WO2022233442A1 - 2,8-dihydropyrazolo[3,4-b]indole derivatives for use in the treatment of cancer - Google Patents

2,8-dihydropyrazolo[3,4-b]indole derivatives for use in the treatment of cancer Download PDF

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Publication number
WO2022233442A1
WO2022233442A1 PCT/EP2021/080349 EP2021080349W WO2022233442A1 WO 2022233442 A1 WO2022233442 A1 WO 2022233442A1 EP 2021080349 W EP2021080349 W EP 2021080349W WO 2022233442 A1 WO2022233442 A1 WO 2022233442A1
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Prior art keywords
substituted
methyl
mmol
ring
unsubstituted
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PCT/EP2021/080349
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French (fr)
Inventor
Timo Heinrich
Sarah SCHLESIGER
Jakub GUNERA
Lisa KOETZNER
Emma Carswell
Andreas Blum
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Merck Patent Gmbh
Cancer Research Technology Ltd.
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Priority claimed from PCT/EP2021/061775 external-priority patent/WO2021224291A1/en
Application filed by Merck Patent Gmbh, Cancer Research Technology Ltd. filed Critical Merck Patent Gmbh
Priority to JP2023568331A priority Critical patent/JP2024516860A/en
Priority to EP21802698.7A priority patent/EP4334319A1/en
Priority to CN202180100272.7A priority patent/CN117616028A/en
Priority to AU2021444255A priority patent/AU2021444255A1/en
Priority to CA3218932A priority patent/CA3218932A1/en
Priority to IL308162A priority patent/IL308162A/en
Publication of WO2022233442A1 publication Critical patent/WO2022233442A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
    • C07D471/14—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • Tricyclic heterocycles Field of the invention
  • the present invention relates to tricyclic heterocycles.
  • These heterocyclic compounds are useful as TEAD binders and/or inhibitors of YAP-TEAD protein-protein interaction or binding and for the prevention and/or treatment of several medical conditions including hyperproliferative disorders and diseases, in particular cancer.
  • Background of the invention In recent years the Hippo pathway has become a target of interest for the treatment of hyperproliferative disorders and diseases, in particular cancer (S. A. Smith et al., J. Med. Chem.2019, 62, 1291-1305; K. C. Lin et al., Annu. Rev. Cancer Biol. 2018, 2: 59-79; C.-L.
  • the Hippo pathway regulates cell growth, proliferation, and migration. It is assumed that in mammals the Hippo pathway acts as a tumor suppressor, and dysfunction of Hippo signaling is frequently observed in human cancers. Furthermore, as the Hippo pathway plays a role in several biological processes – like in self-renewal and differentiation of stem cells and progenitor cells, wound healing and tissue regeneration, interaction with other signaling pathways such as Wnt – its dysfunction may also play a role in human diseases other than cancer (C.-L. Kim et al., Cells (2019), 8, 468; Y.
  • the non- phosphorylated, activated YAP/TAZ co-activators are translocated into the cell nucleus.
  • Their major target transcription factors are the four proteins of the Transcriptional enhanced associate domain (TEAD) transcription factor family (TEAD1-4). Binding of YAP or TAZ to and activation of TEAD (or other transcription factors) have shown to induce the expression of several genes many of which mediate cell survival and proliferation.
  • TEAD Transcriptional enhanced associate domain
  • TEAD Transcriptional enhanced associate domain
  • TEAD Transcriptional enhanced associate domain
  • Binding of YAP or TAZ to and activation of TEAD (or other transcription factors) have shown to induce the expression of several genes many of which mediate cell survival and proliferation.
  • activated, non- phosphorylated YAP and TAZ may act as oncogenes
  • the activated, switched-on Hippo pathway may act as a tumor suppressor by deactivating, i.e. phosphorylating YAP and TAZ.
  • the Hippo pathway may also play a role in resistance mechanisms of cancer cells to oncology and immune-oncology therapy (R. Reggiani et al., BBA – Reviews on Cancer 1873 (2020) 188341, 1-11). Consequently, the dysfunction or aberrant regulation of the Hippo pathway as a tumor suppressor is believed to be an important event in the development of a wide variety of cancer types and diseases. Therefore, inhibition of YAP, TAZ, TEAD, and YAP-TEAD or TAZ-TEAD protein-protein interaction by pharmacological intervention appears to be a reasonable and valuable strategy to prevent and/or treat cancer and other hyperproliferative disorders and diseases associated with the dysfunction of the Hippo pathway.
  • the present invention provides compounds that are useful in the prevention and/or treatment of medical conditions, disorders and/or diseases, in particular of hyperproliferative disorders or diseases, which compounds are TEAD binders and/or inhibitors of YAP-TEAD or TAZ-TEAD protein-protein interaction.
  • the invention refers in one embodiment to a compound of formula I-A I-A wherein Ring A represents a five-membered heteroaromatic ring selected from the group consisting of the following ring moieties: ,
  • R A1 represents H, D, C 1-6 -aliphatic, -CH 2 -Ar A1 or -CH 2 -CH 2 -Ar A1
  • R A2 represents H, D, halogen, C 1-6 -aliphatic, -CH 2 -Ar A2 or -CH 2 -CH 2 -Ar A2
  • R A3 represents H, D, C 1-6 -aliphatic, -CH 2 -Ar A3 or -CH 2 -CH 2 -Ar A3
  • Z 1 is CR Z1 or N
  • Z 2 is CR Z2 or N
  • Z 3 is CR Z3 or N; wherein at least two of Z 1 , Z 2 and Z 3 are not N
  • R 1 represents Ar 1 , Hetar 1 , Cyc 1 , Hetcyc 1 , L 1 -Ar 1 , L 1 -Hetar
  • R A1 represents H, C 1-6 -aliphatic, -CH 2 -Ar A1 or -CH 2 -CH 2 -Ar A1
  • R A2 represents H, halogen, C 1-6 -aliphatic, -CH 2 -Ar A2 or -CH 2 -CH 2 -Ar A2
  • R A3 represents H, C 1-6 -aliphatic, -CH 2 -Ar A3 or -CH 2 -CH 2 -Ar A3
  • Z 1 is CR Z1 or N
  • Z 2 is CR Z2 or N; wherein at least one of Z 1 and Z 2 is not N
  • R 1 represents Ar 1 , Hetar 1 , Cyc 1 , Hetcyc 1 , L 1 -Ar 1 , L 1 -Hetar 1 , L 2 -Cyc 1 , L 2 - Hetcyc 1 , un-substituted or substituted, straight-chain or
  • the invention refers to a compound selected from the list of compounds in Table 1c below, or any pharmaceutically acceptable salt thereof.
  • all residues, radicals, substituents, groups, moieties, variables, etc. which occur more than once may be identical or different, i.e. are independent of one another.
  • the residues and parameters have the meanings indicated for formulas I-A and I, unless expressly indicated otherwise. Accordingly, the invention relates, in particular, to the compounds of formulas I-A and I in which at least one of the said residues, radicals, substituents, variables, has one of the preferred meanings indicated below.
  • PE0a, of PE0 Z 3 is N.
  • PE0b, of PE0 Z 3 is CR Z3 ; R Z3 is H. It will be understood that this particular embodiment PE0b is identical to the particular embodiment PE1 as described below. In other words, a compound of formula I-A can also be described as a compound of formula I, if in formula I-A Z 3 denotes CR Z3 with R Z3 being H.
  • PE1a, of PE1 at least one of R Z1 and R Z2 is H.
  • PE1b, of PE1a both R Z1 and R Z2 are H.
  • the compound of the present invention is a tricyclic heterocycle of formula I-A or I, or any N-oxide, solvate, tautomer or stereoisomer thereof and/or any pharmaceutically acceptable salt of each of the foregoing, including mixtures thereof in all ratios, wherein Ring A represents a five-membered heteroaromatic ring selected from the group consisting of the following ring moieties: , , , , ,
  • R A1 represents C 1-6 -aliphatic, -CH 2 -Ar A1 ;
  • R A2 represents H, C 1-6 -aliphatic;
  • R A3 represents H, C 1-6 -aliphatic;
  • Ar A1 represents phenyl which may be unsubstituted or mono-substituted with R A11 ;
  • R A11 represents halogen; and the remaining radicals and residues are as defined for formula I-A or I above or for any of the further particular embodiments described herein above or below.
  • PE2a, of PE2 R A1 represents C 1-3 -alkyl optionally substituted with 1, 2 or 3 F atoms or CN, C2-4-alkynyl (in particular -CH 2 -C ⁇ CH), -CH 2 -Ar A1 ;
  • R A2 represents H, C 1-6 -aliphatic, in particular H, C 1-3 -alkyl optionally substituted with 1, 2 or 3 F atoms;
  • R A3 represents H;
  • Ar A1 represents phenyl which may be unsubstituted or mono-substituted with R A11 ;
  • R A11 represents F; and the remaining radicals and residues are as defined for formula I-A or I above or for any of the further particular embodiments described herein above or below.
  • Ring A is selected from the group consisting of ring A-1, A-4, A-7, A-9, A-10, A-12, A- 13, A-15, A-17, A-23 and A-24.
  • Ring A is ring A-4 wherein preferably R A1 is methyl, ethyl, n- propyl, or -CH 2 -C ⁇ CH, more preferably methyl, and R A2 is H.
  • the compound of the present invention is a tricyclic heterocycle of formula I-A or I, or any N-oxide, solvate, tautomer or stereoisomer thereof and/or any pharmaceutically acceptable salt of each of the foregoing, including mixtures thereof in all ratios, wherein R 1 represents Ar 1 , Hetar 1 , Cyc 1 , Hetcyc 1 , L 1 -Ar 1 , L 1 -Hetar 1 , L 2 -Cyc 1 , L 2 - Hetcyc 1 , un-substituted or substituted, straight-chain or branched C 1-6 - alkyl, C 2-6 -alkenyl or C 2-6 -alkynyl; wherein Ar 1 is a mono- or bicyclic aryl with 6 or 10 ring carbon atoms, wherein that aryl may be unsubstituted or substituted with substituents R B1 , R B2 and/or R B3 which
  • PE3a, of PE3 R 1 represents Ar 1 , Hetar 1 , Cyc 1 , Hetcyc 1 , L 1 -Ar 1 , L 1 -Hetar 1 , L 2 -Cyc 1 , L 2 - Hetcyc 1 , straight-chain or branched C 1-6 -alkyl, C 2-6 -alkenyl or C 2-6 -alkynyl, wherein said C 1-6 -alkyl, C 2-6 -alkenyl or C 2-6 -alkynyl is unsubstituted or substituted with 1, 2 or 3 halogen; wherein Ar 1 is phenyl or naphthalenyl, in particular phenyl, which may be unsubstituted or substituted with substituents R B1 and or R B2 which may be the same or different; Hetar 1 is a monocyclic heteroaryl with 5 or 6 ring atoms or a bicyclic heteroaryl with 9 or
  • PE3b, of PE3 or PE3a R 1 represents Ar 1 , Hetar 1 , Cyc 1 , Hetcyc 1 , L 1 -Ar 1 , L 1 -Hetar 1 , L 2 -Cyc 1 , L 2 - Hetcyc 1 , 2,2-dimethyl-4,4,4-trifluoropentyl, 4,4,4-trifluorobutyl, 4,4,4- trifluoro-3-methylbutyl, 3,3-dimethyl-4,4,4-trifluorobutyl or 3,3,3 ⁇ trifluoroprop ⁇ 1 ⁇ yn ⁇ 1 ⁇ yl; wherein Ar 1 is phenyl which may be unsubstituted or substituted with substituents R B1 and or R B2 which may be the same or different; Hetar 1 is a heteroaryl selected from the group consisting of furanyl, in particular furan-2-yl; thiophenyl, in particular thiophen-2-yl,
  • R 2a represents H, methyl, ethyl or Cat;
  • Cat represents a monovalent sodium cation; and the remaining radicals and residues are as defined for formula I-A or I above or for any of the further particular embodiments described herein above or below.
  • R 2f , R 2g , R 2h , R 2i , R 2j , R 2k , R 2l , and R 2m are as defined above and below in the specification for formula I-A or I; and the remaining radicals and residues are as defined for formula I-A or I above or for any of the further particular embodiments described herein above or below.
  • PE5a, of PE5 R 2b represents hydrogen
  • R 2c represents hydrogen
  • straight-chain or branched C 1-8 -alkyl which may be unsubstituted or substituted with R E1 , R E2 , R E3 , R E4 and/or R E5 which may be the same or different, Cyc 2 or Hetcyc 2
  • R E1 , R E2 , R E3 , R E4 and/or R E5 represent independently from each other halogen, in particular F
  • -NR Ea R Eb -OH, OR Ec , Ar E , Hetar E , Cyc E , Hetcyc E
  • Ar E is a mono- or bicyclic aryl with 6 or 10 ring carbon atoms, wherein that aryl may be unsubstituted or substituted with substituents R F1 , R F2 and/or R F3 which may be the same or different; preferably phenyl or naphthalen
  • PE5a comprises compounds of the present invention in which R 2b represents hydrogen and R 2c represents straight-chain or branched C 1-8 -alkyl in which 1 or 2 of non-terminal and non-adjacent –CH 2 - (methylene) groups are replaced by –O-, -S- and/or 1 or 2 non-terminal and non-adjacent –CH 2 - or –CH- groups are replaced by – NH- or –N-.
  • PE5aa, of PE5a R 2b represents hydrogen
  • R 2c represents hydrogen
  • straight-chain or branched C 1-8 -alkyl which may be unsubstituted or substituted with R E1 , R E2 , R E3 , R E4 and/or R E5 which may be the same or different
  • Cyc 2 or Hetcyc 2 wherein R E1 , R E2 , R E3 , R E4 and/or R E5 represent independently from each other halogen, in particular F; -NR Ea R Eb , -OH, OR Ec , Ar E , Hetar E , Cyc E , Hetcyc E ;
  • Ar E is a mono- or bicyclic aryl with 6 or 10 ring carbon atoms, wherein that aryl may be unsubstituted or substituted with substituents R F1 , R F2 and/or R F3 which may be the same or different; preferably phenyl or n
  • PE5bb, of PE5b R 2b and R 2c form together with the nitrogen atom to which they are attached a 3-hydroxypyrrolidinyl, 2-methyl-3-hydroxypyrrolidinyl or 3-hydroxypiperidinyl ring.
  • PE5c, of PE5 R 2b represents a straight-chain of branched C 1-4 -alkyl optionally substituted with OH; in particular methyl, 2-hydroxyethyl; and R 2c represents Cyc 2 , Hetcyc 2 or straight-chain or branched C 1-8 -alkyl which may be unsubstituted or substituted with independently from each other R E1 , R E2 , R E3 , R E4 and/or R E5 which may be the same or different; wherein Cyc 2 , Hetcyc 2 , R E1 , R E2 , R E3 , R E4 and R E5 are as defined hereinabove for PE5a or PE5aa.
  • the compound of the present invention is a tricyclic heterocycle of formula I, or any N-oxide, solvate, tautomer or stereoisomer thereof and/or any pharmaceutically acceptable salt of each of the foregoing, including mixtures thereof in all ratios, wherein wherein Ring A represents a five-membered heteroaromatic ring selected from the group consisting of the following ring moieties:
  • R 1 represents phenyl, 3-fluorophenyl, 4-fluorophenyl, 4-chlorophenyl, 4- methylphenyl, 4-ethylphenyl, 4-difluoromethylphenyl, 3-trifluoromethyl- phenyl, 4-trifluoromethylphenyl, 4-(1,1-difluorethyl)phenyl, 4-(2,2,2- trifluorethyl)phenyl, 4-(1-trifluoromethylcyclopropyl)-phen-1-yl, 4- cyclopentylphenyl, 4-ethoxyphenyl, 4-difluormethoxyphenyl, 4- trifluoromethoxyphenyl, 3
  • the compound of the present invention is a tricyclic heterocycle of formula I-A, or any N-oxide, solvate, tautomer or stereoisomer thereof and/or any pharmaceutically acceptable salt of each of the foregoing, including mixtures thereof in all ratios, wherein wherein Ring A represents a five-membered heteroaromatic ring selected from the group consisting of the following ring moieties: , , , , , ,
  • R 1 represents phenyl, 3-fluorophenyl, 4-fluorophenyl, 4-chlorophenyl, 4- methylphenyl, 4-ethylphenyl, 4-difluoromethylphenyl, 3-trifluoromethyl- phenyl, 4-trifluoromethylphenyl, 4-(1,1-difluorethyl)phenyl, 4-(2,2,2- trifluorethyl)phenyl, 4-(1-trifluoromethylcyclopropyl)-phen-1-yl, 4- cyclopentylphenyl, 4-ethoxyphenyl, 4-difluormethoxyphenyl, 4- trifluoromethoxyphenyl, 3 ⁇ (trifluoromethyl)sulfanylphenyl, 4 ⁇ (trifluoromethyl)sulfanylphenyl, 3-trifluor
  • the compound of the present invention is a tricyclic heterocycle of formula I-A or I, or any N- oxide, solvate, tautomer or stereoisomer thereof and/or any pharmaceutically acceptable salt of each of the foregoing, including mixtures thereof in all ratios, wherein R 1 is selected from the group consisting of
  • PE9a, of PE9 R 1 is selected from the group consisting of
  • R 1 is (particular embodiment PE9aa).
  • the compound of the present invention is a tricyclic heterocycle of formula I-A or I, or any N- oxide, solvate, tautomer or stereoisomer thereof and/or any pharmaceutically acceptable salt of each of the foregoing, including mixtures thereof in all ratios, wherein R 2 is selected from the group consisting of -COOH, -COONa, -COOCH 3 , ; -CN, -F, -CH 2 -CN, , , , , , , , , , , , , , , , , , , ,
  • radicals and residues are as defined for formula I-A or I above or for any of the further particular embodiments described herein above or below.
  • PE10a, of PE10 the compound of the present invention is a tricyclic heterocycle of formula I-A or I, or any N-oxide, solvate, tautomer or stereoisomer thereof and/or any pharmaceutically acceptable salt of each of the foregoing, including mixtures thereof in all ratios, wherein R 2 is selected from the group consisting of , , 2 ); and the remaining radicals and residues are as defined for formula I-A or I above or for any of the further particular embodiments described herein above or below.
  • PE10aa, of PE10a R 2 is selected from the group consisting of -COOH.
  • PE10b, of PE10 the compound of the present invention is a tricyclic heterocycle of formula I-A or I, or any N-oxide, solvate, tautomer or stereoisomer thereof and/or any pharmaceutically acceptable salt of each of the foregoing, including mixtures thereof in all ratios, wherein R 2 is selected from the group consisting of
  • PE10bb, of PE10b R 2 is selected from the group consisting of
  • PE10c, of PE10 the compound of the present invention is a tricyclic heterocycle of formula I-A or I, or any N-oxide, solvate, tautomer or stereoisomer thereof and/or any pharmaceutically acceptable salt of each of the foregoing, including mixtures thereof in all ratios, wherein R 2 is selected from the group consisting of
  • PE10cc, of PE10c R 2 is selected from the group consisting of , , , , , It is understood that in the embodiments PE9, PE9a, PE9aa, PE10, PE10a, PE10aa, PE10b, PE10bb, PE10c, and PE10cc shown above the dotted line is used to indicate the position where the individual radicals R 1 and R 2 , respectively, are attached to the remaining of the molecule, i.e. the compound of formula I or I-A.
  • the compound of the present invention is a tricyclic heterocycle of formula I-A or I, or any N- oxide, solvate, tautomer or stereoisomer thereof and/or any pharmaceutically acceptable salt of each of the foregoing, including mixtures thereof in all ratios, wherein R 1 is selected from the group described for PE9 above; and R 2 is selected from the group described for PE10 above; and the remaining radicals and residues are as defined for formula I-A or I above or for any of the further particular embodiments described herein above or below.
  • PE11a of PE11 wherein R 1 is selected from the group described for PE9a above, especially PE9aa; and R 2 is selected from the group described for PE10 above.
  • PE11b of PE11 wherein R 1 is selected from the group described for PE9a above, especially PE9aa; and R 2 is selected from the group described for PE10a above, especially PE10aa.
  • PE11c of PE11 wherein R 1 is selected from the group described for PE9a above, especially PE9aa; and R 2 is selected from the group described for PE10b above, especially PE10bb.
  • PE11d of PE11 wherein R 1 is selected from the group described for PE9a above, especially PE9aa; and R 2 is selected from the group described for PE10c above, especially PE10cc.
  • PE12 wherein Ring A is selected from one of the particular embodiments PE2, PE2a, PE2b, PE2c; and R 1 and R 2 are selected as described for PE11.
  • PE12a, of PE12, R 1 and R 2 are selected as described for PE11a.
  • PE12b, of PE12, R 1 and R 2 are selected as described for PE11b.
  • PE12c, of PE12, R 1 and R 2 are selected as described for PE11c.
  • PE12d, of PE12, R 1 and R 2 are selected as described for PE11d.
  • PE13, the compound of the present invention is a tricyclic heterocycle of formula I-A or I, or any N-oxide, solvate, tautomer or stereoisomer thereof and/or any pharmaceutically acceptable salt of each of the foregoing, including mixtures thereof in all ratios, wherein that compound is selected from the compounds shown in Table 1 and Table 1b below, in particular in Table 1.
  • each single compound depicted in Table 1 and Table 1b as well as any N-oxide, solvate, tautomer or stereoisomer thereof and/or any pharmaceutically acceptable salt of such compound represent a particular embodiment of the present invention.
  • the compound of the present invention is a tricyclic heterocycle selected from the compounds shown in Table 1c below, or any pharmaceutically acceptable salt thereof.
  • PE14a, of PE14 the compound is selected from Table 1c and is a compound of formula I or I-A as described hereinabove. It is understood that each single compound depicted in Table 1c as well as any pharmaceutically acceptable salt thereof of such compound represents a particular embodiment of the present invention.
  • PE14b, of PE14 the compound, or any pharmaceutically acceptable salt thereof is selected from the group of compounds listed in Table 1c and consisting of: C2, C3, C6, C12, C16, C17, C18, C20, C25, , C30, C31, C41, C42, C51, C52, C56, C62, C63, C64, C65, C66, C67, C70, C72, C73, C74, C75, C76, C77, C80, C81, C83, C86, C89, C90, C91, C94, C95, C96, C97, C98, C99, C101, C102, C104, C105, C119, C120, C121, C134, C147, C148, C149, C150, C153, C156, C159, C160, C161, C162, C164, C166, C167, C168, C169, C172, C173, C174, C175, C180, C181, C183
  • aliphatic groups contain 1-8 or 1-6 aliphatic carbon atoms (“C 1-8 -aliphatic” and “C 1-6 - aliphatic”, respectively). In some embodiments, aliphatic groups contain 1-5 aliphatic carbon atoms (“C1-5-aliphatic”). In other embodiments, aliphatic groups contain 1-4 aliphatic carbon atoms (“C 1-4 -aliphatic”). In still other embodiments, aliphatic groups contain 1-3 aliphatic carbon atoms (“C 1-3 - aliphatic”), and in yet other embodiments, aliphatic groups contain 1-2 aliphatic carbon atoms (“C 1-2 -aliphatic”).
  • cycloaliphatic refers to a monocyclic C3-C7 hydrocarbon (i.e., a monocyclic hydrocarbon with 3, 4, 5, 6, or 7 ring carbon atoms) or to a bicyclic C5-8 hydrocarbon (i.e. a bicyclic hydrocarbon with 5, 6, 7, or 8 ring carbon atoms) that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic, that has a single point of attachment to the rest of the molecule.
  • cycloaliphatic or “carbocycle” refers to a monocyclic or bicyclic cycloaliphatic ring system which is fused to an aromatic, heteroaromatic or heterocyclic ring or ring system via 2 adjacent ring atoms of that aromatic, heteroaromatic or heterocyclic ring or ring system; in other words, such carbocycle shares two ring atoms with the ring or ring system to which it is fused thereby having two points of attachment to the rest of the molecule.
  • carbocycle refers to bicyclic spiro-cycles in which two monocyclic carbocycles are fused to each other via the same single carbon atom.
  • aliphatic encompasses, to the extent chemically possible, straight-chain, i.e. unbranched, as well as branched hydrocarbon chains, if not defined differently in a particular instance. Also, in general this term encompasses, to the extent chemically possible, unsubstituted and substituted hydrocarbon moieties, if not defined differently in a particular instance.
  • Typical substituents of an aliphatic group include, but are not limited to halogen, cyano, hydroxy, alkoxy, unsubstituted or mono- or di-substituted amino, aryl, in particular unsubstituted or substituted phenyl, heteroaryl, in particular unsubstituted or substituted pyridyl or pyrimidinyl, heterocyclyl, in particular unsubstituted or substituted pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl.
  • Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl groups and hybrids thereof as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl.
  • alkyl usually refers to a saturated aliphatic and acyclic moiety
  • alkynyl usually refers to an aliphatic and acyclic moiety with one or more C ⁇ C triple bonds.
  • alkenyl comprises all forms of isomers, i.e. E-isomers, Z- isomers as well as mixtures thereof (E/Z-isomers).
  • Exemplary aliphatic groups are linear or branched, substituted or unsubstituted C 1-8 -alkyl, C 1-6 -alkyl, C 1-4 - alkyl, C 1-3 -alkyl, C 1-2 -alkyl, C 2-8 -alkenyl, C 2-6 -alkenyl, C 2-8 -alkynyl, C 2-6 -alkynyl, C2-4-alkynyl, groups and hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl.
  • C 1-3 -alkyl refers to alkyl groups, i.e.
  • C 1-3 -alkyl groups are methyl, ethyl, propyl and isopropyl.
  • C 1-4 -alkyl refers to alkyl groups having 1, 2, 3 or 4 carbon atoms.
  • Exemplary C 1-4 -alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl.
  • C 1-6 - alkyl refers to alkyl groups having 1, 2, 3, 4, 5 or 6 carbon atoms.
  • C 1-6 -alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, n-pentyl, 2-pentyl, n-hexyl, and 2-hexyl.
  • C 1-8 -alkyl refers to alkyl groups having 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms.
  • Exemplary C 1-8 -alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, n-pentyl, 2-pentyl, n-hexyl, 2-hexyl n-heptyl, 2-heptyl, n-octyl, 2-octyl, and 2,2,4- trimethylpentyl.
  • Each of these alkyl groups may be straight-chain or – except for C1-alkyl and C2-alkyl – branched and may be unsubstituted or substituted with 1, 2, 3, 4 or 5 substituents that may be the same or different and may be, if not specified differently elsewhere in this specification and/or the accompanying claims, selected from the group comprising halogen, cyano, hydroxy, alkoxy, unsubstituted or mono- or di-substituted amino, aryl, in particular unsubstituted or substituted phenyl, heteroaryl, in particular unsubstituted or substituted pyridyl or pyrimidinyl, heterocyclyl, in particular unsubstituted or substituted pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl.
  • C 1-3 -alkyl, C 1-4 -alkyl, C 1-6 -alkyl, C 1-8 -alkyl groups may also comprise those residues in which 1 or 2 of non-terminal and non-adjacent –CH 2 - (methylene) groups are replaced by –O-, -S- and/or 1 or 2 non-terminal and non-adjacent –CH 2 - or –CH- groups are replaced by –NH- or –N-.
  • C3-7-cycloalkyl refers to a cycloaliphatic hydrocarbon, as defined above, with 3, 4, 5, 6 or 7 ring carbon atoms.
  • C3-6- cycloalkyl refers to a cycloaliphatic hydrocarbon with 3, 4, 5, or 6 ring carbon atoms.
  • C3-7-cycloalkyl groups may be unsubstituted or substituted with – unless specified differently elsewhere in this specification – 1, 2 or 3 substituents that may be the same of different and are – unless specified differently elsewhere in this specification – selected from the group comprising C 1-6 -alkyl, O-C 1-6 -alkyl (alkoxy), halogen, hydroxy, unsubstituted or mono- or di-substituted amino, aryl, in particular unsubstituted or substituted phenyl. If substituted, C3-7-cycloalkyl comprises all possible stereoisomers.
  • Exemplary C3-7-cycloalkyl groups are cyclopropyl, 2-methyl-cyclopropyl, cyclopropenyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl.
  • the term “bicyclic C5-8-cycloalkyl” refers to a bicyclic cycloaliphatic hydrocarbon, as defined above, with 5, 6, 7, or 8 ring carbon atoms; it includes spirocyclic ring system, i.e.
  • Bicylic C5-8-cycloalkyl groups may be unsubstituted or substituted with – unless specified differently elsewhere in this specification – 1, 2 or 3 substituents that may be the same of different and are – unless specified differently elsewhere in this specification – selected from the group comprising C 1-6 -alkyl, O-C 1-6 -alkyl (alkoxy), halogen, hydroxy, unsubstituted or mono- or di-substituted amino. If substituted, bicyclic C5-8-cycloalkyl comprises all possible stereoisomers.
  • Exemplary bicyclic C5-8-cycloalkyl are spiro[3.3]heptanyl, bicyclo[2.2.1]heptan ⁇ 2 ⁇ yl, bicyclo[2.2.2]octan ⁇ 2 ⁇ yl, bi- cyclo[2.2.1]hept ⁇ 5 ⁇ en ⁇ 2 ⁇ ylmethyl, bicyclo[3.1.1]hept ⁇ 2 ⁇ en ⁇ 2 ⁇ yl.
  • aliphatoxy refers to saturated or unsaturated aliphatic groups or substituents as defined above that are connected to another structural moiety via an oxygen atom (-O-).
  • C 1-6 -aliphatoxy refers to an aliphatoxy radical with 1, 2, 3, 4, 5, or 6 carbon atoms within the aliphatic group.
  • alkoxy refers to a particular subgroup of saturated aliphatoxy, i.e. to alkyl substituents and residues that are connected to another structural moiety via an oxygen atom (-O-). Sometimes, it is also referred to as “O-alkyl” and more specifically as “O-C 1-2 -alkyl”, “O-C 1-3 -alkyl”, “O-C 1-4 -alkyl”, “O-C 1-6 -alkyl”, “O-C1- 8-alkyl”.
  • alkyl groups may be straight-chain or – except for – O-C1-alkyl and –O-C2-alkyl – branched and may be unsubstituted or substituted with 1, 2 or 3 substituents that may be the same or different and are, if not specified differently elsewhere in this specification, selected from the group comprising halogen, unsubstituted or mono- or di-substituted amino.
  • substituents are methoxy, difluoromethoxy, trifluoromethoxy, ethoxy, 2,2,2-trifluoroethoxy, n-propoxy, iso-propoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy.
  • alkylene refers to a divalent (or bivalent) aliphatic group and in particular a divalent alkyl group.
  • An “alkylene chain” is a polymethylene group, i.e., –(CH 2 )y–, wherein y is a positive integer, preferably 1, 2, 3, 4, 5 or 6.
  • C 1-3 -alkylene refers to an alkylene moiety with 1, 2 and 3, respectively, -CH 2 - groups; the term “alkylene”, however, not only comprises linear alkylene groups, i.e. "alkylene chains", but branched alkylene groups as well.
  • C 1-6 -alkylene refers to an alkylene moiety that is either linear, i.e. an alkylene chain, or branched and has 1, 2, 3, 4, 5 or 6 carbon atoms.
  • C 2-6 -alkylene refers to an alkylene moiety with 2, 3, 4, 5, or 6 carbon atoms
  • a "C3-4-alkylene” refers to an alkylene moiety with 3 or 4 carbon atoms
  • C2-3-alkylene refers to an alkylene moiety with 2 or 3 carbon atoms.
  • a substituted alkylene is a group in which one or more methylene hydrogen atoms are replaced by (or with) a substituent.
  • Suitable substituents include those described herein for a substituted alkyl group.
  • 1 or 2 methylene groups of the alkylene chain may be replaced by, for instance, O, S and/or NH or N-C 1-4 -alkyl.
  • alkylene groups are —CH 2 -, –CH 2 –CH 2 -, –CH 2 –CH 2 –CH 2 -, –O–CH 2 –CH 2 -, –O–CH 2 –CH 2 -, –O–CH 2 –CH 2 – CH 2 -, –CH 2 –O–CH 2 –CH 2 -, -O–CH 2 -O-, -O–CH 2 –CH 2 -O-, -O–CH 2 –CH 2 –CH 2 - O-, etcCH 2 -NH–CH 2 –CH 2 -, –CH 2 -N(CH 3 )–CH 2 –CH 2 -.
  • alkenylene refers to a divalent alkenyl group.
  • a substituted alkenylene chain is a polymethylene group containing at least one double bond in which one or more hydrogen atoms are replaced with a substituent. Suitable substituents include those described herein for a substituted aliphatic group.
  • alkenylene not only refers to straight-chain divalent alkenylene radicals, i.e. an alkenylene chain, but to branched alkenylene groups as well.
  • C 2-6 -alkenylene refers to an alkenylene radical having 2, 3, 4, 5, or 6 carbon atoms.
  • alkynylene refers to a divalent alkynyl group.
  • a substituted alkynylene chain is a polymethylene group containing at least one triple bond in which one or more hydrogen atoms are replaced with a substituent. Suitable substituents include those described herein for a substituted aliphatic group.
  • halogen means F, Cl, Br, or I.
  • heteroatom means one or more of oxygen (O), sulfur (S), or nitrogen (N), including, any oxidized form of nitrogen or sulfur, e.g.
  • N-oxides, sulfoxides and sulfones the quaternized form of any basic nitrogen or a substitutable nitrogen of a heterocyclic or heteroaromatic ring, for example N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or N-SUB with SUB being a suitable substituent (as in N-substituted pyrrolidinyl).
  • aryl used alone or as part of a larger moiety as in “aralkyl”, “aralkoxy”, or “aryloxyalkyl”, refers to monocyclic, bicyclic and tricyclic ring systems having a total of five to fourteen ring members, that ring members being carbon atoms, wherein at least one ring in the system is aromatic, i.e., it has (4n+2) ⁇ (pi) electrons (with n being an integer selected from 0, 1, 2, 3), which electrons are delocalized over the system, and wherein each ring in the system contains three to seven ring members.
  • all rings in the aryl system or the entire ring system are aromatic.
  • aryl is used interchangeably with the term “aryl ring”.
  • aryl refers to an “aromatic ring system”. More specifically, those aromatic ring systems may be mono-, bi- or tricyclic with 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 ring carbon atoms. Even more specifically, those aromatic ring systems may be mono- or bicyclic with 6, 7, 8, 9, 10 ring carbon atoms.
  • Exemplary aryl groups are phenyl, biphenyl, naphthyl, anthracyl and the like, which may be unsubstituted or substituted with one or more identical or different substituents.
  • aryl or “aromatic ring system”, as they are used herein, is a group in which an aromatic ring is fused to one or more non–aromatic rings, such as indanyl, phthalimidyl, naphthimidyl, phenanthridinyl, or tetrahydronaphthyl, and the like. In the latter case the "aryl” group or substituent is attached to its pendant group via the aromatic part of the ring system.
  • benzo refers to a six-membered aromatic ring (with carbon ring atoms) that is fused via two adjacent carbon atoms to another ring, being it a cycloaliphatic, aromatic, heteroaromatic or heterocyclic (heteroaliphatic) ring; as a result a ring system with at least two rings is formed in which the benzo ring shares two common carbon atoms with the other ring to which it is fused.
  • a benzo ring is fused to a phenyl ring, a napthaline ring system is formed, while fusing a benzo ring to a pyridine provides for either a quinoline or an isoquinoline; fusing a benzo ring to a cyclopentene ring provides an indene ring.
  • heteroatom refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, and any quaternized form of a basic nitrogen.
  • heteroaryl ring or ring system may also be described as an aromatic heterocycle.
  • Heteroaryl groups include, without limitation, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, furazanyl, pyridyl (pyridinyl), pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, pteridinyl, and pyrrolopyridinyl, in particular pyrrolo[2,3- b]pyridinyl.
  • heteroaryl and “heteroar—”, as used herein, also include groups in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic, or heterocyclyl rings, where the radical or point of attachment is preferably on the heteroaromatic or, if present, the aryl ring.
  • Nonlimiting examples include indolyl, isoindolyl, benzothienyl (benzothiophenyl), benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzothiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H– quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, 9H-carbazolyl, dibenzofuranyl and pyrido[2,3–b]–1,4–oxazin–3(4H)–one.
  • an indolyl ring may be attached via one of the ring atoms of the six-membered aryl ring or via one of the ring atoms of the five-membered heteroaryl ring.
  • a heteroaryl group is optionally mono-, bi- or tricyclic.
  • heteroaryl is used interchangeably with the terms “heteroaryl ring”, “heteroaryl group”, or “heteroaromatic”, any of which terms include rings that are unsubstituted or substituted with one or more identical or different substituents.
  • heteroarylkyl refers to an alkyl group substituted by a heteroaryl, wherein the alkyl and heteroaryl portions independently are optionally substituted.
  • a heteroaryl ring can be attached to its pendant group at any of its hetero or carbon ring atoms which attachment results in a stable structure or molecule: any of the ring atoms may be unsubstituted or substituted.
  • the structures of typical examples of "heteroaryl" substituents as used in the present invention are depicted below: pyrrolyl furanyl thiophenyl 1-oxa-2,3- 1-oxa-2,4- diazolyl diazolyl 1-oxa-3,4- diazolyl 1-oxa-2,5- diazolyl 1-thia-2,3- 1-thia-2,4- 1-thia-3,4- diazolyl diazolyl diazolyl diazolyl 1-thia-2,5- diazolyl oxazolyl isoxazolyl isothiazolyl thiazolyl pyrazolyl imidazolyl 1,2,3-triazolyl 1,3,4-triazolyl tetrazolyl
  • heteroaryl substituents can be attached to any pendant group via any of its ring atoms suitable for such an attachment.
  • the terms “heterocycle”, “heterocyclyl”, “heterocyclic radical”, and “heterocyclic ring” are used interchangeably and refer to a stable mono- bi- or tricyclic heterocyclic moiety with 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 ring atoms wherein 1, 2, 3, 4, 5 of said ring atoms are hetero atoms and wherein that heterocyclic moiety is either saturated or partially unsaturated; heterocyclic moieties that are aromatic rings or ring systems are referred to as “heteroaryl” moieties as described hereinabove.
  • the heterocycle is a stable saturated or partially unsaturated 3-, 4-, 5-, 6-, or 7-membered monocyclic or 7-, 8-, 9-, 10-, or 11-membered bicyclic or 11-, 12-, 13-, or 14-membered tricyclic heterocyclic moiety.
  • nitrogen includes a substituted nitrogen.
  • the nitrogen is N (as in 3,4–dihydro–2H–pyrrolyl), NH (as in pyrrolidinyl), or N-SUB with SUB being a suitable substituent (as in N– substituted pyrrolidinyl).
  • heterocycle the term “saturated” refers to a completely saturated heterocyclic system, like pyrrolidinyl, piperidinyl, morpholinyl, piperidinonyl, tetrahydrofuranyl, thianyl, and dioxothianyl.
  • This first class (i) of "partially unsaturated” heterocycles may also be referred to as “non-aromatic partially unsaturated” heterocycles.
  • This second class (ii) of "partially unsaturated” heterocycles may also be referred to as (bicyclic or tricyclic) "partially aromatic” heterocycles indicating that at least one of the rings of that heterocycle is a saturated or unsaturated but non- aromatic heterocycle that is fused with at least one aromatic or heteroaromatic ring system.
  • Typical examples of these "partially aromatic" heterocycles are 1,2,3,4-tetrahydroquinolinyl and 1,2,3,4-tetrahydroisoquinolinyl.
  • a heterocyclic ring can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure and any of the ring atoms may be unsubstituted or substituted.
  • saturated or partially unsaturated heterocyclic radicals include, without limitation, tetrahydrofuranyl, tetrahydropyranyl, thianyl, dioxothianyl, tetrahydrothiophenyl, pyrrolidinyl, piperidinyl, pyrrolinyl, morpholinyl, tetrahydroquinolinyl, tetrahydro- isoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and quinuclidinyl.
  • heterocycle used interchangeably herein, and also include groups in which a heterocyclyl ring is fused to one or more aryl, heteroaryl, or cycloaliphatic rings, such as indolinyl, 3H–indolyl, chromanyl, phenanthridinyl, or tetrahydroquinolinyl, where the radical or point of attachment is on the heterocyclyl ring.
  • a heterocyclyl group is optionally mono–, bi- or tricyclic.
  • heterocyclylalkyl refers to an alkyl group substituted by a heterocyclyl, wherein the alkyl and heterocyclyl portions independently are unsubstituted or substituted.
  • carbohydrate derived radical refers to monovalent organic radicals derived from any kind of carbohydrate compounds, such as aldoses and ketosis, as well as polyols, i.e. reduced carbohydrates, and carbohydrate acids, i.e. oxidized carbohydrates, derived from such aldoses and ketosis.
  • the term comprises monovalent radicals of monosaccharides and reduced and oxidized derivatives thereof, including, but not being limted to, D/L-glycerol aldehyde, D-glycerol aldehyde, L-glycerol aldehyde, dihydroxy acetone, D/L- erythrose, D-erythrose, L-erythrose, D/L-threose, D-threose, L-threose, D/L- ribose, D-ribose, L-ribose, D/L-arabinose, D-arabinose, L-arabinose, D/L- xylose, D-xylose, L-xylose, D/L-lyxose, D-lyxose, L-lyxose, D/L-allose, D- allose, L-allose, D/L-altrose, D-altrose, L-altrose, D/L-glu
  • It further comprises monovalent radicals of di- and oligosaccharides and their respective reduced and oxidized derivatives, including sucrose, lactose, maltose, cellobiose.
  • carbohydrate derived radicals may be utilized in their pure D- or L-form or as a mixture of D- and L-form in each ratio possible.
  • each of these radicals include their open as well as their cyclic form in pure form or as a mixture in any ratio.
  • carbohydrate derived radicals may further be substituted by suitable substituents, e.g., halogen, cyano, unsubstituted, mono- or disubstituted amino, C 1-6 aliphatic, C 1-6 aliphatoxy, aryl, arylalkyl, and the like.
  • Any carbohydrate derived radical can be attached to its pendant group at any of its hetero or carbon atoms which attachment results in a stable structure or molecule.
  • Examples of carbohydrate derived radicals are D/L- fructose, D-fructose, D/L-glucose, D-glucose, D/L-glucoronic acid, D- glucoronic acid, L-glucoronic acid.
  • bioisostere if used alone or in combination with other terms, e.g., “bioisostere radical”, refers to a compound or a group, radical, moiety, substituent and the like, that elicits a similar biological effect as another compound, group, radical, moiety or substituent though they are structurally different to each other.
  • “bioisosteres” can be understood as compounds or groups that possess near-equal molecular shapes and volumes, approximately the same distribution of electrons, and which exhibit similar physical properties.
  • Typical examples for bioisosteres are carboxylic acid bioisosteres which exhibit similar physico-chemical properties as a carboxylic acid group (“carboxylic acid bioisostere”).
  • Such a carboxylic acid bioisostere group or radical may be utilized in place of a carboxylic acid group or radical thereby providing properties similar to those of the carboxylic group but potentially exhibiting some different properties when compared to the carboxylic acid group, for instance, reduced polarity, increased lipophilicity, or enhanced pharmacokinetic properties.
  • carboxylic acid bioisosteres include, without being limited to, -CN, fluoro, amides, sulfonamides, sulfonimides, and several aromatic and non-aromatic heterocycles such as hydroxy-substituted isoxazoles, sulfonamido-substituted oxadiazoles and oxo-oxadiazoles, e.g., 5 ⁇ oxo ⁇ 2,5 ⁇ dihydro ⁇ 1,2,4 ⁇ oxadiazol, and in particular tetrazoles, e.g. 1H ⁇ 1,2,3,4 ⁇ tetrazole, 2-methyl-2H-1,2,3,4- tetrazole.
  • unsaturated means that a moiety or group or substituent has one or more units of unsaturation.
  • partially unsaturated refers to a ring moiety that includes at least one double or triple bond.
  • partially unsaturated is intended to encompass rings having multiple sites of unsaturation.
  • the first class (i) of "partially unsaturated” rings, ring systems, ring moieties may also be referred to as "non-aromatic partially unsaturated” rings, ring systems, ring moieties, while the second class (ii) may be referred to as "partially aromatic” rings, ring systems, ring moieties.
  • the term “bicyclic”, “bicyclic ring” or “bicyclic ring system” refers to any bicyclic ring system, i.e. carbocyclic or heterocyclic, saturated or having one or more units of unsaturation, i.e. being partially unsaturated or aromatic, having one or more atoms in common between the two rings of the ring system.
  • the term includes any permissible ring fusion, such as ortho- fused or spirocyclic.
  • heterocyclic is a subset of “bicyclic” that requires that one or more heteroatoms are present in one or both rings of the bicycle. Such heteroatoms may be present at ring junctions and are optionally substituted, and may be selected from nitrogen (including N- oxides), oxygen, sulfur (including oxidized forms such as sulfones and sulfonates), phosphorus (including oxidized forms such as phosphates), boron, etc.
  • a bicyclic group has 7-12 ring members and 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • tricyclic refers to any tricyclic ring system, i.e. carbocyclic or heterocyclic, saturated or having one or more units of unsaturation, i.e. being partially unsaturated or aromatic, in which a bicyclic ring system (as defined above) is fused with another, third ring.
  • the term includes any permissible ring fusion.
  • heterotricyclic is a subset of “tricyclic” that requires that one or more heteroatoms are present in one or both rings of the tricycle.
  • Such heteroatoms may be present at ring junctions and are optionally substituted, and may be selected from nitrogen (including N-oxides), oxygen, sulfur (including oxidized forms such as sulfones and sulfonates), phosphorus (including oxidized forms such as phosphates), boron, etc.
  • a tricyclic group has 10-14 ring members and 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • certain compounds of the invention contain “substituted” or “optionally substituted” moieties. In general, the term “substituted”, whether preceded by the term “optionally” or not, means that one or more hydrogens of the designated moiety are replaced with a suitable substituent.
  • “Substituted” applies to one or more hydrogens that are either explicit or implicit from the structure. Unless otherwise indicated, a “substituted” or “optionally substituted” group has a suitable substituent at each substitutable position of the group, and when more than one position in any given structure is substituted with more than one substituent selected from a specified group, the substituent is either the same or different at every position. If a certain group, substituent, moiety or radical is "mono-substituted", it bears one (1) substituent.
  • substituents envisioned by this invention are preferably those that result in the formation of stable or chemically feasible compounds.
  • stable refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein.
  • Ph means phenyl; and that “–(CH 2 )0-4” means that there is either no alkylene group if the subscript is “0” (zero) or an alkylene group with 1, 2, 3 or 4 CH 2 units.
  • Ph means phenyl
  • halo means halogen
  • —(CH 2 )0-2 means that there is either no alkylene group if the subscript is “0” (zero) or an alkylene group with 1 or 2 CH 2 units.
  • R * is C1–6 aliphatic
  • R * is optionally substituted with halogen, – R°, (haloR°), OH, –OR°, –O(haloR°), –CN, –C(O)OH, –C(O)OR°, –NH 2 , –NHR°, –NR°2, or –NO2, wherein each R° is independently selected from C1– 4 aliphatic, –CH 2 Ph, –O(CH 2 )0–1Ph, or a 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and wherein each R° is unsubstituted or where preceded by halo is substituted only with one or more halogens.
  • An optional substituent on a substitutable nitrogen is independently –R ⁇ , – NR ⁇ 2, –C(O)R ⁇ , –C(O)OR ⁇ , –C(O)C(O)R ⁇ , – C(O)CH 2 C(O)R ⁇ , -S(O)2R ⁇ , -S(O)2NR ⁇ 2, –C(S)NR ⁇ 2, –C(NH)NR ⁇ 2, or – N(R ⁇ )S(O)2R ⁇ ; wherein each R ⁇ is independently hydrogen, C1–6 aliphatic, unsubstituted –OPh, or an unsubstituted 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, two independent occurrences of R ⁇ , taken together with their intervening atom(s) form an unsubstituted 3–12
  • solvates means addition forms of the compounds of the present invention with solvents, preferably pharmaceutically acceptable solvents that contain either stoichiometric or non-stoichiometric amounts of solvent. Some compounds have a tendency to trap a fixed molar ratio of solvent molecules in the crystalline solid state, thus forming a solvate. If the solvent is water the solvate formed is a hydrate, e.g. a hemi-, mono- or dihydrate. If the solvent is alcohol, the solvate formed is an alcoholate, e.g., a methanolate or ethanolate.
  • the solvate formed is an etherate, e.g., diethyl etherate.
  • N-oxides means such compounds of the present invention that contain an amine oxide moiety, i.e. the oxide of a tertiary amine group.
  • the compounds of formulas I-A and I and Table 1c may – also depending on the nature of substituents they may bear – have one or more centers of chirality. They may accordingly occur in various enantiomeric and diastereomeric forms, as the case may be, and be in racemic or optically active form.
  • the invention therefore, also relates to the optically active forms, enantiomers, racemates, diastereomers, mixtures thereof in all ratios, collectively: “stereoisomers” for the purpose of the present invention, of these compounds.
  • stereoisomers for the purpose of the present invention, of these compounds.
  • the pharmaceutical activity of the racemates or stereoisomers of the compounds according to the invention may differ, it may be desirable to use a specific stereoisomer, e.g. one specific enantiomer or diastereomer.
  • a compound according to the present invention obtained as a racemate or even intermediates thereof – may be separated into the stereoisomeric (enantiomeric, diastereoisomeric) compounds by chemical or physical measures known to the person skilled in the art.
  • stereoselective synthetic procedures e.g. applying starting material in a stereoisomerically enriched or pure form (for instance using the pure or enriched (R)- or (S)-enantiomer of a particular starting material bearing a chiral center) or utilizing chiral reagents or catalysts, in particular enzymes.
  • the term "pure enantiomer” usually refers to a relative purity of one enantiomer over the other (its antipode) of equal to or greater than 95%, preferably ⁇ 98 %, more preferably ⁇ 98.5%, still more preferably ⁇ 99%.
  • the compounds of the invention which have one or more centers of chirality and which occur as racemates or as mixtures of enantiomers or diastereoisomers can be fractionated or resolved by methods known per se into their optically pure or enriched isomers, i.e. enantiomers or diastereomers.
  • the separation of the compounds of the invention can take place by chromatographic methods, e.g.
  • tautomer refers to compounds of the present invention that may exist in tautomeric forms and show tautomerism; for instance, carbonyl compounds may be present in their keto and/or their enol form and show keto-enol tautomerism. Those tautomers may occur in their individual forms, e.g., the keto or the enol form, or as mixtures thereof and are claimed separately and together as mixtures in any ratio.
  • the compounds of the present invention are in the form of free base or acid – as the case may be -, i.e. in their non-salt (or salt-free) form.
  • the compounds of the present invention are in the form of a pharmaceutically acceptable salt, a pharmaceutically acceptable solvate, or a pharmaceutically acceptable solvate of a pharmaceutically acceptable salt.
  • pharmaceutically acceptable salts refers to salts prepared from pharmaceutically acceptable bases or acids, including inorganic bases or acids and organic bases or acids. In cases where the compounds of the present invention contain one or more acidic or basic groups, the invention also comprises their corresponding pharmaceutically acceptable salts.
  • the compounds of the present invention which contain acidic groups, such as carboxyl groups can be present in salt form, and can be used according to the invention, for example, as alkali metal salts, alkaline earth metal salts, aluminium salts or as ammonium salts. More precise examples of such salts include lithium salts, sodium salts, potassium salts, calcium salts, magnesium salts, barium salts or salts with ammonia or organic amines such as, for example, ethylamine, ethanolamine, diethanolamine, triethanolamine, piperdine, N-methylglutamine or amino acids. These salts are readily available, for instance, by reacting the compound having an acidic group with a suitable base, e.g.
  • Base salts of compounds of the present invention include but are not limited to copper(I), copper(II), iron(II), iron (III), manganese(II) and zinc salts.
  • Compounds of the present invention which contain one or more basic groups, e.g. groups which can be protonated, can be present in salt form, and can be used according to the invention in the form of their addition salts with inorganic or organic acids.
  • acids include hydrogen chloride, hydrogen bromide, hydrogen iodide, phosphoric acid, sulfuric acid, nitric acid, methanesulfonic acid, p- toluenesulfonic acid, naphthalenedisulfonic acid, sulfoacetic acid, trifluoroacetic acid, oxalic acid, acetic acid, tartaric acid, lactic acid, salicylic acid, benzoic acid, carbonic acid, formic acid, propionic acid, pivalic acid, diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, malonic acid, maleic acid, malic acid, embonic acid, mandelic acid, sulfaminic acid, phenylpropionic acid, gluconic acid, ascorbic acid, isonicotinic acid, citric acid, adipic acid, taurocholic acid, glutaric acid, stearic acid, glutamic acid or aspartic acid,
  • the salts which are formed are, inter alia, hydrochlorides, chlorides, hydrobromides, bromides, iodides, sulfates, phosphates, methanesulfonates (mesylates), tosylates, carbonates, bicarbonates, formates, acetates, sulfoacetates, triflates, oxalates, malonates, maleates, succinates, tartrates, malates, embonates, mandelates, fumarates, lactates, citrates, glutarates, stearates, aspartates and glutamates.
  • the stoichiometry of the salts formed from the compounds of the invention may moreover be an integral or non-integral multiple of one.
  • Compounds of the present invention which contain basic nitrogen-containing groups can be quaternized using agents such as (C1-C4)alkyl halides, for example methyl, ethyl, isopropyl and tert-butyl chloride, bromide and iodide; di(C1-C4)alkyl sulfates, for example dimethyl, diethyl and diamyl sulfate; (C10- C18)alkyl halides, for example decyl, dodecyl, lauryl, myristyl and stearyl chloride, bromide and iodide; and aryl(C1-C4)alkyl halides, for example benzyl chloride and phenethyl bromide.
  • (C1-C4)alkyl halides for example methyl
  • Both water- and oil-soluble compounds according to the invention can be prepared using such salts.
  • the invention also includes, in addition to the salt forms mentioned, inner salts or betaines (zwitterions).
  • the respective salts can be obtained by customary methods which are known to a person skilled in the art, for example by contacting these with an organic or inorganic acid or base in a solvent or dispersant, or by anion exchange or cation exchange with other salts.
  • the present invention also includes all salts of the compounds of the present invention which, owing to low physiological compatibility, are not directly suitable for use in pharmaceuticals but which can be used, for example, as intermediates for chemical reactions or for the preparation of pharmaceutically acceptable salts.
  • An isotope-labelled form of a compound of the formula I or I-A or Table 1c is identical to this compound apart from the fact that one or more atoms of the compound have been replaced by an atom or atoms having an atomic mass or mass number which differs from the atomic mass or mass number of the atom which usually occurs naturally.
  • isotopes which are readily commercially available and which can be incorporated into a compound of the present invention by well-known methods include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, for example 2 H (D), 3 H, 13 C, 14 C, 15 N, 18 O, 17 O, 31 P, 32 P, 33 S, 34 S, 35 S, 36 S, 18 F and 36 CI, respectively.
  • a compound of formula I or I- A or Table 1c or a pharmaceutically acceptable salt thereof which contains one or more of the above-mentioned isotopes and/or other isotopes of other atoms is intended to be part of the present invention.
  • An isotope-labelled compound of formula I or I-A or Table 1c can be used in a number of beneficial ways.
  • an isotope-labelled compound of the present invention into which, for example, a radioisotope, such as 3 H or 14 C, has been incorporated is suitable for medicament and/or substrate tissue distribution assays.
  • radioisotopes i.e. tritium ( 3 H) and carbon-14 ( 14 C)
  • 3 H tritium
  • 14 C carbon-14
  • Incorporation of heavier isotopes, for example deuterium ( 2 H) into a compound of formula I or I-A or Table 1c has therapeutic advantages owing to the higher metabolic stability of this isotope-labelled compound.
  • An isotope-labelled compound of formula I or I-A or Table 1c can usually be prepared by carrying out the procedures disclosed in the synthesis schemes and the related description, in the example part and in the preparation part in the present text, replacing a non-isotope-labelled reactant by a readily available isotope-labelled reactant.
  • Deuterium ( 2 H; D) can also be incorporated into a compound of formula I-A or I or Table 1c for the purpose of manipulating the oxidative metabolism of the compound by way of the primary kinetic isotope effect.
  • the primary kinetic isotope effect is a change of the rate for a chemical reaction that results from exchange of isotopic nuclei, which in turn is caused by the change in ground state energies necessary for covalent bond formation after this isotopic exchange.
  • Exchange of a heavier isotope usually results in a lowering of the ground state energy for a chemical bond and thus cause a reduction in the rate in rate-limiting bond breakage.
  • a compound of formula I or I- A or Table 1c which has multiple potential sites of attack for oxidative metabolism for example benzylic hydrogen atoms and hydrogen atoms bonded to a nitrogen atom, is prepared as a series of analogues in which various combinations of hydrogen atoms are replaced by deuterium atoms, so that some, most or all of these hydrogen atoms have been replaced by deuterium atoms.
  • Half-life determinations enable favourable and accurate determination of the extent of the extent to which the improvement in resistance to oxidative metabolism has improved. In this way, it is deter-mined that the half-life of the parent compound can be extended by up to 100% as the result of deuterium-hydrogen exchange of this type.
  • Deuterium-hydrogen exchange in a compound of the present invention can also be used to achieve a favourable modification of the metabolite spectrum of the starting compound in order to diminish or eliminate undesired toxic metabolites.
  • a toxic metabolite arises through oxidative carbon- hydrogen (C-H) bond cleavage
  • C-H oxidative carbon- hydrogen
  • the deuterated analogue will greatly diminish or eliminate production of the unwanted metabolite, even if the particular oxidation is not a rate-determining step.
  • Further information on the state of the art with respect to deuterium- hydrogen exchange may be found, for example in Hanzlik et al., J. Org. Chem. 55, 3992-3997, 1990, Reider et al., J. Org.
  • compositions comprising a compound of formula I or I-A or Table 1c, or its N-oxides, solvates, tautomers or stereoisomers thereof as well as the pharmaceutically acceptable salts of each of the foregoing, including mixtures thereof in all ratios, as active ingredient and a pharmaceutically acceptable carrier.
  • the term “pharmaceutical composition” refers to a composition or product comprising one or more active ingredients, and one or more inert ingredients that make up the carrier, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients.
  • the pharmaceutical compositions of the present invention encompass any composition made by admixing at least one compound of the present invention and a pharmaceutically acceptable carrier.
  • a pharmaceutical composition of the present invention may additionally comprise one or more other compounds as active ingredients (drugs), such as one or more additional compounds of the present invention.
  • the pharmaceutical composition further comprises a second active ingredient or its derivatives, prodrugs, solvates, tautomers or stereoisomers thereof as well as the pharmaceutically acceptable salts of each of the foregoing, including mixtures thereof in all ratios, wherein that second active ingredient is other than a compound of formula I and I-A and/or claim 1(i.e., Table 1c); preferably, that second active ingredient is a compound that is useful in the treatment, prevention, suppression and/or amelioration of medicinal conditions or pathologies for which the compounds of the present invention are useful as well and which are listed elsewhere hereinbefore or hereinafter.
  • Such combination of two or more active ingredients or drugs may be safer or more effective than either drug or active ingredient alone, or the combination is safer or more effective than it would be expected based on the additive properties of the individual drugs.
  • Such other drug(s) may be administered, by a route and in an amount commonly used contemporaneously or sequentially with a compound of the invention.
  • a combination product containing such other drug(s) and the compound of the invention – also referred to as “fixed dose combination” – is preferred.
  • combination therapy also includes therapies in which the compound of the present invention and one or more other drugs are administered on different overlapping schedules.
  • the pharmaceutical compositions of the present invention include those that contain one or more other active ingredients, in addition to a compound of the invention.
  • the compounds of the present invention – or N-oxides, solvates, tautomers or stereoisomers thereof and/or the pharmaceutically acceptable salts of each of the foregoing, including mixtures thereof in all ratios – can be used as medicaments. They have been found to exhibit pharmacological activity by binding to TEAD and/or disrupting and/or inhibiting YAP-TEAD and/or TAZ- TEAD protein-protein interaction.
  • the compounds of the present invention may prevent or reverse dysfunction of the Hippo pathway.
  • the Hippo pathway may be capable of playing its role as a tumor suppressor.
  • the pharmacological activity of the compounds of the present invention may also be useful in other pathophysiological scenarios where inhibition or disruption of TEAD binding and/or aberrant YAP-TEAD and/or aberrant TAZ-TEAD signaling would be beneficial.
  • the compounds of the present invention being TEAD binders and/or inhibitors of YAP-TEAD and/or TAZ-TEAD interaction are useful in particular in the treatment, prevention, suppression and/or amelioration of hyperproliferative disorders and cancer, in particular tumors including solid tumors, of breast cancer, lung cancer, mesothelioma, epithelioid hemangioendothelioma, uveal melanoma, liver cancer, ovarian cancer, squamous cancer, renal cancer, gastric cancer, medulloblastoma, colon cancer, pancreatic cancer, schwannoma, meningioma, glioma, basal cell carcinoma.
  • tumors including solid tumors, of breast cancer, lung cancer, mesothelioma, epithelioid hemangioendothelioma, uveal melanoma, liver cancer, ovarian cancer, squamous cancer, renal cancer, gastric cancer, medullob
  • the compounds of the present invention may also be useful in the treatment, prevention, suppression and/or amelioration of non-cancerous disorders and diseases, e.g. cardiovascular diseases and fibrosis (like liver fibrosis).
