Patent Publication Number: US-8981092-B2

Title: Substituted 3,4-dihydro-2H-pyrrolo[1,2-a]pyrazin-1-ones as modulators of protein kinase activity

Description:
CROSS REFERENCE TO RELATED APPLICATIONS 
     The present application is a divisional of co-pending application having U.S. Ser. No. 13/119,849, filed on Apr. 8, 2011, which is a 371 of International Application having Serial No. PCT/EP2009/062061, filed on Sep. 17, 2009, which claims priority of European Patent Application No. 08164714.1, filed on Sep. 19, 2008, the contents of all of which are incorporated herein by reference. 
    
    
     BACKGROUND 
     The present invention relates to certain 4,7-disubstituted derivatives of 3,4-dihydro-2H-pyrrolo[1,2-a]pyrazin-1-one compounds, which modulate the activity of protein kinases. The compounds of this invention are therefore useful in treating diseases caused by dysregulated protein kinase activity. The present invention also relates to methods for preparing these compounds, combinatorial libraries thereof, pharmaceutical compositions comprising these compounds, and methods of treating diseases utilizing pharmaceutical compositions comprising these compounds. 
     The malfunctioning of protein kinases (PKs) is the hallmark of numerous diseases. 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. 
     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. 
     For general reference to PKs malfunctioning or disregulation see, for instance, Current Opinion in Chemical Biology 1999, 3, 459-465 and Carcinogenesis 2008, 29, 1087-191. 
     8-Hydroxy-3,4-dihydro-2H-pyrrolo[1,2-a]pyrazin-1-one derivatives for prevention and treatment of infection by HIV and in the prevention, delay in the onset and treatment of AIDS are disclosed in WO 2004/047725 in the name of Merck &amp; Co., Inc., USA. The present inventors have now discovered that the new compounds of formula (I), described below, are kinase inhibitors and are thus useful in therapy as antitumor agents. 
     BRIEF SUMMARY OF THE DISCLOSURE 
     Accordingly, a first object of the present invention is to provide a 4,7-disubstituted-3,4-dihydro-2H-pyrrolo[1,2-a]pyrazin-1-one compound represented by formula (I): 
     
       
         
         
             
             
         
       
     
     wherein: 
     R1 is a group —NR a R b  or —OR a  and 
     R2 is —NH 2 , —NHCOR c , —NHCONHR c , —NHSO 2 R c , —C≡CR d  or R d  wherein R a , R b , R c  and R d , the same or different, are each independently hydrogen or a group optionally further substituted, selected from straight or branched C 1 -C 6  alkyl, C 2 -C 6  alkenyl or C 2 -C 6  alkynyl, C 3 -C 6  cycloalkyl, cycloalkyl C 1 -C 6  alkyl, heterocyclyl, heterocyclyl C 1 -C 6  alkyl, aryl, aryl C 1 -C 6  alkyl, heteroaryl and heteroaryl C 1 -C 6  alkyl, or R a  and R b , taken together with the nitrogen atom to which they are bonded, may form an optionally substituted 3 to 7 membered heterocyclyl or heteroaryl, optionally containing one additional heteroatom or heteroatomic group selected from S, O, N or NH, and pharmaceutically acceptable salts thereof. 
     The present invention also provides methods of synthesizing the 4,7-disubstituted-3,4-dihydro-2H-pyrrolo[1,2-a]pyrazin-1-one compounds, represented by formula (I), prepared through a process consisting of standard synthetic transformations. 
     The present invention also provides a method for treating diseases caused by and/or associated with dysregulated protein kinase activity, particularly PLK family, ABL, AKT1, ALK, AUR1, AUR2, BRK, CDC7/DBF4, CDK2/CYCA, CHK1, CK2, EE2FK, EGFR1, ERK2, FAK, FGFR1, FLT3, GSK3beta, IGFR1, IKK2, IR, JAK2, JAK3, KIT, LCK, MAPKAPK2, MET, MPS1, MST4, NEK6, NIM1, P38alpha, PAK-4, PDGFR, PDK1, PERK, PIM1, PIM2, PIM3, PKAalpha, PKCbeta, PLK1, RET, SULU1, SYK, TRKA, VEGFR2, VEGFR3 or ZAP70. 
     A preferred method of the present invention is to treat a disease caused by and/or associated with dysregulated protein kinase activity selected from the group consisting of cancer, viral infection, prevention of AIDS development in HIV-infected individuals, cell proliferative disorders, autoimmune and neurodegenerative disorders. 
     Another preferred method of the present invention is to treat specific types of cancer 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 leukaemia, acute lymphocytic leukaemia, acute lymphoblastic leukaemia, B-cell lymphoma, T-cell-lymphoma, Hodgkin&#39;s lymphoma, non-Hodgkin&#39;s lymphoma, hairy cell lymphoma and Burkitt&#39;s lymphoma; hematopoietic tumors of myeloid lineage, including acute and chronic myelogenous leukemias, myelodysplastic syndrome and promyelocytic leukaemia; 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, keratoxanthoma, thyroid follicular cancer and Kaposi&#39;s sarcoma. 
     Another preferred method of the present invention is to treat specific cellular proliferation disorders such as, for example, benign prostate hyperplasia, familial adenomatosis polyposis, neurofibromatosis, psoriasis, vascular smooth cell proliferation associated with atherosclerosis, pulmonary fibrosis, arthritis, glomerulonephritis and post-surgical stenosis and restenosis. 
     The compounds of this invention may be useful in inhibiting tumour angiogenesis and metastasis, as well as in the treatment of organ transplant rejection and host versus graft disease. 
     The present invention further provides a method of treatment comprising a compound of formula (I) in combination with radiation therapy or chemotherapy regimen for simultaneous, separate or sequential use in anticancer therapy. 
     Moreover the invention provides a method for inhibiting protein kinase activity which comprises contacting the said protein kinase with an effective amount of a compound of formula (I). 
     The present invention also provides a pharmaceutical composition comprising one or more compounds of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient, carrier or diluent. 
     The present invention also provides a pharmaceutical composition comprising a compound of formula (I) in combination with known cytostatic or cytotoxic agents, antibiotic-type agents, DNA damaging or intercalating agents, platin-based agents, alkylating agents, antimetabolite agents, hormonal agents, antihormonal agents such as antiestrogens, antiandrogens and aromatase inhibitors, immunological agents, interferon-type agents, cyclooxygenase inhibitors (e.g. COX-2 inhibitors), matrixmetalloprotease inhibitors, tyrosine kinase inhibitors, other kinase inhibitors, anti-growth factor receptor agents, anti-HER agents, anti-EGFR agents, anti-angiogenesis agents (e.g. angiogenesis inhibitors), farnesyl transferase inhibitors, ras-raf signal transduction pathway inhibitors, cell cycle inhibitors, other cdks inhibitors, tubulin binding agents, topoisomerase I inhibitors, topoisomerase II inhibitors, inhibitors of kinesins, therapeutic monoclonal antibodies, inhibitors of mTOR, histone deacetylase inhibitors, inhibitors of hypoxic response and the like, for simultaneous, separate or sequential use in anticancer therapy. Additionally, the invention provides a product or kit comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, as defined above, or pharmaceutical compositions thereof and one or more chemotherapeutic agents, as a combined preparation for simultaneous, separate or sequential use in anticancer therapy. 
     In yet another aspect the invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, as defined above, for use as a medicament. 
     Moreover the invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof, as defined above, in the manufacture of a medicament with antitumor activity. 
     Finally, the invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, as defined above, for use in a method of treating cancer. 
    
    
     DETAILED DESCRIPTION OF THE DISCLOSURE 
     Unless otherwise specified, when referring to the compounds of formula (I) per se as well as to any pharmaceutical composition thereof or to any therapeutic method of treatment comprising them, the present invention includes all the hydrates, solvates, complexes, metabolites, prodrugs, carriers, N-oxides and pharmaceutically acceptable salts of the compounds of this invention. 
     A metabolite of a compound of formula (I) is any compound into which this same compound of formula (I) is converted in vivo, for instance upon administration to a mammal in need thereof. Typically, without however representing a limiting example, upon administration of a compound of formula (I), this same derivative may be converted into a variety of compounds, for instance including more soluble derivatives like hydroxylated derivatives, which are easily excreted. Hence, depending upon the metabolic pathway thus occurring, any of these hydroxylated derivatives may be regarded as a metabolite of the compounds of formula (I). 
     Prodrugs are any covalently bonded compounds, which release the active parent drug according to formula (I) in vivo. 
     N-oxides are compounds of formula (I) wherein nitrogen and oxygen are tethered through a dative bond. 
     All forms of chiral isomers or other forms of isomers including enantiomers and diastereomers, are intended to be covered herein. Compounds containing a chiral center may be used as a racemic mixture or as an enantiomerically enriched mixture, or the racemic mixture may be separated using well-known techniques and an individual enantiomer may be used alone. 
     In cases wherein compounds may exist in tautomeric forms, such as keto-enol tautomers, each tautomeric form is contemplated as being included within this invention whether existing in equilibrium or predominantly in one form. 
     In the present description, unless otherwise indicated, with the term “straight or branched C 1 -C 6  alkyl” we intend any group such as, for instance, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, and the like. 
     With the term “straight or branched C 2 -C 6  alkenyl” or “straight or branched C 2 -C 6  alkynyl” we intend any of the unsaturated alkenyl or alkynyl groups with from 2 to 6 carbon atoms for instance including vinyl, allyl, 1-propenyl, isopropenyl, 1-, 2- or 3-butenyl, pentenyl, hexenyl, ethynyl, 1- or 2-propynyl, butynyl, pentynyl, hexynyl, and the like. 
     With the term “C 3 -C 6  cycloalkyl” we intend, unless otherwise specified, 3- to 6-membered all-carbon monocyclic ring, which may contain one or more double bonds but does not have a completely conjugated π-electron system. Examples of cycloalkyl groups, without limitation, are cyclopropane, cyclobutane, cyclopentane, cyclopentene, cyclohexane, cyclohexene and cyclohexadiene. 
     With the term “heterocyclyl” we intend a 3- to 7-membered, saturated or partially unsaturated carbocyclic ring where one or more carbon atoms are replaced by heteroatoms such as nitrogen, oxygen and sulfur. Non limiting examples of heterocyclyl groups are, for instance, pyrane, pyrrolidine, pyrroline, imidazoline, imidazolidine, pyrazolidine, pyrazoline, thiazoline, thiazolidine, dihydrofuran, tetrahydrofuran, 1,3-dioxolane, piperidine, piperazine, morpholine and the like. 
     With the term “aryl” we intend a mono-, bi- or poly-carbocyclic hydrocarbon with from 1 to 4 ring systems, optionally further fused or linked to each other by single bonds, wherein at least one of the carbocyclic rings is “aromatic”, wherein the term “aromatic” refers to completely conjugated π-electron bond system. Non-limiting examples of such aryl groups are phenyl, α- or β-naphthyl or biphenyl groups. 
     With the term “heteroaryl” we intend aromatic heterocyclic rings, typically 5- to 7-membered heterocycles with from 1 to 3 heteroatoms selected among N, O or S; the heteroaryl ring can be optionally further fused or linked to aromatic and non-aromatic carbocyclic and heterocyclic rings. Not limiting examples of such heteroaryl groups are, for instance, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, imidazolyl, thiazolyl, isothiazolyl, pyrrolyl, phenyl-pyrrolyl, furyl, phenyl-furyl, oxazolyl, isoxazolyl, pyrazolyl, thienyl, benzothienyl, isoindolinyl, benzoimidazolyl, quinolinyl, isoquinolinyl, 1,2,3-triazolyl, 1-phenyl-1,2,3-triazolyl, 2,3-dihydroindolyl, 2,3-dihydrobenzofuranyl, 2,3-dihydrobenzothiophenyl; benzopyranyl, 2,3-dihydrobenzoxazinyl, 2,3-dihydroquinoxalinyl and the like. 
     According to the meanings provided to R a , R b , R c  and R d , any of the above groups may be further optionally substituted in any of their free positions by one or more groups, for instance 1 to 6 groups, selected from: halogen, nitro, oxo groups (═O), carboxy, cyano, C 1 -C 6  alkyl, polyfluorinated alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 3 -C 6  cycloalkyl, heterocyclyl, aryl, heteroaryl; amino groups and derivatives thereof such as, for instance, alkylamino, dialkylamino, arylamino, diarylamino, ureido, alkylureido or arylureido; carbonylamino groups and derivatives thereof such as, for instance, formylamino, alkylcarbonylamino, alkenylcarbonylamino, arylcarbonylamino, alkoxycarbonylamino; hydroxy groups and derivatives thereof such as, for instance, alkoxy, polyfluorinated alkoxy, aryloxy, alkylcarbonyloxy, arylcarbonyloxy, cycloalkenyloxy or alkylideneaminoxy; carbonyl groups and derivatives thereof such as, for instance, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aryloxycarbonyl, cycloalkyloxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl; sulfurated derivatives such as, for instance, alkylthio, arylthio, alkylsulfonyl, arylsulfonyl, alkylsulfinyl, arylsulfinyl, arylsulfonyloxy, aminosulfonyl, alkylaminosulfonyl or dialkylaminosulfonyl. 
     In their turn, whenever appropriate, each of the above substituents may be further substituted by one or more of the aforementioned groups. 
     In the present description, unless otherwise specified, with the term “cyano” we intend a —CN residue. 
     With the term “nitro” we intend a —NO 2  group. 
     With the term “halogen” we intend a fluorine, chlorine, bromine or iodine atom. 
     With the term “polyfluorinated alkyl or alkoxy” we intend a straight or branched C 1 -C 6  alkyl or alkoxy group as above defined, wherein more than one hydrogen atom is replaced by fluorine atoms such as, for instance, trifluoromethyl, trifluoromethoxy, 2,2,2-trifluoroethyl, 2,2,2-trifluoroethoxy, 1,2-difluoroethyl, 1,1,1,3,3,3-hexafluoropropyl-2-yl, and the like. 
     From all of the above, it is clear to the skilled man that any group which name has been identified as a composite name such as, for instance, cycloalkylalkyl, arylalkyl, heterocyclylalkyl, alkoxy, alkylthio, aryloxy, arylalkyloxy, alkylcarbonyloxy and the like, has to be intended as conventionally construed from the parts to which it derives. So far, as an example, the terms heterocyclyl-alkyl and cycloalkyl-alkyl stand for a straight or branched alkyl group being further substituted by a heterocyclic or cycloalkyl group, respectively, as above defined. 
     The term “pharmaceutically acceptable salts” embraces salts commonly used to form alkali metal salts and to form addition salts of free acids or free bases. The nature of the salt is not critical, provided that it is pharmaceutically acceptable. Suitable pharmaceutically acceptable acid addition salts of the compounds of the present invention may be prepared from an inorganic acid or from an organic acid. Examples of such inorganic acids are hydrochloric, hydrobromic, hydroiodic, nitric, carbonic, sulfuric, and phosphoric acid. Appropriate organic acids may be selected from aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic and sulfonic classes of organic acids, examples of which are formic, acetic, trifluoroacetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, mesylic, salicylic, p-hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic, benzenesulfonic, pantothenic, toluenesulfonic, 2-hydroxyethanesulfonic, sulfanilic, stearic, cyclohexylaminosulfonic, algenic, hydroxybutyric, galactaric and galacturonic acid. Suitable pharmaceutically acceptable base addition salts of the compounds of the present invention include metallic salts made from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc or organic salts made from N,N′-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methyl-glucamine) and procaine. All of these salts may be prepared by conventional means from the corresponding compounds of the present invention, for instance by reacting them with the appropriate acid or base. 
     A preferred class of compounds of formula (I) are the compounds wherein: R1 is a group —NR a R b  and R a  and R b  are both hydrogen atoms or one of them is a hydrogen atom and the remaining one of R a  or R b  is a straight or branched C 1 -C 6  alkyl or C 2 -C 6  alkenyl group or it is an optionally substituted aryl or aryl C 1 -C 6  alkyl group. 
     Another preferred class of compounds of formula (I) are the compounds wherein: 
     R2 is a group —NHCOR wherein R c  is as defined before. 
     A further preferred class of compounds of formula (I) are the compounds wherein: 
     R2 is a group —NHCONHR wherein R c  is as defined before. 
     A more preferred class of compounds of formula (I) are the compounds wherein: 
     R2 is a group —NHSO 2 R c  wherein R c  is as defined before. 
     For a reference to any specific compound of formula (I) of the invention, optionally in the form of pharmaceutically acceptable salts, see the experimental section. 
     The present invention also provides a process for the preparation of a compound of formula (I) as defined above, characterized in that the process comprises: 
     a) nitrating under acidic conditions the compound of formula (II): 
     
       
         
         
             
             
         
       
     
     b) reacting the resultant compound of formula (III): 
     
       
         
         
             
             
         
       
     
     with an ammonium salt of formula (IV): 
     
       
         
         
             
             
         
       
     
     wherein R a  is C 1 -C 6  alkyl; 
     optionally converting the resultant compound of formula (V): 
     
       
         
         
             
             
         
       
     
     wherein R1 represents OR a  and R a  is as defined above, into another compound of formula (V) wherein R1 is as above defined by replacing —OR a  group with a different R1 group, 
     c) reducing said compound of formula (V) to give a compound of formula (I) or a salt thereof: 
     
       
         
         
             
             
         
       
     
     wherein R1 is as defined above, and R2 is NH 2 ; 
     optionally separating the resultant compound of formula (I) into the single isomers; 
     converting the resultant compound of formula (I) into a different compound of formula (I) by derivatizing the amino moiety, and/or by replacing the group —OR a  with a different group which R1 represents, and/or converting it into a pharmaceutically acceptable salt if desired. 
     The present invention further provides a process for the preparation of a compound of formula (I) as defined above, characterized in that the compound of formula (I) is converted into another compound of formula (I), said conversion being carried out by one or more of the following reactions: 
     d) reacting a compound of formula (I) wherein R1 is —OR a  and R a  is C 1 -C 6  alkyl, and R2 is NH 2  according to any one of the alternative steps: 
     d.1) with an acid or an acyl halide of formula (VI):
 
R c COZ  (VI)
 
     wherein R o  is as defined above and Z is a halogen or a group —OH, to give a compound of formula (I): 
     
       
         
         
             
             
         
       
     
     wherein R1 is —OR a  and R a  is C 1 -C 6  alkyl and R c  is as defined above; or 
     d.2) with an isocyanate of formula (VII):
 
R c NCO  (VII)
 
     wherein R c  is as defined above, to give a compound of formula (I): 
     
       
         
         
             
             
         
       
     
     wherein R1 is —OR a  and R a  is C 1 -C 6  alkyl and R c  is as defined above; or 
     d.3) with a sulphonyl halide of formula (VIII):
 
R c SO 2 Z′  (VIII)
 
     wherein R c  is as defined above and Z′ is a halogen, to give a compound of formula (I): 
     
       
         
         
             
             
         
       
     
     wherein R1 is —OR a  and R a  is C 1 -C 6  alkyl and R c  is as defined above, 
     optionally separating the resultant compound of formula (I) into the single isomers; converting the resultant compound of formula (I) into a different compound of formula (I) by replacing the group —OR a  with a different group which R1 represents, and/or into a pharmaceutically acceptable salt if desired. 
     The present invention also provides another process for the preparation of a compound of formula (XI), characterized in that the process comprises: 
     e) iodination of the compound of formula (II): 
     
       
         
         
             
             
         
       
     
     f) reacting the resultant compound of formula (IX): 
     
       
         
         
             
             
         
       
     
     with an ammonium salt of formula (IV): 
     
       
         
         
             
             
         
       
     
     wherein R a  is C 1 -C 6  alkyl; 
     g) cyclizing under basic conditions the resultant compound of formula (X): 
     
       
         
         
             
             
         
       
     
     wherein R a  is as defined above, to give the compound of formula (XI): 
     
       
         
         
             
             
         
       
     
     wherein R a  is as defined above; 
     converting it into a different compound of formula (XI) by replacing the Iodo with a different group that R2 represents, optionally separating it into the single isomers, converting it into a different compound of formula (XI) by replacing the —OR a  group with a different group which R1 represents and/or into a pharmaceutically acceptable salt if desired. 
     The present inventions further provides a process for the preparation of compounds of formula (I) as defined above, characterized in that the process comprises: 
     h) reacting a compound of formula (XI) wherein R1 is —OR a  and R a  is C 1 -C 6  alkyl, according to any one of the alternative steps: 
     h.1) with a boronic acid or ester of formula (XII):
 
R2′B(OZ″Z′″) 2   (XII)
 
     wherein R2′ is R d  and R d  is as defined above, Z″ and Z′″ are either H, alkyl or, taken together with the oxygen atoms to which they are bonded, may form an optionally substituted 5 to 6 membered heterocycle, to give a compound of formula (I): 
     
       
         
         
             
             
         
       
     
     wherein R1 is —OR a  and R a  is C 1 -C 6  alkyl and R2′ is as defined above; or 
     h.2) with a terminal alkyne of formula (XIII):
 
R d C≡CH  (XIII)
 
     wherein R d  is as defined above, to give a compound of formula (I): 
     
       
         
         
             
             
         
       
     
     wherein R1 is —OR a  and R a  is C 1 -C 6  alkyl and R d  is as defined above, optionally separating the resultant compound of formula (I) into the single isomers; converting the resultant compound of formula (I) into a different compound of formula (I) by replacing the group —OR a  with a different group which R1 represents, and/or into a pharmaceutically acceptable salt if desired. 
     The present invention further provides a process for the preparation of a compound of formula (I) as defined above, characterized in that the compound of formula (I) is converted into another compound of formula (I), said conversion is carried out by one or more of the following reactions: 
     m.1) acid or basic hydrolysis of a compound of formula (I), wherein R1 is —OR a  and 
     R a  is C 1 -C 6  alkyl, to give the corresponding compound of formula (I) wherein R1 is —OR a  and R a  is hydrogen, or the corresponding salt; 
     m.2) transesterification of a compound of formula (I) wherein R1 is —OR a  and R a  is C 1 -C 6  alkyl, by reactions with a compound of formula (XIV):
 
R a —OH  (XIV)
 
     to give the corresponding compound of formula (I) wherein R1 is —OR a  and R a  is a different C 1 -C 6  alkyl; 
     m.3) aminolysis of a compound of formula (I) wherein R 1  is —OR a  and R a  is C 1 -C 6  alkyl, by reaction with a compound of formula (XV):
 
HNR a R b   (XV)
 
     to give the corresponding compound of formula (I) wherein R1 is —NR a R b ; 
     m.4) esterification of a compound of formula (I) wherein R1 is a group —OH or its corresponding salt, by reactions with a compound of formula (XIV) as defined above, to give the corresponding compound of formula (I) wherein R1 is —OR a ; 
     m.5) amidation of a compound of formula (I) wherein R1 is a group —OH or its corresponding salt, by reaction with a compound of formula (XV) as defined above, to give the corresponding compound of formula (I) wherein R1 is —NR a R b . 
     The present invention further provides a process for the preparation of a compound of formula (I) as defined above, characterized in that the compound of formula (V) as defined above, is converted into another compound of formula (V), said conversions are carried out by one or more of the following reactions: 
     n.1) acid or basic hydrolysis of a compound of formula (V) wherein R1 is —OR a  and R a  is C 1 -C 6  alkyl, to give a compound of formula (V) wherein R1 is —OR a  and R a  is hydrogen, or the corresponding salt; 
     n.2) transesterification of a compound of formula (V) wherein R1 is —OR a  and R a  is C 1 -C 6  alkyl, by reaction with a compound of formula (XIV) as defined above, to give a compound of formula (V) wherein R1 is —OR a  and R a  is a different C 1 -C 6  alkyl; 
     n.3) amidation of a compound of formula (V) wherein R1 is —OR a  and R a  is C 1 -C 6  alkyl, by reaction with a compound of formula (XV) as defined above, to give a compound of formula (V) wherein R1 is —NR a R b ; 
     n.4) esterification of a compound of formula (V) wherein R1 is —OR a  and R a  is hydrogen, or the corresponding salt, by reaction with a compound of formula (XVI) as defined above, to give a compound of formula (V) wherein R1 is —OR a  and R a  is different from hydrogen; 
     n.5) amidation of a compound of formula (V) wherein R1 is —OR a  and R a  is hydrogen, by reaction with a compound of formula (XV) as defined above, to give a compound of formula (V) wherein R1 is —NR a R b    
     The present invention further provides a process for the preparation of a compound of formula (I) as defined above, characterized in that the compound of formula (XI) as defined above, is converted into another compound of formula (XI), said conversions are carried out by one or more of the following reactions: 
     o.1) acid or basic hydrolysis of a compound of formula (XI) wherein R1 is —OR a  and R a  is C 1 -C 6  alkyl, to give a compound of formula (XI) wherein R1 is —OR a  and R a  is hydrogen, or the corresponding salt; 
     o.2) transesterification of a compound of formula (XI) wherein R1 is —OR a  and R a  is C 1 -C 6  alkyl, by reaction with a compound of formula (XIV) as defined above, to give a compound of formula (XI) wherein R1 is —OR a  and R a  is a different C 1 -C 6  alkyl; 
     o.3) amidation of a compound of formula (XI) wherein R1 is —OR a  and R a  is C 1 -C 6  alkyl, by reaction with a compound of formula (XV) as defined above, to give a compound of formula (XI) wherein R1 is —NR a R b ; 
     o.4) esterification of a compound of formula (XI) wherein R1 is —OR a  and R a  is hydrogen, or the corresponding salt, by reaction with a compound of formula (XVI) as defined above, to give a compound of formula (XI) wherein R1 is —OR a  and R a  is different from hydrogen; 
     o.5) amidation of a compound of formula (XI) wherein R1 is —OR a  and R a  is hydrogen, by reaction with a compound of formula (XV) as defined above, to give a compound of formula (XI) wherein R1 is —NR a R b . 
     From all of the above, it is clear to the skilled person that if a compound of formula (I), (V), or (XI) prepared according to the above processes comprehensive of any variant thereof, 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. 
     Likewise, the conversion of a compound of formula (I) into a pharmaceutically acceptable salt thereof or, alternatively, the conversion into the free compound (I) of a corresponding salt, according to procedures well-known in the art, is still within the scope of the invention. 
     When preparing the compounds of formula (I) according to any variant of the process, which are all to be intended as within the scope of the invention, optional functional groups within the starting materials, the reagents or the intermediates thereof, and which could give rise to unwanted side reactions, need to be properly protected according to conventional techniques. 
     The starting materials of the process object of the present invention, comprehensive of any possible variant, as well as any reactant thereof, are known compounds and if not commercially available per se may be prepared according to well-known methods. For example, the compound of formula (II) is commercially available. 
     The compounds of formula (IV) are prepared starting from the corresponding 4-bromocrotonates that in their turn are commercially available or can be prepared according to well-known methods. 
     For example the 4-amino ethylcrotonate is prepared from the ethyl-4-bromo ethylcrotonate (XVI): 
     
       
         
         
             
             
         
       
     
     i) reacting it with commercially available diformylimide sodium salt (XVII): 
     
       
         
         
             
             
         
       
     
     l) hydrolyzing in acidic conditions the resultant compound of formula (XVIII): 
     
       
         
         
             
             
         
       
     
     to give the compound of formula (IV) wherein R a  is ethyl. 
     The compounds of formula (VI), (VII), (VIII), (XII), (XIII), (XIV) and (XV) are known or easily obtained according to known methods, for a general reference see: Smith, Michael—March&#39;s Advanced Organic Chemistry: reactions mechanisms and structure—5 th  Edition, Michael B. Smith and Jerry March, John Wiley &amp; Sons Inc., New York (NY), 2001. 
     The intermediate compound of formula (V): 
     
       
         
         
             
             
         
       
     
     wherein R1 is as defined above, is novel and hence represents a further object of the invention. 
     The intermediate compound of formula (XI): 
     
       
         
         
             
             
         
       
     
     wherein R1 is as defined above, is novel and hence represents a further object of the invention. 
     According to step (a) of the process, the nitration of the compound of formula (II) under acidic conditions can be carried out in a variety of ways according to conventional methods. Preferably, the reaction is carried out in the presence of nitric acid and acetic anhydride, at a temperature ranging from −40° C. to room temperature and for a time from 6 hours to overnight. 
     According to step (b) of the process, the conversion of the compound of formula (III) into the corresponding amido derivative of formula (V), can be carried out in a variety of ways according to conventional methods for obtaining amido derivatives from the corresponding α,α,α-trichloroketones. Preferably the reaction is carried out by reaction of an ammonium salt of formula (IV) in the presence of N,N-diisopropylethylamine, using dichloromethane as the solvent. 
     According to step (c) of the process, the reduction of the nitro group of the compound of formula (V) to give a compound of formula (I) can be carried out in a variety of ways, according to conventional methods for reducing nitro group to the corresponding amino derivative. Preferably the reaction is carried out in the presence of palladium on carbon in ethanol and hydrochloric acid, under an atmosphere of hydrogen at room temperature for a time ranging from 6 to 8 hours. 
     According to any one of steps (d.1) to (d.3) the preparation of functionalized amino derivatives starting from the corresponding amine can be carried out in a variety of ways, according to conventional methods. 
     Preferably according to step (d.1) and (d.3) of the process, the compound of formula (I) is dissolved in a suitable solvent such as dichloromethane, N,N-dimethylformamide, N,N-dimethylacetamide, tetrahydrofuran, dioxane or the like, and a suitable base such as triethylamine, N,N-diisopropylethylamine or sodium carbonate is added therein. The compounds of general formula (VI) or (VIII) are then added and the mixture stirred for a time of about 2 hours to about 15 hours, at a temperature ranging from about 20° C. to about 80° C. A suitable catalyst such as dimethylamino pyridine may be optionally used. Preferably according to step (d.2) of the process, the reaction conditions are the same as above reported for steps (d.1) and (d.3) except that the base may not be required. The compound of general formula (VII) is then added and the mixture stirred as reported above for steps (d.1) and (d.3). 
     According to step (e) of the process, the iodination of the compound of formula (II) can be carried out in a variety of ways according to conventional methods. Preferably, the reaction is carried out under neutral conditions in the presence of iodine and silver trifluoroacetate, at a temperature ranging from 0° C. to 180 C and for a time from 5 hours to overnight. 
     According to step (f) of the process, the conversion of the compound of formula (IX) into the corresponding amido derivative of formula (X), can be carried out in a variety of ways, according to conventional methods for obtaining amido derivatives from the corresponding α,α,α-trichloroketones. Preferably, the reaction is carried out as described under step (b). 
     According to step (g) of the process, the cyclization of the compound of formula (X) into the corresponding derivative of formula (XIa) can be carried out in a variety of ways according to conventional methods. Preferably, the reaction is carried out using a base such as diaza(1,3)bicyclo[5.4.0]undecane and acetonitrile as the solvent. 
     According to any one of steps (h.1) and (h.2) the conversion of a compound of formula (XIa) into a compound of formula (I) can be carried out in a variety of ways, according to conventional methods. 
     Preferably the reaction of step (h.1) is carried out through the Suzuki coupling between an organoboronic derivative of formula (XII) and a compound of formula (XIa), to give the corresponding compound of formula (I) in the presence of a Pd-catalyst and a base such as sodium or cesium carbonate, in a mixture of solvents, such as dimethoxyethane and water, at a temperature varying from room temperature to 80° C. and for a time between 4 hours and overnight. 
     Preferably the reaction of step (h.2) is carried out through the Sonogashira coupling between an alkyne derivative of formula (XIII) and a compound of formula (XIa), to give the corresponding compound of formula (I) in the presence of a Pd-catalyst, a base such as triethylamine and an additive such as copper(I) iodide, using N,N-dimethylformamide as the solvent, at room temperature and for a time between 4 hours and overnight. 
     According to step (i) of the process, the substitution reaction of ethyl-4-bromocrotonate of formula (XVI) with diformylimide sodium salt of formula (XVII) to give a product of formula (XVIII) is carried out in refluxing acetonitrile for a time between 10 hours to overnight. 
     According to step (1) of the process, the acidic hydrolysis of a compound of formula (XVIII) to give a product of formula (IV) is carried out in a refluxing mixture of ethanol-trifluoroacetic acid for a time between 8 hours and overnight. 
     According to any one of steps (m.1) to (m.5) the conversion of a compound of formula (I) in another compound of formula (I), can be carried out in a variety of ways, according to conventional methods. 
     Preferably according to step (m.1) of the process, the hydrolysis of a compound of formula (I) wherein R1 is —OCH 2 CH 3 , to give the corresponding compound of formula (I) wherein R1 is —OH is carried out under acidic or basic conditions. Preferably, the reaction is carried out as described under step (a). According to the operative conditions being employed, the compound of formula (I) wherein R1 is —OH could be obtained either in its acidic form or, alternatively, as a salt. 
     Preferably according to step (m.2) of the process, the transesterification of a compound of formula (I) wherein R1 is —OCH 2 CH 3 , to give the corresponding compound of formula (I) wherein R1 is —OR a  and R a  is an alkyl different from ethyl, is carried out by reaction with a compound of formula (XV) in an appropriate solvent, such as the compound of formula (XV) itself or dioxane at the refluxing temperature, optionally in the presence of a suitable metal based catalysts, like dibutylin oxide or titanium alkoxides such as, for instance, titanium (IV) ethoxide, titanium (IV) isopropoxide and the like. 
     Preferably according to step (m.3) of the process, the aminolysis of a compound of formula (I) wherein R1 is —OCH 2 CH 3 , to give the corresponding compound of formula (I) wherein R1 is —NR a R b , is carried out in an appropriate solvent such as dioxane or dichloromethane optionally in the presence of a suitable metal based catalysts, like trimethyl aluminium. 
     Preferably according to step (m.4) of the process, the esterification of a compound of formula (I) wherein R1 is a group —OH to give the corresponding compound of formula (I) wherein R1 is —OR a , is carried out in the presence of a suitable condensing agent, for instance dicyclohexylcarbodiimide (DCC), 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide (EDC), 3,4-dihydro-3-hydroxy-4-oxo-1,2,3-benzotriazine (DHBT), O-benzotriazolyltetramethylisouronium tetrafluoroborate (TBTU), benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate (PyBOP), or 2-(1H-Benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU), in an appropriate solvent such as dichloromethane (DCM), N,N-dimethylformamide (DMF) or N,N-dimethylacetamide (DMA). 
     Preferably according to step (m.5) of the process, the amidation of a compound of formula (I) wherein R1 is a group —OH to give the corresponding compound of formula (I) wherein R1 is —NR a R b  can be carried out in a variety of ways, according to conventional methods for obtaining amido derivatives from the corresponding acids. Preferably, the reaction is carried out by reaction with compound of formula (XV) after activation of the carboxylic function of the compound of formula (I) by reaction with thionyl chloride, oxalyl chloride or alternatively in the presence of a suitable condensing agent, for instance dicyclohexylcarbodiimide (DCC), 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide (EDC), 3,4-dihydro-3-hydroxy-4-oxo-1,2,3-benzotriazine (HBTOH), O-benzotriazolyltetramethylisouronium tetrafluoroborate (TBTU) or benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate (PyBOP), in an appropriate solvent such as dichloromethane, and/or N,N-dimethylformamide or N,N-dimethylacetamide. According to any one of steps (n.1) to (n.5) the conversion of a compound of formula (V) into another compound of formula (V) can be carried out in a variety of ways, according to conventional methods. 
     Preferably it is carried out as described under the steps from (m.1) to (m.5). According to any one of steps (o.1) to (on.5) the conversion of a compound of formula (XI) into another compound of formula (XI) can be carried out in a variety of ways, according to conventional methods. 
     Preferably it is carried out as described under the steps from (m.1) to (m.5). In addition to the above, the compounds of formula (I) may be advantageously prepared according to combinatorial chemistry techniques widely known in the art, by accomplishing the aforementioned reactions between the intermediates in a serial manner and by working under solid-phase-synthesis (SPS) conditions. 
     As an example, the intermediate carboxy ester derivatives of formula (Va) being obtained in step (b) of the above processes, can be first converted into the free carboxy acid derivative by means of hydrolysis carried out according to conventional methods, then easily supported onto a polymeric resin, for instance through the formation of a carboxamido group. 
     The intermediate thus supported may be subsequently reacted according to the remaining steps of the process. 
     The above synthetic pathway can be summarized as follows: 
     
