TREA

Heterocyclic compounds and their use as glycogen synthase kinase-3 inhibitors

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Information

  • Patent Grant
  • 9266855
  • Patent Number
    9,266,855
  • Date Filed
    Monday, September 26, 2011
    13 years ago
  • Date Issued
    Tuesday, February 23, 2016
    8 years ago
Information
Abstract
The present invention relates to novel heterocyclic compounds which are useful for inhibiting glycogen synthase kinase 3 (GSK-3), methods of making the compounds, compositions containing the compounds, and methods of treatment using the compounds.
Description
TECHNICAL FIELD

The present invention relates to novel heterocyclic compounds which are useful for inhibiting glycogen synthase kinase 3 (GSK-3), methods of making the compounds, compositions containing the compounds, and methods of treatment using the compounds.


BACKGROUND OF THE INVENTION

Glycogen synthase kinase-3 (GSK-3) is a serine/threonine kinase encoded by two isoforms, GSK-3α and GSK-3β, with molecular weights of 51 and 47 kDa, respectively. These share 97% sequence similarity in their kinase catalytic domains. The GSK-3α isoform has an extended glycine-rich N-terminal tail. A minor splice variant of GSK-3β has been identified (expressed at ˜15% of total) with a 13 amino acid insert within the kinase domain. This variant had a reduced activity towards tau. GSK-3 is highly conserved throughout evolution, and found in all mammalians thus far with high homology in the kinase domain. Both isoforms are ubiquitously expressed in mammalian tissues, including the brain. Pharmacological GSK-3 inhibitors are not able to selectively inhibit one of the isoforms.


GSK-3β plays an important role in the control of metabolism, differentiation and survival. It was initially identified as an enzyme able to phosphorylate and hence inhibit glycogen synthase. Subsequently, it was recognised that GSK-3β was identical to tau protein kinase 1 (TPK1), an enzyme that phosphorylates tau protein in epitopes that are also found to be hyperphosphorylated in Alzheimer's disease and in several tauopathies.


Interestingly, protein kinase B (AKT) phosphorylation of GSK-3β results in a loss of kinase activity, and it has been proposed that this inhibition may mediate some of the effects of neurotrophic factors. Moreover, phosphorylation of β-catenin (a protein involved in cell survival) by GSK-3β, results in its degradation by an ubiquitinilation dependent proteasome pathway.


Therefore it appears that inhibition of GSK-3β activity may result in neurotrophic activity. There is evidence that lithium, an uncompetitive inhibitor of GSK-3β, enhances neuritogenesis in some models and can also increase neuronal survival, through the induction of survival factors such as Bcl-2 and the inhibition of the expression of proapoptotic factors such as P53 and Bax.


Further studies have shown that β-amyloid increases GSK-3β activity and tau protein phosphorylation. Moreover, this hyperphosphorylation as well as the neurotoxic effects of β-amyloid are blocked by lithium chloride and by a GSK-3β antisense mRNA. These observations taken together suggest that GSK-3β may be the link between the two major pathological processes in Alzheimer's disease: abnormal APP (Amyloid Precursor Protein) processing and tau protein hyperphosphorylation.


These experimental observations indicate that compounds which modulate the GSK-3β activity may find application in the treatment of the neuropathological consequences and the cognitive and attention deficits associated with Alzheimer's disease, as well as other acute and chronic neurodegenerative diseases. These include, but are not limited to: Parkinson's disease, tauopathies (e.g. frontotemporoparietal dementia, corticobasal degeneration, Pick's disease, progressive supranuclear palsy, argyophilic grain disease) and other dementia including vascular dementia; acute stroke and others traumatic injuries; cerebrovascular accidents (e.g. age related macular degeneration); brain and spinal cord trauma; peripheral neuropathies; bipolar disorders, retinopathies and glaucoma.


GSK-3β may further have utility in the treatment of inflammatory diseases, such as rheumatoid arthritis and osteoarthritis.


GSK-3β may also have utility in the treatment of other diseases such as: Non-insulin dependent diabetes and obesity; osteoporosis; manic depressive illness; schizophrenia; alopecia; cancers such as breast cancer, non-small cell lung carcinoma, thyroid cancer, T or B-cell leukemia and several virus-induced tumors.


A review on GSK-3, its functions, its therapeutic potential and its possible inhibitors is given in “Glycogen Synthase Kinase 3 (GSK-3) and its inhibitors: Drug Discovery and Developments” by A. Martinez et al. (editors), John Wiley and Sons, 2006.


WO 03/053330 describes 2-oxindoles substituted in the 3-position with a bicyclic hetaryl group and their use for treating conditions related to glycogen synthase kinase-3. WO 03/082853 describes substituted 2-oxindoles substituted in the 3-position with a monocyclic hetaryl group and their use for treating conditions related to glycogen synthase kinase-3. WO 2005/123672 relates to 2-hydroxyindoles carrying in the 3-position an optionally fused pyrid-2-yl ring and their use for inhibiting kinases. WO 2005/061519 relates to 2-hydroxyindoles carrying in the 3-position a pyrid-2-yl ring fused to an aromatic or heteroaromatic ring and their use for inhibiting kinases.


SUMMARY OF THE INVENTION

The object of the present invention is to provide compounds which modulate the GSK-3β activity, in particular compounds which have an inhibitory activity on GSK-3β and which thus are useful as an active ingredient of a composition for preventive and/or therapeutic treatment of a disease caused by abnormal GSK-3β activity, especially of neurodegenerative and/or inflammatory diseases. More specifically, the goal is to provide novel compounds useful as an active ingredient of a composition that enables prevention and/or treatment of neurodegenerative diseases such as Alzheimer's disease.


It was surprisingly found that the problem is solved by providing a heterocyclic compound of the general formulae IA and IB




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the stereoisomers, N-oxides, prodrugs, tautomers and/or physiologically tolerated acid addition salts thereof; and the compounds of the general formulae IA and IB, wherein at least one of the atoms has been replaced by its stable, non-radioactive isotope, wherein

  • X1, X2, X3 and X4 are independently of each other selected from the group consisting of CR1 and N;
  • each R1 is independently selected from the group consisting of hydrogen, cyano, NRaRb, OH, halogen, C1-C6-alkyl, C1-C6-haloalkyl, C3-C7-cycloalkyl, C3-C7-halocycloalkyl, C2-C4-alkenyl, C2-C4-haloalkenyl, C1-C6-alkoxy, C1-C6-haloalkoxy, formyl, C1-C6-alkylcarbonyl, C1-C6-haloalkylcarbonyl, COOH, C1-C6-alkoxycarbonyl, C1-C6-haloalkoxycarbonyl, C1-C6-alkyl-NRaRb, CO—NRaRb, an aromatic radical Ar, which is selected from the group consisting of phenyl and a 5- or 6-membered N- or C-bound heteroaromatic radical comprising 1, 2 or 3 heteroatoms independently selected from O, S and N as ring members, wherein Ar is unsubstituted or carries one or two radicals R7 and wherein Ar may also be bonded via a CH2 group, and saturated or partially unsaturated 3-, 4-, 5-, 6- or 7-membered heterocyclic radical comprising 1, 2 or 3 heteroatoms selected from O, S and N as ring members, wherein the heterocyclic radical is unsubstituted or substituted by 1, 2, 3 or 4 radicals independently selected from halogen, cyano, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy and C1-C4-haloalkoxy;
  • R2 is hydrogen, C1-C4-alkyl, C1-C4-haloalkyl, C2-C4-alkenyl, C2-C4-haloalkenyl, OH or F;
  • R3 and R4; or R4 and R5; or R5 and R6 form together a bridging group —(CH2)m—, wherein m is 3, 4 or 5, where 1, 2 or 3 of the CH2 groups may be replaced by a group or a heteroatom selected from CO, O, S, SO, SO2, NRc and NO, and where 1, 2 or 3 hydrogen atoms of the bridging group may be replaced by a radical R8;
    • where the radicals R3, R4, R5 and R6, which are not part of the bridging group, are independently selected from the group consisting of hydrogen, halogen, cyano, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy and NRaRb;
  • each R7 is independently selected from the group consisting of halogen, OH, CN, C1-C6-alkyl, C1-C6-haloalkyl, C3-C6-cycloalkyl, C3-C6-halocycloalkyl, C1-C6-alkoxy, C1-C6-haloalkoxy, NRaRb, C1-C6-alkylcarbonyl, C1-C6-haloalkylcarbonyl, C1-C6-alkoxycarbonyl, C1-C6-haloalkoxycarbonyl, CO—NRaRb, a phenyl group and a saturated, partially unsaturated or aromatic 5- or 6-membered heterocyclic radical comprising 1, 2 or 3 heteroatoms selected from O, S and N as ring members, wherein phenyl and the heterocyclic radical are, independently of each other, unsubstituted or substituted by 1, 2, 3 or 4 radicals independently selected from halogen, cyano, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy and C1-C4-haloalkoxy, or in the heterocyclic ring two geminally bound radicals may together form a group ═O;
  • each R8 is independently selected from the group consisting of halogen, OH, CN, C1-C6-alkyl, C1-C6-haloalkyl, C3-C6-cycloalkyl, C3-C6-halocycloalkyl, C1-C6-alkoxy, C1-C6-haloalkoxy, NRaRb, C1-C6-alkylcarbonyl, C1-C6-haloalkylcarbonyl, C1-C6-alkoxycarbonyl, C1-C6-haloalkoxycarbonyl, CO—NRaRb, a phenyl group and a saturated, partially unsaturated or aromatic 3-, 4-, 5-, 6- or 7-membered hetero-cyclic radical comprising 1, 2 or 3 heteroatoms selected from O, S and N as ring members, wherein phenyl and the heterocyclic radical are, independently of each other, unsubstituted or substituted by 1, 2, 3 or 4 radicals independently selected from halogen, cyano, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy and C1-C4-haloalkoxy;
  • Ra and Rb are independently of each other selected from the group consisting of hydrogen, C1-C6-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy, C1-C4-alkylcarbonyl, C1-C4-haloalkylcarbonyl, C1-C6-alkoxycarbonyl and C1-C6-haloalkoxycarbonyl; or
    • Ra and Rb form, together with the nitrogen atom to which they are bonded, a 3-, 4-, 5-, 6- or 7-membered saturated or unsaturated aromatic or non-aromatic N-heterocyclic ring, which may contain 1 further heteroatom or heteroatom-containing group selected from N, O, S, SO and SO2 as a ring member, where the N-heterocyclic ring may carry 1 or 2 radicals selected from halogen, cyano, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy and C1-C4-haloalkoxy; and
  • each Rc is independently selected from the group consisting of hydrogen, C1-C6-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy, C1-C4-alkoxy-C1-C4-alkyl, C1-C4-alkylcarbonyl, C1-C4-haloalkylcarbonyl, C1-C6-alkoxycarbonyl and C1-C6-haloalkoxycarbonyl.


Thus, the present invention relates to compounds of the formulae IA and IB as defined herein and in the claims, to the stereoisomers, tautomers, prodrugs and/or physiologically tolerated acid addition salts thereof.


According to a further aspect, the present invention relates to a pharmaceutical composition comprising at least one compound of the formula IA and/or IB as defined herein, a stereoisomer, a tautomer, a prodrug and/or a physiologically tolerated acid addition salt thereof or comprising at least one heterocyclic compound as defined above, wherein at least one of the atoms has been replaced by its stable, non-radioactive isotope, optionally together with at least one physiologically acceptable carrier and/or auxiliary substance.


According to a further aspect, the present invention relates to the use of at least one compound of the formula IA and/or IB as defined herein, the stereoisomers, tautomers, prodrugs and/or physiologically tolerated acid addition salts thereof, for the preparation of a medicament for the treatment of a medical disorder susceptible to treatment with a compound that modulates glycogen synthase kinase 3β activity.


According to a further aspect, the present invention relates to a method for treating a medical disorder susceptible to treatment with a compound that modulates glycogen synthase kinase 3β activity, said method comprising administering an effective amount of at least one compound of the formula IA and/or IB as defined herein, a stereoisomer, a tautomer, a prodrug and/or a physiologically tolerated acid addition salt thereof, to a subject in need thereof.







DETAILED DESCRIPTION OF THE INVENTION

Provided the compounds of the formulae IA and IB of a given constitution may exist in different spatial arrangements, for example if they possess one or more centers of asymmetry, polysubstituted rings or double bonds, or as different tautomers, it is also possible to use enantiomeric mixtures, in particular racemates, diastereomeric mixtures and tautomeric mixtures, preferably, however, the respective essentially pure enantiomers, diastereomers and tautomers of the compounds of formulae IA and IB and/or of their salts.


In case R2 in compound IB is hydrogen, this compound IB is a tautomer of the respective compound IA wherein the remaining variables have the same meaning.


It is likewise possible to use physiologically tolerated salts of the compounds of the formulae IA and/or IB, especially acid addition salts with physiologically tolerated acids. Examples of suitable physiologically tolerated organic and inorganic acids are hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, C1-C4-alkylsulfonic acids, such as methanesulfonic acid, aromatic sulfonic acids, such as benzenesulfonic acid and toluenesulfonic acid, oxalic acid, maleic acid, fumaric acid, lactic acid, tartaric acid, adipic acid and benzoic acid. Other utilizable acids are described in Fortschritte der Arzneimittelforschung [Advances in drug research], Volume 10, pages 224 et seq., Birkhäuser Verlag, Basel and Stuttgart, 1966.


In the terms of the present invention, “prodrugs” are compounds which are metabolized in vivo to give the compounds of the invention of formulae IA or IB. Typical examples for prodrugs are for example described in C. G. Wermeth (editor): The Practice of Medicinal Chemistry, Academic Press, San Diego, 1996, pages 671-715. Examples are phosphates, carbamates, aminoacids, esters, amides, peptides, urea and the like. In the present case, suitable prodrugs can be compounds of formula IA or IB wherein an external nitrogen atom, for example a secondary nitrogen ring atom of the ring fused to the pyridyl ring (i.e. in the group —(CH2)m— formed by R3 together with R4 or R4 together with R5 or R5 together with R6, at least one CH2 group is replaced by a group NRc and at least one Rc is hydrogen) or a nitrogen atom of a primary or secondary amino group being a substituent R1, R3, R4, R5, R6, R7 and/or R8 (=at least one of R1, R3, R4, R5, R6, R7 and R8 is NRaRb, wherein at least one of Ra and Rb is H), forms an amide/peptide bond in that this nitrogen atom is substituted by a C1-C4-alkylcarbonyl group, e.g. by acetyl, propionyl, n-propylcarbonyl, isopropylcarbonyl, n-butylcarbonyl or tert-butylcarbonyl (pivaloyl), by benzoyl, or by an amino acid group bonded via CO, e.g. glycine, alanine, serine, phenylalanine and the like bonded via CO. Suitable prodrugs are furthermore alkylcarbonyloxyalkylcarbamates, wherein said nitrogen atom carries a group —C(═O)—O—CHRx—O—C(═O)—Ry, wherein Rx and Ry independently of each other are C1-C4-alkyl. These carbamate compounds are for example described in J. Alexander, R. Cargill, S. R. Michelson, H. Schwam, J. Medicinal Chem. 1988, 31(2), 318-322. These groups can be removed under metabolic conditions and result in compounds IA/IB wherein said nitrogen atom carries a hydrogen atom instead. Also, R1 may be chosen so as to be hydrolysable under metabolic conditions and thus to be one of the above-listed groups (i.a. a C1-C4-alkylcarbonyl group, an amino acid group bonded via CO or a group —C(═O)—O—CHRx—O—C(═O)—Ry). Another prodrug is e.g. a compound IB, wherein R2 is F.


The compounds of formulae IA or IB may also be present in the form of the respective tautomers. Apart the tautomery already mentioned above of formulae IA and IB, where in formula IB R2 is H, tautomery may also be present in compounds IA and IB wherein R1 is OH and this substituent is bonded to a carbon atom which is in α-position to a nitrogen ring atom. This results for example in following tautomeric formulae (the examples are only given for formula IA, but are analogous for formula IB):




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The organic moieties mentioned in the above definitions of the variables are—like the term halogen—collective terms for individual listings of the individual group members. The prefix Cn-Cm, indicates in each case the possible number of carbon atoms in the group.


The term halogen denotes in each case fluorine, bromine, chlorine or iodine, in particular fluorine, chlorine or bromine.


C1-C2-Alkyl is methyl or ethyl; C1-C3-alkyl is additionally n-propyl or isopropyl.


C1-C4-Alkyl is a straight-chain or branched alkyl group having from 1 to 4 carbon atoms. Examples are methyl, ethyl, n-propyl, isopropyl, n-butyl, 2-butyl (sec-butyl), isobutyl and tert-butyl.


C1-C6-Alkyl is a straight-chain or branched alkyl group having from 1 to 6 carbon atoms. Examples include the residues mentioned above for C1-C4-alkyl and also pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-1-methylpropyl and 1-ethyl-2-methylpropyl.


C1-C2-Haloalkyl is an alkyl group having 1 or 2 carbon atoms (as mentioned above), where at least one of the hydrogen atoms, e.g. 1, 2, 3, 4 or 5 hydrogen atoms in these groups are replaced by halogen atoms as mentioned above, such as chloromethyl, dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, bromomethyl, chlorofluoromethyl, dichlorofluoromethyl, chlorodifluoromethyl, 1-chloroethyl, 1-bromoethyl, 1-fluoroethyl, 2-chloroethyl, 2-bromoethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 2-chloro-2-fluoroethyl, 2-chloro-2,2-difluoroethyl, 2,2-dichloro-2-fluoroethyl, 2,2,2-trichloroethyl or pentafluoroethyl.


C1-C4-Haloalkyl is a straight-chain or branched alkyl group having 1 to 4 carbon atoms (as mentioned above), where at least one of the hydrogen atoms, e.g. 1, 2, 3, 4 or 5 hydrogen atoms in these groups are replaced by halogen atoms as mentioned above. Examples are, apart those listed above for C1-C2-haloalkyl, 1-chloropropyl, 1-bromopropyl, 1-fluoropropyl, 2-chloropropyl, 2-bromopropyl, 2-fluoropropyl, 3-chloropropyl, 3-bromopropyl, 3-fluoropropyl, 1,1-dichloropropyl, 1,1-difluoropropyl, 2,2-dichloropropyl, 2,2-difluoropropyl, 2,3-dichloropropyl, 2,3-difluoropropyl, 1,3-dichloropropyl, 1,3-difluoropropyl, 3,3-dichloropropyl, 3,3-difluoropropyl, 1,1,2-trichloropropyl, 1,1,2-trifluoropropyl, 1,2,2-trichloropropyl, 1,2,2-trifluoropropyl, 1,2,3-trichloropropyl, 1,2,3-trifluoropropyl, 2,2,3-trichloropropyl, 2,2,3-trifluoropropyl, 3,3,3-trichloropropyl, 3,3,3-trifluoropropyl, 1,1,1-trifluoroprop-2-yl, 1-chlorobutyl, 1-bromobutyl, 1-fluorobutyl, 2-chlorobutyl, 2-bromobutyl, 2-fluorobutyl, 3-chlorobutyl, 3-bromobutyl, 3-fluorobutyl, 4-chlorobutyl, 4-bromobutyl, 4-fluorobutyl, and the like.


C1-C6-Haloalkyl is a straight-chain or branched alkyl group having 1 to 6 carbon atoms (as mentioned above), where at least one of the hydrogen atoms in these groups is replaced by halogen atoms as mentioned above. Examples are, apart those listed above for C1-C4-haloalkyl, chloropentyl, bromopentyl, fluoropentyl, chlorohexyl, bromohexyl, fluorohexyl, and the like.


C1-C2-Fluoroalkyl (=fluorinated C1-C2-alkyl) is an alkyl group having 1 or 2 carbon atoms (as mentioned above), where at least one of the hydrogen atoms, e.g. 1, 2, 3, 4 or 5 hydrogen atoms in these groups are replaced by fluorine atoms, such as difluoromethyl, trifluoromethyl, 1-fluoroethyl, (R)-1-fluoroethyl, (S)-1-fluoroethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, or pentafluoroethyl.


C1-C4-Fluoroalkyl (=fluorinated C1-C4-alkyl) is a straight-chain or branched alkyl group having 1 to 4 carbon atoms (as mentioned above), where at least one of the hydrogen atoms, e.g. 1, 2, 3, 4 or 5 hydrogen atoms in these groups are replaced by fluorine atoms. Examples are, apart those listed above for C1-C2-fluoroalkyl, 1-fluoropropyl, (R)-1-fluoropropyl, (S)-1-fluoropropyl, 2-fluoropropyl, (R)-2-fluoropropyl, (S)-2-fluoropropyl, 3-fluoropropyl, 1,1-difluoropropyl, 2,2-difluoropropyl, 1,2-difluoropropyl, 2,3-difluoropropyl, 1,3-difluoropropyl, 3,3-difluoropropyl, 1,1,2-trifluoropropyl, 1,2,2-trifluoropropyl, 1,2,3-trifluoropropyl, 2,2,3-trifluoropropyl, 3,3,3-trifluoropropyl, 1,1,1-trifluoroprop-2-yl, 2-fluoro-1-methylethyl, (R)-2-fluoro-1-methylethyl, (S)-2-fluoro-1-methylethyl, 2,2-difluoro-1-methylethyl, (R)-2,2-difluoro-1-methylethyl, (S)-2,2-difluoro-1-methylethyl, 1,2-difluoro-1-methylethyl, (R)-1,2-difluoro-1-methylethyl, (S)-1,2-difluoro-1-methylethyl, 2,2,2-trifluoro-1-methylethyl, (R)-2,2,2-trifluoro-1-methylethyl, (S)-2,2,2-trifluoro-1-methylethyl, 2-fluoro-1-(fluoromethyl)ethyl, 1-(difluoromethyl)-2,2-difluoroethyl, 1-(trifluoromethyl)-2,2,2-trifluoroethyl, 1-(trifluoromethyl)-1,2,2,2-tetrafluoroethyl, 1-fluorobutyl, (R)-1-fluorobutyl, (S)-1-fluorobutyl, 2-fluorobutyl, (R)-2-fluorobutyl, (S)-2-fluorobutyl, 3-fluorobutyl, (R)-3-fluorobutyl, (S)-3-fluorobutyl, 4-fluorobutyl, 1,1-difluorobutyl, 2,2-difluorobutyl, 3,3-difluorobutyl, 4,4-difluorobutyl, 4,4,4-trifluorobutyl and the like.


C1-C6-Fluoroalkyl (=fluorinated C1-C6-alkyl) is a straight-chain or branched alkyl group having 1 to 6 carbon atoms (as mentioned above), where at least one of the hydrogen atoms, e.g. 1, 2, 3, 4 or 5 hydrogen atoms in these groups are replaced by fluorine atoms. Examples are, apart those listed above for C1-C4-fluoroalkyl, 1-fluoropentyl, (R)-1-fluoropentyl, (S)-1-fluoropentyl, 2-fluoropentyl, (R)-2-fluoropentyl, (S)-2-fluoropentyl, 3-fluoropentyl, (R)-3-fluoropentyl, (S)-3-fluoropentyl, 4-fluoropentyl, (R)-4-fluoropentyl, (S)-4-fluoropentyl, 5-fluoropentyl, (R)-5-fluoropentyl, (S)-5-fluoropentyl, 1-fluorohexyl, (R)-1-fluorohexyl, (S)-1-fluorohexyl, 2-fluorohexyl, (R)-2-fluorohexyl, (S)-2-fluorohexyl, 3-fluorohexyl, (R)-3-fluorohexyl, (S)-3-fluorohexyl, 4-fluorohexyl, (R)-4-fluorohexyl, (S)-4-fluorohexyl, 5-fluorohexyl, (R)-5-fluorohexyl, (S)-5-fluorohexyl, 65-fluorohexyl, (R)-6-fluorohexyl, (S)-6-fluorohexyl, and the like.


C1-C4-Alkoxy is a straight-chain or branched alkyl group having from 1 to 4 carbon atoms, which is bound to the remainder of the molecule via an oxygen atom. Examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, 2-butoxy, isobutoxy and tert-butoxy.


C1-C6-Alkoxy is a straight-chain or branched alkyl group having from 1 to 6 carbon atoms, which is bound to the remainder of the molecule via an oxygen atom. Examples include, apart those listed above for C1-C4-alkoxy, pentyloxy, 1-methylbutoxy, 2-methylbutoxy, 3-methylbutoxy, 2,2-dimethylpropoxy, 1-ethylpropoxy, hexyloxy, 1,1-dimethylpropoxy, 1,2-dimethylpropoxy, 1-methylpentyloxy, 2-methylpentyloxy, 3-methylpentyloxy, 4-methylpentyloxy, 1,1-dimethylbutyloxy, 1,2-dimethylbutyloxy, 1,3-dimethylbutyloxy, 2,2-dimethylbutyloxy, 2,3-dimethylbutyloxy, 3,3-dimethylbutyloxy, 1-ethylbutyloxy, 2-ethylbutyloxy, 1,1,2-trimethylpropoxy, 1,2,2-trimethylpropoxy, 1-ethyl-1-methylpropoxy and 1-ethyl-2-methylpropoxy.


Halogenated C1-C6-alkoxy (which is also termed C1-C6-haloalkoxy), in particular fluorinated C1-C6-alkoxy (also termed C1-C6-fluoroalkoxy) is a straight-chain or branched alkoxy group having from 1 to 6, in particular 1 to 4 carbon atoms (=fluorinated C1-C4-alkoxy), wherein at least one, e.g. 1, 2, 3, 4 or all of the hydrogen atoms are replaced by a halogen atoms, in particular fluorine atoms such as in fluoromethoxy, difluoromethoxy, trifluoromethoxy, (R)-1-fluoroethoxy, (S)-1-fluoroethoxy, 2-fluoroethoxy, 1,1-difluoroethoxy, 2,2-difluoroethoxy, 2,2,2-trifluoroethoxy, 1,1,2,2-tetrafluoroethoxy, (R)-1-fluoropropoxy, (S)-1-fluoropropoxy, (R)-2-fluoropropoxy, (S)-2-fluoropropoxy, 3-fluoropropoxy, 1,1-difluoropropoxy, 2,2-difluoropropoxy, 3,3-difluoropropoxy, 3,3,3-trifluoropropoxy, (R)-2-fluoro-1-methylethoxy, (S)-2-fluoro-1-methylethoxy, (R)-2,2-difluoro-1-methylethoxy, (S)-2,2-difluoro-1-methylethoxy, (R)-1,2-difluoro-1-methylethoxy, (S)-1,2-difluoro-1-methylethoxy, (R)-2,2,2-trifluoro-1-methylethoxy, (S)-2,2,2-trifluoro-1-methylethoxy, 2-fluoro-1-(fluoromethyl)ethoxy, 1-(difluoromethyl)-2,2-difluoroethoxy, (R)-1-fluorobutoxy, (S)-1-fluorobutoxy, 2-fluorobutoxy, 3-fluorobutoxy, 4-fluorobutoxy, 1,1-difluorobutoxy, 2,2-difluorobutoxy, 3,3-difluorobutoxy, 4,4-difluorobutoxy, 4,4,4-trifluorobutoxy, and the like.


C1-C4-Alkylcarbonyl is a straight-chain or branched alkyl group having from 1 to 4 carbon atoms), which is bound to the remainder of the molecule via a carbonyl group (CO), such as in acetyl, propionyl, isopropylcarbonyl, butylcarbonyl, sec-butylcarbonyl, isobutylcarbonyl, and tert-butylcarbonyl.


C1-C6-Alkylcarbonyl is a straight-chain or branched alkyl group having from 1 to 6 carbon atoms, which is bound to the remainder of the molecule via a carbonyl group (CO). Examples include, apart those listed above for C1-C4-alkylcarbonyl, pentylcarbonyl, hexylcarbonyl and the constitutional isomers thereof.


C1-C4-Haloalkylcarbonyl is a straight-chain or branched haloalkyl group having from 1 to 4 carbon atoms as defined above, which is bound to the remainder of the molecule via a carbonyl group (CO)


C1-C6-Haloalkylcarbonyl is a straight-chain or branched haloalkyl group having from 1 to 6 carbon atoms as defined above, which is bound to the remainder of the molecule via a carbonyl group (CO)


C1-C4-Fluoroalkylcarbonyl is a straight-chain or branched fluoroalkyl group having from 1 to 4 carbon atoms as defined above, which is bound to the remainder of the molecule via a carbonyl group (CO)


C1-C6-fluoroalkylcarbonyl is a straight-chain or branched fluoroalkyl group having from 1 to 6 carbon atoms as defined above, which is bound to the remainder of the molecule via a carbonyl group (CO)


C1-C6-Alkoxycarbonyl is a straight-chain or branched alkoxy group having from 1 to 6, especially 1 to 4 carbon atoms (═C1-C4-alkoxycarbonyl), in particular 1 to 3 carbon atoms (═C1-C3-alkoxycarbonyl), which is bound to the remainder of the molecule via a carbonyl group (CO), such as in methoxycarbonyl, ethoxycarbonyl, propyloxycarbonyl, and isopropyloxycarbonyl.


C1-C6-Haloalkoxycarbonyl is a straight-chain or branched haloalkoxy group having from 1 to 6, especially 1 to 4 carbon atoms (═C1-C4-haloalkoxycarbonyl), in particular 1 to 3 carbon atoms (═C1-C3-haloalkoxycarbonyl) as defined above, which is bound to the remainder of the molecule via a carbonyl group (CO).


C1-C6-Fluoroalkoxycarbonyl is a straight-chain or branched fluoroalkoxy group having from 1 to 6, especially 1 to 4 carbon atoms (═C1-C4-fluoroalkoxycarbonyl), in particular 1 to 3 carbon atoms (═C1-C3-fluoroalkoxycarbonyl) as defined above, which is bound to the remainder of the molecule via a carbonyl group (CO).


C3-C6-Cycloalkyl is a cycloaliphatic radical having from 3 to 6 C atoms, such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. C3-C4-cycloalkyl is a cycloaliphatic radical having from 3 to 4 C atoms, such as cyclopropyl and cyclobutyl.


C3-C7-Cycloalkyl is a cycloaliphatic radical having from 3 to 7 C atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.


C3-C6-Halocycloalkyl is a cycloaliphatic radical having from 3 to 6 C atoms, such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, wherein at least one, e.g. 1, 2, 3, 4 or all of the hydrogen atoms are replaced by a halogen atoms, preferably by fluorine atoms such as in 1-fluorocyclopropyl, 2-fluorocyclopropyl, (S)- and (R)-2,2-difluorocyclopropyl, 1,2-difluorocyclopropyl, 2,3-difluorocyclopropyl, penta-fluorocyclopropyl, 1-fluorocyclobutyl, 2-fluorocyclobutyl, 3-fluorocyclobutyl, 2,2-difluorocyclobutyl, 3,3-difluorocyclobutyl, 1,2-difluorocyclobutyl, 1,3-difluorocyclobutyl, 2,3-difluorocyclobutyl, 2,4-difluorocyclobutyl, or 1,2,2-trifluorocyclobutyl.


C3-C7-Halocycloalkyl is a cycloaliphatic radical having from 3 to 7 C atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, wherein at least one, e.g. 1, 2, 3, 4 or all of the hydrogen atoms are replaced by a halogen atoms, preferably by fluorine atoms. Examples include, apart those listed above for C3-C6-fluorocycloalkyl, 1-fluorocycloheptyl, 2-fluorocycloheptyl, 3-fluorocycloheptyl, 4-fluorocycloheptyl, 1,2-difluorocycloheptyl, 1,3-difluorocycloheptyl, 1,4-difluorocycloheptyl, 2,2-difluorocycloheptyl, 2,3-difluorocycloheptyl, 2,4-difluorocycloheptyl, 2,5-difluorocycloheptyl, 2,6-difluorocycloheptyl, 2,7-difluorocycloheptyl, 3,3-difluorocycloheptyl, 3,4-difluorocycloheptyl, 3,5-difluorocycloheptyl, 3,6-difluorocycloheptyl, 4,4-difluorocycloheptyl, 4,5-difluorocycloheptyl, and the like.


C2-C4-Alkenyl is a singly unsaturated hydrocarbon radical having 2, 3 or 4 C-atoms and one C—C double bond, e.g. vinyl, allyl (2-propen-1-yl), 1-propen-1-yl, 2-propen-2-yl, buten-1-yl, buten-2-yl, buten-3-yl, methallyl (2-methylprop-2-en-1-yl) and the like.


