23 ml, 1.89 ml) diluted with dry tetrahydrofurane (2 ml). The reaction mixture was stirred at room temperature for about 20 hours; the solvent was evaporated under vacuum and the crude material was dissolved with dichloromethane (25 ml), washed with water (15 ml), brine (15 ml), dried over sodium sulphate, filtered and dried under vacuum to yield the title compound as a light brown solid which was used without any further purification (0.65 g, yield 96%).  
         [0275]      1 H-NMR (DMSO-d 6 ) δ ppm: 4.5(m, 2H); .4.38(m, 2H); 4.25(m,2H); 2.18(m,2H) 1.32(m,3H); 0.92(m,6H).  
         [0276]     Operating in an analogous way, the following compounds are also obtained:  
         [0277]     1-ethoxycarbonyl-3-iodo-5-isopropylaminocarbonyl-4,6-dihydropyrrolo[3,4-c]pyrazole  1 H-NMR (DMSO-d 6 ) δ ppm: 6.07(m,1H); 4.59(m, 2H); 4.38(m, 2H); 4.21(m,2H); 3.78(m,1H); 1.32(m,3H); 1.08(m,6H).  
       EXAMPLE 7  
       [0278]     Preparation of 5-isopropylaminocarbonyl-3-(pyrrol-2-yl)-4,6-dihydropyrrolo[3,4-c]pyrazole (I, R a ═R b ═R c ═R d ═H, R=pyrrol-2-yl, R 1 =3-isopropylaminocarbonyl, R 2 ═H).  
         [0279]     A mixture of 3-iodo-5-isopropylaminocarbonyl-4,6-dihydropyrrolo[3,4-c]pyrazole (0.15 g, 0.38 mmol), 1-tert-butyloxycarbonyl-pyrrole-2-boronic acid (0.191 g, 0.95 mmol), 2M potassium phosphate in water (1 ml) and palladium(0)tetrakis (22 mg, 5%) in Dimethoxyethane (4 ml) was heated under an Argon atmosphere at 80° C. for about 7 hours. The mixture was diluted with ethyl acetate (8 ml), washed with water (5 ml), brine (5 ml), dried over sodium sulphate, filtered and evaporated to dryness. The crude material was purified by flash chromatography, using dichloromethane:methanol 95:5 as eluent to yield the title compound as a light yellow solid (17 mg).  1 H-NMR (DMSO-d 6 ) δ ppm: 6.82-6.10(m,3H); 5.86(d,1H); 4.42(m, 4H); 3.79(m,1H); 1.10(m,6H).  
         [0280]     Operating in an analogous way, the following compounds were also obtained: using 2M caesium carbonate as a base:  
         [0281]     5-tert-butyloxycarbonyl-3-(1-tert-butyloxycarbonyl-pyrrol-2-yl)-4,6-dihydropyrrolo[3,4-c]pyrazole (I, R a ═R b ═R c ═R d ═H, R=1-tert-butyloxycarbonyl-pyrrol-2-yl, R 1 =tert-butyloxycarbonyl R 2 ═H).  
         [0282]     Using sodium carbonate as a base:  
         [0283]     5-tert-butyloxycarbonyl-3-(1-tert-butyloxycarbonyl-indol-2-yl)-4,6-dihydropyrrolo[3,4-c]pyrazole (I, R a ═R b ═R c ═R d ═H, R=1-tert-butyloxycarbonyl-indol-2-yl, R 1 =tert-butyloxycarbonyl, R 2 ═H);  
         [0284]     3-(1-tert-butyloxycarbonyl-indol-2-yl)-5(3-methylbutanoyl)-4,6-dihydropyrrolo[3,4-c]pyrazole (I, R a ═R b ═R c ═R d ═H, R=1-tert-butyloxycarbonyl-indol-2-yl, R 1 =3-methylbutanoyl, R 2  H).  
         [0285]      1 H-NMR (DMSO-d 6 ) δ ppm: 12.94(s,1H); 7.47(m,4H); 6.91(s,1H); 4.61(m, 4H); 2.18(m,2H); 2.05(m,1H); 1.42(s,9H); 0.91(m,6H).  
         [0286]     Using potassium carbonate as a base and a mixture of toluene:ethanol:water 2:1:1 as solvent:  
         [0287]     5-tert-butyloxycarbonyl-3-(4-methoxyphenyl)-4,6-dihydropyrrolo[3,4-c]pyrazole (I, R a ═R b ═R c ═R d ═H, R=4-methoxyphenyl, R 1 =t-buthoxycarbonyl, R 2 ═H).  
         [0288]      1 H NMR (CDCl 3 ) δ ppm: 7.4-7.31 (2H, m), 6.95-6.89 (2H, m), 4.50-4.31 (4H, m), 3.78 (3br. s), 1.48 (9H, br. s)  
       EXAMPLE 8  
       [0289]     Preparation of 3-(indol-2-yl)-5-(3-methylbutanoyl)-4,6-dihydropyrrolo[3,4-c]pyrazole (I, R a ═R b ═R c ═R d ═H, R=indol-2-yl, R 1 =3-methylbutanoyl, R 2 ═H).  
         [0290]     A solution of 3-(1-tert-butyloxycarbonyl-indol-2-yl)-5-(3-methylbutanoyl)-4,6-dihydropyrrolo[3,4-c]pyrazole (0.2 g, 0.49 mmol) in dichloromethane (3.5 ml) was treated with trifluoroacetic acid (0.74 ml), at room temperature for about 24 hours. After removal of the solvents under vacuum, the mixture was diluted with dichloromethane (15 ml), washed with saturated sodium bicarbonate, dried over sodium sulphate, filtered and evaporated to dryness. The crude material was purified by flash chromatography, using dichloromethane:methanol 95:5, 90:10 to yield the title compound as beige solid (0.1 g, 65%).  
         [0291]      1 H-NMR (DMSO-d 6 ) δ ppm: 13.05(s,1H); 11.22 (bs,1H); 7.47(m,2H); 6.99(m,2H); 6.72(bs,1H); 4.80(m, 4H); 2.27(m,2H); 2.1 1(m,1H); 0.95(m,6H).  
         [0292]     Operating in an analogous way, the following compound was also obtained  
         [0293]     3-(1-H-indol-2-yl)-4,6-dihydropyrrolo[3,4-c]pyrazole (I, R a ═R b ═R c ═R d ═H, R=indol-2-yl, R 1 ═H, R 2 ═H).  
         [0294]      1 H-NMR (DMSO-d 6 ) δ ppm: 12.71(bs,1H); 11.08 (bs,1H); 6.97(m,2H); 6.72 (s,1H); 6.60(bs,1H); 6.72(bs,1H); 4.07-3.89(m, 4H).  
       EXAMPLE 9  
       [0295]     Preparation of 5-tert-butyloxycarbonyl-1-ethoxycarbonyl-3-iodo-4,6-dihydropyrrolo[3,4-c]pyrazole (I, R a ═R b ═R c ═R d ═H, R=Iodo, R 1 =t-Butyloxycarbonyl(BOC), R 2 =ethoxycarbonyl).  
         [0296]     Isoamyl nitrite (18.2 ml, 135.2 mmol) was slowly added to a mixture of Iodine (20.58 g, 81.11 mmol) in 145 mL of anhydrous dichloromethane, at +22° C. To this dark mixture a solution of 5-tert-butyloxycarbonyl-1-ethoxycarbonyl-3-amino-4,6-dihydropyrrolo[3,4-c]pyrazole (20.03 g, 67.6 mmol) in 140 mL of dichloromethane was added dropwise over 100 min at +22° C. The internal temperature rose to +28° C. and gas evolved during the addition. After 1 hour stirring at room temperature, the reaction mixture was slowly poured in 800 ml of 10% sodium metabisulfite. The phases were separated and the aqueous was extracted twice with 300 mL dichloromethane. The combined extracts were dried over anhydrous sodium sulfate and the solvent evaporated 25 under vacuum. This raw material was purified by flash chromatography eluting with 20:80 EtOAc/cyclohexane. A light yellow product (25.5 g) was obtained which was finally purified with MTBE (60 mL) and n-hexane (60 mL): 21.8 g of high purity, white product was isolated (79% yield). m.p. 166-168° C.  
         [0297]      1 H-NM(DMSO-d 6 ) δ ppm: 4.58(m, 2H); 4.38(q,2H); 4.24(m, 2H); 1.43(s,9H); 1.32(t,3H).  
       EXAMPLE 10  
       [0298]     Preparation of 5-tert-butyloxycarbonyl-3-iodo-4,6-dihydropyrrolo[3,4-c]pyrazole (I, R a ═R b ═R c ═R d ═H. R=Iodo, R 1 =t-Butyloxycarbonyl(BOC), R 2 ═H). 1-ethoxycarbonyl-3-iodo-5-tert-butyloxycarbonyl-4,6-dihydropyrrolo[3,4-c]pyrazole (270 mg, 0.66 mmol) was stirred with a mixture of MeOH (2 ml) and triethylamine (0.5 ml) at room temperature for about 30 min.  
         [0299]     The solvents were evaporated and the compound was dried under vacuum. White solid (220 mg).  
       EXAMPLE 11  
       [0300]     Preparation of 5-tert-butyloxycarbonyl-3-phenyl-4,6-dihydropyrrolo[3,4-c]pyrazole (I, R a ═R b ═R c ═R d ═H, R=Phenyl, R 1 =t-Butyloxycarbonyl(BOC), R 2 ═H).  
         [0301]     A mixture of 5-tert-butyloxycarbonyl-1-ethoxycarbonyl-3-iodo-4,6-dihydropyrrolo[3,4-c]pyrazole (60 mg, 0.15 mmol), phenylboronic acid (22 mg, 0.18 mmol), potassium carbonate (31 mg, 0.22 mmol), triethylamine (ml 0.03, 0.22 mmol) and palladiumdichloride-diphenylphosphine (8 mg, 7%) in dioxan/water 10/1 (2 ml) was heated under Argon atmosphere at 80° C. for about 3 hours. The mixture was diluted with ethyl acetate (8 ml), washed with water (5 ml), brine (5 ml), dried over sodium sulphate, filtered and evaporated to dryness. The crude material was purified by flash chromatography, using Ethylacetate/hexane as eluent to yield the title compound as a light yellow solid (27 mg 63%).  