       
         
         
             
             
         
       
     
     wherein the resin is a commercially available polystyrenic resin including, for instance, Wang resin, Trityl resin, Cl-trityl resin, Rink amide resin, Tentagel OH resin and derivatives thereof, R2″ and R a  are as defined above. 
     Any of the above reactions is carried out according to known methods, by working as formerly reported, and allows obtaining compounds of formula (I) as set forth above. According to a preferred embodiment of the invention, the polystyrenic resin is a derivatized formyl polystyrenic resin which may be obtained by reacting a commercially available formyl polystyrenic resin, e.g. 4-(4-formyl-3-methoxyphenoxy)butyryl AM resin, with a suitable amino derivative under reductive conditions, for instance in the presence of sodium triacetoxyborohydride and derivatives thereof, substantially as follows: 
     
       
         
         
             
             
         
       
     
     The reaction may be carried out in a suitable solvent such as tetrahydrofuran and in the presence of acetic acid. 
     The polymer-supported-amino derivatives thus obtained, particularly those, which are referable to as derivatized formyl polystyrenic resin above, are widely known in the art. In general, amines loaded onto formylpolystyrenic resins also known as Acid Sensitive Methoxyl)enzaldehyde polystyrene resins (AMEBA resin) are prepared by standard reductive amination in the presence of an excess of amine in TMOF/DCE and NaBH(OAc) 3  or AcOH/DMF and NaCNBH 3 , for instance as reported in Tetrahedron Letters (1997), 38, 7151-7154; J. Am. Chem. Soc. (1998), 120, 5441; and Chem. Eur. J. (1999), 5, 2787. 
     Therefore, it is a further object of the present invention a process for preparing the compounds of formula (I), and the pharmaceutically acceptable salts thereof, which process comprises: 
     p) hydrolyzing under acid or basic conditions the compound of formula (V) wherein R1 is —OR a  and R a  is C 1 -C 6  alkyl; 
     r) reacting the resultant acid derivative with a derivatized formyl polystyrenic resin of formula (XIX):
 
(P)—CH 2 —NHR a   (XIX)
 
     wherein (P) is the resin and R a  is as defined above; 
     s) reacting of the resultant compound of formula (XX): 
     
       
         
         
             
             
         
       
     
     wherein (P) and R a  are as described above, with a suitable reducing agent such as chromium (II) chloride, tetrabutylammonium hydrogen sulfide or tin (II) chloride; and 
     t) reacting the resultant compound of formula (XXI): 
     
       
         
         
             
             
         
       
     
     wherein (P) and R a  are as described above, as described under any one of steps (d.1) or (d.2); 
     u) cleaving the resin under acidic conditions from the resultant compound of formula (XXII): 
     
       
         
         
             
             
         
       
     
     to give a compound of formula (I), wherein R2″ is —NHCOR c  or —NHCONHR c , wherein R c  is as defined above, and R1 is —NHR a , wherein R a  is as defined above; 
     optionally separating the resultant compound of formula (I) into the single isomers; converting the resultant compound of formula (I) into a different compound of formula (I) and/or into a pharmaceutically acceptable salt if desired. 
     According to step (p) of the process, the hydrolysis of a compound of formula (Va), to give the corresponding compound of formula (V) wherein R1 is —OH is carried out as described under step (m.1). 
     According to step (r) of the process, the reaction with the polystyrene resin is performed in a suitable solvent, for instance DMF, in the presence of N,N-diisopropylethylamine (DIPEA) and of a suitable condensing agent such as, for instance, benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate (PyBOP), O-benzotriazolyl tetramethylisouronium tetrafluoroborate (TBTU) or 2-(1H-Benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU). 
     According to step (s) of the process, the supported compound of formula (XX) is reduced to obtain the corresponding amino derivative; the reaction is carried out in the presence of tin (II) chloride in dimethylformamide (DMF) at room temperature for a time ranging from 4 to 24 hours. 
     According to step (t), the supported compound of formula (XXI) is optionally further reacted to give to a variety of compounds functionalised in position 4 of the 3,4-dihydro-2H-pyrrolo[1,2-a]pyrazin-1-one ring, as described under any one of steps from (d.1) and (d.2). 
     According to step (u), the cleavage of the resin is performed under acidic conditions in the presence of suitable acids such as, for instance, hydrochloric, trifluoroacetic, methanesulfonic or p-toluensulfonic acid. Preferably the reaction is carried out using trifluoroacetic acid in dichloromethane as solvent. 
     As another example, the intermediate carboxy ester derivatives of formula (XIa) being obtained in step (g) of the above processes, can be first converted into the free carboxy acid derivative by means of hydrolysis carried out according to conventional methods, then easily supported onto a polymeric resin, for instance through the formation of a carboxamido group. 
     The intermediate thus supported may be subsequently reacted according to the remaining steps of the process. 
     The above synthetic pathway can be summarized as follows: 
     
       
         
         
             
             
         
       
     
     wherein R2, R2′″, R a  and the resin are as defined above. 
     Therefore, it is a further object of the present invention a process for preparing the compounds of formula (I), and the pharmaceutically acceptable salts thereof, which process comprises: 
     v) hydrolyzing under acid or basic conditions the compound of formula (XI) wherein R1 is —OR a  and R a  is C 1 -C 6  alkyl; 
     w) reacting the resultant acid derivative with a derivatized formyl polystyrenic resin of formula (XIX):
 
(P)—CH 2 —NHR a   (XIX)
 
     wherein (P) is the resin and R a  is as defined above; 
     z) reacting of the resultant compound of formula (XXIII): 
     
       
         
         
             
             
         
       
     
     wherein (P) and R a  are as described above, with a boronic acid or ester of formula (XII):
 
R2′″B(OZ″Z′″) 2   (XII)
 
     wherein R2′″ is R d  and R d  is a group optionally further substituted, selected from straight or branched C 1 -C 6  alkyl, C 3 -C 6  cycloalkyl, cycloalkyl C 1 -C 6  alkyl, heterocyclyl, heterocyclyl C 1 -C 6  alkyl, aryl, aryl C 1 -C 6  alkyl, heteroaryl or heteroaryl C 1 -C 6  alkyl, and Z″ and Z′″ are as defined above; 
     x) cleaving the resin under acidic conditions from the resultant compound of formula (XXVI): 
     
       
         
         
             
             
         
       
     
     to give a compound of formula (I), wherein R2′″ is as defined above and R1 is —NHR a , 
     wherein R a  is as defined above, optionally separating the resultant compound of formula (I) into the single isomers; converting the resultant compound of formula (I) into a different compound of formula (I) and/or into a pharmaceutically acceptable salt if desired. 
     According to step (v) of the process, the hydrolysis of a compound of formula (XIa) is carried out as described under step (m.1) and step (p). 
     According to step (w) of the process, the reaction with the polystyrene resin is performed as described under step (r). 
     According to step (z) of the process, the reaction with the boronic acid or ester of formula (XII) wherein R2′″ is aryl or heteroaryl, is performed as described under step (h.1). 
     According to step (x) of the process, the cleavage of the resin is performed as described under step (u). 
     Clearly, by working according to combinatorial chemistry techniques as formerly indicated, a plurality of compounds of formula (I) may be obtained. 
     Hence, it is a further object of the present invention a library of two or more compounds of formula (I) 
     
       
         
         
             
             
         
       
     
     wherein 
     R1 is a group —NR a R b  or —OR e ; 
     R2 is —NH 2 , —NHCOR c , —NHCONHR c , —NHSO 2 R c , —C≡CR d  or R d    
     wherein R a , R b , R c  and R d , the same or different, are each independently hydrogen or a group optionally further substituted, selected from straight or branched C 1 -C 6  alkyl, C 2 -C 6  alkenyl or C 2 -C 6  alkynyl, C 3 -C 6  cycloalkyl, cycloalkyl C 1 -C 6  alkyl, heterocyclyl, heterocyclyl C 1 -C 6  alkyl, aryl, aryl C 1 -C 6  alkyl, heteroaryl and heteroaryl C 1 -C 6  alkyl, or R a  and R b , taken together with the nitrogen atom to which they are bonded, may form an optionally substituted 3 to 7 membered heterocyclyl or heteroaryl, optionally containing one additional heteroatom or heteroatomic group selected from S, O, N or NH, and pharmaceutically acceptable salts thereof. 
     According to a preferred embodiment of the invention, the aforementioned library comprises the compounds of formula (I) wherein R1 is a group —NR a R b  and R a  and R b  are both hydrogen atoms or one of them is a hydrogen atom and the remaining one of R a  or R b  is a straight or branched C 1 -C 6  alkyl or C 2 -C 6  alkenyl group or it is an optionally substituted aryl or aryl C 1 -C 6  alkyl group. 
     Also preferred is a library of compounds of formula (I) wherein R2 is a group —NHCOR c  with R c C as a straight or branched C 1 -C 6  alkyl, cycloalkyl or optionally substituted aryl or arylalkyl group. 
     Also preferred is a library of compounds of formula (I) wherein R2 is a group —NHCONHR c  with R c  as a hydrogen atom or as a straight or branched C 1 -C 6  alkyl, optionally substituted aryl or arylalkyl group. 
     For a general reference to the above libraries of compounds of formula (I) see the experimental section. 
     From all of the above, it is clear to the skilled person that once a library of 3,4-dihydro-2H-pyrrolo[1,2-a]pyrazin-1-one derivatives is thus prepared, for instance consisting of about a thousands of compounds of formula (I), the said library can be very advantageously used for screening towards given kinases, as formerly reported. 
     See, for a general reference to libraries of compounds and uses thereof as tools for screening biological activities, J. Med. Chem. 1999, 42, 2373-2382; and Bioorg. Med. Chem. Lett. 10 (2000), 223-226. 
     Pharmacology 
     The inhibiting activity of putative kinase inhibitors and the potency of selected compounds is determined through a method of assay based on the use of the Kinase-Glo® Luminescent Kinase Assay (commercially available from Promega corporation and described in Koresawa, M. and Okabe, T. (2004) High-throughput screening with quantitation of ATP consumption: A universal non-radioisotope, homogeneous assay for protein kinase.  Assay Drug Dev. Technol.  2, 153-60). 
     The depletion of ATP as a result of kinase activity can be monitored in a highly sensitive manner through the use of Kinase-Glo® or Kinase-Glo® Plus Reagent, which uses luciferin, oxygen and ATP as substrates in a reaction that produces oxyluciferin and light. 
     The short forms and abbreviations used herein have the following meaning: 
     BSA bovine serum albumine 
     Tris 2-Amino-2-(hydroxymethyl)-1,3-propanediol 
     Hepes N-(2-Hydroxyethyl)piperazine-N′-(2-ethanesulfonic acid) 
     DTT threo-1,4-Dimercapto-2,3-butanediol 
     THF tetrahydrofuran 
     MTBE methyl tertiary butyl ether 
     DIPEA N,N-diisopropylethylamine 
     PyBOP benzotriazol-1-yloxytris(pyrrolidino)phosphonium exafluorophosphate 
     EDC 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide 
     DHBT 3,4-dihydro-3-hydroxy-4-oxo-1,2,3-benzotriazine 
     HBTU 2-(1H-Benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate 
     TFA trifluoroacetic acid 
     TMOF trimethyl orto formate 
     DCE dichloroethane 
     DCM dichloromethane 
     DMF N,N-dimethylformammide 
     DMA N,N-dimethylacetamide 
     DMSO dimethylsulfoxide 
     KDa kiloDalton 
     mg milligram 
     μg microgram 
     ng nanogram 
     L liter 
     mL milliliter 
     μL microliter 
     M molar 
     mM millimolar 
     IM micromolar 
     nM nanomolar 
     Kinase reaction conditions are target (enzyme) dependent and thus undergo individual adaptations. The Kinase-Glo® Luminescent Kinase Assay can be used with virtually any kinase and substrate combination. 
     Also the buffer conditions may vary depending on the kinase of interest (e.g for PKA a composition of 40 mM Tris pH 7.5, 20 mM MgCl 2 , 0.1 mg/ml BSA, in 50 μl final volume is used). Typically the range of ATP titration is 0.1 μM to 10 μM. 
     The optimal kinase substrate results in the greatest change in luminescence when comparing kinase reaction wells with no kinase wells. 
     The optimal amount of kinase is determined by making two fold serial dilutions across plates using the optimal amount of ATP and optimal kinase substrate. The optimal amount of kinase to use in subsequent compound screens and IC 50  determinations is the amount required for luminescence to be within the linear range of the kinase titration curve (sigmoidal dose response). 
     Robotized Kinase-Glo® Assay 
     This assay was set up for the measurement of kinase activity and/or inhibition. It is homogeneous, suitable for all type of protein kinases, quick and radioactivity-free. 
     We established the assay in 384 well-plates: the test mix consisted of: 
     1) 3× Enzyme mix (done in Kinase Buffer 3×), 5 μl/well 
     2) 3× substrate and ATP mix (done in ddH 2 O), 5 μl/well 
     3) 3× compound of formula (I) (diluted into ddH 2 O—3% DMSO)-5 μl/well) 
     As an outcome, the percentage of inhibition at 10 μM was evaluated for each compound tested: see below for compound dilution and assay scheme. Each enzyme had its own buffer constitution, substrate type and concentration. Incubation time instead was 90 min for all targets. 
     Test compounds were received as a 1 mM solution in 100% DMSO into 96 well plates. The plates were diluted to 30 μM in ddH 2 O, 3% DMSO; 4 plates are reorganized in 384 well plate by dispensing 5 μl of each 96 wp into the four quadrants of a 384 wp. In well P23 and P24 the internal standard inhibitor staurosporine was added. 
     Assay Scheme 
     Test plates were first added with 5 μl of the compound dilution (30 μM, corresponding to 3× dilution) and then loaded onto a robotized station together with one reservoir for the Enzyme mix (3×) and one for the ATP mix (3×), specific for each target under study. 
     To start the assay, the robot aspirated 5 μl of ATP/Substrate mix, made an air gap inside the tips (5 μl) and aspirated 5 μl of Enzyme mix. The subsequent dispensation into the test plates allowed the kinase reaction to start after 3 cycles of mixing, done by the robot itself by up and down pipetting. At this point, the correct concentration was restored for all reagents. 
     The robot incubated the plates for 90 minutes at room temperature, and then stopped the reaction by pipetting 15 μl of Kinase-Glo® reagent into the reaction mix. Three cycles of mixing were done immediately after the addition of the reagent. 
     The principle of the Kinase-Glo® technique is the presence in the reagent mixture of oxygen, luciferin and luciferase enzyme: in the presence of ATP, remaining from the kinase reaction, oxi-luciferin is produced with the emission of light, directly dependent on the amount of ATP. For optimal performances of this technique, the kinase reaction should utilize at least 15-20% of the available ATP. 
     After another 60 minutes of incubation to stabilize the luminescent signal, the plates were read on a ViewLux® instrument. Data were analyzed using the software package Assay Explorer® that provided percent inhibition data. 
     As example herein are reported the assay conditions used for testing the compounds of formula (I) against ALK (the ALK protein was prepared as described in WO2009013126, the substrate ALKtide YFF APCo was obtained in batches of &gt;95% peptide purity from American Peptide Company, Inc. (Sunnyvale, Calif., USA). 
     Assay Conditions: 
     ATP concentration: 1 μM 
     Enzyme concentration: 100 nM 
     Substrate concentration ALKtide YFF APCo: 80 μM 
     Reaction buffer: Hepes 50 mM pH 7.5, MgCl2 5 mM, MnCl2 1 mM, DTT 1 mM, NaVO 3  3 uM, 0.2 mg/ml BSA 
     Assay procedure: add 5 ul compound of formula (I) (3×), add 5 μl ATP/S mix(3×) in buffer 1x; add 5 μl enzyme in buffer 2x+3×BSA; for the blank, add 5 μl buffer 2x+3x BSA without enzyme. After 90 minutes of incubation, add 15 μl/well of Kinase-Glo reagent. After 60-90 minutes of incubation to stabilize the luminescent signal, the plates are read on a ViuwLux instrument. 
     The compounds of the present invention were found active at a concentration from to 10000 nM. 
     Biochemical Assay for Inhibitors of PIM-1 Kinase Activity 
     The inhibitory activity of putative kinase inhibitors and the potency of selected compounds were determined using a trans-phosphorylation assay. 
     Specific peptide or protein substrates are trans-phosphorylated by their specific ser-thr or tyr kinase in the presence of ATP traced with  33 P-γ-ATP, and in the presence of their own optimal buffer and cofactors. 
     At the end of the phosphorylation reaction, more than 98% unlabeled ATP and radioactive ATP is captured by an excess of the ion exchange dowex resin; the resin then settles down to the bottom of the reaction plate by gravity. 
     Supernatant is subsequently withdrawn and transferred into a counting plate, then evaluated by β-counting. 
     Reagents/Assay Conditions 
     i. Dowex Resin Preparation 
     500 g of wet resin (SIGMA, custom prepared resin DOWEX 1×8 200-400 mesh, 2.5 Kg) are weighed out and diluted to 2 1 in 150 mM sodium formate, pH 3.00. 
     The resin is allowed to settle down (some hours) and then the supernatant is discarded. 
     After three washes as above over a couple of days, the resin is allowed to settle and two volumes (wrt the resin volume) of 150 mM sodium formate buffer are added. 
     The pH is then measured and should be around 3.00 
     The washed resin is stable for more than one week; the stock resin is kept at 4° C. before use. 
     ii. Kinase Buffer (KB) 
     The buffer for PIM-1 assay was composed of HEPES 50 mM, at pH 7.5, with 10 mM MgCl 2 , 1 mM DTT, 3 μM NaVO 3 , and 0.2 mg/ml BSA 
     Full-length human PIM-1 was expressed and purified as described in Bullock A N, et Al J. Biol. Chem. 2005, 280, 41675-82. 
     The enzyme showed a linear kinetic after a step of pre-activation by auto-phosphorylation in the following conditions: 
     1.7 μM PIM1 was incubated 1 hour RT at 280 C in the presence of 125 μM ATP 
     Iii. Assay Conditions 
     ATP concentration: 200 μM 
       33 P-μ-ATP: 6 nM 
     Enzyme concentration: 1 nM 
     Substrate concentration Aktide (Chemical Abstract Service Registry Number 324029-01-8): 25 μM 
     Robotized Dowex Assay 
     The test mix consisted of: 
     1) 3× Enzyme mix (done in Kinase Buffer 3×), 5 μL/well 
     2) 3× substrate and ATP mix (done in ddH 2 O), together with  33 P-γ-ATP, 5 μL/well 
     3) 3× test compounds (diluted into ddH 2 O-3% DMSO)-5 μL/well 
     See below for compound dilution and assay scheme 
     Compound Dilution and Assay Scheme is Defined Below: 
     i. Dilution of Compounds 
     Test compounds are received as a 1 mM solution in 100% DMSO, distributed into 96 or 384 well plates: 
     a) for percent inhibition studies (HTS), individual dilution plates at 1 mM are diluted at a 3× concentration (30 μM) in ddH 2 O (3% DMSO=final concentration) using a Beckman NX automated pipetting platform. The same instrument is used for distributing the diluted mother plates into the test plates. 
     b) for IC50 determination (KSS platform), 100 μ1 of each compound at 1 mM in 100% DMSO are transferred from the original plate into the first column of another 96 well plate (A1 to G1); well H1 is left empty for the internal standard inhibitor, usually staurosporine. 
     An automated station for serial dilutions (Biomek FX, Beckman) is used for producing 1:3 dilutions in 100% DMSO, from line A1 to A10, and for all the seven compounds in the column. Moreover, 4-5 copies of daughter plates are prepared by reformatting 5 μL of this first set of 100% DMSO dilution plates into 384 deep well-plates: one copy of the daughter plates with the serial dilutions of test compounds will be thaw the day of the experiments, reconstituted at a 3× concentration with water and used in the IC50 determination assays. In a standard experiment, the highest concentration (3×) of all compounds is 30 μM, while the lowest one is 1.5 nM. 
     Each 384 well-plate will contain reference wells (total enzyme activity vs. no enzymatic activity) for the Z′ and signal to background evaluation. 
     ii. Assay Scheme 
     384-well plates, V bottom (test plates) are prepared with 5 μL of the compound dilution (3×) and then placed onto a PlateTrak 12 robotized station (Perkin Elmer; the robot has one 384-tips pipetting head for starting the assay plus one 96-tips head for dispensing the resin) together with one reservoir for the Enzyme mix (3×) and one for the ATP mix (3×). At the start of the run, the robot aspirates 5 μL of ATP mix, makes an air gap inside the tips (2 μL) and aspirates 2 μL of PIM mix. The following dispensation into the plates allows the kinase reaction to start upon 3 cycles of mixing, done by the robot itself. 
     At this point, the correct concentration is restored for all reagents. 
     The robot incubates the plates for 60 minutes at room temperature, and then stops the reaction by pipetting 70 μL of dowex resin suspension into the reaction mix. Three cycles of mixing are done immediately after the addition of the resin. 
     The resin suspension is very dense; in order to avoid tip clogging, wide bore tips are used to dispense it. 
     Another mixing cycle is performed after all the plates are stopped, this time using normal tips: the plates are then allowed to rest for about one hour in order to maximize ATP capture. At this point, 20 μL of the supernatant are transferred into 384-Optiplates (Perkin-Elmer), with 70 μL of Microscint 40 (Perkin-Elmer); after 5 min of orbital shaking the plates are read on a Perkin-Elmer Top Count radioactivity counter. 
     iii. Data Analysis 
     Data are analysed by an internally customized version of the SW package “Assay Explorer” that provides either % inhibition for primary assays or sigmoidal fittings of the ten-dilutions curves for IC50 determination in the secondary assays/hit confirmation routines. 
     Biochemical assay for inhibitors of PIM-2 kinase activity 
     The inhibitory activity of putative kinase inhibitors and the potency of selected compounds were determined using a trans-phosphorylation assay as described above for PIM-1. 
     i. Kinase Buffer (KB) 
     The buffer for PIM-2 assay was composed of HEPES 50 mM, at pH 7.5, with 1 mM MgCl 2 , 1 mM DTT, 3 μM NaVO 3 , and 0.2 mg/ml BSA 
     Full-length human PIM-2 was expressed and purified as described in Fedorov O, et al, PNAS 2007 104, 51, 20523-28). 
     ii. Assay Conditions 
     ATP concentration: 4 μM 
       33 P-μ-ATP: 1 nM 
     Enzyme concentration: 1.5 nM 
     Substrate concentration Aktide (Chemical Abstract Service Registry Number 324029-01-8): 5 μM 
     The enzyme showed a linear kinetic without the need of any step of pre-activation. 
     Robotized Dowex Assay 
     See the same procedure described for PIM-1. 
     The compounds of the present invention showed IC50 of less 10 μM when tested against PIM-1 and PIM-2, see table A below for some examples. 
     In Table A, the tested compounds are identified with a code that is explained below. When the diastereoisomers are resolved, the chirality is to be intended on the 3,4-dihydro-2H-pyrrolo[1,2-a]pyrazin-1-one scaffold. 
     
       
         
           
               
               
               
               
             
               
                   
                 TABLE A 
               
               
                   
                   
               
               
                   
                   
                 PIM-1 
                 PIM-2 
               
               
                   
                 Compound 
                 IC50 μM 
                 IC50 μM 
               
               
                   
                   
               
             
            
               
                   
               
            
           
           
               
               
               
               
            
               
                   
                 A33-M-B22 
                 0.46 
                 5.03 
               
               
                   
                 A33-M-B30 
                 0.58 
                 1.92 
               
               
                   
                 A127-M-B14 
                 0.18 
                 2.74 
               
               
                   
                 A127-M-B22 
                 0.07 
                 2.46 
               
               
                   
                 A127-M-B30 
                 0.19 
                 1.67 
               
               
                   
                 A127-M-B32 
                 0.61 
                 10 
               
               
                   
                 A127-M-B39 
                 0.57 
                 1.15 
               
               
                   
                 A127-M-B40 
                 0.23 
                 4.81 
               
               
                   
                 A127-M-B47 
                 0.52 
                 2.25 
               
               
                   
                 A128-M-B14 
                 0.20 
                 2.11 
               
               
                   
                 A128-M-B22 
                 0.12 
                 3.12 
               
               
                   
                 A128-M-B30 
                 0.27 
                 2.03 
               
               
                   
                 A128-M-B32 
                 0.70 
                 7.55 
               
               
                   
                 A128-M-B39 
                 0.54 
                 0.87 
               
               
                   
                 A128-M-B40 
                 0.25 
                 4.50 
               
               
                   
                 A129-M-B14 
                 0.28 
                 4.51 
               
               
                   
                 A129-M-B22 
                 0.13 
                 5.92 
               
               
                   
                 A129-M-B30 
                 0.12 
                 1.25 
               
               
                   
                 A132-M-B22 
                 0.36 
                 10 
               
               
                   
                 A133-M-B14 
                 0.81 
                 7.40 
               
               
                   
                 A133-M-B22 
                 0.38 
                 10 
               
               
                   
                 A133-M-B28 
                 0.84 
                 3.13 
               
               
                   
                 A133-M-B30 
                 0.61 
                 3.62 
               
               
                   
                 A134-M-B14 
                 0.72 
                 7.22 
               
               
                   
                 A134-M-B28 
                 0.36 
                 1.50 
               
               
                   
                 A134-M-B30 
                 0.89 
                 5.80 
               
               
                   
                 A137-M-B14 
                 0.40 
                 3.46 
               
               
                   
                 A137-M-B39 
                 0.92 
                 3.56 
               
               
                   
                 A139-M-B14 
                 0.22 
                 3.44 
               
               
                   
                 A139-M-B22 
                 0.09 
                 4.47 
               
               
                   
                 A139-M-B30 
                 0.41 
                 3.37 
               
               
                   
                 A139-M-B39 
                 0.98 
                 3.05 
               
               
                   
                 A139-M-B40 
                 0.13 
                 2.22 
               
               
                   
                 A140-M-B30 
                 0.49 
                 10 
               
               
                   
                 A142-M-B14 
                 4.83 
                 6.62 
               
               
                   
                 A142-M-B28 
                 3.72 
                 4.15 
               
               
                   
                 A142-M-B30 
                 2.52 
                 2.58 
               
               
                   
                 A144-M-B14 
                 10.00 
                 4.92 
               
               
                   
                 A144-M-B22 
                 0.48 
                 0.66 
               
               
                   
                 A144-M-B30 
                 1.10 
                 0.68 
               
               
                   
                 A150-M-B14 
                 0.14 
                 1.52 
               
               
                   
                 A150-M-B24 
                 0.21 
                 4.06 
               
               
                   
                 A150-M-B25 
                 0.45 
                 5.86 
               
               
                   
                 A150-M-B26 
                 0.24 
                 5.51 
               
               
                   
                 A150-M-B32 
                 0.23 
                 4.49 
               
               
                   
                 A150-M-B36 
                 1.39 
                 8.98 
               
               
                   
                 A150-M-B38 
                 1.06 
                 7.51 
               
               
                   
                 A150-M-B39 
                 0.22 
                 0.60 
               
               
                   
                 A150-M-B40 
                 0.04 
                 0.98 
               
               
                   
                 A150-M-B42 
                 0.59 
                 10 
               
               
                   
                 A150-M-B43 
                 0.79 
                 5.89 
               
               
                   
                 A150-M-B45 
                 0.58 
                 4.65 
               
               
                   
                 A150-M-B48 
                 0.12 
                 2.86 
               
               
                   
                 A150-M-B49 
                 0.23 
                 1.61 
               
               
                   
                 A150-M-B52 
                 0.43 
                 5.17 
               
               
                   
                 A151-M-B14 
                 0.10 
                 2.25 
               
               
                   
                 A151-M-B32 
                 0.49 
                 10 
               
               
                   
                 A151-M-B39 
                 4.11 
                 3.69 
               
               
                   
                 A133-M-B61 
                 5.94 
                 10 
               
               
                   
                 isomer R 
               
               
                   
                 A127-M-B61 
                 0.38 
                 3.90 
               
               
                   
                 isomer R 
               
               
                   
                 A157-M-B61 
                 0.27 
                 2.83 
               
               
                   
                 isomer R 
               
               
                   
                 A158-M-B61 
                 0.86 
                 5.55 
               
               
                   
                 isomer R 
               
               
                   
                 A133-M-B61 
                 0.07 
                 4.79 
               
               
                   
                 isomer S 
               
               
                   
                 A127-M-B61 
                 0.02 
                 0.25 
               
               
                   
                 isomer S 
               
               
                   
                 A133-M-B62 
                 4.83 
                 10 
               
               
                   
                 isomer R 
               
               
                   
                 A127-M-B62 
                 1.84 
                 2.62 
               
               
                   
                 isomer R 
               
               
                   
                 A157-M-B62 
                 1.14 
                 1.05 
               
               
                   
                 isomer R 
               
               
                   
                 A158-M-B62 
                 0.55 
                 0.66 
               
               
                   
                 isomer R 
               
               
                   
                 A133-M-B62 
                 0.13 
                 1.33 
               
               
                   
                 isomer S 
               
               
                   
                 A127-M-B62 
                 0.09 
                 0.52 
               
               
                   
                 isomer S 
               
               
                   
                 A133-M-B63 
                 2.54 
                 10 
               
               
                   
                 A127-M-B63 
                 0.39 
                 2.44 
               
               
                   
                 A157-M-B63 
                 0.69 
                 2.37 
               
               
                   
                 A158-M-B63 
                 0.40 
                 3.05 
               
               
                   
                 A133-M-B64 
                 2.04 
                 10 
               
               
                   
                 isomer R 
               
               
                   
                 A127-M-B64 
                 2.91 
                 10 
               
               
                   
                 isomer R 
               
               
                   
                 A157-M-B64 
                 0.70 
                 2.81 
               
               
                   
                 isomer R 
               
               
                   
                 A133-M-B64 
                 0.56 
                 2.92 
               
               
                   
                 isomer S 
               
               
                   
                 A127-M-B64 
                 0.14 
                 0.68 
               
               
                   
                 isomer S 
               
               
                   
                 A133-M-B65 
                 0.05 
                 0.82 
               
               
                   
                 isomer S 
               
               
                   
                 A127-M-B65 
                 0.01 
                 0.18 
               
               
                   
                 isomer S 
               
               
                   
                 A157-M-B65 
                 0.01 
                 0.10 
               
               
                   
                 isomer S 
               
               
                   
                 A157-M-B65 
                 0.15 
                 0.50 
               
               
                   
                 isomer R 
               
               
                   
                 A158-M-B65 
                 0.03 
                 0.18 
               
               
                   
                 isomer S 
               
               
                   
                   
               
            
           
         
       
