WO2014048865A1 - New bicyclic derivatives - Google Patents

New bicyclic derivatives Download PDF

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Publication number
WO2014048865A1
WO2014048865A1 PCT/EP2013/069679 EP2013069679W WO2014048865A1 WO 2014048865 A1 WO2014048865 A1 WO 2014048865A1 EP 2013069679 W EP2013069679 W EP 2013069679W WO 2014048865 A1 WO2014048865 A1 WO 2014048865A1
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WO
WIPO (PCT)
Prior art keywords
carbonyl
pyrrolo
substituted
hexahydro
benzotriazole
Prior art date
Application number
PCT/EP2013/069679
Other languages
French (fr)
Inventor
Jérôme HERT
Daniel Hunziker
Patrizio Mattei
Harald Mauser
Guozhi Tang
Lisha Wang
Original Assignee
F. Hoffmann-La Roche Ag
Hoffmann-La Roche Inc.
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Filing date
Publication date
Priority to JP2015533548A priority Critical patent/JP6285444B2/en
Priority to ES13766056T priority patent/ES2753163T3/en
Priority to EP19187624.2A priority patent/EP3590940B1/en
Priority to MX2015002090A priority patent/MX368615B/en
Priority to EP13766056.9A priority patent/EP2900669B1/en
Priority to UAA201503793A priority patent/UA116547C2/en
Application filed by F. Hoffmann-La Roche Ag, Hoffmann-La Roche Inc. filed Critical F. Hoffmann-La Roche Ag
Priority to KR1020157007381A priority patent/KR102179599B1/en
Priority to LT13766056T priority patent/LT2900669T/en
Priority to SG11201500572YA priority patent/SG11201500572YA/en
Priority to RS20191402A priority patent/RS59512B1/en
Priority to MA37940A priority patent/MA37940B1/en
Priority to IN960DEN2015 priority patent/IN2015DN00960A/en
Priority to AU2013322838A priority patent/AU2013322838B2/en
Priority to SI201331606T priority patent/SI2900669T1/en
Priority to EA201590534A priority patent/EA036630B1/en
Priority to BR112015004111A priority patent/BR112015004111A2/en
Priority to DK13766056T priority patent/DK2900669T3/en
Priority to CN201380049392.4A priority patent/CN104684915B/en
Priority to PL13766056T priority patent/PL2900669T3/en
Priority to CA2878442A priority patent/CA2878442A1/en
Publication of WO2014048865A1 publication Critical patent/WO2014048865A1/en
Priority to ZA2015/00345A priority patent/ZA201500345B/en
Priority to IL237126A priority patent/IL237126A/en
Priority to PH12015500263A priority patent/PH12015500263A1/en
Priority to CR20150120A priority patent/CR20150120A/en
Priority to US14/719,063 priority patent/US20150353559A1/en
Priority to HK15107163.9A priority patent/HK1206722A1/en
Priority to US15/291,933 priority patent/US20170050960A1/en
Priority to US15/583,679 priority patent/US10669268B2/en
Priority to HRP20191937TT priority patent/HRP20191937T1/en
Priority to US16/818,409 priority patent/US20200339570A1/en

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    • 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
    • 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
    • C07D471/02—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 two hetero rings
    • C07D471/04—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
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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

  • the present invention relates to organic compounds useful for therapy or prophylaxis in a mammal, and in particular to autotaxin (ATX) inhibitors which are inhibitors of lysophosphatidic acid (LP A) production and thus modulators of LP A levels and associated signaling, for the treatment or prophylaxis of renal conditions, liver conditions, inflammatory conditions, conditions of the nervous system, conditions of the respiratory system, vascular and
  • cardiovascular conditions cardiovascular conditions, fibrotic diseases, cancer, ocular conditions, metabolic conditions, cholestatic and other forms of chronic pruritus and acute and chronic organ transplant rejection.
  • the present invention provides novel compounds of formula (I)
  • R 1 is alkyl, haloalkyl, substituted cycloalkyl, substituted cycloalkylalkyl, substituted
  • piperazinyl substituted piperidinyl, substituted indanyloxyalkyl, substituted phenyl, substituted phenylalkyl, substituted phenoxyalkyl, substituted phenylcyclo alkyl, substituted phenylalkenyl, substituted phenylalkynyl, substituted pyridinyl, substituted pyridinylalkyl, substituted pyridinylalkenyl, substituted pyridinylalkynyl, substituted thiophenyl, substituted thiophenylalkyl, substituted thiophenylalkenyl, substituted thiophenylalkynyl, naphtyl, substituted naphthyl, quinolyl, substituted quinolinyl, isoquinolyl, substituted iso quinolinyl, substituted 2,3-dihydro-lH-isoindol-2-yl, substituted lH-
  • Y is -OC(O)-, -NR 7 C(0)-, -C(O)-, -S(0) 2 -, or ;
  • A is -N- or CR 5 -;
  • W is -0-, -S-, -NR 6 -, -C(O)-, -S(0) 2 -, -C(0)-NR 6 - or -CR 3 R 4 -;
  • R 3 and R 4 are independently selected from H, halogen, alkyl and cycloalkyl;
  • R 5 , R 6 and R 7 are independently selected from H, alkyl and cycloalkyl
  • R 8 , R 9 and R 10 are independently selected from H, alkyl, hydroxyalkyl, haloalkyl,
  • cycloalkylcarbonyl alkylsulfonyl, haloalkylsulfonyl, cycloalkylsulfonyl, substituted aminosulfonyl, substituted amino and substituted aminoalkyl, wherein substituted aminosulfonyl, substituted amino and substituted aminoalkyl are substituted on the nitrogen atom with one to two substituents independently selected from H, alkyl, cycloalkyl, cycloalkylalkyl, hydroxyalkyl, alkoxyalkyl, alkylcarbonyl and
  • cycloalkylcarbonyl and wherein substituted phenyl, substituted pyrrolyl, substituted pyrrolydinyl, substituted tetrahydrofuranyl, and substituted pyridinyl are substituted with one to three substituents independently selected from alkyl, halogen, haloalkyl, alkoxy and haloalkoxy; m, n, p and q are independently selected from 1 or 2;
  • R 11 is H, alkyl, haloalkyl or cycloalkyl
  • R 12 is alkyl, halogen, haloalkyl and alkoxy
  • R 2 is selected from the ring systems B, C, D, E, F, G, H, I, J, K, L, M, N, O, P, Q, R, S, T, U, V, X, Z, AA, AB, AC, AD, AE, AF, AG, AH, AI and AJ; and pharmaceutically acceptable salts.
  • ATX Autotaxin
  • LPC lysophosphatidyl choline
  • LPA bioactive signaling molecule lysophosphatidic acid
  • LPA can elicit a wide range of cellular responses; including smooth muscle cell contraction, platelet activation, cell proliferation, chemotaxis and others.
  • LPA mediates its effects via signaling to several G protein coupled receptors (GPCRs); the first members were originally denoted Edg (endothelial cell differentiation gene) receptors or ventricular zone gene-l(vzg-l) but are now called LPA receptors.
  • GPCRs G protein coupled receptors
  • Edg endothelial cell differentiation gene
  • ventricular zone gene-l(vzg-l) ventricular zone gene-l(vzg-l) but are now called LPA receptors.
  • the prototypic group now consists of LPAl/Edg-2/VZG-l, LPA2/Edg-4, and LPA3/Edg-7.
  • the ATX-LPA signaling axis is involved in a large range of physiological and pathophysiological functions, including, for example, nervous system function, vascular development, cardiovascular physiology, reproduction, immune system function, chronic inflammation, tumor metastasis and progression, organ fibrosis as well as obesity and/or other metabolic diseases such as diabetes mellitus. Therefore, increased activity of ATX and/or increased levels of LPA, altered LPA receptor expression and altered responses to LPA may contribute to the initiation, progression and/or outcome of a number of different pathophysiological conditions related to the ATX/LPA axis.
  • the compounds of formula (I) or their pharmaceutically acceptable salts and esters can be used for the treatment or prophylaxis of diseases, disorders or conditions that are associated with the activity of autotaxin and/or the biological activity of lysophosphatidic acid (LPA).
  • LPA lysophosphatidic acid
  • the compounds of formula (I) or their pharmaceutically acceptable salts and esters herein inhibit autotaxin activity and therefore inhibit LPA production and modulate LPA levels and associated signaling.
  • Autotaxin inhibitors described herein are useful as agents for the treatment or prevention of diseases or conditions in which ATX activity and/or LPA signaling participates, is involved in the etiology or pathology of the disease, or is otherwise associated with at least one symptom of the disease.
  • the ATX-LPA axis has been implicated for example in angiogenesis, chronic inflammation, autoimmune diseases, fibrotic diseases, cancer and tumor metastasis and progression, ocular conditions, metabolic conditions such as obesity and/or diabetes mellitus, conditions such as cholestatic or other forms of chronic pruritus as well as acute and chronic organ transplant rejection.
  • LP A lysophosphatidic acid
  • alkenyl denotes a monovalent linear or branched hydrocarbon group of 2 to 7 carbon atoms with at least one double bond. In particular embodiments, alkenyl has 2 to 4 carbon atoms with at least one double bond. Examples of alkenyl include ethenyl, propenyl, prop-2-enyl, isopropenyl, n-butenyl and iso-butenyl. Particular alkenyl group is ethenyl.
  • alkoxy denotes a group of the formula -O-R', wherein R' is an alkyl group.
  • alkoxy group include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy and tert-butoxy.
  • Particular alkoxy group include methoxy.
  • alkoxyalkoxy denotes an alkoxy group wherein at least one of the hydrogen atoms of the alkoxy group has been replaced by another alkoxy group.
  • alkoxyalkoxy group include methoxymethoxy, ethoxymethoxy, methoxyethoxy, ethoxyethoxy, methoxypropoxy and ethoxypropoxy.
  • Particular alkoxyalkoxy groups include methoxymethoxy and methoxyethoxy.
  • alkoxyalkoxyalkyl denotes an alkyl group wherein at least one of the hydrogen atoms of the alkyl group has been replaced by an alkoxyalkoxy group.
  • alkoxyalkoxyalkyl group include methoxymethoxymethyl, ethoxymethoxymethyl,
  • alkoxyalkyl denotes an alkyl group wherein at least one of the hydrogen atoms of the alkyl group has been replaced by an alkoxy group.
  • alkoxyalkyl groups include methoxymethyl, ethoxymethyl, methoxyethyl, ethoxyethyl, methoxypropyl,
  • alkoxyalkyl group include include
  • alkoxyhaloalkyl denotes a haloalkyl group wherein at least one of the hydrogen atoms of the haloalkyl group has been replaced by an alkoxy group.
  • alkoxyhaloalkyl groups include methoxytrifluoroethyl, ethoxytrifluoroethyl,
  • methoxytrifluoropropyl methoxytrifluoropropyl, ethoxytrifluoropropyl and isopropoxytrifluoroethyl.
  • Particular alkoxyhaloalkyl group include include methoxytrifluoroethyl.
  • alkyl denotes a monovalent linear or branched saturated hydrocarbon group of 1 to 12 carbon atoms. In particular embodiments, alkyl has 1 to 7 carbon atoms, and in more particular embodiments 1 to 4 carbon atoms. Examples of alkyl include methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl and sec-butyl, pentyl. Particular alkyl groups include methyl, ethyl, propyl and isopropyl. More particular alkyl groups are methyl and isoropyl.
  • alkylcarbonyl denotes a group of the formula -C(0)-R', wherein R' is an alkyl group.
  • alkylcarbonyl groups include groups of the formula -C(0)-R', wherein R' is methyl or ethyl.
  • Particular alkylcarbonyl groups include groups of the formula -C(0)-R', wherein R' is methyl.
  • alkylsulfanyl denotes a group of the formula -S-R', wherein R' is an alkyl group.
  • alkylsulfanyl groups include groups of the formula -S-R', wherein R' is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl.
  • Particular alkylsulfanyl groups include group of the formula -S-R', wherein R' is methyl.
  • alkylsulfinyl denotes a group of the formula -S(0)-R', wherein R' is an alkyl group.
  • alkylsulfinyl groups include groups of the formula
  • R' is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl.
  • alkylsulfinyl groups include group of the formula -S(0)-R', wherein R' is methyl.
  • alkylsulfonyl denotes a group of the formula -S(0)2-R', wherein R' is an alkyl group.
  • alkylsulfonyl groups include groups of the formula
  • R' is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl.
  • alkylsulfonyl groups include group of the formula -S(0)2-R', wherein R' is methyl.
  • alkynyl denotes a monovalent linear or branched saturated hydrocarbon group of 2 to 7 carbon atoms comprising one, two or three triple bonds. In particular embodiments alkynyl has from 2 to 4 carbon atoms comprising one or two triple bonds. Examples of alkynyl include ethynyl, propynyl, prop-2-ynyl, isopropynyl and n-butynyl.
  • amino denotes a -NH 2 group.
  • amino alkyl denotes an alkyl group wherein at least one of the hydrogen atoms of the alkyl group has been replaced by an aminogroup.
  • aminoalkyl include aminomethyl, aminoethyl, amino- 1 -methyl- ethyl, aminopropyl, aminomethylpropyl and aminopropyl. Particular examples are aminomethyl and haminoethyl.
  • amino sulfonyl denotes a -S(0) 2 -NH 2 group.
  • carbonyl denotes a -C(O)- group.
  • cyano denotes a -C ⁇ N group.
  • cycloalkoxy denotes a group of the formula -O-R', wherein R' is a cycloalkyl group.
  • examples of cycloalkoxy group include cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy and cyclooctyloxy.
  • Particular cycloalkoxy group is cyclopropoxy.
  • cycloalkoxyalkyl denotes an alkyl group wherein at least one of the hydrogen atoms of the alkyl group has been replaced by a cycloalkoxy group.
  • cycloalkoxyalkyl groups include cyclopropoxymethyl, cyclopropoxyethyl, cyclobutoxymethyl, cyclobutoxyethyl, cyclopentyloxymethyl, cyclopentyloxyethyl, cyclohexyloxymethyl, cyclohexyloxyethyl, cycloheptyloxymethyl, cycloheptyloxyethyl, cyclooctyloxymethyl and cyclooctyloxyethyl.
  • cycloalkyl denotes a monovalent saturated monocyclic or bicyclic hydrocarbon group of 3 to 10 ring carbon atoms.
  • cycloalkyl denotes a monovalent saturated monocyclic hydrocarbon group of 3 to 8 ring carbon atoms.
  • Bicyclic means a ring system consisting of two saturated carbocycles having two carbon atoms in common.
  • monocyclic cycloalkyl are cyclopropyl, cyclobutanyl, cyclopentyl, cyclohexyl or cycloheptyl.
  • bicyclic cycloalkyl are bicyclo[2.2.1]heptanyl or bicyclo[2.2.2]octanyl.
  • Particular monocyclic cycloalkyl groups are cyclopropyl, cyclobutanyl, cyclopentyl and cyclohexyl. More particular monocyclic cycloalkyl group is cyclopropyl.
  • cycloalkylalkoxy denotes an alkoxy group wherein at least one of the hydrogen atoms of the alkoxy group is replaced by a cycloalkyl group.
  • examples of cycloalkylalkoxy include cyclopropylmethoxy, cyclobutylmethoxy, cyclopentylmethoxy, cyclohexylmethoxy, cycloheptylmethoxy and cyclooctylmethoxy.
  • cycloalkylalkoxyalkyl denotes an alkyl group wherein at least one of the hydrogen atoms of the alkyl group is replaced by a cycloalkylalkoxy group.
  • examples of cycloalkylalkoxyalkyl include cyclopropylmethoxymethyl, cyclopropylmethoxyethyl, cyclobutylmethoxymethyl, cyclobutylmethoxyethyl, cyclopentylmethoxyethyl,
  • cycloalkylalkyl denotes an alkyl group wherein at least one of the hydrogen atoms of the alkyl group is replaced by a cycloalkyl group.
  • examples of cycloalkylalkyl include cyclopropylmethyl, cyclopropylethyl, cyclopropylbutyl, cyclobutylpropyl, 2-cyclopropylbutyl, cyclopentylbutyl, cyclohexylmethyl, cyclohexylethyl, bicyclo[4.1.0]heptanylmethyl,
  • cycloalkylalkyl are adamentanylmethyl and adamantanylethyl.
  • Particular examples of cycloalkylalkyl are
  • cycloalkylalkyl are cyclohexylmethyl, cyclohexylethyl, bicyclo[4.1.0]heptanylmethyl, bicyclo[2.2.2]octanylmethyl, adamentanylmethyl and adamantanylethyl.
  • cycloalkylcarbonyP'of the formula -C(0)-R' wherein R' is a cycloalkyl group.
  • cycloalkylcarbonyl groups include groups of the formula -C(0)-R', wherein R' is cyclopropyl.
  • cycloalkylsulfanyl denotes a group of the formula -S-R', wherein R' is a cycloalkyl group.
  • examples of cycloalkylsulfanyl groups include groups of the formula -S-R', wherein R' is cyclopropyl.
  • cycloalkylsulfinyl denotes a group of the formula -S(0)-R', wherein R' is a cycloalkyl group.
  • examples of cycloalkylsulfinyl groups include groups of the formula -S(0)-R', wherein R' is cyclopropyl.
  • cycloalkylsulfonyl denotes a group of the formula -S(0)2-R', wherein R' is a cycloalkyl group.
  • examples of cycloalkylsulfonyl groups include groups of the formula -S(0) 2 - R', wherein R' is cyclopropyl.
  • haloalkoxy denotes an alkoxy group wherein at least one of the hydrogen atoms of the alkoxy group has been replaced by the same or different halogen atoms.
  • perhaloalkoxy denotes an alkoxy group where all hydrogen atoms of the alkoxy group have been replaced by the same or different halogen atoms.
  • haloalkoxy include fluoromethoxy, difluoromethoxy, trifluoromethoxy, trifluoroethoxy, trifluoromethylethoxy, trifluorodimethylethoxy and pentafluoroethoxy.
  • Particular haloalkoxy group is trifluoromethoxy.
  • halo alky 1 denotes an alkyl group wherein at least one of the hydrogen atoms of the alkyl group has been replaced by the same or different halogen atoms.
  • perhaloalkyl denotes an alkyl group where all hydrogen atoms of the alkyl group have been replaced by the same or different halogen atoms.
  • haloalkyl include fluoromethyl, difluoromethyl, trifluoromethyl, trifluoro ethyl, trifluoromethylethyl and pentafluoroethyl.
  • Particular haloalkyl group is trifluoromethyl.
  • halo alky lsulfanyl denotes a group of the formula -S-R', wherein R' is a haloalkyl group.
  • halo alky lsulfanyl groups include groups of the formula -S-R', wherein R' is trifluoromethyl.
  • halo alky lsulfmyl denotes a group of the formula -S(0)-R', wherein R' is a haloalkyl group.
  • halo alky lsulfmyl groups include groups of the formula -S(0)-R', wherein R' is trifluoromethyl.
  • haloalkylsulfonyl denotes a group of the formula -S(0)2-R', wherein R' is a haloalkyl group.
  • haloalkylsulfonyl groups include groups of the formula -S(0)2-R', wherein R' is trifluoromethyl.
  • halogen and "halo" are used interchangeably herein and denote fluoro, chloro, bromo, or iodo. Particular halogens are chloro, fluoro and bromo. More particular halogens are chloro and fluoro.
  • hydroxy denotes an -OH group.
  • hydroxyalkyl denotes an alkyl group wherein at least one of the hydrogen atoms of the alkyl group has been replaced by a hydroxy group.
  • examples of hydroxyalkyl include hydro xymethyl, hydro xyethyl, hydroxy- 1 -methyl-ethyl, hydro xypropyl,
  • hydroxymethylpropyl and dihydroxypropyl Particular examples are hydroxymethyl and hydro xyethyl.
  • hydroxyhaloalkyl denotes a haloalkyl group wherein at least one of the hydrogen atoms of the haloalkyl group has been replaced by an hydroxy group.
  • exemplary hydroxyhaloalkyl groups include hydroxytrifluoroethyl and hydroxytrifluoropropyl.
  • Particular hydroxyhaloalkyl groups include hydroxytrifluoroethyl.
  • indanyloxy denotes a group of the formula -O-R', wherein R' is an indanyl.
  • indanyloxyalkyl denotes an alkyl group wherein at least one of the hydrogen atoms of the alkyl group has been replaced by a indanyloxy group.
  • exemplary indanyloxyalkyl groups include indanylo xymethyl, indanylo xyethyl and indanylo xypropyl.
  • indanyloxyalkyl group is indanyloxymethyl.
  • phenoxy denotes a group of the formula -O-R', wherein R' is a phenyl.
  • phenoxyalkyl denotes an alkyl group wherein at least one of the hydrogen atoms of the alkyl group has been replaced by a phenoxy group.
  • exemplary phenoxyalkyl groups include phenoxymethyl, phenoxyethyl and phenoxypropyl.
  • Particular phenoxyalkyl group is phenoxymethyl.
  • phenylalkenyl denotes an alkenyl group wherein at least one of the hydrogen atoms of the alkenyl group has been replaced a phenyl.
  • Particular phenylalkenyl group is phenylethenyl.
  • phenylalkyl denotes an alkyl group wherein at least one of the hydrogen atoms of the alkyl group has been replaced a phenyl.
  • Particular phenylalkyl groups are benzyl, phenethyl and phenylpropyl. More particular phenylalkyl groups are benzyl and phenethyl. Further particular phenylalkyl group is benzyl.
  • phenylalkynyl denotes an alkynyl group wherein at least one of the hydrogen atoms of the alkynyl group has been replaced a phenyl. Particular phenylalkynyl group is phenylethynyl.
  • phenylcyloalkyl denotes a cycloalkyl group wherein at least one of the hydrogen atoms of the cycloalkyl group has been replaced a phenyl.
  • Particular phenylcycloalkyl group is phenylcyclopropyl.
  • pyridinylalkenyl denotes an alkenyl group wherein at least one of the hydrogen atoms of the alkenyl group has been replaced a pyridinyl. Particular pyridinylalkenyl group is pyridinylethenyl.
  • pyridinylalkyl denotes an alkyl group wherein at least one of the hydrogen atoms of the alkyl group has been replaced a pyridinyl.
  • Particular pyridinylalkyl groups are pyridinylmethyl, pyridinylethyl and pyridinylpropyl. More particular pyridinylalkyl group is pyridinylethyl.
  • pyridinylalkynyl denotes an alkynyl group wherein at least one of the hydrogen atoms of the alkynyl group has been replaced a pyridinyl.
  • Particular pyridinylalkynyl group is pyridinylethynyl.
  • thiophenylalkenyl denotes an alkenyl group wherein at least one of the hydrogen atoms of the alkenyl group has been replaced a thiophenyl.
  • thiophenylalkenyl group is thiophenylethenyl.
  • thiophenylalkyl denotes an alkyl group wherein at least one of the hydrogen atoms of the alkyl group has been replaced a thiophenyl.
  • Particular thiophenylalkyl groups are thiophenylmethyl, thiophenylethyl and thiophenylpropyl. More particular thiophenylalkyl group is thiophenylmethyl.
  • thiophenylalkynyl denotes an alkynyl group wherein at least one of the hydrogen atoms of the alkynyl group has been replaced a thiophenyl.
  • thiophenylalkynyl group is thiophenylethynyl.
  • salts refers to those salts which retain the biological effectiveness and properties of the free bases or free acids, which are not biologically or otherwise undesirable.
  • the salts are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, in particular hydrochloric acid, and organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p- toluenesulfonic acid, salicylic acid, N-acetylcystein and the like.
  • salts derived from an inorganic base include, but are not limited to, the sodium, potassium, lithium, ammonium, calcium, magnesium salts and the like.
  • Salts derived from organic bases include, but are not limited to salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as
  • Particular pharmaceutically acceptable salts of compounds of formula (I) are the hydrochloride salts, methanesulfonic acid salts and citric acid salts.
  • “Pharmaceutically acceptable esters” means that compounds of general formula (I) may be derivatised at functional groups to provide derivatives which are capable of conversion back to the parent compounds in vivo. Examples of such compounds include physiologically acceptable and metabolically labile ester derivatives, such as methoxymethyl esters, methylthio methyl esters and pivaloyloxymethyl esters. Additionally, any physiologically acceptable equivalents of the compounds of general formula (I), similar to the metabolically labile esters, which are capable of producing the parent compounds of general formula (I) in vivo, are within the scope of this invention.
  • protecting group denotes a group which selectively blocks a reactive site in a multifunctional compound such that a chemical reaction can be carried out selectively at another unprotected reactive site in the meaning conventionally associated with it in synthetic chemistry.
  • Protecting groups can be removed at the appropriate point.
  • Exemplary protecting groups are amino -protecting groups, carboxy-protecting groups or hydroxy-protecting groups.
  • Particular protecting groups are the tert-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz), fluorenylmethoxycarbonyl (Fmoc) and benzyl (Bn) groups.
  • protecting groups are the tert-butoxycarbonyl (Boc) and the fluorenylmethoxycarbonyl (Fmoc) groups. More particular protecting group is the tert-butoxycarbonyl (Boc) group.
  • the abbreviation uM means micro Molar and is equivalent to the symbol ⁇ .
  • the abbreviation uL means microliter and is equivalent to the symbol ⁇ .
  • the abbreviation ug means microgram and is equivalent to the symbol ⁇ g.
  • the compounds of formula (I) can contain several asymmetric centers and can be present in the form of optically pure enantiomers, mixtures of enantiomers such as, for example, racemates, optically pure diastereoisomers, mixtures of diastereoisomers, diastereoisomeric racemates or mixtures of diastereoisomeric racemates.
  • the asymmetric carbon atom can be of the "R” or "S” configuration.
  • an embodiment of the present invention are compounds according to formula (I) as described herein and pharmaceutically acceptable salts or esters thereof, in particular compounds according to formula (I) as described herein and pharmaceutically acceptable salts thereof, more particularly compounds according to formula (I) as described herein.
  • R 1 is alkyl, haloalkyl, substituted cycloalkyl, substituted cycloalkylalkyl, substituted phenyl, substituted phenylalkyl, substituted phenoxyalkyl, substituted
  • phenylcyclo alkyl substituted phenylalkenyl, substituted phenylalkynyl, substituted pyridinyl, substituted pyridinylalkyl, substituted pyridinylalkenyl, substituted pyridinylalkynyl, substituted thiophenyl, substituted thiophenylalkyl, substituted thiophenylalkenyl, substituted thiophenylalkynyl, substituted 2,3-dihydro-lH-isoindol- 2-yl, substituted lH-indol-2-yl or substituted benzofuran-2-yl wherein substituted cycloalkyl, substituted cycloalkylalkyl, substituted phenyl, substituted phenylalkyl, substituted phenylalkynyl, substituted phenoxyalkyl, substituted phenylcyclo alkyl, substituted phen
  • Y is -OC(O)-, -NR 7 C(0)-, -C(O)-, -S(0) 2 -, A is -N- or CR 5 -;
  • W is -0-, -S-, -NR 6 -, -C(O)-, -S(0) 2 -, -C(0)-NR 6 - or -CR 3 R 4 -;
  • R 3 and R 4 are independently selected from H, halogen, alkyl and cycloalkyl;
  • R 5 , R 6 and R 7 are independently selected from H, alkyl and cycloalkyl
  • R 8 , R 9 and R 10 are independently selected from H, alkyl, hydroxyalkyl, haloalkyl,
  • hydroxyhaloalkyl cycloalkyl, cycloalkylalkyl, cycloalkylalkoxy, cycloalkoxy, cycloalkoxyalkyl, cycloalkylalkoxyalkyl, alkoxy, alkoxyalkyl, haloalkoxy,
  • alkoxyhaloalkyl alkoxyalkoxy, alkoxyalkoxyalkyl, phenyl, substituted phenyl, pyridinyl, substituted pyridinyl, halogen, hydroxy, cyano, alkylsulfanyl,
  • cycloalkylsulfinyl alkylsulfonyl, haloalkylsulfonyl, cycloalkylsulfonyl, substituted aminosulfonyl, substituted amino and substituted aminoalkyl, wherein substituted aminosulfonyl, substituted amino and substituted aminoalkyl are substituted on the nitrogen atom with one to two substituents independently selected from H, alkyl, cycloalkyl, cycloalkylalkyl, hydroxyalkyl, alkoxyalkyl, alkylcarbonyl and
  • cycloalkylcarbonyl and wherein substituted phenyl and substituted pyridinyl are optionally substituted with one to three substituents independently selected from alkyl, halogen, haloalkyl, alkoxy and haloalkoxy; m, n, p and q are independently selected from 1 or 2;
  • R 11 is H, alkyl, haloalkyl or cycloalkyl
  • R 2 is selected from the ring systems B, C, D, E, F, G, H, I, J, K, L, M, N, O, P, Q, R, S, T, U, V, X, Z, AA, AB, AC, AD and AE; and pharmaceutically acceptable salts.
  • a further embodiment of the present invention are compounds according to formula (I) as described herein, wherein R 1 is substituted cycloalkylalkyl, substituted piperazinyl, substituted piperidinyl, substituted indanyloxyalkyl, substituted phenyl, substituted phenylalkyl, substituted phenoxyalkyl, substituted phenylcycloalkyl, substituted phenylalkenyl, substituted
  • pyridinylalkyl substituted pyridinylalkenyl, naphtyl, substituted naphthyl, substituted quinolinyl, substituted isoquinolinyl, or substituted lH-indol-2-yl, wherein substituted cycloalkylalkyl, substituted piperazinyl, substituted piperidinyl, substituted indanyloxyalkyl, substituted phenyl, substituted phenylalkyl, substituted phenoxyalkyl, substituted phenylcycloalkyl, substituted phenylalkenyl, substituted pyridinylalkyl, substituted pyridinylalkenyl, substituted naphthyl, substituted quinolinyl, substituted isoquinolinyl and substituted lH-indol-2-yl are substituted with R 8 , R 9 and R 10 .
  • R 1 is substituted cycloalkylalkyl, substituted phenyl, substituted phenylalkyl, substituted phenoxyalkyl, substituted phenylcycloalkyl, substituted phenylalkenyl, substituted pyridinylalkyl, substituted pyridinylalkenyl or substituted lH-indol-2-yl, wherein substituted cycloalkylalkyl, substituted phenyl, substituted phenylalkyl, substituted
  • pyridinylalkyl, substituted pyridinylalkenyl, and substituted lH-indol-2-yl are substituted with R 8 , R 9 and R 10 .
  • a particular embodiment of the present invention are compounds according to formula (I) as described herein, wherein R 1 is substituted phenylalkyl or substituted phenylalkenyl, wherein substituted phenylalkyl and substituted phenylalkenyl are substituted with R 8 , R 9 and R 10 .
  • a further particular embodiment of the present invention are compounds according to formula (I) as described herein, wherein Y is -OC(O)- or -C(O)-.
  • Another further embodiment of the present invention are compounds according to formula (I) as described herein, wherein Y is -OC(O)- and of formula (In).
  • Another embodiment of the present invention are compounds according to formula (I) as described herein, wherein Y is -C(O)-.
  • a more particular embodiment of the present invention are compounds according to formula (I) as described herein, wherein A is -N-. Also an embodiment of the present invention are compounds according to formula (I) as described herein, wherein W is -0-, -NR 6 -, -C(O)-, -S(0) 2 -, -C(0)-NR 6 - or -CR 3 R 4 -.
  • Another embodiment of the present invention are compounds according to formula (I) as described herein, wherein W is -C(O)-, -C(0)-NR 6 - or -CR 3 R 4 -.
  • Another embodiment of the present invention are compounds according to formula (I) as described herein, wherein W is -C(O)-.
  • a further particular embodiment of the present invention are compounds according to formula (I) as described herein, wherein R 2 is selected from the ring systems B, C, D, E, G, H, M, O, P, R, S, T, U, V, X, Z, AA, AB, AC, AD, AE, AF, AG, AH and AI.
  • R 2 is selected from the ring systems B, C, D, E, G, H, M, O, P, R, S, T, U, V, X, Z, AA, AB, AC, AD and AE.
  • a further particular embodiment of the present invention are compounds according to formula (I) as described herein, wherein R 2 is selected from the ring systems B, D, H, M, O, R and AJ.
  • a further particular embodiment of the present invention are compounds according to formula (I) as described herein, wherein R 2 is selected from the ring systems B, D, H, O and R.
  • a further particular embodiment of the present invention are compounds according to formula (I) as described herein, wherein R 2 is selected from the ring systems B and D.
  • a further particular embodiment of the present invention are compounds according to formula (I) as described herein, wherein R 2 is the ring system D.
  • a further particular embodiment of the present invention are compounds according to formula (I) as described herein, wherein R 3 and R 4 are H.
  • a further particular embodiment of the present invention are compounds according to formula (I) as described herein, wherein R 5 is H.
  • a further particular embodiment of the present invention are compounds according to formula (I) as described herein, wherein R 6 is H or alkyl.
  • a a further particular embodiment of the present invention are compounds according to formula (I) as described herein, wherein R 8 , R 9 and R 10 are independently selected from H, alkyl, haloalkyl, hydroxyhaloalkyl, alkoxy, haloalkoxy, alkoxyhaloalkyl, phenyl, pyridinyl, halogen, cyano, haloalkylsulfanyl, haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl, pyrrolyl substituted with one alkyl, pyrrolydinyl, tetrahydroiuranyl, alkylcarbonyl, and aminosulfonyl substituted on the nitrogen atom with one to two substituents independently selected from H, alkyl, cyclo
  • R 8 , R 9 and R 10 are independently selected from H, alkyl, haloalkyl, hydroxyhaloalkyl, alkoxy, haloalkoxy, alkoxyhaloalkyl, phenyl, pyridinyl, halogen, cyano, haloalkylsulfanyl, haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl and aminosulfonyl substituted on the nitrogen atom with one to two substituents independently selected from H, alkyl, cycloalkyl, cycloalkylalkyl, hydroxyalkyl, alkoxyalkyl, alkylcarbonyl and
  • a further particular embodiment of the present invention are compounds according to formula (I) as described herein, wherein R 8 , R 9 and R 10 are independently selected from H, alkyl, haloalkyl, hydroxyhaloalkyl, alkoxy, haloalkoxy, alkoxyhaloalkyl, phenyl, pyridinyl, halogen, cyano, haloalkylsulfanyl, haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl and aminosulfonyl substituted on the nitrogen atom with two alkyl.
  • a further particular embodiment of the present invention are compounds according to formula (I) as described herein, wherein R 8 , R 9 and R 10 are independently selected from H, alkyl, haloalkyl, haloalkoxy, halogen and alkylsulfonyl.
  • a further particular embodiment of the present invention are compounds according to formula (I) as described herein, wherein R 8 is H, alkyl, haloalkyl, hydroxyhaloalkyl, alkoxy, haloalkoxy, alkoxyhaloalkyl, phenyl, pyridinyl, halogen, cyano, haloalkylsulfanyl,
  • haloalkylsulfinyl alkylsulfonyl, haloalkylsulfonyl, pyrrolyl substituted with one alkyl, pyrrolydinyl, tetrahydrofuranyl, alkylcarbonyl, or aminosulfonyl substituted on the nitrogen atom with two alkyl.
  • a further particular embodiment of the present invention are compounds according to formula (I) as described herein, wherein R 8 is H, alkyl, haloalkyl, hydroxyhaloalkyl, alkoxy, haloalkoxy, alkoxyhaloalkyl, phenyl, pyridinyl, halogen, cyano, haloalkylsulfanyl,
  • a further particular embodiment of the present invention are compounds according to formula (I) as described herein, wherein R 8 is haloalkyl, haloalkoxy, halogen or alkylsulfonyl.
  • a particular embodiment of the present invention are compounds according to formula (I) as described herein, wherein R 8 is haloalkoxy or halogen.
  • the present invention also relates to compounds according to formula (I) as described herein, wherein R 9 is H, alkyl, haloalkyl, cycloalkyl, cycloalkoxy, alkoxy, haloalkoxy, alkoxyalkoxy, cyano or halogen.
  • the present invention also relates to compounds according to formula (I) as described herein, wherein R 9 is H, alkyl, haloalkyl, alkoxy or halogen.
  • Another embodiment of the present invention are compounds according to formula (I) as described herein, wherein R 9 is H, alkyl or halogen.
  • the present invention also relates to compounds according to formula (I) as described herein, wherein R 8 and R 9 are halogen.
  • R 9 is H, alkyl, haloalkyl, cycloalkyl, cycloalkoxy, alkoxy, haloalkoxy, alkoxyalkoxy, cyano or halogen.
  • an embodiment of the present invention are compounds according to formula (I) as described herein, wherein R 10 is H or alkyl.
  • Another embodiment of the present invention are compounds according to formula (I) as described herein, wherein R 10 is H.
  • a particular embodiment of the present invention are compounds according to formula (I) as described herein, wherein m is 1.
  • a further particular embodiment of the present invention are compounds according to formula (I) as described herein, wherein n is 1.
  • a more particular embodiment of the present invention are compounds according to formula (I) as described herein, wherein m and n are 1.
  • the present invention also relates to compounds according to formula (I) as described herein, wherein m, n, p and q are 1.
  • a furthermore particular embodiment of the present invention are compounds according to formula (I) as described herein, wherein
  • R 1 is substituted phenylalkyl or substituted phenylalkenyl, wherein substituted
  • phenylalkyl and substituted phenylalkenyl are substituted with R 8 , R 9 and R 10 ;
  • Y is -OC(O)- or -C(O)-;
  • A is -N-
  • W is -C(O)-
  • R 8 is haloalkyl, haloalkoxy, halogen or alkylsulfonyl;
  • R 9 is H, alkyl or halogen;
  • R 10 is H or alkyl;
  • m and n are 1 ;
  • p and q are independently selected from 1 or 2;
  • R 2 is selected from the ring systems B, D, H, M, O, R and AJ;
  • R 12 is halogen and pharmaceutically acceptable salts.
  • R 1 is substituted phenylalkyl or substituted phenylalkenyl, wherein substituted
  • phenylalkyl and substituted phenylalkenyl are substituted with R 8 , R 9 and R 10 ;
  • Y is -OC(O)- or -C(O)-;
  • A is -N-
  • W is -C(O)-
  • R 8 is haloalkyl, haloalkoxy, halogen or alkylsulfonyl;
  • R 9 is H, alkyl or halogen;
  • R 10 is H or alkyl;
  • m and n are 1 ;
  • p and q are independently selected from 1 or 2;
  • R 2 is selected from the ring systems B and D; and pharmaceutically acceptable salts.
  • Also further particular examples of compounds of formula (I) as described herein are selected from trans-3 ,5-dichlorobenzyl 2-( 1 H-benzo [d] [ 1 ,2,3]triazole-5-carbonyl)hexahydro- 1 H- pyrrolo [3 ,4-c]pyridine-5 (6H)-carboxylate; trans-3,5-dichlorobenzyl 2-(2-oxo-2,3-dihydrobenzo[d]oxazole-6-carbonyl)hexahydro-lH- pyrrolo [3 ,4-c]pyridine-5 (6H)-carboxylate;
  • the preparation of compounds of formula (I) of the present invention may be carried out in sequential or convergent synthetic routes. Syntheses of the invention are shown in the following general schemes. The skills required for carrying out the reactions and purifications of the resulting products are known to those persons skilled in the art. In case a mixture of enantiomers or diastereoisomers is produced during a reaction, these enantiomers or diastereoisomers can be separated by methods described herein or known to the man skilled in the art such as e.g. (chiral) chromatography or crystallization. The substituents and indices used in the following description of the processes have the significance given herein. Compounds of general formula (I) can be synthesised from amine precursor 1 and appropriate reagents, using methods well known in the art.
  • amine 1 is reacted with a suitable chloroformate ester of formula R ! -0- C(0)-C1 (2), or with an imidazole- 1-carboxylate ester of formula (3 A), or with a succinimidyl carbonate derivative of formula (3B) flesh leading to a compound of formula (I) wherein Y is - OC(O)-.
  • the reaction is performed in a suitable solvent such as dichloromethane, tetrahydrofuran, ⁇ , ⁇ -dimethylformamide, acetonitrile, acetone, water, or mixtures thereof, in the presence or not of a base, e. g., triethylamine, diisopropylethylamine, pyridine, potassium hydrogencarbonate, potassium carbonate, at temperatures between 0°C and the boiling point of the solvent or solvent mixture.
  • a suitable solvent such as dichloromethane, tetrahydrofuran, ⁇ , ⁇ -dimethylformamide, acetonitrile, acetone, water, or mixtures thereof
  • a base e. g., triethylamine, diisopropylethylamine, pyridine, potassium hydrogencarbonate, potassium carbonate, at temperatures between 0°C and the boiling point of the solvent or solvent mixture.
  • Chloroformate esters 2 are commercially available or can be synthesised from the corresponding alcohol of formula R'-OH, by reaction with phosgene or a phosgene equivalent (e. g., diphosgene, triphosgene), as described in the literature.
  • phosgene or a phosgene equivalent e. g., diphosgene, triphosgene
  • Imidazole- 1-carboxylate esters 3A are synthesised from the corresponding alcohols of formula R'-OH, by reaction with ⁇ , ⁇ -carbonyldiimidazole. The reaction is performed at room temperature, in a solvent such as dichloromethane, tetrahydrofuran or acetonitrile.
  • a solvent such as dichloromethane, tetrahydrofuran or acetonitrile.
  • imidazole- 1-carboxylate esters 3 A are typically not isolated but directly reacted with amines 1 as described above.
  • Succinimidyl carbonate derivatives 3B are synthesised from the corresponding alcohols of formula R'-OH, by reaction with ⁇ , ⁇ '-disuccinimidyl carbonate. The reaction is performed at room temperature, in a solvent such as dichloromethane, tetrahydrofuran, or acetonitrile, optionally in the presence of a base, e. g., triethylamine.
  • the succinimidyl carbonate derivatives 3B are typically not isolated but directly reacted with amines 1 as described above.
  • Alcohols of formula R'-OH are commercially available or can be produced by methods described herein or known in the art.
  • amine 1 is reacted with a suitable N-(chlorocarbonyl)amine of formula
  • R'-NCR QC -CI (4) or, in the case where R 7 is H, with an isocyanate of formula R'-NCO (5), leading to compounds of formula (I) wherein Y is -NR 7 C(0)-.
  • N-(Chlorocarbonyl)amines (4) are synthesised from the corresponding amines of formula R 1 -N(R 7 )H by reaction with phosgene or a phosgene equivalent, as described in the literature.
  • Isocyanates 5 are commercially available or can be prepared from the corresponding amines of formula R 1 -NH 2 , by reaction with phosgene or a phosgene equivalent (e. g., diphosgene, triphosgene, ⁇ , ⁇ -carbonyldiimidazole), as described in the literature.
  • amine 1 is reacted with a suitable carboxylic acid of formula R'-COOH (6) leading to a compound of formula (I), wherein Y is -C(O)-.
  • the reaction is performed in the presence of a coupling agent such as ⁇ , ⁇ -carbonyldiimidazole, N,N'-dicyclohexylcarbodiimide, 1 -(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride, 0-(benzotriazol- 1 -yl)- ⁇ , ⁇ , ⁇ ' ,N ' -tetramethyluronium hexafluoro-phosphate, 0-(7-azabenzotriazo 1- 1 -yl)-N,N,N ' ,N ' - tetramethyluronium hexafluoro-phosphate or bromo-tris-pyrrolidino-phosphonium
  • a coupling agent such
  • hexafluorophosphate in aprotic solvents such as dichloromethane, tetrahydrofuran, N,N- dimethylformamide, N-methylpyrrolidinone and mixtures thereof at temperatures between -40°C and 80°C in the presence or absence of a base such as triethylamine, diisopropylethylamine, 4- methylmorpholine and/or 4-(dimethylamino)pyridine.
  • aprotic solvents such as dichloromethane, tetrahydrofuran, N,N- dimethylformamide, N-methylpyrrolidinone and mixtures thereof at temperatures between -40°C and 80°C in the presence or absence of a base such as triethylamine, diisopropylethylamine, 4- methylmorpholine and/or 4-(dimethylamino)pyridine.
  • Amine 1 can also be reacted with suitable acylating reagents such as acyl chlorides of formula R'-COCl (7) to lead to compounds of formula (I) wherein Y is -C(O)-.
  • suitable acylating reagents such as acyl chlorides of formula R'-COCl (7) to lead to compounds of formula (I) wherein Y is -C(O)-.
  • the reaction is performed in a solvent such as dichloromethane, tetrahydrofuran, or ⁇ , ⁇ -dimethylformamide, in the presence of a base such as triethylamine or 4-methylmorpholine, at temperatures between 0°C and 80°C.
  • Carboxylic acids (6) and acyl halides (7) are commercially available or can be prepared as described herein or in the literature.
  • amine 1 is reacted with a suitable sulfonyl chloride of formula R 1 -S0 2 C1 (8), leading to compounds of formula (I) wherein Y is -S(0 2 )-.
  • the reaction is performed in a suitable solvent such as dichloromethane, tetrahydroiuran, ⁇ , ⁇ -dimethylformamide, acetonitrile, acetone, water, or mixtures thereof, in the presence of a base, e. g., triethylamine,
  • diisopropylethylamine pyridine
  • potassium hydrogencarbonate potassium carbonate
  • temperatures between 0°C and the boiling point of the solvent or solvent mixture.
  • Sulfonyl chlorides (8) are commercially available or can be synthesised as described herein or in the literature.
  • amine 1 is reacted with a suitable chloro-oxadiazole reagent of general formula 9, or with oxadiazolone reagent 10, leading to a compound of formula (I), wherein Y is
  • reaction is performed in the presence of a base, e. g., potassium carbonate, triethylamine, or l,8-diazabicyclo[5.4.0]undec-7-ene, in a solvent such as toluene, ethanol, N,N- dimethylformamide, or 1,4-dioxane at temperatures between 20°C and 150°C.
  • a base e. g., potassium carbonate, triethylamine, or l,8-diazabicyclo[5.4.0]undec-7-ene
  • reaction is performed in the presence of a coupling agent, e. g. benzotriazol-l-yl-oxy-tris- (dimethylamino)-phosphonium hexafluorophosphate and a base, e. g., diisopropylethylamine or 4-methylmorpholine, in a solvent such as ⁇ , ⁇ -dimethylformamide, at temperatures between 20°C and 100°C as described in the literature.
  • a coupling agent e. g. benzotriazol-l-yl-oxy-tris- (dimethylamino)-phosphonium hexafluorophosphate
  • a base e. g., diisopropylethylamine or 4-methylmorpholine
  • Oxadiazolones 10 are commercially available or can be produced as described in the literature.
  • Chloro-oxadiazoles 9 are commercially available or can be produced from the corresponding oxadiazolones, by reaction with a suitable halogenating reagent, e. g. phosphorus oxychloride and/or phosphorus pentachloride, at temperatures between 60°C and 120°C.
  • a suitable halogenating reagent e. g. phosphorus oxychloride and/or phosphorus pentachloride
  • reaction is performed in the presence of a base, e. g. potassium carbonate, triethylamine or l,8-diazabicyclo[5.4.0]undec-7-ene, in a solvent such as toluene, ethanol, N,N- dimethylformamide or 1,4-dioxane, at temperatures between 20°C and 150°C.
  • a base e. g. potassium carbonate, triethylamine or l,8-diazabicyclo[5.4.0]undec-7-ene
  • solvent such as toluene, ethanol, N,N- dimethylformamide or 1,4-dioxane
  • thiadiazolethione 12 the reaction is performed in a solvent such as ethanol or N,N- dimethylformamide at temperatures between 20°C and 100°C as described in the literature.
  • Thiadiazolethiones 12 are commercially available or can be produced as described in the literature.
  • Halo-thiadiazoles 11 are commercially available or can be produced as described in the literature.
  • Amines of general formula 1 are synthesised from suitably protected precursors 13.
  • Suitable protective groups are tert-butoxycarbonyl, benzyloxycarbonyl and substituted benzyloxycarbonyl such as 3,5-dichloro benzyloxycarbonyl.
  • the deprotection of intermediates 13 can be performed using methods and reagents known in the art.
  • the deprotection may be performed by hydrogenation at pressures between 1 bar and 100 bar, in the presence of a suitable catalyst such as palladium on activated charcoal, at temperatures between 20°C and 150°C in solvents such as methanol or ethanol.
  • a suitable catalyst such as palladium on activated charcoal
  • the deprotection may be performed in the presence of a suitable acid, e. g, hydrochloric acid or trifluoro acetic acid, in a solvent such as water, 2-propanol, dichloromethane, or 1,4-dioxane at temperatures between 0°C and 30°C.
  • a suitable acid e. g, hydrochloric acid or trifluoro acetic acid
  • a solvent such as water, 2-propanol, dichloromethane, or 1,4-dioxane at temperatures between 0°C and 30°C.
  • Carbamates 13, wherein A is N are represented by general structure 13A.
  • PG is a suitable protective group, e. g., tert-butoxycarbonyl, benzyloxycarbonyl and substituted benzyloxycarbonyl such as 3,5-dichloro benzyloxycarbonyl.
  • Carbamates 13A can be produced from amine precursors of general formula 14 by reaction with appropriate reagents, using methods known in the art.
  • alkylating agents of general formula X-CR 3 R 4 -R 2 (15) where X is a leaving group such as CI, Br, I, or OSO 2 CH 3 , leading to 13A, wherein W is -CR 3 R 4 -.
  • This reaction is performed in a solvent such as tetrahydrofuran or N,N- dimethylformamide, in the presence of a base, e. g. triethylamine or potassium carbonate, at temperatures between 0°C and 100°C.
  • amine 14 is reacted with aldehydes or ketones of general formula R 4 -C(0)-R 2 (16) in a reductive amination reaction, leading to 13A.
  • This reaction is performed in the presence of a suitable reducing agent, e. g., sodium borohydride or sodium triacetoxyborohydride, in a solvent such as methanol, acetic acid, tetrahydrofuran, 1,2- dichloro ethane or mixtures thereof, at temperatures between 0°C and 50°C.
  • amine 14 is reacted with a suitable carboxylic acid of formula R 2 -COOH (17), leading to compounds of formula 13A, wherein W is -C(O)-.
  • the reaction is performed in the presence of a coupling agent such as ⁇ , ⁇ -carbonyldiimidazole, ⁇ , ⁇ '- dicyclohexylcarbodiimide, l-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride, O- (benzotriazo 1- 1 -yl)-N,N,N ' ,N ' -tetramethyluronium hexafluoro-phosphate, 0-(7-azabenzotriazo 1- l-yl)-N,N,N',N' -tetramethyluronium hexafluoro-phosphate or bromo-tris-pyrrolidino- phosphonium hexafluorophosphate, in apro
  • amine 14 is reacted with a suitable sulfonyl chloride of formula
  • R 2 -S0 2 C1 (18), leading to compounds of formula 13A, wherein W is -S(0 2 )-.
  • the reaction is performed in a suitable solvent such as dichloromethane, tetrahydrofuran, N,N- dimethylformamide, acetonitrile, acetone, water, or mixtures thereof, in the presence of a base, e. g. triethylamine, diisopropylethylamine, pyridine, potassium hydrogencarbonate, potassium carbonate, at temperatures between 0°C and the boiling point of the solvent or solvent mixture.
  • a base e. g. triethylamine, diisopropylethylamine, pyridine, potassium hydrogencarbonate, potassium carbonate, at temperatures between 0°C and the boiling point of the solvent or solvent mixture.
  • amine 14 is reacted with a suitable N-(chlorocarbonyl)amine of formula R 2 -N(R 6 )-C(0)-C1 (19) leading to compounds of formula 13A, wherein W is -C(0)-NR 6 -, or with an isocyanate of formula R 2 -NCO (20), leading to compounds of formula 13A, wherein W is -C(0)-NR 6 - and R 6 is H.
  • amine 14 is reacted with phosgene or phosgene equivalent (diphosgene, triphosgene) in the presence of a base (e. g., pyridine, triethylamine) in a solvent such as dichloromethane or tetrahydrofuran, to provide the corresponding N-(chlorocarbonyl)amine of formula 21, which is then reacted with amine of formula HN(R 6 )R 2 (22), in the presence of a base such as triethylamine or diisopropylethylamine, in a solvent such as dichloromethane, tetrahydrofuran, or ⁇ , ⁇ -dimethylformamide, leading to compounds of formula 13A, wherein W is -C(0)-NR 6 -.
  • a base e. pyridine, triethylamine
  • a solvent such as dichloromethane or tetrahydrofuran
  • amine 14 is reacted with phosgene or a phosgene equivalent (diphosgene, triphosgene) in the presence of a base (e. g., pyridine, triethylamine), in a solvent such as dichloromethane or tetrahydroiuran, to the corresponding N-(chlorocarbonyl)amine of formula 21, which is then reacted with amines of formula H-O, H-P, H-Q, H-R, H-T, H-U, H-V, H-X, H-AA or H-AF, in the presence of a base such as triethylamine or diisopropylethylamine, in a solvent such as dichloromethane, tetrahydroiuran, or ⁇ , ⁇ -dimethylformamide, leading to compounds of formula 13 A, wherein W is -C(O)- and R 2 is O, P, Q, R, T, U, V, X,
  • N-(Chlorocarbonyl)amines 19 are synthesised from the corresponding amines 22 by reaction with phosgene or a phosgene equivalent (diphosgene, triphosgene) as described in the literature.
  • Isocyanates 20 are commercially available or can be prepared from the corresponding amines of formula R 2 -NH 2 , by reaction with phosgene or a phosgene equivalent (e. g., diphosgene, triphosgene, ⁇ , ⁇ -carbonyldiimidazole) as described in the literature.
  • phosgene or a phosgene equivalent e. g., diphosgene, triphosgene, ⁇ , ⁇ -carbonyldiimidazole
  • Amines 14, alkylating agents 15, aldehydes/ketones 16, carboxylic acids 17, sulfonyl chlorides 18, and amines 22 are commercially available or can be synthesised as described in the literature.
  • Carbamates 13 wherein A is CR 5 and R 5 is H are represented by general formula 13B, wherein PG is a suitable protective group, e. g tert-butoxycarbonyl, benzyloxycarbonyl and substituted benzyloxycarbonyl such as 3,5-dichloro benzyloxycarbonyl.
  • Compound 13B wherein W is -NR 6 -, is produced from ketone 23 by reaction with an amine of formula HN(R 6 )R 2 (22) in the presence of a suitable reducing agent, e. g. sodium borohydride or sodium triacetoxyborohydride, in a solvent such as methanol, acetic acid, tetrahydroiuran, 1,2-dichloroethane, or mixtures thereof, at temperatures between 0°C and 50°C.
  • a suitable reducing agent e. g. sodium borohydride or sodium triacetoxyborohydride
  • Ketones 23 and amines 22 are commercially available or can be prepared as described in the literature.
  • Compound 13B wherein W is -O- or -S-, is produced from alcohol 24 using methods and reagents known in the art.
  • alcohol 24 is reacted at room temperature with phenol HO-R 2 or thiophenol HS-R 2 in the presence of triphenylphosphine and an dialkylazodicarboxylate, e. g.
  • diisopropylazodicarboxylate or diethylazodicarboxylate in a solvent such as toluene, dichloromethane, or tetrahydroiuran, leading to 13B, wherein W is -O- or -S-.
  • step 1 compounds of formula 13B can also be produced from alcohol 24 in a three-step sequence. Therefore, 24 is reacted in step 1 at room temperature with 2,4-dihydroxybenzoic acid alkyl ester in the presence of triphenylphosphine and an dialkylazodicarboxylate, e. g. diisopropylazodicarboxylate or diethylazodicarboxylate, in a solvent such as toluene, dichloromethane or tetrahydroiuran, converting the hydroxy group into a 3-hydroxy-4-(alkoxycarbonyl)-phenyl ether substituent.
  • dialkylazodicarboxylate e. g. diisopropylazodicarboxylate or diethylazodicarboxylate
  • step 2 This is hydrolysed in step 2 to the corresponding 3-hydroxy-4-carboxyphenyl group, using a base such as sodium hydroxide in water and in the presence of co-solvents such as tetrahydroiuran and/or methanol or ethanol.
  • step 3 the 3-hydroxy-4-carboxyphenyl ether intermediate can be subjected to a Curtius rearrangement as described in the literature, e. g. by using diphenylphorphoryl azide, in a solvent such as toluene, in the presence of a base, e.
  • Compound 13B wherein W is -S0 2 -, is produced from compound 13B, wherein W is -S- by oxidation with a suitable reagent, e. g., hydrogen peroxide or 3-chloroperbenzoic acid, in a solvent such as formic acid, acetic acid, or dichloromethane, at temperatures between 0°C and 50°C.
  • a suitable reagent e. g., hydrogen peroxide or 3-chloroperbenzoic acid
  • a solvent such as formic acid, acetic acid, or dichloromethane
  • Alcohols 24 are produced from ketones 23 using a suitable reducing agent, e. g., sodium borohydride, in a solvent such as methanol, at temperatures between 0°C and 50°C.
  • a suitable reducing agent e. g., sodium borohydride
  • Carbamates 13 wherein A is CR 5 , R 5 is H, and W is-C(0)-N(R 6 )- are represented by general formula 13C, wherein R 12 is N(R 6 )R 2 , O, P, Q, R, T, U, V, X, AA or AF.
  • Amide 13C is produced from carboxylic acid 25 by coupling reaction with an amine of formula HN(R 6 )R 2 (22), H-O, H-P, H-Q, H-R, H-T, H-U, H-V, H-X, H-AA or H-AF.
  • the reaction is performed in the presence of a coupling agent such as ⁇ , ⁇ - carbonyldiimidazole, ⁇ , ⁇ '-dicyclohexylcarbodiimide, 1 -(3-dimethylaminopropyl)-3-ethyl- carbodiimide hydrochloride, 0-(benzotriazol-l-yl)-N,N,N',N'-tetramethyluronium hexafluoro- phosphate, 0-(7-azabenzotriazol-l-yl)-N,N,N',N'-tetramethyluronium hexafluoro -phosphate or bromo-tris-pyrrolidino-phosphonium hexafluorophosphate, in aprotic solvents such as dichloromethane, tetrahydroiuran, ⁇ , ⁇ -dimethylformamide, N-methylpyrrolidinone and mixtures thereof at temperatures between -40°C
  • Carboxylic acids 25 are commercially available or can be produced as described in the literature.
  • Compounds of formula (I), wherein A is N can be produced from amine precursors of general formula 26 by reaction with appropriate reagents, using methods known in the art.
  • X-CR 3 R 4 -R 2 (15) where X is a leaving group such as CI, Br, I, or OSO 2 CH 3 , leading to compounds of formula (I), wherein A is N and W is -CR 3 R 4 -.
  • This reaction is performed in a solvent such as tetrahydrofuran or ⁇ , ⁇ -dimethylformamide, in the presence of a base, e. g., triethylamine or potassium carbonate, at temperatures between 0°C and 100°C.
  • a base e. g., triethylamine or potassium carbonate
  • an amine of formula 26 is reacted with aldehydes or ketones of general formula R 4 -C(0)-R 2 (16) in a reductive amination reaction, leading to compounds of formula (I) wherein A is N, W is -CR 3 R 4 -, R 4 is hydrogen, alkyl or cycloalkyl, and R 3 is H.
  • This reaction is performed in the presence of a suitable reducing agent, e. g. sodium borohydride or sodium triacetoxyborohydride, in a solvent such as methanol, acetic acid, tetrahydrofuran, 1,2- dichloro ethane or mixtures thereof, at temperatures between 0°C and 50°C.
  • amine 26 is reacted with a suitable carboxylic acid of formula R 2 -COOH (17), leading to compounds of formula (I) wherein A is N and W is -C(O)-.
  • the reaction is performed in the presence of a coupling agent such as ⁇ , ⁇ -carbonyldiimidazole, ⁇ , ⁇ '- dicyclohexylcarbodiimide, l-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride, O- (benzotriazol-l-yl)-N,N,N',N' -tetramethyluronium hexafluoro-phosphate, 0-(7-azabenzotriazol- l-yl)-N,N,N',N' -tetramethyluronium hexafluoro-phosphate or bromo-tris-pyrrolidino- phosphonium hexafluorophosphate, in
  • amine 26 is reacted with a suitable sulfonyl chloride of formula
  • R 2 -S0 2 C1 (18), leading to (I) wherein A is N and W is -S(0 2 )-.
  • the reaction is performed in a suitable solvent such as dichloromethane, tetrahydroiuran, ⁇ , ⁇ -dimethylformamide, acetonitrile, acetone, water, or mixtures thereof, in the presence of a base, e. g. triethylamine,
  • amine of formula 26 is reacted with a suitable N-(chlorocarbonyl)amine of formula R 2 -N(R 6 )-C(0)-C1 (19) leading to compounds of formula (I), wherein A is N and W is C(0)-NR 6 , or with isocyanate R 2 -NCO (20), leading to compounds of formula (I), wherein A is N, W is -C(0)-NR 6 - and R 6 is H.
  • amine 26 is reacted with phosgene or a phosgene equivalent (diphosgene, triphosgene) in the presence of a base (e. g., pyridine, triethylamine), in a solvent such as dichloromethane or tetrahydroiuran, to the corresponding N-(chlorocarbonyl)amine of formula 27, which is then reacted with an amine of formula H-O, H-P, H-Q, H-R, H-T, H-U, H-V, H- X, H-AA or H-AF in the presence of a base such as triethylamine or diisopropylethylamine, in a solvent such as dichloromethane, tetrahydroiuran, or ⁇ , ⁇ -dimethylformamide, leading to compounds of formula (I), wherein A is N, W is -C(O)- and R 2 is O, P, Q, R, T, U, V,
  • Amines 26 can be synthesised from their tert-butyl carbamate derivatives of formula 28 by carbamate deprotection.
  • the deprotection may be performed in the presence of a suitable acid, e g, hydrochloric acid or trifluoro acetic acid, in a solvent such as water, 2-propanol,
  • tert-Butyl carbamates 28 can be synthesised from amine precursors of formula
  • an amine of formula 29 is reacted with a suitable chloro formate ester of formula R 1 -0-C(0)-Cl (2), or with an imidazole- 1-carboxylate ester of formula (3 A) or with a succinimidyl carbonate derivative of formula (3B), leading to compounds of formula 28, wherein Y is -OC(O)-.
  • the reaction is performed in a suitable solvent such as dichloromethane, tetrahydroiuran, ⁇ , ⁇ -dimethylformamide, acetonitrile, acetone, water, or mixtures thereof, in the presence or not of a base, e. g. triethylamine, diisopropylethylamine, pyridine, potassium hydrogencarbonate, potassium carbonate, at temperatures between 0°C and the boiling point of the solvent or solvent mixture.
  • a suitable solvent such as dichloromethane, tetrahydroiuran, ⁇ , ⁇ -dimethylformamide, acetonitrile
  • an amine of formula 29 is reacted with a suitable N-(chlorocarbonyl)amine of formula R 1 -N(R 7 )-C(0)-C1 (4) leading to compounds of formula 28, wherein Y is - NR 7 C(0)-, or with an isocyanate of formula R'-NCO (5) leading to compounds of formula 28, wherein Y is -NR 7 C(0)- and R 7 is H.
  • amine 29 is reacted with a suitable carboxylic acid of formula R'-COOH (6) leading to compounds of formula 28, wherein Y is -C(O)-.
  • the reaction is performed in the presence of a coupling agent such as ⁇ , ⁇ -carbonyldiimidazole, N,N'-dicyclohexylcarbodiimide, l-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride, O-(benzotriazol-l-yl)-
  • hexafluorophosphate in aprotic solvents such as dichloromethane, tetrahydrofuran, N,N- dimethylformamide, N-methylpyrrolidinone and mixtures thereof at temperatures between -40°C and 80°C in the presence or absence of a base such as triethylamine, diisopropylethylamine, 4- methylmorpholine and/or 4-(dimethylamino)pyridine.
  • Amine 29 can also be reacted with suitable acylating reagents, such as acyl chlorides of formula R'-COCl (7) to provide compounds of formula 28, wherein Y is -C(O)-.