  • non-cancerous disorders and diseases e.g. cardiovascular diseases and fibrosis (like liver fibrosis).
  • cardiovascular diseases and fibrosis like liver fibrosis
  • the compounds of the present invention are for use in the prevention and/or treatment, especially in the treatment of any of the disorders or diseases listed above, preferably of cancer, in particular tumors including solid tumors, of the specific types of cancer disclosed in the previous paragraph; or of any of the non-cancerous disorders or diseases disclosed in the previous paragraph.
  • Another particular embodiment of the present invention is a method for preventing and/or treating, preferably treating a disorder or disease selected from the group consisting of hyperproliferative disorders and cancer, in particular tumors including solid tumors, of the specific types of cancer disclosed in the previous paragraphs; or of any of the non-cancerous disorders or diseases disclosed in the previous paragraphs.
  • a disorder or disease selected from the group consisting of hyperproliferative disorders and cancer, in particular tumors including solid tumors, of the specific types of cancer disclosed in the previous paragraphs; or of any of the non-cancerous disorders or diseases disclosed in the previous paragraphs.
  • Still another particular embodiment of the invention is the use of a compound of the present invention – or derivatives, N-oxides, prodrugs, solvates, tautomers or stereoisomers thereof and/or the pharmaceutically acceptable salts of each of the foregoing, including mixtures thereof in all ratios – for the manufacturing of a medicament, in particular for preventing and/or treating, preferably treating a disorder or disease selected from the group consisting of hyperproliferative disorders and cancer, in particular tumors including solid tumors, of the specific types of cancer disclosed in the previous paragraphs; or of any of the non-cancerous disorders or diseases disclosed in the previous paragraphs.
  • the present invention relates to a compound of the present invention for use in the prevention and/or treatment of a disease – or, alternatively, a method for preventing and/or treating a disease by administering an effective amount of a compound of the present invention ; or, in another alternative, a use of a compound of the present invention for the manufacturing of a medicament for the prevention and/or treatment of a disease – wherein that disease is a cancer, in particular tumors including solid tumors, of the specific types of cancer disclosed in the previous paragraphs; and more preferably, wherein administration of the compound is simultaneous, sequential or in alternation with administration of at least one other active drug agent.
  • the disclosed compounds of formula I or I-A or Table 1c can be administered in combination with other known therapeutic agents, including anticancer agents.
  • anticancer agent relates to any agent which is administered to a patient with cancer for the purposes of treating the cancer.
  • the anti-cancer treatment defined above may be applied as a monotherapy or may involve, in addition to the herein disclosed compounds of formula I-A or I or Table 1c, conventional surgery or radiotherapy or medicinal therapy.
  • Such medicinal therapy e.g.
  • a chemotherapy or a targeted therapy may include one or more, but preferably one, of the following anti-tumor agents: Alkylating agents such as altretamine, bendamustine, busulfan, carmustine, chlorambucil, chlormethine, cyclophosphamide, dacarbazine, ifosfamide, improsulfan, tosilate, lomustine, melphalan, mitobronitol, mitolactol, nimustine, ranimustine, temozolomide, thiotepa, treosulfan, mechloretamine, carboquone; apaziquone, fotemustine, glufosfamide, palifosfamide, pipobroman, trofosfamide, uramustine, evofosfamide, VAL-083 [4] ; Platinum Compounds such as carboplatin, cisplatin, eptaplatin, miriplatine
  • a set or kit comprising a therapeutically effective amount of at least one compound of the invention and/or at least one pharmaceutical composition as described herein and a therapeutically effective amount of at least one further pharmacologically active substance other than the compounds of the invention.
  • this set or kit comprises separate packs of a) an effective amount of a compound of Table 1c, or any pharmaceutically acceptable salt thereof, and b) an effective amount of a further active ingredient that further active ingredient not being a compound of Table 1c.
  • a further embodiment of the present invention is a process for the manufacture of the pharmaceutical compositions of the present invention, characterized in that one or more compounds according to the invention and one or more compounds selected from the group consisting of solid, liquid or semiliquid excipients, auxiliaries, adjuvants, diluents, carriers and pharmaceutically active agents other than the compounds according to the invention, are converted in a suitable dosage form.
  • the pharmaceutical compositions (formulations) of the present invention may be administered by any means that achieve their intended purpose.
  • administration may be via oral, parenteral, topical, enteral, intravenous, intramuscular, inhalant, nasal, intraarticular, intraspinal, transtracheal, transocular, subcutaneous, intraperitoneal, transdermal, or buccal routes.
  • administration may be via the oral route.
  • the dosage administered will be dependent upon the age, health, and weight of the recipient, kind of concurrent treatment, if any, frequency of treatment, and the nature of the effect desired. Parenteral administration is preferred. Oral administration is especially preferred.
  • Suitable dosage forms include, but are not limited to capsules, tablets, pellets, dragees, semi-solids, powders, granules, suppositories, ointments, creams, lotions, inhalants, injections, cataplasms, gels, tapes, eye drops, solution, syrups, aerosols, suspension, emulsion, which can be produced according to methods known in the art, for example as described below: Tablets: mixing of active ingredient/s and auxiliaries, compression of said mixture into tablets (direct compression), optionally granulation of part of mixture before compression.
  • Capsules mixing of active ingredient/s and auxiliaries to obtain a flowable powder, optionally granulating powder, filling powders/granulate into opened capsules, capping of capsules.
  • Semi-solids (ointments, gels, creams): dissolving/dispersing active ingredient/s in an aqueous or fatty carrier; subsequent mixing of aqueous/fatty phase with complementary fatty/ aqueous phase, homogenization (creams only).
  • Suppositories (rectal and vaginal): dissolving/dispersing active ingredient/s in carrier material liquified by heat (rectal: carrier material normally a wax; vaginal: carrier normally a heated solution of a gelling agent), casting said mixture into suppository forms, annealing and withdrawal suppositories from the forms.
  • Aerosols dispersing/dissolving active agent/s in a propellant, bottling said mixture into an atomizer.
  • non-chemical routes for the production of pharmaceutical compositions and/or pharmaceutical preparations comprise processing steps on suitable mechanical means known in the art that transfer one or more compounds of the invention into a dosage form suitable for administration to a patient in need of such a treatment.
  • the transfer of one or more compounds of the invention into such a dosage form comprises the addition of one or more compounds, selected from the group consisting of carriers, excipients, auxiliaries and pharmaceutical active ingredients other than the compounds of the invention.
  • Suitable processing steps include, but are not limited to combining, milling, mixing, granulating, dissolving, dispersing, homogenizing, casting and/or compressing the respective active and nonactive ingredients.
  • Mechanical means for performing said processing steps are known in the art, for example from Ullmann's Encyclopedia of Industrial Chemistry, 5th Edition.
  • active ingredients are preferably at least one compound of the invention and optionally one or more additional compounds other than the compounds of the invention, which show valuable pharmaceutical properties, preferably those pharmaceutical active agents other than the compounds of the invention, which are disclosed herein.
  • Particularly suitable for oral use are tablets, pills, coated tablets, capsules, powders, granules, syrups, juices or drops, suitable for rectal use are suppositories, suitable for parenteral use are solutions, preferably oil-based or aqueous solutions, furthermore suspensions, emulsions or implants, and suitable for topical use are ointments, creams or powders.
  • the compounds of the invention may also be lyophilized and the resultant lyophilizates used, for example, for the preparation of injection preparations.
  • the preparations indicated may be sterilized and/or comprise assistants, such as lubricants, preservatives, stabilizers and/or wetting agents, emulsifiers, salts for modifying the osmotic pressure, buffer substances, dyes, flavors and/or a plurality of further active ingredients, for example one or more vitamins.
  • assistants such as lubricants, preservatives, stabilizers and/or wetting agents, emulsifiers, salts for modifying the osmotic pressure, buffer substances, dyes, flavors and/or a plurality of further active ingredients, for example one or more vitamins.
  • Suitable excipients are organic or inorganic substances, which are suitable for enteral (for example oral), parenteral or topical administration and do not react with the compounds of the invention, for example water, vegetable oils, benzyl alcohols, alkylene glycols, polyethylene glycols, glycerol triacetate, gelatin, carbohydrates, such as lactose, sucrose, mannitol, sorbitol or starch (maize starch, wheat starch, rice starch, potato starch), cellulose preparations and/or calcium phosphates, for example tricalcium phosphate or calcium hydrogen phosphate, magnesium stearate, talc, gelatin, tragacanth, methyl cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, polyvinyl pyrrolidone and/or vaseline.
  • disintegrating agents may be added such as the above-mentioned starches and also carboxymethyl-starch, cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof, such as sodium alginate.
  • Auxiliaries include, without limitation, flow-regulating agents and lubricants, for example, silica, talc, stearic acid or salts thereof, such as magnesium stearate or calcium stearate, and/or polyethylene glycol.
  • Dragee cores are provided with suitable coatings, which, if desired, are resistant to gastric juices.
  • concentrated saccharide solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, polyethylene glycol and/or titanium dioxide, lacquer solutions and suitable organic solvents or solvent mixtures.
  • the tablet, dragee or pill can comprise an inner dosage and an outer dosage component the latter being in the form of an envelope over the former.
  • the two components can be separated by an enteric layer, which serves to resist disintegration in the stomach and permits the inner component to pass intact into the duodenum or to be delayed in release.
  • enteric layers or coatings such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, acetyl alcohol, solutions of suitable cellulose preparations such as acetyl-cellulose phthalate, cellulose acetate or hydroxypropylmethyl-cellulose phthalate, are used.
  • Dye stuffs or pigments may be added to the tablets or dragee coatings, for example, for identification or in order to characterize combinations of active compound doses.
  • Suitable carrier substances are organic or inorganic substances which are suitable for enteral (e.g.
  • parenteral administration or topical application do not react with the novel compounds, for example water, vegetable oils, benzyl alcohols, polyethylene glycols, gelatin, carbohydrates such as lactose or starch, magnesium stearate, talc and petroleum jelly.
  • novel compounds for example water, vegetable oils, benzyl alcohols, polyethylene glycols, gelatin, carbohydrates such as lactose or starch, magnesium stearate, talc and petroleum jelly.
  • tablets, coated tablets, capsules, syrups, suspensions, drops or suppositories are used for enteral administration, solutions, preferably oily or aqueous solutions, furthermore suspensions, emulsions or implants, are used for parenteral administration, and ointments, creams or powders are used for topical application.
  • the compounds of the invention can also be lyophilized and the lyophilizates obtained can be used, for example, for the production of injection preparations.
  • Other pharmaceutical preparations which can be used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer such as glycerol or sorbitol.
  • the push-fit capsules can contain the active compounds in the form of granules, which may be mixed with fillers such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers.
  • the active compounds are preferably dissolved or suspended in suitable liquids, such as fatty oils, or liquid paraffin.
  • stabilizers may be added.
  • liquid forms in which the novel compositions of the present invention may be incorporated for administration orally include aqueous solutions, suitably flavored syrups, aqueous or oil suspensions, and flavored emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil or peanut oil, as well as elixirs and similar pharmaceutical vehicles.
  • Suitable dispersing or suspending agents for aqueous suspensions include synthetic and natural gums such as tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinyl-pyrrolidone or gelatin.
  • Suitable formulations for parenteral administration include aqueous solutions of the active compounds in water-soluble form, for example, water-soluble salts and alkaline solutions.
  • suspensions of the active compounds as appropriate oily injection suspensions may be administered.
  • Suitable lipophilic solvents or vehicles include fatty oils, for example, sesame oil, or synthetic fatty acid esters, for example, ethyl oleate or triglycerides or polyethylene glycol-400 (the compounds are soluble in PEG-400).
  • Aqueous injection suspensions may contain substances, which increase the viscosity of the suspension, including, for example, sodium carboxymethyl cellulose, sorbitol, and/or dextran, optionally, the suspension may also contain stabilizers.
  • inhalation sprays for administration as an inhalation spray, it is possible to use sprays in which the active ingredient is either dissolved or suspended in a propellant gas or propellant gas mixture (for example CO 2 or chlorofluorocarbons).
  • a propellant gas or propellant gas mixture for example CO 2 or chlorofluorocarbons.
  • the active ingredient is advantageously used here in micronized form, in which case one or more additional physiologically acceptable solvents may be present, for example ethanol.
  • Inhalation solutions can be administered with the aid of conventional inhalers.
  • Possible pharmaceutical preparations, which can be used rectally include, for example, suppositories, which consist of a combination of one or more of the active compounds with a suppository base. Suitable suppository bases are, for example, natural or synthetic triglycerides, or paraffin hydrocarbons.
  • gelatin rectal capsules which consist of a combination of the active compounds with a base.
  • Possible base materials include, for example, liquid triglycerides, polyethylene glycols, or paraffin hydrocarbons.
  • the pharmaceutical preparations can be employed as medicaments in human and veterinary medicine.
  • the term "effective amount" means that amount of a drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system, animal or human that is being sought, for instance, by a researcher or clinician.
  • the term also includes within its scope a "therapeutically effective amount” which means any amount which, as compared to a corresponding subject who has not received such amount, results in improved treatment, healing, prevention, or amelioration of a disease, disorder, or side effect, or a decrease in the rate of advancement of a disease or disorder, or of symptoms associated with such disease or disorder; it may also refer to preventing or providing prophylaxis for the disease or disorder in a subject having or at risk for developing a disease disclosed herein.
  • the term also includes within its scope amounts effective to enhance normal physiological function. Said therapeutic effective amount of one or more of the compounds of the invention is known to the skilled artisan or can be easily determined by standard methods known in the art.
  • Treating means an alleviation, in whole or in part, of symptoms associated with a disorder or disease, or slowing, or halting of further progression or worsening of those symptoms, or prevention or prophylaxis of the disease or disorder in a subject at risk for developing the disease or disorder.
  • the compounds of the present invention and the optional additional active substances are generally administered analogously to commercial preparations.
  • suitable doses that are therapeutically effective lie in the range between 0.0005 mg and 1000 mg, preferably between 0.005 mg and 500 mg and especially between 0.5 mg and 100 mg per dose unit.
  • the daily dose is preferably between about 0.001 mg/kg and 10 mg/kg of body weight.
  • dose levels can vary as a function of the specific compound, the severity of the symptoms and the susceptibility of the subject to side effects. Some of the specific compounds are more potent than others. Preferred dosages for a given compound are readily determinable by those of skill in the art by a variety of means. A preferred means is to measure the physiological potency of a given compound.
  • the specific dose for the individual patient depends, however, on the multitude of factors, for example on the efficacy of the specific compounds employed, on the age, body weight, general state of health, the sex, the kind of diet, on the time and route of administration, on the excretion rate, the kind of administration and the dosage form to be administered, the pharmaceutical combination and severity of the particular disorder to which the therapy relates.
  • the specific therapeutic effective dose for the individual patient can readily be determined by routine experimentation, for example by the doctor or physician, which advises or attends the therapeutic treatment.
  • the compounds of the present invention can be prepared according to the procedures of the following Schemes and Examples, using appropriate materials, and as further exemplified by the following specific examples.
  • the starting materials for the processes claimed and/or utilized may, if desired, also be formed in situ by not isolating them from the reaction mixture, but instead immediately converting them further into the compounds of the invention or intermediate compounds.
  • the reaction stepwise it is possible to carry out the reaction stepwise.
  • the reaction of the compounds is carried out in the presence of a suitable solvent, which is preferably inert under the respective reaction conditions.
  • suitable solvents comprise but are not limited to hydrocarbons, such as hexane, petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons, such as trichlorethylene, 1,2-dichloroethane, tetrachloromethane, chloroform or dichloromethane; alcohols, such as methanol, ethanol, isopropanol, n-propanol, n-butanol or tert-butanol; ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF) or dioxane; glycol ethers, such as ethylene glycol monomethyl or monoethyl ether or ethylene glycol dimethyl ether (diglyme); ketones, such as acetone or butanone; amides, such as acetamide, dimethylacetamide, dimethylformamide (DMF) or N-methyl pyrroli
  • the reaction temperature is between about -100°C and 300°C, depending on the reaction step and the conditions used. Reaction times are generally in the range between a fraction of a minute and several days, depending on the reactivity of the respective compounds and the respective reaction conditions. Suitable reaction times are readily determinable by methods known in the art, for example reaction monitoring. Based on the reaction temperatures given above, suitable reaction times generally lie in the range between 10 minutes and 48 hours. Moreover, by utilizing the procedures described herein, in conjunction with ordinary skills in the art, additional compounds of the present invention claimed herein can be readily prepared. The compounds illustrated in the examples are not, however, to be construed as forming the only genus that is considered as the invention. The examples further illustrate details for the preparation of the compounds of the present invention.
  • the present invention also refers to a process for manufacturing a compound of formula I or I-A or Table 1c in its most general form as well as any of the particular embodiments, PE0, PE0a, PE0b, PE1, PE1a, PE1b, PE2, PE2a, PE2b, PE3, PE3a, PE3b, PE4, PE4a, PE5, PE5a, PE5aa PE5b,PE5bb, PE5c, PE6, PE7, PE8, PE9, PE9a, PE10, PE10a, PE10aa, PE10b, PE10bb, PE10c, PE10cc, PE11, PE11a, PE11b, PE11c, PE12, PE12a, PE12b, PE12c, PE12d, PE13, PE14, PE14a, PE14b described herein, or N-oxides, solvates, tautomers or stereois
  • the compounds of the present invention can readily be synthesized by reacting other compounds of the present invention under suitable conditions, for instance, by converting one particular functional group being present in a compound of the present invention, or a suitable precursor molecule thereof, into another one by applying standard synthetic methods, like reduction, oxidation, addition or substitution reactions; those methods are well known to the skilled person.
  • the skilled artisan will apply – whenever necessary or useful – synthetic protecting (or protective) groups; suitable protecting groups as well as methods for introducing and removing them are well-known to the person skilled in the art of chemical synthesis and are described, in more detail, in, e.g., P.G.M. Wuts, T.W.
  • Scheme A (Z 1 , Z 2 , R 1 , R 2 and ring A are as defined for formula I above and in the claims.)
  • Scheme A-A (Z 1 , Z 2 , Z 3 , R 1 , R 2 and ring A are as defined for formula I-A above and in the claims.) It will be understood that the following explanation of Scheme A also applies analogously to Scheme A-A; instead of compounds B, D, E, and I Scheme A- A and its explanation refer to compounds B-A, D-A, E-A, and I-A. The synthetic procedures and method utilized are the same in Schemes A and A-A.
  • Scheme A above depicts a general synthesis route for preparing tricyclic hetereocycles of formula I and Table 1c.
  • reaction step a the boronic acid B – which is readily available, for instance, by first reacting the respective bromo- substituted aryl or heteroaryl with a suitable organometallic base like n-butyl lithium and subsequent reaction with a suitable boron acid ester like B(OCH 3 )3 – is reacted with the 1-amino-2-bromo-substituted heterocycle C under typical C-C cross coupling conditions, e.g., under conditions typical for Suzuki cross coupling reactions (for instance, reacting a solution of B and C in a suitable solvent like 1,4-dioxane with cesium carbonate in the presence of a Palladium catalyst like Pd(dppf)2Cl2 (1,1'-Bis(diphenylphosphino)ferrocene]palladium(II) dichloride)) to yield compound D.
  • a suitable organometallic base like n-butyl lithium
  • ring A in that 1-amino- 2-bromo-substituted heterocycle C has the same meaning as “ring A” for the compound of the present invention of formula I, i.e. is selected from the five- membered heteroaromatic rings A-1 to A-24 as defined above and in the claims.
  • step b Compound D may then be subjected to an intra-molecular C-N cross-coupling reaction (step b), for instance, under conditions typical for a Hartwig-Buchwald reaction (e.g., reaction with cesium carbonate in a suitable solvent like 1,4- dioxane in the presence of a suitable palladium catalyst like di-tert- butyl[2',4',6'-tris(propan-2-yl)-[1,1'-biphenyl]-2-yl]phosphane ⁇ 2'-amino-[1,1'- biphenyl]-2-yl ⁇ palladiumylium methanesulfonate) to yield the tricyclic heterocycle E.
  • a Hartwig-Buchwald reaction e.g., reaction with cesium carbonate in a suitable solvent like 1,4- dioxane in the presence of a suitable palladium catalyst like di-tert- butyl[2',4',6'-tris(
  • This heterocycle E may then in turn be reacted with the bromide R 1 -Br in another C-N coupling reaction (step c) under similar conditions, for instance with cesium carbonate in the presence of a suitable palladium catalyst (e.g., Chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′- amino-1,1′-biphenyl)]palladium(II), X-Phos aminobiphenyl palladium chloride, XPhosPd G2) to provide the compound of the present invention of formula I.
  • a suitable palladium catalyst e.g., Chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′- amino-1,1′-biphenyl)]palladium(II), X
  • this compound of formula I may optionally converted into further compounds of formula I.
  • compound D as shown in Scheme A above (and D-A in Scheme A-A) – instead of being subjected to the subsequent reaction steps b and c, i.e. two consecutive C-N coupling reactions – may be reacted with a suitable compound R 1 -Br under C-N coupling reactions (with as suitable base like cesium carbonate or sodium hydride in the presence of a suitable palladium catalyst) to directly provide the respective compound of formula I (or I-A in Scheme A-A or Table 1c).
  • a suitable compound R 1 -Br under C-N coupling reactions (with as suitable base like cesium carbonate or sodium hydride in the presence of a suitable palladium catalyst) to directly provide the respective compound of formula I (or I-A in Scheme A-A or Table 1c).
  • starting from compound E compounds of formula I or from compound E-A compounds of formula I-A
  • reaction step a in Schemes A and A-A may also be performed by utilizing a suitably substituted five-memberd ring A bearing a boronic acid or boronic acid ester instead of compound C and a suitably substituted six-membered (hetero)aromatic ring bearing a bromo substituent instead of compound B (or B-A) providing compound D (or D-A).
  • Scheme B Z 1 , Z 2 , R 1 , R 2 and ring A are as defined for formula I above and in the claims.
  • Scheme B-A (Z 1 , Z 2 , Z 3 , R 1 , R 2 and ring A are as defined for formula I-A above and in the claims.) It will be understood that the following explanation of Scheme B also applies analogously to Scheme B-A; instead of compounds B, G, and I Scheme B-A and its explanation refers to compounds B-A, G-A, and I-A. The synthetic procedures and method utilized are the same in Schemes B and B-A. Scheme B above depicts another synthetic route for making compounds of the present invention.
  • boronic acid B (or a suitable boronic acid ester) is reacted in a C-C cross-coupling reaction under similar conditions described for step a in Scheme A with the 1-chloro-2-iodo-substituted heterocycle F (step d) which reaction yields the dichloro-substituted compound G.
  • Compound G may then be converted in a C-N coupling reaction with the primary amine R 1 -NH 2 (step e) in the presence of a suitable base like cesium carbonate and a suitable palladium catalyst (as described for Scheme A) into the desired compound of formula I (or I-A for Scheme B-A).
  • reaction step a in Schemes B and B-A may also be performed by utilizing a suitably substituted five-memberd ring A bearing a boronic acid or boronic acid ester instead of compound F and a suitably substituted six-membered (hetero)aromatic ring bearing an iodo substituent instead of compound B (or B-A) providing compound D (or D-A).
  • a suitably substituted five-memberd ring A bearing a boronic acid or boronic acid ester instead of compound F
  • a suitably substituted six-membered (hetero)aromatic ring bearing an iodo substituent instead of compound B (or B-A) providing compound D (or D-A).
  • the term “compound” in its singular form may also comprise or refer to a plurality of compounds, while the term “compounds” in its plural form may also comprise or refer to a singular compound.
  • Examples and Experimental Part The compounds of the present invention can be prepared according to the procedures of the following Schemes and Examples, using appropriate materials and are further exemplified by the following specific examples. The compounds are shown in Table 1. Analytical data of compounds made according to the following examples are shown in Table 1, too. The invention will be illustrated, but not limited, by reference to the specific embodiments described in the following examples. Unless otherwise indicated in the schemes, the variables have the same meaning as described above and in the claims. Unless otherwise specified, all starting materials are obtained from commercial suppliers and used without further purifications.
  • 1 H NMR 1 H-NMR data is provided in Table 1 below.
  • 1 H NMR spectra were usually acquired on a Bruker Avance DRX 500, Bruker Avance 400.
  • NS Numberer of Scans: 32, SF (Spectrometer Frequency) as indicated.
  • TE Tempoture: 297 K.
  • Chemical shifts ( ⁇ ) are reported in ppm relative to the TMS signal. 1 H NMR data are reported as follows: chemical shift (multiplicity, coupling constants and number of hydrogens). Multiplicity is abbreviated as follows: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), dd (doublet of doublets), tt (triplet of triplets), td (triplet of doublets) br (broad) and coupling constants (J) are reported in Hz.
  • LC-MS LC-MS data provided in Table 1 are given with mass in m/z. The results can be obtained by one of the methods described below.
  • Example 1 4-(benzenesulfonyl)-2-benzyl-2H,4H-pyrrolo[3,4-b]indole-7- carboxylic acid
  • Example 1-1 Synthesis of 1-(benzenesulfonyl)-5-bromo-2,3-dimethyl-1H- indole To a suspension of NaH (1.70 g; 42.50 mmol) in DMF (50 ml) was added 5- bromo-2,3-dimethyl-1H-indole (6.25 g; 27.89 mmol) in DMF (50 ml) at 0 ° C slowly.
  • Example 1-2 Synthesis of product 1-(benzenesulfonyl)-5-bromo-2,3- bis(bromomethyl)-1H-indole
  • 1-(benzenesulfonyl)-5-bromo-2,3-dimethyl-1H-indole (6.40 g; 17.57 mmol) in CCl4 (120 ml) was added 1-bromopyrrolidine-2,5-dione (6.40 g; 36 mmol) and 2-[2-(1-cyano-1-methylethyl)diazen-1-yl]-2-methylpropane- nitrile (288 mg; 1.75 mmol) at 80 ° C.
  • Example 1-4 Synthesis of methyl 4-(benzenesulfonyl)-2-benzyl- 1H,2H,3H,4H-pyrrolo[3,4-b]indole-7-carboxylate
  • 4-(benzenesulfonyl)-2-benzyl-7-bromo-1H,2H,3H,4H- pyrrolo[3,4-b]indole (1.50 g; 2.73 mmol)
  • tris(dibenzylideneacetone)- dipalladium 300 mg; 0.33 mmol) and 4,5-Bis(diphenylphosphino)-9,9- dimethylxanthene (190 mg; 0.33 mmol) in DMF (10 ml) and MeOH (10 ml) was added potassium acetate (900 mg; 9.17 mmol) at 25 ° C.
  • the black brown mixture was stirred at 90 ° C under 1 bar of methanidylidyneoxidanium balloon for 16 hours.
  • the reaction was poured into water (50 mL) and extracted with EA (30 mL) for three times. The organic layers were concentrated to give a residue.
  • Example 1-5 Synthesis of methyl 4-(benzenesulfonyl)-2-benzyl-2H,4H- pyrrolo[3,4-b]indole-7-carboxylate
  • Example 1-6 Synthesis of 4-(benzenesulfonyl)-2-benzyl-2H,4H-pyrrolo[3,4- b]indole-7-carboxylic acid (Compound 1) To a solution of methyl 4-(benzenesulfonyl)-2-benzyl-2H,4H-pyrrolo[3,4- b]indole-7-carboxylate (50 mg; 0.11 mmol) in iPrOH (3 ml) and Water (0.6 ml) was added NaOH (13 mg; 0.33 mmol) at 25°C.
  • Example 2 2-methyl-8-[4-(trifluoromethyl)phenyl]-2H,8H-pyrazolo[3,4- b]indole-5-carboxylic acid
  • Example 2-1 Synthesis of ethyl 3-(3-amino-1-methyl-1H-pyrazol-4-yl)-4- chlorobenzoate To a suspension of 2-chloro-5-(ethoxycarbonyl)phenyl]boronic acid (500 mg; 2.19 mmol) in dioxane (4 ml) and water (0.4 ml) was added 4-bromo-1-methyl- 1H-pyrazol-3-amine (385 mg; 2.19 mmol), K2CO3 (605 mg; 4.38 mmol) and Pd(dppf)Cl2 (160 mg).
  • Example 2-2 Synthesis of ethyl 2-methyl-2H,8H-pyrazolo[3,4-b]indole-5- carboxylate
  • a suspension of ethyl 3-(3-amino-1-methyl-1H-pyrazol-4-yl)-4-chloro- benzoate 300 mg; 1.1 mmol
  • dioxane 15 ml
  • di-tert- butyl[2',4',6'-tris(propan-2-yl)-[1,1'-biphenyl]-2-yl]phosphane ⁇ 2'-amino-[1,1'- biphenyl]-2-yl ⁇ palladiumylium methanesulfonate 85 mg; 0.11 mmol
  • Cs2CO3 699 mg; 2.14 mmol
  • Example 2-3 Synthesis of ethyl 2-methyl-8-[4-(trifluoromethyl)phenyl]-2H,8H- pyrazolo[3,4-b]indole-5-carboxylate
  • a sealed tube was charged with ethyl 2-methyl-2H,8H-pyrazolo[3,4-b]indole- 5-carboxylate (85 mg; 0.35 mmol),1-bromo-4-(trifluoromethyl)benzene (102 mg; 0.45 mmol), XPhosPd G2 (17 mg; 0.02 mmol) and Cs2CO3 (342 mg; 1.05 mmol) in dioxane (5 ml). The mixture was stirred under N2 at 100°C for 2h.
  • the mixture was fittered and concentrated to get crude product as a black oil.
  • Example 2-4 Synthesis of 2-methyl-8-[4-(trifluoromethyl)phenyl]-2H,8H- pyrazolo[3,4-b]indole-5-carboxylic acid
  • MeOH MeOH
  • 1M sodium hydroxide 1 ml
  • Example 3 2-Benzyl-4-phenyl-2H,4H-pyrrolo[3,4-b]indole-7-carboxylic acid
  • Example 3-1 Synthesis of methyl 2-benzyl-1H,2H,3H,4H-pyrrolo[3,4-b]indole- 7-carboxylate
  • MeOH 20 ml
  • Cs2CO3 2.68 g; 8.23 mmol
  • Example 3-2_ Synthesis of methyl 2-benzyl-4-phenyl-1H,2H,3H,4H- pyrrolo[3,4-b]indole-7-carboxylate
  • iodobenzene 140 mg; 0.69 mmol
  • copper iodide 17 mg; 0.1 mmol
  • (2S)-pyrrolidine- 2-carboxylic acid 17.15 mmol
  • K2CO3 150 mg; 1.1 mmol
  • Example 3-3 Synthesis of methyl 2-benzyl-4-phenyl-2H,4H-pyrrolo[3,4- b]indole-7-carboxylate
  • Example 3-4 Synthesis of 2-benzyl-4-phenyl-2H,4H-pyrrolo[3,4-b]indole-7- carboxylic acid To a solution of methyl 2-benzyl-4-phenyl-2H,4H-pyrrolo[3,4-b]indole-7- carboxylate (34 mg; 0.1 mmol) in EtOH (5 ml) and H 2 O (1 ml) was added NaOH (35 mg; 0.9 mmol) at 25 ° C.
  • Example 4 2-methyl-4-[4-(trifluoromethyl)phenyl]-2H,4H-pyrazolo[4,3- b]indole-7-carboxylic acid
  • Example 4-1 Synthesis of ethyl 3-(4-amino-1-methyl-1H-pyrazol-3-yl)-4- chlorobenzoate The mixture of 2-chloro-5-(ethoxycarbonyl)phenyl]boronic acid (1.20 g; 5.20 mmol), 3-bromo-1-methyl-1H-pyrazol-4-amine (915 mg; 5.20 mmol), Cs2CO3 (3.4 g; 10.40 mmol) and Pd(dppf)Cl2 (380 mg; 0.52 mmol) in dioxane (20 ml) and water (2 ml) was stirred under N2 atmosphere at 90°C for 16h.
  • Example 4-2 Synthesis of ethyl 2-methyl-2H,4H-pyrazolo[4,3-b]indole-7- carboxylate
  • a sealed tube was charged with ethyl 3-(4-amino-1-methyl-1H-pyrazol-3-yl)-4- chlorobenzoate (350 mg; 1.24 mmol), di-tert-butyl[2',4',6'-tris(propan-2-yl)- [1,1'-biphenyl]-2-yl]phosphane ⁇ 2'-amino-[1,1'-biphenyl]-2-yl ⁇ palladiumylium methanesulfonate (120 mg; 0.15 mmol) and Cs2CO3 (807 mg; 2.48 mmol) in dioxane (20 ml). The mixture was stirred under N2 at 120°C for 16h.
  • Example 4-3 Synthesis of ethyl 2-methyl-4-[4-(trifluoromethyl)phenyl]-2H,4H- pyrazolo[4,3-b]indole-7-carboxylate
  • a sealed tube was charged with ethyl 2-methyl-2H,4H-pyrazolo[4,3-b]indole- 7-carboxylate (65 mg; 0.25 mmol), 1-bromo-4-(trifluoromethyl)benzene (72 mg; 0.32 mmol), XPhosPd G2 (12 mg; 0.01 mmol) and Cs2CO3 (240 mg; 0.74 mmol) in dioxane (4 ml).
  • the mixture was stirred under N2 at 100°C for 2h.
  • the mixture was fittered and concentrated to get crude product as a black oil.
  • Example 4-4 Synthesis of 2-methyl-4-[4-(trifluoromethyl)phenyl]-2H,4H- pyrazolo[4,3-b]indole-7-carboxylic acid
  • ethyl 2-methyl-4-[4-(trifluoromethyl)phenyl]-2H,4H- pyrazolo[4,3-b]indole-7-carboxylate 80 mg; 0.19 mmol
  • EtOH 4 ml
  • 1M sodium hydroxide aqueous solution (1 ml).
  • the mixture was stirred at 60°C for 1.5h.
  • Example 5 2-Methyl-8- ⁇ [4-(trifluoromethyl)phenyl]methyl ⁇ -2H,8H- pyrazolo[3,4-b]indole-5-carboxylic acid
  • Example 5-1 Synthesis of ethyl 2-methyl-8- ⁇ [4-(trifluoromethyl)phenyl]- methyl ⁇ -2H,8H-pyrazolo[3,4-b]indole-5-carboxylate
  • NaH 49 mg; 2.04 mmol
  • Example 5-2 Synthesis of 2-methyl-8- ⁇ [4-(trifluoromethyl)phenyl]methyl ⁇ - 2H,8H-pyrazolo[3,4-b]indole-5-carboxylic acid
  • ethyl 2-methyl-8- ⁇ [4-(trifluoromethyl)phenyl]methyl ⁇ -2H,8H- pyrazolo[3,4-b]indole-5-carboxylate 120 mg; 0.30 mmol
  • EtOH 40 ml
  • Water was added NaOH (36 mg; 0.90 mmol) at 25°C.
  • the yellow brown solution was stirred at 70°C for 3 hours.
  • the solution was concentrated.
  • Example 6 2-Methyl-8-[3-(trifluoromethyl)phenyl]-2H,8H-pyrazolo[3,4- b]indole-5-carboxylic acid
  • Example 6-1 Synthesis of ethyl 2-methyl-8-[3-(trifluoromethyl)phenyl]-2H,8H- pyrazolo[3,4-b]indole-5-carboxylate
  • Ethyl 3-(3-amino-1-methyl-1H-pyrazol-4-yl)-4-chlorobenzoate 200 mg; 0.64 mmol
  • 1-bromo-3-(trifluoromethyl)benzene 174 mg; 0.77 mmol
  • XPhosPd G2 56 mg; 0.07 mmol
  • Cs2CO3 629 mg; 1.93 mmol
  • Example 6-2 Synthesis of 2methyl-8-[3-(trifluoromethyl)phenyl]-2H,8H- pyrazolo[3,4-b]indole-5-carboxylic acid
  • EtOH a solution of ethyl-2-methyl-8-[3-(trifluoromethyl)phenyl]-2H,8H- pyrazolo[3,4-b]indole-5-carboxylate (230 mg; 0.56 mmol) in EtOH (6 ml) was added 1M sodium hydroxide aqueous solution (2 ml).
  • the reaction mixture was stirred under N2 atmosphere at 60 °C for 2h. The mixture was concentrated to dryness.
  • Example 7 8-(3-fluorophenyl)-2-methyl-2H,8H-pyrazolo[3,4-b]indole-5- carboxylic acid
  • Example 7-1 Synthesis of ethyl 8-(3-fluorophenyl)-2-methyl-2H,8H- pyrazolo[3,4-b]indole-5-carboxylate
  • a mixture of ethyl 3-(3-amino-1-methyl-1H-pyrazol-4-yl)-4-chlorobenzoate 200 mg; 0.64 mmol
  • 1-bromo-3-fluorobenzene (135 mg; 0.77 mmol
  • XPhosPd G2 56 mg; 0.07 mmol
  • Cs2CO3 629 mg; 1.93 mmol
  • the mixture was stirred under N2 atmosphere at 120 °C for 16h.
  • the reaction mixture was filtered.
  • Example 7-2 Synthesis of 8-(3-fluorophenyl)-2-methyl-2H,8H-pyrazolo[3,4- b]indole-5-carboxylic acid
  • EtOH a solution of ethyl 8-(3-fluorophenyl)-2-methyl-2H,8H-pyrazolo[3,4- b]indole-5-carboxylate (210 mg; 0.59 mmol) in EtOH (6 ml) was added 1M sodium hydroxide aqueous solution (2 ml). The mixture was stirred under N2 atmosphere at 60 °C for 2h. The mixture was concentrated to dryness.
  • Example 8 2-Methyl-8- ⁇ [3-(trifluoromethyl)phenyl]methyl ⁇ -2H,8H- pyrazolo[3,4-b]indole-5-carboxylic acid
  • Example 8-1 Synthesis of ethyl 2-methyl-8- ⁇ [3-(trifluoromethyl)phenyl]- methyl ⁇ -2H,8H-pyrazolo[3,4-b]indole-5-carboxylate
  • Example 8-2 Synthesis of 2-Methyl-8- ⁇ [3-(trifluoromethyl)phenyl]methyl ⁇ - 2H,8H-pyrazolo[3,4-b]indole-5-carboxylic acid
  • ethyl 2-methyl-8- ⁇ [3-(trifluoromethyl)phenyl]methyl ⁇ -2H,8H- pyrazolo[3,4-b]indole-5-carboxylate 210 mg; 0.51 mmol
  • EtOH 4 ml
  • Water 1 ml
  • NaOH 63 mg; 1.58 mmol
  • the mixture was concentrated to dryness and water (5 mL) was added.
  • the water phase was adjusted to pH ⁇ 3 by 1N hydrochloric acid aqueous solution (5 drops) and concentrated to dryness.
  • To the residue was added water (10 mL) and the mixture was filtered. The filtered residue was washed with water (5 mL) three times and concentrated to dryness.
  • the purified product could be obtained (150 mg; 78 %; off-white solid).
  • Example 9 2-Methyl-8-(4-methylphenyl)-2H,8H-pyrazolo[3,4-b]indole-5- carboxylic acid
  • Example 9-1 Synthesis of ethyl 2-methyl-8-(4-methylphenyl)-2H,8H- pyrazolo[3,4-b]indole-5-carboxylate
  • a mixture of ethyl 3-(3-amino-1-methyl-1H-pyrazol-4-yl)-4-chlorobenzoate 200 mg; 0.64 mmol
  • 1-bromo-4-methylbenzene 132 mg; 0.77 mmol
  • XPhosPd G2 56 mg; 0.07 mmol
  • Cs2CO3 629 mg; 1.93 mmol
  • Example 9-2 Synthesis of 2-methyl-8-(4-methylphenyl)-2H,8H-pyrazolo[3,4- b]indole-5-carboxylic acid
  • ethyl 2-methyl-8-(4-methylphenyl)-2H,8H-pyrazolo[3,4- b]indole-5-carboxylate 200 mg; 0.57 mmol
  • EtOH 6 ml
  • 1M sodium hydroxide aqueous solution 2 ml
  • the mixture was stirred under N2 atmosphere at 60°C for 2h.
  • the mixture was concentrated.
  • the precipitate was filtered.
  • Example 10 8-(4-fluorophenyl)-2-methyl-2H,8H-pyrazolo[3,4-b]indole-5- carboxylic acid
  • Example 10-1 Synthesis of ethyl 8-(4-fluorophenyl)-2-methyl-2H,8H- pyrazolo[3,4-b]indole-5-carboxylate
  • Example 10-2 Synthesis of 8-(4-fluorophenyl)-2-methyl-2H,8H-pyrazolo[3,4- b]indole-5-carboxylic acid
  • EtOH a solution of ethyl 8-(4-fluorophenyl)-2-methyl-2H,8H-pyrazolo[3,4- b]indole-5-carboxylate (180 mg; 0.51 mmol) in EtOH (5 ml) was added 1M sodium hydroxide aqueous solution (1.7 ml). The mixture was stirred under N2 atmosphere at 60°C for 16h. The mixture was concentrated to dryness. To the residue H 2 O (15ml) was added and pH was adjusted to 1 by 1N hydrochloric acid.
  • Example 11 8-(cyclohexylmethyl)-2-methyl-2H,8H-pyrazolo[3,4-b]indole-5- carboxylic acid
  • Example 11-1 Synthesis of ethyl 8-(cyclohexylmethyl)-2-methyl-2H,8H- pyrazolo[3,4-b]indole-5-carboxylate
  • ethyl 2-methyl-2H,8H-pyrazolo[3,4-b]indole-5-carboxylate 200 mg; 0.82 mmol
  • propan-2-one 5 ml
  • bromomethyl- cyclohexane 0.14 ml; 0.99 mmol
  • KOH 138 mg; 2.47 mmol.
  • Example 12 8-(Benzyl)-2-methyl-2H,8H-pyrazolo[3,4-b]indole-5-carboxylic acid
  • Example 12-1 Synthesis of ethyl 8-(cyclohexylmethyl)-2-methyl-2H,8H- pyrazolo[3,4-b]indole-5-carboxylate
  • bromomethylbenzene (0.18 ml; 1.48 mmol
  • KOH 208 mg; 3.7 mmol
  • Example 12-2 Synthesis of 8-(benzyl)-2-methyl-2H,8H-pyrazolo[3,4-b]indole- 5-carboxylic acid
  • EtOH ethyl 8-(benzyl)-2-methyl-2H,8H-pyrazolo[3,4-b]indole-5- carboxylate
  • sodium hydroxide 320 mg; 8 mmol
  • water 4 ml
  • Example 13 8-(4-chlorophenyl)-2-methyl-2H,8H-pyrazolo[3,4-b]indole-5- carboxylic acid
  • Example 13-1 Synthesis of ethyl 8-(4-chlorophenyl)-2-methyl-2H,8H- pyrazolo[3,4-b]indole-5-carboxylate
  • Example 13-2 Synthesis of 8-(4-chlorophenyl)-2-methyl-2H,8H-pyrazolo[3,4- b]indole-5-carboxylic acid
  • EtOH ethyl 8-(4-chlorophenyl)-2-methyl-2H,8H-pyrazolo[3,4- b]indole-5-carboxylate
  • sodium hydroxide 320 mg; 8 mmol
  • Water 4 ml
  • Example 14 8-(4-methoxyphenyl)-2-methyl-2H,8H-pyrazolo[3,4-b]indole-5- carboxylic acid
  • Example 14-1 Synthesis of ethyl 8-(4-methoxyphenyl)-2-methyl-2H,8H- pyrazolo[3,4-b]indole-5-carboxylate
  • ethyl 3-(3-amino-1-methyl-1H-pyrazol-4-yl)-4-chloro- benzoate 60 mg; 0.21 mmol
  • 1,4-Dioxane (4 ml) was added under argon 4- Bromoanisole (32 ⁇ l; 0.26 mmol), Cesium carbonate (206 mg; 0.64 mmol) and XPhos Pd G4 (19 mg; 0.02 mmol).
  • Example 14-2 Synthesis of 8-(4-methoxyphenyl)-2-methyl-2H,8H- pyrazolo[3,4-b]indole-5-carboxylic acid
  • Example 15 8-(4-Ethoxyphenyl)-2-methyl-2H,8H-pyrazolo[3,4-b]indole-5- carboxylic acid
  • Example 15-1 Synthesis of ethyl 3-(3-amino-1-methyl-1H-pyrazol-4-yl)-4- chlorobenzoate To a suspension of Ethyl 3-borono-4-chlorobenzoate (600 mg; 2.63 mmol) in 1,4-Dioxane (8 ml) and Water (0.8 ml) was added 4-Bromo-1-methyl-1H- pyrazol-3-amine (462 mg; 2.63 mmol), Potassium carbonate (726 mg; 5.25 mmol) and [1,1'-Bis(diphenylphosphino)ferrocene]-dichloropalladium(II), complex with dichloromethane (214 mg) in a microwave vial under argon.
  • the reaction was stirred for 16 hours at 60°C and then diluted with EA at room temperature.
  • the mixture was extracted 3x with water, dried over Na 2 SO 4 and evaporated to dryness.
  • the residue was purified by flash chromatopgraphy. The purified product could be obtained as brown oil (273 mg, 36% yield).
  • Example 15-2 Synthesis of ethyl 8-(4-ethoxyphenyl)-2-methyl-2H,8H- pyrazolo[3,4-b]indole-5-carboxylate
  • ethyl 3-(3-amino-1-methyl-1H-pyrazol-4-yl)-4-chlorobenzoate 60 mg; 0.21 mmol
  • 1,4-Dioxane 4 ml
  • Cesium carbonate (0.62 mmol
  • XPhos Pd G4 (19 mg; 0.02 mmol) in a microwave vial.
  • Example 15-3 Synthesis of 8-(4-ethoxyphenyl)-2-methyl-2H,8H-pyrazolo[3,4- b]indole-5-carboxylic acid
  • ethyl 8-(4-ethoxyphenyl)-2-methyl-2H,8H-pyrazolo[3,4-b]indole-5- carboxylate 10 mg; 0.03 mmol
  • Example 16 Methyl 2-methyl-4-[4-(trifluoromethyl)phenyl] pyrazolo[4,3- b]indole-7-carboxylate Into a sealed tube were combined methyl 3-(4-amino-1-methylpyrazol-3-yl)-4- chlorobenzoate (330 mg, 1.192 mmol), XPhos Pd G3 (99 mg, 0.115 mmol), Cs2CO3 (825 mg, 2.481 mmol), dioxane (160 mL) and 1-bromo-4- (trifluoromethyl)benzene (0.19 mL, 0.004 mmol) at room temperature.
  • Example 18 2-methyl-8-[4-(trifluoromethoxy)phenyl]-2H,8H-pyrazolo[3,4- b]indole-5-carboxylic acid
  • Example 18-1 Synthesis of ethyl 2 ⁇ methyl ⁇ 8 ⁇ [4 ⁇ (trifluoromethoxy)phenyl] ⁇ 2H,8H ⁇ pyrazolo[3,4 ⁇ b]indole ⁇ 5 ⁇ carboxylate
  • To ethyl 3-(3-amino-1-methyl-1H-pyrazol-4-yl)-4-chlorobenzoate (60 mg; 0.21 mmol) in 1,4-Dioxane (4 ml) was added under argon 1-Brom-4- (trifluormethoxy)-benzene (60 mg; 0.25 mmol), Cesium carbonate (202 mg; 0.62 mmol) and XPhos Pd G4 (18.7 mg; 0.02 mmol) in a microwave vial.
  • Example 18-2 Synthesis of 2-methyl-8-[4-(trifluoromethoxy)phenyl]-2H,8H- pyrazolo[3,4-b]indole-5-carboxylic acid
  • ethyl 2-methyl-8-[4-(trifluoromethoxy)phenyl]-2H,8H- pyrazolo[3,4-b]indole-5-carboxylate 28 mg; 0.07 mmol
  • Ethanol 2 ml
  • Sodium hydroxide solution c(NaOH) 2 mol/l (2 N) (104 ⁇ l; 0.21 mmol) and the mixture was stirred for 16 hrs at 60°C.
  • Example 19 2-methyl-4-[4-(trifluoromethyl)phenyl]pyrazolo [4,3-b]indole-7- carbonitrile
  • Example 19-1 Synthesis of 2-methyl-4-[4-(trifluoromethyl)phenyl]pyrazolo [4,3-b]indole-7-carboxamide Into a sealed tube were combined 2-methyl-4-[4-(trifluoromethyl)phenyl] pyrazolo[4,3-b]indole-7-carboxylic acid (Example 4-4) (490 mg, 1.324 mmol), THF (25 mL), CDI (344 mg, 2.079 mmol), NH4OH (30 mL) at room temperature.
  • Example 20 N-[2-methyl-8-[4-(trifluoromethyl)phenyl] pyrazolo[3,4-b]indol-5- yl]prop-2-enamide
  • Example 20-1 Synthesis of 4-(2-chloro-5-nitrophenyl)-1-methylpyrazol-3- amine To a solution of 2-chloro-5-nitrophenylboronic acid (1.0 g, 4.718 mmol) and 4- bromo-1-methylpyrazol-3-amine (437 mg, 2.359 mmol) in dioxane (10 mL) and H 2 O (2 mL) were added Pd(dppf)Cl2 (363 mg, 0.471 mmol) and K2CO3 (1.3 g, 8.936 mmol).
  • Example 20-2 Synthesis of 2-methyl-5-nitro-8-[4-(trifluoromethyl) phenyl]pyrazolo[3,4-b]indole
  • 4-(2-chloro-5-nitrophenyl)-1-methylpyrazol-3-amine 330 mg, 1.124 mmol
  • 1-bromo-4-(trifluoromethyl)benzene 346 mg, 1.461 mmol
  • XPhos Pd G3 50 mg, 0.056 mmol
  • Cs2CO3 (1.16 g, 3.372 mmol
  • Example 20-3 Synthesis of 2-methyl-8-[4-(trifluoromethyl) phenyl]pyrazolo [3,4-b]indol-5-amine
  • 2-methyl-5-nitro-8-[4-(trifluoromethyl)phenyl]pyrazolo[3,4- b]indole 450 mg, 1.048 mmol
  • Pd/C 10%, 450 mg
  • the mixture was hydrogenated at room temperature for 1 h under hydrogen atmosphere using a hydrogen balloon, filtered through a Celite pad and concentrated under reduced pressure.
  • Example 21 N-([2-methyl-8-[4-(trifluoromethyl)phenyl]pyrazolo [3,4-b]indol-5- yl]methyl)prop-2-enamide
  • Example 21-1 Synthesis of 1-[2-methyl-8-[4-(trifluoromethyl)phenyl]pyrazolo [3,4-b]indol-5-yl]methanamine
  • 2-methyl-8-[4-(trifluoromethyl)phenyl]pyrazolo[3,4- b]indole-5-carbonitrile (300 mg, 0.882 mmol) and NH 3 (g) in MeOH (15 mL, 13%) in MeOH (30 mL) was added Raney Ni (300 mg, 3.327 mmol) under nitrogen atmosphere.
  • Example 22 8 ⁇ (4 ⁇ cyclopentylphenyl) ⁇ 2 ⁇ methyl ⁇ 2H,8H ⁇ pyrazolo [3,4 ⁇ b]indole ⁇ 5 ⁇ carboxylic acid
  • Example 22-1 Synthesis of ethyl 8 ⁇ (4 ⁇ cyclopentylphenyl) ⁇ 2 ⁇ methyl ⁇ 2H,8H ⁇ pyrazolo[3,4 ⁇ b]indole ⁇ 5 ⁇ carboxylate
  • Example 22-2 Synthesis of 8 ⁇ (4 ⁇ cyclopentylphenyl) ⁇ 2 ⁇ methyl ⁇ 2H,8H ⁇ pyrazolo [3,4 ⁇ b]indole ⁇ 5 ⁇ carboxylic acid
  • ethyl 8-(4-cyclopentylphenyl)-2-methyl-2H,8H-pyrazolo[3,4-b]indole-5- carboxylate 15 mg; 0.04 mmol
  • Example 23 Synthesis of 2-chloro-N-[2-methyl-8-[4- (trifluoromethyl)phenyl]pyrazolo[3,4-b]indol-5-yl]acetamide
  • 2-methyl-8-[4-(trifluoromethyl)phenyl]pyrazolo[3,4- b]indol-5-amine Example 20-3
  • TEA 122 mg, 1.145 mmol
  • DCM 5 mL
  • Example 21-1 1-[2-methyl-8-[4-(trifluoromethyl)phenyl]pyrazolo[3,4- b]indol-5-yl]methanamine (Example 21-1) (130 mg, 0.339 mmol) and DIPEA (139 mg, 1.022 mmol) in DCM (20 mL) was added chloroacetyl chloride (50 mg, 0.443 mmol) in DCM dropwise at 0°C under nitrogen atmosphere. The resulting mixture was stirred for 1 h at 0°C under nitrogen atmosphere and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EtOAc (1:1).
  • Example 25 2-methyl-4-[4-(trifluoromethyl)phenyl]-[1,3]thiazolo[4,5-b]indole- 7-carboxylic acid
  • Example 25-1 Synthesis of methyl 3-bromo-4-[(2-methyl-1,3-thiazol-4- yl)amino]benzoate
  • XantPhos 0.39 g, 0.640 mmol
  • Pd2(dba)3 (0.21 g, 0.213 mmol
  • Cs2CO3 2.94 g, 8.580 mmol
  • Example 25-2 Synthesis of 2-methyl-4H-[1,3]thiazolo[4,5-b]indole-7- carboxylate
  • methyl 3-bromo-4-[(2-methyl-1,3-thiazol-4-yl)amino]benzoate (1.01 g, 2.624 mmol) and pivalic acid (285 mg, 2.651 mmol) in xylene (45 mL) were added PCy3.HBF4 (153 mg, 0.395 mmol), Pd(AcO)2 (31 mg, 0.131 mmol) and Cs2CO3 (2.7 g, 7.872 mmol) at room temperature under nitrogen atmosphere.
  • Example 25-4 Synthesis of 2-methyl-4-[4-(trifluoromethyl)phenyl]- [1,3]thiazolo[4,5-b]indole-7-carboxylic acid
  • Example 26 7-fluoro-2-methyl-4-[4-(trifluoromethyl)phenyl] pyrazolo[4,3- b]indole
  • Example 26-1 Synthesis of 3-(2-bromo-5-fluorophenyl)-1-methyl-4- nitropyrazole
  • 2-bromo-5-fluorophenylboronic acid 700 mg, 3.039 mmol
  • 3-bromo-1-methyl-4-nitropyrazole 700 mg, 3.330 mmol
  • dioxane 28 mL
  • H 2 O 7 mL
  • NaHCO3 (1.40 g, 15.832 mmol
  • Pd(PPh3)4 350 mg, 0.300 mmol
  • Example 26-2 Synthesis of 3-(2-bromo-5-fluorophenyl)-1-methylpyrazol-4- amine
  • 3-(2-bromo-5-fluorophenyl)-1-methyl-4-nitropyrazole 650 mg, 1.133 mmol
  • NH4Cl 580 mg, 10.301 mmol
  • H 2 O 6.5 mL
  • Fe 609 mg, 10.360 mmol
  • the resulting mixture was stirred for 2 h at 70°C and then diluted with water (20 mL). The resulting mixture was extracted with CH 2 Cl2 (3 x50 mL).
  • Example 26-3 Synthesis of 7-fluoro-2-methyl-4-[4-(trifluoromethyl)phenyl] pyrazolo[4,3-b]indole
  • 3-(2-bromo-5-fluorophenyl)-1-methylpyrazol-4-amine 500 mg, 1.133 mmol
  • 1-bromo-4-(trifluoromethyl)benzene 460 mg, 1.942 mmol
  • dioxane 15 mL
  • Cs2CO3 (1.20 g, 3.499 mmol
  • XPhos Pd G3 (161 mg, 0.181 mmol
  • Example 27 N ⁇ cyclopropyl ⁇ 2 ⁇ methyl ⁇ 8 ⁇ [6 ⁇ (trifluoromethyl)pyridin ⁇ 3 ⁇ yl] ⁇ 2H,8H ⁇ pyrazolo[3,4 ⁇ b]indole ⁇ 5 ⁇ carboxamide
  • Example 27-1 Synthesis of N ⁇ cyclopropyl ⁇ 2 ⁇ methyl ⁇ 8 ⁇ [6 ⁇ (trifluoromethyl)pyridin ⁇ 3 ⁇ yl] ⁇ 2H,8H ⁇ pyrazolo[3,4 ⁇ b]indole ⁇ 5 ⁇ carboxamide
  • 2-methyl-8-[6-(trifluoromethyl)pyridin-3-yl]-2H,8H-pyrazolo[3,4-b]indole-5- carboxylic acid 73 mg; 0.20 mmol
  • DMF 4-ml
  • cyclopropylamine 21 ⁇ l; 0.29 mmol
  • N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydro- chloride 75 mg;
  • Example 28 2 ⁇ methyl ⁇ N ⁇ [(pyridin ⁇ 4 ⁇ yl)methyl] ⁇ 8 ⁇ [4 ⁇ (trifluoromethyl)phenyl] ⁇ 2H,8H ⁇ pyrazolo[3,4 ⁇ b]indole ⁇ 5 ⁇ carboxamide
  • Example 28-1 Synthesis of 2 ⁇ methyl ⁇ N ⁇ [(pyridin ⁇ 4 ⁇ yl)methyl] ⁇ 8 ⁇ [4 ⁇ (trifluoromethyl)phenyl] ⁇ 2H,8H ⁇ pyrazolo[3,4 ⁇ b]indole ⁇ 5 ⁇ carboxamide
  • Example 29 N ⁇ [2 ⁇ hydroxy ⁇ 1 ⁇ (pyridin ⁇ 2 ⁇ yl)ethyl] ⁇ 2 ⁇ methyl ⁇ 8 ⁇ [4 ⁇ (trifluoromethyl)phenyl] ⁇ 2H,8H ⁇ pyrazolo[3,4 ⁇ b]indole ⁇ 5 ⁇ carboxamide
  • Example 29-1 Synthesis of N ⁇ [2 ⁇ hydroxy ⁇ 1 ⁇ (pyridin ⁇ 2 ⁇ yl)ethyl] ⁇ 2 ⁇ methyl ⁇ 8 ⁇ [4 ⁇ (trifluoromethyl)phenyl] ⁇ 2H,8H ⁇ pyrazolo[3,4 ⁇ b]indole ⁇ 5 ⁇ carboxamide
  • Example 29-2 Separation of Enantiomers
  • Example 30 (2S,3S,4S,5R,6S) ⁇ 3,4,5 ⁇ trihydroxy ⁇ 6 ⁇ 2 ⁇ methyl ⁇ 8 ⁇ [4 ⁇ (trifluoromethyl)phenyl] ⁇ 2H,8H ⁇ pyrazolo[3,4 ⁇ b]indole ⁇ 5 ⁇ carbonyloxy ⁇ oxane ⁇ 2 ⁇ carboxylic acid
  • Example 30-1 Synthesis of (2S,3S,4S,5R,6S) ⁇ 3,4,5 ⁇ trihydroxy ⁇ 6 ⁇ 2 ⁇ methyl ⁇ 8 ⁇ [4 ⁇ (trifluoromethyl)phenyl] ⁇ 2H,8H ⁇ pyrazolo[3,4 ⁇ b]indole ⁇ 5 ⁇ carbonyloxy ⁇ oxane ⁇ 2 ⁇ carboxylic acid
  • Example 31 2 ⁇ methyl ⁇ 8 ⁇ (4 ⁇ methylphenyl) ⁇ 5 ⁇ (methylsulfanyl) ⁇ 2H,8H ⁇ pyrazolo[3,4 ⁇ b]indole
  • Example 31-1 Synthesis of 2 ⁇ methyl ⁇ 8 ⁇ (4 ⁇ methylphenyl) ⁇ 5 ⁇ (methylsulfanyl) ⁇ 2H,8H ⁇ pyrazolo[3,4 ⁇ b]indole 4-[2-chloro-5-(methylsulfanyl)phenyl]-1-methyl-1H-pyrazol-3-amine (500 mg; 1.9 mmol), 4-bromotoluene (661 mg; 3.9 mmol) and cesium carbonate (1.9 g; 5.8 mmol) were suspended in 1,4-Dioxane (30 ml) and flushed with argon, then XPhos Pd G4 (175 mg; 0.2 mmol) was added stirred over weekend at 120°C.
  • Example 32 7 ⁇ methanesulfinyl ⁇ 2 ⁇ methyl ⁇ 4 ⁇ [4 ⁇ (trifluoromethyl)phenyl] ⁇ 2H,4H ⁇ pyrazolo[4,3 ⁇ b]indole
  • Example 32-1 Synthesis of 7 ⁇ methanesulfinyl ⁇ 2 ⁇ methyl ⁇ 4 ⁇ [4 ⁇ (trifluoromethyl)phenyl] ⁇ 2H,4H ⁇ pyrazolo[4,3 ⁇ b]indole
  • 2-methyl-7-(methylsulfanyl)-4-[4-(trifluoromethyl)phenyl]- pyrazolo[4,3-b]indole(400 mg, 0.7 mmol) in AcOH (400 mg) and CHCl2 (20 mL) was added H 2 O2 (0.11 mL; 30% in water) at 0°C.