     
     From all of the above, the novel compounds of formula (I) of the invention appear to be particularly advantageous in the therapy of diseases caused by dysregulated protein kinase activity such as cancer. 
     The compounds of the present invention can be administered either as single agents or, alternatively, in 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), matrixmetalloprotease inhibitors, telomerase inhibitors, tyrosine kinase inhibitors, anti-growth factor receptor agents, anti-HER agents, anti-EGFR agents, anti-angiogenesis agents (e.g. angiogenesis inhibitors), 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. 
     If formulated as a fixed dose, such combination products employ the compounds of this invention within the dosage range described below and the other pharmaceutically active agent within the approved dosage range. 
     Compounds of formula (I) may be used sequentially with known anticancer agents when a combination formulation is inappropriate. 
     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 administration route. 
     For example, a suitable dosage adopted for oral administration of a compound of formula (I) may range from about 10 to about 500 mg per dose, from 1 to 5 times daily. The compounds of the invention can be administered in a variety of dosage forms, e.g., orally, in the form tablets, capsules, sugar or film coated tablets, liquid solutions or suspensions; rectally in the form suppositories; parenterally, e.g., intramuscularly, or through intravenous and/or intrathecal and/or intraspinal injection or infusion. 
     The present invention also includes pharmaceutical compositions comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof in association with a pharmaceutically acceptable excipient, which may be a carrier or a diluent. 
     The pharmaceutical compositions containing the compounds of the invention are usually prepared following conventional methods and are administered in a suitable pharmaceutical form. 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 acid, magnesium or calcium stearate, and/or polyethylene glycols; binding agents, e.g., starches, arabic gum, gelatine methylcellulose, carboxymethylcellulose or polyvinyl pyrrolidone; disintegrating agents, e.g., starch, alginic acid, alginates or sodium starch glycolate; effervescing mixtures; dyestuffs; sweeteners; wetting agents such as lecithin, polysorbates, laurylsulphates; and, in general, non-toxic and pharmacologically inactive substances used in pharmaceutical formulations. These pharmaceutical preparations may be manufactured in known manner, for example, by means of mixing, granulating, tabletting, sugar-coating, or film-coating processes. 
     The liquid dispersions for oral administration may be, e.g., syrups, emulsions and suspensions. As an example, the syrups may contain, as carrier, saccharose or saccharose with glycerine and/or mannitol and sorbitol. 
     The suspensions and the emulsions may contain, as examples of carriers, natural gum, agar, sodium alginate, pectin, methylcellulose, carboxymethylcellulose, or polyvinyl alcohol. 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 a carrier, sterile water or preferably they may be in the form of sterile, aqueous, isotonic, saline solutions or they may contain propylene glycol as a carrier. 
     The suppositories may contain, together with the active compound, a pharmaceutically acceptable carrier, e.g., cocoa butter, polyethylene glycol, a polyoxyethylene sorbitan fatty acid ester surfactant or lecithin. 
     With the aim of better illustrating the present invention, without posing any limitation to it, the following examples are now given. 
     EXPERIMENTAL SECTION 
     General Methods 
     Flash Chromatography was performed on silica gel (Merck grade 9395, 60A). The high-pressure liquid chromatography retention times (HPLC: r.t. values) were determined by: 
     HPLC Method 1: 
     A Waters Alliance LC mod. 2795 equipped with a variable UV detector mod 2487, a Chemiluminescence Nitrogen detector (CLND, Antek 8060) and a Waters ZQ2000 mass detector (ESI interface) was used in this application. The total flow was splitted and distributed to the three detectors at a fixed ratio (64:15:21 UV:MS:CLND). The liquid chromatograph was equipped with a 30×3.0 mm I.D. column (Waters xBridge C18, 3.5 um particles), thermostated at 50° C. Two mobile phases were used: phase A was 0.05% w/v formic acid (1 mL/L of 50% formic acid Fluka 09676 in highly purified water) and phase B was 70/25/5 (v/v/v) MeOH/iPrOH/H2O containing 0.035% w/v of formic acid (700 uL/L of 50% formic acid Fluka 09676). 
     A 5 uL volume of 1 mM nominal sample solution in DMSO was injected (sequential, partial loop mode with no air gaps) and a generic reversed phase gradient analysis (classified as method “#IN63SEQ79”) was carried out at 0.8 mL/min from 0% to 100% of phase B (v/v) over 5 min, held 0.7 min at 100% B and steeply reverted to 0% B at 5.71 min, with the run stop time set at 6.3 min. The total analysis time (“between injections”) was 7.9 min. The UV detector was operated at 220 nm, 5 Hz sampling rate. The MS device was operated at 3.2 kV capillary voltage, 30 V cone, 2 V extractor, 0.5 V RF lens, 400 L/hr desolvation flow, 100 L/hr cone flow, 100° C. source temperature, 150° C. desolvation temperature, ESI(+) full scan 120-1200 amu acquisition, at 1.7 Hz sampling rate. The CLND detector was operated at 1050° C. furnace temp, 280 mL/min inlet oxygen flow, 80 mL/min inlet argon, mL/min make-up argon, 30 mL/min ozone, 28 torr vacuum, 750 V PMT voltage, PMT chamber at +10° C., sensitivity high, select 5, 4 Hz sampling rate. 
     HPLC Method 2: 
     HPLC-MS analyses were performed on a Finnigan MAT mod. LCQ ion trap mass spectrometer, equipped with an ESI (Electrospray) ion source, the mass spectrometer is directly connected to a HPLC SSP4000 (Thermo Separation) equipped with an autosampler Lc Pal (CTC Analytics) and an UV6000LP PDA detector. 
     HPLC Conditions: 
     Column: Phenomenex Gemini C18, 3 μm, 50×4.6 mm (default) 
     Temperature 40° C. 
     Mobile phase A: Acetate Buffer 5 mM pH 4.5: acetonitrile 95:5 (v:v) 
     Mobile phase B: Acetate Buffer 5 mM pH 4.5: acetonitrile 5:95 (v:v) 
     Elution Gradient: 
     
       
         
           
               
               
               
             
               
                   
                   
               
               
                   
                 Time (min) 
                 % Mobile Phase A 
               
               
                   
                   
               
             
            
               
                   
               
            
           
           
               
               
               
            
               
                   
                 0 
                 100 
               
               
                   
                 7 
                 0 
               
               
                   
                 9 
                 0 
               
               
                   
                 11 
                 100 
               
               
                   
                 13 
                 100 
               
               
                   
                   
               
            
           
         
       
     
     Flow rate: 1 mL/minInjection volume: 10 μL 
     Column temperature: 40° C. 
     MS conditions: The LCQ mass spectrometer operates with an electrospray ionization (ESI) interface in positive and negative ion mode following the operation parameters reported in table 1. MS/MS experiments are performed on the most intense ion of each scan automatically by Xcalibur software. A 45% collision energy was used for the fragmentation of the precursor ions. 
                     TABLE 1                  Mass Spectrometer Instrument parameters                             Parameter   Value                                         Capillary Temperature (° C.)   255           Source Voltage (kV)   4.00           Capillary Voltage (V)   21.0           Tube Lens Offset (V)   −5.0           Multipole RF Amplifier (Vp-p)   400.0           Multipole 1 Offset (V)   −3.00           Multipole 2 Offset (V)   −6.50           InterMultipole Lens Voltage (V)   −16.00           Trap DC Offset Voltage (V)   −10.00           Full Micro scans   3           Full AGC Target Ions   5*10 7             Full Max Ion Time (ms)   150           MSn Micro scans   3           MSn AGC Target Ions   2*10 7             MSn Max Ion Time (ms)   200           Electron Multiplier (V)   −950.0                        
HPLC Method 3:
 
     HPLC-MS analyses were performed on a Finnigan MAT mod. LCQ ion trap mass spectrometer, equipped with an ESI (Electrospray) ion source, the mass spectrometer is directly connected to a HPLC SSP4000 (Thermo Separation) equipped with an autosampler Lc Pal (CTC Analytics) and an UV6000LP PDA detector. 
     HPLC conditions: 
     Column: Phenomenex Gemini C18, 3 μm, 50×4.6 mm (default) 
     Temperature 40° C. 
     Mobile phase A: Acetate Buffer 5 mM pH 4.5: acetonitrile 95:5 (v:v) 
     Mobile phase B: Acetate Buffer 5 mM pH 4.5: acetonitrile 5:95 (v:v)
         Elution gradient:       

     
       
         
           
               
               
               
             
               
                   
                   
               
               
                   
                 Time (min) 
                 % Mobile Phase A 
               
               
                   
                   
               
             
            
               
                   
               
            
           
           
               
               
               
            
               
                   
                 0 
                 100 
               
               
                   
                 2 
                 80 
               
               
                   
                 9 
                 60 
               
               
                   
                 10 
                 0 
               
               
                   
                 12 
                 0 
               
               
                   
                 12.10 
                 100 
               
               
                   
                   
               
            
           
         
       
     
     Flow rate: 1 mL/min 
     Injection volume: 10 μL 
     Column temperature: 40° C. 
     MS Conditions: 
     The LCQ mass spectrometer operates with an electrospray ionization (ESI) interface in positive and negative ion mode following the operation parameters reported in table 2. MS/MS experiments are performed on the most intense ion of each scan automatically by Xcalibur software. A 45% collision energy was used for the fragmentation of the precursor ions. 
                     TABLE 2                  Mass Spectrometer Instrument parameters                             Parameter   Value                                         Capillary Temperature (° C.)   255           Source Voltage (kV)   4.00           Capillary Voltage (V)   21.0           Tube Lens Offset (V)   −5.0           Multipole RF Amplifier (Vp-p)   400.0           Multipole 1 Offset (V)   −3.00           Multipole 2 Offset (V)   −6.50           InterMultipole Lens Voltage (V)   −16.00           Trap DC Offset Voltage (V)   −10.00           Full Micro scans   3           Full AGC Target Ions   5*10 7             Full Max Ion Time (ms)   150           MSn Micro scans   3           MSn AGC Target Ions   2*10 7             MSn Max Ion Time (ms)   200           Electron Multiplier (V)   −950.0                        
HPLC Method 4:
 
     Analyses were performed on a Waters Acquity UPLC™ System equipped with a 2996 PDA (UV-VIS), and Acquity ELSD™ detectors. The LC system was coupled to a Waters Acquity 3100 SQD™ single quadrupole mass spectrometer for atomic mass determinations. A Waters Acquity UPLC™ BEH C18, 1.7 μm, 2.1×50 mm column at 45° C. was used with a flow rate of 0.7 mL/min of the following binary solvent system and gradient. 
     Mobile Phase A: 0.1% Trifluoroacetic Acid in H 2 0/Acetonitrile (95:5) 
     Mobile Phase B: Acetonitrile/H 2 O (95:5) 
     
       
         
           
               
               
               
             
               
                   
               
               
                 Time (min) 
                 % Mobile Phase A 
                 % Mobile Phase B 
               
               
                   
               
             
            
               
                   
               
            
           
           
               
               
               
            
               
                 0.00 
                 95% 
                  5% 
               
               
                 2.00 
                  5% 
                 95% 
               
               
                   
               
            
           
         
       
     
     MS Conditions: 
     The LCQ mass spectrometer operates with an electrospray ionization (ESI) interface in positive and negative ion mode following the operation parameters reported in table 3. MS/MS experiments are performed on the most intense ion of each scan automatically by Xcalibur software. A 45% collision energy was used for the fragmentation of the precursor ions. 
                     TABLE 3               Mass Spectrometer Instrument parameters                                                Ionization Mode   ESI+ and ESI−                                 Capillary Voltage   3 kV (ES+);   3 kV (ES−)           Cone Voltage   30 V (ES+);   30 V (ES−)           Extractor Voltage   1   V           RF Lens Voltage   0.1   V           Source Temperature   120°   C.           Desolvation Temperature   350°   C.           Cone Gas Flow   100   L/Hr           Desolvation Gas Flow   600   L/Hr                             LM Resolution   15.0           HM Resolution   15.0           Ion Energy    0.3           Gain   1            Scan Mode   Full Scan (Range = 100-800 m/z)               ScanTime = 0.1 s               Inter-Scan Delay = 0.02 s                        
HPLC Method 5:
 
     Analyses were performed on a Waters Alliance HT 2795 System equipped with a 996 PDA (UV-VIS) detector. The LC system was coupled to a Waters/Micromass ZQ™ single quadrupole mass spectrometer for atomic mass determinations. A Waters Ascentis Express C18, 2.7 μm, 4.6×50 mm column was used with a flow rate of 1.0 mL/min of the following binary solvent system and gradient. 
     Mobile Phase A: 0.1% Trifluoroacetic Acid in H 2 O/Acetonitrile (95:5) 
     Mobile Phase B: Acetonitrile/H 2 O (95:5) 
     
       
         
           
               
               
               
             
               
                   
               
               
                 Time (min) 
                 % Mobile Phase A 
                 % Mobile Phase B 
               
               
                   
               
             
            
               
                   
               
            
           
           
               
               
               
            
               
                 0.00 
                 90% 
                 10% 
               
               
                 4.00 
                 10% 
                 90% 
               
               
                 4.10 
                  0% 
                 100%  
               
               
                   
               
            
           
         
       
     
     MS Conditions: 
     The LCQ mass spectrometer operates with an electrospray ionization (ESI) interface in positive and negative ion mode following the operation parameters reported in table 4. MS/MS experiments are performed on the most intense ion of each scan automatically by Xcalibur software. A 45% collision energy was used for the fragmentation of the precursor ions. 
     
       
         
           
               
             
               
                 TABLE 4 
               
               
                   
               
               
                 Mass Spectrometer Instrument parameters 
               
               
                   
               
             
            
               
                   
               
            
           
           
               
               
               
            
               
                   
                 Ionization Mode 
                 ESI+ and ESI− 
               
            
           
           
               
               
               
               
            
               
                   
                 Capillary Voltage 
                 3.48 kV (ES+); 
                 2.76 kV (ES−) 
               
               
                   
                 Cone Voltage 
                 15 V (ES+); 
                 27 V (ES−) 
               
               
                   
                 Extractor Voltage 
                 1 
                 V 
               
               
                   
                 RF Lens Voltage 
                 0.1 
                 V 
               
               
                   
                 Source Temperature 
                 120° 
                 C. 
               
               
                   
                 Desolvation Temperature 
                 240° 
                 C. 
               
               
                   
                 Cone Gas Flow 
                 100 
                 L/Hr 
               
               
                   
                 Desolvation Gas Flow 
                 600 
                 L/Hr 
               
            
           
           
               
               
               
            
               
                   
                 LM Resolution 
                 15.0 
               
               
                   
                 HM Resolution 
                 15.0 
               
               
                   
                 Ion Energy 
                  0.5 
               
               
                   
                 Multiplier 
                 600   
               
               
                   
                 Scan Mode 
                 Full Scan (Range = 100-800 m/z) 
               
               
                   
                   
                 ScanTime = 0.5 s; 
               
               
                   
                   
                 Inter-Scan Delay = 0.3 s 
               
               
                   
                   
               
            
           
         
       
     
     Retention times (HPLC r.t.) are given in minutes at 220 nm or at 254 nm. Mass is given as m/z ratio. 
     When necessary, the compounds were purified by preparative HPLC using one of the following two systems. A Waters X-Bridge Prep Shield RP 18 (19×100 mm, 5 μm) column or a Phenomenex Gemini C18 (21.2×250 mm, 10 μm) column, using a Waters FractionLynx Autopurification System equipped with a 996 Waters PDA detector and a Micromass mod. ZQ single quadrupole mass spectrometer, electron spray ionization, positive mode. Mobile phase A was water 0.05% NH 3 /acetonitrile 95:5, and Mobile phase B was acetonitrile. Gradient from 10 to 90% B in 8 min or 15 min. Flow rate 20 ml/min. 
     Alternatively, purifications were performed on a Biotage Parallex Flex System, equipped with four independent, binary flow-stream pumps, a UV detector with four-channel flow cell monitoring two wavelengths (220 and 254 nm), and four fraction collectors. Fractionation was performed at 254 nm. Waters XTerra Prep RP18, 5 μm, 100×19 mm columns were used at a flow rate of 20 mL/min. Gradients were applied according to the retention time of the desired product obtained from the analytical HPLC analysis. 
     Standard Binary Solvent System: 
     Mobile Phase A: 0.1% Trifluoracetic Acid in H 2 O/Acetonitrile (95:5) 
     Mobile Phase B: Acetonitrile 
     Gradient A: 
                                     Time (min)   % Mobile Phase A   % Mobile Phase B                                            0.0   100%     0%       6.0   80%   20%       8.0   80%   50%       8.5   50%   100%                     
Gradient B:
 
                                     Time (min)   % Mobile Phase A   % Mobile Phase B                                            0.0   100%     0%       6.0   70%   30%       8.0    0%   100%                     
Gradient C:
 
                                     Time (min)   % Mobile Phase A   % Mobile Phase B                                            0.0   100%     0%       6.0   50%   50%       8.0    0%   100%                     
Gradient D:
 
     
       
         
           
               
               
               
             
               
                   
               
               
                 Time (min) 
                 % Mobile Phase A 
                 % Mobile Phase B 
               
               
                   
               
             
            
               
                   
               
            
           
           
               
               
               
            
               
                 0.0 
                 90% 
                 10% 
               
               
                 6.0 
                 30% 
                 70% 
               
               
                 8.0 
                  0% 
                 100%  
               
               
                   
               
            
           
         
       
     
       1 H-NMR spectrometry was performed on a Bruker AVANCE 400 MHz single bay instrument with gradients. It is equipped with a QNP probe (interchangeable 4 nuclei probe— 1 H, 13C, 19F and 31P) (NMR method 1) or on a Mercury VX 400 operating at 400.45 MHz equipped with a 5 mm double resonance probe [1H (15N-31P) ID_PFG Varian] (NMR method 2). 
     The compounds of formula (I), having an asymmetric carbon atom and obtained as racemic mixture, were resolved by HPLC separation on chiral columns. In particular, for example, preparative columns CHIRALPACK® AD, CHIRALPACK® AS, CHIRALCELL® OJ can be used. 
     Alternatively, when R1 contains a chiral center and gives rise to a pair of diastereomers, traditional reversed phase HPLC techniques described above were utilized to resolve the species. 
     Some compounds prepared according to solution and combinatorial chemistry techniques have been conveniently and unambiguously identified, as per the coding system of tables III together with HPLC retention time (methods 1-5) and mass. 
     Each code, which identifies a single specific compound of formula (I), consists of three units A-M-B. 
     A represents any substituent R2—[see formula (I)] and is attached in position 7 of the 3,4-dihydro-2H-pyrrolo[1,2-a]pyrazin-1-one moiety; each A substituent is represented in the following table I. 
     B represents any substituent R1—[see formula (I)] and is attached to the rest of the 3,4-dihydro-2H-pyrrolo[1,2-a]pyrazin-1-one moiety through the carbon atom of the carbonyl group so as to get 3,4-dihydro-2H-pyrrolo[1,2-a]pyrazin-1-one derivatives; each B substituent is represented in the following table II. 
     M refers to the central core of the divalent 3,4-dihydro-2H-pyrrolo[1,2-a]pyrazin-1-one moiety being substituted in position 7 by groups A and at the carbonyl group by groups B, substantially as follows: 
     
       
         
         
             
             
         
       
     
     For ease of reference, each A and B group, in tables I and II respectively, have been identified with the proper chemical formula and an indication of the attachment point with the molecule core M. 
     To illustrate, compound A3-M-B5 of table III (entry 13) represents the core M, 3,4-dihydro-2H-pyrrolo[1,2-a]pyrazin-1-one, being substituted at 7-position by the group A3 and by the group B5 through the carbonyl group; likewise, compound A24-M-B8 of table III (entry 137) represents the core M, 3,4-dihydro-2H-pyrrolo[1,2-a]pyrazin-1-one, being substituted at 7-position by the group A24 and by the group B8 through the carbonyl group, as follows: 
     
       
         
         
             
             
         
       
     
     
       
         
           
               
             
               
                 TABLE I 
               
             
            
               
                   
               
               
                 A groups 
               
            
           
           
               
               
               
            
               
                   
                 Fragment 
                 CODE 
               
               
                   
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A1 
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A2 
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A3 
               
               
                   
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A4 
               
               
                   
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A5 
               
               
                   
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A6 
               
               
                   
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A7 
               
               
                   
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A8 
               
               
                   
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A9 
               
               
                   
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A10 
               
               
                   
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A11 
               
               
                   
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A12 
               
               
                   
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A13 
               
               
                   
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A14 
               
               
                   
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A15 
               
               
                   
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A16 
               
               
                   
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A17 
               
               
                   
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A18 
               
               
                   
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A19 
               
               
                   
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A20 
               
               
                   
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A21 
               
               
                   
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A22 
               
               
                   
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A24 
               
               
                   
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A25 
               
               
                   
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A26 
               
               
                   
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A27 
               
               
                   
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A28 
               
               
                   
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A29 
               
               
                   
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A30 
               
               
                   
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A31 
               
               
                   
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A32 
               
               
                   
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A33 
               
               
                   
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A34 
               
               
                   
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A35 
               
               
                   
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A36 
               
               
                   
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A37 
               
               
                   
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A38 
               
               
                   
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A39 
               
               
                   
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A40 
               
               
                   
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A41 
               
               
                   
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A42 
               
               
                   
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A43 
               
               
                   
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A44 
               
               
                   
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A45 
               
               
                   
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A46 
               
               
                   
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A47 
               
               
                   
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A48 
               
               
                   
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A49 
               
               
                   
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A50 
               
               
                   
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A51 
               
               
                   
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A52 
               
               
                   
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A53 
               
               
                   
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A54 
               
               
                   
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A55 
               
               
                   
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A56 
               
               
                   
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A57 
               
               
                   
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A58 
               
               
                   
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A59 
               
               
                   
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A60 
               
               
                   
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A61 
               
               
                   
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A62 
               
               
                   
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A63 
               
               
                   
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A64 
               
               
                   
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A65 
               
               
                   
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A66 
               
               
                   
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A67 
               
               
                   
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A68 
               
               
                   
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A69 
               
               
                   
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A70 
               
               
                   
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A71 
               
               
                   
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A72 
               
               
                   
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A73 
               
               
                   
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A74 
               
               
                   
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A75 
               
               
                   
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A76 
               
               
                   
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A77 
               
               
                   
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A78 
               
               
                   
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A79 
               
               
                   
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A80 
               
               
                   
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A81 
               
               
                   
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A82 
               
               
                   
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A83 
               
               
                   
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A84 
               
               
                   
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A85 
               
               
                   
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A86 
               
               
                   
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A87 
               
               
                   
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A88 
               
               
                   
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A89 
               
               
                   
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A90 
               
               
                   
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A91 
               
               
                   
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A92 
               
               
                   
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A93 
               
               
                   
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A94 
               
               
                   
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A95 
               
               
                   
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A96 
               
               
                   
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A97 
               
               
                   
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A98 
               
               
                   
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A99 
               
               
                   
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A100 
               
               
                   
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A101 
               
               
                   
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A102 
               
               
                   
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A103 
               
               
                   
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A104 
               
               
                   
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A105 
               
               
                   
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A106 
               
               
                   
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A107 
               
               
                   
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A108 
               
               
                   
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A109 
               
               
                   
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A110 
               
               
                   
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A111 
               
               
                   
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A112 
               
               
                   
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A113 
               
               
                   
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A114 
               
               
                   
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A115 
               
               
                   
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A116 
               
               
                   
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A117 
               
               
                   
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A118 
               
               
                   
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A119 
               
               
                   
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A120 
               
               
                   
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A121 
               
               
                   
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A122 
               
               
                   
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A123 
               
               
                   
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A124 
               
               
                   
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A125 
               
               
                   
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A126 
               
               
                   
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A127 
               
               
                   
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A128 
               
               
                   
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A129 
               
               
                   
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A130 
               
               
                   
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A131 
               
               
                   
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A132 
               
               
                   
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A133 
               
               
                   
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A134 
               
               
                   
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A135 
               
               
                   
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A136 
               
               
                   
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A137 
               
               
                   
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A138 
               
               
                   
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A139 
               
               
                   
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A140 
               
               
                   
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A141 
               
               
                   
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A142 
               
               
                   
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A143 
               
               
                   
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A144 
               
               
                   
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A145 
               
               
                   
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A146 
               
               
                   
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A147 
               
               
                   
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A148 
               
               
                   
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A149 
               
               
                   
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A150 
               
               
                   
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A151 
               
               
                   
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A152 
               
               
                   
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A153 
               
               
                   
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A154 
               
               
                   
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A155 
               
               
                   
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A156 
               
               
                   
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A157 
               
               
                   
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A158 
               
               
                   
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE II 
               
             
            
               
                   
               
               
                 B groups 
               
            
           
           
               
               
               
            
               
                   
                 Fragment 
                 CODE 
               
               
                   
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 B1 
               
               
                   
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 B2 
               
               
                   
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 B3 
               
               
                   
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 B4 
               
               
                   
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 B5 
               
               
                   
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 B6 
               
               
                   
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 B7 
               
               
                   
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 B8 
               
               
                   
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 B9 
               
               
                   
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 B10 
               
               
                   
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 B11 
               
               
                   
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 B12 
               
               
                   
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 B13 
               
               
                   
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 B14 
               
               
                   
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 B15 
               
               
                   
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 B16 
               
               
                   
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 B17 
               
               
                   
                   
               