C2-C4-Haloalkenyl is a singly unsaturated hydrocarbon radical having 2, 3 or 4 C-atoms, wherein at least one, e.g. 1, 2, 3, 4 or all of the hydrogen atoms are replaced by halogen atoms, preferably by fluorine atoms such as in 1-fluorovinyl, 2-fluorovinyl, 2,2-fluorovinyl, 3,3,3-fluoropropenyl, 1,1-difluoro-2-propenyl, 1-fluoro-2-propenyl and the like.


Examples for 5- or 6-membered N- or C-bound heteroaromatic radicals comprising one nitrogen atom and optionally 1, 2 or 3 further heteroatoms independently selected from O, S and N as ring members are pyrrol-1-yl, pyrrol-2-yl, pyrrol-3-yl, pyrazol-1-yl, pyrazol-3-yl, pyrazol-4-yl, pyrazol-5-yl, imidazol-1-yl, imidazol-2-yl, imidazol-4-yl, imidazol-5-yl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, isoxazol-3-yl, isoxazol-4-yl, isoxazol-5-yl, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, isothiazol-3-yl, isothiazol-4-yl, isothiazol-5-yl, [1,2,3]-1H-triazol-1-yl, [1,2,3]-1H-triazol-4-yl, [1,2,3]-1H-triazol-5-yl, [1,2,3]-2H-triazol-2-yl, [1,2,3]-2H-triazol-4-yl, [1,2,3]-2H-triazol-5-yl, [1,2,4]-1H-triazol-1-yl, [1,2,4]-1H-triazol-3-yl, [1,2,4]-1H-triazol-5-yl, [1,2,4]-4H-triazol-3-yl, [1,2,4]-4H-triazol-4-yl, oxadiazolyl, thiadiazolyl, [1,2,3,4]-1H-tetrazol-1-yl, [1,2,3,4]-1H-tetrazol-5-yl, [1,2,3,4]-2H-tetrazol-2-yl, [1,2,3,4]-2H-tetrazol-5-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyridazin-3-yl, pyridazin-4-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, pyrazin-2-yl and triazin-2-yl.


Examples for 5- or 6-membered N- or C-bound heteroaromatic radicals comprising 1, 2 or 3 heteroatoms independently selected from O, S and N as ring members are furan-2-yl, furan-3-yl, thien-2-yl, thien-3-yl, pyrrol-1-yl, pyrrol-2-yl, pyrrol-3-yl, pyrazol-1-yl, pyrazol-3-yl, pyrazol-4-yl, pyrazol-5-yl, imidazol-1-yl, imidazol-2-yl, imidazol-4-yl, imidazol-5-yl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, isoxazol-3-yl, isoxazol-4-yl, isoxazol-5-yl, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, isothiazol-3-yl, isothiazol-4-yl, isothiazol-5-yl, [1,2,3]-1H-triazol-1-yl, [1,2,3]-1H-triazol-4-yl, [1,2,3]-1H-triazol-5-yl, [1,2,3]-2H-triazol-2-yl, [1,2,3]-2H-triazol-4-yl, [1,2,3]-2H-triazol-5-yl, [1,2,4]-1H-triazol-1-yl, [1,2,4]-1H-triazol-3-yl, [1,2,4]-1H-triazol-5-yl, [1,2,4]-4H-triazol-3-yl, [1,2,4]-4H-triazol-4-yl, oxadiazolyl, thiadiazolyl, [1,2,3,4]-1H-tetrazol-1-yl, [1,2,3,4]-1H-tetrazol-5-yl, [1,2,3,4]-2H-tetrazol-2-yl, [1,2,3,4]-2H-tetrazol-5-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyridazin-3-yl, pyridazin-4-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, pyrazin-2-yl and triazin-2-yl.


Examples for N-bound 3-, 4-, 5-, 6- or 7-membered saturated or unsaturated aromatic or non-aromatic N-heterocyclic rings, which may contain 1 further heteroatom or heteroatom-containing group selected from the group consisting of O, S, SO, SO2 and N as a ring member (thus as rings formed by Ra and Rb together with the nitrogen atom to which they are bound), are aziridin-1-yl, azetidin-1-yl, pyrrolidin-1-yl, pyrazolidin-1-yl, imidazolidin-1-yl, oxazolidin-3-yl, isoxazolidin-2-yl, thiazolidin-3-yl, isothiazolidin-1-yl, [1,2,3]-triazolidin-1-yl, [1,2,3]-triazolidin-2-yl, [1,2,4]-triazolidin-1-yl, [1,2,4]-triazolidin-4-yl, piperidin-1-yl, piperazin-1-yl, morpholin-4-yl, thiomorpholin-1-yl, 1-oxothiomorpholin-1-yl, 1,1-dioxothiomorpholin-1-yl, azepan-1-yl, azirin-1-yl, azetin-1-yl, pyrrolin-1-yl, pyrazolin-1-yl, imidazolin-1-yl, oxazolin-3-yl, isoxazolin-2-yl, thiazolin-3-yl, isothiazolin-1-yl, 1,2-dihydropyridin-1-yl, 1,2,3,4-tetrahydropyridin-1-yl, 1,2,5,6-tetrahydropyridin-1-yl, 1,2-dihydropyridazin, 1,6-dihydropyridazin, 1,2,3,4-tetrahydropyridazin-1-yl, 1,2,5,6-tetrahydropyridazin-1-yl, 1,2-dihydropyrimidin, 1,6-dihydropyrimidin, 1,2,3,4-tetrahydropyrimidin-1-yl, 1,2,5,6-tetrahydropyrimidin-1-yl, 1,2-dihydropyrazin-1-yl, 1,2,3,4-tetrahydropyrazin-1-yl, 1,2,5,6-tetrahydropyrazin-1-yl, pyrrol-1-yl, pyrazol-1-yl, imidazol-1-yl, [1,2,3]-1H-triazol-1-yl, [1,2,3]-2H-triazol-2-yl, [1,2,4]-1H-triazol-1-yl and [1,2,4]-4H-triazol-4-yl.


Examples for saturated, partially unsaturated or aromatic 3-, 4-, 5-, 6- or 7-membered heterocyclic radicals comprising 1, 2 or 3 heteroatoms selected from O, S and N as ring members, wherein two geminally bound substituents may together form a group ═O are the above-listed examples for 5- or 6-membered N- or C-bound heteroaromatic radicals and further 2-oxiranyl, 2-thiiranyl, 1- or 2-aziridinyl, 1-, 2- or 3-azetidinyl, 2-tetrahydrofuranyl, 3-tetrahydrofuranyl, 3-tetrahydrofuran-2-onyl, 4-tetrahydrofuran-2-onyl, 5-tetrahydrofuran-2-onyl, 2-tetrahydrofuran-3-onyl, 4-tetrahydrofuran-3-onyl, 5-tetrahydrofuran-3-onyl, 2-tetrahydrothienyl, 3-tetrahydrothienyl, 3-tetrahydrothien-2-onyl, 4-tetrahydrothien-2-onyl, 5-tetrahydrothien-2-onyl, 2-tetrahydrothien-3-onyl, 4-tetrahydrothien-3-onyl, 5-tetrahydrothien-3-onyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 1-pyrrolidin-2-onyl, 3-pyrrolidin-2-onyl, 4-pyrrolidin-2-onyl, 5-pyrrolidin-2-onyl, 1-pyrrolidin-3-onyl, 2-pyrrolidin-3-onyl, 4-pyrrolidin-3-onyl, 5-pyrrolidin-3-onyl, 1-pyrrolidin-2,5-dionyl, 3-pyrrolidin-2,5-dionyl, 3-isoxazolidinyl, 4-isoxazolidinyl, 5-isoxazolidinyl, 3-isothiazolidinyl, 4-isothiazolidinyl, 5-isothiazolidinyl, 3-pyrazolidinyl, 4-pyrazolidinyl, 5-pyrazolidinyl, 2-oxazolidinyl, 4-oxazolidinyl, 5-oxazolidinyl, 2-thiazolidinyl, 4-thiazolidinyl, 5-thiazolidinyl, 2-imidazolidinyl, 4-imidazolidinyl, 1,2,4-oxadiazolidin-3-yl, 1,2,4-oxadiazolidin-5-yl, 1,2,4-thiadiazolidin-3-yl, 1,2,4-thiadiazolidin-5-yl, 1,2,4-triazolidin-3-yl, 1,3,4-oxadiazolidin-2-yl, 1,3,4-thiadiazolidin-2-yl, 1,3,4-triazolidin-2-yl, 2,3-dihydrofur-2-yl, 2,3-dihydrofur-3-yl, 2,4-dihydrofur-2-yl, 2,4-dihydrofur-3-yl, 2,3-dihydrothien-2-yl, 2,3-dihydrothien-3-yl, 2,4-dihydrothien-2-yl, 2,4-dihydrothien-3-yl, 2-pyrrolin-2-yl, 2-pyrrolin-3-yl, 3-pyrrolin-2-yl, 3-pyrrolin-3-yl, 2-isoxazolin-3-yl, 3-isoxazolin-3-yl, 4-isoxazolin-3-yl, 2-isoxazolin-4-yl, 3-isoxazolin-4-yl, 4-isoxazolin-4-yl, 2-isoxazolin-5-yl, 3-isoxazolin-5-yl, 4-isoxazolin-5-yl, 2-isothiazolin-3-yl, 3-isothiazolin-3-yl, 4-isothiazolin-3-yl, 2-isothiazolin-4-yl, 3-isothiazolin-4-yl, 4-isothiazolin-4-yl, 2-isothiazolin-5-yl, 3-isothiazolin-5-yl, 4-isothiazolin-5-yl, 2,3-dihydropyrazol-1-yl, 2,3-dihydropyrazol-2-yl, 2,3-dihydropyrazol-3-yl, 2,3-dihydropyrazol-4-yl, 2,3-dihydropyrazol-5-yl, 3,4-dihydropyrazol-1-yl, 3,4-dihydropyrazol-3-yl, 3,4-dihydropyrazol-4-yl, 3,4-dihydropyrazol-5-yl, 4,5-dihydropyrazol-1-yl, 4,5-dihydropyrazol-3-yl, 4,5-dihydropyrazol-4-yl, 4,5-dihydropyrazol-5-yl, 2,3-dihydrooxazol-2-yl, 2,3-dihydrooxazol-3-yl, 2,3-dihydrooxazol-4-yl, 2,3-dihydrooxazol-5-yl, 3,4-dihydrooxazol-2-yl, 3,4-dihydrooxazol-3-yl, 3,4-dihydrooxazol-4-yl, 3,4-dihydrooxazol-5-yl, 3,4-dihydrooxazol-2-yl, 3,4-dihydrooxazol-3-yl, 3,4-dihydrooxazol-4-yl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, 1,3-dioxan-5-yl, 2-tetrahydropyranyl, 4-tetrahydropyranyl, 2-tetrahydrothienyl, 3-hexahydropyridazinyl, 4-hexahydropyridazinyl, 2-hexahydropyrimidinyl, 4-hexahydropyrimidinyl, 5-hexahydropyrimidinyl, 2-piperazinyl, 1,3,5-hexahydrotriazin-2-yl and 1,2,4-hexahydrotriazin-3-yl. For further examples see also the non-aromatic rings A listed below.


The remarks made above and in the following with respect to preferred aspects of the invention, e.g. to preferred meanings of the variables X1, X2, X3, X4, R1, R2, R3, R4, R5, R6, R7, R8, Ra, Rb, Rc of compounds IA and IB, to preferred compounds IA and IB and to preferred embodiments of the method or the use according to the invention, apply in each case on their own or in particular to combinations thereof.


Preferably, each R1 is independently selected from hydrogen, halogen, CN, C1-C6-alkyl, C1-C6-haloalkyl, C1-C6-alkoxy, C1-C6-haloalkoxy and COOH. More preferably, each R1 is independently selected from hydrogen, halogen, COOH and cyano. Preferably, at most one of R1 is different from hydrogen. In particular, all radicals R1 are hydrogen or one radical R1 is different from hydrogen and is preferably halogen, COOH or cyano and the remaining radicals R1 are hydrogen. Specifically, one R1 is cyano and the others are hydrogen.


Preferably, R2 is hydrogen.


In an alternatively preferred embodiment, R2 is C1-C4-alkyl, C1-C4-haloalkyl, C2-C4-alkenyl or fluorine.


Specifically, R2 is hydrogen, C1-C4-haloalkyl, especially C1-C4-fluoroalkyl, or allyl and very specifically hydrogen.


In one preferred embodiment of the invention, R3 and R4; or R4 and R5; or R5 and R6 form together a bridging group —(CH2)m—, wherein m is 3, 4 or 5, where 1, 2 or 3 of the CH2 groups may be replaced by a group or a heteroatom selected from CO, O, S, SO, SO2, NRc and NO, and where 1, 2 or 3 hydrogen atoms of the bridging group may be replaced by a radical R8;


with the proviso that in case R3 and R4 form together a bridging group —(CH2)m—, the CH2 unit bound in the position of R3 is not replaced by an NRc group (in other words, the fused pyridyl moiety is not




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wherein the bow stands for —(CH2)m-1—, wherein 1 or 2 of the CH2 groups may be replaced by a group or a heteroatom selected from CO, O, S, SO, SO2, NRc and NO, and where 1, 2 or 3 hydrogen atoms of the bridging group may be replaced by a radical R8; and # is the attachment point to the remainder of the molecule);


and with the proviso that R3, when not being part of the bridging group, is not NRaRb (in other words: where the radicals R3, R4, R5 and R6, which are not part of the bridging group, are independently selected from the group consisting of hydrogen, halogen, cyano, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy and C1-C4-haloalkoxy, and where R4, R5 and R6 may independently also be selected from NRaRb).


In an alternatively preferred embodiment, R3 and R4; or R4 and R5; or R5 and R6 form together a bridging group —(CH2)m—, wherein m is 3, 4 or 5, where 1 or 2 of the CH2 groups may be replaced by a group or a heteroatom selected from CO, O and NRc, and where 1 or 2 or 3 hydrogen atoms of the bridging group may be replaced by a radical R8, where Rc and R8 have one of the above-given general or, in particular, one of the below-given preferred meanings. Preferably, the above two provisos (i.e. in case R3 and R4 form together a bridging group —(CH2)m—, the CH2 unit bound in the position of R3 is not replaced by an NRc group; and R3, when not being part of the bridging group, is not NRaRb) apply here, too.


Preferably, m is 3 or 4.


More preferably, the bridging group is selected from —CH2CH2CH2—, —OCH2CH2—, —CH2CH2O—, —CH2OCH2—, —NRcCH2CH2—, —CH2CH2NRc—, —CH2NRcCH2—, —CH2CH2CH2CH2—, —OCH2CH2CH2—, —CH2OCH2CH2—, —CH2CH2OCH2—, —CH2CH2CH2O—, —NRcCH2CH2CH2—, —CH2NRcCH2CH2—, —CH2CH2NRcCH2—, —CH2CH2CH2NRc—, —C(═O)CH2CH2CH2—, —CH2C(═O)CH2CH2—, —CH2CH2C(═O)CH2— and —CH2CH2CH2C(═O)—, where the hydrogen atoms of the above groups may be replaced by 1 or 2 radicals R8, where Rc and R8 have one of the above-given general or, in particular, one of the below-given preferred meanings. Preferably, the above two provisos (i.e. in case R3 and R4 form together a bridging group —(CH2)m—, the CH2 unit bound in the position of R3 is not replaced by an NRc group; and R3, when not being part of the bridging group, is not NRaRb) apply here, too. Thus, even more preferably, the bridging group is selected from —CH2CH2CH2—, —OCH2CH2—, —CH2CH2O—, —CH2OCH2—, —CH2NRcCH2—, —CH2CH2CH2CH2—, —OCH2CH2CH2—, —CH2OCH2CH2—, —CH2CH2OCH2—, —CH2CH2CH2O—, —CH2NRcCH2CH2—, —CH2CH2NRcCH2—, —C(═O)CH2CH2CH2—, —CH2C(═O)CH2CH2—, —CH2CH2C(═O)CH2— and —CH2CH2CH2C(═O)—, where the hydrogen atoms of the above groups may be replaced by 1 or 2 radicals R8, where Rc and R8 have one of the above-given general or, in particular, one of the below-given preferred meanings.


In particular, the bridging group is selected from —CH2CH2CH2—, —CH2NRcCH2—, —NRcCH2CH2—, —CH2CH2NRc—, —CH2OCH2—, —CH2CH2CH2CH2—, —CH2NRcCH2CH2—, —CH2CH2NRcCH2—, —C(═O)CH2CH2CH2—, —CH2OCH2CH2—, —CH2CH2OCH2—, —CH2C(═O)CH2CH2—, —CH2CH2C(═O)CH2— and —CH2CH2CH2C(═O)—, and more particularly from —CH2CH2CH2—, —CH2NRcCH2—, —CH2OCH2—, —CH2CH2CH2CH2—, —CH2NRcCH2CH2—, —CH2CH2NRcCH2—, —C(═O)CH2CH2CH2—, —CH2OCH2CH2—, —CH2CH2OCH2—, —CH2C(═O)CH2CH2—, —CH2CH2C(═O)CH2— and —CH2CH2CH2C(═O)—, where the hydrogen atoms of the above groups may be replaced by 1 or 2 radicals R8, where Rc and R8 have one of the above-given general or, in particular, one of the below-given preferred meanings.


Specifically, the bridging group is selected from —CH2CH2CH2—, —CH2NRcCH2—, —CH2CH2CH2CH2—, —CH2NRcCH2CH2—, —CH2CH2NRcCH2—, —C(═O)CH2CH2CH2—, —CH2C(═O)CH2CH2—, —CH2CH2C(═O)CH2— and —CH2CH2CH2C(═O)—, where the hydrogen atoms of the above groups may be replaced by 1 or 2 radicals R8, where Rc and R8 have one of the above-given general or, in particular, one of the below-given preferred meanings.


Preferably, the radicals R3, R4, R5 and R6, which are not part of the bridging group, are selected from hydrogen, halogen, cyano, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy and C1-C4-haloalkoxy, more preferably from hydrogen, halogen, C1-C2-alkyl and C1-C2-haloalkyl, and are in particular hydrogen.


Preferably, R3 and R4; or R4 and R5 (and not R5 and R6) form together a bridging group as defined above. More preferably, R3 and R4 (and not R4 and R5 or R5 and R6) form together a bridging group as defined above.


Preferably, each R7 is independently selected from halogen, CN, C1-C6-alkyl, C1-C6-haloalkyl, C1-C6-alkoxy and C1-C6-haloalkoxy. And more preferably from CN, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy and C1-C4-haloalkoxy.


Preferably, each R8 is independently selected from the group consisting of halogen, OH, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy, NRaRb, C1-C6-alkylcarbonyl, C1-C6-haloalkylcarbonyl, C1-C6-alkoxycarbonyl and C1-C6-haloalkoxycarbonyl, more preferably from halogen, OH, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy, NRaRb, C1-C4-alkylcarbonyl, C1-C4-haloalkylcarbonyl, C1-C4-alkoxycarbonyl and C1-C4-haloalkoxycarbonyl, where preferably Ra and Rb are independently selected from hydrogen and C1-C4-alkyl, and specifically from OH, halogen, especially fluorine, C1-C4-alkoxy, especially methoxy, C1-C4-haloalkoxy, especially trifluoromethoxy, and NRaRb, where preferably Ra and Rb are independently selected from hydrogen and C1-C4-alkyl. Very specifically, each R8 is independently selected from the group consisting of OH, C1-C4-alkoxy and C1-C4-haloalkoxy.


Ra and Rb are, independently of each other, preferably selected from hydrogen, C1-C6-alkyl, C1-C4-haloalkyl, C1-C4-alkylcarbonyl, C1-C4-haloalkylcarbonyl, C1-C6-alkoxycarbonyl and C1-C6-haloalkoxycarbonyl or form together with the nitrogen atom to which they are bound an N-bound 3-, 4-, 5-, 6- or 7-membered saturated or unsaturated aromatic or non-aromatic N-heterocyclic ring, which may contain 1 further heteroatom or heteroatom-containing group selected from N, O, S, SO and SO2 as a ring member, where the N-heterocyclic ring may carry 1 or 2 radicals selected from halogen, cyano, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy and C1-C4-haloalkoxy, and are more preferably selected from hydrogen, C1-C4-alkyl, C1-C4-haloalkyl, C1-C6-alkoxycarbonyl and C1-C6-haloalkoxycarbonyl or form together with the nitrogen atom to which they are bound an N-bound 5- or 6-membered saturated or unsaturated aromatic or non-aromatic N-heterocyclic ring, which may contain 1 further heteroatom or heteroatom-containing group selected from N and O as a ring member, where the N-heterocyclic ring may carry 1 or 2 radicals selected from halogen, cyano, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy and C1-C4-haloalkoxy.


Preferably, each Rc is independently selected from hydrogen, C1-C6-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy-C1-C4-alkyl, C1-C4-alkylcarbonyl, C1-C4-haloalkylcarbonyl, C1-C6-alkoxycarbonyl and C1-C6-haloalkoxycarbonyl, more preferably from hydrogen, C1-C6-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy-C1-C4-alkyl, C1-C6-alkoxycarbonyl and C1-C6-haloalkoxycarbonyl, even more preferably from hydrogen, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy-C1-C4-alkyl, C1-C6-alkoxycarbonyl and C1-C4-haloalkoxycarbonyl, and in particular from hydrogen, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy-C1-C4-alkyl and C1-C6-alkoxycarbonyl. Specifically, each Rc is independently selected from hydrogen and C1-C6-alkoxycarbonyl.


Preferably, all of X1, X2, X3 and X4 are CR1 or one of X1, X2, X3 and X4 is N and the others are CR1. More preferably, all of X1, X2, X3 and X4 are CR1. Even more preferably, X1, X2 and X4 are CH and X3 is CR1, wherein R1 has one of the above-given general or preferred definitions and is preferably H, COOH or CN. Specifically, X1, X2 and X4 are CH and X3 is CR1, wherein R1 is different from H and is preferably COOH or CN. In particular, X1, X2 and X4 are CH and X3 is CR1, wherein R1 is CN.


A particularly preferred embodiment of the invention relates to compounds of the formulae IA-1 and IB-1




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wherein R2, R3, R4, R5 and R6 have one of the general meanings or, in particular, one of the preferred meanings given above.


Compounds IA-1 and compounds IB-1 wherein R2 is H are tautomers and thus the formulae can be used interchangeably.


Suitable compounds IA and IB are those of formulae I.1 to I.144, the stereoisomers, prodrugs, tautomers and/or physiologically tolerated acid addition salts thereof, wherein R1, R2 and Rc have the above-defined general or preferred meanings and R81 is hydrogen or has one of the above-defined general or preferred meanings given for R8. Particularly preferred meanings of R1, R2, R81 and Rc specifically in compounds of formulae I.1 to I.144 are as defined below.




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Examples of preferred compounds which are represented by the formulae I.1 to I.144 are the individual compounds compiled in the tables 1 to 6192 below, where the variables R1 and R2 have the meanings given in one row of Table A. Moreover, the meanings mentioned for the individual variables in the tables are per se, independently of the combination in which they are mentioned, a particularly preferred embodiment of the substituents in question. Rings A-1 to A-111 mentioned in the tables are defined below.


Table 1


Compounds of the formula I.1 in which the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 2


Compounds of the formula I.2 in which the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 3


Compounds of the formula I.3 in which the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 4


Compounds of the formula I.4 in which the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 5


Compounds of the formula I.5 in which the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 6


Compounds of the formula I.6 in which the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 7


Compounds of the formula I.7 in which the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 8


Compounds of the formula I.8 in which the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 9


Compounds of the formula I.9 in which the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 10


Compounds of the formula I.10 in which the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 11


Compounds of the formula I.11 in which the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 12


Compounds of the formula I.12 in which the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 13


Compounds of the formula I.13 in which the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 14


Compounds of the formula I.14 in which the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 15


Compounds of the formula I.15 in which the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 16


Compounds of the formula I.16 in which the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 17


Compounds of the formula I.17 in which the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 18


Compounds of the formula I.18 in which the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 19


Compounds of the formula I.19 in which the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 20


Compounds of the formula I.20 in which the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 21


Compounds of the formula I.21 in which the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 22


Compounds of the formula I.22 in which the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 23


Compounds of the formula I.23 in which the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 24


Compounds of the formula I.24 in which the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 25


Compounds of the formula I.25 in which the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 26


Compounds of the formula I.26 in which the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 27


Compounds of the formula I.27 in which the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 28


Compounds of the formula I.28 in which the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 29


Compounds of the formula I.29 in which the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 30


Compounds of the formula I.30 in which the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 31


Compounds of the formula I.31 in which the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 32


Compounds of the formula I.32 in which the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 33


Compounds of the formula I.33 in which the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 34


Compounds of the formula I.34 in which the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 35


Compounds of the formula I.35 in which the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 36


Compounds of the formula I.36 in which the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 37


Compounds of the formula I.37 in which R81 is hydrogen and the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 38


Compounds of the formula I.37 in which R81 is methyl and the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 39


Compounds of the formula I.37 in which R81 is ethyl and the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 40


Compounds of the formula I.37 in which R81 is propyl and the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 41


Compounds of the formula I.37 in which R81 is isopropyl and the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 42


Compounds of the formula I.37 in which R81 is CH2F and the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 43


Compounds of the formula I.37 in which R81 is CHF2 and the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 44


Compounds of the formula I.37 in which R81 is CF3 and the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 45


Compounds of the formula I.37 in which R81 is CH2CHF2 and the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 46


Compounds of the formula I.37 in which R81 is CH2CF3 and the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 47


Compounds of the formula I.37 in which R81 is F and the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 48


Compounds of the formula I.37 in which R81 is Cl and the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 49


Compounds of the formula I.37 in which R81 is Br and the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 50


Compounds of the formula I.37 in which R81 is OH and the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 51


Compounds of the formula I.37 in which R81 is methoxy and the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 52


Compounds of the formula I.37 in which R81 is ethoxy and the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 53


Compounds of the formula I.37 in which R81 is propoxy and the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 54


Compounds of the formula I.37 in which R81 is isopropoxy and the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 55


Compounds of the formula I.37 in which R81 is OCHF2 and the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 56


Compounds of the formula I.37 in which R81 is OCF3 and the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 57


Compounds of the formula I.37 in which R81 is OCH2CHF2 and the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 58


Compounds of the formula I.37 in which R81 is OCH2CF3 and the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 59


Compounds of the formula I.37 in which R81 is NH2 and the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 60


Compounds of the formula I.37 in which R81 is methylamino and the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 61


Compounds of the formula I.37 in which R81 is dimethylamino and the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 62


Compounds of the formula I.37 in which R81 is ethylamino and the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 63


Compounds of the formula I.37 in which R81 is diethylamino and the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 64


Compounds of the formula I.37 in which R81 is propylamino and the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 65


Compounds of the formula I.37 in which R81 is dipropylamino and the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 66


Compounds of the formula I.37 in which R81 is NHC(O)CH3 and the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 67


Compounds of the formula I.37 in which R81 is NHC(O)CF3 and the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 68


Compounds of the formula I.37 in which R81 is NHC(O)OCH3 and the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 69


Compounds of the formula I.37 in which R81 is NHC(O)OCF3 and the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 70


Compounds of the formula I.37 in which R81 is NHC(O)OC(CH3)3 and the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 71


Compounds of the formula I.37 in which R81 is cyclopropyl and the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 72


Compounds of the formula I.37 in which R81 is cyclobutyl and the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 73


Compounds of the formula I.37 in which R81 is cyclopentyl and the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 74


Compounds of the formula I.37 in which R81 is cyclohexyl and the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 75


Compounds of the formula I.37 in which R81 is cycloheptyl and the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 76


Compounds of the formula I.37 in which R81 is A-1 and the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 77


Compounds of the formula I.37 in which R81 is A-2 and the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 78


Compounds of the formula I.37 in which R81 is A-3 and the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 79


Compounds of the formula I.37 in which R81 is A-4 and the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 80


Compounds of the formula I.37 in which R81 is A-5 and the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 81


Compounds of the formula I.37 in which R81 is A-6 and the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 82


Compounds of the formula I.37 in which R81 is A-7 and the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 83


Compounds of the formula I.37 in which R81 is A-8 and the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 84


Compounds of the formula I.37 in which R81 is A-9 and the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 85


Compounds of the formula I.37 in which R81 is A-10 and the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 86


Compounds of the formula I.37 in which R81 is A-11 and the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 87


Compounds of the formula I.37 in which R81 is A-12 and the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 88


Compounds of the formula I.37 in which R81 is A-13 and the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 89


Compounds of the formula I.37 in which R81 is A-14 and the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 90


Compounds of the formula I.37 in which R81 is A-15 and the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 91


Compounds of the formula I.37 in which R81 is A-16 and the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 92


Compounds of the formula I.37 in which R81 is A-17 and the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 93


Compounds of the formula I.37 in which R81 is A-18 and the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 94


Compounds of the formula I.37 in which R81 is A-19 and the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 95


Compounds of the formula I.37 in which R81 is A-20 and the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 96


Compounds of the formula I.37 in which R81 is A-21 and the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 97


Compounds of the formula I.37 in which R81 is A-22 and the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 98


Compounds of the formula I.37 in which R81 is A-23 and the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 99


Compounds of the formula I.37 in which R81 is A-24 and the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 100


Compounds of the formula I.37 in which R81 is A-25 and the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 101


Compounds of the formula I.37 in which R81 is A-26 and the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 102


Compounds of the formula I.37 in which R81 is A-27 and the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 103


Compounds of the formula I.37 in which R81 is A-28 and the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 104


Compounds of the formula I.37 in which R81 is A-29 and the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 105


Compounds of the formula I.37 in which R81 is A-30 and the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 106


Compounds of the formula I.37 in which R81 is A-31 and the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 107


Compounds of the formula I.37 in which R81 is A-32 and the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 108


Compounds of the formula I.37 in which R81 is A-33 and the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 109


Compounds of the formula I.37 in which R81 is A-34 and the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 110


Compounds of the formula I.37 in which R81 is A-35 and the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 111


Compounds of the formula I.37 in which R81 is A-36 and the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 112


Compounds of the formula I.37 in which R81 is A-37 and the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 113


Compounds of the formula I.37 in which R81 is A-38 and the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 114


Compounds of the formula I.37 in which R81 is A-39 and the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 115


Compounds of the formula I.37 in which R81 is A-40 and the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 116


Compounds of the formula I.37 in which R81 is A-41 and the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 117


Compounds of the formula I.37 in which R81 is A-42 and the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 118


Compounds of the formula I.37 in which R81 is A-43 and the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 119


Compounds of the formula I.37 in which R81 is A-44 and the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 120


Compounds of the formula I.37 in which R81 is A-45 and the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 121


Compounds of the formula I.37 in which R81 is A-46 and the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 122


Compounds of the formula I.37 in which R81 is A-47 and the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 123


Compounds of the formula I.37 in which R81 is A-48 and the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 124


Compounds of the formula I.37 in which R81 is A-49 and the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 125


Compounds of the formula I.37 in which R81 is A-50 and the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 126


Compounds of the formula I.37 in which R81 is A-51 and the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 127


Compounds of the formula I.37 in which R81 is A-52 and the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 128


Compounds of the formula I.37 in which R81 is A-53 and the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 129


Compounds of the formula I.37 in which R81 is A-54 and the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 130


Compounds of the formula I.37 in which R81 is A-55 and the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 131


Compounds of the formula I.37 in which R81 is A-56 and the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 132


Compounds of the formula I.37 in which R81 is A-57 and the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 133


Compounds of the formula I.37 in which R81 is A-58 and the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 134


Compounds of the formula I.37 in which R81 is A-59 and the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 135


Compounds of the formula I.37 in which R81 is A-60 and the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 136


Compounds of the formula I.37 in which R81 is A-61 and the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 137


Compounds of the formula I.37 in which R81 is A-62 and the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 138


Compounds of the formula I.37 in which R81 is A-63 and the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 139


Compounds of the formula I.37 in which R81 is A-64 and the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 140


Compounds of the formula I.37 in which R81 is A-65 and the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 141