  • the reaction is performed in a solvent such as dichloromethane, tetrahydroiuran, or N,N-dimethylformamide, in the presence of a base such as triethylamine or 4-methylmorpholine, at temperatures between 0°C and 80°C.
  • a solvent such as dichloromethane, tetrahydroiuran, or N,N-dimethylformamide
  • a base such as triethylamine or 4-methylmorpholine
  • amine 29 is reacted with a suitable sulfonyl chloride, of formula R 1 -S0 2 C1 (8), leading to compounds of formula 28, wherein Y is -S(0 2 )-.
  • a suitable solvent such as dichloromethane, tetrahydroiuran, ⁇ , ⁇ -dimethylformamide, acetonitrile, acetone, water, or mixtures thereof, in the presence of a base, e. g. triethylamine,
  • diisopropylethylamine pyridine
  • potassium hydrogencarbonate potassium carbonate
  • temperatures between 0°C and the boiling point of the solvent or solvent mixture.
  • amine 29 is reacted with a suitable chloro-oxadiazole reagent of general formula 9 or with oxadiazolone reagent 10, leading to compounds of formula 28, wherein Y is
  • a suitable chloro-oxadiazole reagent of general formula 9 or with oxadiazolone reagent 10 leading to compounds of formula 28, wherein Y is
  • the reaction is performed in the presence of a base, e. g. potassium carbonate, triethylamine, or 1,8- diazabicyclo[5.4.0]undec-7-ene, in a solvent such as toluene, ethanol, N,N-dimethylformamide, or 1,4-dioxane, at temperatures between 20°C and 150°C.
  • the reaction is performed in the presence of a coupling agent, e. g., benzotriazol-l-yl-oxy-tris-(dimethylamino)- phosphonium hexafluorophosphate, and a base, e. g. diisopropylethylamine or 4- methylmorpholine, in a solvent such as ⁇ , ⁇ -dimethylformamide, at temperatures between 20°C and 100°C, as described in the literature).
  • a coupling agent e. g., benzotriazol-l-yl-oxy-tris-(dimethylamino)- phosphonium hexafluorophosphate
  • a base e. g. diisopropylethylamine or 4- methylmorpholine
  • amine 29 is reacted with a suitable halo-thiadiazole reagent of general formula 11 (X is CI or Br) or with thiadiazolethione reagent 12, leading to compounds of
  • amine 29 is acylated with a haloalkanoyl halide, e. g., bromoacetyl chloride, in the presence of a base, e. g. triethylamine, in a solvent such as dichloromethane or
  • Compounds of formula (I), wherein A is CR 5 and W is-C(0)-N(R 6 )- can be produced from carboxylic acid precursors of general formula 30 by reaction with appropriate amine reagents of general formula HN(R 6 )R 2 , H-O, H-P, H-Q, H-R, H-T, H-U, H-V, H-X, H-AA or H-AF using methods known in the art.
  • this reaction is performed in the presence of a coupling agent such as ⁇ , ⁇ - carbonyldiimidazole, ⁇ , ⁇ '-dicyclohexylcarbodiimide, 1 -(3-dimethylaminopropyl)-3-ethyl- carbodiimide hydrochloride, 0-(benzotriazol-l-yl)-N,N,N',N'-tetramethyluronium hexafluoro- phosphate, 0-(7-azabenzotriazol-l-yl)-N,N,N',N'-tetramethyluronium hexafluoro -phosphate or bromo-tris-pyrrolidino-phosphonium hexafluorophosphate, in aprotic solvents such as dichloromethane, tetrahydrofuran, ⁇ , ⁇ -dimethylformamide, N-methylpyrrolidinone and mixtures thereof at temperatures between -40°
  • Carboxylic acids 30 can be produced from the corresponding ester precursors 31, wherein R a is lower alkyl, e. g. methyl or ethyl, using methods and reagents known in the art. For instance, the reaction is performed in the presence of a base, e. g., potassium hydroxide, sodium hydroxide, or lithium hydroxide, in solvents such as water, methanol, ethanol, tetrahydroiuran, or mixtures thereof, at temperatures between 20°C and 100°C.
  • a base e. g., potassium hydroxide, sodium hydroxide, or lithium hydroxide
  • Compounds of formula 31 can be synthesised from amine precursors of formula 32 and appropriate reagents, using methods well known in the art.
  • an amine of formula 32 is reacted with a suitable chloro formate ester of formula R 1 -0-C(0)-Cl (2), or with an imidazole- 1-carboxylate ester of formula 3, leading to compounds of formula 31, wherein Y is -OC(O)-.
  • the reaction is performed in a suitable solvent such as dichloromethane, tetrahydroiuran, ⁇ , ⁇ -dimethylformamide, acetonitrile, acetone, water, or mixtures thereof, in the presence of a base, e. g. triethylamine, diisopropylethylamine, pyridine, potassium hydrogencarbonate, potassium carbonate, at temperatures between 0°C and the boiling point of the solvent or solvent mixture.
  • a base e. g. triethylamine, diisopropylethylamine, pyridine, potassium hydrogencarbonate, potassium carbonate, at temperatures between 0°C and the boiling point of the solvent or solvent mixture.
  • an amine of formula 32 is reacted with a suitable N-(chlorocarbonyl)amine of formula R 1 -N(R 7 )-C(0)-C1 (4) leading to compounds of formula 31, wherein Y is - NR 7 C(0)-, or with an isocyanate of formula R'-NCO (5) leading to leading to compounds of formula 31, wherein Y is -NR 7 C(0)- and R 7 is H.
  • amine 32 is reacted with a suitable carboxylic acid of formula R'-COOH (6) leading to compounds of formula 31, wherein Y is -C(O)-.
  • the reaction is performed in the presence of a coupling agent such as ⁇ , ⁇ -carbonyldiimidazole, N,N'-dicyclohexylcarbodiimide, 1 -(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride, 0-(benzotriazol- 1 -yl)- ⁇ , ⁇ , ⁇ ' ,N ' -tetramethyluronium hexafluoro-phosphate, 0-(7-azabenzotriazo 1- 1 -yl)-N,N,N ' ,N ' - tetramethyluronium hexafluoro-phosphate or bromo-tris-pyrrolidino-phosphonium
  • hexafluorophosphate in aprotic solvents such as dichloromethane, tetrahydroiuran, N,N- dimethylformamide, N-methylpyrrolidinone and mixtures thereof at temperatures between -40°C and 80°C in the presence or absence of a base such as triethylamine, diisopropylethylamine, 4- methylmorpholine and/or 4-(dimethylamino)pyridine.
  • aprotic solvents such as dichloromethane, tetrahydroiuran, N,N- dimethylformamide, N-methylpyrrolidinone and mixtures thereof at temperatures between -40°C and 80°C in the presence or absence of a base such as triethylamine, diisopropylethylamine, 4- methylmorpholine and/or 4-(dimethylamino)pyridine.
  • Amine 32 can also be reacted with suitable acylating reagents, such as acyl chlorides of formula R'-COCl (7) to lead to compounds of formula 31, wherein Y is -C(O)-.
  • suitable acylating reagents such as acyl chlorides of formula R'-COCl (7) to lead to compounds of formula 31, wherein Y is -C(O)-.
  • the reaction is performed in a solvent such as dichloromethane, tetrahydroiuran, or ⁇ , ⁇ -dimethylformamide, in the presence of a base such as triethylamine or 4-methylmorpholine, at temperatures between 0°C and 80°C.
  • amine 32 is reacted with a suitable sulfonyl chloride of formula R 1 -S0 2 C1 (8), leading to compounds of formula 31, wherein Y is -S(0 2 )-.
  • the reaction is performed in a suitable solvent such as dichloromethane, tetrahydroiuran, ⁇ , ⁇ -dimethylformamide, acetonitrile, acetone, water, or mixtures thereof, in the presence of a base, e. g. triethylamine,
  • diisopropylethylamine pyridine
  • potassium hydrogencarbonate potassium carbonate
  • temperatures between 0°C and the boiling point of the solvent or solvent mixture.
  • amine 32 is reacted with a suitable chloro-oxadiazole reagent of general formula 9, or with oxadiazolone reagent 10, leading to compounds of formula 31, wherein Y
  • 31 is produced from amine 32 and chloro-oxadiazole 9
  • the reaction is performed in the presence of a base, e. g. potassium carbonate, triethylamine, or 1 ,8- diazabicyclo[5.4.0]undec-7-ene, in a solvent such as toluene, ethanol, N,N-dimethylformamide, or 1 ,4-dioxane, at temperatures between 20°C and 150°C.
  • a base e. g. potassium carbonate, triethylamine, or 1 ,8- diazabicyclo[5.4.0]undec-7-ene
  • solvent such as toluene, ethanol, N,N-dimethylformamide, or 1 ,4-dioxane
  • the reaction is performed in the presence of a coupling agent, e. g. benzotriazol-l-yl-oxy-tris-(dimethylamino)- phosphonium hexafluorophosphate, and a base, e. g. diisopropylethylamine or 4- methylmorpholine, in a solvent such as ⁇ , ⁇ -dimethylformamide, at temperatures between 20°C and 100°C, as described in the literature.
  • a coupling agent e. g. benzotriazol-l-yl-oxy-tris-(dimethylamino)- phosphonium hexafluorophosphate
  • a base e. g. diisopropylethylamine or 4- methylmorpholine
  • amine 32 is reacted with a suitable halo-thiadiazole reagent of general formula 11 (X is CI or Br), or with thiadiazolethione reagent 12, leading to compounds of
  • 31 is produced from amine 32 and halo-thiadiazole 11
  • the reaction is performed in the presence of a base, e. g. potassium carbonate, triethylamine, or 1,8- diazabicyclo[5.4.0]undec-7-ene, in a solvent such as toluene, ethanol, N,N-dimethylformamide or 1,4-dioxane, at temperatures between 20°C and 150°C.
  • a base e. g. potassium carbonate, triethylamine, or 1,8- diazabicyclo[5.4.0]undec-7-ene
  • solvent such as toluene, ethanol, N,N-dimethylformamide or 1,4-dioxane
  • Amines of general formula 32 are synthesised from suitably protected precursors 33.
  • Suitable protective groups are tert-butoxycarbonyl or benzyloxycarbonyl.
  • the deprotection of intermediates 33 can be performed using methods and reagents known in the art.
  • the deprotection may be performed by hydrogenation at pressures between 1 bar and 100 bar, in the presence of a suitable catalyst such as palladium on activated charcoal, at temperatures between 20°C and 150°C, in solvents such as methanol or ethanol.
  • a suitable catalyst such as palladium on activated charcoal
  • the deprotection may be performed in the presence of a suitable acid, e. g, hydrochloric acid or trifluoro acetic acid, in a solvent such as water, 2-propanol, dichloromethane, or 1,4-dioxane, at temperatures between
  • Substituents R 5 may be introduced starting from ester precursor 34, using suitable reagents and methods known in the art.
  • 34 is reacted with alkylating agents of general formula R 5 -X wherein R 5 is alkyl or cycloalkyl and X is a leaving group such as CI, Br, I, or OSO 2 CH 3 , leading to 33, wherein R 5 is alkyl or cycloalkyl.
  • This reaction is performed in the presence of a suitable base, e. g., sodium hydride, lithium diisopropylamide, lithium
  • Esters 34 wherein R a is methyl or ethyl, are produced from carboxylic acids 25, using methods and reagents known in the art. For instance, 25 alkylated with methyl iodide or ethyl bromide, in the presence of a base, e. g., potassium carbonate, in a solvent such as N,N- dimethylformamide, at -20°C and +30°C, leading to the methyl or ethyl ester 34, respectively.
  • a base e. g., potassium carbonate
  • an embodiment of the present invention is a process to prepare a compound of formula (I) as defined above comprising the reaction of a compound of formula (II) in the presence of a compound of formula (III);
  • an object of the present invention is a compound according to formula (I) as described herein for use as a therapeutically active substance.
  • an object of the present invention is a pharmaceutical composition
  • a pharmaceutical composition comprising a compound according to formula (I) as described herein and a therapeutically inert carrier.
  • An object of the invention is the use of a compound according to formula (I) as described herein for the treatment or prophylaxis of renal conditions, liver conditions, inflammatory conditions, conditions of the nervous system, conditions of the respiratory system, vascular and cardiovascular conditions, fibrotic diseases, cancer, ocular conditions, metabolic conditions, cholestatic and other forms of chronic pruritus and acute and chronic organ transplant rejection.
  • Renal conditions include, but are not limited to, acute kidney injury and chronic renal disease with and without proteinuria including end-stage renal disease (ESRD).
  • this includes decreased creatinine clearance and decreased glomerular filtration rate, microalbuminuria, albuminuria and proteinuria, glomerulosclerosis with expansion of reticulated mesangial matrix with or without significant hypercellularity (particularly diabetic nephropathy and amyloidosis), focal thrombosis of glomerular capillaries (particularly thrombotic microangiopathies), global fibrinoid necrosis, ischemic lesions, malignant nephrosclerosis (such as ischemic retraction, reduced renal blood flow and renal arteriopathy), swelling and proliferation of intracapillary (endothelial and mesangial) and/or extracapillary cells (crescents) like in glomerular nephritis entities, focal segmental glomerular sclerosis, IgA nephropathy, vasculitides / systemic diseases as well as acute and chronic kidney transplant rejection.
  • Liver conditions include, but are not limited to, liver cirrhosis, hepatic congestion, cholestatic liver disease including pruritus, nonalcoholic steatohepatitis and acute and chronic liver transplant rejection.
  • Inflammatory conditions include, but are not limited to, arthritis, osteoarthritis, multiple sclerosis, systemic lupus erythematodes, inflammatory bowel disease, abnormal evacuation disorder and the like as well as inflammatory airways diseases such as idiopathic pulmonary fibrosis (IPF), chronic obstructive pulmonary disease (COPD) or chronic asthma bronchiale.
  • IPF idiopathic pulmonary fibrosis
  • COPD chronic obstructive pulmonary disease
  • chronic asthma bronchiale chronic asthma bronchiale.
  • Further conditions of the respiratory system include, but are not limited to, other diffuse parenchymal lung diseases of different etiologies including iatrogenic drug-induced fibrosis, occupational and/or environmental induced fibrosis, systemic diseases and vasculitides, granulomatous diseases (sarcoidosis, hypersensitivity pneumonia), collagen vascular disease, alveolar proteinosis, Langerhans cell granulomatosis, lymphangioleiomyomatosis, inherited diseases (Hermansky-Pudlak Syndrome, tuberous sclerosis, neurofibromatosis, metabolic storage disorders, familial interstitial lung disease), radiation induced fibrosis, silicosis, asbestos induced pulmonary fibrosis or acute respiratory distress syndrome (ARDS).
  • iatrogenic drug-induced fibrosis etiologies including iatrogenic drug-induced fibrosis, occupational and/or environmental induced fibrosis, systemic diseases and vasculitides, granulomatous diseases (s
  • Conditions of the nervous system include, but are not limited to, neuropathic pain, schizophrenia, neuro -inflammation (e.g. astro gliosis), peripheral and/or autonomic (diabetic) neuropathies and the like.
  • Vascular conditions include, but are not limited to, atherosclerosis, thrombotic vascular disease as well as thrombotic microangiopathies, proliferative arteriopathy (such as swollen myointimal cells surrounded by mucinous extracellular matrix and nodular thickening), atherosclerosis, decreased vascular compliance (such as stiffness, reduced ventricular compliance and reduced vascular compliance), endothelial dysfunction and the like.
  • Cardiovascular conditions include, but are not limited to, acute coronary syndrome, coronary heart disease, myocardial infarction, arterial and pulmonary hypertension, cardiac arrhythmia such as atrial fibrillation, stroke and other vascular damage.
  • Fibrotic diseases include, but are not limited to myocardial and vascular fibrosis, renal fibrosis, liver fibrosis, pulmonary fibrosis, skin fibrosis, scleroderma and encapsulating peritonitis.
  • the compounds of formula (I) or their pharmaceutically acceptable salts and esters can be used for the treatment or prophylaxis of organ or skin fibrosis.
  • the fibrotic disease is renal tubulo-interstitial fibrosis or glomerulosclerosis.
  • the fibrotic disease is non-alcoholic liver steatosis, liver fibrosis or liver cirrhosis.
  • the fibrotic disease is idiopathic pulmonary fibrosis.
  • Cancer and cancer metastasis include, but are not limited to, breast cancer, ovarian cancer, lung cancer, prostate cancer, mesothelioma, glioma, hepatic carcinoma, gastrointestinal cancers and progression and metastatic aggressiveness thereof.
  • Ocular conditions include, but are not limited to, proliferative and non-pro liferative (diabetic) retinopathy, dry and wet age-related macular degeneration (AMD), macular edema, central arterial /venous occlusion, traumatic injury, glaucoma and the like.
  • proliferative and non-pro liferative (diabetic) retinopathy dry and wet age-related macular degeneration (AMD), macular edema, central arterial /venous occlusion, traumatic injury, glaucoma and the like.
  • AMD age-related macular degeneration
  • Metabolic conditions include, but are not limited to, obesity and diabetes.
  • the compounds of formula (I) or their pharmaceutically acceptable salts and esters can be used for the treatment or prophylaxis of cholestatic or non-cholestatic chronic pruritus.
  • the present invention also relates to the use of a compound according to formula (I) as described herein for the treatment or prophylaxis of renal conditions, liver conditions, inflammatory conditions, conditions of the nervous system, fibrotic diseases and acute and chronic organ transplant rejection.
  • the present invention also relates to the use of a compound according to formula (I) as described herein for the treatment or prophylaxis of renal conditions, liver conditions and fibrotic diseases.
  • a particular embodiment of the present invention is a compound according to formula (I) as described herein for the treatment or prophylaxis of renal conditions, liver conditions, inflammatory conditions, conditions of the nervous system, fibrotic diseases and acute and chronic organ transplant rejection.
  • a particular embodiment of the present invention is a compound according to formula (I) as described herein for the treatment or prophylaxis of renal conditions, liver conditions and fibrotic diseases.
  • the present invention also relates to the use of a compound according to formula (I) as described herein for the preparation of a medicament for the treatment or prophylaxis of renal conditions, liver conditions, inflammatory conditions, conditions of the nervous system, fibrotic diseases and acute and chronic organ transplant rejection.
  • the present invention also relates to the use of a compound according to formula (I) as described herein for the preparation of a medicament for the treatment or prophylaxis of renal conditions, liver conditions and fibrotic diseases.
  • an object of the invention is a method for the treatment or prophylaxis of renal conditions, liver conditions, inflammatory conditions, conditions of the nervous system, fibrotic diseases and acute and chronic organ transplant rejection, which method comprises
  • an object of the invention is a method for the treatment or prophylaxis of renal conditions, liver conditions and fibrotic diseases, which method comprises administering an effective amount of a compound according to formula (I) as described herein.
  • the renal condition is selected from the group consisting of acute kidney injury, chronic kidney disease, diabetic nephropathy, acute kidney transplant rejection and chronic allograft nephropathy.
  • the renal condition is acute kidney injury. In another particular embodiment, the renal condition is chronic kidney disease.
  • the renal condition is diabetic nephropathy.
  • the renal condition is acute kidney transplant rejection.
  • the renal condition is chronic allograft nephropathy.
  • the liver condition is acute and chronic liver transplant rejection
  • the inflammatory condition is arthritis.
  • the condition of the nervous system is neuropathic pain.
  • the fibrotic disease is encapsulating peritonitis.
  • the fibrotic disease is idiopathic pulmonary fibrosis. In another embodiment, the fibrotic disease is non-alcoholic liver steatosis, liver fibrosis or liver cirrhosis.
  • hematopoietic cells total RNA and used as template in overlapping PCR to generate a full length human ENPP2 ORF with or without a 3'-6xHis tag. These full length inserts were cloned into the pcDNA3.1 V5-His TOPO (Invitrogen) vector. The DNA sequences of several single clones were verified. The DNA from a correct full length clone was used to transfect Hek293 cells for verification of protein expression. The sequence of the encoded ENPP2 conforms to Swissprot entry Q 13822, with or without the additional C-terminal 6xHis tag.
  • ATX Fermentation Recombinant protein was produced by large-scale transient transfection in 20 L controlled stirred tank bioreactors (Sartorius). During cell growth and transfection, temperature, stirrer speed, pH and dissolved oxygen concentration were maintained at 37°C, 120 rpm, 7.1 and 30% DO, respectively.
  • FreeStyle 293-F cells (Invitrogen) were cultivated in suspension in FreeStyle 293 medium (Invitrogen) and transfected at ca. 1-1.5 x 10E6 cells/mL with above plasmid DNAs using X-tremeGENE Ro-1539 (commercial product, Roche).
  • ATX Purification 20 liter of culture supernatant were conditioned for ultrafiltration by adding Brij 35 to a final concentration of 0.02% and by adjusting the pH to 7.0 using 1 M HCl. Then the supernatant was first microfiltred through a 0.2 ⁇ Ultran-Pilot Open Channel PES filter (Whatman) and afterwards concentrated to 1 liter through an Ultran-Pilot Screen Channel PES filter with 30 kDa MWCO (Whatman). Prior to IMAC chromatography, NiS0 4 was added to a final concentration of 1 mM.
  • the cleared supernatant was then applied to a HisTrap column (GE Healthcare) previously equilibrated in 50 mM Na 2 HP0 4 pH 7.0, 0.5 M NaCl, 10% glycerol, 0.3% CHAPS, 0.02%) NaN 3 .
  • the column was washed stepwise with the same buffer containing 20 mM , 40 mM and 50 mM imidazole, respectively.
  • the protein was subsequently eluted using a linear gradient to 0.5 M imidazole in 15 column volumes. ATX containing fractions were pooled and concentrated using an Amicon cell equipped with a 30 kDa PES filter membrane.
  • the protein was further purified by size exclusion chromatography on Superdex S-200 prep grade (XK 26/100) (GE Healthcare) in 20 mM BICINE pH 8.5, 0.15 M NaCl, 10% glycerol, 0.3% CHAPS, 0.02% NaN 3 . Final yield of protein after purification was 5-10 mg ATX per liter of culture supernatant. The protein was stored at -80°C.
  • ATX inhibition was measured by a fluorescence quenching assay using a specifically labeled substrate analogue (MR121 substrate).
  • MR121 substrate a specifically labeled substrate analogue
  • BOC and TBS protected 6-amino-hexanoic acid (R)-3-( ⁇ 2-[3-(2- ⁇ 2-[2-(2-amino-ethoxy)-ethoxy]-ethoxy ⁇ -ethoxy)- propionylamino]-ethoxy ⁇ -hydroxy-phosphoryloxy)-2-hydroxy-propyl ester (Ferguson et al, Org Lett 2006, 8 (10), 2023) was labeled with MR121 fluorophore (CAS 185308-24-1, l-(3- carboxypropyl)-l l-ethyl-l,2,3,4,8,9,10,l l-octahydro-dipyrido[3,2-b:2',3'-i]phenoxazin-13-ium) on
  • Assay buffer 50 mM Tris-HCl, 140 mM NaCl, 5 mM KC1, 1 mM CaCl 2 , 1 mM MgCl 2 , 0.01% Triton-X-100, pH 8.0;
  • ATX solution ATX (human His-tagged) stock solution (1.08 mg/mL in 20mM bicine, pH 8.5, 0.15 M NaCl, 10% glycerol, 0.3% CHAPS, 0.02% NaN 3 ), diluted to 1.4 - 2.5x final
  • MR121 substrate solution MR121 substrate stock solution (800 ⁇ MR121 substrate in DMSO), diluted to 2 - 5x final concentration in assay buffer.
  • Test compounds (10 mM stock in DMSO, 8 ⁇ ) were obtained in 384 well sample plates
  • Example IC50 ( ⁇ ) Example IC50 ( ⁇ )
  • Example IC50 ( ⁇ ) Example IC50 ( ⁇ )
  • Example IC50 ( ⁇ ) Example IC50 ( ⁇ )
  • Example IC50 ( ⁇ ) Example IC50 ( ⁇ )
  • Example IC50 ( ⁇ ) Example IC50 ( ⁇ ) Example IC50 ( ⁇ )
  • Example IC50 ( ⁇ ) Example IC50 ( ⁇ )
  • Example IC50 ( ⁇ ) Example IC50 ( ⁇ )
  • Compounds of formula (I) and their pharmaceutically acceptable salts or esters thereof as described herein have IC 50 values between 0.00001 ⁇ and 1000 ⁇ , particular compounds have IC 50 values between 0.0005 ⁇ and 500 ⁇ , further particular compounds have IC 50 values between 0.0005 ⁇ and 50 ⁇ , more particular compounds have IC 50 values between 0.0005 ⁇ and 5 ⁇ . These results have been obtained by using the enzymatic assay described above.
  • the compounds of formula (I) and their pharmaceutically acceptable salts can be used as medicaments (e.g. in the form of pharmaceutical preparations).
  • the pharmaceutical preparations can be administered internally, such as orally (e.g.
  • the administration can also be effected parenterally, such as intramuscularly or intravenously (e.g. in the form of injection solutions).
  • the compounds of formula (I) and their pharmaceutically acceptable salts can be processed with pharmaceutically inert, inorganic or organic adjuvants for the production of tablets, coated tablets, dragees and hard gelatin capsules.
  • Lactose, corn starch or derivatives thereof, talc, stearic acid or its salts etc. can be used, for example, as such adjuvants for tablets, dragees and hard gelatin capsules.
  • Suitable adjuvants for soft gelatin capsules are, for example, vegetable oils, waxes, fats, semi-solid substances and liquid polyols, etc.
  • Suitable adjuvants for the production of solutions and syrups are, for example, water, polyols, saccharose, invert sugar, glucose, etc.
  • Suitable adjuvants for injection solutions are, for example, water, alcohols, polyols, glycerol, vegetable oils, etc.
  • Suitable adjuvants for suppositories are, for example, natural or hardened oils, waxes, fats, semi-solid or liquid polyols, etc.
  • the pharmaceutical preparations can contain preservatives, solubilizers, viscosity-increasing substances, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffers, masking agents or antioxidants. They can also contain still other therapeutically valuable substances.
  • the dosage can vary in wide limits and will, of course, be fitted to the individual requirements in each particular case.
  • the pure enantiomers can be obtained by methods described herein or by methods known to those skilled in the art, such as e.g. chiral chromatography or crystallization.
  • Racemic cis-3,5-dichlorobenzyl 2-(lH-benzo[d][l,2,3]triazole-5-carbonyl)hexahydro-lH- pyrrolo[3,4-c]pyridine-5(6H)-carboxylate (example 1.02; 616 mg, 1.30 mmol) was separated by preparative HPLC using a Reprosil Chiral-NR column as the stationary phase and heptane/ethanol 3:2 as the mobile phase.
  • Step 1 (SVDi-tert-butyl 6-((3aR,8aS -6-((E -3-(4-(trifluoromethoxy phenyl acryloyl - decahydropyrrolo[3,4-d]azepine-2-carbonyl)-6 ,7-dihydro-lH-imidazo[4,5-c]pyridine-l,5(4H)- dicarboxylate
  • the title compound was produced in analogy to example 15 from (E)-l-((3aR,8aS)- octahydropyrrolo[3,4-d]azepin-6(7H)-yl)-3-(4-(trifluoromethoxy)phenyl)prop-2-en-l-one hydrochloride (intermediate 5) and (S)-l,5-bis(tert-butoxycarbonyl)-4,5,6,7-tetrahydro-lH- imidazo[4,5-c]pyridine-6-
  • Step 2 (E -3-[4-(Trifluoro-methoxy -phenyll-l-[(3aS,8aR -2-((S -4,5,6J-tetrahvdro-lH- imidazo[4,5-c]pyridine-6-carbonyl)-octahydro-pyrrolo[3,4-d]azepin-6-yl]-prop-2-en-l-one hydrochloride
  • Step 1 cis-tert-Butyl 5-(lH-benzo[d][l,2,3]triazole-5-carbonyl)hexahydro-lH-pyrrolo[3,4- c]pyridine-2(3H)-carboxylate

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Abstract

The invention provides novel compounds having the general formula (I) wherein R1, Y, A, W, R2, m, n, p and q are as described herein, compositions including the compounds and methods of using the compounds.

Description

New bicyclic derivatives
The present invention relates to organic compounds useful for therapy or prophylaxis in a mammal, and in particular to autotaxin (ATX) inhibitors which are inhibitors of lysophosphatidic acid (LP A) production and thus modulators of LP A levels and associated signaling, for the treatment or prophylaxis of renal conditions, liver conditions, inflammatory conditions, conditions of the nervous system, conditions of the respiratory system, vascular and
cardiovascular conditions, fibrotic diseases, cancer, ocular conditions, metabolic conditions, cholestatic and other forms of chronic pruritus and acute and chronic organ transplant rejection.
The present invention provides novel compounds of formula (I)
Figure imgf000002_0001
wherein
R1 is alkyl, haloalkyl, substituted cycloalkyl, substituted cycloalkylalkyl, substituted
piperazinyl, substituted piperidinyl, substituted indanyloxyalkyl, substituted phenyl, substituted phenylalkyl, substituted phenoxyalkyl, substituted phenylcyclo alkyl, substituted phenylalkenyl, substituted phenylalkynyl, substituted pyridinyl, substituted pyridinylalkyl, substituted pyridinylalkenyl, substituted pyridinylalkynyl, substituted thiophenyl, substituted thiophenylalkyl, substituted thiophenylalkenyl, substituted thiophenylalkynyl, naphtyl, substituted naphthyl, quinolyl, substituted quinolinyl, isoquinolyl, substituted iso quinolinyl, substituted 2,3-dihydro-lH-isoindol-2-yl, substituted lH-indol-2-yl or substituted benzofuran-2-yl wherein substituted cycloalkyl, substituted cycloalkylalkyl, substituted piperazinyl, substituted piperidinyl, substituted indanyloxyalkyl, substituted phenyl, substituted phenylalkyl, substituted phenylalkynyl, substituted phenoxyalkyl, substituted phenylcycloalkyl, substituted phenylalkenyl, substituted pyridinyl, substituted pyridinylalkyl, substituted pyridinylalkenyl, substituted pyridinylalkynyl, substituted thiophenyl, substituted thiophenylalkyl, substituted thiophenylalkenyl, substituted thiophenylalkynyl,
GB / 30.07.2013 substituted naphthyl, substituted quinolinyl, substituted isoquinolinyl, substituted 2,3- dihydro-lH-isoindol-2-yl,substituted lH-indol-2-yl and substituted benzofuran-2-yl are substituted with R8, R9 and R10;
Y is -OC(O)-, -NR7C(0)-, -C(O)-, -S(0)2-,
Figure imgf000003_0001
or ; A is -N- or CR5-;
W is -0-, -S-, -NR6-, -C(O)-, -S(0)2-, -C(0)-NR6- or -CR3R4-;
R3 and R4 are independently selected from H, halogen, alkyl and cycloalkyl;
R5, R6 and R7 are independently selected from H, alkyl and cycloalkyl;
R8, R9 and R10 are independently selected from H, alkyl, hydroxyalkyl, haloalkyl,
hydroxyhaloalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkoxy, cycloalkoxy, cycloalkoxyalkyl, cycloalkylalkoxyalkyl, alkoxy, alkoxyalkyl, haloalkoxy, alkoxyhaloalkyl, alkoxyalkoxy, alkoxyalkoxyalkyl, phenyl, substituted phenyl, pyridinyl, substituted pyridinyl, pyrrolyl, substituted pyrrolyl, pyrrolydinyl, substituted pyrrolydinyl, tetrahydrofuranyl, substituted tetrahydrofuranyl, halogen, hydroxy, cyano, alkylsulfanyl, haloalkylsulfanyl, cycloalkylsulfanyl, alkylsulfinyl,
halo alky lsulfinyl, cycloalkylsulfinyl, alkylcarbonyl, halo alky lcarbonyl,
cycloalkylcarbonyl, alkylsulfonyl, haloalkylsulfonyl, cycloalkylsulfonyl, substituted aminosulfonyl, substituted amino and substituted aminoalkyl, wherein substituted aminosulfonyl, substituted amino and substituted aminoalkyl are substituted on the nitrogen atom with one to two substituents independently selected from H, alkyl, cycloalkyl, cycloalkylalkyl, hydroxyalkyl, alkoxyalkyl, alkylcarbonyl and
cycloalkylcarbonyl, and wherein substituted phenyl, substituted pyrrolyl, substituted pyrrolydinyl, substituted tetrahydrofuranyl, and substituted pyridinyl are substituted with one to three substituents independently selected from alkyl, halogen, haloalkyl, alkoxy and haloalkoxy; m, n, p and q are independently selected from 1 or 2;
Figure imgf000004_0001
Figure imgf000005_0001
Figure imgf000005_0002
Figure imgf000005_0003
Figure imgf000005_0004
AF AG
Figure imgf000005_0005
AI AJ
R11 is H, alkyl, haloalkyl or cycloalkyl; R12 is alkyl, halogen, haloalkyl and alkoxy;
R2 is selected from the ring systems B, C, D, E, F, G, H, I, J, K, L, M, N, O, P, Q, R, S, T, U, V, X, Z, AA, AB, AC, AD, AE, AF, AG, AH, AI and AJ; and pharmaceutically acceptable salts.
Autotaxin (ATX) is a secreted enzyme also called ectonucleotide pyrophosphatase / phosphodiesterase 2 or lysophospholipase D that is important for converting lysophosphatidyl choline (LPC) to the bioactive signaling molecule lysophosphatidic acid (LPA). It has been shown that plasma LPA levels are well correlated with ATX activity and hence ATX is believed to be an important source of extracellular LPA. Early experiments with a prototype ATX inhibitor have shown that such a compound is able to inhibit the LPA synthesizing activity in mouse plasma. Work conducted in the 1970s and early 1980s has demonstrated that LPA can elicit a wide range of cellular responses; including smooth muscle cell contraction, platelet activation, cell proliferation, chemotaxis and others. LPA mediates its effects via signaling to several G protein coupled receptors (GPCRs); the first members were originally denoted Edg (endothelial cell differentiation gene) receptors or ventricular zone gene-l(vzg-l) but are now called LPA receptors. The prototypic group now consists of LPAl/Edg-2/VZG-l, LPA2/Edg-4, and LPA3/Edg-7. Recently, three additional LPA receptors LPA4/p2y9/GPR23, LPA5/GPR92 and LPA6/p2Y5 have been described that are more closely related to nucleotide-selective purinergic receptors than to the prototypic LPA1-3 receptors. The ATX-LPA signaling axis is involved in a large range of physiological and pathophysiological functions, including, for example, nervous system function, vascular development, cardiovascular physiology, reproduction, immune system function, chronic inflammation, tumor metastasis and progression, organ fibrosis as well as obesity and/or other metabolic diseases such as diabetes mellitus. Therefore, increased activity of ATX and/or increased levels of LPA, altered LPA receptor expression and altered responses to LPA may contribute to the initiation, progression and/or outcome of a number of different pathophysiological conditions related to the ATX/LPA axis.
In accordance with the invention, the compounds of formula (I) or their pharmaceutically acceptable salts and esters can be used for the treatment or prophylaxis of diseases, disorders or conditions that are associated with the activity of autotaxin and/or the biological activity of lysophosphatidic acid (LPA).
The compounds of formula (I) or their pharmaceutically acceptable salts and esters herein inhibit autotaxin activity and therefore inhibit LPA production and modulate LPA levels and associated signaling. Autotaxin inhibitors described herein are useful as agents for the treatment or prevention of diseases or conditions in which ATX activity and/or LPA signaling participates, is involved in the etiology or pathology of the disease, or is otherwise associated with at least one symptom of the disease. The ATX-LPA axis has been implicated for example in angiogenesis, chronic inflammation, autoimmune diseases, fibrotic diseases, cancer and tumor metastasis and progression, ocular conditions, metabolic conditions such as obesity and/or diabetes mellitus, conditions such as cholestatic or other forms of chronic pruritus as well as acute and chronic organ transplant rejection.
Objects of the present invention are the compounds of formula (I) and their
aforementioned salts and esters and their use as therapeutically active substances, a process for the manufacture of the said compounds, intermediates, pharmaceutical compositions,
medicaments containing the said compounds, their pharmaceutically acceptable salts or esters, the use of the said compounds, salts or esters for the treatment or prophylaxis of disorders or conditions that are associated with the activity of ATX and/or the biological activity of lysophosphatidic acid (LP A), particularly in the treatment or prophylaxis of renal conditions, liver conditions, inflammatory conditions, conditions of the nervous system, conditions of the respiratory system, vascular and cardiovascular conditions, fibrotic diseases, cancer, ocular conditions, metabolic conditions, cholestatic and other forms of chronic pruritus and acute and- chronic organ transplant rejection, and the use of the said compounds, salts or esters for the production of medicaments for the treatment or prophylaxis of renal conditions, liver conditions, inflammatory conditions, conditions of the nervous system, conditions of the respiratory system, vascular and cardiovascular conditions, fibrotic diseases, cancer, ocular conditions, metabolic conditions, cholestatic and other forms of chronic pruritus and acute and chronic organ transplant rejection.
The term "alkenyl" denotes a monovalent linear or branched hydrocarbon group of 2 to 7 carbon atoms with at least one double bond. In particular embodiments, alkenyl has 2 to 4 carbon atoms with at least one double bond. Examples of alkenyl include ethenyl, propenyl, prop-2-enyl, isopropenyl, n-butenyl and iso-butenyl. Particular alkenyl group is ethenyl.
The term "alkoxy" denotes a group of the formula -O-R', wherein R' is an alkyl group. Examples of alkoxy group include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy and tert-butoxy. Particular alkoxy group include methoxy.
The term "alkoxyalkoxy" denotes an alkoxy group wherein at least one of the hydrogen atoms of the alkoxy group has been replaced by another alkoxy group. Examples of
alkoxyalkoxy group include methoxymethoxy, ethoxymethoxy, methoxyethoxy, ethoxyethoxy, methoxypropoxy and ethoxypropoxy. Particular alkoxyalkoxy groups include methoxymethoxy and methoxyethoxy.
The term "alkoxyalkoxyalkyl" denotes an alkyl group wherein at least one of the hydrogen atoms of the alkyl group has been replaced by an alkoxyalkoxy group. Examples of alkoxyalkoxyalkyl group include methoxymethoxymethyl, ethoxymethoxymethyl,
methoxyethoxymethyl, ethoxyethoxymethyl, methoxypropoxymethyl, ethoxypropoxymethyl, methoxymethoxyethyl, ethoxymethoxyethyl, methoxyethoxyethyl, ethoxyethoxyethyl, methoxypropoxyethyl and ethoxypropoxyethyl.
The term "alkoxyalkyl" denotes an alkyl group wherein at least one of the hydrogen atoms of the alkyl group has been replaced by an alkoxy group. Exemplary alkoxyalkyl groups include methoxymethyl, ethoxymethyl, methoxyethyl, ethoxyethyl, methoxypropyl,
ethoxypropyl and isopropoxymethyl. Particular alkoxyalkyl group include include
methoxymethyl, methoxyethyl and isopropoxymethyl.
The term "alkoxyhaloalkyl" denotes a haloalkyl group wherein at least one of the hydrogen atoms of the haloalkyl group has been replaced by an alkoxy group. Exemplary alkoxyhaloalkyl groups include methoxytrifluoroethyl, ethoxytrifluoroethyl,
methoxytrifluoropropyl, ethoxytrifluoropropyl and isopropoxytrifluoroethyl. Particular alkoxyhaloalkyl group include include methoxytrifluoroethyl.
The term "alkyl" denotes a monovalent linear or branched saturated hydrocarbon group of 1 to 12 carbon atoms. In particular embodiments, alkyl has 1 to 7 carbon atoms, and in more particular embodiments 1 to 4 carbon atoms. Examples of alkyl include methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl and sec-butyl, pentyl. Particular alkyl groups include methyl, ethyl, propyl and isopropyl. More particular alkyl groups are methyl and isoropyl.
The term "alkylcarbonyl" denotes a group of the formula -C(0)-R', wherein R' is an alkyl group. Examples of alkylcarbonyl groups include groups of the formula -C(0)-R', wherein R' is methyl or ethyl. Particular alkylcarbonyl groups include groups of the formula -C(0)-R', wherein R' is methyl.
The term "alkylsulfanyl" denotes a group of the formula -S-R', wherein R' is an alkyl group. Examples of alkylsulfanyl groups include groups of the formula -S-R', wherein R' is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl. Particular alkylsulfanyl groups include group of the formula -S-R', wherein R' is methyl.
The term "alkylsulfinyl" denotes a group of the formula -S(0)-R', wherein R' is an alkyl group. Examples of alkylsulfinyl groups include groups of the formula
-S(0)-R', wherein R' is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl.
Particular alkylsulfinyl groups include group of the formula -S(0)-R', wherein R' is methyl.
The term "alkylsulfonyl" denotes a group of the formula -S(0)2-R', wherein R' is an alkyl group. Examples of alkylsulfonyl groups include groups of the formula
-S(0)2-R', wherein R' is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl.
Particular alkylsulfonyl groups include group of the formula -S(0)2-R', wherein R' is methyl.
The term "alkynyl" denotes a monovalent linear or branched saturated hydrocarbon group of 2 to 7 carbon atoms comprising one, two or three triple bonds. In particular embodiments alkynyl has from 2 to 4 carbon atoms comprising one or two triple bonds. Examples of alkynyl include ethynyl, propynyl, prop-2-ynyl, isopropynyl and n-butynyl. The term "amino" denotes a -NH2 group.
The term "amino alkyl" denotes an alkyl group wherein at least one of the hydrogen atoms of the alkyl group has been replaced by an aminogroup. Examples of aminoalkyl include aminomethyl, aminoethyl, amino- 1 -methyl- ethyl, aminopropyl, aminomethylpropyl and aminopropyl. Particular examples are aminomethyl and haminoethyl. The term "amino sulfonyl" denotes a -S(0)2-NH2 group.
The term "carbonyl" denotes a -C(O)- group.
The term "cyano" denotes a -C≡N group.
The term "cycloalkoxy" denotes a group of the formula -O-R', wherein R' is a cycloalkyl group. Examples of cycloalkoxy group include cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy and cyclooctyloxy. Particular cycloalkoxy group is cyclopropoxy.
The term "cycloalkoxyalkyl" denotes an alkyl group wherein at least one of the hydrogen atoms of the alkyl group has been replaced by a cycloalkoxy group. Examples of
cycloalkoxyalkyl groups include cyclopropoxymethyl, cyclopropoxyethyl, cyclobutoxymethyl, cyclobutoxyethyl, cyclopentyloxymethyl, cyclopentyloxyethyl, cyclohexyloxymethyl, cyclohexyloxyethyl, cycloheptyloxymethyl, cycloheptyloxyethyl, cyclooctyloxymethyl and cyclooctyloxyethyl.
The term "cycloalkyl" denotes a monovalent saturated monocyclic or bicyclic hydrocarbon group of 3 to 10 ring carbon atoms. In particular embodiments, cycloalkyl denotes a monovalent saturated monocyclic hydrocarbon group of 3 to 8 ring carbon atoms. Bicyclic means a ring system consisting of two saturated carbocycles having two carbon atoms in common. Examples for monocyclic cycloalkyl are cyclopropyl, cyclobutanyl, cyclopentyl, cyclohexyl or cycloheptyl. Examples for bicyclic cycloalkyl are bicyclo[2.2.1]heptanyl or bicyclo[2.2.2]octanyl. Particular monocyclic cycloalkyl groups are cyclopropyl, cyclobutanyl, cyclopentyl and cyclohexyl. More particular monocyclic cycloalkyl group is cyclopropyl.
The term "cycloalkylalkoxy" denotes an alkoxy group wherein at least one of the hydrogen atoms of the alkoxy group is replaced by a cycloalkyl group. Examples of cycloalkylalkoxy include cyclopropylmethoxy, cyclobutylmethoxy, cyclopentylmethoxy, cyclohexylmethoxy, cycloheptylmethoxy and cyclooctylmethoxy.
The term "cycloalkylalkoxyalkyl" denotes an alkyl group wherein at least one of the hydrogen atoms of the alkyl group is replaced by a cycloalkylalkoxy group. Examples of cycloalkylalkoxyalkyl include cyclopropylmethoxymethyl, cyclopropylmethoxyethyl, cyclobutylmethoxymethyl, cyclobutylmethoxyethyl, cyclopentylmethoxyethyl,
cyclopentylmethoxyethyl, cyclohexylmethoxymethyl, cyclohexylmethoxyethyl,
cycloheptylmethoxymethyl, cycloheptylmethoxyethyl, cyclooctylmethoxymethyl and
cyclooctylmethoxyethyl.
The term "cycloalkylalkyl" denotes an alkyl group wherein at least one of the hydrogen atoms of the alkyl group is replaced by a cycloalkyl group. Examples of cycloalkylalkyl include cyclopropylmethyl, cyclopropylethyl, cyclopropylbutyl, cyclobutylpropyl, 2-cyclopropylbutyl, cyclopentylbutyl, cyclohexylmethyl, cyclohexylethyl, bicyclo[4.1.0]heptanylmethyl,
bicyclo[4.1.0]heptanylethyl, bicyclo[2.2.2]octanylmethyl, bicyclo[2.2.2]octanylethyl,
adamentanylmethyl and adamantanylethyl. Particular examples of cycloalkylalkyl are
cyclohexylmethyl, cyclohexylethyl, bicyclo[4.1.0]heptanylmethyl, bicyclo[4.1.0]heptanylethyl, bicyclo[2.2.2]octanylmethyl, bicyclo[2.2.2]octanylethyl, adamentanylmethyl and
adamantanylethyl. Further particular examples cycloalkylalkyl are cyclohexylmethyl, cyclohexylethyl, bicyclo[4.1.0]heptanylmethyl, bicyclo[2.2.2]octanylmethyl, adamentanylmethyl and adamantanylethyl.
The term "cycloalkylcarbonyP'of the formula -C(0)-R', wherein R' is a cycloalkyl group. Examples of cycloalkylcarbonyl groups include groups of the formula -C(0)-R', wherein R' is cyclopropyl.
The term "cycloalkylsulfanyl" denotes a group of the formula -S-R', wherein R' is a cycloalkyl group. Examples of cycloalkylsulfanyl groups include groups of the formula -S-R', wherein R' is cyclopropyl.
The term "cycloalkylsulfinyl" denotes a group of the formula -S(0)-R', wherein R' is a cycloalkyl group. Examples of cycloalkylsulfinyl groups include groups of the formula -S(0)-R', wherein R' is cyclopropyl.
The term "cycloalkylsulfonyl" denotes a group of the formula -S(0)2-R', wherein R' is a cycloalkyl group. Examples of cycloalkylsulfonyl groups include groups of the formula -S(0)2- R', wherein R' is cyclopropyl.
The term "haloalkoxy" denotes an alkoxy group wherein at least one of the hydrogen atoms of the alkoxy group has been replaced by the same or different halogen atoms. The term "perhaloalkoxy" denotes an alkoxy group where all hydrogen atoms of the alkoxy group have been replaced by the same or different halogen atoms. Examples of haloalkoxy include fluoromethoxy, difluoromethoxy, trifluoromethoxy, trifluoroethoxy, trifluoromethylethoxy, trifluorodimethylethoxy and pentafluoroethoxy. Particular haloalkoxy group is trifluoromethoxy.
The term "halo alky 1" denotes an alkyl group wherein at least one of the hydrogen atoms of the alkyl group has been replaced by the same or different halogen atoms. The term
"perhaloalkyl" denotes an alkyl group where all hydrogen atoms of the alkyl group have been replaced by the same or different halogen atoms. Examples of haloalkyl include fluoromethyl, difluoromethyl, trifluoromethyl, trifluoro ethyl, trifluoromethylethyl and pentafluoroethyl.
Particular haloalkyl group is trifluoromethyl.
The term "halo alky lsulfanyl" denotes a group of the formula -S-R', wherein R' is a haloalkyl group. Examples of halo alky lsulfanyl groups include groups of the formula -S-R', wherein R' is trifluoromethyl. The term "halo alky lsulfmyl" denotes a group of the formula -S(0)-R', wherein R' is a haloalkyl group. Examples of halo alky lsulfmyl groups include groups of the formula -S(0)-R', wherein R' is trifluoromethyl.
The term "haloalkylsulfonyl" denotes a group of the formula -S(0)2-R', wherein R' is a haloalkyl group. Examples of haloalkylsulfonyl groups include groups of the formula -S(0)2-R', wherein R' is trifluoromethyl.
The term "halogen" and "halo" are used interchangeably herein and denote fluoro, chloro, bromo, or iodo. Particular halogens are chloro, fluoro and bromo. More particular halogens are chloro and fluoro. The term "hydroxy" denotes an -OH group.
The term "hydroxyalkyl" denotes an alkyl group wherein at least one of the hydrogen atoms of the alkyl group has been replaced by a hydroxy group. Examples of hydroxyalkyl include hydro xymethyl, hydro xyethyl, hydroxy- 1 -methyl-ethyl, hydro xypropyl,
hydroxymethylpropyl and dihydroxypropyl. Particular examples are hydroxymethyl and hydro xyethyl.
The term "hydroxyhaloalkyl" denotes a haloalkyl group wherein at least one of the hydrogen atoms of the haloalkyl group has been replaced by an hydroxy group. Exemplary hydroxyhaloalkyl groups include hydroxytrifluoroethyl and hydroxytrifluoropropyl. Particular hydroxyhaloalkyl groups include hydroxytrifluoroethyl. The term "indanyloxy" denotes a group of the formula -O-R', wherein R' is an indanyl.
The term "indanyloxyalkyl" denotes an alkyl group wherein at least one of the hydrogen atoms of the alkyl group has been replaced by a indanyloxy group. Exemplary indanyloxyalkyl groups include indanylo xymethyl, indanylo xyethyl and indanylo xypropyl. Particular
indanyloxyalkyl group is indanyloxymethyl.
The term "phenoxy" denotes a group of the formula -O-R', wherein R' is a phenyl.
The term "phenoxyalkyl" denotes an alkyl group wherein at least one of the hydrogen atoms of the alkyl group has been replaced by a phenoxy group. Exemplary phenoxyalkyl groups include phenoxymethyl, phenoxyethyl and phenoxypropyl. Particular phenoxyalkyl group is phenoxymethyl.
The term "phenylalkenyl" denotes an alkenyl group wherein at least one of the hydrogen atoms of the alkenyl group has been replaced a phenyl. Particular phenylalkenyl group is phenylethenyl.
The term "phenylalkyl" denotes an alkyl group wherein at least one of the hydrogen atoms of the alkyl group has been replaced a phenyl. Particular phenylalkyl groups are benzyl, phenethyl and phenylpropyl. More particular phenylalkyl groups are benzyl and phenethyl. Further particular phenylalkyl group is benzyl. The term "phenylalkynyl" denotes an alkynyl group wherein at least one of the hydrogen atoms of the alkynyl group has been replaced a phenyl. Particular phenylalkynyl group is phenylethynyl.
The term "phenylcyloalkyl" denotes a cycloalkyl group wherein at least one of the hydrogen atoms of the cycloalkyl group has been replaced a phenyl. Particular phenylcycloalkyl group is phenylcyclopropyl.
The term "pyridinylalkenyl" denotes an alkenyl group wherein at least one of the hydrogen atoms of the alkenyl group has been replaced a pyridinyl. Particular pyridinylalkenyl group is pyridinylethenyl.
The term "pyridinylalkyl" denotes an alkyl group wherein at least one of the hydrogen atoms of the alkyl group has been replaced a pyridinyl. Particular pyridinylalkyl groups are pyridinylmethyl, pyridinylethyl and pyridinylpropyl. More particular pyridinylalkyl group is pyridinylethyl.
The term "pyridinylalkynyl" denotes an alkynyl group wherein at least one of the hydrogen atoms of the alkynyl group has been replaced a pyridinyl. Particular pyridinylalkynyl group is pyridinylethynyl.The term "thiophenylalkenyl" denotes an alkenyl group wherein at least one of the hydrogen atoms of the alkenyl group has been replaced a thiophenyl. Particular
thiophenylalkenyl group is thiophenylethenyl.
The term "thiophenylalkyl" denotes an alkyl group wherein at least one of the hydrogen atoms of the alkyl group has been replaced a thiophenyl. Particular thiophenylalkyl groups are thiophenylmethyl, thiophenylethyl and thiophenylpropyl. More particular thiophenylalkyl group is thiophenylmethyl.
The term "thiophenylalkynyl" denotes an alkynyl group wherein at least one of the hydrogen atoms of the alkynyl group has been replaced a thiophenyl. Particular
thiophenylalkynyl group is thiophenylethynyl.
The term "pharmaceutically acceptable salts" refers to those salts which retain the biological effectiveness and properties of the free bases or free acids, which are not biologically or otherwise undesirable. The salts are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, in particular hydrochloric acid, and organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p- toluenesulfonic acid, salicylic acid, N-acetylcystein and the like. In addition, these salts may be prepared by addition of an inorganic base or an organic base to the free acid. Salts derived from an inorganic base include, but are not limited to, the sodium, potassium, lithium, ammonium, calcium, magnesium salts and the like. Salts derived from organic bases include, but are not limited to salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as
isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, lysine, arginine, N-ethylpiperidine, piperidine, polyimine resins and the like. Particular pharmaceutically acceptable salts of compounds of formula (I) are the hydrochloride salts, methanesulfonic acid salts and citric acid salts.
"Pharmaceutically acceptable esters" means that compounds of general formula (I) may be derivatised at functional groups to provide derivatives which are capable of conversion back to the parent compounds in vivo. Examples of such compounds include physiologically acceptable and metabolically labile ester derivatives, such as methoxymethyl esters, methylthio methyl esters and pivaloyloxymethyl esters. Additionally, any physiologically acceptable equivalents of the compounds of general formula (I), similar to the metabolically labile esters, which are capable of producing the parent compounds of general formula (I) in vivo, are within the scope of this invention. The term "protecting group" (PG) denotes a group which selectively blocks a reactive site in a multifunctional compound such that a chemical reaction can be carried out selectively at another unprotected reactive site in the meaning conventionally associated with it in synthetic chemistry. Protecting groups can be removed at the appropriate point. Exemplary protecting groups are amino -protecting groups, carboxy-protecting groups or hydroxy-protecting groups. Particular protecting groups are the tert-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz), fluorenylmethoxycarbonyl (Fmoc) and benzyl (Bn) groups. Further particular protecting groups are the tert-butoxycarbonyl (Boc) and the fluorenylmethoxycarbonyl (Fmoc) groups. More particular protecting group is the tert-butoxycarbonyl (Boc) group. The abbreviation uM means micro Molar and is equivalent to the symbol μΜ.
The abbreviation uL means microliter and is equivalent to the symbol μί.
The abbreviation ug means microgram and is equivalent to the symbol μg.
The compounds of formula (I) can contain several asymmetric centers and can be present in the form of optically pure enantiomers, mixtures of enantiomers such as, for example, racemates, optically pure diastereoisomers, mixtures of diastereoisomers, diastereoisomeric racemates or mixtures of diastereoisomeric racemates.
According to the Cahn-Ingold-Prelog convention the asymmetric carbon atom can be of the "R" or "S" configuration.
Also an embodiment of the present invention are compounds according to formula (I) as described herein and pharmaceutically acceptable salts or esters thereof, in particular compounds according to formula (I) as described herein and pharmaceutically acceptable salts thereof, more particularly compounds according to formula (I) as described herein.
Another embodiment of the present invention are compounds according to formula (I) as described herein, wherein R1 is alkyl, haloalkyl, substituted cycloalkyl, substituted cycloalkylalkyl, substituted phenyl, substituted phenylalkyl, substituted phenoxyalkyl, substituted
phenylcyclo alkyl, substituted phenylalkenyl, substituted phenylalkynyl, substituted pyridinyl, substituted pyridinylalkyl, substituted pyridinylalkenyl, substituted pyridinylalkynyl, substituted thiophenyl, substituted thiophenylalkyl, substituted thiophenylalkenyl, substituted thiophenylalkynyl, substituted 2,3-dihydro-lH-isoindol- 2-yl, substituted lH-indol-2-yl or substituted benzofuran-2-yl wherein substituted cycloalkyl, substituted cycloalkylalkyl, substituted phenyl, substituted phenylalkyl, substituted phenylalkynyl, substituted phenoxyalkyl, substituted phenylcyclo alkyl, substituted phenylalkenyl, substituted pyridinyl, substituted pyridinylalkyl, substituted pyridinylalkenyl, substituted pyridinylalkynyl, substituted thiophenyl, substituted thiophenylalkyl, substituted thiophenylalkenyl, substituted thiophenylalkynyl, substituted 2,3-dihydro-lH-isoindol-2-yl,substituted lH-indol-2-yl and substituted benzofuran-2-yl are substituted with R8, R9 and R10;
Y is -OC(O)-, -NR7C(0)-, -C(O)-, -S(0)2-,
Figure imgf000016_0001
A is -N- or CR5-;
W is -0-, -S-, -NR6-, -C(O)-, -S(0)2-, -C(0)-NR6- or -CR3R4-;
R3 and R4 are independently selected from H, halogen, alkyl and cycloalkyl;
R5, R6 and R7 are independently selected from H, alkyl and cycloalkyl;
R8, R9 and R10 are independently selected from H, alkyl, hydroxyalkyl, haloalkyl,
hydroxyhaloalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkoxy, cycloalkoxy, cycloalkoxyalkyl, cycloalkylalkoxyalkyl, alkoxy, alkoxyalkyl, haloalkoxy,
alkoxyhaloalkyl, alkoxyalkoxy, alkoxyalkoxyalkyl, phenyl, substituted phenyl, pyridinyl, substituted pyridinyl, halogen, hydroxy, cyano, alkylsulfanyl,
halo alky lsulfanyl, eye lo alkylsulfanyl, alkylsulfmyl, halo alky lsulfmyl,
cycloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl, cycloalkylsulfonyl, substituted aminosulfonyl, substituted amino and substituted aminoalkyl, wherein substituted aminosulfonyl, substituted amino and substituted aminoalkyl are substituted on the nitrogen atom with one to two substituents independently selected from H, alkyl, cycloalkyl, cycloalkylalkyl, hydroxyalkyl, alkoxyalkyl, alkylcarbonyl and
cycloalkylcarbonyl, and wherein substituted phenyl and substituted pyridinyl are optionally substituted with one to three substituents independently selected from alkyl, halogen, haloalkyl, alkoxy and haloalkoxy; m, n, p and q are independently selected from 1 or 2;
Figure imgf000018_0001
Figure imgf000019_0001
Figure imgf000019_0002
Figure imgf000019_0003
Figure imgf000019_0004
AE
R11 is H, alkyl, haloalkyl or cycloalkyl;
R2 is selected from the ring systems B, C, D, E, F, G, H, I, J, K, L, M, N, O, P, Q, R, S, T, U, V, X, Z, AA, AB, AC, AD and AE; and pharmaceutically acceptable salts.
A further embodiment of the present invention are compounds according to formula (I) as described herein, wherein R1 is substituted cycloalkylalkyl, substituted piperazinyl, substituted piperidinyl, substituted indanyloxyalkyl, substituted phenyl, substituted phenylalkyl, substituted phenoxyalkyl, substituted phenylcycloalkyl, substituted phenylalkenyl, substituted
pyridinylalkyl, substituted pyridinylalkenyl, naphtyl, substituted naphthyl, substituted quinolinyl, substituted isoquinolinyl, or substituted lH-indol-2-yl, wherein substituted cycloalkylalkyl, substituted piperazinyl, substituted piperidinyl, substituted indanyloxyalkyl, substituted phenyl, substituted phenylalkyl, substituted phenoxyalkyl, substituted phenylcycloalkyl, substituted phenylalkenyl, substituted pyridinylalkyl, substituted pyridinylalkenyl, substituted naphthyl, substituted quinolinyl, substituted isoquinolinyl and substituted lH-indol-2-yl are substituted with R8, R9 and R10.
Another further embodiment of the present invention are compounds according to formula (I) as described herein, wherein R1 is substituted cycloalkylalkyl, substituted phenyl, substituted phenylalkyl, substituted phenoxyalkyl, substituted phenylcycloalkyl, substituted phenylalkenyl, substituted pyridinylalkyl, substituted pyridinylalkenyl or substituted lH-indol-2-yl, wherein substituted cycloalkylalkyl, substituted phenyl, substituted phenylalkyl, substituted
phenoxyalkyl, substituted phenylcycloalkyl, substituted phenylalkenyl, substituted
pyridinylalkyl, substituted pyridinylalkenyl, and substituted lH-indol-2-yl are substituted with R8, R9 and R10. A particular embodiment of the present invention are compounds according to formula (I) as described herein, wherein R1 is substituted phenylalkyl or substituted phenylalkenyl, wherein substituted phenylalkyl and substituted phenylalkenyl are substituted with R8, R9 and R10.
In a further embodiment of the present invention are compounds according to formula (I) as described herein, wherein R1 is phenylalkyl substituted with R8, R9 and R10. The present invention also relates to compounds according to formula (I) as described
' O herein, wherein Y is -OC(O)-, -C(O)-, -S(0)2- or N— N
A further particular embodiment of the present invention are compounds according to formula (I) as described herein, wherein Y is -OC(O)- or -C(O)-.
Another further embodiment of the present invention are compounds according to formula (I) as described herein, wherein Y is -OC(O)- and of formula (In).
Figure imgf000020_0001
Another embodiment of the present invention are compounds according to formula (I) as described herein, wherein Y is -C(O)-.
A more particular embodiment of the present invention are compounds according to formula (I) as described herein, wherein A is -N-. Also an embodiment of the present invention are compounds according to formula (I) as described herein, wherein W is -0-, -NR6-, -C(O)-, -S(0)2-, -C(0)-NR6- or -CR3R4-.
Another embodiment of the present invention are compounds according to formula (I) as described herein, wherein W is -C(O)-, -C(0)-NR6- or -CR3R4-.
Another embodiment of the present invention are compounds according to formula (I) as described herein, wherein W is -C(O)-.
A further particular embodiment of the present invention are compounds according to formula (I) as described herein, wherein R2 is selected from the ring systems B, C, D, E, G, H, M, O, P, R, S, T, U, V, X, Z, AA, AB, AC, AD, AE, AF, AG, AH and AI.
Another further particular embodiment of the present invention are compounds according to formula (I) as described herein, wherein R2 is selected from the ring systems B, C, D, E, G, H, M, O, P, R, S, T, U, V, X, Z, AA, AB, AC, AD and AE.
Also a further particular embodiment of the present invention are compounds according to formula (I) as described herein, wherein R2 is selected from the ring systems B, D, H, M, O, R and AJ. A further particular embodiment of the present invention are compounds according to formula (I) as described herein, wherein R2 is selected from the ring systems B, D, H, O and R.
A further particular embodiment of the present invention are compounds according to formula (I) as described herein, wherein R2 is selected from the ring systems B and D.
A further particular embodiment of the present invention are compounds according to formula (I) as described herein, wherein R2 is the ring system D.
A further particular embodiment of the present invention are compounds according to formula (I) as described herein, wherein R3 and R4 are H. A further particular embodiment of the present invention are compounds according to formula (I) as described herein, wherein R5 is H.
A further particular embodiment of the present invention are compounds according to formula (I) as described herein, wherein R6 is H or alkyl. A a further particular embodiment of the present invention are compounds according to formula (I) as described herein, wherein R8, R9 and R10 are independently selected from H, alkyl, haloalkyl, hydroxyhaloalkyl, alkoxy, haloalkoxy, alkoxyhaloalkyl, phenyl, pyridinyl, halogen, cyano, haloalkylsulfanyl, haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl, pyrrolyl substituted with one alkyl, pyrrolydinyl, tetrahydroiuranyl, alkylcarbonyl, and aminosulfonyl substituted on the nitrogen atom with one to two substituents independently selected from H, alkyl, cycloalkyl, cycloalkylalkyl, hydroxyalkyl, alkoxyalkyl, alkylcarbonyl and cycloalkylcarbonyl.