               
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
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     Preparation of 2,2,2-trichloro-1-(4-nitro-1H-pyrrol-2-yl)ethanone (III) 
     Nitric acid (90%, 2 mL) was added dropwise over a period of 30 minutes to a solution of 2,2,2-trichloro-1-(1H-pyrrol-2-yl)ethanone (II) (1 g, 4.7 mmol) in acetic anhydride (10 ml), cooled to −40° C. The reaction mixture was allowed to warm up slowly to room temperature and stirred for 6 h. The solvent was evaporated under vacuum and the residue purified by flash chromatography (hexane-EtOAc 9:1) to obtain the compound of formula (III) as a yellow solid (670 mg, 55% yield). 2,2,2-Trichloro-1-(5-nitro-1H-pyrrol-2-yl)ethanone was also obtained as side product (349 mg, 29% yield). 
     LCMS (HPLC Method 2): m/z 256 [M−H] −  @ r.t. 5.44 min.  1 H NMR (400 MHz, DMSO-d 6 ) δ=13.65 (br. s., 1 H), 8.39 (dd, J=1.4, 3.6 Hz, 1 H), 7.73 (t, J=1.8 Hz, 1 H) 
     Preparation of ethyl(7-nitro-1-oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-4-yl)acetate (V, where R1=OCH 2 CH 3 ) 
     Ethyl (2E)-4-aminobut-2-enoate trifluoroacetate (IV) (5.99 g, 24.6 mmol) was added to a solution of 2,2,2-trichloro-1-(4-nitro-1H-pyrrol-2-yl)ethanone (III) (3.17 g, 12.3 mmol) and DIPEA (12.6 mL, 73.8 mmol) in dry CH 2 Cl 2  (120 mL) and the reaction mixture was stirred at room temperature overnight. The solvent was evaporated under vacuum and the residue purified by flash chromatography (hexane-EtOAc 2:3), to obtain the compound of formula (V) (where R1=OCH 2 CH 3 ) as a light-yellow solid (3.19 g, 97% yield). 
     LCMS (HPLC Method 2): m/z 268 [M+H] +  @ r.t. 3.48 min.  1 H NMR (400 MHz, DMSO-d 6 )) δ=8.13 (br. s., 1 H), 8.12 (d, J=1.7 Hz, 1 H), 7.14 (d, J=1.8 Hz, 1 H), 4.74-4.84 (m, 1 H), 4.11 (q, J=7.2 Hz, 2 H), 3.75 (ddd, J=1.8, 4.2, 13.4 Hz, 1 H), 3.44 (dt, J=4.2, 13.4 Hz, 1 H), 2.96 (dd, J=1.6, 6.8 Hz, 2 H), 1.19 (t, J=7.1 Hz, 3 H) 
     Example 1 
     Preparation of ethyl(7-amino-1-oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-4-yl)acetate hydrochloride (I) 
     To a solution of ethyl(7-nitro-1-oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-4-yl)acetate (V, where R1=OCH 2 CH 3 ) (0.55 g, 2.1 mmol) in ethanol 100% (20 mL) was added hydrochloric acid (4 M solution in 1,4-dioxane, 0.52 mL, 2.1 mmol). The reaction mixture was stirred at room temperature in the presence of Pd—C (10%) (0.11 g), under hydrogen atmosphere (50 psi). After 7 h the solid was filtered through celite (washed with ethanol) and the solvent evaporated under vacuum, to obtain compound ethyl(7-amino-1-oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-4-yl)acetate hydrochloride (I) as a light-brown solid (0.56 g, 98% yield), used without further purification in the next steps. Very hygroscopic product. To be stored for a short time and under inert gas atmosphere. 
     LCMS (HPLC Method 2): m/z 238 [M−H] −  @ r.t. 1.89 min (broad peak).  1 H NMR (400 MHz, DMSO-d 6 ) δ=9.75 (br. s., 2 H), 7.84 (br. s., 1 H), 7.10 (d, J=1.8 Hz, 1 H), 6.62 (d, J=1.8 Hz, 1 H), 4.64-4.75 (m, 1 H), 4.05-4.15 (m, 2 H), 3.64-3.75 (m, 1 H), 3.34-3.44 (m, 1 H), 2.83-2.94 (m, 1 H), 2.73-2.82 (m, 1 H), 1.20 (t, J=7.1 Hz, 3 H). 
     Example 2 
     Preparation A7-M-B1 (Entry 34, Table III) 
     A solution of 4-fluorobenzoic acid (0.29 g, 2.1 mmol), 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide (EDC) (0.4 g, 2.1 mmol), 3,4-dihydro-3-hydroxy-4-oxo-1,2,3-benzotriazine (DHBT) (0.34 g, 2.1 mmol) and N,N-diisopropylethylamine (DIPEA) (0.75 mL, 4.2 mmol) in dry acetonitrile (10 mL) was stirred at room temperature for 10 min, before adding ethyl(7-amino-1-oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-4-yl)acetate hydrochloride (I) (0.52 g, 1.9 mmol). The reaction mixture was stirred overnight at the same temperature. The solvent was evaporated under vacuum and the residue purified by flash chromatography (EtOAc+5% MeOH), to obtain compound A7-M-B1 (entry 34, table III) as an off-white solid (0.49 g, 71% yield). 
     LCMS (HPLC Method 2): m/z 361 [M+H] +  @ r.t. 3.99 min.  1 H NMR (500 MHz, DMSO-d 6 ) δ=10.37 (s, 1 H), 7.97-8.02 (m, 2 H), 7.66 (br. s., 1 H), 7.44 (d, J=1.6 Hz, 1H), 7.31-7.38 (m, 2 H), 6.73 (d, J=1.6 Hz, 1 H), 4.63 (ddd, J=3.2, 3.3, 6.8 Hz, 1 H), 4.09 (q, J=7.0 Hz, 2 H), 3.66-3.72 (m, 1 H), 3.34-3.39 (m, 1 H), 2.81-2.89 (m, 1 H), 2.68-2.77 (m, 1 H), 1.19 (t, J=7.1 Hz, 3 H). 
     Example 3 
     Preparation A9-M-B1 (Entry 54, Table III) 
     N,N-diisopropylethylamine (DIPEA)(0.19 mL, 1.1 mmol) was added to a solution of 1-fluoro-4-isocyanatobenzene (0.15 mL, 1.2 mmol) and (a suspension of) ethyl(7-amino-1-oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-4-yl)acetate hydrochloride (I) (0.30 g, 1.1 mmol) in dry dichloromethane (10 mL). The reaction mixture was stirred at room temperature overnight, the solvent was evaporated under vacuum and the residue purified by flash chromatography (EtOAc+5% MeOH), to obtain compound A9-M-B1 (entry 54, table III) as an off-white solid (0.33 g, 80% yield). 
     LCMS (HPLC Method 2): m/z 376 [M+H] +  @ r.t. 4.04 min.  1 H NMR (500 MHz, DMSO-d 6 ) δ=8.56 (s, 1 H), 8.37 (s, 1 H), 7.59 (d, J=2.6 Hz, 1 H), 7.38-7.46 (m, 2 H), 7.10-7.11 (m, 1 H), 7.05-7.12 (m, 2 H), 6.48 (d, J=1.8 Hz, 1 H), 4.53-4.59 (m, 1 H), 4.06-4.12 (m, 2 H), 3.64-3.70 (m, 1 H), 3.29-3.36 (m, 1 H), 2.79-2.85 (m, 1 H), 2.69-2.74 (m, 1 H), 1.19 (t, J=7.1 Hz, 3 H). 
     Example 4 
     Preparation A8-M-B1 (Entry 52, Table III) 
     N-methylmorpholine (0.28 mL, 2.6 mmol) was added to a solution of 4-fluorobenzenesulfonyl chloride (0.25 g, 1.3 mmol) and (a suspension of) ethyl(7-amino-1-oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-4-yl)acetate hydrochloride (I) (0.32 g, 1.2 mmol) in dry dichloromethane (10 mL) and the reaction mixture was stirred at room temperature overnight. The solvent was evaporated under vacuum and the residue purified by flash chromatography (EtOAc), to obtain compound A8-M-B1 (entry 52, table III) as an off-white solid (0.30 g, 64% yield). 
     LCMS (HPLC Method 2): m/z 397 [M+H] +  @ r.t. 3.96 min.  1 H NMR (500 MHz, DMSO-d 6 ) δ=9.75 (s, 1 H), 7.70-7.77 (m, 2 H), 7.65 (d, J=2.9 Hz, 1 H), 7.35-7.42 (m, 2 H), 6.67 (d, J=1.8 Hz, 1 H), 6.20 (d, J=1.8 Hz, 1 H), 4.50-4.56 (m, 1 H), 3.99-4.10 (m, J=3.5, 3.7, 7.1, 7.1, 10.6 Hz, 2 H), 3.58-3.64 (m, 1 H), 3.26-3.32 (m, 1 H), 2.78 (dd, J=6.4, 16.0 Hz, 1 H), 2.58-2.68 (m, 1 H), 1.16 (t, J=7.1 Hz, 3 H). 
     Preparation of 2,2,2-trichloro-1-(4-iodo-1H-pyrrol-2-yl)ethanone (IX) 
     Iodine (1.2 g, 4.7 mmol) was added portion wise to a solution of 2,2,2-trichloro-1-(1H-pyrrol-2-yl)ethanone (1 g, 4.7 mmol) and silver trifluoroacetate (1.1 g, 5 mmol) in dry dichloromethane (24 mL), cooled to 0° C. The reaction mixture was allowed to warm up slowly to 18° C. (water bath) and stirred at the same temperature for 5 h. The solid was filtered, the organic phase washed with Na 2 S 2 O 5  (5% aq. solution) until decoloration occurs and finally washed with H 2 O (1×20 mL). The organic phase was dried over Na 2 SO 4  and filtered through a plough of SiO 2  (hexane-EtOAc 4:1), to obtain compound 2,2,2-trichloro-1-(4-iodo-1H-pyrrol-2-yl)ethanone (IX) as an off-white solid (1.49 g, 94% yield). 
     LCMS (HPLC Method 2): m/z 336 [M−H] −  @ r.t. 6.3 min.  1 H NMR (400 MHz, DMSO-d 6 ) δ=12.76 (br. s., 1 H), 7.52 (dd, J=1.3, 3.3 Hz, 1 H), 7.39 (dd, J=1.3, 2.6 Hz, 1 H). 
     Preparation of ethyl (2E)-4-{[(4-iodo-1H-pyrrol-2-yl)carbonyl]amino}but-2-enoate (X, where R1=OCH 2 CH 3 ) 
     Ethyl (2E)-4-aminobut-2-enoate trifluoroacetate (IV) (0.97 g, 4 mmol) was added to a solution of 2,2,2-trichloro-1-(4-iodo-1H-pyrrol-2-yl)ethanone (IX) (0.68 g, 2 mmol) and N,N-diisopropylethylamine (DIPEA) (2.7 mL, 16 mmol) in dichloromethane (20 mL) and the reaction mixture was stirred at room temperature overnight. The solvent was evaporated under vacuum and the residue purified by flash chromatography (SiO 2 , hexane-EtOAc 1:1) to obtain compound ethyl (2E)-4-{[(4-iodo-1H-pyrrol-2-yl)carbonyl]amino}but-2-enoate (X, where R1=OCH 2 CH 3 ) as an off-white solid (0.48 g, 68% yield). 
     LCMS (HPLC Method 2): m/z 349 [M+H] +  @αr.t. 4.7 min.  1 H NMR (400 MHz, DMSO-d 6 ) δ=11.82 (br. s., 1 H), 8.39 (t, J=5.8 Hz, 1 H), 7.01 (dd, J=1.5, 2.9 Hz, 1 H), 6.96 (dd, J=1.5, 2.5 Hz, 1 H), 6.90 (dt, J=4.7, 15.7 Hz, 1 H), 5.87 (dt, J=1.8, 15.7 Hz, 1H), 4.12 (q, J=7.1 Hz, 2 H), 3.99-4.06 (m, 2 H), 1.21 (t, J=7.1 Hz, 3 H). 
     Preparation of ethyl (7-iodo-1-oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-4-yl)acetate (XI, where R1=OCH 2 CH 3 ) 
     Diaza(1,3)bicyclo[5.4.0]undecane (DBU) (0.04 mL, 0.3 mmol) was added to a solution of ethyl (2E)-4-{[(4-iodo-1H-pyrrol-2-yl)carbonyl]amino}but-2-enoate (X, where R1=OCH 2 CH 3 ) (0.45 g, 1.3 mmol) in acetonitrile (8 mL) and the reaction mixture was stirred at room temperature for 30 min. The solvent was evaporated under vacuum and the residue purified by flash chromatography (SiO 2 , hexane-EtOAc 1:1) to obtain compound ethyl (7-iodo-1-oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-4-yl)acetate (XII, where R1=OCH 2 CH 3 ) as an off-white solid (0.35 g, 79% yield). 
     LCMS (HPLC Method 2): m/z 349 [M+H] +  @ r.t. 4.15 min.  1 H NMR (400 MHz, DMSO-d 6 ) δ=7.72 (br. s., 1 H), 7.13 (d, J=1.7 Hz, 1 H), 6.72 (d, J=1.6 Hz, 1 H), 4.59-4.71 (m, 1 H), 4.10 (qd, J=1.8, 7.1 Hz, 2 H), 3.66 (ddd, J=1.7, 4.2, 13.1 Hz, 1 H), 3.30-3.38 (m, 1 H), 2.83 (d, J=6.7 Hz, 2 H), 1.19 (t, J=7.1 Hz, 3 H). 
     Example 5 
     Preparation A21-M-B1 (entry 127, table III) 
     A mixture of ethyl (7-iodo-1-oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-4-yl)acetate (XI, where R1=OCH 2 CH 3 ) (50 mg, 0.14 mmol), 1,1′-bis(diphenylphosphino)ferrocenepalladium(II)dichloride, complex with dichloromethane (1:1) (12 mg, 0.015 mmol) and 4-nitrophenylboronic acid (47 mg, 0.28 mmol) in dimethoxyethane (DME) (1 mL) was degassed before addition of sodium carbonate (45 mg, 0.42 mmol in 0.5 mL of H 2 O) and the reaction mixture was stirred at 80° C. for 3 h, under an argon atmosphere. The reaction mixture was filtered through silica (washed with EtOAc) and the solvent evaporated under vacuum. The residue was purified by flash chromatography (EtOAc-hex), to obtain compound A21-M-B1 (entry 127, table III) (29 mg, 60% yield). 
     LCMS (HPLC Method 2): m/z 345 [M+H] +  @ r.t. 4.61 min.  1 H NMR (400 MHz, DMSO-d 6 ) δ=8.19 (d, J=9.0 Hz, 2 H), 7.87 (d, J=9.0 Hz, 2 H), 7.80 (d, J=1.7 Hz, 1 H), 7.76 (d, J=1.8 Hz, 1 H), 7.24 (d, J=1.8 Hz, 1 H), 4.71 (ddd, J=3.4, 3.6, 6.6 Hz, 1 H), 4.04-4.17 (m, 2 H), 3.74 (ddd, J=1.8, 4.1, 13.3 Hz, 1 H), 3.35-3.45 (m, 1 H), 2.88-2.99 (m, 2H), 1.15-1.22 (m, 3 H). 
     Example 6 
     Preparation A22-M-B1 (entry 128, table III) 
     A mixture of ethyl (7-iodo-1-oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-4-yl)acetate (XI, where R1=OCH 2 CH 3 ) (50 mg, 0.14 mmol), 1,1′-bis(diphenylphosphino)ferrocenepalladium(II)dichloride, complex with dichloromethane (1:1) (12 mg, 0.015 mmol) and trans-2-(4-methoxyphenyl)vinylboronic acid (50 mg, 0.28 mmol) in dimethoxyethane (DME) (1 mL) was degassed before addition of sodium carbonate (45 mg, 0.42 mmol in 0.5 mL of H 2 O) and the reaction mixture was stirred at 80° C. for 6 h, under an argon atmosphere. The reaction mixture was filtered through silica (washed with EtOAc) and the solvent evaporated under vacuum. The residue was purified by flash chromatography (EtOAc-Hex), to obtain compound A22-M-B1 (entry 128, table III) (31 mg, 62% yield). 
     LCMS (HPLC Method 2): m/z 356 [M+H] +  @ r.t. 5.12 min.  1 H NMR (400 MHz, DMSO-d 6 ) δ=7.66 (d, J=3.2 Hz, 1 H), 7.38-7.45 (m, 2 H), 7.13 (d, J=1.6 Hz, 1 H), 6.87-6.93 (m, 4 H), 6.79-6.85 (m, 1 H), 4.58-4.66 (m, 1 H), 4.12 (q, J=7.1 Hz, 2 H), 3.76 (s, 3 H), 3.65-3.73 (m, 1 H), 3.32-3.39 (m, 1 H), 2.76-2.91 (m, 2 H), 1.20 (t, J=7.1 Hz, 3H). 
     Example 7 
     Preparation A27-M-B1 (Entry 151, Table III) 
     A mixture of ethyl (7-iodo-1-oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-4-yl)acetate (XI, where R1=OCH 2 CH 3 ) (500 mg, 1.44 mmol), bis(triphenylphosphine)palladium(II)dichloride (50 mg, 0.07 mmol), copper(I) iodide (41 mg, 0.22 mmol), 1-chloro-4-ethynylbenzene (0.29 g, 2.15 mmol) and triethylamine (0.58 mL, 5.74 mmol) in dry dimethylformamide (14 mL) was degassed and the reaction mixture was stirred at room temperature overnight, under an argon atmosphere. The solvent was evaporated under vacuum and the residue purified by flash chromatography (EtOAc-CH 2 Cl 2 ), to obtain compound A27-M-B1 (entry 151, table III) (0.51 g, 99% yield). 
     LCMS (HPLC Method 2): m/z 358 [M+H] +  @ r.t. 6.48 min.  1 H NMR (400 MHz, DMSO-d 6 ) δ=7.82 (br. s., 1 H), 7.42-7.50 (m, 4 H), 7.37 (d, J=1.6 Hz, 1 H), 6.78 (d, J=1.6 Hz, 1 H), 4.63-4.70 (m, 1 H), 4.11 (q, J=7.1 Hz, 2 H), 3.65-3.74 (m, 1 H), 3.33-3.41 (m, 1 H), 2.81-2.91 (m, 2 H), 1.19 (t, J=7.1 Hz, 3 H). 
     Preparation of ethyl (2E)-4-(diformylamino)but-2-enoate (XV) 
     A solution of ethyl-4-bromo-crotonate (1 g, 5.18 mmol), diformylimide sodium salt (0.59 g, 6.22 mmol) and sodium iodide (0.78 g, 5.18 mmol) in dry acetonitrile (25 mL) was stirred under reflux overnight. The solvent was evaporated under vacuum and the residue partitioned between dichloromethane and water (1:1, 40 mL). The aqueous phase was back-extracted with dichloromethane (3×15 mL) and the combined organic layers were dried over Na 2 SO 4 . The solvent was evaporated under vacuum and the residue purified by flash chromatography (hexane-EtOAc 6:4) to obtain compound ethyl (2E)-4-(diformylamino)but-2-enoate (XV) as a light-brown solid (0.92 g, 96% yield). In alternative, Et 2 O was added to the deep brown oil residue to obtain the product as a crystalline solid. 
     LCMS (HPLC Method 2): m/z 186 [M−H] −  @ r.t. 3.36 min.  1 H NMR (400 MHz, DMSO-d 6 ) δ=9.01 (s, 2 H), 6.78 (dt, J=4.6, 15.9 Hz, 1 H), 5.88 (dt, J=2.0, 15.8 Hz, 1 H), 4.26 (dd, J=2.0, 4.5 Hz, 2 H), 4.12 (q, J=7.1 Hz, 2 H), 1.21 (t, J=7.1 Hz, 3 H) 
     Preparation of ethyl (2E)-4-aminobut-2-enoate trifluoroacetate (IV) 
     A solution of ethyl (2E)-4-(diformylamino)but-2-enoate (XV) (0.89 mg, 4.8 mmol) in a mixture trifluoroacetic acid-ethanol (absolute) (2:1, 10 mL) was stirred under reflux overnight (the reaction was followed by LC-MS and stopped when complete conversion was achieved). The solvent was evaporated under vacuum to obtain compound ethyl (2E)-4-aminobut-2-enoate trifluoroacetate (IV) as brown oil (undetermined yield), which was used without further purification in the next step. 
     Example 8 
     Preparation A2-M-B2 (Entry 8, Table III) 
     To a solution of derivative A2-M-B1 (entry 7, table III) (24 mg, 0.07 mmol) in a mixture tetrahydrofuran-water (1:1, 2 mL) was added lithium hydroxide (6 mg, 0.04 mmol) and the reaction mixture was stirred at room temperature for 3 h. The organic phase was washed with dichloromethane (2×5 mL). The aqueous phase was acidified with hydrochloric acid (1 M) until pH&lt;1 and extracted with EtOAc (4×10 mL). The combined organic layers were dried over Na 2 SO 4  and the solvent was evaporated under vacuum to obtain compound A2-M-B2 (entry 8, table III) as an off-white solid (21 mg, 100% yield). 
     LCMS (HPLC Method 2): m/z 302 [M+H] +  @ r.t. 3.06 min.  1 H NMR (400 MHz, DMSO-d 6 ) δ=7.64 (br. s., 1 H), 7.45-7.50 (m, 2 H), 7.37 (d, J=1.8 Hz, 1 H), 6.96 (d, J=1.8 Hz, 1 H), 6.88-6.94 (m, 2 H), 4.57-4.63 (m, 1 H), 3.76 (s, 3 H), 3.67-3.73 (m, 1 H), 3.37-3.42 (m, 1 H), 2.74-2.86 (m, 2 H). 
     Example 9 
     Preparation A5-M-B5 (Entry 29, Table III) 
     To a solution of derivative A5-M-B2 (entry 23, table III) (45 mg, 0.14 mmol) in a dry mixture acetonitrile-dimethylformamide (3:1, 4 mL), 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide (EDC) (32 mg, 0.17 mmol), 3,4-dihydro-3-hydroxy-4-oxo-1,2,3-benzotriazine (DHBT) (28 mg, 0.17 mmol) and N,N-diisopropylethylamine (DIPEA) (0.024 mL, 0.14 mmol) were added and the reaction mixture was stirred at room temperature for 10 min before adding piperidine (0.028 mL, 0.28 mmol). The reaction mixture was stirred at the same temperature overnight. The reaction mixture was then diluted with water and extracted with EtOAc (4×5 mL). The combined organic layers were dried over Na 2 SO 4 , the solvent evaporated under vacuum and the residue purified by prep-HPLC to obtain compound A5-M-B5 (Entry 29, Table III) as a white solid (13 mg, 23% yield). 
     LCMS (HPLC Method 2): m/z 397 [M+H] +  @ r.t. 3.74 min.  1 H NMR (400 MHz, DMSO-d 6 ) δ=8.50 (s, 1 H), 8.34 (s, 1 H), 7.51 (d, J=2.9 Hz, 1 H), 7.42 (d, J=7.6 Hz, 2H), 7.24 (t, J=8.0 Hz, 2 H), 7.12 (d, J=1.7 Hz, 1 H), 6.92 (t, J=7.3 Hz, 1 H), 6.48 (d, J=1.7 Hz, 1 H), 4.58 (tt, J=3.9, 6.7 Hz, 1 H), 3.67 (ddd, J=1.1, 4.3, 12.9 Hz, 1 H), 2.79 (dd, J=5.7, 16.1 Hz, 1 H), 2.74 (dd, J=7.1, 16.1 Hz, 1 H), 1.55 (quin, J=5.6 Hz, 2 H), 1.37-1.48 (m, 4 H). 
     Preparation of 7-nitro-1-oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-4-carboxylic acid (V, where R1=OH) 
     LiOH.H 2 O (27 mg, 1.12 mmol) was added to a solution of ethyl(7-nitro-1-oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-4-yl)acetate (V, where R1=OCH 2 CH 3 ) (0.15 g, 0.56 mmol) in a mixture tetrahydrofuran-water (1:1, 9 mL) and the reaction mixture was stirred at room temperature for 3 h. The organic phase was washed with dichloromethane (2×10 mL). The aqueous phase was acidified with hydrochloric acid (1 M) to reach pH&lt;1 and extracted with EtOAc (3×10 mL). The combined organic layers were dried over Na 2 SO 4  and the solvent was evaporated under vacuum to obtain compound 7-nitro-1-oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-4-carboxylic acid (V, where R1=OH) as an off-white solid (101 mg, 75% yield). 
     LCMS (HPLC Method 2): m/z 240 [M+H] +  @ r.t. 1.05 min.  1 H NMR (400 MHz, DMSO-d 6 ) δ=8.13 (d, J=1.7 Hz, 1 H), 8.11 (d, J=1.7 Hz, 1 H), 7.14 (d, J=1.8 Hz, 1 H), 4.70-4.79 (m, 1 H), 3.71-3.77 (m, 1 H), 3.44 (dt, J=4.3, 13.4 Hz, 1 H), 2.80-2.96 (m, 2H). 
     General procedure: loading of phenethylamine (corresponding to fragment B6 of Table I) onto Acid Sensitive Methoxy Benzaldehyde polystyrene resin (AMEBA II resin). 
     4-(4-formyl-3-methoxyphenoxy)butyryl aminomethyl resin (copolystyrene-1% DVB) (6.0 g, 5.88 mmol, 0.98 mmol/g, 1 eq.) was suspended in dry THF (60 ml) and phenethylamine (29.4 mmol, 5 eq.) was added. The resultant suspension was shaken at 25° C. for 2 h. Then acetic acid (1.68 ml, 29.4 mmol, 5 eq.) and NaBH(AcO) 3  (3.12 g, 14.7 mmol, 3 eq.) were added and the final suspension was shaken for 16 h at 25° C. The resin was rinsed with THF (2 cycles), MeOH (2 cycles), DCM (2 cycles), MeOH (2 cycles), DMF (2 cycles) and DCM (3 cycles) then dried in nitrogen flux. 
     Loading of the 3,4-dihydro-2H-pyrrolo[1,2-a]pyrazin-1-one scaffold onto the resin prepared as described above. 
     
       
         
         
             
             
         
       
     
     A solution of 7-nitro-1-oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-4-carboxylic acid (V, where R1=OH) (0.24 g, 1 mmol), N,N-diisopropylethylamine (DIPEA) (0.34 ml, 2 mmol) and benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate (PyBOP) (0.52 g, 1 mmol) in dry N,N-dimethylacetamide (7.5 ml) was stirred for 30 min, then was added to resin of example 17 (0.67 mmol, 1 eq) and the final suspension was shaken for 24 h at room temperature. The resin was rinsed with a cycle of DMF, MeOH, DCM (3 times), DCM (3 times) and 1,4-dioxane (once) and dried under nitrogen flux. The resin was then used in the next step. 
     Reduction of the nitro group: 
     
       
         
         
             
             
         
       
     
     The resin of formula (XVIII) (0.67 mmol, 1 eq) was suspended in a 2M solution of SnCl 2 .2H 2 O in N,N-dimethylformamide (10 ml). The final suspension was shaken for 48 hours at room temperature. The resin was rinsed with a cycle of DMF, MeOH, DCM (3 times), DCM (3 times) and 1,4-dioxane (once) and dried under nitrogen flux. The resin was then used in the next step. 
     The above resin bound 3,4-dihydro-2H-pyrrolo[1,2-a]pyrazin-1-one was further reacted according to the alternative steps below so as to get carboxamido and ureido derivatives. 
     Example 10 
     Preparation of A11-M-B6 (Entry 71, Table III) 
     
       
         
         
             
             
         
       
     
     A carboxylic acid of formula (VI), wherein R c  corresponds to the fragment A11 of table II (1.35 mmol, 15 eq.) was added to a solution of 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide (EDC) (0.26 g, 1.35 mmol, 15 eq) and 3,4-dihydro-3-hydroxy-4-oxo-1,2,3-benzotriazine (DHBT) (0.22 g, 1.35 mmol, 15 eq) in dried N-methylpyrrolidone (NMP) (1 ml) and the solution was stirred for 30 min, then was added to resin of example 19 (0.09 mmol, 1 eq.) and shaken overnight at room temperature in a reactor (Quest 210™ or Miniblocks™). The resin was rinsed with a cycle of DMF, MeOH, DCM (3 times), DCM (3 times) and 1,4-dioxane (once) and dried under nitrogen flux. The resin was suspended in a solution of TFA-DCM (1:1, 2 ml) and shaken for 2 h at room temperature. The solution was collected and the resin was rinsed with DCM (collected as well), and a second cycle was performed. The final washing was performed with MeOH. All the collected organic layers were dried under reduced pressure affording compound A11-M-B6 (see entry 71 of table III below). 
     LCMS (HPLC Method 2): m/z 399 [M+H] +  @ r.t. 2.7 min.  1 H NMR (400 MHz, DMSO-d 6 ) δ=10.53 (s, 1 H), 9.74 (br. s., 1 H), 8.07 (t, J=5.6 Hz, 1 H), 7.67 (d, J=3.5 Hz, 1 H), 7.12-7.32 (m, 6 H), 6.60 (d, J=1.7 Hz, 1 H), 4.48-4.67 (m, 1 H), 3.94-4.09 (m, 2H), 3.66 (dd, J=4.6, 13.3 Hz, 1 H), 2.81 (s, 6 H), 2.63-2.75 (m, 2 H). 
     Example 11 
     Preparation of A17-M-B6 (Entry 117, Table III) 
     
       
         
         
             
             
         
       
     
     An isocyanate of formula (VII) wherein R c  corresponds to fragment A17 of table II (1.35 mmol, 15 eq) was added to a suspension of the resin of example 19 (0.09 mmol, 1 eq) in dry dichloromethane (1 ml). The final suspension was shaken overnight at room temperature in a reactor (Quest 210™ or Miniblocks™). The resin was rinsed with a cycle of DMF, MeOH, DCM (3 times), DCM (3 times) and 1,4-dioxane (once) and dried under nitrogen flux. The resin was suspended in a solution of TFA-DCM (1:1, 2 ml) and shaken for 2 h at room temperature. The solution was collected and the resin was rinsed with DCM (collected as well), and a second cycle was performed. The final washing was performed with MeOH. All the collected organic layers were dried under reduced pressure affording compound A17-M-B6 (see entry 117 of table III below). 
     LCMS (HPLC Method 2): m/z 463 [M+H] +  @ r.t. 4.02 min.  1  H NMR (400 MHz, DMSO-d 6 ) δ=8.29 (s, 1 H), 8.26 (s, 1 H), 8.07 (t, J=5.7 Hz, 1 H), 7.52 (d, J=3.0 Hz, 1H), 7.28-7.33 (m, 2 H), 7.10 (d, J=1.8 Hz, 1 H), 6.77-6.85 (m, 2 H), 6.46 (d, J=1.7 Hz, 1 H), 4.50 (tt, J=3.9, 6.9 Hz, 0 H), 3.70 (s, 4 H), 3.63 (ddd, J=1.3, 4.2, 12.8 Hz, 1 H). 
     Preparation of 7-iodo-1-oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-4-carboxylic acid (XI, where R1=OH) 
     LiOH.H 2 O (63 mg, 1.5 mmol) was added to a solution of ethyl(7-iodo-1-oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-4-yl)acetate (XII, where R1=OCH 2 CH 3 ) (0.26 g, 0.75 mmol) in a mixture tetrahydrofuran-water (1:1, 8 mL) and the reaction mixture was stirred at room temperature for 3 h. The organic phase was washed with dichloromethane (2×10 mL). The aqueous phase was acidified with hydrochloric acid (1 M) to reach pH&lt;1 and extracted with EtOAc (3×10 mL). The combined organic layers were dried over Na 2 SO 4  and the solvent was evaporated under vacuum to obtain compound 7-iodo-1-oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-4-carboxylic acid (XII, where R1=OH) as an off-white solid (0.23 g, 75% yield). 
     LCMS (HPLC Method 2): m/z 321 [M+H] +  @ r.t. 2.52 min.  1 H NMR (400 MHz, DMSO-d 6 ) δ=12.63 (br. s., 1 H), 7.71 (br. s., 1 H), 7.14 (d, J=1.7 Hz, 1 H), 6.72 (d, J=1.7 Hz, 1 H), 4.54-4.66 (m, 1 H), 3.59-3.70 (m, 1 H), 3.32-3.38 (m, 1 H), 2.76 (d, J=7.0 Hz, 2 H). 
     Loading of the 3,4-dihydro-2H-pyrrolo[1,2-a]pyrazin-1-one scaffold onto the resin prepared as described previously. 
     
       
         
         
             
             
         
       
     
     A solution of 7-iodo-1-oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-4-carboxylic acid (XI, where R1=OH) (0.92 g, 2.87 mmol), N,N-diisopropylethylamine (DIPEA) (0.99 ml, 5.76 mmol) and benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate (PyBOP) (1.5 g, 2.87 mmol) in dry N,N-dimethylacetamide (9 ml) was stirred for 30 min, then was added to resin of example 17 (1.44 mmol, 1 eq) and the final suspension was shaken for 24 h at room temperature. The resin was rinsed with a cycle of DMF, MeOH, DCM (3 times), DCM (3 times) and 1,4-dioxane (once) and dried under nitrogen flux. The resin was then used in the next step. 
     Example 12 
     Preparation of A24-M-B6 (Entry 135, Table III) 
     
       
         
         
             
             
         
       
     
     A mixture of boronic acid of formula (XII), wherein R c C corresponds to the fragment A24 of table II (0.37 g, 3 mmol*), 1,1′-bis(diphenylphosphino)ferrocenepalladium(II)dichloride complex with dichloromethane (1:1) (PdCl 2 (dppf).CH 2 Cl 2 ) (65 mg, 0.08 mmol), cesium carbonate (0.52 g, 1.6 mmol) and the resin from example 23 (0.2 mmol, 1 eq.) in a mixture dimethoxyethane-water (3:1, 2 mL) was shaken overnight at 80° C. in a reactor (Quest 210™). The resin was rinsed with a cycle of DMF, MeOH, DCM (3 times), DCM (3 times) and 1,4-dioxane (once) and dried under nitrogen flux. The resin was suspended in a solution of TFA-DCM (1:1, 2 ml) and shaken for 2 h at room temperature. The solution was collected and the resin was rinsed with DCM (collected as well), and a second cycle was performed. The final washing was performed with MeOH. All the collected organic layers were dried under reduced pressure affording compound A24-M-B6 (see entry 135 of table III below). 
     LCMS (HPLC Method 2): m/z 376 [M+H] +  @ r.t. 4.17 min.  1 H NMR (400 MHz, DMSO-d 6 ) δ=8.64 (d, J=6.3 Hz, 2 H), 8.11 (s, 1 H), 8.05 (d, J=6.5 Hz, 2 H), 7.95 (d, J=1.6 Hz, 1 H), 7.88 (d, 1 H), 7.47 (d, J=1.7 Hz, 1 H), 7.23 (t, J=7.4 Hz, 2 H), 7.15 (t, J=7.3 Hz, 1 H), 7.10 (dd, J=1.5, 7.4 Hz, 2 H), 4.73 (tt, J=3.7, 7.1 Hz, 1 H), 3.68 (ddd, 1 H). 
     Following the procedure described in examples 4-6, 9-11, 14-15 and 16-24 and by using any proper reactant as per the process of the invention, the following compounds of table III were also prepared. 
     
       
         
           
               
               
               
               
               
             
               
                 TABLE III 
               
               
                   
               
               
                   
                   
                 HPLC 
                 HPLC Rt 
                   
               
               
                 Entry 
                 Compound 
                 Method 
                 (min) 
                 [M + H] +   
               
               
                   
               
             
            
               
                   
               
            
           
           
               
               
               
               
               
            
               
