HK1223921B - New octahydro-cyclobuta [1,2-c;3,4-c']dipyrrol-2-yl - Google Patents

Description

Novel octahydro-cyclobutadiene[1,2-c;3,4-c']dipyrrol-2-yl

The present invention relates to organic compounds useful for treatment or prevention in mammals, and in particular to autotaxin (ATX) inhibitors, which are inhibitors of lysophosphatidic acid (LPA) production and, therefore, modulators of LPA levels and related signaling, for the treatment or prevention of renal disorders, liver disorders, inflammation, nervous system disorders, respiratory disorders, vascular and cardiovascular disorders, fibrotic diseases, cancer, ocular disorders, metabolic disorders, cholestatic and other forms of chronic pruritus, and acute and chronic organ transplant rejection.

The present invention provides novel compounds of formula (I)

in

^R1 is substituted quinolyl, substituted 1,2,3,4-tetrahydroquinolyl, substituted isoquinolyl, substituted 1,2,3,4-tetrahydroisoquinolyl, substituted 9H-carbazolyl, substituted chromanyl, substituted indolyl, substituted naphthyl, substituted oxazolyl, substituted phenyl, substituted phenylalkyl, substituted phenylcycloalkyl, substituted phenoxyalkyl, substituted phenylalkoxy, substituted phenylalkenyl, substituted phenylalkynyl, substituted pyridazine substituted pyridazinylalkyl, substituted pyridazinylalkenyl, substituted pyridazinylalkynyl, substituted pyridinyl, substituted pyridinylalkyl, substituted pyridinylalkenyl, substituted pyridinylalkynyl, substituted pyridonyl, substituted pyridonylalkyl, substituted pyridonylalkenyl, substituted pyridonylalkynyl, substituted thienyl, substituted thienylalkyl, substituted thienylalkenyl, substituted thienylalkynyl, substituted tetralinyl or substituted tetralinonyl, wherein substituted quinolinyl, substituted 1,2,3,4-tetrahydroquinolinyl, substituted isoquinolinyl, substituted 1,2,3,4-tetrahydroisoquinolinyl, substituted 9H-carbazolyl, substituted chromanyl, substituted indolyl, substituted naphthyl, substituted oxazolyl, substituted phenyl, substituted phenylalkyl, substituted phenylcycloalkyl, substituted phenoxyalkyl, substituted phenylalkoxy, substituted phenylalkenyl, substituted phenylalkynyl, substituted pyridazine R 6 , R ⁷ and R ^{8 ;}

Y is -C(O)- or -S(O) ₂ -;

^R2 is substituted pyridyl, substituted phenyl or selected from the ring systems A, B and C, wherein the substituted pyridyl and substituted phenyl are substituted with one substituted aminosulfonyl, wherein the substituted aminosulfonyl is substituted with one to two nitrogen atoms of substituents independently selected from H, alkyl, cycloalkyl, cycloalkylalkyl, hydroxyalkyl and alkoxyalkyl;

R ³ , R ⁴ and R ⁵ are independently selected from H, alkyl, halogen, haloalkyl and alkoxy;

^R6 , ^R7 and ^R8 are independently selected from H, halogen, cyano, cyanoalkyl, alkyl, hydroxyalkyl, haloalkyl, hydroxyhaloalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkoxy, cycloalkyloxy, cycloalkyloxyalkyl, cycloalkylalkoxyalkyl, alkoxy, alkoxyalkyl, haloalkoxy, alkoxyhaloalkyl, alkoxyalkoxy, alkoxyalkoxyalkyl, alkylsulfonyl, furanyl, tetrahydropyranyl, phenyl, substituted phenyl, phenylalkoxy, substituted phenylalkoxy, pyridinyl, substituted pyridinyl, pyrrolyl, substituted pyrrolyl, pyrrolidinyl and substituted pyrrolidinyl, wherein substituted phenyl, substituted phenylalkoxy, substituted pyridinyl, substituted pyrrolyl and substituted pyrrolidinyl are substituted with one to three halogens;

and pharmaceutically acceptable salts.