       EXAMPLE 12  
       [0302]     Preparation of 5-acetyl-3-phenyl-4,6-dihydropyrrolo[3,4-c]pyrazole (I, R a ═R b ═R c ═R d ═H, R=Phenyl, R 1 =Acetyl, R 2 ═H).  
         [0303]     A solution of 5-tert-butyloxycarbonyl-3-phenyl-4,6-dihydropyrrolo[3,4-c]pyrazole (90 mg, 0.31 mmol) in dichloromethane (3.5 ml) was treated with trifluoroacetic acid (0.5 ml), at room temperature for about 4 hours. After removal of the solvents, the crude salt was dissolved with dry dichloromethane (5 ml) and diisopropylethylamine (0.32 ml, 1.86 mmol) and acetyl chloride (0.07 ml, 0.9 mmol) were added. The reaction mixture was stirred at room temperature for about 2 hours; the crude material was diluted with dichloromethane (25 ml), washed with water (15 ml), brine (15 ml), dried over sodium sulphate, filtered and dried under vacuum. The crude was suspended in a solution of sodium bicarbonate and stirred at room temperature for about 3 hours, then extracted with ethylacetate to yield the title compound as a light brown solid (40 mg).  
       EXAMPLE 13  
       [0304]     Preparation of 5-tert-butyloxycarbonyl-3-iodo-1-polystyrenemethylaminocarbonyl-4,6-dihydropyrrolo[3,4-c]pyrazole (III, R a ═R b ═R c ═R d ═H, R=Iodo, R 1 =t-Butyloxycarbonyl(BOC), Q=polystyrenemethylaminocarbonyl).  
         [0305]     The isocyanate methylpolystyrene resin (1.14 g, 1,71 mmol) was swelled with 15 ml of dichloromethane, and a solution of 5-tert-butyloxycarbonyl-3-iodo-4,6-dihydropyrrolo[3,4-c]pyrazole (410 mg, 1.22 mmol) in 3 ml of dimethylformamide was added.  
         [0306]     The mixture was stirred at room temperature for about 24 hours; after filtration; the resin was washed with dichloromethane (2×20 ml), MeOH (2×20 ml), dimethylformamide (2×20 ml) and dichloromethane (3×20 ml).  
         [0307]     The resin was dried under vacuum.  
         [0308]     Operating in an analogous way, the following compound was also obtained 5-tert-butyloxycarbonyl-3-(4methoxyphenyl)-1-polystyrenemethylaminocarbonyl-4,6-dihydropyrrolo[3,4-c]pyrazole (III R a ═R b ═R c ═R d ═H, R=4-methoxyphenyl, R 1 =t-Butyloxycarbonyl(BOC), Q=polystyrenemethylaminocarbonyl).  
       EXAMPLE 14  
       [0309]     Preparation of 5-tert-butyloxycarbonyl-3-phenyl-1-polystyrenemethylaminocarbonyl-4,6-dihydropyrrolo[3,4-c]pyrazole (III, R a ═R b ═R c ═R d ═H, R=Phenyl, R 1 =t-Butyloxycarbonyl(BOC), Q=polystyrenemethylaminocarbonyl).  
         [0310]     To a suspension of 5-tert-butyloxycarbonyl-3-iodo-1-polystyrenemethylaminocarbonyl-4,6-dihydropyrrolo[3,4-c]pyrazole (117 mg, 0.17 mmol) in dioxan/water 10/1 (3 ml), phenylboronic acid (108 mg, 0.88 mmol), potassium carbonate (171 mg, 0.8 mmol), triethylamine (0.18 ml, 0.8 mmol) and palladiumdichloride diphenylphosphine (25 mg, 20%) were added.  
         [0311]     The mixture was stirred at 80° C. for about 8 hours; after filtration, the resin was washed with dichloromethane (2×20 ml), MeoH (2×20 ml), dimethylformamide (2×20 ml) and dichloromethane (3×20 ml).  
         [0312]     The resin was dried under vacuum.  
         [0313]     Operating in an analogous way, using a suitable boronic acid, the following compounds were also obtained:  
         [0314]     5-tert-butyloxycarbonyl-3-(4-phenoxy-phenyl)-1-polystyrenemethylaminocarbonyl-4,6-dihydropyrrolo[3,4-c]pyrazole (III, R a ═R b ═R c ═R d ═H, R=4-phenoxy-phenyl, R 1 =t-Butyloxycarbonyl(BOC), Q=polystyrenemethylaminocarbonyl);  
         [0315]     3-(4benzyloxy-phenyl)-5-tert-butyloxycarbonyl-1-polystyrenemethylaminocarbonyl-4,6-dihydropyrrolo[3,4-c]pyrazole (m, R a ═R b ═R c ═R d ═H, R=4-benzyloxy-phenyl, R 1 =t-Butyloxycarbonyl(BOC), Q=polystyrenemethylaminocarbonyl);  
         [0316]     5-tert-butyloxycarbonyl-3-(5-chloro-thiophen-2-yl)-1-polystyrenemethylaminocarbonyl-4,6-dihydropyrrolo[3,4-c]pyrazole (III, R a ═R b ═R c ═R d ═H, R=5-chloro-thiophen-2-yl, R 1 -t-Butyloxycarbonyl(BOC), Q=polystyrenemethylaminocarbonyl);  
         [0317]     5-tert-butyloxycarbonyl-3-(4-methoxy-phenyl)1-polystyrenemethylaminocarbonyl-4,6-dihydropyrrolo[3,4-c]pyrazole (III, R a ═R b ═R c ═R d ═H, R=4-methoxy-phenyl, R 1 =t-Butyloxycarbonyl(BOC), Q=polystyrenemethylaminocarbonyl) and  
         [0318]     5-tert-butyloxycarbonyl-3-(4-dimethylamino-phenyl)-1-polystyrenemethylaminocarbonyl-4,6-dihydropyrrolo[3,4-c]pyrazole (III, R a ═R b ═R c ═R d ═H, R=4-dimethylamino-phenyl, R 1 =t-Butyloxycarbonyl(BOC), Q=polystyrenemethylaminocarbonyl).  
       EXAMPLE 15  
       [0319]     Preparation of 5-tert-butyloxycarbonyl-3-phenylethynyl-1-polystyrenemethylaminocarbonyl-4,6-dihydropyrrolo[3,4-c]pyrazole (I, R a ═R b ═R c ═R d ═H, R=Phenylethynyl, R 1 =t-Butyloxycarbonyl(BOC), Q=polystyrenemethylaminocarbonyl).  
         [0320]     To a suspension of 5-tert-butyloxycarbonyl-3-iodo-1-polystyrenemethylaminocarbonyl-4,6-dihydropyrrolo[3,4-c]pyrazole (200 mg, 0.21 mmol) in dioxan (2 ml), phenylethyne (0.23 ml, 2 mmol), CuI (20 mg, 50%), triethylamine (0.12 ml, 1.5 mmol) and palladiumdichloride diphenylphosphine (29 mg, 20%) were added.  
         [0321]     The mixture was stirred at 80° C. for about 8 hours; after filtration, the resin was washed with dichlorometane (2×20 ml), MeOH (2×20 ml), dimethylformamide (2×20 ml) and with dichloromethane (3×20 ml).  
         [0322]     The resin was dried under vacuum.  
       EXAMPLE 16  
       [0323]     Preparation of 3-phenyl-1-polystyrenemethylaminocarbonyl-4,6-dihydropyrrolo[3,4-c]pyrazole (III, R a ═R b ═R c ═R d ═H, R=Phenyl, R 1 ═H, Q=polystyrenemethylaminocarbonyl).  
         [0324]     To 5-tert-butyloxycarbonyl-3-phenyl-1-polystyrenemethylaminocarbonyl-4,6-dihydropyrrolo[3,4-c]pyrazole swelled in dichloromethane (5 ml) trifluoroacetic acid (1 ml) was added.  
         [0325]     The mixture was stirred at room temperature for about 4 hours, after filtration, the resin was washed with dichlorometane (2×20 ml), MeOH (2×20 ml), dimethylformamide (2×20 ml) and dichloromethane (3×20 ml).  
         [0326]     The resin was dried under vacuum.  
         [0327]     Operating in an analogous way, the following compounds were also obtained:  
         [0328]     3-(4-phenoxy-phenyl)-1-polystyrenemethylaminocarbonyl-4,6-dihydropyrrolo[3,4-c]pyrazole (III, R a ═R b ═R c ═R d ═H, R=Phenyl, R 1 ═H, Q=polystyrenemethylaminocarbonyl);  
         [0329]     3-(4-benzyloxy-phenyl)-1-polystyrenemethylaminocarbonyl-4,6-dihydropyrrolo[3,4-c]pyrazole (III, R a ═R b ═R c ═R d ═H, R=4-Benzyloxyphenyl, R 1 ═H, Q=polystyrenemethylaminocarbonyl);  
         [0330]     3-(5-chloro-thiophen-2-yl)-1-polystyrenemethylaminocarbonyl-4,6-dihydro-pyrrolo[3,4-c]pyrazole (III, R a ═R b ═R c ═R d ═H, R=5-Chloro-thiophen-2-yl, R 1 ═H, Q=polystyrenemethylaminocarbonyl);  
         [0331]     3-(4-methoxy-phenyl)-1-polystyrenemethylaminocarbonyl-4,6-dihydropyrrolo[3,4-c]pyrazole (III, R a ═R b ═R c ═R d ═H, R=4-Methoxyphenyl, R 1 ═H, Q=polystyrenemethylaminocarbonyl);  
         [0332]     3-(4dimethylamino-phenyl)-1-polystyrenemethylaminocarbonyl-4,6-dihydropyrrolo[3,4-c]pyrazole (III, R a ═R b ═R c ═R d ═H, R=4-Dimethylaminophenyl, R 1 ═H, Q=polystyrenemethylaminocarbonyl);  
         [0333]     3-phenylethynyl-1-polystyrenemethylaminocarbonyl-4,6-dihydropyrrolo[3,4-c]pyrazole (III, R a ═R b ═R c ═R d ═H, R=Phenylethynyl, R 1 ═H, Q=polystyrenemethylaminocarbonyl) and  
         [0334]     3-(4-methoxyphenyl)-1-polystyrenemethylaminocarbonyl-4,6-dihydropyrrolo[3,4-c]pyrazole (III, R a ═R b ═R c ═R d ═H, R=4-methoxyphenyl, R 1 ═H, Q=polystyrenemethylaminocarbonyl).  