                 1 
                 A1-M-B1 
                 2 
                 5.17 
                 323.2 
               
               
                 2 
                 A1-M-B2 
                 2 
                 4.49 
                 295.2 
               
               
                 3 
                 A1-M-B6 
                 2 
                 6.04 
                 398.3 
               
               
                 4 
                 A1-M-B7 
                 2 
                 5.06 
                 352.3 
               
               
                 5 
                 A1-M-B8 
                 2 
                 4.27 
                 380.3 
               
               
                 6 
                 A1-M-B9 
                 2 
                 6.05 
                 364.3 
               
               
                 7 
                 A2-M-B1 
                 2 
                 4.53 
                 329.2 
               
               
                 8 
                 A2-M-B2 
                 2 
                 3.06 
                 301.2 
               
               
                 9 
                 A2-M-B3 
                 2 
                 5.31 
                 357.3 
               
               
                 10 
                 A2-M-B4 
                 2 
                 4.15 
                 398.3 
               
               
                 11 
                 A3-M-B1 
                 2 
                 3.92 
                 372.2 
               
               
                 12 
                 A3-M-B2 
                 2 
                 2.8 
                 344.2 
               
               
                 13 
                 A3-M-B5 
                 2 
                 3.77 
                 411.3 
               
               
                 14 
                 A4-M-B1 
                 2 
                 4.08 
                 392.2 
               
               
                 15 
                 A4-M-B10 
                 2 
                 3.72 
                 461.3 
               
               
                 16 
                 A4-M-B11 
                 2 
                 3.8 
                 461.3 
               
               
                 17 
                 A4-M-B2 
                 2 
                 2.86 
                 364.2 
               
               
                 18 
                 A5-M-B1 
                 2 
                 3.95 
                 357.2 
               
               
                 19 
                 A5-M-B12 
                 1 
                 2.54 
                 412.3 
               
               
                 20 
                 A5-M-B16 
                 1 
                 3.19 
                 432.3 
               
               
                 21 
                 A5-M-B17 
                 1 
                 2.38 
                 356.3 
               
               
                 22 
                 A5-M-B18 
                 1 
                 3.6 
                 424.3 
               
               
                 23 
                 A5-M-B2 
                 2 
                 2.72 
                 329.2 
               
               
                 24 
                 A5-M-B21 
                 1 
                 3.34 
                 432.3 
               
               
                 25 
                 A5-M-B22 
                 1 
                 3.55 
                 424.3 
               
               
                 26 
                 A5-M-B23 
                 1 
                 2.94 
                 384.3 
               
               
                 27 
                 A5-M-B24 
                 1 
                 3.28 
                 410.3 
               
               
                 28 
                 A5-M-B26 
                 1 
                 2.99 
                 396.3 
               
               
                 29 
                 A5-M-B5 
                 2 
                 3.74 
                 396.3 
               
               
                 30 
                 A5-M-B7 
                 2 
                 3.11 
                 386.3 
               
               
                 31 
                 A5-M-B7 
                 1 
                 2.34 
                 386.3 
               
               
                 32 
                 A5-M-B8 
                 2 
                 2.72 
                 413.3 
               
               
                 33 
                 A6-M-B1 
                 2 
                 4.18 
                 321.2 
               
               
                 34 
                 A7-M-B1 
                 2 
                 3.99 
                 360.2 
               
               
                 35 
                 A7-M-B12 
                 1 
                 2.62 
                 415.3 
               
               
                 36 
                 A7-M-B13 
                 1 
                 2.7 
                 373.3 
               
               
                 37 
                 A7-M-B14 
                 1 
                 3.11 
                 421.3 
               
               
                 38 
                 A7-M-B16 
                 1 
                 3.33 
                 435.3 
               
               
                 39 
                 A7-M-B17 
                 1 
                 2.48 
                 359.2 
               
               
                 40 
                 A7-M-B18 
                 1 
                 3.64 
                 427.3 
               
               
                 41 
                 A7-M-B19 
                 1 
                 2.49 
                 371.2 
               
               
                 42 
                 A7-M-B2 
                 2 
                 3.7 
                 332.2 
               
               
                 43 
                 A7-M-B20 
                 1 
                 3.35 
                 435.3 
               
               
                 44 
                 A7-M-B21 
                 1 
                 3.38 
                 435.3 
               
               
                 45 
                 A7-M-B22 
                 1 
                 3.59 
                 427.3 
               
               
                 46 
                 A7-M-B23 
                 1 
                 3 
                 387.3 
               
               
                 47 
                 A7-M-B24 
                 1 
                 3.33 
                 413.3 
               
               
                 48 
                 A7-M-B25 
                 1 
                 2.73 
                 373.3 
               
               
                 49 
                 A7-M-B26 
                 1 
                 3.06 
                 399.3 
               
               
                 50 
                 A7-M-B27 
                 1 
                 2.61 
                 371.2 
               
               
                 51 
                 A7-M-B7 
                 1 
                 2.43 
                 389.3 
               
               
                 52 
                 A8-M-B1 
                 2 
                 3.96 
                 396.2 
               
               
                 53 
                 A8-M-B2 
                 2 
                 3.5 
                 368.2 
               
               
                 54 
                 A9-M-B1 
                 2 
                 4.04 
                 375.2 
               
               
                 55 
                 A9-M-B14 
                 1 
                 3.19 
                 436.3 
               
               
                 56 
                 A9-M-B15 
                 1 
                 3.04 
                 402.3 
               
               
                 57 
                 A9-M-B16 
                 1 
                 3.38 
                 450.3 
               
               
                 58 
                 A9-M-B17 
                 1 
                 2.53 
                 374.3 
               
               
                 59 
                 A9-M-B18 
                 1 
                 3.69 
                 442.3 
               
               
                 60 
                 A9-M-B19 
                 1 
                 2.56 
                 386.3 
               
               
                 61 
                 A9-M-B2 
                 2 
                 3.68 
                 347.2 
               
               
                 62 
                 A9-M-B20 
                 1 
                 3.43 
                 450.3 
               
               
                 63 
                 A9-M-B21 
                 1 
                 3.47 
                 450.3 
               
               
                 64 
                 A9-M-B22 
                 1 
                 3.66 
                 442.3 
               
               
                 65 
                 A9-M-B23 
                 1 
                 3.08 
                 402.3 
               
               
                 66 
                 A9-M-B24 
                 1 
                 3.41 
                 428.3 
               
               
                 67 
                 A9-M-B26 
                 1 
                 3.13 
                 414.3 
               
               
                 68 
                 A9-M-B27 
                 1 
                 2.67 
                 386.3 
               
               
                 69 
                 A9-M-B7 
                 1 
                 2.48 
                 404.3 
               
               
                 70 
                 A10-M-B2 
                 2 
                 1.34 
                 265.2 
               
               
                 71 
                 A11-M-B6 
                 2 
                 2.7 
                 398.3 
               
               
                 72 
                 A11-M-B7 
                 2 
                 1.06 
                 352.3 
               
               
                 73 
                 A11-M-B8 
                 2 
                 3.32 
                 379.3 
               
               
                 74 
                 A11-M-B9 
                 2 
                 2.52 
                 364.3 
               
               
                 75 
                 A12-M-B13 
                 1 
                 1.99 
                 319.3 
               
               
                 76 
                 A12-M-B14 
                 1 
                 2.43 
                 367.3 
               
               
                 77 
                 A12-M-B16 
                 1 
                 2.71 
                 381.3 
               
               
                 78 
                 A12-M-B20 
                 1 
                 2.73 
                 381.3 
               
               
                 79 
                 A12-M-B21 
                 1 
                 2.79 
                 381.3 
               
               
                 80 
                 A12-M-B22 
                 1 
                 3.03 
                 373.3 
               
               
                 81 
                 A12-M-B7 
                 2 
                 3.29 
                 335.3 
               
               
                 82 
                 A12-M-B8 
                 2 
                 2.69 
                 362.3 
               
               
                 83 
                 A13-M-B7 
                 2 
                 2.81 
                 334.2 
               
               
                 84 
                 A13-M-B8 
                 2 
                 1.26 
                 361.3 
               
               
                 85 
                 A13-M-B9 
                 2 
                 3.12 
                 346.3 
               
               
                 86 
                 A14-M-B7 
                 2 
                 3.84 
                 389.2 
               
               
                 87 
                 A14-M-B8 
                 2 
                 3.03 
                 416.3 
               
               
                 88 
                 A15-M-B12 
                 1 
                 2.61 
                 417.3 
               
               
                 89 
                 A15-M-B13 
                 1 
                 2.68 
                 375.2 
               
               
                 90 
                 A15-M-B14 
                 1 
                 3.07 
                 423.2 
               
               
                 91 
                 A15-M-B15 
                 1 
                 2.92 
                 389.3 
               
               
                 92 
                 A15-M-B16 
                 1 
                 3.28 
                 437.3 
               
               
                 93 
                 A15-M-B18 
                 1 
                 3.59 
                 429.3 
               
               
                 94 
                 A15-M-B19 
                 1 
                 2.52 
                 373.2 
               
               
                 95 
                 A15-M-B20 
                 1 
                 3.3 
                 437.3 
               
               
                 96 
                 A15-M-B21 
                 1 
                 3.32 
                 437.3 
               
               
                 97 
                 A15-M-B22 
                 1 
                 3.52 
                 429.3 
               
               
                 98 
                 A15-M-B23 
                 1 
                 2.97 
                 389.3 
               
               
                 99 
                 A15-M-B24 
                 1 
                 3.28 
                 415.3 
               
               
                 100 
                 A15-M-B25 
                 1 
                 2.72 
                 375.2 
               
               
                 101 
                 A15-M-B26 
                 1 
                 3.02 
                 401.3 
               
               
                 102 
                 A15-M-B27 
                 1 
                 2.6 
                 373.2 
               
               
                 103 
                 A15-M-B7 
                 1 
                 2.44 
                 391.2 
               
               
                 104 
                 A15-M-B8 
                 2 
                 2.85 
                 418.3 
               
               
                 105 
                 A16-M-B14 
                 1 
                 3.32 
                 424.3 
               
               
                 106 
                 A16-M-B18 
                 1 
                 3.83 
                 430.4 
               
               
                 107 
                 A16-M-B20 
                 1 
                 3.56 
                 438.3 
               
               
                 108 
                 A16-M-B21 
                 1 
                 3.6 
                 438.3 
               
               
                 109 
                 A16-M-B22 
                 1 
                 3.81 
                 430.4 
               
               
                 110 
                 A16-M-B23 
                 1 
                 3.23 
                 390.3 
               
               
                 111 
                 A16-M-B24 
                 1 
                 3.54 
                 416.4 
               
               
                 112 
                 A16-M-B27 
                 1 
                 2.82 
                 374.3 
               
               
                 113 
                 A16-M-B8 
                 2 
                 2.89 
                 419.4 
               
               
                 114 
                 A17-M-B14 
                 1 
                 2.89 
                 448.3 
               
               
                 115 
                 A17-M-B21 
                 1 
                 3.17 
                 462.3 
               
               
                 116 
                 A17-M-B24 
                 1 
                 3.11 
                 440.3 
               
               
                 117 
                 A17-M-B6 
                 2 
                 4.02 
                 462.3 
               
               
                 118 
                 A17-M-B8 
                 2 
                 2.72 
                 443.3 
               
               
                 119 
                 A17-M-B9 
                 2 
                 3.97 
                 428.3 
               
               
                 120 
                 A18-M-B5 
                 2 
                 3.62 
                 399.3 
               
               
                 121 
                 A19-M-B5 
                 2 
                 4.38 
                 388.3 
               
               
                 122 
                 A20-M-B1 
                 2 
                 5.13 
                 333.2 
               
               
                 123 
                 A20-M-B6 
                 2 
                 5.98 
                 408.2 
               
               
                 124 
                 A20-M-B7 
                 2 
                 4.99 
                 362.2 
               
               
                 125 
                 A20-M-B8 
                 2 
                 3.33 
                 389.2 
               
               
                 126 
                 A20-M-B9 
                 2 
                 5.99 
                 374.3 
               
               
                 127 
                 A21-M-B1 
                 2 
                 4.61 
                 344.2 
               
               
                 128 
                 A22-M-B1 
                 2 
                 5.12 
                 355.3 
               
               
                 129 
                 A22-M-B2 
                 2 
                 4.4 
                 327.2 
               
               
                 130 
                 A22-M-B6 
                 2 
                 5.87 
                 430.3 
               
               
                 131 
                 A22-M-B7 
                 2 
                 4.94 
                 384.3 
               
               
                 132 
                 A22-M-B8 
                 2 
                 4.14 
                 411.3 
               
               
                 133 
                 A22-M-B9 
                 2 
                 5.88 
                 396.3 
               
               
                 135 
                 A24-M-B6 
                 2 
                 4.17 
                 375.3 
               
               
                 136 
                 A24-M-B7 
                 2 
                 2.45 
                 329.3 
               
               
                 137 
                 A24-M-B8 
                 2 
                 1.97 
                 356.3 
               
               
                 138 
                 A24-M-B9 
                 2 
                 4.07 
                 341.3 
               
               
                 139 
                 A25-M-B1 
                 2 
                 6.16 
                 315.3 
               
               
                 140 
                 A25-M-B2 
                 2 
                 4.58 
                 287.2 
               
               
                 141 
                 A25-M-B6 
                 2 
                 6.23 
                 390.3 
               
               
                 142 
                 A25-M-B7 
                 2 
                 5.2 
                 344.3 
               
               
                 143 
                 A25-M-B8 
                 2 
                 4.3 
                 371.3 
               
               
                 144 
                 A25-M-B9 
                 2 
                 6.24 
                 356.3 
               
               
                 145 
                 A26-M-B1 
                 2 
                 5.9 
                 353.2 
               
               
                 146 
                 A26-M-B2 
                 2 
                 4.48 
                 325.2 
               
               
                 147 
                 A26-M-B6 
                 2 
                 5.96 
                 428.3 
               
               
                 148 
                 A26-M-B7 
                 2 
                 5.04 
                 382.3 
               
               
                 149 
                 A26-M-B8 
                 2 
                 4.22 
                 409.3 
               
               
                 150 
                 A26-M-B9 
                 2 
                 5.98 
                 394.3 
               
               
                 151 
                 A27-M-B1 
                 2 
                 6.48 
                 357.2 
               
               
                 152 
                 A27-M-B2 
                 2 
                 4.98 
                 329.2 
               
               
                 153 
                 A27-M-B6 
                 2 
                 6.5 
                 432.2 
               
               
                 154 
                 A27-M-B7 
                 2 
                 5.57 
                 386.2 
               
               
                 155 
                 A27-M-B8 
                 2 
                 4.72 
                 413.3 
               
               
                 156 
                 A27-M-B9 
                 2 
                 6.54 
                 398.3 
               
               
                 157 
                 A28-M-B1 
                 2 
                 6.92 
                 416.3 
               
               
                 158 
                 A28-M-B2 
                 2 
                 5.52 
                 388.3 
               
               
                 159 
                 A28-M-B6 
                 2 
                 6.9 
                 491.3 
               
               
                 160 
                 A28-M-B7 
                 2 
                 6.07 
                 445.3 
               
               
                 161 
                 A28-M-B8 
                 2 
                 5.16 
                 472.4 
               
               
                 162 
                 A28-M-B9 
                 2 
                 6.95 
                 457.4 
               
               
                 163 
                 A29-M-B1 
                 2 
                 5.12 
                 263.2 
               
               
                 164 
                 A29-M-B2 
                 2 
                 3.51 
                 235.2 
               
               
                 165 
                 A29-M-B6 
                 2 
                 5.35 
                 338.3 
               
               
                 166 
                 A29-M-B7 
                 2 
                 4.14 
                 292.3 
               
               
                 167 
                 A29-M-B8 
                 2 
                 3.35 
                 319.3 
               
               
                 168 
                 A29-M-B9 
                 2 
                 5.31 
                 304.3 
               
               
                 169 
                 A30-M-B1 
                 2 
                 6.8 
                 331.3 
               
               
                 170 
                 A30-M-B2 
                 2 
                 5.11 
                 303.3 
               
               
                 171 
                 A30-M-B6 
                 2 
                 6.76 
                 406.3 
               
               
                 172 
                 A30-M-B7 
                 2 
                 5.76 
                 360.3 
               
               
                 173 
                 A30-M-B8 
                 2 
                 4.78 
                 387.4 
               
               
                 174 
                 A30-M-B9 
                 2 
                 6.82 
                 372.4 
               
               
                 175 
                 A31-M-B1 
                 2 
                 5.92 
                 325.2 
               
               
                 176 
                 A31-M-B2 
                 2 
                 4.45 
                 297.2 
               
               
                 177 
                 A31-M-B6 
                 2 
                 5.98 
                 400.3 
               
               
                 178 
                 A31-M-B7 
                 2 
                 5.02 
                 354.3 
               
               
                 179 
                 A31-M-B8 
                 2 
                 4.17 
                 381.3 
               
               
                 180 
                 A31-M-B9 
                 2 
                 5.99 
                 366.3 
               
               
                 181 
                 A32-M-B1 
                 2 
                 6.4 
                 359.2 
               
               
                 182 
                 A32-M-B2 
                 2 
                 4.92 
                 331.2 
               
               
                 183 
                 A32-M-B6 
                 2 
                 6.41 
                 434.3 
               
               
                 184 
                 A32-M-B7 
                 2 
                 5.5 
                 388.2 
               
               
                 185 
                 A32-M-B8 
                 2 
                 4.7 
                 415.3 
               
               
                 186 
                 A32-M-B9 
                 2 
                 6.45 
                 400.3 
               
               
                 187 
                 A33-M-B6 
                 2 
                 5.42 
                 380.2 
               
               
                 188 
                 A33-M-B7 
                 2 
                 4.33 
                 334.2 
               
               
                 189 
                 A33-M-B8 
                 3 
                 3.88 
                 361.2 
               
               
                 190 
                 A33-M-B9 
                 2 
                 5.39 
                 346.3 
               
               
                 191 
                 A34-M-B6 
                 2 
                 5.55 
                 374.3 
               
               
                 192 
                 A34-M-B7 
                 2 
                 4.48 
                 328.3 
               
               
                 193 
                 A34-M-B8 
                 3 
                 4.11 
                 355.3 
               
               
                 194 
                 A34-M-B9 
                 2 
                 5.49 
                 340.3 
               
               
                 195 
                 A35-M-B7 
                 2 
                 4.62 
                 371.3 
               
               
                 196 
                 A36-M-B12 
                 1 
                 3.02 
                 425.3 
               
               
                 197 
                 A36-M-B14 
                 1 
                 3.44 
                 431.3 
               
               
                 198 
                 A36-M-B15 
                 1 
                 3.33 
                 397.3 
               
               
                 199 
                 A36-M-B16 
                 1 
                 3.63 
                 445.3 
               
               
                 200 
                 A36-M-B17 
                 1 
                 2.91 
                 369.3 
               
               
                 201 
                 A36-M-B20 
                 1 
                 3.65 
                 445.3 
               
               
                 202 
                 A36-M-B21 
                 1 
                 3.65 
                 445.3 
               
               
                 203 
                 A36-M-B22 
                 1 
                 3.85 
                 437.3 
               
               
                 204 
                 A36-M-B26 
                 1 
                 3.4 
                 409.3 
               
               
                 205 
                 A36-M-B7 
                 1 
                 2.86 
                 399.3 
               
               
                 206 
                 A37-M-B12 
                 1 
                 2.3 
                 403.2 
               
               
                 207 
                 A37-M-B13 
                 1 
                 2.34 
                 361.2 
               
               
                 208 
                 A37-M-B14 
                 1 
                 2.77 
                 409.2 
               
               
                 209 
                 A37-M-B15 
                 1 
                 2.61 
                 375.2 
               
               
                 210 
                 A37-M-B16 
                 1 
                 3 
                 423.2 
               
               
                 211 
                 A37-M-B17 
                 1 
                 2.14 
                 347.2 
               
               
                 212 
                 A37-M-B18 
                 1 
                 3.33 
                 415.3 
               
               
                 213 
                 A37-M-B19 
                 1 
                 2.17 
                 359.2 
               
               
                 214 
                 A37-M-B20 
                 1 
                 3.02 
                 423.2 
               
               
                 215 
                 A37-M-B21 
                 1 
                 3.05 
                 423.2 
               
               
                 216 
                 A37-M-B22 
                 1 
                 3.26 
                 415.3 
               
               
                 217 
                 A37-M-B23 
                 1 
                 2.65 
                 375.2 
               
               
                 218 
                 A37-M-B24 
                 1 
                 2.98 
                 401.3 
               
               
                 219 
                 A37-M-B25 
                 1 
                 2.37 
                 361.2 
               
               
                 220 
                 A37-M-B26 
                 1 
                 2.7 
                 387.2 
               
               
                 221 
                 A37-M-B27 
                 1 
                 2.26 
                 359.2 
               
               
                 222 
                 A37-M-B7 
                 1 
                 2.11 
                 377.2 
               
               
                 223 
                 A38-M-B12 
                 1 
                 2.75 
                 411.3 
               
               
                 224 
                 A38-M-B13 
                 1 
                 2.84 
                 369.3 
               
               
                 225 
                 A38-M-B14 
                 1 
                 3.21 
                 417.3 
               
               
                 226 
                 A38-M-B15 
                 1 
                 3.07 
                 383.3 
               
               
                 227 
                 A38-M-B16 
                 1 
                 3.41 
                 431.3 
               
               
                 228 
                 A38-M-B17 
                 1 
                 2.63 
                 355.3 
               
               
                 229 
                 A38-M-B18 
                 1 
                 3.7 
                 423.3 
               
               
                 230 
                 A38-M-B19 
                 1 
                 2.66 
                 367.3 
               
               
                 231 
                 A38-M-B20 
                 1 
                 3.43 
                 431.3 
               
               
                 232 
                 A38-M-B21 
                 1 
                 3.46 
                 431.3 
               
               
                 233 
                 A38-M-B22 
                 1 
                 3.65 
                 423.3 
               
               
                 234 
                 A38-M-B23 
                 1 
                 3.1 
                 383.3 
               
               
                 235 
                 A38-M-B24 
                 1 
                 3.41 
                 409.3 
               
               
                 236 
                 A38-M-B25 
                 1 
                 2.87 
                 369.3 
               
               
                 237 
                 A38-M-B26 
                 1 
                 3.16 
                 395.3 
               
               
                 238 
                 A38-M-B27 
                 1 
                 2.74 
                 367.3 
               
               
                 239 
                 A38-M-B7 
                 1 
                 2.58 
                 385.3 
               
               
                 240 
                 A39-M-B12 
                 1 
                 2.33 
                 422.3 
               
               
                 241 
                 A39-M-B13 
                 1 
                 2.39 
                 380.3 
               
               
                 242 
                 A39-M-B14 
                 1 
                 2.79 
                 428.3 
               
               
                 243 
                 A39-M-B15 
                 1 
                 2.64 
                 394.3 
               
               
                 244 
                 A39-M-B16 
                 1 
                 3.02 
                 442.3 
               
               
                 245 
                 A39-M-B18 
                 1 
                 3.32 
                 434.3 
               
               
                 246 
                 A39-M-B19 
                 1 
                 2.22 
                 378.2 
               
               
                 247 
                 A39-M-B20 
                 1 
                 3.02 
                 442.3 
               
               
                 248 
                 A39-M-B21 
                 1 
                 3.04 
                 442.3 
               
               
                 249 
                 A39-M-B22 
                 1 
                 3.24 
                 434.3 
               
               
                 250 
                 A39-M-B23 
                 1 
                 2.67 
                 394.3 
               
               
                 251 
                 A39-M-B24 
                 1 
                 2.98 
                 420.3 
               
               
                 252 
                 A39-M-B25 
                 1 
                 2.42 
                 380.3 
               
               
                 253 
                 A39-M-B26 
                 1 
                 2.72 
                 406.3 
               
               
                 254 
                 A39-M-B27 
                 1 
                 2.32 
                 378.2 
               
               
                 255 
                 A39-M-B7 
                 1 
                 2.18 
                 396.3 
               
               
                 256 
                 A40-M-B12 
                 1 
                 2.31 
                 403.2 
               
               
                 257 
                 A40-M-B13 
                 1 
                 2.36 
                 361.2 
               
               
                 258 
                 A40-M-B14 
                 1 
                 2.8 
                 409.2 
               
               
                 259 
                 A40-M-B15 
                 1 
                 2.63 
                 375.2 
               
               
                 260 
                 A40-M-B16 
                 1 
                 3.04 
                 423.2 
               
               
                 261 
                 A40-M-B18 
                 1 
                 3.38 
                 415.3 
               
               
                 262 
                 A40-M-B19 
                 1 
                 2.17 
                 359.2 
               
               
                 263 
                 A40-M-B20 
                 1 
                 3.06 
                 423.2 
               
               
                 264 
                 A40-M-B21 
                 1 
                 3.1 
                 423.2 
               
               
                 265 
                 A40-M-B22 
                 1 
                 3.31 
                 415.3 
               
               
                 266 
                 A40-M-B23 
                 1 
                 2.67 
                 375.2 
               
               
                 267 
                 A40-M-B24 
                 1 
                 3.03 
                 401.3 
               
               
                 268 
                 A40-M-B25 
                 1 
                 2.39 
                 361.2 
               
               
                 269 
                 A40-M-B26 
                 1 
                 2.73 
                 387.2 
               
               
                 270 
                 A40-M-B27 
                 1 
                 2.27 
                 359.2 
               
               
                 271 
                 A40-M-B7 
                 1 
                 2.13 
                 377.2 
               
               
                 272 
                 A41-M-B12 
                 1 
                 2.88 
                 433.3 
               
               
                 273 
                 A41-M-B13 
                 1 
                 2.97 
                 391.3 
               
               
                 274 
                 A41-M-B14 
                 1 
                 3.36 
                 439.3 
               
               
                 275 
                 A41-M-B15 
                 1 
                 3.22 
                 405.3 
               
               
                 276 
                 A41-M-B16 
                 1 
                 3.56 
                 453.3 
               
               
                 277 
                 A41-M-B18 
                 1 
                 3.8 
                 445.3 
               
               
                 278 
                 A41-M-B19 
                 1 
                 2.78 
                 389.2 
               
               
                 279 
                 A41-M-B20 
                 1 
                 3.59 
                 453.3 
               
               
                 280 
                 A41-M-B21 
                 1 
                 3.6 
                 453.3 
               
               
                 281 
                 A41-M-B22 
                 1 
                 3.8 
                 445.3 
               
               
                 282 
                 A41-M-B23 
                 1 
                 3.26 
                 405.3 
               
               
                 283 
                 A41-M-B24 
                 1 
                 3.57 
                 431.3 
               
               
                 284 
                 A41-M-B25 
                 1 
                 3 
                 391.3 
               
               
                 285 
                 A41-M-B26 
                 1 
                 3.31 
                 417.3 
               
               
                 286 
                 A41-M-B27 
                 1 
                 2.87 
                 389.2 
               
               
                 287 
                 A41-M-B7 
                 1 
                 2.68 
                 407.2 
               
               
                 288 
                 A42-M-B12 
                 1 
                 2.89 
                 425.3 
               
               
                 289 
                 A42-M-B13 
                 1 
                 2.99 
                 383.3 
               
               
                 290 
                 A42-M-B14 
                 1 
                 3.38 
                 431.3 
               
               
                 291 
                 A42-M-B15 
                 1 
                 3.23 
                 397.3 
               
               
                 292 
                 A42-M-B16 
                 1 
                 3.56 
                 445.3 
               
               
                 293 
                 A42-M-B18 
                 1 
                 3.84 
                 437.3 
               
               
                 294 
                 A42-M-B19 
                 1 
                 2.8 
                 381.3 
               
               
                 295 
                 A42-M-B20 
                 1 
                 3.59 
                 445.3 
               
               
                 296 
                 A42-M-B21 
                 1 
                 3.63 
                 445.3 
               
               
                 297 
                 A42-M-B22 
                 1 
                 3.82 
                 437.3 
               
               
                 298 
                 A42-M-B23 
                 1 
                 3.27 
                 397.3 
               
               
                 299 
                 A42-M-B24 
                 1 
                 3.57 
                 423.3 
               
               
                 300 
                 A42-M-B25 
                 1 
                 3.02 
                 383.3 
               
               
                 301 
                 A42-M-B26 
                 1 
                 3.33 
                 409.3 
               
               
                 302 
                 A42-M-B27 
                 1 
                 2.9 
                 381.3 
               
               
                 303 
                 A42-M-B7 
                 1 
                 2.73 
                 399.3 
               
               
                 304 
                 A43-M-B12 
                 1 
                 2.84 
                 449.2 
               
               
                 305 
                 A43-M-B14 
                 1 
                 3.3 
                 455.2 
               
               
                 306 
                 A43-M-B15 
                 1 
                 3.16 
                 421.2 
               
               
                 307 
                 A43-M-B16 
                 1 
                 3.5 
                 469.2 
               
               
                 308 
                 A43-M-B18 
                 1 
                 3.76 
                 461.3 
               
               
                 309 
                 A43-M-B19 
                 1 
                 2.74 
                 405.2 
               
               
                 310 
                 A43-M-B20 
                 1 
                 3.53 
                 469.2 
               
               
                 311 
                 A43-M-B21 
                 1 
                 3.55 
                 469.2 
               
               
                 312 
                 A43-M-B22 
                 1 
                 3.75 
                 461.3 
               
               
                 313 
                 A43-M-B23 
                 1 
                 3.21 
                 421.2 
               
               
                 314 
                 A43-M-B24 
                 1 
                 3.5 
                 447.3 
               
               
                 315 
                 A43-M-B25 
                 1 
                 2.95 
                 407.2 
               
               
                 316 
                 A43-M-B26 
                 1 
                 3.25 
                 433.2 
               
               
                 317 
                 A43-M-B27 
                 1 
                 2.83 
                 405.2 
               
               
                 318 
                 A43-M-B7 
                 1 
                 2.66 
                 423.2 
               
               
                 319 
                 A44-M-B13 
                 1 
                 2.26 
                 429.3 
               
               
                 320 
                 A44-M-B14 
                 1 
                 2.74 
                 381.3 
               
               
                 321 
                 A44-M-B15 
                 1 
                 2.54 
                 347.3 
               
               
                 322 
                 A44-M-B16 
                 1 
                 2.98 
                 395.3 
               
               
                 323 
                 A44-M-B17 
                 1 
                 2.04 
                 319.3 
               
               
                 324 
                 A44-M-B20 
                 1 
                 3.02 
                 395.3 
               
               
                 325 
                 A44-M-B21 
                 1 
                 3.08 
                 395.3 
               
               
                 326 
                 A44-M-B22 
                 1 
                 3.3 
                 387.3 
               
               
                 327 
                 A44-M-B25 
                 1 
                 2.29 
                 333.3 
               
               
                 328 
                 A44-M-B26 
                 1 
                 2.65 
                 359.3 
               
               
                 329 
                 A45-M-B12 
                 1 
                 2.66 
                 391.3 
               
               
                 330 
                 A45-M-B13 
                 1 
                 2.77 
                 349.3 
               
               
                 331 
                 A45-M-B14 
                 1 
                 3.21 
                 397.3 
               
               
                 332 
                 A45-M-B15 
                 1 
                 3.05 
                 363.3 
               
               
                 333 
                 A45-M-B17 
                 1 
                 2.52 
                 335.3 
               
               
                 334 
                 A45-M-B20 
                 1 
                 3.45 
                 411.3 
               
               
                 335 
                 A45-M-B21 
                 1 
                 3.5 
                 411.3 
               
               
                 336 
                 A45-M-B22 
                 1 
                 3.72 
                 403.4 
               
               
                 337 
                 A45-M-B25 
                 1 
                 2.81 
                 349.3 
               
               
                 338 
                 A45-M-B26 
                 1 
                 3.15 
                 375.3 
               
               
                 339 
                 A45-M-B7 
                 1 
                 2.46 
                 365.3 
               
               
                 340 
                 A46-M-B12 
                 1 
                 2.34 
                 422.3 
               
               
                 341 
                 A46-M-B13 
                 1 
                 2.4 
                 380.3 
               
               
                 342 
                 A46-M-B14 
                 1 
                 2.8 
                 428.3 
               
               
                 343 
                 A46-M-B15 
                 1 
                 2.65 
                 394.3 
               
               
                 344 
                 A46-M-B16 
                 1 
                 3.03 
                 442.3 
               
               
                 345 
                 A46-M-B17 
                 1 
                 2.21 
                 366.2 
               
               
                 346 
                 A46-M-B18 
                 1 
                 3.25 
                 434.3 
               
               
                 347 
                 A46-M-B19 
                 1 
                 2.23 
                 378.2 
               
               
                 348 
                 A46-M-B20 
                 1 
                 3.04 
                 442.3 
               
               
                 349 
                 A46-M-B25 
                 1 
                 2.42 
                 380.3 
               
               
                 350 
                 A46-M-B26 
                 1 
                 2.73 
                 406.3 
               
               
                 351 
                 A46-M-B27 
                 1 
                 2.32 
                 378.2 
               
               
                 352 
                 A46-M-B7 
                 1 
                 2.18 
                 396.3 
               
               
                 353 
                 A47-M-B13 
                 1 
                 2.61 
                 369.3 
               
               
                 354 
                 A47-M-B14 
                 1 
                 3.06 
                 417.3 
               
               
                 355 
                 A47-M-B15 
                 1 
                 2.89 
                 383.3 
               
               
                 356 
                 A47-M-B16 
                 1 
                 3.26 
                 431.3 
               
               
                 357 
                 A47-M-B17 
                 1 
                 2.38 
                 355.3 
               
               
                 358 
                 A47-M-B18 
                 1 
                 3.58 
                 423.3 
               
               
                 359 
                 A47-M-B19 
                 1 
                 2.4 
                 367.3 
               
               
                 360 
                 A47-M-B20 
                 1 
                 3.31 
                 431.3 
               
               
                 361 
                 A47-M-B21 
                 1 
                 3.35 
                 431.3 
               
               
                 362 
                 A47-M-B22 
                 1 
                 3.55 
                 423.3 
               
               
                 363 
                 A47-M-B23 
                 1 
                 2.92 
                 383.3 
               
               
                 364 
                 A47-M-B24 
                 1 
                 3.27 
                 409.3 
               
               
                 365 
                 A47-M-B25 
                 1 
                 2.64 
                 369.3 
               
               
                 366 
                 A47-M-B26 
                 1 
                 2.99 
                 395.3 
               
               
                 367 
                 A47-M-B27 
                 1 
                 2.52 
                 367.3 
               
               
                 368 
                 A47-M-B7 
                 1 
                 2.35 
                 385.3 
               
               
                 369 
                 A48-M-B12 
                 1 
                 2.77 
                 411.3 
               
               
                 370 
                 A48-M-B13 
                 1 
                 2.84 
                 369.3 
               
               
                 371 
                 A48-M-B14 
                 1 
                 3.23 
                 417.3 
               
               
                 372 
                 A48-M-B15 
                 1 
                 3.09 
                 383.3 
               
               
                 373 
                 A48-M-B16 
                 1 
                 3.44 
                 431.3 
               
               
                 374 
                 A48-M-B17 
                 1 
                 2.64 
                 355.3 
               
               
                 375 
                 A48-M-B19 
                 1 
                 2.67 
                 367.3 
               
               
                 376 
                 A48-M-B20 
                 1 
                 3.45 
                 431.3 
               
               
                 377 
                 A48-M-B21 
                 1 
                 3.48 
                 431.3 
               
               
                 378 
                 A48-M-B22 
                 1 
                 3.67 
                 423.3 
               
               
                 379 
                 A48-M-B26 
                 1 
                 3.16 
                 395.3 
               
               
                 380 
                 A48-M-B7 
                 1 
                 2.6 
                 385.3 
               
               
                 381 
                 A49-M-B12 
                 1 
                 2.78 
                 403.3 
               
               
                 382 
                 A49-M-B13 
                 1 
                 2.89 
                 361.3 
               
               
                 383 
                 A49-M-B14 
                 1 
                 3.31 
                 409.3 
               
               
                 384 
                 A49-M-B15 
                 1 
                 3.16 
                 375.3 
               
               
                 385 
                 A49-M-B16 