Autotaxin (ATX) is a secreted enzyme, also known as ectonucleotide pyrophosphatase/phosphodiesterase 2 or lysophospholipase D, that is important for converting lysophosphatidylcholine (LPC) into the biologically active signaling molecule lysophosphatidic acid (LPA). Plasma LPA levels have been shown to correlate well with ATX activity, and ATX is therefore believed to be an important source of extracellular LPA. Early experiments with prototype ATX inhibitors demonstrated that such compounds were able to inhibit LAP synthesis activity in mouse plasma. Work conducted in the 1970s and early 1980s demonstrated that LPA can elicit a variety of cellular responses, including smooth muscle cell contraction, platelet activation, cell proliferation, chemotaxis, and more. LPA mediates its effects by signaling through several G protein-coupled receptors (GPCRs); the first members were originally described as Edg (endothelial cell differentiation gene) receptor or ventricular zone gene-1 (vzg-1), but are now called LPA receptors. Currently, the prototypical group consists of LPA1/Edg-2/VZG-1, LPA2/Edg-4, and LPA3/Edg-7. Recently, three additional LAP 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 prototypical LPA1-3 receptors. The ATX-LPA signaling axis is involved in a wide variety 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, and obesity and/or other metabolic diseases such as diabetes mellitus. Therefore, increased ATX activity and/or increased LPA levels, altered LPA receptor expression, and altered responses to LPA may contribute to the initiation, progression, and/or outcome of a wide variety of pathophysiological conditions associated with the ATX/LPA axis.

According to the present invention, the compounds of formula (I) or their pharmaceutically acceptable salts and esters can be used to treat or prevent diseases, disorders or conditions associated with the activity of autotaxin and/or the biological activity of lysophosphatidic acid (LPA).

The compounds of formula (I) herein, or pharmaceutically acceptable salts and esters thereof, inhibit autotaxin activity and, therefore, inhibit LPA production and regulate LAP levels and related signaling. The autotaxin inhibitors described herein can be used as agents for treating or preventing diseases or conditions in which ATX activity and/or LPA signaling are involved in, implicated in the etiology or pathology of the disease, or are otherwise associated with at least one symptom of the disease. The ATX-LPA axis has been implicated in angiogenesis, chronic inflammation, autoimmune diseases, fibrotic diseases, cancer and tumor metastasis and progression, ocular disorders, metabolic disorders such as obesity and/or diabetes, disorders such as cholestatic or other forms of chronic pruritus, and acute and chronic organ transplant rejection.

The present invention relates to compounds of formula (I) and their salts and esters as described above, as well as to their use as therapeutically active substances, processes for the preparation of said compounds, intermediates, pharmaceutical compositions, medicaments containing said compounds, their pharmaceutically acceptable salts or esters, the use of said compounds, salts or esters for the treatment or prevention of disorders or conditions associated with ATX activity and/or the biological activity of lysophosphatidic acid (LPA), in particular for the treatment or prevention of kidney conditions, liver conditions, inflammation, conditions of the nervous system, respiratory conditions, vascular and cardiovascular conditions, fibrotic diseases, cancer, eye conditions, metabolic conditions, cholestatic and other forms of chronic pruritus and acute and chronic organ transplant rejection, and the use of said compounds, salts or esters for the preparation of medicaments for the treatment or prevention of kidney conditions, liver conditions, inflammation, conditions of the nervous system, respiratory conditions, vascular and cardiovascular conditions, fibrotic diseases, cancer, eye conditions, metabolic conditions, cholestatic and other forms of chronic pruritus and acute and chronic organ transplant rejection.

The term "alkenyl" refers to a monovalent straight or branched hydrocarbon radical having 2 to 7 carbon atoms and at least one double bond. In particular embodiments, the alkenyl radical has 2 to 4 carbon atoms and at least one double bond. Examples of alkenyl radicals include ethenyl, propenyl, prop-2-enyl, isopropenyl, n-butenyl, and isobutenyl. A particular alkenyl radical is ethenyl.