Compounds of the formula I.37 in which R81 is A-66 and the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 142


Compounds of the formula I.37 in which R81 is A-67 and the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 143


Compounds of the formula I.37 in which R81 is A-68 and the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 144


Compounds of the formula I.37 in which R81 is A-69 and the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 145


Compounds of the formula I.37 in which R81 is A-70 and the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 146


Compounds of the formula I.37 in which R81 is A-71 and the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 147


Compounds of the formula I.37 in which R81 is A-72 and the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 148


Compounds of the formula I.37 in which R81 is A-73 and the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 149


Compounds of the formula I.37 in which R81 is A-74 and the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 150


Compounds of the formula I.37 in which R81 is A-75 and the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 151


Compounds of the formula I.37 in which R81 is A-76 and the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 152


Compounds of the formula I.37 in which R81 is A-77 and the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 153


Compounds of the formula I.37 in which R81 is A-78 and the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 154


Compounds of the formula I.37 in which R81 is A-79 and the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 155


Compounds of the formula I.37 in which R81 is A-80 and the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 156


Compounds of the formula I.37 in which R81 is A-81 and the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 157


Compounds of the formula I.37 in which R81 is A-82 and the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 158


Compounds of the formula I.37 in which R81 is A-83 and the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 159


Compounds of the formula I.37 in which R81 is A-84 and the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 160


Compounds of the formula I.37 in which R81 is A-85 and the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 161


Compounds of the formula I.37 in which R81 is A-86 and the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 162


Compounds of the formula I.37 in which R81 is A-87 and the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 163


Compounds of the formula I.37 in which R81 is A-88 and the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 164


Compounds of the formula I.37 in which R81 is A-89 and the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 165


Compounds of the formula I.37 in which R81 is A-90 and the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 166


Compounds of the formula I.37 in which R81 is A-91 and the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 167


Compounds of the formula I.37 in which R81 is A-92 and the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 168


Compounds of the formula I.37 in which R81 is A-93 and the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 169


Compounds of the formula I.37 in which R81 is A-94 and the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 170


Compounds of the formula I.37 in which R81 is A-95 and the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 171


Compounds of the formula I.37 in which R81 is A-96 and the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 172


Compounds of the formula I.37 in which R81 is A-97 and the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 173


Compounds of the formula I.37 in which R81 is A-98 and the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 174


Compounds of the formula I.37 in which R81 is A-99 and the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 175


Compounds of the formula I.37 in which R81 is A-100 and the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 176


Compounds of the formula I.37 in which R81 is A-101 and the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 177


Compounds of the formula I.37 in which R81 is A-102 and the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 178


Compounds of the formula I.37 in which R81 is A-103 and the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 179


Compounds of the formula I.37 in which R81 is A-104 and the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 180


Compounds of the formula I.37 in which R81 is A-105 and the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 181


Compounds of the formula I.37 in which R81 is A-106 and the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 182


Compounds of the formula I.37 in which R81 is A-107 and the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 183


Compounds of the formula I.37 in which R81 is A-108 and the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 184


Compounds of the formula I.37 in which R81 is A-109 and the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 185


Compounds of the formula I.37 in which R81 is A-110 and the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 186


Compounds of the formula I.37 in which R81 is A-111 and the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Tables 37 to 336


Compounds of the formula I.38 in which R81 is as defined in tables 37 to 186 and the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Tables 337 to 486


Compounds of the formula I.39 in which R81 is as defined in Tables 37 to 186 and the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Tables 487 to 636


Compounds of the formula I.40 in which R81 is as defined in Tables 37 to 186 and the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Tables 637 to 786


Compounds of the formula I.41 in which R81 is as defined in Tables 37 to 186 and the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Tables 787 to 936


Compounds of the formula I.42 in which R81 is as defined in Tables 37 to 186 and the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Tables 937 to 1086


Compounds of the formula I.43 in which R81 is as defined in Tables 37 to 186 and the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Tables 1087 to 1236


Compounds of the formula I.44 in which R81 is as defined in Tables 37 to 186 and the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Tables 1237 to 1386


Compounds of the formula I.45 in which R81 is as defined in Tables 37 to 186 and the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Tables 1387 to 1536


Compounds of the formula I.46 in which R81 is as defined in Tables 37 to 186 and the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Tables 1537 to 1686


Compounds of the formula I.47 in which R81 is as defined in Tables 37 to 186 and the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Tables 1687 to 1836


Compounds of the formula I.48 in which R81 is as defined in Tables 37 to 186 and the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Tables 1837 to 1986


Compounds of the formula I.49 in which R81 is as defined in Tables 37 to 186 and the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Tables 1987 to 2136


Compounds of the formula I.50 in which R81 is as defined in Tables 37 to 186 and the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Tables 2137 to 2286


Compounds of the formula I.51 in which R81 is as defined in Tables 37 to 186 and the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Tables 2287 to 2436


Compounds of the formula I.52 in which R81 is as defined in Tables 37 to 186 and the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Tables 2437 to 2586


Compounds of the formula I.53 in which R81 is as defined in Tables 37 to 186 and the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Tables 2587 to 2736


Compounds of the formula I.54 in which R81 is as defined in Tables 37 to 186 and the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Tables 2737 to 2886


Compounds of the formula I.55 in which R81 is as defined in Tables 37 to 186 and the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Tables 2887 to 3036


Compounds of the formula I.56 in which R81 is as defined in Tables 37 to 186 and the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Tables 3037 to 3186


Compounds of the formula I.57 in which R81 is as defined in Tables 37 to 186 and the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Tables 3187 to 3336


Compounds of the formula I.58 in which R81 is as defined in Tables 37 to 186 and the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Tables 3337 to 3486


Compounds of the formula I.59 in which R81 is as defined in Tables 37 to 186 and the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Tables 3487 to 3636


Compounds of the formula I.60 in which R81 is as defined in Tables 37 to 186 and the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Tables 3637 to 3786


Compounds of the formula I.61 in which R81 is as defined in Tables 37 to 186 and the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Tables 3787 to 3936


Compounds of the formula I.62 in which R81 is as defined in Tables 37 to 186 and the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Tables 3937 to 4086


Compounds of the formula I.63 in which R81 is as defined in Tables 37 to 186 and the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Tables 4087 to 4236


Compounds of the formula I.64 in which R81 is as defined in Tables 37 to 186 and the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Tables 4237 to 4386


Compounds of the formula I.65 in which R81 is as defined in Tables 37 to 186 and the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Tables 4387 to 4536


Compounds of the formula I.66 in which R81 is as defined in Tables 37 to 186 and the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Tables 4537 to 4686


Compounds of the formula I.67 in which R81 is as defined in Tables 37 to 186 and the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Tables 4687 to 4836


Compounds of the formula I.68 in which R81 is as defined in Tables 37 to 186 and the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Tables 4837 to 4986


Compounds of the formula I.69 in which R81 is as defined in Tables 37 to 186 and the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Tables 4987 to 5136


Compounds of the formula I.70 in which R81 is as defined in Tables 37 to 186 and the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Tables 5137 to 5286


Compounds of the formula I.71 in which R81 is as defined in Tables 37 to 186 and the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Tables 5287 to 5436


Compounds of the formula I.72 in which R81 is as defined in Tables 37 to 186 and the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 5437


Compounds of the formula I.73 in which the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 5438


Compounds of the formula I.74 in which the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 5439


Compounds of the formula I.75 in which the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 5440


Compounds of the formula I.76 in which the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 5441


Compounds of the formula I.77 in which the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 5442


Compounds of the formula I.78 in which the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 5443


Compounds of the formula I.79 in which the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 5444


Compounds of the formula I.80 in which the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 5445


Compounds of the formula I.81 in which the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 5446


Compounds of the formula I.82 in which the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 5447


Compounds of the formula I.83 in which the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 5448


Compounds of the formula I.84 in which the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 5449


Compounds of the formula I.85 in which the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 5450


Compounds of the formula I.86 in which the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 5451


Compounds of the formula I.87 in which the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 5452


Compounds of the formula I.88 in which the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 5453


Compounds of the formula I.89 in which the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 5454


Compounds of the formula I.90 in which the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 5455


Compounds of the formula I.91 in which the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 5456


Compounds of the formula I.92 in which the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 5457


Compounds of the formula I.93 in which the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 5458


Compounds of the formula I.94 in which the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 5459


Compounds of the formula I.95 in which the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 5460


Compounds of the formula I.96 in which the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 5461


Compounds of the formula I.97 in which the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 5462


Compounds of the formula I.98 in which the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 5463


Compounds of the formula I.99 in which the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 5464


Compounds of the formula I.100 in which the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 5465


Compounds of the formula I.101 in which the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 5466


Compounds of the formula I.102 in which the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 5467


Compounds of the formula I.103 in which the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 5468


Compounds of the formula I.104 in which the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 5469


Compounds of the formula I.105 in which the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 5470


Compounds of the formula I.106 in which the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 5471


Compounds of the formula I.107 in which the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 5472


Compounds of the formula I.108 in which the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 5473


Compounds of the formula I.109 in which Rc is hydrogen and the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 5474


Compounds of the formula I.109 in which Rc is methyl and the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 5475


Compounds of the formula I.109 in which Rc is ethyl and the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 5476


Compounds of the formula I.109 in which Rc is propyl and the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 5477


Compounds of the formula I.109 in which Rc is isopropyl and the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 5478


Compounds of the formula I.109 in which Rc is CH2OCH3 and the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 5479


Compounds of the formula I.109 in which Rc is CH2CH2OCH3 and the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 5480


Compounds of the formula I.109 in which Rc is CH2CH2OCH2CH3 and the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 5481


Compounds of the formula I.109 in which Rc is CHF2 and the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 5482


Compounds of the formula I.109 in which Rc is CF3 and the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 5483


Compounds of the formula I.109 in which Rc is CH2CHF2 and the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 5484


Compounds of the formula I.109 in which Rc is CH2CF3 and the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 5485


Compounds of the formula I.109 in which Rc is CF2CF3 and the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 5486


Compounds of the formula I.109 in which Rc is C(O)CH3 and the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 5487


Compounds of the formula I.109 in which Rc is C(O)OCH3 and the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 5488


Compounds of the formula I.109 in which Rc is C(O)OCF3 and the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 5489


Compounds of the formula I.109 in which Rc is C(O)OC(CH3)3 and the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 5490


Compounds of the formula I.109 in which Rc is C(O)NH2 and the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 5491


Compounds of the formula I.109 in which Rc is C(O)NHCH3 and the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Table 5492


Compounds of the formula I.109 in which Rc is C(O)N(CH3)2 and the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Tables 5493 to 5512


Compounds of the formula I.110 in which Rc is as defined in Tables 5472 to 5492 and the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Tables 5513 to 5532


Compounds of the formula I.111 in which Rc is as defined in Tables 5472 to 5492 and the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Tables 5533 to 5552


Compounds of the formula I.112 in which Rc is as defined in Tables 5472 to 5492 and the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Tables 5553 to 5572


Compounds of the formula I.113 in which Rc is as defined in Tables 5472 to 5492 and the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Tables 5573 to 5592


Compounds of the formula I.114 in which Rc is as defined in Tables 5472 to 5492 and the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Tables 5593 to 5612


Compounds of the formula I.115 in which Rc is as defined in Tables 5472 to 5492 and the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Tables 5613 to 5632


Compounds of the formula I.116 in which Rc is as defined in Tables 5472 to 5492 and the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Tables 5633 to 5652


Compounds of the formula I.117 in which Rc is as defined in Tables 5472 to 5492 and the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Tables 5653 to 5672


Compounds of the formula I.118 in which Rc is as defined in Tables 5472 to 5492 and the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Tables 5673 to 5692


Compounds of the formula I.119 in which Rc is as defined in Tables 5472 to 5492 and the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Tables 5693 to 5712


Compounds of the formula I.120 in which Rc is as defined in Tables 5472 to 5492 and the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Tables 5713 to 5732


Compounds of the formula I.121 in which Rc is as defined in Tables 5472 to 5492 and the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Tables 5733 to 5752


Compounds of the formula I.122 in which Rc is as defined in Tables 5472 to 5492 and the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Tables 5753 to 5772


Compounds of the formula I.123 in which Rc is as defined in Tables 5472 to 5492 and the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Tables 5773 to 5792


Compounds of the formula I.124 in which Rc is as defined in Tables 5472 to 5492 and the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Tables 5793 to 5812


Compounds of the formula I.125 in which Rc is as defined in Tables 5472 to 5492 and the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Tables 5813 to 5832


Compounds of the formula I.126 in which Rc is as defined in Tables 5472 to 5492 and the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Tables 5833 to 5852


Compounds of the formula I.127 in which Rc is as defined in Tables 5472 to 5492 and the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Tables 5853 to 5872


Compounds of the formula I.128 in which Rc is as defined in Tables 5472 to 5492 and the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Tables 5873 to 5892


Compounds of the formula I.129 in which Rc is as defined in Tables 5472 to 5492 and the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Tables 5893 to 5912


Compounds of the formula I.130 in which Rc is as defined in Tables 5472 to 5492 and the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Tables 5913 to 5932


Compounds of the formula I.131 in which Rc is as defined in Tables 5472 to 5492 and the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Tables 5933 to 5952


Compounds of the formula I.132 in which Rc is as defined in Tables 5472 to 5492 and the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Tables 5953 to 5972


Compounds of the formula I.133 in which Rc is as defined in Tables 5472 to 5492 and the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Tables 5973 to 5992


Compounds of the formula I.134 in which Rc is as defined in Tables 5472 to 5492 and the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Tables 5993 to 6012


Compounds of the formula I.135 in which Rc is as defined in Tables 5472 to 5492 and the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Tables 6013 to 6032


Compounds of the formula I.136 in which Rc is as defined in Tables 5472 to 5492 and the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Tables 6033 to 6052


Compounds of the formula I.137 in which Rc is as defined in Tables 5472 to 5492 and the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Tables 6053 to 6072


Compounds of the formula I.138 in which Rc is as defined in Tables 5472 to 5492 and the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Tables 6073 to 6092


Compounds of the formula I.139 in which Rc is as defined in Tables 5472 to 5492 and the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Tables 6093 to 6112


Compounds of the formula I.140 in which Rc is as defined in Tables 5472 to 5492 and the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Tables 6113 to 6132


Compounds of the formula I.141 in which Rc is as defined in Tables 5472 to 5492 and the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Tables 6133 to 6152


Compounds of the formula I.142 in which Rc is as defined in Tables 5472 to 5492 and the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Tables 6153 to 6172


Compounds of the formula I.143 in which Rc is as defined in Tables 5472 to 5492 and the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Tables 6173 to 6192


Compounds of the formula I.144 in which Rc is as defined in Tables 5472 to 5492 and the combination of R1 and R2 for a compound corresponds in each case to one row of Table A.


Rings A


“#” marks the attachment point to the remainder of the molecule




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In Table A, the position of R1 is characterized as follows:









TABLE A









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No.
R2
R1







A-1
H
H



A-2
H
4-Cl



A-3
H
5-Cl



A-4
H
6-Cl



A-5
H
7-Cl



A-6
H
4-Br



A-7
H
5-Br



A-8
H
6-Br



A-9
H
7-Br



A-10
H
4-CN



A-11
H
5-CN



A-12
H
6-CN



A-13
H
7-CN



A-14
H
4-OH



A-15
H
5-OH



A-16
H
6-OH



A-17
H
7-OH



A-18
H
4-methyl



A-19
H
5-methyl



A-20
H
6-methyl



A-21
H
7-methyl



A-22
H
4-ethyl



A-23
H
5-ethyl



A-24
H
6-ethyl



A-25
H
7-ethyl



A-26
H
4-propyl



A-27
H
5-propyl



A-28
H
6-propyl



A-29
H
7-propyl



A-30
H
4-isopropyl



A-31
H
5-isopropyl



A-32
H
6-isopropyl



A-33
H
7-isopropyl



A-34
H
4-hydroxymethyl



A-35
H
5-hydroxymethyl



A-36
H
6-hydroxymethyl



A-37
H
7-hydroxymethyl



A-38
H
4-(2-hydroxyethyl)



A-39
H
5-(2-hydroxyethyl)



A-40
H
6-(2-hydroxyethyl)



A-41
H
7-(2-hydroxyethyl)



A-42
H
4-(1-hydroxyethyl)



A-43
H
5-(1-hydroxyethyl)



A-44
H
6-(1-hydroxyethyl)



A-45
H
7-(1-hydroxyethyl)



A-46
H
4-(3-hydroxypropyl)



A-47
H
5-(3-hydroxypropyl)



A-48
H
6-(3-hydroxypropyl)



A-49
H
7-(3-hydroxypropyl)



A-50
H
4-(2-hydroxypropyl)



A-51
H
5-(2-hydroxypropyl)



A-52
H
6-(2-hydroxypropyl)



A-53
H
7-(2-hydroxypropyl)



A-54
H
4-(1-hydroxypropyl)



A-55
H
5-(1-hydroxypropyl)



A-56
H
6-(1-hydroxypropyl)



A-57
H
7-(1-hydroxypropyl)



A-58
H
4-aminomethyl



A-59
H
5-aminomethyl



A-60
H
6-aminomethyl



A-61
H
7-aminomethyl



A-62
H
4-(2-aminoethyl)



A-63
H
5-(2-aminoethyl)



A-64
H
6-(2-aminoethyl)



A-65
H
7-(2-aminoethyl)



A-66
H
4-(1-aminoethyl)



A-67
H
5-(1-aminoethyl)



A-68
H
6-(1-aminoethyl)



A-69
H
7-(1-aminoethyl)



A-70
H
4-(3-aminopropyl)



A-71
H
5-(3-aminopropyl)



A-72
H
6-(3-aminopropyl)



A-73
H
7-(3-aminopropyl)



A-74
H
4-(2-aminopropyl)



A-75
H
5-(2-aminopropyl)



A-76
H
6-(2-aminopropyl)



A-77
H
7-(2-aminopropyl)



A-78
H
4-(1-aminopropyl)



A-79
H
5-(1-aminopropyl)



A-80
H
6-(1-aminopropyl)



A-81
H
7-(1-aminopropyl)



A-82
H
4-COOH



A-83
H
5-COOH



A-84
H
6-COOH



A-85
H
7-COOH



A-86
H
4-COOCH3



A-87
H
5-COOCH3



A-88
H
6-COOCH3



A-89
H
7-COOCH3



A-90
H
4-COOCH2CH3



A-91
H
5-COOCH2CH3



A-92
H
6-COOCH2CH3



A-93
H
7-COOCH2CH3



A-94
H
4-COOCF3



A-95
H
5-COOCF3



A-96
H
6-COOCF3



A-97
H
7-COOCF3



A-98
H
4-CONH2



A-99
H
5-CONH2



A-100
H
6-CONH2



A-101
H
7-CONH2



A-102
H
4-CONHCH3



A-103
H
5-CONHCH3



A-104
H
6-CONHCH3



A-105
H
7-CONHCH3



A-106
H
4-CON(CH3)2



A-107
H
5-CON(CH3)2



A-108
H
6-CON(CH3)2



A-109
H
7-CON(CH3)2



A-110
H
4-CONHCH2CH3



A-111
H
5-CONHCH2CH3



A-112
H
6-CONHCH2CH3



A-113
H
7-CONHCH2CH3



A-114
H
4-CON(CH2CH3)2



A-115
H
5-CON(CH2CH3)2



A-116
H
6-CON(CH2CH3)2



A-117
H
7-CON(CH2CH3)2



A-118
H
4-A-1



A-119
H
5-A-1



A-120
H
6-A-1



A-121
H
7-A-1



A-122
H
4-A-2



A-123
H
5-A-2



A-124
H
6-A-2



A-125
H
7-A-2



A-126
H
4-A-3



A-127
H
5-A-3



A-128
H
6-A-3



A-129
H
7-A-3



A-130
H
4-A-4



A-131
H
5-A-4



A-132
H
6-A-4



A-133
H
7-A-4



A-134
H
4-A-5



A-135
H
5-A-5



A-136
H
6-A-5



A-137
H
7-A-5



A-138
H
4-A-6



A-139
H
5-A-6



A-140
H
6-A-6



A-141
H
7-A-6



A-142
H
4-A-7



A-143
H
5-A-7



A-144
H
6-A-7



A-145
H
7-A-7



A-146
H
4-A-8



A-147
H
5-A-8



A-148
H
6-A-8



A-149
H
7-A-8



A-150
H
4-A-9



A-151
H
5-A-9



A-152
H
6-A-9



A-153
H
7-A-9



A-154
H
4-A-10



A-155
H
5-A-10



A-156
H
6-A-10



A-157
H
7-A-10



A-158
H
4-A-11



A-159
H
5-A-11



A-160
H
6-A-11



A-161
H
7-A-11



A-162
H
4-A-12



A-163
H
5-A-12



A-164
H
6-A-12



A-165
H
7-A-12



A-166
H
4-A-13



A-167
H
5-A-13



A-168
H
6-A-13



A-169
H
7-A-13



A-170
H
4-A-14



A-171
H
5-A-14



A-172
H
6-A-14



A-173
H
7-A-14



A-174
H
4-A-15



A-175
H
5-A-15



A-176
H
6-A-15



A-177
H
7-A-15



A-178
H
4-A-16



A-179
H
5-A-16



A-180
H
6-A-16



A-181
H
7-A-16



A-182
H
4-A-17



A-183
H
5-A-17



A-184
H
6-A-17



A-185
H
7-A-17



A-186
H
4-A-18



A-187
H
5-A-18



A-188
H
6-A-18



A-189
H
7-A-18



A-190
H
4-A-19



A-191
H
5-A-19



A-192
H
6-A-19



A-193
H
7-A-19



A-194
H
4-A-20



A-195
H
5-A-20



A-196
H
6-A-20



A-197
H
7-A-20



A-198
H
4-A-21



A-199
H
5-A-21



A-200
H
6-A-21



A-201
H
7-A-21



A-202
H
4-A-22



A-203
H
5-A-22



A-204
H
6-A-22



A-205
H
7-A-22



A-206
H
4-A-23



A-207
H
5-A-23



A-208
H
6-A-23



A-209
H
7-A-23



A-210
H
4-A-24



A-211
H
5-A-24



A-212
H
6-A-24



A-213
H
7-A-24



A-214
H
4-A-25



A-215
H
5-A-25



A-216
H
6-A-25



A-217
H
7-A-25



A-218
H
4-A-26



A-219
H
5-A-26



A-220
H
6-A-26



A-221
H
7-A-26



A-222
H
4-A-27



A-223
H
5-A-27



A-224
H
6-A-27



A-225
H
7-A-27



A-226
H
4-A-28



A-227
H
5-A-28



A-228
H
6-A-28



A-229
H
7-A-28



A-230
H
4-A-29



A-231
H
5-A-29



A-232
H
6-A-29



A-233
H
7-A-29



A-234
H
4-A-30



A-235
H
5-A-30



A-236
H
6-A-30



A-237
H
7-A-30



A-238
H
4-A-31



A-239
H
5-A-31



A-240
H
6-A-31



A-241
H
7-A-31



A-242
H
4-A-32



A-243
H
5-A-32



A-244
H
6-A-32



A-245
H
7-A-32



A-246
H
4-A-33



A-247
H
5-A-33



A-248
H
6-A-33



A-249
H
7-A-33



A-250
H
4-A-34



A-251
H
5-A-34



A-252
H
6-A-34



A-253
H
7-A-34



A-254
H
4-A-35



A-255
H
5-A-35



A-256
H
6-A-35



A-257
H
7-A-35



A-258
H
4-A-36



A-259
H
5-A-36



A-260
H
6-A-36



A-261
H
7-A-36



A-262
H
4-A-37



A-263
H
5-A-37



A-264
H
6-A-37



A-265
H
7-A-37



A-266
H
4-A-38



A-267
H
5-A-38



A-268
H
6-A-38



A-269
H
7-A-38



A-270
H
4-A-39



A-271
H
5-A-39



A-272
H
6-A-39



A-273
H
7-A-39



A-274
H
4-A-40



A-275
H
5-A-40



A-276
H
6-A-40



A-277
H
7-A-40



A-278
H
4-A-41



A-279
H
5-A-41



A-280
H
6-A-41



A-281
H
7-A-41



A-282
H
4-A-42



A-283
H
5-A-42



A-284
H
6-A-42



A-285
H
7-A-42



A-286
H
4-A-43



A-287
H
5-A-43



A-288
H
6-A-43



A-289
H
7-A-43



A-290
H
4-A-44



A-291
H
5-A-44



A-292
H
6-A-44



A-293
H
7-A-44



A-294
H
4-A-45



A-295
H
5-A-45



A-296
H
6-A-45



A-297
H
7-A-45



A-298
H
4-A-46



A-299
H
5-A-46



A-300
H
6-A-46



A-301
H
7-A-46



A-302
H
4-A-47



A-303
H
5-A-47



A-304
H
6-A-47



A-305
H
7-A-47



A-306
H
4-A-48



A-307
H
5-A-48



A-308
H
6-A-48



A-309
H
7-A-48



A-310
H
4-A-49



A-311
H
5-A-49



A-312
H
6-A-49



A-313
H
7-A-49



A-314
H
4-A-50



A-315
H
5-A-50



A-316
H
6-A-50



A-317
H
7-A-50



A-318
H
4-A-51



A-319
H
5-A-51



A-320
H
6-A-51



A-321
H
7-A-51



A-322
H
4-A-52



A-323
H
5-A-52



A-324
H
6-A-52



A-325
H
7-A-52



A-326
H
4-A-53



A-327
H
5-A-53



A-328
H
6-A-53



A-329
H
7-A-53



A-330
H
4-A-54



A-331
H
5-A-54



A-332
H
6-A-54



A-333
H
7-A-54



A-334
H
4-A-55



A-335
H
5-A-55



A-336
H
6-A-55



A-337
H
7-A-55



A-338
H
4-A-56



A-339
H
5-A-56



A-340
H
6-A-56



A-341
H
7-A-56



A-342
H
4-A-57



A-343
H
5-A-57



A-344
H
6-A-57



A-345
H
7-A-57



A-346
H
4-A-58



A-347
H
5-A-58



A-348
H
6-A-58



A-349
H
7-A-58



A-350
H
4-A-59



A-351
H
5-A-59



A-352
H
6-A-59



A-353
H
7-A-59



A-354
H
4-A-60



A-355
H
5-A-60



A-356
H
6-A-60



A-357
H
7-A-60



A-358
H
4-A-61



A-359
H
5-A-61



A-360
H
6-A-61



A-361
H
7-A-61



A-362
H
4-A-62



A-363
H
5-A-62



A-364
H
6-A-62



A-365
H
7-A-62



A-366
H
4-A-63



A-367
H
5-A-63



A-368
H
6-A-63



A-369
H
7-A-63



A-370
H
4-A-64



A-371
H
5-A-64



A-372
H
6-A-64



A-373
H
7-A-64



A-374
H
4-A-65



A-375
H
5-A-65



A-376
H
6-A-65



A-377
H
7-A-65



A-378
H
4-A-66



A-379
H
5-A-66



A-380
H
6-A-66



A-381
H
7-A-66



A-382
H
4-A-67



A-383
H
5-A-67



A-384
H
6-A-67



A-385
H
7-A-67



A-386
H
4-A-68



A-387
H
5-A-68



A-388
H
6-A-68



A-389
H
7-A-68



A-390
H
4-A-69



A-391
H
5-A-69



A-392
H
6-A-69



A-393
H
7-A-69



A-394
H
4-A-70



A-395
H
5-A-70



A-396
H
6-A-70



A-397
H
7-A-70



A-398
H
4-A-71



A-399
H
5-A-71



A-400
H
6-A-71



A-401
H
7-A-71



A-402
H
4-A-72



A-403
H
5-A-72



A-404
H
6-A-72



A-405
H
7-A-72



A-406
H
4-A-73



A-407
H
5-A-73



A-408
H
6-A-73



A-409
H
7-A-73



A-410
H
4-A-74



A-411
H
5-A-74



A-412
H
6-A-74



A-413
H
7-A-74



A-414
H
4-A-75



A-415
H
5-A-75



A-416
H
6-A-75



A-417
H
7-A-75



A-418
H
4-A-76



A-419
H
5-A-76



A-420
H
6-A-76



A-421
H
7-A-76



A-422
H
4-A-77



A-423
H
5-A-77



A-424
H
6-A-77



A-425
H
7-A-77



A-426
H
4-A-78



A-427
H
5-A-78



A-428
H
6-A-78



A-429
H
7-A-78



A-430
H
4-A-79



A-431
H
5-A-79



A-432
H
6-A-79



A-433
H
7-A-79



A-434
H
4-A-80



A-435
H
5-A-80



A-436
H
6-A-80



A-437
H
7-A-80



A-438
H
4-A-81



A-439
H
5-A-81



A-440
H
6-A-81



A-441
H
7-A-81



A-442
H
4-A-82



A-443
H
5-A-82



A-444
H
6-A-82



A-445
H
7-A-82



A-446
H
4-A-83



A-447
H
5-A-83



A-448
H
6-A-83



A-449
H
7-A-83



A-450
H
4-A-84



A-451
H
5-A-84



A-452
H
6-A-84



A-453
H
7-A-84



A-454
H
4-A-85



A-455
H
5-A-85



A-456
H
6-A-85



A-457
H
7-A-85



A-458
H
4-A-86



A-459
H
5-A-86



A-460
H
6-A-86



A-461
H
7-A-86



A-462
H
4-A-87



A-463
H
5-A-87



A-464
H
6-A-87



A-465
H
7-A-87



A-466
H
4-A-88



A-467
H
5-A-88



A-468
H
6-A-88



A-469
H
7-A-88



A-470
H
4-A-89



A-471
H
5-A-89



A-472
H
6-A-89



A-473
H
7-A-89



A-474
H
4-A-90



A-475
H
5-A-90



A-476
H
6-A-90



A-477
H
7-A-90



A-478
H
4-A-91



A-479
H
5-A-91



A-480
H
6-A-91



A-481
H
7-A-91



A-482
H
4-A-92



A-483
H
5-A-92



A-484
H
6-A-92



A-485
H
7-A-92



A-486
H
4-A-93



A-487
H
5-A-93



A-488
H
6-A-93



A-489
H
7-A-93



A-490
H
4-A-94



A-491
H
5-A-94



A-492
H
6-A-94



A-493
H
7-A-94



A-494
H
4-A-95



A-495
H
5-A-95



A-496
H
6-A-95



A-497
H
7-A-95



A-498
H
4-A-96



A-499
H
5-A-96



A-500
H
6-A-96



A-501
H
7-A-96



A-502
H
4-A-97



A-503
H
5-A-97



A-504
H
6-A-97



A-505
H
7-A-97



A-506
H
4-A-98



A-507
H
5-A-98



A-508
H
6-A-98



A-509
H
7-A-98



A-510
H
4-A-99



A-511
H
5-A-99



A-512
H
6-A-99



A-513
H
7-A-99



A-514
H
4-A-100



A-515
H
5-A-100



A-516
H
6-A-100



A-517
H
7-A-100



A-518
H
4-A-101



A-519
H
5-A-101



A-520
H
6-A-101



A-521
H
7-A-101



A-522
H
4-A-102



A-523
H
5-A-102



A-524
H
6-A-102



A-525
H
7-A-102



A-526
H
4-A-103



A-527
H
5-A-103



A-528
H
6-A-103



A-529
H
7-A-103



A-530
H
4-A-104



A-531
H
5-A-104



A-532
H
6-A-104



A-533
H
7-A-104



A-534
H
4-A-104



A-535
H
5-A-104



A-536
H
6-A-104



A-537
H
7-A-104



A-538
H
4-A-105



A-539
H
5-A-105



A-540
H
6-A-105



A-541
H
7-A-105



A-542
H
4-A-106



A-543
H
5-A-106



A-544
H
6-A-106



A-545
H
7-A-106



A-546
H
4-A-107



A-547
H
5-A-107



A-548
H
6-A-107



A-549
H
7-A-107



A-550
H
4-A-108



A-551
H
5-A-108



A-552
H
6-A-108



A-553
H
7-A-108



A-554
H
4-A-109



A-555
H
5-A-109



A-556
H
6-A-109



A-557
H
7-A-109



A-558
H
4-A-110



A-559
H
5-A-110



A-560
H
6-A-110



A-561
H
7-A-110



A-562
H
4-A-111



A-563
H
5-A-111



A-564
H
6-A-111



A-565
H
7-A-111



A-566
F
H



A-567
F
4-Cl



A-568
F
5-Cl



A-569
F
6-Cl



A-570
F
7-Cl



A-571
F
4-Br



A-572
F
5-Br



A-573
F
6-Br



A-574
F
7-Br



A-575
F
4-CN



A-576
F
5-CN



A-577
F
6-CN



A-578
F
7-CN



A-579
F
4-OH



A-580
F
5-OH



A-581
F
6-OH



A-582
F
7-OH



A-583
F
4-methyl



A-584
F
5-methyl



A-585
F
6-methyl



A-586
F
7-methyl



A-587
F
4-ethyl



A-588
F
5-ethyl



A-589
F
6-ethyl



A-590
F
7-ethyl



A-591
F
4-propyl



A-592
F
5-propyl



A-593
F
6-propyl



A-594
F
7-propyl



A-595
F
4-isopropyl



A-596
F
5-isopropyl



A-597
F
6-isopropyl



A-598
F
7-isopropyl



A-599
F
4-hydroxymethyl



A-600
F
5-hydroxymethyl



A-601
F
6-hydroxymethyl



A-602
F
7-hydroxymethyl



A-603
F
4-(2-hydroxyethyl)