                 1 
                 3.51 
                 423.3 
               
               
                 386 
                 A49-M-B17 
                 1 
                 2.66 
                 347.3 
               
               
                 387 
                 A49-M-B18 
                 1 
                 3.82 
                 415.4 
               
               
                 388 
                 A49-M-B19 
                 1 
                 2.68 
                 359.3 
               
               
                 389 
                 A49-M-B20 
                 1 
                 3.56 
                 423.3 
               
               
                 390 
                 A49-M-B21 
                 1 
                 3.59 
                 423.3 
               
               
                 391 
                 A49-M-B22 
                 1 
                 3.79 
                 415.4 
               
               
                 392 
                 A49-M-B23 
                 1 
                 3.2 
                 375.3 
               
               
                 393 
                 A49-M-B24 
                 1 
                 3.53 
                 401.3 
               
               
                 394 
                 A49-M-B25 
                 1 
                 2.92 
                 361.3 
               
               
                 395 
                 A49-M-B26 
                 1 
                 3.26 
                 387.3 
               
               
                 396 
                 A49-M-B27 
                 1 
                 2.8 
                 359.3 
               
               
                 397 
                 A49-M-B7 
                 1 
                 2.6 
                 377.3 
               
               
                 398 
                 A50-M-B12 
                 1 
                 2.58 
                 391.3 
               
               
                 399 
                 A50-M-B13 
                 1 
                 2.66 
                 349.3 
               
               
                 400 
                 A50-M-B14 
                 1 
                 3.15 
                 397.3 
               
               
                 401 
                 A50-M-B15 
                 1 
                 2.95 
                 363.3 
               
               
                 402 
                 A50-M-B16 
                 1 
                 3.33 
                 411.3 
               
               
                 403 
                 A50-M-B17 
                 1 
                 2.4 
                 335.3 
               
               
                 404 
                 A50-M-B20 
                 1 
                 3.39 
                 411.3 
               
               
                 405 
                 A50-M-B21 
                 1 
                 3.44 
                 411.3 
               
               
                 406 
                 A50-M-B22 
                 1 
                 3.66 
                 403.4 
               
               
                 407 
                 A50-M-B25 
                 1 
                 2.72 
                 349.3 
               
               
                 408 
                 A50-M-B26 
                 1 
                 3.06 
                 375.3 
               
               
                 409 
                 A51-M-B12 
                 1 
                 2.37 
                 377.3 
               
               
                 410 
                 A51-M-B13 
                 1 
                 2.44 
                 335.3 
               
               
                 411 
                 A51-M-B14 
                 1 
                 2.91 
                 383.3 
               
               
                 412 
                 A51-M-B15 
                 1 
                 2.73 
                 349.3 
               
               
                 413 
                 A51-M-B16 
                 1 
                 3.15 
                 397.3 
               
               
                 414 
                 A51-M-B17 
                 1 
                 2.2 
                 321.3 
               
               
                 415 
                 A51-M-B22 
                 1 
                 3.48 
                 389.3 
               
               
                 416 
                 A51-M-B25 
                 1 
                 2.47 
                 335.3 
               
               
                 417 
                 A51-M-B26 
                 1 
                 2.83 
                 361.3 
               
               
                 418 
                 A51-M-B27 
                 1 
                 2.34 
                 333.3 
               
               
                 419 
                 A52-M-B12 
                 1 
                 2.89 
                 425.3 
               
               
                 420 
                 A52-M-B13 
                 1 
                 2.99 
                 383.3 
               
               
                 421 
                 A52-M-B14 
                 1 
                 3.38 
                 431.3 
               
               
                 422 
                 A52-M-B15 
                 1 
                 3.24 
                 397.3 
               
               
                 423 
                 A52-M-B16 
                 1 
                 3.56 
                 445.3 
               
               
                 424 
                 A52-M-B18 
                 1 
                 3.83 
                 437.3 
               
               
                 425 
                 A52-M-B19 
                 1 
                 2.8 
                 381.3 
               
               
                 426 
                 A52-M-B20 
                 1 
                 3.59 
                 445.3 
               
               
                 427 
                 A52-M-B21 
                 1 
                 3.62 
                 445.3 
               
               
                 428 
                 A52-M-B22 
                 1 
                 3.82 
                 437.3 
               
               
                 429 
                 A52-M-B23 
                 1 
                 3.28 
                 397.3 
               
               
                 430 
                 A52-M-B24 
                 1 
                 3.57 
                 423.3 
               
               
                 431 
                 A52-M-B25 
                 1 
                 3.03 
                 383.3 
               
               
                 432 
                 A52-M-B26 
                 1 
                 3.33 
                 409.3 
               
               
                 433 
                 A52-M-B27 
                 1 
                 2.91 
                 381.3 
               
               
                 434 
                 A52-M-B7 
                 1 
                 2.72 
                 399.3 
               
               
                 435 
                 A53-M-B12 
                 1 
                 2.26 
                 433.3 
               
               
                 436 
                 A53-M-B13 
                 1 
                 2.31 
                 391.3 
               
               
                 437 
                 A53-M-B14 
                 1 
                 2.75 
                 439.3 
               
               
                 438 
                 A53-M-B15 
                 1 
                 2.57 
                 405.3 
               
               
                 439 
                 A53-M-B16 
                 1 
                 2.98 
                 453.3 
               
               
                 440 
                 A53-M-B20 
                 1 
                 3.01 
                 453.3 
               
               
                 441 
                 A53-M-B21 
                 1 
                 3 
                 453.3 
               
               
                 442 
                 A53-M-B26 
                 1 
                 2.65 
                 417.3 
               
               
                 443 
                 A53-M-B7 
                 1 
                 2.08 
                 407.2 
               
               
                 444 
                 A54-M-B13 
                 1 
                 2.38 
                 335.3 
               
               
                 445 
                 A54-M-B14 
                 1 
                 2.88 
                 383.3 
               
               
                 446 
                 A54-M-B15 
                 1 
                 2.67 
                 349.3 
               
               
                 447 
                 A54-M-B20 
                 1 
                 3.15 
                 397.3 
               
               
                 448 
                 A54-M-B21 
                 1 
                 3.2 
                 397.3 
               
               
                 449 
                 A54-M-B26 
                 1 
                 2.78 
                 361.3 
               
               
                 450 
                 A55-M-B12 
                 1 
                 2.55 
                 433.3 
               
               
                 451 
                 A55-M-B13 
                 1 
                 2.62 
                 391.3 
               
               
                 452 
                 A55-M-B14 
                 1 
                 3.06 
                 439.3 
               
               
                 453 
                 A55-M-B15 
                 1 
                 2.88 
                 405.3 
               
               
                 454 
                 A55-M-B16 
                 1 
                 3.26 
                 453.3 
               
               
                 455 
                 A55-M-B17 
                 1 
                 2.4 
                 377.2 
               
               
                 456 
                 A55-M-B18 
                 1 
                 3.51 
                 445.3 
               
               
                 457 
                 A55-M-B19 
                 1 
                 2.43 
                 389.2 
               
               
                 458 
                 A55-M-B20 
                 1 
                 3.29 
                 453.3 
               
               
                 459 
                 A55-M-B21 
                 1 
                 3.33 
                 453.3 
               
               
                 460 
                 A55-M-B22 
                 1 
                 3.53 
                 445.3 
               
               
                 461 
                 A55-M-B23 
                 1 
                 2.93 
                 405.3 
               
               
                 462 
                 A55-M-B25 
                 1 
                 2.65 
                 391.3 
               
               
                 463 
                 A55-M-B26 
                 1 
                 2.98 
                 417.3 
               
               
                 464 
                 A55-M-B27 
                 1 
                 2.53 
                 389.2 
               
               
                 465 
                 A55-M-B7 
                 1 
                 2.36 
                 407.2 
               
               
                 466 
                 A56-M-B13 
                 1 
                 2.99 
                 391.3 
               
               
                 467 
                 A56-M-B14 
                 1 
                 3.38 
                 439.3 
               
               
                 468 
                 A56-M-B15 
                 1 
                 3.23 
                 405.3 
               
               
                 469 
                 A56-M-B16 
                 1 
                 3.58 
                 453.3 
               
               
                 470 
                 A56-M-B18 
                 1 
                 3.86 
                 445.3 
               
               
                 471 
                 A56-M-B19 
                 1 
                 2.79 
                 389.2 
               
               
                 472 
                 A56-M-B20 
                 1 
                 3.61 
                 453.3 
               
               
                 473 
                 A56-M-B21 
                 1 
                 3.62 
                 453.3 
               
               
                 474 
                 A56-M-B22 
                 1 
                 3.81 
                 445.3 
               
               
                 475 
                 A56-M-B23 
                 1 
                 3.28 
                 405.3 
               
               
                 476 
                 A56-M-B24 
                 1 
                 3.59 
                 431.3 
               
               
                 477 
                 A56-M-B25 
                 1 
                 3.01 
                 391.3 
               
               
                 478 
                 A56-M-B26 
                 1 
                 3.33 
                 417.3 
               
               
                 479 
                 A56-M-B27 
                 1 
                 2.89 
                 389.2 
               
               
                 480 
                 A56-M-B7 
                 1 
                 2.7 
                 407.2 
               
               
                 481 
                 A57-M-B12 
                 1 
                 3.09 
                 425.3 
               
               
                 482 
                 A57-M-B13 
                 1 
                 3.2 
                 383.3 
               
               
                 483 
                 A57-M-B14 
                 1 
                 3.53 
                 431.3 
               
               
                 484 
                 A57-M-B15 
                 1 
                 3.42 
                 397.3 
               
               
                 485 
                 A57-M-B16 
                 1 
                 3.71 
                 445.3 
               
               
                 486 
                 A57-M-B18 
                 1 
                 3.97 
                 437.3 
               
               
                 487 
                 A57-M-B19 
                 1 
                 3.05 
                 381.3 
               
               
                 488 
                 A57-M-B20 
                 1 
                 3.73 
                 445.3 
               
               
                 489 
                 A57-M-B21 
                 1 
                 3.74 
                 445.3 
               
               
                 490 
                 A57-M-B22 
                 2 
                 5.77 
                 437.3 
               
               
                 491 
                 A57-M-B23 
                 1 
                 3.45 
                 397.3 
               
               
                 492 
                 A57-M-B24 
                 1 
                 3.72 
                 423.3 
               
               
                 493 
                 A57-M-B25 
                 1 
                 3.23 
                 383.3 
               
               
                 494 
                 A57-M-B26 
                 1 
                 3.49 
                 409.3 
               
               
                 495 
                 A57-M-B27 
                 1 
                 3.13 
                 381.3 
               
               
                 496 
                 A57-M-B7 
                 1 
                 2.95 
                 399.3 
               
               
                 497 
                 A58-M-B13 
                 1 
                 2.53 
                 375.2 
               
               
                 498 
                 A58-M-B15 
                 1 
                 2.8 
                 389.3 
               
               
                 499 
                 A58-M-B16 
                 1 
                 3.16 
                 437.3 
               
               
                 500 
                 A58-M-B17 
                 1 
                 2.32 
                 361.2 
               
               
                 501 
                 A58-M-B20 
                 1 
                 3.19 
                 437.3 
               
               
                 502 
                 A58-M-B21 
                 1 
                 3.21 
                 437.3 
               
               
                 503 
                 A58-M-B25 
                 1 
                 2.56 
                 375.2 
               
               
                 504 
                 A58-M-B26 
                 1 
                 2.88 
                 401.3 
               
               
                 505 
                 A59-M-B12 
                 1 
                 2.67 
                 449.2 
               
               
                 506 
                 A59-M-B13 
                 1 
                 2.75 
                 407.2 
               
               
                 507 
                 A59-M-B14 
                 1 
                 3.19 
                 455.2 
               
               
                 508 
                 A59-M-B15 
                 1 
                 3.01 
                 421.2 
               
               
                 509 
                 A59-M-B16 
                 1 
                 3.38 
                 469.2 
               
               
                 510 
                 A59-M-B18 
                 1 
                 3.69 
                 461.3 
               
               
                 511 
                 A59-M-B19 
                 1 
                 2.55 
                 405.2 
               
               
                 512 
                 A59-M-B20 
                 1 
                 3.41 
                 469.2 
               
               
                 513 
                 A59-M-B21 
                 1 
                 3.46 
                 469.2 
               
               
                 514 
                 A59-M-B22 
                 1 
                 3.65 
                 461.3 
               
               
                 515 
                 A59-M-B23 
                 1 
                 3.06 
                 421.2 
               
               
                 516 
                 A59-M-B25 
                 1 
                 2.78 
                 407.2 
               
               
                 517 
                 A59-M-B26 
                 1 
                 3.12 
                 433.2 
               
               
                 518 
                 A59-M-B27 
                 1 
                 2.65 
                 405.2 
               
               
                 519 
                 A59-M-B7 
                 1 
                 2.47 
                 423.2 
               
               
                 520 
                 A60-M-B12 
                 1 
                 2.34 
                 377.3 
               
               
                 521 
                 A60-M-B13 
                 1 
                 2.4 
                 335.3 
               
               
                 522 
                 A60-M-B14 
                 1 
                 2.88 
                 383.3 
               
               
                 523 
                 A60-M-B15 
                 1 
                 2.69 
                 349.3 
               
               
                 524 
                 A60-M-B16 
                 1 
                 3.1 
                 397.3 
               
               
                 525 
                 A60-M-B20 
                 1 
                 3.15 
                 397.3 
               
               
                 526 
                 A60-M-B21 
                 1 
                 3.21 
                 397.3 
               
               
                 527 
                 A60-M-B22 
                 1 
                 3.44 
                 389.3 
               
               
                 528 
                 A60-M-B23 
                 1 
                 2.73 
                 349.3 
               
               
                 529 
                 A60-M-B25 
                 1 
                 2.43 
                 335.3 
               
               
                 530 
                 A60-M-B26 
                 1 
                 2.81 
                 361.3 
               
               
                 531 
                 A60-M-B27 
                 1 
                 2.3 
                 333.3 
               
               
                 532 
                 A61-M-B13 
                 1 
                 2.52 
                 335.3 
               
               
                 533 
                 A61-M-B14 
                 1 
                 2.98 
                 383.3 
               
               
                 534 
                 A61-M-B15 
                 1 
                 2.8 
                 349.3 
               
               
                 535 
                 A61-M-B16 
                 1 
                 3.2 
                 397.3 
               
               
                 536 
                 A61-M-B17 
                 1 
                 2.27 
                 321.3 
               
               
                 537 
                 A61-M-B19 
                 1 
                 2.31 
                 333.3 
               
               
                 538 
                 A61-M-B20 
                 1 
                 3.25 
                 397.3 
               
               
                 539 
                 A61-M-B21 
                 1 
                 3.3 
                 397.3 
               
               
                 540 
                 A61-M-B26 
                 1 
                 2.9 
                 361.3 
               
               
                 541 
                 A62-M-B12 
                 1 
                 2.42 
                 397.3 
               
               
                 542 
                 A62-M-B13 
                 1 
                 2.49 
                 355.3 
               
               
                 543 
                 A62-M-B14 
                 1 
                 2.91 
                 403.3 
               
               
                 544 
                 A62-M-B15 
                 1 
                 2.75 
                 369.3 
               
               
                 545 
                 A62-M-B16 
                 1 
                 3.13 
                 417.3 
               
               
                 546 
                 A62-M-B17 
                 1 
                 2.26 
                 341.3 
               
               
                 547 
                 A62-M-B18 
                 1 
                 3.46 
                 409.3 
               
               
                 548 
                 A62-M-B19 
                 1 
                 2.29 
                 353.3 
               
               
                 549 
                 A62-M-B20 
                 1 
                 3.16 
                 417.3 
               
               
                 550 
                 A62-M-B21 
                 1 
                 3.2 
                 417.3 
               
               
                 551 
                 A62-M-B22 
                 1 
                 3.39 
                 409.3 
               
               
                 552 
                 A62-M-B23 
                 1 
                 2.78 
                 369.3 
               
               
                 553 
                 A62-M-B24 
                 1 
                 3.12 
                 395.3 
               
               
                 554 
                 A62-M-B25 
                 1 
                 2.51 
                 355.3 
               
               
                 555 
                 A62-M-B26 
                 1 
                 2.83 
                 381.3 
               
               
                 556 
                 A62-M-B27 
                 1 
                 2.38 
                 353.3 
               
               
                 557 
                 A62-M-B7 
                 1 
                 2.24 
                 371.3 
               
               
                 558 
                 A63-M-B12 
                 1 
                 2.96 
                 429.3 
               
               
                 559 
                 A63-M-B13 
                 1 
                 3.07 
                 387.3 
               
               
                 560 
                 A63-M-B14 
                 1 
                 3.41 
                 435.3 
               
               
                 561 
                 A63-M-B15 
                 1 
                 3.3 
                 401.3 
               
               
                 562 
                 A63-M-B16 
                 1 
                 3.6 
                 449.3 
               
               
                 563 
                 A63-M-B17 
                 1 
                 2.86 
                 373.3 
               
               
                 564 
                 A63-M-B18 
                 1 
                 3.88 
                 441.3 
               
               
                 565 
                 A63-M-B19 
                 1 
                 2.89 
                 385.3 
               
               
                 566 
                 A63-M-B20 
                 1 
                 3.63 
                 449.3 
               
               
                 567 
                 A63-M-B21 
                 1 
                 3.64 
                 449.3 
               
               
                 568 
                 A63-M-B22 
                 1 
                 3.83 
                 441.3 
               
               
                 569 
                 A63-M-B26 
                 1 
                 3.38 
                 413.3 
               
               
                 570 
                 A63-M-B27 
                 1 
                 2.99 
                 385.3 
               
               
                 571 
                 A63-M-B7 
                 1 
                 2.82 
                 403.3 
               
               
                 572 
                 A64-M-B12 
                 1 
                 2.34 
                 415.3 
               
               
                 573 
                 A64-M-B14 
                 1 
                 2.84 
                 421.3 
               
               
                 574 
                 A64-M-B15 
                 1 
                 2.67 
                 387.3 
               
               
                 575 
                 A64-M-B16 
                 1 
                 3.06 
                 435.3 
               
               
                 576 
                 A64-M-B17 
                 1 
                 2.22 
                 359.2 
               
               
                 577 
                 A64-M-B20 
                 1 
                 3.09 
                 435.3 
               
               
                 578 
                 A64-M-B21 
                 1 
                 3.13 
                 435.3 
               
               
                 579 
                 A64-M-B22 
                 1 
                 3.33 
                 427.3 
               
               
                 580 
                 A64-M-B26 
                 1 
                 2.75 
                 399.3 
               
               
                 581 
                 A64-M-B27 
                 1 
                 2.34 
                 371.2 
               
               
                 582 
                 A64-M-B7 
                 1 
                 2.19 
                 389.3 
               
               
                 583 
                 A65-M-B12 
                 1 
                 2.51 
                 389.3 
               
               
                 584 
                 A65-M-B14 
                 1 
                 3.05 
                 395.3 
               
               
                 585 
                 A65-M-B15 
                 1 
                 2.86 
                 361.3 
               
               
                 586 
                 A65-M-B16 
                 1 
                 3.26 
                 409.3 
               
               
                 587 
                 A65-M-B17 
                 1 
                 2.34 
                 333.3 
               
               
                 588 
                 A65-M-B18 
                 1 
                 3.59 
                 401.3 
               
               
                 589 
                 A65-M-B19 
                 1 
                 2.37 
                 345.3 
               
               
                 590 
                 A65-M-B20 
                 1 
                 3.3 
                 409.3 
               
               
                 591 
                 A65-M-B21 
                 1 
                 3.34 
                 409.3 
               
               
                 592 
                 A65-M-B22 
                 1 
                 3.57 
                 401.3 
               
               
                 593 
                 A65-M-B26 
                 1 
                 2.97 
                 373.3 
               
               
                 594 
                 A65-M-B7 
                 1 
                 2.3 
                 363.3 
               
               
                 595 
                 A66-M-B12 
                 1 
                 2.56 
                 449.2 
               
               
                 596 
                 A66-M-B14 
                 1 
                 3.08 
                 455.2 
               
               
                 597 
                 A66-M-B15 
                 1 
                 2.9 
                 421.2 
               
               
                 598 
                 A66-M-B16 
                 1 
                 3.29 
                 469.2 
               
               
                 599 
                 A66-M-B20 
                 1 
                 3.32 
                 469.2 
               
               
                 600 
                 A66-M-B21 
                 1 
                 3.35 
                 469.2 
               
               
                 601 
                 A66-M-B25 
                 1 
                 2.66 
                 407.2 
               
               
                 602 
                 A66-M-B26 
                 1 
                 3.02 
                 433.2 
               
               
                 603 
                 A67-M-B12 
                 1 
                 2.5 
                 433.3 
               
               
                 604 
                 A67-M-B14 
                 1 
                 3 
                 439.3 
               
               
                 605 
                 A67-M-B15 
                 1 
                 2.84 
                 405.3 
               
               
                 606 
                 A67-M-B16 
                 1 
                 3.21 
                 453.3 
               
               
                 607 
                 A67-M-B18 
                 1 
                 3.45 
                 445.3 
               
               
                 608 
                 A67-M-B19 
                 1 
                 2.37 
                 389.2 
               
               
                 609 
                 A67-M-B20 
                 1 
                 3.24 
                 453.3 
               
               
                 610 
                 A67-M-B21 
                 1 
                 3.28 
                 453.3 
               
               
                 611 
                 A67-M-B26 
                 1 
                 2.92 
                 417.3 
               
               
                 612 
                 A67-M-B27 
                 1 
                 2.49 
                 389.2 
               
               
                 613 
                 A67-M-B7 
                 1 
                 2.32 
                 407.2 
               
               
                 614 
                 A68-M-B12 
                 1 
                 2.43 
                 431.2 
               
               
                 615 
                 A68-M-B14 
                 1 
                 2.95 
                 437.2 
               
               
                 616 
                 A68-M-B15 
                 1 
                 2.78 
                 403.2 
               
               
                 617 
                 A68-M-B16 
                 1 
                 3.17 
                 451.2 
               
               
                 618 
                 A68-M-B17 
                 1 
                 2.29 
                 375.2 
               
               
                 619 
                 A68-M-B18 
                 1 
                 3.47 
                 443.3 
               
               
                 620 
                 A68-M-B19 
                 1 
                 2.31 
                 387.2 
               
               
                 621 
                 A68-M-B20 
                 1 
                 3.19 
                 451.2 
               
               
                 622 
                 A68-M-B21 
                 1 
                 3.24 
                 451.2 
               
               
                 623 
                 A68-M-B26 
                 1 
                 2.87 
                 415.2 
               
               
                 624 
                 A68-M-B27 
                 1 
                 2.41 
                 387.2 
               
               
                 625 
                 A68-M-B7 
                 1 
                 2.25 
                 405.2 
               
               
                 626 
                 A69-M-B14 
                 1 
                 2.61 
                 369.3 
               
               
                 627 
                 A69-M-B15 
                 1 
                 2.38 
                 335.3 
               
               
                 628 
                 A69-M-B16 
                 1 
                 2.85 
                 383.3 
               
               
                 629 
                 A69-M-B20 
                 1 
                 2.9 
                 383.3 
               
               
                 630 
                 A69-M-B21 
                 1 
                 2.95 
                 383.3 
               
               
                 631 
                 A69-M-B25 
                 1 
                 2.15 
                 321.3 
               
               
                 632 
                 A69-M-B26 
                 1 
                 2.5 
                 347.3 
               
               
                 633 
                 A70-M-B12 
                 1 
                 2.62 
                 415.3 
               
               
                 634 
                 A70-M-B14 
                 1 
                 3.12 
                 421.3 
               
               
                 635 
                 A70-M-B15 
                 1 
                 2.97 
                 387.3 
               
               
                 636 
                 A70-M-B16 
                 1 
                 3.33 
                 435.3 
               
               
                 637 
                 A70-M-B17 
                 1 
                 2.48 
                 359.2 
               
               
                 638 
                 A70-M-B18 
                 1 
                 3.63 
                 427.3 
               
               
                 639 
                 A70-M-B19 
                 1 
                 2.5 
                 371.2 
               
               
                 640 
                 A70-M-B20 
                 1 
                 3.35 
                 435.3 
               
               
                 641 
                 A70-M-B21 
                 1 
                 3.37 
                 435.3 
               
               
                 642 
                 A70-M-B26 
                 1 
                 3.06 
                 399.3 
               
               
                 643 
                 A70-M-B27 
                 1 
                 2.61 
                 371.2 
               
               
                 644 
                 A70-M-B7 
                 1 
                 2.43 
                 389.3 
               
               
                 645 
                 A71-M-B14 
                 1 
                 2.58 
                 369.3 
               
               
                 646 
                 A71-M-B16 
                 1 
                 2.84 
                 383.3 
               
               
                 647 
                 A71-M-B20 
                 1 
                 2.87 
                 383.3 
               
               
                 648 
                 A71-M-B21 
                 1 
                 2.93 
                 383.3 
               
               
                 649 
                 A71-M-B25 
                 1 
                 2.11 
                 321.3 
               
               
                 650 
                 A72-M-B14 
                 1 
                 2.52 
                 421.3 
               
               
                 651 
                 A72-M-B16 
                 1 
                 2.74 
                 435.3 
               
               
                 652 
                 A72-M-B18 
                 1 
                 3.06 
                 427.3 
               
               
                 653 
                 A72-M-B20 
                 1 
                 2.75 
                 435.3 
               
               
                 654 
                 A72-M-B21 
                 1 
                 2.77 
                 435.3 
               
               
                 655 
                 A72-M-B27 
                 1 
                 2.07 
                 371.3 
               
               
                 656 
                 A73-M-B12 
                 1 
                 2.66 
                 430.3 
               
               
                 657 
                 A73-M-B14 
                 1 
                 3.17 
                 436.3 
               
               
                 658 
                 A73-M-B17 
                 1 
                 2.17 
                 374.3 
               
               
                 659 
                 A73-M-B20 
                 1 
                 3.4 
                 450.3 
               
               
                 660 
                 A73-M-B21 
                 1 
                 3.45 
                 450.3 
               
               
                 661 
                 A73-M-B24 
                 1 
                 3.38 
                 428.3 
               
               
                 662 
                 A73-M-B26 
                 1 
                 3.11 
                 414.3 
               
               
                 663 
                 A74-M-B16 
                 1 
                 2.87 
                 453.3 
               
               
                 664 
                 A74-M-B17 
                 1 
                 2.04 
                 377.2 
               
               
                 665 
                 A75-M-B18 
                 1 
                 2.95 
                 399.3 
               
               
                 666 
                 A75-M-B19 
                 1 
                 1.91 
                 343.2 
               
               
                 667 
                 A75-M-B20 
                 1 
                 2.72 
                 407.3 
               
               
                 668 
                 A75-M-B21 
                 1 
                 2.75 
                 407.3 
               
               
                 669 
                 A75-M-B22 
                 1 
                 2.98 
                 399.3 
               
               
                 670 
                 A75-M-B23 
                 1 
                 2.34 
                 359.3 
               
               
                 671 
                 A75-M-B24 
                 1 
                 2.68 
                 385.3 
               
               
                 672 
                 A75-M-B25 
                 1 
                 2.09 
                 345.2 
               
               
                 673 
                 A75-M-B27 
                 1 
                 1.98 
                 343.2 
               
               
                 674 
                 A76-M-B18 
                 1 
                 2.69 
                 410.3 
               
               
                 675 
                 A76-M-B19 
                 1 
                 1.7 
                 354.2 
               
               
                 676 
                 A76-M-B20 
                 1 
                 2.45 
                 418.3 
               
               
                 677 
                 A76-M-B21 
                 1 
                 2.5 
                 418.3 
               
               
                 678 
                 A76-M-B22 
                 1 
                 2.72 
                 410.3 
               
               
                 679 
                 A76-M-B23 
                 1 
                 2.06 
                 370.3 
               
               
                 680 
                 A76-M-B24 
                 1 
                 2.4 
                 396.3 
               
               
                 681 
                 A76-M-B25 
                 1 
                 1.85 
                 356.3 
               
               
                 682 
                 A77-M-B14 
                 1 
                 2.64 
                 421.3 
               
               
                 683 
                 A77-M-B16 
                 1 
                 2.9 
                 435.3 
               
               
                 684 
                 A77-M-B18 
                 1 
                 3.2 
                 427.3 
               
               
                 685 
                 A77-M-B20 
                 1 
                 2.89 
                 435.3 
               
               
                 686 
                 A77-M-B21 
                 1 
                 2.92 
                 435.3 
               
               
                 687 
                 A77-M-B27 
                 1 
                 2.19 
                 371.3 
               
               
                 688 
                 A78-M-B12 
                 1 
                 2.69 
                 442.3 
               
               
                 689 
                 A78-M-B14 
                 1 
                 3.16 
                 448.3 
               
               
                 690 
                 A78-M-B15 
                 1 
                 3.02 
                 414.3 
               
               
                 691 
                 A78-M-B16 
                 1 
                 3.38 
                 462.3 
               
               
                 692 
                 A78-M-B17 
                 1 
                 2.57 
                 386.3 
               
               
                 693 
                 A78-M-B18 
                 1 
                 3.65 
                 454.3 
               
               
                 694 
                 A78-M-B19 
                 1 
                 2.59 
                 398.3 
               
               
                 695 
                 A78-M-B20 
                 1 
                 3.38 
                 462.3 
               
               
                 696 
                 A78-M-B21 
                 1 
                 3.42 
                 462.3 
               
               
                 697 
                 A78-M-B22 
                 1 
                 3.62 
                 454.3 
               
               
                 698 
                 A78-M-B23 
                 1 
                 3.07 
                 414.3 
               
               
                 699 
                 A78-M-B24 
                 1 
                 3.37 
                 440.3 
               
               
                 700 
                 A78-M-B26 
                 1 
                 3.12 
                 426.3 
               
               
                 701 
                 A78-M-B7 
                 1 
                 2.51 
                 416.3 
               
               
                 702 
                 A79-M-B14 
                 1 
                 3.69 
                 466.3 
               
               
                 703 
                 A79-M-B18 
                 1 
                 4.09 
                 472.3 
               
               
                 704 
                 A79-M-B21 
                 1 
                 3.9 
                 480.3 
               
               
                 705 
                 A79-M-B22 
                 1 
                 4.07 
                 472.3 
               
               
                 706 
                 A79-M-B24 
                 1 
                 3.86 
                 458.3 
               
               
                 707 
                 A79-M-B26 
                 1 
                 3.65 
                 444.3 
               
               
                 708 
                 A80-M-B14 
                 1 
                 3.66 
                 470.2 
               
               
                 709 
                 A80-M-B15 
                 1 
                 3.56 
                 436.2 
               
               
                 710 
                 A80-M-B18 
                 1 
                 4.06 
                 476.3 
               
               
                 711 
                 A80-M-B19 
                 1 
                 3.19 
                 420.2 
               
               
                 712 
                 A80-M-B21 
                 1 
                 3.87 
                 484.2 
               
               
                 713 
                 A80-M-B22 
                 1 
                 4.04 
                 476.3 
               
               
                 714 
                 A80-M-B24 
                 1 
                 3.87 
                 462.3 
               
               
                 715 
                 A81-M-B14 
                 1 
                 3.64 
                 466.3 
               
               
                 716 
                 A81-M-B18 
                 1 
                 4.06 
                 472.3 
               
               
                 717 
                 A81-M-B19 
                 1 
                 3.11 
                 416.2 
               
               
                 718 
                 A81-M-B21 
                 1 
                 3.88 
                 480.3 
               
               
                 719 
                 A81-M-B22 
                 1 
                 4.06 
                 472.3 
               
               
                 720 
                 A81-M-B24 
                 1 
                 3.83 
                 458.3 
               
               
                 721 
                 A82-M-B14 
                 1 
                 3.4 
                 446.3 
               
               
                 722 
                 A82-M-B18 
                 1 
                 3.86 
                 452.4 
               
               
                 723 
                 A82-M-B19 
                 1 
                 2.8 
                 396.3 
               
               
                 724 
                 A82-M-B20 
                 1 
                 3.62 
                 460.3 
               
               
                 725 
                 A82-M-B21 
                 1 
                 3.66 
                 460.3 
               
               
                 726 
                 A82-M-B22 
                 1 
                 3.86 
                 452.4 
               
               
                 727 
                 A82-M-B24 
                 1 
                 3.59 
                 438.3 
               
               
                 728 
                 A83-M-B14 
                 1 
                 3.45 
                 446.3 
               
               
                 729 
                 A83-M-B18 
                 1 
                 3.89 
                 452.4 
               
               
                 730 
                 A83-M-B19 
                 1 
                 2.87 
                 396.3 
               
               
                 731 
                 A83-M-B20 
                 1 
                 3.65 
                 460.3 
               
               
                 732 
                 A83-M-B22 
                 1 
                 3.89 
                 452.4 
               
               
                 733 
                 A83-M-B24 
                 1 
                 3.64 
                 438.3 
               
               
                 734 
                 A84-M-B14 
                 1 
                 3.03 
                 432.3 
               
               
                 735 
                 A84-M-B18 
                 1 
                 3.58 
                 438.3 
               
               
                 736 
                 A84-M-B19 
                 1 
                 2.38 
                 382.3 
               
               
                 737 
                 A84-M-B20 
                 1 
                 3.27 
                 446.3 
               
               
                 738 
                 A84-M-B21 
                 1 
                 3.32 
                 446.3 
               
               
                 739 
                 A84-M-B22 
                 1 
                 3.54 
                 438.3 
               
               
                 740 
                 A85-M-B14 
                 1 
                 3.56 
                 450.3 
               
               
                 741 
                 A85-M-B17 
                 1 
                 3.04 
                 388.3 
               
               
                 742 
                 A85-M-B20 
                 1 
                 3.76 
                 464.3 
               
               
                 743 
                 A85-M-B21 
                 1 
                 3.79 
                 464.3 
               
               
                 744 
                 A85-M-B22 
                 2 
                 5.71 
                 456.3 
               
               
                 745 
                 A86-M-B14 
                 1 
                 3.02 
                 410.3 
               
               
                 746 
                 A86-M-B20 
                 1 
                 3.27 
                 424.3 
               
               
                 747 
                 A86-M-B21 
                 1 
                 3.32 
                 424.3 
               
               
                 748 
                 A86-M-B25 
                 1 
                 2.61 
                 362.3 
               
               
                 749 
                 A87-M-B14 
                 1 
                 3.33 
                 446.3 
               
               
                 750 
                 A87-M-B20 
                 1 
                 3.55 
                 460.3 
               
               
                 751 
                 A88-M-B14 
                 1 
                 3.31 
                 454.3 
               
               
                 752 
                 A88-M-B16 
                 1 
                 3.49 
                 468.3 
               
               
                 753 
                 A88-M-B17 
                 1 
                 2.63 
                 392.2 
               
               
                 754 
                 A88-M-B19 
                 1 
                 2.66 
                 404.2 
               
               
                 755 
                 A88-M-B20 
                 1 
                 3.53 
                 468.3 
               
               
                 756 
                 A88-M-B21 
                 1 
                 3.57 
                 468.3 
               
               
                 757 
                 A89-M-B14 
                 1 
                 2.64 
                 422.3 
               
               
                 758 
                 A89-M-B20 
                 1 
                 2.91 
                 436.3 
               
               
                 759 
                 A89-M-B21 
                 1 
                 2.97 
                 436.3 
               
               
                 760 
                 A90-M-B13 
                 1 
                 1.89 
                 349.3 
               
               
                 761 
                 A90-M-B16 
                 1 
                 2.56 
                 411.3 
               
               
                 762 
                 A90-M-B20 
                 1 
                 2.6 
                 411.3 
               
               
                 763 
                 A90-M-B21 
                 1 
                 2.68 
                 411.3 
               
               
                 764 
                 A91-M-B14 
                 1 
                 2.4 
                 407.3 
               
               
                 765 
                 A91-M-B16 
                 1 
                 2.68 
                 421.3 
               
               
                 766 
                 A91-M-B18 
                 1 