  • Example 33 7 ⁇ methanesulfonyl ⁇ 2 ⁇ methyl ⁇ 4 ⁇ [4 ⁇ (trifluoromethyl)phenyl] ⁇ 2H,4H ⁇ pyrazolo[4,3 ⁇ b]indole
  • Example 33-1 Synthesis of 7 ⁇ methanesulfonyl ⁇ 2 ⁇ methyl ⁇ 4 ⁇ [4 ⁇ (trifluoromethyl)phenyl] ⁇ 2H,4H ⁇ pyrazolo[4,3 ⁇ b]indole
  • 2-methyl-7-(methylsulfanyl)-4-[4-(trifluoromethyl)- phenyl]pyrazolo[4,3-b]indole 20 mg, 0.036 mmol
  • DCM 1 mL
  • MCPBA 22 mg, 0.089 mmol
  • the resulting mixture was stirred for 3 h at RT under air atmosphere.
  • the reaction mixture was diluted with water, washed with 10% aqueous sodium sulfite solution and saturated aqueous sodium hydrogen carbonate solution. After phase separation and extraction of the aqueous phase with DCM the combined organic layers were washed with brine (2 x 100 mL) and dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure.
  • the crude was purified by HPLC giving the product (48 mg, 17%) as a yellow solid.
  • Example 34 2 ⁇ methyl ⁇ 4 ⁇ [4 ⁇ (trifluoromethyl)phenyl] ⁇ 2H,4H ⁇ pyrazolo[4,3 ⁇ b]indole ⁇ 7 ⁇ sulfonamide
  • Example 34-1 Synthesis of 2 ⁇ methyl ⁇ 4 ⁇ [4 ⁇ (trifluoromethyl)phenyl] ⁇ 2H,4H ⁇ pyrazolo[4,3 ⁇ b]indole ⁇ 7 ⁇ sulfonamide
  • 2-methyl-4-[4-(trifluoromethyl)phenyl]- pyrazolo[4,3-b]indole 1.6 g, 4.8 mmol
  • Example 35 Imino(methyl) ⁇ 2 ⁇ methyl ⁇ 4 ⁇ [4 ⁇ (trifluoromethyl)phenyl] ⁇ 2H,4H ⁇ pyrazolo[4,3 ⁇ b]indol ⁇ 7 ⁇ yl ⁇ lambda6 ⁇ sulfanone
  • Example 35-1 Synthesis of imino(methyl) ⁇ 2 ⁇ methyl ⁇ 4 ⁇ [4 ⁇ (trifluoromethyl)phenyl] ⁇ 2H,4H ⁇ pyrazolo[4,3 ⁇ b]indol ⁇ 7 ⁇ yl ⁇ lambda6 ⁇ sulfanone
  • a mixture of 7-methanesulfinyl-2-methyl-4-[4-(trifluoromethyl)phenyl]pyrazolo- [4,3-b]indole 300 mg, 0.674 mmol
  • Rh2(OAc)4 9 mg, 0.019 mmol
  • DIB 347 mg, 1.02 mmol
  • BocNH 2 124 mg
  • Example 36 N,N,2 ⁇ Trimethyl ⁇ 4 ⁇ [4 ⁇ (trifluoromethyl)phenyl] ⁇ 2H,4H ⁇ pyrazolo[4,3 ⁇ b]indole ⁇ 7 ⁇ sulfonoimidamide
  • Example 36-1 Synthesis of N,N,2 ⁇ trimethyl ⁇ 4 ⁇ [4 ⁇ (trifluoromethyl)phenyl] ⁇ 2H,4H ⁇ pyrazolo[4,3 ⁇ b]indole ⁇ 7 ⁇ sulfonoimidamide
  • 2-methyl-4-[4-(trifluoromethyl)phenyl]pyrazolo[4,3- b]indole-7-sulfonamide 280 mg, 0.68 mmol
  • NaH 42 mg, 1.1 mmol
  • Example 37 4-methyl-7-[4-(trifluoromethyl)phenyl]-4,5,7,9- tetraazatricyclo[6.4.0.0 2,6 ]dodeca-1(8),2,5,9,11-pentaene-11-carboxylic acid
  • Step 1 To a solution of ⁇ 4-Bromo-1-methyl-1H-pyrazol-amine (4.0 g, 22.73 mmol) in ⁇ DCM (60mL) at 0°C was added Triethylamine (6.34 mL, 45.45 mmol). The reaction was stirred for 5 mins ⁇ then ⁇ Acetyl chloride (2.42 mL, 34.09 mmol) was added dropwise to the reaction mixture.
  • Step 2 To a degassed solution of ⁇ N-(4-bromo-1-methyl-pyrazol-3-yl)acetamide (3.0 g, 13.76 mmol), Bis(pinacolato)diboron (4.3 g, 16.51 mmol) andpotassium acetate (4.1 g, 41.28 mmol) in ioxane (70 mL) was added1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (562 mg, 0.69 mmol). The reaction was heated to 90°C for 2 hours.
  • Step 4 To a solution of ⁇ m thyl 5-(3-acetamido-1-methyl-pyrazol-4-yl)-6-chloro- pyridine-3-carboxylate (367 mg, 1.19 mmol) in ⁇ methanol (10mL) was added hydrogen chloride (1.43 mL, 1.78 mmol) (1.25 M solution in methanol).
  • the reaction was heated at 70°C under nitrogen for ⁇ 48 hours.
  • the reaction mixture was concentrated under vacuum and purified by column chromatography to yield ⁇ methyl 5-(3-amino-1-methyl-pyrazol-4-yl)-6-chloro-pyridine-3- carboxylate (196 mg, 62 %) as a brown solid.
  • the sample was taken onto the next stage of the reaction sequence.
  • Step 5 To a degassed solution of methyl 5-(3-amino-1-methyl-pyrazol-4-yl)-6-chloro- pyridine-3-carboxylate (196 mg, 0.74 mmol), 4-Bromobenzotrifluoride (0.1 mL, 0.74 mmol) and Cesium carbonate (718 mg, 2.21 mmol) in dioxane (6mL) was added XPhos Pd G2 (58 mg, 0.07 mmol). The reaction was heated under nitrogen at 100°C for 16 hours. LCMS confirmed the product formation and no starting material remained. The reaction was cooled to room temperature and diluted with water (10 mL) The reaction mixture was extracted with Ethyl Acetate three times (3x 10 mL).
  • Step 6 To a solution of methyl 4-methyl-7-[4-(trifluoromethyl)phenyl]-4,5,7,9-tetraza- tricyclo[6.4.0.0 2,6 ]dodeca-1(8),2,5,9,11-pentaene-11-carboxylate (34 mg, 0.09 mmol) in THF (0.5 mL) and Water (0.13 mL) was added lithium hydroxide monohydrate (4.19 mg, 0.1 mmol).
  • Example 38 Synthesis of N-[(2S)-1-hydroxypropan-2-yl]-3-methyl-4-[4- (trifluoromethyl)phenyl]-3H,4H-[1,2,3]triazolo[4,5-b]indole-7-sulfonamide
  • Step 1 To a stirred mixture of 4-bromo-1-methyl-1H-1,2,3-triazole (10.50 g; 61.58 mmol), 2-nitrophenyl)boronic acid (16.20 g; 92.20 mmol), K3PO4 (28 g; 125.32 mmol) in dioxane (140 ml) and H 2 O (28 ml) was added Pd(DTBPF)Cl2 (4.30 g; 6.27 mmol) at room temperature.
  • Step 2 To a stirred mixture of 1-methyl-4-(2-nitrophenyl)-1H-1,2,3-triazole (8.25 g; 40.40 mmol) in 1,2-dichlorobenzene (200 ml) was added DPPE (20 g; 47.69 mmol) at room temperature. The resulting mixture was stirred for 48 h at 165°C. For work-up the mixture was concentrated under vacuum.
  • Step 3 A suspension of 3-methyl-3H,4H-[1,2,3]triazolo[4,5-b]indole (1.50 g; 7.87 mmol), XPhos Pd G4 (0.75 g; 0.84 mmol), Cs2CO3 (5.60 g; 16.33 mmol) and 1-iodo-4-(trifluoromethyl)benzene (4.60 g; 16.07 mmol) in dioxane (200 ml) was stirred for overnight at 120°C under nitrogen atmosphere.For work-up the mixture was concentrated under vacuum.
  • Step 4 A solution of 3-methyl-4-[4-(trifluoromethyl)phenyl]-3H,4H-[1,2,3]triazolo[4,5- b]indole (1.40 g; 4.43 mmol) in chlorosulfonic acid (40 ml) was stirred for 2h at 0°C under nitrogen atmosphere. The reaction was quenched by the addition of ice water.
  • Step 5 A solution of 3-methyl-4-[4-(trifluoromethyl)phenyl]-3H,4H-[1,2,3]triazolo[4,5- b]indole-7-sulfonyl chloride (150 mg; 0.35 mmol), TEA (0.16 ml; 1.13 mmol) and (2S)-2-aminopropan-1-ol (50 mg; 0.63 mmol) in DCM (5 ml) was stirred for 1h at 80°C under nitrogen atmosphere. For work-up the mixture was concentrated under vacuum. The crude product was purified by Prep-HPLC. This resulted in 22.40 mg (14 %) of the product as off-white solid.
  • Example 39 Synthesis of 3- ⁇ 1-methyl-4-[4-(trifluoromethyl)phenyl]-1H,4H- imidazo[4,5-b]indol-7-yl ⁇ -4,5-dihydro-1,2,4-oxadiazol-5-one
  • Step 1 To a mixture of 1-methyl-4-[4-(trifluoromethyl)phenyl]-1H,4H-imidazo[4,5- b]indole-7-carboxylic acid (170 mg; 0.47 mmol), NH4Cl (120 mg; 2.13 mmol) in DMF (10 ml) were added DIEA (0.62 ml; 3.38 mmol) and HATU (1.40 g; 3.50 mmol) at room temperature under N2 atmosphere.
  • Step 2 To a suspension of 1-methyl-4-[4-(trifluoromethyl)phenyl]-1H,4H-imidazo[4,5- b]indole-7-carboxamide (450 mg; 1.26 mmol) in DMF (10 ml) was added POCl3 (1 ml; 10.73 mmol) at room temperature. The resulting mixture was stirred for 1 h at 25°C. For work-up the reaction was quenched with water at room temperature. The resulting mixture was extracted with EtOAc (3 x 150 mL). The combined organic layers were washed with brine (1x100 mL) and dried over anhydrous Na2SO4.
  • Step 3 To a stirred mixture of 1-methyl-4-[4-(trifluoromethyl)phenyl]-1H,4H- imidazo[4,5-b]indole-7-carbonitrile (350 mg; 1.01 mmol) and hydroxylamine hydrochloride (100 mg; 1.37 mmol) in EtOH (21 ml) and H 2 O (1 ml) was added Na2CO3 (150 mg; 1.34 mmol) at room temperature.
  • Step 4 To a solution of N-hydroxy-1-methyl-4-[4-(trifluoromethyl)phenyl]-1H,4H- imidazo[4,5-b]indole-7-carboximidamide (180 mg; 0.34 mmol) in DMSO (5 ml) was added CDI (69 mg; 0.40 mmol) at room temperature. The resulting mixture was stirred for 3 h at 95°C. For work-up the reaction was quenched with water at room temperature. The resulting mixture was extracted with EtOAc (3 x 150 mL). The combined organic layers were washed with brine (1 x 100 mL) and dried over anhydrous Na 2 SO 4 .
  • Example 40 Synthesis of 5-[(5- ⁇ 1-methyl-4-[4-(trifluoromethyl)phenyl]-1H,4H- imidazo[4,5-b]indol-7-yl ⁇ -4,5-dihydro-1,2-oxazol-3-yl)oxy]pyrimidine
  • Step 1 To a stirred mixture of 1-methyl-4-[4-(trifluoromethyl)phenyl]-1H,4H- imidazo[4,5-b]indole-7-carboxylic acid (1.55 g; 4.27 mmol), methoxy(methyl)- amine hydrochloride (0.66 g; 6.41 mmol) and DIEA (2.40 ml; 12.82 mmol) in DMF (10 ml) was added HATU (3.42 g; 8.55 mmol) at room temperature.
  • Step 2 To a mixture of N-methoxy-N,1-dimethyl-4-[4-(trifluoromethyl)phenyl]-1H,4H- imidazo[4,5-b]indole-7-carboxamide (1.45 g; 3.60 mmol) in DCM (50 ml) was added DIBAL-H (11.10 ml; 11.10 mmol) at -78°C. The resulting mixture was stirred for 1 h at -78°C.
  • Step 3 To a mixture of 1-methyl-4-[4-(trifluoromethyl)phenyl]-1H,4H-imidazo[4,5- b]indole-7-carbaldehyde (0.98 g; 2.37 mmol) and Ph3PMeBr (1.28 g; 3.55 mmol) in dioxane (30 ml) was added potassiumcarbonate (1.03 g; 7.10 mmol) at room temperature.
  • Step 4 To a mixture of 7-ethenyl-1-methyl-4-[4-(trifluoromethyl)phenyl]-1H,4H- imidazo[4,5-b]indole (232 mg; 0.67 mmol) in EtOAc (5 ml) were added 1- bromo-N-hydroxymethanecarbonimidoyl bromide (216 mg; 1.01 mmol) and Sodium bicarbonate (286 mg; 3.37 mmol) at room temperature. The resulting mixture was stirred for overnight at room temperature. For work-up the reaction was quenched with water at room temperature. The resulting mixture was extracted with EtOAc (3 x 150 mL).
  • Step 6 To a stirred mixture of 3-chloro-5- ⁇ 1-methyl-4-[4-(trifluoromethyl)phenyl]- 1H,4H-imidazo[4,5-b]indol-7-yl ⁇ -4,5-dihydro-1,2-oxazole (80 mg; 0.17 mmol) and pyrimidin-5-ol (25 mg; 0.25 mmol) in DMF (2 ml) was added Cs2CO3 (117 mg; 0.34 mmol) at room temperature. The resulting mixture was stirred for 48 h at 120°C. For work-up the reaction was quenched with water at room temperature. The resulting mixture was extracted with EtOAc (3 x 150 mL).
  • TFA trifluoroacetate LC-MS conditions: 1 Column: Waters XBridge C183.5 ⁇ m, 50*4.6 mm; 5-95 %: Flow Rate:1.5 mL/min; Analysis Time:6.5 min; MS scan range: 100-1000; Mobil Phase A: 0.02 % NH4OAc in water; Mobil Phase B: acetonitrile; Gradient: 0.15 min: 5 % B, 4.5 min: 95 % B, 6.0 min: 95 % B, 6.1 min: 5% B, 6.5 min: 5% B.
  • Table 1b shows further exemplary compounds of the present invention. They can be synthesized by adapting the methods and procedures described in the Examples above. LC-MS and Chiral HPLC/SFC conditions are as defined above for Table 1.
  • B30 [5-(1- ⁇ 2-methyl-8-[4-(trifluoro- methyl)phenyl]-2H,8H-pyrazolo[ b]indole-5-carbonyl ⁇ azetidin-3-yl oxazol-4-yl]methanol
  • B31 N-[cyclopropyl(1,2,4-oxadiazol-3 yl)methyl]-2-methyl-8-[4- (trifluoromethyl)phenyl]-2H,8H- pyrazolo[3,4-b]indole-5-carboxa
  • B30 [5-(1- ⁇ 2-methyl-8-[4-(trifluoro- methyl)phenyl]-2H,8H-pyrazolo[ b]indole-5-carbox
  • B135 1- ⁇ 2-methyl-8-[4- (trifluoromethyl)phenyl]-2H,8H- pyrazolo[3,4-b]indole-5-carbonyl (thiophen-3-yl)azetidin-3-ol
  • B136 N-[(3-methoxy-1,2-thiazol-5-yl)m N,2-dimethyl-8-[4- (trifluoromethyl)phenyl]-2H,8H- pyrazolo[3,4-b]indole-5-carboxa Compound Structure and Name No.
  • B137 N-[(5-cyclopropyl-1,2,4-oxadiazo yl)methyl]-N,2-dimethyl-8-[4- (trifluoromethyl)phenyl]-2H,8H- pyrazolo[3,4-b]indole-5-carboxa
  • B138 2-methyl-N-[(1-propyl-1H-1,2,4-t yl)methyl]-8-[4-(trifluoromethyl) 2H,8H-pyrazolo[3,4-b]indole-5- carboxamide Compound Structure and Name No.
  • B141 1- ⁇ 2-methyl-8-[4- (trifluoromethyl)phenyl]-2H,8H- pyrazolo[3,4-b]indole-5-carbonyl (pyrimidin-4-yl)azetidin-3-ol
  • B142 2-methyl-N-[3-(1H-pyrazol-3-yl)p 8-[4-(trifluoromethyl)phenyl]-2H pyrazolo[3,4-b]indole-5-carboxa
  • Table 1c shows compounds of the present invention. They can be synthesized by utilizing and/or adapting the methods and procedures described in the Examples above. LC-MS and Chiral HPLC/SFC conditions are as defined below at the end of Table 1c.
  • Method D LC-MS Agilent 1200 Series Chromolith RP-18e 50-4,6mm; 3.3 ml/min solvent A: Water + 0.05% HCOOH solvent B: Acetonitrile + 0.04% HCOOH 2 20 nm 0 to 2.0 min:0%B to 100%B 2.0 to 2.5 min: 100%B
  • Method E Chromolith® HR RP-185.0 ⁇ m 50-4.6mm; A: H 2 O+0.1% TFA; B: MeCN+0.1% TFA; 1%->99% B: 0->2.0min; 99% B: 2.0->2.5min; T:40°C; Flow: 3.3mL/min; MS: 61-1000 amu positive Method F: Kinetex EVO C185,0 ⁇ m 50-4.6mm; A: H 2 O+0.05% HCOOH B: MeCN+0.04% HCOOH + 1% H 2 O ; 0%->100% B: 0->1.8 min ; 100% B: 1.8->2.1 min ; T: 40°C ; Flow: 3.3
  • Method L Kinetex EVO C185,0 ⁇ m 50-4.6mm; A: H 2 O+0.1% TFA B: MeCN+0.1% TFA ; 1%- >99% B: 0->1.8 min ; 99% B: 1.8->2.1 min ; T: 40°C ; Flow: 3.3 mL/min.
  • Biological Activity SK-HEP-1 reporter assay To identify inhibitors of YAP-TEAD interaction, 8x TEAD responsive elements driving the NanoLuc® luciferase gene were stably integrated into SK-HEP-1 cells (ECACC #: 91091816). For the assay, cells were treated in duplicates with the test compounds in a 10-point dose, with the top concentration starting at 30 ⁇ M (final concentration in assay).
  • a luciferase substrate / lysis reagent mix (NanoGloTM, Promega) was added to the cells, allowing the quantification of cellular luciferase activity.
  • Cell Media The cells were cultured in the following media: MEM, +10% FBS, +1x GlutaMAX, +1mM Sodium-Pyruvate, + 100 ⁇ M Non-essential amino acids, +0.1mg/ml Hygromycin.
  • the media used for the assay was: MEM (w/o Phenol Red), +10% FBS, +1x GlutaMAX, +1mM Sodium-Pyruvate, + 100 ⁇ M Non- essential amino acids, +0.5% Pen/Strep Reagents: The reagents used are listed below:
  • Cell culture The cells were examined using an inverted microscope to check for health and cell density. To dissociate adherent cells, the monolayer of cells was washed once with pre-warmed PBS. After removing the PBS, 3 ml pre- warmed Accutase® was added to a F75 flask, dispersed evenly and the flask was allowed to sit in incubator for ⁇ 4-5 minutes.
  • cells were treated in duplicates with the test compounds in a 10-point dose, 1:3 dilution steps, with the top concentration starting at 30 ⁇ M (final concentration in assay). After a 96 hour incubation at 37°C, 95% rH, and 5% CO 2 , a cell-permeant DNA-binding dye that stains only healthy cells (CyQUANT®, Promega) was added to the cells, allowing the quantification of cell viability.
  • Cell Media The NCI-H226 cells were cultured in the following media: RPMI 1640, +10% FBS, +1x GlutaMAX, +10mM HEPES, + 0.5% Pen/Strep.
  • the SW620-KO cells were cultured in the following media: DMEM/F-12, +10% FBS, +1x GlutaMAX, +10mM HEPES, +0.5% Pen/Strep.
  • Reagents The reagents used are listed below:
  • Cell culture The cells were examined using an inverted microscope to check for health, cell density, etc. To dissociate adherent cells, the monolayer of cells was washed once with pre-warmed PBS. After removing the PBS, 3ml pre- warmed Accutase was added to a F75 flask, dispersed evenly and the flask was allowed to sit in incubator for ⁇ 4-5 minutes.
  • the plates were then incubated for 1 hour at 37°C, 95% rH and 5% CO 2 . Thereafter, the assay plates were removed from the incubator and allowed to equilibrate to RT for 30min in the dark without lid. Finally, they were measured using an EnVision microplate reader with a FITC bottom read program.
  • Compound no. 2 was tested at dosing levels of 1, 3, 10, 30, and 100mg/kg, respectively. Results are depicted in Figure 1 (tumor growth over time for vehicle group and each dosage group) and Figure 2 (final tumor volume of vehicle group and each dosage group).
  • Example A Injection vials A solution of 100 g of an active ingredient of the formula I or I-A or Table 1c and 5 g of disodium hydrogenphosphate in 3 l of bidistilled water is adjusted to pH 6.5 using 2 N hydrochloric acid, sterile filtered, transferred into injection vials, lyophilised under sterile conditions and sealed under sterile conditions. Each injection vial contains 5 mg of active ingredient.
  • Example B Suppositories A mixture of 20 g of an active ingredient of the formula I or I-A or Table 1c with 100 g of soya lecithin and 1400 g of cocoa butter is melted, poured into moulds and allowed to cool. Each suppository contains 20 mg of active ingredient.
  • Example C Solution A solution is prepared from 1 g of an active ingredient of the formula I or I-A or Table 1c, 9.38 g of NaH 2 PO4 ⁇ 2 H 2 O, 28.48 g of Na2HPO4 ⁇ 12 H 2 O and 0.1 g of benzalkonium chloride in 940 mL of bidistilled water. The pH is adjusted to 6.8, and the solution is made up to 1 l and sterilised by irradiation. This solution can be used in the form of eye drops.
  • Example D Ointment 500 mg of an active ingredient of the formula I or I-A or Table 1c are mixed with 99.5 g of Vaseline under aseptic conditions.
  • Example E Tablets A mixture of 1 kg of active ingredient of the formula I or I-A or Table 1c, 4 kg of lactose, 1.2 kg of potato starch, 0.2 kg of talc and 0.1 kg of magnesium stearate is pressed in a conventional manner to give tablets in such a way that each tablet contains 10 mg of active ingredient.
  • Example F Dragees Tablets are pressed analogously to Example E and subsequently coated in a conventional manner with a coating of sucrose, potato starch, talc, tragacanth and dye.
  • Example G Capsules 2 kg of active ingredient of the formula I or I-A or Table 1c are introduced into hard gelatine capsules in a conventional manner in such a way that each capsule contains 20 mg of the active ingredient.
  • Example H Ampoules A solution of 1 kg of active ingredient of the formula I or I-A or Table 1c in 60 l of bidistilled water is sterile filtered, transferred into ampoules, lyophilised under sterile conditions and sealed under sterile conditions. Each ampoule contains 10 mg of active ingredient.

Abstract

The present invention relates to tricyclic heterocycles. These heterocyclic compounds are useful as TEAD binders and/or inhibitors of YAP-TEAD and TAZ-TEAD protein-protein interaction or binding and for the prevention and/or treatment of several medical conditions including hyperproliferative disorders and diseases, in particular cancer.

Description

Tricyclic heterocycles Field of the invention The present invention relates to tricyclic heterocycles. These heterocyclic compounds are useful as TEAD binders and/or inhibitors of YAP-TEAD protein-protein interaction or binding and for the prevention and/or treatment of several medical conditions including hyperproliferative disorders and diseases, in particular cancer. Background of the invention In recent years the Hippo pathway has become a target of interest for the treatment of hyperproliferative disorders and diseases, in particular cancer (S. A. Smith et al., J. Med. Chem.2019, 62, 1291-1305; K. C. Lin et al., Annu. Rev. Cancer Biol. 2018, 2: 59-79; C.-L. Kim et al., Cells (2019), 8, 468; K. F. Harvey et al., Nature Reviews Cancer, Vol.13, 246–257 (2013)). The Hippo pathway regulates cell growth, proliferation, and migration. It is assumed that in mammals the Hippo pathway acts as a tumor suppressor, and dysfunction of Hippo signaling is frequently observed in human cancers. Furthermore, as the Hippo pathway plays a role in several biological processes – like in self-renewal and differentiation of stem cells and progenitor cells, wound healing and tissue regeneration, interaction with other signaling pathways such as Wnt – its dysfunction may also play a role in human diseases other than cancer (C.-L. Kim et al., Cells (2019), 8, 468; Y. Xiao et al., Genes & Development (2019) 33: 1491-1505; K. F. Harvey et al., Nature Reviews Cancer, Vol. 13, 246–257 (2013)). While several aspects of the pathway activity and regulation are still subject to further research, it is already established that in its “switched-on”-state the Hippo pathway involves a cascade of kinases (including Mst 1/2 and Lats 1/2) in the cytoplasm which results in the phosphorylation of two transcriptional co- activators, YAP (Yes-associated protein) and TAZ (Transcription co-activator with PDZ binding motif). Phosphorylation of YAP/TAZ leads to their sequestration in the cytoplasm and eventually to their degradation. In contrast, when the Hippo pathway is “switched-off” or dysfunctions, the non- phosphorylated, activated YAP/TAZ co-activators are translocated into the cell nucleus. Their major target transcription factors are the four proteins of the Transcriptional enhanced associate domain (TEAD) transcription factor family (TEAD1-4). Binding of YAP or TAZ to and activation of TEAD (or other transcription factors) have shown to induce the expression of several genes many of which mediate cell survival and proliferation. Thus, activated, non- phosphorylated YAP and TAZ may act as oncogenes, while the activated, switched-on Hippo pathway may act as a tumor suppressor by deactivating, i.e. phosphorylating YAP and TAZ. Furthermore, the Hippo pathway may also play a role in resistance mechanisms of cancer cells to oncology and immune-oncology therapy (R. Reggiani et al., BBA – Reviews on Cancer 1873 (2020) 188341, 1-11). Consequently, the dysfunction or aberrant regulation of the Hippo pathway as a tumor suppressor is believed to be an important event in the development of a wide variety of cancer types and diseases. Therefore, inhibition of YAP, TAZ, TEAD, and YAP-TEAD or TAZ-TEAD protein-protein interaction by pharmacological intervention appears to be a reasonable and valuable strategy to prevent and/or treat cancer and other hyperproliferative disorders and diseases associated with the dysfunction of the Hippo pathway. Description of the invention The present invention provides compounds that are useful in the prevention and/or treatment of medical conditions, disorders and/or diseases, in particular of hyperproliferative disorders or diseases, which compounds are TEAD binders and/or inhibitors of YAP-TEAD or TAZ-TEAD protein-protein interaction. The invention refers in one embodiment to a compound of formula I-A
Figure imgf000004_0002
I-A wherein Ring A represents a five-membered heteroaromatic ring selected from the group consisting of the following ring moieties: ,
Figure imgf000004_0001
, , , , , , , , , , , ,
, , , , , , , , , , , , , , wherein RA1 represents H, D, C1-6-aliphatic, -CH2-ArA1 or -CH2-CH2-ArA1; RA2 represents H, D, halogen, C1-6-aliphatic, -CH2-ArA2 or -CH2-CH2-ArA2; RA3 represents H, D, C1-6-aliphatic, -CH2-ArA3 or -CH2-CH2-ArA3; Z1 is CRZ1 or N; Z2 is CRZ2 or N; Z3 is CRZ3 or N; wherein at least two of Z1, Z2 and Z3 are not N; R1 represents Ar1, Hetar1, Cyc1, Hetcyc1, L1-Ar1, L1-Hetar1, L2-Cyc1, L2- Hetcyc1, un-substituted or substituted, straight-chain or branched C1-8- aliphatic; R2 represents -C(=O)-OR2a, -C(=O)-NR2bR2c, -(CH2)w-C(=O)-NR2bR2c, - (CH2)x-NR2d-C(=O)-R2e, -S-R2f, -S(=O)-R2f, -S(=O)2-R2g, -S(=O)2- NR2hR2i, -S(=O)2-OH, -S(=O)(=NR2j)-OH, -S(=O)(=NR2j)-R2g, - S(=O)(=NR2k)-NR2lR2m, F, Cl, Br, I, -CN, -(CH2)v-CN, - P(=O)(OR2o)(OR2p), -(CH2)y-NR2qR2r, -(CH2)z-NR2d-S(=O)2-R2g, -C(=O)- N=S(=O)-R2sR2t, -C(=O)-N=S(=N-R2u)-R2sR2t, -B(OH)2 or HetcycX; ArA1, ArA2, ArA3 represent independently from each other phenyl which may be unsubstituted or mono- or di-substituted with independently from each other RA11 and/or RA12; RZ1. represents H or halogen; RZ2 represents H or halogen; or forms together with R2 a divalent radical - S(=O)2-N(H)-C(=O)-; RZ3 represents H or halogen; R2a represents H, un-substituted or substituted C1-8-aliphatic, aryl, heteroaryl, saturated or partially unsaturated heterocyclyl, or carbohydrate derived radical, or Cat; Cat represents a monovalent cation; R2b, R2c, R2q, R2r represent independently from each other H, un-substituted or substituted C1-8-aliphatic including C3-7-cycloaliphatic ; or form together with the nitrogen atom to which they are attached to an unsubstituted or substituted saturated, partially unsaturated or aromatic heterocycle with 3, 4, 5, 6, 7 ring atoms wherein 1 of said ring atoms is said nitrogen atom and no or one further ring atom is a hetero atom selected from N, O or S and the remaining are carbon atoms; wherein said heterocycle may optionally be fused with HetarZ; or one of R2b and R2c represents -CN, -NH2, -OH, -O-C1-6-alkyl, -S(=O)2-R2g, Ar2, Hetar2, Cyc2 or Hetcyc2, while the other represents H or un- substituted or substituted C1-8-aliphatic; R2d, R2j, R2k, R2o, R2p represent independently from each other H, un- substituted or substituted C1-8-aliphatic; R2e represents H, halogen, un-substituted or substituted C1-8-aliphatic, heteroaryl; R2f, R2g represent independently from each other un-substituted or substituted C1-8-aliphatic; R2h, R2i represent independently from each other H, un-substituted or substituted C1-8-aliphatic, aryl, heterocyclyl, heteroaryl; or form together with the nitrogen atom to which they are attached to an unsubstituted or substituted saturated, partially unsaturated or aromatic heterocycle with 3, 4, 5, 6, 7 ring atoms wherein 1 of said ring atoms is said nitrogen atom and no or one further ring atom is a hetero atom selected from N, O or S and the remaining are carbon atoms; R2l, R2m represent independently from each other H, un-substituted or substituted C1-8-aliphatic; or form together with the nitrogen atom to which they are attached to an unsubstituted or substituted saturated, partially unsaturated or aromatic heterocycle with 3, 4, 5, 6, 7 ring atoms wherein 1 of said ring atoms is said nitrogen atom and no or one further ring atom is a hetero atom selected from N, O or S and the remaining are carbon atoms; R2s, R2t represent independently from each other unsubstituted or substituted C1-8-aliphatic; or form together an unsubstituted or substituted divalent C3-6-alkylene radical; R2u represents hydrogen or unsubstituted or substituted C1-6-aliphatic; Ar1 is a mono-, bi- or tricyclic aryl with 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 ring carbon atoms, wherein that aryl may be unsubstituted or substituted with substituents RB1, RB2, RB3, RB4, RB5, RB6 and/or RB7 which may be the same or different; Hetar1 is a mono-, bi- or tricyclic heteroaryl with 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 ring atoms wherein 1, 2, 3, 4, 5 of said ring atoms is/are a hetero atom(s) selected from N, O and/or S and the remaining are carbon atoms, wherein that heteroaryl may be unsubstituted or substituted with substituents RB1, RB2, RB3, RB4, RB5, RB6 and/or RB7 which may be the same or different; Cyc1 is a saturated or partially unsaturated, mono-, bi- or tricyclic carbocycle with 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 ring carbon atoms, wherein that carbocycle may be unsubstituted or substituted with RB8, RB9, RB10, RB11 RB12 and/or RB13 which may be the same or different; and wherein that carbocycle may optionally be fused to Arx via 2 adjacent ring atoms of said Arx and wherein that fused carbocycle may further be unsubstituted or substituted with RC1, RC2, RC3, RC4, RC5, RC6 which may be the same or different; Hetcyc1 is a saturated or partially unsaturated, mono-, bi- or tricyclic heterocycle with 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 ring atoms wherein 1, 2, 3, 4, 5 of said ring atoms is/are a hetero atom(s) selected from N, O and/or S and the remaining are carbon atoms, wherein that heterocycle may be unsubstituted or substituted with RB8, RB9, RB10, RB11, RB12 and/or RB13 which may be the same or different; L1 is a divalent radical selected from the group consisting of -S(=O)2-, - C(=O)-, un-substituted or substituted, straight-chain or branched C1-6- alkylene or C2-6-alkenylene, in both of which one of the carbon units of the alkylene or alkenylene chain may be replaced by -O-; L2 is a divalent radical selected from the group consisting of un-substituted or substituted, straight-chain or branched C1-6-alkylene or C2-6 alkenylene, in both of which one of the carbon units of the alkylene or alkenylene chain may be replaced by -O-; RA11, RA12 represent independently from each other halogen or un- substituted or substituted, straight-chain or branched C1-6-aliphatic; RB1, RB2, RB3, RB4, RB5, RB6, RB7 represent independently from each other un-substituted or substituted, straight-chain or branched C1-6- aliphatic, C1-6-aliphatoxy, -S-C1-6-aliphatic; halogen, -CN, -S(=O)-Rb1, S(=O)2-Rb1, -NRb2NRb3, Ar2, -CH2-Ar2, Hetar2, Cyc2, Hetcyc2; and/or two adjacent RB1, RB2, RB3, RB4, RB5, RB6 and/or RB7 form together a divalent -C2-4-alkylene radical in which one of the alkylene carbon units may be replaced by a carbonyl unit (-C(=O)-), or a divalent -O-C1-3- alkylene radical or a divalent -O-C1-3-alkylene-O- radical; Rb1 represents un-substituted or substituted C1-8-aliphatic; Rb2, Rb3 represent independently from each other H, un-substituted or substituted C1-8-aliphatic; or form together with the nitrogen atom to which they are attached to an unsubstituted or substituted saturated, partially unsaturated or aromatic heterocycle with 3, 4, 5, 6, 7 ring atoms wherein 1 of said ring atoms is said nitrogen atom and no or one further ring atom is a hetero atom selected from N, O or S and the remaining are carbon atoms; RB8, RB9, RB10, RB11, RB12, RB13 represent independently from each other halogen, un-substituted or substituted C1-6-aliphatic, C1-6-aliphatoxy, ArY; and/or two of RB8, RB9, RB10, RB11, RB12, RB13 which are attached to the same carbon atom of said carbocycle or said heterocycle form a divalent oxo (=O) group; and/or two of RB8, RB9, RB10, RB11, RB12, RB13 or four of RB8, RB9, RB10, RB11, RB12, RB13 which are attached to the same sulfur atom of said heterocycle form a divalent oxo (=O) group thereby forming either an -S(=O)- or an -S(=O)2- moiety; Ar2 is a mono- or bicyclic aryl with 5, 6, 7, 8, 9, 10 ring carbon atoms, wherein that aryl may be unsubstituted or substituted with substituents RD1, RD2, RD3, RD4 and/or RD5 which may be the same or different Hetar2 is a mono- or bicyclic heteroaryl with 5, 6, 7, 8, 9, 10 ring atoms wherein 1, 2, 3, 4, 5 of said ring atoms is/are a hetero atom(s) selected from N, O and/or S and the remaining are carbon atoms, wherein that heteroaryl may be unsubstituted or substituted with substituents RD1, RD2, RD3, RD4 and/or RD5 which may be the same or different; Cyc2 is a saturated or partially unsaturated monocyclic carbocycle with 3, 4, 5, 6 or 7 ring carbon atoms, wherein that carbocycle may be unsubstituted or substituted with RD6, RD7, RD8, RD9 and/or RD10 which may be the same or different; wherein that carbocycle may optionally be fused to ArZ or HetarZ via 2 adjacent ring atoms of said ArZ or HetarZ and wherein that fused carbocycle may further be unsubstituted or substituted with RC1, RC2, RC3, RC4, RC5, RC6 which may be the same or different; Hetcyc2 is a saturated or partially unsaturated, monocyclic heterocycle with 3, 4, 5, 6, 7 ring atoms wherein 1 or 2 of said ring atoms is/are a hetero atom(s) selected from N, O and/or S and the remaining are carbon atoms, wherein that heterocycle may be unsubstituted or substituted with RD6, RD7, RD8, RD9 and/or RD10 which may be the same or different; wherein that heterocycle may optionally be fused to ArZ or HetarZ via 2 adjacent ring atoms of said ArZ or HetarZ and wherein that fused heterocycle may further be unsubstituted or substituted with RC1, RC2, RC3, RC4, RC5, RC6 which may be the same or different; Arx, ArZ independently from each other an un-substituted or substituted benzo ring; ArY is an un-substituted or mono- or di-substituted phenyl; HetarY1 is a 5 or 6 membered monocyclic heteroaryl wherein 1, 2, 3, 4 ring atoms are hetero atoms selected from N, O and/or S and the remaining are carbon atoms, wherein that heteroaryl may be unsubstituted or substituted with halogen, C1-4-alkyl which may optionally be substituted with OH; HetarZ is an unsubstituted or substituted 5 or 6 membered heteroaryl ring selected from the group consisting of pyrrole, furan, thiophene, pyrazole, imidazole, oxaole, isoxazole, thiazole, oxadiazole, triazole, tetrazole, pyridine, pyrimidine, pyrazine, pyrane; CycY1 is a saturated monocyclic carbocycle with 3, 4, 5, 6 or 7 ring carbon atoms, wherein that carbocycle may be unsubstituted or substituted with halogen, OH, C1-4-alkyl; HetcycX is a saturated, partially unsaturated or aromatic, monocyclic heterocycle with 3, 4, 5, 6, 7 ring atoms wherein 1, 2, 3, 4 of said ring atoms is/are a hetero atom(s) selected from N, O and/or S and the remaining are carbon atoms, wherein said heterocycle may be unsubstituted or substituted with RX1, RX2, RX3, RX4, RX5, RX6, RX7 and/or RX8 which may be the same or different, and wherein that heterocycle is optionally a carboxylic acid bioisostere; HetcycY is a saturated, partially unsaturated or aromatic, monocyclic heterocycle with 3, 4, 5, 6, 7 ring atoms wherein 1, 2, 3, 4 of said ring atoms is/are a hetero atom(s) selected from N, O and/or S and the remaining are carbon atoms; HetcycY1 is a saturated or partially unsaturated monocyclic heterocycle with 5 or 6 ring atoms wherein 1 or 2 of said ring atoms are heteroatoms selected from N, O, and/or S and the remaining are carbon atoms; RC1, RC2, RC3, RC4, RC5, RC6 represent independently from each other un- substituted or substituted C1-6-aliphatic; RD1, RD2, RD3, RD4, RD5 represent independently from each other un- substituted or substituted C1-6-aliphatic; RD6, RD7, RD8, RD9, RD10 represent independently from each other un- substituted or substituted C1-6-aliphatic, unsubstituted or substituted C1- 6-aliphatoxy, halogen, hydroxy; HetarY1, CH2-HetarY1, CycY1, HetcycY1, - CH2-HetcycY1; and/or two of RD6, RD7, RD8, RD9, RD10 which are attached to the same ring atom of said carbocycle or heterocycle may form a divalent C2-6-alkylene radical, wherein one or two non-adjacent carbon units of said alkylene radical may optionally be replaced by independently from each other O, N-H, or N-C1-4-alkyl, and wherein that alkylene radical may optionally be substituted with OH, C1-4-alkyl or -O-C1-4-alkyl; and/or two of RD6, RD7, RD8, RD9, RD10 which are attached to different ring atoms of said carbocycle or heterocycle may form a divalent C1-6-alkylene radical, wherein one or two non-adjacent carbon units of said alkylene radical may optionally be replaced by independently from each other O, N-H, or N-C1-4-alkyl; RX1, RX2, RX3, RX4, RX5, RX6, RX7, RX8 represent independently from each other un-substituted or substituted C1-6-aliphatic, C1-6-aliphatoxy, halogen, -OH, -NR2d-S(=O)2-R2g, HetcycY, O-HetcycY; and/or two of RX1, RX2, RX3, RX4, RX5, RX6, RX7, RX8 which are attached to the same carbon atom of said heterocycle form a divalent oxo (=O) group; and/or two of RX1, RX2, RX3, RX4, RX5, RX6, RX7, RX8 or four of RX1, RX2, RX3, RX4, RX5, RX6, RX7, RX8 which are attached to the same sulfur atom of said heterocycle form a divalent oxo (=O) group thereby forming either an -S(=O)- or an -S(=O)2- moiety; halogen is F, Cl, Br, I; v is 1 or 2; w is 1 or 2; x is 0, 1 or 2; y is 0, 1 or 2; z is 0, 1 or 2; or any N-oxide, solvate, tautomer or stereoisomer thereof and/or any pharmaceutically acceptable salt of each of the foregoing, including mixtures thereof in all ratios. The invention refers in a further embodiment to a compound of formula I
Figure imgf000013_0001
I wherein Ring A represents a five-membered heteroaromatic ring selected from the group consisting of the following ring moieties: ,
Figure imgf000014_0001
, , ,
, , , ,
Figure imgf000015_0001
, , ,
,
Figure imgf000016_0001
, , ; wherein RA1 represents H, C1-6-aliphatic, -CH2-ArA1 or -CH2-CH2-ArA1; RA2 represents H, halogen, C1-6-aliphatic, -CH2-ArA2 or -CH2-CH2-ArA2; RA3 represents H, C1-6-aliphatic, -CH2-ArA3 or -CH2-CH2-ArA3; Z1 is CRZ1 or N; Z2 is CRZ2 or N; wherein at least one of Z1 and Z2 is not N; R1 represents Ar1, Hetar1, Cyc1, Hetcyc1, L1-Ar1, L1-Hetar1, L2-Cyc1, L2- Hetcyc1, un-substituted or substituted, straight-chain or branched C1-8- aliphatic; R2 represents -C(=O)-OR2a, -C(=O)-NR2bR2c, -(CH2)w-C(=O)-NR2bR2c, - (CH2)x-NR2d-C(=O)-R2e, -S-R2f, -S(=O)-R2f, -S(=O)2-R2g, -S(=O)2- NR2hR2i, -S(=O)2-OH, -S(=O)(=NR2j)-OH, -S(=O)(=NR2j)-R2g, - S(=O)(=NR2k)-NR2lR2m, F, Cl, Br, I, -CN, -(CH2)v-CN, - P(=O)(OR2o)(OR2p), -(CH2)y-NR2qR2r, -(CH2)z-NR2d-S(=O)2-R2g, -C(=O)- N=S(=O)-R2sR2t, -C(=O)-N=S(=N-R2u)-R2sR2t, -B(OH)2 or HetcycX; ArA1, ArA2, ArA3 represent independently from each other phenyl which may be unsubstituted or mono- or di-substituted with independently from each other RA11 and/or RA12; RZ1 represents H or halogen; RZ2 represents H or halogen; or forms together with R2 a divalent radical - S(=O)2-N(H)-C(=O)-; R2a represents H, un-substituted or substituted C1-8-aliphatic, aryl, heteroaryl, saturated or partially unsaturated heterocyclyl, or carbohydrate derived radical,or Cat; Cat represents a monovalent cation; R2b, R2c, R2q, R2r represent independently from each other H, un-substituted or substituted C1-8-aliphatic including C3-7-cycloaliphatic; or form together with the nitrogen atom to which they are attached to an unsubstituted or substituted saturated, partially unsaturated or aromatic heterocycle with 3, 4, 5, 6, 7 ring atoms wherein 1 of said ring atoms is said nitrogen atom and no or one further ring atom is a hetero atom selected from N, O or S and the remaining are carbon atoms; wherein said heterocycle may optionally be fused with HetarZ; or one of R2b and R2c represents -CN, -NH2, -OH, -O-C1-6-alkyl, -S(=O)2- R2g, Ar2, Hetar2, Cyc2 or Hetcyc2, while the other of R2b and R2c represents H or un-substituted or substituted C1-8-aliphatic; R2d, R2j, R2k, R2o, R2p represent independently from each other H, un- substituted or substituted C1-8-aliphatic; R2e represents H, halogen, un-substituted or substituted C1-8-aliphatic, heteroaryl; R2f, R2g represent independently from each other un-substituted or substituted C1-8-aliphatic; R2h, R2i represent independently from each other H, un-substituted or substituted C1-8-aliphatic, aryl, heterocyclyl, heteroaryl; or form together with the nitrogen atom to which they are attached to an unsubstituted or substituted saturated, partially unsaturated or aromatic heterocycle with 3, 4, 5, 6, 7 ring atoms wherein 1 of said ring atoms is said nitrogen atom and no or one further ring atom is a hetero atom selected from N, O or S and the remaining are carbon atoms; R2l, R2m represent independently from each other H, un-substituted or substituted C1-8-aliphatic; or form together with the nitrogen atom to which they are attached to an unsubstituted or substituted saturated, partially unsaturated or aromatic heterocycle with 3, 4, 5, 6, 7 ring atoms wherein 1 of said ring atoms is said nitrogen atom and no or one further ring atom is a hetero atom selected from N, O or S and the remaining are carbon atoms; R2s, R2t represent independently from each other unsubstituted or substituted C1-8-aliphatic; or form together an unsubstituted or substituted divalent C3-6-alkylene radical; R2u represents hydrogen or unsubstituted or substituted C1-6-aliphatic; Ar1 is a mono-, bi- or tricyclic aryl with 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 ring carbon atoms, wherein that aryl may be unsubstituted or substituted with substituents RB1, RB2, RB3, RB4, RB5, RB6 and/or RB7 which may be the same or different; Hetar1 is a mono-, bi- or tricyclic heteroaryl with 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 ring atoms wherein 1, 2, 3, 4, 5 of said ring atoms is/are a hetero atom(s) selected from N, O and/or S and the remaining are carbon atoms, wherein that heteroaryl may be unsubstituted or substituted with substituents RB1, RB2, RB3, RB4, RB5, RB6 and/or RB7 which may be the same or different; Cyc1 is a saturated or partially unsaturated, mono-, bi- or tricyclic carbocycle with 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 ring carbon atoms, wherein that carbocycle may be unsubstituted or substituted with RB8, RB9, RB10, RB11 RB12 and/or RB13 which may be the same or different; and wherein that carbocycle may optionally be fused to Arx via 2 adjacent ring atoms of said Arx and wherein that fused carbocycle may further be unsubstituted or substituted with RC1, RC2, RC3, RC4, RC5, RC6 which may be the same or different; Hetcyc1 is a saturated or partially unsaturated, mono-, bi- or tricyclic heterocycle with 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 ring atoms wherein 1, 2, 3, 4, 5 of said ring atoms is/are a hetero atom(s) selected from N, O and/or S and the remaining are carbon atoms, wherein that heterocycle may be unsubstituted or substituted with RB8, RB9, RB10, RB11, RB12 and/or RB13 which may be the same or different; L1 is a divalent radical selected from the group consisting of -S(=O)2-, - C(=O)-, un-substituted or substituted, straight-chain or branched C1-6- alkylene or C2-6-alkenylene, in both of which one of the carbon units of the alkylene or alkenylene chain may be replaced by -O-; L2 is a divalent radical selected from the group consisting of un-substituted or substituted, straight-chain or branched C1-6-alkylene or C2-6- alkenylene, in both of which one of the carbon units of the alkylene or alkenylene chain may be replaced by -O-; RA11, RA12 represent independently from each other halogen or un- substituted or substituted, straight-chain or branched C1-6-aliphatic; RB1, RB2, RB3, RB4, RB5, RB6, RB7 represent independently from each other un-substituted or substituted, straight-chain or branched C1-6- aliphatic, C1-6-aliphatoxy, -S-C1-6-aliphatic; halogen, -CN, -S(=O)-Rb1, S(=O)2-Rb1, -NRb2NRb3, Ar2, -CH2-Ar2, Hetar2, Cyc2, Hetcyc2; and/or two adjacent RB1, RB2, RB3, RB4, RB5, RB6 and/or RB7 form together a divalent -C2-4-alkylene radical in which one of the alkylene carbon units may be replaced by a carbonyl unit (-C(=O)-), or a divalent -O-C1-3- alkylene radical or a divalent -O-C1-3-alkylene-O- radical; Rb1 represents un-substituted or substituted C1-8-aliphatic; Rb2, Rb3 represent independently from each other H, un-substituted or substituted C1-8-aliphatic; or form together with the nitrogen atom to which they are attached to an unsubstituted or substituted saturated, partially unsaturated or aromatic heterocycle with 3, 4, 5, 6, 7 ring atoms wherein 1 of said ring atoms is said nitrogen atom and no or one further ring atom is a hetero atom selected from N, O or S and the remaining are carbon atoms; RB8, RB9, RB10, RB11, RB12, RB13 represent independently from each other halogen, un-substituted or substituted C1-6-aliphatic, C1-6-aliphatoxy, ArY; and/or two of RB8, RB9, RB10, RB11, RB12, RB13 which are attached to the same carbon atom of said carbocycle or said heterocycle form a divalent oxo (=O) group; and/or two of RB8, RB9, RB10, RB11, RB12, RB13 or four of RB8, RB9, RB10, RB11, RB12, RB13 which are attached to the same sulfur atom of said heterocycle form a divalent oxo (=O) group thereby forming either an -S(=O)- or an -S(=O)2- moiety; Ar2 is a mono- or bicyclic aryl with 5, 6, 7, 8, 9, 10 ring carbon atoms, wherein that aryl may be unsubstituted or substituted with substituents RD1, RD2, RD3, RD4 and/or RD5 which may be the same or different Hetar2 is a mono- or bicyclic heteroaryl with 5, 6, 7, 8, 9, 10 ring atoms wherein 1, 2, 3, 4, 5 of said ring atoms is/are a hetero atom(s) selected from N, O and/or S and the remaining are carbon atoms, wherein that heteroaryl may be unsubstituted or substituted with substituents RD1, RD2, RD3, RD4 and/or RD5 which may be the same or different; Cyc2 is a saturated or partially unsaturated monocyclic carbocycle with 3, 4, 5, 6 or 7 ring carbon atoms, wherein that carbocycle may be unsubstituted or substituted with RD6, RD7, RD8, RD9 and/or RD10 which may be the same or different; wherein that carbocycle may optionally be fused to ArZ or HetarZ via 2 adjacent ring atoms of said ArZ or HetarZ and wherein that fused carbocycle may further be unsubstituted or substituted with RC1, RC2, RC3, RC4, RC5, RC6 which may be the same or different; Hetcyc2 is a saturated or partially unsaturated, monocyclic heterocycle with 3, 4, 5, 6, 7 ring atoms wherein 1 or 2 of said ring atoms is/are a hetero atom(s) selected from N, O and/or S and the remaining are carbon atoms, wherein that heterocycle may be unsubstituted or substituted with RD6, RD7, RD8, RD9 and/or RD10 which may be the same or different; wherein that heterocycle may optionally be fused to ArZ or HetarZ via 2 adjacent ring atoms of said ArZ or HetarZ and wherein that fused heterocycle may further be unsubstituted or substituted with RC1, RC2, RC3, RC4, RC5, RC6 which may be the same or different; Arx, ArZ independently from each other an un-substituted or substituted benzo ring; ArY is an un-substituted or mono- or di-substituted phenyl; HetarY1 is a 5 or 6 membered monocyclic heteroaryl wherein 1, 2, 3, 4 ring atoms are hetero atoms selected from N, O and/or S and the remaining are carbon atoms, wherein that heteroaryl may be unsubstituted or substituted with halogen, C1-4-alkyl which may optionally be substituted with OH; HetarZ is an unsubstituted or substituted 5 or 6 membered heteroaryl ring selected from the group consisting of pyrrole, furan, thiophene, pyrazole, imidazole, oxaole, isoxazole, thiazole, oxadiazole, triazole, tetrazole, pyridine, pyrimidine, pyrazine, pyrane; CycY1 is a saturated monocyclic carbocycle with 3, 4, 5, 6 or 7 ring carbon atoms, wherein that carbocycle may be unsubstituted or substituted with halogen, OH, C1-4-alkyl; HetcycX is a saturated, partially unsaturated or aromatic, monocyclic heterocycle with 3, 4, 5, 6, 7 ring atoms wherein 1, 2, 3, 4 of said ring atoms is/are a hetero atom(s) selected from N, O and/or S and the remaining are carbon atoms, wherein said heterocycle may be unsubstituted or substituted with RX1, RX2, RX3, RX4, RX5, RX6, RX7 and/or RX8 which may be the same or different, and wherein that heterocycle is optionally a carboxylic acid bioisostere; HetcycY is a saturated, partially unsaturated or aromatic, monocyclic heterocycle with 3, 4, 5, 6, 7 ring atoms wherein 1, 2, 3, 4 of said ring atoms is/are a hetero atom(s) selected from N, O and/or S and the remaining are carbon atoms; HetcycY1 is a saturated or partially unsaturated monocyclic heterocycle with 5 or 6 ring atoms wherein 1 or 2 of said ring atoms are heteroatoms selected from N, O, and/or S and the remaining are carbon atoms; RC1, RC2, RC3, RC4, RC5, RC6 represent independently from each other un- substituted or substituted C1-6-aliphatic; RD1, RD2, RD3, RD4, RD5 represent independently from each other un- substituted or substituted C1-6-aliphatic;; RD6, RD7, RD8, RD9, RD10 represent independently from each other un- substituted or substituted C1-6-aliphatic, unsubstituted or substituted C1- 6-aliphatoxy, halogen, hydroxy; HetarY1, CH2-HetarY1, CycY1, HetcycY1, - CH2-HetcycY1; and/or two of RD6, RD7, RD8, RD9, RD10 which are attached to the same ring atom of said carbocycle or heterocycle may form a divalent C2-6-alkylene radical, wherein one or two non-adjacent carbon units of said alkylene radical may optionally be replaced by independently from each other O, N-H, or N-C1-4-alkyl, and wherein that alkylene radical may optionally be substituted with OH, C1-4-alkyl or -O-C1-4-alkyl; and/or two of RD6, RD7, RD8, RD9, RD10 which are attached to different ring atoms of said carbocycle or heterocycle may form a divalent C1-6-alkylene radical, wherein one or two non-adjacent carbon units of said alkylene radical may optionally be replaced by independently from each other O, N-H, or N-C1-4-alkyl; RX1, RX2, RX3, RX4, RX5, RX6, RX7, RX8 represent independently from each other un-substituted or substituted C1-6-aliphatic, C1-6-aliphatoxy, halogen, -OH, -NR2d-S(=O)2-R2g, HetcycY, O-HetcycY; and/or two of RX1, RX2, RX3, RX4, RX5, RX6, RX7, RX8 which are attached to the same carbon atom of said heterocycle form a divalent oxo (=O) group; and/or two of RX1, RX2, RX3, RX4, RX5, RX6, RX7, RX8 or four of RX1, RX2, RX3, RX4, RX5, RX6, RX7, RX8 which are attached to the same sulfur atom of said heterocycle form a divalent oxo (=O) group thereby forming either an -S(=O)- or an -S(=O)2- moiety; halogen is F, Cl, Br, I; v is 1 or 2; w is 1 or 2; x is 0, 1 or 2; y is 0, 1 or 2; z is 0, 1 or 2; or any N-oxide, solvate, tautomer or stereoisomer thereof and/or any pharmaceutically acceptable salt of each of the foregoing, including mixtures thereof in all ratios. In yet another embodiment the invention refers to a compound selected from the list of compounds in Table 1c below, or any pharmaceutically acceptable salt thereof. In general, all residues, radicals, substituents, groups, moieties, variables, etc. which occur more than once may be identical or different, i.e. are independent of one another. Above and below, the residues and parameters have the meanings indicated for formulas I-A and I, unless expressly indicated otherwise. Accordingly, the invention relates, in particular, to the compounds of formulas I-A and I in which at least one of the said residues, radicals, substituents, variables, has one of the preferred meanings indicated below. Any of those particular or even preferred embodiments of the present invention as specified below and in the claims do not only refer to the specified compounds of formulas I-A and I but to N-oxides, solvates, tautomers or stereoisomers thereof as well as the pharmaceutically acceptable salts of each of the foregoing, including mixtures thereof in all ratios, too, unless indicated otherwise. In a particular embodiment, PE0, the compound of the present invention is a tricyclic heterocycle of formula I-A, or any N-oxide, solvate, tautomer or stereoisomer thereof and/or any pharmaceutically acceptable salt of each of the foregoing, including mixtures thereof in all ratios, wherein Z1 is CRZ1; Z2 is CRZ2; Z3 is CRZ3 or N; RZ1 is H or F; preferably H; RZ2 is H or F; or forms together with R2 a divalent radical -S(=O)2-N(H)-C(=O)- ; is preferably H; RZ3 is H or F; preferably H. In another particular embodiment, PE0a, of PE0 Z3 is N. In still another particular embodiment, PE0b, of PE0 Z3 is CRZ3; RZ3 is H. It will be understood that this particular embodiment PE0b is identical to the particular embodiment PE1 as described below. In other words, a compound of formula I-A can also be described as a compound of formula I, if in formula I-A Z3 denotes CRZ3 with RZ3 being H. In a particular embodiment, PE1, the compound of the present invention is a tricyclic heterocycle of formula I, or any N-oxide, solvate, tautomer or stereoisomer thereof and/or any pharmaceutically acceptable salt of each of the foregoing, including mixtures thereof in all ratios, wherein Z1 is CRZ1; Z2 is CRZ2; RZ1 is H or F; RZ2 is H or F; or forms together with R2 a divalent radical -S(=O)2-N(H)- C(=O)-; and the remaining radicals and residues are as defined for formula I above or for any of the further particular embodiments described herein below. In another particular embodiment, PE1a, of PE1 at least one of RZ1 and RZ2 is H. In still another particular embodiment, PE1b, of PE1a both RZ1 and RZ2 are H. In a further particular embodiment, PE2, the compound of the present invention is a tricyclic heterocycle of formula I-A or I, or any N-oxide, solvate, tautomer or stereoisomer thereof and/or any pharmaceutically acceptable salt of each of the foregoing, including mixtures thereof in all ratios, wherein Ring A represents a five-membered heteroaromatic ring selected from the group consisting of the following ring moieties:
Figure imgf000025_0001
, , , ,