       EXAMPLE 17  
       [0335]     Preparation of 5-acetyl-3-phenyl-1-polystyrenemethylaminocarbonyl-4,6-dihydropyrrolo[3,4-c]pyrazole (III, R a ═R b ═R c ═R d ═H, R=Phenyl, R 1 =Acetyl, Q=polystyrenemethylaminocarbonyl).  
         [0336]     To 3-phenyl-1-polystyrenemethylaminocarbonyl-4,6-dihydropyrrolo[3,4-c]pyrazole swelled in dichloromethane (5 ml) diisopropylethylamine (0.21 ml, 1.24 mmol) and acetylchloride (0.06 ml. 0.88 mmol) were added.  
         [0337]     The mixture was stirred at room temperature for about 24 hours; after filtration, the resin was washed with dichlorometane (2×20 ml), MeOH (2×20 ml), dimethylformamide (2×20 ml) and dichloromethane (3×20 ml). The resin was dried under vacuum.  
         [0338]     Operating in an analogous way, the following compounds were also obtained:  
         [0339]     5-acetyl-3-(4-phenoxy-phenyl)-1-polystyrenemethylaminocarbonyl-4,6-dihydropyrrolo[3,4-c]pyrazole (III, R a ═R b ═R c ═R d ═H, R=4-Phenoxyphenyl, R 1 =Acetyl, Q=polystyrenemethylaminocarbonyl);  
         [0340]     5-acetyl-3-(4-benzyloxy-phenyl)-1-polystyrenemethylaminocarbonyl-4,6-dihydropyrrolo[3,4-c]pyrazole (III, R a ═R b ═R c ═R d ═H, R=4-Benzyloxyphenyl, R 1 =Acetyl, Q=polystyrenemethylaminocarbonyl);  
         [0341]     5-acetyl-3-(5-chloro-thiophen-2-yl)-1-polystyrenemethylaminocarbonyl-4,6-dihydropyrrolo[3,4-c]pyrazole (III, R a ═R b ═R c ═R d ═H, R=5-Chloro-thiophen-2-yl, R 1 =Acetyl, Q=polystyrenemethylaminocarbonyl);  
         [0342]     5-acetyl-3-(4-methoxy-phenyl)-1-polystyrenemethylaminocarbonyl-4,6-dihydropyrrolo[3,4-c]pyrazole (III R a ═R b ═R c ═R d ═H, R=4-Methoxyoxyphenyl, R 1 =Acetyl, Q=polystyrenemethylaminocarbonyl);  
         [0343]     5-acetyl-3-(4-dimethylamino-phenyl)-1-polystyrenemethylaminocarbonyl-4,6-dihydropyrrolo[3,4-c]pyrazole (III, R a ═R b ═R c ═R d ═H, R=4-Dimethylamino-phenyl R 1 =Acetyl, Q=polystyrenemethylaminocarbonyl);  
         [0344]     5-acetyl-3-phenylethynyl-1-polystyrenemethylaminocarbonyl-4,6-dihydropyrrolo[3,4-c]pyrazole (III, R a ═R b ═R c ═R d ═H, R=Phenylethynyl, R 1 =Acetyl Q=polystyrenemethylaminocarbonyl) and  
         [0345]     3-(4-t-butylphenyl-5-(2-phenoxypropionyl)-1-polystyrenemethylaminocarbonyl-4,6-dihydropyrrolo[3,4-c]pyrazole (III, R a ═R b ═R c ═R d ═H=4-t-butylyphenyl, R 1 -2-phenoxypropionyl, Q=polystyrenemethylaminocarbonyl).  
       EXAMPLE 18  
       [0346]     Preparation of 5-isopropylaminocarbonyl-3-phenyl-1-polystyrenemethylaminocarbonyl-4,6-dihydropyrrolo[3,4-c]pyrazole (III, R a ═R b ═R c ═R d ═H, R=Phenyl, R 1 =Isopropylaminocarbonyl, Q=polystyrenemethylaminocarbonyl).  
         [0347]     To 3-phenyl-1-polystyrenemethylaminocarbonyl-4,6-dihydropyrrolo[3,4-c]pyrazole swelled in dichloromethane (5 ml) isopropylisocyanate (0.09 ml. 0.88 mmol) was added. The mixture was stirred at room temperature for about 24 hours; after filtration, the resin was washed with dichloromethane (2×20 ml), MeOH (2×20 ml), dimethylformamide (2×20 ml) and dichloromethane (3×20 ml). The resin was dried under vacuum.  
         [0348]     Operating in an analogous way, the following compounds were also obtained:  
         [0349]     5-isopropylaminocarbonyl-3-(4-phenoxy-phenyl)-1-polystyrenemethylaminocarbonyl-4,6-dihydropyrrolo[3,4-c]pyrazole (III, R a ═R b ═R c ═R d ═H, R=4-Phenoxyphenyl, R 1 =Isopropylaminocarbonyl, Q=polystyrenemethylaminocarbonyl);  
         [0350]     3-(4-benzyloxy-phenyl)-5-isopropylaminocarbonyl-1-polystyrenemethylaminocarbonyl-4,6-dihydropyrrolo[3,4-c]pyrazole (III, R a ═R b ═R c ═R d ═H, R=4-Benzyloxyphenyl, R 1 =Isopropylaminocarbonyl, Q=polystyrenemethylaminocarbonyl);  
         [0351]     3-(5-chloro-thiophen-2-yl)-5-isopropylaminocarbonyl-1-polystyrenemethylaminocarbonyl-4,6-dihydropyrrolo[3,4-c]pyrazole (III, R a ═R b ═R c ═R d ═H, R=5-Chloro-thiophen-2-yl, R 1 =Isopropylaminocarbonyl, Q=polystyrenemethylaminocarbonyl);  
         [0352]     5-isopropylaminocarbonyl-3-(4-methoxy-phenyl)-1-polystyrenemethylamino carbonyl-4,6-dihydro-pyrrolo[3,4-c]pyrazole (III, R a ═R b ═R c ═R d ═H, R=4Methoxy-phenyl, R 1 =Isopropylaminocarbonyl, Q=polystyrenemethylaminocarbonyl);  
         [0353]     3-(4-dimethylamino-phenyl)-5-isopropylaminocarbonyl-1-polystyrenemethylaminocarbonyl-4,6-dihydropyrrolo[3,4-c]pyrazole (III, R a ═R b ═R c ═R d ═H, R=Dimethylamino-phenyl, R 1 =Isopropylaminocarbonyl, Q=polystyrenemethylaminocarbonyl);  
         [0354]     5-isopropylaminocarbonyl-3-phenylethynyl-1-polystyrenemethylaminocarbonyl-4,6-dihydropyrrolo[3,4-c]pyrazole (III, R a ═R b ═R c ═R d ═H, R=Phenylethynyl, R 1 =Isopropylaminocarbonyl, Q=polystyrenemethylaminocarbonyl) and  
         [0355]     3-(2,5-dimethylphenyl)-5-n-propylaminocarbonyl-1-polystyrenemethylaminocarbonyl-4,6-dihydropyrrolo[3,4-c]pyrazole (III, R a ═R b ═R c ═R d ═H, R=4-(2,5-dimethylphenyl), R 1 =n-propylaminocarbonyl, Q=polystyrenemethylaminocarbonyl).  
       EXAMPLE 19  
       [0356]     Preparation of 5-acetyl-3-phenyl-4,6-dihydropyrrolo[3,4-c]pyrazole (R a ═R b ═R c ═R d ═H, R=Phenyl, R 1 =Acetyl, R 2 ═H).  
         [0357]     To 5-acetyl-3-phenyl-1-polystyrenemethylaminocarbonyl-4,6-dihydropyrrolo[3,4-c]pyrazole (200 mg) swelled in dioxan (3 ml), sodium hydroxide (35% in water) was added (0.4 ml) and the mixture was stirred at 40° C. for about 90 hours.  
         [0358]     After neutralization of the solution, the mixture was filtered and the desired product was dried under vacuum: a white solid (40 mg) was obtained.  
         [0359]     Operating in an analogous way, the following compounds were also obtained.  
         [0360]     5-Isopropylaminocarbonyl-3-phenyl-4,6-dihydropyrrolo[3,4-c]pyrazole (R a ═R b ═R c ═R d ═H, R=Phenyl, R 1 =Isopropylaminocarbonyl, R 2 ═H).  
         [0361]      1 H-NMR (DMSO-d 6 ) δ ppm: 13.12 (s,1H); 7.58-7.32(m,5H); 5.97(d,1H); 4.53(m, 4H); 3.38(m,1H); 1.10(m,6H);  
         [0362]     5Acetyl-3-(4-phenoxy-phenyl)-4,6-dihydropyrrolo[3,4-c]pyrazole (R a ═R b ═R c ═R d ═H, R=4-Phenoxy-phenyl, R 1 =Acetyl, R 2 ═H).  
         [0363]      1 H-NMR (DMSO-d 6 ) δ ppm: 13.11(s,1H); 7.62-7.05(m,9H); 4.78(m, 4H); 2.06(s,3H)  
         [0364]     5-Isopropylaminocarbonyl-3-(4-phenoxy-phenyl)-4,6-dihydropyrrolo[3,4-c]pyrazole (R a ═R b ═R c ═R d ═H, R=Phenoxy-phenyl, R 1 =Isopropylaminocarbonyl, R 2 ═H).  
         [0365]      1 H-NMR (DMSO-d 6 ) δ ppm: 13.06 (s,1H); 7.59-7.04(m,9H); 5.93(d,1H); 4.51-4.42(m, 4H); 3.80(m,1H); 1.09(m,6H).  
         [0366]     5-Acetyl-3-(4-benzyloxy-phenyl)-4,6-dihydropyrrolo[3,4-c]pyrazole (R a ═R b ═R c ═R d ═H, R=4-Benzyloxy-phenyl, R 1 =Acetyl, R 2 ═H):  
         [0367]     3-(4-benzyloxy-phenyl)-5-isopropylaminocarbonyl-4,6-dihydropyrrolo[3,4-c]pyrazole (R a ═R b ═R c ═R d ═H, R=4-Benzyloxy-phenyl , R 1 =Isopropylaminocarbonyl, R 2 ═H).  