                 2.99 
                 413.3 
               
               
                 767 
                 A91-M-B20 
                 1 
                 2.65 
                 421.3 
               
               
                 768 
                 A91-M-B21 
                 1 
                 2.69 
                 421.3 
               
               
                 769 
                 A91-M-B26 
                 1 
                 2.35 
                 385.3 
               
               
                 770 
                 A92-M-B12 
                 1 
                 3.15 
                 446.3 
               
               
                 771 
                 A92-M-B14 
                 1 
                 3.58 
                 452.2 
               
               
                 772 
                 A92-M-B17 
                 1 
                 3.05 
                 390.2 
               
               
                 773 
                 A92-M-B20 
                 1 
                 3.78 
                 466.3 
               
               
                 774 
                 A92-M-B21 
                 1 
                 3.8 
                 466.3 
               
               
                 775 
                 A92-M-B22 
                 1 
                 3.97 
                 458.3 
               
               
                 776 
                 A92-M-B24 
                 1 
                 3.78 
                 444.3 
               
               
                 777 
                 A92-M-B26 
                 1 
                 3.56 
                 430.3 
               
               
                 778 
                 A92-M-B7 
                 1 
                 2.98 
                 420.2 
               
               
                 779 
                 A93-M-B14 
                 1 
                 3.41 
                 452.2 
               
               
                 780 
                 A93-M-B16 
                 1 
                 3.6 
                 466.3 
               
               
                 781 
                 A93-M-B17 
                 1 
                 2.82 
                 390.2 
               
               
                 782 
                 A93-M-B20 
                 1 
                 3.63 
                 466.3 
               
               
                 783 
                 A93-M-B21 
                 1 
                 3.66 
                 466.3 
               
               
                 784 
                 A93-M-B22 
                 1 
                 3.85 
                 458.3 
               
               
                 785 
                 A93-M-B24 
                 1 
                 3.63 
                 444.3 
               
               
                 786 
                 A93-M-B26 
                 1 
                 3.37 
                 430.3 
               
               
                 787 
                 A93-M-B27 
                 1 
                 2.96 
                 402.2 
               
               
                 788 
                 A93-M-B7 
                 1 
                 2.76 
                 420.2 
               
               
                 789 
                 A94-M-B14 
                 1 
                 3.58 
                 452.2 
               
               
                 790 
                 A94-M-B17 
                 1 
                 3.04 
                 390.2 
               
               
                 791 
                 A94-M-B21 
                 1 
                 3.81 
                 466.3 
               
               
                 792 
                 A94-M-B24 
                 1 
                 3.78 
                 444.3 
               
               
                 793 
                 A94-M-B26 
                 1 
                 3.55 
                 430.3 
               
               
                 794 
                 A95-M-B14 
                 1 
                 3.16 
                 432.3 
               
               
                 795 
                 A95-M-B20 
                 1 
                 3.39 
                 446.3 
               
               
                 796 
                 A95-M-B21 
                 1 
                 3.45 
                 446.3 
               
               
                 797 
                 A95-M-B24 
                 1 
                 3.37 
                 424.3 
               
               
                 798 
                 A95-M-B26 
                 1 
                 3.09 
                 410.3 
               
               
                 799 
                 A96-M-B14 
                 1 
                 3.36 
                 432.3 
               
               
                 800 
                 A96-M-B20 
                 1 
                 3.58 
                 446.3 
               
               
                 801 
                 A96-M-B21 
                 1 
                 3.62 
                 446.3 
               
               
                 802 
                 A96-M-B22 
                 1 
                 3.81 
                 438.3 
               
               
                 803 
                 A96-M-B24 
                 1 
                 3.57 
                 424.3 
               
               
                 804 
                 A97-M-B12 
                 1 
                 2.59 
                 442.3 
               
               
                 805 
                 A97-M-B14 
                 1 
                 3.1 
                 448.3 
               
               
                 806 
                 A97-M-B16 
                 1 
                 3.26 
                 462.3 
               
               
                 807 
                 A97-M-B17 
                 1 
                 2.46 
                 386.3 
               
               
                 808 
                 A97-M-B18 
                 1 
                 3.56 
                 454.3 
               
               
                 809 
                 A97-M-B20 
                 1 
                 3.29 
                 462.3 
               
               
                 810 
                 A97-M-B22 
                 1 
                 3.52 
                 454.3 
               
               
                 811 
                 A97-M-B24 
                 1 
                 3.26 
                 440.3 
               
               
                 812 
                 A97-M-B26 
                 1 
                 3.02 
                 426.3 
               
               
                 813 
                 A98-M-B14 
                 1 
                 2.97 
                 443.3 
               
               
                 814 
                 A98-M-B17 
                 1 
                 2.4 
                 381.3 
               
               
                 815 
                 A98-M-B20 
                 1 
                 3.2 
                 457.3 
               
               
                 816 
                 A98-M-B22 
                 1 
                 3.4 
                 449.3 
               
               
                 817 
                 A98-M-B24 
                 1 
                 3.21 
                 435.3 
               
               
                 818 
                 A98-M-B7 
                 1 
                 2.35 
                 411.3 
               
               
                 819 
                 A99-M-B14 
                 1 
                 3.86 
                 466.3 
               
               
                 820 
                 A99-M-B20 
                 1 
                 3.99 
                 480.3 
               
               
                 821 
                 A99-M-B22 
                 1 
                 4.17 
                 472.3 
               
               
                 822 
                 A99-M-B24 
                 1 
                 3.98 
                 458.3 
               
               
                 823 
                 A99-M-B26 
                 1 
                 3.79 
                 444.3 
               
               
                 824 
                 A100-M-B14 
                 1 
                 3.65 
                 446.3 
               
               
                 825 
                 A100-M-B22 
                 1 
                 4.04 
                 452.4 
               
               
                 826 
                 A100-M-B24 
                 1 
                 3.84 
                 438.3 
               
               
                 827 
                 A100-M-B26 
                 1 
                 3.62 
                 424.3 
               
               
                 828 
                 A101-M-B14 
                 1 
                 3.33 
                 412.3 
               
               
                 829 
                 A101-M-B19 
                 1 
                 2.71 
                 362.3 
               
               
                 830 
                 A101-M-B20 
                 1 
                 3.54 
                 426.3 
               
               
                 831 
                 A101-M-B21 
                 1 
                 3.59 
                 426.3 
               
               
                 832 
                 A101-M-B22 
                 1 
                 3.8 
                 418.4 
               
               
                 833 
                 A102-M-B14 
                 1 
                 3.29 
                 436.3 
               
               
                 834 
                 A102-M-B17 
                 1 
                 2.67 
                 374.3 
               
               
                 835 
                 A102-M-B19 
                 1 
                 2.69 
                 386.3 
               
               
                 836 
                 A102-M-B20 
                 1 
                 3.51 
                 450.3 
               
               
                 837 
                 A102-M-B21 
                 1 
                 3.55 
                 450.3 
               
               
                 838 
                 A102-M-B22 
                 1 
                 3.74 
                 442.3 
               
               
                 839 
                 A103-M-B14 
                 1 
                 2.95 
                 398.3 
               
               
                 840 
                 A103-M-B20 
                 1 
                 3.21 
                 412.3 
               
               
                 841 
                 A103-M-B21 
                 1 
                 3.27 
                 412.3 
               
               
                 842 
                 A103-M-B22 
                 1 
                 3.5 
                 404.4 
               
               
                 843 
                 A104-M-B16 
                 1 
                 3.36 
                 460.3 
               
               
                 844 
                 A104-M-B22 
                 1 
                 3.68 
                 452.4 
               
               
                 845 
                 A105-M-B14 
                 1 
                 3.65 
                 446.3 
               
               
                 846 
                 A105-M-B20 
                 1 
                 3.83 
                 460.3 
               
               
                 847 
                 A105-M-B21 
                 1 
                 3.86 
                 460.3 
               
               
                 848 
                 A105-M-B22 
                 1 
                 4.05 
                 452.4 
               
               
                 849 
                 A106-M-B14 
                 1 
                 3.64 
                 446.3 
               
               
                 850 
                 A106-M-B16 
                 1 
                 3.82 
                 460.3 
               
               
                 851 
                 A106-M-B17 
                 1 
                 3.12 
                 384.3 
               
               
                 852 
                 A106-M-B20 
                 1 
                 3.85 
                 460.3 
               
               
                 853 
                 A106-M-B21 
                 1 
                 3.87 
                 460.3 
               
               
                 854 
                 A106-M-B24 
                 1 
                 3.84 
                 438.3 
               
               
                 855 
                 A106-M-B26 
                 1 
                 3.63 
                 424.3 
               
               
                 856 
                 A107-M-B14 
                 1 
                 3.67 
                 466.3 
               
               
                 857 
                 A107-M-B16 
                 1 
                 3.83 
                 480.3 
               
               
                 858 
                 A107-M-B24 
                 1 
                 3.91 
                 458.3 
               
               
                 859 
                 A107-M-B26 
                 1 
                 3.65 
                 444.3 
               
               
                 860 
                 A108-M-B20 
                 1 
                 3.81 
                 437.3 
               
               
                 861 
                 A108-M-B25 
                 1 
                 3.28 
                 375.3 
               
               
                 862 
                 A108-M-B27 
                 1 
                 3.17 
                 373.3 
               
               
                 863 
                 A109-M-B13 
                 1 
                 2.47 
                 407.2 
               
               
                 864 
                 A109-M-B16 
                 1 
                 3.12 
                 469.2 
               
               
                 865 
                 A110-M-B14 
                 1 
                 3.57 
                 450.3 
               
               
                 866 
                 A110-M-B17 
                 1 
                 3.03 
                 388.3 
               
               
                 867 
                 A110-M-B20 
                 1 
                 3.76 
                 464.3 
               
               
                 868 
                 A111-M-B14 
                 1 
                 3.59 
                 454.3 
               
               
                 869 
                 A111-M-B17 
                 1 
                 3.05 
                 392.2 
               
               
                 870 
                 A111-M-B22 
                 1 
                 3.99 
                 460.3 
               
               
                 871 
                 A112-M-B16 
                 1 
                 2.55 
                 369.3 
               
               
                 872 
                 A112-M-B21 
                 1 
                 2.64 
                 369.3 
               
               
                 873 
                 A113-M-B16 
                 1 
                 2.66 
                 419.3 
               
               
                 874 
                 A114-M-B16 
                 1 
                 2.38 
                 405.3 
               
               
                 875 
                 A115-M-B16 
                 1 
                 2.59 
                 419.3 
               
               
                 876 
                 A116-M-B20 
                 1 
                 2.39 
                 385.3 
               
               
                 877 
                 A116-M-B21 
                 1 
                 2.48 
                 385.3 
               
               
                 878 
                 A117-M-B20 
                 1 
                 2.59 
                 428.3 
               
               
                 879 
                 A118-M-B20 
                 1 
                 2.69 
                 440.3 
               
               
                 880 
                 A118-M-B21 
                 1 
                 2.76 
                 440.3 
               
               
                 881 
                 A119-M-B20 
                 1 
                 2.87 
                 398.3 
               
               
                 882 
                 A120-M-B21 
                 1 
                 3.32 
                 412.3 
               
               
                 883 
                 A121-M-B21 
                 1 
                 2.53 
                 414.3 
               
               
                 884 
                 A122-M-B21 
                 1 
                 2.03 
                 433.3 
               
               
                 885 
                 A122-M-B22 
                 1 
                 2.21 
                 425.3 
               
               
                 886 
                 A123-M-B25 
                 1 
                 2.16 
                 345.2 
               
               
                 887 
                 A20-M-B14 
                 1 
                 3.92 
                 394.2 
               
               
                 888 
                 A20-M-B17 
                 1 
                 3.41 
                 332.2 
               
               
                 889 
                 A20-M-B19 
                 1 
                 3.41 
                 344.2 
               
               
                 890 
                 A20-M-B24 
                 1 
                 4.09 
                 386.3 
               
               
                 891 
                 A20-M-B25 
                 1 
                 3.63 
                 346.2 
               
               
                 892 
                 A20-M-B26 
                 1 
                 3.88 
                 372.2 
               
               
                 893 
                 A20-M-B31 
                 1 
                 3.31 
                 332.2 
               
               
                 894 
                 A20-M-B32 
                 1 
                 4.07 
                 374.3 
               
               
                 895 
                 A20-M-B33 
                 1 
                 2.59 
                 450.3 
               
               
                 896 
                 A20-M-B35 
                 1 
                 3.24 
                 318.2 
               
               
                 897 
                 A20-M-B36 
                 1 
                 3.93 
                 394.2 
               
               
                 898 
                 A20-M-B39 
                 1 
                 2.4 
                 395.2 
               
               
                 899 
                 A20-M-B40 
                 1 
                 3.67 
                 384.2 
               
               
                 900 
                 A20-M-B42 
                 1 
                 3.39 
                 376.2 
               
               
                 901 
                 A20-M-B56 
                 1 
                 2.42 
                 387.3 
               
               
                 902 
                 A20-M-B59 
                 1 
                 2.44 
                 401.3 
               
               
                 903 
                 A33-M-B14 
                 4 
                 1.172 
                 366.1 
               
               
                 904 
                 A33-M-B22 
                 4 
                 1.33 
                 372.2 
               
               
                 905 
                 A33-M-B28 
                 4 
                 0.929 
                 360.1 
               
               
                 906 
                 A33-M-B29 
                 4 
                 0.645 
                 367.1 
               
               
                 907 
                 A33-M-B30 
                 4 
                 1.205 
                 384.1 
               
               
                 908 
                 A124-M-B9 
                 4 
                 0.655 
                 341.2 
               
               
                 909 
                 A125-M-B9 
                 4 
                 0.74 
                 355.2 
               
               
                 910 
                 A126-M-B9 
                 4 
                 1.018 
                 356.2 
               
               
                 911 
                 A127-M-B14 
                 4 
                 1.29 
                 378.2 
               
               
                 912 
                 A127-M-B19 
                 1 
                 3.06 
                 328.2 
               
               
                 913 
                 A127-M-B22 
                 4 
                 1.405 
                 384.2 
               
               
                 914 
                 A127-M-B24 
                 1 
                 3.79 
                 370.3 
               
               
                 915 
                 A127-M-B25 
                 1 
                 3.28 
                 330.3 
               
               
                 916 
                 A127-M-B26 
                 1 
                 3.56 
                 356.3 
               
               
                 917 
                 A127-M-B28 
                 4 
                 1 
                 372.2 
               
               
                 918 
                 A127-M-B29 
                 4 
                 0.757 
                 379.1 
               
               
                 919 
                 A127-M-B30 
                 4 
                 1.279 
                 396.1 
               
               
                 920 
                 A127-M-B31 
                 1 
                 2.95 
                 316.2 
               
               
                 921 
                 A127-M-B32 
                 1 
                 3.8 
                 358.3 
               
               
                 922 
                 A127-M-B33 
                 1 
                 2.28 
                 434.3 
               
               
                 923 
                 A127-M-B36 
                 1 
                 3.63 
                 378.3 
               
               
                 924 
                 A127-M-B37 
                 1 
                 3.83 
                 378.3 
               
               
                 925 
                 A127-M-B38 
                 1 
                 2.1 
                 401.3 
               
               
                 926 
                 A127-M-B39 
                 1 
                 2.06 
                 379.2 
               
               
                 927 
                 A127-M-B40 
                 1 
                 3.35 
                 368.2 
               
               
                 928 
                 A127-M-B41 
                 1 
                 2.68 
                 399.3 
               
               
                 929 
                 A127-M-B42 
                 1 
                 3.04 
                 360.3 
               
               
                 930 
                 A127-M-B43 
                 1 
                 3.59 
                 344.3 
               
               
                 931 
                 A127-M-B46 
                 1 
                 3.38 
                 344.3 
               
               
                 932 
                 A127-M-B47 
                 1 
                 3.6 
                 382.2 
               
               
                 933 
                 A127-M-B48 
                 1 
                 3.36 
                 342.3 
               
               
                 934 
                 A127-M-B49 
                 1 
                 2.26 
                 397.3 
               
               
                 935 
                 A127-M-B50 
                 1 
                 3.12 
                 342.3 
               
               
                 936 
                 A127-M-B51 
                 1 
                 2.9 
                 358.2 
               
               
                 937 
                 A127-M-B52 
                 1 
                 3.62 
                 364.2 
               
               
                 938 
                 A127-M-B53 
                 1 
                 2.12 
                 413.3 
               
               
                 939 
                 A127-M-B54 
                 1 
                 3.04 
                 410.3 
               
               
                 940 
                 A127-M-B56 
                 1 
                 2.08 
                 371.3 
               
               
                 941 
                 A127-M-B57 
                 1 
                 1.74 
                 454.4 
               
               
                 942 
                 A127-M-B58 
                 1 
                 2.79 
                 435.2 
               
               
                 943 
                 A127-M-B60 
                 1 
                 2.09 
                 359.3 
               
               
                 944 
                 A127-M-B7 
                 1 
                 2.96 
                 346.2 
               
               
                 945 
                 A127-M-B9 
                 4 
                 1.311 
                 358.2 
               
               
                 946 
                 A128-M-B14 
                 4 
                 1.23 
                 378.2 
               
               
                 947 
                 A128-M-B14 
                 1 
                 3.56 
                 378.3 
               
               
                 948 
                 A128-M-B17 
                 1 
                 2.98 
                 316.2 
               
               
                 949 
                 A128-M-B19 
                 1 
                 2.98 
                 328.2 
               
               
                 950 
                 A128-M-B22 
                 4 
                 1.401 
                 384.2 
               
               
                 951 
                 A128-M-B25 
                 1 
                 3.24 
                 330.3 
               
               
                 952 
                 A128-M-B26 
                 1 
                 3.5 
                 356.3 
               
               
                 953 
                 A128-M-B28 
                 4 
                 0.952 
                 372.2 
               
               
                 954 
                 A128-M-B29 
                 4 
                 0.73 
                 379.1 
               
               
                 955 
                 A128-M-B30 
                 4 
                 1.268 
                 396.1 
               
               
                 956 
                 A128-M-B31 
                 1 
                 2.9 
                 316.2 
               
               
                 957 
                 A128-M-B32 
                 1 
                 3.76 
                 358.3 
               
               
                 958 
                 A128-M-B33 
                 1 
                 2.26 
                 434.3 
               
               
                 959 
                 A128-M-B34 
                 1 
                 3.23 
                 374.2 
               
               
                 960 
                 A128-M-B35 
                 1 
                 2.79 
                 302.2 
               
               
                 961 
                 A128-M-B36 
                 1 
                 3.56 
                 378.3 
               
               
                 962 
                 A128-M-B37 
                 1 
                 3.77 
                 378.3 
               
               
                 963 
                 A128-M-B38 
                 1 
                 2.08 
                 401.3 
               
               
                 964 
                 A128-M-B39 
                 1 
                 2.03 
                 379.2 
               
               
                 965 
                 A128-M-B40 
                 1 
                 3.29 
                 368.2 
               
               
                 966 
                 A128-M-B41 
                 1 
                 2.64 
                 399.3 
               
               
                 967 
                 A128-M-B42 
                 1 
                 2.98 
                 360.3 
               
               
                 968 
                 A128-M-B43 
                 1 
                 3.54 
                 344.3 
               
               
                 969 
                 A128-M-B45 
                 1 
                 3.52 
                 370.3 
               
               
                 970 
                 A128-M-B46 
                 1 
                 3.35 
                 344.3 
               
               
                 971 
                 A128-M-B47 
                 1 
                 3.51 
                 382.2 
               
               
                 972 
                 A128-M-B48 
                 1 
                 3.31 
                 342.3 
               
               
                 973 
                 A128-M-B49 
                 1 
                 2.21 
                 397.3 
               
               
                 974 
                 A128-M-B50 
                 1 
                 3.08 
                 342.3 
               
               
                 975 
                 A128-M-B51 
                 1 
                 2.86 
                 358.2 
               
               
                 976 
                 A128-M-B54 
                 1 
                 3 
                 410.3 
               
               
                 977 
                 A128-M-B55 
                 1 
                 3.06 
                 438.3 
               
               
                 978 
                 A128-M-B56 
                 1 
                 2.1 
                 371.3 
               
               
                 979 
                 A128-M-B57 
                 1 
                 1.75 
                 454.4 
               
               
                 980 
                 A128-M-B58 
                 1 
                 2.76 
                 435.2 
               
               
                 981 
                 A128-M-B59 
                 1 
                 2.1 
                 385.3 
               
               
                 982 
                 A128-M-B60 
                 1 
                 2.08 
                 359.3 
               
               
                 983 
                 A128-M-B7 
                 1 
                 2.89 
                 346.2 
               
               
                 984 
                 A128-M-B9 
                 4 
                 1.304 
                 358.2 
               
               
                 985 
                 A129-M-B14 
                 4 
                 1.242 
                 378.2 
               
               
                 986 
                 A129-M-B22 
                 4 
                 1.399 
                 384.2 
               
               
                 987 
                 A129-M-B28 
                 4 
                 0.96 
                 372.2 
               
               
                 988 
                 A129-M-B29 
                 4 
                 0.752 
                 379.1 
               
               
                 989 
                 A129-M-B30 
                 4 
                 1.31 
                 396.1 
               
               
                 990 
                 A129-M-B9 
                 4 
                 1.303 
                 358.2 
               
               
                 991 
                 A130-M-B9 
                 4 
                 0.984 
                 366.2 
               
               
                 992 
                 A131-M-B9 
                 4 
                 1.164 
                 382.2 
               
               
                 993 
                 A132-M-B14 
                 4 
                 1.16 
                 404.2 
               
               
                 994 
                 A132-M-B22 
                 4 
                 1.309 
                 410.2 
               
               
                 995 
                 A132-M-B28 
                 4 
                 0.878 
                 398.2 
               
               
                 996 
                 A132-M-B29 
                 4 
                 0.693 
                 405.1 
               
               
                 997 
                 A132-M-B30 
                 4 
                 1.24 
                 422.1 
               
               
                 998 
                 A132-M-B9 
                 4 
                 1.219 
                 384.2 
               
               
                 999 
                 A133-M-B14 
                 4 
                 1.406 
                 428.2 
               
               
                 1000 
                 A133-M-B22 
                 4 
                 1.6 
                 434.2 
               
               
                 1001 
                 A133-M-B28 
                 4 
                 1.158 
                 422.2 
               
               
                 1002 
                 A133-M-B29 
                 4 
                 0.95 
                 429.1 
               
               
                 1003 
                 A133-M-B30 
                 4 
                 1.427 
                 446.1 
               
               
                 1004 
                 A133-M-B9 
                 4 
                 1.473 
                 408.2 
               
               
                 1005 
                 A134-M-B14 
                 4 
                 1.45 
                 444.1 
               
               
                 1006 
                 A134-M-B22 
                 4 
                 1.593 
                 450.2 
               
               
                 1007 
                 A134-M-B28 
                 4 
                 1.206 
                 438.2 
               
               
                 1008 
                 A134-M-B29 
                 4 
                 1.002 
                 445.1 
               
               
                 1009 
                 A134-M-B30 
                 4 
                 1.471 
                 462.1 
               
               
                 1010 
                 A134-M-B9 
                 4 
                 1.516 
                 424.2 
               
               
                 1011 
                 A135-M-B9 
                 4 
                 1.526 
                 424.2 
               
               
                 1012 
                 A136-M-B9 
                 4 
                 0.674 
                 355.2 
               
               
                 1013 
                 A137-M-B14 
                 4 
                 1.314 
                 374.2 
               
               
                 1014 
                 A137-M-B14 
                 1 
                 3.76 
                 374.3 
               
               
                 1015 
                 A137-M-B22 
                 4 
                 1.477 
                 380.2 
               
               
                 1016 
                 A137-M-B24 
                 1 
                 3.93 
                 366.3 
               
               
                 1017 
                 A137-M-B25 
                 1 
                 3.45 
                 326.3 
               
               
                 1018 
                 A137-M-B26 
                 1 
                 3.7 
                 352.3 
               
               
                 1019 
                 A137-M-B28 
                 4 
                 1.08 
                 368.2 
               
               
                 1020 
                 A137-M-B29 
                 4 
                 0.808 
                 375.2 
               
               
                 1021 
                 A137-M-B30 
                 4 
                 1.346 
                 392.2 
               
               
                 1022 
                 A137-M-B32 
                 1 
                 3.95 
                 354.3 
               
               
                 1023 
                 A137-M-B33 
                 1 
                 2.4 
                 430.3 
               
               
                 1024 
                 A137-M-B34 
                 1 
                 3.42 
                 370.3 
               
               
                 1025 
                 A137-M-B35 
                 1 
                 3.01 
                 298.2 
               
               
                 1026 
                 A137-M-B36 
                 1 
                 3.77 
                 374.3 
               
               
                 1027 
                 A137-M-B39 
                 1 
                 2.19 
                 375.3 
               
               
                 1028 
                 A137-M-B40 
                 1 
                 3.49 
                 364.3 
               
               
                 1029 
                 A137-M-B43 
                 1 
                 3.73 
                 340.3 
               
               
                 1030 
                 A137-M-B48 
                 1 
                 3.5 
                 338.3 
               
               
                 1031 
                 A137-M-B49 
                 1 
                 2.4 
                 393.3 
               
               
                 1032 
                 A137-M-B50 
                 1 
                 3.27 
                 338.3 
               
               
                 1033 
                 A137-M-B52 
                 1 
                 3.76 
                 360.3 
               
               
                 1034 
                 A137-M-B54 
                 1 
                 3.19 
                 406.3 
               
               
                 1035 
                 A137-M-B55 
                 1 
                 3.24 
                 434.3 
               
               
                 1036 
                 A137-M-B56 
                 1 
                 2.25 
                 367.3 
               
               
                 1037 
                 A137-M-B58 
                 1 
                 2.93 
                 431.3 
               
               
                 1038 
                 A137-M-B59 
                 1 
                 2.25 
                 381.3 
               
               
                 1039 
                 A138-M-B14 
                 4 
                 1.206 
                 390.2 
               
               
                 1040 
                 A138-M-B22 
                 4 
                 1.43 
                 396.2 
               
               
                 1041 
                 A138-M-B28 
                 4 
                 0.926 
                 384.2 
               
               
                 1042 
                 A138-M-B29 
                 4 
                 0.726 
                 391.2 
               
               
                 1043 
                 A138-M-B30 
                 4 
                 1.23 
                 408.2 
               
               
                 1044 
                 A139-M-B14 
                 1 
                 3.75 
                 396.2 
               
               
                 1045 
                 A139-M-B17 
                 1 
                 3.22 
                 334.2 
               
               
                 1046 
                 A139-M-B19 
                 1 
                 3.23 
                 346.2 
               
               
                 1047 
                 A139-M-B22 
                 4 
                 1.441 
                 402.2 
               
               
                 1048 
                 A139-M-B24 
                 1 
                 3.93 
                 388.3 
               
               
                 1049 
                 A139-M-B25 
                 1 
                 3.46 
                 348.2 
               
               
                 1050 
                 A139-M-B26 
                 1 
                 3.71 
                 374.3 
               
               
                 1051 
                 A139-M-B28 
                 4 
                 1.023 
                 390.2 
               
               
                 1052 
                 A139-M-B29 
                 4 
                 0.822 
                 397.1 
               
               
                 1053 
                 A139-M-B30 
                 4 
                 1.32 
                 414.1 
               
               
                 1054 
                 A139-M-B31 
                 1 
                 3.12 
                 334.2 
               
               
                 1055 
                 A139-M-B32 
                 1 
                 3.91 
                 376.3 
               
               
                 1056 
                 A139-M-B33 
                 1 
                 2.45 
                 452.3 
               
               
                 1057 
                 A139-M-B35 
                 1 
                 3.03 
                 320.2 
               
               
                 1058 
                 A139-M-B36 
                 1 
                 3.77 
                 396.2 
               
               
                 1059 
                 A139-M-B37 
                 1 
                 3.95 
                 396.2 
               
               
                 1060 
                 A139-M-B38 
                 1 
                 2.29 
                 419.3 
               
               
                 1061 
                 A139-M-B39 
                 1 
                 2.23 
                 397.2 
               
               
                 1062 
                 A139-M-B40 
                 1 
                 3.51 
                 386.2 
               
               
                 1063 
                 A139-M-B41 
                 1 
                 2.87 
                 417.3 
               
               
                 1064 
                 A139-M-B42 
                 1 
                 3.21 
                 378.3 
               
               
                 1065 
                 A139-M-B43 
                 1 
                 3.71 
                 362.3 
               
               
                 1066 
                 A139-M-B45 
                 1 
                 3.71 
                 388.3 
               
               
                 1067 
                 A139-M-B46 
                 1 
                 3.53 
                 362.3 
               
               
                 1068 
                 A139-M-B48 
                 1 
                 3.51 
                 360.2 
               
               
                 1069 
                 A139-M-B49 
                 1 
                 2.38 
                 415.3 
               
               
                 1070 
                 A139-M-B50 
                 1 
                 3.29 
                 360.2 
               
               
                 1071 
                 A139-M-B51 
                 1 
                 3.08 
                 376.2 
               
               
                 1072 
                 A139-M-B52 
                 1 
                 3.77 
                 382.2 
               
               
                 1073 
                 A139-M-B53 
                 1 
                 2.3 
                 431.3 
               
               
                 1074 
                 A139-M-B56 
                 1 
                 2.28 
                 389.3 
               
               
                 1075 
                 A139-M-B57 
                 1 
                 1.89 
                 472.3 
               
               
                 1076 
                 A139-M-B58 
                 1 
                 2.96 
                 453.2 
               
               
                 1077 
                 A139-M-B60 
                 1 
                 2.24 
                 377.3 
               
               
                 1078 
                 A139-M-B7 
                 1 
                 3.13 
                 364.2 
               
               
                 1079 
                 A140-M-B14 
                 4 
                 1.36 
                 406.2 
               
               
                 1080 
                 A140-M-B22 
                 4 
                 1.474 
                 412.2 
               
               
                 1081 
                 A140-M-B28 
                 4 
                 1.06 
                 400.2 
               
               
                 1082 
                 A140-M-B29 
                 4 
                 0.846 
                 407.1 
               
               
                 1083 
                 A140-M-B30 
                 4 
                 1.352 
                 424.1 
               
               
                 1084 
                 A141-M-B14 
                 4 
                 1.176 
                 418.2 
               
               
                 1085 
                 A141-M-B22 
                 4 
                 1.321 
                 424.2 
               
               
                 1086 
                 A141-M-B28 
                 4 
                 0.932 
                 412.2 
               
               
                 1087 
                 A141-M-B29 
                 4 
                 0.745 
                 419.2 
               
               
                 1088 
                 A141-M-B30 
                 4 
                 1.206 
                 436.2 
               
               
                 1089 
                 A142-M-B14 
                 4 
                 1.197 
                 418.2 
               
               
                 1090 
                 A142-M-B22 
                 4 
                 1.345 
                 424.2 
               
               
                 1091 
                 A142-M-B28 
                 4 
                 0.933 
                 412.2 
               
               
                 1092 
                 A142-M-B29 
                 4 
                 0.756 
                 419.2 
               
               
                 1093 
                 A142-M-B30 
                 4 
                 1.225 
                 436.2 
               
               
                 1094 
                 A143-M-B14 
                 4 
                 1.45 
                 428.2 
               
               
                 1095 
                 A143-M-B22 
                 4 
                 1.562 
                 434.2 
               
               
                 1096 
                 A143-M-B28 
                 4 
                 1.178 
                 422.2 
               
               
                 1097 
                 A143-M-B29 
                 4 
                 0.977 
                 429.1 
               
               
                 1098 
                 A143-M-B30 
                 4 
                 1.443 
                 446.1 
               
               
                 1099 
                 A144-M-B14 
                 4 
                 0.649 
                 350.2 
               
               
                 1100 
                 A144-M-B22 
                 4 
                 0.83 
                 356.2 
               
               
                 1101 
                 A144-M-B30 
                 4 
                 0.686 
                 368.1 
               
               
                 1102 
                 A145-M-B14 
                 4 
                 1.52 
                 477.1 
               
               
                 1103 
                 A145-M-B22 
                 4 
                 1.594 
                 483.1 
               
               
                 1104 
                 A146-M-B14 
                 1 
                 3.6 
                 408.3 
               
               
                 1105 
                 A146-M-B17 
                 1 
                 3.06 
                 346.2 
               
               
                 1106 
                 A146-M-B19 
                 1 
                 3.07 
                 358.2 
               
               
                 1107 
                 A146-M-B24 
                 1 
                 3.77 
                 400.3 
               
               
                 1108 
                 A146-M-B25 
                 1 
                 3.29 
                 360.3 
               
               
                 1109 
                 A146-M-B26 
                 1 
                 3.55 
                 386.3 
               
               
                 1110 
                 A146-M-B31 
                 1 
                 2.97 
                 346.2 
               
               
                 1111 
                 A146-M-B32 
                 1 
                 3.77 
                 388.3 
               
               
                 1112 
                 A146-M-B33 
                 1 
                 2.32 
                 464.3 
               
               
                 1113 
                 A146-M-B34 
                 1 
                 3.27 
                 404.2 
               
               
                 1114 
                 A146-M-B35 
                 1 
                 2.88 
                 332.2 
               
               
                 1115 
                 A146-M-B36 
                 1 
                 3.64 
                 408.3 
               
               
                 1116 
                 A146-M-B37 
                 1 
                 3.83 
                 408.3 
               
               
                 1117 
                 A146-M-B38 
                 1 
                 2.24 
                 431.3 
               
               
                 1118 
                 A146-M-B39 
                 1 
                 2.17 
                 409.3 
               
               
                 1119 
                 A146-M-B40 
                 1 
                 3.34 
                 398.2 
               
               
                 1120 
                 A146-M-B41 
                 1 
                 2.73 
                 429.3 
               
               
                 1121 
                 A146-M-B42 
                 1 
                 3.05 
                 390.3 
               
               
                 1122 
                 A146-M-B43 
                 1 
                 3.57 
                 374.3 
               
               
                 1123 
                 A146-M-B44 
                 1 
                 2.28 
                 415.3 
               
               
                 1124 
                 A146-M-B45 
                 1 
                 3.56 
                 400.3 
               
               
                 1125 
                 A146-M-B46 
                 1 
                 3.38 
                 374.3 
               
               
                 1126 
                 A146-M-B47 
                 1 
                 3.58 
                 412.3 
               
               
                 1127 
                 A146-M-B48 
                 1 
                 3.34 
                 372.3 
               
               
                 1128 
                 A146-M-B49 
                 1 
                 2.33 
                 427.3 
               
               
                 1129 
                 A146-M-B50 
                 1 
                 3.13 
                 372.3 
               
               
                 1130 
                 A146-M-B51 
                 1 
                 2.92 
                 388.3 
               
               
                 1131 
                 A146-M-B52 
                 1 
                 3.63 
                 394.2 
               
               
                 1132 
                 A146-M-B53 
                 1 
                 2.19 
                 443.3 
               
               
                 1133 
                 A146-M-B54 
                 1 
                 3.04 
                 440.3 
               
               
                 1134 
                 A146-M-B55 
                 1 
                 3.11 
                 468.3 
               
               
                 1135 
                 A146-M-B58 
                 1 
                 2.84 
                 465.3 
               
               
                 1136 
                 A146-M-B7 
                 1 
                 2.97 
                 376.3 
               
               
                 1137 
                 A147-M-B14 
                 1 
                 3.76 
                 374.3 
               
               
                 1138 
                 A147-M-B17 
                 1 
                 3.2 
                 312.3 
               
               
                 1139 
                 A147-M-B24 
                 1 
                 3.93 
                 366.3 
               
               
                 1140 
                 A147-M-B25 
                 1 
                 3.46 
                 326.3 
               
               
                 1141 
                 A147-M-B26 
                 1 
                 3.71 
                 352.3 
               
               
                 1142 
                 A147-M-B31 
                 1 
                 3.12 
                 312.3 
               
               
                 1143 
                 A147-M-B32 
                 1 
                 3.95 
                 354.3 
               
               
                 1144 