, , , , , ; RA1 represents C1-6-aliphatic, -CH2-ArA1; RA2 represents H, C1-6-aliphatic; RA3 represents H, C1-6-aliphatic; ArA1 represents phenyl which may be unsubstituted or mono-substituted with RA11; RA11 represents halogen; and the remaining radicals and residues are as defined for formula I-A or I above or for any of the further particular embodiments described herein above or below. In another particular embodiment, PE2a, of PE2 RA1 represents C1-3-alkyl optionally substituted with 1, 2 or 3 F atoms or CN, C2-4-alkynyl (in particular -CH2-C≡CH), -CH2-ArA1; RA2 represents H, C1-6-aliphatic, in particular H, C1-3-alkyl optionally substituted with 1, 2 or 3 F atoms; RA3 represents H; ArA1 represents phenyl which may be unsubstituted or mono-substituted with RA11; RA11 represents F; and the remaining radicals and residues are as defined for formula I-A or I above or for any of the further particular embodiments described herein above or below. In still another particular embodiment, PE2b, of PE2 or PE2a, Ring A is selected from the group consisting of ring A-1, A-4, A-7, A-9, A-10, A-12, A- 13, A-15, A-17, A-23 and A-24. In yet another particular embodiment of, PE2c, of PE2 or PE2a, Ring A is ring A-4 wherein preferably RA1 is methyl, ethyl, n- propyl, or -CH2-C≡CH, more preferably methyl, and RA2 is H. In a further particular embodiment, PE3, the compound of the present invention is a tricyclic heterocycle of formula I-A or I, or any N-oxide, solvate, tautomer or stereoisomer thereof and/or any pharmaceutically acceptable salt of each of the foregoing, including mixtures thereof in all ratios, wherein R1 represents Ar1, Hetar1, Cyc1, Hetcyc1, L1-Ar1, L1-Hetar1, L2-Cyc1, L2- Hetcyc1, un-substituted or substituted, straight-chain or branched C1-6- alkyl, C2-6-alkenyl or C2-6-alkynyl; wherein Ar1 is a mono- or bicyclic aryl with 6 or 10 ring carbon atoms, wherein that aryl may be unsubstituted or substituted with substituents RB1, RB2 and/or RB3 which may be the same or different; Hetar1 is a monocyclic heteroaryl with 5 or 6 ring atoms or a bicyclic heteroaryl with 9 or 10 ring atoms wherein 1, 2 or 3 of said ring atoms is/are a hetero atom(s) selected from N, O and/or S and the remaining are carbon atoms, wherein that heteroaryl may be unsubstituted or substituted with substituents RB1, RB2 and/or RB3 which may be the same or different; preferably the heteroaryl is unsubstituted or substituted with substituents RB1 and/or RB2 which may be the same or different; Cyc1 is a saturated or partially unsaturated, mono- or bicyclic carbocycle with 3, 4, 5, 6, 7 or 8 ring carbon atoms, wherein that carbocycle may be unsubstituted or substituted with RB8 and/or RB9 which may be the same or different; and wherein that carbocycle may optionally be fused to Arx via 2 adjacent ring atoms of said Arx and wherein that fused carbocycle may further be unsubstituted or substituted with RC1 and/or RC2 which may be the same or different; Hetcyc1 is a saturated or partially unsaturated, monocyclic heterocycle with 5 or 6 ring atoms wherein 1 or 2 of said ring atoms is/are a hetero atom(s) selected from N, O and/or S and the remaining are carbon atoms, wherein that heterocycle may be unsubstituted or substituted with RB8 and/or RB9 which may be the same or different, wherein, if one of the heteroatoms is S, then that heterocycle may also be substituted with RB8, RB9, RB10 and RB11; L1 is a divalent radical selected from the group consisting of -S(=O)2-, un- substituted or substituted, straight-chain or branched C1-6-alkylene or C2- 6-alkenylene, in both of which one of the carbon units of the alkylene or alkenylene chain may be replaced by -O-; L2 is a divalent radical selected from the group consisting of un-substituted or substituted, straight-chain or branched C1-6-alkylene or C2-6- alkenylene, in both of which one of the carbon units of the alkylene or alkenylene chain may be replaced by -O-; RB1, RB2, RB3 represent independently from each other straight-chain or branched C1-6-alkyl, which C1-6-alkyl may be unsubstituted or monosubstituted with -CN or substituted with 1, 2 or 3 halogen, straight- chain or branched C1-4-alkoxy, which C1-4-alkoxy may be unsubstituted or substituted with 1, 2 or 3 halogen, -O-CH-C≡CH, straight-chain or branched -S-C1-4-alkyl, which -S-C1-4-alkyl may be unsubstituted or substituted with 1, 2 or 3 halogen, F, Cl, Br, -CN, -S(=O)-C1-3-alkyl, S(=O)2-C1-3-alkyl, -N(C1-3-alkyl)2, Ar2, -CH2-Ar2, Hetar2, Cyc2, Hetcyc2; or two adjacent RB1, RB2 and/or RB3 form together a divalent -C3-4- alkylene radical in which one of the alkylene carbon units may be replaced by a carbonyl unit (-C(=O)-), or a divalent -O-C2-3-alkylene radical; Ar2 is phenyl; Hetar2 is a monocyclic heteroaryl with 5 or 6 ring atoms wherein 1, 2, 3, 4, 5 of said ring atoms is/are a hetero atom(s) selected from N, O and/or S and the remaining are carbon atoms; Cyc2 is cyclopropyl, cyclobutyl, cyclopentyl, each of which may be unsubstituted or mono-substituted with RD6 or di-substituted with independently from each other RD6 and RD7; in particular unsubstituted or mono-substituted with RD6; Hetcyc2 is pyrrolidinyl, piperidinyl, each of which may unsubstituted or mono-substituted with RD6 or di-substituted with independently from each other RD6 and RD7; in particular unsubstituted or mono-substituted with RD6; RB8, RB9 represent independently from each other F, C1-2-alkyl, which C1-2- alkyl may be unsubstituted or substituted with 1, 2 or 3 F, C1-2-alkoxy, ArY; or RB8 and RB9 are attached to the same carbon atom of said carbocycle Cyc1 or said heterocycle Hetcyc1 and form a divalent oxo (=O) group; or RB8 and RB9 and RB10 and RB11 are attached to the same sulfur atom of said heterocycle and form two divalent oxo (=O) groups thereby forming an -S(=O)2- moiety; Arx is an unsubstituted benzo ring; ArY is phenyl; RC1 and RC2 represent independently from each other C1-6-alkyl which may be independently from each other be substituted with 1, 2, or 3 F atoms; RD6, RD7 represents independently from each other C1-6-alkyl which may be substituted with 1, 2, or 3 F atoms or 1 hydroxy group; or hydroxy; halogen is F, Cl, Br; and the remaining radicals and residues are as defined for formula I-A or I above or for any of the further particular embodiments described herein above or below. In another particular embodiment, PE3a, of PE3 R1 represents Ar1, Hetar1, Cyc1, Hetcyc1, L1-Ar1, L1-Hetar1, L2-Cyc1, L2- Hetcyc1, straight-chain or branched C1-6-alkyl, C2-6-alkenyl or C2-6-alkynyl, wherein said C1-6-alkyl, C2-6-alkenyl or C2-6-alkynyl is unsubstituted or substituted with 1, 2 or 3 halogen; wherein Ar1 is phenyl or naphthalenyl, in particular phenyl, which may be unsubstituted or substituted with substituents RB1 and or RB2 which may be the same or different; Hetar1 is a monocyclic heteroaryl with 5 or 6 ring atoms or a bicyclic heteroaryl with 9 or 10 ring atoms wherein 1, 2 or 3 of said ring atoms is/are a hetero atom(s) selected from N, O and/or S and the remaining are carbon atoms, wherein that heteroaryl may be unsubstituted or substituted with substituents RB1 and/or RB2 which may be the same or different; Cyc1 is a saturated or partially unsaturated, mono- or bicyclic carbocycle with 3, 4, 5, 6, 7 or 8 ring carbon atoms, wherein that carbocycle may be unsubstituted or substituted with RB8 and/or RB9 which may be the same or different; and wherein that carbocycle may optionally be fused to Arx via 2 adjacent ring atoms of said Arx and wherein that fused carbocycle may further be unsubstituted or substituted with RC1 and/or RC2 which may be the same or different; Hetcyc1 is a saturated monocyclic heterocycle with 5 or 6 ring atoms wherein 1 of said ring atoms is a hetero atom selected from O and S and the remaining are carbon atoms, wherein that heterocycle may be unsubstituted or substituted with RB8 and/or RB9 which may be the same or different, wherein, if one of the heteroatoms is S, then that heterocycle may also be substituted with RB8, RB9, RB10 and RB11; L1 is a divalent radical selected from the group consisting of -S(=O)2-, -CH2- , -CH2-CH2-, -CH2-CH2-C(CH3)H-, -CH2-CH2-C(CH3)2-, -CH2-CH2-O-CH2- , -CH2-CH=CH-; L2 is a divalent radical selected from the group consisting of -CH2-, -CH2- CH2-; RB1, RB2 represent independently from each other straight-chain or branched C1-6-alkyl, which C1-6-alkyl may be unsubstituted or monosubstituted with -CN or substituted with 1, 2 or 3 halogen, e.g. -CF3, straight-chain or branched C1-4-alkoxy, which C1-4-alkoxy may be unsubstituted or substituted with 1, 2 or 3 halogen, e.g. -OCF3, -O-CH- C≡CH, straight-chain or branched -S-C1-4-alkyl, which -S-C1-4-alkyl may be unsubstituted or substituted with 1, 2 or 3 halogen, F, Cl, Br, -CN, - S(=O)-C1-3-alkyl, S(=O)2-C1-3-alkyl, -N(C1-3-alkyl)2, Ar2, -CH2-Ar2, Hetar2, Cyc2, Hetcyc2; or two adjacent RB1, RB2 form together a divalent -C3-4-alkylene radical in which one of the alkylene carbon units may be replaced by a carbonyl unit (-C(=O)-), or a divalent -O-C2-3-alkylene radical; Ar2 is phenyl; Hetar2 is a monocyclic heteroaryl with 5 ring atoms wherein 1 of said ring atoms is N and the remaining are carbon atoms or 1 of said ring atoms is N and 1 of said ring atoms is S and the remaining are carbon atoms; Cyc2 is cyclopropyl, 1-trifluoromethylcyclopropyl, cyclopentyl; Hetcyc2 is pyrrolidinyl; RB8, RB9 represent independently from each other F, C1-2-alkyl, which C1-2- alkyl may be unsubstituted or substituted with 1, 2 or 3 F, C1-2-alkoxy, ArY; or RB8 and RB9 are attached to the same carbon atom of said carbocycle Cyc1 or said heterocycle Hetcyc1 and form a divalent oxo (=O) group; or RB8 and RB9 and RB10 and RB11 are attached to the same sulfur atom of said heterocycle and form two divalent oxo (=O) groups thereby forming an -S(=O)2- moiety; Arx is an unsubstituted benzo ring; ArY is phenyl; RC1 and RC2 represent independently from each other C1-2-alkyl which may be independently from each other be substituted with 1, 2, or 3 F atoms; halogen is F, Cl, Br; and the remaining radicals and residues are as defined for formula I-A or I above or for any of the further particular embodiments described herein above or below. In still another particular embodiment, PE3b, of PE3 or PE3a R1 represents Ar1, Hetar1, Cyc1, Hetcyc1, L1-Ar1, L1-Hetar1, L2-Cyc1, L2- Hetcyc1, 2,2-dimethyl-4,4,4-trifluoropentyl, 4,4,4-trifluorobutyl, 4,4,4- trifluoro-3-methylbutyl, 3,3-dimethyl-4,4,4-trifluorobutyl or 3,3,3‐ trifluoroprop‐1‐yn‐1‐yl; wherein Ar1 is phenyl which may be unsubstituted or substituted with substituents RB1 and or RB2 which may be the same or different; Hetar1 is a heteroaryl selected from the group consisting of furanyl, in particular furan-2-yl; thiophenyl, in particular thiophen-2-yl, thiophen-3-yl; thiazolyl, in particular 1,3-thiazol-2-yl or 1,3-thiazol-4-yl; pyrazolyl, in particular pyrazol-5-yl (1H-pyrazol-5-yl); imidazolyl, in particular imidazol- 2-yl (1H-imidazol-2-yl), imidazol-5-yl (1H-imidazol-5-yl); oxazolyl, in particular 1,3-oxazol-2-yl; pyridinyl (pyridyl), in particular pyridin-2-yl, pyridin-3-yl, pyridin-4-yl; 5H,6H,7H‐cyclopenta[b]pyridin‐2‐yl, 5‐oxo‐ 5H,6H,7H‐cyclopenta[b]pyridin‐2‐yl; pyrimidinyl, in particular pyrimidin-2- yl; indolyl, in particular 1H‐indol‐6‐yl; quinolinyl, in particular quinolin-2-yl and quinolin-4-yl; 5,6,7,8‐tetrahydroquinolin‐2‐yl, 5‐oxo‐5,6,7,8‐ tetrahydroquinolin‐2‐yl; isoquinolinyl, in particular isoquinolin-3-yl; benzofuranyl, in particular 1‐benzofuran‐3‐yl; benzothiophenyl, in particular 1‐benzothiophen‐3‐yl; isoquinolinyl, in particular isoquinolin‐3‐ yl; furo[3,2‐b]pyridinyl, in particular quinazolin‐2‐yl; pyrrolo[1,2‐ b]pyrazolyl, in particular 4H,5H,6H‐pyrrolo[1,2‐b]pyrazol-3-yl; pyrazolo[1,5‐a]pyridinyl, in particular pyrazolo[1,5‐a]pyridin‐3‐yl, pyrazolo[1,5‐a]pyridin‐7‐yl; imidazo[1,2‐a]pyridinyl, in particular imidazo[1,2‐a]pyridin‐3‐yl, imidazo[1,2‐a]pyridin‐5‐yl; imidazo[1,5‐ a]pyridinyl, in particular imidazo[1,5‐a]pyridin‐1‐yl, imidazo[1,5‐a]pyridin‐ 3‐yl, imidazo[1,5‐a]pyridin‐5‐yl; pyrazolo[1,5‐c]pyrimidinyl, in particular pyrazolo[1,5‐c]pyrimidin‐3‐yl; quinazolinyl, in particular quinazolin‐2‐yl; naphthyridinyl, in particular 1,5-naphthyridin-2-yl; wherein said heteroaryl may be unsubstituted or substituted with substituents RB1 and/or RB2 which may be the same or different; Cyc1 is selected from the group consisting of cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, spiro[3.3]heptanyl, bicyclo[2.2.1]heptanyl, bicyclo[2.2.2]octanyl, bicyclo[2.2.1]heptenyl, methylbicyclo[3.1.1]heptenyl, wherein that carbocycle may be unsubstituted or substituted with RB8 and/or RB9 which may be the same or different; and wherein that carbocycle may optionally be fused to Arx via 2 adjacent ring atoms of said Arx and wherein that fused carbocycle may further be unsubstituted or substituted with RC1 and/or RC2 which may be the same or different; Hetcyc1 is selected from the group consisting of pyrrolidinyl, tetrahydrofuranyl and thianyl, wherein that heterocycle may be unsubstituted or substituted with RB8 and/or RB9 which may be the same or different, wherein, if one of the heteroatoms is S, then that heterocycle may also be substituted with RB8, RB9, RB10 and RB11; L1 is a divalent radical selected from the group consisting of -S(=O)2-, -CH2- , -CH2-CH2-, -CH2-CH2-CH2-, -CH2-CH2-CH2-CH2-, -CH2-CH2-C(CH3)H-, -CH2-CH2-C(CH3)2-, -CH2-CH2-O-CH2-, -CH2-CH=CH-; L2 is a divalent radical selected from the group consisting of -CH2-, -CH2- CH2-; RB1, RB2 represent independently from each other methyl, ethyl, n-propyl, 2-propyl, tert.-butyl, cyanomethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluorethyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, -O-CH2-C≡CH, straight-chain or branched -S-methyl, - S-CF3, F, Cl, Br, -CN, -S(=O)-methyl, S(=O)2-methyl, -N(CH3)2, phenyl, - CH2-phenyl (benzyl), -O-CH2-phenyl (benzyloxy), pyrrolyl, thiazolyl, cyclopropyl, cyclopentyl, pyrrolidinyl; or two adjacent RB1, RB2 form together a divalent radical selected from the group consisting of -CH2-CH2-CH2-, -CH2-CH2-CH2-CH2-, -O-CH2- CH2-, -O-CH2-CH2-CH2-, -C(=O)-CH2-CH2-, -C(=O)-CH2-CH2-CH2-, RB8, RB9 represent independently from each other F, methyl, ethyl, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy, phenyl; or RB8 and RB9 are attached to the same carbon atom of said carbocycle Cyc1 or said heterocycle Hetcyc1 to form a divalent oxo (=O) group; or RB8 and RB9 and RB10 and RB11 are attached to the same sulfur atom of said heterocycle and form two divalent oxo (=O) groups thereby forming an -S(=O)2- moiety; Arx is an unsubstituted benzo ring; ArY is phenyl; RC1 and RC2 represent independently from each other CF3; and the remaining radicals and residues are as defined for formula I-A or I above or for any of the further particular embodiments described herein above or below. In a further particular embodiment, PE4, the compound of the present invention is a tricyclic heterocycle of formula I-A or I, or any N-oxide, solvate, tautomer or stereoisomer thereof and/or any pharmaceutically acceptable salt of each of the foregoing, including mixtures thereof in all ratios, wherein R2 represents -C(=O)-OR2a or HetcycX; R2a represents H, straight-chain or branched, unsubstituted or substituted C1- 4-alkyl or Cat; Cat represents a monovalent cation selected from the group consisting of lithium (Li), sodium (Na) and potassium (K); HetcycX represents 1H‐1,2,3,4‐tetrazol‐5‐yl, , 2H‐1,2,3,4‐tetrazol‐5‐yl, 2- methyl-2H‐1,2,3,4‐tetrazol‐5‐yl, 5‐oxo‐2,5‐dihydro‐1,2,4‐oxadiazol‐3‐yl (2H-1,2,4-oxadiazol-5-on-3-yl), 5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl (4H-1,2,4-oxadiazol-5-on-3-yl), 3-bromo-4,5-dihydro-1,2-oxazol-5-yl, 3- chloro-4,5-dihydro-1,2-oxazol-5-yl, 3-(1H-1,2,3-triazol-1-yl)-4,5-dihydro- 1,2-oxazol-5-yl, 3-(2H-1,2,3-triazol-2-yl)-4,5-dihydro-1,2-oxazol-5-yl, 3- (pyrimidin-5-yloxy)-4,5-dihydro-1,2-oxazol-5-yl, 3-hydroxy-oxetan-3-yl, 5-hydroxy-4H-pyran-4-on-2-yl, 3,3-difluoropyrrolidin-2-on-4-yl, 3,3- difluoropyrrolidin-2-on-5-yl, 3,3-difluoro-2,3-dihydro-1H-pyrrol-2-on-4-yl, 3,3-difluoro-2,3-dihydro-1H-pyrrol-2-on-5-yl; and the remaining radicals and residues are as defined for formula I-A or I above or for any of the further particular embodiments described herein above or below. In another particular embodiment, PE4a, of PE4 R2 represents -C(=O)-OR2a; R2a represents H, methyl, ethyl or Cat; Cat represents a monovalent sodium cation; and the remaining radicals and residues are as defined for formula I-A or I above or for any of the further particular embodiments described herein above or below. In yet another particular embodiment, PE4b, of PE4 R2 represents -C(=O)-OR2a; R2a represents C1-4-alkyl substituted with -S(=O)-R2f, -S(=O)2-R2g, -S(=O)2- NR2hR2i, -S(=O)2-OH, -S(=O)(=NR2j)-OH, -S(=O)(=NR2j)-R2g, -S(=O)(=NR2k)- NR2lR2m wherein R2f, R2g, R2h, R2i, R2j, R2k, R2l, and R2m are as defined above and below in the specification for formula I-A or I; and the remaining radicals and residues are as defined for formula I-A or I above or for any of the further particular embodiments described herein above or below. In a further particular embodiment, PE5, the compound of the present invention is a tricyclic heterocycle of formula I-A or I, or any N-oxide, solvate, tautomer or stereoisomer thereof and/or any pharmaceutically acceptable salt of each of the foregoing, including mixtures thereof in all ratios, wherein R2 represents -C(=O)-NR2bR2c; R2b and R2c represent independently from each other H or straight-chain or branched C1-8-aliphatic which may be unsubstituted or substituted with 1, 2, 3, 4, or 5 substituents which may be the same or different; or form together with the nitrogen atom to which they are attached to an unsubstituted or substituted saturated, partially unsaturated or aromatic heterocycle with 3, 4, 5, 6, 7 ring atoms wherein 1 of said ring atoms is said nitrogen atom and no or one further ring atom is a hetero atom selected from N, O or S and the remaining are carbon atoms; wherein said heterocycle may optionally be fused with HetarZ which is as defined in any of the preceding claims; in particular a pyrrolidinyl ring or piperidinyl ring each of which is unsubstituted or mono-substituted with -OH or di-substituted with independently from each other C1-4-alkyl and/or -OH; or one of R2b and R2c represents H and the other represents Cyc2 or Hetcyc2; in particular it represents cyclopropyl or cyclobutyl, each of which is unsubstituted or substituted with -CH2OH, or tetrahydrofuranyl, which is unsubstituted or mono-substituted with -OH; and the remaining radicals and residues are as defined for formula I-A or I above or for any of the further particular embodiments described herein above or below. In another particular embodiment, PE5a, of PE5 R2b represents hydrogen, R2c represents hydrogen; straight-chain or branched C1-8-alkyl which may be unsubstituted or substituted with RE1, RE2, RE3, RE4 and/or RE5 which may be the same or different, Cyc2 or Hetcyc2, wherein RE1, RE2, RE3, RE4 and/or RE5 represent independently from each other halogen, in particular F; -NREaREb, -OH, OREc, ArE, HetarE, CycE, HetcycE; ArE is a mono- or bicyclic aryl with 6 or 10 ring carbon atoms, wherein that aryl may be unsubstituted or substituted with substituents RF1, RF2 and/or RF3 which may be the same or different; preferably phenyl or naphthalenyl, in particular phenyl; HetarE is a monocyclic heteroaryl with 5 or 6 ring atoms or a bicyclic heteroaryl with 9 or 10 ring atoms wherein 1, 2, 3, or 4 of said ring atoms is/are a hetero atom(s) selected from N, O and/or S and the remaining are carbon atoms, wherein that heteroaryl may be unsubstituted or substituted with substituents RF1, RF2 and/or RF3 which may be the same or different; in particular the heteroaryl is a moncyclic heteroaryl with 5 or 6 ring atoms which may be unsubstituted or substituted with substituents RF1 and/or RF2 which may be the same or different; preferably the heteroaryl is selected from the group consisting of imidazolyl, 1H-imidazol-1-yl, 1H-imidazol-2-yl, each of which unsubstituted or monosubstituted with C1-4-alkyl; pyridyl, pyrid-2-yl, pyrid-3-yl, pyrid-4-yl, each of which may be unsubstituted or monosubstituted with -F; pyrimidinyl, pyrimidin-2-yl, pyrimidin-3-yl, pyrimidin-4-yl, pyrimidin-5-yl; pyrazinyl, pyrazin-2-yl; pyridazinyl, pyridazin-3-yl; furanyl, pyrrolyl, pyrazolyl, oxazolyl, isoxazolyl; oxadiazolyl, triazolyl, thiazolyl, isothiazolyl; CycE is a saturated or partially unsaturated, mono- or bicyclic carbocycle with 3, 4, 5, 6, 7 or 8 ring carbon atoms, wherein that carbocycle may be unsubstituted or substituted with RG1 and/or RG2 which may be the same or different: in particular, a saturated monocyclic carbocycle with 3, 4, 5, or 6 ring carbon atoms, wherein that carbocycle may be unsubstituted or substituted with RG1 and/or RG2 which may be the same or different; preferably cyclopropyl, cyclobutyl, cyclohexenyl; HetcycE is a saturated or partially unsaturated, monocyclic heterocycle with 4, 5 or 6 ring atoms wherein 1 or 2 of said ring atoms is/are a hetero atom(s) selected from N, O and/or S and the remaining are carbon atoms, wherein that heterocycle may be unsubstituted or substituted with RG1 and/or RG2 which may be the same or different; in particular a saturated monocyclic heterocycle with 5 or 6 ring atoms wherein 1 or 2 of said ring atoms is/are a hetero atom(s) selected from N and/or O and the remaining are carbon atoms, wherein that heterocycle may be unsubstituted or substituted with RG1 and/or RG2; preferably tetrahydrofuranyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl each of which may be unsubstituted or monosubstituted with -OH; pyrrolindinyl, pyrrolindin-1-yl, pyrrolindin-2-yl, pyrrolindin-3-yl, each of which may be unsubstituted or monosubstituted with -OH; piperidinyl, piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, each of which may be unsubstituted or monosubstituted with -OH; morpholinyl, morpholin-1-yl, morpholin-2-yl each of which may be unsubstituted or mono-substituted with methyl; 1,4-dioxanyl; dihydropyranyl, tetrahydropyranyl, tetrahydropyran-3-yl; REa, REb represent independently from each other H, C1-4-alkyl, -C(=O)- OC1-4-alkyl; in particular both represent H or one represents H and the other represents C(=O)-O-tert.-butyl; REc represents H or C1-4-alkyl, in particular H or methyl; RF1, RF2 and/or RF3 represent independently from each other straight- chain or branched C1-6-alkyl, which C1-6-alkyl may be unsubstituted or monosubstituted with -CN, OH, -O-C1-4-alkyl or substituted with 1, 2 or 3 halogen, straight-chain or branched C1-4-alkoxy, which C1-4-alkoxy may be unsubstituted or substituted with 1, 2 or 3 halogen, straight-chain or branched -S-C1-4-alkyl, which -S-C1-4-alkyl may be unsubstituted or substituted with 1, 2 or 3 halogen; C3-7-cyclopropyl optionally substituted with halogen, OH and/or C1-4-alkyl; F, Cl, Br, -CN, -S(=O)-C1-3-alkyl, S(=O)2-C1-3-alkyl, -NH2, -NH(C1-3- alkyl) -N(C1-3-alkyl)2, -OH; in particular methyl, hydroxymethyl, methoxymethyl, F, cyclopropyl, cyclobutyl; preferably only one of RF1, RF2 and RF3 is present and represents methyl or F; and/or two of RF1, RF2, RF3 which are attached to two different ring atoms of that aryl or heteroaryl form a divalent C1-6-alkylene radical wherein optionally one or two non-adjacent carbon units of that alkylene radical may be replaced by independently from each other O, NH, N-C1-4-alkyl, in particular –(CH2)4-, - CH2-O-(CH2)2-; RG1 and/or RG2 represent independently from each other halogen, hydroxy, unsubstituted or substituted C1-6-aliphatic, in particular C1-4-alkyl optionally substituted with OH, C1-6-aliphatoxy, in particular -O-C1-4-alkyl, -C(=O)-O-C1-4- alkyl, HetarY2, -CH2-HetarY2, HetcycY2; preferably only one of RG1 and RG2 is present and represents hydroxy; and/or RG1 and RG2 which are attached to the same ring atom of that carbocycle or heterocycle form a divalent C2-6-alkylene radical wherein optionally one or two non-adjacent carbon units of that alkylene radical may be replaced by independently from each other O, NH, N-C1-4-alkyl, and wherein that alkylene radical may optionally be substituted with OH, C1-4-alkyl or -O-C1-4-alkyl, in particular –(CH2)2-O-CH2-, –(CH2)2-O-(CH2)2-;and/or RG1 and RG2 which are attached to two different ring atoms of that carbocycle or heterocycle form a divalent C1-6-alkylene radical wherein optionally one or two non-adjacent carbon units of that alkylene radical may be replaced by independently from each other O, NH, N-C1-4-alkyl, in particular -CH2-; Cyc2 is a saturated monocyclic carbocycle with 3, 4, 5, 6 or 7 ring carbon atoms, wherein that carbocycle may be unsubstituted or substituted independently from each other with RD6, RD7, RD8, RD9 and/or RD10, wherein that carbocycle may optionally be fused to ArZ or HetarZ via 2 adjacent ring atoms and wherein that fused carbocycle may optionally further be substituted with independently from each other RC1, RC2 and/or RC3; Hetcyc2 is a saturated monocyclic heterocycle with 4, 5 or 6 ring atoms wherein 1 or 2 of said ring atoms is/are a hetero atom(s) selected from N, O and/or S and the remaining are carbon atoms, wherein that heterocycle may be unsubstituted or substituted independently from each other with RD6, RD7, RD8, RD9 and/orRD10 wherein that heterocycle may optionally be fused to ArZ or HetarZ and wherein that fused heterocycle may optionally further be substituted with independently from each other RC1, RC2 and/or RC3; RC1, RC2, RC3 represent C1-4-alkyl; RD6, RD7, RD8, RD9, RD10 represent independently from each other halogen, in particular F; hydroxy; C1-4-alkyl optionally substituted with -OH and/or halogen, in particular methyl, hydroxymethyl, 2-fluorethyl; -O-C1-4-alkyl, in particular methoxy, ethoxy; HetarY1, -CH2-HetarY1, CycY1, HetcycY1, - CH2-HetcycY1; and/or two of RD6, RD7, RD8, RD9, RD10 which are attached to the same ring atom of that carbocycle or heterocycle form a divalent C2-6-alkylene radical wherein optionally one or two non-adjacent carbon units of that alkylene radical may be replaced by independently from each other O, NH, N-C1-4-alkyl, and wherein that alkylene radical may optionally be substituted with OH, C1-4-alkyl or -O-C1-4-alkyl, in particular –(CH2)3-, – CH2-CH(OC2H5)-CH2-, –(CH2)2-O-(CH2)2-; and/or two of RD6, RD7, RD8, RD9, RD10 which are attached to two different ring atoms of that carbocycle or heterocycle form a divalent C1-6-alkylene radical wherein optionally one or two non-adjacent carbon units of that alkylene radical may be replaced by independently from each other O, NH, N-C1-4-alkyl, in particular -CH2-, –(CH2)3-, -O-(CH2)2-, -O-(CH2)3-; ArZ is benzo; HetarY1 is a 5 or 6 membered monocyclic heteroaryl wherein 1, 2, 3, 4 ring atoms are hetero atoms selected from N, O and/or S and the remaining are carbon atoms, wherein that heteroaryl may be unsubstituted or substituted with F, C1-4-alkyl which may optionally be substituted with OH; in particular pyrrolyl, thiophenyl, pyrazolyl, methylpyrazolyl, imidazolyl, methylimidazolyl, triazolyl, oxadiazolyl, methyloxadiazolyl, pyrdinyl, fluoropyrdinyl, methylpyridinyl, pyrimidinyl, methylpyrimidinyl; HetarY2 is a 5 or 6 membered monocyclic heteroaryl wherein 1, 2, 3, 4 ring atoms are hetero atoms selected from N, O and/or S and the remaining are carbon atoms, wherein that heteroaryl may be unsubstituted or substituted with halogen, C1-4-alkyl which may optionally be substituted with OH; in particular pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, hydroxymethyloxazolyl; HetarZ is pyrrole, N-methyl-pyrrole, pyrazole, imidazole, triazole; CycY1 is a saturated monocyclic carbocycle with 3, 4, 5, 6 or 7 ring carbon atoms, wherein that carbocycle may be unsubstituted or substituted with halogen, OH, C1-4-alkyl, in particular cyclopropyl; HetcycY1 is a saturated or partially unsaturated monocyclic heterocycle with 5 or 6 ring atoms wherein 1 or 2 of said ring atoms are heteroatoms selected from N, O, and/or S and the remaining are carbon atoms; in particular tetrahydrofuranyl; HetcycY2 is a saturated or partially unsaturated monocyclic heterocycle with 5 or 6 ring atoms wherein 1 or 2 of said ring atoms are heteroatoms selected from N, O, and/or S and the remaining are carbon atoms; in particular tetrahydrofuranyl, morpholinyl, tetrahydropyranyl; and the remaining radicals and residues are as defined for formula I-A or I above or for any of the further particular embodiments described herein above or below. It is understood that this particular embodiment PE5a comprises compounds of the present invention in which R2b represents hydrogen and R2c represents straight-chain or branched C1-8-alkyl in which 1 or 2 of non-terminal and non-adjacent –CH2- (methylene) groups are replaced by –O-, -S- and/or 1 or 2 non-terminal and non-adjacent –CH2- or –CH- groups are replaced by – NH- or –N-. In yet another particular embodiment, PE5aa, of PE5a R2b represents hydrogen, R2c represents hydrogen; straight-chain or branched C1-8-alkyl which may be unsubstituted or substituted with RE1, RE2, RE3, RE4 and/or RE5 which may be the same or different, Cyc2 or Hetcyc2, wherein RE1, RE2, RE3, RE4 and/or RE5 represent independently from each other halogen, in particular F; -NREaREb, -OH, OREc, ArE, HetarE, CycE, HetcycE; ArE is a mono- or bicyclic aryl with 6 or 10 ring carbon atoms, wherein that aryl may be unsubstituted or substituted with substituents RF1, RF2 and/or RF3 which may be the same or different; preferably phenyl or naphthalenyl, in particular phenyl; HetarE is a monocyclic heteroaryl with 5 or 6 ring atoms or a bicyclic heteroaryl with 9 or 10 ring atoms wherein 1, 2, 3, or 4 of said ring atoms is/are a hetero atom(s) selected from N, O and/or S and the remaining are carbon atoms, wherein that heteroaryl may be unsubstituted or substituted with substituents RF1, RF2 and/or RF3 which may be the same or different; in particular the heteroaryl is a moncyclic heteroaryl with 5 or 6 ring atoms which may be unsubstituted or substituted with substituents RF1 and/or RF2 which may be the same or different; preferably the heteroaryl is selected from the group consisting of imidazolyl, 1H- imidazol-1-yl, 1H-imidazol-2-yl, each of which unsubstituted or monosubstituted with C1-4-alkyl; pyridyl, pyrid-2-yl, pyrid-3-yl, pyrid-4-yl, each of which may be unsubstituted or monosubstituted with -F; pyrimidinyl, pyrimidin-2-yl, pyrimidin-3-yl, pyrimidin-4-yl, pyrimidin-5-yl; pyrazinyl, pyrazin-2-yl; CycE is a saturated or partially unsaturated, mono- or bicyclic carbocycle with 3, 4, 5, 6, 7 or 8 ring carbon atoms, wherein that carbocycle may be unsubstituted or substituted with RG1 and/or RG2 which may be the same or different: in particular, a saturated monocyclic carbocycle with 3, 4, 5, or 6 ring carbon atoms, wherein that carbocycle may be unsubstituted or substituted with RG1 and/or RG2 which may be the same or different; preferably cyclobutyl; HetcycE is a saturated or partially unsaturated, monocyclic heterocycle with 5 or 6 ring atoms wherein 1 or 2 of said ring atoms is/are a hetero atom(s) selected from N, O and/or S and the remaining are carbon atoms, wherein that heterocycle may be unsubstituted or substituted with RG1 and/or RG2 which may be the same or different; in particular a saturated monocyclic heterocycle with 5 or 6 ring atoms wherein 1 or 2 of said ring atoms is/are a hetero atom(s) selected from N and/or O and the remaining are carbon atoms, wherein that heterocycle may be unsubstituted or monosubstituted with RG1; preferably tetrahydrofuranyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl each of which may be unsubstituted or monosubstituted with -OH; pyrrolindinyl, pyrrolindin-1-yl, pyrrolindin-2-yl, pyrrolindin-3-yl, each of which may be unsubstituted or monosubstituted with -OH; piperidinyl, piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, each of which may be unsubstituted or monosubstituted with -OH; morpholinyl, morpholin-1-yl, morpholin-2-yl; REa, REb represent independently from each other H, C1-4-alkyl, -C(=O)- OC1-4-alkyl; in particular both represent H or one represents H and the other represents C(=O)-O-tert.-butyl; REc represents H or C1-4-alkyl, in particular H or methyl; RF1, RF2 and/or RF3 represent independently from each other straight- chain or branched C1-6-alkyl, which C1-6-alkyl may be unsubstituted or monosubstituted with -CN OH, -O-C1-4-alkyl or substituted with 1, 2 or 3 halogen, straight-chain or branched C1-4-alkoxy, which C1-4-alkoxy may be unsubstituted or substituted with 1, 2 or 3 halogen, straight-chain or branched -S-C1-4-alkyl, which -S-C1-4-alkyl may be unsubstituted or substituted with 1, 2 or 3 halogen, C3-7-cyclopropyl optionally substituted with halogen, OH and/or C1-4-alkyl, F, Cl, Br, -CN, -S(=O)-C1-3-alkyl, S(=O)2-C1-3-alkyl, -NH2, -NH(C1-3-alkyl) -N(C1-3-alkyl)2, -OH; in particular methyl, F; preferably only one of RF1, RF2 and RF3 is present and represents methyl or F; RG1 and/or RG2 represent independently from each other halogen, hydroxy, unsubstituted or substituted C1-4-alkyl, -O-C1-4-alkyl, in particular hydroxy; preferably only one of RG1 and RG2 is present and represents hydroxy; Cyc2 is a saturated monocyclic carbocycle with 3, 4, 5, 6 or 7 ring carbon atoms, wherein that carbocycle may be unsubstituted or mono- substituted with RD6, wherein RD6 is C1-4-alkyl which is unsubstituted or mono-substituted with - OH, in particular -CH2OH; in particular Cyc2 is cyclopropyl, cyclobutyl or 1-hydroxymethyl- cyclobutyl; Hetcyc2 is a saturated monocyclic heterocycle with 5 or 6 ring atoms wherein 1 or 2 of said ring atoms is/are a hetero atom(s) selected from N, O and/or S and the remaining are carbon atoms, wherein that heterocycle may be unsubstituted or mono-substituted with hydroxy; in particular tetrahydrofuranyl or hydroxytetrahydrofuranyl; preferably 4- hydroxytetrahydrofuran-3-yl; In still another particular embodiment, PE5b, of PE5 R2b and R2c form together with the nitrogen atom to which they are attached to a saturated or partially unsaturated heterocycle optionally substituted with independently from each other RY1, RY2, RY3, RY4 and/or RY5; wherein that heterocycle may optionally be fused with HetarZ; and wherein that heterocycle is selected from the group consisting of: azetidine, pyrrolidine, piperidine, piperazine, morpholine; wherein RY1, RY2, RY3, RY4, RY5 represent independently from each other halogen, in particular F; -NH2, -N(H)-C1-4-alkyl, -N(H)-C(=O)-O-C1-4-alkyl, -N(C1-4- alkyl)2; -OH; C1-4-alkyl optionally substituted with -OH, -O-C1-4-alkyl, -O- C3-7-cycloalkyl, -O-CH2-C3-7-cycloalkyl, in particular methyl, -CH2OH, - (CH2)2OH, -(CH2)3OH, -CH2OCH3, -(CH2)2OCH3, cyclopropylmethoxy; - O-C1-4-alkyl, in particular methoxy; HetarY2; -CH2-HetarY2; HetcycY2; and/or two of RY1, RY2, RY3, RY4, RY5 which are attached to the same ring atom of that heterocycle form a divalent C2-6-alkylene radical wherein optionally one or two non-adjacent carbon units of that alkylene radical may be replaced by independently from each other O, NH, N-C1-4-alkyl, in particular –(CH2)4-, –(CH2)2-O-(CH2)2-, –(CH2)2-O-(CH2)3-; and/or two of RY1, RY2, RY3, RY4, RY5 which are attached to two different ring atoms of that heterocycle form a divalent C1-6-alkylene radical wherein optionally one or two non-adjacent carbon units of that alkylene radical may be replaced by independently from each other O, NH, N-C1- 4-alkyl, in particular –(CH2)4-; ArZ is benzo; HetarY2 is a 5 or 6 membered monocyclic heteroaryl wherein 1, 2, 3, 4 ring atoms are hetero atoms selected from N, O and/or S and the remaining are carbon atoms, wherein that heteroaryl may be unsubstituted or substituted with halogen, C1-4-alkyl which may optionally be substituted with OH; in particular pyrrolyl, thiophenyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, hydroxymethyloxazolyl, pyrimidinyl; HetarZ is pyrrole, N-methyl-pyrrole, pyrazole, imidazole, triazole; HetcycY2 is a saturated or partially unsaturated monocyclic heterocycle with 5 or 6 ring atoms wherein 1 or 2 of said ring atoms are heteroatoms selected from N, O, and/or S and the remaining are carbon atoms; in particular tetrahydrofuranyl, morpholinyl, tetrahydropyranyl; and the remaining radicals and residues are as defined for formula I-A or I above or for any of the further particular embodiments described herein above or below. In yet another particular embodiment, PE5bb, of PE5b R2b and R2c form together with the nitrogen atom to which they are attached a 3-hydroxypyrrolidinyl, 2-methyl-3-hydroxypyrrolidinyl or 3-hydroxypiperidinyl ring. In still another particular embodiment, PE5c, of PE5 R2b represents a straight-chain of branched C1-4-alkyl optionally substituted with OH; in particular methyl, 2-hydroxyethyl; and R2c represents Cyc2, Hetcyc2 or straight-chain or branched C1-8-alkyl which may be unsubstituted or substituted with independently from each other RE1, RE2, RE3, RE4 and/or RE5 which may be the same or different; wherein Cyc2, Hetcyc2, RE1, RE2, RE3, RE4 and RE5 are as defined hereinabove for PE5a or PE5aa. In a further particular embodiment, PE6, the compound of the present invention is a tricyclic heterocycle of formula I-A or I, or any N-oxide, solvate, tautomer or stereoisomer thereof and/or any pharmaceutically acceptable salt of each of the foregoing, including mixtures thereof in all ratios, wherein R2 represents -(CH2)x-NR2d-C(=O)-R2e, -S-R2f, -S(=O)-R2f, -S(=O)2-R2g, - S(=O)2-NR2hR2i, -S(=O)2-OH, -S(=O)(=NR2j)-OH, -S(=O)(=NR2j)-R2g, - S(=O)(=NR2k)-NR2lR2m, -(CH2)z-NR2d-S(=O)2-R2g; in particular, -S-CH3, - S(=O)-R2f, -S(=O)2-R2g, -S(=O)2-NR2hR2i, -S(=O)(=NR2j)-R2g, -S(=O)(=NR2k)- NR2lR2m, -(CH2)z-NR2d-S(=O)2-R2g, -C(=O)-N=S(=O)-R2sR2t, -C(=O)-N=S(=N- R2u)-R2sR2t; preferably, -S(=O)-CH3, -S(=O)2-CH3, -S(=O)2-NH2, -S(=O)2- NHCH3, -S(=O)(=NH)-CH3, S(=O)(=NH)-N(CH3)2, -NH-S(=O)2-CH3, -N(CH3)- S(=O)2-CH3, -NH-S(=O)2-CH=CH2, -CH2-NH-S(=O)2-CH=CH2; R2e represents H, C1-6-alkyl optionally substituted with -OH or a monocyclic 5- or 6-membered heteroaryl; C3-7-cycloalkyl, monocyclic 5- or 6-membered heteroaryl; in particular H, methyl, hydroxymethyl, methylpyridin-2-yl, methylpyridine-3-yl, methylpyridine-4-yl, cyclopropyl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl; R2f, R2g represent independently from each other un-substituted or substituted C1-8-aliphatic; in particular independently from each other C1-4-alkyl or C2-4-alkenyl; preferably independently from each other methyl or -CH=CH2: R2h, R2i represent independently from each other H, un-substituted or substituted C1-8-aliphatic, aryl, heterocyclyl, heteroaryl; or form together with the nitrogen atom to which they are attached to an unsubstituted or substituted saturated, partially unsaturated or aromatic heterocycle with 3, 4, 5, 6, 7 ring atoms wherein 1 of said ring atoms is said nitrogen atom and no or one further ring atom is a hetero atom selected from N, O or S and the remaining are carbon atoms; in particular independently from each other H or C1-4-alkyl optionally substituted with -OH, pyridyl, pyrimidyl, pyrazinyl or pyridazinyl or form together with the nitrogen atom to which they are attached to a pyrrolidinyl ring which ring is optionally substituted with -OH and/or phenyl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrimidin-5-yl; R2d, R2j, R2k represent independently from each other H, un-substituted or substituted C1-8-aliphatic; in particular H, methyl; R2l, R2m represent independently from each other H, un-substituted or substituted C1-8-aliphatic; or form together with the nitrogen atom to which they are attached to an unsubstituted or substituted saturated, partially unsaturated or aromatic heterocycle with 3, 4, 5, 6, 7 ring atoms wherein 1 of said ring atoms is said nitrogen atom and no or one further ring atom is a hetero atom selected from N, O or S and the remaining are carbon atoms; in particular C1- 4-alkyl; preferably methyl; R2s, R2t represent independently from each other C1-6-alkyl which may optionally be substituted with -OH, O-C1-4-alkyl, NH2, NHC1-4-alkyl, N(C1-4- alkyl)2, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl; in particular methyl, ethyl, 2-hydroxyethyl, 3-hydroxy propyl, 2-aminoethyl, 3-(N,N- dimethylamino)propyl; or form together a divalent C3-4-alkylene radical which may optionally be substituted with -NH2, -CN, or a divalent C2-5-alkylene radical wherein optionally one of the carbon units of said C2-5-alkylene radical may be replaced by O, NH or N-C1-4-alkyl; in particular –(CH2)3-, -CH2-C(NH2)H-CH2-, -CH2-C(CN)H-CH2-, -CH2-C(CH2-NH-CH2)-CH2-, –(CH2)4-; R2u represents hydrogen or C1-4-alkyl; x represents 0 or 1; z is 0 or 1: and the remaining radicals and residues are as defined for formula I-A or I above or for any of the further particular embodiments described herein above or below. In yet a further particular embodiment, PE7, the compound of the present invention is a tricyclic heterocycle of formula I, or any N-oxide, solvate, tautomer or stereoisomer thereof and/or any pharmaceutically acceptable salt of each of the foregoing, including mixtures thereof in all ratios, wherein wherein Ring A represents a five-membered heteroaromatic ring selected from the group consisting of the following ring moieties:
; , , , , , , , , ; , ; , ; , ; ; ; , ; , ; ; , ; , ; , , ; , ; Z1 is CH; Z2 is CH; R1 represents phenyl, 3-fluorophenyl, 4-fluorophenyl, 4-chlorophenyl, 4- methylphenyl, 4-ethylphenyl, 4-difluoromethylphenyl, 3-trifluoromethyl- phenyl, 4-trifluoromethylphenyl, 4-(1,1-difluorethyl)phenyl, 4-(2,2,2- trifluorethyl)phenyl, 4-(1-trifluoromethylcyclopropyl)-phen-1-yl, 4- cyclopentylphenyl, 4-ethoxyphenyl, 4-difluormethoxyphenyl, 4- trifluoromethoxyphenyl, 3‐(trifluoromethyl)sulfanylphenyl, 4‐ (trifluoromethyl)sulfanylphenyl, 3-trifluoromethyl-4-methylphenyl, 2- fluoro-4-trifluoromethylphenyl, 2-fluoro-4-trifluoromethoxyphenyl, 3- fluoro-4-(n-propyl)phenyl, 2,3-dimethyl-4-methoxyphenyl, 6- fluoronaphth-2-yl; 5-trifluoromethylfuran-2-yl; 5‐trifluoromethylthiophen‐ 2‐yl, 2-trifluoromethyl-1,3-thiazol-4-yl, 3-fluoropyridin-2-yl, 6- methylpyridin-3-yl, 6-methoxypyridin-3-yl, 3-ethylpyridin-2-yl, 6- ethylpyridin-3-yl, 4-difluoromethylpyridin-2-yl, 4-trifluoromethylpyridin-2- yl, 4-trifluoromethoxypyridin-2-yl, 4-cyanopyridin-2-yl, 5- trifluoromethylpyridin-2-yl, 6-trifluoromethylpyridin-2-yl, 6- trifluoromethylpyridin-3-yl (2-trifluoromethylpyridin-5-yl), 6- trifluoromethoxypyridin-3-yl (2-trifluoromethoxypyridin-5-yl), 5- cyanopyridin-2-yl, 5-cyanomethylpyridin-2-yl, 5‐methanesulfonylpyridin‐ 2‐yl, 6-methoxypyridin-2-yl, 4-methylpyrimidin-2-yl, 4-ethylpyrimidin-2-yl, 4-methylsulfanylpyrimidin-2-yl, 5‐cyclopropylpyrimidin‐2‐yl, 5-ethyl- pyrimidin-2-yl, 5-difluoromethylpyrimidin-2-yl, 5-trifluoromethylpyrimidin- 2-yl, 5-cyanopyrimidin-2-yl, 5‐cyano‐3‐fluoropyridin‐2‐yl, 5-cyano-6- methylpyridin-2-yl, 3‐fluoro‐5‐(trifluoromethyl)pyridin‐2‐yl, 5‐oxo‐ 5H,6H,7H‐cyclopenta[b]pyridin‐2‐yl, 5,6,7,8‐tetrahydroquinolin‐2‐yl, 5‐ oxo‐5,6,7,8‐tetrahydroquinolin‐2‐yl, 5H,6H,7H‐cyclopenta[b]pyridin‐2‐yl, quinolin-2-yl, isoquinolin‐3‐yl, 6-methylquinolin-2-yl, 8‐methoxyquinolin‐ 4‐yl, furo[3,2‐b]pyridin‐5‐yl, quinazolin‐2‐yl, 6‐fluoroquinazolin‐2‐yl, 1,5- naphthyridin-2-yl; 3-methylcyclobutyl, cyclopentyl, 3-methylcyclopentyl, 3,3-dimethylcyclopentyl, 3-trifluoromethyl-bicyclo[1.1.1]petan-1-yl, cyclohexyl, 4-methylcyclohexyl, 4‐(trifluoromethyl)cyclohexyl, 4,4- difluorocyclohexyl, cyclohex-1-enyl, 2-oxocycloheptyl, 6,6‐ difluorospiro[3.3]heptan‐2‐yl, 1H‐inden‐2‐yl; benzenesulfonyl (phenylsulfonyl), 3-methylphenylsulfonyl, benzyl, 2-ethoxyphenylmethyl, 3-chlorophenylmethyl, 3-fluorophenylmethyl, 4-chlorophenylmethyl, 3- (pyrrolidine-1-yl)phenylmethyl, 3-methylphenylmethyl, 4- methylphenylmethyl, 3-ethylphenylmethyl, 3‐(propan‐2‐yl)phenylmethyl, 3‐tert‐butylphenylmethyl, 3‐(difluoromethoxy)phenylmethyl, 2‐ (difluoromethyl)phenylmethyl, 3‐(difluoromethyl)phenylmethyl, 3‐ (trifluoromethyl)phenylmethyl, 4‐(trifluoromethyl)phenyl]methyl, 2‐(prop‐ 2‐yn‐1‐yloxy)phenylmethyl, 3‐(1,3‐thiazol‐2‐yl)phenylmethyl, 3‐ (trifluoromethyl)sulfanylphenylmethyl, 3‐methanesulfonylphenylmethyl, 3‐(dimethylamino)phenylmethyl, 3‐(pyrrol‐1‐yl)phenylmethyl, 2-methyl-3- methoxyphenylmethyl, 3-trifluoromethyl-5-methylphenylmethyl, 2‐ methyl‐3‐(trifluoromethyl)phenylmethyl, 3-trifluoromethyl-4-fluorophenyl- methyl, 2‐fluoro‐5‐(trifluoromethoxy)phenylmethyl, 2-methoxy-3-trifluoro- methoxyphenylmethyl, 2‐fluoro‐3‐methoxyphenylmethyl, 2‐fluoro‐3‐ (trifluoromethyl)phenyl]methyl, 2-fluor-3-fluoromethoxyphenylmethyl, 2- trifluoromethoxy-5-fluorophenylmethyl, 2-fluor-5-chlor-phenylmethyl, 3‐ fluoro‐5‐methylphenyl)methyl, 3,5-difluorophenylmethyl, 5‐fluoro‐2‐ (trifluoromethyl)phenylmethyl, 3‐fluoro‐5‐(trifluoromethyl)phenylmethyl, 2‐chloro‐3‐(trifluoromethyl)phenylmethyl, naphthalin-1-ylmethyl, 5,6,7,8‐ tetrahydronaphthalen‐1‐ylmethyl, 2,3‐dihydro‐1‐benzofuran‐7‐ylmethyl, 3,4‐dihydro‐2H‐1‐benzopyran‐8‐ylmethyl, 2-phenylethyl, 2-(2-methyl- phenyl)ethyl, 2-(2‐methoxyphenyl)ethyl, 2‐(3‐methoxyphenyl)ethyl, 2‐(4‐ methoxyphenyl)ethyl, 2-(2-fluorophenyl)-ethyl, 2-(3-fluorophenyl)-ethyl, 2-(4-fluorophenyl)-ethyl, 2-(2-chlorophenyl)-ethyl, 2-(4-chlorophenyl)- ethyl, 2-(4-bromophenyl)-ethyl, 2‐[4‐(trifluoromethyl)phenyl]ethyl, 2‐(2,4‐ difluorophenyl)ethyl, 2‐(difluoromethoxy)‐5‐fluorophenylmethyl, 2‐ phenylpropyl, 3‐phenylpropyl, 3-methyl-3-phenylbutyl, 2‐(benzyl- oxy)ethyl; 5-ethylfuran-2-ylmethyl, 5‐(trifluoromethyl)furan‐2‐ylmethyl, 4‐ (propan‐2‐yl)‐1,3‐thiazol‐2‐ylmethyl, 2‐methyl-1,3‐thiazol‐4‐ylmethyl, 2‐ trifluoromethyl‐1,3‐thiazol‐4‐ylmethyl, 1-ethylpyrazol-5-ylmethyl, 1-(2- propyl)pyrazol-5-ylmethyl, 1-ethylimidazol-5-ylmethyl, 1-ethylimidazol-2- ylmethyl, 1‐propylimidazol‐2‐ylmethyl, 1‐benzylimidazol‐2‐yl)methyl, 1‐ (2‐methylpropyl)‐1H‐imidazol‐5‐ylmethyl, 5‐tert‐butyl‐1,3‐oxazol‐2‐ ylmethyl, 3-fluoropyridin-2-ylmethyl, 2-methylpyridin-4-ylmethyl, 4- trifluoromethylpyridin-2-ylmethyl, 6‐(fluoromethyl)pyridin‐2‐ylmethyl, 6- trifluoromethylpyridin-2-ylmethyl, 2-(trifluoromethyl)pyridin‐4‐ylmethyl, 4- methylpyrimidin-2-ylmethyl, 2-(thiophen-3-yl)ethyl, 5- trifluoromethylthiophen-2-ylmethyl, 1‐methyl‐1H‐indol‐6‐yl)methyl, 1‐ benzofuran‐3‐ylmethyl, 1‐benzothiophen‐3‐ylmethyl, 4H,5H,6H‐ pyrrolo[1,2‐b]pyrazol‐3‐ylmethyl, pyrazolo[1,5‐a]pyridin‐7‐ylmethyl, pyrazolo[1,5‐a]pyridin‐3‐ylmethyl, imidazo[1,2‐a]pyridin‐3‐ylmethyl, 6‐ methylimidazo[1,2‐a]pyridin‐3‐ylmethyl, imidazo[1,2‐a]pyridin‐5‐ ylmethyl, imidazo[1,5‐a]pyridin‐1‐ylmethyl, imidazo[1,5‐a]pyridin‐3‐ ylmethyl, imidazo[1,5‐a]pyridin‐5‐ylmethyl, pyrazolo[1,5‐c]pyrimidin‐3‐ ylmethyl, 3‐(furan‐2‐yl)prop‐2‐en‐1‐yl; 3-trifluormethylcyclobutylmethyl, 3‐fluoro‐3‐phenylcyclobutylmethyl, cyclohexylmethyl, 4-methylcyclo- hexylmethyl, 4-trifluoromethylcyclohexylmethyl, 4-methoxycyclohexyl- methyl, 4,4‐dimethylcyclohexylmethyl, 4,4‐difluorocyclohexylmethyl, 3- trifluoromethyl-bicyclo[1.1.1]petan-1-ylmethyl, bicyclo[2.2.1]heptan‐2‐ ylmethyl, bicyclo[2.2.2]octan‐2‐ylmethyl, bicyclo[2.2.1]hept‐5‐en‐2‐ ylmethyl, 6,6‐dimethylbicyclo[3.1.1]hept‐2‐en‐2‐yl]methyl; 3,3- dimethyltetrahydrofuran-2-ylmethyl, 1,1‐dioxothian‐4‐ylmethyl, 2‐(thian‐ 4‐yl)ethyl; 2,2-dimethyl-4,4,4-trifluoropentyl, 4,4,4-trifluorobutyl, 4,4,4- trifluoro-3-methylbutyl, 3,3-dimethyl-4,4,4-trifluorobutyl, 3,3,3‐ trifluoroprop‐1‐yn‐1‐yl; and R2 represents -C(=O)-OH, -C(=O)-ONa, -C(=O)-OCH3, -C(=O)-NH2, -C(=O)- NHCH3, -C(=O)-NHCH2CH3, -C(=O)-NH(CH2)2CH3, -C(=O)-N(H)- cyclopropyl, -C(=O)-N(H)-(1-hydroxymethyl)cyclobutan-1-yl, -C(=O)- N(H)-CH2CH2-OH, -C(=O)-N(H)-CH2CH2-OCH3, -C(=O)-N(H)-CH2- C(H)(OH)-CH3, -C(=O)-N(H)-CH2C(CH3)2OH, -C(=O)-N(H)-C(H)(CH3)- CH2OH, -C(=O)-N(H)-C(H)(CH2CH3)-CH2OH, -C(=O)-N(H)- C(H)(CH2OH)-CH2CH2-O-CH3, -C(=O)-N(H)-C(CH3)2CH2CH2OH, - C(=O)-N(H)-C(H)(CH2OH)-phenyl, -C(=O)-N(H)-C(CH3)(CH2OH)- phenyl, -C(=O)-N(H)-C(H)(CH(OH)CH3)-phenyl, -C(=O)-N(H)-CH2-1H— 1-methylimidazol-2-yl, -C(=O)-N(H)-(CH2)2-1H-imidazol-1-yl, -C(=O)- N(H)-CH2-pyridin-2-yl, -C(=O)-N(H)-CH2-pyridin-3-yl, -C(=O)-N(H)-CH2- pyridin-4-yl, -C(=O)-N(H)-C(H)(CH2OH)-pyridin-2-yl, -C(=O)-N(H)-CH2- 1,3-pyrimidin-2-yl, -C(=O)-N(H)-CH2-1,3-pyrimidin-4-yl, -C(=O)-N(H)- CH2-pyridazin-2-yl, -C(=O)-NH-C(CH2OH)-cyclobutyl, -C(=O)-3-hydroxy- pyrrolidin-1-yl, -NH-C(=O)-CH=CH2, -NH-C(=O)-CF=CH2, -NH-C(=O)- CH2Cl, -NH-C(=O)-C≡CH, -CH2-NH-C(=O)-CH=CH2, -CH2-NH-C(=O)- CH2Cl, -S(=O)-CH3, -S(=O)2-CH3, -S(=O)2-OH, -S(=O)2-NH2, -S(=O)2- NHCH3, -S(=O)(=NH)-N(CH3)2, -S(=O)(=N-CH3)-N(CH3)2, -S(=O)(=N- CH3)-OH, -S(=O)(=NH)-CH3, -P(=O)(OH)2, F, -CN; preferably -C(=O)- OH, -C(=O)-ONa. In yet a further particular embodiment, PE8, the compound of the present invention is a tricyclic heterocycle of formula I-A, or any N-oxide, solvate, tautomer or stereoisomer thereof and/or any pharmaceutically acceptable salt of each of the foregoing, including mixtures thereof in all ratios, wherein wherein Ring A represents a five-membered heteroaromatic ring selected from the group consisting of the following ring moieties: , ,
Figure imgf000053_0001
, , ,
;
Figure imgf000054_0001
; , ; , , ; , ; Z1 is CH; Z2 is CH; Z3 is CH or N; R1 represents phenyl, 3-fluorophenyl, 4-fluorophenyl, 4-chlorophenyl, 4- methylphenyl, 4-ethylphenyl, 4-difluoromethylphenyl, 3-trifluoromethyl- phenyl, 4-trifluoromethylphenyl, 4-(1,1-difluorethyl)phenyl, 4-(2,2,2- trifluorethyl)phenyl, 4-(1-trifluoromethylcyclopropyl)-phen-1-yl, 4- cyclopentylphenyl, 4-ethoxyphenyl, 4-difluormethoxyphenyl, 4- trifluoromethoxyphenyl, 3‐(trifluoromethyl)sulfanylphenyl, 4‐ (trifluoromethyl)sulfanylphenyl, 3-trifluoromethyl-4-methylphenyl, 2- fluoro-4-trifluoromethylphenyl, 2-fluoro-4-trifluoromethoxyphenyl, 3- fluoro-4-(n-propyl)phenyl, 2,3-dimethyl-4-methoxyphenyl, 6- fluoronaphth-2-yl; 5-trifluoromethylfuran-2-yl; 5‐trifluoromethylthiophen‐ 2‐yl, 2-trifluoromethyl-1,3-thiazol-4-yl, 3-fluoropyridin-2-yl, 6- methylpyridin-3-yl, 6-methoxypyridin-3-yl, 3-ethylpyridin-2-yl, 6- ethylpyridin-3-yl, 4-difluoromethylpyridin-2-yl, 4-trifluoromethylpyridin-2- yl, 4-trifluoromethoxypyridin-2-yl, 4-cyanopyridin-2-yl, 5- trifluoromethylpyridin-2-yl, 6-trifluoromethylpyridin-2-yl, 6- trifluoromethylpyridin-3-yl (2-trifluoromethylpyridin-5-yl), 6- trifluoromethoxypyridin-3-yl (2-trifluoromethoxypyridin-5-yl), 5- cyanopyridin-2-yl, 5-cyanomethylpyridin-2-yl, 5‐methanesulfonylpyridin‐ 2‐yl, 6-methoxypyridin-2-yl, 4-methylpyrimidin-2-yl, 4-ethylpyrimidin-2-yl, 4-methylsulfanylpyrimidin-2-yl, 5‐cyclopropylpyrimidin‐2‐yl, 5-ethyl- pyrimidin-2-yl, 5-difluoromethylpyrimidin-2-yl, 5-trifluoromethylpyrimidin- 2-yl, 5-cyanopyrimidin-2-yl, 5‐cyano‐3‐fluoropyridin‐2‐yl, 5-cyano-6- methylpyridin-2-yl, 3‐fluoro‐5‐(trifluoromethyl)pyridin‐2‐yl, 5‐oxo‐ 5H,6H,7H‐cyclopenta[b]pyridin‐2‐yl, 5,6,7,8‐tetrahydroquinolin‐2‐yl, 5‐ oxo‐5,6,7,8‐tetrahydroquinolin‐2‐yl, 5H,6H,7H‐cyclopenta[b]pyridin‐2‐yl, quinolin-2-yl, isoquinolin‐3‐yl, 6-methylquinolin-2-yl, 8‐methoxyquinolin‐ 4‐yl, furo[3,2‐b]pyridin‐5‐yl, quinazolin‐2‐yl, 6‐fluoroquinazolin‐2‐yl, 1,5- naphthyridin-2-yl; 3-methylcyclobutyl, cyclopentyl, 3-methylcyclopentyl, 3,3-dimethylcyclopentyl, 3-trifluoromethyl-bicyclo[1.1.1]petan-1-yl, cyclohexyl, 4-methylcyclohexyl, 4‐(trifluoromethyl)cyclohexyl, 4,4- difluorocyclohexyl, cyclohex-1-enyl, 2-oxocycloheptyl, 6,6‐ difluorospiro[3.3]heptan‐2‐yl, 1H‐inden‐2‐yl; benzenesulfonyl (phenylsulfonyl), 3-methylphenylsulfonyl, benzyl, 2-ethoxyphenylmethyl, 3-chlorophenylmethyl, 3-fluorophenylmethyl, 4-chlorophenylmethyl, 3- (pyrrolidine-1-yl)phenylmethyl, 3-methylphenylmethyl, 4- methylphenylmethyl, 3-ethylphenylmethyl, 3‐(propan‐2‐yl)phenylmethyl, 3‐tert‐butylphenylmethyl, 3‐(difluoromethoxy)phenylmethyl, 2‐ (difluoromethyl)phenylmethyl, 3‐(difluoromethyl)phenylmethyl, 3‐ (trifluoromethyl)phenylmethyl, 4‐(trifluoromethyl)phenyl]methyl, 2‐(prop‐ 2‐yn‐1‐yloxy)phenylmethyl, 3‐(1,3‐thiazol‐2‐yl)phenylmethyl, 3‐ (trifluoromethyl)sulfanylphenylmethyl, 3‐methanesulfonylphenylmethyl, 3‐(dimethylamino)phenylmethyl, 3‐(pyrrol‐1‐yl)phenylmethyl, 2-methyl-3- methoxyphenylmethyl, 3-trifluoromethyl-5-methylphenylmethyl, 2‐ methyl‐3‐(trifluoromethyl)phenylmethyl, 3-trifluoromethyl-4-fluorophenyl- methyl, 2‐fluoro‐5‐(trifluoromethoxy)phenylmethyl, 2-methoxy-3-trifluoro- methoxyphenylmethyl, 2‐fluoro‐3‐methoxyphenylmethyl, 2‐fluoro‐3‐ (trifluoromethyl)phenyl]methyl, 2-fluor-3-fluoromethoxyphenylmethyl, 2- trifluoromethoxy-5-fluorophenylmethyl, 2-fluor-5-chlor-phenylmethyl, 3‐ fluoro‐5‐methylphenyl)methyl, 3,5-difluorophenylmethyl, 5‐fluoro‐2‐ (trifluoromethyl)phenylmethyl, 3‐fluoro‐5‐(trifluoromethyl)phenylmethyl, 2‐chloro‐3‐(trifluoromethyl)phenylmethyl, naphthalin-1-ylmethyl, 5,6,7,8‐ tetrahydronaphthalen‐1‐ylmethyl, 2,3‐dihydro‐1‐benzofuran‐7‐ylmethyl, 3,4‐dihydro‐2H‐1‐benzopyran‐8‐ylmethyl, 2-phenylethyl, 2-(2-methyl- phenyl)ethyl, 2-(2‐methoxyphenyl)ethyl, 2‐(3‐methoxyphenyl)ethyl, 2‐(4‐ methoxyphenyl)ethyl, 2-(2-fluorophenyl)-ethyl, 2-(3-fluorophenyl)-ethyl, 2-(4-fluorophenyl)-ethyl, 2-(2-chlorophenyl)-ethyl, 2-(4-chlorophenyl)- ethyl, 2-(4-bromophenyl)-ethyl, 2‐[4‐(trifluoromethyl)phenyl]ethyl, 2‐(2,4‐ difluorophenyl)ethyl, 2‐(difluoromethoxy)‐5‐fluorophenylmethyl, 2‐ phenylpropyl, 3‐phenylpropyl, 3-methyl-3-phenylbutyl, 2‐(benzyl- oxy)ethyl; 5-ethylfuran-2-ylmethyl, 5‐(trifluoromethyl)furan‐2‐ylmethyl, 4‐ (propan‐2‐yl)‐1,3‐thiazol‐2‐ylmethyl, 2‐methyl-1,3‐thiazol‐4‐ylmethyl, 2‐ trifluoromethyl‐1,3‐thiazol‐4‐ylmethyl, 1-ethylpyrazol-5-ylmethyl, 1-(2- propyl)pyrazol-5-ylmethyl, 1-ethylimidazol-5-ylmethyl, 1-ethylimidazol-2- ylmethyl, 1‐propylimidazol‐2‐ylmethyl, 1‐benzylimidazol‐2‐yl)methyl, 1‐ (2‐methylpropyl)‐1H‐imidazol‐5‐ylmethyl, 5‐tert‐butyl‐1,3‐oxazol‐2‐ ylmethyl, 3-fluoropyridin-2-ylmethyl, 2-methylpyridin-4-ylmethyl, 4- trifluoromethylpyridin-2-ylmethyl, 6‐(fluoromethyl)pyridin‐2‐ylmethyl, 6- trifluoromethylpyridin-2-ylmethyl, 2-(trifluoromethyl)pyridin‐4‐ylmethyl, 4- methylpyrimidin-2-ylmethyl, 2-(thiophen-3-yl)ethyl, 5- trifluoromethylthiophen-2-ylmethyl, 1‐methyl‐1H‐indol‐6‐yl)methyl, 1‐ benzofuran‐3‐ylmethyl, 1‐benzothiophen‐3‐ylmethyl, 4H,5H,6H‐ pyrrolo[1,2‐b]pyrazol‐3‐ylmethyl, pyrazolo[1,5‐a]pyridin‐7‐ylmethyl, pyrazolo[1,5‐a]pyridin‐3‐ylmethyl, imidazo[1,2‐a]pyridin‐3‐ylmethyl, 6‐ methylimidazo[1,2‐a]pyridin‐3‐ylmethyl, imidazo[1,2‐a]pyridin‐5‐ ylmethyl, imidazo[1,5‐a]pyridin‐1‐ylmethyl, imidazo[1,5‐a]pyridin‐3‐ ylmethyl, imidazo[1,5‐a]pyridin‐5‐ylmethyl, pyrazolo[1,5‐c]pyrimidin‐3‐ ylmethyl, 3‐(furan‐2‐yl)prop‐2‐en‐1‐yl; 3-trifluormethylcyclobutylmethyl, 3‐fluoro‐3‐phenylcyclobutylmethyl, cyclohexylmethyl, 4-methylcyclo- hexylmethyl, 4-trifluoromethylcyclohexylmethyl, 4-methoxycyclohexyl- methyl, 4,4‐dimethylcyclohexylmethyl, 4,4‐difluorocyclohexylmethyl, 3- trifluoromethyl-bicyclo[1.1.1]petan-1-ylmethyl, bicyclo[2.2.1]heptan‐2‐ ylmethyl, bicyclo[2.2.2]octan‐2‐ylmethyl, bicyclo[2.2.1]hept‐5‐en‐2‐ ylmethyl, 6,6‐dimethylbicyclo[3.1.1]hept‐2‐en‐2‐yl]methyl; 3,3- dimethyltetrahydrofuran-2-ylmethyl, 1,1‐dioxothian‐4‐ylmethyl, 2‐(thian‐ 4‐yl)ethyl; 2,2-dimethyl-4,4,4-trifluoropentyl, 4,4,4-trifluorobutyl, 4,4,4- trifluoro-3-methylbutyl, 3,3-dimethyl-4,4,4-trifluorobutyl, 3,3,3‐ trifluoroprop‐1‐yn‐1‐yl; and R2 represents -C(=O)-OH, -C(=O)-ONa, -C(=O)-OCH3, -C(=O)-NH2, -C(=O)- NHCH3, -C(=O)-NHCH2CH3, -C(=O)-NH(CH2)2CH3, -C(=O)-N(H)- cyclopropyl, -C(=O)-N(H)-(1-hydroxymethyl)cyclobutan-1-yl, -C(=O)- N(H)-CH2CH2-OH, -C(=O)-N(H)-CH2CH2-OCH3, -C(=O)-N(H)-CH2- C(H)(OH)-CH3, -C(=O)-N(H)-CH2C(CH3)2OH, -C(=O)-N(H)-C(H)(CH3)- CH2OH, -C(=O)-N(H)-C(H)(CH2CH3)-CH2OH, -C(=O)-N(H)- C(H)(CH2OH)-CH2CH2-O-CH3, -C(=O)-N(H)-C(CH3)2CH2CH2OH, - C(=O)-N(H)-C(H)(CH2OH)-phenyl, -C(=O)-N(H)-C(CH3)(CH2OH)- phenyl, -C(=O)-N(H)-C(H)(CH(OH)CH3)-phenyl, -C(=O)-N(H)-CH2-1H— 1-methylimidazol-2-yl, -C(=O)-N(H)-(CH2)2-1H-imidazol-1-yl, -C(=O)- N(H)-CH2-pyridin-2-yl, -C(=O)-N(H)-CH2-pyridin-3-yl, -C(=O)-N(H)-CH2- pyridin-4-yl, -C(=O)-N(H)-C(H)(CH2OH)-pyridin-2-yl, -C(=O)-N(H)-CH2- 1,3-pyrimidin-2-yl, -C(=O)-N(H)-CH2-1,3-pyrimidin-4-yl, -C(=O)-N(H)- CH2-pyridazin-2-yl, -C(=O)-NH-C(CH2OH)-cyclobutyl, -C(=O)-3-hydroxy- pyrrolidin-1-yl, -NH-C(=O)-CH=CH2, -NH-C(=O)-CF=CH2, -NH-C(=O)- CH2Cl, -NH-C(=O)-C≡CH, -CH2-NH-C(=O)-CH=CH2, -CH2-NH-C(=O)- CH2Cl, -CH2-NH-C(=O)-C≡CH, -S(=O)-CH3, -S(=O)2-CH3, -S(=O)2-OH, - S(=O)2-NH2, -S(=O)2-NHCH3, -S(=O)(=NH)-N(CH3)2, -S(=O)(=N-CH3)- N(CH3)2, -S(=O)(=N-CH3)-OH, -S(=O)(=NH)-CH3, -P(=O)(OH)2, F, -CN; preferably -C(=O)-OH, -C(=O)-ONa. In still another particular embodiment of the invention, PE9, the compound of the present invention is a tricyclic heterocycle of formula I-A or I, or any N- oxide, solvate, tautomer or stereoisomer thereof and/or any pharmaceutically acceptable salt of each of the foregoing, including mixtures thereof in all ratios, wherein R1 is selected from the group consisting of