A-604
F
5-(2-hydroxyethyl)



A-605
F
6-(2-hydroxyethyl)



A-606
F
7-(2-hydroxyethyl)



A-607
F
4-(1-hydroxyethyl)



A-608
F
5-(1-hydroxyethyl)



A-609
F
6-(1-hydroxyethyl)



A-610
F
7-(1-hydroxyethyl)



A-611
F
4-(3-hydroxypropyl)



A-612
F
5-(3-hydroxypropyl)



A-613
F
6-(3-hydroxypropyl)



A-614
F
7-(3-hydroxypropyl)



A-615
F
4-(2-hydroxypropyl)



A-616
F
5-(2-hydroxypropyl)



A-617
F
6-(2-hydroxypropyl)



A-618
F
7-(2-hydroxypropyl)



A-619
F
4-(1-hydroxypropyl)



A-620
F
5-(1-hydroxypropyl)



A-621
F
6-(1-hydroxypropyl)



A-622
F
7-(1-hydroxypropyl)



A-623
F
4-aminomethyl



A-624
F
5-aminomethyl



A-625
F
6-aminomethyl



A-626
F
7-aminomethyl



A-627
F
4-(2-aminoethyl)



A-628
F
5-(2-aminoethyl)



A-629
F
6-(2-aminoethyl)



A-630
F
7-(2-aminoethyl)



A-631
F
4-(1-aminoethyl)



A-632
F
5-(1-aminoethyl)



A-633
F
6-(1-aminoethyl)



A-634
F
7-(1-aminoethyl)



A-635
F
4-(3-aminopropyl)



A-636
F
5-(3-aminopropyl)



A-637
F
6-(3-aminopropyl)



A-638
F
7-(3-aminopropyl)



A-639
F
4-(2-aminopropyl)



A-640
F
5-(2-aminopropyl)



A-641
F
6-(2-aminopropyl)



A-642
F
7-(2-aminopropyl)



A-643
F
4-(1-aminopropyl)



A-644
F
5-(1-aminopropyl)



A-645
F
6-(1-aminopropyl)



A-646
F
7-(1-aminopropyl)



A-647
F
4-COOH



A-648
F
5-COOH



A-649
F
6-COOH



A-650
F
7-COOH



A-651
F
4-COOCH3



A-652
F
5-COOCH3



A-653
F
6-COOCH3



A-654
F
7-COOCH3



A-655
F
4-COOCH2CH3



A-656
F
5-COOCH2CH3



A-657
F
6-COOCH2CH3



A-658
F
7-COOCH2CH3



A-659
F
4-COOCF3



A-660
F
5-COOCF3



A-661
F
6-COOCF3



A-662
F
7-COOCF3



A-663
F
4-CONH2



A-664
F
5-CONH2



A-665
F
6-CONH2



A-666
F
7-CONH2



A-667
F
4-CONHCH3



A-668
F
5-CONHCH3



A-669
F
6-CONHCH3



A-670
F
7-CONHCH3



A-671
F
4-CON(CH3)2



A-672
F
5-CON(CH3)2



A-673
F
6-CON(CH3)2



A-674
F
7-CON(CH3)2



A-675
F
4-CONHCH2CH3



A-676
F
5-CONHCH2CH3



A-677
F
6-CONHCH2CH3



A-678
F
7-CONHCH2CH3



A-679
F
4-CON(CH2CH3)2



A-680
F
5-CON(CH2CH3)2



A-681
F
6-CON(CH2CH3)2



A-682
F
7-CON(CH2CH3)2



A-683
F
4-A-1



A-684
F
5-A-1



A-685
F
6-A-1



A-686
F
7-A-1



A-687
F
4-A-2



A-688
F
5-A-2



A-689
F
6-A-2



A-690
F
7-A-2



A-691
F
4-A-3



A-692
F
5-A-3



A-693
F
6-A-3



A-694
F
7-A-3



A-695
F
4-A-4



A-696
F
5-A-4



A-697
F
6-A-4



A-698
F
7-A-4



A-699
F
4-A-5



A-700
F
5-A-5



A-701
F
6-A-5



A-702
F
7-A-5



A-703
F
4-A-6



A-704
F
5-A-6



A-705
F
6-A-6



A-706
F
7-A-6



A-707
F
4-A-7



A-708
F
5-A-7



A-709
F
6-A-7



A-710
F
7-A-7



A-711
F
4-A-8



A-712
F
5-A-8



A-713
F
6-A-8



A-714
F
7-A-8



A-715
F
4-A-9



A-716
F
5-A-9



A-717
F
6-A-9



A-718
F
7-A-9



A-719
F
4-A-10



A-720
F
5-A-10



A-721
F
6-A-10



A-722
F
7-A-10



A-723
F
4-A-11



A-724
F
5-A-11



A-725
F
6-A-11



A-726
F
7-A-11



A-727
F
4-A-12



A-728
F
5-A-12



A-729
F
6-A-12



A-730
F
7-A-12



A-731
F
4-A-13



A-732
F
5-A-13



A-733
F
6-A-13



A-734
F
7-A-13



A-735
F
4-A-14



A-736
F
5-A-14



A-737
F
6-A-14



A-738
F
7-A-14



A-739
F
4-A-15



A-740
F
5-A-15



A-741
F
6-A-15



A-742
F
7-A-15



A-743
F
4-A-16



A-744
F
5-A-16



A-745
F
6-A-16



A-746
F
7-A-16



A-747
F
4-A-17



A-748
F
5-A-17



A-749
F
6-A-17



A-750
F
7-A-17



A-751
F
4-A-18



A-752
F
5-A-18



A-753
F
6-A-18



A-754
F
7-A-18



A-755
F
4-A-19



A-756
F
5-A-19



A-757
F
6-A-19



A-758
F
7-A-19



A-759
F
4-A-20



A-760
F
5-A-20



A-761
F
6-A-20



A-762
F
7-A-20



A-763
F
4-A-21



A-764
F
5-A-21



A-765
F
6-A-21



A-766
F
7-A-21



A-767
F
4-A-22



A-768
F
5-A-22



A-769
F
6-A-22



A-770
F
7-A-22



A-771
F
4-A-23



A-772
F
5-A-23



A-773
F
6-A-23



A-774
F
7-A-23



A-775
F
4-A-24



A-776
F
5-A-24



A-777
F
6-A-24



A-778
F
7-A-24



A-779
F
4-A-25



A-780
F
5-A-25



A-781
F
6-A-25



A-782
F
7-A-25



A-783
F
4-A-26



A-784
F
5-A-26



A-785
F
6-A-26



A-786
F
7-A-26



A-787
F
4-A-27



A-788
F
5-A-27



A-789
F
6-A-27



A-790
F
7-A-27



A-791
F
4-A-28



A-792
F
5-A-28



A-793
F
6-A-28



A-794
F
7-A-28



A-795
F
4-A-29



A-796
F
5-A-29



A-797
F
6-A-29



A-798
F
7-A-29



A-799
F
4-A-30



A-800
F
5-A-30



A-801
F
6-A-30



A-802
F
7-A-30



A-803
F
4-A-31



A-804
F
5-A-31



A-805
F
6-A-31



A-806
F
7-A-31



A-807
F
4-A-32



A-808
F
5-A-32



A-809
F
6-A-32



A-810
F
7-A-32



A-811
F
4-A-33



A-812
F
5-A-33



A-813
F
6-A-33



A-814
F
7-A-33



A-815
F
4-A-34



A-816
F
5-A-34



A-817
F
6-A-34



A-818
F
7-A-34



A-819
F
4-A-35



A-820
F
5-A-35



A-821
F
6-A-35



A-822
F
7-A-35



A-823
F
4-A-36



A-824
F
5-A-36



A-825
F
6-A-36



A-826
F
7-A-36



A-827
F
4-A-37



A-828
F
5-A-37



A-829
F
6-A-37



A-830
F
7-A-37



A-831
F
4-A-38



A-832
F
5-A-38



A-833
F
6-A-38



A-834
F
7-A-38



A-835
F
4-A-39



A-836
F
5-A-39



A-837
F
6-A-39



A-838
F
7-A-39



A-839
F
4-A-40



A-840
F
5-A-40



A-841
F
6-A-40



A-842
F
7-A-40



A-843
F
4-A-41



A-844
F
5-A-41



A-845
F
6-A-41



A-846
F
7-A-41



A-847
F
4-A-42



A-848
F
5-A-42



A-849
F
6-A-42



A-850
F
7-A-42



A-851
F
4-A-43



A-852
F
5-A-43



A-853
F
6-A-43



A-854
F
7-A-43



A-855
F
4-A-44



A-856
F
5-A-44



A-857
F
6-A-44



A-858
F
7-A-44



A-859
F
4-A-45



A-860
F
5-A-45



A-861
F
6-A-45



A-862
F
7-A-45



A-863
F
4-A-46



A-864
F
5-A-46



A-865
F
6-A-46



A-866
F
7-A-46



A-867
F
4-A-47



A-868
F
5-A-47



A-869
F
6-A-47



A-870
F
7-A-47



A-871
F
4-A-48



A-872
F
5-A-48



A-873
F
6-A-48



A-874
F
7-A-48



A-875
F
4-A-49



A-876
F
5-A-49



A-877
F
6-A-49



A-878
F
7-A-49



A-879
F
4-A-50



A-880
F
5-A-50



A-881
F
6-A-50



A-882
F
7-A-50



A-883
F
4-A-51



A-884
F
5-A-51



A-885
F
6-A-51



A-886
F
7-A-51



A-887
F
4-A-52



A-888
F
5-A-52



A-889
F
6-A-52



A-890
F
7-A-52



A-891
F
4-A-53



A-892
F
5-A-53



A-893
F
6-A-53



A-894
F
7-A-53



A-895
F
4-A-54



A-896
F
5-A-54



A-897
F
6-A-54



A-898
F
7-A-54



A-899
F
4-A-55



A-900
F
5-A-55



A-901
F
6-A-55



A-902
F
7-A-55



A-903
F
4-A-56



A-904
F
5-A-56



A-905
F
6-A-56



A-906
F
7-A-56



A-907
F
4-A-57



A-908
F
5-A-57



A-909
F
6-A-57



A-910
F
7-A-57



A-911
F
4-A-58



A-912
F
5-A-58



A-913
F
6-A-58



A-914
F
7-A-58



A-915
F
4-A-59



A-916
F
5-A-59



A-917
F
6-A-59



A-918
F
7-A-59



A-919
F
4-A-60



A-920
F
5-A-60



A-921
F
6-A-60



A-922
F
7-A-60



A-923
F
4-A-61



A-924
F
5-A-61



A-925
F
6-A-61



A-926
F
7-A-61



A-927
F
4-A-62



A-928
F
5-A-62



A-929
F
6-A-62



A-930
F
7-A-62



A-931
F
4-A-63



A-932
F
5-A-63



A-933
F
6-A-63



A-934
F
7-A-63



A-935
F
4-A-64



A-936
F
5-A-64



A-937
F
6-A-64



A-938
F
7-A-64



A-939
F
4-A-65



A-940
F
5-A-65



A-941
F
6-A-65



A-942
F
7-A-65



A-943
F
4-A-66



A-944
F
5-A-66



A-945
F
6-A-66



A-946
F
7-A-66



A-947
F
4-A-67



A-948
F
5-A-67



A-949
F
6-A-67



A-950
F
7-A-67



A-951
F
4-A-68



A-952
F
5-A-68



A-953
F
6-A-68



A-954
F
7-A-68



A-955
F
4-A-69



A-956
F
5-A-69



A-957
F
6-A-69



A-958
F
7-A-69



A-959
F
4-A-70



A-960
F
5-A-70



A-961
F
6-A-70



A-962
F
7-A-70



A-963
F
4-A-71



A-964
F
5-A-71



A-965
F
6-A-71



A-966
F
7-A-71



A-967
F
4-A-72



A-968
F
5-A-72



A-969
F
6-A-72



A-970
F
7-A-72



A-971
F
4-A-73



A-972
F
5-A-73



A-973
F
6-A-73



A-974
F
7-A-73



A-975
F
4-A-74



A-976
F
5-A-74



A-977
F
6-A-74



A-978
F
7-A-74



A-979
F
4-A-75



A-980
F
5-A-75



A-981
F
6-A-75



A-982
F
7-A-75



A-983
F
4-A-76



A-984
F
5-A-76



A-985
F
6-A-76



A-986
F
7-A-76



A-987
F
4-A-77



A-988
F
5-A-77



A-989
F
6-A-77



A-990
F
7-A-77



A-991
F
4-A-78



A-992
F
5-A-78



A-993
F
6-A-78



A-994
F
7-A-78



A-995
F
4-A-79



A-996
F
5-A-79



A-997
F
6-A-79



A-998
F
7-A-79



A-999
F
4-A-80



A-1000
F
5-A-80



A-1001
F
6-A-80



A-1002
F
7-A-80



A-1003
F
4-A-81



A-1004
F
5-A-81



A-1005
F
6-A-81



A-1006
F
7-A-81



A-1007
F
4-A-82



A-1008
F
5-A-82



A-1009
F
6-A-82



A-1010
F
7-A-82



A-1011
F
4-A-83



A-1012
F
5-A-83



A-1013
F
6-A-83



A-1014
F
7-A-83



A-1015
F
4-A-84



A-1016
F
5-A-84



A-1017
F
6-A-84



A-1018
F
7-A-84



A-1019
F
4-A-85



A-1020
F
5-A-85



A-1021
F
6-A-85



A-1022
F
7-A-85



A-1023
F
4-A-86



A-1024
F
5-A-86



A-1025
F
6-A-86



A-1026
F
7-A-86



A-1027
F
4-A-87



A-1028
F
5-A-87



A-1029
F
6-A-87



A-1030
F
7-A-87



A-1031
F
4-A-88



A-1032
F
5-A-88



A-1033
F
6-A-88



A-1034
F
7-A-88



A-1035
F
4-A-89



A-1036
F
5-A-89



A-1037
F
6-A-89



A-1038
F
7-A-89



A-1039
F
4-A-90



A-1040
F
5-A-90



A-1041
F
6-A-90



A-1042
F
7-A-90



A-1043
F
4-A-91



A-1044
F
5-A-91



A-1045
F
6-A-91



A-1046
F
7-A-91



A-1047
F
4-A-92



A-1048
F
5-A-92



A-1049
F
6-A-92



A-1050
F
7-A-92



A-1051
F
4-A-93



A-1052
F
5-A-93



A-1053
F
6-A-93



A-1054
F
7-A-93



A-1055
F
4-A-94



A-1056
F
5-A-94



A-1057
F
6-A-94



A-1058
F
7-A-94



A-1059
F
4-A-95



A-1060
F
5-A-95



A-1061
F
6-A-95



A-1062
F
7-A-95



A-1063
F
4-A-96



A-1064
F
5-A-96



A-1065
F
6-A-96



A-1066
F
7-A-96



A-1067
F
4-A-97



A-1068
F
5-A-97



A-1069
F
6-A-97



A-1070
F
7-A-97



A-1071
F
4-A-98



A-1072
F
5-A-98



A-1073
F
6-A-98



A-1074
F
7-A-98



A-1075
F
4-A-99



A-1076
F
5-A-99



A-1077
F
6-A-99



A-1078
F
7-A-99



A-1079
F
4-A-100



A-1080
F
5-A-100



A-1081
F
6-A-100



A-1082
F
7-A-100



A-1083
F
4-A-101



A-1084
F
5-A-101



A-1085
F
6-A-101



A-1086
F
7-A-101



A-1087
F
4-A-102



A-1088
F
5-A-102



A-1089
F
6-A-102



A-1090
F
7-A-102



A-1091
F
4-A-103



A-1092
F
5-A-103



A-1093
F
6-A-103



A-1094
F
7-A-103



A-1095
F
4-A-104



A-1096
F
5-A-104



A-1097
F
6-A-104



A-1098
F
7-A-104



A-1099
F
4-A-104



A-1100
F
5-A-104



A-1101
F
6-A-104



A-1102
F
7-A-104



A-1103
F
4-A-105



A-1104
F
5-A-105



A-1105
F
6-A-105



A-1106
F
7-A-105



A-1107
F
4-A-106



A-1108
F
5-A-106



A-1109
F
6-A-106



A-1110
F
7-A-106



A-1111
F
4-A-107



A-1112
F
5-A-107



A-1113
F
6-A-107



A-1114
F
7-A-107



A-1115
F
4-A-108



A-1116
F
5-A-108



A-1117
F
6-A-108



A-1118
F
7-A-108



A-1119
F
4-A-109



A-1120
F
5-A-109



A-1121
F
6-A-109



A-1122
F
7-A-109



A-1123
F
4-A-110



A-1124
F
5-A-110



A-1125
F
6-A-110



A-1126
F
7-A-110



A-1127
F
4-A-111



A-1128
F
5-A-111



A-1129
F
6-A-111



A-1130
F
7-A-111



A-1131
allyl
H



A-1132
allyl
4-Cl



A-1133
allyl
5-Cl



A-1134
allyl
6-Cl



A-1135
allyl
7-Cl



A-1136
allyl
4-Br



A-1137
allyl
5-Br



A-1138
allyl
6-Br



A-1139
allyl
7-Br



A-1140
allyl
4-CN



A-1141
allyl
5-CN



A-1142
allyl
6-CN



A-1143
allyl
7-CN



A-1144
allyl
4-OH



A-1145
allyl
5-OH



A-1146
allyl
6-OH



A-1147
allyl
7-OH



A-1148
allyl
4-methyl



A-1149
allyl
5-methyl



A-1150
allyl
6-methyl



A-1151
allyl
7-methyl



A-1152
allyl
4-ethyl



A-1153
allyl
5-ethyl



A-1154
allyl
6-ethyl



A-1155
allyl
7-ethyl



A-1156
allyl
4-propyl



A-1157
allyl
5-propyl



A-1158
allyl
6-propyl



A-1159
allyl
7-propyl



A-1160
allyl
4-isopropyl



A-1161
allyl
5-isopropyl



A-1162
allyl
6-isopropyl



A-1163
allyl
7-isopropyl



A-1164
allyl
4-hydroxymethyl



A-1165
allyl
5-hydroxymethyl



A-1166
allyl
6-hydroxymethyl



A-1167
allyl
7-hydroxymethyl



A-1168
allyl
4-(2-hydroxyethyl)



A-1169
allyl
5-(2-hydroxyethyl)



A-1170
allyl
6-(2-hydroxyethyl)



A-1171
allyl
7-(2-hydroxyethyl)



A-1172
allyl
4-(1-hydroxyethyl)



A-1173
allyl
5-(1-hydroxyethyl)



A-1174
allyl
6-(1-hydroxyethyl)



A-1175
allyl
7-(1-hydroxyethyl)



A-1176
allyl
4-(3-hydroxypropyl)



A-1177
allyl
5-(3-hydroxypropyl)



A-1178
allyl
6-(3-hydroxypropyl)



A-1179
allyl
7-(3-hydroxypropyl)



A-1180
allyl
4-(2-hydroxypropyl)



A-1181
allyl
5-(2-hydroxypropyl)



A-1182
allyl
6-(2-hydroxypropyl)



A-1183
allyl
7-(2-hydroxypropyl)



A-1184
allyl
4-(1-hydroxypropyl)



A-1185
allyl
5-(1-hydroxypropyl)



A-1186
allyl
6-(1-hydroxypropyl)



A-1187
allyl
7-(1-hydroxypropyl)



A-1188
allyl
4-aminomethyl



A-1189
allyl
5-aminomethyl



A-1190
allyl
6-aminomethyl



A-1191
allyl
7-aminomethyl



A-1192
allyl
4-(2-aminoethyl)



A-1193
allyl
5-(2-aminoethyl)



A-1194
allyl
6-(2-aminoethyl)



A-1195
allyl
7-(2-aminoethyl)



A-1196
allyl
4-(1-aminoethyl)



A-1197
allyl
5-(1-aminoethyl)



A-1198
allyl
6-(1-aminoethyl)



A-1199
allyl
7-(1-aminoethyl)



A-1200
allyl
4-(3-aminopropyl)



A-1201
allyl
5-(3-aminopropyl)



A-1202
allyl
6-(3-aminopropyl)



A-1203
allyl
7-(3-aminopropyl)



A-1204
allyl
4-(2-aminopropyl)



A-1205
allyl
5-(2-aminopropyl)



A-1206
allyl
6-(2-aminopropyl)



A-1207
allyl
7-(2-aminopropyl)



A-1208
allyl
4-(1-aminopropyl)



A-1209
allyl
5-(1-aminopropyl)



A-1210
allyl
6-(1-aminopropyl)



A-1211
allyl
7-(1-aminopropyl)