         [0368]     5-Acetyl-3-(5-chloro-thiophen-2-yl)-4,6-dihydropyrrolo[3,4-c]pyrazole (R a ═R b ═R c ═R d ═H, R=5-Chloro-thiophen-2-yl, R 1 =Acetyl, R 2 ═H).  
         [0369]      1 H-NMR (DMSO-d 6 ) δ ppm: 13.07(s,1H); 7.14(m,2H); 4.69(m, 4H); 2.04(s,3H).  
         [0370]     3-(5-Chloro-thiophen-2-yl)-5-isopropylaminocarbonyl-4,6-dihydropyrrolo[3,4-c]pyrazole (R a ═R b ═R c ═R d ═H, R=5-Chloro-thiophen-2-yl, R 1 =Isopropylaminocarbonyl, R 2 ═H).  
         [0371]      1 H-NMR (DMSO-d 6 ) δ ppm: 13.13(s,1H); 7.14(m,2H); 5.94(d,1H); 4.41(m, 4H); 3.79(m,1H); 1.10(m,6H).  
         [0372]     5-Acetyl-3-(4-methoxy-phenyl)-4,6-dihydropyrrolo[3,4-c]pyrazole (R a ═R b ═R c ═R d ═H, R=4-Methoxy-phenyl, R 1 =Acetyl, R 2 ═H);  
         [0373]     5-isopropylaminocarbonyl-3-(4-methoxy-phenyl)-4,6-dihydropyrrolo[3,4-c]pyrazole (R a ═R b ═R c   50  R d ═H, R=4-Methoxy-phenyl, R 1 =Isopropylaminocarbonyl, R 2 ═H);  
         [0374]     5-acetyl-3-(4-dimethylamino-phenyl)-4,6-dihydropyrrolo[3,4-c]pyrazole (R a ═R b ═R c ═R d ═H, R=4-Dimethylamino-phenyl, R 1 =Acetyl, R 2 ═H).  
         [0375]      1 H-NMR (DMSO-d 6 ) δ ppm: 7.44-7.41(dd,2H); 6.75-6.77(d,2H); 4.74-4.21(m, 4H); 2.87(s,6H); 2.00(s,3H).  
         [0376]     3-(4-Dimethylamino-phenyl)-5-isopropylaminocarbonyl-4,6-dihydropyrrolo[3,4-c]pyrazole (R a ═R b ═R c ═R d ═H, R=4-Dimethylamino-phenyl, R 1 =Isopropylaminocarbonyl, R 2 ═H).  
         [0377]      1 H-NMR (DMSO-d 6 ) δ ppm: 7.40(m,2H); 6.77(m,2H); 4.18(m, 4H); 3.78(m,1H); 2.92 (s,6H); 1.11(m,6H).  
         [0378]     5-Acetyl-3-phenylethynyl-4,6-dihydropyrrolo[3,4-c]pyrazole (R a ═R b ═R c ═R d ═H, R=Phenylethynyl, R 1 =Acetyl, R 2 ═H).  
         [0379]      1 H-NMR (DMSO-d 6 ) δ ppm: 7.53-7.42(m,5H); 4.35(m, 4H); 3.80(m,1H); 1.03 (m,6H)  
         [0380]     5-Isopropylaminocarbonyl-3-phenylethynyl-4,6-dihydropyrrolo[3,4-c]pyrazole (R a ═R b ═R c ═R d ═H, R=Phenylethynyl, R 1 =Isopropylaminocarbonyl, R 2 ═H)  
         [0381]     3-(2,5-dimethylphenyl)-5-n-propylaminocarbonyl-4,6-dihydropyrrolo[3,4-c]pyrazole (I, R a ═R b ═R c ═R d ═H, R=4-(2,5-dimethylphenyl), R 1 =n-propylaminocarbonyl, R2=H).  
         [0382]     LCMS: m/z 299 [M+H] +  @ R T  1:21 min (81% by ELS detection).  
         [0383]     3-(4-t-butylphenyl)-5-(2-phenoxypropionyl)-4,6-dihydropyrrolo [3,4-c]pyrazole (I, R a ═R b ═R c ═R d ═H, R=t-butylphenyl, R 1 =2-phenoxypropionyl, R2=H).  
         [0384]      1 H NMR (DMSO-d 6 ) δ ppm: 7.61-7.53 (2H, m), 7.52-7.45 (2H, m), 7.30-7.22 (2H, m), 6.96-6.87 (3H, m), 5.22-5.12 (1H, m), 4.97-4.84 (1H, m), 4.72-4.62 (2H, m), 4.51-4.47 (1H, m), 1.60-1.50 (3H, m), 1.32 (9H, br. S), pyrazole NH not observed;  
         [0385]     LCMS: m/z 390 [M+H] +  @ R T  1.57 min (88% by ELS detection).  
         [0386]     By proceeding in the same way as described in examples 7, 13, 16, 17, 18 and 19, 1048 products were synthesized in parallel and coded in table III, as formerly indicated; related HPLC retention time together with experimentally found [M+H]+ are reported.  
                                             TABLE III                               r.t.           Entry   Compound   (min)   [M + H]+                                1   A1-M-B1   1.24   304.1       2   A2-M-B1   1.26   304.1       3   A3-M-B1   1.1   280.1       4   A4-M-B1   1.22   350.1       5   A5-M-B1   1.24   310.1       6   A1-M-B2   1.3   318.2       7   A2-M-B2   1.33   318.2       8   A5-M-B2   1.31   324.1       9   A1-M-B3   1.38   310.2       10   A2-M-B3   1.4   310.2       11   A6-M-B3   1.29   302.1       12   A3-M-B3   1.24   286.1       13   A4-M-B3   1.35   356.2       14   A5-M-B3   1.38   316.1       15   A1-M-B4   1.02   242.1       16   A2-M-B4   1.06   242.1       17   A7-M-B4   0.98   258.1       18   A3-M-B4   0.88   218.1       19   A1-M-B5   1.5   324.2       20   A8-M-B5   1.48   370.2       21   A3-M-B5   1.37   300.2       22   A5-M-B5   1.52   330.2       23   A1-M-B6   1.35   338.1       24   A2-M-B6   1.37   338.1       25   A6-M-B6   1.27   330.0       26   A8-M-B6   1.34   384.1       27   A3-M-B6   1.22   314.1       28   A5-M-B6   1.36   344.1       29   A1-M-B7   1.29   348.2       30   A9-M-B7   1.32   348.2       31   A2-M-B7   1.32   348.2       32   A3-M-B7   1.17   324.1       33   A4-M-B7   1.27   394.2       34   A1-M-B8   1.24   348.1       35   A9-M-B8   1.26   348.1       36   A2-M-B8   1.26   348.1       37   A8-M-B8   1.22   394.1       38   A3-M-B8   1.1   324.1       39   A5-M-B8   1.24   354.1       40   A1-M-B9   1.31   334.1       41   A3-M-B9   1.2   310.1       42   A4-M-B9   1.3   380.2       43   A1-M-B10   1.36   298.2       44   A8-M-B10   1.34   344.2       45   A3-M-B10   1.23   274.1       46   A5-M-B10   1.37   304.1       47   A1-M-B11   1.27   322.1       48   A9-M-B11   1.3   322.1       49   A2-M-B11   1.3   322.1       50   A6-M-B11   1.2   314.1       51   A8-M-B11   1.27   368.1       52   A3-M-B11   1.15   298.1       53   A5-M-B11   1.28   328.1       54   A9-M-B12   1.27   339.1       55   A1-M-B13   1.24   310.1       56   A3-M-B13   1.11   286.1       57   A5-M-B13   1.25   316.1       58   A1-M-B14   1.18   364.2       59   A2-M-B14   1.21   364.2       60   A6-M-B14   1.11   356.1       61   A3-M-B14   1.06   340.1       62   A5-M-B14   1.18   370.1       63   A1-M-B15   1.14   268.1       64   A3-M-B15   1.01   244.1       65   A5-M-B15   1.17   274.1       66   A1-M-B16   1.25   334.1       67   A9-M-B16   1.28   334.1       68   A2-M-B16   1.28   334.1       69   A3-M-B16   1.13   310.1       70   A5-M-B16   1.25   340.1       71   A1-M-B17   1.2   256.1       72   A4-M-B17   1.12   302.1       73   A1-M-B18   1.33   340.1       74   A6-M-B18   1.26   332.1       75   A8-M-B18   1.32   386.1       76   A3-M-B18   1.21   316.1       77   A5-M-B18   1.33   346.1       78   A1-M-B19   1.25   334.1       79   A9-M-B19   1.27   334.1       80   A2-M-B19   1.27   334.1       81   A6-M-B19   1.17   326.1       82   A3-M-B19   1.12   310.1       83   A5-M-B19   1.25   340.1       84   A1-M-B20   1.14   323.1       85   A9-M-B20   1.18   323.1       86   A2-M-B20   1.17   323.1       87   A6-M-B20   1.07   315.1       88   A8-M-B20   1.14   369.1       89   A7-M-B20   1.1   339.1       90   A3-M-B20   1.01   299.1       91   A5-M-B20   1.15   329.1       92   A1-M-B21   1.27   322.1       93   A9-M-B21   1.29   322.1       94   A2-M-B21   1.29   322.1       95   A6-M-B21   1.19   314.1       96   A8-M-B21   1.25   368.1       97   A7-M-B21   1.21   338.1       98   A3-M-B21   1.14   298.1       99   A5-M-B21   1.3   328.1       100   A1-M-B22   1.32   296.2       101   A9-M-B22   1.38   296.2       102   A2-M-B22   1.35   296.2       103   A6-M-B22   1.23   288.1       104   A8-M-B22   1.31   342.2       105   A3-M-B22   1.18   272.1       106   A5-M-B22   1.32   302.1       107   A1-M-B23   1.36   332.2       108   A8-M-B23   1.35   378.2       109   A3-M-B23   1.25   308.1       110   A1-M-B24   1.34   348.2       111   A9-M-B24   1.37   348.2       112   A7-M-B24   1.29   364.2       113   A3-M-B24   1.22   324.1       114   A1-M-B25   1.32   338.1       115   A9-M-B25   1.33   338.1       116   A2-M-B25   1.33   338.1       117   A8-M-B25   1.29   384.1       118   A7-M-B25   1.25   354.1       119   A3-M-B25   1.18   314.1       120   A8-M-B26   1.22   375.1       121   A1-M-B27   1.24   282.2       122   A2-M-B27   1.28   282.2       123   A3-M-B27   1.11   258.1       124   A1-M-B28   1.32   340.1       125   A2-M-B28   1.37   340.1       126   A8-M-B28   1.31   386.1       127   A3-M-B28   1.2   316.1       128   A1-M-B29   1.04   272.1       129   A1-M-B30   1.21   394.2       130   A9-M-B30   1.24   394.2       131   A2-M-B30   1.24   394.2       132   A6-M-B30   1.24   386.1       133   A7-M-B30   1.17   410.2       134   A4-M-B30   1.21   440.2       135   A1-M-B31   1.31   340.1       136   A9-M-B31   1.33   340.1       137   A2-M-B31   1.33   340.1       138   A6-M-B31   1.23   332.1       139   A8-M-B31   1.29   386.1       140   A7-M-B31   1.26   356.1       141   A3-M-B31   1.18   316.1       142   A1-M-B32   1.28   322.1       143   A2-M-B32   1.3   322.1       144   A6-M-B32   1.21   314.1       145   A3-M-B32   1.16   298.1       146   A1-M-B33   1.3   