,
Figure imgf000059_0001
, ,
Figure imgf000060_0001
Figure imgf000061_0001
and the remaining radicals and residues are as defined for formula I-A or I above or for any of the further particular embodiments described herein above or below. In a particular embodiment, PE9a, of PE9 R1 is selected from the group consisting of
Figure imgf000062_0001
and the remaining radicals and residues are as defined for formula I-A or I above or for any of the further particular embodiments described herein above
Figure imgf000062_0002
or below. Especially, R1 is (particular embodiment PE9aa). In yet another particular embodiment of the invention, PE10, the compound of the present invention is a tricyclic heterocycle of formula I-A or I, or any N- oxide, solvate, tautomer or stereoisomer thereof and/or any pharmaceutically acceptable salt of each of the foregoing, including mixtures thereof in all ratios, wherein R2 is selected from the group consisting of -COOH, -COONa, -COOCH3,
Figure imgf000063_0001
; -CN, -F, -CH2-CN, ,
Figure imgf000063_0002
,
Figure imgf000064_0001
Figure imgf000064_0002
,
Figure imgf000064_0004
,
Figure imgf000064_0005
,
Figure imgf000064_0003
, ,
Figure imgf000064_0006
,
,
Figure imgf000065_0001
Figure imgf000066_0001
,
Figure imgf000067_0001
Figure imgf000068_0001
,
Figure imgf000069_0001
,
Figure imgf000070_0001
, , , , , , , , , , , , , , , , , , , , , , ,
Figure imgf000072_0001
Figure imgf000073_0001
,
Figure imgf000074_0001
,
Figure imgf000075_0001
, , , , , , , , , , , , , , , , , , , , , , , , , , ,
Figure imgf000077_0001
and the remaining radicals and residues are as defined for formula I-A or I above or for any of the further particular embodiments described herein above or below. In a particular embodiment, PE10a, of PE10 the compound of the present invention is a tricyclic heterocycle of formula I-A or I, or any N-oxide, solvate, tautomer or stereoisomer thereof and/or any pharmaceutically acceptable salt of each of the foregoing, including mixtures thereof in all ratios, wherein R2 is selected from the group consisting of
Figure imgf000077_0002
, ,
Figure imgf000078_0001
2); and the remaining radicals and residues are as defined for formula I-A or I above or for any of the further particular embodiments described herein above or below. In a particular embodiment. PE10aa, of PE10a R2 is selected from the group consisting of -COOH. In a particular embodiment, PE10b, of PE10 the compound of the present invention is a tricyclic heterocycle of formula I-A or I, or any N-oxide, solvate, tautomer or stereoisomer thereof and/or any pharmaceutically acceptable salt of each of the foregoing, including mixtures thereof in all ratios, wherein R2 is selected from the group consisting of
Figure imgf000079_0001
Figure imgf000080_0001
Figure imgf000081_0001
Figure imgf000082_0001
Figure imgf000083_0001
,
Figure imgf000084_0001
Figure imgf000085_0001
Figure imgf000086_0001
Figure imgf000087_0001
Figure imgf000088_0001
Figure imgf000089_0001
, ,
Figure imgf000090_0001
and the remaining radicals and residues are as defined for formula I-A or I above or for any of the further particular embodiments described herein above or below. In a particular embodiment. PE10bb, of PE10b R2 is selected from the group consisting of
Figure imgf000090_0002
Figure imgf000091_0001
In another particular embodiment, PE10c, of PE10 the compound of the present invention is a tricyclic heterocycle of formula I-A or I, or any N-oxide, solvate, tautomer or stereoisomer thereof and/or any pharmaceutically acceptable salt of each of the foregoing, including mixtures thereof in all ratios, wherein R2 is selected from the group consisting of
Figure imgf000092_0001
Figure imgf000093_0001
Figure imgf000094_0002
, , ; and the remaining radicals and residues are as defined for formula I-A or I above or for any of the further particular embodiments described herein above or below. In a particular embodiment, PE10cc, of PE10c R2 is selected from the group consisting of ,
Figure imgf000094_0001
, , , It is understood that in the embodiments PE9, PE9a, PE9aa, PE10, PE10a, PE10aa, PE10b, PE10bb, PE10c, and PE10cc shown above the dotted line is used to indicate the position where the individual radicals R1 and
Figure imgf000094_0003
R2, respectively, are attached to the remaining of the molecule, i.e. the compound of formula I or I-A. In still another particular embodiment of the invention, PE11, the compound of the present invention is a tricyclic heterocycle of formula I-A or I, or any N- oxide, solvate, tautomer or stereoisomer thereof and/or any pharmaceutically acceptable salt of each of the foregoing, including mixtures thereof in all ratios, wherein R1 is selected from the group described for PE9 above; and R2 is selected from the group described for PE10 above; and the remaining radicals and residues are as defined for formula I-A or I above or for any of the further particular embodiments described herein above or below. It is a particular embodiment, PE11a, of PE11 wherein R1 is selected from the group described for PE9a above, especially PE9aa; and R2 is selected from the group described for PE10 above. It is still another particular embodiment, PE11b, of PE11 wherein R1 is selected from the group described for PE9a above, especially PE9aa; and R2 is selected from the group described for PE10a above, especially PE10aa. It is still another particular embodiment, PE11c, of PE11 wherein R1 is selected from the group described for PE9a above, especially PE9aa; and R2 is selected from the group described for PE10b above, especially PE10bb. It is still another particular embodiment, PE11d, of PE11 wherein R1 is selected from the group described for PE9a above, especially PE9aa; and R2 is selected from the group described for PE10c above, especially PE10cc. It is still another particular embodiment of the invention, PE12, wherein Ring A is selected from one of the particular embodiments PE2, PE2a, PE2b, PE2c; and R1 and R2 are selected as described for PE11. In a particular embodiment, PE12a, of PE12, R1 and R2 are selected as described for PE11a. In another particular embodiment, PE12b, of PE12, R1 and R2 are selected as described for PE11b. In yet another particular embodiment, PE12c, of PE12, R1 and R2 are selected as described for PE11c. In still a further particular embodiment, PE12d, of PE12, R1 and R2 are selected as described for PE11d. In still another particular embodiment, PE13, the compound of the present invention is a tricyclic heterocycle of formula I-A or I, or any N-oxide, solvate, tautomer or stereoisomer thereof and/or any pharmaceutically acceptable salt of each of the foregoing, including mixtures thereof in all ratios, wherein that compound is selected from the compounds shown in Table 1 and Table 1b below, in particular in Table 1. It is understood that each single compound depicted in Table 1 and Table 1b as well as any N-oxide, solvate, tautomer or stereoisomer thereof and/or any pharmaceutically acceptable salt of such compound represent a particular embodiment of the present invention. In still another particular embodiment, PE14, the compound of the present invention is a tricyclic heterocycle selected from the compounds shown in Table 1c below, or any pharmaceutically acceptable salt thereof. In yet another particular embodiment, PE14a, of PE14, the compound is selected from Table 1c and is a compound of formula I or I-A as described hereinabove. It is understood that each single compound depicted in Table 1c as well as any pharmaceutically acceptable salt thereof of such compound represents a particular embodiment of the present invention. In still another particular embodiment, PE14b, of PE14 the compound, or any pharmaceutically acceptable salt thereof, is selected from the group of compounds listed in Table 1c and consisting of: C2, C3, C6, C12, C16, C17, C18, C20, C25, , C30, C31, C41, C42, C51, C52, C56, C62, C63, C64, C65, C66, C67, C70, C72, C73, C74, C75, C76, C77, C80, C81, C83, C86, C89, C90, C91, C94, C95, C96, C97, C98, C99, C101, C102, C104, C105, C119, C120, C121, C134, C147, C148, C149, C150, C153, C156, C159, C160, C161, C162, C164, C166, C167, C168, C169, C172, C173, C174, C175, C180, C181, C183, C184, C185, C187, C189, C191, C192, C198, C213, C214, C220, C225, C226, C227, C236, C237, C240, C242, C245, C247, C248, C250, C254, C256, C257, C258, C260, C261, C273, C276, C277. As used herein, the following definitions shall apply unless otherwise indicated or defined specifically elsewhere in the description and/or the claims for specific substituents, radicals, residues, groups or moieties. The term “aliphatic” or “aliphatic group”, as used herein, means a straight- chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is completely saturated or that contains one or more units of unsaturation, or a monocyclic hydrocarbon or bicyclic hydrocarbon or tricyclic hydrocarbon that is completely saturated or that contains one or more units of unsaturation, such as one or more C=C double bond(s) and/or C≡C triple bond(s), but which is not aromatic (also referred to herein as “carbocycle”, “cycloaliphatic” or “cycloalkyl”), that has – in general and if not defined otherwise in this specification or the accompanied claims – a single point of attachment to the rest of the molecule. Unless otherwise specified, aliphatic groups contain 1-8 or 1-6 aliphatic carbon atoms (“C1-8-aliphatic” and “C1-6- aliphatic”, respectively). In some embodiments, aliphatic groups contain 1-5 aliphatic carbon atoms (“C1-5-aliphatic”). In other embodiments, aliphatic groups contain 1-4 aliphatic carbon atoms (“C1-4-aliphatic”). In still other embodiments, aliphatic groups contain 1-3 aliphatic carbon atoms (“C1-3- aliphatic”), and in yet other embodiments, aliphatic groups contain 1-2 aliphatic carbon atoms (“C1-2-aliphatic”). In some embodiments, “cycloaliphatic” (“cycloalkyl”) refers to a monocyclic C3-C7 hydrocarbon (i.e., a monocyclic hydrocarbon with 3, 4, 5, 6, or 7 ring carbon atoms) or to a bicyclic C5-8 hydrocarbon (i.e. a bicyclic hydrocarbon with 5, 6, 7, or 8 ring carbon atoms) that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic, that has a single point of attachment to the rest of the molecule. In another embodiment the term “cycloaliphatic” or “carbocycle” refers to a monocyclic or bicyclic cycloaliphatic ring system which is fused to an aromatic, heteroaromatic or heterocyclic ring or ring system via 2 adjacent ring atoms of that aromatic, heteroaromatic or heterocyclic ring or ring system; in other words, such carbocycle shares two ring atoms with the ring or ring system to which it is fused thereby having two points of attachment to the rest of the molecule. In another embodiment the term “carbocycle” refers to bicyclic spiro-cycles in which two monocyclic carbocycles are fused to each other via the same single carbon atom. In general, the term “aliphatic” encompasses, to the extent chemically possible, straight-chain, i.e. unbranched, as well as branched hydrocarbon chains, if not defined differently in a particular instance. Also, in general this term encompasses, to the extent chemically possible, unsubstituted and substituted hydrocarbon moieties, if not defined differently in a particular instance. Typical substituents of an aliphatic group include, but are not limited to halogen, cyano, hydroxy, alkoxy, unsubstituted or mono- or di-substituted amino, aryl, in particular unsubstituted or substituted phenyl, heteroaryl, in particular unsubstituted or substituted pyridyl or pyrimidinyl, heterocyclyl, in particular unsubstituted or substituted pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl. Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl groups and hybrids thereof as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl. The term "alkyl" usually refers to a saturated aliphatic and acyclic moiety, while the term "alkenyl" usually refers to an unsaturated aliphatic and acyclic moiety with one or more C=C double bonds and the term "alkynyl" usually refers to an aliphatic and acyclic moiety with one or more C≡C triple bonds. It is understood that the term “alkenyl” comprises all forms of isomers, i.e. E-isomers, Z- isomers as well as mixtures thereof (E/Z-isomers). Exemplary aliphatic groups are linear or branched, substituted or unsubstituted C1-8-alkyl, C1-6-alkyl, C1-4- alkyl, C1-3-alkyl, C1-2-alkyl, C2-8-alkenyl, C2-6-alkenyl, C2-8-alkynyl, C2-6-alkynyl, C2-4-alkynyl, groups and hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl. In particular, the term “C1-3-alkyl” refers to alkyl groups, i.e. saturated acyclic aliphatic groups, having 1, 2 or 3 carbon atoms. Exemplary C1-3-alkyl groups are methyl, ethyl, propyl and isopropyl. The term “C1-4-alkyl” refers to alkyl groups having 1, 2, 3 or 4 carbon atoms. Exemplary C1-4-alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl. The term “C1-6- alkyl” refers to alkyl groups having 1, 2, 3, 4, 5 or 6 carbon atoms. Exemplary C1-6-alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, n-pentyl, 2-pentyl, n-hexyl, and 2-hexyl. The term "C1-8-alkyl" refers to alkyl groups having 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms. Exemplary C1-8-alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, n-pentyl, 2-pentyl, n-hexyl, 2-hexyl n-heptyl, 2-heptyl, n-octyl, 2-octyl, and 2,2,4- trimethylpentyl. Each of these alkyl groups may be straight-chain or – except for C1-alkyl and C2-alkyl – branched and may be unsubstituted or substituted with 1, 2, 3, 4 or 5 substituents that may be the same or different and may be, if not specified differently elsewhere in this specification and/or the accompanying claims, selected from the group comprising halogen, cyano, hydroxy, alkoxy, unsubstituted or mono- or di-substituted amino, aryl, in particular unsubstituted or substituted phenyl, heteroaryl, in particular unsubstituted or substituted pyridyl or pyrimidinyl, heterocyclyl, in particular unsubstituted or substituted pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl. In some instances the C1-3-alkyl, C1-4-alkyl, C1-6-alkyl, C1-8-alkyl groups may also comprise those residues in which 1 or 2 of non-terminal and non-adjacent –CH2- (methylene) groups are replaced by –O-, -S- and/or 1 or 2 non-terminal and non-adjacent –CH2- or –CH- groups are replaced by –NH- or –N-. These replacements yield, for instance, (modified) alkyl groups like –CH2-CH2-O-CH3, –CH2-CH2-CH2-S-CH3, CH2-CH2-NH-CH2-CH3, CH2-CH2-O-CH2-CH2-O-CH3, CH2-CH2-N(CH3)-CH2-CH3, and the like. Further and/or different replacements of –CH– and –CH2– groups may be defined for specific alkyl substituents or radicals elsewhere in the description and/or the claims. The term “C3-7-cycloalkyl” refers to a cycloaliphatic hydrocarbon, as defined above, with 3, 4, 5, 6 or 7 ring carbon atoms. Likewise, the term “C3-6- cycloalkyl” refers to a cycloaliphatic hydrocarbon with 3, 4, 5, or 6 ring carbon atoms. C3-7-cycloalkyl groups may be unsubstituted or substituted with – unless specified differently elsewhere in this specification – 1, 2 or 3 substituents that may be the same of different and are – unless specified differently elsewhere in this specification – selected from the group comprising C1-6-alkyl, O-C1-6-alkyl (alkoxy), halogen, hydroxy, unsubstituted or mono- or di-substituted amino, aryl, in particular unsubstituted or substituted phenyl. If substituted, C3-7-cycloalkyl comprises all possible stereoisomers. Exemplary C3-7-cycloalkyl groups are cyclopropyl, 2-methyl-cyclopropyl, cyclopropenyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl. The term “bicyclic C5-8-cycloalkyl” refers to a bicyclic cycloaliphatic hydrocarbon, as defined above, with 5, 6, 7, or 8 ring carbon atoms; it includes spirocyclic ring system, i.e. ring systems in which the two carbocycles of the bicyclic C5-8-cycloalkyl are attached to each other via the same carbon atom. Bicylic C5-8-cycloalkyl groups may be unsubstituted or substituted with – unless specified differently elsewhere in this specification – 1, 2 or 3 substituents that may be the same of different and are – unless specified differently elsewhere in this specification – selected from the group comprising C1-6-alkyl, O-C1-6-alkyl (alkoxy), halogen, hydroxy, unsubstituted or mono- or di-substituted amino. If substituted, bicyclic C5-8-cycloalkyl comprises all possible stereoisomers. Exemplary bicyclic C5-8-cycloalkyl are spiro[3.3]heptanyl, bicyclo[2.2.1]heptan‐2‐yl, bicyclo[2.2.2]octan‐2‐yl, bi- cyclo[2.2.1]hept‐5‐en‐2‐ylmethyl, bicyclo[3.1.1]hept‐2‐en‐2‐yl. The term “aliphatoxy” refers to saturated or unsaturated aliphatic groups or substituents as defined above that are connected to another structural moiety via an oxygen atom (-O-). The term “C1-6-aliphatoxy” refers to an aliphatoxy radical with 1, 2, 3, 4, 5, or 6 carbon atoms within the aliphatic group. The term “alkoxy” refers to a particular subgroup of saturated aliphatoxy, i.e. to alkyl substituents and residues that are connected to another structural moiety via an oxygen atom (-O-). Sometimes, it is also referred to as “O-alkyl” and more specifically as “O-C1-2-alkyl”, “O-C1-3-alkyl”, “O-C1-4-alkyl”, “O-C1-6-alkyl”, “O-C1- 8-alkyl”. Like the similar alkyl groups, it may be straight-chain or – except for – O-C1-alkyl and –O-C2-alkyl – branched and may be unsubstituted or substituted with 1, 2 or 3 substituents that may be the same or different and are, if not specified differently elsewhere in this specification, selected from the group comprising halogen, unsubstituted or mono- or di-substituted amino. Exemplary alkoxy groups are methoxy, difluoromethoxy, trifluoromethoxy, ethoxy, 2,2,2-trifluoroethoxy, n-propoxy, iso-propoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy. The term “alkylene” refers to a divalent (or bivalent) aliphatic group and in particular a divalent alkyl group. An “alkylene chain” is a polymethylene group, i.e., –(CH2)y–, wherein y is a positive integer, preferably 1, 2, 3, 4, 5 or 6. In the context of the present invention "C1-3-alkylene" refers to an alkylene moiety with 1, 2 and 3, respectively, -CH2- groups; the term "alkylene", however, not only comprises linear alkylene groups, i.e. "alkylene chains", but branched alkylene groups as well. The term "C1-6-alkylene" refers to an alkylene moiety that is either linear, i.e. an alkylene chain, or branched and has 1, 2, 3, 4, 5 or 6 carbon atoms. The term "C2-6-alkylene" refers to an alkylene moiety with 2, 3, 4, 5, or 6 carbon atoms, while a "C3-4-alkylene" refers to an alkylene moiety with 3 or 4 carbon atoms and "C2-3-alkylene" refers to an alkylene moiety with 2 or 3 carbon atoms. A substituted alkylene is a group in which one or more methylene hydrogen atoms are replaced by (or with) a substituent. Suitable substituents include those described herein for a substituted alkyl group. In some instances 1 or 2 methylene groups of the alkylene chain may be replaced by, for instance, O, S and/or NH or N-C1-4-alkyl. Exemplary alkylene groups are –CH2-, –CH2–CH2-, –CH2–CH2–CH2–CH2-, –O–CH2–CH2-, –O–CH2–CH2– CH2-, –CH2–O–CH2–CH2-, -O–CH2-O-, -O–CH2–CH2-O-, -O–CH2–CH2–CH2- O-,–CH2-NH–CH2–CH2-, –CH2-N(CH3)–CH2–CH2-. The term “alkenylene” refers to a divalent alkenyl group. A substituted alkenylene chain is a polymethylene group containing at least one double bond in which one or more hydrogen atoms are replaced with a substituent. Suitable substituents include those described herein for a substituted aliphatic group. The term “alkenylene” not only refers to straight-chain divalent alkenylene radicals, i.e. an alkenylene chain, but to branched alkenylene groups as well. The term “C2-6-alkenylene” refers to an alkenylene radical having 2, 3, 4, 5, or 6 carbon atoms. The term “alkynylene” refers to a divalent alkynyl group. A substituted alkynylene chain is a polymethylene group containing at least one triple bond in which one or more hydrogen atoms are replaced with a substituent. Suitable substituents include those described herein for a substituted aliphatic group. The term “halogen” means F, Cl, Br, or I. The term “heteroatom” means one or more of oxygen (O), sulfur (S), or nitrogen (N), including, any oxidized form of nitrogen or sulfur, e.g. N-oxides, sulfoxides and sulfones; the quaternized form of any basic nitrogen or a substitutable nitrogen of a heterocyclic or heteroaromatic ring, for example N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or N-SUB with SUB being a suitable substituent (as in N-substituted pyrrolidinyl). The term “aryl” used alone or as part of a larger moiety as in “aralkyl”, “aralkoxy”, or “aryloxyalkyl”, refers to monocyclic, bicyclic and tricyclic ring systems having a total of five to fourteen ring members, that ring members being carbon atoms, wherein at least one ring in the system is aromatic, i.e., it has (4n+2) π (pi) electrons (with n being an integer selected from 0, 1, 2, 3), which electrons are delocalized over the system, and wherein each ring in the system contains three to seven ring members. Preferably, all rings in the aryl system or the entire ring system are aromatic. The term “aryl” is used interchangeably with the term “aryl ring”. In certain embodiments of the present invention, “aryl” refers to an “aromatic ring system”. More specifically, those aromatic ring systems may be mono-, bi- or tricyclic with 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 ring carbon atoms. Even more specifically, those aromatic ring systems may be mono- or bicyclic with 6, 7, 8, 9, 10 ring carbon atoms. Exemplary aryl groups are phenyl, biphenyl, naphthyl, anthracyl and the like, which may be unsubstituted or substituted with one or more identical or different substituents. Also included within the scope of the terms “aryl” or “aromatic ring system”, as they are used herein, is a group in which an aromatic ring is fused to one or more non–aromatic rings, such as indanyl, phthalimidyl, naphthimidyl, phenanthridinyl, or tetrahydronaphthyl, and the like. In the latter case the "aryl" group or substituent is attached to its pendant group via the aromatic part of the ring system. The term “benzo” refers to a six-membered aromatic ring (with carbon ring atoms) that is fused via two adjacent carbon atoms to another ring, being it a cycloaliphatic, aromatic, heteroaromatic or heterocyclic (heteroaliphatic) ring; as a result a ring system with at least two rings is formed in which the benzo ring shares two common carbon atoms with the other ring to which it is fused. For example, if a benzo ring is fused to a phenyl ring, a napthaline ring system is formed, while fusing a benzo ring to a pyridine provides for either a quinoline or an isoquinoline; fusing a benzo ring to a cyclopentene ring provides an indene ring. The terms “heteroaryl” and “heteroar–”, used alone or as part of a larger moiety, e.g., “heteroaralkyl”, or “heteroaralkoxy”, refer to groups having 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 ring atoms (which atoms are carbon and hetero atoms), preferably 5, 6, 9 or 10 ring atoms; having 6, 10, or 14 π (pi) electrons shared in a cyclic array; and having, in addition to carbon atoms, 1, 2, 3, 4 or 5 heteroatoms. The term “heteroatom” refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, and any quaternized form of a basic nitrogen. In other words, a “heteroaryl” ring or ring system may also be described as an aromatic heterocycle. Heteroaryl groups include, without limitation, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, furazanyl, pyridyl (pyridinyl), pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, pteridinyl, and pyrrolopyridinyl, in particular pyrrolo[2,3- b]pyridinyl. The terms “heteroaryl” and “heteroar–”, as used herein, also include groups in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic, or heterocyclyl rings, where the radical or point of attachment is preferably on the heteroaromatic or, if present, the aryl ring. Nonlimiting examples include indolyl, isoindolyl, benzothienyl (benzothiophenyl), benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzothiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H– quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, 9H-carbazolyl, dibenzofuranyl and pyrido[2,3–b]–1,4–oxazin–3(4H)–one. For example, an indolyl ring may be attached via one of the ring atoms of the six-membered aryl ring or via one of the ring atoms of the five-membered heteroaryl ring. A heteroaryl group is optionally mono-, bi- or tricyclic. The term “heteroaryl” is used interchangeably with the terms “heteroaryl ring”, “heteroaryl group”, or “heteroaromatic”, any of which terms include rings that are unsubstituted or substituted with one or more identical or different substituents. The term “heteroaralkyl” refers to an alkyl group substituted by a heteroaryl, wherein the alkyl and heteroaryl portions independently are optionally substituted. A heteroaryl ring can be attached to its pendant group at any of its hetero or carbon ring atoms which attachment results in a stable structure or molecule: any of the ring atoms may be unsubstituted or substituted. The structures of typical examples of "heteroaryl" substituents as used in the present invention are depicted below:
Figure imgf000105_0001
pyrrolyl furanyl thiophenyl 1-oxa-2,3- 1-oxa-2,4- diazolyl diazolyl
Figure imgf000105_0002
1-oxa-3,4- diazolyl 1-oxa-2,5- diazolyl 1-thia-2,3- 1-thia-2,4- 1-thia-3,4- diazolyl diazolyl diazolyl
Figure imgf000105_0003
1-thia-2,5- diazolyl oxazolyl isoxazolyl isothiazolyl thiazolyl
Figure imgf000105_0004
pyrazolyl imidazolyl 1,2,3-triazolyl 1,3,4-triazolyl tetrazolyl
Figure imgf000105_0005
pyridinyl pyrimidinyl pyrazinyl pyridazinyl (pyridyl)
Figure imgf000105_0006
indolyl benzofuranyl benzothiophenyl isoindolyl
Figure imgf000106_0001
Figure imgf000107_0001
Those heteroaryl substituents can be attached to any pendant group via any of its ring atoms suitable for such an attachment. As used herein, the terms “heterocycle”, “heterocyclyl”, “heterocyclic radical”, and “heterocyclic ring” are used interchangeably and refer to a stable mono- bi- or tricyclic heterocyclic moiety with 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 ring atoms wherein 1, 2, 3, 4, 5 of said ring atoms are hetero atoms and wherein that heterocyclic moiety is either saturated or partially unsaturated; heterocyclic moieties that are aromatic rings or ring systems are referred to as “heteroaryl” moieties as described hereinabove. Preferably, the heterocycle is a stable saturated or partially unsaturated 3-, 4-, 5-, 6-, or 7-membered monocyclic or 7-, 8-, 9-, 10-, or 11-membered bicyclic or 11-, 12-, 13-, or 14-membered tricyclic heterocyclic moiety. When used in reference to a ring atom of a heterocycle, the term “nitrogen” includes a substituted nitrogen. As an example, in a saturated or partially unsaturated ring having 1–3 heteroatoms selected from oxygen, sulfur or nitrogen, the nitrogen is N (as in 3,4–dihydro–2H–pyrrolyl), NH (as in pyrrolidinyl), or N-SUB with SUB being a suitable substituent (as in N– substituted pyrrolidinyl). In the context of the term "heterocycle" the term "saturated" refers to a completely saturated heterocyclic system, like pyrrolidinyl, piperidinyl, morpholinyl, piperidinonyl, tetrahydrofuranyl, thianyl, and dioxothianyl. With regard to the term "heterocycle" the term "partially unsaturated" refers to heterocyclic systems (i) that contain one or more units of unsaturation, e.g. a C=C or a C=Heteroatom bond, but that are not aromatic, for instance, tetrahydropyridinyl; or (ii) in which a (saturated or unsaturated but non- aromatic) heterocyclic ring is fused with an aromatic or heteroaromatic ring system, wherein, however, the "partially unsaturated heterocycle" is attached to the rest of the molecule (its pendant group) via one of the ring atoms of the "heterocyclic" part of the system and not via the aromatic or heteroaromatic part. This first class (i) of "partially unsaturated" heterocycles may also be referred to as "non-aromatic partially unsaturated" heterocycles. This second class (ii) of "partially unsaturated" heterocycles may also be referred to as (bicyclic or tricyclic) "partially aromatic" heterocycles indicating that at least one of the rings of that heterocycle is a saturated or unsaturated but non- aromatic heterocycle that is fused with at least one aromatic or heteroaromatic ring system. Typical examples of these "partially aromatic" heterocycles are 1,2,3,4-tetrahydroquinolinyl and 1,2,3,4-tetrahydroisoquinolinyl. A heterocyclic ring can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure and any of the ring atoms may be unsubstituted or substituted. Examples of such saturated or partially unsaturated heterocyclic radicals include, without limitation, tetrahydrofuranyl, tetrahydropyranyl, thianyl, dioxothianyl, tetrahydrothiophenyl, pyrrolidinyl, piperidinyl, pyrrolinyl, morpholinyl, tetrahydroquinolinyl, tetrahydro- isoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and quinuclidinyl. The terms “heterocycle”, “heterocyclyl”, “heterocyclyl ring”, “heterocyclic group”, “heterocyclic moiety”, and “heterocyclic radical”, are used interchangeably herein, and also include groups in which a heterocyclyl ring is fused to one or more aryl, heteroaryl, or cycloaliphatic rings, such as indolinyl, 3H–indolyl, chromanyl, phenanthridinyl, or tetrahydroquinolinyl, where the radical or point of attachment is on the heterocyclyl ring. A heterocyclyl group is optionally mono–, bi- or tricyclic. The term “heterocyclylalkyl” refers to an alkyl group substituted by a heterocyclyl, wherein the alkyl and heterocyclyl portions independently are unsubstituted or substituted. The term “carbohydrate derived radical” refers to monovalent organic radicals derived from any kind of carbohydrate compounds, such as aldoses and ketosis, as well as polyols, i.e. reduced carbohydrates, and carbohydrate acids, i.e. oxidized carbohydrates, derived from such aldoses and ketosis. The term comprises monovalent radicals of monosaccharides and reduced and oxidized derivatives thereof, including, but not being limted to, D/L-glycerol aldehyde, D-glycerol aldehyde, L-glycerol aldehyde, dihydroxy acetone, D/L- erythrose, D-erythrose, L-erythrose, D/L-threose, D-threose, L-threose, D/L- ribose, D-ribose, L-ribose, D/L-arabinose, D-arabinose, L-arabinose, D/L- xylose, D-xylose, L-xylose, D/L-lyxose, D-lyxose, L-lyxose, D/L-allose, D- allose, L-allose, D/L-altrose, D-altrose, L-altrose, D/L-glucose, D-glucose, L- glucose, D/L-mannose, D-mannose, L-mannose, D/L-gulose, D-gulose, D- gulose, D/L-idose, D-idose, L-idose, D/L-galactose, D-galactose, L-galactose, D/L-talose, D-talose, L-talose, D/L-fructose, D-fructose, L-fructose; D/L- sorbose, D-sorbose, L-sorbose; D/L-sorbit, D-sorbit, L-sorbit, D/L-mannit, D- mannit, L-mannit, D/L-allit, D-allit, L-allit, D/L-galacit, D-galacit, L-galacit, D/L- glucit, D-glucit, L-glucit, D/L-idit, D-idit, L-idit, D/L-altrit, D-altrit, L-altrit; D/L- glucon acid, D-glucon acid, L-glucon acid, D/L-mannon acid, D-mannon acid, L-mannon acid, D/L-allon acid, D-allon acid, L-allon acid, D/L-glucoronic acid, D-glucoronic acid, L-glucoronic acid. It further comprises monovalent radicals of di- and oligosaccharides and their respective reduced and oxidized derivatives, including sucrose, lactose, maltose, cellobiose. These carbohydrate derived radicals may be utilized in their pure D- or L-form or as a mixture of D- and L-form in each ratio possible. Likewise, each of these radicals include their open as well as their cyclic form in pure form or as a mixture in any ratio. Each of these carbohydrate derived radicals may further be substituted by suitable substituents, e.g., halogen, cyano, unsubstituted, mono- or disubstituted amino, C1-6aliphatic, C1-6aliphatoxy, aryl, arylalkyl, and the like. Any carbohydrate derived radical can be attached to its pendant group at any of its hetero or carbon atoms which attachment results in a stable structure or molecule. Examples of carbohydrate derived radicals are D/L- fructose, D-fructose, D/L-glucose, D-glucose, D/L-glucoronic acid, D- glucoronic acid, L-glucoronic acid. The term “bioisostere”, if used alone or in combination with other terms, e.g., “bioisostere radical”, refers to a compound or a group, radical, moiety, substituent and the like, that elicits a similar biological effect as another compound, group, radical, moiety or substituent though they are structurally different to each other. In a broader sense, “bioisosteres” can be understood as compounds or groups that possess near-equal molecular shapes and volumes, approximately the same distribution of electrons, and which exhibit similar physical properties. Typical examples for bioisosteres are carboxylic acid bioisosteres which exhibit similar physico-chemical properties as a carboxylic acid group (“carboxylic acid bioisostere”). Such a carboxylic acid bioisostere group or radical may be utilized in place of a carboxylic acid group or radical thereby providing properties similar to those of the carboxylic group but potentially exhibiting some different properties when compared to the carboxylic acid group, for instance, reduced polarity, increased lipophilicity, or enhanced pharmacokinetic properties. Typical examples of carboxylic acid bioisosteres include, without being limited to, -CN, fluoro, amides, sulfonamides, sulfonimides, and several aromatic and non-aromatic heterocycles such as hydroxy-substituted isoxazoles, sulfonamido-substituted oxadiazoles and oxo-oxadiazoles, e.g., 5‐oxo‐2,5‐dihydro‐1,2,4‐oxadiazol, and in particular tetrazoles, e.g. 1H‐1,2,3,4‐tetrazole, 2-methyl-2H-1,2,3,4- tetrazole. The term “unsaturated”, as used herein, means that a moiety or group or substituent has one or more units of unsaturation. As used herein with reference to any rings, ring systems, ring moieties, and the like, the term “partially unsaturated” refers to a ring moiety that includes at least one double or triple bond. The term “partially unsaturated” is intended to encompass rings having multiple sites of unsaturation. In particular, it encompasses (i) non-saturated (mono-, bi- or tricyclic) ring systems without any aromatic or heteroaromatic moiety or part; and (ii) bi- or tricyclic ring systems in which one of the rings of that system is an aromatic or heteroaromatic ring which is fused with another ring that is neither an aromatic nor a heteroaromatic ring, e.g. tetrahydronaphthyl or tetrahydroquinolinyl. The first class (i) of "partially unsaturated" rings, ring systems, ring moieties may also be referred to as "non-aromatic partially unsaturated" rings, ring systems, ring moieties, while the second class (ii) may be referred to as "partially aromatic" rings, ring systems, ring moieties. As used herein, the term “bicyclic”, “bicyclic ring” or “bicyclic ring system” refers to any bicyclic ring system, i.e. carbocyclic or heterocyclic, saturated or having one or more units of unsaturation, i.e. being partially unsaturated or aromatic, having one or more atoms in common between the two rings of the ring system. Thus, the term includes any permissible ring fusion, such as ortho- fused or spirocyclic. As used herein, the term “heterobicyclic” is a subset of “bicyclic” that requires that one or more heteroatoms are present in one or both rings of the bicycle. Such heteroatoms may be present at ring junctions and are optionally substituted, and may be selected from nitrogen (including N- oxides), oxygen, sulfur (including oxidized forms such as sulfones and sulfonates), phosphorus (including oxidized forms such as phosphates), boron, etc. In some embodiments, a bicyclic group has 7-12 ring members and 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Likewise, the term “tricyclic”, “tricyclic ring” or “tricyclic ring system” refers to any tricyclic ring system, i.e. carbocyclic or heterocyclic, saturated or having one or more units of unsaturation, i.e. being partially unsaturated or aromatic, in which a bicyclic ring system (as defined above) is fused with another, third ring. Thus, the term includes any permissible ring fusion. As used herein, the term “heterotricyclic” is a subset of “tricyclic” that requires that one or more heteroatoms are present in one or both rings of the tricycle. Such heteroatoms may be present at ring junctions and are optionally substituted, and may be selected from nitrogen (including N-oxides), oxygen, sulfur (including oxidized forms such as sulfones and sulfonates), phosphorus (including oxidized forms such as phosphates), boron, etc. In some embodiments, a tricyclic group has 10-14 ring members and 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur. As described herein, certain compounds of the invention contain “substituted” or “optionally substituted” moieties. In general, the term “substituted”, whether preceded by the term “optionally” or not, means that one or more hydrogens of the designated moiety are replaced with a suitable substituent. “Substituted” applies to one or more hydrogens that are either explicit or implicit from the structure. Unless otherwise indicated, a “substituted” or “optionally substituted” group has a suitable substituent at each substitutable position of the group, and when more than one position in any given structure is substituted with more than one substituent selected from a specified group, the substituent is either the same or different at every position. If a certain group, substituent, moiety or radical is "mono-substituted", it bears one (1) substituent. If it is "di- substituted", it bears two (2) substituents, being either the same or different; if it is "tri-substituted", it bears three (3) substituents, wherein all three are the same or two are the same and the third is different or all three are different from each other. Combinations of substituents envisioned by this invention are preferably those that result in the formation of stable or chemically feasible compounds. The term “stable”, as used herein, refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein. If not specified otherwise elsewhere in the specification or the accompanying claims it is understood that each optional substituent on a substitutable carbon is a monovalent substituent independently selected from halogen; –(CH2)0– 4R°; –(CH2)0–4OR°; -O(CH2)0-4Ro, –O–(CH2)0–4C(O)OR°; –(CH2)0–4CH(O R°)2; –(CH2)0–4SR°; –(CH2)0–4Ph, which may be substituted with one or more R°; – (CH2)0–4O(CH2)0–1Ph which may be substituted with one or more R°; – CH=CHPh, which may be substituted with one or more R°; –(CH2)0–4O(CH2)0– 1-pyridyl which may be substituted with one or more R°; –NO2; –CN; – N3; -(CH2)0–4N(R°)2; –(CH2)0–4N(R°)C(O)R°; –N(R°)C(S)R°; –(CH2)0– 4N(R°)C(O)NR°2; -N(R°)C(S)NR°2; –(CH2)0–4N(R°)C(O)OR°; – N(R°)N(R°)C(O)R°; -N(R°)N(R°)C(O)NR°2; -N(R°)N(R°)C(O)OR°; –(CH2)0– 4C(O)R°; –C(S)R°; –(CH2)0–4C(O)OR°; –(CH2)0–4C(O)SR°; -(CH2)0– 4C(O)OSiR°3; –(CH2)0–4OC(O)R°; –OC(O)(CH2)0–4SR–, SC(S)SR°; –(CH2)0– 4SC(O)R°; –(CH2)0–4C(O)NR°2; –C(S)NR°2; –C(S)SR°; –SC(S)SR°, -(CH2)0– 4OC(O)NR°2; -C(O)N(OR°)R°; –C(O)C(O)R°; –C(O)CH2C(O)R°; – C(NOR°)R°; -(CH2)0–4SSR°; –(CH2)0–4S(O)2R°; –(CH2)0–4S(O)2OR°; –(CH2)0– 4OS(O)2R°; –S(O)2NR°2; –S(O)(NR°)R°; –S(O)2N=C(NR°2)2; -(CH2)0– §S(O)R°; -N(R°)S(O)2NR°2; –N(R°)S(O)2R°; –N(OR°) R°; –C(NH)NR°2; – P(O)2R°; -P(O)R°2; -OP(O)R°2; –OP(O)(OR°)2; SiR°3; –( C1-4 straight or branched alkylene)O–N(R°)2; or –(C1-4 straight or branched alkylene)C(O)O– N(R°)2. It is understood that “Ph” means phenyl; and that “–(CH2)0-4” means that there is either no alkylene group if the subscript is “0” (zero) or an alkylene group with 1, 2, 3 or 4 CH2 units. Each R° is independently hydrogen, halogen, C1–6 aliphatic, –CH2Ph, – O(CH2)0–1Ph, -CH2-(5-6 membered heteroaryl ring), or a 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R°, taken together with their intervening atom(s), form a 3–12–membered saturated, partially unsaturated, or aryl mono– or bicyclic ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, which may be substituted by a divalent substituent on a saturated carbon atom of R° selected from =O and =S; or each R° is optionally substituted with a monovalent substituent independently selected from halogen, –(CH2)0–2 R°, –(haloR°), – (CH2)0–2OH, –(CH2)0–2OR°, –(CH2)0–2CH(OR°)2; O(haloR°), –CN, –N3, – (CH2)0–2C(O)R°, –(CH2)0–2C(O)OH, –(CH2)0–2C(O)OR°, –(CH2)0–2SR°, – (CH2)0–2SH, –(CH2)0–2NH2, –(CH2)0–2NHR°, –(CH2)0–2NR°2, –NO2, –SiR°3, – OSiR°3, C(O)SR°, –(C1-4 straight or branched alkylene)C(O)OR°, or –SSR°. It is understood that “Ph” means phenyl; “halo” means halogen; and “–(CH2)0-2” means that there is either no alkylene group if the subscript is “0” (zero) or an alkylene group with 1 or 2 CH2 units. Each R° is independently selected from C1-4 aliphatic, –CH2Ph, –O(CH2)0–1Ph, or a 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and wherein each R° is unsubstituted or where preceded by halo is substituted only with one or more halogens; or wherein an optional substituent on a saturated carbon is a divalent substituent independently selected from =O, =S, =NNR*2, =NNHC(O)R*, =NNHC(O)OR*, =NNHS(O)2R*, =NR*, =NOR*, –O(C(R*2))2–3O– , or –S(C(R*2))2–3S–, or a divalent substituent bound to vicinal substitutable carbons of an “optionally substituted” group is –O(CR*2)2–3O–, wherein each independent occurrence of R* is selected from hydrogen, C1–6 aliphatic or an unsubstituted 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. When R* is C1–6 aliphatic, R* is optionally substituted with halogen, – R°, (haloR°), OH, –OR°, –O(haloR°), –CN, –C(O)OH, –C(O)OR°, –NH2, –NHR°, –NR°2, or –NO2, wherein each R° is independently selected from C1– 4 aliphatic, –CH2Ph, –O(CH2)0–1Ph, or a 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and wherein each R° is unsubstituted or where preceded by halo is substituted only with one or more halogens. An optional substituent on a substitutable nitrogen is independently –R†, – NR†2, –C(O)R†, –C(O)OR†, –C(O)C(O)R†, – C(O)CH2C(O)R†, -S(O)2R†, -S(O)2NR†2, –C(S)NR†2, –C(NH)NR†2, or – N(R†)S(O)2R†; wherein each R† is independently hydrogen, C1–6 aliphatic, unsubstituted –OPh, or an unsubstituted 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, two independent occurrences of R†, taken together with their intervening atom(s) form an unsubstituted 3–12–membered saturated, partially unsaturated, or aryl mono– or bicyclic ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; wherein when R† is C1–6 aliphatic, R† is optionally substituted with halogen, – R°, -(haloR°), -OH, –OR°, –O(haloR°), –CN, –C(O)OH, –C(O)OR°, –NH2, – NHR°, –NR°2, or –NO2, wherein each R° is independently selected from C1– 4 aliphatic, –CH2Ph, –O(CH2)0–1Ph, or a 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and wherein each R° is unsubstituted or where preceded by halo is substituted only with one or more halogens. It is understood that “Ph” means phenyl; and “halo” means halogen. The term “solvates” means addition forms of the compounds of the present invention with solvents, preferably pharmaceutically acceptable solvents that contain either stoichiometric or non-stoichiometric amounts of solvent. Some compounds have a tendency to trap a fixed molar ratio of solvent molecules in the crystalline solid state, thus forming a solvate. If the solvent is water the solvate formed is a hydrate, e.g. a hemi-, mono- or dihydrate. If the solvent is alcohol, the solvate formed is an alcoholate, e.g., a methanolate or ethanolate. If the solvent is an ether, the solvate formed is an etherate, e.g., diethyl etherate. The term "N-oxides" means such compounds of the present invention that contain an amine oxide moiety, i.e. the oxide of a tertiary amine group. The compounds of formulas I-A and I and Table 1c may – also depending on the nature of substituents they may bear – have one or more centers of chirality. They may accordingly occur in various enantiomeric and diastereomeric forms, as the case may be, and be in racemic or optically active form. The invention, therefore, also relates to the optically active forms, enantiomers, racemates, diastereomers, mixtures thereof in all ratios, collectively: “stereoisomers” for the purpose of the present invention, of these compounds. Since the pharmaceutical activity of the racemates or stereoisomers of the compounds according to the invention may differ, it may be desirable to use a specific stereoisomer, e.g. one specific enantiomer or diastereomer. In these cases, a compound according to the present invention obtained as a racemate or even intermediates thereof – may be separated into the stereoisomeric (enantiomeric, diastereoisomeric) compounds by chemical or physical measures known to the person skilled in the art. Another approach that may be applied to obtain one or more specific stereoisomers of a compound of the present invention in an enriched or pure form makes use of stereoselective synthetic procedures, e.g. applying starting material in a stereoisomerically enriched or pure form (for instance using the pure or enriched (R)- or (S)-enantiomer of a particular starting material bearing a chiral center) or utilizing chiral reagents or catalysts, in particular enzymes. In the context of the present invention the term "pure enantiomer" usually refers to a relative purity of one enantiomer over the other (its antipode) of equal to or greater than 95%, preferably ≥ 98 %, more preferably ≥ 98.5%, still more preferably ≥ 99%. Thus, for example, the compounds of the invention which have one or more centers of chirality and which occur as racemates or as mixtures of enantiomers or diastereoisomers can be fractionated or resolved by methods known per se into their optically pure or enriched isomers, i.e. enantiomers or diastereomers. The separation of the compounds of the invention can take place by chromatographic methods, e.g. column separation on chiral or nonchiral phases, or by recrystallization from an optionally optically active solvent or by use of an optically active acid or base or by derivatization with an optically active reagent such as, for example, an optically active alcohol, and subsequent elimination of the radical. In the context of the present invention the term “tautomer” refers to compounds of the present invention that may exist in tautomeric forms and show tautomerism; for instance, carbonyl compounds may be present in their keto and/or their enol form and show keto-enol tautomerism. Those tautomers may occur in their individual forms, e.g., the keto or the enol form, or as mixtures thereof and are claimed separately and together as mixtures in any ratio. The same applies for cis/trans isomers, E/Z isomers, conformers and the like. In one embodiment the compounds of the present invention are in the form of free base or acid – as the case may be -, i.e. in their non-salt (or salt-free) form. In another embodiment the compounds of the present invention are in the form of a pharmaceutically acceptable salt, a pharmaceutically acceptable solvate, or a pharmaceutically acceptable solvate of a pharmaceutically acceptable salt. The term "pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable bases or acids, including inorganic bases or acids and organic bases or acids. In cases where the compounds of the present invention contain one or more acidic or basic groups, the invention also comprises their corresponding pharmaceutically acceptable salts. Thus, the compounds of the present invention which contain acidic groups, such as carboxyl groups, can be present in salt form, and can be used according to the invention, for example, as alkali metal salts, alkaline earth metal salts, aluminium salts or as ammonium salts. More precise examples of such salts include lithium salts, sodium salts, potassium salts, calcium salts, magnesium salts, barium salts or salts with ammonia or organic amines such as, for example, ethylamine, ethanolamine, diethanolamine, triethanolamine, piperdine, N-methylglutamine or amino acids. These salts are readily available, for instance, by reacting the compound having an acidic group with a suitable base, e.g. lithium hydroxide, sodium hydroxide, sodium propoxide, potassium hydroxide, potassium ethoxide, magnesium hydroxide, calcium hydroxide or barium hydroxide. Other base salts of compounds of the present invention include but are not limited to copper(I), copper(II), iron(II), iron (III), manganese(II) and zinc salts. Compounds of the present invention which contain one or more basic groups, e.g. groups which can be protonated, can be present in salt form, and can be used according to the invention in the form of their addition salts with inorganic or organic acids. Examples of suitable acids include hydrogen chloride, hydrogen bromide, hydrogen iodide, phosphoric acid, sulfuric acid, nitric acid, methanesulfonic acid, p- toluenesulfonic acid, naphthalenedisulfonic acid, sulfoacetic acid, trifluoroacetic acid, oxalic acid, acetic acid, tartaric acid, lactic acid, salicylic acid, benzoic acid, carbonic acid, formic acid, propionic acid, pivalic acid, diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, malonic acid, maleic acid, malic acid, embonic acid, mandelic acid, sulfaminic acid, phenylpropionic acid, gluconic acid, ascorbic acid, isonicotinic acid, citric acid, adipic acid, taurocholic acid, glutaric acid, stearic acid, glutamic acid or aspartic acid, and other acids known to the person skilled in the art. The salts which are formed are, inter alia, hydrochlorides, chlorides, hydrobromides, bromides, iodides, sulfates, phosphates, methanesulfonates (mesylates), tosylates, carbonates, bicarbonates, formates, acetates, sulfoacetates, triflates, oxalates, malonates, maleates, succinates, tartrates, malates, embonates, mandelates, fumarates, lactates, citrates, glutarates, stearates, aspartates and glutamates. The stoichiometry of the salts formed from the compounds of the invention may moreover be an integral or non-integral multiple of one. Compounds of the present invention which contain basic nitrogen-containing groups can be quaternized using agents such as (C1-C4)alkyl halides, for example methyl, ethyl, isopropyl and tert-butyl chloride, bromide and iodide; di(C1-C4)alkyl sulfates, for example dimethyl, diethyl and diamyl sulfate; (C10- C18)alkyl halides, for example decyl, dodecyl, lauryl, myristyl and stearyl chloride, bromide and iodide; and aryl(C1-C4)alkyl halides, for example benzyl chloride and phenethyl bromide. Both water- and oil-soluble compounds according to the invention can be prepared using such salts. If the compounds of the present invention simultaneously contain acidic and basic groups in the molecule, the invention also includes, in addition to the salt forms mentioned, inner salts or betaines (zwitterions). The respective salts can be obtained by customary methods which are known to a person skilled in the art, for example by contacting these with an organic or inorganic acid or base in a solvent or dispersant, or by anion exchange or cation exchange with other salts. The present invention also