The term "alkoxy" refers to a radical of the formula -O-R', where R' is an alkyl radical. Examples of alkoxy radicals include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, and tert-butoxy. Particular alkoxy radicals include methoxy, ethoxy, and isopropoxy. A more particular alkoxy radical is isopropoxy.

The term "alkoxyalkoxy" refers to an alkoxy group in which at least one of the hydrogen atoms of the alkoxy group has been replaced by another alkoxy group. Examples of alkoxyalkoxy groups include methoxymethoxy, ethoxymethoxy, methoxyethoxy, ethoxyethoxy, methoxypropoxy, and ethoxypropoxy. A particular alkoxyalkoxy group is methoxyethoxy.

The term "alkoxyalkoxyalkyl" refers to an alkyl group in which at least one of the hydrogen atoms of the alkyl group has been replaced by an alkoxyalkoxy group. Examples of alkoxyalkoxyalkyl groups include methoxymethoxymethyl, ethoxymethoxymethyl, methoxyethoxymethyl, ethoxyethoxymethyl, methoxypropoxymethyl, ethoxypropoxymethyl, methoxymethoxyethyl, ethoxymethoxyethyl, methoxyethoxyethyl, ethoxyethoxyethyl, methoxypropoxyethyl, and ethoxypropoxyethyl.

The term "alkoxyalkyl" refers to an alkyl group in which at least one of the alkyl group's hydrogen atoms has been replaced by an alkoxy group. Exemplary alkoxyalkyl groups include methoxymethyl, ethoxymethyl, methoxyethyl, ethoxyethyl, methoxypropyl, ethoxypropyl, and isopropoxymethyl. A particular alkoxyalkyl group is methoxypropyl.

The term "alkoxyhaloalkyl" refers to a haloalkyl group in which at least one hydrogen atom of the haloalkyl group is replaced by an alkoxy group. Exemplary alkoxyalkyl groups include methoxytrifluoroethyl, ethoxytrifluoroethyl, methoxytrifluoropropyl, and ethoxytrifluoropropyl.

The term "alkyl" refers to a monovalent straight or branched saturated hydrocarbon radical of 1 to 12 carbon atoms. In particular embodiments, the alkyl radical has 1 to 7 carbon atoms, and in more particular embodiments, has 1 to 4 carbon atoms. Examples of alkyl radicals include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl and sec-butyl, and pentyl. Particular alkyl radicals include methyl, isopropyl, and isobutyl.

The term "alkylsulfonyl" refers to a radical of the formula -S(O) ₂ -R', wherein R' is an alkyl group. Examples of alkylsulfonyl groups include radicals of the formula -S(O) ₂ -R', wherein R' is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or tert-butyl. In particular, alkylsulfonyl groups include radicals of the formula -S(O) ₂ -R', wherein R' is a methyl group.

The term "amino" refers to a _-NH2 group.

The term "aminosulfonyl" refers to the -S(O) ₂ - _NH2 group.

The term "cyano" refers to a -C≡N group.

The term "cyanoalkyl" refers to an alkyl group in which a hydrogen atom of the alkyl group is replaced by a cyano group. Exemplary cyanoalkyl groups include cyanomethyl, cyanoethyl, and cyanopropyl. A particular alkoxyalkyl group is cyanomethyl.

The term "cycloalkoxy" refers to a group of formula -O-R', wherein R' is a cycloalkyl group. Examples of cycloalkoxy groups include cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy, and cyclooctyloxy. A particular cycloalkoxy group is cyclopropyloxy.

The term "cycloalkoxyalkyl" refers to an alkyl group in which at least one of the hydrogen atoms of the alkyl group has been replaced by a cycloalkoxy group. Examples of cycloalkoxyalkyl groups include cyclopropyloxymethyl, cyclopropyloxyethyl, cyclobutyloxymethyl, cyclobutyloxyethyl, cyclopentyloxymethyl, cyclopentyloxyethyl, cyclohexyloxymethyl, cyclohexyloxyethyl, cycloheptyloxymethyl, cycloheptyloxyethyl, cyclooctyloxymethyl, and cyclooctyloxyethyl.