284.2       147   A2-M-B33   1.33   284.2       148   A8-M-B33   1.29   330.2       149   A3-M-B33   1.17   260.1       150   A1-M-B34   1.51   326.2       151   A9-M-B34   1.54   326.2       152   A2-M-B34   1.53   326.2       153   A6-M-B34   1.42   318.2       154   A8-M-B34   1.48   372.2       155   A7-M-B34   1.44   342.2       156   A3-M-B34   1.38   302.2       157   A1-M-B35   1.33   382.0       158   A9-M-B35   1.34   382.0       159   A2-M-B35   1.34   382.0       160   A6-M-B35   1.24   374.0       161   A7-M-B35   1.26   398.0       162   A3-M-B35   1.19   358.0       163   A1-M-B36   1.28   324.1       164   A2-M-B36   1.31   324.1       165   A3-M-B36   1.16   300.1       166   A1-M-B37   1.44   346.2       167   A2-M-B37   1.47   346.2       168   A6-M-B37   1.51   338.1       169   A8-M-B37   1.43   392.2       170   A3-M-B37   1.32   322.1       171   A1-M-B38   1.52   376.2       172   A9-M-B38   1.55   376.2       173   A1-M-B39   1.29   397.2       174   A8-M-B39   1.28   443.2       175   A7-M-B39   1.25   413.2       176   A1-M-B40   1.28   340.1       177   A9-M-B40   1.3   340.1       178   A2-M-B40   1.3   340.1       179   A6-M-B40   1.2   332.1       180   A8-M-B40   1.27   386.1       181   A7-M-B40   1.23   356.1       182   A3-M-B40   1.15   316.1       183   A1-M-B41   1.38   382.0       184   A8-M-B41   1.37   428.1       185   A3-M-B41   1.25   358.0       186   A1-M-B42   1.32   318.2       187   A2-M-B42   1.34   318.2       188   A8-M-B42   1.31   364.2       189   A3-M-B42   1.19   294.1       190   A1-M-B43   1.21   302.1       191   A2-M-B43   1.24   302.1       192   A8-M-B43   1.21   348.1       193   A1-M-B44   1.33   336.1       194   A9-M-B44   1.36   336.1       195   A3-M-B44   1.21   312.1       196   A1-M-B45   1.4   352.1       197   A8-M-B45   1.39   398.1       198   A3-M-B45   1.29   328.1       199   A1-M-B46   1.39   310.2       200   A8-M-B46   1.38   356.2       201   A3-M-B46   1.27   286.1       202   A1-M-B47   1.28   282.2       203   A2-M-B47   1.28   282.2       204   A8-M-B47   1.25   328.2       205   A3-M-B47   1.12   258.1       206   A1-M-B48   1.27   284.2       207   A9-M-B48   1.3   284.2       208   A2-M-B48   1.3   284.2       209   A6-M-B48   1.19   276.1       210   A8-M-B48   1.26   330.2       211   A7-M-B48   1.22   300.2       212   A3-M-B48   1.14   260.1       213   A1-M-B49   1.39   362.2       214   A2-M-B49   1.42   362.2       215   A8-M-B49   1.38   408.2       216   A3-M-B49   1.28   338.1       217   A1-M-B50   1.13   285.2       218   A9-M-B50   1.34   285.2       219   A2-M-B50   1.18   285.2       220   A6-M-B50   1.05   277.1       221   A7-M-B50   1.1   301.2       222   A3-M-B50   1   261.1       223   A1-M-B51   1.33   333.2       224   A2-M-B51   1.37   333.2       225   A1-M-B52   1.41   397.1       226   A9-M-B52   1.44   397.1       227   A2-M-B52   1.45   397.1       228   A6-M-B52   1.35   389.0       229   A8-M-B52   1.42   443.1       230   A1-M-B53   1.31   349.2       231   A9-M-B53   1.31   349.2       232   A2-M-B53   1.31   349.2       233   A6-M-B53   1.21   341.1       234   A10-M-B54   1.26   392.1       235   A11-M-B55   1.41   374.1       236   A1-M-B56   1.05   271.1       237   A9-M-B56   1.09   271.1       238   A2-M-B56   1.09   271.1       239   A6-M-B56   0.97   263.1       240   A8-M-B56   1.08   317.2       241   A1-M-B57   1.4   325.2       242   A9-M-B57   1.33   325.2       243   A2-M-B57   1.33   325.2       244   A6-M-B57   1.23   317.1       245   A8-M-B57   1.31   371.2       246   A1-M-B58   1.28   355.1       247   A2-M-B58   1.31   355.1       248   A1-M-B59   1.28   337.1       249   A9-M-B59   1.32   337.1       250   A2-M-B59   1.32   337.1       251   A6-M-B59   1.22   329.1       252   A1-M-B60   1.39   353.1       253   A2-M-B60   1.43   353.1       254   A6-M-B60   1.33   345.0       255   A1-M-B61   1.24   349.2       256   A9-M-B61   1.27   349.2       257   A2-M-B61   1.27   349.2       258   A6-M-B61   1.17   341.1       259   A8-M-B61   1.25   395.2       260   A1-M-B62   1.47   361.2       261   A9-M-B62   1.5   361.2       262   A2-M-B62   1.5   361.2       263   A6-M-B62   1.41   353.1       264   A8-M-B62   1.48   407.2       265   A1-M-B63   1.27   347.2       266   A9-M-B63   1.3   347.2       267   A2-M-B63   1.3   347.2       268   A6-M-B63   1.35   339.1       269   A8-M-B63   1.29   393.2       270   A1-M-B64   1.36   353.1       271   A12-M-B64   1.34   369.1       272   A1-M-B65   1.38   353.1       273   A12-M-B65   1.38   369.1       274   A8-M-B65   1.4   399.1       275   A1-M-B66   1.32   337.1       276   A12-M-B66   1.32   353.1       277   A2-M-B66   1.49   337.1       278   A6-M-B66   1.26   329.1       279   A1-M-B67   1.3   313.2       280   A12-M-B67   1.29   329.2       281   A2-M-B67   1.34   313.2       282   A6-M-B67   1.23   305.1       283   A8-M-B67   1.32   359.2       284   A1-M-B68   1.23   361.2       285   A12-M-B68   1.22   377.2       286   A2-M-B68   1.27   361.2       287   A1-M-B69   1.33   347.2       288   A12-M-B69   1.32   363.2       289   A2-M-B69   1.36   347.2       290   A8-M-B69   1.34   393.2       291   A1-M-B70   1.33   351.2       292   A12-M-B70   1.31   367.1       293   A1-M-B71   1.57   347.2       294   A12-M-B71   1.38   363.2       295   A2-M-B71   1.41   347.2       296   A6-M-B71   1.31   339.1       297   A8-M-B71   1.39   393.2       298   A1-M-B72   1.35   355.1       299   A12-M-B72   1.35   371.1       300   A1-M-B73   1.22   361.2       301   A12-M-B73   1.21   377.2       302   A2-M-B73   1.26   361.2       303   A1-M-B74   1.52   392.1       304   A12-M-B74   1.49   408.1       305   A2-M-B74   1.54   392.1       306   A1-M-B75   1.37   359.1       307   A12-M-B75   1.35   375.1       308   A2-M-B75   1.4   359.1       309   A1-M-B76   1.36   400.1       310   A12-M-B76   1.35   416.1       311   A2-M-B76   1.4   400.1       312   A1-M-B77   1.49   374.1       313   A12-M-B77   1.46   390.1       314   A2-M-B77   1.52   374.1       315   A1-M-B78   1.43   374.1       316   A12-M-B78   1.41   390.1       317   A2-M-B78   1.46   374.1       318   A1-M-B79   1.28   306.1       319   A12-M-B79   1.27   322.1       320   A2-M-B79   1.32   306.1       321   A1-M-B80   1.51   380.0       322   A12-M-B80   1.49   396.0       323   A2-M-B80   1.55   380.0       324   A1-M-B81   1.18   382.2       325   A1-M-B82   1.37   365.1       326   A1-M-B83   1.23   311.2       327   A2-M-B83   1.27   311.2       328   A2-M-B84   1.19   278.1       329   A12-M-B85   1.42   370.1       330   A2-M-B85   1.47   354.1       331   A12-M-B86   1.47   390.1       332   A1-M-B87   1.51   418.0       333   A12-M-B87   1.75   434.0       334   A1-M-B88   1.2   292.1       335   A2-M-B88   1.24   292.1       336   A1-M-B89   1.39   358.1       337   A12-M-B89   1.37   374.1       338   A2-M-B89   1.42   358.1       339   A1-M-B54   1.36   346.1       340   A12-M-B54   1.34   362.1       341   A2-M-B54   1.4   346.1       342   A1-M-B55   1.41   358.1       343   A12-M-B55   1.39   374.1       344   A2-M-B55   1.44   358.1       345   A1-M-B90   1.52   424.0       346   A1-M-B91   1.32   400.1       347   A2-M-B91   1.36   400.1       348   A1-M-B92   1.42   358.1       349   A12-M-B92   1.4   374.1       350   A2-M-B92   1.45   358.1       351   A1-M-B93   1.44   354.1       352   A12-M-B93   1.42   370.1       353   A2-M-B93   1.47   354.1       354   A1-M-B94   1.49   448.0       355   A12-M-B94   1.46   464.0       356   A2-M-B94   1.52   448.0       357   A13-M-B1   1.24   336.1       358   A14-M-B1   1.3   318.2       359   A13-M-B2   1.3   350.1       360   A14-M-B2   1.41   332.2       361   A15-M-B3   1.44   324.2       362   A13-M-B3   1.38   342.2       363   A16-M-B3   1.42   340.2       364   A15-M-B5   1.58   338.2       365   A17-M-B5   1.35   360.0       366   A13-M-B5   1.48   356.2       367   A18-M-B5   1.28   300.2       368   A11-M-B5   1.47   340.2       369   A17-M-B6   1.21   373.9       370   A13-M-B6   1.36   370.1       371   A13-M-B7   1.29   380.1       372   A16-M-B7   1.34   378.2       373   A17-M-B8   1.08   384.0       374   A15-M-B10   1.43   312.2       375   A10-M-B10   1.22   344.2       376   A17-M-B10   1.19   