Also a further particular embodiment of the present invention are compounds according to formula (I) as described herein, wherein R8, R9 and R10 are independently selected from H, alkyl, haloalkyl, hydroxyhaloalkyl, alkoxy, haloalkoxy, alkoxyhaloalkyl, phenyl, pyridinyl, halogen, cyano, haloalkylsulfanyl, haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl and aminosulfonyl substituted on the nitrogen atom with one to two substituents independently selected from H, alkyl, cycloalkyl, cycloalkylalkyl, hydroxyalkyl, alkoxyalkyl, alkylcarbonyl and
cycloalkylcarbonyl.
A further particular embodiment of the present invention are compounds according to formula (I) as described herein, wherein R8, R9 and R10 are independently selected from H, alkyl, haloalkyl, hydroxyhaloalkyl, alkoxy, haloalkoxy, alkoxyhaloalkyl, phenyl, pyridinyl, halogen, cyano, haloalkylsulfanyl, haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl and aminosulfonyl substituted on the nitrogen atom with two alkyl.
A further particular embodiment of the present invention are compounds according to formula (I) as described herein, wherein R8, R9 and R10 are independently selected from H, alkyl, haloalkyl, haloalkoxy, halogen and alkylsulfonyl.
A further particular embodiment of the present invention are compounds according to formula (I) as described herein, wherein R8 is H, alkyl, haloalkyl, hydroxyhaloalkyl, alkoxy, haloalkoxy, alkoxyhaloalkyl, phenyl, pyridinyl, halogen, cyano, haloalkylsulfanyl,
haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl, pyrrolyl substituted with one alkyl, pyrrolydinyl, tetrahydrofuranyl, alkylcarbonyl, or aminosulfonyl substituted on the nitrogen atom with two alkyl.
A further particular embodiment of the present invention are compounds according to formula (I) as described herein, wherein R8 is H, alkyl, haloalkyl, hydroxyhaloalkyl, alkoxy, haloalkoxy, alkoxyhaloalkyl, phenyl, pyridinyl, halogen, cyano, haloalkylsulfanyl,
halo alky lsulfinyl, alkylsulfonyl, haloalkylsulfonyl or aminosulfonyl substituted on the nitrogen atom with two alkyl.
A further particular embodiment of the present invention are compounds according to formula (I) as described herein, wherein R8 is haloalkyl, haloalkoxy, halogen or alkylsulfonyl. A particular embodiment of the present invention are compounds according to formula (I) as described herein, wherein R8 is haloalkoxy or halogen.
Also an embodiment of the present invention are compounds according to formula (I) as described herein, wherein R8 is halogen.
The present invention also relates to compounds according to formula (I) as described herein, wherein R9 is H, alkyl, haloalkyl, cycloalkyl, cycloalkoxy, alkoxy, haloalkoxy, alkoxyalkoxy, cyano or halogen.
The present invention also relates to compounds according to formula (I) as described herein, wherein R9 is H, alkyl, haloalkyl, alkoxy or halogen.
Another embodiment of the present invention are compounds according to formula (I) as described herein, wherein R9 is H, alkyl or halogen.
The present invention also relates to compounds according to formula (I) as described herein, wherein R8 and R9 are halogen.
Also an embodiment of the present invention are compounds according to formula (I) as described herein, wherein R9 is H, alkyl, haloalkyl, cycloalkyl, cycloalkoxy, alkoxy, haloalkoxy, alkoxyalkoxy, cyano or halogen.
Also an embodiment of the present invention are compounds according to formula (I) as described herein, wherein R10 is H or alkyl. Another embodiment of the present invention are compounds according to formula (I) as described herein, wherein R10 is H.
Also an embodiment of the present invention are compounds according to formula (I) as described herein, wherein R11 is haloalkyl.
A particular embodiment of the present invention are compounds according to formula (I) as described herein, wherein m is 1.
A further particular embodiment of the present invention are compounds according to formula (I) as described herein, wherein n is 1.
A more particular embodiment of the present invention are compounds according to formula (I) as described herein, wherein m and n are 1.
Also a particular embodiment of the present invention are compounds according to formula (I) as described herein, wherein p and q are 1.
The present invention also relates to compounds according to formula (I) as described herein, wherein m, n, p and q are 1.
A furthermore particular embodiment of the present invention are compounds according to formula (I) as described herein, wherein
R1 is substituted phenylalkyl or substituted phenylalkenyl, wherein substituted
phenylalkyl and substituted phenylalkenyl are substituted with R8, R9 and R10;
Y is -OC(O)- or -C(O)-;
A is -N-;
W is -C(O)-;
R8 is haloalkyl, haloalkoxy, halogen or alkylsulfonyl; R9 is H, alkyl or halogen; R10 is H or alkyl; m and n are 1 ; p and q are independently selected from 1 or 2;
R2 is selected from the ring systems B, D, H, M, O, R and AJ;
R12 is halogen and pharmaceutically acceptable salts.
Also a furthermore particular embodiment of the present invention are compounds according to formula (I) as described herein, wherein
R1 is substituted phenylalkyl or substituted phenylalkenyl, wherein substituted
phenylalkyl and substituted phenylalkenyl are substituted with R8, R9 and R10;
Y is -OC(O)- or -C(O)-;
A is -N-;
W is -C(O)-;
R8 is haloalkyl, haloalkoxy, halogen or alkylsulfonyl; R9 is H, alkyl or halogen; R10 is H or alkyl; m and n are 1 ; p and q are independently selected from 1 or 2; R2 is selected from the ring systems B and D; and pharmaceutically acceptable salts.
Particular examples of compounds of formula (I) as described herein are selected from
(E)-l-[(3aS,8aR)-2-(4,5,6,7-tetrahydro-lH-benzotriazole-5-carbonyl)-octahydro- pyrrolo[3,4-d]azepin-6-yl]-3-(4-trifluoromethoxy-phenyl)-prop-2-ene-l-one; l-((3aR,6aS)-5-(lH-benzo[d][l,2,3]triazole-5-carbonyl)hexahydropyrrolo[3,4-c]pyrrol- 2(1 H)-yl)-3 -(3 ,5 -dichlorophenyl)propan- 1 -one; 6-((3aR,6aS)-5-(3-(3,5-dichlorophenyl)propanoyl)octahydropyrrolo[3,4-c]pyrrole-2- carbonyl)benzo[d]oxazol-2(3H)-one;
(3aR,6aS)-3,5-dichlorobenzyl 5-(lH-benzo[d][l,2,3]triazole-5- carbonyl)hexahydropyrrolo [3 ,4-c]pyrro le-2( 1 H)-carboxylate;
(3 aR,6aS)-3 ,5 -dichlorobenzyl 5 -(9H-pyrido [3 ,4-b]indo le-3 - carbonyl)hexahydropyrrolo [3 ,4-c]pyrro le-2( 1 H)-carboxylate;
(3aR,6aS)-3,5-dichlorobenzyl 5-(lH-indole-5-carbonyl)hexahydropyrrolo[3,4-c]pyrrole- 2(1 H)-carboxylate;
(3aR,6aS)-3,5-dichlorobenzyl 5-(9H-carbazole-3-carbonyl)hexahydropyrrolo[3,4- c]pyrrole-2( 1 H)-carboxylate;
(3aR,6aS)-3,5-dichlorobenzyl 5-(lH-indazole-5-carbonyl)hexahydropyrrolo[3,4-c]pyrrole- 2(1 H)-carboxylate;
(3aR,6aS)-3,5-dichlorobenzyl 5-(lH-benzo[d]imidazole-5-carbonyl)hexahydropyrrolo[3,4- c]pyrrole-2( 1 H)-carboxylate; trans-3 ,5-dichlorobenzyl 2-( 1 H-benzo [d] [ 1 ,2,3]triazole-5-carbonyl)hexahydro- 1 H- pyrrolo [3 ,4-c]pyridine-5 (6H)-carboxylate; cis-3 ,5-dichlorobenzyl 2-( 1 H-benzo [d] [ 1 ,2,3]triazole-5-carbonyl)hexahydro- 1 H- pyrrolo [3 ,4-c]pyridine-5 (6H)-carboxylate;
(3aR,8aS)-3,5-dichlorobenzyl 2-(lH-benzo[d][l,2,3]triazole-5- carbonyl)octahydropyrro lo [3 ,4-d] azepine-6(7H)-carboxylate;
(lH-benzotriazol-5-yl)-{(3aS,6aR)-5-[2-(3-chloro-phenyl)-ethanesulfonyl]-hexahydro- pyrrolo [3 ,4-c]pyrrol-2-yl} -methanone;
(3aR,6aS)-3,5-dichlorobenzyl 5-(4,5,6,7-tetrahydro-lH-benzo[d][l,2,3]triazole-5- carbonyl)hexahydropyrrolo [3 ,4-c]pyrro le-2( 1 H)-carboxylate; l-((3aR,8aS)-2-(lH-benzo[d][l,2,3]triazole-5-carbonyl)octahydropyrrolo[3,4-d]azepin- 6(7H)-yl)-3-(3-chlorophenyl)-2,2-dimethylpropan- 1 -one; (E)-l-((3aR,8aS)-2-(lH-benzo[d][l,2,3]triazole-5-carbonyl)octahydropyrrolo[3,4- d]azepin-6(7H)-yl)-3-(3-fluoro-4-(trifluoromethoxy)phenyl)prop-2-en-l-one;
(3aSR,6SR,7aSR)-6-{(3aS,8aR)-6-[(E)-3-(4-trifluoromethoxy-phenyl)-acryloyl]- octahydro-pyrrolo[3,4-d]azepine-2-carbonyl}-hexahydro-benzooxazol-2-one; (E)-l-[(3aS,8aR)-2-(benzo[c][l,2,5]oxadiazole-5-carbonyl)-octahydro-pyrrolo[3,4- d]azepin-6-yl]-3-(4-trifluoromethoxy-phenyl)-prop-2-ene- 1 -one;
(E)-l-((3aR,8aS)-2-(lH-benzo[d][l,2,3]triazole-5-carbonyl)octahydropyrrolo[3,4- d] azepin-6(7H)-yl)-3 -(2-methyl-4-(trifluoromethoxy)phenyl)prop-2-en- 1 -one;
(E)-l-((3aR,8aS)-2-(lH-benzo[d][l,2,3]triazole-5-carbonyl)octahydropyrrolo[3,4- d]azepin-6(7H)-yl)-3-(3-fluoro-4-methoxyphenyl)prop-2-en- 1 -one;
(E)-l-[(3aS,8aR)-2-((S)-4,5,6,7-tetrahydro-lH-benzotriazole-5-carbonyl)-octahydro- pyrrolo[3,4-d]azepin-6-yl]-3-(4-trifluoromethoxy-phenyl)-prop-2-ene-l-one
(E)-l-[(3aS,8aR)-2-((R)-4,5,6,7-tetrahydro-lH-benzotriazole-5-carbonyl)-octahydro- pyrrolo[3,4-d]azepin-6-yl]-3-(4-trifluoromethoxy-phenyl)-prop-2-ene- 1 -one (E)- 1 - [(3aS,8aR)-2-(lH-benzotriazole-5-carbonyl)-octahydro-pyrrolo[3,4-d]azepin-6-yl]-3-(2- isopropyl-phenyl)-prop-2-ene- 1 -one; trans-3,5-dichlorobenzyl 2-(2-oxo-2,3-dihydrobenzo[d]oxazole-6-carbonyl)hexahydro-lH- pyrrolo [3 ,4-c]pyridine-5 (6H)-carboxylate;
(3aR,6aS)-3,5-dichlorobenzyl 5-(2-oxo-2,3-dihydrobenzo[d]oxazole-6- carbonyl)hexahydropyrrolo [3 ,4-c]pyrro le-2( 1 H)-carboxylate;
6-{(3aS,8aR)-6-[(E)-3-(4-trifluoromethoxy-phenyl)-acryloyl]-octahydro-pyrrolo[3,4- d]azepine-2-carbonyl}-3H-benzooxazol-2-one;
(3aR,5s,6aS)-3,5-dichlorobenzyl 5-(2-oxo-2,3-dihydrobenzo[d]oxazol-6- yloxy)hexahydrocyclopenta[c]pyrrole-2( 1 H)-carboxylate; (3aR,5r,6aS)-3,5-dichlorobenzyl 5-(2-oxo-2,3-dihydrobenzo[d]oxazol-6- yloxy)hexahydrocyclopenta[c]pyrrole-2( 1 H)-carboxylate; (3aS,6aS)-3,5-dichlorobenzyl 5 -(1 H-benzo [d][ 1,2,3 ]triazole-5 - carbonyl)hexahydropyrrolo [3 ,4-c]pyrro le-2( 1 H)-carboxylate; trans-5-(lH-benzotriazole-5-carbonyl)-octahydro-pyrrolo[3,4-c]pyridine-2-carboxylic acid 3 -methanesulfonyl-5 -trifluoromethyl-benzyl ester;
(3aR,6aR)-3,5-dichlorobenzyl 5 -(1 H-benzo [d][ 1,2,3 ]triazole-5 - carbonyl)hexahydropyrrolo [3 ,4-c]pyrro le-2( 1 H)-carboxylate;
(3aS,6aS)-5-(lH-benzotriazole-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid 3-chloro-5-methanesulfonyl-benzyl ester;
(3aS,6aR)-5-(lH-benzotriazole-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid 3-chloro-5-methanesulfonyl-benzyl ester;
(3aS,8aR)-2-(lH-benzotriazole-5-carbonyl)-octahydro-pyrrolo[3,4-d]azepine-6-carboxylic acid 3 -methanesulfonyl-5 -trifluoromethyl-benzyl ester;
(3aS,8aR)-2-(lH-benzotriazole-5-carbonyl)-octahydro-pyrrolo[3,4-d]azepine-6-carboxylic acid 3-chloro-5-methanesulfonyl-benzyl ester;
(3aS,6aR)-5-(lH-benzotriazole-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid 3 -methanesulfonyl-5 -trifluoromethyl-benzyl ester; cis-3,5-dichlorobenzyl 5-(lH-benzo[d][l,2,3]triazole-5-carbonyl)hexahydro-lH- pyrrolo[3,4-c]pyridine-2(3H)-carboxylate;
(3aS,7aR)-5-(lH-benzotriazole-5-carbonyl)-octahydro-pyrrolo[3,4-c]pyridine-2-carboxylic acid 3-chloro-5-methanesulfonyl-benzyl ester; trans-3 ,5-dichlorobenzyl 5-( 1 H-benzo [d] [ 1 ,2,3]triazole-5-carbonyl)hexahydro- 1 H- pyrrolo[3,4-c]pyridine-2(3H)-carboxylate;
(3aR,8aS)-3,5-dichlorobenzyl 6-(lH-benzo[d][l,2,3]triazole-5- carbonyl)octahydropyrro lo [3 ,4-d] azepine-2( 1 H)-carboxylate;
(3aS,6aR)-5-(lH-benzotriazole-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid l-(3-chloro-phenyl)-cyclopropyl ester; (3aS,6aR)-5-(lH-benzotriazole-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid bicyclo[4.1.0]hept-7-ylmethyl ester;
(3aS,6aR)-5-(lH-benzotriazole-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid adamantan-2-ylmethyl ester;
(3aS,6aR)-5-(lH-benzotriazole-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid 1-fluoro-cyclohexylmethyl ester;
(3aS,6aR)-5-(lH-benzotriazole-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid 2-adamantan-2-yl-ethyl ester;
(3aS,6aR)-5-(lH-benzotriazole-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid 2-adamantan-l-yl-ethyl ester;
(3aS,6aR)-5-(lH-benzotriazole-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid adamantan-l-ylmethyl ester;
(3aS,6aR)-5-(lH-benzotriazole-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid cyclohexylmethyl ester; cis-5-(lH-benzotriazole-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid 3- (2,2,2-trifluoro- 1 -methoxy-ethyl)-benzyl ester; cis-5-(lH-benzotriazole-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid 3- (2,2,2-trifluoro- 1 -hydro xy-ethyl)-benzyl ester;
(3aR,6aS)-2-cyclohexylethyl 5-(lH-benzo[d][l,2,3]triazole-5- carbonyl)hexahydropyrrolo [3 ,4-c]pyrro le-2( 1 H)-carboxylate;
(3aS,6aR)-5-(lH-benzotriazole-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid 3-fluoro-5-trifluoromethoxy-benzyl ester;
(3aR,6aS)-3-chloro-5-cyanobenzyl 5-(lH-benzo[d][l,2,3]triazole-5- carbonyl)hexahydropyrrolo [3 ,4-c]pyrro le-2( 1 H)-carboxylate;
(3aS,6aR)-5-(lH-benzotriazole-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid 3-trifluoromethoxy-benzyl ester; (3aS,6aR)-5-(lH-benzotriazole-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid 3-fluoro-5-trifluoromethyl-benzyl ester;
(3aS,6aR)-5-(lH-benzotriazole-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid 3-chloro-5-trifluoromethoxy-benzyl ester; (3aS,6aR)-5-(lH-benzotriazole-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid 4-fluoro-3-trifluoromethoxy-benzyl ester;
(3aR,6aS)-3-cyano-5-fluorobenzyl 5-(lH-benzo[d][l,2,3]triazole-5- carbonyl)hexahydropyrrolo [3 ,4-c]pyrro le-2( 1 H)-carboxylate;
(3aR,6aS)-3-chloro-5-methoxybenzyl 5-(lH-benzo[d][l,2,3]triazole-5- carbonyl)hexahydropyrrolo [3 ,4-c]pyrro le-2( 1 H)-carboxylate;
(3aS,6aR)-5-(lH-benzotriazole-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid (lS,4R)-3-methyl-bicyclo[2.2.1]hept-2-ylmethyl ester;
(3aS,6aR)-5-(lH-benzotriazole-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid (lR,4S)-l-bicyclo[2.2.1]hept-2-ylmethyl ester; (3aR,5S,6aS)-5-[(3H-[l,2,3]triazol-4-ylmethyl)-carbamoyl]-hexahydro- cyclopenta[c]pyrrole-2-carboxylic acid 3,5-dichloro-benzyl ester;
(3aS,6aS)-5-(l,4,6,7-tetrahydro-[l,2,3]triazolo[4,5-c]pyridine-5-carbonyl)-hexahydro- pyrrolo[3,4-c]pyrrole-2-carboxylic acid 3-chloro-5-methanesulfonyl-benzyl ester;
(3aS,6aR)-5-[(lH-[l,2,3]triazol-4-ylmethyl)-carbamoyl]-hexahydro-pyrrolo[3,4-c]pyrrole- 2-carboxylic acid 3,5-dichloro-benzyl ester;
(3aS,6aS)-5-(lH-benzotriazole-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid 4-trifluoromethoxy-benzyl ester;
(3aR,5r,6aS)-3,5-dichlorobenzyl 5-(2-oxo-2,3-dihydrobenzo[d]oxazol-6- ylamino)hexahydrocyclopenta[c]pyrrole-2(lH)-carboxylate; (3aR,6aS)-3,5-dichlorobenzyl 5-((lH-benzo[d]imidazol-5- yl)methyl)hexahydropyrrolo [3 ,4-c]pyrrole-2( 1 H)-carboxylate; l-((3aR,6aS)-5-((lH-benzo[d][l,2,3]triazol-5-yl)methyl)hexahydropyrrolo[3,4-c]pyrrol- 2(1 H)-yl)-3 -(3 ,5 -dichlorophenyl)propan- 1 -one;
(3aR,6aS)-3,5-dichlorobenzyl 5-((lH-indazol-5-yl)methyl)hexahydropyrrolo[3,4- c] pyrrole-2( 1 H)-carboxylate;
(3aR,6aS)-3,5-dichlorobenzyl 5-((2-oxo-2,3-dihydrobenzo[d]oxazol-6- yl)methyl)hexahydropyrrolo [3 ,4-c]pyrrole-2( 1 H)-carboxylate;
6-(((3aR,6aS)-5-(3-(3,5-dichlorophenyl)propanoyl)hexahydropyrrolo[3,4-c]pyrrol-2(lH)- yl)methyl)benzo[d]oxazol-2(3H)-one;
4-{(E)-3-[(3aS,8aR)-2-(lH-benzotriazol-5-ylmethyl)-octahydro-pyrrolo[3,4-d]azepin-6- yl]-3-oxo-propenyl}-benzonitrile;
(E)- 1 - [(3 aS , 8aR)-2-( 1 H-benzotriazo 1-5 -ylmethyl)-octahydro-pyrrolo [3 ,4-d] azepin-6-yl] -3 - (4-trifluoromethoxy-phenyl)-prop-2-ene- 1 -one;
(3aR,6aS)-3,5-dichlorobenzyl 5-(2-oxo-2,3-dihydrobenzo[d]oxazol-6- ylsulfonyl)hexahydropyrro lo [3 ,4-c]pyrrole-2( 1 H)-carboxylate;
(3aR,6aS)-3,5-dichlorobenzyl 5-(4,5,6,7-tetrahydro-lH-[l,2,3]triazolo[4,5-c]pyridine-5- carbonyl)hexahydropyrrolo [3 ,4-c]pyrro le-2( 1 H)-carboxylate;
(E)-l-[(3aS,8aR)-2-(l,4,6,7-tetrahydro-[l,2,3]triazolo[4,5-c]pyridine-5-carbonyl)- octahydro-pyrrolo[3,4-d]azepin-6-yl]-3-(4-trifluoromethoxy-phenyl)-prop-2-ene-l-one;
(E)-l-[(3aS,8aR)-2-(l,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carbonyl)-octahydro- pyrrolo[3,4-d]azepin-6-yl]-3-(4-trifluoromethoxy-phenyl)-prop-2-ene-l-one; cis-5-((3aR,8aS)-6-((E)-3-(4-(trifluoromethoxy)phenyl)acryloyl)decahydropyrrolo[3,4- d] azepine-2-carbonyl)hexahydrooxazolo [5 ,4-c]pyridin-2( 1 H)-one;
6-{(3aS,8aR)-6-[(E)-3-(4-trifluoromethoxy-phenyl)-acryloyl]-octahydro-pyrrolo[3,4- d]azepine-2-carbonyl} -5,6,7,8-tetrahydro- 1Η-[ 1 ,6]naphthyridin-2-one;
(3aR,7aR)-5-{(3aS,8aR)-6-[(E)-3-(4-trifluoromethoxy-phenyl)-acryloyl]-octahydro- pyrrolo [3 ,4-d]azepine-2-carbonyl} -hexahydro-oxazolo [5 ,4-c]pyridin-2-one; (E)- 1 -[(3aS,8aR)-2-(7,8-Dihydro-5H-[ 1 ,6]naphthyridine-6-carbonyl)-octahydro- pyrrolo[3,4-d]azepin-6-yl]-3-(4-trifluoromethoxy-phenyl)-prop-2-ene-l-one;
(E)-3-(4-trifluoromethoxy-phenyl)-l-[(3aS,8aR)-2-(2-trifluoromethyl-5,6-dihydro-8H-
[l,2,4]triazolo[l,5-a]pyrazine-7-carbonyl)-octahydro-pyrrolo[3,4-d]azepin-6-yl]-prop-2- ene-l-one;
(3aS,8aR)-6-[(E)-3-(3-trifluoromethoxy-phenyl)-acryloyl]-octahydro-pyrrolo[3,4- d]azepine-2-carboxylic acid (lH-[l,2,3]triazol-4-ylmethyl)-amide;
(3aR,8aS)-N-((lH-l,2,3-triazol-5-yl)methyl)-6-((E)-3-(4-
(trifluoromethoxy)phenyl)acryloyl)octahydropyrrolo [3 ,4-d]azepine-2( 1 H)-carboxamide;
(3aS,6aR)-5-[(E)-3-(4-trifluoromethoxy-phenyl)-acryloyl]-hexahydro-pyrrolo[3,4- c] pyrrole-2-carboxylic acid (lH-[l,2,3]triazol-4-ylmethyl)-amide;
(3aR,8aS)-N-((lH-l,2,3-triazol-5-yl)methyl)-6-((E)-3-(3-fluoro-4- (trifluoromethoxy)phenyl)acryloyl)octahydropyrrolo [3 ,4-d]azepine-2( 1 H)-carboxamide;
(3aS,8aR)-6-[(E)-3-(4-trifluoromethoxy-phenyl)-acryloyl]-octahydro-pyrrolo[3,4- d] azepine-2-carboxylic acid (4H-[ 1 ,2,4]triazol-3-ylmethyl)-amide;
(E)- 1 -[(3aS,8aR)-2-(6,7-dihydro-4H-[ 1 ,2,3]triazolo[ 1 ,5-a]pyrazine-5-carbonyl)-octahydro- pyrrolo[3,4-d]azepin-6-yl]-3-(4-trifluoromethoxy-phenyl)-prop-2-ene-l-one;
(E)-l-[(3aS,8aR)-2-(l,4,6,7-tetrahydro-imidazo[4,5-c]pyridine-5-carbonyl)-octahydro- pyrrolo[3,4-d]azepin-6-yl]-3-(4-trifluoromethoxy-phenyl)-prop-2-ene-l-one;
(3aR,8aS)-N-((lH-l,2,3-triazol-5-yl)methyl)-N-methyl-6-((E)-3-(4- (trifluoromethoxy)phenyl)acryloyl)octahydropyrrolo [3 ,4-d]azepine-2( 1 H)-carboxamide;
(3aS,8aR)-6-[3-(3-chloro-phenyl)-2,2-dimethyl-propionyl]-octahydro-pyrrolo[3,4- d]azepine-2-carboxylic acid (3H-[ 1 ,2,3]triazol-4-ylmethyl)-amide;
(3aR,8aS)-N-(2-(lH-l,2,3-triazol-5-yl)ethyl)-6-((E)-3-(4-
(trifluoromethoxy)phenyl)acryloyl)octahydropyrrolo [3 ,4-d]azepine-2( 1 H)-carboxamide; (3aR,7aS)-2-(lH-benzotriazole-5-carbonyl)-octahydro-pyrrolo[3,4-c]pyridine-5-carboxylic acid 3,5-dichloro-benzyl ester;
(3aS,7aR)-2-(lH-benzotriazole-5-carbonyl)-octahydro-pyrrolo[3,4-c]pyridine-5-carboxylic acid 3,5-dichloro-benzyl ester;
(+)-trans-3 ,5-dichlorobenzyl 2-( 1 H-benzo [d] [ 1 ,2,3]triazole-5-carbonyl)hexahydro- 1 H- pyrrolo [3 ,4-c]pyridine-5 (6H)-carboxylate;
(-)-trans-3,5-dichlorobenzyl 2-(lH-benzo[d][l,2,3]triazole-5-carbonyl)hexahydro-lH- pyrrolo [3 ,4-c]pyridine-5 (6H)-carboxylate;
(-)-trans-3,5-dichlorobenzyl 5-(lH-benzo[d][l,2,3]triazole-5-carbonyl)hexahydro-lH- pyrrolo[3,4-c]pyridine-2(3H)-carboxylate;
(+)-trans-3,5-dichlorobenzyl 5-(lH-benzo[d][l,2,3]triazole-5-carbonyl)hexahydro-lH- pyrrolo[3,4-c]pyridine-2(3H)-carboxylate;
(E)- 1 - [trans-2-( 1 H-benzo triazo le-5 -carbonyl)-octahydro-pyrrolo [3 ,4-c]pyridin-5 -yl] -3 - (3 ,5-dichloro-phenyl)-prop-2-en- 1 -one;
(lH-benzo triazo l-5-yl)-{trans-2-[5-(4-chloro-phenyl)-[l,3,4]oxadiazol-2-yl]-octahydro- pyrrolo [3 ,4-c]pyridin-5-yl} -methanone;
(E)-l-((3aR,6aS)-5-(lH-benzo[d][l,2,3]triazole-5-carbonyl)hexahydropyrrolo[3,4- c]pyrrol-2( 1 H)-yl)-3 -(4-(trifluoromethoxy)phenyl)prop-2-en- 1 -one;
(lH-benzotriazol-5-yl)-[(3aR,6aS)-5-(5-chloro-lH-indole-2-carbonyl)-hexahydro- pyrrolo [3 ,4-c]pyrrol-2-yl]-methanone;
(E)-l-[(3aR,6aS)-5-(lH-benzo triazo le-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]- 3-(3-fluoro-5-trifluoromethyl-phenyl)-prop-2-ene- 1 -one; l-[(3aR,6aS)-5-(lH-benzo triazo le-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-3-(3- fluoro-5-trifluoromethyl-phenyl)-propan- 1 -one;
(lH-benzotriazol-5-yl)-[(3aR,6aS)-5-(6-chloro-lH-indole-2-carbonyl)-hexahydro- pyrrolo [3 ,4-c]pyrrol-2-yl]-methanone; (E)-l-((3aR,8aS)-2-(lH-benzo[d][l,2,3]triazole-5-carbonyl)octahydropyrrolo[3,4- d]azepin-6(7H)-yl)-3-(4-(trifluoromethylsulfonyl)phenyl)prop-2-en-l-one;
(E)-l-((3aR,8aS)-2-(lH-benzo[d][l,2,3]triazole-5-carbonyl)octahydropyrrolo[3,4- d]azepin-6(7H)-yl)-3-(4-chlorophenyl)prop-2-en- 1 -one;
(E)-l-((3aR,8aS)-2-(lH-benzo[d][l,2,3]triazole-5-carbonyl)octahydropyrrolo[3,4- d]azepin-6(7H)-yl)-3-p-tolylprop-2-en- 1 -one;
4-((E)-3-((3aR,8aS)-2-(lH-benzo[d][l,2,3]triazole-5-carbonyl)octahydropyrrolo[3,4- d]azepin-6(7H)-yl)-3-oxoprop-l-enyl)-N,N-dimethylbenzenesulfonamide;
(E)-l-((3aR,8aS)-2-(lH-benzo[d][l,2,3]triazole-5-carbonyl)octahydropyrrolo[3,4- d]azepin-6(7H)-yl)-3-(4-methoxyphenyl)prop-2-en- 1 -one;
(E)-l-((3aR,8aS)-6-(lH-benzo[d][l,2,3]triazole-5-carbonyl)octahydropyrrolo[3,4- d] azepin-2( 1 H)-yl)-3 -(4-(trifluoromethoxy)phenyl)prop-2-en- 1 -one;
4-((E)-3-((3aR,8aS)-2-(lH-benzo[d][l,2,3]triazole-5-carbonyl)octahydropyrrolo[3,4- d]azepin-6(7H)-yl)-3-oxoprop- 1 -enyl)benzonitrile;
(E)- 1 -((3aR,6aR)-5-( 1 H-benzo [d] [ 1 ,2,3]triazole-5-carbonyl)hexahydropyrrolo [3 ,4- c] pyrrol-2( 1 H)-yl)-3 -(4-(trifluoromethoxy)phenyl)prop-2-en- 1 -one; l-((3aR,6aS)-5-(lH-benzo[d][l,2,3]triazole-5-carbonyl)hexahydropyrrolo[3,4-c]pyrrol- 2(1 H)-yl)-3 -(4-(trifluoromethoxy)phenyl)propan- 1 -one;
(E)-l-((3aR,8aS)-2-(lH-benzo[d][l,2,3]triazole-5-carbonyl)octahydropyrrolo[3,4- d] azepin-6(7H)-yl)-3-(4-fluorophenyl)prop-2-en- 1 -one;
(E)-l-((3aR,8aS)-2-(lH-benzo[d][l,2,3]triazole-5-carbonyl)octahydropyrrolo[3,4- d]azepin-6(7H)-yl)-3-phenylprop-2-en- 1 -one;
(E)-l-((3aR,8aS)-2-(lH-benzo[d][l,2,3]triazole-5-carbonyl)octahydropyrrolo[3,4- d]azepin-6(7H)-yl)-3-(pyridin-2-yl)prop-2-en- 1 -one;
(E)-l-((3aR,8aS)-2-(lH-benzo[d][l,2,3]triazole-5-carbonyl)octahydropyrrolo[3,4- d]azepin-6(7H)-yl)-3-(pyridin-3-yl)prop-2-en- 1 -one; (E)-l-((3aR,8aS)-2-(lH-benzo[d][l,2,3]triazole-5-carbonyl)octahydropyrrolo[3,4- d]azepin-6(7H)-yl)-3-(3-chlorophenyl)prop-2-en- 1 -one;
(E)-l-((3aR,8aS)-6-(lH-benzo[d][l,2,3]triazole-5-carbonyl)octahydropyrrolo[3,4- d]azepin-2(lH)-yl)-3-(4-chlorophenyl)prop-2-en-l-one; (E)-l-((3aR,8aS)-6-(lH-benzo[d][l,2,3]triazole-5-carbonyl)octahydropyrrolo[3,4- d] azepin-2( 1 H)-yl)-3 -(3 -(trifluoromethoxy)phenyl)prop-2-en- 1 -one;
(E)-l-((3aR,8aS)-2-(lH-benzo[d][l,2,3]triazole-5-carbonyl)octahydropyrrolo[3,4- d]azepin-6(7H)-yl)-3-(4-(difluoromethoxy)phenyl)prop-2-en-l-one;
(E)- 1 -((3aR,6aR)-5-( 1 H-benzo [d] [ 1 ,2,3]triazole-5-carbonyl)hexahydropyrrolo [3 ,4- c]pyrrol-2(lH)-yl)-3-(3-(trifluoromethoxy)phenyl)prop-2-en-l-one;
4-((E)-3-((3aR,6aR)-5-(lH-benzo[d][l,2,3]triazole-5-carbonyl)hexahydropyrrolo[3,4- c] pyrrol-2( 1 H)-yl)-3-oxoprop- 1 -enyl)benzonitrile;
(E)-l-((3aS,6aS)-5-(lH-benzo[d][l,2,3]triazole-5-carbonyl)hexahydropyrrolo[3,4-c]pyrrol- 2(1 H)-yl)-3 -(4-(trifluoromethoxy)phenyl)prop-2-en- 1 -one; (-)-(E)-l-[trans-5-(lH-benzotriazole-5-carbonyl)-octahydro-pyrrolo[3,4-c]pyridin-2-yl]-3- (4-trifluoromethoxy-phenyl)-prop-2-ene- 1 -one;
(+)-(E)-l-[trans-5-(lH-benzotriazole-5-carbonyl)-octahydro-pyrrolo[3,4-c]pyridin-2-yl]-3- (4-trifluoromethoxy-phenyl)-prop-2-ene- 1 -one;
(E)-l-((3aR,8aS)-2-(lH-benzo[d][l,2,3]triazole-5-carbonyl)octahydropyrrolo[3,4- d]azepin-6(7H)-yl)-3-(3,5-dichlorophenyl)prop-2-en-l-one;
(E)-l-((3aR,8aS)-2-(lH-benzo[d][l,2,3]triazole-5-carbonyl)octahydropyrrolo[3,4- d] azepin-6(7H)-yl)-3-(pyridin-4-yl)prop-2-en- 1 -one;
(E)-l-((3aR,8aS)-2-(lH-benzo[d][l,2,3]triazole-5-carbonyl)octahydropyrrolo[3,4- d]azepin-6(7H)-yl)-3-(2,4-difluorophenyl)prop-2-en- 1 -one; (E)-l-((3aR,8aS)-2-(lH-benzo[d][l,2,3]triazole-5-carbonyl)octahydropyrrolo[3,4- d]azepin-6(7H)-yl)-3-(2,4-dichlorophenyl)prop-2-en- 1 -one; (E)-l-((3aR,8aS)-2-(lH-benzo[d][l,2,3]triazole-5-carbonyl)octahydropyrrolo[3,4- d]azepin-6(7H)-yl)-3-(3,4-dichlorophenyl)prop-2-en-l-one;
(E)-l-[(3aS,7aS)-5-(lH-benzotriazole-5-carbonyl)-octahydro-pyrrolo[3,4-c]pyridin-2-yl]-
3- (4-difluoromethoxy-phenyl)-prop-2-ene- 1 -one;
4- {(E)-3-[(3aS,7aS)-5-(lH-benzotriazole-5-carbonyl)-octahydro-pyrrolo[3,4-c]pyridin-2- yl]-3-oxo-propenyl}-benzonitrile;
4-((E)-3-((3aR,8aS)-2-(lH-benzo[d][l,2,3]triazole-5-carbonyl)octahydropyrrolo[3,4- d]azepin-6(7H)-yl)-3-oxoprop- 1 -enyl)-3-fluorobenzonitrile;
4-((E)-3-((3aR,6aR)-5-(lH-benzo[d][l,2,3]triazole-5-carbonyl)hexahydropyrrolo[3,4- c]pyrrol-2(lH)-yl)-3-oxoprop-l-enyl)-3-fluorobenzonitrile;
(E)- 1 -((3aR,6aR)-5-( 1 H-benzo [d] [ 1 ,2,3]triazole-5-carbonyl)hexahydropyrrolo [3 ,4- c] pyrrol-2( 1 H)-yl)-3 -(4-(difluoromethoxy)phenyl)prop-2-en- 1 -one;
(E)-l-[cis-2-(lH-benzotriazole-5-carbonyl)-octahydro-pyrrolo[3,4-c]pyridin-5-yl]-3-(4- trifluoromethoxy-phenyl)-prop-2-ene- 1 -one;
3-((E)-3-((3aR,8aS)-2-(lH-benzo[d][l,2,3]triazole-5-carbonyl)octahydropyrrolo[3,4- d] azepin-6(7H)-yl)-3-oxoprop- 1 -enyl)benzonitrile;
(E)-l-((3aR,8aS)-2-(lH-benzo[d][l,2,3]triazole-5-carbonyl)octahydropyrrolo[3,4- d]azepin-6(7H)-yl)-3-(2-fluoro-4-(trifluoromethoxy)phenyl)prop-2-en-l-one;
(E)- 1 -((3aR,6aR)-5-( 1 H-benzo [d] [ 1 ,2,3]triazole-5-carbonyl)hexahydropyrrolo [3 ,4- c]pyrrol-2( 1 H)-yl)-3-(2-fluoro-4-(trifluoromethoxy)phenyl)prop-2-en- 1 -one;
(E)- 1 -((3aR,6aR)-5-( 1 H-benzo [d] [ 1 ,2,3]triazole-5-carbonyl)hexahydropyrrolo [3 ,4- c]pyrrol-2( 1 H)-yl)-3-(4-chloro-2-fluorophenyl)prop-2-en- 1 -one;
(E)- 1 -((3aR,6aR)-5-( 1 H-benzo [d] [ 1 ,2,3]triazole-5-carbonyl)hexahydropyrrolo [3 ,4- c]pyrrol-2(lH)-yl)-3-(3,5-dichlorophenyl)prop-2-en-l-one; (E)-l-((3aR,6aS)-5-(4,5,6,7-tetrahydro-lH-benzo[d][l,2,3]triazole-5- carbonyl)hexahydropyrrolo[3,4-c]pyrrol-2(lH)-yl)-3-(4-(trifluoromethoxy)phenyl)prop-2- en-l-one; l-[(3aR,6aR)-5-(lH-benzotriazole-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-3-(4- trifluoromethoxy-phenyl)-propan- 1 -one;
(E)-l-[(3aS,6aR)-5-(l,4,6,7-tetrahydro-[l,2,3]triazolo[4,5-c]pyridine-5-carbonyl)- hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-3-(4-trifluoromethoxy-phenyl)-prop-2-ene-l-one;
(E)-l-[(3aR,6aR)-5-(lH-benzotriazole-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]- 3-(3-chloro-5-methanesulfonyl-phenyl)-prop-2-ene- 1 -one;
(E)-l-[(3aR,6aR)-5-(lH-benzotriazole-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]- 3-(3,5-dimethoxy-phenyl)-prop-2-ene-l-one;
(E)-l-[(3aR,6aR)-5-(lH-benzotriazole-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]- 3-(3-chloro-5-trifluoromethoxy-phenyl)-prop-2-ene- 1 -one;
(E)-l-[(3aR,6aR)-5-(lH-benzotriazole-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]- 3-(3-chloro-5-methoxy-phenyl)-prop-2-ene- 1 -one;
3-{(E)-3-[(3aR,6aR)-5-(lH-benzotriazole-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2- yl]-3-oxo-propenyl}-5-chloro-benzonitrile;
(E)-l-[(3aR,6aR)-5-(lH-benzotriazole-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]- 3-(3-methoxy-5-trifluoromethoxy-phenyl)-prop-2-ene- 1 -one;
(E)-l-[(3aR,6aR)-5-(l,4,6,7-tetrahydro-[l,2,3]triazolo[4,5-c]pyridine-5-carbonyl)- hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-3-(4-trifluoromethoxy-phenyl)-prop-2-ene-l-one; l-[(3aR,6aR)-5-(l,4,6,7-tetrahydro-[l,2,3]triazolo[4,5-c]pyridine-5-carbonyl)-hexahydro- pyrrolo[3,4-c]pyrrol-2-yl]-3-(4-trifluoromethoxy-phenyl)-propan-l-one;
(3aR,7aR)-5-{(3aR,6aR)-5-[(E)-3-(4-trifluoromethoxy-phenyl)-acryloyl]-hexahydro- pyrrolo [3 ,4-c]pyrrole-2-carbonyl} -hexahydro-oxazolo [5 ,4-c]pyridin-2-one; (3aR,7aR)-5-{(3aR,6aR)-5-[3-(4-trifluoromethoxy-phenyl)-propionyl]-hexahydro- pyrrolo [3 ,4-c]pyrrole-2-carbonyl} -hexahydro-oxazolo [5 ,4-c]pyridin-2-one;
(E)-l-[(3aR,6aR)-5-(lH-benzotriazole-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]- 3-phenyl-prop-2-ene- 1 -one; l-[(3aR,6aR)-5-(lH-benzotriazole-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-3- phenyl-propan- 1 -one;
(E)-l-[(3aR,6aR)-5-(lH-benzotriazole-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]- 3-(4-trifluoromethyl-phenyl)-prop-2-ene- 1 -one; l-[(3aR,6aR)-5-(lH-benzotriazole-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-3-(4- trifluoromethyl-phenyl)-propan- 1 -one;
(3aR,6aS)-N-((lH-l,2,3-triazol-5-yl)methyl)-N-methyl-5-(3-(4-
(trifluoromethoxy)phenyl)propanoyl)hexahydropyrrolo [3 ,4-c]pyrrole-2( 1 H)-carboxamide;
(3aR,8aS)-N-((lH-l,2,3-triazol-5-yl)methyl)-6-((E)-3-(3-fluoro-4- (trifluoromethoxy)phenyl)acryloyl)-N-methyloctahydropyrrolo [3 ,4-d]azepine-2( 1 H)- carboxamide; l-[(3aR,6aR)-5-(lH-benzotriazole-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-3-(6- trifluoromethyl-pyridin-3 -yl)-propan- 1 -one; l-[(3aS,6aS)-5-(lH-benzotriazole-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2-(4- trifluoromethoxy-phenoxy)-ethanone; l-[(3aS,6aS)-5-(lH-benzotriazole-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2-(4- chloro-2-isopropyl-5-methyl-phenoxy)-ethanone; l-[(3aR,6aR)-5-(lH-benzotriazole-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-3- biphenyl-4-yl-propan- 1 -one;
(E)-l-((3aR,8aS)-2-(lH-benzo[d][l,2,3]triazole-5-carbonyl)octahydropyrrolo[3,4- d]azepin-6(7H)-yl)-3-(4-fluoro-2-(trifluoromethyl)phenyl)prop-2-en-l-one; l-[(3aS,6aR)-5-(lH-Benzotriazole-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2- (4-chloro-2-isopropyl-5-methyl-phenoxy)-ethanone;
(E)-l-((3aR,8aS)-2-(lH-benzo[d][l,2,3]triazole-5-carbonyl)octahydropyrrolo[3,4- d]azepin-6(7H)-yl)-3-(4-(methylsulfonyl)phenyl)prop-2-en-l-one;
(E)-l-((3aR,8aS)-2-(lH-benzo[d][l,2,3]triazole-5-carbonyl)octahydropyrrolo[3,4- d]azepin-6(7H)-yl)-3-(4-(trifluoromethylthio)phenyl)prop-2-en-l-one;
(E)-l-((3aR,8aS)-2-(lH-benzo[d][l,2,3]triazole-5-carbonyl)octahydropyrrolo[3,4- d]azepin-6(7H)-yl)-3-(4-(trifluoromethoxy)phenyl)prop-2-en-l-one; l-((3aR,6aS)-5-(lH-benzo[d][l,2,3]triazole-5-carbonyl)hexahydropyrrolo[3,4-c]pyrrol- 2(lH)-yl)-2-(3-(trifluoromethoxy)phenoxy)ethanone;
(E)-l-((3aR,8aS)-2-(lH-benzo[d][l,2,3]triazole-5-carbonyl)octahydropyrrolo[3,4- d]azepin-6(7H)-yl)-3-(3-(trifluoromethoxy)phenyl)prop-2-en-l-one;
(E)- 1 - [trans-5 -( 1 H-benzotriazo le-5 -carbonyl)-octahydro-pyrrolo [3 ,4-c]pyridin-2-yl] -3 -(3 trifluoromethoxy-phenyl)-prop-2-en- 1 -one;
(E)- 1 - [trans-5 -( 1 H-benzotriazo le-5 -carbonyl)-octahydro-pyrrolo [3 ,4-c]pyridin-2-yl] -3 -(4 trifluoromethoxy-phenyl)-prop-2-en- 1 -one;
(E)- 1 - [trans-5 -( 1 H-benzotriazo le-5 -carbonyl)-octahydro-pyrrolo [3 ,4-c]pyridin-2-yl] -3 -(3 chloro-5-trifluoromethoxy-phenyl)-prop-2-en- 1 -one;
(E)- 1 - [trans-5 -( 1 H-benzotriazo le-5 -carbonyl)-octahydro-pyrrolo [3 ,4-c]pyridin-2-yl] -3 - (3 ,5-dichloro-phenyl)-prop-2-en- 1 -one;
(E)-l-[(3aR,6aR)-5-(lH-benzotriazole-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl] 3-(6-phenyl-pyridin-3-yl)-prop-2-ene- 1 -one;
(E)-l-[(3aR,6aR)-5-(lH-benzotriazole-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl] 3-(5-trifluoromethyl-pyridin-2-yl)-prop-2-ene- 1 -one;
(E)-l-[(3aR,6aR)-5-(lH-benzotriazole-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl] 3-(4-pyridin-4-yl-phenyl)-prop-2-ene- 1 -one; (E)-l-[(3aR,6aR)-5-(lH-benzotriazole-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]- 3-(4-pyridin-3-yl-phenyl)-prop-2-ene- 1 -one;
(E)-l-[(3aR,6aR)-5-(lH-benzotriazole-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]- 3-(4-pyridin-2-yl-phenyl)-prop-2-ene- 1 -one; l-[(3aS,6aR)-5-(lH-benzotriazole-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2-(4- chloro-3-methyl-phenoxy)-ethanone; l-[(3aS,6aR)-5-(lH-benzotriazole-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2-(4- chloro-2-methyl-phenoxy)-ethanone;
(E)-l-[(3aR,6aR)-5-(lH-benzotriazole-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]- 3-(5-phenyl-pyridin-2-yl)-prop-2-ene- 1 -one;
(E)-l-((3aR,8aS)-2-(lH-benzo[d][l,2,3]triazole-5-carbonyl)octahydropyrrolo[3,4- d] azepin-6(7H)-yl)-3 -(4-(trifluoromethylsulfinyl)phenyl)prop-2-en- 1 -one; l-((3aR,8aS)-2-(lH-benzo[d][l,2,3]triazole-5-carbonyl)octahydropyrrolo[3,4-d]azepin- 6(7H)-yl)-3-(3-fluoro-4-(trifluoromethoxy)phenyl)propan- 1 -one;
(3aR,8aS)-N-((lH-l,2,3-triazol-5-yl)methyl)-N-methyl-6-(3-(4-
(trifluoromethoxy)phenyl)propanoyl)octahydropyrrolo [3 ,4-d]azepine-2( 1 H)-carboxamide; (3aR,8aS)-N-((lH-l,2,3-triazol-5-yl)methyl)-6-(3-(3-fluoro-4-
(trifluoromethoxy)phenyl)propanoyl)-N-methyloctahydropyrrolo [3 ,4-d]azepine-2( 1 H)- carboxamide; l-[(3aR,6aR)-5-(lH-benzotriazole-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-3-(4- difluoromethoxy-phenyl)-propan- 1 -one; l-[(3aR,6aR)-5-(lH-benzotriazole-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-3-(2- fluoro-4-trifluoromethoxy-phenyl)-propan- 1 -one; l-((3aR,8aS)-2-(lH-benzo[d][l,2,3]triazole-5-carbonyl)octahydropyrrolo[3,4-d]azepin- 6(7H)-yl)-3-(4-fluoro-2-(trifluoromethyl)phenyl)propan- 1 -one; l-((3aR,8aS)-2-(lH-benzo[d][l,2,3]triazole-5-carbonyl)octahydropyrrolo[3,4-d]azepin- 6(7H)-yl)-3-(2-methyl-4-(trifluoromethoxy)phenyl)propan- 1 -one; l-((3aR,8aS)-2-(lH-benzo[d][l,2,3]triazole-5-carbonyl)octahydropyrrolo[3,4-d]azepin- 6(7H)-yl)-3-(3-fluoro-4-methoxyphenyl)propan- 1 -one; l-[(3aS,8aR)-2-(lH-benzotriazole-5-carbonyl)-octahydro-pyrrolo[3,4-d]azepin-6-yl]-3-(2- isopropyl-phenyl)-propan- 1 -one; l-[(3aR,6aR)-5-(lH-benzotriazole-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-3-(5- trifluoromethyl-pyridin-2-yl)-propan- 1 -one; l-[(3aR,6aR)-5-(lH-benzotriazole-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-3-(5- phenyl-pyridin-2-yl)-propan- 1 -one; l-[(3aR,6aR)-5-(lH-benzotriazole-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-3-(4- pyridin-4-yl-phenyl)-propan- 1 -one; l-[(3aR,6aR)-5-(lH-benzotriazole-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-3-(4- pyridin-3-yl-phenyl)-propan- 1 -one;
1- [(3aR,6aR)-5-(lH-benzotriazole-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-3-(4- pyridin-2-yl-phenyl)-propan- 1 -one;
(3aS,8aR)-6-[3-(4-trifluoromethoxy-phenyl)-propionyl]-octahydro-pyrrolo[3,4-d]azepine-
2- carboxylic acid [2-(3H-[l,2,3]triazol-4-yl)-ethyl]-amide;
(E)-3-[4-(trifluoro-methoxy)-phenyl]-l-[(3aS,8aR)-2-((S)-4,5,6,7-tetrahydro-lH- imidazo[4,5-c]pyridine-6-carbonyl)-octahydro-pyrrolo[3,4-d]azepin-6-yl]-prop-2-ene-l- one hydrochloride; and pharmaceutically acceptable salts thereof.