includes all salts of the compounds of the present invention which, owing to low physiological compatibility, are not directly suitable for use in pharmaceuticals but which can be used, for example, as intermediates for chemical reactions or for the preparation of pharmaceutically acceptable salts. Therefore, the following items are also in accordance with the invention: (a) all stereoisomers or tautomers of the compounds, including mixtures thereof in all ratios; (b) pharmaceutically acceptable salts of the compounds and of the items mentioned under (a); (c) pharmaceutically acceptable solvates of the compounds and of the items mentioned under (a) and (b); (d) N-oxides of the compounds and of the items mentioned under (a), (b), and (c). It should be understood that all references to compounds above and below are meant to include these items, in particular pharmaceutically acceptable solvates of the compounds, or pharmaceutically acceptable solvates of their pharmaceutically acceptable salts. There is furthermore intended that a compound of the present invention includes isotope-labelled forms thereof. An isotope-labelled form of a compound of the formula I or I-A or Table 1c is identical to this compound apart from the fact that one or more atoms of the compound have been replaced by an atom or atoms having an atomic mass or mass number which differs from the atomic mass or mass number of the atom which usually occurs naturally. Examples of isotopes which are readily commercially available and which can be incorporated into a compound of the present invention by well-known methods include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, for example 2H (D), 3H, 13C, 14C, 15N, 18O, 17O, 31P, 32P, 33S, 34S, 35S, 36S, 18F and 36CI, respectively. A compound of formula I or I- A or Table 1c or a pharmaceutically acceptable salt thereof which contains one or more of the above-mentioned isotopes and/or other isotopes of other atoms is intended to be part of the present invention. An isotope-labelled compound of formula I or I-A or Table 1c can be used in a number of beneficial ways. For example, an isotope-labelled compound of the present invention into which, for example, a radioisotope, such as 3H or 14C, has been incorporated is suitable for medicament and/or substrate tissue distribution assays. These radioisotopes, i.e. tritium (3H) and carbon-14 (14C), are particularly preferred owing to simple preparation and excellent detectability. Incorporation of heavier isotopes, for example deuterium (2H), into a compound of formula I or I-A or Table 1c has therapeutic advantages owing to the higher metabolic stability of this isotope-labelled compound. Higher metabolic stability translates directly into an increased in vivo half-life or lower dosages, which under most circumstances would represent a preferred embodiment of the present invention. An isotope-labelled compound of formula I or I-A or Table 1c can usually be prepared by carrying out the procedures disclosed in the synthesis schemes and the related description, in the example part and in the preparation part in the present text, replacing a non-isotope-labelled reactant by a readily available isotope-labelled reactant. Deuterium (2H; D) can also be incorporated into a compound of formula I-A or I or Table 1c for the purpose of manipulating the oxidative metabolism of the compound by way of the primary kinetic isotope effect. The primary kinetic isotope effect is a change of the rate for a chemical reaction that results from exchange of isotopic nuclei, which in turn is caused by the change in ground state energies necessary for covalent bond formation after this isotopic exchange. Exchange of a heavier isotope usually results in a lowering of the ground state energy for a chemical bond and thus cause a reduction in the rate in rate-limiting bond breakage. If the bond breakage occurs in or in the vicinity of a saddle-point region along the coordinate of a multi-product reaction, the product distribution ratios can be altered substantially. For explanation: if deuterium is bonded to a carbon atom at a non-exchangeable position, rate differences of kM/kD = 2-7 are typical. If this rate difference is successfully applied to a compound of the formula I or I-A or Table 1c that is susceptible to oxidation, the profile of this compound in vivo can be drastically modified and result in improved pharmacokinetic properties. When discovering and developing therapeutic agents, the person skilled in the art attempts to optimize pharmacokinetic parameters while retaining desirable in vitro properties. It is reasonable to assume that many compounds with poor pharmacokinetic profiles are susceptible to oxidative metabolism. In vitro liver microsomal assays currently available provide valuable information on the course of oxidative metabolism of this type, which in turn permits the rational design of deuterated compounds of the formula I or I-A or Table 1c with improved stability through resistance to such oxidative meta-bolism. Significant improvements in the pharmacokinetic profiles of compounds of the formula I or I-A or Table 1c are thereby obtained, and can be expressed quantitatively in terms of increases in the in vivo half-life (t1/2), concentration at maximum therapeutic effect (Cmax), area under the dose response curve (AUC), and F; and in terms of reduced clearance, dose and materials costs. The following is intended to illustrate the above: a compound of formula I or I- A or Table 1c which has multiple potential sites of attack for oxidative metabolism, for example benzylic hydrogen atoms and hydrogen atoms bonded to a nitrogen atom, is prepared as a series of analogues in which various combinations of hydrogen atoms are replaced by deuterium atoms, so that some, most or all of these hydrogen atoms have been replaced by deuterium atoms. Half-life determinations enable favourable and accurate determination of the extent of the extent to which the improvement in resistance to oxidative metabolism has improved. In this way, it is deter-mined that the half-life of the parent compound can be extended by up to 100% as the result of deuterium-hydrogen exchange of this type. Deuterium-hydrogen exchange in a compound of the present invention can also be used to achieve a favourable modification of the metabolite spectrum of the starting compound in order to diminish or eliminate undesired toxic metabolites. For example, if a toxic metabolite arises through oxidative carbon- hydrogen (C-H) bond cleavage, it can reasonably be assumed that the deuterated analogue will greatly diminish or eliminate production of the unwanted metabolite, even if the particular oxidation is not a rate-determining step. Further information on the state of the art with respect to deuterium- hydrogen exchange may be found, for example in Hanzlik et al., J. Org. Chem. 55, 3992-3997, 1990, Reider et al., J. Org. Chem. 52, 3326-3334, 1987, Foster, Adv. Drug Res.14, 1-40, 1985, Gillette et al, Biochemistry 33(10) 2927- 2937, 1994, and Jarman et al. Carcinogenesis 16(4), 683-688, 1995. Furthermore, the present invention relates to pharmaceutical compositions comprising a compound of formula I or I-A or Table 1c, or its N-oxides, solvates, tautomers or stereoisomers thereof as well as the pharmaceutically acceptable salts of each of the foregoing, including mixtures thereof in all ratios, as active ingredient and a pharmaceutically acceptable carrier. For the purpose of the present invention the term “pharmaceutical composition” (or “pharmaceutical formulation”) refers to a composition or product comprising one or more active ingredients, and one or more inert ingredients that make up the carrier, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients. Accordingly, the pharmaceutical compositions of the present invention encompass any composition made by admixing at least one compound of the present invention and a pharmaceutically acceptable carrier. It may further comprise physiologically acceptable excipients, auxiliaries, adjuvants, diluents and/or additional pharmaceutically active substance other than the compounds of the invention. The pharmaceutical compositions include compositions and pharmaceutical formulations suitable for oral, rectal, topical, parenteral (including subcutaneous, intramuscular, and intravenous), ocular (ophthalmic), pulmonary (nasal or buccal inhalation), or nasal administration, although the most suitable route in any given case will depend on the nature and severity of the conditions being treated and on the nature of the active ingredient. They may be conveniently presented in unit dosage form and prepared by any of the methods well-known in the art of pharmacy. A pharmaceutical composition of the present invention may additionally comprise one or more other compounds as active ingredients (drugs), such as one or more additional compounds of the present invention. In a particular embodiment the pharmaceutical composition further comprises a second active ingredient or its derivatives, prodrugs, solvates, tautomers or stereoisomers thereof as well as the pharmaceutically acceptable salts of each of the foregoing, including mixtures thereof in all ratios, wherein that second active ingredient is other than a compound of formula I and I-A and/or claim 1(i.e., Table 1c); preferably, that second active ingredient is a compound that is useful in the treatment, prevention, suppression and/or amelioration of medicinal conditions or pathologies for which the compounds of the present invention are useful as well and which are listed elsewhere hereinbefore or hereinafter. Such combination of two or more active ingredients or drugs may be safer or more effective than either drug or active ingredient alone, or the combination is safer or more effective than it would be expected based on the additive properties of the individual drugs. Such other drug(s) may be administered, by a route and in an amount commonly used contemporaneously or sequentially with a compound of the invention. When a compound of the invention is used contemporaneously with one or more other drugs or active ingredients, a combination product containing such other drug(s) and the compound of the invention – also referred to as “fixed dose combination” – is preferred. However, combination therapy also includes therapies in which the compound of the present invention and one or more other drugs are administered on different overlapping schedules. It is contemplated that when used in combination with other active ingredients, the compound of the present invention or the other active ingredient or both may be used effectively in lower doses than when each is used alone. Accordingly, the pharmaceutical compositions of the present invention include those that contain one or more other active ingredients, in addition to a compound of the invention. The compounds of the present invention – or N-oxides, solvates, tautomers or stereoisomers thereof and/or the pharmaceutically acceptable salts of each of the foregoing, including mixtures thereof in all ratios – can be used as medicaments. They have been found to exhibit pharmacological activity by binding to TEAD and/or disrupting and/or inhibiting YAP-TEAD and/or TAZ- TEAD protein-protein interaction. It is assumed that by this activity the compounds of the present invention may prevent or reverse dysfunction of the Hippo pathway. By preventing its dysfunction, the Hippo pathway may be capable of playing its role as a tumor suppressor. Apart from preventing or reversing dysfunction of the Hippo pathway and independent of upstream Hippo regulation, the pharmacological activity of the compounds of the present invention may also be useful in other pathophysiological scenarios where inhibition or disruption of TEAD binding and/or aberrant YAP-TEAD and/or aberrant TAZ-TEAD signaling would be beneficial. Thus, the compounds of the present invention being TEAD binders and/or inhibitors of YAP-TEAD and/or TAZ-TEAD interaction are useful in particular in the treatment, prevention, suppression and/or amelioration of hyperproliferative disorders and cancer, in particular tumors including solid tumors, of breast cancer, lung cancer, mesothelioma, epithelioid hemangioendothelioma, uveal melanoma, liver cancer, ovarian cancer, squamous cancer, renal cancer, gastric cancer, medulloblastoma, colon cancer, pancreatic cancer, schwannoma, meningioma, glioma, basal cell carcinoma. Without wishing to commit to any specific theory or explanation it may be assumed that the compounds might be able to achieve this by direct effects on the cancer cells and/or indirectly by modulating the response of the immune system against the tumor. Furthermore, the compounds of the present invention may also be useful in the treatment, prevention, suppression and/or amelioration of non-cancerous disorders and diseases, e.g. cardiovascular diseases and fibrosis (like liver fibrosis). In a particular embodiment the compounds of the present invention are for use in the prevention and/or treatment, especially in the treatment of any of the disorders or diseases listed above, preferably of cancer, in particular tumors including solid tumors, of the specific types of cancer disclosed in the previous paragraph; or of any of the non-cancerous disorders or diseases disclosed in the previous paragraph. Another particular embodiment of the present invention is a method for preventing and/or treating, preferably treating a disorder or disease selected from the group consisting of hyperproliferative disorders and cancer, in particular tumors including solid tumors, of the specific types of cancer disclosed in the previous paragraphs; or of any of the non-cancerous disorders or diseases disclosed in the previous paragraphs. Still another particular embodiment of the invention is the use of a compound of the present invention – or derivatives, N-oxides, prodrugs, solvates, tautomers or stereoisomers thereof and/or the pharmaceutically acceptable salts of each of the foregoing, including mixtures thereof in all ratios – for the manufacturing of a medicament, in particular for preventing and/or treating, preferably treating a disorder or disease selected from the group consisting of hyperproliferative disorders and cancer, in particular tumors including solid tumors, of the specific types of cancer disclosed in the previous paragraphs; or of any of the non-cancerous disorders or diseases disclosed in the previous paragraphs. Preferably, the present invention relates to a compound of the present invention for use in the prevention and/or treatment of a disease – or, alternatively, a method for preventing and/or treating a disease by administering an effective amount of a compound of the present invention ; or, in another alternative, a use of a compound of the present invention for the manufacturing of a medicament for the prevention and/or treatment of a disease – wherein that disease is a cancer, in particular tumors including solid tumors, of the specific types of cancer disclosed in the previous paragraphs; and more preferably, wherein administration of the compound is simultaneous, sequential or in alternation with administration of at least one other active drug agent. The disclosed compounds of formula I or I-A or Table 1c can be administered in combination with other known therapeutic agents, including anticancer agents. As used here, the term "anticancer agent" relates to any agent which is administered to a patient with cancer for the purposes of treating the cancer. The anti-cancer treatment defined above may be applied as a monotherapy or may involve, in addition to the herein disclosed compounds of formula I-A or I or Table 1c, conventional surgery or radiotherapy or medicinal therapy. Such medicinal therapy, e.g. a chemotherapy or a targeted therapy, may include one or more, but preferably one, of the following anti-tumor agents: Alkylating agents such as altretamine, bendamustine, busulfan, carmustine, chlorambucil, chlormethine, cyclophosphamide, dacarbazine, ifosfamide, improsulfan, tosilate, lomustine, melphalan, mitobronitol, mitolactol, nimustine, ranimustine, temozolomide, thiotepa, treosulfan, mechloretamine, carboquone; apaziquone, fotemustine, glufosfamide, palifosfamide, pipobroman, trofosfamide, uramustine, evofosfamide, VAL-083[4]; Platinum Compounds such as carboplatin, cisplatin, eptaplatin, miriplatine hydrate, oxaliplatin, lobaplatin, nedaplatin, picoplatin, satraplatin; DNA altering agents such as amrubicin, bisantrene, decitabine, mitoxantrone, procarbazine, trabectedin, clofarabine; amsacrine, brostallicin, pixantrone, laromustine[1],[3]; Topoisomerase Inhibitors such as etoposide, irinotecan, razoxane, sobuzoxane, teniposide, topotecan; amonafide, belotecan, elliptinium acetate, voreloxin; Microtubule modifiers such as cabazitaxel, docetaxel, eribulin, ixabepilone, paclitaxel, vinblastine, vincristine, vinorelbine, vindesine, vinflunine; fosbretabulin, tesetaxel; Antimetabolites such as asparaginase[3], azacitidine, calcium levofolinate, capecitabine, cladribine, cytarabine, enocitabine, floxuridine, fludarabine, fluorouracil, gemcitabine, mercaptopurine, methotrexate, nelarabine, pemetrexed, pralatrexate, azathioprine, thioguanine, carmofur; doxifluridine, elacytarabine, raltitrexed, sapacitabine, tegafur[2],[3], trimetrexate; Anticancer antibiotics such as bleomycin, dactinomycin, doxorubicin, epirubicin, idarubicin, levamisole, miltefosine, mitomycin C, romidepsin, streptozocin, valrubicin, zinostatin, zorubicin, daunurobicin, plicamycin; aclarubicin, peplomycin, pirarubicin; Hormones/Antagonists such as abarelix, abiraterone, bicalutamide, buserelin, calusterone, chlorotrianisene, degarelix, dexamethasone, estradiol, fluocortolone, fluoxymesterone, flutamide, fulvestrant, goserelin, histrelin, leuprorelin, megestrol, mitotane, nafarelin, nandrolone, nilutamide, octreotide, prednisolone, raloxifene, tamoxifen, thyrotropin alfa, toremifene, trilostane, triptorelin, diethylstilbestrol; acolbifene, danazol, deslorelin, epitiostanol, orteronel, enzalutamide [1],[3]; Aromatase inhibitors such as aminoglutethimide, anastrozole, exemestane, fadrozole, letrozole, testolactone; formestane; Small molecule kinase inhibitors such as crizotinib, dasatinib, erlotinib, imatinib, lapatinib, nilotinib, pazopanib, regorafenib, ruxolitinib, sorafenib, sunitinib, vandetanib, vemurafenib, bosutinib, gefitinib, axitinib; afatinib, alisertib, dabrafenib, dacomitinib, dinaciclib, dovitinib, enzastaurin, nintedanib, lenvatinib, linifanib, linsitinib, masitinib, midostaurin, motesanib, neratinib, orantinib, perifosine, ponatinib, radotinib, rigosertib, tepotinib, tipifarnib, tivantinib, tivozanib, trametinib, pimasertib, brivanib alaninate, cediranib, apatinib[4], cabozantinib S- malate[1],[3], ibrutinib[1],[3], icotinib[4], buparlisib[2], cipatinib[4], cobimetinib[1],[3], idelalisib[1],[3], fedratinib[1],tesevatinib; Photosensitizers such as methoxsalen[3]; porfimer sodium, talaporfin, temoporfin; Antibodies such as alemtuzumab, besilesomab, brentuximab vedotin, cetuximab, denosumab, ipilimumab, ofatumumab, panitumumab, rituximab, tositumomab, trastuzumab, bevacizumab, pertuzumab[2],[3]; catumaxomab, elotuzumab, epratuzumab, farletuzumab, mogamulizumab, necitumumab, nimotuzumab, obinutuzumab, ocaratuzumab, oregovomab, ramucirumab, rilotumumab, siltuximab, tocilizumab, zalutumumab, zanolimumab, matuzumab, dalotuzumab[1],[2],[3], onartuzumab[1],[3], racotumomab[1], tabalumab[1],[3], EMD- 525797[4], atezolizumab, durvalumab, pembrolizumab, nivolumab[1],[3]; Cytokines such as aldesleukin, interferon alfa2, interferon alfa2a[3], interferon alfa2b[2],[3]; celmoleukin, tasonermin, teceleukin, oprelvekin[1],[3], recombinant interferon beta-1a[4]; Drug Conjugates such as denileukin diftitox, ibritumomab tiuxetan, iobenguane I 123, prednimustine, trastuzumab emtansine, estramustine, gemtuzumab, ozogamicin, aflibercept; cintredekin besudotox, edotreotide, inotuzumab ozogamicin, naptumomab estafenatox, oportuzumab monatox, technetium (99mTc) arcitumomab[1],[3], vintafolide[1],[3]; Vaccines such as sipuleucel[3]; vitespen[3], emepepimut-S[3], oncoVAX[4], rindopepimut[3], troVax[4], MGN-1601[4], MGN-1703[4]; Miscellaneous alitretinoin, bexarotene, bortezomib, everolimus, ibandronic acid, imiquimod, lenalidomide, lentinan, metirosine, mifamurtide, pamidronic acid, pegaspargase, pentostatin, sipuleucel[3], sizofiran, tamibarotene, temsirolimus, thalidomide, tretinoin, vismodegib, zoledronic acid, vorinostat; celecoxib, cilengitide, entinostat, etanidazole, ganetespib, idronoxil, iniparib, ixazomib, lonidamine, nimorazole, panobinostat, peretinoin, plitidepsin, pomalidomide, procodazol, ridaforolimus, tasquinimod, telotristat, thymalfasin, tirapazamine, tosedostat, trabedersen, ubenimex, valspodar, gendicine[4], picibanil[4], reolysin[4], retaspimycin hydrochloride[1],[3], trebananib[2],[3], virulizin[4], carfilzomib[1],[3], endostatin[4], immucothel[4], belinostat[3]; PARP inhibitors Olaparib, Veliparib. MCT1 inhibitors AZD3965[4], BAY-8002[4]. [1] Prop. INN (Proposed International Nonproprietary Name) [2] Rec. INN (Recommended International Nonproprietary Names) [3] USAN (United States Adopted Name) [4] no INN. In another aspect of the invention, a set or kit is provided comprising a therapeutically effective amount of at least one compound of the invention and/or at least one pharmaceutical composition as described herein and a therapeutically effective amount of at least one further pharmacologically active substance other than the compounds of the invention. It is preferred that this set or kit comprises separate packs of a) an effective amount of a compound of Table 1c, or any pharmaceutically acceptable salt thereof, and b) an effective amount of a further active ingredient that further active ingredient not being a compound of Table 1c. A further embodiment of the present invention is a process for the manufacture of the pharmaceutical compositions of the present invention, characterized in that one or more compounds according to the invention and one or more compounds selected from the group consisting of solid, liquid or semiliquid excipients, auxiliaries, adjuvants, diluents, carriers and pharmaceutically active agents other than the compounds according to the invention, are converted in a suitable dosage form. The pharmaceutical compositions (formulations) of the present invention may be administered by any means that achieve their intended purpose. For example, administration may be via oral, parenteral, topical, enteral, intravenous, intramuscular, inhalant, nasal, intraarticular, intraspinal, transtracheal, transocular, subcutaneous, intraperitoneal, transdermal, or buccal routes. Alternatively, or concurrently, administration may be via the oral route. The dosage administered will be dependent upon the age, health, and weight of the recipient, kind of concurrent treatment, if any, frequency of treatment, and the nature of the effect desired. Parenteral administration is preferred. Oral administration is especially preferred. Suitable dosage forms include, but are not limited to capsules, tablets, pellets, dragees, semi-solids, powders, granules, suppositories, ointments, creams, lotions, inhalants, injections, cataplasms, gels, tapes, eye drops, solution, syrups, aerosols, suspension, emulsion, which can be produced according to methods known in the art, for example as described below: Tablets: mixing of active ingredient/s and auxiliaries, compression of said mixture into tablets (direct compression), optionally granulation of part of mixture before compression. Capsules: mixing of active ingredient/s and auxiliaries to obtain a flowable powder, optionally granulating powder, filling powders/granulate into opened capsules, capping of capsules. Semi-solids (ointments, gels, creams): dissolving/dispersing active ingredient/s in an aqueous or fatty carrier; subsequent mixing of aqueous/fatty phase with complementary fatty/ aqueous phase, homogenization (creams only). Suppositories (rectal and vaginal): dissolving/dispersing active ingredient/s in carrier material liquified by heat (rectal: carrier material normally a wax; vaginal: carrier normally a heated solution of a gelling agent), casting said mixture into suppository forms, annealing and withdrawal suppositories from the forms. Aerosols: dispersing/dissolving active agent/s in a propellant, bottling said mixture into an atomizer. In general, non-chemical routes for the production of pharmaceutical compositions and/or pharmaceutical preparations comprise processing steps on suitable mechanical means known in the art that transfer one or more compounds of the invention into a dosage form suitable for administration to a patient in need of such a treatment. Usually, the transfer of one or more compounds of the invention into such a dosage form comprises the addition of one or more compounds, selected from the group consisting of carriers, excipients, auxiliaries and pharmaceutical active ingredients other than the compounds of the invention. Suitable processing steps include, but are not limited to combining, milling, mixing, granulating, dissolving, dispersing, homogenizing, casting and/or compressing the respective active and nonactive ingredients. Mechanical means for performing said processing steps are known in the art, for example from Ullmann's Encyclopedia of Industrial Chemistry, 5th Edition. In this respect, active ingredients are preferably at least one compound of the invention and optionally one or more additional compounds other than the compounds of the invention, which show valuable pharmaceutical properties, preferably those pharmaceutical active agents other than the compounds of the invention, which are disclosed herein. Particularly suitable for oral use are tablets, pills, coated tablets, capsules, powders, granules, syrups, juices or drops, suitable for rectal use are suppositories, suitable for parenteral use are solutions, preferably oil-based or aqueous solutions, furthermore suspensions, emulsions or implants, and suitable for topical use are ointments, creams or powders. The compounds of the invention may also be lyophilized and the resultant lyophilizates used, for example, for the preparation of injection preparations. The preparations indicated may be sterilized and/or comprise assistants, such as lubricants, preservatives, stabilizers and/or wetting agents, emulsifiers, salts for modifying the osmotic pressure, buffer substances, dyes, flavors and/or a plurality of further active ingredients, for example one or more vitamins. Suitable excipients are organic or inorganic substances, which are suitable for enteral (for example oral), parenteral or topical administration and do not react with the compounds of the invention, for example water, vegetable oils, benzyl alcohols, alkylene glycols, polyethylene glycols, glycerol triacetate, gelatin, carbohydrates, such as lactose, sucrose, mannitol, sorbitol or starch (maize starch, wheat starch, rice starch, potato starch), cellulose preparations and/or calcium phosphates, for example tricalcium phosphate or calcium hydrogen phosphate, magnesium stearate, talc, gelatin, tragacanth, methyl cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, polyvinyl pyrrolidone and/or vaseline. If desired, disintegrating agents may be added such as the above-mentioned starches and also carboxymethyl-starch, cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof, such as sodium alginate. Auxiliaries include, without limitation, flow-regulating agents and lubricants, for example, silica, talc, stearic acid or salts thereof, such as magnesium stearate or calcium stearate, and/or polyethylene glycol. Dragee cores are provided with suitable coatings, which, if desired, are resistant to gastric juices. For this purpose, concentrated saccharide solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, polyethylene glycol and/or titanium dioxide, lacquer solutions and suitable organic solvents or solvent mixtures. In order to produce coatings resistant to gastric juices or to provide a dosage form affording the advantage of prolonged action, the tablet, dragee or pill can comprise an inner dosage and an outer dosage component the latter being in the form of an envelope over the former. The two components can be separated by an enteric layer, which serves to resist disintegration in the stomach and permits the inner component to pass intact into the duodenum or to be delayed in release. A variety of materials can be used for such enteric layers or coatings, such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, acetyl alcohol, solutions of suitable cellulose preparations such as acetyl-cellulose phthalate, cellulose acetate or hydroxypropylmethyl-cellulose phthalate, are used. Dye stuffs or pigments may be added to the tablets or dragee coatings, for example, for identification or in order to characterize combinations of active compound doses. Suitable carrier substances are organic or inorganic substances which are suitable for enteral (e.g. oral) or parenteral administration or topical application and do not react with the novel compounds, for example water, vegetable oils, benzyl alcohols, polyethylene glycols, gelatin, carbohydrates such as lactose or starch, magnesium stearate, talc and petroleum jelly. In particular, tablets, coated tablets, capsules, syrups, suspensions, drops or suppositories are used for enteral administration, solutions, preferably oily or aqueous solutions, furthermore suspensions, emulsions or implants, are used for parenteral administration, and ointments, creams or powders are used for topical application. The compounds of the invention can also be lyophilized and the lyophilizates obtained can be used, for example, for the production of injection preparations. Other pharmaceutical preparations, which can be used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer such as glycerol or sorbitol. The push-fit capsules can contain the active compounds in the form of granules, which may be mixed with fillers such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In soft capsules, the active compounds are preferably dissolved or suspended in suitable liquids, such as fatty oils, or liquid paraffin. In addition, stabilizers may be added. The liquid forms in which the novel compositions of the present invention may be incorporated for administration orally include aqueous solutions, suitably flavored syrups, aqueous or oil suspensions, and flavored emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil or peanut oil, as well as elixirs and similar pharmaceutical vehicles. Suitable dispersing or suspending agents for aqueous suspensions include synthetic and natural gums such as tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinyl-pyrrolidone or gelatin. Suitable formulations for parenteral administration include aqueous solutions of the active compounds in water-soluble form, for example, water-soluble salts and alkaline solutions. In addition, suspensions of the active compounds as appropriate oily injection suspensions may be administered. Suitable lipophilic solvents or vehicles include fatty oils, for example, sesame oil, or synthetic fatty acid esters, for example, ethyl oleate or triglycerides or polyethylene glycol-400 (the compounds are soluble in PEG-400). Aqueous injection suspensions may contain substances, which increase the viscosity of the suspension, including, for example, sodium carboxymethyl cellulose, sorbitol, and/or dextran, optionally, the suspension may also contain stabilizers. For administration as an inhalation spray, it is possible to use sprays in which the active ingredient is either dissolved or suspended in a propellant gas or propellant gas mixture (for example CO2 or chlorofluorocarbons). The active ingredient is advantageously used here in micronized form, in which case one or more additional physiologically acceptable solvents may be present, for example ethanol. Inhalation solutions can be administered with the aid of conventional inhalers. Possible pharmaceutical preparations, which can be used rectally include, for example, suppositories, which consist of a combination of one or more of the active compounds with a suppository base. Suitable suppository bases are, for example, natural or synthetic triglycerides, or paraffin hydrocarbons. In addition, it is also possible to use gelatin rectal capsules, which consist of a combination of the active compounds with a base. Possible base materials include, for example, liquid triglycerides, polyethylene glycols, or paraffin hydrocarbons. The pharmaceutical preparations can be employed as medicaments in human and veterinary medicine. As used herein, the term "effective amount" means that amount of a drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system, animal or human that is being sought, for instance, by a researcher or clinician. Furthermore, the term also includes within its scope a "therapeutically effective amount" which means any amount which, as compared to a corresponding subject who has not received such amount, results in improved treatment, healing, prevention, or amelioration of a disease, disorder, or side effect, or a decrease in the rate of advancement of a disease or disorder, or of symptoms associated with such disease or disorder; it may also refer to preventing or providing prophylaxis for the disease or disorder in a subject having or at risk for developing a disease disclosed herein. The term also includes within its scope amounts effective to enhance normal physiological function. Said therapeutic effective amount of one or more of the compounds of the invention is known to the skilled artisan or can be easily determined by standard methods known in the art. "Treating" or “treatment” as used herein, means an alleviation, in whole or in part, of symptoms associated with a disorder or disease, or slowing, or halting of further progression or worsening of those symptoms, or prevention or prophylaxis of the disease or disorder in a subject at risk for developing the disease or disorder. The compounds of the present invention and the optional additional active substances are generally administered analogously to commercial preparations. Usually, suitable doses that are therapeutically effective lie in the range between 0.0005 mg and 1000 mg, preferably between 0.005 mg and 500 mg and especially between 0.5 mg and 100 mg per dose unit. The daily dose is preferably between about 0.001 mg/kg and 10 mg/kg of body weight. Those of skill will readily appreciate that dose levels can vary as a function of the specific compound, the severity of the symptoms and the susceptibility of the subject to side effects. Some of the specific compounds are more potent than others. Preferred dosages for a given compound are readily determinable by those of skill in the art by a variety of means. A preferred means is to measure the physiological potency of a given compound. The specific dose for the individual patient, in particular for the individual human patient, depends, however, on the multitude of factors, for example on the efficacy of the specific compounds employed, on the age, body weight, general state of health, the sex, the kind of diet, on the time and route of administration, on the excretion rate, the kind of administration and the dosage form to be administered, the pharmaceutical combination and severity of the particular disorder to which the therapy relates. The specific therapeutic effective dose for the individual patient can readily be determined by routine experimentation, for example by the doctor or physician, which advises or attends the therapeutic treatment. The compounds of the present invention can be prepared according to the procedures of the following Schemes and Examples, using appropriate materials, and as further exemplified by the following specific examples. They may also be prepared by methods known per se, as described in the literature (for example in standard works, such as Houben-Weyl, Methoden der Organischen Chemie [Methods of Organic Chemistry], Georg Thieme Verlag, Stuttgart; Organic Reactions, John Wiley & Sons, Inc., New York), to be precise under reaction conditions which are known and suitable for the said reactions. Use can also be made of variants which are known per se, but are not mentioned here in greater detail. Likewise, the starting materials for the preparation of compounds of the present invention can be prepared by methods as described in the examples or by methods known per se, as described in the literature of synthetic organic chemistry and known to the skilled person, or can be obtained commercially. The starting materials for the processes claimed and/or utilized may, if desired, also be formed in situ by not isolating them from the reaction mixture, but instead immediately converting them further into the compounds of the invention or intermediate compounds. On the other hand, in general it is possible to carry out the reaction stepwise. Preferably, the reaction of the compounds is carried out in the presence of a suitable solvent, which is preferably inert under the respective reaction conditions. Examples of suitable solvents comprise but are not limited to hydrocarbons, such as hexane, petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons, such as trichlorethylene, 1,2-dichloroethane, tetrachloromethane, chloroform or dichloromethane; alcohols, such as methanol, ethanol, isopropanol, n-propanol, n-butanol or tert-butanol; ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF) or dioxane; glycol ethers, such as ethylene glycol monomethyl or monoethyl ether or ethylene glycol dimethyl ether (diglyme); ketones, such as acetone or butanone; amides, such as acetamide, dimethylacetamide, dimethylformamide (DMF) or N-methyl pyrrolidinone (NMP); nitriles, such as acetonitrile; sulfoxides, such as dimethyl sulfoxide (DMSO); nitro compounds, such as nitromethane or nitrobenzene; esters, such as ethyl acetate, or mixtures of the said solvents or mixtures with water. The reaction temperature is between about -100°C and 300°C, depending on the reaction step and the conditions used. Reaction times are generally in the range between a fraction of a minute and several days, depending on the reactivity of the respective compounds and the respective reaction conditions. Suitable reaction times are readily determinable by methods known in the art, for example reaction monitoring. Based on the reaction temperatures given above, suitable reaction times generally lie in the range between 10 minutes and 48 hours. Moreover, by utilizing the procedures described herein, in conjunction with ordinary skills in the art, additional compounds of the present invention claimed herein can be readily prepared. The compounds illustrated in the examples are not, however, to be construed as forming the only genus that is considered as the invention. The examples further illustrate details for the preparation of the compounds of the present invention. Those skilled in the art will readily understand that known variations of the conditions and processes of the following preparative procedures can be used to prepare these compounds. The present invention also refers to a process for manufacturing a compound of formula I or I-A or Table 1c in its most general form as well as any of the particular embodiments, PE0, PE0a, PE0b, PE1, PE1a, PE1b, PE2, PE2a, PE2b, PE3, PE3a, PE3b, PE4, PE4a, PE5, PE5a, PE5aa PE5b,PE5bb, PE5c, PE6, PE7, PE8, PE9, PE9a, PE10, PE10a, PE10aa, PE10b, PE10bb, PE10c, PE10cc, PE11, PE11a, PE11b, PE11c, PE12, PE12a, PE12b, PE12c, PE12d, PE13, PE14, PE14a, PE14b described herein, or N-oxides, solvates, tautomers or stereoisomers thereof as well as the pharmaceutically acceptable salts of each of the foregoing, the process being characterized in that either (a) a compound of formula II-a or II-A-a
Figure imgf000140_0001
wherein Z1, Z2, Z3, ring A and R2 are as defined for the compound of formula I or I-A above and in the claims wherein R2 is not -C(=O)-OH or -C(=O)-OCat; is either (a) (1) reacted with a compound of formula III R1-Hal III, wherein R1 is as defined for the compound of formula I or I-A above or in any of the claims and Hal represents Cl, Br or I, in a C-N cross coupling reaction under suitable reaction conditions; or (a) (2) is first converted into the tricyclic compound of formula IV or IV-A
Figure imgf000140_0002
in a C-N cross coupling reaction under suitable reaction conditions; and then reacted with a compound of formula III R1-Hal III, in another C-N cross coupling reaction under suitable reaction conditions; to provide (a) (3) a compound of formula I or I-A as defined above or in any of the claims; and optionally (a) (4) if in the compound of formula I or I-A R2 is -C(=O)-OR2a with R2a being unsubstituted or substituted C1-8-aliphatic, then this compound of formula I or I-A is subjected to a saponification reaction under suitable conditions to provide the respective compound of formula I or I-A with R2 being -C(=O)-OH or -C(=O)-OCat; or (b) a compound of formula II-b or II-A-b
Figure imgf000141_0001
wherein Z1, Z2, Z3, ring A and R2 are as defined for the compound of formula I or I-A above or in any of the claims wherein R2 is not -C(=O)-OH or -C(=O)- OCat; (b) (1) is reacted with a compound of formula V
Figure imgf000141_0002
wherein R1 is as defined for the compound of formula I or I-A above or in any of the claims, in a C-N cross coupling reaction under suitable reaction conditions to provide a compound of formula I or I-A as defined above or in any of the claims; and optionally (b) (2) if in the compound of formula I or I-A R2 is -C(=O)-OR2a with R2a being unsubstituted or substituted C1-8-aliphatic, then this compound of formula I or I-A is subjected to a saponification reaction under suitable conditions to provide the respective compound of formula I or I-A with R2 being -C(=O)-OH or -C(=O)-OCat. As will be understood by the person skilled in the art of organic synthesis compounds of the present invention, in particular compounds of formula I and I-A and Table 1c, are readily accessible by various synthetic routes, some of which are exemplified in the accompanying Experimental Part. The skilled artisan will easily recognize which kind of reagents and reactions conditions are to be used and how they are to be applied and adapted in any particular instance – wherever necessary or useful – in order to obtain the compounds of the present invention. Furthermore, some of the compounds of the present invention can readily be synthesized by reacting other compounds of the present invention under suitable conditions, for instance, by converting one particular functional group being present in a compound of the present invention, or a suitable precursor molecule thereof, into another one by applying standard synthetic methods, like reduction, oxidation, addition or substitution reactions; those methods are well known to the skilled person. Likewise, the skilled artisan will apply – whenever necessary or useful – synthetic protecting (or protective) groups; suitable protecting groups as well as methods for introducing and removing them are well-known to the person skilled in the art of chemical synthesis and are described, in more detail, in, e.g., P.G.M. Wuts, T.W. Greene, “Greene’s Protective Groups in Organic Synthesis”, 4th edition (2006) (John Wiley & Sons). In the following general synthetic routes that may be utilized to prepare compounds of the present invention are described in more detail in Schemes A, A-A, B and B-A below:
Figure imgf000143_0001
Scheme A (Z1, Z2, R1, R2 and ring A are as defined for formula I above and in the claims.)
Figure imgf000143_0002
c Scheme A-A (Z1, Z2, Z3, R1, R2 and ring A are as defined for formula I-A above and in the claims.) It will be understood that the following explanation of Scheme A also applies analogously to Scheme A-A; instead of compounds B, D, E, and I Scheme A- A and its explanation refer to compounds B-A, D-A, E-A, and I-A. The synthetic procedures and method utilized are the same in Schemes A and A-A. Scheme A above depicts a general synthesis route for preparing tricyclic hetereocycles of formula I and Table 1c. In reaction step a the boronic acid B – which is readily available, for instance, by first reacting the respective bromo- substituted aryl or heteroaryl with a suitable organometallic base like n-butyl lithium and subsequent reaction with a suitable boron acid ester like B(OCH3)3 – is reacted with the 1-amino-2-bromo-substituted heterocycle C under typical C-C cross coupling conditions, e.g., under conditions typical for Suzuki cross coupling reactions (for instance, reacting a solution of B and C in a suitable solvent like 1,4-dioxane with cesium carbonate in the presence of a Palladium catalyst like Pd(dppf)2Cl2 (1,1'-Bis(diphenylphosphino)ferrocene]palladium(II) dichloride)) to yield compound D. It is understood that ring A in that 1-amino- 2-bromo-substituted heterocycle C has the same meaning as “ring A” for the compound of the present invention of formula I, i.e. is selected from the five- membered heteroaromatic rings A-1 to A-24 as defined above and in the claims. For instance, if ring A is selected to be ring A-1, then the respective compound C would have the following formula C-1:
Figure imgf000144_0001
Compound D may then be subjected to an intra-molecular C-N cross-coupling reaction (step b), for instance, under conditions typical for a Hartwig-Buchwald reaction (e.g., reaction with cesium carbonate in a suitable solvent like 1,4- dioxane in the presence of a suitable palladium catalyst like di-tert- butyl[2',4',6'-tris(propan-2-yl)-[1,1'-biphenyl]-2-yl]phosphane {2'-amino-[1,1'- biphenyl]-2-yl}palladiumylium methanesulfonate) to yield the tricyclic heterocycle E. This heterocycle E may then in turn be reacted with the bromide R1-Br in another C-N coupling reaction (step c) under similar conditions, for instance with cesium carbonate in the presence of a suitable palladium catalyst (e.g., Chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′- amino-1,1′-biphenyl)]palladium(II), X-Phos aminobiphenyl palladium chloride, XPhosPd G2) to provide the compound of the present invention of formula I. Depending on the nature of the various substituent R1, R2 and on ring A, this compound of formula I may optionally converted into further compounds of formula I. For instance, if R2 is a carboxylic ester (-C(=O)-OR2a), then this ester may be subjected to a saponification reaction using suitable acids or bases thereby providing either the respective carboxylic acid (R2 = -C(=O)-OH) or a salt thereof (e.g., R2 = -C(=O)-OCat with Cat being Li, Na, K or NH4). In some instances compound D as shown in Scheme A above (and D-A in Scheme A-A) – instead of being subjected to the subsequent reaction steps b and c, i.e. two consecutive C-N coupling reactions – may be reacted with a suitable compound R1-Br under C-N coupling reactions (with as suitable base like cesium carbonate or sodium hydride in the presence of a suitable palladium catalyst) to directly provide the respective compound of formula I (or I-A in Scheme A-A or Table 1c). Furthermore, it is well understood that starting from compound E compounds of formula I (or from compound E-A compounds of formula I-A) may be synthesized by utilizing suitable reaction partners other than the bromo- substituted compound R1-Br under suitable reaction conditions. For instance, if R1 is chosen to be L1-Ar or L1-Hetar1 with L1 being -S(=O)2-, then compound E may be reacted with the respective thionyl chloride under suitable reaction conditions to yield the respective sulfonyl derivative of formula I (or I-A). It will also be recognized that reaction step a in Schemes A and A-A may also be performed by utilizing a suitably substituted five-memberd ring A bearing a boronic acid or boronic acid ester instead of compound C and a suitably substituted six-membered (hetero)aromatic ring bearing a bromo substituent instead of compound B (or B-A) providing compound D (or D-A).
Figure imgf000146_0001
Scheme B (Z1, Z2, R1, R2 and ring A are as defined for formula I above and in the claims.)
Figure imgf000147_0001
Scheme B-A (Z1, Z2, Z3, R1, R2 and ring A are as defined for formula I-A above and in the claims.) It will be understood that the following explanation of Scheme B also applies analogously to Scheme B-A; instead of compounds B, G, and I Scheme B-A and its explanation refers to compounds B-A, G-A, and I-A. The synthetic procedures and method utilized are the same in Schemes B and B-A. Scheme B above depicts another synthetic route for making compounds of the present invention. Here the boronic acid B (or a suitable boronic acid ester) is reacted in a C-C cross-coupling reaction under similar conditions described for step a in Scheme A with the 1-chloro-2-iodo-substituted heterocycle F (step d) which reaction yields the dichloro-substituted compound G. Compound G may then be converted in a C-N coupling reaction with the primary amine R1-NH2 (step e) in the presence of a suitable base like cesium carbonate and a suitable palladium catalyst (as described for Scheme A) into the desired compound of formula I (or I-A for Scheme B-A). It will also be recognized that reaction step a in Schemes B and B-A may also be performed by utilizing a suitably substituted five-memberd ring A bearing a boronic acid or boronic acid ester instead of compound F and a suitably substituted six-membered (hetero)aromatic ring bearing an iodo substituent instead of compound B (or B-A) providing compound D (or D-A). It is to be noted that – except for instances where it is specifically stated or the context provides for a different meaning – in general the number of a term, i.e. its singular and plural form, is used and can be read interchangeably. For example, the term “compound” in its singular form may also comprise or refer to a plurality of compounds, while the term “compounds” in its plural form may also comprise or refer to a singular compound. Examples and Experimental Part The compounds of the present invention can be prepared according to the procedures of the following Schemes and Examples, using appropriate materials and are further exemplified by the following specific examples. The compounds are shown in Table 1. Analytical data of compounds made according to the following examples are shown in Table 1, too. The invention will be illustrated, but not limited, by reference to the specific embodiments described in the following examples. Unless otherwise indicated in the schemes, the variables have the same meaning as described above and in the claims. Unless otherwise specified, all starting materials are obtained from commercial suppliers and used without further purifications. Unless otherwise specified, all temperatures are expressed in °C and all reactions are conducted at room temperature (RT). Compounds are purified by either silica chromatography or preparative HPLC. 1H NMR: 1H-NMR data is provided in Table 1 below. 1H NMR spectra were usually acquired on a Bruker Avance DRX 500, Bruker Avance 400. a Bruker DPX 300 or a Bruker Avance III 700 MHz (equipped with a TXI cryoprobe) NMR spectrometer under standard conditions using TMS (tetramethylsilane) as internal reference and DMSO-d6 as standard solvents, if not reported otherwise. NS (Number of Scans): 32, SF (Spectrometer Frequency) as indicated. TE (Temperature): 297 K. Chemical shifts (δ) are reported in ppm relative to the TMS signal.1H NMR data are reported as follows: chemical shift (multiplicity, coupling constants and number of hydrogens). Multiplicity is abbreviated as follows: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), dd (doublet of doublets), tt (triplet of triplets), td (triplet of doublets) br (broad) and coupling constants (J) are reported in Hz. LC-MS: LC-MS data provided in Table 1 are given with mass in m/z. The results can be obtained by one of the methods described below. Syntheses Example 1: 4-(benzenesulfonyl)-2-benzyl-2H,4H-pyrrolo[3,4-b]indole-7- carboxylic acid Example 1-1: Synthesis of 1-(benzenesulfonyl)-5-bromo-2,3-dimethyl-1H- indole
Figure imgf000149_0001
To a suspension of NaH (1.70 g; 42.50 mmol) in DMF (50 ml) was added 5- bromo-2,3-dimethyl-1H-indole (6.25 g; 27.89 mmol) in DMF (50 ml) at 0°C slowly. The yellow brown mixture was stirred at 0°C for 1 h, then benzenesulfonyl chloride (6 g; 34 mmol) was added at 0°C. After that, the mixture was stirred at 25°C for 2 hours. The reaction was poured into water (500 mL) and extracted with EA (100 mL) for three times. The organic layer was washed with brine (50 mL), dried over Na2SO4, filtered and concentrated to give a residue. The residue was purified by silica gel column chromatography (petroleum ether/EA = 4:1) to give the desired product. (7.20 g; 71 %; pink solid). 1H NMR (400 MHz, CDCl3) δ 8.06 (d, J = 8.4 Hz, 1H), 7.73 - 7.70 (m, 2H), 7.55 - 7.52 (m, 1H), 7.49 (d, J = 2.0 Hz, 1H), 7.44 - 7.40 (m, 2H), 7.36 (dd, J = 8.8, 2.0 Hz, 1H), 2.51 (s, 3H), 2.09 (s, 3H). Example 1-2: Synthesis of product 1-(benzenesulfonyl)-5-bromo-2,3- bis(bromomethyl)-1H-indole