334.0       377   A13-M-B10   1.36   330.2       378   A11-M-B10   1.33   314.2       379   A16-M-B10   1.41   328.2       380   A15-M-B11   1.35   336.1       381   A17-M-B11   1.12   358.0       382   A13-M-B11   1.28   354.1       383   A14-M-B11   1.38   336.1       384   A15-M-B12   1.29   353.1       385   A13-M-B12   1.22   371.1       386   A19-M-B12   1.15   369.1       387   A20-M-B12   1.29   377.0       388   A15-M-B13   1.32   324.1       389   A17-M-B13   1.07   345.9       390   A13-M-B13   1.25   342.1       391   A15-M-B14   1.25   378.2       392   A17-M-B14   1.02   400.0       393   A13-M-B14   1.18   396.1       394   A15-M-B15   1.24   282.2       395   A13-M-B15   1.16   300.1       396   A11-M-B15   1.14   284.1       397   A15-M-B16   1.32   348.2       398   A17-M-B16   1.09   370.0       399   A14-M-B16   1.35   348.2       400   A13-M-B17   1.14   288.1       401   A17-M-B18   1.18   376.0       402   A13-M-B18   1.34   372.1       403   A17-M-B19   1.1   370.0       404   A13-M-B19   1.25   366.1       405   A11-M-B19   1.23   350.1       406   A16-M-B19   1.3   364.2       407   A15-M-B20   1.23   337.2       408   A17-M-B20   0.95   359.0       409   A13-M-B20   1.15   355.1       410   A11-M-B20   1.14   339.1       411   A14-M-B20   1.26   337.2       412   A13-M-B21   1.27   354.1       413   A11-M-B21   1.25   338.1       414   A14-M-B21   1.38   336.1       415   A17-M-B23   1.23   368.0       416   A13-M-B23   1.36   364.1       417   A15-M-B25   1.4   352.1       418   A13-M-B25   1.3   370.1       419   A19-M-B25   1.24   368.1       420   A17-M-B26   1.04   365.0       421   A13-M-B26   1.22   361.1       422   A17-M-B27   1.07   318.0       423   A13-M-B27   1.26   314.1       424   A16-M-B27   1.31   312.2       425   A17-M-B28   1.2   376.0       426   A13-M-B28   1.33   372.1       427   A11-M-B29   1.02   288.1       428   A14-M-B29   1.16   286.1       429   A19-M-B29   0.99   302.1       430   A16-M-B29   1.1   302.1       431   A17-M-B95   1.22   373.9       432   A13-M-B95   1.37   370.1       433   A17-M-B31   1.16   376.0       434   A13-M-B31   1.32   372.1       435   A14-M-B31   1.41   354.1       436   A19-M-B31   1.25   370.1       437   A15-M-B32   1.37   336.1       438   A17-M-B32   1.12   358.0       439   A13-M-B32   1.29   354.1       440   A11-M-B32   1.26   338.1       441   A14-M-B34   1.6   340.2       442   A19-M-B34   1.42   356.2       443   A20-M-B34   1.58   364.2       444   A16-M-B34   1.54   356.2       445   A14-M-B90   1.62   438.0       446   A15-M-B96   1.6   404.1       447   A14-M-B35   1.42   396.1       448   A13-M-B36   1.29   356.1       449   A15-M-B37   1.52   360.2       450   A17-M-B37   1.31   382.0       451   A13-M-B37   1.44   378.2       452   A11-M-B37   1.42   362.2       453   A17-M-B38   1.4   412.0       454   A13-M-B38   1.52   408.2       455   A17-M-B97   1.36   416.0       456   A13-M-B97   1.47   412.1       457   A15-M-B40   1.37   354.1       458   A17-M-B40   1.12   376.0       459   A13-M-B40   1.28   372.1       460   A14-M-B40   1.38   354.1       461   A16-M-B40   1.33   370.1       462   A17-M-B41   1.23   417.9       463   A13-M-B41   1.37   414.0       464   A13-M-B42   1.32   350.1       465   A20-M-B45   1.48   390.0       466   A17-M-B46   1.25   346.0       467   A13-M-B46   1.4   342.2       468   A15-M-B47   1.33   296.2       469   A17-M-B47   1.08   318.0       470   A13-M-B47   1.27   314.1       471   A15-M-B48   1.35   298.2       472   A10-M-B48   1.14   330.2       473   A17-M-B48   1.1   320.0       474   A13-M-B48   1.28   316.1       475   A11-M-B48   1.26   300.2       476   A14-M-B48   1.39   298.2       477   A19-M-B48   1.21   314.1       478   A20-M-B48   1.36   322.1       479   A15-M-B50   1.21   299.2       480   A10-M-B50   1.04   331.2       481   A17-M-B50   0.94   321.0       482   A14-M-B50   1.25   299.2       483   A15-M-B51   1.4   347.2       484   A17-M-B51   1.19   369.0       485   A13-M-B51   1.34   365.1       486   A11-M-B51   1.33   349.2       487   A20-M-B51   1.43   371.1       488   A17-M-B52   1.29   432.9       489   A13-M-B52   1.42   429.0       490   A11-M-B52   1.42   413.1       491   A20-M-B52   1.51   435.0       492   A15-M-B53   1.35   363.2       493   A17-M-B53   1.13   385.0       494   A13-M-B53   1.29   381.1       495   A14-M-B53   1.39   363.2       496   A10-M-B56   0.97   317.2       497   A14-M-B56   1.18   285.2       498   A19-M-B56   1.02   301.1       499   A10-M-B57   1.21   371.2       500   A17-M-B57   1.16   361.0       501   A13-M-B57   1.31   357.2       502   A14-M-B57   1.41   339.2       503   A19-M-B57   1.27   355.2       504   A20-M-B57   1.41   363.1       505   A10-M-B58   1.2   401.1       506   A17-M-B58   1.13   391.0       507   A13-M-B58   1.3   387.1       508   A10-M-B59   1.22   383.1       509   A17-M-B59   1.14   373.0       510   A13-M-B59   1.31   369.1       511   A20-M-B59   1.4   375.1       512   A13-M-B60   1.41   385.1       513   A19-M-B60   1.37   383.1       514   A20-M-B60   1.5   391.0       515   A20-M-B62   1.57   399.1       516   A15-M-B63   1.36   361.2       517   A10-M-B63   1.19   393.2       518   A17-M-B63   1.13   383.0       519   A13-M-B63   1.29   379.2       520   A11-M-B63   1.28   363.2       521   A14-M-B63   1.39   361.2       522   A19-M-B63   1.25   377.2       523   A17-M-B64   1.22   389.0       524   A17-M-B65   1.26   389.0       525   A13-M-B65   1.4   385.1       526   A20-M-B65   1.49   391.0       527   A14-M-B66   1.43   351.2       528   A20-M-B66   1.43   375.1       529   A13-M-B98   1.29   376.1       530   A14-M-B67   1.42   327.2       531   A13-M-B68   1.25   393.1       532   A17-M-B69   1.21   383.0       533   A13-M-B69   1.35   379.2       534   A11-M-B69   1.32   363.2       535   A10-M-B70   1.25   397.2       536   A17-M-B70   1.18   387.0       537   A13-M-B70   1.34   383.1       538   A13-M-B72   1.36   387.1       539   A14-M-B84   1.28   292.1       540   A17-M-B87   1.38   453.9       541   A13-M-B88   1.22   324.1       542   A14-M-B88   1.32   306.1       543   A17-M-B74   1.39   427.9       544   A13-M-B75   1.37   391.1       545   A17-M-B76   1.24   436.0       546   A13-M-B76   1.37   432.1       547   A14-M-B76   1.47   414.1       548   A15-M-B99   1.69   410.2       549   A10-M-B99   1.51   442.2       550   A17-M-B99   1.51   432.0       551   A13-M-B99   1.62   428.1       552   A15-M-B77   1.56   388.1       553   A17-M-B77   1.35   409.9       554   A10-M-B78   1.33   420.1       555   A13-M-B78   1.43   406.0       556   A17-M-B79   1.1   342.0       557   A15-M-B80   1.58   394.0       558   A17-M-B80   1.37   415.9       559   A14-M-B80   1.62   394.0       560   A15-M-B81   1.65   396.2       561   A10-M-B81   1.47   428.2       562   A17-M-B81   1.47   418.0       563   A13-M-B81   1.58   414.1       564   A15-M-B100   1.44   354.1       565   A17-M-B100   1.22   376.0       566   A13-M-B100   1.38   372.1       567   A11-M-B100   1.37   356.1       568   A14-M-B100   1.47   354.1       569   A15-M-B54   1.44   360.1       570   A17-M-B54   1.21   381.9       571   A13-M-B54   1.36   378.0       572   A11-M-B54   1.34   362.1       573   A14-M-B54   1.47   360.1       574   A15-M-B55   1.49   372.1       575   A17-M-B55   1.27   393.9       576   A13-M-B55   1.4   390.1       577   A14-M-B55   1.5   372.1       578   A17-M-B90   1.38   459.8       579   A13-M-B90   1.51   455.9       580   A10-M-B96   1.4   436.1       581   A17-M-B96   1.4   426.0       582   A13-M-B96   1.51   422.1       583   A14-M-B96   1.61   404.1       584   A10-M-B101   1.49   454.0       585   A15-M-B91   1.4   414.1       586   A10-M-B91   1.22   446.1       587   A13-M-B91   1.32   432.1       588   A17-M-B102   1.43   459.9       589   A13-M-B102   1.54   456.1       590   A15-M-B92   1.49   372.1       591   A17-M-B92   1.27   393.9       592   A13-M-B92   1.42   390.1       593   A15-M-B103   1.66   422.0       594   A10-M-B103   1.47   454.0       595   A17-M-B93   1.3   390.0       596   A13-M-B93   1.44   386.1       597   A10-M-B94   1.38   494.0       598   A17-M-B94   1.36   483.9       599   A13-M-B94   1.49   480.0       600   A17-M-B104   1.4   443.9       601   