A-1212
allyl
4-COOH



A-1213
allyl
5-COOH



A-1214
allyl
6-COOH



A-1215
allyl
7-COOH



A-1216
allyl
4-COOCH3



A-1217
allyl
5-COOCH3



A-1218
allyl
6-COOCH3



A-1219
allyl
7-COOCH3



A-1220
allyl
4-COOCH2CH3



A-1221
allyl
5-COOCH2CH3



A-1222
allyl
6-COOCH2CH3



A-1223
allyl
7-COOCH2CH3



A-1224
allyl
4-COOCF3



A-1225
allyl
5-COOCF3



A-1226
allyl
6-COOCF3



A-1227
allyl
7-COOCF3



A-1228
allyl
4-CONH2



A-1229
allyl
5-CONH2



A-1230
allyl
6-CONH2



A-1231
allyl
7-CONH2



A-1232
allyl
4-CONHCH3



A-1233
allyl
5-CONHCH3



A-1234
allyl
6-CONHCH3



A-1235
allyl
7-CONHCH3



A-1236
allyl
4-CON(CH3)2



A-1237
allyl
5-CON(CH3)2



A-1238
allyl
6-CON(CH3)2



A-1239
allyl
7-CON(CH3)2



A-1240
allyl
4-CONHCH2CH3



A-1241
allyl
5-CONHCH2CH3



A-1242
allyl
6-CONHCH2CH3



A-1243
allyl
7-CONHCH2CH3



A-1244
allyl
4-CON(CH2CH3)2



A-1245
allyl
5-CON(CH2CH3)2



A-1246
allyl
6-CON(CH2CH3)2



A-1247
allyl
7-CON(CH2CH3)2



A-1248
allyl
4-A-1



A-1249
allyl
5-A-1



A-1250
allyl
6-A-1



A-1251
allyl
7-A-1



A-1252
allyl
4-A-2



A-1253
allyl
5-A-2



A-1254
allyl
6-A-2



A-1255
allyl
7-A-2



A-1256
allyl
4-A-3



A-1257
allyl
5-A-3



A-1258
allyl
6-A-3



A-1259
allyl
7-A-3



A-1260
allyl
4-A-4



A-1261
allyl
5-A-4



A-1262
allyl
6-A-4



A-1263
allyl
7-A-4



A-1264
allyl
4-A-5



A-1265
allyl
5-A-5



A-1266
allyl
6-A-5



A-1267
allyl
7-A-5



A-1268
allyl
4-A-6



A-1269
allyl
5-A-6



A-1270
allyl
6-A-6



A-1271
allyl
7-A-6



A-1272
allyl
4-A-7



A-1273
allyl
5-A-7



A-1274
allyl
6-A-7



A-1275
allyl
7-A-7



A-1276
allyl
4-A-8



A-1277
allyl
5-A-8



A-1278
allyl
6-A-8



A-1279
allyl
7-A-8



A-1280
allyl
4-A-9



A-1281
allyl
5-A-9



A-1282
allyl
6-A-9



A-1283
allyl
7-A-9



A-1284
allyl
4-A-10



A-1285
allyl
5-A-10



A-1286
allyl
6-A-10



A-1287
allyl
7-A-10



A-1288
allyl
4-A-11



A-1289
allyl
5-A-11



A-1290
allyl
6-A-11



A-1291
allyl
7-A-11



A-1292
allyl
4-A-12



A-1293
allyl
5-A-12



A-1294
allyl
6-A-12



A-1295
allyl
7-A-12



A-1296
allyl
4-A-13



A-1297
allyl
5-A-13



A-1298
allyl
6-A-13



A-1299
allyl
7-A-13



A-1300
allyl
4-A-14



A-1301
allyl
5-A-14



A-1302
allyl
6-A-14



A-1303
allyl
7-A-14



A-1304
allyl
4-A-15



A-1305
allyl
5-A-15



A-1306
allyl
6-A-15



A-1307
allyl
7-A-15



A-1308
allyl
4-A-16



A-1309
allyl
5-A-16



A-1310
allyl
6-A-16



A-1311
allyl
7-A-16



A-1312
allyl
4-A-17



A-1313
allyl
5-A-17



A-1314
allyl
6-A-17



A-1315
allyl
7-A-17



A-1316
allyl
4-A-18



A-1317
allyl
5-A-18



A-1318
allyl
6-A-18



A-1319
allyl
7-A-18



A-1320
allyl
4-A-19



A-1321
allyl
5-A-19



A-1322
allyl
6-A-19



A-1323
allyl
7-A-19



A-1324
allyl
4-A-20



A-1325
allyl
5-A-20



A-1326
allyl
6-A-20



A-1327
allyl
7-A-20



A-1328
allyl
4-A-21



A-1329
allyl
5-A-21



A-1330
allyl
6-A-21



A-1331
allyl
7-A-21



A-1332
allyl
4-A-22



A-1333
allyl
5-A-22



A-1334
allyl
6-A-22



A-1335
allyl
7-A-22



A-1336
allyl
4-A-23



A-1337
allyl
5-A-23



A-1338
allyl
6-A-23



A-1339
allyl
7-A-23



A-1340
allyl
4-A-24



A-1341
allyl
5-A-24



A-1342
allyl
6-A-24



A-1343
allyl
7-A-24



A-1344
allyl
4-A-25



A-1345
allyl
5-A-25



A-1346
allyl
6-A-25



A-1347
allyl
7-A-25



A-1348
allyl
4-A-26



A-1349
allyl
5-A-26



A-1350
allyl
6-A-26



A-1351
allyl
7-A-26



A-1352
allyl
4-A-27



A-1353
allyl
5-A-27



A-1354
allyl
6-A-27



A-1355
allyl
7-A-27



A-1356
allyl
4-A-28



A-1357
allyl
5-A-28



A-1358
allyl
6-A-28



A-1359
allyl
7-A-28



A-1360
allyl
4-A-29



A-1361
allyl
5-A-29



A-1362
allyl
6-A-29



A-1363
allyl
7-A-29



A-1364
allyl
4-A-30



A-1365
allyl
5-A-30



A-1366
allyl
6-A-30



A-1367
allyl
7-A-30



A-1368
allyl
4-A-31



A-1369
allyl
5-A-31



A-1370
allyl
6-A-31



A-1371
allyl
7-A-31



A-1372
allyl
4-A-32



A-1373
allyl
5-A-32



A-1374
allyl
6-A-32



A-1375
allyl
7-A-32



A-1376
allyl
4-A-33



A-1377
allyl
5-A-33



A-1378
allyl
6-A-33



A-1379
allyl
7-A-33



A-1380
allyl
4-A-34



A-1381
allyl
5-A-34



A-1382
allyl
6-A-34



A-1383
allyl
7-A-34



A-1384
allyl
4-A-35



A-1385
allyl
5-A-35



A-1386
allyl
6-A-35



A-1387
allyl
7-A-35



A-1388
allyl
4-A-36



A-1389
allyl
5-A-36



A-1390
allyl
6-A-36



A-1391
allyl
7-A-36



A-1392
allyl
4-A-37



A-1393
allyl
5-A-37



A-1394
allyl
6-A-37



A-1395
allyl
7-A-37



A-1396
allyl
4-A-38



A-1397
allyl
5-A-38



A-1398
allyl
6-A-38



A-1399
allyl
7-A-38



A-1400
allyl
4-A-39



A-1401
allyl
5-A-39



A-1402
allyl
6-A-39



A-1403
allyl
7-A-39



A-1404
allyl
4-A-40



A-1405
allyl
5-A-40



A-1406
allyl
6-A-40



A-1407
allyl
7-A-40



A-1408
allyl
4-A-41



A-1409
allyl
5-A-41



A-1410
allyl
6-A-41



A-1411
allyl
7-A-41



A-1412
allyl
4-A-42



A-1413
allyl
5-A-42



A-1414
allyl
6-A-42



A-1415
allyl
7-A-42



A-1416
allyl
4-A-43



A-1417
allyl
5-A-43



A-1418
allyl
6-A-43



A-1419
allyl
7-A-43



A-1420
allyl
4-A-44



A-1421
allyl
5-A-44



A-1422
allyl
6-A-44



A-1423
allyl
7-A-44



A-1424
allyl
4-A-45



A-1425
allyl
5-A-45



A-1426
allyl
6-A-45



A-1427
allyl
7-A-45



A-1428
allyl
4-A-46



A-1429
allyl
5-A-46



A-1430
allyl
6-A-46



A-1431
allyl
7-A-46



A-1432
allyl
4-A-47



A-1433
allyl
5-A-47



A-1434
allyl
6-A-47



A-1435
allyl
7-A-47



A-1436
allyl
4-A-48



A-1437
allyl
5-A-48



A-1438
allyl
6-A-48



A-1439
allyl
7-A-48



A-1440
allyl
4-A-49



A-1441
allyl
5-A-49



A-1442
allyl
6-A-49



A-1443
allyl
7-A-49



A-1444
allyl
4-A-50



A-1445
allyl
5-A-50



A-1446
allyl
6-A-50



A-1447
allyl
7-A-50



A-1448
allyl
4-A-51



A-1449
allyl
5-A-51



A-1450
allyl
6-A-51



A-1451
allyl
7-A-51



A-1452
allyl
4-A-52



A-1453
allyl
5-A-52



A-1454
allyl
6-A-52



A-1455
allyl
7-A-52



A-1456
allyl
4-A-53



A-1457
allyl
5-A-53



A-1458
allyl
6-A-53



A-1459
allyl
7-A-53



A-1460
allyl
4-A-54



A-1461
allyl
5-A-54



A-1462
allyl
6-A-54



A-1463
allyl
7-A-54



A-1464
allyl
4-A-55



A-1465
allyl
5-A-55



A-1466
allyl
6-A-55



A-1467
allyl
7-A-55



A-1468
allyl
4-A-56



A-1469
allyl
5-A-56



A-1470
allyl
6-A-56



A-1471
allyl
7-A-56



A-1472
allyl
4-A-57



A-1473
allyl
5-A-57



A-1474
allyl
6-A-57



A-1475
allyl
7-A-57



A-1476
allyl
4-A-58



A-1477
allyl
5-A-58



A-1478
allyl
6-A-58



A-1479
allyl
7-A-58



A-1480
allyl
4-A-59



A-1481
allyl
5-A-59



A-1482
allyl
6-A-59



A-1483
allyl
7-A-59



A-1484
allyl
4-A-60



A-1485
allyl
5-A-60



A-1486
allyl
6-A-60



A-1487
allyl
7-A-60



A-1488
allyl
4-A-61



A-1489
allyl
5-A-61



A-1490
allyl
6-A-61



A-1491
allyl
7-A-61



A-1492
allyl
4-A-62



A-1493
allyl
5-A-62



A-1494
allyl
6-A-62



A-1495
allyl
7-A-62



A-1496
allyl
4-A-63



A-1497
allyl
5-A-63



A-1498
allyl
6-A-63



A-1499
allyl
7-A-63



A-1500
allyl
4-A-64



A-1501
allyl
5-A-64



A-1502
allyl
6-A-64



A-1503
allyl
7-A-64



A-1504
allyl
4-A-65



A-1505
allyl
5-A-65



A-1506
allyl
6-A-65



A-1507
allyl
7-A-65



A-1508
allyl
4-A-66



A-1509
allyl
5-A-66



A-1510
allyl
6-A-66



A-1511
allyl
7-A-66



A-1512
allyl
4-A-67



A-1513
allyl
5-A-67



A-1514
allyl
6-A-67



A-1515
allyl
7-A-67



A-1516
allyl
4-A-68



A-1517
allyl
5-A-68



A-1518
allyl
6-A-68



A-1519
allyl
7-A-68



A-1520
allyl
4-A-69



A-1521
allyl
5-A-69



A-1522
allyl
6-A-69



A-1523
allyl
7-A-69



A-1524
allyl
4-A-70



A-1525
allyl
5-A-70



A-1526
allyl
6-A-70



A-1527
allyl
7-A-70



A-1528
allyl
4-A-71



A-1529
allyl
5-A-71



A-1530
allyl
6-A-71



A-1531
allyl
7-A-71



A-1532
allyl
4-A-72



A-1533
allyl
5-A-72



A-1534
allyl
6-A-72



A-1535
allyl
7-A-72



A-1536
allyl
4-A-73



A-1537
allyl
5-A-73



A-1538
allyl
6-A-73



A-1539
allyl
7-A-73



A-1540
allyl
4-A-74



A-1541
allyl
5-A-74



A-1542
allyl
6-A-74



A-1543
allyl
7-A-74



A-1544
allyl
4-A-75



A-1545
allyl
5-A-75



A-1546
allyl
6-A-75



A-1547
allyl
7-A-75



A-1548
allyl
4-A-76



A-1549
allyl
5-A-76



A-1550
allyl
6-A-76



A-1551
allyl
7-A-76



A-1552
allyl
4-A-77



A-1553
allyl
5-A-77



A-1554
allyl
6-A-77



A-1555
allyl
7-A-77



A-1556
allyl
4-A-78



A-1557
allyl
5-A-78



A-1558
allyl
6-A-78



A-1559
allyl
7-A-78



A-1560
allyl
4-A-79



A-1561
allyl
5-A-79



A-1562
allyl
6-A-79



A-1563
allyl
7-A-79



A-1564
allyl
4-A-80



A-1565
allyl
5-A-80



A-1566
allyl
6-A-80



A-1567
allyl
7-A-80



A-1568
allyl
4-A-81



A-1569
allyl
5-A-81



A-1570
allyl
6-A-81



A-1571
allyl
7-A-81



A-1572
allyl
4-A-82



A-1573
allyl
5-A-82



A-1574
allyl
6-A-82



A-1575
allyl
7-A-82



A-1576
allyl
4-A-83



A-1577
allyl
5-A-83



A-1578
allyl
6-A-83



A-1579
allyl
7-A-83



A-1580
allyl
4-A-84



A-1581
allyl
5-A-84



A-1582
allyl
6-A-84



A-1583
allyl
7-A-84



A-1584
allyl
4-A-85



A-1585
allyl
5-A-85



A-1586
allyl
6-A-85



A-1587
allyl
7-A-85



A-1588
allyl
4-A-86



A-1589
allyl
5-A-86



A-1590
allyl
6-A-86



A-1591
allyl
7-A-86



A-1592
allyl
4-A-87



A-1593
allyl
5-A-87



A-1594
allyl
6-A-87



A-1595
allyl
7-A-87



A-1596
allyl
4-A-88



A-1597
allyl
5-A-88



A-1598
allyl
6-A-88



A-1599
allyl
7-A-88



A-1600
allyl
4-A-89



A-1601
allyl
5-A-89



A-1602
allyl
6-A-89



A-1603
allyl
7-A-89



A-1604
allyl
4-A-90



A-1605
allyl
5-A-90



A-1606
allyl
6-A-90



A-1607
allyl
7-A-90



A-1608
allyl
4-A-91



A-1609
allyl
5-A-91



A-1610
allyl
6-A-91



A-1611
allyl
7-A-91



A-1612
allyl
4-A-92



A-1613
allyl
5-A-92



A-1614
allyl
6-A-92



A-1615
allyl
7-A-92



A-1616
allyl
4-A-93



A-1617
allyl
5-A-93



A-1618
allyl
6-A-93



A-1619
allyl
7-A-93



A-1620
allyl
4-A-94



A-1621
allyl
5-A-94



A-1622
allyl
6-A-94



A-1623
allyl
7-A-94



A-1624
allyl
4-A-95



A-1625
allyl
5-A-95



A-1626
allyl
6-A-95



A-1627
allyl
7-A-95



A-1628
allyl
4-A-96



A-1629
allyl
5-A-96



A-1630
allyl
6-A-96



A-1631
allyl
7-A-96



A-1632
allyl
4-A-97



A-1633
allyl
5-A-97



A-1634
allyl
6-A-97



A-1635
allyl
7-A-97



A-1636
allyl
4-A-98



A-1637
allyl
5-A-98



A-1638
allyl
6-A-98



A-1639
allyl
7-A-98



A-1640
allyl
4-A-99



A-1641
allyl
5-A-99



A-1642
allyl
6-A-99



A-1643
allyl
7-A-99



A-1644
allyl
4-A-100



A-1645
allyl
5-A-100



A-1646
allyl
6-A-100



A-1647
allyl
7-A-100



A-1648
allyl
4-A-101



A-1649
allyl
5-A-101



A-1650
allyl
6-A-101



A-1651
allyl
7-A-101



A-1652
allyl
4-A-102



A-1653
allyl
5-A-102



A-1654
allyl
6-A-102



A-1655
allyl
7-A-102



A-1656
allyl
4-A-103



A-1657
allyl
5-A-103



A-1658
allyl
6-A-103



A-1659
allyl
7-A-103



A-1660
allyl
4-A-104



A-1661
allyl
5-A-104



A-1662
allyl
6-A-104



A-1663
allyl
7-A-104



A-1664
allyl
4-A-104



A-1665
allyl
5-A-104



A-1666
allyl
6-A-104



A-1667
allyl
7-A-104



A-1668
allyl
4-A-105



A-1669
allyl
5-A-105



A-1670
allyl
6-A-105



A-1671
allyl
7-A-105



A-1672
allyl
4-A-106



A-1673
allyl
5-A-106



A-1674
allyl
6-A-106



A-1675
allyl
7-A-106



A-1676
allyl
4-A-107



A-1677
allyl
5-A-107



A-1678
allyl
6-A-107



A-1679
allyl
7-A-107



A-1680
allyl
4-A-108



A-1681
allyl
5-A-108



A-1682
allyl
6-A-108



A-1683
allyl
7-A-108



A-1684
allyl
4-A-109



A-1685
allyl
5-A-109



A-1686
allyl
6-A-109



A-1687
allyl
7-A-109



A-1688
allyl
4-A-110



A-1689
allyl
5-A-110



A-1690
allyl
6-A-110



A-1691
allyl
7-A-110



A-1692
allyl
4-A-111



A-1693
allyl
5-A-111



A-1694
allyl
6-A-111



A-1695
allyl
7-A-111



A-1696
CH2CHF2
H



A-1697
CH2CHF2
4-Cl



A-1698
CH2CHF2
5-Cl



A-1699
CH2CHF2
6-Cl



A-1700
CH2CHF2
7-Cl



A-1701
CH2CHF2
4-Br



A-1702
CH2CHF2
5-Br



A-1703
CH2CHF2
6-Br



A-1704
CH2CHF2
7-Br



A-1705
CH2CHF2
4-CN



A-1706
CH2CHF2
5-CN



A-1707
CH2CHF2
6-CN



A-1708
CH2CHF2
7-CN



A-1709
CH2CHF2
4-OH



A-1710
CH2CHF2
5-OH



A-1711
CH2CHF2
6-OH



A-1712
CH2CHF2
7-OH



A-1713
CH2CHF2
4-methyl



A-1714
CH2CHF2
5-methyl



A-1715
CH2CHF2
6-methyl



A-1716
CH2CHF2
7-methyl



A-1717
CH2CHF2
4-ethyl



A-1718
CH2CHF2
5-ethyl



A-1719
CH2CHF2
6-ethyl



A-1720
CH2CHF2
7-ethyl



A-1721
CH2CHF2
4-propyl



A-1722
CH2CHF2
5-propyl



A-1723
CH2CHF2
6-propyl



A-1724
CH2CHF2
7-propyl



A-1725
CH2CHF2
4-isopropyl



A-1726
CH2CHF2
5-isopropyl



A-1727
CH2CHF2
6-isopropyl



A-1728
CH2CHF2
7-isopropyl



A-1729
CH2CHF2
4-hydroxymethyl



A-1730
CH2CHF2
5-hydroxymethyl



A-1731
CH2CHF2
6-hydroxymethyl



A-1732
CH2CHF2
7-hydroxymethyl



A-1733
CH2CHF2
4-(2-hydroxyethyl)



A-1734
CH2CHF2
5-(2-hydroxyethyl)



A-1735
CH2CHF2
6-(2-hydroxyethyl)



A-1736
CH2CHF2
7-(2-hydroxyethyl)



A-1737
CH2CHF2
4-(1-hydroxyethyl)



A-1738
CH2CHF2
5-(1-hydroxyethyl)



A-1739
CH2CHF2
6-(1-hydroxyethyl)



A-1740
CH2CHF2
7-(1-hydroxyethyl)



A-1741
CH2CHF2
4-(3-hydroxypropyl)



A-1742
CH2CHF2
5-(3-hydroxypropyl)



A-1743
CH2CHF2
6-(3-hydroxypropyl)



A-1744
CH2CHF2
7-(3-hydroxypropyl)



A-1745
CH2CHF2
4-(2-hydroxypropyl)



A-1746
CH2CHF2
5-(2-hydroxypropyl)



A-1747
CH2CHF2
6-(2-hydroxypropyl)



A-1748
CH2CHF2
7-(2-hydroxypropyl)



A-1749
CH2CHF2
4-(1-hydroxypropyl)



A-1750
CH2CHF2
5-(1-hydroxypropyl)



A-1751
CH2CHF2
6-(1-hydroxypropyl)



A-1752
CH2CHF2
7-(1-hydroxypropyl)



A-1753
CH2CHF2
4-aminomethyl



A-1754
CH2CHF2
5-aminomethyl



A-1755
CH2CHF2
6-aminomethyl



A-1756
CH2CHF2
7-aminomethyl



A-1757
CH2CHF2
4-(2-aminoethyl)



A-1758
CH2CHF2
5-(2-aminoethyl)



A-1759
CH2CHF2
6-(2-aminoethyl)



A-1760
CH2CHF2
7-(2-aminoethyl)



A-1761
CH2CHF2
4-(1-aminoethyl)



A-1762
CH2CHF2
5-(1-aminoethyl)



A-1763
CH2CHF2
6-(1-aminoethyl)



A-1764
CH2CHF2
7-(1-aminoethyl)



A-1765
CH2CHF2
4-(3-aminopropyl)



A-1766
CH2CHF2
5-(3-aminopropyl)



A-1767
CH2CHF2
6-(3-aminopropyl)



A-1768
CH2CHF2
7-(3-aminopropyl)



A-1769
CH2CHF2
4-(2-aminopropyl)



A-1770
CH2CHF2
5-(2-aminopropyl)



A-1771
CH2CHF2
6-(2-aminopropyl)



A-1772
CH2CHF2
7-(2-aminopropyl)



A-1773
CH2CHF2
4-(1-aminopropyl)



A-1774
CH2CHF2
5-(1-aminopropyl)



A-1775
CH2CHF2
6-(1-aminopropyl)



A-1776
CH2CHF2
7-(1-aminopropyl)



A-1777
CH2CHF2
4-COOH



A-1778
CH2CHF2
5-COOH



A-1779
CH2CHF2
6-COOH



A-1780
CH2CHF2
7-COOH



A-1781
CH2CHF2
4-COOCH3



A-1782
CH2CHF2
5-COOCH3



A-1783
CH2CHF2
6-COOCH3



A-1784
CH2CHF2
7-COOCH3



A-1785
CH2CHF2
4-COOCH2CH3



A-1786
CH2CHF2
5-COOCH2CH3



A-1787
CH2CHF2
6-COOCH2CH3



A-1788
CH2CHF2
7-COOCH2CH3



A-1789
CH2CHF2
4-COOCF3



A-1790
CH2CHF2
5-COOCF3



A-1791
CH2CHF2
6-COOCF3



A-1792
CH2CHF2
7-COOCF3



A-1793
CH2CHF2
4-CONH2



A-1794
CH2CHF2
5-CONH2



A-1795
CH2CHF2
6-CONH2



A-1796
CH2CHF2
7-CONH2



A-1797
CH2CHF2
4-CONHCH3



A-1798
CH2CHF2
5-CONHCH3



A-1799
CH2CHF2
6-CONHCH3



A-1800
CH2CHF2
7-CONHCH3



A-1801
CH2CHF2
4-CON(CH3)2



A-1802
CH2CHF2
5-CON(CH3)2



A-1803
CH2CHF2
6-CON(CH3)2



A-1804
CH2CHF2
7-CON(CH3)2



A-1805
CH2CHF2
4-CONHCH2CH3



A-1806
CH2CHF2
5-CONHCH2CH3



A-1807
CH2CHF2
6-CONHCH2CH3



A-1808
CH2CHF2
7-CONHCH2CH3



A-1809
CH2CHF2
4-CON(CH2CH3)2



A-1810
CH2CHF2
5-CON(CH2CH3)2



A-1811
CH2CHF2
6-CON(CH2CH3)2



A-1812
CH2CHF2
7-CON(CH2CH3)2



A-1813
CH2CHF2
4-A-1



A-1814
CH2CHF2
5-A-1



A-1815
CH2CHF2
6-A-1



A-1816
CH2CHF2
7-A-1



A-1817
CH2CHF2
4-A-2



A-1818
CH2CHF2
5-A-2



A-1819
CH2CHF2
6-A-2



A-1820
CH2CHF2
7-A-2



A-1821
CH2CHF2
4-A-3



A-1822
CH2CHF2
5-A-3



A-1823
CH2CHF2
6-A-3



A-1824
CH2CHF2
7-A-3



A-1825
CH2CHF2
4-A-4



A-1826
CH2CHF2
5-A-4



A-1827
CH2CHF2
6-A-4



A-1828
CH2CHF2
7-A-4



A-1829
CH2CHF2
4-A-5



A-1830
CH2CHF2
5-A-5



A-1831
CH2CHF2
6-A-5



A-1832
CH2CHF2
7-A-5



A-1833
CH2CHF2
4-A-6



A-1834
CH2CHF2
5-A-6



A-1835
CH2CHF2
6-A-6



A-1836
CH2CHF2
7-A-6



A-1837
CH2CHF2
4-A-7



A-1838
CH2CHF2
5-A-7



A-1839
CH2CHF2
6-A-7



A-1840
CH2CHF2
7-A-7



A-1841
CH2CHF2
4-A-8



A-1842
CH2CHF2
5-A-8



A-1843
CH2CHF2
6-A-8



A-1844
CH2CHF2
7-A-8



A-1845
CH2CHF2
4-A-9



A-1846
CH2CHF2
5-A-9



A-1847
CH2CHF2
6-A-9



A-1848
CH2CHF2
7-A-9



A-1849
CH2CHF2
4-A-10



A-1850
CH2CHF2
5-A-10



A-1851
CH2CHF2
6-A-10



A-1852
CH2CHF2
7-A-10



A-1853
CH2CHF2
4-A-11



A-1854
CH2CHF2
5-A-11



A-1855
CH2CHF2
6-A-11



A-1856
CH2CHF2
7-A-11



A-1857
CH2CHF2
4-A-12



A-1858
CH2CHF2
5-A-12



A-1859
CH2CHF2
6-A-12



A-1860
CH2CHF2
7-A-12



A-1861
CH2CHF2
4-A-13



A-1862
CH2CHF2
5-A-13



A-1863
CH2CHF2
6-A-13



A-1864
CH2CHF2
7-A-13



A-1865
CH2CHF2
4-A-14



A-1866
CH2CHF2
5-A-14



A-1867
CH2CHF2
6-A-14



A-1868
CH2CHF2
7-A-14



A-1869
CH2CHF2
4-A-15



A-1870
CH2CHF2
5-A-15



A-1871
CH2CHF2
6-A-15



A-1872
CH2CHF2
7-A-15



A-1873
CH2CHF2
4-A-16



A-1874
CH2CHF2
5-A-16



A-1875
CH2CHF2
6-A-16



A-1876
CH2CHF2
7-A-16



A-1877
CH2CHF2
4-A-17



A-1878
CH2CHF2
5-A-17



A-1879
CH2CHF2
6-A-17



A-1880
CH2CHF2
7-A-17



A-1881
CH2CHF2
4-A-18



A-1882
CH2CHF2
5-A-18



A-1883
CH2CHF2
6-A-18



A-1884
CH2CHF2
7-A-18



A-1885
CH2CHF2
4-A-19



A-1886
CH2CHF2
5-A-19



A-1887
CH2CHF2
6-A-19



A-1888
CH2CHF2
7-A-19



A-1889
CH2CHF2
4-A-20



A-1890
CH2CHF2
5-A-20



A-1891
CH2CHF2
6-A-20



A-1892
CH2CHF2
7-A-20



A-1893
CH2CHF2
4-A-21



A-1894
CH2CHF2
5-A-21



A-1895
CH2CHF2
6-A-21



A-1896
CH2CHF2
7-A-21



A-1897
CH2CHF2
4-A-22



A-1898
CH2CHF2
5-A-22



A-1899
CH2CHF2
6-A-22



A-1900
CH2CHF2
7-A-22



A-1901
CH2CHF2
4-A-23



A-1902
CH2CHF2
5-A-23



A-1903
CH2CHF2
6-A-23



A-1904
CH2CHF2
7-A-23



A-1905
CH2CHF2
4-A-24



A-1906
CH2CHF2
5-A-24



A-1907
CH2CHF2
6-A-24



A-1908
CH2CHF2
7-A-24



A-1909
CH2CHF2
4-A-25



A-1910
CH2CHF2
5-A-25



A-1911
CH2CHF2
6-A-25



A-1912
CH2CHF2
7-A-25



A-1913
CH2CHF2
4-A-26



A-1914
CH2CHF2
5-A-26



A-1915
CH2CHF2
6-A-26



A-1916
CH2CHF2
7-A-26



A-1917
CH2CHF2
4-A-27



A-1918
CH2CHF2
5-A-27



A-1919
CH2CHF2
6-A-27



A-1920
CH2CHF2
7-A-27



A-1921
CH2CHF2
4-A-28



A-1922
CH2CHF2
5-A-28



A-1923
CH2CHF2
6-A-28



A-1924
CH2CHF2
7-A-28



A-1925
CH2CHF2
4-A-29



A-1926
CH2CHF2
5-A-29



A-1927
CH2CHF2
6-A-29



A-1928
CH2CHF2
7-A-29



A-1929
CH2CHF2
4-A-30



A-1930
CH2CHF2
5-A-30



A-1931
CH2CHF2
6-A-30



A-1932
CH2CHF2
7-A-30



A-1933
CH2CHF2
4-A-31



A-1934
CH2CHF2
5-A-31



A-1935
CH2CHF2
6-A-31



A-1936
CH2CHF2
7-A-31



A-1937
CH2CHF2
4-A-32



A-1938
CH2CHF2
5-A-32



A-1939
CH2CHF2
6-A-32



A-1940
CH2CHF2
7-A-32



A-1941
CH2CHF2
4-A-33



A-1942
CH2CHF2
5-A-33



A-1943
CH2CHF2
6-A-33



A-1944
CH2CHF2
7-A-33



A-1945
CH2CHF2
4-A-34



A-1946
CH2CHF2
5-A-34



A-1947
CH2CHF2
6-A-34



A-1948
CH2CHF2
7-A-34



A-1949
CH2CHF2
4-A-35



A-1950
CH2CHF2
5-A-35



A-1951
CH2CHF2
6-A-35



A-1952
CH2CHF2
7-A-35



A-1953
CH2CHF2
4-A-36



A-1954
CH2CHF2
5-A-36



A-1955
CH2CHF2
6-A-36



A-1956
CH2CHF2
7-A-36



A-1957
CH2CHF2
4-A-37



A-1958
CH2CHF2
5-A-37



A-1959
CH2CHF2
6-A-37



A-1960
CH2CHF2
7-A-37



A-1961
CH2CHF2
4-A-38



A-1962
CH2CHF2
5-A-38



A-1963
CH2CHF2
6-A-38



A-1964
CH2CHF2
7-A-38



A-1965
CH2CHF2
4-A-39



A-1966
CH2CHF2
5-A-39



A-1967
CH2CHF2
6-A-39



A-1968
CH2CHF2
7-A-39



A-1969
CH2CHF2
4-A-40



A-1970
CH2CHF2
5-A-40



A-1971
CH2CHF2
6-A-40



A-1972
CH2CHF2
7-A-40



A-1973
CH2CHF2
4-A-41



A-1974
CH2CHF2
5-A-41



A-1975
CH2CHF2
6-A-41



A-1976
CH2CHF2
7-A-41



A-1977
CH2CHF2
4-A-42



A-1978
CH2CHF2
5-A-42



A-1979
CH2CHF2
6-A-42



A-1980
CH2CHF2
7-A-42



A-1981
CH2CHF2
4-A-43



A-1982
CH2CHF2
5-A-43



A-1983
CH2CHF2
6-A-43



A-1984
CH2CHF2
7-A-43



A-1985
CH2CHF2
4-A-44



A-1986
CH2CHF2
5-A-44



A-1987
CH2CHF2
6-A-44



A-1988
CH2CHF2
7-A-44



A-1989
CH2CHF2
4-A-45



A-1990
CH2CHF2
5-A-45



A-1991
CH2CHF2
6-A-45



A-1992
CH2CHF2
7-A-45



A-1993
CH2CHF2
4-A-46



A-1994
CH2CHF2
5-A-46



A-1995
CH2CHF2
6-A-46



A-1996
CH2CHF2
7-A-46



A-1997
CH2CHF2
4-A-47



A-1998
CH2CHF2
5-A-47



A-1999
CH2CHF2
6-A-47



A-2000
CH2CHF2
7-A-47



A-2001
CH2CHF2
4-A-48



A-2002
CH2CHF2
5-A-48



A-2003
CH2CHF2
6-A-48



A-2004
CH2CHF2
7-A-48



A-2005
CH2CHF2
4-A-49



A-2006
CH2CHF2
5-A-49



A-2007
CH2CHF2
6-A-49



A-2008
CH2CHF2
7-A-49



A-2009
CH2CHF2
4-A-50



A-2010
CH2CHF2
5-A-50



A-2011
CH2CHF2
6-A-50



A-2012
CH2CHF2
7-A-50



A-2013
CH2CHF2
4-A-51



A-2014
CH2CHF2
5-A-51



A-2015
CH2CHF2
6-A-51



A-2016
CH2CHF2
7-A-51



A-2017
CH2CHF2
4-A-52



A-2018
CH2CHF2
5-A-52



A-2019
CH2CHF2
6-A-52



A-2020
CH2CHF2
7-A-52



A-2021
CH2CHF2
4-A-53



A-2022
CH2CHF2
5-A-53



A-2023
CH2CHF2
6-A-53



A-2024
CH2CHF2
7-A-53



A-2025
CH2CHF2
4-A-54



A-2026
CH2CHF2
5-A-54



A-2027
CH2CHF2
6-A-54



A-2028
CH2CHF2
7-A-54



A-2029
CH2CHF2
4-A-55



A-2030
CH2CHF2
5-A-55



A-2031
CH2CHF2
6-A-55



A-2032
CH2CHF2
7-A-55



A-2033
CH2CHF2
4-A-56



A-2034
CH2CHF2
5-A-56



A-2035
CH2CHF2
6-A-56



A-2036
CH2CHF2
7-A-56



A-2037
CH2CHF2
4-A-57



A-2038
CH2CHF2
5-A-57



A-2039
CH2CHF2
6-A-57



A-2040
CH2CHF2
7-A-57



A-2041
CH2CHF2
4-A-58



A-2042
CH2CHF2
5-A-58



A-2043
CH2CHF2
6-A-58



A-2044
CH2CHF2
7-A-58



A-2045
CH2CHF2
4-A-59



A-2046
CH2CHF2
5-A-59



A-2047
CH2CHF2
6-A-59



A-2048
CH2CHF2
7-A-59



A-2049
CH2CHF2
4-A-60



A-2050
CH2CHF2
5-A-60



A-2051
CH2CHF2
6-A-60



A-2052
CH2CHF2
7-A-60



A-2053
CH2CHF2
4-A-61



A-2054
CH2CHF2
5-A-61



A-2055
CH2CHF2
6-A-61



A-2056
CH2CHF2
7-A-61



A-2057
CH2CHF2
4-A-62



A-2058
CH2CHF2
5-A-62



A-2059
CH2CHF2
6-A-62



A-2060
CH2CHF2
7-A-62



A-2061
CH2CHF2
4-A-63



A-2062
CH2CHF2
5-A-63



A-2063
CH2CHF2
6-A-63



A-2064
CH2CHF2
7-A-63



A-2065
CH2CHF2
4-A-64



A-2066
CH2CHF2
5-A-64



A-2067
CH2CHF2
6-A-64



A-2068
CH2CHF2
7-A-64



A-2069
CH2CHF2
4-A-65



A-2070
CH2CHF2
5-A-65



A-2071
CH2CHF2
6-A-65



A-2072
CH2CHF2
7-A-65



A-2073
CH2CHF2
4-A-66



A-2074
CH2CHF2
5-A-66



A-2075
CH2CHF2
6-A-66



A-2076
CH2CHF2
7-A-66



A-2077
CH2CHF2
4-A-67



A-2078
CH2CHF2
5-A-67



A-2079
CH2CHF2
6-A-67



A-2080
CH2CHF2
7-A-67



A-2081
CH2CHF2
4-A-68



A-2082
CH2CHF2
5-A-68



A-2083
CH2CHF2
6-A-68



A-2084
CH2CHF2
7-A-68



A-2085
CH2CHF2
4-A-69



A-2086
CH2CHF2
5-A-69



A-2087
CH2CHF2
6-A-69



A-2088
CH2CHF2
7-A-69



A-2089
CH2CHF2
4-A-70



A-2090
CH2CHF2
5-A-70



A-2091
CH2CHF2
6-A-70



A-2092
CH2CHF2
7-A-70



A-2093
CH2CHF2
4-A-71



A-2094
CH2CHF2
5-A-71



A-2095
CH2CHF2
6-A-71



A-2096
CH2CHF2
7-A-71



A-2097
CH2CHF2
4-A-72



A-2098
CH2CHF2
5-A-72



A-2099
CH2CHF2
6-A-72



A-2100
CH2CHF2
7-A-72



A-2101
CH2CHF2
4-A-73



A-2102
CH2CHF2
5-A-73



A-2103
CH2CHF2
6-A-73



A-2104
CH2CHF2
7-A-73



A-2105
CH2CHF2
4-A-74



A-2106
CH2CHF2
5-A-74



A-2107
CH2CHF2
6-A-74



A-2108
CH2CHF2
7-A-74



A-2109
CH2CHF2
4-A-75



A-2110
CH2CHF2
5-A-75



A-2111
CH2CHF2
6-A-75



A-2112
CH2CHF2
7-A-75



A-2113
CH2CHF2
4-A-76



A-2114
CH2CHF2
5-A-76



A-2115
CH2CHF2
6-A-76



A-2116
CH2CHF2
7-A-76



A-2117
CH2CHF2
4-A-77



A-2118
CH2CHF2
5-A-77



A-2119
CH2CHF2
6-A-77



A-2120
CH2CHF2
7-A-77



A-2121
CH2CHF2
4-A-78



A-2122
CH2CHF2
5-A-78



A-2123
CH2CHF2
6-A-78



A-2124
CH2CHF2
7-A-78



A-2125
CH2CHF2
4-A-79



A-2126
CH2CHF2
5-A-79



A-2127
CH2CHF2
6-A-79



A-2128
CH2CHF2
7-A-79



A-2129
CH2CHF2
4-A-80



A-2130
CH2CHF2
5-A-80



A-2131
CH2CHF2
6-A-80



A-2132
CH2CHF2
7-A-80



A-2133
CH2CHF2
4-A-81



A-2134
CH2CHF2
5-A-81



A-2135
CH2CHF2
6-A-81



A-2136
CH2CHF2
7-A-81



A-2137
CH2CHF2
4-A-82



A-2138
CH2CHF2
5-A-82



A-2139
CH2CHF2
6-A-82



A-2140
CH2CHF2
7-A-82



A-2141
CH2CHF2
4-A-83



A-2142
CH2CHF2
5-A-83



A-2143
CH2CHF2
6-A-83



A-2144
CH2CHF2
7-A-83



A-2145
CH2CHF2
4-A-84



A-2146
CH2CHF2
5-A-84



A-2147
CH2CHF2
6-A-84



A-2148
CH2CHF2
7-A-84



A-2149
CH2CHF2
4-A-85



A-2150
CH2CHF2
5-A-85



A-2151
CH2CHF2
6-A-85



A-2152
CH2CHF2
7-A-85



A-2153
CH2CHF2
4-A-86



A-2154
CH2CHF2
5-A-86



A-2155
CH2CHF2
6-A-86



A-2156
CH2CHF2
7-A-86



A-2157
CH2CHF2
4-A-87



A-2158
CH2CHF2
5-A-87



A-2159
CH2CHF2
6-A-87



A-2160
CH2CHF2
7-A-87



A-2161
CH2CHF2
4-A-88



A-2162
CH2CHF2
5-A-88



A-2163
CH2CHF2
6-A-88



A-2164
CH2CHF2
7-A-88



A-2165
CH2CHF2
4-A-89



A-2166
CH2CHF2
5-A-89



A-2167
CH2CHF2
6-A-89



A-2168
CH2CHF2
7-A-89



A-2169
CH2CHF2
4-A-90



A-2170
CH2CHF2
5-A-90



A-2171
CH2CHF2
6-A-90



A-2172
CH2CHF2
7-A-90



A-2173
CH2CHF2
4-A-91



A-2174
CH2CHF2
5-A-91



A-2175
CH2CHF2
6-A-91



A-2176
CH2CHF2
7-A-91



A-2177
CH2CHF2
4-A-92



A-2178
CH2CHF2
5-A-92



A-2179
CH2CHF2
6-A-92



A-2180
CH2CHF2
7-A-92



A-2181
CH2CHF2
4-A-93



A-2182
CH2CHF2
5-A-93



A-2183
CH2CHF2
6-A-93



A-2184
CH2CHF2
7-A-93



A-2185
CH2CHF2
4-A-94



A-2186
CH2CHF2
5-A-94



A-2187
CH2CHF2
6-A-94



A-2188
CH2CHF2
7-A-94



A-2189
CH2CHF2
4-A-95



A-2190
CH2CHF2
5-A-95



A-2191
CH2CHF2
6-A-95



A-2192
CH2CHF2
7-A-95



A-2193
CH2CHF2
4-A-96



A-2194
CH2CHF2
5-A-96



A-2195
CH2CHF2
6-A-96



A-2196
CH2CHF2
7-A-96



A-2197
CH2CHF2
4-A-97



A-2198
CH2CHF2
5-A-97



A-2199
CH2CHF2
6-A-97



A-2200
CH2CHF2
7-A-97



A-2201
CH2CHF2
4-A-98



A-2202
CH2CHF2
5-A-98



A-2203
CH2CHF2
6-A-98



A-2204
CH2CHF2
7-A-98



A-2205
CH2CHF2
4-A-99



A-2206
CH2CHF2
5-A-99



A-2207
CH2CHF2
6-A-99



A-2208
CH2CHF2
7-A-99



A-2209
CH2CHF2
4-A-100



A-2210
CH2CHF2
5-A-100



A-2211
CH2CHF2
6-A-100



A-2212
CH2CHF2
7-A-100



A-2213
CH2CHF2
4-A-101



A-2214
CH2CHF2
5-A-101



A-2215
CH2CHF2
6-A-101



A-2216
CH2CHF2
7-A-101



A-2217
CH2CHF2
4-A-102



A-2218
CH2CHF2
5-A-102



A-2219
CH2CHF2
6-A-102



A-2220
CH2CHF2
7-A-102



A-2221
CH2CHF2
4-A-103



A-2222
CH2CHF2
5-A-103



A-2223
CH2CHF2
6-A-103



A-2224
CH2CHF2
7-A-103



A-2225
CH2CHF2
4-A-104



A-2226
CH2CHF2
5-A-104



A-2227
CH2CHF2
6-A-104



A-2228
CH2CHF2
7-A-104



A-2229
CH2CHF2
4-A-104



A-2230
CH2CHF2
5-A-104



A-2231
CH2CHF2
6-A-104



A-2232
CH2CHF2
7-A-104



A-2233
CH2CHF2
4-A-105



A-2234
CH2CHF2
5-A-105



A-2235
CH2CHF2
6-A-105



A-2236
CH2CHF2
7-A-105



A-2237
CH2CHF2
4-A-106



A-2238
CH2CHF2
5-A-106



A-2239
CH2CHF2
6-A-106



A-2240
CH2CHF2
7-A-106



A-2241
CH2CHF2
4-A-107



A-2242
CH2CHF2
5-A-107



A-2243
CH2CHF2
6-A-107



A-2244
CH2CHF2
7-A-107



A-2245
CH2CHF2
4-A-108



A-2246
CH2CHF2
5-A-108



A-2247
CH2CHF2
6-A-108



A-2248
CH2CHF2
7-A-108



A-2249
CH2CHF2
4-A-109



A-2250
CH2CHF2
5-A-109



A-2251
CH2CHF2
6-A-109



A-2252
CH2CHF2
7-A-109



A-2253
CH2CHF2
4-A-110



A-2254
CH2CHF2
5-A-110



A-2255
CH2CHF2
6-A-110



A-2256
CH2CHF2
7-A-110



A-2257
CH2CHF2
4-A-111



A-2258
CH2CHF2
5-A-111



A-2259
CH2CHF2
6-A-111



A-2260
CH2CHF2
7-A-111



A-2261
CH3
H



A-2262
CH3
4-Cl



A-2263
CH3
5-Cl



A-2264
CH3
6-Cl



A-2265
CH3
7-Cl



A-2266
CH3
4-Br



A-2267
CH3
5-Br



A-2268
CH3
6-Br



A-2269
CH3
7-Br



A-2270
CH3
4-CN



A-2271
CH3
5-CN



A-2272
CH3
6-CN



A-2273
CH3
7-CN



A-2274
CH3
4-OH



A-2275
CH3
5-OH



A-2276
CH3
6-OH



A-2277
CH3
7-OH



A-2278
CH3
4-methyl



A-2279
CH3
5-methyl



A-2280
CH3
6-methyl



A-2281
CH3
7-methyl



A-2282
CH3
4-ethyl



A-2283
CH3
5-ethyl



A-2284
CH3
6-ethyl



A-2285
CH3
7-ethyl



A-2286
CH3
4-propyl



A-2287
CH3
5-propyl



A-2288
CH3
6-propyl



A-2289
CH3
7-propyl



A-2290
CH3
4-isopropyl



A-2291
CH3
5-isopropyl



A-2292
CH3
6-isopropyl



A-2293
CH3
7-isopropyl



A-2294
CH3
4-hydroxymethyl



A-2295
CH3
5-hydroxymethyl



A-2296
CH3
6-hydroxymethyl



A-2297
CH3
7-hydroxymethyl



A-2298
CH3
4-(2-hydroxyethyl)