The term "cycloalkyl" refers to a monovalent saturated monocyclic or bicyclic hydrocarbon radical of 3 to 10 ring carbon atoms. In particular embodiments, cycloalkyl refers to a monovalent saturated monocyclic hydrocarbon radical of 3 to 8 ring carbon atoms. Bicyclic refers to a ring system consisting of two saturated carbocyclic rings having two common carbon atoms. Examples of monocyclic cycloalkyls are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl. Examples of bicyclic cycloalkyls are bicyclo[2.2.1]heptyl or bicyclo[2.2.2]octyl. Particular monocyclic cycloalkyls are cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. A more particular monocyclic cycloalkyl is cyclopropyl.

The term "cycloalkylalkoxy" refers to an alkoxy group in which at least one of the hydrogen atoms of the alkoxy group has been replaced by a cycloalkyl group. Examples of cycloalkylalkoxy groups include cyclopropylmethoxy, cyclobutylmethoxy, cyclopentylmethoxy, cyclohexylmethoxy, cycloheptylmethoxy, and cyclooctylmethoxy. A particular cycloalkylalkoxy group is cyclopropylmethoxy.

The term "cycloalkylalkoxyalkyl" refers to an alkyl group in which at least one of the hydrogen atoms of the alkyl group has been replaced by a cycloalkylalkoxy group. Examples of cycloalkylalkoxyalkyl groups include cyclopropylmethoxymethyl, cyclopropylmethoxyethyl, cyclobutylmethoxymethyl, cyclobutylmethoxyethyl, cyclopentylmethoxyethyl, cyclopentylmethoxyethyl, cyclohexylmethoxymethyl, cyclohexylmethoxyethyl, cycloheptylmethoxymethyl, cycloheptylmethoxyethyl, cyclooctylmethoxymethyl, and cyclooctylmethoxyethyl.

The term "cycloalkylalkyl" represents an alkyl group in which at least one of the hydrogen atoms of the alkyl group has been replaced by a cycloalkyl group. Examples of cycloalkylalkyl groups include cyclopropylmethyl, cyclopropylethyl, cyclopropylbutyl, cyclobutylpropyl, 2-cyclopropylbutyl, cyclopentylbutyl, cyclohexylmethyl, cyclohexylethyl, bicyclo[4.1.0]heptylmethyl, bicyclo[4.1.0]heptylethyl, bicyclo[2.2.2]octylmethyl, bicyclo[2.2.2]octylethyl, adamantylmethyl and adamantylethyl. The special example of cycloalkylalkyl groups is cyclohexylmethyl, cyclohexylethyl, bicyclo[4.1.0]heptylmethyl, bicyclo[4.1.0]heptylethyl, bicyclo[2.2.2]octylmethyl, bicyclo[2.2.2]octylethyl, adamantylmethyl and adamantylethyl. Further particular examples of cycloalkylalkyl are cyclohexylmethyl, cyclohexylethyl, bicyclo[4.1.0]heptylmethyl, bicyclo[2.2.2]octylmethyl, adamantylmethyl and adamantylethyl.

The term "haloalkoxy" refers to an alkoxy group in which at least one of the hydrogen atoms of the alkoxy group has been replaced by the same or different halogen atoms. The term "perhaloalkoxy" refers to an alkoxy group in which all of the hydrogen atoms of the alkoxy group have been replaced by the same or different halogen atoms. Examples of haloalkoxy groups include fluoromethoxy, difluoromethoxy, trifluoromethoxy, trifluoroethoxy, trifluoromethylethoxy, trifluorodimethylethoxy, and pentafluoroethoxy. Special haloalkoxy groups include trifluoromethoxy and trifluoroethoxy.