Also particular examples of compounds of formula (I) as described herein are selected from trans-2-(lH-benzotriazole-5-carbonyl)-octahydro-pyrrolo[3,4-c]pyridine-5-carboxylic acid
3 - chloro-5 -methanesulfonyl-benzyl ester; trans-2-(lH-benzotriazole-5-carbonyl)-octahydro-pyrrolo[3,4-c]pyridine-5-carboxylic acid 4-trifluoromethoxy-benzyl ester;
1 - [trans-2-( 1 H-benzotriazo le-5 -carbonyl)-octahydro-pyrrolo [3 ,4-c]pyridin-5 -yl] -2-(4- trifluoromethoxy-phenoxy)-ethanone;
(E)- 1 - [trans-2-( 1 H-benzotriazo le-5 -carbonyl)-octahydro-pyrrolo [3 ,4-c]pyridin-5 -yl] -3 -(4- trifluoromethoxy-phenyl)-propenone;
(E)-l-((3aR,8aS)-2-(lH-benzo[d][l,2,3]triazole-5-carbonyl)octahydropyrrolo[3,4- d]azepin-6(7H)-yl)-3-(3-chloro-5-(trifluoromethyl)phenyl)prop-2-en-l-one;
(E)-l-((3aR,8aS)-2-(lH-benzo[d][l,2,3]triazole-5-carbonyl)octahydropyrrolo[3,4- d]azepin-6(7H)-yl)-3-(4-methoxy-2-(trifluoromethyl)phenyl)prop-2-en-l-one;
(E)-l-((3aR,8aS)-2-(lH-benzo[d][l,2,3]triazole-5-carbonyl)octahydropyrrolo[3,4- d]azepin-6(7H)-yl)-3-(2-cyclopropylphenyl)prop-2-en- 1 -one; trans-2-(lH-benzotriazole-5-carbonyl)-octahydro-pyrrolo[3,4-c]pyridine-5-carboxylic acid 4-fluoro-2-trifluoromethyl-benzyl ester; trans-2-(lH-benzotriazole-5-carbonyl)-octahydro-pyrrolo[3,4-c]pyridine-5-carboxylic acid 2-cyclopropyl-4-trifluoromethyl-benzyl ester;
1- [(3aS,8aR)-2-(lH-benzotriazole-5-carbonyl)-octahydro-pyrrolo[3,4-d]azepin-6-yl]-2-(2- trifluoromethoxy-phenoxy)-ethanone; trans-2-(lH-benzotriazole-5-carbonyl)-octahydro-pyrrolo[3,4-c]pyridine-5-carboxylic acid
2- methoxy-4-trifluoromethoxy-benzyl ester;
4-{2-[(3aS,8aR)-2-(lH-benzotriazole-5-carbonyl)-octahydro-pyrrolo[3,4-d]azepin-6-yl]-2- oxo-ethoxy}-3-trifluoromethyl-benzonitrile; l-[(3aS,8aR)-2-(lH-benzotriazole-5-carbonyl)-octahydro-pyrrolo[3,4-d]azepin-6-yl]-2-(4- chloro-2-isopropyl-5-methyl-phenoxy)-ethanone; l-[(3aS,8aR)-2-(lH-benzotriazole-5-carbonyl)-octahydro-pyrrolo[3,4-d]azepin-6-yl]-2-[4- methyl-2-(l-methyl-pyrrolidin-3-yl)-phenoxy]-ethanone; l-[(3aS,8aR)-2-(lH-benzotriazole-5-carbonyl)-octahydro-pyrrolo[3,4-d]azepin-6-yl]-2-(2- chloro-4-fluoro-phenoxy)-ethanone; l-((3aR,8aS)-2-(lH-benzo[d][l,2,3]triazole-5-carbonyl)octahydropyrrolo[3,4-d]azepin- 6(7H)-yl)-2-(2-chloro-4-(trifluoromethyl)phenoxy)ethanone; l-((3aR,8aS)-2-(lH-benzo[d][l,2,3]triazole-5-carbonyl)octahydropyrrolo[3,4-d]azepin- 6(7H)-yl)-2-(6-isopropyl-3,3-dimethyl-2,3-dihydro-lH-inden-5-yloxy)ethanone;
(3aS,8aR)-2-(lH-benzotriazole-5-carbonyl)-octahydro-pyrrolo[3,4-d]azepine-6-carboxylic acid 2-fluoro-4-trifluoromethoxy-benzyl ester; l-((3aR,8aS)-2-(lH-benzo[d][l,2,3]triazole-5-carbonyl)octahydropyrrolo[3,4-d]azepin- 6(7H)-yl)-2-(5-chloro-2-(trifluoromethyl)phenoxy)ethanone; l-[(3aS,8aR)-2-(lH-benzotriazole-5-carbonyl)-l,3,3a,4,5,7,8,8a-octahydropyrrolo[3,4- d]azepin-6-yl]-2-(2-tert-butyl-4-methoxyphenoxy)ethanone;
4-[2-[(3aS,8aR)-2-(lH-benzotriazole-5-carbonyl)-l,3,3a,4,5,7,8,8a-octahydropyrrolo[3,4- d]azepin-6-yl]-2-oxoethoxy]-3-propan-2-ylbenzonitrile; l-[(3aS,8aR)-2-(lH-benzotriazole-5-carbonyl)-l,3,3a,4,5,7,8,8a-octahydropyrrolo[3,4- d]azepin-6-yl]-3-[3-fluoro-4-(2,2,2-trifluoroethoxy)phenyl]propan-l-one; l-[(3aS,8aR)-2-(lH-benzotriazole-5-carbonyl)-l,3,3a,4,5,7,8,8a-octahydropyrrolo[3,4- d]azepin-6-yl]-3-[2-fluoro-4-(2,2,2-trifluoroethoxy)phenyl]propan-l-one;
(3aS,8aR)-2-(lH-benzotriazole-5-carbonyl)-octahydro-pyrrolo[3,4-d]azepine-6-carboxylic acid 3-fluoro-4-(2,2,2-trifluoro-ethoxy)-benzyl ester;
(3aS,8aR)-2-(lH-benzotriazole-5-carbonyl)-octahydro-pyrrolo[3,4-d]azepine-6-carboxylic acid 2-fluoro-4-(2,2,2-trifluoro-ethoxy)-benzyl ester;
(3aS,8aR)-2-(lH-benzotriazole-5-carbonyl)-octahydro-pyrrolo[3,4-d]azepine-6-carboxylic acid 4-(2,2,2-trifluoro-ethoxy)-benzyl ester;
(3aS,6aS)-5-(3H-[l,2,3]triazolo[4,5-b]pyridine-6-carbonyl)-hexahydro-pyrrolo[3,4- c]pyrrole-2-carboxylic acid 4-trifluoromethoxy-benzyl ester; l-[(3aR,6aR)-5-(lH-triazolo[4,5-b]pyridine-5-carbonyl)-l,3,3a,4,6,6a- hexahydropyrrolo[3,4-c]pyrrol-2-yl]-3-[4-(trifluoromethoxy)phenyl]propan-l-one;
(3aS,6aS)-5-(3H-[l,2,3]triazolo[4,5-c]pyridine-6-carbonyl)-hexahydro-pyrrolo[3,4- c]pyrrole-2-carboxylic acid 4-trifluoromethoxy-benzyl ester;
(3aS,6aS)-5-(4-fluoro-lH-berizotriazole-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2- carboxylic acid 4-trifluoromethoxy-benzyl ester;
(3aS,6aS)-5-(7-fluoro-lH-benzotriazole-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2- carboxylic acid 4-trifluoromethoxy-benzyl ester;
(3aS,6aS)-5-(6-fluoro-lH-benzotriazole-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2- carboxylic acid 4-trifluoromethoxy-benzyl ester;
(3aS,6aS)-5-(4-chloro-lH-benzotriazole-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2- carboxylic acid 4-trifluoromethoxy-benzyl ester;
(3 aS ,6aS)-5 -(6-trifluoromethyl- 1 H-benzotriazo le-5 -carbonyl)-hexahydro-pyrro lo [3 ,4- c]pyrrole-2-carboxylic acid 4-trifluoromethoxy-benzyl ester;
(3aS,6aS)-5-(4-methyl-lH-benzotriazole-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2- carboxylic acid 4-trifluoromethoxy-benzyl ester;
(3aS,6aS)-5-(6-methyl-lH-benzotriazole-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2- carboxylic acid 4-trifluoromethoxy-benzyl ester; l-[(3aR,6aR)-5-(4-fluoro-lH-benzotriazole-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2- yl] -3 -(4-trifluoromethoxy-phenyl)-propan- 1 -one;
(4-ethoxyquinolin-2-yl)((3aS,6aS)-5-((R)-4,5,6,7-tetrahydro-lH-benzo[d][l,2,3]triazole-5- carbonyl)hexahydropyrrolo [3 ,4-c]pyrrol-2( 1 H)-yl)methanone;
(4-ethoxyquinolin-2-yl)((3aS,6aS)-5-(4-fluoro-lH-benzo[d][l,2,3]triazole-5- carbonyl)hexahydropyrrolo [3 ,4-c]pyrrol-2( 1 H)-yl)methanone;
6-[(3aR,6aR)-2-[3-[4-(trifluoromethoxy)phenyl]propanoyl]-l,3,3a,4,6,6a- hexahydropyrrolo[3,4-c]pyrrole-5-carbonyl]-3H-l,3-benzoxazol-2-one; (3aS,6aS)-5-(2-oxo-2,3-dihydro-benzooxazole-6-carbonyl)-hexahydro-pyrrolo[3,4- c]pyrrole-2-carboxylic acid 4-trifluoromethoxy-benzyl ester;
(3aS,6aS)-5-(lH-benzotriazole-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid 4-cyano-benzyl ester;
(3aS,6aS)-5-(lH-benzotriazole-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid 4-(l,l,2,2-tetrafluoro-ethoxy)-benzyl ester;
(3aS,6aS)-5-(lH-benzotriazole-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid 4-difluoromethoxy-3-fluoro-benzyl ester;
(3aS,6aS)-5-(lH-[l,2,3]triazolo[4,5-b]pyridine-5-carbonyl)-hexahydro-pyrrolo[3,4- c]pyrrole-2-carboxylic acid 3-fluoro-4-trifluoromethoxy-benzyl ester;
(3aS,6aS)-5-(lH-benzotriazole-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid 4-difluoromethoxy-benzyl ester;
(3aS,6aS)-5-(lH-[l,2,3]triazolo[4,5-b]pyridine-5-carbonyl)-hexahydro-pyrrolo[3,4- c]pyrrole-2-carboxylic acid 4-trifluoromethoxy-benzyl ester;
(3aS,6aS)-5-(lH-benzotriazole-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid 3-fiuoro-4-trifluoromethoxy-benzyl ester;
(3aS,6aS)-5-(lH-benzotriazole-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid 4-(2,2,2-trifluoro-ethoxy)-benzyl ester;
(3aS,6aS)-5-(lH-benzotriazole-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid 5-trifiuoromethoxy-pyridin-2-ylmethyl ester;
(3aS,6aS)-5-((R)-4,5,6,7-tetrahydro-lH-benzotriazole-5-carbonyl)-hexahydro-pyrrolo[3,4- c]pyrrole-2-carboxylic acid 4-cyano-2-isopropyl-benzyl ester;
(3aS,6aS)-5-((R)-4,5,6,7-tetrahydro-lH-benzotriazole-5-carbonyl)-hexahydro-pyrrolo[3,4- c]pyrrole-2-carboxylic acid 4-cyano-2-isopropyl-5 -methyl-benzyl ester;
(3aS,6aS)-5-((R)-4,5,6,7-tetrahydro-lH-benzotriazole-5-carbonyl)-hexahydro-pyrrolo[3,4- c]pyrrole-2-carboxylic acid 2-fiuoro-4-trifluoromethoxy-benzyl ester; (3aS,6aS)-5-(lH-benzotriazole-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid 2-fluoro-4-trifluoromethoxy-benzyl ester;
(3aS,6aS)-5-(lH-benzotriazole-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid 4-cyano-2-ethoxy-benzyl ester;
(3aS,6aS)-5-((R)-4,5,6,7-tetrahydro-lH-benzotriazole-5-carbonyl)-hexahydro-pyrrolo[3,4- c]pyrrole-2-carboxylic acid 3-fluoro-4-trifluoromethoxy-benzyl ester;
(3aS,6aS)-5-(lH-benzotriazole-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid 4-cyano-2-isopropyl-benzyl ester;
(3aS,6aS)-5-(lH-benzotriazole-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid 4-cyano-2-isopropyl-5-methyl-benzyl ester;
(3aS,6aS)-5-(l,4,6,7-tetrahydro-[l,2,3]triazolo[4,5-c]pyridine-5-carbonyl)-hexahydro- pyrrolo[3,4-c]pyrrole-2-carboxylic acid 4-trifluoromethoxy-benzyl ester;
(3aR,6aR)-5-(lH-benzotriazole-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid 4-trifluoromethoxy-benzyl ester;
(3aS,6aS)-5-(lH-benzotriazole-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid 2-fluoro-4-trifluoromethyl-benzyl ester;
(3aS,6aS)-5-(lH-benzotriazole-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid 4-trifluoromethyl-benzyl ester;
(3aS,6aS)-5-((R)-4,5,6,7-Tetrahydro-lH-benzotriazole-5-carbonyl)-hexahydro- pyrrolo[3,4-c]pyrrole-2-carboxylic acid 4-trifluoromethoxy-benzyl ester;
(3aS,6aS)-5-((R)-4,5,6,7-Tetrahydro-lH-benzotriazole-5-carbonyl)-hexahydro- pyrrolo[3,4-c]pyrrole-2-carboxylic acid 4-trifluoromethyl-benzyl ester;
(3aS,6aS)-5-((R)-4,5,6,7-Tetrahydro-lH-benzotriazole-5-carbonyl)-hexahydro- pyrrolo[3,4-c]pyrrole-2-carboxylic acid 3-chloro-5-methanesulfonyl-benzyl ester;
(3aS,6aS)-5-(lH-benzotriazole-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid 4-cyano-2-methanesulfonyl-benzyl ester; (3aS,6aS)-5-(lH-benzotriazole-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid 4-cyano-2-ethoxy-5-fluoro-benzyl ester;
(3aS,6aS)-5-(4-methoxy-lH-benzotriazole-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2- carboxylic acid 4-trifluoromethoxy-benzyl ester; (3aS,6aS)-5-(lH-benzotriazole-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid 4-cyano-2-cyclobutoxy-benzyl ester;
(3aS,6aS)-5-(lH-benzotriazole-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid 4-cyano-2-isopropoxy-benzyl ester;
(3aS,6aS)-5-(lH-benzotriazole-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid 4-cyano-2-(2,2,2-trifluoro-ethoxy)-benzyl ester;
(3aS,6aS)-5-(lH-benzotriazole-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid 4-chloro-2-ethoxy-5-fluoro-benzyl ester;
(E)- 1 - [trans-2-( 1 H-benzotriazo 1-5 -ylmethyl)-octahydro-pyrrolo [3 ,4-c]pyridin-5 -yl] -3 -(4- trifluoromethoxy-phenyl)-propenone; (3aS,6aS)-5-(4-sulfamoyl-piperidine-l-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2- carboxylic acid 4-trifluoromethoxy-benzyl ester; l-[(3aR,6aR)-5-(lH-benzotriazole-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-3-(6- phenyl-pyridin-3-yl)-propan- 1 -one; l-[(3aS,6aS)-5-(lH-benzotriazole-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2-(2- isopropyl-phenoxy)-ethanone; l-[(3aS,6aS)-5-(lH-benzotriazole-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2-(2- trifluoromethyl-phenoxy)-ethanone; l-[(3aS,6aS)-5-(lH-benzotriazole-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2- (biphenyl-2-yloxy)-ethanone; (E)-l-[(3aS,6aS)-5-((R)-4,5,6,7-Tetrahydro-lH-benzotriazole-5-carbonyl)-hexahydro- pyrrolo[3,4-c]pyrrol-2-yl]-3-(4-trifluoromethoxy-phenyl)-propenone; l-((3aR,6aR)-5-((R)-4,5,6,7-tetrahydro-lH-benzo[d][l,2,3]triazole-5- carbonyl)hexahydropyrrolo[3,4-c]pyrrol-2(lH)-yl)-3-(4-(trifluoromethoxy)phenyl)propan
1-one; l-[(3aS,6aS)-5-(lH-benzotriazole-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2-(2- chloro-4-trifluoromethoxy-phenoxy)-ethanone; l-[(3aS,6aS)-5-(lH-benzotriazole-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2-(2- pyrrol- 1 -yl-phenoxy)-ethanone;
4-{2-[(3aS,6aS)-5-(lH-benzotriazole-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2- oxo-ethoxy}-3-methoxy-benzonitrile;
4-{2-[(3aS,6aS)-5-(lH-benzotriazole-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2- oxo-ethoxy} -benzonitrile;
1- [(3aS,6aS)-5-(lH-benzotriazole-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2- phenoxy-ethanone;
2- {2-[(3aS,6aS)-5-(lH-benzotriazole-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2- oxo-ethoxy} -5-trifluoromethoxy-benzonitrile; l-((3aR,8aS)-2-(lH-benzo[d][l,2,3]triazole-5-carbonyl)octahydropyrrolo[3,4-d]azepin- 6(7H)-yl)-2-(2-isopropyl-5-methylphenoxy)ethanone;
(lH-benzotriazol-5-yl)-[(3aS,6aS)-5-(6-trifluoromethoxy-lH-indole-2-carbonyl)- hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-methanone;
( 1 H-benzotriazol-5 -yl)- [(3 aS ,6aS)-5 -(5 -trifluoroniethoxy- 1 H-indo le-2-carbonyl)- hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-methanone;
1 - [trans-2-( 1 H-benzotriazo le-5 -carbonyl)-octahydro-pyrrolo [3 ,4-c]pyridin-5 -yl] -3 -(4- trifluoromethoxy-phenyl)-propan- 1 -one;
1 - [trans-2-( 1 H-benzotriazo 1-5 -ylmethyl)-octahydro-pyrrolo [3 ,4-c]pyridin-5 -yl] -3 -(4- trifluoromethoxy-phenyl)-propan- 1 -one; l-((3aR,8aS)-2-(lH-benzo[d][l,2,3]triazole-5-carbonyl)octahydropyrrolo[3,4-d]azepin- 6(7H)-yl)-3-(3-chloro-5-(trifluoromethyl)phenyl)propan- 1 -one; l-((3aR,8aS)-2-(lH-benzo[d][l,2,3]triazole-5-carbonyl)octahydropyrrolo[3,4-d]azepin- 6(7H)-yl)-3-(4-methoxy-2-(trifluoromethyl)phenyl)propan- 1 -one; l-((3aR,8aS)-2-(lH-benzo[d][l,2,3]triazole-5-carbonyl)octahydropyrrolo[3,4-d]azepin- 6(7H)-yl)-3-(2-cyclopropylphenyl)propan- 1 -one; l-[(3aR,6aR)-5-(lH-benzotriazole-5-carbonyl)-l,3,3a,4,6,6a-hexahydropyrrolo[3,4- c]pyrrol-2-yl] -3 - [3 -methoxy-5 -(trifluoromethoxy)phenyl]propan- 1 -one; l-[(3aS,6aS)-5-(lH-benzotriazole-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2-(2- isopropyl-5-methyl-phenoxy)-ethanone;
1- [(3aS,6aS)-5-(lH-benzotriazole-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2-(2- bromo-4-trifluoromethoxy-phenoxy)-ethanone;
(lH-benzotriazol-5-yl)-[(3aR,6aR)-5-(4'-chloro-biphenyl-4-carbonyl)-hexahydro- pyrrolo [3 ,4-c]pyrrol-2-yl]-methanone;
4-{2-[(3aS,6aS)-5-(lH-benzotriazole-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2 oxo-ethoxy}-3-isopropyl-benzonitrile;
2- (2-Acetyl-phenoxy)-l-[(3aS,6aS)-5-(lH-benzotriazole-5-carbonyl)-hexahydro- pyrrolo [3 ,4-c]pyrrol-2-yl]-ethanone;
4-{2-[(3aS,6aS)-5-(lH-benzotriazole-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2 oxo-ethoxy}-5-isopropyl-2-methyl-benzonitrile;
(lH-benzotriazol-5-yl)-[(3aR,6aR)-5-(naphthalene-2-carbonyl)-hexahydro-pyrrolo[3,4- c]pyrrol-2-yl]-methanone;
(lH-benzotriazol-5-yl)-[(3aS,6aS)-5-(4-methoxy-naphthalene-2-carbonyl)-hexahydro- pyrrolo [3 ,4-c]pyrrol-2-yl]-methanone;
4-{2-[(3aS,6aS)-5-(lH-benzotriazole-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2 oxo-ethoxy}-3-ethoxy-benzonitrile; l-[(3aR,6aR)-5-(lH-benzotriazole-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-3-(3- fluoro-4-trifluoromethoxy-phenyl)-propan- 1 -one; l-[(3aS,6aS)-5-(lH-benzotriazole-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2-(4- chloro-2-isopropyl-phenoxy)-ethanone; [(3aS,6aS)-5-(4'-Chloro-biphenyl-4-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-(R)- 4 , 5 , 6, 7-tetrahydro - 1 H-benzotriazo 1-5 -yl-methanone; l-[(3aS,6aS)-5-(lH-benzotriazole-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-3-(4- trifluoromethoxy-phenyl)-propan- 1 -one;
(lH-benzotriazol-5-yl)-[(3aS,6aS)-5-(4'-chloro-biphenyl-4-carbonyl)-hexahydro- pyrrolo[3,4-c]pyrrol-2-yl]-methanone; l-[(3aS,6aS)-5-(lH-benzotriazole-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2-[2- (tetrahydro-furan-2-yl)-phenoxy]-ethanone;
(lH-benzotriazol-5-yl)-[(3aR,6aR)-5-(4-methoxy-naphthalene-2-carbonyl)-hexahydro- pyrrolo [3 ,4-c]pyrrol-2-yl]-methanone; l-[(3aS,6aS)-5-(lH-benzotriazole-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2-(2- tert-butyl-phenoxy)-ethanone;
[(3 aR,6aR)-5 -( 1 H-benzotriazo le-5 -carbonyl)-hexahydro-pyrrolo [3 ,4-c]pyrrol-2-yl] - [trans- 4-(4-chloro-phenyl)-cyclohexyl]-methanone; l-[(3aR,6aR)-5-(lH-benzotriazole-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-3-(3- fluoro-4-trifluoromethyl-phenyl)-propan- 1 -one; l-[(3aR,6aR)-5-(lH-benzotriazole-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-3-(2- fluoro-4-trifluoromethyl-phenyl)-propan- 1 -one; l-[(3aS,6aS)-5-(lH-benzotriazole-5-carbonyl)-l,3,3a,4,6,6a-hexahydropyrrolo[3,4- c]pyrrol-2-yl]-2-(2-pyridin-3-ylphenoxy)ethanone; 4-[3-[(3aR,6aR)-5-(lH-benzotriazole-5-carbonyl)-l,3,3a,4,6,6a-hexahydropyrrolo[3,4- c]pyrrol-2-yl]-3-oxopropyl]-2-methyl-5-propan-2-ylbenzonitrile; 4-[3-[(3aR,6aR)-5-(lH-benzotriazole-5-carbonyl)-l,3,3a,4,6,6a-hexahydropyrrolo[3,4- c]pyrrol-2-yl]-3-oxopropyl]-3-propan-2-ylbenzonitrile;
[(3aR,6aR)-5-[l-(4-chlorophenyl)piperidine-4-carbonyl]-l,3,3a,4,6,6a- hexahydropyrrolo [3 ,4-c]pyrrol-2-yl]-( 1 H-benzotriazol-5-yl)methanone;
[(3aS,6aS)-5-[(5R)-4,5,6,7-tetrahydro-lH-benzotriazole-5-carbonyl]-l,3,3a,4,6,6a- hexahydropyrrolo[3,4-c]pyrrol-2-yl]-(4-propan-2-yloxynaphthalen-2-yl)methanone;
[(3aS,6aS)-5-[(5R)-4,5,6,7-tetrahydro-lH-benzotriazole-5-carbonyl]-l,3,3a,4,6,6a- hexahydropyrrolo[3,4-c]pyrrol-2-yl]-(4-propan-2-yloxyquinolin-2-yl)methanone; l-[(3aR,6aR)-5-[(5R)-4,5,6,7-tetrahydro-lH-benzotriazole-5-carbonyl]-l,3,3a,4,6,6a- hexahydropyrrolo[3,4-c]pyrrol-2-yl]-3-[2-fluoro^
one;
4-[2-[(3aS,6aS)-5-[(5R)-4,5,6,7-tetrahydro-lH-benzotriazole-5-carbonyl]-l,3,3a,4,6,6a- hexahydropyrrolo[3,4-c]pyrrol-2-yl]-2-oxoethoxy]-2-methyl-5-propan-2-ylbenzonitrile;
[(3aS,6aS)-5-[(5R)-4,5,6,7-tetrahydro-lH-benzotriazole-5-carbonyl]-l,3,3a,4,6,6a- hexahydropyrrolo[3,4-c]pyrrol-2-yl]-[l-(2,2,2-trifluoroethoxy)isoquinolin-3-yl]metha l-[(3aS,6aS)-5-[(5R)-4,5,6,7-tetrahydro-lH-benzotriazole-5-carbonyl]-l,3,3a,4,6,6a- hexahydropyrrolo[3,4-c]pyrrol-2-yl]-2-(4-bromo-2-tert-butylphenoxy)ethanone; l-[(3aS,6aS)-5-(lH-benzotriazole-5-carbonyl)-l,3,3a,4,6,6a-hexahydropyrrolo[3,4- c]pyrrol-2-yl]-2-(4-bromo-2-tert-butylphenoxy)ethanone;
4-[2-[(3aS,6aS)-5-[(5R)-4,5,6,7-tetrahydro-lH-benzotriazole-5-carbonyl]-l,3,3a,4,6,6a- hexahydropyrrolo[3,4-c]pyrrol-2-yl]-2-oxoethoxy]-3-tert-butylbenzonitrile;
4-[2-[(3aS,6aS)-5-(lH-benzotriazole-5-carbonyl)-l,3,3a,4,6,6a-hexahydropyrrolo[3,4- c]pyrrol-2-yl]-2-oxoethoxy]-3-tert-butylbenzonitrile;
[(3aS,6aS)-5-[(5R)-4,5,6,7-tetrahydro-lH-benzotriazole-5-carbonyl]-l,3,3a,4,6,6a- hexahydropyrrolo[3,4-c]pyrrol-2-yl]-[l-methyl-5-(trifluoromethoxy)indol-2-yl]metha l-[(3aS,6aS)-5-[(5R)-4,5,6,7-tetrahydro-lH-benzotriazole-5-carbonyl]-l,3,3a,4,6,6a- hexahydropyrrolo[3,4-c]pyrrol-2-yl]-2-[4-(trifluoromethoxy)phenoxy]ethanone;
[(3aS,6aS)-5-[(5R)-4,5,6,7-tetrahydro-lH-benzotriazole-5-carbonyl]-l,3,3a,4,6,6a- hexahydropyrrolo[3,4-c]pyrrol-2-yl]-(l-ethoxyisoquinolin-3-yl)methanone; l-[(3aS,6aS)-5-(lH-benzotriazole-5-carbonyl)-l,3,3a,4,6,6a-hexahydropyrrolo[3,4- c]pyrrol-2-yl]-2-(2-tert-butyl-4-methoxyphenoxy)ethanone;
((3aS,6aS)-5-(lH-benzo[d][l,2,3]triazole-5-carbonyl)hexahydropyrrolo[3,4-c]pyrrol- 2(lH)-yl)(4-ethoxyquinolin-2-yl)methanone;
((3aS,6aS)-5-(lH-benzo[d][l,2,3]triazole-5-carbonyl)hexahydropyrrolo[3,4-c]pyrrol- 2(lH)-yl)(4-(2,2,2-trifluoroethoxy)quinolin-2-yl)methanone;
((3aS,6aS)-5-(lH-benzo[d][l,2,3]triazole-5-carbonyl)hexahydropyrrolo[3,4-c]pyrrol- 2(1 H)-yl)(6-cyclobutoxy-5 -(trifluoromethyl)pyridin-3 -yl)methanone;
((3aS,6aS)-5-(lH-benzo[d][l,2,3]triazole-5-carbonyl)hexahydropyrrolo[3,4-c]pyrrol- 2(1 H)-yl)(5 -bromo-6-(2-methoxyethoxy)pyridin-3 -yl)methanone;
((3aS,6aS)-5-(lH-benzo[d][l,2,3]triazole-5-carbonyl)hexahydropyrrolo[3,4-c]pyrrol- 2(lH)-yl)(5-bromo-6-(cyclopropylmethoxy)pyridin-3-yl)methanone;
((3aS,6aS)-5-(lH-benzo[d][l,2,3]triazole-5-carbonyl)hexahydropyrrolo[3,4-c]pyrrol- 2(lH)-yl)(5-cyclopropyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methanone;
((3aS,6aS)-5-(lH-benzo[d][l,2,3]triazole-5-carbonyl)hexahydropyrrolo[3,4-c]pyrrol- 2(lH)-yl)(6-(2,2,2-trifluoroethoxy)-5-(trifluoromethyl)pyridin-3-yl)methanone;
(lH-benzotriazol-5-yl)-{(3aS,6aS)-5-[4-(4-chloro-phenyl)-piperidine-l-carbonyl]- hexahydro-pyrrolo[3,4-c]pyrrol-2-yl}-methanone;
(lH-benzotriazol-5-yl)-{(3aS,6aS)-5-[4-(4-chloro-phenyl)-piperazine-l-carbonyl]- hexahydro-pyrrolo[3,4-c]pyrrol-2-yl}-methanone; harmaceutically acceptable salts thereof. Further particular examples of compounds of formula (I) as described herein are selected from trans-3 ,5-dichlorobenzyl 2-( 1 H-benzo [d] [ 1 ,2,3]triazole-5-carbonyl)hexahydro- 1 H- pyrrolo [3 ,4-c]pyridine-5 (6H)-carboxylate; trans-3, 5-dichlorobenzyl 2-(2-oxo-2,3-dihydrobenzo[d]oxazole-6-carbonyl)hexahydro-lH- pyrrolo [3 ,4-c]pyridine-5 (6H)-carboxylate;
(3aS,6aS)-5-(lH-benzotriazole-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid 3-chloro-5-methanesulfonyl-benzyl ester;
(3aS,6aS)-5-(lH-benzotriazole-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid 4-trifluoromethoxy-benzyl ester;
(E)- 1 -((3aR,6aR)-5-( 1 H-benzo [d] [ 1 ,2,3]triazole-5-carbonyl)hexahydropyrrolo [3 ,4- c]pyrrol-2( 1 H)-yl)-3 -(4-(trifluoromethoxy)phenyl)prop-2-en- 1 -one; l-((3aR,6aS)-5-(lH-benzo[d][l,2,3]triazole-5-carbonyl)hexahydropyrrolo[3,4-c]pyrrol- 2(1 H)-yl)-3 -(4-(trifluoromethoxy)phenyl)propan- 1 -one; l-[(3aR,6aR)-5-(lH-benzotriazole-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-3-(4- trifluoromethoxy-phenyl)-propan- 1 -one; l-[(3aR,6aR)-5-(lH-benzotriazole-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-3-(4- trifluoromethyl-phenyl)-propan- 1 -one; l-[(3aS,6aS)-5-(lH-benzotriazole-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2-(4- chloro-2-isopropyl-5-methyl-phenoxy)-ethanone; and pharmaceutically acceptable salts thereof.
Also further particular examples of compounds of formula (I) as described herein are selected from trans-3 ,5-dichlorobenzyl 2-( 1 H-benzo [d] [ 1 ,2,3]triazole-5-carbonyl)hexahydro- 1 H- pyrrolo [3 ,4-c]pyridine-5 (6H)-carboxylate; trans-3,5-dichlorobenzyl 2-(2-oxo-2,3-dihydrobenzo[d]oxazole-6-carbonyl)hexahydro-lH- pyrrolo [3 ,4-c]pyridine-5 (6H)-carboxylate;
(3aS,6aS)-5-(lH-benzotriazole-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid 3-chloro-5-methanesulfonyl-benzyl ester; (3aS,6aS)-5-(lH-benzotriazole-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid 4-trifluoromethoxy-benzyl ester;
(E)- 1 -((3aR,6aR)-5-( 1 H-benzo [d] [ 1 ,2,3]triazole-5-carbonyl)hexahydropyrrolo [3 ,4- c]pyrrol-2( 1 H)-yl)-3 -(4-(trifluoromethoxy)phenyl)prop-2-en- 1 -one; l-((3aR,6aS)-5-(lH-benzo[d][l,2,3]triazole-5-carbonyl)hexahydropyrrolo[3,4-c]pyrrol- 2(1 H)-yl)-3 -(4-(trifluoromethoxy)phenyl)propan- 1 -one; l-[(3aR,6aR)-5-(lH-benzotriazole-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-3-(4- trifluoromethoxy-phenyl)-propan- 1 -one; l-[(3aR,6aR)-5-(lH-benzotriazole-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-3-(4- trifluoromethyl-phenyl)-propan- 1 -one; l-[(3aS,6aS)-5-(lH-benzotriazole-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2-(4- chloro-2-isopropyl-5-methyl-phenoxy)-ethanone; and pharmaceutically acceptable salts thereof.
Processes for the manufacture of compounds of formula (I) as described herein are an object of the invention.
The preparation of compounds of formula (I) of the present invention may be carried out in sequential or convergent synthetic routes. Syntheses of the invention are shown in the following general schemes. The skills required for carrying out the reactions and purifications of the resulting products are known to those persons skilled in the art. In case a mixture of enantiomers or diastereoisomers is produced during a reaction, these enantiomers or diastereoisomers can be separated by methods described herein or known to the man skilled in the art such as e.g. (chiral) chromatography or crystallization. The substituents and indices used in the following description of the processes have the significance given herein. Compounds of general formula (I) can be synthesised from amine precursor 1 and appropriate reagents, using methods well known in the art.
Figure imgf000055_0001
For instance, amine 1 is reacted with a suitable chloroformate ester of formula R!-0- C(0)-C1 (2), or with an imidazole- 1-carboxylate ester of formula (3 A), or with a succinimidyl carbonate derivative of formula (3B)„ leading to a compound of formula (I) wherein Y is - OC(O)-.
Figure imgf000055_0002
The reaction is performed in a suitable solvent such as dichloromethane, tetrahydrofuran, Ν,Ν-dimethylformamide, acetonitrile, acetone, water, or mixtures thereof, in the presence or not of a base, e. g., triethylamine, diisopropylethylamine, pyridine, potassium hydrogencarbonate, potassium carbonate, at temperatures between 0°C and the boiling point of the solvent or solvent mixture.
Chloroformate esters 2 are commercially available or can be synthesised from the corresponding alcohol of formula R'-OH, by reaction with phosgene or a phosgene equivalent (e. g., diphosgene, triphosgene), as described in the literature.
Imidazole- 1-carboxylate esters 3Aare synthesised from the corresponding alcohols of formula R'-OH, by reaction with Ι,Γ-carbonyldiimidazole. The reaction is performed at room temperature, in a solvent such as dichloromethane, tetrahydrofuran or acetonitrile. The
imidazole- 1-carboxylate esters 3 A are typically not isolated but directly reacted with amines 1 as described above.
Succinimidyl carbonate derivatives 3B are synthesised from the corresponding alcohols of formula R'-OH, by reaction with Ν,Ν'-disuccinimidyl carbonate. The reaction is performed at room temperature, in a solvent such as dichloromethane, tetrahydrofuran, or acetonitrile, optionally in the presence of a base, e. g., triethylamine. The succinimidyl carbonate derivatives 3B are typically not isolated but directly reacted with amines 1 as described above.
Alcohols of formula R'-OH are commercially available or can be produced by methods described herein or known in the art. Alternatively, amine 1 is reacted with a suitable N-(chlorocarbonyl)amine of formula
R'-NCR QC -CI (4), or, in the case where R7 is H, with an isocyanate of formula R'-NCO (5), leading to compounds of formula (I) wherein Y is -NR7C(0)-.
N-(Chlorocarbonyl)amines (4) are synthesised from the corresponding amines of formula R1-N(R7)H by reaction with phosgene or a phosgene equivalent, as described in the literature. Isocyanates 5 are commercially available or can be prepared from the corresponding amines of formula R1-NH2, by reaction with phosgene or a phosgene equivalent (e. g., diphosgene, triphosgene, Ι,Γ-carbonyldiimidazole), as described in the literature.
Alternatively, amine 1 is reacted with a suitable carboxylic acid of formula R'-COOH (6) leading to a compound of formula (I), wherein Y is -C(O)-. The reaction is performed in the presence of a coupling agent such as Ι,Γ-carbonyldiimidazole, N,N'-dicyclohexylcarbodiimide, 1 -(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride, 0-(benzotriazol- 1 -yl)- Ν,Ν,Ν ' ,N ' -tetramethyluronium hexafluoro-phosphate, 0-(7-azabenzotriazo 1- 1 -yl)-N,N,N ' ,N ' - tetramethyluronium hexafluoro-phosphate or bromo-tris-pyrrolidino-phosphonium
hexafluorophosphate, in aprotic solvents such as dichloromethane, tetrahydrofuran, N,N- dimethylformamide, N-methylpyrrolidinone and mixtures thereof at temperatures between -40°C and 80°C in the presence or absence of a base such as triethylamine, diisopropylethylamine, 4- methylmorpholine and/or 4-(dimethylamino)pyridine.
Amine 1 can also be reacted with suitable acylating reagents such as acyl chlorides of formula R'-COCl (7) to lead to compounds of formula (I) wherein Y is -C(O)-. The reaction is performed in a solvent such as dichloromethane, tetrahydrofuran, or Ν,Ν-dimethylformamide, in the presence of a base such as triethylamine or 4-methylmorpholine, at temperatures between 0°C and 80°C.
Carboxylic acids (6) and acyl halides (7) are commercially available or can be prepared as described herein or in the literature. Alternatively, amine 1 is reacted with a suitable sulfonyl chloride of formula R1-S02C1 (8), leading to compounds of formula (I) wherein Y is -S(02)-. The reaction is performed in a suitable solvent such as dichloromethane, tetrahydroiuran, Ν,Ν-dimethylformamide, acetonitrile, acetone, water, or mixtures thereof, in the presence of a base, e. g., triethylamine,
diisopropylethylamine, pyridine, potassium hydrogencarbonate, potassium carbonate, at temperatures between 0°C and the boiling point of the solvent or solvent mixture.
Sulfonyl chlorides (8) are commercially available or can be synthesised as described herein or in the literature.
Alternatively, amine 1 is reacted with a suitable chloro-oxadiazole reagent of general formula 9, or with oxadiazolone reagent 10, leading to a compound of formula (I), wherein Y is
Figure imgf000057_0001
9 10
In the case where compounds of formula (I) are produced from amine 1 and chloro- oxadiazole 9, the reaction is performed in the presence of a base, e. g., potassium carbonate, triethylamine, or l,8-diazabicyclo[5.4.0]undec-7-ene, in a solvent such as toluene, ethanol, N,N- dimethylformamide, or 1,4-dioxane at temperatures between 20°C and 150°C.
In the case where compounds of formula (I) are produced from amine 1 and oxadiazolone 10, the reaction is performed in the presence of a coupling agent, e. g. benzotriazol-l-yl-oxy-tris- (dimethylamino)-phosphonium hexafluorophosphate and a base, e. g., diisopropylethylamine or 4-methylmorpholine, in a solvent such as Ν,Ν-dimethylformamide, at temperatures between 20°C and 100°C as described in the literature.
Oxadiazolones 10 are commercially available or can be produced as described in the literature. Chloro-oxadiazoles 9 are commercially available or can be produced from the corresponding oxadiazolones, by reaction with a suitable halogenating reagent, e. g. phosphorus oxychloride and/or phosphorus pentachloride, at temperatures between 60°C and 120°C.
Alternatively, amine 1 is reacted with a suitable halo -thiadiazole reagent of general formula 11 (X = CI or Br or with thiadiazolethione reagent 12, leading to compounds of (I)
wherein Y is
Figure imgf000058_0001
11 12
In the case where compounds of formula (I) are produced from amine 1 and halo- thiadiazole 11, the reaction is performed in the presence of a base, e. g. potassium carbonate, triethylamine or l,8-diazabicyclo[5.4.0]undec-7-ene, in a solvent such as toluene, ethanol, N,N- dimethylformamide or 1,4-dioxane, at temperatures between 20°C and 150°C.
In the case where compounds of formula (I) are produced from amine 1 and
thiadiazolethione 12, the reaction is performed in a solvent such as ethanol or N,N- dimethylformamide at temperatures between 20°C and 100°C as described in the literature. Thiadiazolethiones 12 are commercially available or can be produced as described in the literature.
Halo-thiadiazoles 11 are commercially available or can be produced as described in the literature.
Amines of general formula 1 are synthesised from suitably protected precursors 13.
PG— N A— W 13 Suitable protective groups (PG) are tert-butoxycarbonyl, benzyloxycarbonyl and substituted benzyloxycarbonyl such as 3,5-dichloro benzyloxycarbonyl. The deprotection of intermediates 13 can be performed using methods and reagents known in the art.
For instance, in the case where PG is optionally substituted benzyloxycarbonyl, the deprotection may be performed by hydrogenation at pressures between 1 bar and 100 bar, in the presence of a suitable catalyst such as palladium on activated charcoal, at temperatures between 20°C and 150°C in solvents such as methanol or ethanol.
Alternatively, in the case where PG is tert-butoxycarbonyl, the deprotection may be performed in the presence of a suitable acid, e. g, hydrochloric acid or trifluoro acetic acid, in a solvent such as water, 2-propanol, dichloromethane, or 1,4-dioxane at temperatures between 0°C and 30°C.
Carbamates 13, wherein A is N are represented by general structure 13A.
Figure imgf000059_0001
PG is a suitable protective group, e. g., tert-butoxycarbonyl, benzyloxycarbonyl and substituted benzyloxycarbonyl such as 3,5-dichloro benzyloxycarbonyl.
Carbamates 13A can be produced from amine precursors of general formula 14 by reaction with appropriate reagents, using methods known in the art.
Figure imgf000059_0002
For instance, 14 is reacted with alkylating agents of general formula X-CR3R4-R2 (15) where X is a leaving group such as CI, Br, I, or OSO2CH3, leading to 13A, wherein W is -CR3R4-. This reaction is performed in a solvent such as tetrahydrofuran or N,N- dimethylformamide, in the presence of a base, e. g. triethylamine or potassium carbonate, at temperatures between 0°C and 100°C. Alternatively, for compounds of formula 13A, wherein W is -CR3R4-, R4 is hydrogen, alkyl or cycloalkyl, and R3 is H, amine 14 is reacted with aldehydes or ketones of general formula R4-C(0)-R2 (16) in a reductive amination reaction, leading to 13A. This reaction is performed in the presence of a suitable reducing agent, e. g., sodium borohydride or sodium triacetoxyborohydride, in a solvent such as methanol, acetic acid, tetrahydrofuran, 1,2- dichloro ethane or mixtures thereof, at temperatures between 0°C and 50°C.
Alternatively, amine 14 is reacted with a suitable carboxylic acid of formula R2-COOH (17), leading to compounds of formula 13A, wherein W is -C(O)-. The reaction is performed in the presence of a coupling agent such as Ι,Γ-carbonyldiimidazole, Ν,Ν'- dicyclohexylcarbodiimide, l-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride, O- (benzotriazo 1- 1 -yl)-N,N,N ' ,N ' -tetramethyluronium hexafluoro-phosphate, 0-(7-azabenzotriazo 1- l-yl)-N,N,N',N' -tetramethyluronium hexafluoro-phosphate or bromo-tris-pyrrolidino- phosphonium hexafluorophosphate, in aprotic solvents such as dichloromethane, tetrahydrofuran, Ν,Ν-dimethylformamide, N-methylpyrrolidinone and mixtures thereof at temperatures between - 40°C and 80°C in the presence or absence of a base such as triethylamine, diisopropylethylamine, 4-methylmorpholine and/or 4-(dimethylamino)pyridine.
Alternatively, amine 14 is reacted with a suitable sulfonyl chloride of formula
R2-S02C1 (18), leading to compounds of formula 13A, wherein W is -S(02)-. The reaction is performed in a suitable solvent such as dichloromethane, tetrahydrofuran, N,N- dimethylformamide, acetonitrile, acetone, water, or mixtures thereof, in the presence of a base, e. g. triethylamine, diisopropylethylamine, pyridine, potassium hydrogencarbonate, potassium carbonate, at temperatures between 0°C and the boiling point of the solvent or solvent mixture.
Alternatively, amine 14 is reacted with a suitable N-(chlorocarbonyl)amine of formula R2-N(R6)-C(0)-C1 (19) leading to compounds of formula 13A, wherein W is -C(0)-NR6-, or with an isocyanate of formula R2-NCO (20), leading to compounds of formula 13A, wherein W is -C(0)-NR6- and R6 is H.
Alternatively, amine 14 is reacted with phosgene or phosgene equivalent (diphosgene, triphosgene) in the presence of a base (e. g., pyridine, triethylamine) in a solvent such as dichloromethane or tetrahydrofuran, to provide the corresponding N-(chlorocarbonyl)amine of formula 21, which is then reacted with amine of formula HN(R6)R2 (22), in the presence of a base such as triethylamine or diisopropylethylamine, in a solvent such as dichloromethane, tetrahydrofuran, or Ν,Ν-dimethylformamide, leading to compounds of formula 13A, wherein W is -C(0)-NR6-.
Figure imgf000061_0001
Alternatively, amine 14 is reacted with phosgene or a phosgene equivalent (diphosgene, triphosgene) in the presence of a base (e. g., pyridine, triethylamine), in a solvent such as dichloromethane or tetrahydroiuran, to the corresponding N-(chlorocarbonyl)amine of formula 21, which is then reacted with amines of formula H-O, H-P, H-Q, H-R, H-T, H-U, H-V, H-X, H-AA or H-AF, in the presence of a base such as triethylamine or diisopropylethylamine, in a solvent such as dichloromethane, tetrahydroiuran, or Ν,Ν-dimethylformamide, leading to compounds of formula 13 A, wherein W is -C(O)- and R2 is O, P, Q, R, T, U, V, X, AA or AF.
N-(Chlorocarbonyl)amines 19 are synthesised from the corresponding amines 22 by reaction with phosgene or a phosgene equivalent (diphosgene, triphosgene) as described in the literature.
Isocyanates 20 are commercially available or can be prepared from the corresponding amines of formula R2-NH2, by reaction with phosgene or a phosgene equivalent (e. g., diphosgene, triphosgene, Ι,Γ-carbonyldiimidazole) as described in the literature.
Amines 14, alkylating agents 15, aldehydes/ketones 16, carboxylic acids 17, sulfonyl chlorides 18, and amines 22 are commercially available or can be synthesised as described in the literature. Carbamates 13 wherein A is CR5 and R5 is H are represented by general formula 13B, wherein PG is a suitable protective group, e. g tert-butoxycarbonyl, benzyloxycarbonyl and substituted benzyloxycarbonyl such as 3,5-dichloro benzyloxycarbonyl.
Figure imgf000061_0002
Compound 13B, wherein W is -NR6-, is produced from ketone 23 by reaction with an amine of formula HN(R6)R2 (22) in the presence of a suitable reducing agent, , e. g. sodium borohydride or sodium triacetoxyborohydride, in a solvent such as methanol, acetic acid, tetrahydroiuran, 1,2-dichloroethane, or mixtures thereof, at temperatures between 0°C and 50°C.
Figure imgf000062_0001
Ketones 23 and amines 22 are commercially available or can be prepared as described in the literature.
Compound 13B, wherein W is -O- or -S-, is produced from alcohol 24 using methods and reagents known in the art.
Figure imgf000062_0002
For instance, alcohol 24 is reacted at room temperature with phenol HO-R2 or thiophenol HS-R2 in the presence of triphenylphosphine and an dialkylazodicarboxylate, e. g.
diisopropylazodicarboxylate or diethylazodicarboxylate, in a solvent such as toluene, dichloromethane, or tetrahydroiuran, leading to 13B, wherein W is -O- or -S-.
In the case wherein W is -O- or and R2 is B, compounds of formula 13B can also be produced from alcohol 24 in a three-step sequence. Therefore, 24 is reacted in step 1 at room temperature with 2,4-dihydroxybenzoic acid alkyl ester in the presence of triphenylphosphine and an dialkylazodicarboxylate, e. g. diisopropylazodicarboxylate or diethylazodicarboxylate, in a solvent such as toluene, dichloromethane or tetrahydroiuran, converting the hydroxy group into a 3-hydroxy-4-(alkoxycarbonyl)-phenyl ether substituent. This is hydrolysed in step 2 to the corresponding 3-hydroxy-4-carboxyphenyl group, using a base such as sodium hydroxide in water and in the presence of co-solvents such as tetrahydroiuran and/or methanol or ethanol. In step 3, the 3-hydroxy-4-carboxyphenyl ether intermediate can be subjected to a Curtius rearrangement as described in the literature, e. g. by using diphenylphorphoryl azide, in a solvent such as toluene, in the presence of a base, e. g., triethylamine, at temperatures between 60°C and 110°C, leading to the corresponding 2-oxo-2,3-dihydro-benzooxazol-6-yl ether 13B, wherein W is -O- and R2 is B. Alternatively, conversion of alcohol 24 to the corresponding methanesulfonate using methanesulfonyl chloride in the presence of a base, e. g. triethylamine, in a solvent such as dichloromethane or tetrahydroiuran, at temperatures between -20°C and +30°C, and treatment of the methanesulfonate intermediate with phenol HO-R2 or thiophenol HS-R2 in the presence of a base, e. g., potassium carbonate, in a solvent such as Ν,Ν-dimethylformamide or acetonitrile, at temperatures between 20°C and 100°C, leads to 13B, wherein W is -O- or -S-.
Compound 13B, wherein W is -S02-, is produced from compound 13B, wherein W is -S- by oxidation with a suitable reagent, e. g., hydrogen peroxide or 3-chloroperbenzoic acid, in a solvent such as formic acid, acetic acid, or dichloromethane, at temperatures between 0°C and 50°C.
Alcohols 24 are produced from ketones 23 using a suitable reducing agent, e. g., sodium borohydride, in a solvent such as methanol, at temperatures between 0°C and 50°C.
Carbamates 13 wherein A is CR5, R5 is H, and W is-C(0)-N(R6)- are represented by general formula 13C, wherein R12 is N(R6)R2, O, P, Q, R, T, U, V, X, AA or AF.
Figure imgf000063_0001
Amide 13C is produced from carboxylic acid 25 by coupling reaction with an amine of formula HN(R6)R2 (22), H-O, H-P, H-Q, H-R, H-T, H-U, H-V, H-X, H-AA or H-AF.
Figure imgf000063_0002
The reaction is performed in the presence of a coupling agent such as Ι,Γ- carbonyldiimidazole, Ν,Ν'-dicyclohexylcarbodiimide, 1 -(3-dimethylaminopropyl)-3-ethyl- carbodiimide hydrochloride, 0-(benzotriazol-l-yl)-N,N,N',N'-tetramethyluronium hexafluoro- phosphate, 0-(7-azabenzotriazol-l-yl)-N,N,N',N'-tetramethyluronium hexafluoro -phosphate or bromo-tris-pyrrolidino-phosphonium hexafluorophosphate, in aprotic solvents such as dichloromethane, tetrahydroiuran, Ν,Ν-dimethylformamide, N-methylpyrrolidinone and mixtures thereof at temperatures between -40°C and 80°C in the presence or absence of a base such as triethylamine, diisopropylethylamine, 4-methylmorpholine and/or 4- (dimethylamino)pyridine.
Carboxylic acids 25 are commercially available or can be produced as described in the literature.
Compounds of formula (I), wherein A is N can be produced from amine precursors of general formula 26 by reaction with appropriate reagents, using methods known in the art.
Figure imgf000064_0001
For instance, an amine of formula 26 is reacted with alkylating agents of general formula
X-CR3R4-R2 (15) where X is a leaving group such as CI, Br, I, or OSO2CH3, leading to compounds of formula (I), wherein A is N and W is -CR3R4-. This reaction is performed in a solvent such as tetrahydrofuran or Ν,Ν-dimethylformamide, in the presence of a base, e. g., triethylamine or potassium carbonate, at temperatures between 0°C and 100°C. Alternatively, an amine of formula 26 is reacted with aldehydes or ketones of general formula R4-C(0)-R2 (16) in a reductive amination reaction, leading to compounds of formula (I) wherein A is N, W is -CR3R4-, R4 is hydrogen, alkyl or cycloalkyl, and R3 is H. This reaction is performed in the presence of a suitable reducing agent, e. g. sodium borohydride or sodium triacetoxyborohydride, in a solvent such as methanol, acetic acid, tetrahydrofuran, 1,2- dichloro ethane or mixtures thereof, at temperatures between 0°C and 50°C.
Alternatively, amine 26 is reacted with a suitable carboxylic acid of formula R2-COOH (17), leading to compounds of formula (I) wherein A is N and W is -C(O)-. The reaction is performed in the presence of a coupling agent such as Ι,Γ-carbonyldiimidazole, Ν,Ν'- dicyclohexylcarbodiimide, l-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride, O- (benzotriazol-l-yl)-N,N,N',N' -tetramethyluronium hexafluoro-phosphate, 0-(7-azabenzotriazol- l-yl)-N,N,N',N' -tetramethyluronium hexafluoro-phosphate or bromo-tris-pyrrolidino- phosphonium hexafluorophosphate, in aprotic solvents such as dichloromethane, tetrahydrofuran, Ν,Ν-dimethylformamide, N-methylpyrrolidinone and mixtures thereof at temperatures between - 40°C and 80°C in the presence or absence of a base such as triethylamine, diisopropylethylamine, 4-methylmorpholine and/or 4-(dimethylamino)pyridine.
Alternatively, amine 26 is reacted with a suitable sulfonyl chloride of formula
R2-S02C1 (18), leading to (I) wherein A is N and W is -S(02)-. The reaction is performed in a suitable solvent such as dichloromethane, tetrahydroiuran, Ν,Ν-dimethylformamide, acetonitrile, acetone, water, or mixtures thereof, in the presence of a base, e. g. triethylamine,
diisopropylethylamine, pyridine, potassium hydrogencarbonate, potassium carbonate, at temperatures between 0°C and the boiling point of the solvent or solvent mixture. Alternatively, amine of formula 26 is reacted with a suitable N-(chlorocarbonyl)amine of formula R2-N(R6)-C(0)-C1 (19) leading to compounds of formula (I), wherein A is N and W is C(0)-NR6, or with isocyanate R2-NCO (20), leading to compounds of formula (I), wherein A is N, W is -C(0)-NR6- and R6 is H.
Alternatively, amine 26 is reacted with phosgene or a phosgene equivalent (diphosgene, triphosgene) in the presence of a base (e. g., pyridine, triethylamine), in a solvent such as dichloromethane or tetrahydroiuran, to the corresponding N-(chlorocarbonyl)amine of formula 27, which is then reacted with an amine of formula H-O, H-P, H-Q, H-R, H-T, H-U, H-V, H- X, H-AA or H-AF in the presence of a base such as triethylamine or diisopropylethylamine, in a solvent such as dichloromethane, tetrahydroiuran, or Ν,Ν-dimethylformamide, leading to compounds of formula (I), wherein A is N, W is -C(O)- and R2 is O, P, Q, R, T, U, V, X, AA or AF.
Figure imgf000065_0001
Amines 26 can be synthesised from their tert-butyl carbamate derivatives of formula 28 by carbamate deprotection. The deprotection may be performed in the presence of a suitable acid, e g, hydrochloric acid or trifluoro acetic acid, in a solvent such as water, 2-propanol,
dichloromethane, or 1,4-dioxane, at temperatures between 0°C and 30°C.
Figure imgf000066_0001
tert-Butyl carbamates 28 can be synthesised from amine precursors of formula
29 and appropriate reagents, using methods well known in the art.
Figure imgf000066_0002
For instance,an amine of formula 29 is reacted with a suitable chloro formate ester of formula R1-0-C(0)-Cl (2), or with an imidazole- 1-carboxylate ester of formula (3 A) or with a succinimidyl carbonate derivative of formula (3B), leading to compounds of formula 28, wherein Y is -OC(O)-. The reaction is performed in a suitable solvent such as dichloromethane, tetrahydroiuran, Ν,Ν-dimethylformamide, acetonitrile, acetone, water, or mixtures thereof, in the presence or not of a base, e. g. triethylamine, diisopropylethylamine, pyridine, potassium hydrogencarbonate, potassium carbonate, at temperatures between 0°C and the boiling point of the solvent or solvent mixture.
Alternatively, an amine of formula 29 is reacted with a suitable N-(chlorocarbonyl)amine of formula R1-N(R7)-C(0)-C1 (4) leading to compounds of formula 28, wherein Y is - NR7C(0)-, or with an isocyanate of formula R'-NCO (5) leading to compounds of formula 28, wherein Y is -NR7C(0)- and R7 is H.
Alternatively, amine 29 is reacted with a suitable carboxylic acid of formula R'-COOH (6) leading to compounds of formula 28, wherein Y is -C(O)-. The reaction is performed in the presence of a coupling agent such as Ι,Γ-carbonyldiimidazole, N,N'-dicyclohexylcarbodiimide, l-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride, O-(benzotriazol-l-yl)-
Ν,Ν,Ν ' ,N ' -tetramethyluronium hexafluoro-phosphate, 0-(7-azabenzotriazo 1- 1 -yl)-N,N,N ' ,N ' - tetramethyluronium hexafluoro-phosphate or bromo-tris-pyrrolidino-phosphonium
hexafluorophosphate, in aprotic solvents such as dichloromethane, tetrahydrofuran, N,N- dimethylformamide, N-methylpyrrolidinone and mixtures thereof at temperatures between -40°C and 80°C in the presence or absence of a base such as triethylamine, diisopropylethylamine, 4- methylmorpholine and/or 4-(dimethylamino)pyridine. Amine 29 can also be reacted with suitable acylating reagents, such as acyl chlorides of formula R'-COCl (7) to provide compounds of formula 28, wherein Y is -C(O)-. The reaction is performed in a solvent such as dichloromethane, tetrahydroiuran, or N,N-dimethylformamide, in the presence of a base such as triethylamine or 4-methylmorpholine, at temperatures between 0°C and 80°C.
Alternatively, amine 29 is reacted with a suitable sulfonyl chloride, of formula R1-S02C1 (8), leading to compounds of formula 28, wherein Y is -S(02)-. The reaction is performed in a suitable solvent such as dichloromethane, tetrahydroiuran, Ν,Ν-dimethylformamide, acetonitrile, acetone, water, or mixtures thereof, in the presence of a base, e. g. triethylamine,
diisopropylethylamine, pyridine, potassium hydrogencarbonate, potassium carbonate, at temperatures between 0°C and the boiling point of the solvent or solvent mixture.
Alternatively, amine 29 is reacted with a suitable chloro-oxadiazole reagent of general formula 9 or with oxadiazolone reagent 10, leading to compounds of formula 28, wherein Y is
Figure imgf000067_0001
In the case where 28 is produced from amine 29 and chloro-oxadiazole 9, the reaction is performed in the presence of a base, e. g. potassium carbonate, triethylamine, or 1,8- diazabicyclo[5.4.0]undec-7-ene, in a solvent such as toluene, ethanol, N,N-dimethylformamide, or 1,4-dioxane, at temperatures between 20°C and 150°C.
In the case where 28 is produced from amine 29 and oxadiazolone 10, the reaction is performed in the presence of a coupling agent, e. g., benzotriazol-l-yl-oxy-tris-(dimethylamino)- phosphonium hexafluorophosphate, and a base, e. g. diisopropylethylamine or 4- methylmorpholine, in a solvent such as Ν,Ν-dimethylformamide, at temperatures between 20°C and 100°C, as described in the literature).
Alternatively, amine 29 is reacted with a suitable halo-thiadiazole reagent of general formula 11 (X is CI or Br) or with thiadiazolethione reagent 12, leading to compounds of
formula 28, wherein Y is
Figure imgf000067_0002
In the case where 28 is produced from amine 29 and halo-thiadiazole 11, the reaction is performed in the presence of a base, e. g. potassium carbonate, triethylamine, or 1,8- diazabicyclo[5.4.0]undec-7-ene, in a solvent such as toluene, ethanol, N,N-dimethylformamide, or 1,4-dioxane, at temperatures between 20°C and 150°C. In the case where 28 is produced from amine 29 and thiadiazolethione 12, the reaction is performed in a solvent such as ethanol or Ν,Ν-dimethylformamide, at temperatures between 20°C and 100°C, as described in the literature.
Alternatively, amine 29 is acylated with a haloalkanoyl halide, e. g., bromoacetyl chloride, in the presence of a base, e. g. triethylamine, in a solvent such as dichloromethane or
tetrahydrofuran, at temperatures between -78°C and +20°C, leading to the corresponding haloalkanamide intermediate, which in the presence of a base, e. g. potassium carbonate or caesium carbonate, in a solvent such as Ν,Ν-dimethylformamide undergoes a nucleophilic substitution reaction with a substituted phenol, leading to compounds of formula 28, wherein Y is -C(O)- and R1 is substituted phenoxyalkyl. Amines of formula 29 are commercially available or can be produced as described in the literature.
Compounds of formula (I), wherein A is CR5 and W is-C(0)-N(R6)- can be produced from carboxylic acid precursors of general formula 30 by reaction with appropriate amine reagents of general formula HN(R6)R2, H-O, H-P, H-Q, H-R, H-T, H-U, H-V, H-X, H-AA or H-AF using methods known in the art.
Figure imgf000068_0001
For instance, this reaction is performed in the presence of a coupling agent such as Ι,Γ- carbonyldiimidazole, Ν,Ν'-dicyclohexylcarbodiimide, 1 -(3-dimethylaminopropyl)-3-ethyl- carbodiimide hydrochloride, 0-(benzotriazol-l-yl)-N,N,N',N'-tetramethyluronium hexafluoro- phosphate, 0-(7-azabenzotriazol-l-yl)-N,N,N',N'-tetramethyluronium hexafluoro -phosphate or bromo-tris-pyrrolidino-phosphonium hexafluorophosphate, in aprotic solvents such as dichloromethane, tetrahydrofuran, Ν,Ν-dimethylformamide, N-methylpyrrolidinone and mixtures thereof at temperatures between -40°C and 80°C in the presence or absence of a base such as triethylamine, diisopropylethylamine, 4-methylmorpholine and/or 4- (dimethylamino)pyridine.
Carboxylic acids 30 can be produced from the corresponding ester precursors 31, wherein Ra is lower alkyl, e. g. methyl or ethyl, using methods and reagents known in the art. For instance, the reaction is performed in the presence of a base, e. g., potassium hydroxide, sodium hydroxide, or lithium hydroxide, in solvents such as water, methanol, ethanol, tetrahydroiuran, or mixtures thereof, at temperatures between 20°C and 100°C.
Figure imgf000069_0001
Compounds of formula 31 can be synthesised from amine precursors of formula 32 and appropriate reagents, using methods well known in the art.
Figure imgf000069_0002
For instance, an amine of formula 32 is reacted with a suitable chloro formate ester of formula R1-0-C(0)-Cl (2), or with an imidazole- 1-carboxylate ester of formula 3, leading to compounds of formula 31, wherein Y is -OC(O)-. The reaction is performed in a suitable solvent such as dichloromethane, tetrahydroiuran, Ν,Ν-dimethylformamide, acetonitrile, acetone, water, or mixtures thereof, in the presence of a base, e. g. triethylamine, diisopropylethylamine, pyridine, potassium hydrogencarbonate, potassium carbonate, at temperatures between 0°C and the boiling point of the solvent or solvent mixture.
Alternatively, an amine of formula 32 is reacted with a suitable N-(chlorocarbonyl)amine of formula R1-N(R7)-C(0)-C1 (4) leading to compounds of formula 31, wherein Y is - NR7C(0)-, or with an isocyanate of formula R'-NCO (5) leading to leading to compounds of formula 31, wherein Y is -NR7C(0)- and R7 is H.
Alternatively, amine 32 is reacted with a suitable carboxylic acid of formula R'-COOH (6) leading to compounds of formula 31, wherein Y is -C(O)-. The reaction is performed in the presence of a coupling agent such as Ι,Γ-carbonyldiimidazole, N,N'-dicyclohexylcarbodiimide, 1 -(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride, 0-(benzotriazol- 1 -yl)- Ν,Ν,Ν ' ,N ' -tetramethyluronium hexafluoro-phosphate, 0-(7-azabenzotriazo 1- 1 -yl)-N,N,N ' ,N ' - tetramethyluronium hexafluoro-phosphate or bromo-tris-pyrrolidino-phosphonium
hexafluorophosphate, in aprotic solvents such as dichloromethane, tetrahydroiuran, N,N- dimethylformamide, N-methylpyrrolidinone and mixtures thereof at temperatures between -40°C and 80°C in the presence or absence of a base such as triethylamine, diisopropylethylamine, 4- methylmorpholine and/or 4-(dimethylamino)pyridine.
Amine 32 can also be reacted with suitable acylating reagents, such as acyl chlorides of formula R'-COCl (7) to lead to compounds of formula 31, wherein Y is -C(O)-. The reaction is performed in a solvent such as dichloromethane, tetrahydroiuran, or Ν,Ν-dimethylformamide, in the presence of a base such as triethylamine or 4-methylmorpholine, at temperatures between 0°C and 80°C.
Alternatively, amine 32 is reacted with a suitable sulfonyl chloride of formula R1-S02C1 (8), leading to compounds of formula 31, wherein Y is -S(02)-. The reaction is performed in a suitable solvent such as dichloromethane, tetrahydroiuran, Ν,Ν-dimethylformamide, acetonitrile, acetone, water, or mixtures thereof, in the presence of a base, e. g. triethylamine,
diisopropylethylamine, pyridine, potassium hydrogencarbonate, potassium carbonate, at temperatures between 0°C and the boiling point of the solvent or solvent mixture.
Alternatively, amine 32 is reacted with a suitable chloro-oxadiazole reagent of general formula 9, or with oxadiazolone reagent 10, leading to compounds of formula 31, wherein Y
Figure imgf000070_0001
In the case where 31 is produced from amine 32 and chloro-oxadiazole 9, the reaction is performed in the presence of a base, e. g. potassium carbonate, triethylamine, or 1 ,8- diazabicyclo[5.4.0]undec-7-ene, in a solvent such as toluene, ethanol, N,N-dimethylformamide, or 1 ,4-dioxane, at temperatures between 20°C and 150°C.
In the case where 31 is produced from amine 32 and oxadiazolone 10, the reaction is performed in the presence of a coupling agent, e. g. benzotriazol-l-yl-oxy-tris-(dimethylamino)- phosphonium hexafluorophosphate, and a base, e. g. diisopropylethylamine or 4- methylmorpholine, in a solvent such as Ν,Ν-dimethylformamide, at temperatures between 20°C and 100°C, as described in the literature.
Alternatively, amine 32 is reacted with a suitable halo-thiadiazole reagent of general formula 11 (X is CI or Br), or with thiadiazolethione reagent 12, leading to compounds of
formula 31, wherein Y is
Figure imgf000071_0001
In the case where 31 is produced from amine 32 and halo-thiadiazole 11, the reaction is performed in the presence of a base, e. g. potassium carbonate, triethylamine, or 1,8- diazabicyclo[5.4.0]undec-7-ene, in a solvent such as toluene, ethanol, N,N-dimethylformamide or 1,4-dioxane, at temperatures between 20°C and 150°C.
In the case where 31 is produced from amine 32 and thiadiazolethione 12, the reaction is performed in a solvent such as ethanol or Ν,Ν-dimethylformamide, at temperatures between 20°C and 100°C, as described in the literature.
Amines of general formula 32 are synthesised from suitably protected precursors 33.
Figure imgf000071_0002
Suitable protective groups (PG) are tert-butoxycarbonyl or benzyloxycarbonyl. The deprotection of intermediates 33 can be performed using methods and reagents known in the art.
For instance, in the case where PG is benzyloxycarbonyl, the deprotection may be performed by hydrogenation at pressures between 1 bar and 100 bar, in the presence of a suitable catalyst such as palladium on activated charcoal, at temperatures between 20°C and 150°C, in solvents such as methanol or ethanol.
Alternatively, in the case where PG is tert-butoxycarbonyl, the deprotection may be performed in the presence of a suitable acid, e. g, hydrochloric acid or trifluoro acetic acid, in a solvent such as water, 2-propanol, dichloromethane, or 1,4-dioxane, at temperatures between
0°C and 30°C.
Figure imgf000072_0001
Substituents R5 may be introduced starting from ester precursor 34, using suitable reagents and methods known in the art. For instance, 34 is reacted with alkylating agents of general formula R5-X wherein R5 is alkyl or cycloalkyl and X is a leaving group such as CI, Br, I, or OSO2CH3, leading to 33, wherein R5 is alkyl or cycloalkyl. This reaction is performed in the presence of a suitable base, e. g., sodium hydride, lithium diisopropylamide, lithium
bis(trimethylsilyl)amide, or lithium pyrrolidide, in a solvent such as tetrahydrofuran or toluene, at temperatures between -78°C and +50°C.
Esters 34, wherein Ra is methyl or ethyl, are produced from carboxylic acids 25, using methods and reagents known in the art. For instance, 25 alkylated with methyl iodide or ethyl bromide, in the presence of a base, e. g., potassium carbonate, in a solvent such as N,N- dimethylformamide, at -20°C and +30°C, leading to the methyl or ethyl ester 34, respectively.
Also an embodiment of the present invention is a process to prepare a compound of formula (I) as defined above comprising the reaction of a compound of formula (II) in the presence of a compound of formula (III);
Figure imgf000072_0002
(ID (I) wherein R1, R2, A, W, m, n, p and q are as defined above, Y is -OC(O)-.
In particular, in the presence of a coupling agent such as 0-(7-azabenzotriazol-l-yl)- Ν,Ν,Ν',Ν'-tetramethyluronium hexafluoro-phosphate, in a solvent such as N,N- dimethylformamide, in the presence of a base such as 4-methylmorpholine and at a temperature comprised between -78°C and reflux, particularly between -10°C and room temperature. Also an object of the present invention is a compound according to formula (I) as described herein for use as a therapeutically active substance.
Likewise an object of the present invention is a pharmaceutical composition comprising a compound according to formula (I) as described herein and a therapeutically inert carrier. An object of the invention is the use of a compound according to formula (I) as described herein for the treatment or prophylaxis of renal conditions, liver conditions, inflammatory conditions, conditions of the nervous system, conditions of the respiratory system, vascular and cardiovascular conditions, fibrotic diseases, cancer, ocular conditions, metabolic conditions, cholestatic and other forms of chronic pruritus and acute and chronic organ transplant rejection. Renal conditions include, but are not limited to, acute kidney injury and chronic renal disease with and without proteinuria including end-stage renal disease (ESRD). In more detail, this includes decreased creatinine clearance and decreased glomerular filtration rate, microalbuminuria, albuminuria and proteinuria, glomerulosclerosis with expansion of reticulated mesangial matrix with or without significant hypercellularity (particularly diabetic nephropathy and amyloidosis), focal thrombosis of glomerular capillaries (particularly thrombotic microangiopathies), global fibrinoid necrosis, ischemic lesions, malignant nephrosclerosis (such as ischemic retraction, reduced renal blood flow and renal arteriopathy), swelling and proliferation of intracapillary (endothelial and mesangial) and/or extracapillary cells (crescents) like in glomerular nephritis entities, focal segmental glomerular sclerosis, IgA nephropathy, vasculitides / systemic diseases as well as acute and chronic kidney transplant rejection.
Liver conditions include, but are not limited to, liver cirrhosis, hepatic congestion, cholestatic liver disease including pruritus, nonalcoholic steatohepatitis and acute and chronic liver transplant rejection.
Inflammatory conditions include, but are not limited to, arthritis, osteoarthritis, multiple sclerosis, systemic lupus erythematodes, inflammatory bowel disease, abnormal evacuation disorder and the like as well as inflammatory airways diseases such as idiopathic pulmonary fibrosis (IPF), chronic obstructive pulmonary disease (COPD) or chronic asthma bronchiale.
Further conditions of the respiratory system include, but are not limited to, other diffuse parenchymal lung diseases of different etiologies including iatrogenic drug-induced fibrosis, occupational and/or environmental induced fibrosis, systemic diseases and vasculitides, granulomatous diseases (sarcoidosis, hypersensitivity pneumonia), collagen vascular disease, alveolar proteinosis, Langerhans cell granulomatosis, lymphangioleiomyomatosis, inherited diseases (Hermansky-Pudlak Syndrome, tuberous sclerosis, neurofibromatosis, metabolic storage disorders, familial interstitial lung disease), radiation induced fibrosis, silicosis, asbestos induced pulmonary fibrosis or acute respiratory distress syndrome (ARDS).
Conditions of the nervous system include, but are not limited to, neuropathic pain, schizophrenia, neuro -inflammation (e.g. astro gliosis), peripheral and/or autonomic (diabetic) neuropathies and the like.
Vascular conditions include, but are not limited to, atherosclerosis, thrombotic vascular disease as well as thrombotic microangiopathies, proliferative arteriopathy (such as swollen myointimal cells surrounded by mucinous extracellular matrix and nodular thickening), atherosclerosis, decreased vascular compliance (such as stiffness, reduced ventricular compliance and reduced vascular compliance), endothelial dysfunction and the like.
Cardiovascular conditions include, but are not limited to, acute coronary syndrome, coronary heart disease, myocardial infarction, arterial and pulmonary hypertension, cardiac arrhythmia such as atrial fibrillation, stroke and other vascular damage.
Fibrotic diseases include, but are not limited to myocardial and vascular fibrosis, renal fibrosis, liver fibrosis, pulmonary fibrosis, skin fibrosis, scleroderma and encapsulating peritonitis. In a particular embodiment, the compounds of formula (I) or their pharmaceutically acceptable salts and esters can be used for the treatment or prophylaxis of organ or skin fibrosis.
In another embodiment, the fibrotic disease is renal tubulo-interstitial fibrosis or glomerulosclerosis.
In another embodiment, the fibrotic disease is non-alcoholic liver steatosis, liver fibrosis or liver cirrhosis.
In another embodiment, the fibrotic disease is idiopathic pulmonary fibrosis. Cancer and cancer metastasis include, but are not limited to, breast cancer, ovarian cancer, lung cancer, prostate cancer, mesothelioma, glioma, hepatic carcinoma, gastrointestinal cancers and progression and metastatic aggressiveness thereof.
Ocular conditions include, but are not limited to, proliferative and non-pro liferative (diabetic) retinopathy, dry and wet age-related macular degeneration (AMD), macular edema, central arterial /venous occlusion, traumatic injury, glaucoma and the like.
Metabolic conditions include, but are not limited to, obesity and diabetes.
In another embodiment, the compounds of formula (I) or their pharmaceutically acceptable salts and esters can be used for the treatment or prophylaxis of cholestatic or non-cholestatic chronic pruritus.
The present invention also relates to the use of a compound according to formula (I) as described herein for the treatment or prophylaxis of renal conditions, liver conditions, inflammatory conditions, conditions of the nervous system, fibrotic diseases and acute and chronic organ transplant rejection. The present invention also relates to the use of a compound according to formula (I) as described herein for the treatment or prophylaxis of renal conditions, liver conditions and fibrotic diseases.
A particular embodiment of the present invention is a compound according to formula (I) as described herein for the treatment or prophylaxis of renal conditions, liver conditions, inflammatory conditions, conditions of the nervous system, fibrotic diseases and acute and chronic organ transplant rejection.
A particular embodiment of the present invention is a compound according to formula (I) as described herein for the treatment or prophylaxis of renal conditions, liver conditions and fibrotic diseases. The present invention also relates to the use of a compound according to formula (I) as described herein for the preparation of a medicament for the treatment or prophylaxis of renal conditions, liver conditions, inflammatory conditions, conditions of the nervous system, fibrotic diseases and acute and chronic organ transplant rejection. The present invention also relates to the use of a compound according to formula (I) as described herein for the preparation of a medicament for the treatment or prophylaxis of renal conditions, liver conditions and fibrotic diseases.
Also an object of the invention is a method for the treatment or prophylaxis of renal conditions, liver conditions, inflammatory conditions, conditions of the nervous system, fibrotic diseases and acute and chronic organ transplant rejection, which method comprises
administering an effective amount of a compound according to formula (I) as described herein.
Also an object of the invention is a method for the treatment or prophylaxis of renal conditions, liver conditions and fibrotic diseases, which method comprises administering an effective amount of a compound according to formula (I) as described herein.
In a particular embodiment, the renal condition is selected from the group consisting of acute kidney injury, chronic kidney disease, diabetic nephropathy, acute kidney transplant rejection and chronic allograft nephropathy.
In another particular embodiment, the renal condition is acute kidney injury. In another particular embodiment, the renal condition is chronic kidney disease.
In a further particular embodiment, the renal condition is diabetic nephropathy.
In another particular embodiment, the renal condition is acute kidney transplant rejection.
In another particular embodiment, the renal condition is chronic allograft nephropathy.
In a particular embodiment, the liver condition is acute and chronic liver transplant rejection
In a particular embodiment, the inflammatory condition is arthritis.
In a particular embodiment, the condition of the nervous system is neuropathic pain.
In another embodiment, the fibrotic disease is encapsulating peritonitis.
In another embodiment, the fibrotic disease is idiopathic pulmonary fibrosis. In another embodiment, the fibrotic disease is non-alcoholic liver steatosis, liver fibrosis or liver cirrhosis.