Figure imgf000150_0001
To a solution of 1-(benzenesulfonyl)-5-bromo-2,3-dimethyl-1H-indole (6.40 g; 17.57 mmol) in CCl4 (120 ml) was added 1-bromopyrrolidine-2,5-dione (6.40 g; 36 mmol) and 2-[2-(1-cyano-1-methylethyl)diazen-1-yl]-2-methylpropane- nitrile (288 mg; 1.75 mmol) at 80°C. The yellow brown mixture was stirred at 80°C under 1 bar of nitrogen balloon for 3 hours. The reaction was filtered and the filtrate was concentrated to give the crude product (8.15 g; 81 %; yellow brown solid). 1H NMR (400 MHz, CDCl3) δ 8.00 (d, J = 5.6 Hz, 1H), 7.93 - 7.90 (m, 2H), 7.75 (d, J = 2.0 Hz, 1H), 7.61 - 7.58 (m, 1H), 7.50 - 7.45 (m, 3H), 5.08 (s, 2H), 4.59 (s, 2H). Example 1-3: Synthesis of 4-(benzenesulfonyl)-2-benzyl-7-bromo- 1H,2H,3H,4H-pyrrolo[3,4-b]indole
To a solution of 1-(benzenesulfonyl)-5-bromo-2,3-bis(bromomethyl)-1H-indole (8.15 g; 14.21 mmol) and K2CO3 (6.68 g; 48.34 mmol) in THF (190 mL) was added 1-phenylmethanamine (1.52 g; 14.19 mmol) in THF (280 mL) at 80°C slowly. The yellow brown mixture was stirred at 80°C under 1 bar of nitrogen balloon for 16 hours. The reaction was filtered and the filtrate was concentrated to give a residue. The residue was purified by silica gel column chromatography (dichloromethane/EA = 5:1) to give the desired product. (3.16 g; 41 %; yellow brown solid). 1H NMR (400 MHz, CDCl3) δ 7.85 - 7.79 (m, 3H), 7.57 - 7.53 (m, 1H), 7.46 - 7.24 (m, 9H), 4.28 - 4.26 (m, 2H), 4.01 (s, 2H), 3.91 - 3.89 (m, 2H). Example 1-4: Synthesis of methyl 4-(benzenesulfonyl)-2-benzyl- 1H,2H,3H,4H-pyrrolo[3,4-b]indole-7-carboxylate
Figure imgf000151_0001
To a solution of 4-(benzenesulfonyl)-2-benzyl-7-bromo-1H,2H,3H,4H- pyrrolo[3,4-b]indole (1.50 g; 2.73 mmol), tris(dibenzylideneacetone)- dipalladium (300 mg; 0.33 mmol) and 4,5-Bis(diphenylphosphino)-9,9- dimethylxanthene (190 mg; 0.33 mmol) in DMF (10 ml) and MeOH (10 ml) was added potassium acetate (900 mg; 9.17 mmol) at 25°C. The black brown mixture was stirred at 90°C under 1 bar of methanidylidyneoxidanium balloon for 16 hours. The reaction was poured into water (50 mL) and extracted with EA (30 mL) for three times. The organic layers were concentrated to give a residue. The residue was purified by silica gel column chromatography (petroleum ether/EA = 5:1) to give the desired product. (510 mg; 39.8 %; yellow brown solid). 1H NMR (400 MHz, CDCl3) δ 8.03 - 8.01 (m, 2H), 7.97 - 7.94 (m, 1H), 7.86 - 7.84 (m, 2H), 7.57 - 7.55 (m, 1H), 7.48 - 7.44 (m, 3H), 7.40 - 7.37 (m, 3H), 7.33 - 7.32 (m, 1H), 4.31 (s, 2H), 4.05 (s, 2H), 3.98 (s, 2H), 3.90 (s, 3H). Example 1-5: Synthesis of methyl 4-(benzenesulfonyl)-2-benzyl-2H,4H- pyrrolo[3,4-b]indole-7-carboxylate
Figure imgf000152_0001
To a solution of methyl 4-(benzenesulfonyl)-2-benzyl-1H,2H,3H,4H- pyrrolo[3,4-b]indole-7-carboxylate (84 mg; 0.19 mmol) in Toluene (2 ml) was added 4,5-dichloro-3,6-dioxocyclohexa-1,4-diene-1,2-dicarbonitrile (43 mg; 0.19 mmol) at 25°C. The yellow brown mixture solution was stirred at 25°C for 3 hours. The reaction was filtered and the filtrate was concentrated to give the crude product (60 mg; 67 %; yellow brown solid). Example 1-6: Synthesis of 4-(benzenesulfonyl)-2-benzyl-2H,4H-pyrrolo[3,4- b]indole-7-carboxylic acid (Compound 1)
Figure imgf000152_0002
To a solution of methyl 4-(benzenesulfonyl)-2-benzyl-2H,4H-pyrrolo[3,4- b]indole-7-carboxylate (50 mg; 0.11 mmol) in iPrOH (3 ml) and Water (0.6 ml) was added NaOH (13 mg; 0.33 mmol) at 25°C. The yellow brown mixture was stirred at 70°C for 16 hours. The reaction was diluted with water (20 mL) and extracted with ethyl acetate (20 mL) three times. The combined organic layer was concentrated to give a residue. The residue was purified by C- 18 column (ACN:water = 10 % - 95 %) to give the desired product in 55 % yield (25 mg; off-white solid). 1H NMR (400 MHz, DMSO-d6) δ 12.86 (brs, 1H), 8.15 (d, J = 1.6 Hz, 1H), 8.03 - 8.01 (m, 1H), 7.90 - 7.87 (m, 1H), 7.80 - 7.78 (m, 2H), 7.63 - 7.61 (m, 1H), 7.49 - 7.45 (m, 2H), 7.38 - 7.35 (m, 2H), 7.32 - 7.27 (m, 2H), 7.24 - 7.22 (m, 3H), 5.31 (s, 2H). Example 2: 2-methyl-8-[4-(trifluoromethyl)phenyl]-2H,8H-pyrazolo[3,4- b]indole-5-carboxylic acid Example 2-1: Synthesis of ethyl 3-(3-amino-1-methyl-1H-pyrazol-4-yl)-4- chlorobenzoate
Figure imgf000153_0001
To a suspension of 2-chloro-5-(ethoxycarbonyl)phenyl]boronic acid (500 mg; 2.19 mmol) in dioxane (4 ml) and water (0.4 ml) was added 4-bromo-1-methyl- 1H-pyrazol-3-amine (385 mg; 2.19 mmol), K2CO3 (605 mg; 4.38 mmol) and Pd(dppf)Cl2 (160 mg). The mixture was stirred at 60°C under N2 atmosphere for 6h. The mixture was poured into water (5 ml), and then extracted with EA (6 ml*3). The combined organic phase was collected and evaporated under vacuum. The residue was purified by C18 column chromatography (ACN/H20 = 5% - 95%) and the purified product could be obtained (500 mg; 74 %; white powder). 1H NMR (400 MHz, DMSO) ^ 8.07 (d, J = 2.1 Hz, 1H), 7.77 (dd, J = 8.4, 2.2 Hz, 1H), 7.67 (s, 1H), 7.63 (d, J = 8.4 Hz, 1H), 4.58 (s, 2H), 4.32 (q, J = 7.1 Hz, 2H), 3.66 (s, 3H), 1.31 (t, J = 7.1 Hz, 3H). Example 2-2: Synthesis of ethyl 2-methyl-2H,8H-pyrazolo[3,4-b]indole-5- carboxylate To a suspension of ethyl 3-(3-amino-1-methyl-1H-pyrazol-4-yl)-4-chloro- benzoate (300 mg; 1.1 mmol) in dioxane (15 ml) was added di-tert- butyl[2',4',6'-tris(propan-2-yl)-[1,1'-biphenyl]-2-yl]phosphane {2'-amino-[1,1'- biphenyl]-2-yl}palladiumylium methanesulfonate (85 mg; 0.11 mmol) and Cs2CO3 (699 mg; 2.14 mmol). The mixture was stirred at 120°C under N2 atmosphere for 6h. The mixture was poured into water (5 ml), and then extracted with EA (6 ml*3). The combined organic phase was collected and evaporated under vacuum. The residue was purified by C18 column chromatography (ACN/H20 = 5% - 95%) and the purified product could be obtained. (110 mg; 42 %; white solid). 1H NMR (400 MHz, DMSO) δ 8.31 (d, J = 1.7 Hz, 1H), 8.03 (s, 1H), 7.83 (dd, J = 8.5, 1.8 Hz, 1H), 7.32 (d, J = 8.5 Hz, 1H), 4.31 (q, J = 7.1 Hz, 2H), 3.97 (s, 3H), 1.34 (t, J = 7.1 Hz, 3H). Example 2-3: Synthesis of ethyl 2-methyl-8-[4-(trifluoromethyl)phenyl]-2H,8H- pyrazolo[3,4-b]indole-5-carboxylate
Figure imgf000154_0001
A sealed tube was charged with ethyl 2-methyl-2H,8H-pyrazolo[3,4-b]indole- 5-carboxylate (85 mg; 0.35 mmol),1-bromo-4-(trifluoromethyl)benzene (102 mg; 0.45 mmol), XPhosPd G2 (17 mg; 0.02 mmol) and Cs2CO3 (342 mg; 1.05 mmol) in dioxane (5 ml). The mixture was stirred under N2 at 100°C for 2h. The mixture was fittered and concentrated to get crude product as a black oil. The crude product was purifited by C18 (ACN/H2O = 5% - 95%) to get the product as a white solid. (92 mg; 62 %; white solid). 1H NMR (400 MHz, DMSO) δ 8.45 (d, J = 1.5 Hz, 1H), 8.23 (s, 1H), 8.08 (d, J = 8.5 Hz, H), 7.98 (d, J = 8.6 Hz, 2H), 7.93 (d, J = 1.8 Hz, 1H), 7.80 (d, J = 8.7 Hz, 1H), 4.35 (d, J = 7.1 Hz, 2H), 4.04 (s, 3H), 1.36 (t, J = 7.1 Hz, 2H). Example 2-4: Synthesis of 2-methyl-8-[4-(trifluoromethyl)phenyl]-2H,8H- pyrazolo[3,4-b]indole-5-carboxylic acid
Figure imgf000155_0001
To a solution of ethyl 2-methyl-8-[4-(trifluoromethyl)phenyl]-2H,8H- pyrazolo[3,4-b]indole-5-carboxylate (90 mg; 0.21 mmol) in MeOH (40 ml) was added an aqueous solution of 1M sodium hydroxide (1 ml). The mixture was stirred under N2 at 60°C for 6h. The mixture was concentrated and adjusted by 1N hydrochloric acid to pH=1~2. The mixture was purified by C18 (0.1% TFA/H2O = 20% - 95%) to get the product. (59 mg; 73 %; white solid). 1H NMR (400 MHz, DMSO) δ 12.74 (s, 1H), 8.43 (d, J = 1.7 Hz, 1H), 8.22 (s, 1H), 8.08 (d, J = 8.5 Hz, 2H), 7.98 (d, J = 8.6 Hz, 2H), 7.93 (dd, J = 8.7, 1.8 Hz, 1H), 7.78 (d, J = 8.7 Hz, 1H), 4.03 (s, 3H). Example 3: 2-Benzyl-4-phenyl-2H,4H-pyrrolo[3,4-b]indole-7-carboxylic acid Example 3-1: Synthesis of methyl 2-benzyl-1H,2H,3H,4H-pyrrolo[3,4-b]indole- 7-carboxylate
Figure imgf000156_0001
To a solution of methyl 4-(benzenesulfonyl)-2-benzyl-1H,2H,3H,4H- pyrrolo[3,4-b]indole-7-carboxylate (460 mg; 1 mmol) (see Example 1-4) in MeOH (20 ml) was added Cs2CO3 (2.68 g; 8.23 mmol) at 25°C. The yellow brown mixture was stirred at 30°C for 16 hours. The reaction was poured into water (100 mL) and extracted with EA (30 mL) for three times. The organic layers were concentrated to give a residue. The residue was purified by C18 (ACN/H2O = 10 % - 95 %) to give the desired product. (200 mg; 67 %; yellow brown solid). Example 3-2_ Synthesis of methyl 2-benzyl-4-phenyl-1H,2H,3H,4H- pyrrolo[3,4-b]indole-7-carboxylate
Figure imgf000156_0002
To a suspension of methyl 2-benzyl-1H,2H,3H,4H-pyrrolo[3,4-b]indole-7- carboxylate (170 mg; 0.55 mmol), iodobenzene (140 mg; 0.69 mmol) and copper iodide (17 mg; 0.1 mmol) in DMSO (5 ml) was added (2S)-pyrrolidine- 2-carboxylic acid (17 mg; 0.15 mmol) and K2CO3 (150 mg; 1.1 mmol) at 25°C. The black brown mixture was stirred at 110°C under 1 bar of nitrogen balloon for 16 hours. The reaction was poured into water (30 mL) and extracted with EA (10 mL) for three times. The combined organic layers were concentrated to give a residue. The residue was purified by silica gel chromatography (petroleum ether/EA = 10:1) to give the desired product. (200 mg; 91 %; yellow brown gel). Example 3-3: Synthesis of methyl 2-benzyl-4-phenyl-2H,4H-pyrrolo[3,4- b]indole-7-carboxylate
Figure imgf000157_0001
To a solution of methyl 2-benzyl-4-phenyl-1H,2H,3H,4H-pyrrolo[3,4-b]indole- 7-carboxylate (170 mg; 0.43 mmol.) in toluene (5 ml) was added 4,5-dichloro- 3,6-dioxocyclohexa-1,4-diene-1,2-dicarbonitrile (100 mg; 0.44 mmol) at 25°C. The yellow brown mixture was stirred at 25°C for 3 hours. The reaction was filtered and concentrated to give a residue. The residue was purified by silica gel column chromatography (petroleum ether/EA = 10:1) to give the desired product. (34 mg; 20 %; yellow brown gel). Example 3-4: Synthesis of 2-benzyl-4-phenyl-2H,4H-pyrrolo[3,4-b]indole-7- carboxylic acid
Figure imgf000157_0002
To a solution of methyl 2-benzyl-4-phenyl-2H,4H-pyrrolo[3,4-b]indole-7- carboxylate (34 mg; 0.1 mmol) in EtOH (5 ml) and H2O (1 ml) was added NaOH (35 mg; 0.9 mmol) at 25°C. The yellow brown mixture was stirred at 70°C for 16 hours. The reaction was concentrated and water was added (5 mL). The water phase was adjusted to pH ~ 5 and extracted with EA (10 mL) for three times. The combined organic layers were concentrated to give a residue. The residue was purified by C18 column (ACN/H2O = 10 % - 95 %) to give the desired product. (17 mg; 53 %; greyish green solid). 1H NMR (400 MHz, DMSO-d6) δ 12.48 (s, 1H), 8.33 (d, J = 1.6 Hz, 1H), 7.84 - 7.82 (m, 1H), 7.68 - 7.66 (m, 2H), 7.60 - 7.55 (m, 3H), 7.39 - 7.27 (m, 7H), 6.98 (d, J = 1.6 Hz, 1H), 5.30 (s, 2H). Example 4: 2-methyl-4-[4-(trifluoromethyl)phenyl]-2H,4H-pyrazolo[4,3- b]indole-7-carboxylic acid Example 4-1: Synthesis of ethyl 3-(4-amino-1-methyl-1H-pyrazol-3-yl)-4- chlorobenzoate
Figure imgf000158_0001
The mixture of 2-chloro-5-(ethoxycarbonyl)phenyl]boronic acid (1.20 g; 5.20 mmol), 3-bromo-1-methyl-1H-pyrazol-4-amine (915 mg; 5.20 mmol), Cs2CO3 (3.4 g; 10.40 mmol) and Pd(dppf)Cl2 (380 mg; 0.52 mmol) in dioxane (20 ml) and water (2 ml) was stirred under N2 atmosphere at 90°C for 16h. The mixture was filtered and concentrated to get crude product as a black oil. The crude was purified by C18 (ACN/H2O = 20% - 95%) to get the product. (355 mg; 23 %; light brown oil). 1H NMR (400 MHz, DMSO) δ 7.97 (d, J = 2.2 Hz, 1H), 7.92 ¨C 7.87 (m, 1H), 7.67 (d, J = 8.4 Hz, 1H), 7.17 (s, 1H), 4.32 (d, J = 7.1 Hz, 2H), 3.76 (s, 3H), 1.32 (t, J = 7.1 Hz, 3H). Example 4-2: Synthesis of ethyl 2-methyl-2H,4H-pyrazolo[4,3-b]indole-7- carboxylate
Figure imgf000158_0002
A sealed tube was charged with ethyl 3-(4-amino-1-methyl-1H-pyrazol-3-yl)-4- chlorobenzoate (350 mg; 1.24 mmol), di-tert-butyl[2',4',6'-tris(propan-2-yl)- [1,1'-biphenyl]-2-yl]phosphane {2'-amino-[1,1'-biphenyl]-2-yl}palladiumylium methanesulfonate (120 mg; 0.15 mmol) and Cs2CO3 (807 mg; 2.48 mmol) in dioxane (20 ml).The mixture was stirred under N2 at 120°C for 16h. The LCMS showed starting materials were not gone. Di-tert-butyl[2',4',6'-tris(propan-2-yl)- [1,1'-biphenyl]-2-yl]phosphane {2'-amino-[1,1'-biphenyl]-2-yl}palladiumylium methanesulfonate (120 mg; 0.15 mmol) was added to the mixture and stirring was continued at 140°C for 24h. The mixture was filtered and concentrated to get crude product as a black oil. The crude product was purified by C18 (ACN/H2O = 5% - 95%) to get the product. (50 mg; 23 %; white powder). 1H NMR (400 MHz, DMSO) δ 10.71 (s, 1H), 8.38 (d, J = 1.6 Hz, 1H), 7.89 (dd, J = 8.6, 1.7 Hz, 1H), 7.71 (s, 1H), 7.39 (d, J = 8.6 Hz, 1H), 4.32 (t, J = 7.1 Hz, 2H), 4.05 (s, 3H), 1.35 (dd, J = 9.9, 4.3 Hz, 3H). Example 4-3: Synthesis of ethyl 2-methyl-4-[4-(trifluoromethyl)phenyl]-2H,4H- pyrazolo[4,3-b]indole-7-carboxylate
Figure imgf000159_0001
A sealed tube was charged with ethyl 2-methyl-2H,4H-pyrazolo[4,3-b]indole- 7-carboxylate (65 mg; 0.25 mmol), 1-bromo-4-(trifluoromethyl)benzene (72 mg; 0.32 mmol), XPhosPd G2 (12 mg; 0.01 mmol) and Cs2CO3 (240 mg; 0.74 mmol) in dioxane (4 ml). The mixture was stirred under N2 at 100°C for 2h. The mixture was fittered and concentrated to get crude product as a black oil. The crude product was purified by C18 (ACN/H2O = 5% - 95%) to get product as a white powder. (80 mg; 76 %; white powder). 1H NMR (400 MHz, DMSO) δ 8.48 (d, J = 1.6 Hz, 1H), 8.12 (s, 1H), 8.01 (dd, J = 8.8, 1.7 Hz, 1H), 7.94 (s, 4H), 7.88 (d, J = 8.8 Hz, 1H), 4.36 (q, J = 7.1 Hz, 2H), 4.10 (s, 3H), 1.37 (t, J = 7.1 Hz, 3H). Example 4-4: Synthesis of 2-methyl-4-[4-(trifluoromethyl)phenyl]-2H,4H- pyrazolo[4,3-b]indole-7-carboxylic acid
Figure imgf000160_0001
To a solution of ethyl 2-methyl-4-[4-(trifluoromethyl)phenyl]-2H,4H- pyrazolo[4,3-b]indole-7-carboxylate (80 mg; 0.19 mmol) in EtOH (4 ml) was added 1M sodium hydroxide aqueous solution (1 ml).The mixture was stirred at 60°C for 1.5h. The mixture was concentrated and adjusted by 1N hydrochloric acid (1ml) to pH=1~2. The mixture was purified by HPLC to get 2-methyl-4-[4-(trifluoromethyl)phenyl]-2H,4H-pyrazolo[4,3-b]indole-7- carboxylic acid (40 mg; 59 %; white solid). 1H NMR (400 MHz, DMSO) δ 8.44 (d, J = 1.4 Hz, 1H), 8.10 (s, 1H), 7.99 (d, J = 1.7 Hz, 1H), 7.94 (s, 4H), 7.84 (d, J = 8.8 Hz, 1H), 4.10 (s, 3H). Example 5: 2-Methyl-8-{[4-(trifluoromethyl)phenyl]methyl}-2H,8H- pyrazolo[3,4-b]indole-5-carboxylic acid Example 5-1: Synthesis of ethyl 2-methyl-8-{[4-(trifluoromethyl)phenyl]- methyl}-2H,8H-pyrazolo[3,4-b]indole-5-carboxylate
Figure imgf000160_0002
To a solution of ethyl 2-methyl-2H,8H-pyrazolo[3,4-b]indole-5-carboxylate (220 mg; 0.81 mmol) in DMF (3 ml) was added NaH (49 mg; 2.04 mmol) at 0°C. The solution was stirred at 0°C for 30 minutes and then 1-(bromomethyl)- 4-(trifluoromethyl)benzene (230 mg; 0.96 mmol) was added. The solution was stirred at 25°C for 3 hours. The reaction mixture was filtered by filter membrane. The filtrate was purified by C-18 column (acetonitrile : water = 5 % to 95 %) to obtain the desired purified product (260 mg; 79 %; off-white solid). 1H NMR (400 MHz, CDCl3) δ 8.44 (d, J = 1.6 Hz, 1H), 7.98 (dd, J = 8.4, 1.6 Hz, 1H), 7.66 (s, 1H), 7.53 (d, J = 8.4 Hz, 2H), 7.34 (d, J = 8.0 Hz, 2H), 7.12 (d, J = 8.4 Hz, 1H), 5.44 (s, 2H), 4.39 (q, J = 7.2 Hz, 2H), 4.06 (s, 3H), 1.41 (t, J = 7.2 Hz, 3H). Example 5-2: Synthesis of 2-methyl-8-{[4-(trifluoromethyl)phenyl]methyl}- 2H,8H-pyrazolo[3,4-b]indole-5-carboxylic acid
Figure imgf000161_0001
To a solution of ethyl 2-methyl-8-{[4-(trifluoromethyl)phenyl]methyl}-2H,8H- pyrazolo[3,4-b]indole-5-carboxylate (120 mg; 0.30 mmol) in EtOH (40 ml) and Water (1 ml) was added NaOH (36 mg; 0.90 mmol) at 25°C. The yellow brown solution was stirred at 70°C for 3 hours. The solution was concentrated. To the resulting residue water (5 mL) was added. The water phase was adjusted to pH ~ 3 by 1N hydrochloric acid aqueous solution (5 drops) and concentrated. The resulting residue was suspended in pure water (10 mL) and filtered. The filter residue was washed three times with water (5 mL) and concentrated to obtain the desired purified product. (101 mg; 88 %; off-white solid). 1H NMR (400 MHz, DMSO-d6) δ 12.49 (s, 1H), 8.34 (d, J = 1.6 Hz, 1H), 8.10 (s, 1H), 7.85 (dd, J = 8.8, 1.6 Hz, 1H), 7.68 (d, J = 8.4 Hz, 2H), 7.51 - 7.43 (m, 3H), 5.52 (s, 2H), 3.99 (s, 3H). Example 6: 2-Methyl-8-[3-(trifluoromethyl)phenyl]-2H,8H-pyrazolo[3,4- b]indole-5-carboxylic acid Example 6-1: Synthesis of ethyl 2-methyl-8-[3-(trifluoromethyl)phenyl]-2H,8H- pyrazolo[3,4-b]indole-5-carboxylate
Figure imgf000162_0001
Ethyl 3-(3-amino-1-methyl-1H-pyrazol-4-yl)-4-chlorobenzoate (200 mg; 0.64 mmol), 1-bromo-3-(trifluoromethyl)benzene (174 mg; 0.77 mmol), XPhosPd G2 (56 mg; 0.07 mmol) and Cs2CO3 (629 mg; 1.93 mmol) were suspended in Dioxane-1,4 (10 ml). The mixture was stirred under N2 atmosphere at 120 °C for 16h. The mixture was filtered. The organic phase was concentrated and purifited by silica gel (PE/EA = 10:1) to obtain the purified product as an off- white solid. (230 mg; 88 %). 1H NMR (400 MHz, DMSO) δ 8.45 (s, 1H), 8.22 (s, 1H), 8.17 ¨C 8.08 (m, 2H), 7.94 (d, J = 8.7 Hz, 1H), 7.86 (d, J = 7.9 Hz, 1H), 7.76 (d, J = 7.8 Hz, 1H), 7.68 (d, J = 8.8 Hz, 1H), 4.35 (q, J = 7.1 Hz, 2H), 4.03 (s, 3H), 1.36 (t, J = 7.1 Hz, 3H). Example 6-2: Synthesis of 2methyl-8-[3-(trifluoromethyl)phenyl]-2H,8H- pyrazolo[3,4-b]indole-5-carboxylic acid
Figure imgf000162_0002
To a solution of ethyl-2-methyl-8-[3-(trifluoromethyl)phenyl]-2H,8H- pyrazolo[3,4-b]indole-5-carboxylate (230 mg; 0.56 mmol) in EtOH (6 ml) was added 1M sodium hydroxide aqueous solution (2 ml). The reaction mixture was stirred under N2 atmosphere at 60 °C for 2h. The mixture was concentrated to dryness. Then water (10 ml) was added and the mixture was adjusted by 1N hydrochloric acid to pH=1. The solution was filtered and the residue was washed three times with H2O (10ml). The residue was dried under vacuum to obtain the purified product. (180 mg; 89 %; off-white solid). 1H NMR (400 MHz, DMSO) δ 12.69 (d, J = 0.6 Hz, 1H), 8.43 (d, J = 1.5 Hz, 1H), 8.21 (s, 1H), 8.13 (d, J = 12.1 Hz, 2H), 7.93 (dd, J = 8.7, 1.7 Hz, 1H), 7.86 (t, J = 7.9 Hz, H), 7.76 (d, J = 7.8 Hz, 1H), 7.67 (d, J = 8.7 Hz, 1H), 4.03 (s, 3H). Example 7: 8-(3-fluorophenyl)-2-methyl-2H,8H-pyrazolo[3,4-b]indole-5- carboxylic acid Example 7-1: Synthesis of ethyl 8-(3-fluorophenyl)-2-methyl-2H,8H- pyrazolo[3,4-b]indole-5-carboxylate
Figure imgf000163_0001
A mixture of ethyl 3-(3-amino-1-methyl-1H-pyrazol-4-yl)-4-chlorobenzoate (200 mg; 0.64 mmol), 1-bromo-3-fluorobenzene (135 mg; 0.77 mmol), XPhosPd G2 (56 mg; 0.07 mmol) and Cs2CO3 (629 mg; 1.93 mmol) were added to Dioxane-1,4 (10 ml). The mixture was stirred under N2 atmosphere at 120 °C for 16h. The reaction mixture was filtered. The organic phase was concentrated and purified by silica gel (PE/EA = 5:1) to obtain the purified product (210 mg; 92 %; off-white solid). 1H NMR (400 MHz, DMSO) δ 8.43 (d, J = 1.4 Hz, 1H), 8.21 (s, 1H), 7.91 (d, J = 1.7 Hz, 1H), 7.72 (d, J = 8.7 Hz, 1H), 7.67 (dd, J = 6.5, 2.6 Hz, 3H), 7.28 ¨C 7.21 (m, H), 4.35 (d, J = 7.1 Hz, 2H), 4.03 (s, 3H), 1.36 (t, J = 7.1 Hz, 3H). Example 7-2: Synthesis of 8-(3-fluorophenyl)-2-methyl-2H,8H-pyrazolo[3,4- b]indole-5-carboxylic acid
Figure imgf000164_0001
To a solution of ethyl 8-(3-fluorophenyl)-2-methyl-2H,8H-pyrazolo[3,4- b]indole-5-carboxylate (210 mg; 0.59 mmol) in EtOH (6 ml) was added 1M sodium hydroxide aqueous solution (2 ml). The mixture was stirred under N2 atmosphere at 60 °C for 2h. The mixture was concentrated to dryness. To the residue was added H2O (10 ml) and the mixture was adjusted by 1N hydrochloric acid to pH=1~2. The solution was filtered. The residue was washed with H2O (3 *10 ml) and dried under vacuum to get the crude product. Ethylacetate/N-hexane = 1:1 (10ml) was added and the mixture was stirred for 30min. Then the solution was filtered, the residue was dried under vacuum to obtain the purified product. (120 mg; 65 %; off-white solid). 1H NMR (400 MHz, DMSO) δ 12.68 (s, 1H), 8.41 (d, J = 1.4 Hz, 1H), 8.19 (s, 1H), 7.92 (dd, J = 8.7, 1.6 Hz, 1H), 7.72 ¨C 7.63 (m, 4H), 7.27 ¨C 7.20 (m, 1H), 4.03 (s, 3H). Example 8: 2-Methyl-8-{[3-(trifluoromethyl)phenyl]methyl}-2H,8H- pyrazolo[3,4-b]indole-5-carboxylic acid Example 8-1: Synthesis of ethyl 2-methyl-8-{[3-(trifluoromethyl)phenyl]- methyl}-2H,8H-pyrazolo[3,4-b]indole-5-carboxylate
Figure imgf000165_0001
To a solution of ethyl-2-methyl-2H,8H-pyrazolo[3,4-b]indole-5-carboxylate (220 mg; 0.81 mmol) in DMF (3 ml) was added NaH (49 mg; 2.04 mmol) at 0°C. The mixture was stirred at 0°C for 30 minutes and 1-(bromomethyl)-3- (trifluoromethyl)benzene (230 mg; 0.96 mmol) was added. The solution was stirred at 25°C for 3 hours. The reaction was filtered, concentrated in vacuum and purified by C- 18 column chromatography (ACN/H2O = 5 % - 95 %) and the product could be obtained (213 mg; 64 %; yellow brown solid). 1H NMR (400 MHz, CDCl3) δ 8.44 (d, J = 2.0 Hz, 1H), 7.98 (dd, J = 8.8, 1.6 Hz, 1H), 7.65 (s, 1H), 7.57 (s, 1H), 7.52 - 7.50 (m, 1H), 7.41 - 7.37 (m, 2H), 7.12 (d, J = 9.2 Hz, 1H), 5.43 (s, 2H), 4.39 (q, J = 7.2 Hz, 2H), 4.07 (s, 3H), 1.41 (t, J = 7.2 Hz, 3H). Example 8-2: Synthesis of 2-Methyl-8-{[3-(trifluoromethyl)phenyl]methyl}- 2H,8H-pyrazolo[3,4-b]indole-5-carboxylic acid
Figure imgf000165_0002
To a solution of ethyl 2-methyl-8-{[3-(trifluoromethyl)phenyl]methyl}-2H,8H- pyrazolo[3,4-b]indole-5-carboxylate (210 mg; 0.51 mmol) in EtOH (4 ml) and Water (1 ml) was added NaOH (63 mg; 1.58 mmol) at 25°C. The yellow brown mixture was stirred at 70°C for 3 hours. The mixture was concentrated to dryness and water (5 mL) was added. The water phase was adjusted to pH ~ 3 by 1N hydrochloric acid aqueous solution (5 drops) and concentrated to dryness. To the residue was added water (10 mL) and the mixture was filtered. The filtered residue was washed with water (5 mL) three times and concentrated to dryness. The purified product could be obtained (150 mg; 78 %; off-white solid). 1H NMR (400 MHz, DMSO-d6) δ 12.51 (s, 1H), 8.34 (d, J = 1.6 Hz, 1H), 8.10 (s, 1H), 7.85 (dd, J = 8.8, 2.0 Hz, 1H), 7.72 (s, 1H), 7.64 - 7.62 (m, 1H), 7.56 - 7.47 (m, 3H), 5.52 (s, 2H), 3.99 (s, 3H). Example 9: 2-Methyl-8-(4-methylphenyl)-2H,8H-pyrazolo[3,4-b]indole-5- carboxylic acid Example 9-1: Synthesis of ethyl 2-methyl-8-(4-methylphenyl)-2H,8H- pyrazolo[3,4-b]indole-5-carboxylate
Figure imgf000166_0001
A mixture of ethyl 3-(3-amino-1-methyl-1H-pyrazol-4-yl)-4-chlorobenzoate (200 mg; 0.64 mmol), 1-bromo-4-methylbenzene (132 mg; 0.77 mmol), XPhosPd G2 (56 mg; 0.07 mmol) and Cs2CO3 (629 mg; 1.93 mmol) was added to Dioxane-1,4 (10 ml). The mixture was stirred under N2 atmosphere at 120°C for 16h. The mixture was filtered. The organic phase was concentrated and purified by silica gel chromatography (PE/EA = 10:1) and the product was obtained (207 mg; 91 %; light yellow solid). 1H NMR (400 MHz, CDCl3) δ 8.46 (d, J = 2.0 Hz, 1H), 7.99 (dd, J = 8.7, 2.4 Hz, 1H), 7.67 (d, J = 3.8 Hz, 1H), 7.63 - 7.57 (m, 2H), 7.52 - 7.46 (m, 1H), 7.40 - 7.33 (m, 2H), 4.45 - 4.38 (m, 2H), 4.07 (d, J = 3.9 Hz, 3H), 2.43 (d, J = 3.3 Hz, 3H), 1.44 (td, J = 7.1, 4.1 Hz, 3H). Example 9-2: Synthesis of 2-methyl-8-(4-methylphenyl)-2H,8H-pyrazolo[3,4- b]indole-5-carboxylic acid
Figure imgf000167_0001
To a solution of ethyl 2-methyl-8-(4-methylphenyl)-2H,8H-pyrazolo[3,4- b]indole-5-carboxylate (200 mg; 0.57 mmol) in EtOH (6 ml) was added 1M sodium hydroxide aqueous solution (2 ml).The mixture was stirred under N2 atmosphere at 60°C for 2h. The mixture was concentrated. To the residue H2O (10 ml) was added and the mixture was adjusted to pH = 1 by 1N hydrochloric acid. The precipitate was filtered. The resulting crude product was washed three times with H2O (15 ml). The filtered residue was dried under vacuum and the purified product could be obtained (160 mg; 87 %; off-white solid). 1H NMR (400 MHz, DMSO) δ 12.60 (s, 1H), 8.40 (d, J = 1.5 Hz, 1H), 8.17 (s, 1H), 7.89 (dt, J = 5.2, 3.3 Hz, 1H), 7.63 (d, J = 8.3 Hz, 2H), 7.54 (d, J = 8.7 Hz, 1H), 7.41 (d, J = 8.2 Hz, 2H), 4.00 (s, 3H), 2.40 (s, 3H). Example 10: 8-(4-fluorophenyl)-2-methyl-2H,8H-pyrazolo[3,4-b]indole-5- carboxylic acid Example 10-1: Synthesis of ethyl 8-(4-fluorophenyl)-2-methyl-2H,8H- pyrazolo[3,4-b]indole-5-carboxylate
Figure imgf000168_0001
A mixture of ethyl 3-(3-amino-1-methyl-1H-pyrazol-4-yl)-4-chlorobenzoate (200 mg; 0.64 mmol), 1-bromo-4-fluorobenzene (135 mg; 0.77 mmol), XPhosPd G2 (56 mg; 0.07 mmol) and Cs2CO3 (629 mg; 1.93 mmol) was added to Dioxane-1,4 (10 ml).The mixture was stirred under N2 atmosphere at 120°C for 16h. The mixture was filtered and the phases were separated. The organic phase was concentrated and purified by silica gel chromatography (PE/EA = 10:1). The purified product could be obtained (186 mg; 81 %; light yellow solid). 1H NMR (400 MHz, CDCl3) δ 8.47 (d, J = 1.5 Hz, 1H), 8.05 - 7.98 (m, 1H), 7.74 - 7.66 (m, 3H), 7.49 - 7.42 (m, 1H), 7.26 (d, J = 3.6 Hz, 2H), 4.42 (dd, J = 7.1, 3.5 Hz, 2H), 4.07 (d, J = 3.4 Hz, 3H), 1.47 - 1.41 (m, 3H). Example 10-2: Synthesis of 8-(4-fluorophenyl)-2-methyl-2H,8H-pyrazolo[3,4- b]indole-5-carboxylic acid
Figure imgf000168_0002
To a solution of ethyl 8-(4-fluorophenyl)-2-methyl-2H,8H-pyrazolo[3,4- b]indole-5-carboxylate (180 mg; 0.51 mmol) in EtOH (5 ml) was added 1M sodium hydroxide aqueous solution (1.7 ml). The mixture was stirred under N2 atmosphere at 60°C for 16h. The mixture was concentrated to dryness. To the residue H2O (15ml) was added and pH was adjusted to 1 by 1N hydrochloric acid. The precipitate was filered. The residue was washed 3 times with H2O (10 ml). To the residue ethylacetate (3 ml) and n-hexane (3 ml) was added and the mixture was stirred 30 min. The suspension was filtered and the residue was dried under vacuum. The purified product could be obtained (100 mg; 62 %; white solid). 1H NMR (400 MHz, DMSO) δ 12.65 (s, 1H), 8.41 (d, J = 1.4 Hz, 1H), 8.18 (s, 1H), 7.90 (dd, J = 8.7, 1.6 Hz, 1H), 7.83 - 7.77 (m, 2H), 7.54 (d, J = 8.7 Hz, 1H), 7.49 - 7.42 (m, 2H), 4.01 (s, 3H). Example 11: 8-(cyclohexylmethyl)-2-methyl-2H,8H-pyrazolo[3,4-b]indole-5- carboxylic acid Example 11-1: Synthesis of ethyl 8-(cyclohexylmethyl)-2-methyl-2H,8H- pyrazolo[3,4-b]indole-5-carboxylate
Figure imgf000169_0001
To a suspension of ethyl 2-methyl-2H,8H-pyrazolo[3,4-b]indole-5-carboxylate (200 mg; 0.82 mmol) in propan-2-one (5 ml) was added bromomethyl- cyclohexane (0.14 ml; 0.99 mmol) and KOH (138 mg; 2.47 mmol.). The mixture was stirred at 65°C under N2 atmosphere for 12h. The mixture was poured into water (10 ml), and then extracted 3 times with EA (5 ml). The combined organic phase was collected and evaporated under vacuum. The residue was purified by C18 column chromatography (ACN/H20 = 5% - 95%) and the product could be obtained (170 mg; 57 %; yellow gel). Example 11-2: Synthesis of 8-(cyclohexylmethyl)-2-methyl-2H,8H- pyrazolo[3,4-b]indole-5-carboxylic acid
Figure imgf000170_0001
To a suspension of ethyl 8-(cyclohexylmethyl)-2-methyl-2H,8H-pyrazolo[3,4- b]indole-5-carboxylate (170 mg; 0.47 mmol) in EtOH (24 ml) was added Water (8 ml) and sodium hydroxide (320 mg; 8 mmol) The mixture was stirred at 65°C under N2 atmosphere for 12 h. The mixture was evaporated under vacuum. The residue was acidified with 1N HCl solution and evaporated. The residue was purified by C18 column chromatography (ACN/H20 = 5% - 95%) and the product could be obtained (50 mg; 33 %; white solid). 1H NMR (400 MHz, CDCl3) δ 7.63 (s, 1H), 7.31 ¨C 7.26 (m, 3H), 4.09 (s, 3H), 4.01 (d, J = 7.5 Hz, 2H), 2.49 (s, 1H), 2.01 (s, 1H), 1.75 - 1.63 (m, 5H), 1.26 - 1.15 (m, 3H), 1.13 - 1.03 (m, 2H). Example 12: 8-(Benzyl)-2-methyl-2H,8H-pyrazolo[3,4-b]indole-5-carboxylic acid Example 12-1: Synthesis of ethyl 8-(cyclohexylmethyl)-2-methyl-2H,8H- pyrazolo[3,4-b]indole-5-carboxylate
Figure imgf000170_0002
To a suspension of ethyl 2-methyl-2H,8H-pyrazolo[3,4-b]indole-5-carboxylate (300 mg; 1.23 mmol) in propan-2-one (5 ml) was added bromomethylbenzene (0.18 ml; 1.48 mmol) and KOH (208 mg; 3.7 mmol). The mixture was stirred at 65°C under N2 atmosphere for 12h. The mixture was poured into water (10 ml), and then extracted 3 times with EA (5 ml). The combined organic phase was collected and evaporated under vacuum. The residue was purified by C18 column chromatography (ACN/H20 = 5% - 95%) and the product could be obtained (180 mg; 41 %; off white powder). Example 12-2: Synthesis of 8-(benzyl)-2-methyl-2H,8H-pyrazolo[3,4-b]indole- 5-carboxylic acid
Figure imgf000171_0001
To a suspension of ethyl 8-(benzyl)-2-methyl-2H,8H-pyrazolo[3,4-b]indole-5- carboxylate (170 mg; 0.48 mmol) in EtOH (12 ml) was added sodium hydroxide (320 mg; 8 mmol) and water (4 ml). The mixture was stirred at 65°C under N2 atmosphere for 12 h. The residue was acidified with 1N HCl solution and evaporated under vacuum. The residue was purified by C18 column chromatography (ACN/H20 = 5% - 95%) and the product could be obtained (60 mg; 41 %; white solid). 1H NMR (300 MHz, DMSO) δ 12.58 - 12.44 (m, 1H), 8.35 (d, J = 1.4 Hz, 1H), 8.12 (s, 1H), 7.87 (dd, J = 8.5, 1.6 Hz, 1H), 7.52 (d, J = 8.6 Hz, 1H), 7.39 - 7.24 (m, 6H), 5.43 (s, 2H), 4.02 (s, 3H). Example 13: 8-(4-chlorophenyl)-2-methyl-2H,8H-pyrazolo[3,4-b]indole-5- carboxylic acid Example 13-1: Synthesis of ethyl 8-(4-chlorophenyl)-2-methyl-2H,8H- pyrazolo[3,4-b]indole-5-carboxylate
To a suspension of ethyl 3-(3-amino-1-methyl-1H-pyrazol-4-yl)-4-chloro- benzoate (300 mg; 0.97 mmol) in Dioxane-1,4 (10 ml) was added 1-bromo-4- chlorobenzene (222 mg; 1.16 mmol), XPhosPd G2 (84 mg; 0.11 mmol) and Cs2CO3 (944 mg; 2.90 mmol). The mixture was stirred at 120°C under N2 atmosphere for 12h. The mixture was poured into water (10 ml), and then extracted three times with EA (5 ml). The combined organic phase was collected and evaporated under vacuum. The residue was purified by C18 column chromatography (ACN/H20 = 5% - 95%) and the purified product could be obtained (180 mg; 52 %; off-white solid). Example 13-2: Synthesis of 8-(4-chlorophenyl)-2-methyl-2H,8H-pyrazolo[3,4- b]indole-5-carboxylic acid
Figure imgf000172_0001
To a suspension of ethyl 8-(4-chlorophenyl)-2-methyl-2H,8H-pyrazolo[3,4- b]indole-5-carboxylate (150 mg; 0.42 mmol) in EtOH (12 ml) was added sodium hydroxide (320 mg; 8 mmol) and Water (4 ml). The mixture was stirred at 65°C under N2 atmosphere for 12h. The mixture was evaporated under vacuum. The residue was acidified with 1N HCl solution and evaporated. The reminder was purified by C18 column chromatography (ACN/H2O = 5% - 95%) and the purified product could be obtained (30 mg; 21 %; white solid). 1H NMR (300 MHz, DMSO) δ 12.70 (s, 1H), 8.44 (d, J = 1.4 Hz, 1H), 8.22 (s, 1H), 7.93 (dd, J = 8.7, 1.7 Hz, 1H), 7.86 (d, J = 8.8 Hz, 2H), 7.72 (d, J = 2.9 Hz, 1H), 7.67 (dd, J = 7.1, 4.0 Hz, 2H), 4.04 (s, 3H). Example 14: 8-(4-methoxyphenyl)-2-methyl-2H,8H-pyrazolo[3,4-b]indole-5- carboxylic acid Example 14-1: Synthesis of ethyl 8-(4-methoxyphenyl)-2-methyl-2H,8H- pyrazolo[3,4-b]indole-5-carboxylate
Figure imgf000173_0001
In a microwave vial ethyl 3-(3-amino-1-methyl-1H-pyrazol-4-yl)-4-chloro- benzoate (60 mg; 0.21 mmol) in 1,4-Dioxane (4 ml) was added under argon 4- Bromoanisole (32 µl; 0.26 mmol), Cesium carbonate (206 mg; 0.64 mmol) and XPhos Pd G4 (19 mg; 0.02 mmol). The reaction was stirred for 16 hours at 120°C. The reaction mixture was diluted with EA and extracted 3x with water, dried over Na2SO4 and evaporated to dryness. The residue was purified by prep. HPLC. The purified product could be obtained. (56 mg, 68 %, beige solid). Example 14-2: Synthesis of 8-(4-methoxyphenyl)-2-methyl-2H,8H- pyrazolo[3,4-b]indole-5-carboxylic acid
To ethyl 8-(4-methoxyphenyl)-2-methyl-2H,8H-pyrazolo[3,4-b]indole-5- carboxylate (56 mg; 0,15 mmol) in Ethanol (0.3 ml) was added Sodium hydroxide solution c(NaOH) = 2 mol/l (0.2 ml) and the mixture was stirred for 16 hours at 60°C. The reaction was evaporated to dryness and the residue was purified by prep. HPLC. The purified product could be obtained (19 mg, 40 %, white solid). 1H NMR (500 MHz, DMSO-d6) δ 12.58 - 12.54 (m, 1H), 8.40 - 8.38 (m, 1H), 8.15 (s, 1H), 7.87 (dd, J = 8.6, 1.8 Hz, 1H), 7.65 - 7.61 (m, 2H), 7.44 (d, J = 8.7 Hz, 1H), 7.18 - 7.14 (m, 2H), 4.00 (s, 3H), 3.85 (s, 3H). Example 15: 8-(4-Ethoxyphenyl)-2-methyl-2H,8H-pyrazolo[3,4-b]indole-5- carboxylic acid Example 15-1: Synthesis of ethyl 3-(3-amino-1-methyl-1H-pyrazol-4-yl)-4- chlorobenzoate
Figure imgf000174_0001
To a suspension of Ethyl 3-borono-4-chlorobenzoate (600 mg; 2.63 mmol) in 1,4-Dioxane (8 ml) and Water (0.8 ml) was added 4-Bromo-1-methyl-1H- pyrazol-3-amine (462 mg; 2.63 mmol), Potassium carbonate (726 mg; 5.25 mmol) and [1,1'-Bis(diphenylphosphino)ferrocene]-dichloropalladium(II), complex with dichloromethane (214 mg) in a microwave vial under argon. The reaction was stirred for 16 hours at 60°C and then diluted with EA at room temperature. The mixture was extracted 3x with water, dried over Na2SO4 and evaporated to dryness. The residue was purified by flash chromatopgraphy. The purified product could be obtained as brown oil (273 mg, 36% yield). Example 15-2: Synthesis of ethyl 8-(4-ethoxyphenyl)-2-methyl-2H,8H- pyrazolo[3,4-b]indole-5-carboxylate
Figure imgf000175_0001
To ethyl 3-(3-amino-1-methyl-1H-pyrazol-4-yl)-4-chlorobenzoate (60 mg; 0.21 mmol) in 1,4-Dioxane (4 ml) was added under argon 4-Bromophenetole (35 µl; 0.25 mmol), Cesium carbonate (0.62 mmol) and XPhos Pd G4 (19 mg; 0.02 mmol) in a microwave vial. The reaction was stirred for 16 hours at 120°C and diluted with EA at room temperature. The mixture was extracted 3x with water, dried over Na2SO4 and evaporated to dryness. The residue was purified by prep. HPLC and the purified product could be obtained as yellow solid (10 mg, 12% yield). Example 15-3: Synthesis of 8-(4-ethoxyphenyl)-2-methyl-2H,8H-pyrazolo[3,4- b]indole-5-carboxylic acid
Figure imgf000175_0002
To ethyl 8-(4-ethoxyphenyl)-2-methyl-2H,8H-pyrazolo[3,4-b]indole-5- carboxylate (10 mg; 0.03 mmol) in ethanol (2 ml) was added sodium hydroxide solution c(NaOH) = 2 mol/l (2 N) (76 µl; 0.15 mmol) and the mixture was stirred for 16 h at 60°C. As the reaction was not completed more sodium hydroxide solution c(NaOH) = 2 mol/l (2 N) (76 µl; 0.15 mmol) was added and the mixture was stirred for additional 16 hours at 60°C. The reaction was evaporated to dryness at room temperature and the residue was purified by prep. HPLC column chromatography. The purified product could be obtained was off white solid (13 mg, 99% yield). Example 16: Methyl 2-methyl-4-[4-(trifluoromethyl)phenyl] pyrazolo[4,3- b]indole-7-carboxylate
Figure imgf000176_0001
Into a sealed tube were combined methyl 3-(4-amino-1-methylpyrazol-3-yl)-4- chlorobenzoate (330 mg, 1.192 mmol), XPhos Pd G3 (99 mg, 0.115 mmol), Cs2CO3 (825 mg, 2.481 mmol), dioxane (160 mL) and 1-bromo-4- (trifluoromethyl)benzene (0.19 mL, 0.004 mmol) at room temperature. The resulting mixture was stirred for 24 h at 120°C under argon atmosphere. The resulting mixture was concentrated under vacuum. The crude product was purified by Prep-HPLC giving the product methyl 2-methyl-4-[4- (trifluoromethyl)phenyl]pyrazolo[4,3-b]indole-7-carboxylate as a white solid (40 mg, 9 %). Example 17: N,2-dimethyl-4-[4-(trifluoromethyl) phenyl]pyrazolo [4,3-b]indole- 7-carboxamide
Into a sealed tube were added 2-methyl-4-[4-(trifluoromethyl) phenyl]pyrazolo[4,3-b]indole-7-carboxylic acid (Example 4-4) (70 mg, 0.189 mmol), HATU (153 mg, 0.393 mmol), DCM (6.80 mL), Methylamine, 2M in THF (0.19 mL, 6.248 mmol) and DIEA (0.07 mL, 0.525 mmol) at room temperature. The resulting mixture was stirred for 2 h at 30°C and concentrated under vacuum afterwards. The crude product was purified by Prep-HPLC giving N,2- dimethyl-4-[4-(trifluoromethyl)phenyl]pyrazolo[4,3-b]indole-7-carboxamide (41 mg, 58%) as a white solid. 1H NMR (400 MHz, DMSO, ppm) δ 8.52 (d, J = 4.6 Hz, 1 H), 8.46 (d, J = 1.8 Hz, 1 H), 8.10 (s, 1 H), 7.93 (s, 5 H), 7.85 (d, J = 8.7 Hz, 1 H), 4.10 (s, 3 H), 2.83 (d, J = 4.4 Hz, 3 H). Example 18: 2-methyl-8-[4-(trifluoromethoxy)phenyl]-2H,8H-pyrazolo[3,4- b]indole-5-carboxylic acid Example 18-1: Synthesis of ethyl 2‐methyl‐8‐[4‐(trifluoromethoxy)phenyl]‐ 2H,8H‐pyrazolo[3,4‐b]indole‐5‐carboxylate
Figure imgf000177_0001
To ethyl 3-(3-amino-1-methyl-1H-pyrazol-4-yl)-4-chlorobenzoate (60 mg; 0.21 mmol) in 1,4-Dioxane (4 ml) was added unter argon 1-Brom-4- (trifluormethoxy)-benzene (60 mg; 0.25 mmol), Cesium carbonate (202 mg; 0.62 mmol) and XPhos Pd G4 (18.7 mg; 0.02 mmol) in a microwave vial. The reaction was stirred for 16 hrs at 120°C. At room temperature the reaction mixture was diluted with EA and extracted 3x with water, dried over Na2SO4 and evaporated to dryness. The residue was purified by prep. HPLC giving the procut as white solid (28 mg; 34%). 1H NMR (500 MHz, DMSO-d6) ^ 8.45 - 8.43 (m, 1H), 8.21 (s, 1H), 7.94 - 7.90 (m, 3H), 7.68 - 7.65 (m, 1H), 7.64 - 7.60 (m, 2H), 4.35 (q, J = 7.1 Hz, 2H), 4.02 (s, 3H), 1.36 (t, J = 7.1 Hz, 3H). Example 18-2: Synthesis of 2-methyl-8-[4-(trifluoromethoxy)phenyl]-2H,8H- pyrazolo[3,4-b]indole-5-carboxylic acid
Figure imgf000178_0001
To a solution of ethyl 2-methyl-8-[4-(trifluoromethoxy)phenyl]-2H,8H- pyrazolo[3,4-b]indole-5-carboxylate (28 mg; 0.07 mmol) in Ethanol (2 ml) was added Sodium hydroxide solution c(NaOH) = 2 mol/l (2 N) (104 µl; 0.21 mmol) and the mixture was stirred for 16 hrs at 60°C. The reaction was evaporated to dryness and the residue was purified by prep. HPLC giving the product as white solid (20 mg; 76%). 1H NMR (400 MHz, DMSO-d6) ^ 12.67 - 12.62 (m, 1H), 8.41 (d, J = 1.7 Hz, 1H), 8.19 (s, 1H), 7.95 - 7.90 (m, 2H), 7.93 - 7.88 (m, 1H), 7.65 (d, J = 8.7 Hz, 1H), 7.63 - 7.59 (m, 2H), 4.02 (s, 3H). Example 19: 2-methyl-4-[4-(trifluoromethyl)phenyl]pyrazolo [4,3-b]indole-7- carbonitrile Example 19-1: Synthesis of 2-methyl-4-[4-(trifluoromethyl)phenyl]pyrazolo [4,3-b]indole-7-carboxamide
Figure imgf000179_0001
Into a sealed tube were combined 2-methyl-4-[4-(trifluoromethyl)phenyl] pyrazolo[4,3-b]indole-7-carboxylic acid (Example 4-4) (490 mg, 1.324 mmol), THF (25 mL), CDI (344 mg, 2.079 mmol), NH4OH (30 mL) at room temperature. The resulting mixture was stirred for 3 h at 30°C. The reaction was quenched with water at room temperature. The aqueous layer was extracted with EtOAc (3x100 mL). The resulting mixture was concentrated under vacuum. This resulted in 2-methyl-4-[4- (trifluoromethyl)phenyl]pyrazolo[4,3-b]indole-7-carboxamide (520 mg, 98 %) as a white solid. 1H NMR (300 MHz, DMSO, ppm) ^ 8.45 (d, J = 1.7 Hz, 1 H), 8.10 (s, 1 H), 8.04 - 7.95 (m, 1 H), 7.93 (s, 4 H), 7.86 (d, J = 8.8 Hz, 1 H), 4.09 (s, 3 H), 3.88 (s, 3 H). Example 19-2: Synthesis of 2-methyl-4-[4-(trifluoromethyl)phenyl]pyrazolo [4,3-b]indole-7-carbonitrile
Into a sealed tube were added 2-methyl-4-[4-(trifluoromethyl)phenyl] pyrazolo[4,3-b]indole-7-carboxamide (150 mg, 0.419 mmol), THF (7.5 mL) and POCl3 (0.15 mL) at room temperature. The resulting mixture was stirred for 3 h at room temperature. The reaction was quenched with ice at 0°C. The aqueous layer was extracted with EtOAc (3x50 mL). The resulting mixture was concentrated under vacuum. The crude product was purified by Prep-HPLC. This resulted in 2-methyl-4-[4-(trifluoromethyl)phenyl]pyrazolo[4,3-b]indole-7- carbonitrile (37 mg, 25 %) as a white solid. 1H NMR (300 MHz, DMSO, ppm) δ 8.44 (d, J = 1.7 Hz, 1 H), 8.15 (s, 1 H), 7.95 (s, 4 H), 8.02 - 7.87 (m, 1 H), 7.85 - 7.75 (m, 1 H), 4.12 (s, 3 H). Example 20: N-[2-methyl-8-[4-(trifluoromethyl)phenyl] pyrazolo[3,4-b]indol-5- yl]prop-2-enamide Example 20-1: Synthesis of 4-(2-chloro-5-nitrophenyl)-1-methylpyrazol-3- amine
Figure imgf000180_0001
To a solution of 2-chloro-5-nitrophenylboronic acid (1.0 g, 4.718 mmol) and 4- bromo-1-methylpyrazol-3-amine (437 mg, 2.359 mmol) in dioxane (10 mL) and H2O (2 mL) were added Pd(dppf)Cl2 (363 mg, 0.471 mmol) and K2CO3 (1.3 g, 8.936 mmol). After stirring for 4 h at 80°C under a nitrogen atmosphere. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with PE/EtOAc (1:1) to afford 4- (2-chloro-5-nitrophenyl)-1-methylpyrazol-3-amine (190 mg, 15%) as a yellow solid. Example 20-2: Synthesis of 2-methyl-5-nitro-8-[4-(trifluoromethyl) phenyl]pyrazolo[3,4-b]indole
Figure imgf000181_0001
To a stirred solution of 4-(2-chloro-5-nitrophenyl)-1-methylpyrazol-3-amine (330 mg, 1.124 mmol) and 1-bromo-4-(trifluoromethyl)benzene (346 mg, 1.461 mmol) in dioxane (10 mL) was added XPhos Pd G3 (50 mg, 0.056 mmol), Cs2CO3 (1.16 g, 3.372 mmol) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred overnight at 120°C under nitrogen atmosphere. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with PE/EtOAc (1:2) to afford 2-methyl-5-nitro-8-[4-(trifluoromethyl) phenyl]- pyrazolo[3,4-b]indole (460 mg, 95%) as a yellow solid. Example 20-3: Synthesis of 2-methyl-8-[4-(trifluoromethyl) phenyl]pyrazolo [3,4-b]indol-5-amine
Figure imgf000181_0002
To a solution of 2-methyl-5-nitro-8-[4-(trifluoromethyl)phenyl]pyrazolo[3,4- b]indole (450 mg, 1.048 mmol) in 20 mL MeOH was added Pd/C (10%, 450 mg) under nitrogen atmosphere in a 250 mL round-bottom flask. The mixture was hydrogenated at room temperature for 1 h under hydrogen atmosphere using a hydrogen balloon, filtered through a Celite pad and concentrated under reduced pressure. This resulted in 2-methyl-8-[4-(trifluoromethyl) phenyl]pyrazolo[3,4-b]indol-5-amine (360 mg, 99%) as a yellow solid. Example 20-4: Synthesis of N-[2-methyl-8-[4-(trifluoromethyl)phenyl] pyrazolo[3,4-b]indol-5-yl]prop-2-enamide
Figure imgf000182_0001
To a stirred solution of 2-methyl-8-[4-(trifluoromethyl)phenyl]pyrazolo[3,4- b]indol-5-amine (160 mg, 0.463 mmol) and TEA (99 mg, 0.929 mmol) in DCM (5 mL) was added acryloyl chloride (52 mg, 0.546 mmol) dropwise at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 2 h at room temperature under nitrogen atmosphere. The reaction was quenched with Water/Ice and the resulting mixture was extracted with CH2Cl2 (3 x 30 mL). The combined organic layers were washed with brine (1x30 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and purified by Prep-HPLC giving N-[2-methyl-8-[4- (trifluoromethyl)phenyl]pyrazolo[3,4-b]indol-5-yl]prop-2-enamide as a white solid (45 mg, 25%). 1H-NMR (400 MHz, DMSO, ppm) 10.20 (s, 1 H), 8.27 (d, J = 2.1 Hz, 1 H), 8.17 (s, 1 H), 8.08 (d, J = 8.5 Hz, 2 H), 7.92 (d, J = 8.5 Hz, 2 H), 7.74 (d, J = 8.9 Hz, 1 H), 7.47 (dd, J = 8.9, 2.1 Hz, 1 H), 6.47 (dd, J = 16.9, 10.1 Hz, 1 H), 6.27 (dd, J = 16.9, 2.1 Hz, 1 H), 5.75 (dd, J = 10.0, 2.1 Hz, 1 H), 4.01 (s, 3 H). Example 21: N-([2-methyl-8-[4-(trifluoromethyl)phenyl]pyrazolo [3,4-b]indol-5- yl]methyl)prop-2-enamide Example 21-1: Synthesis of 1-[2-methyl-8-[4-(trifluoromethyl)phenyl]pyrazolo [3,4-b]indol-5-yl]methanamine
Figure imgf000183_0001
To a stirred mixture of 2-methyl-8-[4-(trifluoromethyl)phenyl]pyrazolo[3,4- b]indole-5-carbonitrile (Example 19) (300 mg, 0.882 mmol) and NH3 (g) in MeOH (15 mL, 13%) in MeOH (30 mL) was added Raney Ni (300 mg, 3.327 mmol) under nitrogen atmosphere. The resulting mixture was stirred for 6 h at room temperature under hydrogen atmosphere, filtered and the filter cake was washed with MeOH (5x15 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 (Et3N) / MeOH (24:1) to afford 1-[2-methyl-8-[4- (trifluoromethyl)phenyl]pyrazolo[3,4-b]indol-5-yl]methanamine (300 mg, 89 %) as a light yellow solid. Example 21-2: Synthesis of N-([2-methyl-8-[4-(trifluoromethyl)phenyl]pyrazolo [3,4-b]indol-5-yl]methyl)prop-2-enamide
Figure imgf000184_0001
To a stirred solution of 1-[2-methyl-8-[4-(trifluoromethyl)phenyl]pyrazolo[3,4- b]indol-5-yl]methanamine (125 mg, 0.326 mmol) and DIPEA (133 mg, 0.979 mmol) in DCM (20 mL) was added acryloyl chloride (38 mg, 0.399 mmol) in DCM dropwise at 0°C under nitrogen atmosphere. The resulting mixture was stirred for 1 h at 0°C under nitrogen atmosphere and then concentrated under reduced pressure. The crude product was purified by Prep-HPLC resulting in N-([2-methyl-8-[4-(trifluoromethyl)phenyl]pyrazolo[3,4-b]indol-5- yl]methyl)prop-2-enamide (62 mg, 48%) as a white solid. 1H-NMR (300 MHz, DMSO-d6) ^ 8.64 (t, J = 5.8 Hz, 1H), 8.13 (s, 1H), 8.05 (d, J = 8.4 Hz, 2H), 7.92 (d, J = 8.7 Hz, 2H), 7.75 - 7.66 (m, 2H), 7.22 (dd, J = 8.5, 1.9 Hz, 1H), 6.29 (dd, J = 17.1, 10.0 Hz, 1H), 6.13 (dd, J = 17.1, 2.4 Hz, 1H), 5.61 (dd, J = 10.0, 2.4 Hz, 1H), 4.45 (d, J = 5.8 Hz, 2H), 3.99 (s, 3H). Example 22: 8‐(4‐cyclopentylphenyl)‐2‐methyl‐2H,8H‐pyrazolo [3,4‐b]indole‐ 5‐carboxylic acid Example 22-1: Synthesis of ethyl 8‐(4‐cyclopentylphenyl)‐2‐methyl‐2H,8H‐ pyrazolo[3,4‐b]indole‐5‐carboxylate
Figure imgf000185_0001
To a mixture of ethyl 3-(3-amino-1-methyl-1H-pyrazol-4-yl)-4-chlorobenzoate (60 mg; 0.21 mmol) in 1,4-dioxane (4 ml) was added unter argon 1-Bromo-4- cyclopentylbenzene (56 mg; 0.25 mmol), Cesium carbonate (202 mg; 0.62 mmol) and XPhos Pd G4 (19 mg; 0.02 mmol) in a microwave vial. The reaction was stirred for 16 hrs at 120°C. At room temperature the reaction was diluted with EA and extracted 3x with water, dried over Na2SO4 and evaporated to dryness. The residue was purified by prep. HPLC giving the product as white solid (15 mg; 18%). Example 22-2: Synthesis of 8‐(4‐cyclopentylphenyl)‐2‐methyl‐2H,8H‐pyrazolo [3,4‐b]indole‐5‐carboxylic acid
Figure imgf000185_0002
To ethyl 8-(4-cyclopentylphenyl)-2-methyl-2H,8H-pyrazolo[3,4-b]indole-5- carboxylate (15 mg; 0.04 mmol) in Ethanol (2 ml) was added Sodium hydroxide solution c(NaOH) = 2 mol/l (2 N) (57 µl; 0.11 mmol) and the mixture was stirred for 2 days at 60°C. The reaction was evaporated to dryness and the residue was purified by prep. HPLC giving 14 mg (quantitative yield) of the desired product as off-white solid. Example 23: Synthesis of 2-chloro-N-[2-methyl-8-[4- (trifluoromethyl)phenyl]pyrazolo[3,4-b]indol-5-yl]acetamide
Figure imgf000186_0001
To a stirred solution of 2-methyl-8-[4-(trifluoromethyl)phenyl]pyrazolo[3,4- b]indol-5-amine (Example 20-3) (170 mg, 0.492 mmol) and TEA (122 mg, 1.145 mmol) in DCM (5 mL) was added chloroacetyl chloride (81 mg, 0.681 mmol) dropwise at 0°C under nitrogen atmosphere. The resulting mixture was stirred for 1 h at room temperature. The reaction was quenched with water/ice and extracted with CH2Cl2 (3 x 40 mL). The combined organic layers were washed with brine (1x 30 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (10:1) and the crude product was purified by Prep-HPLC giving 2-chloro-N-[2- methyl-8-[4-(trifluoromethyl)phenyl]pyrazolo[3,4-b]indol-5-yl]acetamide (45 mg, 22%) as an off-white solid. Example 24: 2-chloro-N-([2-methyl-8-[4-(trifluoromethyl)phenyl]pyrazolo[3,4- b]indol-5-yl]methyl)acetamide
To a stirred solution of 1-[2-methyl-8-[4-(trifluoromethyl)phenyl]pyrazolo[3,4- b]indol-5-yl]methanamine (Example 21-1) (130 mg, 0.339 mmol) and DIPEA (139 mg, 1.022 mmol) in DCM (20 mL) was added chloroacetyl chloride (50 mg, 0.443 mmol) in DCM dropwise at 0°C under nitrogen atmosphere. The resulting mixture was stirred for 1 h at 0°C under nitrogen atmosphere and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EtOAc (1:1). The crude product was purified by Prep-HPLC giving 2-chloro-N-([2-methyl-8-[4-(trifluoromethyl)- phenyl] pyrazolo[3,4-b]indol-5-yl]methyl)acetamide (75 mg, 52%) as a white solid. 1H NMR (400 MHz, DMSO-d6) ^ 8.77 (t, J = 5.9 Hz, 1H), 8.15 (s, 1H), 8.08 (d, J = 8.4 Hz, 2H), 7.94 (d, J = 8.5 Hz, 2H), 7.77 - 7.69 (m, 2H), 7.25 (dd, J = 8.5, 1.9 Hz, 1H), 4.43 (d, J = 5.8 Hz, 2H), 4.15 (s, 2H), 4.02 (s, 3H). Example 25: 2-methyl-4-[4-(trifluoromethyl)phenyl]-[1,3]thiazolo[4,5-b]indole- 7-carboxylic acid Example 25-1: Synthesis of methyl 3-bromo-4-[(2-methyl-1,3-thiazol-4- yl)amino]benzoate
Figure imgf000187_0001
To a solution of methyl 4-amino-3-bromobenzoate (1.03 g, 4.268 mmol) and 4-bromo-2-methyl-1,3-thiazole (0.80 g, 4.268 mmol) in Toluene (16 mL) were added XantPhos (0.39 g, 0.640 mmol), Pd2(dba)3 (0.21 g, 0.213 mmol) and Cs2CO3 (2.94 g, 8.580 mmol) at room temperature under nitrogen atmosphere. The final reaction mixture was irradiated with microwave radiation for 2 h at 130°C and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EtOAc (8:1) to afford methyl 3-bromo-4-[(2-methyl-1,3-thiazol-4-yl)amino]benzoate (220 mg, 14%) as a light yellow solid. Example 25-2: Synthesis of 2-methyl-4H-[1,3]thiazolo[4,5-b]indole-7- carboxylate
Figure imgf000188_0001
To a mixture of methyl 3-bromo-4-[(2-methyl-1,3-thiazol-4-yl)amino]benzoate (1.01 g, 2.624 mmol) and pivalic acid (285 mg, 2.651 mmol) in xylene (45 mL) were added PCy3.HBF4 (153 mg, 0.395 mmol), Pd(AcO)2 (31 mg, 0.131 mmol) and Cs2CO3 (2.7 g, 7.872 mmol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 2 days at 120°C under nitrogen atmosphere and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EtOAc (1:1) to afford methyl 2-methyl-4H-[1,3]thiazolo[4,5-b]indole-7- carboxylate (380 mg, 59%) as a light yellow solid. Example 25-3: Synthesis of methyl 2-methyl-4-[4-(trifluoromethyl)phenyl]- [1,3]thiazolo[4,5-b]indole-7-carboxylate
Figure imgf000189_0001
To a stirred mixture of methyl 2-methyl-4H-[1,3]thiazolo[4,5-b]indole-7- carboxylate (230 mg, 0.934 mmol) and 1-bromo-4-(trifluoromethyl)benzene (332 mg, 1.402 mmol) in dioxane (10 mL) was added XPhos Pd G3 (83 mg, 0.093 mmol) and Cs2CO3 (960 mg, 2.799 mmol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred overnight at 100°C under nitrogen atmosphere and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EtOAc (1:1) to afford methyl 2-methyl-4-[4-(trifluoromethyl)phenyl]- [1,3]thiazolo[4,5-b]indole-7-carboxylate (230 mg,63%) as a light yellow solid. Example 25-4: Synthesis of 2-methyl-4-[4-(trifluoromethyl)phenyl]- [1,3]thiazolo[4,5-b]indole-7-carboxylic acid
Figure imgf000189_0002
A mixture of methyl 2-methyl-4-[4-(trifluoromethyl)phenyl]-[1,3]thiazolo[4,5- b]indole-7-carboxylate (210 mg, 0.538 mmol) and LiOH (82 mg, 3.253 mmol) in THF (5 mL) and H2O (5 mL) was stirred for overnight at 50°C. At room temperature THF is removed under reduced pressure. The remainder was acidified to pH 4 with 1 M HCl (aq.) and the resulting mixture was extracted with EtOAc (5 x 20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure and the crude product was purified by Prep-HPLC giving 2-methyl-4-[4-(trifluoromethyl)phenyl]- [1,3]thiazolo[4,5-b]indole-7-carboxylic acid (57mg, 28%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 8.50 (d, J = 1.7 Hz, 1H), 7.99 (s, 3H), 7.92 (dd, J = 8.8, 1.7 Hz, 2H), 7.70 (d, J = 8.8 Hz, 1H), 2.82 (s, 3H). Example 26: 7-fluoro-2-methyl-4-[4-(trifluoromethyl)phenyl] pyrazolo[4,3- b]indole Example 26-1: Synthesis of 3-(2-bromo-5-fluorophenyl)-1-methyl-4- nitropyrazole
Figure imgf000190_0001
To a stirred mixture of 2-bromo-5-fluorophenylboronic acid (700 mg, 3.039 mmol) and 3-bromo-1-methyl-4-nitropyrazole (700 mg, 3.330 mmol) in dioxane (28 mL) and H2O (7 mL) were added NaHCO3 (1.40 g, 15.832 mmol) and Pd(PPh3)4 (350 mg, 0.300 mmol). The resulting mixture was stirred overnight at 110°C under nitrogen atmosphere and then concentrated under vacuum. The residue was extracted with EtOAc (3 x 30mL) and the combined organic layers were washed with brine (1x50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EtOAc (4:1) to afford 3-(2-bromo-5-fluorophenyl)-1-methyl-4-nitropyrazole (700 mg, 40%) as a white solid. Example 26-2: Synthesis of 3-(2-bromo-5-fluorophenyl)-1-methylpyrazol-4- amine To a stirred solution of 3-(2-bromo-5-fluorophenyl)-1-methyl-4-nitropyrazole (650 mg, 1.133 mmol) and NH4Cl (580 mg, 10.301 mmol) in MeOH (13 mL) and H2O (6.5 mL) was added Fe (609 mg, 10.360 mmol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 2 h at 70°C and then diluted with water (20 mL). The resulting mixture was extracted with CH2Cl2 (3 x50 mL). The combined organic layers were washed with brine (1x100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. This resulted in 3-(2-bromo-5- fluorophenyl)-1-methylpyrazol-4-amine (500 mg, 100.00%) as a brown oil. Example 26-3: Synthesis of 7-fluoro-2-methyl-4-[4-(trifluoromethyl)phenyl] pyrazolo[4,3-b]indole
Figure imgf000191_0001
To a stirred solution of 3-(2-bromo-5-fluorophenyl)-1-methylpyrazol-4-amine (500 mg, 1.133 mmol) and 1-bromo-4-(trifluoromethyl)benzene (460 mg, 1.942 mmol) in dioxane (15 mL) were added Cs2CO3 (1.20 g, 3.499 mmol) and XPhos Pd G3 (161 mg, 0.181 mmol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred overnight at 120°C and then quenched with water. This mixture was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (1x50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by Prep-HPLC giving 7-fluoro-2- methyl-4-[4-(trifluoromethyl)phenyl]pyrazolo[4,3-b]indole (26 mg, 7%) as a white solid. 1H NMR (300 MHz, DMSO-d6, ppm) 8.07 (s, 1H), 7.88 (s, 4H), 7.84 - 7.78 (m, 1H), 7.76 - 7.66 (m, 1H), 7.30 - 7.17 (m, 1H), 4.07 (s, 3H). Example 27: N‐cyclopropyl‐2‐methyl‐8‐[6‐(trifluoromethyl)pyridin‐3‐yl]‐2H,8H‐ pyrazolo[3,4‐b]indole‐5‐carboxamide Example 27-1: Synthesis of N‐cyclopropyl‐2‐methyl‐8‐[6‐ (trifluoromethyl)pyridin‐3‐yl]‐2H,8H‐pyrazolo[3,4‐b]indole‐5‐carboxamide