A21-M-B105   1.25   288.1       602   A21-M-B106   1.4   376.1       603   A21-M-B8   1.23   352.1       604   A22-M-B105   1.22   270.2       605   A22-M-B107   1.17   256.1       606   A22-M-B8   1.2   334.1       607   A22-M-B108   1.49   346.2       608   A23-M-B1   1.49   346.2       609   A23-M-B105   1.52   326.2       610   A23-M-B3   1.63   352.2       611   A23-M-B5   1.74   366.2       612   A23-M-B7   1.54   390.2       613   A23-M-B107   1.47   312.2       614   A23-M-B10   1.62   340.2       615   A24-M-B1   1.36   346.1       616   A24-M-B105   1.39   326.1       617   A24-M-B3   1.49   352.1       618   A24-M-B4   1.16   284.1       619   A24-M-B7   1.42   390.1       620   A24-M-B107   1.34   312.1       621   A24-M-B106   1.5   414.1       622   A24-M-B8   1.35   390.1       623   A24-M-B109   1.44   360.1       624   A24-M-B10   1.48   340.1       625   A21-M-B11   1.28   326.1       626   A21-M-B110   1.49   410.0       627   A21-M-B18   1.33   344.1       628   A21-M-B19   1.24   338.1       629   A21-M-B111   1.19   274.1       630   A21-M-B21   1.26   326.1       631   A22-M-B11   1.24   308.1       632   A22-M-B110   1.47   392.0       633   A22-M-B15   1.12   254.1       634   A22-M-B18   1.3   326.1       635   A22-M-B19   1.21   320.1       636   A22-M-B111   1.15   256.1       637   A22-M-B21   1.23   308.1       638   A23-M-B13   1.5   352.1       639   A23-M-B15   1.42   310.2       640   A23-M-B17   1.39   298.2       641   A23-M-B18   1.56   382.2       642   A23-M-B19   1.49   376.2       643   A23-M-B111   1.46   312.2       644   A23-M-B112   1.54   326.2       645   A23-M-B21   1.5   364.2       646   A24-M-B11   1.39   364.1       647   A24-M-B110   1.64   448.0       648   A24-M-B13   1.37   352.1       649   A24-M-B15   1.28   310.1       650   A24-M-B17   1.25   298.1       651   A24-M-B18   1.44   382.1       652   A24-M-B19   1.37   376.1       653   A24-M-B111   1.32   312.1       654   A24-M-B112   1.41   326.1       655   A24-M-B21   1.39   364.1       656   A21-M-B113   1.31   344.1       657   A21-M-B24   1.34   352.1       658   A21-M-B25   1.31   342.1       659   A21-M-B27   1.25   286.1       660   A21-M-B28   1.32   344.1       661   A21-M-B30   1.21   398.1       662   A21-M-B31   1.32   344.1       663   A21-M-B32   1.28   326.1       664   A22-M-B113   1.28   326.1       665   A22-M-B25   1.29   324.1       666   A22-M-B27   1.2   268.1       667   A22-M-B28   1.29   326.1       668   A22-M-B30   1.17   380.2       669   A22-M-B31   1.27   326.1       670   A22-M-B32   1.25   308.1       671   A23-M-B113   1.53   382.2       672   A23-M-B23   1.61   374.2       673   A23-M-B24   1.57   390.2       674   A23-M-B25   1.56   380.1       675   A23-M-B27   1.51   324.2       676   A23-M-B30   1.45   436.2       677   A23-M-B31   1.55   382.2       678   A24-M-B113   1.42   382.1       679   A24-M-B23   1.48   374.1       680   A24-M-B24   1.46   390.1       681   A24-M-B25   1.44   380.1       682   A24-M-B27   1.37   324.1       683   A24-M-B28   1.44   382.1       684   A24-M-B30   1.34   436.1       685   A24-M-B95   1.48   380.1       686   A24-M-B31   1.43   382.1       687   A24-M-B32   1.4   364.1       688   A21-M-B114   1.3   352.1       689   A21-M-B115   1.54   444.1       690   A21-M-B34   1.49   330.2       691   A21-M-B116   1.3   352.1       692   A21-M-B40   1.27   344.1       693   A21-M-B117   1.48   376.0       694   A22-M-B114   1.27   334.1       695   A22-M-B115   1.53   426.1       696   A22-M-B34   1.47   312.2       697   A22-M-B38   1.5   362.2       698   A22-M-B39   1.26   383.1       699   A22-M-B40   1.24   326.1       700   A22-M-B118   1.12   280.1       701   A23-M-B33   1.56   326.2       702   A23-M-B114   1.54   390.2       703   A23-M-B115   1.74   482.2       704   A23-M-B34   1.75   368.3       705   A23-M-B36   1.52   366.2       706   A23-M-B38   1.74   418.2       707   A23-M-B116   1.54   390.2       708   A23-M-B39   1.52   439.2       709   A23-M-B40   1.52   382.2       710   A23-M-B118   1.42   336.2       711   A24-M-B33   1.41   326.1       712   A24-M-B114   1.42   390.1       713   A24-M-B115   1.64   482.1       714   A24-M-B34   1.63   368.2       715   A24-M-B36   1.39   366.1       716   A24-M-B116   1.41   390.1       717   A24-M-B40   1.4   382.1       718   A24-M-B41   1.48   424.0       719   A24-M-B118   1.28   336.1       720   A21-M-B119   1.35   376.0       721   A21-M-B120   1.36   394.1       722   A21-M-B50   1.12   289.1       723   A21-M-B121   1.27   323.1       724   A21-M-B51   1.33   337.1       725   A21-M-B53   1.29   353.1       726   A22-M-B119   1.32   358.0       727   A22-M-B120   1.32   376.1       728   A22-M-B50   1.09   271.1       729   A22-M-B121   1.24   305.1       730   A22-M-B51   1.31   319.1       731   A22-M-B53   1.26   335.1       732   A22-M-B122   1.22   285.2       733   A23-M-B119   1.59   414.1       734   A23-M-B120   1.59   432.2       735   A23-M-B44   1.54   378.2       736   A23-M-B45   1.63   394.2       737   A23-M-B49   1.57   404.2       738   A23-M-B50   1.38   327.2       739   A23-M-B51   1.56   375.2       740   A23-M-B53   1.51   391.2       741   A23-M-B122   1.49   341.2       742   A24-M-B120   1.48   432.1       743   A24-M-B44   1.43   378.1       744   A24-M-B46   1.5   352.1       745   A24-M-B50   1.24   327.1       746   A24-M-B121   1.37   361.1       747   A24-M-B51   1.43   375.1       748   A24-M-B53   1.38   391.1       749   A24-M-B122   1.37   341.1       750   A22-M-B56   1.02   257.1       751   A22-M-B57   1.27   311.2       752   A22-M-B123   1.43   373.1       753   A22-M-B59   1.27   323.1       754   A22-M-B124   1.09   271.1       755   A22-M-B60   1.38   339.1       756   A22-M-B125   1.23   323.1       757   A22-M-B126   1.31   319.1       758   A22-M-B61   1.21   335.1       759   A23-M-B56   1.31   313.2       760   A23-M-B58   1.51   397.2       761   A23-M-B124   1.38   327.2       762   A23-M-B127   1.81   497.2       763   A23-M-B125   1.5   379.2       764   A23-M-B128   1.58   429.2       765   A23-M-B61   1.46   391.2       766   A24-M-B56   1.16   313.1       767   A24-M-B58   1.38   397.1       768   A24-M-B123   1.54   429.1       769   A24-M-B124   1.24   327.1       770   A24-M-B60   1.49   395.1       771   A24-M-B127   1.7   497.1       772   A24-M-B125   1.37   379.1       773   A24-M-B126   1.43   375.1       774   A24-M-B128   1.46   429.1       775   A24-M-B61   1.34   391.1       776   A22-M-B62   1.45   347.2       777   A22-M-B129   1.21   319.1       778   A22-M-B63   1.24   333.2       779   A22-M-B66   1.3   323.1       780   A22-M-B67   1.27   299.2       781   A22-M-B130   1.25   333.2       782   A22-M-B131   1.38   333.2       783   A23-M-B129   1.44   375.2       784   A23-M-B63   1.49   389.2       785   A23-M-B64   1.61   395.2       786   A23-M-B132   1.62   405.2       787   A23-M-B67   1.5   355.2       788   A24-M-B62   1.56   403.2       789   A24-M-B133   1.43   411.1       790   A24-M-B66   1.42   379.1       791   A24-M-B132   1.51   405.1       792   A24-M-B70   1.43   393.1       793   A22-M-B134   1.34   351.1       794   A22-M-B135   1.38   333.2       795   A22-M-B88   1.15   278.1       796   A22-M-B74   1.49   378.0       797   A22-M-B76   1.34   386.1       798   A22-M-B136   1.35   356.1       799   A22-M-B99   1.58   382.2       800   A22-M-B78   1.4   360.0       801   A22-M-B137   1.41   362.1       802   A22-M-B138   1.53   394.0       803   A23-M-B134   1.59   407.2       804   A23-M-B135   1.63   389.2       805   A23-M-B88   1.44   334.2       806   A23-M-B74   1.72   434.1       807   A23-M-B76   1.57   442.2       808   A23-M-B136   1.6   412.2       809   A23-M-B99   1.8   438.2       810   A23-M-B78   1.64   416.1       811   A23-M-B137   1.67   418.1       812   A23-M-B138   1.78   450.1       813   A24-M-B135   1.51   389.1       814   A24-M-B86   1.61   416.0       815   A24-M-B74   1.63   434.0       816   A24-M-B76   1.4   442.1       817   A24-M-B136   1.43   412.1       818   A24-M-B99   1.74   438.1       819   A24-M-B78   1.47   416.0       820   A24-M-B138   1.66   450.0       821   A22-M-B79   1.24   292.1       822   A22-M-B139   1.43   394.1       823   A22-M-B140   1.32   