Also an embodiment of the present invention are compounds of formula (I) as described herein, when manufactured according to any one of the described processes. Assay procedures
PRODUCTION OF HUMAN FULL LENGTH ATX, WITH AND WITHOUT HIS TAG
Autotaxin (ATX - ENPP2) cloning: cDNA was prepared from commercial human
hematopoietic cells total RNA and used as template in overlapping PCR to generate a full length human ENPP2 ORF with or without a 3'-6xHis tag. These full length inserts were cloned into the pcDNA3.1 V5-His TOPO (Invitrogen) vector. The DNA sequences of several single clones were verified. The DNA from a correct full length clone was used to transfect Hek293 cells for verification of protein expression. The sequence of the encoded ENPP2 conforms to Swissprot entry Q 13822, with or without the additional C-terminal 6xHis tag.
ATX Fermentation: Recombinant protein was produced by large-scale transient transfection in 20 L controlled stirred tank bioreactors (Sartorius). During cell growth and transfection, temperature, stirrer speed, pH and dissolved oxygen concentration were maintained at 37°C, 120 rpm, 7.1 and 30% DO, respectively. FreeStyle 293-F cells (Invitrogen) were cultivated in suspension in FreeStyle 293 medium (Invitrogen) and transfected at ca. 1-1.5 x 10E6 cells/mL with above plasmid DNAs using X-tremeGENE Ro-1539 (commercial product, Roche
Diagnostics) as complexing agent. Cells were fed a concentrated nutrient solution (J Immunol Methods 194 (1996), 19, 1-199 (page 193)) and induced by sodium butyrate (2 mM) at 72 h post-transfection and harvested at 96 h post-transfection. Expression was analyzed by Western Blot, enzymatic assay and/or analytical IMAC chromatography. After cooling the cell suspension to 4°C in a flow-through heat exchanger, cell separation and sterile filtration of supernatant was performed by filtration through Zeta Plus 60M02 E16 (Cuno) and Sartopore 2 XLG (Sartorius) filter units. The supernatant was stored at 4°C prior to purification.
ATX Purification: 20 liter of culture supernatant were conditioned for ultrafiltration by adding Brij 35 to a final concentration of 0.02% and by adjusting the pH to 7.0 using 1 M HCl. Then the supernatant was first microfiltred through a 0.2 μιη Ultran-Pilot Open Channel PES filter (Whatman) and afterwards concentrated to 1 liter through an Ultran-Pilot Screen Channel PES filter with 30 kDa MWCO (Whatman). Prior to IMAC chromatography, NiS04 was added to a final concentration of 1 mM. The cleared supernatant was then applied to a HisTrap column (GE Healthcare) previously equilibrated in 50 mM Na2HP04 pH 7.0, 0.5 M NaCl, 10% glycerol, 0.3% CHAPS, 0.02%) NaN3. The column was washed stepwise with the same buffer containing 20 mM , 40 mM and 50 mM imidazole, respectively. The protein was subsequently eluted using a linear gradient to 0.5 M imidazole in 15 column volumes. ATX containing fractions were pooled and concentrated using an Amicon cell equipped with a 30 kDa PES filter membrane. The protein was further purified by size exclusion chromatography on Superdex S-200 prep grade (XK 26/100) (GE Healthcare) in 20 mM BICINE pH 8.5, 0.15 M NaCl, 10% glycerol, 0.3% CHAPS, 0.02% NaN3. Final yield of protein after purification was 5-10 mg ATX per liter of culture supernatant. The protein was stored at -80°C.
HUMAN ATX ENZYME INHIBITION ASSAY
ATX inhibition was measured by a fluorescence quenching assay using a specifically labeled substrate analogue (MR121 substrate). To obtain this MR121 substrate, BOC and TBS protected 6-amino-hexanoic acid (R)-3-( {2-[3-(2- {2-[2-(2-amino-ethoxy)-ethoxy]-ethoxy} -ethoxy)- propionylamino]-ethoxy}-hydroxy-phosphoryloxy)-2-hydroxy-propyl ester (Ferguson et al, Org Lett 2006, 8 (10), 2023) was labeled with MR121 fluorophore (CAS 185308-24-1, l-(3- carboxypropyl)-l l-ethyl-l,2,3,4,8,9,10,l l-octahydro-dipyrido[3,2-b:2',3'-i]phenoxazin-13-ium) on the free amine of the ethanolamine side and then, after deprotection, subsequently with tryptophan on the side of the aminohexanoic acid.
Assay working solutions were made as follows:
Assay buffer (50 mM Tris-HCl, 140 mM NaCl, 5 mM KC1, 1 mM CaCl2, 1 mM MgCl2, 0.01% Triton-X-100, pH 8.0;
ATX solution: ATX (human His-tagged) stock solution (1.08 mg/mL in 20mM bicine, pH 8.5, 0.15 M NaCl, 10% glycerol, 0.3% CHAPS, 0.02% NaN3), diluted to 1.4 - 2.5x final
concentration in assay buffer;
MR121 substrate solution: MR121 substrate stock solution (800 μΜ MR121 substrate in DMSO), diluted to 2 - 5x final concentration in assay buffer.
Test compounds (10 mM stock in DMSO, 8 μί) were obtained in 384 well sample plates
(Corning Costar #3655) and diluted with 8 DMSO. Row-wise serial dilutions were made by transferring 8 μΐ, cpd solution to the next row up to row O. The compound and control solutions were mixed five times and 2 μΙ_, were transferred to 384 well assay plates (Corning Costar # 3702). Then, 15 of 41.7 nM ATX solution was added (30 nM final concentration), mixed five times and then incubated for 15 minutes at 30°C. 10 of MR121 substrate solution was added (ΙμΜ final concentration), mixed 30 times and then incubated for 15 minutes at 30 °C.
Fluorescence was then measured every 2 minutes for 1 hour (Perkin Elmer plate: vision multimode reader); light intensity: 2.5%; exp. time: 1.4 sec, Filter: Fluo_630/690 nm) and IC50 values were calculated from these readouts.
Example IC50 (μΜ) Example IC50 (μΜ) Example IC50 (μΜ)
1 0.008 1.18 0.01 4.08 0.047
1.01 0.035 1.19 0.012 4.09 0.049
1.02 0.077 1.20 0.083 4.10 0.004
1.03 0.025 1.21 0.005 4.11 0.007
1.04 0.127 1.22 0.009 4.12 1.476
1.05 0.09 2 0.01 4.13 2.907
1.06 0.255 2.01 0.005 4.14 4.194
1.07 1.034 2.02 0.006 4.15 17.63
1.08 0.503 3 0.036 4.16 0.398
1.09 0.009 3.01 1.093 4.17 0.799
1.10 0.078 4 0.008 4.18 5.617
1.11 0.004 4.01 0.041 4.19 1.583
1.12 9.26 4.02 0.011 4.20 0.722
1.13 0.226 4.03 0.011 4.21 3.48
1.14 0.81 4.04 0.046 4.22 1.381
1.15 0.001 4.05 0.011 4.23 0.017
1.16 0.382 4.06 0.012 4.24 0.056
1.17 0.651 4.07 0.016 4.25 0.122 Example IC50 (μΜ) Example IC50 (μΜ) Example IC50 (μΜ)
4.26 0.051 8.05 0.149 15.04 2.019
4.27 0.004 8.06 0.192 15.05 0.015
4.28 0.123 8.07 1.845 15.06 0.012
4.29 0.643 9 0.709 15.07 0.021
4.30 0.05 9.01 0.038 15.08 0.977
4.31 1.817 9.02 1.6 15.09 0.042
4.32 3.854 9.03 0.042 15.10 0.034
4.33 0.036 9.04 0.713 15.11 0.013
4.34 0.019 9.05 0.406 15.12 0.006
4.35 0.98 9.06 0.247 15.13 0.114
4.36 0.009 9.07 0.074 15.14 0.062
5 0.248 9.08 3.402 15.15 0.156
6 10.42 9.09 0.162 15.16 5.786
6.01 0.077 10A 0.036 15.17 3.953
6.02 2.809 10B 0.118 15.18 0.02
6.03 0.531 11A 0.022 15.19 0.009
6.04 0.282 11B 0.009 15.20 0.049
6.05 0.179 12A 0.011 15.21 0.005
6.06 0.008 12B 0.005 15.22 0.053
7 0.022 13 0.057 15.23 0.032
8 0.108 14 0.926 15.24 0.01
8.01 0.002 15 0.026 15.25 0.044
8.02 0.186 15.01 1.615 15.26 0.008
8.03 0.911 15.02 0.096 15.27 0.002
8.04 0.192 15.03 0.362 15.28 4.42 Example IC50 (μΜ) Example IC50 (μΜ) Example IC50 (μΜ)
15.29 0.034 15.54 0.28 15.79 0.135
15.30 0.014 15.55 0.478 15.80 0.06
15.31 0.038 15.56 0.655 15.81 0.019
15.32 0.019 15.57 0.494 15.82 1.995
15.33 0.328 15.58 0.005 15.83 6.859
15.34 0.003 15.59 0.011 15.84 0.012
15.35 0.031 15.60 1.037 16 0.015
15.36 0.003 15.61 0.054 17 0.004
15.37 0.093 15.62 0.068 17.01 0.085
15.38 0.05 15.63 0.012 17.02 0.101
15.39 0.005 15.64 0.005 17.03 0.016
15.40 0.005 15.65 0.003 17.04 0.008
15.41 0.017 15.66 0.013 17.05 0.006
15.42 0.006 15.67 0.014 17.06 0.01
15.43 0.13 15.68 0.171 17.07 0.043
15.44 0.006 15.69 0.008 17.08 0.016
15.45 0.039 15.70 0.007 17.09 0.058
15.46 0.018 15.71 1.365 17.10 0.021
15.47 0.096 15.72 0.015 17.11 0.028
15.48 0.006 15.73 0.116 17.12 0.032
15.49 0.016 15.74 0.012 17.13 0.031
15.50 0.006 15.75 0.005 17.14 0.464
15.51 0.006 15.76 0.013 18 6.735
15.52 0.003 15.77 0.008 1.23 0.058
15.53 0.007 15.78 0.009 1.24 0.013 Example IC50 (μΜ) Example IC50 (μΜ) Example IC50 (μΜ)
1.25 0.114 1.50 0.017 4.48 0.003
1.26 0.009 1.51 0.041 4.49 0.003
1.27 0.008 1.52 0.016 4.50 0.006
1.28 0.006 1.53 0.052 4.51 0.002
1.29 0.008 1.54 0.022 4.52 0.01
1.30 0.02 1.55 0.014 4.53 0.005
1.31 0.021 1.56 0.2 4.54 0.014
1.32 0.04 1.57 0.025 4.55 0.005
1.33 0.021 1.58 0.057 4.56 0.009
1.34 0.013 1.59 0.006 4.57 0.011
1.35 0.01 1.60 0.012 4.58 0.0052
1.36 7.455 1.61 0.021 4.59 0.009
1.37 0.025 2.03 0.005 4.60 0.005
1.38 0.01 2.04 0.008 4.61 0.239
1.39 0.007 4.37 0.132 4.62 0.012
1.40 0.007 4.38 0.024 4.63 0.037
1.41 0.002 4.39 0.006 4.64 0.019
1.42 0.007 4.40 0.016 4.65 0.014
1.43 0.014 4.41 0.009 4.66 0.04
1.44 0.003 4.42 0.024 4.67 0.008
1.45 0.007 4.43 0.004 6.07 0.207
1.46 0.002 4.44 0.006 9.10 0.007
1.47 0.002 4.45 0.007 15.85 0.029
1.48 0.0075 4.46 0.005 15.86 0.019
1.49 0.218 4.47 0.004 15.87 0.103 Example IC50 (μΜ) Example IC50 (μΜ) Example IC50 (μΜ)
15.88 0.027 19.04 1.708 19.26 0.005
15.89 0.007 19.05 0.005 19.27 0.006
15.90 0.007 19.06 0.25 19.28 0.002
15.91 0.012 19.07 0.024 19.29 0.001
15.92 0.249 19.08 0.036 19.30 0.005
15.93 0.921 19.09 0.01 19.31 0.002
15.94 1.018 19.10 0.006 19.32 0.002
15.95 1.896 19.11 0.008 19.33 0.006
15.96 0.074 19.12 0.01 19.34 0.003
15.97 0.009 19.13 0.01 19.35 0.002
15.98 0.013 19.14 0.273 19.36 0.005
15.99 0.012 19.15 0.02 19.37 0.015
17.15 0.047 19.16 0.031 19.38 0.005
17.16 0.309 19.17 0.01 19.39 0.007
17.17 0.004 19.18 0.011 19.40 0.1
17.18 0.014 19.19 0.005 19.41 0.685
17.19 0.012 19.20 0.459 19.42 0.01
17.20 0.002 19.21 0.003 19.43 0.014
19 0.007 19.22 0.002 20 0.029
19.01 0.012 19.23 0.025 20.01 0.305
19.02 0.007 19.24 0.007
19.03 0.008 19.25 0.015
Compounds of formula (I) and their pharmaceutically acceptable salts or esters thereof as described herein have IC50 values between 0.00001 μΜ and 1000 μΜ, particular compounds have IC50 values between 0.0005 μΜ and 500 μΜ, further particular compounds have IC50 values between 0.0005 μΜ and 50 μΜ, more particular compounds have IC50 values between 0.0005 μΜ and 5 μΜ. These results have been obtained by using the enzymatic assay described above. The compounds of formula (I) and their pharmaceutically acceptable salts can be used as medicaments (e.g. in the form of pharmaceutical preparations). The pharmaceutical preparations can be administered internally, such as orally (e.g. in the form of tablets, coated tablets, dragees, hard and soft gelatin capsules, solutions, emulsions or suspensions), nasally (e.g. in the form of nasal sprays) or rectally (e.g. in the form of suppositories). However, the administration can also be effected parenterally, such as intramuscularly or intravenously (e.g. in the form of injection solutions).
The compounds of formula (I) and their pharmaceutically acceptable salts can be processed with pharmaceutically inert, inorganic or organic adjuvants for the production of tablets, coated tablets, dragees and hard gelatin capsules. Lactose, corn starch or derivatives thereof, talc, stearic acid or its salts etc. can be used, for example, as such adjuvants for tablets, dragees and hard gelatin capsules.
Suitable adjuvants for soft gelatin capsules, are, for example, vegetable oils, waxes, fats, semi-solid substances and liquid polyols, etc.
Suitable adjuvants for the production of solutions and syrups are, for example, water, polyols, saccharose, invert sugar, glucose, etc.
Suitable adjuvants for injection solutions are, for example, water, alcohols, polyols, glycerol, vegetable oils, etc.
Suitable adjuvants for suppositories are, for example, natural or hardened oils, waxes, fats, semi-solid or liquid polyols, etc. Moreover, the pharmaceutical preparations can contain preservatives, solubilizers, viscosity-increasing substances, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffers, masking agents or antioxidants. They can also contain still other therapeutically valuable substances. The dosage can vary in wide limits and will, of course, be fitted to the individual requirements in each particular case. In general, in the case of oral administration a daily dosage of about 0.1 mg to 20 mg per kg body weight, preferably about 0.5 mg to 4 mg per kg body weight (e.g. about 300 mg per person), divided into preferably 1-3 individual doses, which can consist, for example, of the same amounts, should be appropriate. It will, however, be clear that the upper limit given herein can be exceeded when this is shown to be indicated.
The invention is illustrated hereinafter by Examples, which have no limiting character.
In case the preparative examples are obtained as a mixture of enantiomers, the pure enantiomers can be obtained by methods described herein or by methods known to those skilled in the art, such as e.g. chiral chromatography or crystallization.
Examples
All examples and intermediates were prepared under nitrogen atmosphere if not specified otherwise.
Abbreviations: aq. = aqueous; CAS-R = Chemical Abstracts Service Registry Number; e.r. = enantiomeric ratio; HPLC = high performance liquid chromatography; MS = mass spectrum; sat. = saturated
Example 1
(E)-l-[(3aS,8aR)-2-(4,5,6,7-Tetrahydro-lH-benzotriazole-5-carbonyl)-octahydro- pyrrolo[3,4-d]azepin-6-yl]-3-(4-trifluoromethoxy-phenyl)-prop-2-en-l-one
Figure imgf000086_0001
To a solution of (E)-l-((3aR,8aS)-octahydropyrrolo[3,4-d]azepin-6(7H)-yl)-3-(4- (trifluoromethoxy)phenyl)prop-2-en-l-one hydrochloride (intermediate 5; 40 mg, 102 μιηοΐ) in N,N-dimethylformamide (2 mL) were added N-methylmorpho line (51.8 mg, 512 μιηοΐ), 4,5,6,7- tetrahydro-lH-benzo[d][l,2,3]triazole-5-carboxylic acid (CAS-RN 33062-47-4; 17.1 mg, 102 μιηοΐ) and 0-(7-azabenzotriazol-l-yl)-N,N,N',N'-tetramethyluronium hexafluoro -phosphate (42.8 mg, 113 μιηοΐ) at room temperature, then after 16 h the reaction mixture was partitioned between ethyl acetate and sat. aq. ammonium chloride solution. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and evaporated. Chromatography (silica gel; gradient dichloromethane to dichloromethane/methanol/25% aq. ammonia solution 90: 10:0.25) produced the title compound (41 mg, 80%). Colourless gum, MS: 504.7 (M+H)+.
The following examples were prepared according to example 1, replacing (E)-l-((3aR,8aS)- octahydropyrrolo[3,4-d]azepin-6(7H)-yl)-3-(4-(trifluoromethoxy)phenyl)prop-2-en-l-one hydrochloride and 4,5,6,7-tetrahydro-lH-benzo[d][l,2,3]triazole-5-carboxylic acid by the appropriate amine and carboxylic acid reagents, respectively.
Carboxylic MS,
No. Systematic Name Amine
acid m/e
Figure imgf000087_0001
Figure imgf000088_0001
Figure imgf000089_0001
Figure imgf000090_0001
Figure imgf000091_0001
Figure imgf000092_0001
Figure imgf000093_0001
Figure imgf000094_0001
Figure imgf000095_0001
Figure imgf000096_0001
Figure imgf000097_0001
Figure imgf000098_0001
Figure imgf000099_0001
Figure imgf000100_0001
Figure imgf000101_0001
Figure imgf000102_0001
Figure imgf000103_0001
Figure imgf000104_0001
Figure imgf000105_0001
Figure imgf000106_0001
Figure imgf000107_0001
Example 2 trans-3,5-Dichlorobenzyl 2-(2-oxo-2,3-dihydrobenzo [d] oxazole-6-carbonyl)hexahyd pyrrolo[3,4-c]pyridine-5(6H)-carboxylate
Figure imgf000107_0002
To a solution of trans-3,5-dichlorobenzyl hexahydro-lH-pyrrolo[3,4-c]pyridine-5(6H)- carboxylate hydrochloride (intermediate 1.1; 50 mg, 137 μιηοΐ) in Ν,Ν-dimethylformamide (1 mL) were added 4-methylmorpholine (69.1 mg, 684 μιηοΐ), 4-amino-3-hydroxybenzoic acid (20.9 mg, 137 μιηοΐ) and 0-(7-azabenzotriazol-l-yl)-N,N,N',N'-tetramethyluronium hexafiuoro- phosphate (62.4 mg, 164 μιηοΐ) at room temperature, then after 18 h Ι,Γ-carbonyldiimidazole (50.3 mg, 301 μιηοΐ) was added. After 1 h, the reaction mixture was partitioned between ethyl acetate and 1 M aq. hydrochloric acid solution. The organic layer was washed with brine, dried over magnesium sulfate, filtered and evaporated in vacuo. Chromatography (silica gel, gradient dichloromethane dichloromethane/methanol/25% aq. ammonia solution 90: 10:0.25) produced the title compound (35 mg, 52%). Light yellow gum, MS: 490.5 (M+H)+. The following examples were prepared according to example 2, replacing trans-3,5- dichlorobenzyl hexahydro-lH-pyrrolo[3,4-c]pyridine-5(6H)-carboxylate hydrochloride by the appropriate starting material.
MS,
Ex. Systematic Name Starting material
m/e
(3aR,6aS)-3,5-dichlorobenzyl 5-(2-oxo-2,3- (3aR,6aS)-3,5- dihydrobenzo [d]oxazole-6- dichlorobenzyl
carbonyl)hexahydropyrrolo [3 ,4-c]pyrro le-2( 1 H)- hexahydropyrrolo [3 ,4-
476.2
2.01 carboxylate c]pyrrole-2(lH)-
0 (M+H)+ carboxylate
hydrochloride
0 (intermediate 1)
(E)-l-((3aR,8aS)-
6-{(3aS,8aR)-6-[(E)-3-(4-trifiuoromethoxy- octahydropyrrolo [3 ,4- phenyl)-acryloyl]-octahydro-pyrrolo [3 ,4- d]azepin-6(7H)-yl)-3-(4- d]azepine-2-carbonyl}-3H-benzooxazol-2-one 514.6
2.02 o (trifluoromethoxy)- (M-H) phenyl)prop-2-en- 1 -one hydrochloride
o
(intermediate 5)
6-[(3aR,6aR)-2-[3-[4- l-((3aS,6aS)-
(trifluoromethoxy)phenyl]propanoyl]- hexahydropyrrolo [3 ,4- l,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrole-5- c]pyrrol-2(lH)-yl)-3-(4-
490.4
2.03 carbonyl]-3H- 1 ,3-benzoxazol-2-one (trifluoromethoxy)-
(M+H)+ o phenyl)propan- 1 -one
dihydro chloride
o (intermediate 5.5)
Figure imgf000109_0001
Example 3
(3aR,5s,6aS)-3,5-Dichlorobenzyl 5-(2-oxo-2,3-dihydrobenzo [d] oxazol-6- yloxy)hexahydrocyclopenta[c]pyrrole-2(lH)-carboxylate
Figure imgf000109_0002
A mixture of 4-((3aR,5s,6aS)-2-((3,5-dichlorobenzyloxy)carbonyl)octahydrocyclo- penta[c]pyrrol-5-yloxy)-2-hydroxybenzoic acid (intermediate 12.1; 63 mg, 135 μιηοΐ), triethylamine (13.7 mg, 135 μιηοΐ) and diphenylphosphoryl azide (37.2 mg, 135 μιηοΐ) in toluene (2 mL) was heated at 110°C for 20 h. After evaporation of the solvent, the residue was purified by chromatography (silica gel; heptane - ethyl acetate gradient) to produce the title compound (19 mg, 30%). White solid, MS: 463.2 (M+H)+.
Example 3.01
(3aR,5r,6aS)-3,5-Dichlorobenzyl 5-(2-oxo-2,3-dihydrobenzo [d] oxazol-6- yloxy)hexahydrocyclopenta[c]pyrrole-2(lH)-carboxylate
Figure imgf000109_0003
The title compound was produced in analogy to example 3 from 4-((3aR,5r,6aS)-2-((3,5- dichlorobenzyloxy)carbonyl)octahydrocyclopenta[c]pyrrol-5-yloxy)-2-hydroxybenzoic acid (intermediate 12). White solid, MS: 463.2 (M+H)+. Example 4
(3aS,6aS)-3,5-Dichlorobenzyl 5-(lH-benzo[d] [l,2,3]triazole-5-carbonyl)hexahydro- pyrrolo[3,4-c]pyrrole-2(lH)-carboxylate
Figure imgf000110_0001
To a solution of (3,5-dichlorophenyl)methanol (21.4 mg, 121 μηιοΐ) in acetonitrile (5 mL) was added N,N'-carbonyldiimidazole (20.6 mg, 127 μmol) at room temperature, then after 3 h triethylamine (61.3 mg, 606 μιηοΐ) and (lH-benzo[d][l,2,3]triazol-5-yl)((3aR,6aR)- hexahydropyrrolo[3,4-c]pyrrol-2(lH)-yl)methanone dihydro chloride (intermediate 2.4; 40 mg, 121 μιηοΐ) were added and the reaction mixture was heated at reflux. After 16 h the reaction mixture was partitioned between ethyl acetate and sat. aq. ammonium chloride, the organic layer was washed with sat. aq. sodium hydrogen carbonate solution and brine, dried over magnesium sulfate, filtered, and evaporated. Chromatography (silica gel; gradient dichloromethane to dichloromethane/methanol/25% aq. ammonia solution 90: 10:0.25) produced the title compound (38 mg, 68%). Light yellow foam, MS: 460.4 (M+H)+.
The following compounds were produced in analogy to example 4, replacing (1H- benzo[d][l,2,3]triazol-5-yl)((3aR,6aR)-hexahydropyrrolo[3,4-c]pyrrol-2(lH)-yl)methanone dihydro chloride and (3,5-dichlorophenyl)methanol by the appropriate amine and alcohol precursors, respectively.
No. Systematic Name Amine Alcohol MS, m/e
Figure imgf000111_0001
Figure imgf000112_0001
Figure imgf000113_0001
Figure imgf000114_0001
Figure imgf000115_0001
Figure imgf000116_0001
Figure imgf000117_0001
Figure imgf000118_0001
Figure imgf000119_0001
Figure imgf000120_0001
Figure imgf000121_0001
Figure imgf000122_0001
Figure imgf000123_0001
Figure imgf000124_0001
Figure imgf000125_0001
Figure imgf000126_0001
Figure imgf000127_0001
Figure imgf000128_0001
Systematic Name Amine Alcohol MS, m/e
(3aR,6aR)-5-(lH-benzotriazole-5- (1H- carbonyl)-hexahydro-pyrrolo [3 ,4- benzo[d] [ 1 ,2,3]triazol- c]pyrrole-2-carboxylic acid 4- 5-yl)((3aS,6aS)- (4-(trifluoro- trifluoromethoxy-benzyl ester hexahydropyrrolo [3 ,4- methoxy)- 476.4 c]pyrrol-2(lH)- phenyl)- (M+H)+ yl)methanone methanol
dihydro chloride
Figure imgf000129_0001
(intermediate 8)
(3 aS ,6aS)-5 -( 1 H-benzotriazo le-5 - (1H- carbonyl)-hexahydro-pyrrolo [3 ,4- benzo[d] [ 1 ,2,3]triazol-
(2-fluoro-4- c]pyrrole-2-carboxylic acid 2-fluoro- 5-yl)((3aR,6aR)-
(trifluoro- 4-trifluoromethyl-benzyl ester hexahydropyrrolo [3 ,4- 478.4 methyl)- c]pyrrol-2(lH)- (M+H)+ phenyl)- yl)methanone
methanol
dihydro chloride
Figure imgf000129_0002
(intermediate 2.4)
(3 aS ,6aS)-5 -( 1 H-benzotriazo le-5 - (1H- carbonyl)-hexahydro-pyrrolo [3 ,4- benzo[d] [ 1 ,2,3]triazol- c]pyrrole-2-carboxylic acid 4- 5-yl)((3aR,6aR)- (4-(trifluoro- trifluoromethyl-benzyl ester hexahydropyrrolo [3 ,4- methyl)- 460.5 c]pyrrol-2(lH)- phenyl)- (M+H)+ yl)methanone methanol
dihydro chloride
Figure imgf000129_0003
(intermediate 2.4)
Figure imgf000130_0001
Figure imgf000131_0001
Figure imgf000132_0001
Figure imgf000133_0001
Example 5
(3aR,5r,6aS)-3,5-Dichlorobenzyl 5-(2-oxo-2,3-dihydrobenzo [d] oxazol-6- ylamino)hexahydrocyclopenta[c]pyrrole-2(lH)-carboxylate
Figure imgf000133_0002
Sodium triacetoxyborohydride (121 mg, 556 μιηοΐ,) was added at room temperature to a solution of (3aR,6aS)-3,5-dichlorobenzyl 5-oxohexahydrocyclopenta[c]pyrrole-2(lH)-carboxylate (intermediate 13; 128 mg, 371 μιηοΐ), 6-aminobenzo[d]oxazol-2(3H)-one (CAS-RN 22876-17-1; 57.3 mg, 371 μιηοΐ) and acetic acid (134 mg, 2.22 mmol) in 1,2-dichloroethane (2.5 mL), then after 16 h another portion of sodium triacetoxyborohydride (39.3 mg, 185 μιηοΐ) was added. After another 6 h the reaction mixture was partitioned between ethyl acetate and sat. aq. sodium hydrogen carbonate solution. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and evaporated. Chromatography (silica gel; dichloromethane to
dichloromethane/methanol/25% aq. ammonia solution 95:5:0.25), followed by HPLC
chromatography (Reprosil Chiral-NR, heptane/ethanol 3:2) produced the title compound (70 mg, 41%). White solid, MS: 462.2 (M+H)+.
Example 6 (3aR,6aS)-3,5-Dichlorobenzyl 5-((lH-benzo[d]imidazol-5-yl)methyl)hexahydropyrrolo[3,4- c]pyrrole-2(lH)-carboxylate
Figure imgf000134_0001
To a white suspension of (3aR,6aS)-3,5-dichlorobenzyl hexahydropyrrolo[3,4-c]pyrrole-2(lH)- carboxylate hydrochloride (intermediate 1; 35 mg, 99.5 μιηοΐ) and lH-benzo[d]imidazole-5- carbaldehyde (15.0 mg, 99.5 μιηοΐ) in tetrahydrofuran (2 mL) were added sodium
triacetoxyborohydride (31.6 mg, 149 μιηοΐ) and acetic acid (9.0 mg, 150 μιηοΐ), then after 3 h the reaction mixture was partitioned between ethyl acetate and sat. aq. sodium hydrogen carbonate solution. The organic layer was washed with brine, dried over magnesium sulfate, filtered and evaporated. Chromatography (silica gel; gradient dichloromethane to
dichloromethane/methanol/25% aq. ammonia solution 90: 10:0.25) produced the title compound (42 mg, 95%). White foam, MS: 445.3 (M+H)+.
The following compounds were produced in analogy to example 6, replacing (3aR,6aS)-3,5- dichlorobenzyl hexahydropyrrolo[3,4-c]pyrrole-2(lH)-carboxylate hydrochloride and 1H- benzo[d]imidazole-5-carbaldehyde by the appropriate amine and aldehyde reagents, respectively.
Figure imgf000134_0002
Figure imgf000135_0001
Figure imgf000136_0001
Example 7 (3aR,6aS)-3,5-Dichlorobenzyl 5-(2-oxo-2,3-dihydrobenzo[d]oxazol-6-ylsulfonyl)hexa- hydropyrrolo[3,4-c]pyrrole-2(lH)-carboxylate
Figure imgf000137_0001
To a suspension of (3aR,6aS)-3,5-dichlorobenzyl hexahydropyrrolo[3,4-c]pyrrole-2(lH)- carboxylate hydrochloride (intermediate 1; 40 mg, 114 μιηοΐ) and pyridine (45.0 mg, 569 μιηοΐ) in acetone (2 mL) was added 2-oxo-2,3-dihydrobenzo[d]oxazole-6-sulfonyl chloride (25.2 mg, 108 μιηοΐ) at room temperature, then after 40 h the reaction mixture was partitioned between sat. aq. sodium hydro gencarbonate solution and ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and evaporated. The residue was dissolved in ethyl acetate, then after 40 min the suspension formed was treated with ethyl acetate/heptane 1 : 1 and the precipitate was collected by filtration to afford the title compound (24 mg, 41%). White solid, MS: 512.2 (M+H)+.
Example 8
(3aR,6aS)-3,5-Dichlorobenzyl 5-(4,5,6,7-tetrahydro-lH-[l,2,3]triazolo[4,5-c]pyridine-5- carbonyl)hexahydropyrrolo[3,4-c]pyrrole-2(lH)-carboxylate
Figure imgf000137_0002
To a suspension of 4,5,6,7-tetrahydro-lH-[l,2,3]triazolo[4,5-c]pyridine (CAS-R 706757-05-3; 52.5 mg, 423 μιηοΐ) in dichloromethane (8 mL) was added a solution of (3aR,6aS)-3,5- dichlorobenzyl 5-(chlorocarbonyl)hexahydropyrrolo[3,4-c]pyrrole-2(lH)-carboxylate
(intermediate 9; 168 mg, 423 μιηοΐ) in dichloromethane (2 mL) dropwise at room temperature, then after 1 h, Ν,Ν-dimethylformamide (1 mL) was added. After 96 h, the reaction mixture was washed with sat. aq. ammonium chloride solution and brine, dried over magnesium sulfate, filtered, and evaporated. Chromatography (silica gel; gradient dichloromethane to
dichloromethane/methanol/25% aq. ammonia solution 90: 10:0.25) produced the title compound (136 mg, 69%). Colourless oil, MS: 465.5 (M+H)+. The following examples were produced in analogy to example 8, replacing (3aR,6aS)-3,5- dichlorobenzyl 5-(chlorocarbonyl)hexahydropyrrolo[3,4-c]pyrrole-2(lH)-carboxylate by (3aR,8aS)-6-((E)-3-(4-(trifiuoromethoxy)phenyl)acryloyl)octahydropyrrolo[3,4-d]azepine- 2(lH)-carbonyl chloride (intermediate 9.1) and 4,5,6,7-tetrahydro-lH-[l,2,3]triazolo[4,5- c]pyridine by the appropriate amine precursor.
Figure imgf000138_0001
Figure imgf000139_0001
Figure imgf000140_0001
Example 9
(3aR,8aS)-N-((lH-l,2,3-Triazol-5-yl)methyl)-6-((E)-3-(4-(trifluoromethoxy)phenyl)- acryloyl)octahydropyrrolo [3,4-d] azepine-2(lH)-carboxamide
Figure imgf000140_0002
A solution of bis(trichloromethyl)-carbonate (73.7 mg, 248 μηιοΐ) in ethyl acetate (10 mL) was added dropwise at 0°C over a period of 5 minutes to a solution of (E)-l-((3aR,8aS)- octahydropyrrolo[3,4-d]azepin-6(7H)-yl)-3-(4-(trifluoromethoxy)phenyl)prop-2-en-l-one (intermediate 5; 176 mg, 497 μιηοΐ) in tetrahydrofuran (5 mL). The ice bath was removed, then after 30 min the reaction mixture was heated at reflux for 2 h. After concentration under vacuum, the residue was dissolved in tetrahydrofuran (7 mL), then after addition of (lH-l,2,3-triazol-4- yl)methanamine hydrochloride (66.8 mg, 497 μιηοΐ) and triethylamine (251 mg, 2.48 mmol) the reaction mixture was stirred at room temperature for 17 hours andthen partitioned between sat. aq. sodium hydrogen carbonate solution and ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered, and evaporated. Chromatography (silica gel;
heptane/ethyl acetate 4: 1, then dichloromethane/methanol 95:5) afforded the title compound (68 mg, 28%). White solid, MS: 479.5 (M+H)+. The following examples were produced in analogy to example 8, replacing (E)-l-((3aR,8aS)- octahydropyrrolo[3,4-d]azepin-6(7H)-yl)-3-(4-(trifluoromethoxy)phenyl)prop-2-en-l-one by the appropriate starting material and (lH-l,2,3-triazol-4-yl)methanamine hydrochloride by the appropriate amine reagent.
Figure imgf000141_0001
Figure imgf000142_0001
Figure imgf000143_0001
Figure imgf000144_0001
Examples 10A and 10B
(3aR,7aS)-2-(lH-Benzotriazole-5-carbonyl)-octahydro-pyrrolo[3,4-c]pyridine-5-carboxylic acid 3,5-dichloro-benzyl ester and (3aS,7aR)-2-(lH-benzotriazole-5-carbonyl)-octahydro- pyrrolo[3,4-c]pyridine-5-carboxylic acid 3,5-dichloro-benzyl ester
H
Figure imgf000144_0002
and
Racemic cis-3,5-dichlorobenzyl 2-(lH-benzo[d][l,2,3]triazole-5-carbonyl)hexahydro-lH- pyrrolo[3,4-c]pyridine-5(6H)-carboxylate (example 1.02; 616 mg, 1.30 mmol) was separated by preparative HPLC using a Reprosil Chiral-NR column as the stationary phase and heptane/ethanol 3:2 as the mobile phase. This produced the faster eluting enantiomer (example 10A; 227 mg, 37%; orange foam, MS: 474.5 (M+H)+), and the slower eluting enantiomer (example 10B; 211 mg, 34%; orange foam, MS: 474.5 (M+H)+).
The following examples were prepared in analogy to examples 10A and 10B by HPLC separation of their racemates:
Figure imgf000145_0002
Example 13
(E)-l- [trans-2-(lH-Benzotriazole-5-carbonyl)-octahydro-pyrrolo [3,4-c] pyridin-5-yl] -3-(3,5- dichloro-phenyl)-prop-2-en-l-one
H
Figure imgf000145_0001
A solution of trans-3,5-dichlorobenzyl 2-(lH-benzo[d][l,2,3]triazole-5-carbonyl)hexahydro-lH- pyrrolo[3,4-c]pyridine-5(6H)-carboxylate (example 1.08; 105 mg, 221 μιηοΐ) in ethanol (2 mL) was stirred for 72 h under a hydrogen atmosphere (1 bar) in the presence of palladium (10% on carbon, 100 mg, 94 μιηοΐ), then insoluble material was removed by filtration through
diatomaceous earth. The filtrate was evaporated, taken up in hydrochloric acid solution (5-6 M in 2-propanol, 1 mL), then after 1 h concentrated in vacuo and the residue was triturated in ethyl acetate to produce an off-white solid (32 mg). This material was dissolved in N,N- dimethylformamide (1 mL), then 4-methylmorpholine (44.8 mg, 443 μιηοΐ), 3,5- dichlorocinnamic acid (19.2 mg, 88.5 μιηοΐ) and 0-(7-azabenzotriazol-l-yl)-N,N,N',N'- tetramethyluronium hexafluoro -phosphate (50.5 mg, 133 μιηοΐ) were added at room temperature, then after 18 h the reaction mixture was partitioned between sat. aq. ammonium chloride solution and ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and evaporated. Chromatography (silica gel, gradient dichlormethane to
dichlormethane/methanol/25% aq. ammonia solution 90: 10:0.25) produced the title compound (9 mg, 9%). Colourless gum, MS: 470.5 (M+H)+.
Example 14
(lH-Benzotriazol-5-yl)-{trans-2-[5-(4-chloro-phenyl)-[l,3,4]oxadiazol-2-yl]-octahydro- pyrrolo [3,4-c] pyridin-5-yl}-methanone
Figure imgf000146_0001
To a solution of 5-(4-chlorophenyl)-l,3,4-oxadiazol-2(3H)-one (CAS-R 1711-61-1; 30 mg, 153 μιηοΐ) and N,N-diisopropylethylamine (98.6 mg, 763 μιηοΐ) in N,N-dimethylformamide (3.00 mL) was added (lH-benzotriazol-5-yl)-trans-octahydro-pyrrolo[3,4-c]pyridin-5-yl- methanone hydrochloride (intermediate 2.1; 51.7 mg, 168 μιηοΐ) at room temperature, then after 10 min benzotriazol-l-yl-oxy-tris-(dimethylamino)-phosphonium hexafluorophosphate (75.8 mg, 168 μιηοΐ) was added. After 16 h the reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed with sat. aq. ammonium chloride solution and brine, dried over magnesium sulfate, filtered, and evaporated. Chromatography (silica gel; gradient dichloromethane to dichloromethane/methanol/25% aq. ammonia solution 90: 10:0.25) produced the title compound (42 mg, 61%). White solid, MS: 450.4 (M+H)+. Example 15 (E)-l-((3aR,6aS)-5-(lH-Benzo[d] [l,2,3]triazole-5-carbonyl)hexahydropyrrolo[3,4-c]pyrrol-
2(lH)-yl)-3-(4-(trifluoromethoxy)phenyl)prop-2-en-l-one
Figure imgf000147_0001
To a solution of (lH-benzo[d][l,2,3]triazol-5-yl)((3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol- 2(lH)-yl)methanone hydrochloride (intermediate 2.2; 30 mg, 102 μιηοΐ), 4-methylmorpholine (51.6 mg, 511 μιηοΐ) and (E)-3-(4-(trifiuoromethoxy)phenyl)acrylic acid (23.7 mg, 102 μιηοΐ) in N,N-dimethylformamide (1.5 mL) was added 0-(7-azabenzotriazol-l-yl)-N,N,N',N'- tetramethyluronium hexafiuoro -phosphate (38.8 mg, 102 μιηοΐ) at 0°C, then the reaction mixture was allowed to reach room temperature over a period of 16 h. After partitioning between ethyl acetate and sat. aq. sodium hydrogen carbonate solution the organic layer was washed with water and brine, dried over magnesium sulfate, filtered, and evaporated. Chromatography (silica gel; gradient dichloromethane to dichloromethane/methanol/25% aq. ammonia solution 90: 10:0.25) produced the title compound (38 mg, 79%). White foam, MS: 472.4 (M+H)+.
The following compounds were produced in analogy to example 15, replacing (1H- benzo[d][l,2,3]triazol-5-yl)((3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol-2(lH)-yl)methanone hydrochloride and (E)-3-(4-(trifluoromethoxy)phenyl)acrylic acid by the appropriate amine and carboxylic acid, respectively.
Carboxylic MS,
Ex. Systematic Name Amine
acid m/e
Figure imgf000148_0001
Figure imgf000149_0001
Figure imgf000150_0001
Figure imgf000151_0001
Figure imgf000152_0001
Figure imgf000153_0001
Figure imgf000154_0001
Figure imgf000155_0001
Figure imgf000156_0001
Figure imgf000157_0001
Figure imgf000158_0001
Figure imgf000159_0001
Figure imgf000160_0001
Figure imgf000161_0001
Figure imgf000162_0001
Figure imgf000163_0001
Figure imgf000164_0001
Figure imgf000165_0001
Figure imgf000166_0001
Figure imgf000167_0001
Figure imgf000168_0001
Figure imgf000169_0001
Figure imgf000170_0001
Figure imgf000171_0001
Figure imgf000172_0001
Figure imgf000173_0001
Figure imgf000174_0001
Figure imgf000175_0001
Figure imgf000176_0001
Figure imgf000177_0001
Figure imgf000178_0001
Figure imgf000179_0001
Figure imgf000180_0001
Figure imgf000181_0001
Example 16
(E)-l-((3aR,8aS)-2-(lH-benzo[d] [l,2,3]triazole-5-carbonyl)octahydropyrrolo[3,4-d]azepin- -yl)-3-(4-(trifluoromethylsulfinyl)phenyl)prop-2-en-l-one
Figure imgf000181_0002
To solution of (E)-l-((3aR,8aS)-2-(lH-benzo[d][l,2,3]triazole-5-carbonyl)octahydropyrrolo[3,4- d]azepin-6(7H)-yl)-3-(4-(trifluoromethylthio)phenyl)prop-2-en-l-one (example 15.69; 25 mg, 48.5 μιηοΐ) in acetic acid (1 mL) was added 35% aq. hydrogen peroxide solution (9.43 mg, 97.0 μιηοΐ). The reaction mixture was heated at 95°C, then after 3 h another portion of 35% aq.
hydrogen peroxide solution (18.9 mg, 194 μιηοΐ) was added. After another 15 h the reaction mixture was partitioned between ethyl acetate and sat. aq. sodium hydrogencarbonate solution. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and evaporated. Chromatography (silica gel; gradient dichloromethane to dichloromethane/methanol/25% aq. ammonia solution 90: 10:0.25) produced the title compound (11 mg, 43%). White foam, MS: 532.4 (M+H)+.
Example 17 l-((3aR,8aS)-2-(lH-Benzo[d] [l,2,3]triazole-5-carbonyl)octahydropyrrolo[3,4-d]azepin-
6(7H)-yl)-3-(3-fluoro-4-(trifluoromethoxy)phenyl)propan-l-one
Figure imgf000182_0001
A solution of (E)-l-((3aR,8aS)-2-(lH-benzo[d][l,2,3]triazole-5-carbonyl)octahydropyrrolo[3,4- d]azepin-6(7H)-yl)-3-(3-fluoro-4-(trifluoromethoxy)phenyl)prop-2-en-l-one (example 1.15; 63 mg, 122 μιηοΐ) in methanol (4 mL) was stirred at room temperature under a hydrogen
atmosphere (1 bar) in the presence of palladium (10% on activated charcoal, 39 mg, 0.37 mmol), then after 18 h insoluble material was removed by filtration through diatomaceous earth. The filtrate was evaporated and purified by chromatography (silica gel; heptane - ethyl acetate gradient) to produce the title compound (48 mg, 74%). White foam, MS: 520.7 (M+H)+.
The following examples were produced in analogy to example 17, replacing of (E)-l-((3aR,8aS)- 2-(lH-benzo[d][l,2,3]triazole-5-carbonyl)octahydropyrrolo[3,4-d]azepin-6(7H)-yl)-3-(3-fluoro- 4-(trifluoromethoxy)phenyl)prop-2-en-l-one by the appropriate starting material.
Ex. Systematic Name Starting material MS
(3aR,8aS)-N-((lH-l,2,3-triazol-5-yl)methyl)-N- (3aR,8aS)-N-((lH-l,2,3- methyl-6-(3-(4-(trifluoromethoxy)phenyl)- triazo 1-5 -yl)methyl)-N- propanoyl)octahydropyrrolo [3 ,4-d]azepine- methyl-6-((E)-3-(4- 2(1 H)-carboxamide (trifluoromethoxy)phenyl)- 495.6
17.01
0 acryloy l)o ctahydro - (M+H)+ pyrrolo [3 ,4-d] azepine- 2(1 H)-carboxamide
0 (example 9.07)
Figure imgf000183_0001
Figure imgf000184_0001
Figure imgf000185_0001
Figure imgf000186_0001
Figure imgf000187_0001
Figure imgf000188_0001
Example 18
(E)-3-[4-(Trifluoro-methoxy)-phenyl]-l-[(3aS,8aR)-2-((S)-4,5,6,7-tetrahydro-lH- imidazo [4,5-c] pyridine-6-carbonyl)-octahydro-pyrrolo [3,4-d] azepin-6-yl] -prop-2-en-l-one hydrochloride
Figure imgf000188_0002
Step 1 : (SVDi-tert-butyl 6-((3aR,8aS -6-((E -3-(4-(trifluoromethoxy phenyl acryloyl - decahydropyrrolo[3,4-d]azepine-2-carbonyl)-6 ,7-dihydro-lH-imidazo[4,5-c]pyridine-l,5(4H)- dicarboxylate The title compound was produced in analogy to example 15 from (E)-l-((3aR,8aS)- octahydropyrrolo[3,4-d]azepin-6(7H)-yl)-3-(4-(trifluoromethoxy)phenyl)prop-2-en-l-one hydrochloride (intermediate 5) and (S)-l,5-bis(tert-butoxycarbonyl)-4,5,6,7-tetrahydro-lH- imidazo[4,5-c]pyridine-6-carboxylic acid (CAS-RN 175289-42-6). White foam, MS: 704.3 (M+H)+.
Step 2: (E -3-[4-(Trifluoro-methoxy -phenyll-l-[(3aS,8aR -2-((S -4,5,6J-tetrahvdro-lH- imidazo[4,5-c]pyridine-6-carbonyl)-octahydro-pyrrolo[3,4-d]azepin-6-yl]-prop-2-en-l-one hydrochloride
The title compound was produced in analogy to intermediate 1, step 2 from (S)-di-tert-butyl 6- ((3aR,8aS)-6-((E)-3-(4-(trifluoromethoxy)phenyl)acryloyl)decahydropyrrolo[3,4-d]azepine-2- carbonyl)-6,7-dihydro-lH-imidazo[4,5-c]pyridine-l,5(4H)-dicarboxylate. White solid, MS: 504.2 (M+H)+.
Example 19
1- [(3aS,6aS)-5-(lH-benzotriazole-5-carbonyl)-hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -2-(2- isopropyl-5-methyl-phenoxy)-ethanone To a suspension of (lH-benzo[d][l,2,3]triazol-5-yl)((3aR,6aR)-hexahydropyrrolo[3,4-c]pyrrol- 2(lH)-yl)methanone hydrochloride (intermediate 2.04; 25 mg, 85.1 μιηοΐ, Eq: 1.00), N- methylmorpholine (43.0 mg, 426 μmol) and 2-(2-isopropyl-5-methylphenoxy)acetic acid (17.7 mg, 85.1 μιηοΐ) in N,N-dimethylformamide (4 mL) was added 0-(7-azabenzotriazol-l-yl)- Ν,Ν,Ν',Ν'-tetramethyluronium hexafluoro -phosphate (32.4 mg, 85.1 μιηοΐ) at 0°C, then the reaction mixture was allowed to reach room temperature over a period of 16 h. After partitioning between ethyl acetate and sat. aq. sodium hydrogen carbonate solution the organic layer was washed with water and brine, dried over magnesium sulfate, filtered, and evaporated. Chromatography (silica gel; gradient dichloromethane to dichloromethane/methanol/25% aq. ammonia solution 90: 10:0.25) produced the title compound (37 mg, 97%). White foam, MS: 448.6 (M+H)+.
The following compounds were produced in analogy to example 19, replacing (1H- benzo[d][l,2,3]triazol-5-yl)((3aR,6aR)-hexahydropyrrolo[3,4-c]pyrrol-2(lH)-yl)methanone hydrochloride and 2-(2-isopropyl-5-methylphenoxy)acetic acid by the appropriate amine and carboxylic acid, respectively.
Figure imgf000190_0001
Figure imgf000191_0001
Figure imgf000192_0001
Figure imgf000193_0001
Figure imgf000194_0001
Figure imgf000195_0001
Figure imgf000196_0001
Figure imgf000197_0001
Figure imgf000198_0001
Figure imgf000199_0001
Figure imgf000200_0001
Figure imgf000201_0001
Figure imgf000202_0001
Figure imgf000203_0001
Figure imgf000204_0001
Figure imgf000205_0001
Figure imgf000206_0001
Example 20
(lH-Benzotriazol-5-yl)-{(3aS,6aS)-5-[4-(4-chloro-phenyl)-piperidine-l-carbonyl]- hexah dro-pyrrolo [3,4-c] pyrrol-2-yl}-methanone
Figure imgf000206_0002
To a white suspension of (lH-benzo[d][l,2,3]triazol-5-yl)((3aR,6aR)-hexahydropyrrolo[3,4- c]pyrrol-2(lH)-yl)methanone hydrochloride (intermediate 2.4; 40 mg, 136 μιηοΐ) and triethylamine (68.9 mg, 681 μιηοΐ) in dichloromethane (4 mL) was added a solution of 4-(4- chlorophenyl)piperidine-l-carbonyl chloride (intermediate 9.3; 44.9 mg, 163 μιηοΐ) in dichloromethane (2 mL) at room temperature, then after 19 the reaction mixture was partitioned between sat. aq. sodium hydrogencarbonate solution and dichloromethane. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and evaporated.
Chromatography (silica gel; graident dichloromethane to dichloromethane/methanol/25% aq. ammonia solution 90: 10:0.25) produced te title compound (50 mg, 77%). White foam, MS: 479.6 (M+H)+. The following example was produced in analogy to example 20, replacing
chlorophenyl)piperidine-l-carbonyl chloride by the appropriate reagent.
Figure imgf000207_0001
Intermediates
Intermediate 1
(3aR,6aS)-3,5-Dichlorobenzyl hexahydropyrrolo[3,4-c]pyrrole-2(lH)-carboxylate hydrochloride Step 1 : (3aR,6aS)-2-tert-Butyl 5-(3,5-dichlorobenzyl) tetrahydropyrrolo[3,4-c]pyrrole- 2,5(lH,3H -dicarboxylate
To a light brown solution of (3,5-dichlorophenyl)methanol (425 mg, 2.35 mmol) in
dichloromethane (7 mL) was added N,N'-carbonyldiimidazole (401 mg, 2.47 mmol). The solution was stirred at room temperature for 3 h, then (3aR,6aS)-tert-butyl
hexahydropyrrolo[3,4-c]pyrrole-2(lH)-carboxylate (CAS-RN 250275-15-1; 526 mg, 2.35 mmol) was added, then after 15 h the reaction mixture was partitioned between 1 M aq. hydrochloric acid solution and dichloromethane. The organic layer was washed with brine, dried over magnesium sulfate, filtered and evaporated to afford the title compound (972 mg, 99%). Light brown viscous oil, MS: 359.2 (M+H-isobutene)+. Step 2: (3aR,6aS)-3,5-Dichlorobenzyl hexahydropyrrolo[3,4-c]pyrrole-2(lH)-carboxylate hydrochloride
To a solution of (3aR,6aS)-2-tert-butyl 5-(3,5-dichlorobenzyl) tetrahydropyrrolo[3,4-c]pyrrole- 2,5(lH,3H)-dicarboxylate (962 mg, 2.32 mmol) in 2-propanol (4 mL) was added hydrochloric acid (5-6 M in 2-propanol) (11.6 mL, 57.9 mmol), then after 3 h the reaction mixture was evaporated. The residue was taken up in ethyl acetate and a few drops of ethanol, then the precipitate was collected by filtration to produce the title compound (738 mg, 91%). White solid, MS: 315.3 (M+H)+.
The following intermediates were prepared according to intermediate 1, replacing (3aR,6aS)- tert-butyl hexahydropyrrolo[3,4-c]pyrrole-2(lH)-carboxylate and (3,5-dichlorophenyl)methanol by the appropriate amine and alcohol, respectively.
No. Systematic Name Amine Alcohol MS, m/e trans-tert-butyl
(3aS,7aS)-3,5- hexahydro-lH- dichlorobenzyl hexahydro- pyrrolo[3,4- (3,5-dichloro- 329.4
1.1 1 H-pyrrolo [3 ,4-c]pyridine- c]pyridine-2(3H)- pheny l)methano 1 (M+H)+ 5(6H)-carboxylate
carboxylate (CAS- hydrochloride
RN 1251014-37-5) cis-tert-butyl
cis-3,5-dichlorobenzyl
hexahydro-lH- hexahydro-lH- pyrrolo[3,4- (3,5-dichloro- 329.4
1.2 pyrrolo [3 ,4-c]pyridine- c]pyridine-2(3H)- pheny l)methano 1 (M+H)+ 5(6H)-carboxylate
carboxylate
hydrochloride
(intermediate 14) Systematic Name Amine Alcohol MS, m/e cis-o ctahydro -
(3aR,8aS)-3,5- pyrrolo[3,4- dichlorobenzyl
d]azepine-2- (3,5-dichloro- 343.4 octahydropyrrolo [3 ,4- carboxylic acid tert- pheny l)methano 1 (M+H)+ d]azepine-6(7H)- butyl ester (CAS-RN
carboxylate hydrochloride
1251013-07-6) trans-tert-butyl
trans-o ctahydro - hexahydro-lH- pyrrolo [3 ,4-c]pyridine-5 - (4-(trifluoro- pyrrolo[3,4- 345.6 carboxylic acid 4- methoxy)phenyl)- c]pyridine-2(3H)- (M+H)+ trifluoromethoxy-benzyl methanol
carboxylate (CAS- ester hydrochloride
RN 1251014-37-5) trans-tert-butyl
trans-o ctahydro - hexahydro-lH- (3-chloro-5- pyrrolo [3 ,4-c]pyridine-5 - pyrrolo[3,4- (methylsulfonyl)- 373.6 carboxylic acid 3-chloro- c]pyridine-2(3H)- pheny l)methano 1 (M+H)+ 5 -methanesulfonyl-benzyl
carboxylate (CAS- (intermediate 17)
ester hydrochloride
RN 1251014-37-5) cis-o ctahydro -
(3aR,8aS)-4-(2,2,2- (4-(2,2,2- pyrrolo[3,4- trifluoroethoxy)benzyl trifluoroethoxy)- d]azepine-2- octahydropyrrolo [3 ,4- pheny l)methano 1 n.a.
carboxylic acid tert- d]azepine-6(7H)- (CAS-RN
butyl ester (CAS-RN
carboxylate hydrochloride 1020949-12-5)
1251013-07-6) No. Systematic Name Amine Alcohol MS, m/e
(3aR,8aS)-2-fluoro-4- cis-octahydro- (2,2,2- pyrrolo[3,4- (2-fluoro-4-(2,2,2- trifluoroethoxy)benzyl d]azepine-2- trifluoroethoxy)-
1.7 n.a.
octahydropyrrolo [3 ,4- carboxylic acid tert- pheny l)methano 1
d]azepine-6(7H)- butyl ester (CAS-R (intermediate 38)
carboxylate hydrochloride 1251013-07-6)
(3aS,6aS)-4- (3aR,6aR)-tert-butyl
(trifluoromethoxy)benzyl hexahydropyrrolo [3 , (4-
331.5
1.8 hexahydropyrrolo [3 ,4- 4-c]pyrro le-2( 1 H)- (trifluoromethoxy)-
(M+H)+ c]pyrrole-2(lH)- carboxylate pheny l)methano 1
carboxylate hydrochloride (intermediate 15.1)
Intermediate 2
(lH-Benzotriazol-5-yl)-cis-octahydro-pyrrolo [3,4-c] yridin-5-yl-methanone hydrochloride
Step 1 : cis-tert-Butyl 5-(lH-benzo[d][l,2,3]triazole-5-carbonyl)hexahydro-lH-pyrrolo[3,4- c]pyridine-2(3H)-carboxylate
To a solution of cis-tert-butyl hexahydro-lH-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate
(intermediate 14; 50 mg, 210 μιηοΐ) in Ν,Ν-dimethylformamide (1 mL) were added 4- methylmorpholine (84.9 mg, 840 μιηοΐ), lH-benzo[d][l,2,3]triazole-5-carboxylic acid (36.0 mg, 220 μιηοΐ) and 0-(7-azabenzotriazol-l-yl)-N,N,N',N'-tetramethyluronium hexafluoro -phosphate (120 mg, 315 μιηοΐ) at room temperature, then after 16 h the reaction mixture was partitioned between ethyl acetate and sat. aq. ammonium chloride solution. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and evaporated. Chromatography (silica gel; gradient dichloromethane to dichloromethane/methanol/25% aq. ammonia solution 90: 10:0.25) produced the title compound (52 mg, 67%). Light yellow gum, MS: 370.5 (M-H) . Step 2 : ( 1 H-Benzotriazol-5-yl)-cis-octahydro-pyrrolo [3 ,4-c]pyridin-5-yl-methanone;
hydrochloride The title compound was produced in analogy to intermediate 1, step 2 from (3aS,7aS)-tert-butyl 5 -( 1 H-benzo [d] [ 1 ,2,3 Jtriazo le-5 -carbonyl)hexahydro- 1 H-pyrrolo [3 ,4-c]pyridine-2(3H)- carboxylate. White solid,MS: 272.5 (M+H)+.
The following intermediates were prepared according to intermediate 2, replacing (3aR,6aS)- tert-butyl hexahydropyrrolo[3,4-c]pyrrole-2(lH)-carboxylate and lH-benzo[d][l,2,3]triazole-5- carboxylic acid by the appropriate amine and carboxylic acid, respectively.
MS,
No. Systematic Name Amine Carboxylic acid
m/e trans-tert-butyl
( 1 H-benzo triazo 1-5 -yl)- hexahydro-lH- lH-benzo[d]- trans-o ctahydro - pyrrolo[3,4- 272.5
2.1 [l,2,3]triazole-5- pyrrolo [3 ,4-c]pyridin-5 -yl- c]pyridine-2(3H)- (M+H)+ carboxylic acid
methanone; hydrochloride carboxylate (CAS- RN 1251014-37-5)
(lH-benzo[d]-
(3aR,6aS)-tert-butyl
[ 1 ,2,3]triazol-5-yl)(trans- hexahydropyrrolo [3 , lH-benzo[d]- hexahydropyrrolo [3 ,4- 258.5
2.2 4-c]pyrro le-2( 1 H)- [l,2,3]triazole-5- c]pyrrol-2(lH)- (M+H)+ carboxylate (CAS- carboxylic acid
yl)methanone
RN 250275-15-1)
hydrochloride
(lH-benzo[d]- cis-o ctahydro -
[l,2,3]triazol-5-yl)- pyrrolo[3,4- lH-benzo[d]-
((3aR,8aS)-octahydro- d]azepine-2- 286.5
2.3 [l,2,3]triazole-5- pyrrolo [3 ,4-d] azepin- carboxylic acid tert- (M+H)+ carboxylic acid
6(7H)-yl)methanone butyl ester (CAS-RN
hydrochloride 1251013-07-6) MS,
No. Systematic Name Amine Carboxylic acid
m/e
(lH-benzo[d]-
(3aS,6aS)-tert-butyl
[l,2,3]triazol-5- hexahydropyrrolo [3 , lH-benzo[d]- yl)((3aR,6aR)-hexahydro- 258.5
2.4 4-c]pyrro le-2( 1 H)- [l,2,3]triazole-5- pyrrolo [3 ,4-c]pyrrol- (M+H)+ carboxylate carboxylic acid
2(1 H)-yl)methanone
(intermediate 15)
dihydro chloride
((3aR,6aR)-hexahydro- (+)-(R)-4,5,6,7-
(3aS,6aS)-tert-butyl
pyrrolo [3 ,4-c]pyrrol- tetrahydro-lH- hexahydropyrrolo [3 ,
2(lH)-yl)((R)-4,5,6,7- benzo[d]- 262.6
2.5 4-c]pyrro le-2( 1 H)- tetrahydro- 1 H-benzo [d] - [l,2,3]triazole-5- (M+H)+ carboxylate
[l,2,3]triazol-5-yl)- carboxylic acid
(intermediate 15)
methanone hydrochloride (intermediate 3 OA)
(lH-[l,2,3]triazolo[4,5- lH-[l,2,3]tri-
(3aS,6aS)-tert-butyl
b] pyridin-5-yl)((3aR,6aR)- azolo[4,5- hexahydropyrrolo [3 ,
hexahydropyrrolo [3 ,4- b]pyridine-5- 257.5
2.6 4-c]pyrro le-2( 1 H)- c] pyrrol-2(lH)- carboxylic acid (M-H) carboxylate
yl)methanone (CAS-RN 1216149- (intermediate 15)
hydrochloride 55-1)
Intermediate 3
3-(3,5-Dichlorophenyl)-l-((3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol-2(lH)-yl)propan-l- hydrochloride
Step 1 : (3aR,6aS)-tert-Butyl 5-(3-(3,5-dichlorophenyl)propanoyl)hexahydropyrrolo[3,4- c]pyrrole-2( 1 H)-carboxylate
To a solution of 3-(3,5-dichlorophenyl)propanoic acid (103 mg, 470 μιηοΐ), (3aR,6aS)-tert-butyl hexahydropyrrolo [3, 4-c]pyrrole-2(lH)-carboxylate (CAS-RN 250275-15-1; 100 mg, 471 μιηοΐ) and 4-methylmorpholine (238 mg, 2.35 mmol) in Ν,Ν-dimethylformamide (1 mL) was added O- (7-azabenzotriazol-l-yl)-N,N,N',N'-tetramethyluronium hexafluoro-phosphate (268 mg, 705 μηιοΐ) at room temperature, then after 16 h the reaction mixture was partitioned between ethyl acetate and sat. aq. sodium hydrogencarbonate solution. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and evaporated. Chromatography (silica gel;
heptane - ethyl acetate gradient) afforded the title compound (161 mg, 83%). Colourless oil, MS: 357.1 (M-isobutene+H)+.
Step 2: 3-(3,5-Dichlorophenyl)-l-((3aR,6aS)-hexahydropyrrolo[3^-c]pyrrol-2(lH)-yl)propan-l- one hydrochloride
The title compound was produced in analogy to intermediate 1, step 2 from (3aR,6aS)-tert-butyl 5-(3-(3,5-dichlorophenyl)propanoyl)hexahydropyrrolo[3,4-c]pyrrole-2(lH)-carboxylate. White solid, MS: 313.1 (M+H)+.