Figure imgf000192_0001
To 2-methyl-8-[6-(trifluoromethyl)pyridin-3-yl]-2H,8H-pyrazolo[3,4-b]indole-5- carboxylic acid (73 mg; 0.20 mmol) in DMF (4 ml) was added cyclopropylamine (21 µl; 0.29 mmol), N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydro- chloride (75 mg; 0.39 mmol), 1-hydroxybenzotriazole hydrate (30 mg; 0.20 mmol) and 4-methylmorpholine (108 µl; 0.98 mmol). The reaction was stirred for 16 h at RT and directly purified by HPLC giving the product in 72% yield (58 mg) as white solid. Example 28: 2‐methyl‐N‐[(pyridin‐4‐yl)methyl]‐8‐[4‐(trifluoromethyl)phenyl]‐ 2H,8H‐pyrazolo[3,4‐b]indole‐5‐carboxamide Example 28-1: Synthesis of 2‐methyl‐N‐[(pyridin‐4‐yl)methyl]‐8‐[4‐ (trifluoromethyl)phenyl]‐2H,8H‐pyrazolo[3,4‐b]indole‐5‐carboxamide
Figure imgf000193_0001
To sodium 2-methyl-8-[4-(trifluoromethyl)phenyl]-2H,8H-pyrazolo[3,4- b]indole-5-carboxylate (50 mg; 0.13 mmol) in DMF (3 ml) was added 4- picolylamine (21 µl; 0.20 mmol), N-(3-dimethylaminopropyl)-N'- ethylcarbodiimide hydro chloride (50 mg; 0.26 mmol), 1-hydroxybenzotriazole hydrate (20 mg; 0.13 mmol) and 4-methylmorpholine (72 µl; 0.65 mmol). The reaction was stirred for 16 h at RT. The reaction was directly purified by HPLC giving the product in 57% (34 mg) yield as off-white solid. Example 29: N‐[2‐hydroxy‐1‐(pyridin‐2‐yl)ethyl]‐2‐methyl‐8‐[4‐ (trifluoromethyl)phenyl]‐2H,8H‐pyrazolo[3,4‐b]indole‐5‐carboxamide Example 29-1: Synthesis of N‐[2‐hydroxy‐1‐(pyridin‐2‐yl)ethyl]‐2‐methyl‐8‐[4‐ (trifluoromethyl)phenyl]‐2H,8H‐pyrazolo[3,4‐b]indole‐5‐carboxamide
Figure imgf000193_0002
A solution of 2-methyl-8-[4-(trifluoromethyl)phenyl]pyrazolo[3,4-b]indole-5- carboxylic acid (150 mg, 0.42 mmol), DIEA (162 mg, 1.13 mmol) and HATU (191 mg, 0.45 mmol) in DMF (2 mL) was stirred for 1h at RT. To the above mixture was added 2-amino-2-(pyridin-2-yl)ethanol (87 mg, 0.57 mmol). The resulting mixture was stirred for additional 3 h at RT. The crude product was purified by HPLC giving the product (82 mg, 41%) as white solid. Example 29-2: Separation of Enantiomers
Figure imgf000194_0001
The enantiomers of N‐[2‐hydroxy‐1‐(pyridin‐2‐yl)ethyl]‐2‐methyl‐8‐[4‐ (trifluoromethyl) phenyl]‐2H,8H‐pyrazolo[3,4‐b]indole‐5‐carboxamide were separated by SCF on a YMC Cellulose-SC column with the eluent of CO2/Methanol = 60:40 and a flow of 5 ml/min.50 mg of the racemic mixture delivered 22 mg and 23 mg of the respective enantiomers. Example 30: (2S,3S,4S,5R,6S)‐3,4,5‐trihydroxy‐6‐{2‐methyl‐8‐[4‐ (trifluoromethyl)phenyl]‐2H,8H‐pyrazolo[3,4‐b]indole‐5‐carbonyloxy}oxane‐2‐ carboxylic acid Example 30-1: Synthesis of (2S,3S,4S,5R,6S)‐3,4,5‐trihydroxy‐6‐{2‐methyl‐8‐ [4‐(trifluoromethyl)phenyl]‐2H,8H‐pyrazolo[3,4‐b]indole‐5‐carbonyloxy}oxane‐ 2‐carboxylic acid
Figure imgf000195_0001
To a DMF (35 ml) solution of (2S,3S,4S,5R,6R)-3,4,5,6-tetrahydroxyoxane-2- carboxylic acid (5 g; 24 mmol) and TBAF in THF (1 Mol/L; 31 ml; 24 mmol) was added BnBr (4.60 g; 25.55 mmol) at 0°C. The resulting mixture was stirred over night at RT under N2 atmosphere. Then the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford benzyl (2S,3S,4S,5R,6R)-3,4,5,6- tetrahydroxyoxane-2-carboxylate (4 g; 13.90 mmol; 57 %) as yellow oil. To a stirred solution of benzyl (2S,3S,4S,5R,6R)-3,4,5,6-tetrahydroxyoxane-2- carboxylate (4 g; 13.90 mmol) and 2-methyl-8-[4-(trifluoromethyl)phenyl]- 2H,8H-pyrazolo[3,4-b]indole-5-carboxylic acid (2.50 g; 6.71 mmol) in Dioxane- 1,4 (80 ml) were added HATU (4 g; 9.99 mmol) and NMM (2 g; 18.79 mmol) at RT under N2 atmosphere. The resulting mixture was stirred for overnight at RT. For work up the reaction was quenched with water. The resulting mixture was extracted with EtOAc (3 x 40 ml). The combined organic layers were washed with brine (3 x 100ml) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography to afford (2S,3R,4S,5S,6S)- 6-[(benzyloxy)carbonyl]-3,4,5-trihydroxyoxan-2-yl 2-methyl-8-[4-(trifluoro- methyl)phenyl]-2H,8H-pyrazolo[3,4-b]indole-5-carboxylate (500 mg; 0.70 mmol; 11 %) as yellow solid. To a stirred solution of (2S,3R,4S,5S,6S)-6-[(benzyloxy)carbonyl]-3,4,5- trihydroxyoxan-2-yl 2-methyl-8-[4-(trifluoromethyl)phenyl]-2H,8H-pyrazolo- [3,4-b]indole-5-carboxylate (500 mg; 0.70 mmol) and tert-butyldimethylsilane (180 mg; 1.47 mmol) in DCE (3 ml) was added triethylamine (0.50 ml; 3.66 mmol) and Pd(AcO)2 (360 mg; 1.52 mmol) at RT under N2 atmosphere. The mixture was stirred for 2 h at 60°C and then filtered. The filter cake was washed with DCM (3 x 5 ml) and the filtrate was concentrated under reduced pressure. The residue was treated with TBAF in THF (1M) (4 ml) at RT. The resulting mixture was stirred for 1 h at RT and then acidified to pH 5 with HCl (aq.), extracted with EtOAc (3 x 20 ml) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude was purified by HPLC giving the product (53 mg; 15 %) as white solid. Example 31: 2‐methyl‐8‐(4‐methylphenyl)‐5‐(methylsulfanyl)‐2H,8H‐ pyrazolo[3,4‐b]indole Example 31-1: Synthesis of 2‐methyl‐8‐(4‐methylphenyl)‐5‐(methylsulfanyl)‐ 2H,8H‐pyrazolo[3,4‐b]indole
Figure imgf000196_0001
4-[2-chloro-5-(methylsulfanyl)phenyl]-1-methyl-1H-pyrazol-3-amine (500 mg; 1.9 mmol), 4-bromotoluene (661 mg; 3.9 mmol) and cesium carbonate (1.9 g; 5.8 mmol) were suspended in 1,4-Dioxane (30 ml) and flushed with argon, then XPhos Pd G4 (175 mg; 0.2 mmol) was added stirred over weekend at 120°C. Then XPhos Pd G4 (175 mg; 0.2 mmol) was added again and stirred for 2 days at 100°C. The reactions was filtered over Celite and the residue was washed with ethyl acetate and the filtrat was concentrated under the reduced pressure. The crude was purified by chromatography . giving the product (385 mg; 62 %) as light yellow solid. Example 32: 7‐methanesulfinyl‐2‐methyl‐4‐[4‐(trifluoromethyl)phenyl]‐2H,4H‐ pyrazolo[4,3‐b]indole Example 32-1: Synthesis of 7‐methanesulfinyl‐2‐methyl‐4‐[4‐ (trifluoromethyl)phenyl]‐2H,4H‐pyrazolo[4,3‐b]indole
Figure imgf000197_0001
To a solution of 2-methyl-7-(methylsulfanyl)-4-[4-(trifluoromethyl)phenyl]- pyrazolo[4,3-b]indole(400 mg, 0.7 mmol) in AcOH (400 mg) and CHCl2 (20 mL) was added H2O2 (0.11 mL; 30% in water) at 0°C. The resulting mixture was stirred for 16 h at RT under nitrogen atmosphere. The reaction was quenched by the addition of Water (100 mL) at RT. The resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude was purified by HPLC giving the product (23 mg, 8 %) as a white solid. Example 33: 7‐methanesulfonyl‐2‐methyl‐4‐[4‐(trifluoromethyl)phenyl]‐2H,4H‐ pyrazolo[4,3‐b]indole Example 33-1: Synthesis of 7‐methanesulfonyl‐2‐methyl‐4‐[4‐ (trifluoromethyl)phenyl]‐2H,4H‐pyrazolo[4,3‐b]indole
Figure imgf000197_0002
To a stirred mixture of 2-methyl-7-(methylsulfanyl)-4-[4-(trifluoromethyl)- phenyl]pyrazolo[4,3-b]indole (20 mg, 0.036 mmol) in DCM (1 mL) was added MCPBA (22 mg, 0.089 mmol) at RT. The resulting mixture was stirred for 3 h at RT under air atmosphere. The reaction mixture was diluted with water, washed with 10% aqueous sodium sulfite solution and saturated aqueous sodium hydrogen carbonate solution. After phase separation and extraction of the aqueous phase with DCM the combined organic layers were washed with brine (2 x 100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude was purified by HPLC giving the product (48 mg, 17%) as a yellow solid. Example 34: 2‐methyl‐4‐[4‐(trifluoromethyl)phenyl]‐2H,4H‐pyrazolo[4,3‐ b]indole‐7‐sulfonamide Example 34-1: Synthesis of 2‐methyl‐4‐[4‐(trifluoromethyl)phenyl]‐2H,4H‐ pyrazolo[4,3‐b]indole‐7‐sulfonamide
Figure imgf000198_0001
To a stirred HSO3Cl (25 mL) was added 2-methyl-4-[4-(trifluoromethyl)phenyl]- pyrazolo[4,3-b]indole (1.6 g, 4.8 mmol) at 0°C under nitrogen atmosphere. The resulting mixture was stirred for 1 h at 0°C under nitrogen atmosphere. The reaction was quenched by the addition to Water/Ice. The resulting mixture was extracted with CH2Cl2 (3 x 100 mL). The combined organic layers were concentrated under reduced pressure. This resulted in crude 2-methyl-4-[4- (trifluoromethyl)phenyl]pyrazolo[4,3-b]indole-7-sulfonyl chloride (900 mg, 24 %) as a yellow solid. To the reactant 2-methyl-4-[4-(trifluoromethyl)phenyl]pyrazolo[4,3-b]indole-7- sulfonyl chloride (140 mg, 0.18 mmol) was added a mixture of NH3.H2O (3 mL) and THF (3 mL) dropwise. The resulting mixture was stirred for 30 min at RT. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography giving the product (47 mg, 68 %) as a white solid. Example 35: Imino(methyl){2‐methyl‐4‐[4‐(trifluoromethyl)phenyl]‐2H,4H‐ pyrazolo[4,3‐b]indol‐7‐yl}‐lambda6‐sulfanone Example 35-1: Synthesis of imino(methyl){2‐methyl‐4‐[4‐ (trifluoromethyl)phenyl]‐2H,4H‐pyrazolo[4,3‐b]indol‐7‐yl}‐lambda6‐sulfanone
Figure imgf000199_0001
A mixture of 7-methanesulfinyl-2-methyl-4-[4-(trifluoromethyl)phenyl]pyrazolo- [4,3-b]indole (300 mg, 0.674 mmol), MgO (1.14 g, 27 mmol), Rh2(OAc)4 (9 mg, 0.019 mmol), DIB (347 mg, 1.02 mmol) and BocNH2 (124 mg, 1 mmol) in CH2Cl2 (15 mL) was stirred for 8 h at 40°C. The reaction was quenched by the addition of Water (100 mL) at RT. The mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (2 x 100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography giving tert-butyl N-[methyl([2-methyl-4-[4-(trifluoromethyl)- phenyl]pyrazolo[4,3-b]indol-7-yl])oxo-lambda6-sulfanylidene]carbamate (45 mg, 7 %) as a brown solid. A mixture of tert-butyl N-[methyl([2-methyl-4-[4-(trifluoromethyl)phenyl]- pyrazolo[4,3-b]indol-7-yl])oxo-lambda6-sulfanylidene]carbamate (40 mg, 0.04 mmol) in HCl (g) in MeOH (8 mL) was stirred for 3 h at RT under air atmosphere. The reaction was quenched by the addition of Water (50 mL) at RT. The resulting mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude was purified by HPLC giving the product (10 mg, 65 %) as a white solid. Example 36: N,N,2‐Trimethyl‐4‐[4‐(trifluoromethyl)phenyl]‐2H,4H‐ pyrazolo[4,3‐b]indole‐7‐sulfonoimidamide Example 36-1: Synthesis of N,N,2‐trimethyl‐4‐[4‐(trifluoromethyl)phenyl]‐ 2H,4H‐pyrazolo[4,3‐b]indole‐7‐sulfonoimidamide
Figure imgf000200_0001
To a stirred solution of 2-methyl-4-[4-(trifluoromethyl)phenyl]pyrazolo[4,3- b]indole-7-sulfonamide (280 mg, 0.68 mmol) in THF (15) was added NaH (42 mg, 1.1 mmol) at 0°C under nitrogen atmosphere. The resulting mixture was stirred for 1 h at RT under nitrogen atmosphere. To the above mixture was added TBSCl (141 mg, 0.89 mmol) in portions at 0°C. The reaction mixture was stirred for additional 2 h at room temperature and quenched by the addition of sat. NH4Cl (aq.) at 0°C. The resulting mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography to afford N-(tert-butyldimethylsilyl)-2-methyl-4-[4-(trifluoro- methyl)phenyl]pyrazolo[4,3-b]indole-7-sulfonamide(150 mg, 42 %) as off- white solid. In a sealed tube a solution of PPh3 (200 mg, 0.72 mmol) and CCl3CCl3 (181 mg, 0.73 mmol) in CHCl3 (2 mL) was stirred for 6 h at 70°C under nitrogen atmosphere. To the mixture was added TEA (52 mg, 0.49 mmol) dropwise at RT and stirred for additional 10 min at RT. To the above mixture was added N-(tert-butyldimethylsilyl)-2-methyl-4-[4-(trifluoromethyl)phenyl]pyrazolo[4,3- b]indole-7-sulfonamide (130 mg, 0.24 mmol) in CHCl3 dropwise at 0°C. The mixture was stirred for 20 min at 0°C. Then dimethylamine (35 mg, 0.74 mmol) in THF (0.37 mL) was added dropwise at 0°C. The resulting mixture was stirred for additional 30 min at 0°C and overnight at RT. After concentration in vacuum the residue was resolved in ACN (1 mL) and a solution of HCOOH (1 mL) in H2O (1 mL) was added dropwise at 0°C. The resulting mixture was stirred for 1 h at room temperature and then concentrated under vacuum. The residue was purified by silica gel column chromatography giving the product (46 mg, 40 %) as off-white solid. Example 37: 4-methyl-7-[4-(trifluoromethyl)phenyl]-4,5,7,9- tetraazatricyclo[6.4.0.02,6]dodeca-1(8),2,5,9,11-pentaene-11-carboxylic acid Step 1: To a solution of^4-Bromo-1-methyl-1H-pyrazol-amine (4.0 g, 22.73 mmol) in^DCM (60mL) at 0°C was added Triethylamine (6.34 mL, 45.45 mmol). The reaction was stirred for 5 mins^then^Acetyl chloride (2.42 mL, 34.09 mmol) was added dropwise to the reaction mixture. The reaction was allowed to warm to room temperature and the reaction was stirred for 48 hours over the weekend. TLC showed consumption of starting material and formation of a new spot. LCMS confirmed desired product. Sat. NaHCO3 (aq) solution (100mL) was added to the reaction mixture and the phases separated. The aqueous layer was extracted a further three times with DCM (3 x 75 mL). The combined organic layers were dried overphase separating^paper and solvent was removed^in vacuo. This crude material was purified by normal phase chromatography to giveN-(4-bromo-1-methyl-pyrazol-3-yl)acetamide, (4.05g, 82%)^ as an off-white solid. Step 2: To a degassed solution of^N-(4-bromo-1-methyl-pyrazol-3-yl)acetamide (3.0 g, 13.76 mmol), Bis(pinacolato)diboron (4.3 g, 16.51 mmol) andpotassium acetate (4.1 g, 41.28 mmol) in ioxane (70 mL) was added1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (562 mg, 0.69 mmol). The reaction was heated to 90°C for 2 hours. The reaction mixture was cooled to room temperature and diluted with Water (50 mL).^The aqueous layer was extracted three times with Ethyl Acetate (3x50 mL).^The combined organics were dried over hydrophobic filter paper and concentrated under vacuo to yield a red oil. Crude mass = 4.2 g . LCMS showed 93 % of the desired boronic ester product by UV. Assume a quantitative yield at 93 % purity. Sample was taken directly onto the next stage of the reaction sequence Step 3: To a degassed solution of^methyl 5-bromo-6-chloro-pyridine-3-carboxylate (2 g, 7.99 mmol),^N-[1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)- pyrazol-3-yl]acetamide (3.2 g, 11.98 mmol)^and sodium carbonate (2.5 g, 23.95 mmol) in DMF (30mL) and^Water (7mL)^was added dichlorobis{[4-(N,N- dimethylamino)phenyl]di-t-butylphosphino}palladium(II) (848 mg, 1.20 mmol).^ The reaction was heated at 95 °C for 45 mins until all starting material was consumed.^The reaction mixture was cooled to room temperature and diluted with Water (75 mL). The mixture was extracted with Ethyl Acetate (4x40 mL) and the combined organics were washed with brine twice (2x70 mL).T he combined organics were dried over hydrophobic filter paper and concentrated under vacuo. The crude residue was purified by column chromatography to yieldmethyl 5-(5-acetamido-1-methyl-pyrazol-4-yl)-6-chloro-pyridine-3- carboxylate (367 mg, 15%) as a red oil.^ Step 4: To a solution of^m thyl 5-(3-acetamido-1-methyl-pyrazol-4-yl)-6-chloro- pyridine-3-carboxylate (367 mg, 1.19 mmol) in^methanol (10mL) was added hydrogen chloride (1.43 mL, 1.78 mmol) (1.25 M solution in methanol). The reaction was heated at 70°C under nitrogen for^48 hours. The reaction mixture was concentrated under vacuum and purified by column chromatography to yield^methyl 5-(3-amino-1-methyl-pyrazol-4-yl)-6-chloro-pyridine-3- carboxylate (196 mg, 62 %) as a brown solid. The sample was taken onto the next stage of the reaction sequence. Step 5: To a degassed solution of methyl 5-(3-amino-1-methyl-pyrazol-4-yl)-6-chloro- pyridine-3-carboxylate (196 mg, 0.74 mmol), 4-Bromobenzotrifluoride (0.1 mL, 0.74 mmol) and Cesium carbonate (718 mg, 2.21 mmol) in dioxane (6mL) was added XPhos Pd G2 (58 mg, 0.07 mmol). The reaction was heated under nitrogen at 100°C for 16 hours. LCMS confirmed the product formation and no starting material remained. The reaction was cooled to room temperature and diluted with water (10 mL) The reaction mixture was extracted with Ethyl Acetate three times (3x 10 mL). The combined organics were, washed with brine (20mL) dried over hydrophobic filter paper and concentrated under vacuo. The residue was purified by column chromatography to yield a brown solid (213 mg). The sample was taken onto the next stage of the reaction sequence as the mixture. Step 6: To a solution of methyl 4-methyl-7-[4-(trifluoromethyl)phenyl]-4,5,7,9-tetraza- tricyclo[6.4.0.02,6]dodeca-1(8),2,5,9,11-pentaene-11-carboxylate (34 mg, 0.09 mmol) in THF (0.5 mL) and Water (0.13 mL) was added lithium hydroxide monohydrate (4.19 mg, 0.1 mmol). The reaction was stirred at room temperature for 48 hours until complete by LCMS. The reaction was concentrated under vacuo and purified by preparative HPLC to yield 4-methyl- 7-[4-(trifluoromethyl)phenyl]-4,5,7,9-tetrazatricyclo[6.4.0.02,6]dodeca- 1(8),2,5,9,11-pentaene-11-carboxylic acid (2.75 mg, 8 %). Example 38: Synthesis of N-[(2S)-1-hydroxypropan-2-yl]-3-methyl-4-[4- (trifluoromethyl)phenyl]-3H,4H-[1,2,3]triazolo[4,5-b]indole-7-sulfonamide Step 1: To a stirred mixture of 4-bromo-1-methyl-1H-1,2,3-triazole (10.50 g; 61.58 mmol), 2-nitrophenyl)boronic acid (16.20 g; 92.20 mmol), K3PO4 (28 g; 125.32 mmol) in dioxane (140 ml) and H2O (28 ml) was added Pd(DTBPF)Cl2 (4.30 g; 6.27 mmol) at room temperature. The resulting mixture was stirred for 16 h at 100°C. For work-up the mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography to afford 1-methyl- 4-(2-nitrophenyl)-1H-1,2,3-triazole (8.25 g; 66 %) as brown orange solid. Step 2: To a stirred mixture of 1-methyl-4-(2-nitrophenyl)-1H-1,2,3-triazole (8.25 g; 40.40 mmol) in 1,2-dichlorobenzene (200 ml) was added DPPE (20 g; 47.69 mmol) at room temperature. The resulting mixture was stirred for 48 h at 165°C. For work-up the mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography to afford 3-methyl-3H,4H- [1,2,3]triazolo[4,5-b]indole (1.85 g; 24 %) as yellow solid. Step 3: A suspension of 3-methyl-3H,4H-[1,2,3]triazolo[4,5-b]indole (1.50 g; 7.87 mmol), XPhos Pd G4 (0.75 g; 0.84 mmol), Cs2CO3 (5.60 g; 16.33 mmol) and 1-iodo-4-(trifluoromethyl)benzene (4.60 g; 16.07 mmol) in dioxane (200 ml) was stirred for overnight at 120°C under nitrogen atmosphere.For work-up the mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography to afford 3-methyl-4-[4-(trifluoromethyl)phenyl]- 3H,4H-[1,2,3]triazolo[4,5-b]indole (1.44 g; 58 %) as brown powder. Step 4: A solution of 3-methyl-4-[4-(trifluoromethyl)phenyl]-3H,4H-[1,2,3]triazolo[4,5- b]indole (1.40 g; 4.43 mmol) in chlorosulfonic acid (40 ml) was stirred for 2h at 0°C under nitrogen atmosphere. The reaction was quenched by the addition of ice water. The resulting mixture was extracted with DCM and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. This resulted in 1.60 g (84 %) of the crude product 3-methyl-4-[4- (trifluoromethyl)phenyl]-3H,4H-[1,2,3]triazolo[4,5-b]indole-7-sulfonyl chloride as light yellow powder. Step 5: A solution of 3-methyl-4-[4-(trifluoromethyl)phenyl]-3H,4H-[1,2,3]triazolo[4,5- b]indole-7-sulfonyl chloride (150 mg; 0.35 mmol), TEA (0.16 ml; 1.13 mmol) and (2S)-2-aminopropan-1-ol (50 mg; 0.63 mmol) in DCM (5 ml) was stirred for 1h at 80°C under nitrogen atmosphere. For work-up the mixture was concentrated under vacuum. The crude product was purified by Prep-HPLC. This resulted in 22.40 mg (14 %) of the product as off-white solid. Example 39: Synthesis of 3-{1-methyl-4-[4-(trifluoromethyl)phenyl]-1H,4H- imidazo[4,5-b]indol-7-yl}-4,5-dihydro-1,2,4-oxadiazol-5-one Step 1: To a mixture of 1-methyl-4-[4-(trifluoromethyl)phenyl]-1H,4H-imidazo[4,5- b]indole-7-carboxylic acid (170 mg; 0.47 mmol), NH4Cl (120 mg; 2.13 mmol) in DMF (10 ml) were added DIEA (0.62 ml; 3.38 mmol) and HATU (1.40 g; 3.50 mmol) at room temperature under N2 atmosphere. The mixture was stirred for 1 h at room temperature. For work-up the reaction was quenched with water at room temperature. The mixture was extracted with EtOAc (3 x 150 mL). The combined organic layers were washed with brine (1 x 100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford 1-methyl-4-[4-(trifluoromethyl)phenyl]-1H,4H-imidazo[4,5- b]indole-7-carboxamide (471 mg; 85 %) as yellow solid. Step 2: To a suspension of 1-methyl-4-[4-(trifluoromethyl)phenyl]-1H,4H-imidazo[4,5- b]indole-7-carboxamide (450 mg; 1.26 mmol) in DMF (10 ml) was added POCl3 (1 ml; 10.73 mmol) at room temperature. The resulting mixture was stirred for 1 h at 25°C. For work-up the reaction was quenched with water at room temperature. The resulting mixture was extracted with EtOAc (3 x 150 mL). The combined organic layers were washed with brine (1x100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford 1-methyl-4-[4-(trifluoromethyl)phenyl]-1H,4H- imidazo[4,5-b]indole-7-carbonitrile (370 mg; 85 %) as yellow solid. Step 3: To a stirred mixture of 1-methyl-4-[4-(trifluoromethyl)phenyl]-1H,4H- imidazo[4,5-b]indole-7-carbonitrile (350 mg; 1.01 mmol) and hydroxylamine hydrochloride (100 mg; 1.37 mmol) in EtOH (21 ml) and H2O (1 ml) was added Na2CO3 (150 mg; 1.34 mmol) at room temperature. The resulting mixture was stirred for 16 h at 80°C. For work-up the mixture was poured into 1 L of ice water. The resulting white precipitate was filtered and washed on the filter with water giving N-hydroxy-1-methyl-4-[4-(trifluoromethyl)phenyl]-1H,4H- imidazo[4,5-b]indole-7-carboximidamide (205 mg; 38 %) as off-white solid. Step 4: To a solution of N-hydroxy-1-methyl-4-[4-(trifluoromethyl)phenyl]-1H,4H- imidazo[4,5-b]indole-7-carboximidamide (180 mg; 0.34 mmol) in DMSO (5 ml) was added CDI (69 mg; 0.40 mmol) at room temperature. The resulting mixture was stirred for 3 h at 95°C. For work-up the reaction was quenched with water at room temperature. The resulting mixture was extracted with EtOAc (3 x 150 mL). The combined organic layers were washed with brine (1 x 100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure and purified by chromatography to afford 3-{1-methyl- 4-[4-(trifluoromethyl)phenyl]-1H,4H-imidazo[4,5-b]indol-7-yl}-4,5-dihydro- 1,2,4-oxadiazol-5-one (38.20 mg; 28 %) as off-white solid. Example 40: Synthesis of 5-[(5-{1-methyl-4-[4-(trifluoromethyl)phenyl]-1H,4H- imidazo[4,5-b]indol-7-yl}-4,5-dihydro-1,2-oxazol-3-yl)oxy]pyrimidine Step 1: To a stirred mixture of 1-methyl-4-[4-(trifluoromethyl)phenyl]-1H,4H- imidazo[4,5-b]indole-7-carboxylic acid (1.55 g; 4.27 mmol), methoxy(methyl)- amine hydrochloride (0.66 g; 6.41 mmol) and DIEA (2.40 ml; 12.82 mmol) in DMF (10 ml) was added HATU (3.42 g; 8.55 mmol) at room temperature. The resulting mixture was stirred for 1 h at 25°C. The reaction was quenched with water at room temperature. The resulting mixture was extracted with EtOAc (3 x 150 mL). The combined organic layers were washed with brine (1 x 100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford N-methoxy-N,1-dimethyl-4-[4-(trifluoromethyl)- phenyl]-1H,4H-imidazo[4,5-b]indole-7-carboxamide (1.65 g; 96 %) as yellow oil. Step 2: To a mixture of N-methoxy-N,1-dimethyl-4-[4-(trifluoromethyl)phenyl]-1H,4H- imidazo[4,5-b]indole-7-carboxamide (1.45 g; 3.60 mmol) in DCM (50 ml) was added DIBAL-H (11.10 ml; 11.10 mmol) at -78°C. The resulting mixture was stirred for 1 h at -78°C. For work-up the crude product was purified by distillation under reduced pressure and the fraction was collected at room temperature to give 1-methyl-4-[4-(trifluoromethyl)phenyl]-1H,4H-imidazo[4,5- b]indole-7-carbaldehyde (1.38 g; 93 %) as off-white solid Step 3: To a mixture of 1-methyl-4-[4-(trifluoromethyl)phenyl]-1H,4H-imidazo[4,5- b]indole-7-carbaldehyde (0.98 g; 2.37 mmol) and Ph3PMeBr (1.28 g; 3.55 mmol) in dioxane (30 ml) was added potassiumcarbonate (1.03 g; 7.10 mmol) at room temperature. The resulting mixture was stirred for 16 h at 100°C. The reaction was quenched with water at room temperature. The resulting mixture was extracted with EtOAc (3 x 150 mL). The combined organic layers were washed with brine (1 x 100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford 7-ethenyl-1-methyl-4-[4- (trifluoromethyl)phenyl]-1H,4H-imidazo[4,5-b]indole (342 mg; 42 %) as off- white solid. Step 4: To a mixture of 7-ethenyl-1-methyl-4-[4-(trifluoromethyl)phenyl]-1H,4H- imidazo[4,5-b]indole (232 mg; 0.67 mmol) in EtOAc (5 ml) were added 1- bromo-N-hydroxymethanecarbonimidoyl bromide (216 mg; 1.01 mmol) and Sodium bicarbonate (286 mg; 3.37 mmol) at room temperature. The resulting mixture was stirred for overnight at room temperature. For work-up the reaction was quenched with water at room temperature. The resulting mixture was extracted with EtOAc (3 x 150 mL). The combined organic layers were washed with brine (1 x 100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford 3-bromo-5-{1-methyl-4-[4- (trifluoromethyl)phenyl]-1H,4H-imidazo[4,5-b]indol-7-yl}-4,5-dihydro-1,2- oxazole (302 mg; 89 %) as yellow oil Step 5: To a mixture of 3-bromo-5-{1-methyl-4-[4-(trifluoromethyl)phenyl]-1H,4H- imidazo[4,5-b]indol-7-yl}-4,5-dihydro-1,2-oxazole (295 mg; 0.59 mmol) in dioxane (5 ml) was added HCl (1 ml; 12 mmol) at room temperature. The resulting mixture was stirred for 4 h at 25°C. For work-up the reaction was quenched with NaHCO3 (a.q.) at room temperature. The resulting mixture was extracted with EtOAc (3 x 150 mL). The combined organic layers were washed with brine (1x100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford 3-chloro-5-{1- methyl-4-[4-(trifluoromethyl)phenyl]-1H,4H-imidazo[4,5-b]indol-7-yl}-4,5- dihydro-1,2-oxazole (255 mg; 93 %) as yellow solid. Step 6: To a stirred mixture of 3-chloro-5-{1-methyl-4-[4-(trifluoromethyl)phenyl]- 1H,4H-imidazo[4,5-b]indol-7-yl}-4,5-dihydro-1,2-oxazole (80 mg; 0.17 mmol) and pyrimidin-5-ol (25 mg; 0.25 mmol) in DMF (2 ml) was added Cs2CO3 (117 mg; 0.34 mmol) at room temperature. The resulting mixture was stirred for 48 h at 120°C. For work-up the reaction was quenched with water at room temperature. The resulting mixture was extracted with EtOAc (3 x 150 mL). The combined organic layers were washed with brine (1 x 100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure and purified by chromatography to afford 5-[(5-{1-methyl-4- [4-(trifluoromethyl)phenyl]-1H,4H-imidazo[4,5-b]indol-7-yl}-4,5-dihydro-1,2- oxazol-3-yl)oxy]pyrimidine (13.10 mg; 16 %) as off-white solid. Table 1 Table 1 below shows exemplary compounds of the present invention. They have been synthesized as described in the Examples above or similar thereto.
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87 88 89
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425 426
Figure imgf000370_0001
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440 441 442
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478 479 480
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580 581
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TFA = trifluoroacetate LC-MS conditions: 1 Column: Waters XBridge C183.5 µm, 50*4.6 mm; 5-95 %: Flow Rate:1.5 mL/min; Analysis Time:6.5 min; MS scan range: 100-1000; Mobil Phase A: 0.02 % NH4OAc in water; Mobil Phase B: acetonitrile; Gradient: 0.15 min: 5 % B, 4.5 min: 95 % B, 6.0 min: 95 % B, 6.1 min: 5% B, 6.5 min: 5% B. 224Column: Waters XBridge C183.5um, 50*4.6mm; Solvent A: water+0.1% TFA; Solvent: ACN; Flow:1.5ml/min; Time: 6.5min; Gradient: 0.15 min: 10 % B, 4.5 min: 80 % B, 4.6 min: 95 % B, 6.0 min: 95 % B, 6.1 min: 5% B, 6.5 min: 5% B. 3 Column: Waters XBridge C183.5 µm, 50*4.6 mm; 20-70 %: Flow Rate:1.5 mL/min; Analysis Time:6.5 min; MS scan range: 100-1000; Mobil Phase A:0.1% TFA in water; Mobil Phase B:acetonitrile; Gradient: 0.15 min: 20 % B, 4.5 min: 70 % B, 4.6 min: 95 % B, 6.0 min: 95 % B, 6.1 min: 5% B, 6.5 min: 5% B 4 Column: Waters XBridge C183.5 µm, 50*4.6 mm; 30-95 %: Flow Rate:1.5 mL/min; Analysis Time:6.5 min; MS scan range: 100-1000; Mobil Phase A:0.1% TFA in water; Mobil Phase B:acetonitrile; Gradient: 0.15 min: 30 % B, 4.5 min: 95 % B, 4.6 min: 95 % B, 6.0 min: 95 % B, 6.1 min: 5% B, 6.5 min: 5% B 5 Column: waters XBridge C18 5um, 50*4.6mm;SolventA:water+0.1% TFA; Solvent: ACN; Flow: 1.5ml/min; Time:6.5min; Gradient :0.15 min: 10 % B, 4.5 min£º80 % B£¬4.6 min: 95 % B, 6.0 min: 95 % B, 6.1 min: 5% B, 6.5 min: 5% B 6 Column: XBridge C18, 3.5 µm, 3.0 * 30 mm; Solvent A: water + 0.1 % TFA; Solvent B: ACN + 0.1 % TFA; Flow: 2 ml/min; Gradient: 0 min: 5 % B, 8 min: 100 % B, 8.1 min: 100 % B, 8.5 min: 5% B, 10 min 5% B. 7 Column: Titank C181.8 µm, 30*2.1 mm; Column Oven: 40C; Mobile Phase A: 0.04% NH4OH, Mobile Phase B: ACN; Flow rate: 0.8 mL/min; Gradient: 10% B to 95% B in 2.1 min, hold 0.6 min;254nm 8 Agilent 1200 Series; Chromolith RP-18e 50-4,6mm;3.3 ml/min; solvent A: Water + 0.05% HCOOH; solvent B: Acetonitrile + 0.04% HCOOH; 220 nm; 0 to 2.0 min:0%B to 100%B; 2.0 to 2.5 min: 100%B 9 Column: HALO, 3.0*30mm, 2um; Column Oven: 40°C; Mobile Phase A: Water/0.05% TFA, Mobile Phase B: ACN/0.05% TFA; Flow rate: 1.5mL/min; Gradient:5%B to 100%B in 1.2min, hold 0.5 min 10 Column: HALO C18, 3.0*30mm, 2.0um;Column Oven: 40°C; Mobile phase A: Water/0.1% FA; Mobile phase B: Acetonitrile/0.1% FA; Flow rate: 1.5 mL/min; Gradient: 5%B to 100%B in 1.2min, hold 0.6 min 11 Column: Shim-pack XR-ODS, 3.0*50 mm, 2.2um; Mobile Phase A: Water/0.05% TFA, Mobile Phase B: ACN/0.05% TFA; Flow rate: 1.2 mL/min; Gradient:5%B to 100%B in 2.0min, hold 0.7 min 12 Column: HALO C18, 3.0*30mm, 2.0um; Column Oven: 40°C; Mobile phase A:Water/0.1% FA, Mobile phase B: Acetonitrile/0.1% TFA; Flow rate: 1.5mL/min; Gradient: 5% B to 100% B in 1.2min, hold 0.5 min; 254nm 13 Column: Chromolith RP-18e 50-4,6 mm; A: H2O + 0,05% HCOOH | B: MeCN + 0,04% HCOOH / 4% -> 100% B: 0 -> 2,8 min | 100% B: 2,8 -> 3,3 min 14 Waters Acquity UPLC; A: H2O + 0,05% HCOOH | B: MeCN + 0,04% HCOOH + 1% H2O T: 40 °C | Flow: 0,9 ml/min | Column: Kinetex EVO-C181,7 μm 50-2,1 mm 1% -> 99% B: 0 -> 1,0 min | 99% B: 1,0 -> 1,3 min 15 Column: Poroshell HPH-C18 2.7um, 3.0*50 mm; Column Oven: 40°C; Mobile Phase A:water/5mM NH4HCO3, Mobile Phase B: Acetonitrile; Flow rate: 1.2 mL/min; Gradient: 10% B to 95% B in2.1min, hold 0.6 min; 254nm 16 Column: Kinetex EVO 2.6um, 3.0*50 mm; Column Oven: 40°C; Mobile Phase A: water/5mM NH4HCO3, Mobile Phase B: Acetonitrile; Flow rate: 1.2 mL/min; Gradient: 10% B to 95% B in 2.1min, hold 0.6 min; 254nm 17 Column: Kinetex® EVO C185.0µm 50-4.6mm; A: H2O+0.05% HCOOH; B: MeCN+0.04% HCOOH+1% H2O; 1% -> 99% B: 0 -> 0.8min; 99% B: 0.8 -> 1.1min; T:40°C; Flow: 3.3mL/min; MS: 61-1000 amu positive 18 Kinetex EVO C185.0µm 50-4.6mm; A: H2O+0.1% TFA B: MeCN+0.1% TFA ; 1%->99% B: 0- >1.8 min ; 99% B: 1.8->2.1 min ; T: 40°C ; Flow: 3.3 mL/min ; MS: 61-1000 amu positive A: Column: Waters Cortecs C182.1*50mm, 1.6 micron particle size, column oven 45oC; Mobile phase A: Water/0.1% FA, Mobile phase B:Acetonitrile/0.1% FA; Flow rate: 0.8mL/min; Gradient:5%B to 95%B in 3min, hold 0.8 min, 254nm B: Column: Waters Xbridge C184.6*50mm, 5.0 micron particle size, column oven room temperature; Mobile phase A: Water/0.1% ammonium hydroxide, Mobile phase B:Acetonitrile/0.1% ammonium hydroxide; Flow rate: 1.5mL/min; Gradient:5%B to 95%B in 5.5min, hold 1 min, 254nm Chiral HPLC/SFC: a SFC; column: ChiralPak IC; eluent: CO2:ethanol (55:45); wave length: 220nm; flow: 5mL/min. b SFC:Column: YMC Cellulose-SC, eluent CO2 : Methanol 65:35, wavelength 254, flow: 5 mL/min. c SFC: Column: Lux Cellulose-2, Eluent CO2 : Methanol 65:35, Wavelength 270nm, Flow : 5ml/min. Melting point of selected compounds of Table 1 were determined by using a Tianjin Analytical Instrument RY-1 meting point detector and are depicted in Table 1a below: Table 1a
Figure imgf000456_0001
Figure imgf000457_0001
Table 1b Table 1b below shows further exemplary compounds of the present invention. They can be synthesized by adapting the methods and procedures described in the Examples above. LC-MS and Chiral HPLC/SFC conditions are as defined above for Table 1.
Figure imgf000457_0002
Figure imgf000458_0001
Figure imgf000459_0001
Figure imgf000460_0001
Figure imgf000461_0001
Figure imgf000462_0001
Figure imgf000463_0001
Figure imgf000464_0001
Figure imgf000465_0001
Figure imgf000466_0001
Figure imgf000467_0001
Figure imgf000468_0001
Figure imgf000469_0001
Compound Structure and Name No. B30 [5-(1-{2-methyl-8-[4-(trifluoro- methyl)phenyl]-2H,8H-pyrazolo[ b]indole-5-carbonyl}azetidin-3-yl oxazol-4-yl]methanol B31 N-[cyclopropyl(1,2,4-oxadiazol-3 yl)methyl]-2-methyl-8-[4- (trifluoromethyl)phenyl]-2H,8H- pyrazolo[3,4-b]indole-5-carboxa
Figure imgf000470_0001
Figure imgf000471_0001
Compound Structure and Name No. B34 N-[2-methoxy-1-(5-methylfuran- yl)ethyl]-2-methyl-8-[4- (trifluoromethyl)phenyl]-2H,8H- pyrazolo[3,4-b]indole-5-carboxa B35 (4,4-difluoro-2-methyl-1-{2-met (trifluoromethyl)phenyl]-2H,8H- pyrazolo[3,4-b]indole-5- carbonyl}pyrrolidin-2-yl)methan
Figure imgf000472_0001
Figure imgf000473_0001
Figure imgf000474_0001
Figure imgf000475_0001
Figure imgf000476_0001
Compound Structure and Name No. B45 2-methyl-N-[2-(3-methyl-1H-pyr yl)ethyl]-8-[4-(trifluoromethyl)ph 2H,8H-pyrazolo[3,4-b]indole-5- carboxamide B46 2-methyl-N-[(5-methyl-1H-imida yl)methyl]-8-[4-(trifluoromethyl) 2H,8H-pyrazolo[3,4-b]indole-5- carboxamide
Figure imgf000477_0001
Compound Structure and Name No. B47 1-{2-methyl-8-[4-(trifluoromethy phenyl]-2H,8H-pyrazolo[3,4-b]in carbonyl}-3-[(1H-pyrazol-5- yl)methyl]azetidin-3-ol B48 diastereomeric mixture 1-{2-methyl-8-[4- (trifluoromethyl)phenyl]-2H,8H- pyrazolo[3,4-b]indole-5-carbony (oxolan-2-yl)pyrrolidine
Figure imgf000478_0001
Figure imgf000479_0001
Compound Structure and Name No. B52 2-(1-{2-methyl-8-[4- (trifluoromethyl)phenyl]-2H,8H- pyrazolo[3,4-b]indole-5- carbonyl}pyrrolidin-2-yl)-1H-imid B53 diastereomeric mixture N-{5-ethoxyspiro[2.3]hexan-1-yl} methyl-8-[4-(trifluoromethyl)phe 2H,8H-pyrazolo[3,4-b]indole-5- carboxamide
Figure imgf000480_0001
Figure imgf000481_0001
Figure imgf000482_0001
Figure imgf000483_0001
Figure imgf000484_0001
Figure imgf000485_0001
Figure imgf000486_0001
Figure imgf000487_0001
Figure imgf000488_0001
Figure imgf000489_0001
Compound Structure and Name No. B76 2-methyl-N-{4H,5H,6H,7H-pyraz a]pyridin-4-yl}-8-[4- (trifluoromethyl)phenyl]-2H,8H- pyrazolo[3,4-b]indole-5-carboxa B77 2-methyl-N-{1-[(3-methyl-1,2,4- oxadiazol-5-yl)methyl]cycloprop (trifluoromethyl)phenyl]-2H,8H- pyrazolo[3,4-b]indole-5-carboxa
Figure imgf000490_0001
Figure imgf000491_0001
Figure imgf000492_0001
Figure imgf000493_0001
Figure imgf000494_0001
Compound Structure and Name No. B87 diastereomeric mixture N-{7,7-dimethyl-2- oxabicyclo[3.2.0]heptan-6-yl}-2- 8-[4-(trifluoromethyl)phenyl]-2H pyrazolo[3,4-b]indole-5-carboxa B88 N-[(3-cyclopropyl-1,2-oxazol-4- yl)methyl]-N,2-dimethyl-8-[4- (trifluoromethyl)phenyl]-2H,8H- pyrazolo[3,4-b]indole-5-carboxa
Figure imgf000495_0001
Figure imgf000496_0001
Figure imgf000497_0001
Compound Structure and Name No. B94 diastereomeric mixture N-[(2-methoxycyclopentyl)meth methyl-8-[4-(trifluoromethyl)phe 2H,8H-pyrazolo[3,4-b]indole-5- carboxamide B95 N-[2-(5-cyclopropyl-1,2-oxazol-3 yl)ethyl]-2-methyl-8-[4- (trifluoromethyl)phenyl]-2H,8H- pyrazolo[3,4-b]indole-5-carboxa
Figure imgf000498_0001
Figure imgf000499_0001
Compound Structure and Name No. B98 N-[2-(3-cyclopropyl-4H-1,2,4-tria yl)ethyl]-2-methyl-8-[4- (trifluoromethyl)phenyl]-2H,8H- pyrazolo[3,4-b]indole-5-carboxa B99 diastereomeric mixture N-(3-ethoxy-2,2-dimethylcyclobu N,2-dimethyl-8-[4- (trifluoromethyl)phenyl]-2H,8H- pyrazolo[3,4-b]indole-5-carboxa
Figure imgf000500_0001
Figure imgf000501_0001
Figure imgf000502_0001
Figure imgf000503_0001
Figure imgf000504_0001
Figure imgf000505_0001
Figure imgf000506_0001
Figure imgf000507_0001
Figure imgf000508_0001
Compound Structure and Name No. B119 N-[(1-ethyl-5-fluoro-1H-pyrazol-4 yl)methyl]-2-methyl-8-[4- (trifluoromethyl)phenyl]-2H,8H- pyrazolo[3,4-b]indole-5-carboxa B120 N-{2-[3-(dimethylamino)-1,2,4- oxadiazol-5-yl]ethyl}-2-methyl-8- (trifluoromethyl)phenyl]-2H,8H- pyrazolo[3,4-b]indole-5-carboxa
Figure imgf000509_0001
Figure imgf000510_0001
Figure imgf000511_0001
Figure imgf000512_0001
Compound Structure and Name No. B127 N-[1-(3-fluoropyridin-4-yl)cyclop 2-methyl-8-[4-(trifluoromethyl)p 2H,8H-pyrazolo[3,4-b]indole-5- carboxamide B128 racemic diastereomer with know relative stereochemistry, trans N-{[(1R,2R)-2-(furan-2- yl)cyclopropyl]methyl}-2-methyl- (trifluoromethyl)phenyl]-2H,8H- pyrazolo[3,4-b]indole-5-carboxa
Figure imgf000513_0001
Compound Structure and Name No. B129 N-[(4-ethyl-4H-1,2,4-triazol-3-yl) 2-methyl-8-[4-(trifluoromethyl)p 2H,8H-pyrazolo[3,4-b]indole-5- carboxamide B130 (1-{2-methyl-8-[4- (trifluoromethyl)phenyl]-2H,8H- pyrazolo[3,4-b]indole-5-carbonyl pyrazol-1-yl)azetidin-3-yl)metha
Figure imgf000514_0001
Compound Structure and Name No. B131 racemic diastereomer with know relative stereochemistry, trans N-[(3R,4R)-4-methoxyoxan-3-yl]- methyl-8-[4-(trifluoromethyl)phe 2H,8H-pyrazolo[3,4-b]indole-5- carboxamide B132 2-methyl-N-[3-(5-methyl-1H-pyr yl)propyl]-8-[4-(trifluoromethyl)p 2H,8H-pyrazolo[3,4-b]indole-5- carboxamide
Figure imgf000515_0001
Compound Structure and Name No. B133 diastereomeric mixture N-(4-cyclopropyloxolan-3-yl)-2-m [4-(trifluoromethyl)phenyl]-2H,8 pyrazolo[3,4-b]indole-5-carboxa B134 2-methyl-N-[1-(4H-1,2,4-triazol-3 yl)cyclopropyl]-8-[4- (trifluoromethyl)phenyl]-2H,8H- pyrazolo[3,4-b]indole-5-carboxa
Figure imgf000516_0001
Compound Structure and Name No. B135 1-{2-methyl-8-[4- (trifluoromethyl)phenyl]-2H,8H- pyrazolo[3,4-b]indole-5-carbonyl (thiophen-3-yl)azetidin-3-ol B136 N-[(3-methoxy-1,2-thiazol-5-yl)m N,2-dimethyl-8-[4- (trifluoromethyl)phenyl]-2H,8H- pyrazolo[3,4-b]indole-5-carboxa
Figure imgf000517_0001
Compound Structure and Name No. B137 N-[(5-cyclopropyl-1,2,4-oxadiazo yl)methyl]-N,2-dimethyl-8-[4- (trifluoromethyl)phenyl]-2H,8H- pyrazolo[3,4-b]indole-5-carboxa B138 2-methyl-N-[(1-propyl-1H-1,2,4-t yl)methyl]-8-[4-(trifluoromethyl) 2H,8H-pyrazolo[3,4-b]indole-5- carboxamide
Figure imgf000518_0001
Figure imgf000519_0001
Compound Structure and Name No. B141 1-{2-methyl-8-[4- (trifluoromethyl)phenyl]-2H,8H- pyrazolo[3,4-b]indole-5-carbonyl (pyrimidin-4-yl)azetidin-3-ol B142 2-methyl-N-[3-(1H-pyrazol-3-yl)p 8-[4-(trifluoromethyl)phenyl]-2H pyrazolo[3,4-b]indole-5-carboxa
Figure imgf000520_0001
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Figure imgf000522_0001
Table 1c Table 1c below shows compounds of the present invention. They can be synthesized by utilizing and/or adapting the methods and procedures described in the Examples above. LC-MS and Chiral HPLC/SFC conditions are as defined below at the end of Table 1c.
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Method A: Column Kinetex EVO C18, 3.0 * 50 mm, 2.6um;Mobile Phase A: 6.5mM NH4HCO3 + NH4OH (pH=10), Mobile Phase B: Acetonitrile Method B: Column:Halo C18, 100 mm, 4.6 mm; Column Oven: 40°C Mobile phase A:Water/0.05% TFA Mobile phase B: Acetonitrile / 0.05% TFA Method C: Column Poroshell HPH-C1850*3.0mm, 2.7 um; Mobile Phase A: water/5mM NH4HCO3; Mobile phase B: Acetonitrile. Method D: LC-MS Agilent 1200 Series Chromolith RP-18e 50-4,6mm; 3.3 ml/min solvent A: Water + 0.05% HCOOH solvent B: Acetonitrile + 0.04% HCOOH220 nm 0 to 2.0 min:0%B to 100%B 2.0 to 2.5 min: 100%B Method E: Chromolith® HR RP-185.0µm 50-4.6mm; A: H2O+0.1% TFA; B: MeCN+0.1% TFA; 1%->99% B: 0->2.0min; 99% B: 2.0->2.5min; T:40°C; Flow: 3.3mL/min; MS: 61-1000 amu positive Method F: Kinetex EVO C185,0µm 50-4.6mm; A: H2O+0.05% HCOOH B: MeCN+0.04% HCOOH + 1% H2O ; 0%->100% B: 0->1.8 min ; 100% B: 1.8->2.1 min ; T: 40°C ; Flow: 3.3 mL/min ; MS: 61-1000 amu positive / (Kinetex2 FA) Method G: Column: Shim-Pack C18, 3 um, 3.0 x 33 mm;Solvent A:water/5mM NH4HCO3; Solvent B:Acetonitrile Method H: HALO C1890A, 3.0 mm x 30 mm;Mobile Phase A :Water+0.05%TFA; Mobile Phase B:Acetonitrile+0.05%TFA Method I: Column: Waters Cortecs C182.1*50mm, 1.6 micron particle size, column oven 45oC; Mobile phase A: Water/0.1% FA, Mobile phase B:Acetonitrile/0.1% FA; Flow rate: 0.8mL/min; Gradient:5%B to 95%B in 3min, hold 0.8 min, 254nm Method K: Cloumn: HALO C18, 3.0*30mm, 2.0um; Column Oven: 40 °C; Mobile phase A: Water/0.1% FA, Mobile phase B: Acetonitrile/0.1% FA; 254nm. Method L: Kinetex EVO C185,0µm 50-4.6mm; A: H2O+0.1% TFA B: MeCN+0.1% TFA ; 1%- >99% B: 0->1.8 min ; 99% B: 1.8->2.1 min ; T: 40°C ; Flow: 3.3 mL/min. Biological Activity SK-HEP-1 reporter assay To identify inhibitors of YAP-TEAD interaction, 8x TEAD responsive elements driving the NanoLuc® luciferase gene were stably integrated into SK-HEP-1 cells (ECACC #: 91091816). For the assay, cells were treated in duplicates with the test compounds in a 10-point dose, with the top concentration starting at 30µM (final concentration in assay). After a 24 hour incubation at 37°C, 95% rH, and 5% CO2, a luciferase substrate / lysis reagent mix (NanoGlo™, Promega) was added to the cells, allowing the quantification of cellular luciferase activity. Cell Media: The cells were cultured in the following media: MEM, +10% FBS, +1x GlutaMAX, +1mM Sodium-Pyruvate, + 100µM Non-essential amino acids, +0.1mg/ml Hygromycin. The media used for the assay was: MEM (w/o Phenol Red), +10% FBS, +1x GlutaMAX, +1mM Sodium-Pyruvate, + 100µM Non- essential amino acids, +0.5% Pen/Strep Reagents: The reagents used are listed below:
Figure imgf000655_0001
Cell culture: The cells were examined using an inverted microscope to check for health and cell density. To dissociate adherent cells, the monolayer of cells was washed once with pre-warmed PBS. After removing the PBS, 3 ml pre- warmed Accutase® was added to a F75 flask, dispersed evenly and the flask was allowed to sit in incubator for ~4-5 minutes. When a single cell suspension was obtained, 7 ml of prewarmed growth media was added and resuspended with the cells. The cell suspension was transferred to a sterile 15 ml conical centrifuge tube, and spun for 5 min at 300xg, RT. The supernatant was discarded and the pellet was resuspended in 10 ml of pre-warmed growth media. The total cell count was determined, and 20 µl of the desired cell number was added to each well of a 384 well plate using a Multidrop Combi. The plates were then incubated for 24 hours at 37°C, 95% rH, and 5% CO2. Compound treatment: 24 hours after seeding, the cells were treated with compounds. A 1:333 dilution of compounds, diluted in DMSO, was made to get a final concentration of 0.3% DMSO per well. To transfer the compounds to the assay plate,120nl was shot from Labcyte low dead volume plates to the cell plates containing 20µl media/well with the ECHO 555 liquid handling system. After treatment, the cells were fed with 20µl fresh pre-warmed assay media using a Multidrop combi. The assay plates were then incubated for another 24h at 37°C, 95% rH, and 5% CO2. Luciferase readout: 24 h after treatment, the plates were taken out of the incubator and were allowed to equilibrate to RT. 30 µl of NanoGlo® reagent was added to the plates in the dark. Plates were shaken for 20 min on a Teleshake (~1500 rpm) in the dark. The luminescence was then measured using an EnVision microplate reader. The IC50 values were generated using Genedata Screener®. Viability assay in NCI-H226 (Yap-dependent) and SW620 Yap KO (Yap independent) cells The ability of YAP-TEAD inhibitors to inhibit tumor cell growth was evaluated using two different cell lines: NCI-H226, which is a YAP dependent cell line, and SW620 cells, where YAP and TAZ were knocked out using CRISPR to generate a YAP independent cell line. For the assay, cells were treated in duplicates with the test compounds in a 10-point dose, 1:3 dilution steps, with the top concentration starting at 30µM (final concentration in assay). After a 96 hour incubation at 37°C, 95% rH, and 5% CO2, a cell-permeant DNA-binding dye that stains only healthy cells (CyQUANT®, Promega) was added to the cells, allowing the quantification of cell viability. Cell Media: The NCI-H226 cells were cultured in the following media: RPMI 1640, +10% FBS, +1x GlutaMAX, +10mM HEPES, + 0.5% Pen/Strep. The SW620-KO cells were cultured in the following media: DMEM/F-12, +10% FBS, +1x GlutaMAX, +10mM HEPES, +0.5% Pen/Strep. Reagents: The reagents used are listed below:
Figure imgf000657_0001
Cell culture: The cells were examined using an inverted microscope to check for health, cell density, etc. To dissociate adherent cells, the monolayer of cells was washed once with pre-warmed PBS. After removing the PBS, 3ml pre- warmed Accutase was added to a F75 flask, dispersed evenly and the flask was allowed to sit in incubator for ~4-5 minutes. When a single cell suspension was obtained, 7ml of prewarmed growth media was added and resuspended with the cells. The cell suspension was transferred to a sterile 15 ml conical centrifuge tube, and spun for 5min at 300xg, RT. The supernatant was discarded and the pellet was resuspended in 10ml of pre-warmed growth media. The total cell count was determined, and 20µl of the desired cell number was added to each well of a 384 well plate using a Multidrop Combi. The plates were then incubated for 24 hours at 37°C, 95% rH, and 5% CO2. Compound treatment: 24 hours after seeding, the cells were treated with compounds. A 1:333 dilution of compounds, diluted in DMSO, was made to get a final concentration of 0.3% DMSO per well. To transfer the compounds to the assay plate,120nl was shot from Labcyte low dead volume plates to the cell plates containing 20µl media/well with the ECHO 555 liquid handling system. After treatment, the cells were fed with 20µl fresh pre-warmed assay media using a Multidrop combi. The assay plates were then incubated for 96h at 37°C, 95% rH, and 5% CO2. CyQuant® Measurement 96h after treatment 30µl of CyQuant® reagent was added to the assay plates using a Multidrop combi in the dark. The plates were then incubated for 1 hour at 37°C, 95% rH and 5% CO2. Thereafter, the assay plates were removed from the incubator and allowed to equilibrate to RT for 30min in the dark without lid. Finally, they were measured using an EnVision microplate reader with a FITC bottom read program. Experimental data in SK-HEP-1 reporter assay of the compounds shown in Table 1 are shown in Table 2 below and classified in the following groups: Group A IC50 is in the range of 1 nM to 10nM Group B IC50 is in the range of >10 nM to 100 nM Group C IC50 is in the range of >100 nM to 10000 nM Group D IC50 is in the range >10000 nM Experimental data in the Viability assay of the compounds shown in Table 1 are shown in Table 2 below and classified in the following groups: For the viability assay in NCI-H226 cells: Group A IC50 is in the range of 1 nM to 100 nM Group B IC50 is in the range of >100 nM to 1000 nM Group C IC50 is in the range of >1000 nM to 10000 nM Group D IC50 is in the range >10000 nM For the viability assay in SW620 Yap KO cells: Group A IC50 is in the range of 0.1 µM to 1 µM Group B IC50 is in the range of >1 µM to 10 µM Group C IC50 is in the range of >10 µM to 30 µM Group D IC50 is in the range >30 µM ND = Not determinable within the entire range n.d. = Value not detectable below threshold given in parantheses Table 2
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NCI-H226 In Vivo Efficacy Study 7-9-week-old H2d Rag2 female mice (own breeding, Taconic-Denmark) were inoculated subcutaneously with 5 x 10^6 NCI-H226 human mesothelioma tumor cells in the right flank. Tumor growth and body weight was measured twice weekly using caliper. Tumor volume was calculated using the formula TV = L x W x W /2. When tumor volume reached approximately 75-150 mm³, animals were randomized (Day 0) into treatment groups (n=9-10/group) and treated perorally (po) once daily (qd) for 29 days with either vehicle (20% hydroxypropyl β-cyclodextrin in 50 mM PBS pH 7.4) or Compound no. 2. Compound no. 2 was tested at dosing levels of 1, 3, 10, 30, and 100mg/kg, respectively. Results are depicted in Figure 1 (tumor growth over time for vehicle group and each dosage group) and Figure 2 (final tumor volume of vehicle group and each dosage group). Significant tumor growth inhibition was achieved compared to vehicle treated group for all tested dosing levels (Figure 1 – graphs b and c; p -value <0.001) showing maximal inhibition at dosing levels >10mg/kg. Statistical analysis of tumor volumes between treatment groups was done using repeated measures analysis of covariance (RM-ANCOVA) in a linear mixed effects model followed by least-squares means pairwise comparisons. The animal experiment was performed under regulation of the German animal welfare act and in accordance with the EU laboratory animal directive for the area of animal experiments. The following examples relate to medicaments: Example A: Injection vials A solution of 100 g of an active ingredient of the formula I or I-A or Table 1c and 5 g of disodium hydrogenphosphate in 3 l of bidistilled water is adjusted to pH 6.5 using 2 N hydrochloric acid, sterile filtered, transferred into injection vials, lyophilised under sterile conditions and sealed under sterile conditions. Each injection vial contains 5 mg of active ingredient. Example B: Suppositories A mixture of 20 g of an active ingredient of the formula I or I-A or Table 1c with 100 g of soya lecithin and 1400 g of cocoa butter is melted, poured into moulds and allowed to cool. Each suppository contains 20 mg of active ingredient. Example C: Solution A solution is prepared from 1 g of an active ingredient of the formula I or I-A or Table 1c, 9.38 g of NaH2PO4 ∙ 2 H2O, 28.48 g of Na2HPO4 ∙ 12 H2O and 0.1 g of benzalkonium chloride in 940 mL of bidistilled water. The pH is adjusted to 6.8, and the solution is made up to 1 l and sterilised by irradiation. This solution can be used in the form of eye drops. Example D: Ointment 500 mg of an active ingredient of the formula I or I-A or Table 1c are mixed with 99.5 g of Vaseline under aseptic conditions. Example E: Tablets A mixture of 1 kg of active ingredient of the formula I or I-A or Table 1c, 4 kg of lactose, 1.2 kg of potato starch, 0.2 kg of talc and 0.1 kg of magnesium stearate is pressed in a conventional manner to give tablets in such a way that each tablet contains 10 mg of active ingredient. Example F: Dragees Tablets are pressed analogously to Example E and subsequently coated in a conventional manner with a coating of sucrose, potato starch, talc, tragacanth and dye. Example G: Capsules 2 kg of active ingredient of the formula I or I-A or Table 1c are introduced into hard gelatine capsules in a conventional manner in such a way that each capsule contains 20 mg of the active ingredient. Example H: Ampoules A solution of 1 kg of active ingredient of the formula I or I-A or Table 1c in 60 l of bidistilled water is sterile filtered, transferred into ampoules, lyophilised under sterile conditions and sealed under sterile conditions. Each ampoule contains 10 mg of active ingredient.

Claims

Claims 1. Compound, or any pharmaceutically acceptable salt thereof, selected from the list of compounds in Table 1c.
2. Compound according to claim 1, or any pharmaceutically acceptable salt thereof, selected from the group of compounds consisting of: C2, C3, C6, C12, C16, C17, C18, C20, C25, C30, C31, C41, C42, C51, C52, C56, C62, C63, C64, C65, C66, C67, C70, C72, C73, C74, C75, C76, C77, C80, C81, C83, C86, C89, C90, C91, C94, C95, C96, C97, C98, C99, C101, C102, C104, C105, C119, C120, C121, C134, C147, C148, C149, C150, C153, C156, C159, C160, C161, C162, C164, C166, C167, C168, C169, C172, C173, C174, C175, C180, C181, C183, C184, C185, C187, C189, C191, C192, C198, C213, C214, C220, C225, C226, C227, C236, C237, C240, C242, C245, C247, C248, C250, C254, C256, C257, C258, C260, C261, C273, C276, C277.
3. Compound according to any of claims 1 or 2, or any pharmaceutically acceptable salt thereof, for use as a medicament.
4. Compound according to any of claims 1 or 2, or any pharmaceutically acceptable salt thereof, for use in the prevention and/or treatment of a medical condition or disease that is affected by inhibiting YAP-TEAD and/or TAZ-TEAD interaction.
5. Compound according to any of claims 1 or 2, or any pharmaceutically acceptable salt thereof, for use in the prevention and/or treatment of a medical condition or disease selected from the group consisting of: cancer, in particular tumors including solid tumors, of breast cancer, lung cancer, liver cancer, ovarian cancer, squamous cancer, renal cancer, gastric cancer, medulloblastoma, colon cancer, pancreatic cancer; cardiovascular diseases and fibrosis, in particular, liver fibrosis.
6. A pharmaceutical composition comprising a compound according to any of claims 1 or 2, or any N pharmaceutically acceptable salt thereof, as active ingredient and a pharmaceutically acceptable carrier.
7. The pharmaceutical composition according to claim 6 that further comprises a second active ingredient or any pharmaceutically acceptable salt thereof, wherein that second active ingredient is other than a compound of claim 1.
8. Set (kit) comprising separate packs of a) an effective amount of a compound of claim 1, or any acceptable salt thereof; and b) an effective amount of a further active ingredient that further active ingredient not being a compound of claim 1.
PCT/EP2021/080349 2021-02-10 2021-11-02 2,8-dihydropyrazolo[3,4-b]indole derivatives for use in the treatment of cancer WO2022233442A1 (en)

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