The term "haloalkyl" refers to an alkyl group in which at least one of the alkyl group's hydrogen atoms has been replaced by the same or different halogen atoms. The term "perhaloalkyl" refers to an alkyl group in which all of the alkyl group's hydrogen atoms have been replaced by the same or different halogen atoms. Examples of haloalkyl groups include fluoromethyl, difluoromethyl, trifluoromethyl, trifluoroethyl, trifluoromethylethyl, and pentafluoroethyl. Particular haloalkyl groups are trifluoromethyl and trifluoroethyl.

The terms "halogen" and "halo" are used interchangeably herein and refer to fluorine, chlorine, bromine or iodine. Particular halogens are chlorine and fluorine. More particular halogen is chlorine.

The term "hydroxy" refers to an -OH group.

The term "hydroxyalkyl" refers to an alkyl group in which at least one of the hydrogen atoms of the alkyl group has been replaced by a hydroxy group. Examples of hydroxyalkyl groups include hydroxymethyl, hydroxyethyl, hydroxy-1-methyl-ethyl, hydroxypropyl, hydroxymethylpropyl, and dihydroxypropyl. Specific examples are hydroxymethyl and hydroxyethyl.

The term "hydroxyhaloalkyl" refers to a haloalkyl group in which at least one of the hydrogen atoms of the haloalkyl group is replaced by a hydroxy group. Exemplary hydroxyhaloalkyl groups include hydroxytrifluoroethyl and hydroxytrifluoropropyl. Particular hydroxyhaloalkyl groups include hydroxytrifluoroethyl.

The term "phenoxy" denotes a radical of the formula -O-R', wherein R' is phenyl.

The term "phenoxyalkyl" refers to an alkyl group in which 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. A particular alkoxyalkyl 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 by a phenyl group. A particular phenylalkenyl group is phenylvinyl.

The term "phenylalkoxy" refers to an alkoxy group in which at least one of the hydrogen atoms of the alkoxy group is replaced by a phenyl group. Examples of phenylalkoxy groups include phenylmethoxy and phenylethoxy. A particular phenylalkoxy group is phenylmethoxy.

The term "phenylalkyl" refers to an alkyl group in which at least one of the hydrogen atoms of the alkyl group has been replaced by a phenyl group. Particular phenylalkyl groups are benzyl, phenethyl and phenylpropyl. More particular phenylalkyl groups are benzyl and phenethyl. More 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 by a phenyl group. A particular phenylalkynyl group is phenylethynyl.

The term "phenylcycloalkyl" denotes a cycloalkyl group wherein at least one of the hydrogen atoms of the cycloalkyl group has been replaced by a phenyl group. A particular phenylcycloalkyl group is phenylcyclopropyl.

The term "pyridazinylalkenyl" refers to an alkenyl group wherein at least one of the hydrogen atoms of the alkenyl group is replaced by a pyridazinyl group. A particular pyridazinylalkenyl group is pyridazinylvinyl.

The term "pyridazinylalkyl" refers to an alkyl group in which at least one of the hydrogen atoms of the alkyl group is replaced by a pyridazinyl group. Particular pyridazinylalkyl groups are pyridazinylmethyl, pyridazinylethyl and pyridazinylpropyl. More particular pyridazinylalkyl group is pyridazinylethyl.

The term "pyridazinylalkynyl" refers to an alkynyl group wherein at least one of the hydrogen atoms of the alkynyl group is replaced by a pyridazinyl group. A particular pyridazinylalkynyl group is pyridazinylethynyl.

The term "pyridonylalkenyl" refers to an alkenyl group wherein at least one of the hydrogen atoms of the alkenyl group is replaced by a pyridonyl group. A particular pyridonylalkenyl group is pyridonylvinyl.

The term "pyridonylalkyl" refers to an alkyl group in which at least one hydrogen atom of the alkyl group is replaced by a pyridonyl group. Particular pyridonylalkyl groups are pyridonylmethyl, pyridonylethyl and pyridonylpropyl. More particular pyridonylalkyl group is pyridonylethyl.