306.1       824   A22-M-B100   1.33   326.1       825   A22-M-B54   1.32   332.0       826   A22-M-B55   1.37   344.1       827   A22-M-B141   1.5   376.1       828   A23-M-B79   1.48   348.2       829   A23-M-B81   1.74   424.2       830   A23-M-B139   1.63   450.1       831   A23-M-B100   1.62   382.2       832   A23-M-B54   1.54   388.1       833   A23-M-B55   1.59   400.1       834   A23-M-B141   1.67   432.2       835   A23-M-B103   1.82   450.1       836   A23-M-B89   1.57   400.1       837   A24-M-B79   1.41   348.1       838   A24-M-B81   1.71   424.1       839   A24-M-B54   1.48   388.0       840   A24-M-B141   1.62   432.1       841   A24-M-B142   1.34   348.1       842   A12-M-B83   1.23   327.2       843   A1-M-B84   1.14   278.1       844   A12-M-B84   1.13   294.1       845   A1-M-B85   1.44   354.1       846   A1-M-B86   1.49   374.1       847   A2-M-B86   1.52   374.1       848   A2-M-B87   1.6   418.0       849   A1-M-B143   1.37   354.1       850   A12-M-B143   1.35   370.1       851   A2-M-B143   1.4   354.1       852   A12-M-B88   1.18   308.1       853   A22-M-B86   1.47   360.0       854   A23-M-B86   1.72   416.1       855   A24-M-B85   1.53   396.1       856   A13-M-B101   1.6   440.0       857   A10-M-B92   1.31   404.1       858   A13-M-B103   1.58   440.0       859   A10-M-B93   1.33   400.1       860   A15-M-B104   1.6   422.0       861   A21-M-B3   1.37   314.2       862   A22-M-B106   1.37   358.1       863   A22-M-B109   1.28   304.1       864   A22-M-B10   1.32   284.2       865   A23-M-B11   1.52   364.2       866   A21-M-B95   1.37   342.1       867   A22-M-B23   1.35   318.2       868   A22-M-B95   1.34   324.1       869   A23-M-B28   1.56   382.2       870   A23-M-B32   1.53   364.2       871   A21-M-B41   1.36   386.0       872   A22-M-B33   1.25   270.2       873   A22-M-B116   1.28   334.1       874   A22-M-B41   1.34   368.0       875   A22-M-B117   1.45   358.0       876   A21-M-B44   1.33   340.1       877   A22-M-B44   1.3   322.1       878   A22-M-B58   1.25   341.1       879   A22-M-B127   1.6   441.1       880   A23-M-B66   1.54   379.2       881   A6-M-B1   1.15   296.1       882   A8-M-B3   1.37   356.2       883   A4-M-B4   1.03   288.1       884   A5-M-B4   1.03   248.1       885   A2-M-B12   1.27   339.1       886   A2-M-B15   1.19   268.1       887   A8-M-B15   1.15   314.1       888   A6-M-B16   1.17   326.1       889   A8-M-B16   1.24   380.2       890   A8-M-B17   1.12   302.1       891   A8-M-B19   1.24   380.2       892   A7-M-B19   1.2   350.1       893   A6-M-B26   1.17   321.1       894   A3-M-B30   1.12   370.1       895   A9-M-B32   1.3   322.1       896   A8-M-B32   1.27   368.1       897   A8-M-B35   1.3   428.1       898   A3-M-B38   1.41   352.2       899   A2-M-B41   1.39   382.0       900   A6-M-B41   1.29   374.0       901   A1-M-B144   1.29   364.2       902   A9-M-B144   1.31   364.2       903   A6-M-B144   1.22   356.1       904   A7-M-B144   1.24   380.2       905   A6-M-B42   1.24   310.1       906   A3-M-B43   1.08   278.1       907   A9-M-B49   1.45   362.2       908   A6-M-B51   1.27   325.1       909   A8-M-B51   1.34   379.2       910   A11-M-B96   1.5   406.1       911   A17-M-B101   1.47   443.9       912   A1-M-B98   1.27   344.1       913   A2-M-B98   1.3   344.1       914   A6-M-B98   1.2   336.1       915   A6-M-B68   1.15   353.1       916   A8-M-B70   1.33   397.2       917   A12-M-B82   1.35   381.1       918   A15-M-B1   1.33   318.2       919   A17-M-B2   1.15   354.0       920   A15-M-B8   1.3   362.1       921   A13-M-B8   1.24   380.1       922   A14-M-B8   1.34   362.1       923   A17-M-B9   1.15   370.0       924   A19-M-B14   1.13   394.1       925   A13-M-B16   1.25   366.1       926   A19-M-B16   1.2   364.1       927   A20-M-B18   1.41   378.1       928   A14-M-B19   1.36   348.2       929   A20-M-B20   1.24   361.1       930   A16-M-B20   1.21   353.2       931   A17-M-B24   1.2   384.0       932   A14-M-B24   1.44   362.2       933   A10-M-B37   1.32   392.2       934   A19-M-B40   1.22   370.1       935   A14-M-B42   1.42   332.2       936   A13-M-B43   1.22   334.1       937   A20-M-B44   1.41   374.1       938   A11-M-B81   1.57   398.1       939   A17-M-B49   1.27   398.0       940   A13-M-B50   1.14   317.1       941   A14-M-B52   1.52   411.1       942   A10-M-B100   1.27   386.1       943   A19-M-B59   1.27   367.1       944   A17-M-B61   1.08   385.0       945   A17-M-B62   1.37   397.0       946   A13-M-B62   1.49   393.2       947   A14-M-B65   1.49   367.1       948   A13-M-B67   1.31   345.2       949   A14-M-B69   1.44   361.2       950   A17-M-B82   1.23   401.0       951   A13-M-B87   1.51   450.0       952   A13-M-B143   1.37   386.1       953   A19-M-B143   1.32   384.1       954   A11-M-B88   1.19   308.1       955   A15-M-B74   1.59   406.1       956   A13-M-B74   1.51   424.0       957   A14-M-B99   1.72   410.2       958   A15-M-B79   1.37   320.1       959   A13-M-B79   1.29   338.1       960   A14-M-B79   1.4   320.1       961   A9-M-B1   1.26   304.1       962   A8-M-B1   1.23   350.1       963   A9-M-B2   1.34   318.2       964   A8-M-B2   1.29   364.2       965   A7-M-B2   1.25   334.1       966   A9-M-B3   1.41   310.2       967   A23-M-B85   1.68   396.2       968   A6-M-B4   0.94   234.1       969   A6-M-B7   1.22   340.1       970   A7-M-B7   1.24   364.2       971   A6-M-B15   1.07   260.1       972   A7-M-B15   1.1   284.1       973   A7-M-B22   1.26   312.2       974   A2-M-B24   1.39   348.2       975   A6-M-B24   1.29   340.1       976   A8-M-B24   1.37   394.2       977   A9-M-B27   1.31   282.2       978   A6-M-B27   1.19   274.1       979   A8-M-B27   1.27   328.2       980   A2-M-B29   1.09   272.1       981   A7-M-B29   1.01   288.1       982   A8-M-B30   1.24   440.2       983   A9-M-B33   1.33   284.2       984   A7-M-B33   1.25   300.2       985   A24-M-B88   1.31   334.1       986   A2-M-B144   1.31   364.2       987   A8-M-B144   1.28   410.2       988   A3-M-B144   1.17   340.1       989   A8-M-B44   1.34   382.1       990   A7-M-B46   1.37   326.2       991   A9-M-B47   1.31   282.2       992   A7-M-B47   1.23   298.1       993   A7-M-B49   1.38   378.2       994   A8-M-B50   1.18   331.2       995   A9-M-B51   1.36   333.2       996   A8-M-B59   1.3   383.1       997   A8-M-B60   1.4   399.1       998   A8-M-B64   1.37   399.1       999   A8-M-B66   1.34   383.1       1000   A8-M-B68   1.24   407.2       1001   A6-M-B72   1.28   347.1       1002   A8-M-B72   1.37   401.1       1003   A17-M-B1   1.09   340.0       1004   A15-M-B2   1.39   332.2       1005   A16-M-B14   1.23   394.2       1006   A14-M-B15   1.27   282.2       1007   A11-M-B23   1.36   348.2       1008   A13-M-B24   1.34   380.1       1009   A17-M-B25   1.15   373.9       1010   A17-M-B42   1.17   354.0       1011   A16-M-B43   1.27   332.1       1012   A19-M-B52   1.39   427.0       1013   A13-M-B122   1.26   331.2       1014   A13-M-B61   1.25   381.1       1015   A14-M-B61   1.36   363.2       1016   A19-M-B66   1.3   367.1       1017   A11-M-B98   1.27   360.1       1018   A17-M-B68   1.06   397.0       1019   A14-M-B68   1.34   375.2       1020   A19-M-B87   1.45   448.0       1021   A14-M-B75   1.47   373.1       1022   A11-M-B99   1.61   412.2       1023   A13-M-B77   1.48   406.0       1024   A11-M-B77   1.47   390.1       1025   A14-M-B77   1.58   388.1       1026   A14-M-B78   1.53   388.1       1027   A10-M-B90   1.41   470.0       1028   A14-M-B101   1.71   422.0       1029   A10-M-B102   1.44   470.1       1030   A17-M-B103   1.46   443.9       1031   A10-M-B104   1.42   454.0       1032   A13-M-B104   1.52   440.0       1033   A21-M-B1   1.23   308.1       1034   A21-M-B108   1.52   364.2       1035   A21-M-B109   1.31   322.1       1036   A21-M-B10   1.36   302.2       1037   A22-M-B1   1.19   290.1       1038   A22-M-B3   1.34   296.2       1039   A22-M-B4   0.99   228.1       1040   A22-M-B7   1.27   334.1       1041   A23-M-B8   1.47   390.2       1042   A21-M-B15   1.16   272.1       1043   A23-M-B110   1.77   448.1       1044   A21-M-B36   1.27   328.1       1045   A22-M-B46   1.36   296.2       1046   A23-M-B121   1.49   361.2       1047   A23-M-B126   1.54   375.2       1048   A22-M-B85   1.4   340.1