Intermediate 4
(3aR,5s,6aS)-N-((lH-l,2,3-Triazol-4-yl)methyl)octahydrocyclopenta[c]pyrrole-5- carboxamide 2,2,2-trifluoroacetate Step 1 : (3aR,5s,6aS)-tert-butyl 5-((lH-l,2,3-triazol-4-yl)methylcarbamoyl)hexahydro- cyclopenta[c]pyrrole-2( 1 H)-carboxylate
To a solution of (3aR,5s,6aS)-2-(tert-butoxycarbonyl)octahydrocyclopenta[c]pyrrole-5- carboxylic acid (WuXi AppTec (Wuhan) Co., Ltd.; catalogue No. WX110047; 100 mg, 392 μιηοΐ) and (lH-l,2,3-triazol-4-yl)methanamine hydrochloride (52.7 mg, 392 μιηοΐ) in
dichloromethane (2 mL) were added at 0°C diisopropylethylamine (127 mg, 979 μιηοΐ) and benzotriazol-l-yl-oxy-tris-(dimethylamino)-phosphonium hexafluorophosphate (182 mg, 411 μιηοΐ), then after 15 h at room temperature the reaction mixture was evaporated and the residue partitioned between ethyl acetate and water. The organic layer was dried over magnesium sulfate, filtered, and evaporated. Chromatography (silica gel, ethyl acetate-methanol gradient) produced the title compound (100 mg, 75%). White foam, MS: 334.5 (M-H) .
Step 2: (3aR,5s,6aS)-N-((lH-l,2,3-Triazol-4-yl)methyl)octahydrocyclopenta[c]pyrrole-5- carboxamide 2,2,2-trifluoroacetate
Trifluoro acetic acid (340 mg, 2.98 mmol) was added at room temperature to a solution of (3aR,5s,6aS)-tert-butyl 5-((lH-l,2,3-triazol-4-yl)methylcarbamoyl)hexahydrocyclo- penta[c]pyrrole-2(lH)-carboxylate (100 mg, 298 μηιοΐ) in dichloromethane, then after 4 h the reaction mixture was evaporated to produce the title compound, which was used directly in the next step. Light yellow oil, MS: 236.5 (M+H)+.
Intermediate 5 (E)-l-((3aR,8aS)-Octahydropyrrolo[3,4-d]azepin-6(7H)-yl)-3-(4-(trifluoromethoxy)- phenyl)prop-2-en-l-one hydrochloride
Step 1 : (3aR,8aS)-tert-Butyl 6-((E)-3-(4-(trifluoromethoxy)phenyl)acryloyl)octahydro- pyrrolo [3 ,4-d] azepine-2( 1 H)-carboxylate
To a solution of (3aR,8aS)-tert-butyl octahydropyrrolo[3,4-d]azepine-2(lH)-carboxylate hydrochloride (CAS-RN 1251013-07-6; 1.50 g, 5.42 mmol), 4-methylmorpholine (2.19 g, 21.7 mmol) and (E)-3-(4-(trifluoromethoxy)phenyl)acrylic acid (1.26 g, 5.42 mmol) in N,N- dimethylformamide (30 mL) was added added 0-(7-azabenzotriazol-l-yl)-N,N,N',N'- tetramethyluronium hexafluoro -phosphate (2.06 g, 5.42 mmol) at 0°C. After 60 min the ice bath was removed, then after 16 h the reaction mixture was partitioned between ethyl acetate and sat. aq. sodium hydro gencarbonate solution. The organic layer was washed with sat. aq. ammonium chloride solution, water, and brine, dried over magnesium sulfate, filtered, and evaporated. The residue was triturated in heptane/ethyl acetate 9: 1 to produce the title compound (2.20 g, 89%). White solid, MS: 399.5 (M+H-isobutene)+.
Step 2: (E -l-((3aR,8aS -Octahvdropyrrolo[3.4-dlazepin-6(7H -yl -3-(4-(trifiuoromethoxy - phenyl)prop-2-en- 1 -one hydrochloride
The title compound was produced in analogy to intermediate 1, step 2 from (3aR,8aS)-tert-butyl 6-((E)-3-(4-(trifluoromethoxy)phenyl)acryloyl)octahydropyrrolo [3 ,4-d]azepine-2( 1 H)- carboxylate. White solid, MS: 355.5 (M+H)+.
The following intermediates were produced according to intermediate 5, replacing (3aR,8aS)- tert-butyl octahydropyrrolo[3,4-d]azepine-2(lH)-carboxylate hydrochloride and (E)-3-(4- (trifluoromethoxy)phenyl)acrylic acid by the appropriate amine and carboxylic acid precursors, respectively. Systematic Name Amine Carboxylic acid MS
4-((E)-3-((3aR,8aS)- (3aR,8aS)-tert-butyl
octahydropyrrolo [3 ,4- octahydropyrrolo [3 ,4-
(E)-3-(4- d]azepin-6(7H)-yl)-3- d]azepine-2(lH)- 296.5 cyanophenyl)- oxoprop-1- carboxylate (M+H)+ acrylic acid
enyl)benzonitrile hydrochloride (CAS- hydrochloride RN 1251013-07-6)
2-(4-chloro-2-isopropyl-5- 2-[4-chloro-5-
(3aR,6aS)-tert-butyl
methylphenoxy)- 1 - methyl-2-(l- hexahydropyrrolo [3 ,4- ((3aR,6aS)-hexahydro- methylethyl)- 337.6 c]pyrrole-2(lH)- pyrrolo [3 ,4-c]pyrrol- phenoxy] -acetic (M+H)+ carboxylate (CAS-RN
2(1 H)-yl)ethanone acid (CAS-RN
250275-15-1)
hydrochloride 5411-11-0)
(E)- 1 -(trans-octahydro- trans-tert-butyl
(E)-3-(4- pyrrolo [3 ,4-c]pyridin-5 - hexahydro-lH-
(trifluoro- yl)-3-(4- pyrrolo [3 ,4-c]pyridine- 341.6 methoxy)-
(trifluoromethoxy)- 2(3H)-carboxylate (M+H)+ phenyl)acrylic
phenyl)prop-2-en- 1 -one (CAS-RN 1251014-37- acid
hydrochloride 5)
1 -(trans-octahydro- trans-tert-butyl
pyrrolo [3 ,4-c]pyridin-5 - hexahydro-lH- 2-(4-(trifluoro- yl)-2-(4- pyrrolo [3 ,4-c]pyridine- methoxy)- 345.6
(trifluoromethoxy)- 2(3H)-carboxylate phenoxy)acetic (M+H)+ phenoxy)ethanone (CAS-RN 1251014-37- acid
hydrochloride 5) No. Systematic Name Amine Carboxylic acid MS l-((3aS,6aS)-
(3aR,6aR)-tert-butyl
hexahydropyrrolo [3 ,4- 3-(4-(trifluoro- hexahydropyrrolo [3 ,4- c]pyrrol-2(lH)-yl)-3-(4- methoxy)- 329.5
5.5 c]pyrrole-2(lH)- (trifluoromethoxy)- phenyl)propanoic (M+H)+ carboxylate
phenyl)propan- 1 -one acid
(intermediate 15.1)
dihydro chloride
(4-ethoxyquino lin-2-
(3aR,6aR)-tert-butyl 4-ethoxyyl)((3aS,6aS)- hexahydropyrrolo [3 ,4- quino line-2- hexahydropyrrolo [3 ,4- 329.5
5.6 c]pyrrole-2(lH)- carboxylic acid
c]pyrrol-2(lH)- (M+H)+ carboxylate (CAS-RN 40609- yl)methanone
(intermediate 15.1) 78-7)
hydrochloride
Intermediate 6 cis-3,5-Dichlorobenzyl 2-(lH-benzo[d] [l,2,3]triazole-5-carbonyl)hexahydro-lH- pyrrolo[3,4-c]pyridine-5(6H)-carboxylate A solution of cis-3,5-dichlorobenzyl 2-(lH-benzo[d][l,2,3]triazole-5-carbonyl)hexahydro-lH- pyrrolo[3,4-c]pyridine-5(6H)-carboxylate (example 1.02; 100 mg, 211 μιηοΐ) in methanol (3 mL) was stirred for 20 h at 100°C under a hydrogen atmosphere (10 bar) in the presence of palladium (10% on carbon, 10 mg), then insoluble material was removed by filtration through
diatomaceous earth and the filtrate was evaporated to produce the title compound (62 mg), which was used directly in the next step. Light yellow foam, MS: 272.5 (M+H)+.
The following intermediates were prepared according to intermediate 6, replacing cis-3,5- dichlorobenzyl 2-( 1 H-benzo [d] [ 1 ,2,3]triazole-5-carbonyl)hexahydro- 1 H-pyrrolo [3 ,4-c]pyridine- 5(6H)-carboxylate by the appropriate starting material. No. Systematic Name Starting material MS, m/e
(3aR,8aS)-3,5-dichlorobenzyl 2-
( 1 H-benzo [d] [ 1 ,2,3]triazol-5- (lH-benzo[d][l,2,3]triazole-5- yl)((3aR,8aS)- 286.5
6.1 carbonyl)octahydropyrro lo [3 ,4- octahydropyrrolo [3 ,4-d]azepin- (M+H)+ d]azepine-6(7H)-carboxylate
2(1 H)-yl)methanone
(example 1.04)
(3aR,6aS)-3,5-dichlorobenzyl 5-
(6,7-dihydro-lH- (4,5,6,7-tetrahydro-lH-
[l,2,3]triazolo[4,5-c]pyridin-5(4H)- [l,2,3]triazolo[4,5-c]pyridine-5- 263.5
6.2 yl)((3aR,6aS)- carbonyl)hexahydropyrrolo [3 ,4- (M+H)+ hexahydropyrrolo [3 ,4-c]pyrrol- c]pyrrole-2( 1 H)-carboxylate
2(1 H)-yl)methanone
(example 8)
(3aR,6aS)-3,5-dichlorobenzyl 5-
((3aR,6aS)-hexahydropyrrolo [3 ,4- (4,5,6,7-tetrahydro-lH- c]pyrrol-2(lH)-yl)(4,5,6,7- benzo[d][l,2,3]triazole-5- 262.4
6.3 tetrahydro-lH- carbonyl)hexahydropyrrolo [3 ,4- (M+H)+ benzo[d][l,2,3]triazol-5- c]pyrrole-2( 1 H)-carboxylate
yl)methanone
(example 1.01)
Intermediate 7A
(lH-Benzotriazol-5-yl)-trans-octahydro-pyrrolo[3,4-c]pyridin-5-yl-methanone hydrochloride, enantiomer A Step 1 : trans-tert-Butyl 5-(lH-benzo[d][l,2,3]triazole-5-carbonyl)hexahydro-lH-pyrrolo[3,4- c]pyridine-2(3H)-carboxylate
The title compound was produced in analogy to intermediate 2, step 1 from trans-tert-butyl hexahydro-lH-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate (CAS-RN 1251014-37-5) and 1H- benzo[d][l,2,3]triazole-5-carboxylic acid. Light yellow foam, MS: 370.4 (M-H)~. Step 2: (-)-trans-tert-Butyl 5-(lH-benzo[d][l,2,3]triazole-5-carbonyl)hexahydro-lH-pyrrolo[3,4- c]pyridine-2(3H)-carboxylate and (+)-trans-tert-butyl 5-(lH-benzo[d][l,2,3]triazole-5- carbonyDhexahydro- 1 H-pyrrolo [3 ,4-c]pyridine-2(3H)-carboxylate
HPLC separation of racemic trans-tert-butyl 5-(lH-benzo[d][l,2,3]triazole-5- carbonyl)hexahydro-l H-pyrrolo [3, 4-c]pyridine-2(3H)-carboxylate (668 mg, 1.80 mmol) using a Reprosil Chiral-NR column as the stationary phase and heptane/ethanol 3:2 as the eluent produced the faster eluting (-)-enantiomer (251 mg, 37%; colourless gum, MS: 370.6 (M-H) ), followed by the slower eluting (+)-enantiomer (212 mg, 32%; colourless gum, MS: 370.6 (M- H) ). Step 3 : (lH-Benzotriazol-5-yl)-trans-octahydro-pyrrolo[3,4-c]pyridin-5-yl-methanone
hydrochloride enantiomer A
The title compound was produced in analogy to intermediate 1, step 2 from (-)-trans-tert-butyl 5- ( 1 H-benzo [d] [ 1 ,2,3]triazole-5-carbonyl)hexahydro- 1 H-pyrrolo [3 ,4-c]pyridine-2(3H)-carboxylate. White solid, MS: 272.5 (M+H)+. Intermediate 7B
(lH-Benzotriazol-5-yl)-trans-octahydro-pyrrolo[3,4-c]pyridin-5-yl-methanone
hydrochloride, enantiomer B
The following intermediate was prepared according to intermediate 7 A, step 3 from (+)-trans- tert-butyl 5 -( 1 H-benzo [d] [ 1 ,2,3 Jtriazo le-5 -carbonyl)hexahydro- 1 H-pyrrolo [3 ,4-c]pyridine- 2(3H)-carboxylate (intermediate 7A, step 2). White solid, MS: 272.5 (M+H)+.
Intermediate 8
(lH-Benzo[d] [l,2,3]triazol-5-yl)((3aS,6aS)-hexahydropyrrolo[3,4-c]pyrrol-2(lH)- yl)methanone dihydrochloride
Step 1 : trans-tert-Butyl 5-(lH-benzo[d][l,2,3]triazole-5-carbonyl)hexahydropyrrolo[3,4- c]pyrrole-2( 1 H)-carboxylate
The title compound was produced in analogy to intermediate 2, step 1 from trans-tert-butyl hexahydropyrrolo[3,4-c]pyrrole-2(lH)-carboxylate (intermediate 16) and 1H- benzo[d][l,2,3]triazole-5-carboxylic acid. Light yellow foam, MS: 358.5 (M+H)+. Step 2: (+)-(3aR.6aR)-tert-Butyl 5-(lH-benzo[dl[1.2,31triazole-5- carbonyl)hexahydropyrrolo[3,4-c]pyrrole-2(lH)-carboxylate and (-)-(3aS,6aS)- tert-butyl 5-ΠΗ- benzo [d] [ 1 ,2,3 Jtriazo le-5 -carbonyDhexahydropyrrolo [3 ,4-c]pyrrole-2( 1 H)-carboxylate
HPLC separation of racemic trans-tert-butyl 5-(lH-benzo[d][l,2,3]triazole-5- carbonyl)hexahydropyrrolo[3,4-c]pyrrole-2(lH)-carboxylate (790 mg, 2.21 mmol) using a
Chiralpak AD column as the stationary phase and heptane/ethanol 7:3 as the eluent produced the faster eluting (+)-(R,R)-enantiomer (350 mg, 44%; light yellow foam, MS: 358.5 (M+H)+; e. r. 100:0), followed by the slower eluting (-)-(S,S)-enantiomer (388 mg, 49%; light yellow foam, MS: 358.5 (M+H)+; e. r. 4:96). Step 3: (lH-Benzo[dl[l,2,31triazol-5-yl ((3aS,6aSVhexahvdropyrrolo[3,4-clpyrrol-2(lH - yPmethanone dihydro chloride
The title compound was produced in analogy to intermediate 1, step 2 from (3aR,6aR)-tert-butyl 5-(lH-benzo[d][l,2,3]triazole-5-carbonyl)hexahydropyrrolo[3,4-c]pyrrole-2(lH)-carboxylate. White solid, MS: 258.5 (M+H)+. Intermediate 9
(3aR,6aS)-3,5-Dichlorobenzyl 5-(chlorocarbonyl)hexahydropyrrolo[3,4-c]pyrrole-2(lH)- carboxylate
To a colourless solution of (3aR,6aS)-3,5-dichlorobenzyl hexahydropyrrolo[3,4-c]pyrrole-2(lH)- carboxylate hydrochloride (intermediate 1; 152 mg, 432 μιηοΐ) and pyridine (106 mg, 1.34 mmol) in dichloromethane (2 mL) was added dropwise a solution of triphosgene (57.7 mg, 195 μιηοΐ) in dichloromethane (2 mL) at 0°C, then after 30 min the ice bath was removed. After 16 h the reaction mixture was partitioned between 1 M aq. hydrochloric acid solution and
dichloromethane. The organic layer was washed with water and brine, dried over magnesium sulfate, filtered and evaporated to afford the title compound (172 mg), which was used directly in the next step. Colourless oil, MS: 401.3 (M+Na)+.
The following intermediates were prepared according to intermediate 9, replacing (3aR,6aS)-3,5- dichlorobenzyl hexahydropyrrolo[3,4-c]pyrrole-2(lH)-carboxylate hydrochloride by the appropriate starting material. No. Systematic Name Starting material MS, m/e
(E)-l-((3aR,8aS)-
(3aR,8aS)-6-((E)-3-(4- octahydropyrrolo [3 ,4-d]azepin- (trifluoromethoxy)phenyl)acryloyl) 6(7H)-yl)-3-(4- 416
9.1
octahydropyrrolo [3 ,4-d]azepine- (trifluoromethoxy)phenyl)prop-2- (M)+ 2(lH)-carbonyl chloride en-l-one hydrochloride
(intermediate 5)
(3aS,6aS)-tert-butyl
(3aR,6aR)-tert-butyl 5- hexahydropyrrolo [3 ,4-c]pyrrole- 274
9.2 (chlorocarbonyl)hexahydropyrrolo [
2(lH)-carboxylate (intermediate (M)+ 3 ,4-c]pyrrole-2( 1 H)-carboxylate
15)
4-(4-chlorophenyl)piperidine- 1 - 4-(4-chlorophenyl)piperidine 257.0
9.3
carbonyl chloride hydrochloride (M)+
Intermediate 10
(3aR,5r,6aS)-3,5-Dichlorobenzyl 5-hydroxyhexahydrocyclopenta[c]pyrrole-2(lH)- carboxylate Step 1 : (3aR,5r,6aS)-tert-Butyl 5-hydroxyhexahydrocyclopenta[c]pyrrole-2(lH)-carboxylate
To a solution of (3aR,6aS)-tert-butyl 5-oxohexahydrocyclopenta[c]pyrrole-2(lH)-carboxylate (CAS-RN 146231-54-1; 4.3 g, 19.1 mmol) in methanol (100 mL) was added sodium borohydride (1.44 g, 38.2 mmol) at 0°C, then after 1 h the reaction mixture was treated with ice water and the methanol was removed under reduced pressure. The reaction mixture was partitioned between ethyl acetate and brine. The organic layer was dried over magnesium sulfate, filtered and evaporated to produce the title compound (4.38 g, 100%). Off-white solid, MS: 228.3 (M+H)+.
Step 2: (3aR,5r,6aS)-Octahydrocyclopenta[c]pyrrol-5-ol hydrochloride
(3aR,5r,6aS)-tert-butyl 5-hydroxyhexahydrocyclopenta[c]pyrrole-2(lH)-carboxylate (4.37 g, 19.0 mmol) was combined with hydrochloric acid solution (5-6 M in 2-propanol) (49 mL, 245 mmol), then after 2 h the reaction mixture was evaporated und the residue was triturated in ethyl acetate to afford the title compound as an off-white solid (2.84 g, 91%).
Step 3: (3aR,5r,6aS)-3,5-Dichlorobenzyl 5-hydroxyhexahydrocyclopenta[c]pyrrole-2(lH)- carboxylate To a solution of (3,5-dichlorophenyl)methanol (541 mg, 3.06 mmol) in dichloromethane (10 mL) was added Ι,Γ-carbonyldiimidazole (520 mg, 3.21 mmol) at room temperature. Then after 3 h (3aR,5r,6aS)-octahydrocyclopenta[c]pyrrol-5-ol hydrochloride (500 mg, 3.06 mmol) and triethylamine (309 mg, 3.06 mmol) were added, then after 18 h the reaction mixture was partitioned between dichloromethane and water. The organic layer was washed with brine, dried over magnesium sulfate, filtered and evaporated. Chromatography (silica gel; heptane - ethyl acetate gradient) produced the title compound (847 mg, 84%). Colourless oil, MS: 330.1 (M+H)+.
Intermediate 11
(3aR,5s,6aS)-3,5-Dichlorobenzyl 5-hydroxyhexahydrocyclopenta[c]pyrrole-2(lH)- carboxylate
Step 1 : (3aR,5s,6aS)-3,5-Dichlorobenzyl 5-(4-nitrobenzoyloxy)hexahydrocyclopenta[c]pyrrole- 2(1 H)-carboxylate
Diethyl azodicarboxylate solution (40% in toluene; 168 μί, 424 μιηοΐ) was added at room temperature to a solution of (3aR,5r,6aS)-3,5-dichlorobenzyl 5-hydroxyhexahydrocyclo- penta[c]pyrrole-2(lH)-carboxylate (intermediate 10; 140 mg, 424 μιηοΐ), 4-nitrobenzoic acid (85.0 mg, 509 μιηοΐ), and triphenylphosphine (111 mg, 424 μιηοΐ) in toluene (10 mL), then after 16 h another portion of triphenylphosphine (33.4 mg, 127 μιηοΐ) and diethyl azodicarboxylate solution (40%) in toluene; 50 μί, 127 μιηοΐ) was added. The reaction mixture was stirred for another 5 h at room temperature, evaporated and the residue was purified by chromatography (silica gel; heptane - ethyl acetate gradient) to produce the title compound (167mg, 82%>).
Colourless oil, MS 479.0 (M+H)+.
Step 2: (3aR,5s,6aS)-3,5-Dichlorobenzyl 5-hydroxyhexahydrocyclopenta[c]pyrrole-2(lH)- carboxylate A mixture of (3aR,5s,6aS)-3,5-dichlorobenzyl 5-(4-nitrobenzoyloxy)hexahydrocyclo- penta[c]pyrrole-2(lH)-carboxylate (163 mg, 340 μιηοΐ) and 2 M aq. sodium hydroxide solution (1 mL, 2 mmol) in tetrahydrofuran (2 mL) was stirred at room temperature for 6 h. After evaporation of volatile material the residue was partitioned between 1 M aq. hydrochloric acid solution and ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, filtered and evaporated in vacuo to give the title compound (109 mg, 97%). Colourless oil, MS: 330.1 (M+H)+.
Intermediate 12
4-((3aR,5r,6aS)-2-((3,5-Dichlorobenzyloxy)carbonyl)octahydrocyclopenta[c]pyrrol-5- yloxy)-2-hydroxybenzoic acid
Step 1 : (3aR,5r,6aS)-3,5-Dichlorobenzyl 5-(3-hydroxy-4-(methoxycarbonyl)phenoxy)- hexahydrocyclopenta[c]pyrrole-2( 1 H)-carboxylate
Diethyl azodicarboxylate solution (40% in toluene, 157 μί, 398 μιηοΐ) was added at room temperature to a solution of (3aR,5s,6aS)-3,5-dichlorobenzyl 5-hydroxyhexahydrocyclo- penta[c]pyrrole-2(lH)-carboxylate (101 mg, 306 μιηοΐ), methyl 2,4-dihydroxybenzoate (68.9 mg, 398 μιηοΐ), and triphenylphosphine (104 mg, 398 μιηοΐ) in toluene (2 mL). Then after 18 h the reaction mixture was concentrated and the residue purified by chromatography (silica gel;
heptane - ethyl acetate gradient) to produce the title compound (144 mg, 98%>). Colourless gum, MS: 480.1 (M+H+). Step 2: 4-((3aR,5r,6aS)-2-((3,5-Dichlorobenzyloxy)carbonyl)octahydrocyclopenta[c]pyrrol-5- yloxy)-2-hydroxybenzoic acid
The title compound was produced in analogy to intermediate 11, step 2 from (3aR,5r,6aS)-3,5- dichlorobenzyl 5-(3-hydroxy-4-(methoxycarbonyl)phenoxy)hexahydrocyclopenta[c]pyrrole- 2(lH)-carboxylate. Colourless gum, MS: 466.2 (M+H)+. Intermediate 12.1
4-((3aR,5s,6aS)-2-((3,5-Dichlorobenzyloxy)carbonyl)octahydrocyclopenta[c]pyrrol-5- yloxy)-2-hydroxybenzoic acid The title compound was produced in analogy to intermediate 12 from (3aR,5r,6aS)-3,5- dichlorobenzyl 5-hydroxyhexahydrocyclopenta[c]pyrrole-2(lH)-carboxylate (intermediate 10). Colourless gum, MS: 466.2 (M+H)+.
Intermediate 13
(3aR,6aS)-3,5-Dichlorobenzyl 5-oxohexahydrocyclopenta[c]pyrrole-2(lH)-carboxylate
To a stirred solution of (3aR,5r,6aS)-3,5-dichlorobenzyl 5-hydroxyhexahydrocyclo- penta[c]pyrrole-2(lH)-carboxylate (intermediate 10; 144 mg, 436 μιηοΐ) in dichloromethane (3 mL) was added l,l,l-triacetoxy-l,l-dihydro-l,2-benziodoxol-3(lH)-one solution (15% in dichloromethane; 1.48 g, 523 μιηοΐ) at 0°C. Then after 2.5 h solid sodium bicarbonate (256 mg, 3.05 mmol) was added and the reaction mixture was stirred for another 5 min and was then filtered through diatomaceous earth. The filtrate was evaporated and purified by
chromatography (silica gel; heptane - ethyl acetate gradient) to produce the title compound (132 mg, 88%). Colourless oil, MS *:328.2 (M+H)+. Intermediate 14 cis-tert-Butyl hexahydro-lH-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate
Step 1 : cis-tert-Butyl 6-oxohexahydropyrano[3,4-c]pyrrole-2(lH)-carboxylate
(3aR,6aS)-tert-Butyl 5-oxohexahydrocyclopenta[c]pyrrole-2(lH)-carboxylate (CAS-RN 146231- 54-1; 5.00 g, 17.8 mmol) was dissolved in dry dichloromethane (250 mL) and then disodium hydrogen phosphate (63.0 g, 444 mmol) and 3-chloroperbenzoic acid (10.9 g, 44.4 mmol) were added. The suspension was stirred at room temperature for 72 h, then 2 M aq. sodium sulfite solution (200 mL) was added. After stirring for another 30 min, the organic layer was washed with sat. aq. sodium hydro gencarbonate solution, dried over magnesium sulfate, filtered, and evaporated to produce a mixture (4.66 g) containing the title compound (MS: 264.5 (M+Na)+) as the main product, along with some unreacted starting material.
Step 2: cis-tert-Butyl 3-(2-hydroxyethyl)-4-(hydroxymethyl)pyrrolidine-l-carboxylate cis-tert-Butyl 6-oxohexahydropyrano[3,4-c]pyrrole-2(lH)-carboxylate (crude mixture from step 1; 4.46 g) was dissolved in ethanol (300 mL), then freshly powdered anhydrous calcium chloride (3.69 g, 33.3 mmol) was added at once, then sodium borohydride (2.52 g, 66.5 mmol) was added portionwise at room temperature. After 1 h, the reaction was poured onto ice water (800 mL) and ethyl acetate (800 mL). The two phases were saturated with solid sodium chloride and stirred for 15 min, then the organic layer was separated, washed with brine, dried over magnesium sulfate, filtered, and evaporated. Chromatography (silica gel; heptane - ethyl acetate gradient) produced the title compound (2.57 g, ca. 60% yield over 2 steps). Colourless oil, MS: 268.5 (M+Na)+.
Step 3: cis-tert-Butyl 3-(2-(methylsulfonyloxy)ethyl)-4-((methylsulfonyloxy)methyl)pyrrolidine- 1-carboxylate
A solution of methanesulfonyl chloride (3.60 g, 31.4 mmol) in dichloromethane (5 mL) was added at 0°C to a solution of cis-tert-butyl 3-(2-hydroxyethyl)-4-(hydroxymethyl)pyrrolidine-l- carboxylate (2.57 g, 10.5 mmol) and N,N-diisopropylethylamine (8.12 g, 62.9 mmol) in dichloromethane (70 mL), then after 1 h the mixture was partitioned between ethyl acetate and sat. aq. ammonium chloride solution. The organic layer was washed with sat. aq. sodium hydro gencarbonate solution, dried over magnesium sulfate, filtered, and evaporated.
Chromatography (silica gel, heptane - ethyl acetate gradient afforded the title compound (3.47 g, 83%). Light yellow oil, MS: 424.5 (M+Na)+.
Step 4: cis-tert-Butyl 5-benzylhexahydro-lH-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate
To a solution of cis-tert-butyl 3-(2-(methylsulfonyloxy)ethyl)-4-((methylsulfonyloxy)- methyl)pyrrolidine-l-carboxylate (3.05 g, 7.60 mmol) inacetonitrile (100 mL) were added phenylmethanamine (2.44 g, 22.8 mmol) and potassium carbonate (5.25 g, 38.0 mmol). The reaction mixture was heated at 95 °C for 22 h and wasthen partitioned between ethyl acetate and water. The organic layer was washed with sat. aq. ammonium chloride solution and brine, dried over magnesium sulfate, filtered, and evaporated. Chromatography (silica gel, gradient dichloromethane to dichloromethane/methanol/25% aq. ammonia solution 95:5:0.25) produced the title compound (1.63 g, 64%). Light yellow oil, MS: 317.6 (M+H)+.
Step 5: cis-tert-Butyl hexahydro-lH-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate
To a solution of cis-tert-butyl 5-benzylhexahydro-lH-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate (1.63 g, 4.89 mmol) in methanol (33 mL) was added palladium (10%> on carbon; 260 mg, 245 μιηοΐ), and the reaction mixture was stirred under a hydrogen atmosphere (1 bar) at room temperature for 24 h, then insoluble material was removed by filtration through diatomaceous earth. The filtrate was concentrated and the residue was chromatographed (silica gel, gradient dichloromethane to dichloromethane/methanol/25% aq. ammonia solution 95:5:0.25) to produce the title compound (895 mg, 81%). Light yellow oil, MS: 227.5 (M+H)+.
Intermediate 15 (3aS,6aS)-tert-Butyl hexahydropyrrolo[3,4-c]pyrrole-2(lH)-carboxylate
Step 1 : (3R,4R)-tert-Butyl 3,4-bis((methylsulfonyloxy)methyl)pyrrolidine-l-carboxylate
The title compound was produced in analogy to intermediate 14, step 3 from (3R,4R)-3,4-bis- hydroxymethyl-pyrrolidine-l-carboxylic acid tert-butyl ester (CAS-RN 895245-32-6). Light yellow oil, MS: 332.4 (M-isobutene+H)+. Step 2: (3aS,6aS)-tert-Butyl 5-benzylhexahydropyrrolo[3,4-c]pyrrole-2(lH)-carboxylate
The title compound was produced in analogy to intermediate 14, step 4 from (3R,4R)-tert-butyl 3,4-bis((methylsulfonyloxy)methyl)pyrrolidine-l-carboxylate. Light yellow solid, MS: 303.5 (M+H)+.
Step 3: (3aS,6aS)-tert-Butyl hexahydropyrrolo[3,4-c]pyrrole-2(lH)-carboxylate
To a solution of (3aS,6aS)-tert-butyl 5-benzylhexahydropyrrolo[3,4-c]pyrrole-2(lH)-carboxylate (2.22 g, 7.34 mmol) in methanol (20 mL) was added palladium (10% on carbon, 220 mg, 7.34 mmol), and the reaction mixture was stirred under a hydrogen atmosphere (1 bar) at room temperature for 24 h, then insoluble material was removed by filtration through diatomaceous earth. The filtrate was concentrated to produce the title compound (1.60 g, 100%). White waxy solid, MS: 213.5 (M+H)+.
Intermediate 15.1
(3aR,6aR)-tert-Butyl hexahydropyrrolo[3,4-c]pyrrole-2(lH)-carboxylate
The title compound was produced in analogy to intermediate 15, replacing (3R,4R)-3,4-bis- hydroxymethyl-pyrrolidine-l-carboxylic acid tert-butyl ester by (3S,4S)-3,4-bis-hydroxymethyl- pyrrolidine- 1 -carboxylic acid tert-butyl ester (CAS-RN 895245-30-4). White waxy solid, MS : 213.3 (M+H)+. Inter mediate 16 trans-tert-Butyl hexahydropyrrolo[3,4-c]pyrrole-2(lH)-carboxylate
The title compound was produced in analogy to intermediate 15 from trans-3,4- bis(hydroxymethyl)pyrrolidine-l-carboxylic acid tert-butyl ester (CAS-RN 895245-31-5).
White waxy solid, MS : 213.5 (M+H)+.
Intermediate 17
(3-Chloro-5-(methylsulfonyl)phenyl)methanol
To a solution of 3-chloro-5-(methylsulfonyl)benzoic acid (CAS-RN 151104-63-1; 500 mg, 2.13 mmol) in tetrahydrofuran (5 mL) was added slowly borane-tetrahydrofuran complex solution (1 M solution in tetrahydrofuran, 5.33 mL, 5.33 mmol) at 0°C, then after 3 h the ice-bath was removed and the reaction mixture was stirred at room temperature overnight. The mixture was then carefully treated with methanol (3 mL) and evaporated. The residue was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and evaporated. Chromatography (silica gel; heptane - ethyl acetate gradient afforded the title compound (428 mg, 91 %). White solid, MS : 221.3 (M+H)+.
The following intermediate was produced according to intermediate 17, replacing 3-chloro-5- (methylsulfonyl)benzoic acid with the appropriate carboxylic acid
Figure imgf000226_0001
Intermediate 18
2,2,2-Trifluoro-l-(3-(hydroxymethyl)phenyl)ethanol Lithium boro hydride solution (2 M in tetrahydrofuran, 1.15 mL, 2.31 mmol) was added dropwise at 0°C to a solution of methyl 3-(2,2,2-trifluoro-l-hydroxyethyl)benzoate (CAS-RN 1188323-28- 5; 180 mg, 769 μιηοΐ) in tetrahydrofuran (6 mL), then after 15 min the ice bath was removed and the reaction mixture was heated at reflux for 21 h. Then another portion of lithium boro hydride solution (2 M in tetrahydrofuran, 0.77 mL, 1.54 mmol) was added and the reaction mixture was heated at reflux for another 5 h. After cooling, the reaction mixture was partitioned between 1 M aq. hydrochloric acid solution and ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered, and evaporated. Chromatography (silica gel; heptane - ethyl acetate gradient afforded the title compound (86 mg, 53%). White solid, MS: 206.0 (M+). Intermediate 19
(3-(2,2,2-Trifluoro-l-methoxyethyl)phenyl)methanol
Step 1 : Methyl 3-(2,2,2-trifluoro-l-methoxyethyl)benzoate
Sodium hydride dispersion (60% in mineral oil, 93.2 mg, 2.33 mmol) was added at -5°C to a solution of methyl 3-(2,2,2-trifluoro-l -hydro xyethyl)benzoate (303 mg, 1.29 mmol) in tetrahydrofuran (8 mL), then after 30 min iodomethane (643 mg, 4.53 mmol) was added dropwise over a period of 5 min. After 1 h, the ice bath was removed and the reaction mixture was stirred for another 90 min. The reaction mixture was then partitioned between ethyl acetate and water, the organic layer was washed with brine, dried over sodium sulfate, filtered, and evaporated to produce the title compound (purity ca. 90%>; 263 mg, 74%). Light yellow liquid, MS: 248.0 (M+).
Step 2: (3-(2,2,2-Trifluoro-l-methoxyethyl)phenyl)methanol
The title compound was produced in analogy to intermediate 18 from methyl 3-(2,2,2-trifluoro- l-methoxyethyl)benzoate. Colourless liquid, MS: 220.0 (M+).
Intermediate 20 (3aR,6aS)-N-((lH-l,2,3-Triazol-4-yl)methyl)hexahydropyrrolo[3,4-c]pyrrole-2(lH)- carboxamide 2,2,2-trifluoroacetate
Step 1 : (3aR,6aS)-tert-Butyl 5-((lH-l,2,3-triazol-4-yl)methylcarbamoyl)hexahydropyrrolo[3,4- c]pyrrole-2( 1 H)-carboxylate A solution of triphosgene (140 mg, , 471 μηιοΐ) in ethyl acetate (12 mL) was added at 0°C to a solution of (3aR,6aS)-tert-butyl hexahydropyrrolo[3,4-c]pyrrole-2(lH)-carboxylate (CAS-RN 250275-15-1; 200 mg, 942 μιηοΐ) in tetrahydrofuran (5 mL). The ice bath was removed, then after 30 min the reaction mixture was heated at reflux for 2 h and was then concentrated in vacuo. The residue was taken up in tetrahydrofuran (20 mL), then after the addition of triethylamine (286 mg, 2.83 mmol) and (lH-l,2,3-triazol-4-yl)methanamine hydrochloride (127 mg, 942 μιηοΐ) the reaction mixture was stirred at room temperature for 15 h. After partitioning between water and ethyl acetate, the organic layer was dried over sodium sulfate, filtered, and evaporated. Chromatography (silica gel; dichloromethane - methanol gradient) produced the title compound (110 mg, 34%). White foam, MS: MS: 337.5 (M+H)+.
Step 2 : (3 aR,6aS VN-(Y 1 H- 1 ,2,3 -Triazol-4- yl methyl hexahvdrop yrrolo [3 ,4-clpyrro le-2( 1 HV carboxamide 2,2,2-trifluoroacetate
The title compound was produced in analogy to intermediate 4, step 2 from (3aR,6aS)-tert-butyl 5-(( 1 H- 1 ,2,3-triazol-4-yl)methylcarbamoyl)hexahydropyrrolo [3 ,4-c]pyrrole-2( 1 H)-carboxylate. Light yellow oil, MS: 237.5 (M+H)+.
The following intermediate was produced according to intermediate 20, replacing (1H-1,2,3- triazol-4-yl)methanamine hydrochloride by the appropriate amine.
Figure imgf000228_0001
Intermediate 21
(3aR,6aS)-2-(3-Chlorophenethylsulfonyl)octahydropyrrolo[3,4-c]pyrrole Step 1 : (3aR,6aS)-tert-Butyl 5-(3-chlorophenethylsulfonyl)hexahydropyrrolo[3,4-c]pyrrole- 2(1 H)-carboxylate
To a solution of (3aR,6aS)-tert-butyl hexahydropyrrolo[3,4-c]pyrrole-2(lH)-carboxylate (CAS- R 250275-15-1; 300 mg, 1.34 mmol) in N,N-dimethylformamide (5 mL) was added 2-(3- chlorophenyl)ethanesulfonyl chloride (321 mg, 1.34 mmol) triethylamine (291 mg, 2.87 mmol), and 4-(dimethylamino)pyridine, then after 16 h the reaction mixture was concentrated in vacuo. The residue was partitioned between sat. aq. sodium hydrogencarbonate solution and ethyl aceate. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and evaporated to produce the title compound (520 mg, 93%), which was directly used in the next step.
Step 2: (3aR,6aS)-2-(3-Chlorophenethylsulfonyl)octahydropyrrolo[3,4-c]pyrrole
To a solution of (3aR,6aS)-tert-butyl 5-(3-chlorophenethylsulfonyl)hexahydropyrrolo[3,4- c]pyrrole-2(lH)-carboxylate (520 mg, 1.25 mmol) in methanol (10 mL) was added hydrogen chloride solution (4 M in 1,4-dioxane, 6.3 mL), then after 1 h a few drops of 37% aq.
hydrochloric acid solution were added, then after another 2 h the reaction mixture was concentrated to ½ of the volume. This was basified to pH 7 with 2 M aq. sodium hydroxide solution and was extracted with ethyl acetate. The organic layer was washed with brine and was dried over magnesium sulfate to produce the title compound (320 mg, 81%). Colourless oil, MS: 315.4 (M+H)+. Intermediate 22
3-Chloro-5-(methylsulfonyl)benzaldehyde
To a clear colourless solution of (3-chloro-5-(methylsulfonyl)phenyl)methanol (intermediate 17; 505 mg, 2.29 mmol) in dichloromethane (10 mL) was added l,l,l-triacetoxy-l,l-dihydro-l,2- benziodoxol-3(lH)-one solution (15% in dichlomethane; 5.7 mL, 2.75 mmol) at 0°C, then after 1 h the reaction mixture was allowed to reach room temperature over 1 h. After partitioning between dichloromethane and 1 M aq. sodium thiosulfate solution, the organic layer was washed with water and brine, dried over magnesium sulfate, filtered, and evaporated. Chromatography (silica gel; dichloromethane) afforded the title compound (376 mg, 75%). White solid, MS: 218 (M+). The following intermediate was produced according to intermediate 20, replacing (1H-1,2,3- triazol-4-yl)methanamine hydrochloride by the appropriate amine.
Figure imgf000230_0001
Intermediate 23
(E)-3-(3-chloro-5-(methylsulfonyl)phenyl)acrylic acid
To a clear yellow solution of 3-chloro-5-(methylsulfonyl)benzaldehyde (intermediate 22; 370 mg, 1.69 mmol) and malonic acid (352 mg, 3.38 mmol) in pyridine (3 mL) was added piperidine (28.8 mg, 338 μιηοΐ) and the reaction mixture was heated at reflux for 2 h. After cooling, the reaction mixture was treated with 4 M aq. hydrochloric acid solution. The precipitate was collected by filtration, washed with water, and dried to afford the title compound (352 mg, 78%). White solid, MS: 259.5 (M-H) .
The following intermediates were prepared according to intermediate 23, replacing 3-chloro-5- (methylsulfonyl)benzaldehyde by the appropriate aldehyde.
No. Systematic Name Aldehyde MS, m/e
(E)-3-(3-chloro-5- 3 -chloro-5 -methoxybenzaldehyde 211.1
23.01
methoxyphenyl)acrylic acid (CAS-R 164650-68-4) (M+H)+ No. Systematic Name Aldehyde MS, m/e
(E)-3-(2-fluoro-4- 2-fluoro-4-
249.1
23.02 (trifluoromethoxy)phenyl)acrylic (trifluoromethoxy)benzaldehyde
(M-H) acid (CAS-R 1227628-83-2)
(E)-3-(3-fluoro-4- 3-fluoro-4-
249.5
23.03 (trifluoromethoxy)phenyl)acrylic (trifluoromethoxy)benzaldehyde
(M-H) acid (CAS-RN 473917-15-6)
(E)-3-(4-fluoro-2-
4-fluoro-2- 224.3
23.04 (trifluoromethyl)phenyl)acrylic
(trifluoromethyl)benzaldehyde (M-H) acid
(E)-3-(6-phenylpyridin-3-yl)acrylic 224.3
23.05 6-phenylnicotinaldehyde
acid (M-H)
(E)-3-(5-phenylpyridin-2-yl)acrylic 224.3
23.06 5 -phenylpico linaldehyde
acid (M-H)
(E)-3-(4-(pyridin-4- 224.3
23.07 4-(pyridin-4-yl)benzaldehyde
yl)phenyl)acrylic acid (M-H)
(E)-3-(4-(pyridin-3- 224.3
23.08 4-(pyridin-3 -yl)benzaldehyde
yl)phenyl)acrylic acid (M-H)
(E)-3-(4-(pyridin-2- 224.3
23.09 4-(pyridin-2-yl)benzaldehyde
yl)phenyl)acrylic acid (M-H)
(E)-3-(2-cyclopropylphenyl)acrylic 187.4
23.10 2-cyclopropylbenzaldehyde
acid (M-H)
(E)-3-(2-fluoro-4-(2,2,2- 2-fluoro-4-(2,2,2- 263.0
23.11
trifluoroethoxy)phenyl)acrylic acid trifluoroethoxy)benzaldehyde (M-H)
Intermediate 24 (E)-3-(3-Methoxy-5-(trifluoromethoxy)phenyl)acrylic acid
Step 1 (E)-tert-Butyl 3-(3-methoxy-5-(trifluoromethoxy)phenyl)acrylate
To a colourless solution of l-bromo-3-methoxy-5-(trifluoromethoxy)benzene (CAS-R
1330750-28-1; 1.00 g, 3.62 mmol) in N,N-dimethylformamide (10 mL) was added triethylamine (1.1 g, 10.8 mmol), tert-butyl acrylate (567 mg, 4.34 mmol), palladium(II) acetate (16.2 mg, 72.3 μιηοΐ) and tri-o-tolylphosphine (88 mg, 289 μιηοΐ). The light yellow reaction mixture was evacuated and backfilled with argon, three times. The reaction mixture was heated at 120°C, then after 16 h partitioned between ethyl acetate and sat. aq. sodium hydro gencarbonate solution. The organic layer was washed with water, sat. aq. ammonium chloride solution, and brine, dried over magnesium sulfate, filtered, and evaporated. Chromatography (silica gel; heptane - ethyl acetate gradient) afforded the title compound (984 mg, 85%). Colourless oil, MS: 318 (M+).
Step 2: (E)-3-(3-Methoxy-5-(trifluoromethoxy)phenyl)acrylic acid
To a solution of (E)-tert-butyl 3-(3-methoxy-5-(trifluoromethoxy)phenyl)acrylate (966 mg, 3.03 mmol) in dichloromethane (9 mL) was added trifluoro acetic acid (3.5 mL), then after 2 h the reaction mixture was concentrated in vacuo. The residue was triturated in heptane to afford the title compound (752 mg, 95%). White solid, MS: 261.2 (M-H)".
The following intermediate was prepared according to intermediate 24, replacing l-bromo-3- methoxy-5-(trifluoromethoxy)benzene by the appropriate starting material.
Figure imgf000232_0001
Intermediate 25
(6,7-Dihydro-lH-[l,2,3]triazolo[4,5-c]pyridin-5(4H)-yl)((3aR,6aR)-hexahydropyrrolo[3,4- c]pyrrol-2(lH)-yl)methanone hydrochloride Step 1 : (3aS.6aSVtert-Butyl 5-(4,5.6J-tetrahvdro-lH-[l,2,31triazolo[4,5-clpyridine-5- carbonyDhexahydropyrrolo [3 ,4-c]pyrro le-2( 1 H)-carboxylate
To a colourless solution of 4,5,6,7-tetrahydro-lH-[l,2,3]triazolo[4,5-c]pyridine (CAS-R
706757-05-3; 102 mg, 819 μmol) and N,N-diisopropylethylamine (222 mg, 1.72 mmol) in N,N- dimethylformamide (4 mL) was added a solution of (3aR,6aR)-tert-butyl 5-
(chlorocarbonyl)hexahydropyrrolo[3,4-c]pyrrole-2(lH)-carboxylate (intermediate 9.2; 225 mg, 819 μιηοΐ) in dichloromethane (8 mL), then after 70 h the reaction mixture was partitioned between dichloromethane and sat. aq. ammonium chloride solution. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and evaporated. Chromatography (silica gel; gradient dichloromethane to dichloromethane/methanol/25% aq. ammonia solution 90: 10:0.25) produced the title compound (225 mg, 76%). White foam, MS: 363.6 (M+H)+.
Step 2: (6J-Dihvdro-lH-[l,2,31triazolo[4,5-clpyridin-5(4H -yl ((3aR,6aR - hexahydropyrrolo [3 ,4-c]pyrrol-2( 1 H)-yl)methanone hydrochloride
The title compound was produced in analogy to intermediate 1, step 2 from (3aS,6aS)-tert-butyl 5-(4,5,6,7-tetrahydro-lH-[l,2,3]triazolo[4,5-c]pyridine-5-carbonyl)hexahydropyrrolo[3,4- c]pyrrole-2(lH)-carboxylate. White solid, MS: 263.5 (M+H)+.
The following intermediate was produced according to intermediate 25, replacing 4,5,6,7- tetrahydro-lH-[l,2,3]triazolo[4,5-c]pyridine by the appropriate amine:
Figure imgf000233_0001
Intermediate 26
(E)-l-((3aR,8aS)-Octahydropyrrolo[3,4-d]azepin-6(7H)-yl)-3-(3-(trifluoromethoxy)- phenyl)prop-2-en-l-one Step 1 : from (3aR,8aS)-tert-butyl 6-((E)-3-(3-(trifluoromethoxy)phenyl)acryloyl)- octahydropyrrolo [3 ,4-d]azepine-2( 1 H)-carboxylate
To a solution of (3aR,8aS)-tert-butyl octahydropyrrolo[3,4-d]azepine-2(lH)-carboxylate (CAS- RN 1251013-07-6; 353 mg, 1.47 mmol) and (E)-3-(3-(trifluoromethoxy)phenyl)acrylic acid (341 mg, 1.47 mmol) in N,N-dimethylformamide (10 mL) were added N-ethyldiisopropylamine (570 mg, 4.41 mmol) dropwise over a period of 2 minutes at room temperature under an argon atmosphere. The mixture was cooled down to 0°C and 0-(7-azabenzotriazol-l-yl)-N,N,N',N'- tetramethyluronium hexafluoro -phosphate (563 mg, 1.47 mmol) was added, then after 1 h the ice bath was removed. The reaction mixture was stirred for 16 h at room temperature, then partitioned between ethyl acetate and sat. aq. sodium hydrogencarbonate solution. The organic layer was washed with brine, dried over sodium sulfate, filtered, and evaporated.
Chromatography (silica gel; heptane - ethyl acetate gradient) produced the title compound (768 mg, 87%). White foam, MS: 399.5 (M+H-isobutene)+.
Step 2: (E -l-((3aR,8aS -Octahvdropyrrolo[3,4-dlazepin-6(7H -yl -3-(3- (trifluoromethoxy)phenyl)prop-2-en- 1 -one
Trifluoro acetic acid (1.1 mL, 15 mmol) was added over 5 min to a solution of (3aR,8aS)-tert- butyl 6-((E)-3 -(3 -(trifluoromethoxy)phenyl)acryloyl)octahydropyrro lo [3 ,4-d] azepine-2( 1 H)- carboxylate (768 mg, 1.49 mmol) in dichloromethane (12 mL) at room temperature, then after 5 h the reaction mixture was poured onto ice water, basified to pH 10 with 2 M aq. sodium hydroxide solution, and extracted with chloroform. The organic layer was washed with brine, dried over sodium sulfate, filtered, and evaporated. Chromatography (silica gel;
dichloromethane/methanol 9: 1) produced the title compound (526 mg, 95%). Yellow gum, MS: 355.5 (M+H)+.
The following intermediate was prepared according to intermediate 26, replacing (3aR,8aS)-tert- butyl octahydropyrrolo[3,4-d]azepine-2(lH)-carboxylate by the appropriate amine and (E)-3-(3- (trifluoromethoxy)phenyl)acrylic acid by the appropriate carboxylic acid.
MS,
No. Systematic Name Amine Carboxylic acid
m/e MS,
Systematic Name Amine Carboxylic acid
m/e
(E)-l-((3aR,6aS)- (3aR,6aS)-tert-butyl
hexahydropyrrolo [3 ,4- hexahydropyrrolo [3 ,4- (E)-3-(4-(trifluoro-
327.5 c]pyrrol-2(lH)-yl)-3-(4- c]pyrrole-2(lH)- methoxy)-
(M+H)+ (trifluoromethoxy)phenyl)p carboxylate (CAS-RN phenyl)acrylic acid rop-2-en-l-one 250275-15-1)
3-(3-chlorophenyl)-2,2- cis-octahydro- 3-(3- dimethyl-l-((3aR,8aS)- pyrrolo [3 ,4-d] azepine-2- chlorophenyl)-2,2-
335.6 octahydropyrrolo [3 ,4- carboxylic acid tert-butyl dimethylpropanoic
(M+H)+ d]azepin-6(7H)-yl)propan- ester hydrochloride (CAS- acid (CAS-RN
1-one RN 1251013-07-6) 1225505-29-2)
(E)-3-(3-fluoro-4- cis-octahydro- (E)-3-(3-fluoro-4-
(trifluoromethoxy)phenyl)- pyrrolo [3 ,4-d] azepine-2- (trifluoro- l-((3aR,8aS)- 373.6 carboxylic acid tert-butyl methoxy)- octahydropyrrolo [3 ,4- (M+H)+ ester hydrochloride (CAS- phenyl)acrylic acid d]azepin-6(7H)-yl)prop-2- RN 1251013-07-6) (intermediate 23.3) en-l-one
(E)-3-(4-fluoro-2- cis-octahydro- (trifluoromethyl)phenyl)- 1 - (E)-3-(4-fluoro-2- pyrrolo [3 ,4-d] azepine-2- ((3aR,8aS)- (trifluoromethyl)- 357.6 carboxylic acid tert-butyl
octahydropyrrolo [3 ,4- phenyl)acrylic acid (M+H)+ ester hydrochloride (CAS- d]azepin-6(7H)-yl)prop-2- (intermediate 23.4)
RN 1251013-07-6)
en-l-one MS,
Systematic Name Amine Carboxylic acid
m/e
(E)-3-(2-methyl-4- cis-octahydro- (E)-3-(2-methyl-4-
(trifluoromethoxy)phenyl)- pyrrolo [3 ,4-d] azepine-2- (trifluoro- l-((3aR,8aS)- 369.6 carboxylic acid tert-butyl methoxy)phenyl)- octahydropyrrolo [3 ,4- (M+H)+ ester hydrochloride (CAS- acrylic acid (CAS- d]azepin-6(7H)-yl)prop-2- RN 1251013-07-6) RN 1262012-31-6) en-l-one
(E)-3-(3-fluoro-4- cis-octahydro- methoxyphenyl)- 1 - (E)-3-(3-fluoro-4- pyrrolo [3 ,4-d] azepine-2- ((3aR,8aS)- methoxyphenyl)- 319.6 carboxylic acid tert-butyl
octahydropyrrolo [3 ,4- acrylic acid (CAS- (M+H)+ ester hydrochloride (CAS- d]azepin-6(7H)-yl)prop-2- RN 147906-08-9)
RN 1251013-07-6)
en-l-one cis-octahydro-
(E)-3-(2-isopropyl-phenyl)- (E)-3 -(2-isopropyl- pyrrolo [3 ,4-d] azepine-2- l-(3aS,8aR)-octahydro- phenyl)-acrylic 313.2 carboxylic acid tert-butyl
pyrrolo [3 ,4-d] azepin-6-yl- acid (CAS-RN (M+H)+ ester hydrochloride (CAS- prop-2-en-l-one 1379383-70-6)
RN 1251013-07-6)
(E)-3-(2- cis-octahydro- (E)-3-(2- cyclopropylphenyl)- 1 - pyrrolo [3 ,4-d] azepine-2- cyclopropyl- (trans- 311.6 carboxylic acid tert-butyl phenyl)acrylic acid octahydropyrrolo [3 ,4- (M+H)+ ester hydrochloride (CAS- (intermediate
d]azepin-6(7H)-yl)prop-2- RN 1251013-07-6) 23.10)
en-l-one MS,
No. Systematic Name Amine Carboxylic acid
m/e
(E)-3-(4-methoxy-2- (E)-3-(4-methoxy- cis-octahydro- (trifluoromethyl)phenyl)- 1 - 2-(trifluoro- pyrrolo [3 ,4-d] azepine-2- ((3aR,8aS)- methyl)phenyl)- 369.6
26.09 carboxylic acid tert-butyl
octahydropyrrolo [3 ,4- acrylic acid (CAS- (M+H)+ ester hydrochloride (CAS- d]azepin-6(7H)-yl)prop-2- RN
RN 1251013-07-6)
en-l-one 773131-66-1)
(E)-3-(3-chloro-5- cis-octahydro- (E)-3-(3-chloro-5- (trifluoromethyl)phenyl)- 1 - pyrrolo [3 ,4-d] azepine-2- (trifluoromethyl)- ((3aR,8aS)- 373.6
26.10 carboxylic acid tert-butyl phenyl)acrylic acid
octahydropyrrolo [3 ,4- (M+H)+ ester hydrochloride (CAS- (CAS-RN 886761- d]azepin-6(7H)-yl)prop-2- RN 1251013-07-6) 69-9)
en-l-one
3-(3-fluoro-4-(2,2,2- cis-octahydro- trifluoroethoxy)phenyl)- 1 - 3-(3-fluoro-4- pyrrolo [3 ,4-d] azepine-2- ((3aR,8aS)- (2,2,2-trifluoro- 389.2
26.11 carboxylic acid tert-butyl
octahydropyrrolo [3 ,4- ethoxy)phenyl)- (M+H)+ ester hydrochloride (CAS- d]azepin-6(7H)-yl)propan- propanoic acid
RN 1251013-07-6)
1-one
3-(2-fluoro-4-(2,2,2- 3-(2-fluoro-4- cis-octahydro- trifluoroethoxy)phenyl)- 1 - (2,2,2-trifluoro- pyrrolo [3 ,4-d] azepine-2- ((3aR,8aS)- ethoxy)- 389.2
26.12 carboxylic acid tert-butyl
octahydropyrrolo [3 ,4- phenyl)propanoic (M+H)+ ester (CAS-RN 1251013- d]azepin-6(7H)-yl)propan- acid (intermediate
07-6)
1-one 35.3)
Intermediate 27
(3aR,7aR)-Hexahydrooxazolo[5,4-c]pyridin-2(lH)-one hydrochloride Step 1 : (3aR,7aR)-tert-butyl 2-oxohexahydrooxazolo[5,4-c]pyridine-5(6H)-carboxylate
To a solution of (3R,4R)-tert-butyl 4-amino-3-hydroxypiperidine-l-carboxylate (CAS-RN 1007596-95-3; 500 mg, 2.31 mmol) in N,N-dimethylformamide (5.00 mL) was added imidazole (157 mg, 2.31 mmol) and Ι,Γ-carbonyldiimidazole (375 mg, 2.31 mmol) at room temperature, then after 18 h the reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over magnesium sulfate, filtered and evaporated. The residue was chromato graphed (silica gel; gradient dichloromethane to
dichloromethane/methanol/25% aq. ammonia solution 95:5:0.25) to produce the title compound (401 mg, 72%) as a white solid. Step 2: (3aR,7aR)-Hexahydrooxazolo[5,4-c]pyridin-2(lH)-one hydrochloride
The title compound was produced in analogy to intermediate 1, step 2 from (3aR,7aR)-tert-butyl 2-oxohexahydrooxazolo[5,4-c]pyridine-5(6H)-carboxylate. White solid, MS: 143.2 (M+H)+.
Intermediate 28 cis-Hexahydrooxazolo [5,4-c] yridin-2(lH)-one hydrochloride Step 1 : cis-tert-butyl 2-oxohexahydrooxazolo[5,4-c]pyridine-5(6H)-carboxylate
To a light yellow solution of l-(tert-butoxycarbonyl)-3-hydroxypiperidine-4-carboxylic acid (CAS-RN 1260876-51-4; 196 mg, 799 μιηοΐ) in toluene (2 mL) was added triethylamine (97 mg, 0.96 mmol) and diphenylphosphoryl azide (269 mg, 959 μιηοΐ). The reaction mixture was heated at reflux for 18 h and was then partitioned between ethyl acetate and sat. aq. sodium hydrogen carbonate solution. The organic layer was washed with water and brine, dried over magnesium sulfate, filtered and evaporated. Chromatography (silica gel; ethyl acetate-methanol gradient) produced the title compound (66 mg, 34%). White solid, MS: 241.4 (M-H) .
Step 2: cis-Hexahydrooxazolo [5, 4-c]pyridin-2(lH)-one hydrochloride
The title compound was produced in analogy to intermediate 1, step 2 from cis-tert-butyl 2- oxohexahydrooxazolo[5,4-c]pyridine-5(6H)-carboxylate. White solid, MS: 142.1 (M+).
Intermediate 29
(3aSR,6SR,7aSR)-2-Oxooctahydrobenzo[d]oxazole-6-carboxylic acid Step 1 : (1SR,3SR,4RS)-Methyl 4-bromo-3-(phenoxycarbonyloxy)cyclohexanecarboxylate
To a solution of (lSR,3SR,4RS)-methyl 4-bromo-3-hydroxycyclohexanecarboxylate (CAS 38361-11-4; 500 mg, 2.11 mmol) and pyridine (175 mg, 2.21 mmol) in dichloromethane (8 mL) was added a solution of phenyl carbonochloridate (347 mg, 2.21 mmol) in dichloromethane (1 mL) at -5°C, then after 1 h the reaction mixture was partitioned between dichloromethane and water. The organic layer was washed with sat. aq. ammonium chloride solution and brine, dried over magnesium sulfate, filtered, and evaporated. Chromatography (silica gel; heptane - ethyl acetate gradient) produced the title compound (545 mg, 72%). Colourless oil, MS: 357.4 (M+H)+. Step 2: (1SR,3SR,4SR)-Methyl 4-azido-3-(phenoxycarbonyloxy)cyclohexanecarboxylate
To a solution of (lSR,3SR,4RS)-methyl 4-bromo-3-(phenoxycarbonyloxy)cyclohexane- carboxylate (533 mg, 1.49 mmol) and 15-crown-5 (23.0 mg, 104 μιηοΐ) ίη Ν,Ν- dimethylformamide (4 mL) was added sodium azide (437 mg, 6.71 mmol). The reaction mixture was heated at 75°C for 72 h and was then partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and evaporated. Chromatography (silica gel; dichloromethane) produced the title compound (60 mg, 13%). Colourless oil, MS: 337.2 (M+NH4)+.
Step 3: (3aSR,6SR,7aSR)-Methyl 2-oxooctahydrobenzo[d]oxazole-6-carboxylate
To a colourless solution of (lR,3R,4R)-methyl 4-azido-3- (phenoxycarbonyloxy)cyclohexanecarboxylate (56 mg, 175 μιηοΐ) in tetrahydrofuran (2 mL) and water (50 μί) was added triphenylphosphine (138 mg, 526 μιηοΐ). The solution was heated to 50°C for 3 h and was then partitioned between ethyl acetate and brine. The organic layer was dried over magnesium sulfate, filtered, andevaporated. Chromatography (silica gel; gradient dichloromethane to dichloromethane/methanol/25% aq. ammonia solution 95:5:0.25 produced the title compound (49 mg), which contained triphenylphosphine oxide as an inseparable impurity.
Step 4: (3aSR,6SR,7aSR)-2-Oxooctahydrobenzo[d]oxazole-6-carboxylic acid
The title compound was produced in analogy to intermediate 11, step 2 from (3aSR,6SR,7aSR)- methyl 2-oxooctahydrobenzo[d]oxazole-6-carboxylate. White solid, MS: 184.3 (M-H)~. Intermediate 30A and 30B
(+)-(R)-4,5,6,7-Tetrahydro-lH-benzo[d] [l,2,3]triazole-5-carboxylic acid and (-)-(S)-4,5,6,7- tetrahydro-lH-benzo[d] [l,2,3]triazole-5-carboxylic acid
Racemic 4,5,6,7-tetrahydro-lH-benzo[d][l,2,3]triazole-5-carboxylic acid (CAS-RN 33062-47-4; 1.10 g, 6.58 mmol) was separated by preparative HPLC using a Chiralpak AD column as the stationary phase and heptane/ethanol 3:2 as the mobile phase. This produced the faster eluting (+)-(R)-enantiomer (452 mg, 41%), followed by the slower eluting (-)-(S)-enantiomer (381 mg, 35%).
Intermediate 31 2-(4-Chloro-2-methylphenoxy)-l-((3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol-2(lH)- yl)ethanone hydrochloride
Step 1 : (3aR,6aS)-tert-Butyl 5-(2-bromoacetyl)hexahydropyrrolo[3,4-c]pyrrole-2(lH)- carboxylate
To a solution of (3aR,6aS)-tert-butyl hexahydropyrrolo[3,4-c]pyrrole-2(lH)-carboxylate (CAS- RN 250275-15-l; 400 mg, 1.88 mmo 1) and triethylamine ( 191 mg, 1.88 mmo 1) was added 2- bromoacetyl chloride (297 mg, 1.88 mmol) at -40°C, then after 2 h the reaction mixture was washed with water at 0°C. The organic layer was dried over magnesium sulfate, filtered, and evaporated to produce the title compound (628 mg, 100%), which was directly used in the next step. Step 2: (3aR,6aS)-tert-Butyl 5-(2-(4-chloro-2-methylphenoxy)acetyl)hexahydropyrrolo[3,4- c]pyrrole-2( 1 H)-carboxylate
To a solution of (3aR,6aS)-tert-butyl 5-(2-bromoacetyl)hexahydropyrrolo[3,4-c]pyrrole-2(lH)- carboxylate (100.6 mg, 302 μιηοΐ) and 4-chloro-2-methylphenol (64.6 mg, 453 μιηοΐ,) ίη Ν,Ν- dimethylformamide (5 mL) was added caesium carbonate (197 mg, 604 μιηοΐ) at room
temperature, then after 16 h the reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. Chromatography (silica gel; heptane - ethyl acetate gradient) produced the title compound (57 mg, 48%). Colourless oil, MS: 339.5 (M+H-isobutene)+. Step 3: 2-(4-Chloro-2-methylphenoxy)-l-((3aR,6aS)-hexahydropyrrolo[3^-c]pyrrol-2(lH)- yPethanone hydrochloride
The title compound was produced in analogy to intermediate 1, step 2 from (3aR,6aS)-tert-butyl 5-(2-(4-chloro-2-methylphenoxy)acetyl)hexahydropyrrolo [3 ,4-c]pyrrole-2( 1 H)-carboxylate. Light brown solid, MS : 295.5 (M+H)+.