A-2299
CH3
5-(2-hydroxyethyl)



A-2300
CH3
6-(2-hydroxyethyl)



A-2301
CH3
7-(2-hydroxyethyl)



A-2302
CH3
4-(1-hydroxyethyl)



A-2303
CH3
5-(1-hydroxyethyl)



A-2304
CH3
6-(1-hydroxyethyl)



A-2305
CH3
7-(1-hydroxyethyl)



A-2306
CH3
4-(3-hydroxypropyl)



A-2307
CH3
5-(3-hydroxypropyl)



A-2308
CH3
6-(3-hydroxypropyl)



A-2309
CH3
7-(3-hydroxypropyl)



A-2310
CH3
4-(2-hydroxypropyl)



A-2311
CH3
5-(2-hydroxypropyl)



A-2312
CH3
6-(2-hydroxypropyl)



A-2313
CH3
7-(2-hydroxypropyl)



A-2314
CH3
4-(1-hydroxypropyl)



A-2315
CH3
5-(1-hydroxypropyl)



A-2316
CH3
6-(1-hydroxypropyl)



A-2317
CH3
7-(1-hydroxypropyl)



A-2318
CH3
4-aminomethyl



A-2319
CH3
5-aminomethyl



A-2320
CH3
6-aminomethyl



A-2321
CH3
7-aminomethyl



A-2322
CH3
4-(2-aminoethyl)



A-2323
CH3
5-(2-aminoethyl)



A-2324
CH3
6-(2-aminoethyl)



A-2325
CH3
7-(2-aminoethyl)



A-2326
CH3
4-(1-aminoethyl)



A-2327
CH3
5-(1-aminoethyl)



A-2328
CH3
6-(1-aminoethyl)



A-2329
CH3
7-(1-aminoethyl)



A-2330
CH3
4-(3-aminopropyl)



A-2331
CH3
5-(3-aminopropyl)



A-2332
CH3
6-(3-aminopropyl)



A-2333
CH3
7-(3-aminopropyl)



A-2334
CH3
4-(2-aminopropyl)



A-2335
CH3
5-(2-aminopropyl)



A-2336
CH3
6-(2-aminopropyl)



A-2337
CH3
7-(2-aminopropyl)



A-2338
CH3
4-(1-aminopropyl)



A-2339
CH3
5-(1-aminopropyl)



A-2340
CH3
6-(1-aminopropyl)



A-2341
CH3
7-(1-aminopropyl)



A-2342
CH3
4-COOH



A-2343
CH3
5-COOH



A-2344
CH3
6-COOH



A-2345
CH3
7-COOH



A-2346
CH3
4-COOCH3



A-2347
CH3
5-COOCH3



A-2348
CH3
6-COOCH3



A-2349
CH3
7-COOCH3



A-2350
CH3
4-COOCH2CH3



A-2351
CH3
5-COOCH2CH3



A-2352
CH3
6-COOCH2CH3



A-2353
CH3
7-COOCH2CH3



A-2354
CH3
4-COOCF3



A-2355
CH3
5-COOCF3



A-2356
CH3
6-COOCF3



A-2357
CH3
7-COOCF3



A-2358
CH3
4-CONH2



A-2359
CH3
5-CONH2



A-2360
CH3
6-CONH2



A-2361
CH3
7-CONH2



A-2362
CH3
4-CONHCH3



A-2363
CH3
5-CONHCH3



A-2364
CH3
6-CONHCH3



A-2365
CH3
7-CONHCH3



A-2366
CH3
4-CON(CH3)2



A-2367
CH3
5-CON(CH3)2



A-2368
CH3
6-CON(CH3)2



A-2369
CH3
7-CON(CH3)2



A-2370
CH3
4-CONHCH2CH3



A-2371
CH3
5-CONHCH2CH3



A-2372
CH3
6-CONHCH2CH3



A-2373
CH3
7-CONHCH2CH3



A-2374
CH3
4-CON(CH2CH3)2



A-2375
CH3
5-CON(CH2CH3)2



A-2376
CH3
6-CON(CH2CH3)2



A-2377
CH3
7-CON(CH2CH3)2



A-2378
CH3
4-A-1



A-2379
CH3
5-A-1



A-2380
CH3
6-A-1



A-2381
CH3
7-A-1



A-2382
CH3
4-A-2



A-2383
CH3
5-A-2



A-2384
CH3
6-A-2



A-2385
CH3
7-A-2



A-2386
CH3
4-A-3



A-2387
CH3
5-A-3



A-2388
CH3
6-A-3



A-2389
CH3
7-A-3



A-2390
CH3
4-A-4



A-2391
CH3
5-A-4



A-2392
CH3
6-A-4



A-2393
CH3
7-A-4



A-2394
CH3
4-A-5



A-2395
CH3
5-A-5



A-2396
CH3
6-A-5



A-2397
CH3
7-A-5



A-2398
CH3
4-A-6



A-2399
CH3
5-A-6



A-2400
CH3
6-A-6



A-2401
CH3
7-A-6



A-2402
CH3
4-A-7



A-2403
CH3
5-A-7



A-2404
CH3
6-A-7



A-2405
CH3
7-A-7



A-2406
CH3
4-A-8



A-2407
CH3
5-A-8



A-2408
CH3
6-A-8



A-2409
CH3
7-A-8



A-2410
CH3
4-A-9



A-2411
CH3
5-A-9



A-2412
CH3
6-A-9



A-2413
CH3
7-A-9



A-2414
CH3
4-A-10



A-2415
CH3
5-A-10



A-2416
CH3
6-A-10



A-2417
CH3
7-A-10



A-2418
CH3
4-A-11



A-2419
CH3
5-A-11



A-2420
CH3
6-A-11



A-2421
CH3
7-A-11



A-2422
CH3
4-A-12



A-2423
CH3
5-A-12



A-2424
CH3
6-A-12



A-2425
CH3
7-A-12



A-2426
CH3
4-A-13



A-2427
CH3
5-A-13



A-2428
CH3
6-A-13



A-2429
CH3
7-A-13



A-2430
CH3
4-A-14



A-2431
CH3
5-A-14



A-2432
CH3
6-A-14



A-2433
CH3
7-A-14



A-2434
CH3
4-A-15



A-2435
CH3
5-A-15



A-2436
CH3
6-A-15



A-2437
CH3
7-A-15



A-2438
CH3
4-A-16



A-2439
CH3
5-A-16



A-2440
CH3
6-A-16



A-2441
CH3
7-A-16



A-2442
CH3
4-A-17



A-2443
CH3
5-A-17



A-2444
CH3
6-A-17



A-2445
CH3
7-A-17



A-2446
CH3
4-A-18



A-2447
CH3
5-A-18



A-2448
CH3
6-A-18



A-2449
CH3
7-A-18



A-2450
CH3
4-A-19



A-2451
CH3
5-A-19



A-2452
CH3
6-A-19



A-2453
CH3
7-A-19



A-2454
CH3
4-A-20



A-2455
CH3
5-A-20



A-2456
CH3
6-A-20



A-2457
CH3
7-A-20



A-2458
CH3
4-A-21



A-2459
CH3
5-A-21



A-2460
CH3
6-A-21



A-2461
CH3
7-A-21



A-2462
CH3
4-A-22



A-2463
CH3
5-A-22



A-2464
CH3
6-A-22



A-2465
CH3
7-A-22



A-2466
CH3
4-A-23



A-2467
CH3
5-A-23



A-2468
CH3
6-A-23



A-2469
CH3
7-A-23



A-2470
CH3
4-A-24



A-2471
CH3
5-A-24



A-2472
CH3
6-A-24



A-2473
CH3
7-A-24



A-2474
CH3
4-A-25



A-2475
CH3
5-A-25



A-2476
CH3
6-A-25



A-2477
CH3
7-A-25



A-2478
CH3
4-A-26



A-2479
CH3
5-A-26



A-2480
CH3
6-A-26



A-2481
CH3
7-A-26



A-2482
CH3
4-A-27



A-2483
CH3
5-A-27



A-2484
CH3
6-A-27



A-2485
CH3
7-A-27



A-2486
CH3
4-A-28



A-2487
CH3
5-A-28



A-2488
CH3
6-A-28



A-2489
CH3
7-A-28



A-2490
CH3
4-A-29



A-2491
CH3
5-A-29



A-2492
CH3
6-A-29



A-2493
CH3
7-A-29



A-2494
CH3
4-A-30



A-2495
CH3
5-A-30



A-2496
CH3
6-A-30



A-2497
CH3
7-A-30



A-2498
CH3
4-A-31



A-2499
CH3
5-A-31



A-2500
CH3
6-A-31



A-2501
CH3
7-A-31



A-2502
CH3
4-A-32



A-2503
CH3
5-A-32



A-2504
CH3
6-A-32



A-2505
CH3
7-A-32



A-2506
CH3
4-A-33



A-2507
CH3
5-A-33



A-2508
CH3
6-A-33



A-2509
CH3
7-A-33



A-2510
CH3
4-A-34



A-2511
CH3
5-A-34



A-2512
CH3
6-A-34



A-2513
CH3
7-A-34



A-2514
CH3
4-A-35



A-2515
CH3
5-A-35



A-2516
CH3
6-A-35



A-2517
CH3
7-A-35



A-2518
CH3
4-A-36



A-2519
CH3
5-A-36



A-2520
CH3
6-A-36



A-2521
CH3
7-A-36



A-2522
CH3
4-A-37



A-2523
CH3
5-A-37



A-2524
CH3
6-A-37



A-2525
CH3
7-A-37



A-2526
CH3
4-A-38



A-2527
CH3
5-A-38



A-2528
CH3
6-A-38



A-2529
CH3
7-A-38



A-2530
CH3
4-A-39



A-2531
CH3
5-A-39



A-2532
CH3
6-A-39



A-2533
CH3
7-A-39



A-2534
CH3
4-A-40



A-2535
CH3
5-A-40



A-2536
CH3
6-A-40



A-2537
CH3
7-A-40



A-2538
CH3
4-A-41



A-2539
CH3
5-A-41



A-2540
CH3
6-A-41



A-2541
CH3
7-A-41



A-2542
CH3
4-A-42



A-2543
CH3
5-A-42



A-2544
CH3
6-A-42



A-2545
CH3
7-A-42



A-2546
CH3
4-A-43



A-2547
CH3
5-A-43



A-2548
CH3
6-A-43



A-2549
CH3
7-A-43



A-2550
CH3
4-A-44



A-2551
CH3
5-A-44



A-2552
CH3
6-A-44



A-2553
CH3
7-A-44



A-2554
CH3
4-A-45



A-2555
CH3
5-A-45



A-2556
CH3
6-A-45



A-2557
CH3
7-A-45



A-2558
CH3
4-A-46



A-2559
CH3
5-A-46



A-2560
CH3
6-A-46



A-2561
CH3
7-A-46



A-2562
CH3
4-A-47



A-2563
CH3
5-A-47



A-2564
CH3
6-A-47



A-2565
CH3
7-A-47



A-2566
CH3
4-A-48



A-2567
CH3
5-A-48



A-2568
CH3
6-A-48



A-2569
CH3
7-A-48



A-2570
CH3
4-A-49



A-2571
CH3
5-A-49



A-2572
CH3
6-A-49



A-2573
CH3
7-A-49



A-2574
CH3
4-A-50



A-2575
CH3
5-A-50



A-2576
CH3
6-A-50



A-2577
CH3
7-A-50



A-2578
CH3
4-A-51



A-2579
CH3
5-A-51



A-2580
CH3
6-A-51



A-2581
CH3
7-A-51



A-2582
CH3
4-A-52



A-2583
CH3
5-A-52



A-2584
CH3
6-A-52



A-2585
CH3
7-A-52



A-2586
CH3
4-A-53



A-2587
CH3
5-A-53



A-2588
CH3
6-A-53



A-2589
CH3
7-A-53



A-2590
CH3
4-A-54



A-2591
CH3
5-A-54



A-2592
CH3
6-A-54



A-2593
CH3
7-A-54



A-2594
CH3
4-A-55



A-2595
CH3
5-A-55



A-2596
CH3
6-A-55



A-2597
CH3
7-A-55



A-2598
CH3
4-A-56



A-2599
CH3
5-A-56



A-2600
CH3
6-A-56



A-2601
CH3
7-A-56



A-2602
CH3
4-A-57



A-2603
CH3
5-A-57



A-2604
CH3
6-A-57



A-2605
CH3
7-A-57



A-2606
CH3
4-A-58



A-2607
CH3
5-A-58



A-2608
CH3
6-A-58



A-2609
CH3
7-A-58



A-2610
CH3
4-A-59



A-2611
CH3
5-A-59



A-2612
CH3
6-A-59



A-2613
CH3
7-A-59



A-2614
CH3
4-A-60



A-2615
CH3
5-A-60



A-2616
CH3
6-A-60



A-2617
CH3
7-A-60



A-2618
CH3
4-A-61



A-2619
CH3
5-A-61



A-2620
CH3
6-A-61



A-2621
CH3
7-A-61



A-2622
CH3
4-A-62



A-2623
CH3
5-A-62



A-2624
CH3
6-A-62



A-2625
CH3
7-A-62



A-2626
CH3
4-A-63



A-2627
CH3
5-A-63



A-2628
CH3
6-A-63



A-2629
CH3
7-A-63



A-2630
CH3
4-A-64



A-2631
CH3
5-A-64



A-2632
CH3
6-A-64



A-2633
CH3
7-A-64



A-2634
CH3
4-A-65



A-2635
CH3
5-A-65



A-2636
CH3
6-A-65



A-2637
CH3
7-A-65



A-2638
CH3
4-A-66



A-2639
CH3
5-A-66



A-2640
CH3
6-A-66



A-2641
CH3
7-A-66



A-2642
CH3
4-A-67



A-2643
CH3
5-A-67



A-2644
CH3
6-A-67



A-2645
CH3
7-A-67



A-2646
CH3
4-A-68



A-2647
CH3
5-A-68



A-2648
CH3
6-A-68



A-2649
CH3
7-A-68



A-2650
CH3
4-A-69



A-2651
CH3
5-A-69



A-2652
CH3
6-A-69



A-2653
CH3
7-A-69



A-2654
CH3
4-A-70



A-2655
CH3
5-A-70



A-2656
CH3
6-A-70



A-2657
CH3
7-A-70



A-2658
CH3
4-A-71



A-2659
CH3
5-A-71



A-2660
CH3
6-A-71



A-2661
CH3
7-A-71



A-2662
CH3
4-A-72



A-2663
CH3
5-A-72



A-2664
CH3
6-A-72



A-2665
CH3
7-A-72



A-2666
CH3
4-A-73



A-2667
CH3
5-A-73



A-2668
CH3
6-A-73



A-2669
CH3
7-A-73



A-2670
CH3
4-A-74



A-2671
CH3
5-A-74



A-2672
CH3
6-A-74



A-2673
CH3
7-A-74



A-2674
CH3
4-A-75



A-2675
CH3
5-A-75



A-2676
CH3
6-A-75



A-2677
CH3
7-A-75



A-2678
CH3
4-A-76



A-2679
CH3
5-A-76



A-2680
CH3
6-A-76



A-2681
CH3
7-A-76



A-2682
CH3
4-A-77



A-2683
CH3
5-A-77



A-2684
CH3
6-A-77



A-2685
CH3
7-A-77



A-2686
CH3
4-A-78



A-2687
CH3
5-A-78



A-2688
CH3
6-A-78



A-2689
CH3
7-A-78



A-2690
CH3
4-A-79



A-2691
CH3
5-A-79



A-2692
CH3
6-A-79



A-2693
CH3
7-A-79



A-2694
CH3
4-A-80



A-2695
CH3
5-A-80



A-2696
CH3
6-A-80



A-2697
CH3
7-A-80



A-2698
CH3
4-A-81



A-2699
CH3
5-A-81



A-2700
CH3
6-A-81



A-2701
CH3
7-A-81



A-2702
CH3
4-A-82



A-2703
CH3
5-A-82



A-2704
CH3
6-A-82



A-2705
CH3
7-A-82



A-2706
CH3
4-A-83



A-2707
CH3
5-A-83



A-2708
CH3
6-A-83



A-2709
CH3
7-A-83



A-2710
CH3
4-A-84



A-2711
CH3
5-A-84



A-2712
CH3
6-A-84



A-2713
CH3
7-A-84



A-2714
CH3
4-A-85



A-2715
CH3
5-A-85



A-2716
CH3
6-A-85



A-2717
CH3
7-A-85



A-2718
CH3
4-A-86



A-2719
CH3
5-A-86



A-2720
CH3
6-A-86



A-2721
CH3
7-A-86



A-2722
CH3
4-A-87



A-2723
CH3
5-A-87



A-2724
CH3
6-A-87



A-2725
CH3
7-A-87



A-2726
CH3
4-A-88



A-2727
CH3
5-A-88



A-2728
CH3
6-A-88



A-2729
CH3
7-A-88



A-2730
CH3
4-A-89



A-2731
CH3
5-A-89



A-2732
CH3
6-A-89



A-2733
CH3
7-A-89



A-2734
CH3
4-A-90



A-2735
CH3
5-A-90



A-2736
CH3
6-A-90



A-2737
CH3
7-A-90



A-2738
CH3
4-A-91



A-2739
CH3
5-A-91



A-2740
CH3
6-A-91



A-2741
CH3
7-A-91



A-2742
CH3
4-A-92



A-2743
CH3
5-A-92



A-2744
CH3
6-A-92



A-2745
CH3
7-A-92



A-2746
CH3
4-A-93



A-2747
CH3
5-A-93



A-2748
CH3
6-A-93



A-2749
CH3
7-A-93



A-2750
CH3
4-A-94



A-2751
CH3
5-A-94



A-2752
CH3
6-A-94



A-2753
CH3
7-A-94



A-2754
CH3
4-A-95



A-2755
CH3
5-A-95



A-2756
CH3
6-A-95



A-2757
CH3
7-A-95



A-2758
CH3
4-A-96



A-2759
CH3
5-A-96



A-2760
CH3
6-A-96



A-2761
CH3
7-A-96



A-2762
CH3
4-A-97



A-2763
CH3
5-A-97



A-2764
CH3
6-A-97



A-2765
CH3
7-A-97



A-2766
CH3
4-A-98



A-2767
CH3
5-A-98



A-2768
CH3
6-A-98



A-2769
CH3
7-A-98



A-2770
CH3
4-A-99



A-2771
CH3
5-A-99



A-2772
CH3
6-A-99



A-2773
CH3
7-A-99



A-2774
CH3
4-A-100



A-2775
CH3
5-A-100



A-2776
CH3
6-A-100



A-2777
CH3
7-A-100



A-2778
CH3
4-A-101



A-2779
CH3
5-A-101



A-2780
CH3
6-A-101



A-2781
CH3
7-A-101



A-2782
CH3
4-A-102



A-2783
CH3
5-A-102



A-2784
CH3
6-A-102



A-2785
CH3
7-A-102



A-2786
CH3
4-A-103



A-2787
CH3
5-A-103



A-2788
CH3
6-A-103



A-2789
CH3
7-A-103



A-2790
CH3
4-A-104



A-2791
CH3
5-A-104



A-2792
CH3
6-A-104



A-2793
CH3
7-A-104



A-2794
CH3
4-A-104



A-2795
CH3
5-A-104



A-2796
CH3
6-A-104



A-2797
CH3
7-A-104



A-2798
CH3
4-A-105



A-2799
CH3
5-A-105



A-2800
CH3
6-A-105



A-2801
CH3
7-A-105



A-2802
CH3
4-A-106



A-2803
CH3
5-A-106



A-2804
CH3
6-A-106



A-2805
CH3
7-A-106



A-2806
CH3
4-A-107



A-2807
CH3
5-A-107



A-2808
CH3
6-A-107



A-2809
CH3
7-A-107



A-2810
CH3
4-A-108



A-2811
CH3
5-A-108



A-2812
CH3
6-A-108



A-2813
CH3
7-A-108



A-2814
CH3
4-A-109



A-2815
CH3
5-A-109



A-2816
CH3
6-A-109



A-2817
CH3
7-A-109



A-2818
CH3
4-A-110



A-2819
CH3
5-A-110



A-2820
CH3
6-A-110



A-2821
CH3
7-A-110



A-2822
CH3
4-A-111



A-2823
CH3
5-A-111



A-2824
CH3
6-A-111



A-2825
CH3
7-A-111



A-2826
OH
H



A-2827
OH
4-Cl



A-2828
OH
5-Cl



A-2829
OH
6-Cl



A-2830
OH
7-Cl



A-2831
OH
4-Br



A-2832
OH
5-Br



A-2833
OH
6-Br



A-2834
OH
7-Br



A-2835
OH
4-CN



A-2836
OH
5-CN



A-2837
OH
6-CN



A-2838
OH
7-CN



A-2839
OH
4-OH



A-2840
OH
5-OH



A-2841
OH
6-OH



A-2842
OH
7-OH



A-2843
OH
4-methyl



A-2844
OH
5-methyl



A-2845
OH
6-methyl



A-2846
OH
7-methyl



A-2847
OH
4-ethyl



A-2848
OH
5-ethyl



A-2849
OH
6-ethyl



A-2850
OH
7-ethyl



A-2851
OH
4-propyl



A-2852
OH
5-propyl



A-2853
OH
6-propyl



A-2854
OH
7-propyl



A-2855
OH
4-isopropyl



A-2856
OH
5-isopropyl



A-2857
OH
6-isopropyl



A-2858
OH
7-isopropyl



A-2859
OH
4-hydroxymethyl



A-2860
OH
5-hydroxymethyl



A-2861
OH
6-hydroxymethyl



A-2862
OH
7-hydroxymethyl



A-2863
OH
4-(2-hydroxyethyl)



A-2864
OH
5-(2-hydroxyethyl)



A-2865
OH
6-(2-hydroxyethyl)



A-2866
OH
7-(2-hydroxyethyl)



A-2867
OH
4-(1-hydroxyethyl)



A-2868
OH
5-(1-hydroxyethyl)



A-2869
OH
6-(1-hydroxyethyl)



A-2870
OH
7-(1-hydroxyethyl)



A-2871
OH
4-(3-hydroxypropyl)



A-2872
OH
5-(3-hydroxypropyl)



A-2873
OH
6-(3-hydroxypropyl)



A-2874
OH
7-(3-hydroxypropyl)



A-2875
OH
4-(2-hydroxypropyl)



A-2876
OH
5-(2-hydroxypropyl)



A-2877
OH
6-(2-hydroxypropyl)



A-2878
OH
7-(2-hydroxypropyl)



A-2879
OH
4-(1-hydroxypropyl)



A-2880
OH
5-(1-hydroxypropyl)



A-2881
OH
6-(1-hydroxypropyl)



A-2882
OH
7-(1-hydroxypropyl)



A-2883
OH
4-aminomethyl



A-2884
OH
5-aminomethyl



A-2885
OH
6-aminomethyl



A-2886
OH
7-aminomethyl



A-2887
OH
4-(2-aminoethyl)



A-2888
OH
5-(2-aminoethyl)



A-2889
OH
6-(2-aminoethyl)



A-2890
OH
7-(2-aminoethyl)



A-2891
OH
4-(1-aminoethyl)



A-2892
OH
5-(1-aminoethyl)



A-2893
OH
6-(1-aminoethyl)



A-2894
OH
7-(1-aminoethyl)



A-2895
OH
4-(3-aminopropyl)



A-2896
OH
5-(3-aminopropyl)



A-2897
OH
6-(3-aminopropyl)



A-2898
OH
7-(3-aminopropyl)



A-2899
OH
4-(2-aminopropyl)



A-2900
OH
5-(2-aminopropyl)



A-2901
OH
6-(2-aminopropyl)



A-2902
OH
7-(2-aminopropyl)



A-2903
OH
4-(1-aminopropyl)



A-2904
OH
5-(1-aminopropyl)



A-2905
OH
6-(1-aminopropyl)



A-2906
OH
7-(1-aminopropyl)