The term "pyridonylalkynyl" refers to an alkynyl group wherein at least one of the hydrogen atoms of the alkynyl group is replaced by a pyridonyl group. Particular pyridonylalkynyl group is pyridonylethynyl.

The term "pyridylalkenyl" denotes an alkenyl group wherein at least one of the hydrogen atoms of the alkenyl group has been replaced by a pyridyl group. A particular pyridylalkenyl group is pyridylvinyl.

The term "pyridylalkyl" denotes an alkyl group in which at least one of the hydrogen atoms of the alkyl group has been replaced by a pyridyl group. Particular pyridylalkyl groups are pyridylmethyl, pyridylethyl and pyridylpropyl. More particular pyridylalkyl group is pyridylethyl.

The term "pyridylalkynyl" denotes an alkynyl group wherein at least one of the hydrogen atoms of the alkynyl group has been replaced by a pyridyl group. A particular pyridylalkynyl group is pyridylethynyl.

The term "thienylalkenyl" denotes an alkenyl group wherein at least one of the hydrogen atoms of the alkenyl group has been replaced by a thienyl group. A particular thienylalkenyl group is thienylethenyl.

The term "thienylalkyl" denotes an alkyl group in which at least one of the hydrogen atoms of the alkyl group has been replaced by a thienyl group. Particular thienylalkyl groups are thienylmethyl, thienylethyl and thienylpropyl. More particular thienylalkyl groups are thienylmethyl.

The term "thienylalkynyl" denotes an alkynyl group wherein at least one of the hydrogen atoms of the alkynyl group has been replaced by a thienyl group. A particular thienylalkynyl group is thienylethynyl.

The term "pharmaceutical salt" refers to those salts that keep the biological effectiveness and property of free alkali or free acid, and they are not biologically or otherwise unsuitable. Said salt is formed with following acid: inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid etc., particularly hydrochloric acid, and organic acid 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-acetylcysteine etc. In addition, these salts can be prepared by adding inorganic alkali or organic base in free acid. Salt derived from inorganic alkali includes but is not limited to sodium salt, potassium salt, lithium salt, ammonium salt, calcium salt, magnesium salt etc. 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, etc. Particular pharmaceutically acceptable salts of the compounds of formula (I) are the sodium and potassium salts.

"Pharmaceutically acceptable esters" means that the compounds of formula (I) can be derivatized at functional groups to provide derivatives that are capable of conversion back to the parent compound in vivo. Examples of such compounds include physiologically acceptable and metabolically labile ester derivatives such as methoxymethyl ester, methylthiomethyl ester, and pivaloyloxymethyl ester. In addition, similar to the metabolically labile esters, any physiologically acceptable equivalents of the compounds of formula (I) that are capable of generating the parent compound of formula (I) in vivo are within the scope of the present invention.

The term "protecting group" (PG) represents a group that selectively blocks a reactive site in a multifunctional compound in its traditional sense in synthetic chemistry so that a chemical reaction can be selectively carried out at another unprotected reactive site. The protecting group can be removed at a suitable point. Exemplary protecting groups are amino-protecting groups, carboxyl-protecting groups or hydroxyl-protecting groups. Special protecting groups are tert-butyloxycarbonyl (Boc), benzyloxycarbonyl (Cbz), fluorenylmethoxycarbonyl (Fmoc) and benzyl (Bn) groups. More special protecting groups are tert-butyloxycarbonyl (Boc) and fluorenylmethoxycarbonyl (Fmoc) groups. More special protecting groups are tert-butyloxycarbonyl (Boc) and fluorenylmethoxycarbonyl (Fmoc) groups.

The abbreviation uM stands for micromolar concentration and is equivalent to the symbol μM.

The abbreviation uL stands for microliter and is equivalent to the symbol μL.

The abbreviation ug stands for microgram and is equivalent to the symbol μg.