The following intermediate was produced in analogy to intermediate 31, replacing 4-chloro-2- methylphenol in step 2 by the appropriate phenol.
Figure imgf000241_0001
Intermediate 32
(3aR,8aS)-2-Fluoro-4-(trifluoromethoxy)benzyl octahydropyrrolo [3,4-d] azepine-6(7H)- carboxylate
Step 1 : (3aR,8aS)-2-tert-Butyl 6-(2-fluoro-4-(trifluoromethoxy)benzyl) hexahydropyrrolo[3,4- d]azepine-2,6(lH,7H)-dicarboxylate The title compound was produced in analogy to intermediate 1, step 1 from cis-octahydro- pyrrolo[3,4-d]azepine-2-carboxylic acid tert-butyl ester hydrochloride (CAS-RN 1251013-07-6) and (2-fiuoro-4-(trifluoromethoxy)phenyl)methanol (CAS-RN 1240257-07-1).
Step 2: (3aR,8aS)-2-Fluoro-4-(trifluoromethoxy)benzyl octahydropyrrolo[3,4-d]azepine-6(7H)- carboxylate
The title compound was produced in analogy to intermediate 4, step 2 from (3aR,8aS)-2-tert- butyl 6-(2-fluoro-4-(trifluoromethoxy)benzyl) hexahydropyrrolo [3 ,4-d]azepine-2,6( 1 H,7H)- dicarboxylate. Light brown gum, MS: 377.6 (M+H)+. The following intermediates were produced according to intermediate 32, replacing cis- octahydro-pyrrolo[3,4-d]azepine-2-carboxylic acid tert-butyl ester hydrochloride and (2-fluoro- 4-(trifluoromethoxy)phenyl)methanol by the appropriate amine and alcohol, respectively.
Figure imgf000242_0001
Intermediate 33 2-(2-(Tetrahydrofuran-2-yl)phenoxy)acetic acid
Step 1 : Ethyl 2-(2-(tetrahydrofuran-2-yl)phenoxy)acetate
To a solution of 2-(tetrahydrofuran-2-yl)phenol (CAS-R 40324-49-0; 510 mg, 3.11 mmol) in acetone (4 mL) were added potassium carbonate (859 mg, 6.21 mmol) and ethyl 2-bromoacetate (545 mg, 3.26 mmol) at room temperature, then after 3 h the reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and evaporated to produce the title compound (754 mg, 97%). Light yellow oil, MS:251.5 (M+H)+.
Step 2: 2-(2-(Tetrahydrofuran-2-yl)phenoxy)acetic acid To a solution of ethyl 2-(2-(tetrahydrofuran-2-yl)phenoxy)acetate (754mg, 3.01 mmol) in methanol (2.5 mL) and tetrahydroiuran (12 mL) was added 1 M aq. lithium hydroxide solution (5.12 mL, 5.12 mmol), then after 90 min the reaction mixture was acidified with 2 M aq.
hydrochloric acid solution and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and evaporated to produce the title compound (650 mg, 97%). White solid, MS : 221.2 (M-H) .
The following intermediates were produced according to intermediate 33, replacing 2- (tetrahydrofuran-2-yl)phenol by the appropriate phenol.
No. Systematic Name Phenol MS, m/e
2-(2-bromo-4-(trifluoromethoxy)- 2-bromo-4-(trifluoromethoxy)- 313.3
33.1
phenoxy)acetic acid phenol (CAS-RN 200956-13-4) (M-H)
2-(2-(lH-pyrrol-l- 2-(lH-pyrrol-l-yl)phenol (CAS- 216.5
33.2
yl)phenoxy)acetic acid RN 32277-91-1) (M-H)
2-(2-chloro-4- 2-chloro-4-(trifluoro-
269.5
33.3 (trifluoromethoxy)phenoxy)acetic methoxy)phenol (CAS-RN 70783- (M-H) acid 75-4) Intermediate 34
2-(4-Cyano-2-isopropyl-5-methylphenoxy)acetic acid
Step 1 : tert-Butyl 2-(4-cyano-2-isopropyl-5-methylphenoxy)acetate
To a solution of 4-hydroxy-5-isopropyl-2-methylbenzonitrile (CAS-RN 858026-56-9; 156 mg, 890 μιηοΐ) in acetone (4 mL) were added potassium carbonate (246 mg, 1.78 mmol) and tert- butyl 2-bromoacetate (188 mg, 935 μιηοΐ) at room temperature, then after 3 h the reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and evaporated to produce the title compound (253 mg 98%). White solid, MS: 290.5 (M+H)+. Step 2: 2-(4-Cyano-2-isopropyl-5-methylphenoxy)acetic acid
To a colourless solution of tert-butyl 2-(4-cyano-2-isopropyl-5-methylphenoxy)acetate (248 mg, 857 μιηοΐ) in dichloromethane (3 mL) was added trifluoro acetic acid (1.95 g, 17.1 mmol), then after 3 h the reaction mixture was concentrated and the residue triturated in heptane. The crude product was purified by chromatography (silica gel; dichloromethane-methanol gradient) to afford the title compound (179 mg, 90%). White solid, MS: 232.5 (M-H) .
The following intermediates were produced according to intermediate 34, replacing 4-hydroxy- 5-isopropyl-2-methylbenzonitrile by the appropriate phenol.
No. Systematic Name Phenol MS, m/e
2-(4-cyano-2- 3-isopropyl-4-hydroxy-benzonitrile 218.3
34.1
isopropylphenoxy)acetic acid (CAS-RN 46057-54-9) (M-H)
2-(2-cyano-4-
2-hydroxy-5 -(trifluoromethoxy)- 260.5
34.2 (trifluoromethoxy)phenoxy)acetic
benzonitrile (M-H) acid
2-(2-(pyridin-3-yl)phenoxy)acetic 2-(3-pyridinyl)-phenol (CAS-RN 230.2
34.3
acid 54168-07-9) (M+H)+ Intermediate 35
3-(3-Fluoro-4-(trifluoromethoxy)phenyl)propanoic acid
A solution of (E)-3-(3-fluoro-4-(trifluoromethoxy)phenyl)acrylic acid (intermediate 23.3; 500 mg, 2.00 mmol) in methanol (7 mL) was stirred under a hydrogen atmosphere (1 bar) in the presence of palladium (10% on activated charcoal; 50 mg), then after 20 h insoluble material was removed by filtration through diatomaceous earth. The filtrate was concentrated to produce the title compound (485 mg, 96%). White solid, MS: 251.2 (M-H)".
The following intermediates were produced according to intermediate 35, replacing (E)-3-(3- fluoro-4-(trifluoromethoxy)phenyl)acrylic acid by the appropriate starting material.
Figure imgf000245_0001
Intermediate 36 2-(5-Chloro-2-(trifluoromethyl)phenoxy)-l-((3aR,8aS)-octahydropyrrolo[3,4-d]azepin- 6(7H)-yl)ethanone
Step 1 : (3aR,8aS -tert-butyl 6-(2-(5-chloro-2-
(trifluoromethyl)phenoxy)acetyl)octahydropyrrolo[3^-d]azepine-2(lH)-carboxylate. Caesium carbonate (132 mg, 404 μιηοΐ) was added to a solution of 5-chloro-2- (trifluoromethyl)phenol (47.7 mg, 242 μιηοΐ) and (3aR,8aS)-tert-butyl 6-(2- bromoacetyl)octahydropyrrolo[3,4-d]azepine-2(lH)-carboxylate (intermediate 37; 73 mg, 202 μιηοΐ) in N,N-dimethylformamide (5 mL) at room temperature, then after 18 h the reaction mixture was partitioned between ice water and ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered, and evaporated. Chromatography (silica gel; heptane- ethyl acetate gradient) produced the title compound (82 mg, 83%). White foam, MS: 421.5 (M+H-isobutene)+.
Step 2: 2-(5-Chloro-2-(trifluoromethyl)phenoxy)-l-((3aR,8aS)-octahydropyrrolo[3,4-d]azepin- 6(7H)-yl)ethanone The title compound was produced in analogy to intermediate 26, step 2 from (3aR,8aS)-tert-butyl 6-(2-(5-chloro-2-(trifluoromethyl)phenoxy)acetyl)octahydropyrrolo [3 ,4-d]azepine-2( 1 H)- carboxylate. Light yellow foam, MS: 377.5 (M+H)+.
The following intermediates were produced according to intermediate 36, replacing 5-chloro-2- (trifluoromethyl)phenol by the appropriate phenol.
MS,
No. Systematic Name Phenol
m/e
2-(6-isopropyl-3,3-dimethyl-2,3-dihydro-lH- inden-5-yloxy)-l-((3aR,8aS)- 6-isopropyl-3,3-dimethyl- 385.7
36.01
octahydropyrrolo [3 ,4-d]azepin-6(7H)- 2 , 3 -dihydro - 1 H-inden-5 -o 1 (M+H)+ yl)ethanone MS,
Systematic Name Phenol
m/e
2-(2-isopropyl-5-methylphenoxy)- 1 -
331.6
((3 aR, 8aS)-octahydropyrro lo [3 ,4-d] azepin- 2-isopropyl-5 -methylpheno 1
(M+H)+
6(7H)-yl)ethanone
2-(2-chloro-4-fluorophenoxy)- 1 -((3aR,8aS)-
327.1 octahydropyrrolo [3 ,4-d]azepin-6(7H)- 2-chloro-4-fluorophenol
(M+H)+ yl)ethanone
2-(4-methyl-2-(l-methylpyrrolidin-3- yl)phenoxy)-l-((3aR,8aS)- 4-methyl-2-(l- 372.3 octahydropyrrolo [3 ,4-d]azepin-6(7H)- methylpyrro lidin-3 -yl)pheno 1 (M+H)+ yl)ethanone
4-(2-((3aR,8aS)-octahydropyrrolo[3,4-
4-hydroxy-3- 368.1 d]azepin-6(7H)-yl)-2-oxoethoxy)-3-
(trifluoromethyl)benzonitrile (M+H)+
(trifluoromethyl)benzonitrile
2-(4-chloro-2-isopropyl-5-methylphenoxy)- 1 -
4-chloro-2-isopropyl-5- 365.2 ((3 aR, 8aS)-octahydropyrro lo [3 ,4-d] azepin- methylphenol (M+H)+ 6(7H)-yl)ethanone l-(3aS,8aR)-octahydro-pyrrolo[3,4-d]azepin-
359.6
6-yl-2-(2-trifluoromethoxy-phenoxy)- 2-(trifluoromethoxy)pheno 1
(M+H)+ ethanone
2-(2-tert-butyl-4-methoxyphenoxy)- 1 -
2-tert-butyl-4- 361.6
((3 aR, 8aS)-octahydropyrro lo [3 ,4-d] azepin- methoxyphenol (M+H)+
6(7H)-yl)ethanone
3-isopropyl-4-(2-((3aR,8aS)- 4-hydroxy-3-
342.6 octahydropyrrolo[3,4-d]azepin-6(7H)-yl)-2- isopropylbenzonitrile (CAS-
(M+H)+ oxoethoxy)benzonitrile RN CAS-RN 46057-54-9) MS,
No. Systematic Name Phenol
m/e
2-(2-chloro-4-(trifluoromethyl)phenoxy)- 1 -
2-chloro-4-
36.10 ((3 aR, 8aS)-octahydropyrro lo [3 ,4-d] azepin- n.a.
(trifluoromethyl)pheno 1
6(7H)-yl)ethanone
Intermediate 37
(3aR,8aS)-tert-Butyl 6-(2-bromoacetyl)octahydropyrrolo[3,4-d]azepine-2(lH)-carboxylate
To a suspension of (3aR,8aS)-tert-butyl octahydropyrrolo[3,4-d]azepine-2(lH)-carboxylate hydrochloride (CAS-RN 1251013-07-6; 600 mg, 2.17 mmol) and triethylamine (439 mg, 4.34 mmol) in dichloromethane (40 mL) was added 2-bromoacetyl chloride (341 mg, 2.17 mmol) dropwise at -40°C, then the reaction mixture was allowed to reach room temperature over 2 h and partitioned between water and dichloromethane. The organic layer was dried over sodium sulfate, filtered, and evaporated to produce the title compound (600 mg, 69%; brown oil), which was directly used in the next step.
Intermediate 38
[2-Fluoro-4-(2,2,2-trifluoroethoxy)phenyl] methanol
Sodium borohydride was added portionwise at 0°C to a solution of 2-fluoro-4-(2,2,2- trifluoroethoxy)benzaldehyde (intermediate 39; 500 mg, 2.25 mmol) in methanol (3 mL), then the reaction mixture was allowed to reach room temperature over 3 h. After addition of water (5 mL) and evaporation of methanol, the reaction mixture was partitioned between ethyl acetate and water. The organic layer was dried over sodium sulfate, filtered, and evaporated to produce the title compound (450 mg, 87%). Colourless oil, MS: 224 (M+).
Intermediate 39 2-Fluoro-4-(2,2,2-trifluoroethoxy)benzaldehyde
To a solution of 2-fluoro-4-hydroxybenzaldehyde (1.00 g, 7.14 mmol) in N,N- dimethylformamide (6 mL) were added potassium carbonate (1.48 g, 10.7 mmol) and 2,2,2- trifluoro ethyl trifluoromethanesulfonate (1.99 g, 8.56 mmol) at room temperature. The reaction mixture was heated at 50°C for 2 h, then partitioned between ethyl acetate and water. The organic layer was dried over sodium sulfate, filtered, and evaporated to produce the title compound (1.30 g, 80%). White solid, MS: 222 (M+).
Intermediate 40 2-(2-tert-Butyl-4-cyanophenoxy)acetic acid
A mixture of 2-(4-bromo-2-tert-butylphenoxy)acetic acid (CAS-RN 425372-86-7; 453mg, 1.58 mmol,), l,l'-bis(diphenylphosphino)ferrocene (26.2 mg, 47.3 μιηοΐ),
tris(dibenzylideneacetone)dipalladium(0) (14.4 mg, 15.8 μιηοΐ), zinc cyanide (102 mg, 868 μιηοΐ,), zinc powder (4.13 mg, 63.1 μιηοΐ) and zinc acetate (11.6 mg, 63.1 μιηοΐ), Ν,Ν- dimethylformamide (4.5 mL) and water (45 μΐ) was heated at 180°C for 15 min under
microwave irradiation, then evaporated under vacuum. The residue was taken up in ethyl acetate, then insoluble material was removed by filtration through diatomaceous earth. The filtrate was evaporated and the residue purified by chromatography (silica gel; ethyl acetate-methanol gradient, then dichloromethane-methanol gradient) to produce the title compound (64 mg, 22%). Dark brown solid. MS : 232.5 (M-H) .
Intermediate 41
4-(Hydroxymethyl)-3-isopropylbenzonitrile
Step 1 : 4-Cyano-2-isopropylphenyl trifluoromethanesulfonate To a solution of pyridine (895 mg, 11.3 mmol) in dichloromethane (70 mL) was added
trifluoromethanesulfonic anhydride (2.93 g, 10.4 mmol) at 0°C, then after 10 min a solution of 4- hydroxy-3-isopropylbenzonitrile (CAS-RN 46057-54-9; 1.52 g, 9.43 mmol) in dichloromethane (40 mL) was added dropwise to the white suspension that had formed. The ice bath was removed, then after 75 min the reaction mixture was partitioned between dichloromethane and water. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and evaporated. Chromatography (silica gel; heptane-dichloromethane gradient) produced the title compound (2.63 g, 95%). Yellow liquid, MS: 292.1 (M-H) . Step 2: Methyl 4-cyano-2-isopropylbenzoate
A solution of 4-cyano-2-isopropylphenyl trifluoromethanesulfonate (2.62 g, 8.93 mmol), triethylamine (2.26 g, 22.3 mmol), and bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (365 mg, 447 μιηοΐ) was stirred for 20 h under a carbon monoxide atmosphere (50 bar) at 110°C. After cooling the reaction mixture was evaporated and the residue was purified by chromatography (silica gel; dichloromethane/heptane 1 : 1) to produce the title compound (1.40 g, 77%). Light yellow oil, MS: 218.5 (M+H)+.
Step 3: 4-(Hydroxymethyl)-3-isopropylbenzonitrile
Lithium boro hydride solution (2 M in tetrahydrofuran, 9.06 mL, 18.1 mmol) was added at room temperature to a solution of methyl 4-cyano-2-isopropylbenzoate (1.227 g, 6.04 mmol) in tetrahydrofuran (15 mL). The reaction mixture was heated at reflux for 1 h, then partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and evaporated. Chromatography (silica gel; gradient
dichloromethane to dichloromethane/methanol/25% aq. ammonia solution 95:5:0.25) afforded the title compound (802 mg, 76%). Light yellow oil, MS: 176.2 (M+H)+.
The following intermediates were produced according to intermediate 41, replacing 4-hydroxy- 3-isopropylbenzonitrile by the appropriate phenol.
MS,
No. Systematic Name Phenol
m/e
4-(hydroxymethyl)-5-isopropyl-2- 4-hydroxy-5 -isopropyl-2-methyl- 190.3
41.1
methylbenzonitrile benzonitrile (CAS-R 858026-56-9) (M+H)+ MS,
No. Systematic Name Phenol
m/e
3-ethoxy-4- 3 -ethoxy-4-hydroxy-benzonitrile 177
41.2
(hydroxymethyl)benzonitrile (CAS-R 60758-79-4) (M)+
Intermediate 42
3-(4-Cyano-2-isopropylphenyl)propanoic acid
Triethylamine (1.22 g, 12.1 mmol) was added dropwise to formic acid (1.36 g, 29.6 mmol) at 0°C. This was added to 4-formyl-3-isopropylbenzonitrile (190 mg, 1.1 mmol) and 2,2-dimethyl- l,3-dioxane-4,6-dione (158 mg, 1.1 mmol). The solution was stirred at room temperature for 3 h, then poured upon ice water, acidified with 4 M aq. hydrochloric acid solution, and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and evaporated to afford crude 4-[(2,2-dimethyl-4,6-dioxo-l,3-dioxan-5-yl)methyl]-3-isopropyl- benzonitrile (334 mg) as a light yellow foam, MS: 302.4 (M+H) . This was dissolved in acetonitrile/water 100: 1 (2 mL) and heated at 100°C for 30 min under microwave irradiation, then concentrated in vacuo. The resiude was partitioned between 2 M hydrochloric acid solution and ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and evaporated to afford the title compound (240 mg), which was used directly in the next step. Yellow oil, MS: 216.3 (M+H)+.
The following intermediate was produced according to intermediate 42, replacing 4-formyl-3- isopropylbenzonitrile by the appropriate aldehyde.
MS,
No. Systematic Name Phenol
m/e MS,
No. Systematic Name Phenol
m/e
3-(4-cyano-2-isopropyl-5- 4-formyl-5-isopropyl-2-methyl- 230.2
42.1
methylphenyl)propanoic acid benzonitrile (intermediate 22.2) (M-H)
Intermediate 43
6-Fluoro-lH-benzo[d] [l,2,3]triazole-5-carboxylic acid
Step 1 : Methyl 6-fluoro-lH-benzo[d][l,2,3]triazole-5-carboxylate A solution of 5-bromo-6-fiuoro-lH-benzo[d][l,2,3]triazole (CAS-RN 1242336-69-1; 492 mg, 2.28 mmol), triethylamine (576 mg, 5.69 mmol), and l,l'-bis(diphenylphosphino)ferrocene- palladium(II) dichloride dichloromethane complex (74.4 mg, 91.1 μιηοΐ), in methanol (6 mL) was stirred at 110°C under a carbon monoxide atmosphere (70 bar) for 18 h. After cooling insoluble material was separated by filtration through diatomaceous earth. The filtrate was evaporated and purified by chromatography (silica gel; dichloromethane-methanol gradient) to produce the title compound (281 mg, 63%). Light red solid, MS: 194.2 (M-H)".
Step 2: 6-Fluoro-lH-benzo[d][l,2,3]triazole-5-carboxylic acid
To a solution of methyl 6-fluoro-lH-benzo[d][l,2,3]triazole-5-carboxylate (276 mg, 1.41 mmol) in tetrahydrofuran (3 mL) and methanol (1.5 mL) was added 1 M aq. lithium hydroxide solution 1 M in water (4.24 mL, 4.24 mmol). After 5 h most of the organic solvents were removed by concentration under reduced pressure, then the aqueous solution was acidified with 1 M aq. hydrochloric acid solution. The precipitate was collected by filtration and dried to afford the title compound (266 mg, 100 %). Off-white solid, MS: 180.2 (M-H)".
The following intermediates were produced according to intermediate 43, replacing 5-bromo-6- fluoro-lH-benzo[d][l,2,3]triazole by the appropriate starting material. MS,
No. Systematic Name Starting material
m/e
5-bromo-7-fluoro-lH-
7-fluoro- 1 H-benzo [d] [ 1 ,2,3]triazole- 180.2
43.1 benzo [d] [ 1 ,2,3 Jtriazo le (intermediate
5-carboxylic acid (M-H)
44)
5-bromo-4-fluoro-lH-
4- fluoro- 1 H-benzo [d] [ 1 ,2,3]triazole- 180.2
43.2 benzo [d] [ 1 ,2,3 Jtriazo le (intermediate
5- carboxylic acid (M-H)
44.1)
5-bromo-4-methyl-lH-
4- methyl- 1 H-benzo [d] [ 1 ,2,3]triazole- 176.2
43.3 benzo[d][l,2,3]triazole (CAS-R
5- carboxylic acid (M-H)
1372795-26-0)
6-(trifluoromethyl)- 1 H- 5-bromo-6-(trifluoromethyl)-lH-
230.1
43.4 benzo[d] [ 1 ,2,3]triazole-5-carboxylic benzo[d][l,2,3]triazole (CAS-RN
(M-H) acid 157590-65-3)
5-bromo-4-chloro-lH-
4- chloro- 1 H-benzo [d] [ 1 ,2,3]triazole- 196.2
43.5 benzo[d][l,2,3]triazole (CAS-RN
5- carboxylic acid (M-H)
1388044-33-4)
5-bromo-6-methyl-lH-
6-methyl- 1 H-benzo [d] [ 1 ,2,3]triazole- 176.4
43.6 benzo[d][l,2,3]triazole (CAS-RN
5-carboxylic acid (M-H)
1388070-91-4)
Example 44
5-bromo-7-fluoro-lH-benzo[d] [l,2,3]triazole
A solution of sodium nitrite (185 mg, 2.68 mmol) in water (0.5 mL) was added dropwise at room temperature to a solution of 5-bromo-3-fluorobenzene-l,2-diamine (500 mg, 2.44 mmol) in water (5 mL) and acetic acid (1.8 mL). The reaction mixture was stirred at room temperature for 1 h, then heated at 85°C for another hour, then partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and evaporated to produce the title compound (498 mg, 94%). Light brown solid, MS: 214.1 (M-H) .
The following intermediate was produced according to intermediate 44, replacing 5-bromo-6- fluoro-lH-benzo[d][l,2,3]triazole by the appropriate starting material.
Figure imgf000254_0001
Intermediate 45
3H- [ 1 ,2,3] triazolo [4,5-c] yridine-6-carbox lic acid
Step 1 : Methyl 3H-[l,2,3]triazolo[4,5-c]pyridine-6-carboxylate
A solution of sodium nitrite (413 mg, 5.99 mmol) in water (1.5 mL) was added dropwise at 0°C to a solution of methyl 4,5-diaminopicolinate (CAS-R 850689-13-3; 910 mg, 5.44 mmol) in water (10 mL) and acetic acid (2 mL) at 0°C, then after 1 h acetic acid (2 mL) was added to the suspension formed. The reaction mixture was stirred for 1 h at 85°C and filtered hot. The precipitate was triturated in methanol to produce the title compound (758 mg, 78%). Red solid, MS: 177.2 (M-H) .
Step 2: 3H-[l,2,3]Triazolo[4,5-c]pyridine-6-carboxylic acid
The title compound was produced in analogy to intermediate 43, step 2 from ethyl 3H- [l,2,3]triazolo[4,5-c]pyridine-6-carboxylate. Light brown solid, MS: 163.1 (M-H) .
The following intermediate was produced according to intermediate 45, replacing methyl 4,5- diaminopicolinate by the appropriate starting material. MS,
No. Systematic Name Starting material
m/e
4-methoxy- 1 H-benzo [d] [ 1 ,2,3 ]tri- methyl 3,4-diamino-2-methoxy- 192.3
45.1
azole-5-carboxylic acid benzoate (CAS-R 538372-37-1) (M-H)
Intermediate 46
3-Cyclobutoxy-4-(hydroxymethyl)benzonitrile Step 1 : 4-Cyano-2-cyclobutoxybenzoic acid
To a suspension of sodium hydride (60% dispersion in mineral oil, 545 mg, 13.6 mmol) in N,N- dimethylformamide (20 mL) was added cyclobutanol (1.05 g, 13.9 mmol) dropwise below 30°C. The clear solution obtained was stirred for 2 h, then a solution of 4-cyano-2-fluorobenzoic acid (1.00 g, 6.06 mmol) in N,N-dimethylformamide (15 mL) was added dropwise below 35°C. The light yellow suspension was stirred for 66 h at room temperature, then partitioned between water and heptane. The aqueous layer was seperated and acidified to pH 2.5with 3 M aq. hydrochloric acid solution to pH 2.5. The precipitate was collected by filtration, washed with water and dried to afford the title compound (1.03 g, 79%). White foam, MS: 216.2 (M-H) .
Step 2: 3-Cyclobutoxy-4-(hydroxymethyl)benzonitrile Borane dimethyl sulfide complex (429 mg, 5.64 mmol) was added at 0°C to a solution of 4- cyano-2-cyclobutoxybenzoic acid (613 mg, 2.82 mmol) in tetrahydrofuran (8 mL). After 30 min the ice bath was removed, then after 3 h the reaction was stopped by careful addition of water. The reaction mixture was extracted with ethyl acetate, the organic layer was washed with sat. aq. ammonium chloride solution and brine, dried over magnesium sulfate, filtered, and evaporated. Chromatography (silica gel; dichloromethane) afforded the title compound (452 mg, 79%). White solid , MS: 203 (M+). The following intermediate was produced according to intermediate 46, replacing cyclobutanol by the appropriate alcohol.
Figure imgf000256_0001
Intermediate 47 (4-Chloro-2-ethoxy-5-fluorophenyl)methanol
Step 1 : Ethyl 4-chloro-2-ethoxy-5-fluorobenzoate
To a solution of methyl 4-chloro-2,5-difiuorobenzoate (CAS-RN 1214361-01-9; 848 mg, 4.11 mmol) in N,N-dimethylformamide (8 mL) was added a freshly prepared sodium ethoxide solution (94.4 mg/4.11 mmol sodium in 2 mL ethanol) at 0 °C. The reaction mixture was allowed to reach room temperature over 30 min, then partitioned between ethyl acetate and 1 M hydrochloric acid solution. The organic layer was washed with water and brine, dried over magnesium sulfate, filtered, and evaporated. Chromatography (silica gel; heptane-ethyl acetate gradient) afforded the title compound (484 mg, 48%) and methyl 4-chloro-2-ethoxy-5- fluorobenzoate (192 mg, 20%). White solid, MS: 247.2 (M+H)+. Step 2: (4-Chloro-2-ethoxy-5-fluorophenyl)methanol
The title compound was produced in analogy to intermediate 41, step 3 from ethyl 4-chloro-2- ethoxy-5-fluorobenzoate. White solid, MS: 204 (M+).
The following intermediate was produced according to intermediate 47, replacing methyl 4- chloro-2,5-difluorobenzoate tert-butyl ester hydrochloride and ethanol by the appropriate ester and alcohol, respectively.
MS,
No. Systematic Name Ester Alcohol
m/e MS,
No. Systematic Name Ester Alcohol
m/e
4-(hydroxymethyl)-3 - methyl 4-cyano-2- 2,2,2- 231
47.1 (2,2,2- fluorobenzoate trifluoroethanol (M+) trifluoroethoxy)benzonitrile
Intermediate 48
4-(Hydroxymethyl)-3-(methylsulfonyl)benzonitrile
Step 1 : 4-Cyano-2-(methylthio)benzoate To a solution of methyl 4-cyano-2-fluorobenzoate (500 mg, 2.79 mmol) in N,N- dimethylformamide (5 mL) was added sodium thiomethoxide (293 mg, 4.19 mmol, Eq: 1.5) at 0°C. After 2 h the reaction mixture was partitioned between sat. aq sodium hydrogen carbonate solution and ethyl acetate 3 times. The organic layer was washed with water and brine, dried over magnesium sulfate, filterd and evaporated to afford the title compound (434 mg, 75%). White solid, MS : 207 (M+).
Step 2: 4-Cyano-2-(methylsulfonyl)benzoate
To a of methyl 4-cyano-2-(methylthio)benzoate (420 mg, 2.03 mmol) in dichloromethane (10 mL) was added a suspension of 3-chloroperoxybenzoic acid (1.82 g, 8.11 mmol) in
dichloromethane (15 mL) portionwise at 0°C. The reaction mixture was stirred at 0°C for 45 min and at room temperature for 45 min, then partitioned between dichloromethane and 1 M sodium sulfite solution. The organic layer was washed with sat. aq. sodium hydrogen carbonate solution and brine, dried over magnesium sulfate, filtered, and evaporated. The residue was triturated in heptane/ethyl acetate 7:3 to afford the title compound (453 g, 93%). White solid, MS: 239 (M+).
Step 3: 4-(Hydroxymethyl)-3-(methylsulfonyl)benzonitrile A solution of calcium chloride (390 mg, 3.51 mmo) in ethanol (10 mL) was added at room temperature to a solution of methyl 4-cyano-2-(methylsulfonyl)benzoate (420 mg, 1.76 mmol) in tetrahydrofuran (10 mL). Then sodium borohydride (266 mg, 7.02 mmol) was added portionwise over 20 min. After 2 h the reaction mixture was partitioned between sat aq. ammonium chloride solution and ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and evaporated. Chromatography (silica gel, dichloromethane/ethanol 19: 1) afforded the title compound (123 mg, 33%). White soilid, MS: 211 (M+).
Intermediate 49
5-Ethoxy-2-fluoro-4-(hydroxymethyl)benzonitrile
Step 1 : Ethyl 4-bromo-2-ethoxy-5-fluorobenzoate
The title compound was produced in analogy to intermediate 47, step 1 from methyl 4-bromo- 2,5-difluorobenzoate (CAS-R 1193162-21-8). White solid, MS: 290 (M+). Step 2: Ethyl 4-cyano-2-ethoxy-5-fluorobenzoate
A mixture of ethyl 4-bromo-2-ethoxy-5-fluorobenzoate (50mg, 172 μιηοΐ), zinc cyanide (11.1 mg, 94.5 μιηοΐ), zinc powder (0.4 mg, 7 μιηοΐ, Eq: .04), zinc acetate (1.3 mg, 7 μιηοΐ, Eq: .04) l,l'-bis(diphenylphosphino)ferrocene (2.9 mg, 5.2 μιηοΐ), and
tris(dibenzylideneacetone)dipalladium(0) (1.6 mg, 1.8 μιηοΐ) in N,N-dimethylformamide (500 μΐ) and water (5 μΐ) was heated at 120°C for 15 min under microwave irradiation, then insoluble material was removed by filtration through diatomaceous earth and the filtrate was evaporated. The residue was purified by chromatography (silica gel; heptane-dichloromethane gradient) to produce the title compound (41 mg, quant.). White solid. MS: 237 (M+).
Step 3: 5-Ethoxy-2-fluoro-4-(hydroxymethyl)benzonitrile The title compound was produced in analogy to intermediate 41, step 3 from ethyl 4-cyano-2- ethoxy-5-fluorobenzoate. White solid. MS: 195 (M+).
Example A
A compound of formula (I) can be used in a manner known per se as the active ingredient for the production of tablets of the following composition:
Per tablet Active ingredient 200 mg
Micro crystalline cellulose 155 mg
Corn starch 25 mg
Talc 25 mg
Hydro xypropylmethylcellulo se 20 mg
425 mg
Example B
A compound of formula (I) can be used in a manner known per se as the active ingredient for the production of capsules of the following composition: Per capsule
Active ingredient 100.0 mg
Corn starch 20.0 mg
Lactose 95.0 mg
Talc 4.5 mg
Magnesium stearate 0.5 mg
220.0 mg

Claims

Claims
Compounds of formula (I)
Figure imgf000260_0001
wherein
R1 is alkyl, haloalkyl, substituted cycloalkyl, substituted cycloalkylalkyl, substituted
piperazinyl, substituted piperidinyl, substituted indanyloxyalkyl, substituted phenyl, substituted phenylalkyl, substituted phenoxyalkyl, substituted phenylcyclo alkyl, substituted phenylalkenyl, substituted phenylalkynyl, substituted pyridinyl, substituted pyridinylalkyl, substituted pyridinylalkenyl, substituted pyridinylalkynyl substituted thiophenyl, substituted thiophenylalkyl, substituted thiophenylalkenyl, substituted thiophenylalkynyl, naphtyl, substituted naphthyl, quinolyl, substituted quinolinyl, isoquinolyl, substituted iso quinolinyl, substituted 2,3-dihydro-lH-isoindol-2-yl, substituted lH-indol-2-yl or substituted benzofuran-2-yl wherein substituted cycloalkyl, substituted cycloalkylalkyl, substituted piperazinyl, substituted piperidinyl, substituted indanyloxyalkyl, substituted phenyl, substituted phenylalkyl, substituted phenylalkynyl, substituted phenoxyalkyl, substituted phenylcycloalkyl, substituted phenylalkenyl, substituted pyridinyl, substituted pyridinylalkyl, substituted
pyridinylalkenyl, substituted pyridinylalkynyl, substituted thiophenyl, substituted thiophenylalkyl, substituted thiophenylalkenyl, substituted thiophenylalkynyl, substituted naphthyl, substituted quinolinyl, substituted iso quinolinyl, substituted 2,3- dihydro-lH-isoindol-2-yl,substituted lH-indol-2-yl and substituted benzofuran-2-yl are substituted with R8, R9 and R10;
Y is -OC(O)-, -NR7C(0)-, -C(O)-, -S(0)2-,
Figure imgf000260_0002
A is -N- or CR5-; W is -0-, -S-, -NR6-, -C(O)-, -S(0)2-, -C(0)-NR6- or -CR3R4-;
R3 and R4 are independently selected from H, halogen, alkyl and cycloalkyl;
R5, R6 and R7 are independently selected from H, alkyl and cycloalkyl;
R8, R9 and R10 are independently selected from H, alkyl, hydroxyalkyl, haloalkyl,
hydroxyhaloalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkoxy, cycloalkoxy, cycloalkoxyalkyl, cycloalkylalkoxyalkyl, alkoxy, alkoxyalkyl, haloalkoxy, alkoxyhaloalkyl, alkoxyalkoxy, alkoxyalkoxyalkyl, phenyl, substituted phenyl, pyridinyl, substituted pyridinyl, pyrrolyl, substituted pyrrolyl, pyrrolydinyl, substituted pyrrolydinyl, tetrahydroftiranyl, substituted tetrahydroftiranyl, halogen, hydroxy, cyano, alkylsulfanyl, haloalkylsulfanyl, cycloalkylsulfanyl, alkylsulfinyl,
halo alky lsulfinyl, cycloalkylsulfinyl, alkylcarbonyl, halo alky lcarbonyl,
cycloalkylcarbonyl, alkylsulfonyl, haloalkylsulfonyl, cycloalkylsulfonyl, substituted aminosulfonyl, substituted amino and substituted aminoalkyl, wherein substituted aminosulfonyl, substituted amino and substituted aminoalkyl are substituted on the nitrogen atom with one to two substituents independently selected from H, alkyl, cycloalkyl, cycloalkylalkyl, hydroxyalkyl, alkoxyalkyl, alkylcarbonyl and
cycloalkylcarbonyl, and wherein substituted phenyl, substituted pyrrolyl, substituted pyrrolydinyl, substituted tetrahydroftiranyl, and substituted pyridinyl are substituted with one to three substituents independently selected from alkyl, halogen, haloalkyl, alkoxy and haloalkoxy; m, n, p and q are independently selected from 1 or 2;
Figure imgf000262_0001
Figure imgf000263_0001
Figure imgf000263_0002
Figure imgf000263_0003
Figure imgf000263_0004
AE AF AG
Figure imgf000263_0005
AH Al AJ s H, alkyl, haloalkyl or cycloalkyl; s alkyl, halogen, haloalkyl and alkoxy;R2is selected from the ring systems B, C, D, E, F, G, H, I, J, K, L, M, N, O, P, Q, R, S, T, U, V, X, Z, AA, AB, AC, AD, AE, AF, AG, AH, AI and AJ; and pharmaceutically acceptable salts.
A compound according to claim 1 , wherein
R1 is alkyl, haloalkyl, substituted cycloalkyl, substituted cycloalkylalkyl, substituted
phenyl, substituted phenylalkyl, substituted phenoxyalkyl, substituted
phenylcyclo alkyl, substituted phenylalkenyl, substituted phenylalkynyl, substituted pyridinyl, substituted pyridinylalkyl, substituted pyridinylalkenyl, substituted pyridinylalkynyl, substituted thiophenyl, substituted thiophenylalkyl, substituted thiophenylalkenyl, substituted thiophenylalkynyl, substituted 2,3-dihydro-lH-isoindol- 2-yl, substituted lH-indol-2-yl or substituted benzofuran-2-yl wherein substituted cycloalkyl, substituted cycloalkylalkyl, substituted phenyl, substituted phenylalkyl, substituted phenylalkynyl, substituted phenoxyalkyl, substituted phenylcyclo alkyl, substituted phenylalkenyl, substituted pyridinyl, substituted pyridinylalkyl, substituted pyridinylalkenyl, substituted pyridinylalkynyl, substituted thiophenyl, substituted thiophenylalkyl, substituted thiophenylalkenyl, substituted thiophenylalkynyl, substituted 2,3-dihydro-lH-isoindol-2-yl,substituted lH-indol-2-yl and substituted benzofuran-2-yl are substituted with R8, R9 and R10;
Y is -OC(O)-, -NR7C(0)-, -C(O)-, -S(0)2-,
Figure imgf000264_0001
or ; A is -N- or CR5-;
W is -0-, -S-, -NR6-, -C(O)-, -S(0)2-, -C(0)-NR6- or -CR3R4-;
R3 and R4 are independently selected from H, halogen, alkyl and cycloalkyl;
R5, R6 and R7 are independently selected from H, alkyl and cycloalkyl;
R8, R9 and R10 are independently selected from H, alkyl, hydroxyalkyl, haloalkyl,
hydroxyhaloalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkoxy, cycloalkoxy, cycloalkoxyalkyl, cycloalkylalkoxyalkyl, alkoxy, alkoxyalkyl, haloalkoxy,
alkoxyhaloalkyl, alkoxyalkoxy, alkoxyalkoxyalkyl, phenyl, substituted phenyl, pyridinyl, substituted pyridinyl, halogen, hydroxy, cyano, alkylsulfanyl,
halo alky lsulfanyl, eye lo alkylsulfanyl, alkylsulfmyl, halo alky lsulfmyl, cycloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl, cycloalkylsulfonyl, substituted aminosulfonyl, substituted amino and substituted aminoalkyl, wherein substituted aminosulfonyl, substituted amino and substituted aminoalkyl are substituted on the nitrogen atom with one to two substituents independently selected from H, alkyl, cycloalkyl, cycloalkylalkyl, hydroxyalkyl, alkoxyalkyl, alkylcarbonyl and
cycloalkylcarbonyl, and wherein substituted phenyl and substituted pyridinyl are optionally substituted with one to three substituents independently selected from alkyl, halogen, haloalkyl, alkoxy and haloalkoxy;
, n, p and q are independently selected from 1 or 2;
Figure imgf000266_0001
Figure imgf000267_0001
Figure imgf000267_0002
Figure imgf000267_0003
Figure imgf000267_0004
AE
R11 is H, alkyl, haloalkyl or cycloalkyl;
R2 is selected from the ring systems B, C, D, E, F, G, H, I, J, K, L, M, N, O, P, Q, R, S, T, U, V, X, Z, AA, AB, AC, AD and AE; and pharmaceutically acceptable salts.
A compound according to claim 1, wherein R1 is substituted cycloalkylalkyl, substituted piperazinyl, substituted piperidinyl, substituted indanyloxyalkyl, substituted phenyl, substituted phenylalkyl, substituted phenoxyalkyl, substituted phenylcyclo alkyl, substituted phenylalkenyl, substituted pyridinylalkyl, substituted pyridinylalkenyl, naphtyl, substituted naphthyl, substituted quinolinyl, substituted isoquinolinyl, or substituted 1H- indol-2-yl, wherein substituted cycloalkylalkyl, substituted piperazinyl, substituted piperidinyl, substituted indanyloxyalkyl, substituted phenyl, substituted phenylalkyl, substituted phenoxyalkyl, substituted phenylcycloalkyl, substituted phenylalkenyl, substituted pyridinylalkyl, substituted pyridinylalkenyl, substituted naphthyl, substituted quinolinyl, substituted isoquinolinyl and substituted lH-indol-2-yl are substituted with R8,
R9 and R10.
4. A compound according to any one of claims 1 to 3, wherein R1 is substituted
cycloalkylalkyl, substituted phenyl, substituted phenylalkyl, substituted phenoxyalkyl, substituted phenylcycloalkyl, substituted phenylalkenyl, substituted pyridinylalkyl, substituted pyridinylalkenyl or substituted lH-indol-2-yl, wherein substituted
cycloalkylalkyl, substituted phenyl, substituted phenylalkyl, substituted phenoxyalkyl, substituted phenylcycloalkyl, substituted phenylalkenyl, substituted pyridinylalkyl, substituted pyridinylalkenyl, and substituted lH-indol-2-yl are substituted with R8, R9 and R10. 5. A compound according to any one of claims 1 to 4, wherein R1 is substituted phenylalkyl or substituted phenylalkenyl, wherein substituted phenylalkyl and substituted
phenylalkenyl are substituted with R8, R9 and R10.
6. A compound according to any one of claims 1 to 5, wherein R1 is phenylalkyl substituted with R8, R9 and R10. 7. A compound according to any one of claims 1 to 6, wherein Y is -OC(O)-, -C(O)-, -S(0)2-
Figure imgf000268_0001
8. A compound according to any one of claims 1 to 7, wherein Y is -OC(O)- or -C(O)-.
9. A compound according to any one of claims 1 to 8, wherein Y is -OC(O)-.
10. A compound according to any one of claims 1 to 8, wherein Y is -C(O)-. 11. A compound according to any one of claims 1 to 10, wherein A is -N-.
12. A compound according to any one of claims 1 to 11, wherein W is -0-, -NR6-, -C(O)-, - S(0)2-, -C(0)-NR6- or -CR3R4-.
13. A compound according to any one of claims 1 to 12, wherein W is -C(O)-, -C(0)-NR6- or CR3R4-.
14. A compound according to any one of claims 1 to 13, wherein W is -C(O)-.
15. A compound according to any one of claims 1 or 3 to 14, wherein R2 is selected from the ring systems B, C, D, E, G, H, M, O, P, R, S, T, U, V, X, Z, AA, AB, AC, AD, AE, AF, AG, AH and AI.
16. A compound according to any one of claims 1 to 15, wherein R2 is selected from the ring systems B, C, D, E, G, H, M, O, P, R, S, T, U, V, X, Z, AA, AB, AC, AD and AE.
17. A compound according to any one of claims 1 to 16, wherein R2 is selected from the ring systems B, D, H, M, O, R and AJ.
18. A compound according to any one of claims 1 to 17, wherein R2 is selected from the ring systems B, D, H, O and R. 19. A compound according to any one of claims 1 to 18, wherein R2 is selected from the ring systems B and D.
20. A compound according to any one of claims 1 to 19, wherein R2 is the ring system D.
21. A compound according to any one of claims 1 to 20, wherein R3 and R4 are H.
22. A compound according to any one of claims 1 to 10 and 12 to 21, wherein R5 is H. 23. A compound according to any one of claims 1 to 13 and 14 to 22, wherein R6 is H or alkyl.
24. A compound according to any one of claims 1 to 23, wherein R8, R9 and R10 are
independently selected from H, alkyl, haloalkyl, hydroxyhaloalkyl, alkoxy, haloalkoxy, alkoxyhaloalkyl, phenyl, pyridinyl, halogen, cyano, halo alky lsulfanyl, halo alky lsulfinyl, alkylsulfonyl, haloalkylsulfonyl, pyrrolyl substituted with one alkyl, pyrrolydinyl, tetrahydroiuranyl, alkylcarbonyl, and aminosulfonyl substituted on the nitrogen atom with one to two substituents independently selected from H, alkyl, cycloalkyl, cycloalkylalkyl, hydroxyalkyl, alkoxyalkyl, alkylcarbonyl and cycloalkylcarbonyl.
25. A compound according to any one of claims 1 to 24, wherein R8, R9 and R10 are
independently selected from H, alkyl, haloalkyl, hydroxyhaloalkyl, alkoxy, haloalkoxy, alkoxyhaloalkyl, phenyl, pyridinyl, halogen, cyano, halo alky Isulfanyl, halo alky lsulfinyl, alkylsulfonyl, haloalkylsulfonyl and aminosulfonyl substituted on the nitrogen atom with one to two substituents independently selected from H, alkyl, cycloalkyl, cycloalkylalkyl, hydroxyalkyl, alkoxyalkyl, alkylcarbonyl and cycloalkylcarbonyl.
26. A compound according to any one of claims 1 to 25, wherein R8, R9 and R10 are
independently selected from H, alkyl, haloalkyl, hydroxyhaloalkyl, alkoxy, haloalkoxy, alkoxyhaloalkyl, phenyl, pyridinyl, halogen, cyano, halo alky Isulfanyl, halo alky lsulfinyl, alkylsulfonyl, haloalkylsulfonyl and aminosulfonyl substituted on the nitrogen atom with two alkyl.
27. A compound according to any one of claims 1 to 26, wherein R8, R9 and R10 are
independently selected from H, alkyl, haloalkyl, haloalkoxy, halogen and alkylsulfonyl.
28. A compound according to any one of claims 1 to 27, wherein R8 is H, alkyl, haloalkyl, hydroxyhaloalkyl, alkoxy, haloalkoxy, alkoxyhaloalkyl, phenyl, pyridinyl, halogen, cyano, halo alky Isulfanyl, halo alky lsulfinyl, alkylsulfonyl, haloalkylsulfonyl, pyrrolyl substituted with one alkyl, pyrrolydinyl, tetrahydrofuranyl, alkylcarbonyl, or aminosulfonyl substituted on the nitrogen atom with two alkyl.
29. A compound according to any one of claims 1 to 28, wherein R8 is haloalkyl, haloalkoxy, halogen or alkylsulfonyl.
30. A compound according to any one of claims 1 to 29, wherein R8 is haloalkoxy or halogen.
31. A compound according to any one of claims 1 to 30, wherein R8 is halogen. 32. A compound according to any one of claims 1 to 31, wherein R9 is H, alkyl, haloalkyl, cycloalkyl, cycloalkoxy, alkoxy, haloalkoxy, alkoxyalkoxy, cyano or halogen.
33. A compound according to any one of claims 1 to 32, wherein R9 is H, alkyl, haloalkyl, alkoxy or halogen. 34 A compound according to any one of claims 1 to 33, wherein R9 is H, alkyl or halogen.