A-2907
OH
4-COOH



A-2908
OH
5-COOH



A-2909
OH
6-COOH



A-2910
OH
7-COOH



A-2911
OH
4-COOCH3



A-2912
OH
5-COOCH3



A-2913
OH
6-COOCH3



A-2914
OH
7-COOCH3



A-2915
OH
4-COOCH2CH3



A-2916
OH
5-COOCH2CH3



A-2917
OH
6-COOCH2CH3



A-2918
OH
7-COOCH2CH3



A-2919
OH
4-COOCF3



A-2920
OH
5-COOCF3



A-2921
OH
6-COOCF3



A-2922
OH
7-COOCF3



A-2923
OH
4-CONH2



A-2924
OH
5-CONH2



A-2925
OH
6-CONH2



A-2926
OH
7-CONH2



A-2927
OH
4-CONHCH3



A-2928
OH
5-CONHCH3



A-2929
OH
6-CONHCH3



A-2930
OH
7-CONHCH3



A-2931
OH
4-CON(CH3)2



A-2932
OH
5-CON(CH3)2



A-2933
OH
6-CON(CH3)2



A-2934
OH
7-CON(CH3)2



A-2935
OH
4-CONHCH2CH3



A-2936
OH
5-CONHCH2CH3



A-2937
OH
6-CONHCH2CH3



A-2938
OH
7-CONHCH2CH3



A-2939
OH
4-CON(CH2CH3)2



A-2940
OH
5-CON(CH2CH3)2



A-2941
OH
6-CON(CH2CH3)2



A-2942
OH
7-CON(CH2CH3)2



A-2943
OH
4-A-1



A-2944
OH
5-A-1



A-2945
OH
6-A-1



A-2946
OH
7-A-1



A-2947
OH
4-A-2



A-2948
OH
5-A-2



A-2949
OH
6-A-2



A-2950
OH
7-A-2



A-2951
OH
4-A-3



A-2952
OH
5-A-3



A-2953
OH
6-A-3



A-2954
OH
7-A-3



A-2955
OH
4-A-4



A-2956
OH
5-A-4



A-2957
OH
6-A-4



A-2958
OH
7-A-4



A-2959
OH
4-A-5



A-2960
OH
5-A-5



A-2961
OH
6-A-5



A-2962
OH
7-A-5



A-2963
OH
4-A-6



A-2964
OH
5-A-6



A-2965
OH
6-A-6



A-2966
OH
7-A-6



A-2967
OH
4-A-7



A-2968
OH
5-A-7



A-2969
OH
6-A-7



A-2970
OH
7-A-7



A-2971
OH
4-A-8



A-2972
OH
5-A-8



A-2973
OH
6-A-8



A-2974
OH
7-A-8



A-2975
OH
4-A-9



A-2976
OH
5-A-9



A-2977
OH
6-A-9



A-2978
OH
7-A-9



A-2979
OH
4-A-10



A-2980
OH
5-A-10



A-2981
OH
6-A-10



A-2982
OH
7-A-10



A-2983
OH
4-A-11



A-2984
OH
5-A-11



A-2985
OH
6-A-11



A-2986
OH
7-A-11



A-2987
OH
4-A-12



A-2988
OH
5-A-12



A-2989
OH
6-A-12



A-2990
OH
7-A-12



A-2991
OH
4-A-13



A-2992
OH
5-A-13



A-2993
OH
6-A-13



A-2994
OH
7-A-13



A-2995
OH
4-A-14



A-2996
OH
5-A-14



A-2997
OH
6-A-14



A-2998
OH
7-A-14



A-2999
OH
4-A-15



A-3000
OH
5-A-15



A-3001
OH
6-A-15



A-3002
OH
7-A-15



A-3003
OH
4-A-16



A-3004
OH
5-A-16



A-3005
OH
6-A-16



A-3006
OH
7-A-16



A-3007
OH
4-A-17



A-3008
OH
5-A-17



A-3009
OH
6-A-17



A-3010
OH
7-A-17



A-3011
OH
4-A-18



A-3012
OH
5-A-18



A-3013
OH
6-A-18



A-3014
OH
7-A-18



A-3015
OH
4-A-19



A-3016
OH
5-A-19



A-3017
OH
6-A-19



A-3018
OH
7-A-19



A-3019
OH
4-A-20



A-3020
OH
5-A-20



A-3021
OH
6-A-20



A-3022
OH
7-A-20



A-3023
OH
4-A-21



A-3024
OH
5-A-21



A-3025
OH
6-A-21



A-3026
OH
7-A-21



A-3027
OH
4-A-22



A-3028
OH
5-A-22



A-3029
OH
6-A-22



A-3030
OH
7-A-22



A-3031
OH
4-A-23



A-3032
OH
5-A-23



A-3033
OH
6-A-23



A-3034
OH
7-A-23



A-3035
OH
4-A-24



A-3036
OH
5-A-24



A-3037
OH
6-A-24



A-3038
OH
7-A-24



A-3039
OH
4-A-25



A-3040
OH
5-A-25



A-3041
OH
6-A-25



A-3042
OH
7-A-25



A-3043
OH
4-A-26



A-3044
OH
5-A-26



A-3045
OH
6-A-26



A-3046
OH
7-A-26



A-3047
OH
4-A-27



A-3048
OH
5-A-27



A-3049
OH
6-A-27



A-3050
OH
7-A-27



A-3051
OH
4-A-28



A-3052
OH
5-A-28



A-3053
OH
6-A-28



A-3054
OH
7-A-28



A-3055
OH
4-A-29



A-3056
OH
5-A-29



A-3057
OH
6-A-29



A-3058
OH
7-A-29



A-3059
OH
4-A-30



A-3060
OH
5-A-30



A-3061
OH
6-A-30



A-3062
OH
7-A-30



A-3063
OH
4-A-31



A-3064
OH
5-A-31



A-3065
OH
6-A-31



A-3066
OH
7-A-31



A-3067
OH
4-A-32



A-3068
OH
5-A-32



A-3069
OH
6-A-32



A-3070
OH
7-A-32



A-3071
OH
4-A-33



A-3072
OH
5-A-33



A-3073
OH
6-A-33



A-3074
OH
7-A-33



A-3075
OH
4-A-34



A-3076
OH
5-A-34



A-3077
OH
6-A-34



A-3078
OH
7-A-34



A-3079
OH
4-A-35



A-3080
OH
5-A-35



A-3081
OH
6-A-35



A-3082
OH
7-A-35



A-3083
OH
4-A-36



A-3084
OH
5-A-36



A-3085
OH
6-A-36



A-3086
OH
7-A-36



A-3087
OH
4-A-37



A-3088
OH
5-A-37



A-3089
OH
6-A-37



A-3090
OH
7-A-37



A-3091
OH
4-A-38



A-3092
OH
5-A-38



A-3093
OH
6-A-38



A-3094
OH
7-A-38



A-3095
OH
4-A-39



A-3096
OH
5-A-39



A-3097
OH
6-A-39



A-3098
OH
7-A-39



A-3099
OH
4-A-40



A-3100
OH
5-A-40



A-3101
OH
6-A-40



A-3102
OH
7-A-40



A-3103
OH
4-A-41



A-3104
OH
5-A-41



A-3105
OH
6-A-41



A-3106
OH
7-A-41



A-3107
OH
4-A-42



A-3108
OH
5-A-42



A-3109
OH
6-A-42



A-3110
OH
7-A-42



A-3111
OH
4-A-43



A-3112
OH
5-A-43



A-3113
OH
6-A-43



A-3114
OH
7-A-43



A-3115
OH
4-A-44



A-3116
OH
5-A-44



A-3117
OH
6-A-44



A-3118
OH
7-A-44



A-3119
OH
4-A-45



A-3120
OH
5-A-45



A-3121
OH
6-A-45



A-3122
OH
7-A-45



A-3123
OH
4-A-46



A-3124
OH
5-A-46



A-3125
OH
6-A-46



A-3126
OH
7-A-46



A-3127
OH
4-A-47



A-3128
OH
5-A-47



A-3129
OH
6-A-47



A-3130
OH
7-A-47



A-3131
OH
4-A-48



A-3132
OH
5-A-48



A-3133
OH
6-A-48



A-3134
OH
7-A-48



A-3135
OH
4-A-49



A-3136
OH
5-A-49



A-3137
OH
6-A-49



A-3138
OH
7-A-49



A-3139
OH
4-A-50



A-3140
OH
5-A-50



A-3141
OH
6-A-50



A-3142
OH
7-A-50



A-3143
OH
4-A-51



A-3144
OH
5-A-51



A-3145
OH
6-A-51



A-3146
OH
7-A-51



A-3147
OH
4-A-52



A-3148
OH
5-A-52



A-3149
OH
6-A-52



A-3150
OH
7-A-52



A-3151
OH
4-A-53



A-3152
OH
5-A-53



A-3153
OH
6-A-53



A-3154
OH
7-A-53



A-3155
OH
4-A-54



A-3156
OH
5-A-54



A-3157
OH
6-A-54



A-3158
OH
7-A-54



A-3159
OH
4-A-55



A-3160
OH
5-A-55



A-3161
OH
6-A-55



A-3162
OH
7-A-55



A-3163
OH
4-A-56



A-3164
OH
5-A-56



A-3165
OH
6-A-56



A-3166
OH
7-A-56



A-3167
OH
4-A-57



A-3168
OH
5-A-57



A-3169
OH
6-A-57



A-3170
OH
7-A-57



A-3171
OH
4-A-58



A-3172
OH
5-A-58



A-3173
OH
6-A-58



A-3174
OH
7-A-58



A-3175
OH
4-A-59



A-3176
OH
5-A-59



A-3177
OH
6-A-59



A-3178
OH
7-A-59



A-3179
OH
4-A-60



A-3180
OH
5-A-60



A-3181
OH
6-A-60



A-3182
OH
7-A-60



A-3183
OH
4-A-61



A-3184
OH
5-A-61



A-3185
OH
6-A-61



A-3186
OH
7-A-61



A-3187
OH
4-A-62



A-3188
OH
5-A-62



A-3189
OH
6-A-62



A-3190
OH
7-A-62



A-3191
OH
4-A-63



A-3192
OH
5-A-63



A-3193
OH
6-A-63



A-3194
OH
7-A-63



A-3195
OH
4-A-64



A-3196
OH
5-A-64



A-3197
OH
6-A-64



A-3198
OH
7-A-64



A-3199
OH
4-A-65



A-3200
OH
5-A-65



A-3201
OH
6-A-65



A-3202
OH
7-A-65



A-3203
OH
4-A-66



A-3204
OH
5-A-66



A-3205
OH
6-A-66



A-3206
OH
7-A-66



A-3207
OH
4-A-67



A-3208
OH
5-A-67



A-3209
OH
6-A-67



A-3210
OH
7-A-67



A-3211
OH
4-A-68



A-3212
OH
5-A-68



A-3213
OH
6-A-68



A-3214
OH
7-A-68



A-3215
OH
4-A-69



A-3216
OH
5-A-69



A-3217
OH
6-A-69



A-3218
OH
7-A-69



A-3219
OH
4-A-70



A-3220
OH
5-A-70



A-3221
OH
6-A-70



A-3222
OH
7-A-70



A-3223
OH
4-A-71



A-3224
OH
5-A-71



A-3225
OH
6-A-71



A-3226
OH
7-A-71



A-3227
OH
4-A-72



A-3228
OH
5-A-72



A-3229
OH
6-A-72



A-3230
OH
7-A-72



A-3231
OH
4-A-73



A-3232
OH
5-A-73



A-3233
OH
6-A-73



A-3234
OH
7-A-73



A-3235
OH
4-A-74



A-3236
OH
5-A-74



A-3237
OH
6-A-74



A-3238
OH
7-A-74



A-3239
OH
4-A-75



A-3240
OH
5-A-75



A-3241
OH
6-A-75



A-3242
OH
7-A-75



A-3243
OH
4-A-76



A-3244
OH
5-A-76



A-3245
OH
6-A-76



A-3246
OH
7-A-76



A-3247
OH
4-A-77



A-3248
OH
5-A-77



A-3249
OH
6-A-77



A-3250
OH
7-A-77



A-3251
OH
4-A-78



A-3252
OH
5-A-78



A-3253
OH
6-A-78



A-3254
OH
7-A-78



A-3255
OH
4-A-79



A-3256
OH
5-A-79



A-3257
OH
6-A-79



A-3258
OH
7-A-79



A-3259
OH
4-A-80



A-3260
OH
5-A-80



A-3261
OH
6-A-80



A-3262
OH
7-A-80



A-3263
OH
4-A-81



A-3264
OH
5-A-81



A-3265
OH
6-A-81



A-3266
OH
7-A-81



A-3267
OH
4-A-82



A-3268
OH
5-A-82



A-3269
OH
6-A-82



A-3270
OH
7-A-82



A-3271
OH
4-A-83



A-3272
OH
5-A-83



A-3273
OH
6-A-83



A-3274
OH
7-A-83



A-3275
OH
4-A-84



A-3276
OH
5-A-84



A-3277
OH
6-A-84



A-3278
OH
7-A-84



A-3279
OH
4-A-85



A-3280
OH
5-A-85



A-3281
OH
6-A-85



A-3282
OH
7-A-85



A-3283
OH
4-A-86



A-3284
OH
5-A-86



A-3285
OH
6-A-86



A-3286
OH
7-A-86



A-3287
OH
4-A-87



A-3288
OH
5-A-87



A-3289
OH
6-A-87



A-3290
OH
7-A-87



A-3291
OH
4-A-88



A-3292
OH
5-A-88



A-3293
OH
6-A-88



A-3294
OH
7-A-88



A-3295
OH
4-A-89



A-3296
OH
5-A-89



A-3297
OH
6-A-89



A-3298
OH
7-A-89



A-3299
OH
4-A-90



A-3300
OH
5-A-90



A-3301
OH
6-A-90



A-3302
OH
7-A-90



A-3303
OH
4-A-91



A-3304
OH
5-A-91



A-3305
OH
6-A-91



A-3306
OH
7-A-91



A-3307
OH
4-A-92



A-3308
OH
5-A-92



A-3309
OH
6-A-92



A-3310
OH
7-A-92



A-3311
OH
4-A-93



A-3312
OH
5-A-93



A-3313
OH
6-A-93



A-3314
OH
7-A-93



A-3315
OH
4-A-94



A-3316
OH
5-A-94



A-3317
OH
6-A-94



A-3318
OH
7-A-94



A-3319
OH
4-A-95



A-3320
OH
5-A-95



A-3321
OH
6-A-95



A-3322
OH
7-A-95



A-3323
OH
4-A-96



A-3324
OH
5-A-96



A-3325
OH
6-A-96



A-3326
OH
7-A-96



A-3327
OH
4-A-97



A-3328
OH
5-A-97



A-3329
OH
6-A-97



A-3330
OH
7-A-97



A-3331
OH
4-A-98



A-3332
OH
5-A-98



A-3333
OH
6-A-98



A-3334
OH
7-A-98



A-3335
OH
4-A-99



A-3336
OH
5-A-99



A-3337
OH
6-A-99



A-3338
OH
7-A-99



A-3339
OH
4-A-100



A-3340
OH
5-A-100



A-3341
OH
6-A-100



A-3342
OH
7-A-100



A-3343
OH
4-A-101



A-3344
OH
5-A-101



A-3345
OH
6-A-101



A-3346
OH
7-A-101



A-3347
OH
4-A-102



A-3348
OH
5-A-102



A-3349
OH
6-A-102



A-3350
OH
7-A-102



A-3351
OH
4-A-103



A-3352
OH
5-A-103



A-3353
OH
6-A-103



A-3354
OH
7-A-103



A-3355
OH
4-A-104



A-3356
OH
5-A-104



A-3357
OH
6-A-104



A-3358
OH
7-A-104



A-3359
OH
4-A-104



A-3360
OH
5-A-104



A-3361
OH
6-A-104



A-3362
OH
7-A-104



A-3363
OH
4-A-105



A-3364
OH
5-A-105



A-3365
OH
6-A-105



A-3366
OH
7-A-105



A-3367
OH
4-A-106



A-3368
OH
5-A-106



A-3369
OH
6-A-106



A-3370
OH
7-A-106



A-3371
OH
4-A-107



A-3372
OH
5-A-107



A-3373
OH
6-A-107



A-3374
OH
7-A-107



A-3375
OH
4-A-108



A-3376
OH
5-A-108



A-3377
OH
6-A-108



A-3378
OH
7-A-108



A-3379
OH
4-A-109



A-3380
OH
5-A-109



A-3381
OH
6-A-109



A-3382
OH
7-A-109



A-3383
OH
4-A-110



A-3384
OH
5-A-110



A-3385
OH
6-A-110



A-3386
OH
7-A-110



A-3387
OH
4-A-111



A-3388
OH
5-A-111



A-3389
OH
6-A-111



A-3390
OH
7-A-111










Among the above compounds, preference is given to compounds of formulae I.1 to I.21, I.37 to I.57, I.73 to I.93 and I.109 to I.129. More preference is given to compounds I.1 to I.6, I.10 to I.17, I.37 to I.42, I.46 to I.53, I.73 to I.78, I.82 to I.89, I.109 to I.114 and I.118 to I.125. Even more preference is given to compounds of formulae I.1, I.2, I.3, I.10, I.11, I.12, I.13, I.14, I.15, I.16, I.17, I.37, I.38, I.39, I.46, I.47, I.48, I.49, I.50, I.51, I.52, I.53, I.74, I.77, I.83, I.84, I.87, I.88, I.109, I.110, I.111, I.113, I.118, I.119, I.120 and I.124. Particular preference is given to compounds of formulae I.10, I.11, I.12, I.13, I.46, I.47, I.48, I.49, I.110 and I.120. Specific preference is given to compounds of formulae I.13, I.46, I.49, I.110 and I.120.


The compounds of the present invention can be prepared by analogy to routine techniques a skilled person is familiar with. In particular, the compounds of the formula IA and IB can be prepared according to the following schemes, wherein the variables, if not stated otherwise, are as defined above. In the below schemes, compounds of formula IA are expressed as target molecules. However, the same reactions apply to the syntheses of compounds IB.


Compounds of formula IA can be prepared by reacting the indolol compound 1 with the pyridyl derivative 2, where X is Cl or Br. The reaction can be carried out under the conditions of a Heck reaction, via Pd-catalysed cross coupling, generally in the presence of a base. Alternatively, 1 and 2 can be reacted in a nucleophilic aromatic substitution reaction in the presence of a strong, non-nucleophilic base, such as NaH, LDA or preferably sodium bis(trimethylsilyl)amide (NaHMDS). If suitable, the nucleophilic aromatic substitution reaction can also be carried out with the N-oxide of the pyridyl compound 2.




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Compounds 1 are either commercially available or can be synthesized by procedures generally known in the art. For example, generally known substitution reactions for introducing different substituents R1 (different from hydrogen) can be applied. For instance, a compound 1 wherein at least one substituent R1 is hydrogen can be halogenated, for example by reaction with N-chlorosuccinimide, N-bromosuccinimide or N-iodosuccinimide, to give a compound 1 wherein this R1 is Cl, Br or I. This in turn can be reacted with CuCN to give a compound 1 wherein this R1 is CN. An exemplary reaction pattern using indolone as a scaffold for compound 1 is shown in scheme 2.




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If R1 is Ar, this substituent can be introduced via a Suzuki coupling reaction, as shown in schemes 3 and 4 exemplarily for indolone as a scaffold for compound 1. BRR′ is a boronic acid residue [B(OH)2] or a boronic ester group, such as B(O-t-butyl)2, B(—O—C(CH3)2—C(CH3)2—O—) and the like. The reaction is carried in the presence of a palladium catalyst, especially a palladium phosphane catalyst, such as tetrakis(triphenyl-phosphine) palladium(0), and of a base, such as NaOH, Na2CO3, NaHCO3, Na3PO4, sodium methanolate, sodium ethanolate and the like.




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Compounds 2 are either commercially available or can be synthesized by procedures generally known in the art.


Compounds 2, wherein R3 and R4 form together a group —(CH2)3—C(O)— (compound 2.1), can for example be prepared by reacting 3-aminocyclohex-2-enone 9 with an alkylpropiolate, e.g. methylpropiolate 10, and subsequently halogenating the keto/enol group of 11 with a halogenating agent, such as POCl3, as shown in scheme 5. The same reaction sequence can be applied for producing compounds, wherein R3 and R4 form together a group —(CH2)2—C(O)— by using 3-aminocyclopent-2-enone instead of 9, for producing compounds, wherein R3 and R4 form together a group —C(O)—(CH2)3— by using 2-aminocyclohex-2-enone instead of 9, for producing compounds, wherein R3 and R4 form together a group —C(O)—(CH2)2— by using 2-aminocyclopent-2-enone instead of 9, etc.




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For producing compounds 2, wherein R4 and R5 form together a group —C(O)—O—CH2— or —CH2—NRc—CH2—, the reaction sequence shown in scheme 6 can be used. The carboxyl group of 12 is suitably first converted into its acid chloride, e.g. via reaction with thionyl chloride or oxalylchloride, and the acid chloride is then reacted with diisopropylamine to the amide 13. Deprotonation with LDA in the activated 4-position yields a carbanion which nucleophilicaly attacks dimethylformamide to give the amide-aldehyde 14. Reduction of the aldehyde group, e.g. with NaBH4, and subsequent esterification leads to the furanone 15. If desired, this can be subjected to a reductive ring-opening reaction to the dimethylol 16, which is converted into the respective dimethylchloride 17. Reaction of 17 with a primary amine R—NH2, where advantageously R is a group which can be easily removed, such as benzyl or PMB (PMB=para-methoxybenzyl), yields the pyrrolidinypyridine 18, which is deprotected to 19. Deprotection is carried out depending on the group R, e.g. with HCl or 1-chloroethylchloroformiate if R is benzyl or a substituted benzyl, such as PMB.




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Compounds 2, wherein R5 and R6 form together a group —C(O)—O—CH2— or —CH2—NRc—CH2—, can be prepared in an analogous reaction sequence, however starting from 2-chloro-nicotinic acid.


Compounds 2, wherein R4 and R5 form together a group —(CH2)4—, can be prepared by the reaction sequence shown in scheme 7. 20 is subjected to a ring-closing reaction with ammonium carbonate under heating (230° C.), as described in Chemische Berichte 1948, 81, 279-285. Alternatively, 21 is reacted according to the procedure described in J. Chem. Soc. 1932, 2426-2430 to 22. The diol 22 is then converted into the respective dichloride 23, e.g. with phosphoryl chloride. Reaction with zinc powder and aqueous HCl as described in Chemische Berichte 1948, 81, 279-285 finally yields 24.




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Compounds 2, wherein R4 and R5 form together a group —CH2—O—CH2— or —CH2—O—CH2—CH2—, can be prepared as shown in scheme 8. 25 or 28 are reacted with triethylsilane, Mn(IV) oxide and trifluoroacetic acid as described in Tetrahedron Lett. 2008, 49(47), 6701-6703. Removal of one chlorine atom is accomplished using zinc powder and aqueous HCl, as described in Chemische Berichte 1948, 81, 279-285.




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Compounds 2, wherein R4 and R5 form together a group —CH2—CH2—NRc—C(O)— are known and described, for example, in EP-A-1180514. Compounds 2, wherein R4 and R5 form together a group —CH2—CH2—NRc—CH2—, can be prepared by reducing compound 31, as shown in scheme 9. Reduction can be carried out, for example, by using a borane reduction agent, such as 9-BBN. Compound 31 is known from EP-A-1180514.




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Compounds IA can be converted into compounds IB, wherein R2 is fluorine, by reaction of IA with a suitable fluorinating agent, such as 1-fluoro-2,4,6-trimethylpyridinium triflate in the presence of a suitable base, such as n-butyllithium or sodium bis(trimethylsilyl)-amide in a suitable solvent, such as tetrahydrofuran or dioxane at from −40° C. to 80° C.


If not indicated otherwise, the above-described reactions are generally carried out in a solvent at temperatures between room temperature and the boiling temperature of the solvent employed. Alternatively, the activation energy which is required for the reaction can be introduced into the reaction mixture using microwaves, something which has proved to be of value, in particular, in the case of the reactions catalyzed by transition metals (with regard to reactions using microwaves, see Tetrahedron 2001, 57, p. 9199 ff. p. 9225 ff. and also, in a general manner, “Microwaves in Organic Synthesis”, André Loupy (Ed.), Wiley-VCH 2002.


The acid addition salts of compounds IA and IB are prepared in a customary manner by mixing the free base with a corresponding acid, where appropriate in solution in an organic solvent, for example a lower alcohol, such as methanol, ethanol or propanol, an ether, such as methyl tert-butyl ether or diisopropyl ether, a ketone, such as acetone or methyl ethyl ketone, or an ester, such as ethyl acetate.


The present invention moreover relates to compounds of formula I as defined above, wherein at least one of the atoms has been replaced by its stable, non-radioactive isotope (e.g., hydrogen by deuterium, 13C by 13C, 14N by 15N, 16O by 18O) and preferably wherein at least one hydrogen atom has been replaced by a deuterium atom.


Of course, the compounds according to the invention contain more of the respective isotope than this naturally occurs and thus is anyway present in the compounds I.


Stable isotopes (e.g., deuterium, 13C, 15N, 18O) are nonradioactive isotopes which contain one additional neutron than the normally abundant isotope of the respective atom. Deuterated compounds have been used in pharmaceutical research to investigate the in vivo metabolic fate of the compounds by evaluation of the mechanism of action and metabolic pathway of the non deuterated parent compound (Blake et al. J. Pharm. Sci. 64, 3, 367-391 (1975)). Such metabolic studies are important in the design of safe, effective therapeutic drugs, either because the in vivo active compound administered to the patient or because the metabolites produced from the parent compound prove to be toxic or carcinogenic (Foster et al., Advances in Drug Research Vol. 14, pp. 2-36, Academic press, London, 1985; Kato et al., J. Labelled Comp. Radiopharmaceut., 36(10):927-932 (1995); Kushner et al., Can. J. Physiol. Pharmacol., 77, 79-88 (1999).


Incorporation of a heavy atom particularly substitution of deuterium for hydrogen, can give rise to an isotope effect that could alter the pharmacokinetics of the drug. This effect is usually insignificant if the label is placed at a metabolically inert position of the molecule.


Stable isotope labeling of a drug can alter its physico-chemical properties such as pKa and lipid solubility. These changes may influence the fate of the drug at different steps along its passage through the body. Absorption, distribution, metabolism or excretion can be changed. Absorption and distribution are processes that depend primarily on the molecular size and the lipophilicity of the substance. These effects and alterations can affect the pharmacodynamic response of the drug molecule if the isotopic substitution affects a region involved in a ligand-receptor interaction.


Drug metabolism can give rise to large isotopic effect if the breaking of a chemical bond to a deuterium atom is the rate limiting step in the process. While some of the physical properties of a stable isotope-labeled molecule are different from those of the unlabeled one, the chemical and biological properties are the same, with one important exception: because of the increased mass of the heavy isotope, any bond involving the heavy isotope and another atom will be stronger than the same bond between the light isotope and that atom. In any reaction in which the breaking of this bond is the rate limiting step, the reaction will proceed slower for the molecule with the heavy isotope due to “kinetic isotope effect”. A reaction involving breaking a C-D bond can be up to 700 percent slower than a similar reaction involving breaking a C—H bond. If the C-D bond is not involved in any of the steps leading to the metabolite, there may not be any effect to alter the behavior of the drug. If a deuterium is placed at a site involved in the metabolism of a drug, an isotope effect will be observed only if breaking of the C-D bond is the rate limiting step. There is evidence to suggest that whenever cleavage of an aliphatic C—H bond occurs, usually by oxidation catalyzed by a mixed-function oxidase, replacement of the hydrogen by deuterium will lead to observable isotope effect. It is also important to understand that the incorporation of deuterium at the site of metabolism slows its rate to the point where another metabolite produced by attack at a carbon atom not substituted by deuterium becomes the major pathway a process called “metabolic switching”.


Deuterium tracers, such as deuterium-labeled drugs and doses, in some cases repeatedly, of thousands of milligrams of deuterated water, are also used in healthy humans of all ages, including neonates and pregnant women, without reported incident (e.g. Pons G and Rey E, Pediatrics 1999 104: 633; Coward W A et al., Lancet 1979 7: 13; Schwarcz H P, Control. Clin. Trials 1984 5(4 Suppl): 573; Rodewald L E et al., J. Pediatr. 1989 114: 885; Butte N F et al. Br. J. Nutr. 1991 65: 3; MacLennan A H et al. Am. J. Obstet. Gynecol. 1981 139: 948). Thus, it is clear that any deuterium released, for instance, during the metabolism of compounds of this invention poses no health risk.


The weight percentage of hydrogen in a mammal (approximately 9%) and natural abundance of deuterium (approximately 0.015%) indicates that a 70 kg human normally contains nearly a gram of deuterium. Furthermore, replacement of up to about 15% of normal hydrogen with deuterium has been effected and maintained for a period of days to weeks in mammals, including rodents and dogs, with minimal observed adverse effects (Czajka D M and Finkel A J, Ann. N.Y. Acad. Sci. 1960 84: 770; Thomson J F, Ann. New York Acad. Sci. 1960 84: 736; Czakja D M et al., Am. J. Physiol. 1961 201: 357). Higher deuterium concentrations, usually in excess of 20%, can be toxic in animals. However, acute replacement of as high as 15%-23% of the hydrogen in humans' fluids with deuterium was found not to cause toxicity (Blagojevic N et al. in “Dosimetry & Treatment Planning for Neutron Capture Therapy”, Zamenhof R, Solares G and Harling O Eds. 1994. Advanced Medical Publishing, Madison Wis. pp. 125-134; Diabetes Metab. 23: 251 (1997)).


Increasing the amount of deuterium present in a compound above its natural abundance is called enrichment or deuterium-enrichment. Examples of the amount of enrichment include from about 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 16, 21, 25, 29, 33, 37, 42, 46, 50, 54, 58, 63, 67, 71, 75, 79, 84, 88, 92, 96, to about 100 mol %.


The hydrogens present on a particular organic compound have different capacities for exchange with deuterium. Certain hydrogen atoms are easily exchangeable under physiological conditions and, if replaced by deuterium atoms, it is expected that they will readily exchange for protons after administration to a patient. Certain hydrogen atoms may be exchanged for deuterium atoms by the action of a deuteric acid such as D2SO4/D2O. Alternatively, deuterium atoms may be incorporated in various combinations during the synthesis of compounds of the invention. Certain hydrogen atoms are not easily exchangeable for deuterium atoms. However, deuterium atoms at the remaining positions may be incorporated by the use of deuterated starting materials or intermediates during the construction of compounds of the invention.


Deuterated and deuterium-enriched compounds of the invention can be prepared by using known methods described in the literature. Such methods can be carried out utilizing corresponding deuterated and optionally, other isotope-containing reagents and/or intermediates to synthesize the compounds delineated herein, or invoking standard synthetic protocols known in the art for introducing isotopic atoms to a chemical structure. Relevant procedures and intermediates are disclosed, for instance in Lizondo, J et al., Drugs Fut, 21(11), 1116 (1996); Brickner, S J et al., J Med Chem, 39(3), 673 (1996); Mallesham, B et al., Org Lett, 5(7), 963 (2003); PCT publications WO1997010223, WO2005099353, WO1995007271, WO2006008754; U.S. Pat. Nos. 7,538,189; 7,534,814; 7,531,685; 7,528,131; 7,521,421; 7,514,068; 7,511,013; and US Patent Application Publication Nos. 20090137457; 20090131485; 20090131363; 20090118238; 20090111840; 20090105338; 20090105307; 20090105147; 20090093422; 20090088416; 20090082471, the methods are hereby incorporated by reference.


The present invention further relates to a pharmaceutical composition comprising at least one compound of formulae IA or IB, a stereoisomer, prodrug, tautomer and/or physiologically tolerated acid addition salt thereof and optionally at least one physiologically acceptable carrier and/or auxiliary substance.


The invention also relates to the use of the compounds of formulae IA or IB or of a stereoisomer, prodrug, tautomer or physiologically tolerated acid addition salt thereof for the preparation of a medicament for the treatment of a disorder susceptible to the treatment with a compound that modulates, preferably inhibits, the activity of glycogen synthase kinase 3β.


Furthermore, the invention relates to a method for treating a medical disorder susceptible to treatment with a compound that modulates glycogen synthase kinase 3β activity, said method comprising administering an effective amount of at least one compound of formulae IA or IB or of a stereoisomer, prodrug, tautomer or physiologically tolerated acid addition salt thereof or of a pharmaceutical composition as defined above to a subject in need thereof.


The compounds of the of formulae IA or IB according to the present invention, as well as the stereoisomers, the tautomers, the prodrugs and physiologically tolerated acid addition salts thereof, are capable of modulating the activity on glycogen synthase kinase 3β. In particular, the compounds of the of formulae IA or IB, as well as the stereoisomers, the tautomers, the prodrugs and physiologically tolerated acid addition salts thereof, have an inhibitory activity on glycogen synthase kinase 3β. Amongst the compounds of formulae IA or IB those are preferred which achieve effective inhibition at low concentrations. In particular, compounds of the formulae IA and IB are preferred which inhibit glycogen synthase kinase 3β at a level of IC50<1 μMol, more preferably at a level of IC50<0.5 μMol, particularly preferably at a level of IC50<0.2 μMol and most preferably at a level of IC50<0.1 μMol.


Therefore the compounds of the of formulae IA or IB according to the present invention, their stereoisomers, tautomers, their prodrugs and their physiologically tolerated acid addition salts are useful for the treatment of a medical disorder susceptible to treatment with a compound that modulates glycogen synthase kinase 3β activity. As mentioned above, diseases caused by abnormal GSK-3β activity and which thus can be treated by supplying the compound of the formulae IA and IB, a steroisomer, tautomer, prodrug and/or a physiologically tolerated acid addition salt thereof, include in particular neurodegenerative diseases such as Alzheimer's disease. In addition, the compounds of the present invention are also useful for treatment of other neurodegenerative diseases such as Parkinson's disease, tauopathies (e.g. frontotemporoparietal dementia, corticobasal degeneration, Pick's disease, progressive supranuclear palsy, argyophilic brain disease) and other dementia including vascular dementia; acute stroke and others traumatic injuries; cerebrovascular accidents (e.g. age related macular degeneration); brain and spinal cord trauma; peripheral neuropathies; bipolar disorders, retinopathies and glaucoma. In addition, the compounds of the present invention are also useful for treatment of schizophrenia.


Diseases which can be treated by supplying the compound of the of formulae IA or IB, a steroisomer, tautomer, prodrug and/or a physiologically tolerated acid addition salt thereof, include furthermore inflammatory diseases, such as rheumatoid arthritis and osteoarthritis.


Within the meaning of the invention, a treatment also includes a preventive treatment (prophylaxis), in particular as relapse prophylaxis or phase prophylaxis, as well as the treatment of acute or chronic signs, symptoms and/or malfunctions. The treatment can be orientated symptomatically, for example as the suppression of symptoms. It can be effected over a short period, be orientated over the medium term or can be a long-term treatment, for example within the context of a maintenance therapy.


Within the context of the treatment, the use according to the invention of the compounds of the formulae IA or IB involves a method. In this method, an effective quantity of one or more compounds IA or IB, a steroisomer, tautomer, prodrug or physiologically tolerable acid addition salt thereof, as a rule formulated in accordance with pharmaceutical and veterinary practice, is administered to the individual to be treated, preferably a mammal, in particular a human being, productive animal or domestic animal. Whether such a treatment is indicated, and in which form it is to take place, depends on the individual case and is subject to medical assessment (diagnosis) which takes into consideration signs, symptoms and/or malfunctions which are present, the risks of developing particular signs, symptoms and/or malfunctions, and other factors.


As a rule, the treatment is effected by means of single or repeated daily administration, where appropriate together, or alternating, with other active compounds or active compound-containing preparations such that a daily dose of preferably from about 0.1 to 1000 mg/kg of bodyweight, in the case of oral administration, or of from about 0.1 to 100 mg/kg of bodyweight, in the case of parenteral administration, is supplied to an individual to be treated.


The invention also relates to pharmaceutical compositions for treating an individual, preferably a mammal, in particular a human being, productive animal or domestic animal. Thus, the compounds according to the invention are customarily administered in the form of pharmaceutical compositions which comprise a pharmaceutically acceptable excipient together with at least one compound according to the invention and, where appropriate, other active compounds. These compositions can, for example, be administered orally, rectally, transdermally, subcutaneously, intravenously, intramuscularly or intranasally.