                 A147-M-B33 
                 1 
                 2.42 
                 430.3 
               
               
                 1145 
                 A147-M-B34 
                 1 
                 3.43 
                 370.3 
               
               
                 1146 
                 A147-M-B36 
                 1 
                 3.76 
                 374.3 
               
               
                 1147 
                 A147-M-B37 
                 1 
                 3.96 
                 374.3 
               
               
                 1148 
                 A147-M-B39 
                 1 
                 2.24 
                 375.3 
               
               
                 1149 
                 A147-M-B40 
                 1 
                 3.5 
                 364.3 
               
               
                 1150 
                 A147-M-B41 
                 1 
                 2.86 
                 395.3 
               
               
                 1151 
                 A147-M-B42 
                 1 
                 3.19 
                 356.3 
               
               
                 1152 
                 A147-M-B43 
                 1 
                 3.75 
                 340.3 
               
               
                 1153 
                 A147-M-B45 
                 1 
                 3.73 
                 366.3 
               
               
                 1154 
                 A147-M-B46 
                 1 
                 3.55 
                 340.3 
               
               
                 1155 
                 A147-M-B47 
                 1 
                 3.74 
                 378.3 
               
               
                 1156 
                 A147-M-B48 
                 1 
                 3.52 
                 338.3 
               
               
                 1157 
                 A147-M-B50 
                 1 
                 3.29 
                 338.3 
               
               
                 1158 
                 A147-M-B51 
                 1 
                 3.08 
                 354.3 
               
               
                 1159 
                 A147-M-B52 
                 1 
                 3.76 
                 360.3 
               
               
                 1160 
                 A147-M-B54 
                 1 
                 3.19 
                 406.3 
               
               
                 1161 
                 A147-M-B58 
                 1 
                 2.95 
                 431.3 
               
               
                 1162 
                 A147-M-B7 
                 1 
                 3.12 
                 342.3 
               
               
                 1163 
                 A148-M-B14 
                 1 
                 3.57 
                 408.3 
               
               
                 1164 
                 A148-M-B17 
                 1 
                 3.01 
                 346.2 
               
               
                 1165 
                 A148-M-B19 
                 1 
                 3.03 
                 358.2 
               
               
                 1166 
                 A148-M-B24 
                 1 
                 3.72 
                 400.3 
               
               
                 1167 
                 A148-M-B25 
                 1 
                 3.24 
                 360.3 
               
               
                 1168 
                 A148-M-B26 
                 1 
                 3.51 
                 386.3 
               
               
                 1169 
                 A148-M-B31 
                 1 
                 2.93 
                 346.2 
               
               
                 1170 
                 A148-M-B32 
                 1 
                 3.74 
                 388.3 
               
               
                 1171 
                 A148-M-B33 
                 1 
                 2.3 
                 464.3 
               
               
                 1172 
                 A148-M-B34 
                 1 
                 3.23 
                 404.2 
               
               
                 1173 
                 A148-M-B35 
                 1 
                 2.85 
                 332.2 
               
               
                 1174 
                 A148-M-B36 
                 1 
                 3.59 
                 408.3 
               
               
                 1175 
                 A148-M-B37 
                 1 
                 3.78 
                 408.3 
               
               
                 1176 
                 A148-M-B39 
                 1 
                 2.13 
                 409.3 
               
               
                 1177 
                 A148-M-B40 
                 1 
                 3.3 
                 398.2 
               
               
                 1178 
                 A148-M-B41 
                 1 
                 2.69 
                 429.3 
               
               
                 1179 
                 A148-M-B42 
                 1 
                 3.02 
                 390.3 
               
               
                 1180 
                 A148-M-B43 
                 1 
                 3.52 
                 374.3 
               
               
                 1181 
                 A148-M-B45 
                 1 
                 3.52 
                 400.3 
               
               
                 1182 
                 A148-M-B46 
                 1 
                 3.35 
                 374.3 
               
               
                 1183 
                 A148-M-B47 
                 1 
                 3.54 
                 412.3 
               
               
                 1184 
                 A148-M-B48 
                 1 
                 3.31 
                 372.3 
               
               
                 1185 
                 A148-M-B50 
                 1 
                 3.11 
                 372.3 
               
               
                 1186 
                 A148-M-B51 
                 1 
                 2.9 
                 388.3 
               
               
                 1187 
                 A148-M-B52 
                 1 
                 3.59 
                 394.2 
               
               
                 1188 
                 A148-M-B53 
                 1 
                 2.17 
                 443.3 
               
               
                 1189 
                 A148-M-B54 
                 1 
                 3.01 
                 440.3 
               
               
                 1190 
                 A148-M-B55 
                 1 
                 3.07 
                 468.3 
               
               
                 1191 
                 A148-M-B56 
                 1 
                 2.2 
                 401.3 
               
               
                 1192 
                 A148-M-B58 
                 1 
                 2.8 
                 465.3 
               
               
                 1193 
                 A148-M-B7 
                 1 
                 2.94 
                 376.3 
               
               
                 1194 
                 A149-M-B14 
                 1 
                 3.83 
                 396.2 
               
               
                 1195 
                 A149-M-B17 
                 1 
                 3.3 
                 334.2 
               
               
                 1196 
                 A149-M-B19 
                 1 
                 3.3 
                 346.2 
               
               
                 1197 
                 A149-M-B24 
                 1 
                 3.99 
                 388.3 
               
               
                 1198 
                 A149-M-B25 
                 1 
                 3.53 
                 348.2 
               
               
                 1199 
                 A149-M-B26 
                 1 
                 3.79 
                 374.3 
               
               
                 1200 
                 A149-M-B31 
                 1 
                 3.2 
                 334.2 
               
               
                 1201 
                 A149-M-B33 
                 1 
                 2.49 
                 452.3 
               
               
                 1202 
                 A149-M-B34 
                 1 
                 3.49 
                 392.2 
               
               
                 1203 
                 A149-M-B35 
                 1 
                 3.09 
                 320.2 
               
               
                 1204 
                 A149-M-B36 
                 1 
                 3.73 
                 396.2 
               
               
                 1205 
                 A149-M-B38 
                 1 
                 2.32 
                 419.3 
               
               
                 1206 
                 A149-M-B39 
                 1 
                 2.29 
                 397.2 
               
               
                 1207 
                 A149-M-B40 
                 1 
                 3.58 
                 386.2 
               
               
                 1208 
                 A149-M-B41 
                 1 
                 2.93 
                 417.3 
               
               
                 1209 
                 A149-M-B42 
                 1 
                 3.29 
                 378.3 
               
               
                 1210 
                 A149-M-B43 
                 1 
                 3.81 
                 362.3 
               
               
                 1211 
                 A149-M-B44 
                 1 
                 2.37 
                 403.3 
               
               
                 1212 
                 A149-M-B45 
                 1 
                 3.78 
                 388.3 
               
               
                 1213 
                 A149-M-B46 
                 1 
                 3.58 
                 362.3 
               
               
                 1214 
                 A149-M-B47 
                 1 
                 3.81 
                 400.2 
               
               
                 1215 
                 A149-M-B48 
                 1 
                 3.59 
                 360.2 
               
               
                 1216 
                 A149-M-B49 
                 1 
                 2.44 
                 415.3 
               
               
                 1217 
                 A149-M-B50 
                 1 
                 3.36 
                 360.2 
               
               
                 1218 
                 A149-M-B51 
                 1 
                 3.15 
                 376.2 
               
               
                 1219 
                 A149-M-B52 
                 1 
                 3.83 
                 382.2 
               
               
                 1220 
                 A149-M-B53 
                 1 
                 2.29 
                 431.3 
               
               
                 1221 
                 A149-M-B54 
                 1 
                 3.26 
                 428.3 
               
               
                 1222 
                 A149-M-B55 
                 1 
                 3.34 
                 456.3 
               
               
                 1223 
                 A149-M-B56 
                 1 
                 2.32 
                 389.3 
               
               
                 1224 
                 A149-M-B57 
                 1 
                 1.92 
                 472.3 
               
               
                 1225 
                 A149-M-B58 
                 1 
                 3.02 
                 453.2 
               
               
                 1226 
                 A149-M-B60 
                 1 
                 2.27 
                 377.3 
               
               
                 1227 
                 A150-M-B14 
                 1 
                 3.88 
                 394.2 
               
               
                 1228 
                 A150-M-B17 
                 1 
                 3.38 
                 332.2 
               
               
                 1229 
                 A150-M-B19 
                 1 
                 3.38 
                 344.2 
               
               
                 1230 
                 A150-M-B24 
                 1 
                 4.05 
                 386.3 
               
               
                 1231 
                 A150-M-B25 
                 1 
                 3.6 
                 346.2 
               
               
                 1232 
                 A150-M-B26 
                 1 
                 3.83 
                 372.2 
               
               
                 1233 
                 A150-M-B31 
                 1 
                 3.29 
                 332.2 
               
               
                 1234 
                 A150-M-B32 
                 1 
                 4.04 
                 374.3 
               
               
                 1235 
                 A150-M-B33 
                 1 
                 2.59 
                 450.3 
               
               
                 1236 
                 A150-M-B35 
                 1 
                 3.2 
                 318.2 
               
               
                 1237 
                 A150-M-B36 
                 1 
                 3.89 
                 394.2 
               
               
                 1238 
                 A150-M-B37 
                 1 
                 4.06 
                 394.2 
               
               
                 1239 
                 A150-M-B38 
                 1 
                 2.39 
                 417.3 
               
               
                 1240 
                 A150-M-B39 
                 1 
                 2.35 
                 395.2 
               
               
                 1241 
                 A150-M-B40 
                 1 
                 3.65 
                 384.2 
               
               
                 1242 
                 A150-M-B41 
                 1 
                 3.04 
                 415.2 
               
               
                 1243 
                 A150-M-B42 
                 1 
                 3.35 
                 376.2 
               
               
                 1244 
                 A150-M-B43 
                 1 
                 3.86 
                 360.2 
               
               
                 1245 
                 A150-M-B45 
                 1 
                 3.85 
                 386.3 
               
               
                 1246 
                 A150-M-B46 
                 1 
                 3.68 
                 360.2 
               
               
                 1247 
                 A150-M-B48 
                 1 
                 3.65 
                 358.2 
               
               
                 1248 
                 A150-M-B49 
                 1 
                 2.51 
                 413.3 
               
               
                 1249 
                 A150-M-B50 
                 1 
                 3.43 
                 358.2 
               
               
                 1250 
                 A150-M-B51 
                 1 
                 3.23 
                 374.2 
               
               
                 1251 
                 A150-M-B52 
                 1 
                 3.89 
                 380.2 
               
               
                 1252 
                 A150-M-B53 
                 1 
                 2.38 
                 429.3 
               
               
                 1253 
                 A150-M-B54 
                 1 
                 3.34 
                 426.3 
               
               
                 1254 
                 A150-M-B55 
                 1 
                 3.39 
                 454.3 
               
               
                 1255 
                 A150-M-B56 
                 1 
                 2.44 
                 387.3 
               
               
                 1256 
                 A150-M-B57 
                 1 
                 1.98 
                 470.3 
               
               
                 1257 
                 A150-M-B58 
                 1 
                 3.11 
                 451.2 
               
               
                 1258 
                 A150-M-B59 
                 1 
                 2.41 
                 401.3 
               
               
                 1259 
                 A150-M-B7 
                 1 
                 3.28 
                 362.2 
               
               
                 1260 
                 A151-M-B14 
                 1 
                 3.72 
                 396.2 
               
               
                 1261 
                 A151-M-B17 
                 1 
                 3.18 
                 334.2 
               
               
                 1262 
                 A151-M-B19 
                 1 
                 3.18 
                 346.2 
               
               
                 1263 
                 A151-M-B24 
                 1 
                 3.89 
                 388.3 
               
               
                 1264 
                 A151-M-B25 
                 1 
                 3.42 
                 348.2 
               
               
                 1265 
                 A151-M-B26 
                 1 
                 3.68 
                 374.3 
               
               
                 1266 
                 A151-M-B31 
                 1 
                 3.09 
                 334.2 
               
               
                 1267 
                 A151-M-B32 
                 1 
                 3.9 
                 376.3 
               
               
                 1268 
                 A151-M-B33 
                 1 
                 2.41 
                 452.3 
               
               
                 1269 
                 A151-M-B35 
                 1 
                 2.99 
                 320.2 
               
               
                 1270 
                 A151-M-B36 
                 1 
                 3.84 
                 396.2 
               
               
                 1271 
                 A151-M-B37 
                 1 
                 3.91 
                 396.2 
               
               
                 1272 
                 A151-M-B38 
                 1 
                 2.23 
                 419.3 
               
               
                 1273 
                 A151-M-B39 
                 1 
                 2.2 
                 397.2 
               
               
                 1274 
                 A151-M-B41 
                 1 
                 2.83 
                 417.3 
               
               
                 1275 
                 A151-M-B42 
                 1 
                 3.17 
                 378.3 
               
               
                 1276 
                 A151-M-B43 
                 1 
                 3.72 
                 362.3 
               
               
                 1277 
                 A151-M-B45 
                 1 
                 3.69 
                 388.3 
               
               
                 1278 
                 A151-M-B46 
                 1 
                 3.51 
                 362.3 
               
               
                 1279 
                 A151-M-B48 
                 1 
                 3.48 
                 360.2 
               
               
                 1280 
                 A151-M-B49 
                 1 
                 2.34 
                 415.3 
               
               
                 1281 
                 A151-M-B50 
                 1 
                 3.25 
                 360.2 
               
               
                 1282 
                 A151-M-B51 
                 1 
                 3.05 
                 376.2 
               
               
                 1283 
                 A151-M-B52 
                 1 
                 3.74 
                 382.2 
               
               
                 1284 
                 A151-M-B53 
                 1 
                 2.23 
                 431.3 
               
               
                 1285 
                 A151-M-B54 
                 1 
                 3.16 
                 428.3 
               
               
                 1286 
                 A151-M-B56 
                 1 
                 2.24 
                 389.3 
               
               
                 1287 
                 A151-M-B57 
                 1 
                 1.86 
                 472.3 
               
               
                 1288 
                 A151-M-B58 
                 1 
                 2.93 
                 453.2 
               
               
                 1289 
                 A151-M-B59 
                 1 
                 2.24 
                 403.3 
               
               
                 1290 
                 A151-M-B60 
                 1 
                 2.21 
                 377.3 
               
               
                 1291 
                 A151-M-B7 
                 1 
                 3.07 
                 364.2 
               
               
                 1292 
                 A152-M-B14 
                 1 
                 3.95 
                 352.3 
               
               
                 1293 
                 A152-M-B17 
                 1 
                 3.42 
                 290.3 
               
               
                 1294 
                 A152-M-B19 
                 1 
                 3.43 
                 302.3 
               
               
                 1295 
                 A152-M-B24 
                 1 
                 4.12 
                 344.3 
               
               
                 1296 
                 A152-M-B25 
                 1 
                 3.66 
                 304.3 
               
               
                 1297 
                 A152-M-B26 
                 1 
                 3.92 
                 330.3 
               
               
                 1298 
                 A152-M-B31 
                 1 
                 3.32 
                 290.3 
               
               
                 1299 
                 A152-M-B32 
                 1 
                 4.13 
                 332.3 
               
               
                 1300 
                 A152-M-B33 
                 1 
                 2.69 
                 408.3 
               
               
                 1301 
                 A152-M-B34 
                 1 
                 3.63 
                 348.3 
               
               
                 1302 
                 A152-M-B35 
                 1 
                 3.23 
                 276.3 
               
               
                 1303 
                 A152-M-B36 
                 1 
                 3.95 
                 352.3 
               
               
                 1304 
                 A152-M-B37 
                 1 
                 4.15 
                 352.3 
               
               
                 1305 
                 A152-M-B38 
                 1 
                 2.42 
                 375.3 
               
               
                 1306 
                 A152-M-B39 
                 1 
                 2.49 
                 353.3 
               
               
                 1307 
                 A152-M-B40 
                 1 
                 3.69 
                 342.3 
               
               
                 1308 
                 A152-M-B41 
                 1 
                 3.04 
                 373.3 
               
               
                 1309 
                 A152-M-B42 
                 1 
                 3.4 
                 334.3 
               
               
                 1310 
                 A152-M-B43 
                 1 
                 3.95 
                 318.3 
               
               
                 1311 
                 A152-M-B45 
                 1 
                 3.91 
                 344.3 
               
               
                 1312 
                 A152-M-B46 
                 1 
                 3.74 
                 318.3 
               
               
                 1313 
                 A152-M-B47 
                 1 
                 3.9 
                 356.3 
               
               
                 1314 
                 A152-M-B48 
                 1 
                 3.72 
                 316.3 
               
               
                 1315 
                 A152-M-B49 
                 1 
                 2.52 
                 371.3 
               
               
                 1316 
                 A152-M-B50 
                 1 
                 3.49 
                 316.3 
               
               
                 1317 
                 A152-M-B51 
                 1 
                 3.28 
                 332.3 
               
               
                 1318 
                 A152-M-B52 
                 1 
                 3.96 
                 338.3 
               
               
                 1319 
                 A152-M-B53 
                 1 
                 2.46 
                 387.4 
               
               
                 1320 
                 A152-M-B54 
                 1 
                 3.38 
                 384.3 
               
               
                 1321 
                 A152-M-B55 
                 1 
                 3.44 
                 412.4 
               
               
                 1322 
                 A152-M-B56 
                 1 
                 2.42 
                 345.3 
               
               
                 1323 
                 A152-M-B57 
                 1 
                 1.99 
                 428.4 
               
               
                 1324 
                 A152-M-B58 
                 1 
                 3.14 
                 409.3 
               
               
                 1325 
                 A152-M-B7 
                 1 
                 3.33 
                 320.3 
               
               
                 1326 
                 A153-M-B48 
                 1 
                 3.64 
                 350.3 
               
               
                 1327 
                 A154-M-B14 
                 1 
                 3.34 
                 324.3 
               
               
                 1328 
                 A154-M-B17 
                 1 
                 2.58 
                 262.2 
               
               
                 1329 
                 A154-M-B19 
                 1 
                 2.6 
                 274.2 
               
               
                 1330 
                 A154-M-B24 
                 1 
                 3.54 
                 316.3 
               
               
                 1331 
                 A154-M-B25 
                 1 
                 2.9 
                 276.3 
               
               
                 1332 
                 A154-M-B26 
                 1 
                 3.25 
                 302.3 
               
               
                 1333 
                 A154-M-B31 
                 1 
                 2.46 
                 262.2 
               
               
                 1334 
                 A154-M-B32 
                 1 
                 3.53 
                 304.3 
               
               
                 1335 
                 A154-M-B33 
                 1 
                 2 
                 380.3 
               
               
                 1336 
                 A154-M-B34 
                 1 
                 2.88 
                 320.2 
               
               
                 1337 
                 A154-M-B35 
                 1 
                 2.32 
                 248.2 
               
               
                 1338 
                 A154-M-B36 
                 1 
                 3.29 
                 324.3 
               
               
                 1339 
                 A154-M-B42 
                 1 
                 2.63 
                 306.3 
               
               
                 1340 
                 A154-M-B43 
                 1 
                 3.29 
                 290.3 
               
               
                 1341 
                 A154-M-B45 
                 1 
                 3.27 
                 316.3 
               
               
                 1342 
                 A154-M-B47 
                 1 
                 3.25 
                 328.3 
               
               
                 1343 
                 A154-M-B48 
                 1 
                 2.99 
                 288.3 
               
               
                 1344 
                 A154-M-B49 
                 1 
                 1.85 
                 343.3 
               
               
                 1345 
                 A154-M-B51 
                 1 
                 2.45 
                 304.3 
               
               
                 1346 
                 A154-M-B52 
                 1 
                 3.32 
                 310.2 
               
               
                 1347 
                 A154-M-B53 
                 1 
                 1.83 
                 359.3 
               
               
                 1348 
                 A154-M-B54 
                 1 
                 2.65 
                 355.2 
               
               
                 1349 
                 A154-M-B55 
                 1 
                 2.73 
                 384.3 
               
               
                 1350 
                 A154-M-B58 
                 1 
                 2.38 
                 381.3 
               
               
                 1351 
                 A154-M-B7 
                 1 
                 2.49 
                 292.3 
               
               
                 1352 
                 A155-M-B17 
                 1 
                 2.03 
                 323.2 
               
               
                 1353 
                 A155-M-B19 
                 1 
                 2.05 
                 335.2 
               
               
                 1354 
                 A155-M-B25 
                 1 
                 2.28 
                 337.3 
               
               
                 1355 
                 A155-M-B31 
                 1 
                 2 
                 323.2 
               
               
                 1356 
                 A155-M-B32 
                 1 
                 2.9 
                 365.3 
               
               
                 1357 
                 A155-M-B33 
                 1 
                 1.86 
                 441.3 
               
               
                 1358 
                 A155-M-B35 
                 1 
                 1.87 
                 309.2 
               
               
                 1359 
                 A155-M-B36 
                 1 
                 2.71 
                 385.3 
               
               
                 1360 
                 A155-M-B39 
                 1 
                 1.72 
                 386.3 
               
               
                 1361 
                 A155-M-B40 
                 1 
                 2.37 
                 375.2 
               
               
                 1362 
                 A155-M-B43 
                 1 
                 2.61 
                 351.3 
               
               
                 1363 
                 A155-M-B45 
                 1 
                 2.66 
                 377.3 
               
               
                 1364 
                 A155-M-B53 
                 1 
                 1.74 
                 420.3 
               
               
                 1365 
                 A155-M-B7 
                 1 
                 2.02 
                 353.3 
               
               
                 1366 
                 A156-M-B24 
                 1 
                 3.19 
                 403.3 
               
               
                 1367 
                 A156-M-B34 
                 1 
                 2.59 
                 407.2 
               
               
                 1368 
                 A156-M-B37 
                 1 
                 3.23 
                 411.3 
               
               
                 1369 
                 A156-M-B45 
                 1 
                 2.96 
                 403.3 
               
               
                 1370 
                 A156-M-B49 
                 1 
                 2.01 
                 430.3 
               
               
                 1371 
                 A156-M-B51 
                 1 
                 2.21 
                 391.3 
               
               
                 1372 
                 A156-M-B52 
                 1 
                 2.94 
                 397.3 
               
               
                 1373 
                 A156-M-B54 
                 1 
                 2.4 
                 443.3 
               
               
                   
               
            
           
         
       
     
     When R1 is a substituent with a chiral center the compounds obtained were mixture of diastereoisomers and they were separated by preparative HPLC. 
     When the diastereoisomers are resolved, the chirality is to be intended on the 3,4-dihydro-2H-pyrrolo[1,2-a]pyrazin-1-one scaffold. 
     Working in a parallel manner, the following compounds were prepared: 
     
       
         
           
               
               
               
               
               
               
             
               
                   
               
               
                   
                   
                   
                   
                 HPLC 
                   
               
               
                   
                   
                   
                 HPLC 
                 r.t. 
               
               
                 Entry 
                 Compound 
                   1 H NMR (400 MHz, DMSO-d 6 ) 
                 Method 
                 min. 
                 [M + H] +   
               
               
                   
               
             
            
               
                   
               
            
           
           
               
               
               
               
               
               
            
               
                 1374 
                 A157-M-B65 
                 δ = 8.50 (d, J = 8.5 Hz, 1H), 8.09 
                 4 
                 1.196 
                 408.2 
               
               
                   
                 isomer S 
                 (d, J = 5.4 Hz, 1H), 7.83 (br. s., 
               
               
                   
                   
                 1H), 7.44 (d, J = 1.7 Hz, 1H), 7.28 
               
               
                   
                   
                 (s, 1H), 5.08-5.17 (m, 1H), 4.61- 
               
               
                   
                   
                 4.75 (m, 1H), 3.73 (dd, J = 13.1, 4.0 
               
               
                   
                   
                 Hz, 1H), 3.36-3.46 (m, 1H), 3.10- 
               
               
                   
                   
                 3.18 (m, 1H), 2.90-3.04 (m, 1H), 
               
               
                   
                   
                 2.68-2.84 (m, 2H). 
               
               
                 1375 
                 A157-M-B65 
                 δ = 8.61 (d, J = 8.5 Hz, 1H), 8.11 
                 4 
                 1.224 
                 408.2 
               
               
                   
                 isomer R 
                 (d, J = 5.4 Hz, 1H), 7.68 (d, J = 1.7 
               
               
                   
                   
                 Hz, 1H), 5.11 (td, J = 8.9, 4.6 Hz, 
               
               
                   
                   
                 1H), 4.63-4.72 (m, 1H), 2.78 (d, J = 
               
               
                   
                   
                 6.7 Hz, 2H) 
               
               
                 1376 
                 A133-M-B61 
                   
                 4 
                 1.373 
                 464.2 
               
               
                   
                 isomer R 
               
               
                 1377 
                 A127-M-B61 
                   
                 4 
                 1.332 
                 414.2 
               
               
                   
                 isomer R 
               
               
                 1378 
                 A157-M-B161 
                 8.41-8.60 (m, 1H), 6.90-8.36 (m, 
                 4 
                 1.052 
                 415.2 
               
               
                   
                 isomer R 
                 5H), 4.71 (dd, J = 33.3, 3.3 Hz, 2H), 
               
               
                   
                   
                 3.56-3.82 (m, 1H), 2.61-2.82 (m, 
               
               
                   
                   
                 2H), 1.37-1.75 (m, 2H), 0.80- 
               
               
                   
                   
                 1.23 (m, 10H) 
               
               
                 1379 
                 A158-M-B61 
                   
                 4 
                 1.238 
                 432.2 
               
               
                   
                 isomer R 
               
               
                 1380 
                 A133-M-B61 
                 7.54 (t, J = 7.7 Hz, 1H), 7.45 (d, J = 
                 4 
                 1.375 
                 464.2 
               
               
                   
                 isomer S 
                 1.8 Hz, 1H), 7.16 (d, J = 1.7 Hz, 
               
               
                   
                   
                 1H), 4.69 (sxt, J = 4.2 Hz, 1H), 4.49 
               
               
                   
                   
                 (br. s., 1H), 3.72 (dd, J = 13.0, 4.1 
               
               
                   
                   
                 Hz, 1H), 3.59 (dq, J = 8.9, 5.8 Hz, 
               
               
                   
                   
                 1H), 2.82 (dd, J = 14.9, 8.7 Hz, 1H), 
               
               
                   
                   
                 2.57 (dd, J = 14.5, 5.4 Hz, 1H) 
               
               
                 1381 
                 A127-M-B61 
                 7.68 (d, J = 3.4 Hz, 1H), 7.63 (d, J = 
                 4 
                 1.363 
                 414.2 
               
               
                   
                 isomer S 
                 9.2 Hz, 1H), 7.28-7.42 (m, 4H), 
               
               
                   
                   
                 7.09 (d, J = 1.8 Hz, 1H), 6.90-6.99 
               
               
                   
                   
                 (m, 1H), 4.61-4.72 (m, 1H), 4.50 
               
               
                   
                   
                 (t, J = 5.4 Hz, 1H), 3.69 (ddd, J = 
               
               
                   
                   
                 13.0, 4.2, 1.2 Hz, 1H), 3.60 (dq, J = 
               
               
                   
                   
                 9.2, 5.8 Hz, 1H), 2.79 (dd, J = 14.6, 
               
               
                   
                   
                 8.4 Hz, 1H), 2.58 (dd, J = 14.8, 5.8 
               
               
                   
                   
                 Hz, 1H) 
               
               
                 1382 
                 A133-M-B62 
                 7.60 (d, J = 1.7 Hz, 1H), 7.17 (d, J = 
                 4 
                 1.426 
                 458.2 
               
               
                   
                 isomer R 
                 1.8 Hz, 1H), 4.89 (dt, J = 7.9, 6.3 
               
               
                   
                   
                 Hz, 1H), 4.73-4.95 (m, 1H), 4.59- 
               
               
                   
                   
                 4.69 (m, 1H), 2.83 (dd, J = 14.8, 6.5 
               
               
                   
                   
                 Hz, 1H), 2.74 (dd, J = 14.9, 7.2 Hz, 
               
               
                   
                   
                 1H) 
               
               
                 1383 
                 A127-M-B62 
                 8.49 (d, J = 8.3 Hz, 1H), 7.47 (d, J = 
                 4 
                 1.092 
                 408.2 
               
               
                   
                 isomer R 
                 1.8 Hz, 1H), 7.08 (d, J = 1.8 Hz, 
               
               
                   
                   
                 1H), 6.91-7.00 (m, 1H), 4.82- 
               
               
                   
                   
                 4.94 (m, 1H), 4.62 (dd, J = 9.5, 2.8 
               
               
                   
                   
                 Hz, 1H), 3.57-3.66 (m, 1H), 3.50 
               
               
                   
                   
                 (d, J = 6.0 Hz, 2H), 2.68-2.83 (m, 
               
               
                   
                   
                 2H) 
               
               
                 1384 
                 A157-M-B62 
                 8.51 (d, J = 8.3 Hz, 1H), 8.11 (d, J = 
                 4 
                 409.2 
                 1.003 
               
               
                   
                 isomer R 
                 5.4 Hz, 1H), 7.72 (d, J = 1.8 Hz, 
               
               
                   
                   
                 1H), 7.18-7.27 (m, 1H), 4.84- 
               
               
                   
                   
                 4.93 (m, 1H), 4.61-4.72 (m, 1H), 
               
               
                   
                   
                 3.64 (d, J = 5.2 Hz, 1H), 3.34 (br. s., 
               
               
                   
                   
                 1H), 2.69-2.87 (m, 2H) 
               
               
                 1385 
                 A158-M-B62 
                 8.45 (d, J = 8.2 Hz, 1H), 7.76 (br. s., 
                 4 
                 1.109 
                 426.2 
               
               
                   
                 isomer R 
                 1H), 7.55 (ddd, J = 9.8, 6.3, 3.2 Hz, 
               
               
                   
                   
                 1H), 7.45-7.50 (m, 1H), 7.26- 
               
               
                   
                   
                 7.34 (m, 5H), 7.18-7.25 (m, 1H), 
               
               
                   
                   
                 7.13-7.16 (m, 1H), 6.99-7.08 (m, 
               
               
                   
                   
                 1H), 4.82-4.90 (m, 1H), 4.79 (br. 
               
               
                   
                   
                 s., 1H), 4.68 (s, 1H), 3.65 (dd, J = 
               
               
                   
                   
                 9.0, 1.8 Hz, 1H), 3.50 (br. s., 2H), 
               
               
                   
                   
                 3.37 (d, J = 2.3 Hz, 9H), 2.68-2.85 
               
               
                   
                   
                 (m, 2H) 
               
               
                 1386 
                 A133-M-B62 
                 8.41 (d, J = 8.3 Hz, 1H), 7.41 (d, J = 
                 4 
                 1.332 
                 458.2 
               
               
                   
                 isomer S 
                 1.8 Hz, 1H), 7.15-7.18 (m, 1H), 
               
               
                   
                   
                 4.79-4.90 (m, 2H), 4.66 (br. s., 
               
               
                   
                   
                 1H), 3.68 (d, J = 1.2 Hz, 1H), 3.45- 
               
               
                   
                   
                 3.61 (m, 1H), 3.34-3.43 (m, 1H), 
               
               
                   
                   
                 2.79-2.88 (m, 1H), 2.70 (dd, J = 
               
               
                   
                   
                 15.0, 6.8 Hz, 1H) 
               
               
                 1387 
                 A127-M-B62 
                 8.43 (d, J = 8.3 Hz, 1H), 7.08 (d, J = 
                 4 
                 1.121 
                 408.2 
               
               
                   
                 isomer S 
                 1.8 Hz, 1H), 7.03-7.43 (m, 11H), 
               
               
                   
                   
                 6.93-7.01 (m, J = 5.1, 4.0, 0.9, 0.9, 
               
               
                   
                   
                 0.9 Hz, 1H), 4.88 (q, J = 6.0 Hz, 
               
               
                   
                   
                 1H), 4.64 (q, J = 3.3 Hz, 1H), 3.62- 
               
               
                   
                   
                 3.71 (m, 2H), 3.55 (dd, J = 7.4, 5.5 
               
               
                   
                   
                 Hz, 2H), 3.34 (br. s., 2H), 2.65- 
               
               
                   
                   
                 2.73 (m, 1H) 
               
               
                 1388 
                 A133-M-B63 
                 7.85 (br. s., 1H), 7.65 (br. s., 2H), 
                 4 
                 1.173 
                 497.2 
               
               
                   
                 Unresolved 
                 7.49 (s, 2H), 7.36 (br. s., 2H), 7.17 
               
               
                   
                 mixture of 
                 (s, 2H), 4.75 (br. s., 1H), 2.18 (s, 
               
               
                   
                 diast. 
                 1H), 2.07 (s, 1H), 1.96 (s, 1H), 1.75 
               
               
                   
                   
                 (s, 1H), 1.63 (s, 7H), 1.23 (br. s., 
               
               
                   
                   
                 2H), 0.14-0.34 (m, 2H) 
               
               
                 1389 
                 A127-M-B63 
                 7.59 (d, J = 1.1 Hz, 1H), 7.49 (s, 
                 4 
                 1.02 
                 447.2 
               
               
                   
                 unresolved 
                 1H), 7.40 (br. s., 2H), 5.44-6.15 
               
               
                   
                 mixture of 
                 (m, J = 155.3 Hz, 1H), 4.33-5.20 
               
               
                   
                 diast. 
                 (m, 1H), 4.17 (dd, J = 13.4, 11.8 
               
               
                   
                   
                 Hz, 1H), 3.67-3.94 (m, 1H), 2.80 
               
               
                   
                   
                 (d, J = 16.4 Hz, 1H), 0.15-0.35 (m, 
               
               
                   
                   
                 1H) 
               
               
                 1390 
                 A157-M-B63 
                   
                 4 
                 0.782 
                 448.2 
               
               
                   
                 unresolved 
               
               
                   
                 mixture of 
               
               
                   
                 diast. 
               
               
                 1391 
                 A158-M-B63 
                 7.13-7.40 (m, 1H), 3.28-3.58 (m, 
                 4 
                 1.031 
                 465.2 
               
               
                   
                 P26 
                 16H), 3.08-3.28 (m, 1H), 2.41- 
               
               
                   
                 unresolved 
                 2.60 (m, 5H) 
               
               
                   
                 mixture of 
               
               
                   
                 diast. 
               
               
                 1392 
                 A133-M-B64 
                 7.96 (s, 1H), 7.36-7.90 (m, 1H), 
                 4 
                 1.44 
                 472.2 
               
               
                   
                 isomer R 
                 7.12-7.31 (m, 1H), 7.09-7.39 (m, 
               
               
                   
                   
                 1H), 4.54 (s, 1H), 3.95 (d, J = 4.9 
               
               
                   
                   
                 Hz, 1H), 3.53 (br. s., 1H), 3.33 (s, 
               
               
                   
                   
                 13H), 3.15-3.41 (m, 1H), 3.08- 
               
               
                   
                   
                 3.29 (m, 1H), 2.52-2.90 (m, 1H), 
               
               
                   
                   
                 2.41-2.62 (m, 4H) 
               
               
                 1393 
                 A127-M-B64 
                 8.00 (d, J = 8.4 Hz, 1H), 7.65 (br. s., 
                 4 
                 1.148 
                 422.2 
               
               
                   
                 isomer R 
                 1H), 7.39-7.41 (m, 1H), 7.24- 
               
               
                   
                   
                 7.30 (m, 2H), 7.18-7.22 (m, 2H), 
               
               
                   
                   
                 7.08 (d, J = 1.8 Hz, 1H), 6.92-7.00 
               
               
                   
                   
                 (m, 1H), 4.53 (s, 1H), 3.93 (br. s., 
               
               
                   
                   
                 1H), 3.51 (s, 3H), 2.53-2.93 (m, 4H) 
               
               
                 1394 
                 A157-M-B64 
                 8.10 (d, J = 5.4 Hz, 1H), 7.94 (d, J = 
                 4 
                 0.92 
                 423.2 
               
               
                   
                 isomer R 
                 8.5 Hz, 1H), 7.73 (br. s., 1H), 7.63 
               
               
                   
                   
                 (d, J = 1.7 Hz, 1H), 7.44-7.54 (m, 
               
               
                   
                   
                 1H), 7.27 (d, J = 1.8 Hz, 1H), 4.56 
               
               
                   
                   
                 (br. s., 1H), 3.92 (br. s., 1H), 3.49- 
               
               
                   
                   
                 3.60 (m, 1H), 3.26-3.38 (m, 1H), 
               
               
                   
                   
                 3.23 (br. s., 1H), 3.16 (s, 1H), 2.82 
               
               
                   
                   
                 (s, 1H), 2.65 (s, 1H), 2.48-2.56 (m, 
               
               
                   
                   
                 4H) 
               
               
                 1395 
                 A158-M-B64 
                 7.94 (d, J = 8.4 Hz, 1H), 7.56 (d, J = 
                 4 
                 1.331 
                 472.2 
               
               
                   
                 isomer S 
                 1.8 Hz, 1H), 7.15-7.16 (m, 1H), 
               
               
                   
                   
                 7.14-7.20 (m, 2H), 7.09-7.13 (m, 
               
               
                   
                   
                 2H), 7.03-7.08 (m, 1H), 4.77 (t, J = 
               
               
                   
                   
                 5.5 Hz, 1H), 4.56 (br. s., 1H), 
               
               
                   
                   
                 3.87-3.99 (m, 1H), 3.56-3.63 (m, 
               
               
                   
                   
                 1H), 2.54-2.80 (m, 4H) 
               
               
                 1396 
                 A127-M-B64 
                 6.91-7.00 (m, 1H), 4.50-4.59 (m, 
                 4 
                 1.181 
                 422.2 
               
               
                   
                 isomer S 
                 J = 7.1, 3.4, 3.4 Hz, 1H), 3.89-3.99 
               
               
                   
                   
                 (m, J = 5.9 Hz, 1H), 3.53-3.63 (m, 
               
               
                   
                   
                 J = 13.6, 3.2 Hz, 1H), 2.76 (dd, J = 
               
               
                   
                   
                 13.5, 5.7 Hz, 1H), 2.62-2.70 (m, 
               
               
                   
                   
                 1H), 2.52-2.62 (m, 2H) 
               
               
                 1397 
                 A133-M-B65 
                 8.62 (d, J = 8.5 Hz, 1H), 8.49 (d, J = 
                 4 
                 1.571 
                 457.2 
               
               
                   
                 isomer S 
                 8.4 Hz, 1H), 7.81-8.00 (m, 2H), 
               
               
                   
                   
                 7.75 (d, J = 7.9 Hz, 2H), 5.00-5.18 
               
               
                   
                   
                 (m, J = 2.7 Hz, 1H), 4.60-4.75 (m, 
               
               
                   
                   
                 J = 4.3 Hz, 1H) 
               
               
                 1398 
                 A127-M-B65 
                 8.62 (d, J = 8.4 Hz, 1H), 8.50 (d, J = 
                 4 
                 1.44 
                 407.2 
               
               
                   
                 isomer S 
                 8.7 Hz, 1H), 7.89 (br. s., 3H), 7.73 
               
               
                   
                   
                 (br. s., 1H), 5.05-5.22 (m, J = 3.5 
               
               
                   
                   
                 Hz, 1H), 4.58-4.72 (m, J = 6.9, 
               
               
                   
                   
                 6.9, 3.3 Hz, 1H) 
               
               
                 1399 
                 A158-M-B65 
                 8.58 (d, J = 8.3 Hz, 1H), 8.45 (d, J = 
                 4 
                 1.451 
                 425.2 
               
               
                   
                 isomer S 
                 8.3 Hz, 1H), 5.02-5.26 (m, J = 9.0, 
               
               
                   
                   
                 4.6, 4.6 Hz, 1H), 4.63-4.77 (m, 1H)