35 A compound according to any one of claims 1 to 34, wherein R8 and R9 are halogen.
36 A compound according to any one of claims 1 to 35, wherein R10 is H, alkyl, alkoxy or halogen.
37 A compound according to any one of claims 1 to 36, wherein R10 is H or alkyl.
38 A compound according to any one of claims 1 to 37, wherein R10 is H.
39 A compound according to any one of claims 1 to 38, wherein R11 is haloalkyl.
40. A compound according to any one of claims 1 to 39, wherein m is 1.
41. A compound according to any one of claims 1 to 40, wherein n is 1.
42. A compound according to any one of claims 1 to 41 , wherein m and n are 1.
43. A compound according to any one of claims 1 to 42, wherein p and q are 1.
44. A compound according to any one of claims 1 to 43, wherein m, n, p and q are 1.
45. A compound according to any one of claims 1 to 44, selected from
(E)-l-[(3aS,8aR)-2-(4,5,6,7-tetrahydro-lH-benzotriazole-5-carbonyl)-octahydro- pyrrolo[3,4-d]azepin-6-yl]-3-(4-trifluoromethoxy-phenyl)-prop-2-ene-l-one; l-((3aR,6aS)-5-(lH-benzo[d][l,2,3]triazole-5-carbonyl)hexahydropyrrolo[3,4-c]pyrrol- 2(1 H)-yl)-3 -(3 ,5 -dichlorophenyl)propan- 1 -one;
6-((3aR,6aS)-5-(3-(3,5-dichlorophenyl)propanoyl)octahydropyrrolo[3,4-c]pyrrole-2- carbonyl)benzo[d]oxazol-2(3H)-one;
(3aR,6aS)-3,5-dichlorobenzyl 5-(lH-benzo[d][l,2,3]triazole-5- carbonyl)hexahydropyrrolo [3 ,4-c]pyrro le-2( 1 H)-carboxylate;
(3 aR,6aS)-3 ,5 -dichlorobenzyl 5 -(9H-pyrido [3 ,4-b]indo le-3 - carbonyl)hexahydropyrrolo [3 ,4-c]pyrro le-2( 1 H)-carboxylate; (3aR,6aS)-3,5-dichlorobenzyl 5-(lH-indole-5-carbonyl)hexahydropyrrolo[3,4-c]pyrrole- 2(1 H)-carboxylate;
(3aR,6aS)-3,5-dichlorobenzyl 5-(9H-carbazole-3-carbonyl)hexahydropyrrolo[3,4- c]pyrrole-2( 1 H)-carboxylate;
(3aR,6aS)-3,5-dichlorobenzyl 5-(lH-indazole-5-carbonyl)hexahydropyrrolo[3,4-c]pyrrole- 2(1 H)-carboxylate;
(3aR,6aS)-3,5-dichlorobenzyl 5-(lH-benzo[d]imidazole-5-carbonyl)hexahydropyrrolo[3,4- c] pyrrole-2( 1 H)-carboxylate; trans-3 ,5-dichlorobenzyl 2-( 1 H-benzo [d] [ 1 ,2,3]triazole-5-carbonyl)hexahydro- 1 H- pyrrolo [3 ,4-c]pyridine-5 (6H)-carboxylate; cis-3 ,5-dichlorobenzyl 2-( 1 H-benzo [d] [ 1 ,2,3]triazole-5-carbonyl)hexahydro- 1 H- pyrrolo [3 ,4-c]pyridine-5 (6H)-carboxylate;
(3aR,8aS)-3,5-dichlorobenzyl 2-(lH-benzo[d][l,2,3]triazole-5- carbonyl)octahydropyrro lo [3 ,4-d] azepine-6(7H)-carboxylate;
(lH-benzotriazol-5-yl)-{(3aS,6aR)-5-[2-(3-chloro-phenyl)-ethanesulfonyl]-hexahydro- pyrrolo [3 ,4-c]pyrrol-2-yl} -methanone;
(3aR,6aS)-3,5-dichlorobenzyl 5-(4,5,6,7-tetrahydro-lH-benzo[d][l,2,3]triazole-5- carbonyl)hexahydropyrrolo [3 ,4-c]pyrro le-2( 1 H)-carboxylate; l-((3aR,8aS)-2-(lH-benzo[d][l,2,3]triazole-5-carbonyl)octahydropyrrolo[3,4-d]azepin- 6(7H)-yl)-3-(3-chlorophenyl)-2,2-dimethylpropan- 1 -one;
(E)-l-((3aR,8aS)-2-(lH-benzo[d][l,2,3]triazole-5-carbonyl)octahydropyrrolo[3,4- d] azepin-6(7H)-yl)-3-(3-fluoro-4-(trifluoromethoxy)phenyl)prop-2-en-l-one;
(3aSR,6SR,7aSR)-6-{(3aS,8aR)-6-[(E)-3-(4-trifluoromethoxy-phenyl)-acryloyl]- octahydro-pyrrolo[3,4-d]azepine-2-carbonyl}-hexahydro-benzooxazol-2-one;
(E)-l-[(3aS,8aR)-2-(benzo[c][l,2,5]oxadiazole-5-carbonyl)-octahydro-pyrrolo[3,4- d]azepin-6-yl]-3-(4-trifluoromethoxy-phenyl)-prop-2-ene- 1 -one; (E)-l-((3aR,8aS)-2-(lH-benzo[d][l,2,3]triazole-5-carbonyl)octahydropyrrolo[3,4- d] azepin-6(7H)-yl)-3 -(2-methyl-4-(trifluoromethoxy)phenyl)prop-2-en- 1 -one;
(E)-l-((3aR,8aS)-2-(lH-benzo[d][l,2,3]triazole-5-carbonyl)octahydropyrrolo[3,4- d]azepin-6(7H)-yl)-3-(3-fluoro-4-methoxyphenyl)prop-2-en- 1 -one; (E)-l-[(3aS,8aR)-2-((S)-4,5,6,7-tetrahydro-lH-benzotriazole-5-carbonyl)-octahydro- pyrrolo[3,4-d]azepin-6-yl]-3-(4-trifluoromethoxy-phenyl)-prop-2-ene-l-one
(E)-l-[(3aS,8aR)-2-((R)-4,5,6,7-tetrahydro-lH-benzotriazole-5-carbonyl)-octahydro- pyrrolo[3,4-d]azepin-6-yl]-3-(4-trifluoromethoxy-phenyl)-prop-2-ene- 1 -one (E)- 1 - [(3aS,8aR)-2-(lH-benzotriazole-5-carbonyl)-octahydro-pyrrolo[3,4-d]azepin-6-yl]-3-(2- isopropyl-phenyl)-prop-2-ene- 1 -one; trans-3,5-dichlorobenzyl 2-(2-oxo-2,3-dihydrobenzo[d]oxazole-6-carbonyl)hexahydro-lH- pyrrolo [3 ,4-c]pyridine-5 (6H)-carboxylate;
(3aR,6aS)-3,5-dichlorobenzyl 5-(2-oxo-2,3-dihydrobenzo[d]oxazole-6- carbonyl)hexahydropyrrolo [3 ,4-c]pyrro le-2( 1 H)-carboxylate; 6-{(3aS,8aR)-6-[(E)-3-(4-trifluoromethoxy-phenyl)-acryloyl]-octahydro-pyrrolo[3,4- d]azepine-2-carbonyl}-3H-benzooxazol-2-one;
(3aR,5s,6aS)-3,5-dichlorobenzyl 5-(2-oxo-2,3-dihydrobenzo[d]oxazol-6- yloxy)hexahydrocyclopenta[c]pyrrole-2( 1 H)-carboxylate;
(3aR,5r,6aS)-3,5-dichlorobenzyl 5-(2-oxo-2,3-dihydrobenzo[d]oxazol-6- yloxy)hexahydrocyclopenta[c]pyrrole-2( 1 H)-carboxylate;
(3aS,6aS)-3,5-dichlorobenzyl 5-(lH-benzo[d][l,2,3]triazole-5- carbonyl)hexahydropyrrolo [3 ,4-c]pyrro le-2( 1 H)-carboxylate; trans-5-(lH-benzotriazole-5-carbonyl)-octahydro-pyrrolo[3,4-c]pyridine-2-carboxylic acid 3 -methanesulfonyl-5 -trifluoromethyl-benzyl ester; (3aR,6aR)-3,5-dichlorobenzyl 5-(lH-benzo[d][l,2,3]triazole-5- carbonyl)hexahydropyrrolo [3 ,4-c]pyrro le-2( 1 H)-carboxylate; (3aS,6aS)-5-(lH-benzotriazole-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid 3-chloro-5-methanesulfonyl-benzyl ester;
(3aS,6aR)-5-(lH-benzotriazole-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid 3-chloro-5-methanesulfonyl-benzyl ester;
(3aS,8aR)-2-(lH-benzotriazole-5-carbonyl)-octahydro-pyrrolo[3,4-d]azepine-6-carboxylic acid 3-methanesulfonyl-5-trifluoromethyl-benzyl ester;
(3aS,8aR)-2-(lH-benzotriazole-5-carbonyl)-octahydro-pyrrolo[3,4-d]azepine-6-carboxylic acid 3-chloro-5-methanesulfonyl-benzyl ester;
(3aS,6aR)-5-(lH-benzotriazole-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid 3-methanesulfonyl-5-trifluoromethyl-benzyl ester; cis-3,5-dichlorobenzyl 5-(lH-benzo[d][l,2,3]triazole-5-carbonyl)hexahydro-lH- pyrrolo[3,4-c]pyridine-2(3H)-carboxylate;
(3aS,7aR)-5-(lH-benzotriazole-5-carbonyl)-octahydro-pyrrolo[3,4-c]pyridine-2-carboxylic acid 3-chloro-5-methanesulfonyl-benzyl ester; trans-3 ,5-dichlorobenzyl 5-( 1 H-benzo [d] [ 1 ,2,3]triazole-5-carbonyl)hexahydro- 1 H- pyrrolo[3,4-c]pyridine-2(3H)-carboxylate;
(3aR,8aS)-3,5-dichlorobenzyl 6-(lH-benzo[d][l,2,3]triazole-5- carbonyl)octahydropyrro lo [3 ,4-d] azepine-2( 1 H)-carboxylate;
(3aS,6aR)-5-(lH-benzotriazole-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid l-(3-chloro-phenyl)-cyclopropyl ester;
(3aS,6aR)-5-(lH-benzotriazole-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid bicyclo[4.1.0]hept-7-ylmethyl ester;
(3aS,6aR)-5-(lH-benzotriazole-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid adamantan-2-ylmethyl ester;
(3aS,6aR)-5-(lH-benzotriazole-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid l-fluoro-cyclohexylmethyl ester; (3aS,6aR)-5-(lH-benzotriazole-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid 2-adamantan-2-yl-ethyl ester;
(3aS,6aR)-5-(lH-berizotriazole-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid 2-adamantan-l-yl-ethyl ester;
(3aS,6aR)-5-(lH-benzotriazole-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid adamantan-l-ylmethyl ester;
(3aS,6aR)-5-(lH-benzotriazole-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid cyclohexylmethyl ester; cis-5-(lH-benzotriazole-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid 3- (2,2,2-trifluoro- 1 -methoxy-ethyl)-benzyl ester; cis-5-(lH-benzotriazole-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid 3- (2,2,2-trifluoro- 1 -hydro xy-ethyl)-benzyl ester;
(3aR,6aS)-2-cyclohexylethyl 5-(lH-benzo[d][l,2,3]triazole-5- carbonyl)hexahydropyrrolo [3 ,4-c]pyrro le-2( 1 H)-carboxylate;
(3aS,6aR)-5-(lH-benzotriazole-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid 3-fluoro-5-trifluoromethoxy-benzyl ester;
(3aR,6aS)-3-chloro-5-cyanobenzyl 5-(lH-benzo[d][l,2,3]triazole-5- carbonyl)hexahydropyrrolo [3 ,4-c]pyrro le-2( 1 H)-carboxylate;
(3aS,6aR)-5-(lH-benzotriazole-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid 3-trifluoromethoxy-benzyl ester;
(3aS,6aR)-5-(lH-benzotriazole-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid 3-fluoro-5-trifluoromethyl-benzyl ester;
(3aS,6aR)-5-(lH-benzotriazole-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid 3-chloro-5-trifluoromethoxy-benzyl ester;
(3aS,6aR)-5-(lH-benzotriazole-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid 4-fluoro-3-trifluoromethoxy-benzyl ester; (3aR,6aS)-3-cyano-5-fluorobenzyl 5-(lH-benzo[d][l,2,3]triazole-5- carbonyl)hexahydropyrrolo [3 ,4-c]pyrro le-2( 1 H)-carboxylate;
(3aR,6aS)-3-chloro-5-methoxybenzyl 5-(lH-benzo[d][l,2,3]triazole-5- carbonyl)hexahydropyrrolo [3 ,4-c]pyrro le-2( 1 H)-carboxylate;
(3aS,6aR)-5-(lH-benzotriazole-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid (lS,4R)-3-methyl-bicyclo[2.2.1]hept-2-ylmethyl ester;
(3aS,6aR)-5-(lH-benzotriazole-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid (lR,4S)-l-bicyclo[2.2.1]hept-2-ylmethyl ester;
(3aR,5S,6aS)-5-[(3H-[l,2,3]triazol-4-ylmethyl)-carbamoyl]-hexahydro- cyclopenta[c]pyrrole-2-carboxylic acid 3,5-dichloro-benzyl ester;
(3aS,6aS)-5-(l,4,6,7-tetrahydro-[l,2,3]triazolo[4,5-c]pyridine-5-carbonyl)-hexahydro- pyrrolo[3,4-c]pyrrole-2-carboxylic acid 3-chloro-5-methanesulfonyl-benzyl ester;
(3aS,6aR)-5-[(lH-[l,2,3]triazol-4-ylmethyl)-carbamoyl]-hexahydro-pyrrolo[3,4-c]pyrrole- 2-carboxylic acid 3,5-dichloro-benzyl ester;
(3aS,6aS)-5-(lH-benzotriazole-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid 4-trifluoromethoxy-benzyl ester;
(3aR,5r,6aS)-3,5-dichlorobenzyl 5-(2-oxo-2,3-dihydrobenzo[d]oxazol-6- ylamino)hexahydrocyclopenta[c]pyrrole-2(lH)-carboxylate;
(3 aR,6aS)-3 ,5 -dichlorobenzyl 5 -(( 1 H-benzo [d]imidazol-5 - yl)methyl)hexahydropyrrolo [3 ,4-c]pyrrole-2( 1 H)-carboxylate; l-((3aR,6aS)-5-((lH-benzo[d][l,2,3]triazol-5-yl)methyl)hexahydropyrrolo[3,4-c]pyrrol- 2(1 H)-yl)-3 -(3 ,5 -dichlorophenyl)propan- 1 -one;
(3aR,6aS)-3,5-dichlorobenzyl 5-((lH-indazol-5-yl)methyl)hexahydropyrrolo[3,4- c]pyrrole-2( 1 H)-carboxylate;
(3aR,6aS)-3,5-dichlorobenzyl 5-((2-oxo-2,3-dihydrobenzo[d]oxazol-6- yl)methyl)hexahydropyrrolo [3 ,4-c]pyrrole-2( 1 H)-carboxylate; 6-(((3aR,6aS)-5-(3-(3,5-dichlorophenyl)propanoyl)hexahydropyrrolo[3,4-c]pyrrol-2(lH)- yl)methyl)benzo[d]oxazol-2(3H)-one;
4-{(E)-3-[(3aS,8aR)-2-(lH-benzotriazol-5-ylmethyl)-octahydro-pyrrolo[3,4-d]azepin-6- yl]-3-oxo-propenyl}-benzonitrile;
(E)- 1 - [(3 aS , 8aR)-2-( 1 H-benzotriazo 1-5 -ylmethyl)-octahydro-pyrrolo [3 ,4-d] azepin-6-yl] -3 - (4-trifluoromethoxy-phenyl)-prop-2-ene- 1 -one;
(3aR,6aS)-3,5-dichlorobenzyl 5-(2-oxo-2,3-dihydrobenzo[d]oxazol-6- ylsulfonyl)hexahydropyrro lo [3 ,4-c]pyrrole-2( 1 H)-carboxylate;
(3aR,6aS)-3,5-dichlorobenzyl 5-(4,5,6,7-tetrahydro-lH-[l,2,3]triazolo[4,5-c]pyridine-5- carbonyl)hexahydropyrrolo [3 ,4-c]pyrro le-2( 1 H)-carboxylate;
(E)-l-[(3aS,8aR)-2-(l,4,6,7-tetrahydro-[l,2,3]triazolo[4,5-c]pyridine-5-carbonyl)- octahydro-pyrrolo[3,4-d]azepin-6-yl]-3-(4-trifluoromethoxy-phenyl)-prop-2-ene-l-one;
(E)-l-[(3aS,8aR)-2-(l,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carbonyl)-octahydro- pyrrolo[3,4-d]azepin-6-yl]-3-(4-trifluoromethoxy-phenyl)-prop-2-ene-l-one; cis-5-((3aR,8aS)-6-((E)-3-(4-(trifluoromethoxy)phenyl)acryloyl)decahydropyrrolo[3,4- d]azepine-2-carbonyl)hexahydrooxazolo [5 ,4-c]pyridin-2( 1 H)-one;
6-{(3aS,8aR)-6-[(E)-3-(4-trifluoromethoxy-phenyl)-acryloyl]-octahydro-pyrrolo[3,4- d]azepine-2-carbonyl} -5,6,7,8-tetrahydro- 1Η-[ 1 ,6]naphthyridin-2-one;
(3aR,7aR)-5-{(3aS,8aR)-6-[(E)-3-(4-trifluoromethoxy-phenyl)-acryloyl]-octahydro- pyrrolo [3 ,4-d]azepine-2-carbonyl} -hexahydro-oxazolo [5 ,4-c]pyridin-2-one;
(E)- 1 -[(3aS,8aR)-2-(7,8-Dihydro-5H-[ 1 ,6]naphthyridine-6-carbonyl)-octahydro- pyrrolo[3,4-d]azepin-6-yl]-3-(4-trifluoromethoxy-phenyl)-prop-2-ene-l-one;
(E)-3-(4-trifluoromethoxy-phenyl)-l-[(3aS,8aR)-2-(2-trifluoromethyl-5,6-dihydro-8H-
[l,2,4]triazolo[l,5-a]pyrazine-7-carbonyl)-octahydro-pyrrolo[3,4-d]azepin-6-yl]-prop-2- ene-l-one; (3aS,8aR)-6-[(E)-3-(3-trifluoromethoxy-phenyl)-acryloyl]-octahydro-pyrrolo[3,4- d]azepine-2-carboxylic acid (lH-[l,2,3]triazol-4-ylmethyl)-amide;
(3aR,8aS)-N-((lH-l,2,3-triazol-5-yl)methyl)-6-((E)-3-(4-
(trifluoromethoxy)phenyl)acryloyl)octahydropyrrolo [3 ,4-d]azepine-2( 1 H)-carboxamide;
(3aS,6aR)-5-[(E)-3-(4-trifluoromethoxy-phenyl)-acryloyl]-hexahydro-pyrrolo[3,4- c] pyrrole-2-carboxylic acid (lH-[l,2,3]triazol-4-ylmethyl)-amide;
(3aR,8aS)-N-((lH-l,2,3-triazol-5-yl)methyl)-6-((E)-3-(3-fluoro-4- (trifluoromethoxy)phenyl)acryloyl)octahydropyrrolo [3 ,4-d]azepine-2( 1 H)-carboxamide;
(3aS,8aR)-6-[(E)-3-(4-trifluoromethoxy-phenyl)-acryloyl]-octahydro-pyrrolo[3,4- d] azepine-2-carboxylic acid (4H-[ 1 ,2,4]triazol-3-ylmethyl)-amide;
(E)- 1 -[(3aS,8aR)-2-(6,7-dihydro-4H-[ 1 ,2,3]triazolo[ 1 ,5-a]pyrazine-5-carbonyl)-octahydro- pyrrolo[3,4-d]azepin-6-yl]-3-(4-trifluoromethoxy-phenyl)-prop-2-ene-l-one;
(E)-l-[(3aS,8aR)-2-(l,4,6,7-tetrahydro-imidazo[4,5-c]pyridine-5-carbonyl)-octahydro- pyrrolo[3,4-d]azepin-6-yl]-3-(4-trifluoromethoxy-phenyl)-prop-2-ene-l-one;
(3aR,8aS)-N-((lH-l,2,3-triazol-5-yl)methyl)-N-methyl-6-((E)-3-(4- (trifluoromethoxy)phenyl)acryloyl)octahydropyrrolo [3 ,4-d]azepine-2( 1 H)-carboxamide;
(3aS,8aR)-6-[3-(3-chloro-phenyl)-2,2-dimethyl-propionyl]-octahydro-pyrrolo[3,4- d]azepine-2-carboxylic acid (3H-[ 1 ,2,3]triazol-4-ylmethyl)-amide;
(3aR,8aS)-N-(2-(lH-l,2,3-triazol-5-yl)ethyl)-6-((E)-3-(4-
(trifluoromethoxy)phenyl)acryloyl)octahydropyrrolo [3 ,4-d]azepine-2( 1 H)-carboxamide;
(3aR,7aS)-2-(lH-benzotriazole-5-carbonyl)-octahydro-pyrrolo[3,4-c]pyridine-5-carboxylic acid 3,5-dichloro-benzyl ester;
(3aS,7aR)-2-(lH-berizotriazole-5-carbonyl)-octahydro-pyrrolo[3,4-c]pyridine-5-carboxylic acid 3,5-dichloro-benzyl ester;
(+)-trans-3 ,5-dichlorobenzyl 2-( 1 H-benzo [d] [ 1 ,2,3]triazole-5-carbonyl)hexahydro- 1 H- pyrrolo [3 ,4-c]pyridine-5 (6H)-carboxylate; (-)-trans-3,5-dichlorobenzyl 2-(lH-benzo[d][l,2,3]triazole-5-carbonyl)hexahydro-lH- pyrrolo [3 ,4-c]pyridine-5 (6H)-carboxylate;
(-)-trans-3,5-dichlorobenzyl 5-(lH-benzo[d][l,2,3]triazole-5-carbonyl)hexahydro-lH- pyrrolo[3,4-c]pyridine-2(3H)-carboxylate;
(+)-trans-3,5-dichlorobenzyl 5-(lH-benzo[d][l,2,3]triazole-5-carbonyl)hexahydro-lH- pyrrolo[3,4-c]pyridine-2(3H)-carboxylate;
(E)- 1 - [trans-2-( 1 H-benzotriazo le-5 -carbonyl)-octahydro-pyrrolo [3 ,4-c]pyridin-5 -yl] -3 - (3 ,5-dichloro-phenyl)-prop-2-en- 1 -one;
(lH-benzotriazol-5-yl)-{trans-2-[5-(4-chloro-phenyl)-[l,3,4]oxadiazol-2-yl]-octahydro- pyrrolo [3 ,4-c]pyridin-5-yl} -methanone;
(E)-l-((3aR,6aS)-5-(lH-benzo[d][l,2,3]triazole-5-carbonyl)hexahydropyrrolo[3,4- c] pyrrol-2( 1 H)-yl)-3 -(4-(trifluoromethoxy)phenyl)prop-2-en- 1 -one;
(lH-benzotriazol-5-yl)-[(3aR,6aS)-5-(5-chloro-lH-indole-2-carbonyl)-hexahydro- pyrrolo [3 ,4-c]pyrrol-2-yl]-methanone;
(E)-l-[(3aR,6aS)-5-(lH-benzotriazole-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]- 3-(3-fluoro-5-trifluoromethyl-phenyl)-prop-2-ene- 1 -one; l-[(3aR,6aS)-5-(lH-benzotriazole-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-3-(3- fluoro-5-trifluoromethyl-phenyl)-propan- 1 -one;
(lH-benzotriazol-5-yl)-[(3aR,6aS)-5-(6-chloro-lH-indole-2-carbonyl)-hexahydro- pyrrolo [3 ,4-c]pyrrol-2-yl]-methanone;
(E)-l-((3aR,8aS)-2-(lH-benzo[d][l,2,3]triazole-5-carbonyl)octahydropyrrolo[3,4- d] azepin-6(7H)-yl)-3-(4-(trifluoromethylsulfonyl)phenyl)prop-2-en-l-one;
(E)-l-((3aR,8aS)-2-(lH-benzo[d][l,2,3]triazole-5-carbonyl)octahydropyrrolo[3,4- d]azepin-6(7H)-yl)-3-(4-chlorophenyl)prop-2-en- 1 -one;
(E)-l-((3aR,8aS)-2-(lH-benzo[d][l,2,3]triazole-5-carbonyl)octahydropyrrolo[3,4- d]azepin-6(7H)-yl)-3-p-tolylprop-2-en- 1 -one; 4-((E)-3-((3aR,8aS)-2-(lH-benzo[d][l,2,3]triazole-5-carbonyl)octahydropyrrolo[3,4- d]azepin-6(7H)-yl)-3-oxoprop-l-enyl)-N,N-dimethylbenzenesulfonamide;
(E)-l-((3aR,8aS)-2-(lH-benzo[d][l,2,3]triazole-5-carbonyl)octahydropyrrolo[3,4- d]azepin-6(7H)-yl)-3-(4-methoxyphenyl)prop-2-en- 1 -one;
(E)-l-((3aR,8aS)-6-(lH-benzo[d][l,2,3]triazole-5-carbonyl)octahydropyrrolo[3,4- d] azepin-2( 1 H)-yl)-3 -(4-(trifluoromethoxy)phenyl)prop-2-en- 1 -one;
4-((E)-3-((3aR,8aS)-2-(lH-benzo[d][l,2,3]triazole-5-carbonyl)octahydropyrrolo[3,4- d]azepin-6(7H)-yl)-3-oxoprop- 1 -enyl)benzonitrile;
(E)- 1 -((3aR,6aR)-5-( 1 H-benzo [d] [ 1 ,2,3]triazole-5-carbonyl)hexahydropyrrolo [3 ,4- c] pyrrol-2( 1 H)-yl)-3 -(4-(trifluoromethoxy)phenyl)prop-2-en- 1 -one; l-((3aR,6aS)-5-(lH-benzo[d][l,2,3]triazole-5-carbonyl)hexahydropyrrolo[3,4-c]pyrrol- 2(1 H)-yl)-3 -(4-(trifluoromethoxy)phenyl)propan- 1 -one;
(E)-l-((3aR,8aS)-2-(lH-benzo[d][l,2,3]triazole-5-carbonyl)octahydropyrrolo[3,4- d] azepin-6(7H)-yl)-3-(4-fluorophenyl)prop-2-en- 1 -one;
(E)-l-((3aR,8aS)-2-(lH-benzo[d][l,2,3]triazole-5-carbonyl)octahydropyrrolo[3,4- d]azepin-6(7H)-yl)-3-phenylprop-2-en- 1 -one;
(E)-l-((3aR,8aS)-2-(lH-benzo[d][l,2,3]triazole-5-carbonyl)octahydropyrrolo[3,4- d]azepin-6(7H)-yl)-3-(pyridin-2-yl)prop-2-en- 1 -one;
(E)-l-((3aR,8aS)-2-(lH-benzo[d][l,2,3]triazole-5-carbonyl)octahydropyrrolo[3,4- d]azepin-6(7H)-yl)-3-(pyridin-3-yl)prop-2-en- 1 -one;
(E)-l-((3aR,8aS)-2-(lH-benzo[d][l,2,3]triazole-5-carbonyl)octahydropyrrolo[3,4- d]azepin-6(7H)-yl)-3-(3-chlorophenyl)prop-2-en- 1 -one;
(E)-l-((3aR,8aS)-6-(lH-benzo[d][l,2,3]triazole-5-carbonyl)octahydropyrrolo[3,4- d]azepin-2(lH)-yl)-3-(4-chlorophenyl)prop-2-en-l-one;
(E)-l-((3aR,8aS)-6-(lH-benzo[d][l,2,3]triazole-5-carbonyl)octahydropyrrolo[3,4- d] azepin-2( 1 H)-yl)-3 -(3 -(trifluoromethoxy)phenyl)prop-2-en- 1 -one; (E)-l-((3aR,8aS)-2-(lH-benzo[d][l,2,3]triazole-5-carbonyl)octahydropyrrolo[3,4- d]azepin-6(7H)-yl)-3-(4-(difluoromethoxy)phenyl)prop-2-en-l-one;
(E)- 1 -((3aR,6aR)-5-( 1 H-benzo [d] [ 1 ,2,3]triazole-5-carbonyl)hexahydropyrrolo [3 ,4- c]pyrrol-2( 1 H)-yl)-3 -(3 -(trifluoromethoxy)phenyl)prop-2-en- 1 -one;
4-((E)-3-((3aR,6aR)-5-(lH-benzo[d][l,2,3]triazole-5-carbonyl)hexahydropyrrolo[3,4- c] pyrrol-2( 1 H)-yl)-3-oxoprop- 1 -enyl)benzonitrile;
(E)-l-((3aS,6aS)-5-(lH-benzo[d][l,2,3]triazole-5-carbonyl)hexahydropyrrolo[3,4-c]pyrrol- 2(1 H)-yl)-3 -(4-(trifluoromethoxy)phenyl)prop-2-en- 1 -one;
(-)-(E)-l-[trans-5-(lH-benzotriazole-5-carbonyl)-octahydro-pyrrolo[3,4-c]pyridin-2-yl]-3- (4-trifluoromethoxy-phenyl)-prop-2-ene- 1 -one;
(+)-(E)-l-[trans-5-(lH-benzotriazole-5-carbonyl)-octahydro-pyrrolo[3,4-c]pyridin-2-yl]-3- (4-trifluoromethoxy-phenyl)-prop-2-ene- 1 -one;
(E)-l-((3aR,8aS)-2-(lH-benzo[d][l,2,3]triazole-5-carbonyl)octahydropyrrolo[3,4- d] azepin-6(7H)-yl)-3-(3,5-dichlorophenyl)prop-2-en-l-one;
(E)-l-((3aR,8aS)-2-(lH-benzo[d][l,2,3]triazole-5-carbonyl)octahydropyrrolo[3,4- d]azepin-6(7H)-yl)-3-(pyridin-4-yl)prop-2-en- 1 -one;
(E)-l-((3aR,8aS)-2-(lH-benzo[d][l,2,3]triazole-5-carbonyl)octahydropyrrolo[3,4- d]azepin-6(7H)-yl)-3-(2,4-difluorophenyl)prop-2-en- 1 -one;
(E)-l-((3aR,8aS)-2-(lH-benzo[d][l,2,3]triazole-5-carbonyl)octahydropyrrolo[3,4- d]azepin-6(7H)-yl)-3-(2,4-dichlorophenyl)prop-2-en- 1 -one;
(E)-l-((3aR,8aS)-2-(lH-benzo[d][l,2,3]triazole-5-carbonyl)octahydropyrrolo[3,4- d]azepin-6(7H)-yl)-3-(3,4-dichlorophenyl)prop-2-en-l-one;
(E)-l-[(3aS,7aS)-5-(lH-benzotriazole-5-carbonyl)-octahydro-pyrrolo[3,4-c]pyridin-2-yl]-
3- (4-difluoromethoxy-phenyl)-prop-2-ene- 1 -one;
4- {(E)-3-[(3aS,7aS)-5-(lH-benzotriazole-5-carbonyl)-octahydro-pyrrolo[3,4-c]pyridin-2- yl]-3-oxo-propenyl}-benzonitrile; 4-((E)-3-((3aR,8aS)-2-(lH-benzo[d][l,2,3]triazole-5-carbonyl)octahydropyrrolo[3,4- d]azepin-6(7H)-yl)-3-oxoprop- 1 -enyl)-3-fluorobenzonitrile;
4-((E)-3-((3aR,6aR)-5-(lH-benzo[d][l,2,3]triazole-5-carbonyl)hexahydropyrrolo[3,4- c]pyrrol-2(lH)-yl)-3-oxoprop-l-enyl)-3-fluorobenzonitrile;
(E)- 1 -((3aR,6aR)-5-( 1 H-benzo [d] [ 1 ,2,3]triazole-5-carbonyl)hexahydropyrrolo [3 ,4- c] pyrrol-2( 1 H)-yl)-3 -(4-(difluoromethoxy)phenyl)prop-2-en- 1 -one;
(E)-l-[cis-2-(lH-benzotriazole-5-carbonyl)-octahydro-pyrrolo[3,4-c]pyridin-5-yl]-3-(4- trifluoromethoxy-phenyl)-prop-2-ene- 1 -one;
3-((E)-3-((3aR,8aS)-2-(lH-benzo[d][l,2,3]triazole-5-carbonyl)octahydropyrrolo[3,4- d] azepin-6(7H)-yl)-3-oxoprop- 1 -enyl)benzonitrile;
(E)-l-((3aR,8aS)-2-(lH-benzo[d][l,2,3]triazole-5-carbonyl)octahydropyrrolo[3,4- d]azepin-6(7H)-yl)-3-(2-fluoro-4-(trifluoromethoxy)phenyl)prop-2-en-l-one;
(E)- 1 -((3aR,6aR)-5-( 1 H-benzo [d] [ 1 ,2,3]triazole-5-carbonyl)hexahydropyrrolo [3 ,4- c]pyrrol-2( 1 H)-yl)-3-(2-fluoro-4-(trifluoromethoxy)phenyl)prop-2-en- 1 -one;
(E)- 1 -((3aR,6aR)-5-( 1 H-benzo [d] [ 1 ,2,3]triazole-5-carbonyl)hexahydropyrrolo [3 ,4- c]pyrrol-2( 1 H)-yl)-3-(4-chloro-2-fluorophenyl)prop-2-en- 1 -one;
(E)- 1 -((3aR,6aR)-5-( 1 H-benzo [d] [ 1 ,2,3]triazole-5-carbonyl)hexahydropyrrolo [3 ,4- c]pyrrol-2(lH)-yl)-3-(3,5-dichlorophenyl)prop-2-en-l-one;
(E)-l-((3aR,6aS)-5-(4,5,6,7-tetrahydro-lH-benzo[d][l,2,3]triazole-5- carbonyl)hexahydropyrrolo[3,4-c]pyrrol-2(lH)-yl)-3-(4-(trifluoromethoxy)phenyl)prop-2- en- 1 -one; l-[(3aR,6aR)-5-(lH-benzotriazole-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-3-(4- trifluoromethoxy-phenyl)-propan- 1 -one;
(E)-l-[(3aS,6aR)-5-(l,4,6,7-tetrahydro-[l,2,3]triazolo[4,5-c]pyridine-5-carbonyl)- hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-3-(4-trifluoromethoxy-phenyl)-prop-2-ene-l-one; (E)-l-[(3aR,6aR)-5-(lH-benzotriazole-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]- 3-(3-chloro-5-methanesulfonyl-phenyl)-prop-2-ene- 1 -one;
(E)-l-[(3aR,6aR)-5-(lH-benzotriazole-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]- 3-(3,5-dimethoxy-phenyl)-prop-2-ene-l-one;
(E)-l-[(3aR,6aR)-5-(lH-benzotriazole-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]- 3-(3-chloro-5-trifluoromethoxy-phenyl)-prop-2-ene- 1 -one;
(E)-l-[(3aR,6aR)-5-(lH-benzotriazole-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]- 3-(3-chloro-5-methoxy-phenyl)-prop-2-ene- 1 -one;
3-{(E)-3-[(3aR,6aR)-5-(lH-benzotriazole-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2- yl]-3-oxo-propenyl}-5-chloro-benzonitrile;
(E)-l-[(3aR,6aR)-5-(lH-benzotriazole-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]- 3-(3-methoxy-5-trifluoromethoxy-phenyl)-prop-2-ene- 1 -one;
(E)-l-[(3aR,6aR)-5-(l,4,6,7-tetrahydro-[l,2,3]triazolo[4,5-c]pyridine-5-carbonyl)- hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-3-(4-trifluoromethoxy-phenyl)-prop-2-ene-l-one; l-[(3aR,6aR)-5-(l,4,6,7-tetrahydro-[l,2,3]triazolo[4,5-c]pyridine-5-carbonyl)-hexahydro- pyrrolo[3,4-c]pyrrol-2-yl]-3-(4-trifluoromethoxy-phenyl)-propan-l-one;
(3aR,7aR)-5-{(3aR,6aR)-5-[(E)-3-(4-trifluoromethoxy-phenyl)-acryloyl]-hexahydro- pyrrolo [3 ,4-c]pyrrole-2-carbonyl} -hexahydro-oxazolo [5 ,4-c]pyridin-2-one;
(3aR,7aR)-5-{(3aR,6aR)-5-[3-(4-trifluoromethoxy-phenyl)-propionyl]-hexahydro- pyrrolo [3 ,4-c]pyrrole-2-carbonyl} -hexahydro-oxazolo [5 ,4-c]pyridin-2-one;
(E)-l-[(3aR,6aR)-5-(lH-benzotriazole-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]- 3-phenyl-prop-2-ene- 1 -one; l-[(3aR,6aR)-5-(lH-benzotriazole-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-3- phenyl-propan- 1 -one;
(E)-l-[(3aR,6aR)-5-(lH-benzotriazole-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]- 3-(4-trifluoromethyl-phenyl)-prop-2-ene- 1 -one; l-[(3aR,6aR)-5-(lH-benzotriazole-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-3-(4- trifluoromethyl-phenyl)-propan- 1 -one;
(3aR,6aS)-N-((lH-l,2,3-triazol-5-yl)methyl)-N-methyl-5-(3-(4-
(trifluoromethoxy)phenyl)propanoyl)hexahydropyrrolo [3 ,4-c]pyrrole-2( 1 H)-carboxamide;
(3aR,8aS)-N-((lH-l,2,3-triazol-5-yl)methyl)-6-((E)-3-(3-fluoro-4- (trifluoromethoxy)phenyl)acryloyl)-N-methyloctahydropyrrolo [3 ,4-d]azepine-2( 1 H)- carboxamide; l-[(3aR,6aR)-5-(lH-benzotriazole-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-3-(6- trifluoromethyl-pyridin-3 -yl)-propan- 1 -one; l-[(3aS,6aS)-5-(lH-benzotriazole-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2-(4- trifluoromethoxy-phenoxy)-ethanone; l-[(3aS,6aS)-5-(lH-benzotriazole-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2-(4- chloro-2-isopropyl-5-methyl-phenoxy)-ethanone; l-[(3aR,6aR)-5-(lH-benzotriazole-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-3- biphenyl-4-yl-propan- 1 -one;
(E)-l-((3aR,8aS)-2-(lH-benzo[d][l,2,3]triazole-5-carbonyl)octahydropyrrolo[3,4- d]azepin-6(7H)-yl)-3-(4-fluoro-2-(trifluoromethyl)phenyl)prop-2-en-l-one; l-[(3aS,6aR)-5-(lH-Benzotriazole-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2- (4-chloro-2-isopropyl-5-methyl-phenoxy)-ethanone;
(E)-l-((3aR,8aS)-2-(lH-benzo[d][l,2,3]triazole-5-carbonyl)octahydropyrrolo[3,4- d]azepin-6(7H)-yl)-3-(4-(methylsulfonyl)phenyl)prop-2-en-l-one;
(E)-l-((3aR,8aS)-2-(lH-benzo[d][l,2,3]triazole-5-carbonyl)octahydropyrrolo[3,4- d]azepin-6(7H)-yl)-3-(4-(trifluoromethylthio)phenyl)prop-2-en-l-one;
(E)-l-((3aR,8aS)-2-(lH-benzo[d][l,2,3]triazole-5-carbonyl)octahydropyrrolo[3,4- d]azepin-6(7H)-yl)-3-(4-(trifluoromethoxy)phenyl)prop-2-en-l-one; l-((3aR,6aS)-5-(lH-benzo[d][l,2,3]triazole-5-carbonyl)hexahydropyrrolo[3,4-c]pyrrol- 2(lH)-yl)-2-(3-(trifluoromethoxy)phenoxy)ethanone;
(E)-l-((3aR,8aS)-2-(lH-benzo[d][l,2,3]triazole-5-carbonyl)octahydropyrrolo[3,4- d]azepin-6(7H)-yl)-3-(3-(trifluoromethoxy)phenyl)prop-2-en-l-one;
(E)- 1 - [trans-5 -( 1 H-benzotriazo le-5 -carbonyl)-octahydro-pyrrolo [3 ,4-c]pyridin-2-yl] -3 -(3 - trifluoromethoxy-phenyl)-prop-2-en- 1 -one;
(E)- 1 - [trans-5 -( 1 H-benzotriazo le-5 -carbonyl)-octahydro-pyrrolo [3 ,4-c]pyridin-2-yl] -3 -(4- trifluoromethoxy-phenyl)-prop-2-en- 1 -one;
(E)- 1 - [trans-5 -( 1 H-benzotriazo le-5 -carbonyl)-octahydro-pyrrolo [3 ,4-c]pyridin-2-yl] -3 -(3 - chloro-5-trifluoromethoxy-phenyl)-prop-2-en- 1 -one;
(E)- 1 - [trans-5 -( 1 H-benzotriazo le-5 -carbonyl)-octahydro-pyrrolo [3 ,4-c]pyridin-2-yl] -3 - (3 ,5-dichloro-phenyl)-prop-2-en- 1 -one;
(E)-l-[(3aR,6aR)-5-(lH-benzotriazole-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]- 3-(6-phenyl-pyridin-3-yl)-prop-2-ene- 1 -one;
(E)-l-[(3aR,6aR)-5-(lH-benzotriazole-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]- 3-(5-trifluoromethyl-pyridin-2-yl)-prop-2-ene- 1 -one;
(E)-l-[(3aR,6aR)-5-(lH-benzotriazole-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]- 3-(4-pyridin-4-yl-phenyl)-prop-2-ene- 1 -one;
(E)-l-[(3aR,6aR)-5-(lH-benzotriazole-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]- 3-(4-pyridin-3-yl-phenyl)-prop-2-ene- 1 -one;
(E)-l-[(3aR,6aR)-5-(lH-benzotriazole-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]- 3-(4-pyridin-2-yl-phenyl)-prop-2-ene- 1 -one; l-[(3aS,6aR)-5-(lH-benzotriazole-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2-(4 chloro-3-methyl-phenoxy)-ethanone; l-[(3aS,6aR)-5-(lH-benzotriazole-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2-(4 chloro-2-methyl-phenoxy)-ethanone; (E)-l-[(3aR,6aR)-5-(lH-benzotriazole-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]- 3-(5-phenyl-pyridin-2-yl)-prop-2-ene- 1 -one;
(E)-l-((3aR,8aS)-2-(lH-benzo[d][l,2,3]triazole-5-carbonyl)octahydropyrrolo[3,4- d] azepin-6(7H)-yl)-3 -(4-(trifluoromethylsulfinyl)phenyl)prop-2-en- 1 -one; l-((3aR,8aS)-2-(lH-benzo[d][l,2,3]triazole-5-carbonyl)octahydropyrrolo[3,4-d]azepin- 6(7H)-yl)-3-(3-fluoro-4-(trifluoromethoxy)phenyl)propan- 1 -one;
(3aR,8aS)-N-((lH-l,2,3-triazol-5-yl)methyl)-N-methyl-6-(3-(4-
(trifluoromethoxy)phenyl)propanoyl)octahydropyrrolo [3 ,4-d]azepine-2( 1 H)-carboxamide; (3aR,8aS)-N-((lH-l,2,3-triazol-5-yl)methyl)-6-(3-(3-fluoro-4-
(trifluoromethoxy)phenyl)propanoyl)-N-methyloctahydropyrrolo [3 ,4-d]azepine-2( 1 H)- carboxamide; l-[(3aR,6aR)-5-(lH-benzotriazole-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-3-(4- difluoromethoxy-phenyl)-propan- 1 -one; l-[(3aR,6aR)-5-(lH-benzotriazole-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-3-(2- fluoro-4-trifluoromethoxy-phenyl)-propan- 1 -one; l-((3aR,8aS)-2-(lH-benzo[d][l,2,3]triazole-5-carbonyl)octahydropyrrolo[3,4-d]azepin- 6(7H)-yl)-3-(4-fluoro-2-(trifluoromethyl)phenyl)propan- 1 -one; l-((3aR,8aS)-2-(lH-benzo[d][l,2,3]triazole-5-carbonyl)octahydropyrrolo[3,4-d]azepin- 6(7H)-yl)-3-(2-methyl-4-(trifluoromethoxy)phenyl)propan- 1 -one; l-((3aR,8aS)-2-(lH-benzo[d][l,2,3]triazole-5-carbonyl)octahydropyrrolo[3,4-d]azepin- 6(7H)-yl)-3-(3-fluoro-4-methoxyphenyl)propan- 1 -one; l-[(3aS,8aR)-2-(lH-benzotriazole-5-carbonyl)-octahydro-pyrrolo[3,4-d]azepin-6-yl]-3-(2- isopropyl-phenyl)-propan- 1 -one; l-[(3aR,6aR)-5-(lH-benzotriazole-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-3-(5- trifluoromethyl-pyridin-2-yl)-propan- 1 -one; l-[(3aR,6aR)-5-(lH-benzotriazole-5 -carbonyl)-hexahydro-pyrro lo [3 ,4-c]pyrrol-2-yl] -3 -(5 - phenyl-pyridin-2-yl)-propan- 1 -one; l-[(3aR,6aR)-5-(lH-benzotriazole-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-3-(4- pyridin-4-yl-phenyl)-propan- 1 -one; l-[(3aR,6aR)-5-(lH-benzotriazole-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-3-(4- pyridin-3-yl-phenyl)-propan- 1 -one;
1- [(3aR,6aR)-5-(lH-benzotriazole-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-3-(4- pyridin-2-yl-phenyl)-propan- 1 -one;
(3aS,8aR)-6-[3-(4-trifluoromethoxy-phenyl)-propionyl]-octahydro-pyrrolo[3,4-d]azepine-
2- carboxylic acid [2-(3H-[l,2,3]triazol-4-yl)-ethyl]-amide;
(E)-3-[4-(trifluoro-methoxy)-phenyl]-l-[(3aS,8aR)-2-((S)-4,5,6,7-tetrahydro-lH- imidazo[4,5-c]pyridine-6-carbonyl)-octahydro-pyrrolo[3,4-d]azepin-6-yl]-prop-2-ene-l- one hydrochloride; and pharmaceutically acceptable salts thereof.
A compound according to any one of claims 1 to 44, selected from trans-2-(lH-benzotriazole-5-carbonyl)-octahydro-pyrrolo[3,4-c]pyridine-5-carboxylic acid
3 - chloro-5 -methanesulfonyl-benzyl ester; trans-2-(lH-benzotriazole-5-carbonyl)-octahydro-pyrrolo[3,4-c]pyridine-5-carboxylic acid
4- trifluoromethoxy-benzyl ester;
1 - [trans-2-( 1 H-benzotriazo le-5 -carbonyl)-octahydro-pyrrolo [3 ,4-c]pyridin-5 -yl] -2-(4- trifluoromethoxy-phenoxy)-ethanone;
(E)- 1 - [trans-2-( 1 H-benzotriazo le-5 -carbonyl)-octahydro-pyrrolo [3 ,4-c]pyridin-5 -yl] -3 -(4- trifluoromethoxy-phenyl)-propenone;
(E)-l-((3aR,8aS)-2-(lH-benzo[d][l,2,3]triazole-5-carbonyl)octahydropyrrolo[3,4- d]azepin-6(7H)-yl)-3-(3-chloro-5-(trifluoromethyl)phenyl)prop-2-en- 1 -one; (E)-l-((3aR,8aS)-2-(lH-benzo[d][l,2,3]triazole-5-carbonyl)octahydropyrrolo[3,4- d] azepin-6(7H)-yl)-3 -(4-methoxy-2-(trifluoromethyl)phenyl)prop-2-en- 1 -one;
(E)-l-((3aR,8aS)-2-(lH-benzo[d][l,2,3]triazole-5-carbonyl)octahydropyrrolo[3,4- d]azepin-6(7H)-yl)-3-(2-cyclopropylphenyl)prop-2-en- 1 -one; trans-2-(lH-benzotriazole-5-carbonyl)-octahydro-pyrrolo[3,4-c]pyridine-5-carboxylic acid 4-fluoro-2-trifluoromethyl-benzyl ester; trans-2-(lH-benzotriazole-5-carbonyl)-octahydro-pyrrolo[3,4-c]pyridine-5-carboxylic acid 2-cyclopropyl-4-trifluoromethyl-benzyl ester;
1- [(3aS,8aR)-2-(lH-benzotriazole-5-carbonyl)-octahydro-pyrrolo[3,4-d]azepin-6-yl]-2-(2- trifluoromethoxy-phenoxy)-ethanone; trans-2-(lH-benzotriazole-5-carbonyl)-octahydro-pyrrolo[3,4-c]pyridine-5-carboxylic acid
2- methoxy-4-trifluoromethoxy-benzyl ester;
4-{2-[(3aS,8aR)-2-(lH-benzotriazole-5-carbonyl)-octahydro-pyrrolo[3,4-d]azepin-6-yl]-2- oxo-ethoxy}-3-trifluoromethyl-benzonitrile; l-[(3aS,8aR)-2-(lH-benzotriazole-5-carbonyl)-octahydro-pyrrolo[3,4-d]azepin-6-yl]-2-(4- chloro-2-isopropyl-5-methyl-phenoxy)-ethanone; l-[(3aS,8aR)-2-(lH-benzotriazole-5-carbonyl)-octahydro-pyrrolo[3,4-d]azepin-6-yl]-2-[4- methyl-2-(l-methyl-pyrrolidin-3-yl)-phenoxy]-ethanone; l-[(3aS,8aR)-2-(lH-benzotriazole-5-carbonyl)-octahydro-pyrrolo[3,4-d]azepin-6-yl]-2-(2- chloro-4-fluoro-phenoxy)-ethanone; l-((3aR,8aS)-2-(lH-benzo[d][l,2,3]triazole-5-carbonyl)octahydropyrrolo[3,4-d]azepin- 6(7H)-yl)-2-(2-chloro-4-(trifluoromethyl)phenoxy)ethanone; l-((3aR,8aS)-2-(lH-benzo[d][l,2,3]triazole-5-carbonyl)octahydropyrrolo[3,4-d]azepin- 6(7H)-yl)-2-(6-isopropyl-3,3-dimethyl-2,3-dihydro-lH-inden-5-yloxy)ethanone;
(3aS,8aR)-2-(lH-benzotriazole-5-carbonyl)-octahydro-pyrrolo[3,4-d]azepine-6-carboxylic acid 2-fluoro-4-trifluoromethoxy-benzyl ester; l-((3aR,8aS)-2-(lH-benzo[d][l,2,3]triazole-5-carbonyl)octahydropyrrolo[3,4-d]azepin- 6(7H)-yl)-2-(5-chloro-2-(trifluoromethyl)phenoxy)ethanone; l-[(3aS,8aR)-2-(lH-benzotriazole-5-carbonyl)-l,3,3a,4,5,7,8,8a-octahydropyrrolo[3,4- d]azepin-6-yl]-2-(2-tert-butyl-4-methoxyphenoxy)ethanone; 4-[2-[(3aS,8aR)-2-(lH-benzotriazole-5-carbonyl)-l,3,3a,4,5,7,8,8a-octahydropyrrolo[3,4- d]azepin-6-yl]-2-oxoethoxy]-3-propan-2-ylbenzonitrile; l-[(3aS,8aR)-2-(lH-benzotriazole-5-carbonyl)-l,3,3a,4,5,7,8,8a-octahydropyrrolo[3,4- d]azepin-6-yl]-3-[3-fluoro-4-(2,2,2-trifluoroethoxy)phenyl]propan-l-one; l-[(3aS,8aR)-2-(lH-benzotriazole-5-carbonyl)-l,3,3a,4,5,7,8,8a-octahydropyrrolo[3,4- d]azepin-6-yl]-3-[2-fluoro-4-(2,2,2-trifluoroethoxy)phenyl]propan- 1 -one;
(3aS,8aR)-2-(lH-benzotriazole-5-carbonyl)-octahydro-pyrrolo[3,4-d]azepine-6-carboxylic acid 3-fluoro-4-(2,2,2-trifluoro-ethoxy)-benzyl ester;
(3aS,8aR)-2-(lH-benzotriazole-5-carbonyl)-octahydro-pyrrolo[3,4-d]azepine-6-carboxylic acid 2-fluoro-4-(2,2,2-trifluoro-ethoxy)-benzyl ester; (3aS,8aR)-2-(lH-benzotriazole-5-carbonyl)-octahydro-pyrrolo[3,4-d]azepine-6-carboxylic acid 4-(2,2,2-trifluoro-ethoxy)-benzyl ester;
(3aS,6aS)-5-(3H-[l,2,3]triazolo[4,5-b]pyridine-6-carbonyl)-hexahydro-pyrrolo[3,4- c]pyrrole-2-carboxylic acid 4-trifluoromethoxy-benzyl ester; l-[(3aR,6aR)-5-(lH-triazolo[4,5-b]pyridine-5-carbonyl)-l,3,3a,4,6,6a- hexahydropyrrolo[3,4-c]pyrrol-2-yl]-3-[4-(trifluoromethoxy)phenyl]propan-l-one;
(3aS,6aS)-5-(3H-[l,2,3]triazolo[4,5-c]pyridine-6-carbonyl)-hexahydro-pyrrolo[3,4- c]pyrrole-2-carboxylic acid 4-trifluoromethoxy-benzyl ester;
(3aS,6aS)-5-(4-fluoro-lH-benzotriazole-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2- carboxylic acid 4-trifluoromethoxy-benzyl ester; (3aS,6aS)-5-(7-fluoro-lH-benzotriazole-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2- carboxylic acid 4-trifluoromethoxy-benzyl ester; (3aS,6aS)-5-(6-fluoro-lH-benzotriazole-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2- carboxylic acid 4-trifluoromethoxy-benzyl ester;
(3aS,6aS)-5-(4-chloro-lH-berizotriazole-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2- carboxylic acid 4-trifluoromethoxy-benzyl ester;
(3 aS ,6aS)-5 -(6-trifluoromethyl- 1 H-benzotriazo le-5 -carbonyl)-hexahydro-pyrro lo [3 ,4- c]pyrrole-2-carboxylic acid 4-trifluoromethoxy-benzyl ester;
(3aS,6aS)-5-(4-methyl-lH-benzotriazole-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2- carboxylic acid 4-trifluoromethoxy-benzyl ester;
(3aS,6aS)-5-(6-methyl-lH-benzotriazole-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2- carboxylic acid 4-trifluoromethoxy-benzyl ester; l-[(3aR,6aR)-5-(4-fluoro-lH-benzotriazole-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2- yl] -3 -(4-trifluoromethoxy-phenyl)-propan- 1 -one;
(4-ethoxyquinolin-2-yl)((3aS,6aS)-5-((R)-4,5,6,7-tetrahydro-lH-benzo[d][l,2,3]triazole-5- carbonyl)hexahydropyrrolo [3 ,4-c]pyrrol-2( 1 H)-yl)methanone;
(4-ethoxyquinolin-2-yl)((3aS,6aS)-5-(4-fluoro-lH-benzo[d][l,2,3]triazole-5- carbonyl)hexahydropyrrolo [3 ,4-c]pyrrol-2( 1 H)-yl)methanone;
6-[(3aR,6aR)-2-[3-[4-(trifluoromethoxy)phenyl]propanoyl]-l,3,3a,4,6,6a- hexahydropyrrolo[3,4-c]pyrrole-5-carbonyl]-3H-l,3-benzoxazol-2-one;
(3aS,6aS)-5-(2-oxo-2,3-dihydro-benzooxazole-6-carbonyl)-hexahydro-pyrrolo[3,4- c]pyrrole-2-carboxylic acid 4-trifluoromethoxy-benzyl ester;
(3aS,6aS)-5-(lH-benzotriazole-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid 4-cyano-benzyl ester;
(3aS,6aS)-5-(lH-benzotriazole-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid 4-(l,l,2,2-tetrafluoro-ethoxy)-benzyl ester;
(3aS,6aS)-5-(lH-benzotriazole-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid 4-difluoromethoxy-3-fluoro-benzyl ester; (3aS,6aS)-5-(lH-[l,2,3]triazolo[4,5-b]pyridine-5-carbonyl)-hexahydro-pyrrolo[3,4- c]pyrrole-2-carboxylic acid 3-fluoro-4-trifluoromethoxy-benzyl ester;
(3aS,6aS)-5-(lH-berizotriazole-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid 4-difluoromethoxy-benzyl ester;
(3aS,6aS)-5-(lH-[l,2,3]triazolo[4,5-b]pyridine-5-carbonyl)-hexahydro-pyrrolo[3,4- c]pyrrole-2-carboxylic acid 4-trifluoromethoxy-benzyl ester;
(3aS,6aS)-5-(lH-benzotriazole-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid 3-fluoro-4-trifluoromethoxy-benzyl ester;
(3aS,6aS)-5-(lH-benzotriazole-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid 4-(2,2,2-trifluoro-ethoxy)-benzyl ester;
(3aS,6aS)-5-(lH-benzotriazole-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid 5-trifluoromethoxy-pyridin-2-ylmethyl ester;
(3aS,6aS)-5-((R)-4,5,6,7-tetrahydro-lH-benzotriazole-5-carbonyl)-hexahydro-pyrrolo[3,4- c]pyrrole-2-carboxylic acid 4-cyano-2-isopropyl-benzyl ester;
(3aS,6aS)-5-((R)-4,5,6,7-tetrahydro-lH-benzotriazole-5-carbonyl)-hexahydro-pyrrolo[3,4- c]pyrrole-2-carboxylic acid 4-cyano-2-isopropyl-5 -methyl-benzyl ester;
(3aS,6aS)-5-((R)-4,5,6,7-tetrahydro-lH-benzotriazole-5-carbonyl)-hexahydro-pyrrolo[3,4- c]pyrrole-2-carboxylic acid 2-fluoro-4-trifluoromethoxy-benzyl ester;
(3aS,6aS)-5-(lH-benzotriazole-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid 2-fluoro-4-trifluoromethoxy-benzyl ester;
(3aS,6aS)-5-(lH-benzotriazole-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid 4-cyano-2-ethoxy-benzyl ester;
(3aS,6aS)-5-((R)-4,5,6,7-tetrahydro-lH-benzotriazole-5-carbonyl)-hexahydro-pyrrolo[3,4- c]pyrrole-2-carboxylic acid 3-fluoro-4-trifluoromethoxy-benzyl ester;
(3aS,6aS)-5-(lH-benzotriazole-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid 4-cyano-2-isopropyl-benzyl ester; (3aS,6aS)-5-(lH-benzotriazole-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid 4-cyano-2-isopropyl-5-methyl-benzyl ester;
(3aS,6aS)-5-(l,4,6,7-tetrahydro-[l,2,3]triazolo[4,5-c]pyridine-5-carbonyl)-hexahydro- pyrrolo[3,4-c]pyrrole-2-carboxylic acid 4-trifluoromethoxy-benzyl ester;
(3aR,6aR)-5-(lH-benzotriazole-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid 4-trifluoromethoxy-benzyl ester;
(3aS,6aS)-5-(lH-benzotriazole-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid 2-fluoro-4-trifluoromethyl-benzyl ester;
(3aS,6aS)-5-(lH-benzotriazole-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid 4-trifluoromethyl-benzyl ester;
(3aS,6aS)-5-((R)-4,5,6,7-Tetrahydro-lH-benzotriazole-5-carbonyl)-hexahydro- pyrrolo[3,4-c]pyrrole-2-carboxylic acid 4-trifluoromethoxy-benzyl ester;
(3aS,6aS)-5-((R)-4,5,6,7-Tetrahydro-lH-benzotriazole-5-carbonyl)-hexahydro- pyrrolo[3,4-c]pyrrole-2-carboxylic acid 4-trifluoromethyl-benzyl ester;
(3aS,6aS)-5-((R)-4,5,6,7-Tetrahydro-lH-benzotriazole-5-carbonyl)-hexahydro- pyrrolo[3,4-c]pyrrole-2-carboxylic acid 3-chloro-5-methanesulfonyl-benzyl ester;
(3aS,6aS)-5-(lH-benzotriazole-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid 4-cyano-2-methanesulfonyl-benzyl ester;
(3aS,6aS)-5-(lH-benzotriazole-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid 4-cyano-2-ethoxy-5-fluoro-benzyl ester;
(3aS,6aS)-5-(4-methoxy-lH-benzotriazole-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2- carboxylic acid 4-trifluoromethoxy-benzyl ester;
(3aS,6aS)-5-(lH-benzotriazole-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid 4-cyano-2-cyclobutoxy-benzyl ester;
(3aS,6aS)-5-(lH-benzotriazole-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid 4-cyano-2-isopropoxy-benzyl ester; (3aS,6aS)-5-(lH-benzotriazole-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid 4-cyano-2-(2,2,2-trifluoro-ethoxy)-benzyl ester;
(3aS,6aS)-5-(lH-berizotriazole-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid 4-chloro-2-ethoxy-5-fluoro-benzyl ester; (E)-l-[trans-2-(lH-benzotriazol-5-ylmethyl)-octahydro-pyrrolo[3,4-c]pyridin-5-yl]-3-(4- trifluoromethoxy-phenyl)-propenone;
(3aS,6aS)-5-(4-sulfamoyl-piperidine-l-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2- carboxylic acid 4-trifluoromethoxy-benzyl ester; l-[(3aR,6aR)-5-(lH-benzotriazole-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-3-(6- phenyl-pyridin-3-yl)-propan- 1 -one; l-[(3aS,6aS)-5-(lH-benzotriazole-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2-(2- isopropyl-phenoxy)-ethanone; l-[(3aS,6aS)-5-(lH-benzotriazole-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2-(2- trifluoromethyl-phenoxy)-ethanone; l-[(3aS,6aS)-5-(lH-benzotriazole-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2- (biphenyl-2-yloxy)-ethanone;
(E)-l-[(3aS,6aS)-5-((R)-4,5,6,7-Tetrahydro-lH-benzotriazole-5-carbonyl)-hexahydro- pyrrolo[3,4-c]pyrrol-2-yl]-3-(4-trifluoromethoxy-phenyl)-propenone; l-((3aR,6aR)-5-((R)-4,5,6,7-tetrahydro-lH-benzo[d][l,2,3]triazole-5- carbonyl)hexahydropyrrolo[3,4-c]pyrrol-2(lH)-yl)-3-(4-(trifluoromethoxy)phenyl)propan- 1-one; l-[(3aS,6aS)-5-(lH-benzotriazole-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2-(2- chloro-4-trifluoromethoxy-phenoxy)-ethanone; l-[(3aS,6aS)-5-(lH-benzotriazole-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2-(2- pyrrol- l-yl-phenoxy)-ethanone; 4-{2-[(3aS,6aS)-5-(lH-benzotriazole-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2 oxo-ethoxy}-3-methoxy-benzonitrile;
4-{2-[(3aS,6aS)-5-(lH-benzotriazole-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2 oxo-ethoxy} -benzonitrile;
1- [(3aS,6aS)-5-(lH-benzotriazole-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2- phenoxy-ethanone;
2- {2-[(3aS,6aS)-5-(lH-benzotriazole-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2 oxo-ethoxy} -5-trifluoromethoxy-benzonitrile; l-((3aR,8aS)-2-(lH-benzo[d][l,2,3]triazole-5-carbonyl)octahydropyrrolo[3,4-d]azepin- 6(7H)-yl)-2-(2-isopropyl-5-methylphenoxy)ethanone;
(lH-benzotriazol-5-yl)-[(3aS,6aS)-5-(6-trifluoromethoxy-lH-indole-2-carbonyl)- hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-methanone;
( 1 H-benzotriazol-5 -yl)- [(3 aS ,6aS)-5 -(5 -trifluoroniethoxy- 1 H-indo le-2-carbonyl)- hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-methanone;
1 - [trans-2-( 1 H-benzotriazo le-5 -carbonyl)-octahydro-pyrrolo [3 ,4-c]pyridin-5 -yl] -3 -(4- trifluoromethoxy-phenyl)-propan- 1 -one;
1 - [trans-2-( 1 H-benzotriazo 1-5 -ylmethyl)-octahydro-pyrrolo [3 ,4-c]pyridin-5 -yl] -3 -(4- trifluoromethoxy-phenyl)-propan- 1 -one; l-((3aR,8aS)-2-(lH-benzo[d][l,2,3]triazole-5-carbonyl)octahydropyrrolo[3,4-d]azepin- 6(7H)-yl)-3-(3-chloro-5-(trifluoromethyl)phenyl)propan- 1 -one; l-((3aR,8aS)-2-(lH-benzo[d][l,2,3]triazole-5-carbonyl)octahydropyrrolo[3,4-d]azepin- 6(7H)-yl)-3-(4-methoxy-2-(trifluoromethyl)phenyl)propan- 1 -one; l-((3aR,8aS)-2-(lH-benzo[d][l,2,3]triazole-5-carbonyl)octahydropyrrolo[3,4-d]azepin- 6(7H)-yl)-3-(2-cyclopropylphenyl)propan- 1 -one; l-[(3aR,6aR)-5-(lH-benzotriazole-5-carbonyl)-l,3,3a,4,6,6a-hexahydropyrrolo[3,4- c]pyrrol-2-yl] -3 - [3 -methoxy-5 -(trifluoromethoxy)phenyl]propan- 1 -one; l-[(3aS,6aS)-5-(lH-benzotriazole-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2-(2- isopropyl-5-methyl-phenoxy)-ethanone;
1- [(3aS,6aS)-5-(lH-benzotriazole-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2-(2- bromo-4-trifluoromethoxy-phenoxy)-ethanone;
(lH-benzotriazol-5-yl)-[(3aR,6aR)-5-(4'-chloro-biphenyl-4-carbonyl)-hexahydro- pyrrolo [3 ,4-c]pyrrol-2-yl]-methanone;
4-{2-[(3aS,6aS)-5-(lH-benzotriazole-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2- oxo-ethoxy}-3-isopropyl-benzonitrile;
2- (2-Acetyl-phenoxy)-l-[(3aS,6aS)-5-(lH-benzotriazole-5-carbonyl)-hexahydro- pyrrolo [3 ,4-c]pyrrol-2-yl]-ethanone;
4-{2-[(3aS,6aS)-5-(lH-benzotriazole-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2- oxo-ethoxy}-5-isopropyl-2-methyl-benzonitrile;
(lH-benzotriazol-5-yl)-[(3aR,6aR)-5-(naphthalene-2-carbonyl)-hexahydro-pyrrolo[3,4- c]pyrrol-2-yl]-methanone;
(lH-benzotriazol-5-yl)-[(3aS,6aS)-5-(4-methoxy-naphthalene-2-carbonyl)-hexahydro- pyrrolo [3 ,4-c]pyrrol-2-yl]-methanone;
4-{2-[(3aS,6aS)-5-(lH-benzotriazole-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2- oxo-ethoxy}-3-ethoxy-benzonitrile; l-[(3aR,6aR)-5-(lH-benzotriazole-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-3-(3 fluoro-4-trifluoromethoxy-phenyl)-propan- 1 -one; l-[(3aS,6aS)-5-(lH-benzotriazole-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2-(4- chloro-2-isopropyl-phenoxy)-ethanone;
[(3aS,6aS)-5-(4'-Chloro-biphenyl-4-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-(R)- 4 , 5 , 6, 7-tetrahydro - 1 H-benzotriazo 1-5 -yl-methanone; l-[(3aS,6aS)-5-(lH-benzotriazole-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-3-(4- trifluoromethoxy-phenyl)-propan- 1 -one; (lH-benzotriazol-5-yl)-[(3aS,6aS)-5-(4'-chloro-biphenyl-4-carbonyl)-hexahydro- pyrrolo [3 ,4-c]pyrrol-2-yl]-methanone; l-[(3aS,6aS)-5-(lH-benzotriazole-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2-[2- (tetrahydro-furan-2-yl)-phenoxy]-ethanone; (lH-benzotriazol-5-yl)-[(3aR,6aR)-5-(4-methoxy-naphthalene-2-carbonyl)-hexahydro- pyrrolo [3 ,4-c]pyrrol-2-yl]-methanone; l-[(3aS,6aS)-5-(lH-benzotriazole-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2-(2- tert-butyl-phenoxy)-ethanone;
[(3 aR,6aR)-5 -( 1 H-benzotriazo le-5 -carbonyl)-hexahydro-pyrrolo [3 ,4-c]pyrrol-2-yl] - [trans- 4-(4-chloro-phenyl)-cyclohexyl]-methanone; l-[(3aR,6aR)-5-(lH-benzotriazole-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-3-(3- fluoro-4-trifluoromethyl-phenyl)-propan- 1 -one; l-[(3aR,6aR)-5-(lH-benzotriazole-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-3-(2- fluoro-4-trifluoromethyl-phenyl)-propan- 1 -one; l-[(3aS,6aS)-5-(lH-benzotriazole-5-carbonyl)-l,3,3a,4,6,6a-hexahydropyrrolo[3,4- c]pyrrol-2-yl]-2-(2-pyridin-3-ylphenoxy)ethanone;
4-[3-[(3aR,6aR)-5-(lH-benzotriazole-5-carbonyl)-l,3,3a,4,6,6a-hexahydropyrrolo[3,4- c]pyrrol-2-yl]-3-oxopropyl]-2-methyl-5-propan-2-ylbenzonitrile;
4-[3-[(3aR,6aR)-5-(lH-benzotriazole-5-carbonyl)-l,3,3a,4,6,6a-hexahydropyrrolo[3,4- c]pyrrol-2-yl]-3-oxopropyl]-3-propan-2-ylbenzonitrile;
[(3aR,6aR)-5-[l-(4-chlorophenyl)piperidine-4-carbonyl]-l,3,3a,4,6,6a- hexahydropyrrolo [3 ,4-c]pyrrol-2-yl]-( 1 H-benzotriazo l-5-yl)methanone;
[(3aS,6aS)-5-[(5R)-4,5,6,7-tetrahydro-lH-benzotriazole-5-carbonyl]-l,3,3a,4,6,6a- hexahydropyrrolo[3,4-c]pyrrol-2-yl]-(4-propan-2-yloxynaphthalen-2-yl)methanone; [(3aS,6aS)-5-[(5R)-4,5,6,7-tetrahydro-lH-benzotriazole-5-carbonyl]-l,3,3a,4,6,6a- hexahydropyrrolo[3,4-c]pyrrol-2-yl]-(4-propan-2-yloxyquinolin-2-yl)methanone; l-[(3aR,6aR)-5-[(5R)-4,5,6,7-tetrahydro-lH-benzotriazole-5-carbonyl]-l,3,3a,4,6,6a- hexahydropyrrolo[3,4-c]pyrrol-2-yl]-3-[2-fluoro
one;
4-[2-[(3aS,6aS)-5-[(5R)-4,5,6,7-tetrahydro-lH-benzotriazole-5-carbonyl]-l,3,3a,4,6,6a- hexahydropyrrolo[3,4-c]pyrrol-2-yl]-2-oxoethoxy]-2-methyl-5-propan-2-ylbenzonitrile;
[(3aS,6aS)-5-[(5R)-4,5,6,7-tetrahydro-lH-benzotriazole-5-carbonyl]-l,3,3a,4,6,6a- hexahydropyrrolo[3,4-c]pyrrol-2-yl]-[l-(2,2,2-trifluoroethoxy)isoquinolin-3-yl]meth^ l-[(3aS,6aS)-5-[(5R)-4,5,6,7-tetrahydro-lH-benzotriazole-5-carbonyl]-l,3,3a,4,6,6a- hexahydropyrrolo[3,4-c]pyrrol-2-yl]-2-(4-bromo-2-tert-butylphenoxy)ethanone; l-[(3aS,6aS)-5-(lH-benzotriazole-5-carbonyl)-l,3,3a,4,6,6a-hexahydropyrrolo[3,4- c]pyrrol-2-yl]-2-(4-bromo-2-tert-butylphenoxy)ethanone;
4-[2-[(3aS,6aS)-5-[(5R)-4,5,6,7-tetrahydro-lH-benzotriazole-5-carbonyl]-l,3,3a,4,6,6a- hexahydropyrrolo[3,4-c]pyrrol-2-yl]-2-oxoethoxy]-3-tert-butylbenzonitrile;
4-[2-[(3aS,6aS)-5-(lH-benzotriazole-5-carbonyl)-l,3,3a,4,6,6a-hexahydropyrrolo[3,4- c]pyrrol-2-yl]-2-oxoethoxy]-3-tert-butylbenzonitrile;
[(3aS,6aS)-5-[(5R)-4,5,6,7-tetrahydro-lH-benzotriazole-5-carbonyl]-l,3,3a,4,6,6a- hexahydropyrrolo[3,4-c]pyrrol-2-yl]-[l-met^ l-[(3aS,6aS)-5-[(5R)-4,5,6,7-tetrahydro-lH-benzotriazole-5-carbonyl]-l,3,3a,4,6,6a- hexahydropyrrolo[3,4-c]pyrrol-2-yl]-2-[4-(trifluoromethoxy)phenoxy]ethanone;
[(3aS,6aS)-5-[(5R)-4,5,6,7-tetrahydro-lH-benzotriazole-5-carbonyl]-l,3,3a,4,6,6a- hexahydropyrrolo[3,4-c]pyrrol-2-yl]-(l-ethoxyisoquinolin-3-yl)methanone; l-[(3aS,6aS)-5-(lH-benzotriazole-5-carbonyl)-l,3,3a,4,6,6a-hexahydropyrrolo[3,4- c]pyrrol-2-yl]-2-(2-tert-butyl-4-methoxyphenoxy)ethanone;
((3aS,6aS)-5-(lH-benzo[d][l,2,3]triazole-5-carbonyl)hexahydropyrrolo[3,4-c]pyrrol- 2(lH)-yl)(4-ethoxyquinolin-2-yl)methanone; ((3aS,6aS)-5-(lH-benzo[d][l,2,3]triazole-5-carbonyl)hexahydropyrrolo[3,4-c]pyrrol- 2(lH)-yl)(4-(2,2,2-trifluoroethoxy)quinolin-2-yl)methanone;
((3aS,6aS)-5-(lH-benzo[d][l,2,3]triazole-5-carbonyl)hexahydropyrrolo[3,4-c]pyrrol- 2(1 H)-yl)(6-cyclobutoxy-5 -(trifluoromethyl)pyridin-3 -yl)methanone; ((3aS,6aS)-5-(lH-benzo[d][l,2,3]triazole-5-carbonyl)hexahydropyrrolo[3,4-c]pyrrol- 2(1 H)-yl)(5 -bromo-6-(2-methoxyethoxy)pyridin-3 -yl)methanone;
((3aS,6aS)-5-(lH-benzo[d][l,2,3]triazole-5-carbonyl)hexahydropyrrolo[3,4-c]pyrrol- 2(lH)-yl)(5-bromo-6-(cyclopropylmethoxy)pyridin-3-yl)methanone;
((3aS,6aS)-5-(lH-benzo[d][l,2,3]triazole-5-carbonyl)hexahydropyrrolo[3,4-c]pyrrol- 2(lH)-yl)(5-cyclopropyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methanone;
((3aS,6aS)-5-(lH-benzo[d][l,2,3]triazole-5-carbonyl)hexahydropyrrolo[3,4-c]pyrrol- 2(lH)-yl)(6-(2,2,2-trifluoroethoxy)-5-(trifluoromethyl)pyridin-3-yl)methanone;
(lH-benzotriazol-5-yl)-{(3aS,6aS)-5-[4-(4-chloro-phenyl)-piperidine-l-carbonyl]- hexahydro-pyrrolo[3,4-c]pyrrol-2-yl}-methanone; (lH-benzotriazol-5-yl)-{(3aS,6aS)-5-[4-(4-chloro-phenyl)-piperazine-l-carbonyl]- hexahydro-pyrrolo[3,4-c]pyrrol-2-yl}-methanonea; nd pharmaceutically acceptable salts thereof.
47. A compound according to any one of claims 1 to 45, selected from trans-3 ,5-dichlorobenzyl 2-( 1 H-benzo [d] [ 1 ,2,3]triazole-5-carbonyl)hexahydro- 1 H- pyrrolo [3 ,4-c]pyridine-5 (6H)-carboxylate; trans-3, 5-dichlorobenzyl 2-(2-oxo-2,3-dihydrobenzo[d]oxazole-6-carbonyl)hexahydro-lH- pyrrolo [3 ,4-c]pyridine-5 (6H)-carboxylate;
(3aS,6aS)-5-(lH-benzotriazole-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid 3-chloro-5-methanesulfonyl-benzyl ester; (3aS,6aS)-5-(lH-benzotriazole-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid 4-trifluoromethoxy-benzyl ester; (E)- 1 -((3aR,6aR)-5-( 1 H-benzo [d] [ 1 ,2,3]triazole-5-carbonyl)hexahydropyrrolo [3 ,4- c]pyrrol-2( 1 H)-yl)-3 -(4-(trifluoromethoxy)phenyl)prop-2-en- 1 -one; l-((3aR,6aS)-5-(lH-benzo[d][l,2,3]triazole-5-carbonyl)hexahydropyrrolo[3,4-c]pyrrol- 2(1 H)-yl)-3 -(4-(trifluoromethoxy)phenyl)propan- 1 -one; l-[(3aR,6aR)-5-(lH-benzotriazole-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-3-(4- trifluoromethoxy-phenyl)-propan- 1 -one; l-[(3aR,6aR)-5-(lH-benzotriazole-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-3-(4- trifluoromethyl-phenyl)-propan- 1 -one; l-[(3aS,6aS)-5-(lH-benzotriazole-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2-(4- chloro-2-isopropyl-5-methyl-phenoxy)-ethanone; and pharmaceutically acceptable salts thereof.
A compound according to any one of claims 1 to 44 or 46, selected from
(3aS,6aS)-5-(4-fluoro-lH-benzotriazole-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2- carboxylic acid 4-trifluoromethoxy-benzyl ester; l-[(3aR,6aR)-5-(4-fluoro-lH-benzotriazole-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2- yl] -3 -(4-trifluoromethoxy-phenyl)-propan- 1 -one;
(3aS,6aS)-5-(lH-benzotriazole-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid 4-difluoromethoxy-3-fluoro-benzyl ester;
(3aS,6aS)-5-(l,4,6,7-tetrahydro-[l,2,3]triazolo[4,5-c]pyridine-5-carbonyl)-hexahydro- pyrrolo[3,4-c]pyrrole-2-carboxylic acid 4-trifluoromethoxy-benzyl ester;
(3aS,6aS)-5-((R)-4,5,6,7-Tetrahydro-lH-benzotriazole-5-carbonyl)-hexahydro- pyrrolo[3,4-c]pyrrole-2-carboxylic acid 4-trifluoromethoxy-benzyl ester; and pharmaceutically acceptable salts thereof.
A process to prepare a compound according to any one of claims 1 to 48 comprising the reaction of a compound of formula (II) in the presence of a compound of formula (III), wherein R1, R2, A, W, m, n, p and q are as defined above, Y is -OC(O)-.
Figure imgf000300_0001
(I I) (I)
50. A compound according to any one of claims 1 to 48 for use as therapeutically active
substance.
51. A pharmaceutical composition comprising a compound according to any one of claims 1 to 48 and a therapeutically inert carrier.
52 The use of a compound according to any one of claims 1 to 48 for the treatment or
prophylaxis of renal conditions, liver conditions, inflammatory conditions, conditions of the nervous system, fibrotic diseases and acute and chronic organ transplant rejection.
53. A compound according to any one of claims 1 to 48 for the treatment or prophylaxis of renal conditions, liver conditions, inflammatory conditions, conditions of the nervous system, fibrotic diseases and acute and chronic organ transplant rejection.
54. The use of a compound according to any one of claims 1 to 48 for the preparation of a medicament for the treatment or prophylaxis of renal conditions, liver conditions, inflammatory conditions, conditions of the nervous system, fibrotic diseases and acute and chronic organ transplant rejection.
55. A method for the treatment or prophylaxis a renal condition selected from the group
consisting of renal conditions, liver conditions, inflammatory conditions, conditions of the nervous system, fibrotic diseases and acute and chronic organ transplant rejection, which method comprises administering an effective amount of a compound according to any one of claims 1 to 48.
56. A compound according to any one of claims 1 to 48, when manufactured according to a process of claim 49.
57. The invention as hereinbefore described.
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