Examples of suitable pharmaceutical formulations are solid medicinal forms, such as powders, granules, tablets, in particular film tablets, lozenges, sachets, cachets, sugar-coated tablets, capsules, such as hard gelatin capsules and soft gelatin capsules, suppositories or vaginal medicinal forms, semisolid medicinal forms, such as ointments, creams, hydrogels, pastes or plasters, and also liquid medicinal forms, such as solutions, emulsions, in particular oil-in-water emulsions, suspensions, for example lotions, injection preparations and infusion preparations, and eyedrops and eardrops. Implanted release devices can also be used for administering inhibitors according to the invention. In addition, it is also possible to use liposomes or microspheres.


When producing the pharmaceutical compositions, the compounds according to the invention are optionally mixed or diluted with one or more excipients. Excipients can be solid, semisolid or liquid materials which serve as vehicles, carriers or medium for the active compound.


Suitable excipients are listed in the specialist medicinal monographs. In addition, the formulations can comprise pharmaceutically acceptable carriers or customary auxiliary substances, such as glidants; wetting agents; emulsifying and suspending agents; preservatives; antioxidants; antiirritants; chelating agents; coating auxiliaries; emulsion stabilizers; film formers; gel formers; odor masking agents; taste corrigents; resin; hydrocolloids; solvents; solubilizers; neutralizing agents; diffusion accelerators; pigments; quaternary ammonium compounds; refatting and overfatting agents; raw materials for ointments, creams or oils; silicone derivatives; spreading auxiliaries; stabilizers; sterilants; suppository bases; tablet auxiliaries, such as binders, fillers, glidants, disintegrants or coatings; propellants; drying agents; opacifiers; thickeners; waxes; plasticizers and white mineral oils. A formulation in this regard is based on specialist knowledge as described, for example, in Fiedler, H. P., Lexikon der Hilfsstoffe für Pharmazie, Kosmetik and angrenzende Gebiete [Encyclopedia of auxiliary substances for pharmacy, cosmetics and related fields], 4th edition, Aulendorf: ECV-Editio-Kantor-Verlag, 1996.


The following examples serve to explain the invention without limiting it.


EXAMPLES

The compounds were either characterized via proton-NMR in d6-dimethylsulfoxide or d-chloroform on a 400 MHz or 500 MHz NMR instrument (Bruker AVANCE), or by mass spectrometry, generally recorded via HPLC-MS in a fast gradient on C18-material (electrospray-ionisation (ESI) mode), or melting point.


The magnetic nuclear resonance spectral properties (NMR) refer to the chemical shifts (δ) expressed in parts per million (ppm). The relative area of the shifts in the 1H-NMR spectrum corresponds to the number of hydrogen atoms for a particular functional type in the molecule. The nature of the shift, as regards multiplicity, is indicated as singlet (s), broad singlet (s. br.), doublet (d), broad doublet (d br.), triplet (t), broad triplet (t br.), quartet (q), quintet (quint.) and multiplet (m).


Abbreviations:


DMSO dimethylsulfoxide


DCM dichloromethane


DMF dimethylformamide


MeOH methanol


EtOAc ethylacetate


THF tetrahydrofurane


TBDMS tert-butyldimethylsilyl


TBFA tert-butylammonium fluoride


RT room temperature


d days


I. PREPARATION EXAMPLES
Example 1
3-(5-Hydroxy-5,6,7,8-tetrahydroquinolin-2-yl)-2-oxoindoline-5-carbonitrile



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1.1 5-(tert-Butyldimethylsilyloxy)-2-chloro-5,6,7,8-tetrahydroquinoline

A solution of 2-chloro-5,6,7,8-tetrahydroquinolin-5-ol (500 mg, 2.72 mmol) in DMF (10 mL) was treated with imidazole (260 mg, 3.81 mmol). After complete dissolution TBDMS-Cl was added and the resulting mixture was stirred at RT for 16 h. The reaction mixture was diluted with EtOAc (40 mL) and was washed with brine (5×). The organic layer was collected, dried with Na2SO4, filtered, and the solvent was evaporated at reduced pressure yielding the titled compound as an oil. Amount 760 mg. Yield 94%.



1H-NMR (DMSO-d6, 400 MHz) δ 0.16 (d, 6H), 0.89 (s, 9H), 1.70 (m, 1H), 1.78 (m, 1H), 1.95 (m, 2H), 2.79 (m, 2H), 4.84 (dd, 1H), 7.31 (d, 1H), 7.66 (d, 1H);


MS (ES-API) m/z 298.1 (M+H+, 100%).


1.2 3-(5-(tert-Butyldimethylsilyloxy)-5,6,7,8-tetrahydroquinolin-2-yl)-2-oxoindoline-5-carbonitrile

To a suspension of 2-oxoindoline-5-carbonitrile (30 mg, 0.190 mmol) in THF placed in a microwave vial were added sequentially 5-(tert-butyldimethylsilyloxy)-2-chloro-5,6,7,8-tetrahydroquinoline (67.8 mg, 0.228 mmol), K2CO3 (52.4 mg, 0.379 mmol), X-PHOS (7.23 mg, 0.015 mmol), and Pd2(dba)3 (3.47 mg, 3.79 μmol). The vial was sealed and flushed with argon. The mixture was heated in a microwave oven at 80° C. for 95 min. The mixture was cooled to RT and diluted with water and ethyl acetate. The organic layer was separated and the remaining aqueous layer was extracted with dichloromethane. The combined dichloromethane extracts were dried over sodium sulfate, filtered, and evaporated to dryness. Amount 32 mg. Yield 40%.



1H-NMR (DMSO-d6, 400 MHz) δ 0.19 (d, 6H), 0.92 (s, 9H), 1.73 (m, 1H), 1.81 (m, 1H), 1.97 (m, 2H), 2.79 (m, 1H), 2.87 (m, 1H), 4.79 (m, 1H), 7.04 (dd, 1H), 7.29 (dd, 1H), 7.74 (m, 2H), 7.92 (s, 1H), 10.90 (s, 1H)


MS (ES-API) m/z 420.2 (M+H+, 100%).


1.3 3-(5-Hydroxy-5,6,7,8-tetrahydroquinolin-2-yl)-2-oxoindoline-5-carbonitrile

A suspension of 3-(5-(tert-butyldimethylsilyloxy)-5,6,7,8-tetrahydroquinolin-2-yl)-2-oxoindoline-5-carbonitrile (26 mg, 0.062 mmol) in tetrahydrofuran (5 mL) was cooled to 0° C. To this mixture was added dropwise a 1.0M solution of TBAF in THF (0.124 ml, 0.124 mmol) resulting in a clear yellow solution. The reaction was stirred for 1 h at 0° C. and then warmed to RT. After 3 h another portion of TBAF (1.0M in THF, 0.124 ml, 0.124 mmol) was added and the reaction was stirred at RT for 16 h. The mixture was diluted with ethyl acetate and the organic layer was washed with water (2×) and brine (1×). The organic layer was dried over sodium sulfate, filtered, and evaporated to dryness. The crude was purified by flash chromatography (silica gel, DCM/MeOH) yielding a yellow solid. Amount 11 mg. Yield 59%.



1H-NMR (DMSO-d6, 400 MHz) δ 1.75 (m, 2H), 1.93 (m, 2H), 2.78 (m, 2H), 4.54 (bs, 1H), 5.38 (bs, 1H), 7.02 (d, 1H), 7.28 (dd, 1H), 7.68 (d, 1H), 7.84 (d, 1H), 7.89 (s, 1H), 10.88 (s, 1H), 14.90 (bs, 1H)


MS (ES-API) m/z 306.1 (M+H+, 100%).


Example 2
2-Oxo-3-(5,6,7,8-tetrahydro-1,6-naphthyridin-2-yl)indoline-5-carbonitrile



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2.1 tert-Butyl 2-chloro-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate

To a solution of 2-chloro-5,6,7,8-tetrahydro-1,6-naphthyridine (500 mg, 2.97 mmol) in dioxane (7.4 mL) and water (7.4 mL) was added sodium bicarbonate in as a solid in one portion (498 mg, 5.93 mmol). After stirring the resulting suspension for 10 min at RT Boc2O (777 mg, 3.56 mmol) was added and the mixture was stirred for 16 h. The mixture was diluted with ethyl acetate and the organic layer was washed with water and brine. The organic phase was dried over sodium sulfate, filtered, and evaporated to dryness. Amount 693 mg. Yield 87%.



1H-NMR (CDCl3, 400 MHz) δ 1.52 (s, 9H), 2.99 (t, 2H), 3.75 (t, 2H), 4.58 (s, 2H), 7.17 (d, 1H), 7.39 (d, 1H)


MS (ES-API) m/z 369.1 (M+H+, 100%).


2.2 tert-Butyl 2-(5-cyano-2-oxoindolin-3-yl)-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate



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The title compound was prepared as described for Example 1.2 using 2-oxoindoline-5-carbonitrile (59 mg, 0.373 mmol), X-PHOS (14.23 mg, 0.030 mmol), K2CO3 (103 mg, 0.746 mmol), tert-butyl 2-chloro-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate (120 mg, 0.448 mmol), and Pd2(dba)3 (6.83 mg, 7.46 μmol). The mixture was heated in a microwave oven at 100° C. for 2 h min. The mixture was cooled to RT and the resulting precipitate was removed by filtration. The remaining residue was dissolved in a mixture of dichloromethane and 2-propanol and the solution was washed with water. The aqueous layer was re-extracted with dichloromethane/2-propanol (3/1, v/v). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and evaporated to dryness. Amount 86 mg. Yield 59%.



1H-NMR (DMSO-d6, 400 MHz) δ 1.47 (s, 9H), 2.91 (t, 2H), 3.69 (t, 2H), 4.45 (s, 2H), 7.02 (d, 1H), 7.28 (d, 1H), 7.72 (s, 1H), 7.93 (s, 1H), 10.92 (bs, 1H), 15.05 (bs, 1H)


MS (ES-API) m/z 391.2 (M+H+, 100%).


2.3 2-Oxo-3-(5,6,7,8-tetrahydro-1,6-naphthyridin-2-yl)indoline-5-carbonitrile

A solution of tert-butyl 2-(5-cyano-2-oxoindolin-3-yl)-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate (73 mg, 0.187 mmol) in 4N HCl in dioxane (5 mL) was stirred at RT for 3 h. After this period all volatiles were removed in vacuo. The residue was dissolved in water and washed with ethyl acetate. The aqueous layer was neutralized with saturated solution of sodium bicarbonate and extracted with ethyl acetate. The latter extracts were dried over sodium sulfate, filtered, and evaporated to dryness. Quant. yield.



1H-NMR (DMSO-d6, 400 MHz) δ 2.76 (t, 2H), 3.04 (m, 2H), 3.76 (s, 2H), 7.00 (m, 1H), 7.19 (m, 1H), 7.54 (m, 1H), 7.66 (m, 1H), 7.87 (bs, 1H), 10.59 (bs, 1H)


MS (ES-API) m/z 291.0 (M+H+, 100%).


Example 3
2-Hydroxy-3-(5-oxo-5,6,7,8-tetrahydroquinolin-2-yl)-1H-indole-5-carbonitrile



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3.1 7,8-Dihydroquinoline-2,5(1H,6H)-dione

Methyl propiolate (5.03 ml, 56.2 mmol) was added to finely ground 3-aminocyclohex-2-enone (5 g, 45.0 mmol). The resulting mixture was heated to 105° C. resulting in a dark brown solution and stirred under reflux for 60 min. Then the reflux condenser was removed and the excess methyl propiolate was distilled off by raising the temperature to 170° C. The reaction mixture was cooled to RT and the resulting solid was triturated with dichloromethane (10 mL) and heated to 40° C. for 25 min. The hot mixture was filtered and the yellow residue was washed with dichloromethane (10 mL). The solid was dried under reduced pressure. Amount 2.07 g. Yield 28%.



1H-NMR (DMSO-d6, 400 MHz) δ 2.03 (m, 2H), 2.45 (m, 2H), 2.81 (t, 2H), 6.25 (d, 1H), 7.78 (d, 1H), 12.05 (bs, 1H)


MS (ES-API) m/z 164.1 (M+H+, 100%).


3.2 2-Chloro-7,8-dihydroquinolin-5(6H)-one

To a suspension of 7,8-dihydroquinoline-2,5(1H,6H)-dione (1.5 g, 9.19 mmol) in acetonitrile (22 mL) was added dropwise phosphorous oxychloride (1.714 mL, 18.39 mmol). The resulting solution was heated to 100° C. and stirred for 2 h. The reaction was cooled to RT and poured into ice-cold water. After basifying the mixture with 2 M sodium hydroxide solution it was extracted with ethyl acetate (3×). After each extraction the pH of the aqueous phase was checked and if necessary adjusted by adding 1 M sodium hydroxide solution. The combined organic layers were dried over sodium sulfate, filtered, and evaporated to dryness. The crude was purified by flash chromatography (silica gel, cyclohexane/ethyl acetate) yielding a colourless solid. Amount 1.23 g. Yield 74%.



1H-NMR (DMSO-d6, 400 MHz) δ 2.13 (m, 2H), 2.68 (m, 2H), 3.08 (t, 2H), 7.53 (d, 1H), 8.20 (d, 1H)


MS (ES-API) m/z 182.0 (M+H+, 100%).


3.3 2-Hydroxy-3-(5-oxo-5,6,7,8-tetrahydroquinolin-2-yl)-1H-indole-5-carbonitrile

To a suspension of 2-chloro-7,8-dihydroquinolin-5(6H)-one (50 mg, 0.275 mmol) and 2-oxoindoline-5-carbonitrile (45.7 mg, 0.289 mmol) in tetrahydrofuran (1.4 mL) was added a 1.0 M solution of sodium bis(trimethylsilyl)amide (641 μL, 0.641 mmol). The mixture was stirred for 3 min at RT and then heated in a microwave oven to 110° C. for 10 min. After cooling to RT the reaction was quenched by addition of methanol (1 mL). The resulting solution was evaporated to dryness. The crude was purified by flash chromatography (silica gel, dichloromethane/methanol) yielding an orange solid. Amount 17 mg. Yield 20%.



1H-NMR (DMSO-d6, 400 MHz) δ 2.17 (m, 2H), 2.59 (t, 2H), 3.08 (t, 2H), 7.06 (d, 1H), 7.38 (dd, 1H), 7.68 (d, 1H), 7.98 (m, 2H), 11.11 (s, 1H), 14.78 (bs, 1H)


MS (ES-API) m/z 304 (M+H+, 100%).


Example 4
2-Hydroxy-3-(8-hydroxy-5,6,7,8-tetrahydroquinolin-2-yl)-1H-indole-5-carbonitrile



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4.1 2-Chloro-8-hydroxy-5,6,7,8-tetrahydroquinoline 1-oxide

To an ice-cold solution of 2-chloro-5,6,7,8-tetrahydroquinolin-8-ol (300 mg, 1.634 mmol) in dichloromethane (5 mL) was added 3-chloroperbenzoic acid (604 mg, 2.451 mmol) in small portions over a period of 5 min. The reaction mixture was slowly warmed to RT and stirred for 20 h. The reaction was quenched by the addition of water. The aqueous phase was removed and the organic layer was washed with a 10% aqueous sodium thiosulfate solution (2×), with a 2M sodium carbonate solution (2×), and with brine (1×). The organic layer was dried over sodium sulfate, filtered, and evaporated to dryness furnishing a beige solid. Amount 320 mg. Yield 98%.



1H-NMR (CDCl3, 400 MHz) δ 1.80 (m, 1H), 1.93 (m, 1H), 2.13 (m, 2H), 2.72 (m, 1H), 2.84 (m, 1H), 5.13 (t, 1H), 7.09 (d, 1H), 7.40 (d, 1H)


MS (ES-API) m/z 200.1 (M+H+, 100%).


4.2 2-(5-Cyano-2-oxoindolin-3-yl)-8-hydroxy-5,6,7,8-tetrahydroquinoline 1-oxide

The title compound was prepared as described for Example 3.3 using 2-chloro-8-hydroxy-5,6,7,8-tetrahydroquinoline 1-oxide (100 mg, 0.501 mmol), 2-oxoindoline-5-carbonitrile (83 mg, 0.526 mmol), tetrahydrofuran (2.5 mL), and a 1.0 M solution of sodium bis(trimethylsilyl)amide (1.668 μL, 1.668 mmol). The reaction was quenched by addition of methanol (2.5 mL). The resulting solution was evaporated to dryness. The crude was used in the following reaction step without further purification.


MS (ES-API) m/z 322.1 (M+H+, 100%).


4.3 2-Hydroxy-3-(8-hydroxy-5,6,7,8-tetrahydroquinolin-2-yl)-1H-indole-5-carbonitrile

To a suspension of crude 2-(5-cyano-2-oxoindolin-3-yl)-8-hydroxy-5,6,7,8-tetrahydroquinoline 1-oxide (263 mg, 0.819 mmol) in ethyl acetate (12 mL) and acetonitrile (12 mL) was added dropwise a solution of phosphorous trichloride (0.644 mL, 7.37 mmol) in ethyl acetate (4 mL). The resulting suspension was stirred at RT. After 24 h the mixture was diluted with ethyl acetate and washed with a saturated sodium bicarbonate solution (2×). The aqueous phase was re-extracted with ethyl acetate (1×) and the combined organic extracts were dried over sodium sulfate, filtered, and evaporated to dryness (52 mg). The crude was dissolved in a mixture of water (2 mL) and dimethylformamide (3 mL) and the solution was heated in a microwave oven at 120° C. for 5 min. After cooling to RT the reaction mixture was diluted with ethyl acetate was washed with brine (5×). The organic layer was dried over sodium sulfate, filtered, and evaporated to dryness. The crude was purified by flash chromatography (silica gel, dichloromethane/methanol) yielding yellow solid. Amount 8.6 mg. Yield 18%.



1H-NMR (DMSO-d6, 400 MHz) δ 1.70 (m, 2H), 1.90 (m, 1H), 2.10 (m, 1H), 2.63 (m, 2H), 4.66 (m, 1H), 6.04 (d, 1H), 6.98 (d, 1H), 7.24 (d, 1H), 7.61 (d, 1H), 7.70 (d, 1H), 7.88 (s, 1H), 10.81 (s, 1H), 15.05 (bs, 1H)


MS (ES-API) m/z 306.0 (M+H+, 100%).


Example 5
3-(6,7-Dihydro-5H-pyrrolo[3,4-b]pyridin-2-yl)-2-oxoindoline-5-carbonitrile hydrochloride



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5.1 tert-Butyl 2-chloro-5H-pyrrolo[3,4-b]pyridine-6(7H)-carboxylate

The title compound was prepared as described for Example 2.1 using 2-chloro-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine (500 mg, 3.23 mmol), sodium bicarbonate (543 mg, 6.47 mmol), and Boc2O (870 mg, 3.987 mmol) in a mixture of dioxane (7.4 mL) and water (7.4 mL). After work up as described in Example 4 the titled compound was obtained as a beige solid. Amount 814 mg. Yield 99%.



1H-NMR (CDCl3, 400 MHz) δ 1.55 (s, 9H), 4.69 (m, 4H), 7.26 (d, 1H), 7.54 (m, 1H); MS (ES-API) m/z 255.1 (M+H+, 10%).


5.2 tert-Butyl 2-(5-cyano-2-oxoindolin-3-yl)-5H-pyrrolo[3,4-b]pyridine-6(7H)-carboxylate



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The title compound was prepared as described for Example 1.2 using 2-oxoindoline-5-carbonitrile (200 mg, 1.265 mmol), tert-butyl 2-chloro-5H-pyrrolo[3,4-b]pyridine-6(7H)-carboxylate (387 mg, 1.517 mmol), K2CO3 (350 mg, 2.53 mmol), X-PHOS (48.2 mg, 0.101 mmol), Pd2(dba)3 (23.16 mg, 0.025 mmol), and tetrahydrofuran (4 mL). The reaction mixture was heated in a microwave oven at 100° C. for 90 min. After cooling to RT the mixture was filtered and the yellow residue was washed with tetrahydrofuran (10 mL) and water (10 mL). The solid was dried under reduced pressure. Amount 193 mg. Yield 40%.



1H-NMR (DMSO-d6, 400 MHz) δ 1.47 (s, 9H), 4.52 (m, 2H), 4.72 (d, 2H), 7.04 (d, 1H), 7.28 (d, 1H), 7.80 (m, 2H), 7.98 (s, 1H), 11.05 (s, 1H)


MS (ES-API) m/z 377.1 (M+H+, 10%).


5.3 3-(6,7-Dihydro-5H-pyrrolo[3,4-b]pyridin-2-yl)-2-oxoindoline-5-carbonitrile hydrochloride

To a suspension of tert-butyl 2-(5-cyano-2-oxoindolin-3-yl)-5H-pyrrolo[3,4-b]pyridine-6(7H)-carboxylate (70 mg, 0.186 mmol) in dioxane (2 mL) was added dropwise 4N HCl in dioxane (2.5 mL). After stirring the resulting mixture at RT for 3 d all volatiles were removed under reduced pressure. The residue was suspended in diethylether and stirred at RT for 2 h. The suspension was filtered, the remaining solid was washed with diethylether and dried under reduced pressure. Amount 55 mg. Yield 95%.



1H-NMR (DMSO-d6, 400 MHz) δ 4.48 (m, 2H), 4.67 (s, 2H), 7.09 (m, 1H), 7.40 (m, 1H), 7.85 (m, 2H), 8.12 (s, 1H), 9.87 (m, 2H), 11.18 (m, 1H)


MS (ES-API) m/z 277.1 (M+H+, 100%).


Example 6
3-(5-Methoxy-5,6,7,8-tetrahydroquinolin-2-yl)-2-oxoindoline-5-carbonitrile



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6.1 2-Chloro-5-methoxy-5,6,7,8-tetrahydroquinoline

To a solution of 2-chloro-5,6,7,8-tetrahydroquinolin-5-ol (319 mg, 1.737 mmol) in tetrahydrofuran (8 mL) was added in small portions sodium hydride (83 mg, 2.085 mmol; 60 on mineral oil). After stirring the resulting suspension for 20 min at RT methyl iodide (0.119 ml, 1.911 mmol) was added dropwise. The reaction mixture was stirred at RT for 20 h. The reaction was quenched by addition of a saturated ammonium chloride solution. The layers were separated and the aqueous layer was extracted with ethyl acetate (3×). The combined organic layers were washed with brine and dried over sodium sulfate, filtered, and evaporated to dryness. The crude was purified by flash chromatography (silica gel, cyclohexane/ethylacetate) yielding a slightly yellow oil. Amount 210 mg. Yield 61%.



1H-NMR (DMSO-d6, 400 MHz) δ 1.77 (m, 1H), 1.90 (m, 3H), 2.79 (m, 2H), 3.37 (s, 3H), 4.37 (m, 1H), 7.32 (d, 1H), 7.77 (d, 1H)


MS (ES-API) m/z 198.1 (M+H+, 100%).


6.2 3-(5-Methoxy-5,6,7,8-tetrahydroquinolin-2-yl)-2-oxoindoline-5-carbonitrile

The title compound was prepared as described for Example 1.2 using 2-oxoindoline-5-carbonitrile (60 mg, 0.379 mmol), 2-chloro-5-methoxy-5,6,7,8-tetrahydroquinoline (90 mg, 0.455 mmol), K2CO3 (105 mg, 0.76 mmol), X-PHOS (14.47 mg, 0.030 mmol), Pd2(dba)3 (6.95 mg, 7.59 μmol), and tetrahydrofuran (1.9 mL). The reaction mixture was heated in a microwave oven at 100° C. for 120 min. After cooling to RT the mixture was diluted with ethyl acetate. The organic layer was separated and the aqueous layer was extracted with ethyl acetate (2×). The combined organic layers were dried over sodium sulfate, filtered, and evaporated to dryness. The crude was purified by flash chromatography (silica gel, dichloromethane/methanol). The product containing fractions were combined, evaporated to dryness, and the resulting solid was triturated with diethylether. Amount 27 mg. Yield 22%.



1H-NMR (DMSO-d6, 400 MHz) δ 1.87 (m, 4H), 2.81 (m, 2H), 3.40 (s, 3H), 4.28 (s, 1H), 7.04 (d, 1H), 7.31 (d, 1H), 7.68 (d, 1H), 7.77 (d, 1H), 7.91 (s, 1H), 10.96 (s, 1H), 14.93 (bs, 1H)


MS (ES-API) m/z 320.1 (M+H+, 100%).


II. BIOLOGICAL TESTS

The compounds according to the invention exhibit very good affinities for GSK-3 (<1 μM, frequently <100 nM) and exhibited good selectivity against multiple kinase targets.


Methods—biochemical hGSK-3beta assay


Compounds were tested for their ability to inhibit human Glycogen Synthase Kinase-3 beta (hGSK-3β) to phosphorylate biotin-YRRAAVPPSPSLSRHSSPHQ(pS)EDEEE. Compounds were incubated with 0.5 μCi 33P-ATP, 10 μM ATP, 0.0125U hGSK-3β (Upstate cell signaling solutions) and 1 μM substrate (biotin-YRRAAVPPSPSLSRHSSPHQ(pS)EDEEE) in 50 mM HEPES, 10 mM MgCl2, 100 mM Na3VO4, 1 mM DTT, 0.0075% Triton, 2% DMSO (total volume 50 μL) for 30 minutes at room temperature. The incubation was stopped by addition of an equal volume of 100 mM EDTA, 4M NaCl. 80 μL of this mixture was added to streptavidin-coated Flash-plates (PerkinElmer). Following a wash step, 33P incorporation was quantified on a MicroBeta microplate liquid scintillation counter (Perkin Elmer). IC50's were determined by fitting a sigmoidal dose-response curve to the counts obtained at the different concentrations in GraphPad Prism.


The results of the binding tests are given in the table below.
















Example #
GSK-3β IC50 (nM)









1
+++



  2.2
+++



2
+++



3
+++



4
+++



5
+++



6
+++







n.d. not determined



GSK-3β IC50 (nM):



Ranges:



+ >10 μM



++ from 100 nM to 10 μM



+++ <100 nM





Claims
  • 1. A heterocyclic compound of the general formulae IA or IB
  • 2. The heterocyclic compound of claim 1, wherein the CH2 unit bound in the position of R3 is not replaced by a NRc group.
  • 3. The heterocyclic compound of claim 1, wherein R3 and R4 form together a bridging group —(CH2)m—, wherein m is 3, 4 or 5, where 1 or 2 of the CH2 groups may be replaced by a group or a heteroatom selected from the group consisting of CO, O and NRc, and where 1 or 2 or 3 hydrogen atoms of the bridging group may be replaced by a radical R8.
  • 4. The heterocyclic compound of claim 1, where m is 3 or 4.
  • 5. The heterocyclic compound of claim 3, where the bridging group is selected from the group consisting of —CH2CH2CH2—, —OCH2CH2—, —CH2CH2O—, —CH2OCH2—, —NRcCH2CH2—, —CH2CH2NRc—, —CH2NRcCH2—, —CH2CH2CH2CH2—, —OCH2CH2CH2—, —CH2OCH2CH2—, —CH2CH2OCH2—, —CH2CH2CH2O—, —NRcCH2CH2CH2—, —CH2NRcCH2CH2—, —CH2CH2NRcCH2—, —CH2CH2CH2NRc—, —C(═O)CH2CH2CH2—, —CH2C(═O)CH2CH2—, —CH2CH2C(═O)CH2— and —CH2CH2CH2C(═O)—, where the hydrogen atoms of the above groups may be replaced by 1 or 2 radicals R8.
  • 6. The heterocyclic compound of claim 5, where the bridging group is selected from the group consisting of —CH2CH2CH2—, —OCH2CH2—, —CH2CH2O—, —CH2OCH2—, —CH2NRcCH2—, —CH2CH2CH2CH2—, —OCH2CH2CH2—, —CH2OCH2CH2—, —CH2CH2OCH2—, —CH2CH2CH2O—, —CH2NRcCH2CH2—, —CH2CH2NRcCH2—, —C(═O)CH2CH2CH2—, —CH2C(═O)CH2CH2—, —CH2CH2C(═O)CH2— and —CH2CH2CH2C(═O)—, where the hydrogen atoms of the above groups may be replaced by 1 or 2 radicals R8.
  • 7. The heterocyclic compound of claim 6, where the bridging group is selected from the group consisting of —CH2CH2CH2—, —CH2NRcCH2—, —CH2CH2CH2CH2—, —CH2NRcCH2CH2—, —CH2CH2NRcCH2—, —C(═O)CH2CH2CH2—, —CH2C(═O)CH2CH2—, —CH2CH2C(═O)CH2— and —CH2CH2CH2C(═O)—, where the hydrogen atoms of the above groups may be replaced by 1 or 2 radicals R8.
  • 8. The heterocyclic compound of claim 1, where the radicals R5 and R6 are hydrogen.
  • 9. The heterocyclic compound of claim 1, where each R8 is independently selected from the group consisting of halogen, OH, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy, NRaRb, C1-C6-alkylcarbonyl, C1-C6-haloalkylcarbonyl, C1-C6-alkoxycarbonyl and C1-C6-haloalkoxycarbonyl.
  • 10. The heterocyclic compound of claim 9, where each R8 is independently selected from the group consisting of OH, C1-C4-alkoxy and C1-C4-haloalkoxy.
  • 11. The heterocyclic compound of claim 1, where Rc is hydrogen or C1-C6-alkoxycarbonyl.
  • 12. The heterocyclic compound of claim 1, where all of X1, X2, X3 and X4 are CR1 or one of X1, X2, X3 and X4 is N and the others are CR1.
  • 13. The heterocyclic compound of claim 12, where all of X1, X2, X3 and X4 are CR1.
  • 14. The heterocyclic compound of claim 13, where X1, X2 and X4 are CH and X3 is CR1.
  • 15. The heterocyclic compound of claim 14, where X3 is CR1, wherein R1 is H, CN or COOH.
  • 16. The heterocyclic compound of claim 1, where R2 is hydrogen.
  • 17. The heterocyclic compound of claim 1, where R2 is C1-C4-alkyl, C1-C4-fluoroalkyl, C2-C4-alkenyl or fluorine.
  • 18. The heterocyclic compound of claim 1, of the formulae IA-1 or IB-1
  • 19. The heterocyclic compound of claim 1, wherein at least one hydrogen atom has been replaced by a deuterium atom.
  • 20. A pharmaceutical composition comprising: at least one heterocyclic compound as defined in claim 1, a stereoisomer, N-oxide, tautomer and/or physiologically tolerated acid addition salt thereof, or at least one heterocyclic compound as defined in claim 1 wherein at least one of the atoms has been replaced by its stable, non-radioactive isotope; andat least one physiologically acceptable carrier.
  • 21. The heterocyclic compound of claim 14, where X3 is CR1, wherein R1 is CN.
  • 22. The heterocyclic compound of claim 1, or a stereoisomer, N-oxide, tautomer and/or physiologically tolerated acid addition salt thereof, selected from the group consisting of: 3-(5-hydroxy-5,6,7,8-tetrahydroquinolin-2-yl)-2-oxoindoline-5-carbonitrile;2-oxo-3-(5,6,7,8-tetrahydro-1,6-naphthyridin-2-yl)indoline-5-carbonitrile;2-hydroxy-3-(5-oxo-5,6,7,8-tetrahydroquinolin-2-yl)-1H-indole-5-carbonitrile;2-hydroxy-3-(8-hydroxy-5,6,7,8-tetrahydroquinolin-2-yl)-1H-indole-5-carbonitrile;3-(6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-2-yl)-2-oxoindoline-5-carbonitrile; and3-(5-methoxy-5,6,7,8-tetrahydroquinolin-2-yl)-2-oxoindoline-5-carbonitrile.
CROSS-REFERENCE TO RELATED APPLICATION

This claims priority to U.S. Provisional Patent Application No. 61/386,849, filed on Sep. 27, 2010, the contents of which are hereby incorporated by reference.

US Referenced Citations (4)
Number Name Date Kind
7205314 Berg et al. Apr 2007 B2
7399780 Berg et al. Jul 2008 B2
7572914 Gangloff et al. Aug 2009 B2
20080153869 Bressi et al. Jun 2008 A1
Foreign Referenced Citations (4)
Number Date Country
03053330 Jul 2003 WO
03082853 Oct 2003 WO
2005061519 Jul 2005 WO
2005123672 Dec 2005 WO
Related Publications (1)
Number Date Country
20120077840 A1 Mar 2012 US
Provisional Applications (1)
Number Date Country
61386849 Sep 2010 US