The compounds of formula (I) may contain several asymmetric centers and may exist as optically pure enantiomers, mixtures of enantiomers, such as, for example, racemates, optically pure diastereomers, mixtures of diastereomers, diastereomeric racemates or mixtures of diastereomeric racemates.

According to the Cahn-Ingold-Prelog Convention, an asymmetric carbon atom can be in the "R" or "S" configuration.

Yet another embodiment of the present invention is a compound according to formula (I) as described herein and a pharmaceutically acceptable salt or ester thereof, in particular a compound according to formula (I) as described herein and a pharmaceutically acceptable salt thereof, more in particular a compound according to formula (I) as described herein.

A more particular embodiment of the present invention is a compound according to formula (I) as described herein, wherein said compound is of formula (Ic).

Another embodiment of the present invention are compounds according to formula (I) as described herein, wherein ^R is substituted quinolyl, substituted 1,2,3,4-tetrahydroquinolyl, substituted isoquinolyl, substituted 1,2,3,4-tetrahydroisoquinolyl, substituted 9H-carbazolyl, substituted chromanyl, substituted indolyl, substituted naphthyl, substituted oxazolyl, substituted phenyl, substituted phenylalkyl, substituted phenoxyalkyl, substituted phenylalkoxy, substituted phenylalkenyl, substituted pyridazinyl, substituted pyridinyl, substituted pyridonyl, substituted tetralinyl or substituted tetralinonyl, wherein substituted quinolyl, substituted 1,2,3,4-tetrahydroquinolyl, substituted isoquinolyl, substituted 1,2,3,4-tetrahydroisoquinolyl, substituted 9H-carbazolyl, substituted chromanyl, substituted indolyl, substituted naphthyl, substituted oxazolyl, substituted phenyl, substituted phenylalkyl, substituted phenoxyalkyl, substituted phenylalkoxy, substituted phenylalkenyl, substituted pyridazinyl, substituted pyridyl, substituted pyridonyl, substituted tetralinyl and substituted tetralinonyl are substituted by R ⁶ , R ⁷ and R ⁸ .

A certain embodiment of the present invention are compounds according to formula (I) as described herein, wherein R ¹ is substituted quinolinyl, substituted indolyl, substituted naphthyl, substituted phenylalkoxy, substituted phenylalkenyl or substituted pyridinyl, wherein substituted quinolinyl, substituted indolyl, substituted naphthyl, substituted phenylalkoxy, substituted phenylalkenyl and substituted pyridinyl are substituted with R ⁶ , R ⁷ and R ⁸ .

In a further embodiment of the present invention are compounds according to formula (I) as described herein, wherein R ¹ is substituted quinolinyl, substituted indolyl, substituted naphthyl or substituted pyridinyl, wherein substituted quinolinyl, substituted indolyl, substituted naphthyl and substituted pyridinyl are substituted with R ⁶ , R ⁷ and R ⁸ .

The present invention also relates to compounds according to formula (I) as described herein, wherein R ² is selected from the ring systems A and C.

A further particular embodiment of the present invention are compounds according to formula (I) as described herein, wherein R ² is ring system A and is of formula (Ia).

Also an embodiment of the present invention are compounds according to formula (I) as described herein, wherein Y is -C(O)-.

Another embodiment of the present invention are compounds according to formula (I) as described herein, wherein R ³ , R ⁴ and R ⁵ are independently selected from H and halogen.

A further embodiment of the present invention are compounds according to formula (I) as described herein, wherein R ³ , R ⁴ and R ⁵ are H.

The present invention also relates to compounds according to formula (I) as described herein, wherein ^R6 is H, halogen, cyano, cyanoalkyl, alkyl, haloalkyl, cycloalkylalkoxy, alkoxy, alkoxyalkyl, haloalkoxy, alkoxyalkoxy, phenyl, phenylalkoxy or phenyl substituted by one to three halogens.

The present invention is a further embodiment of the compounds according to formula (I) as described herein, wherein ^R6 is alkoxy, haloalkoxy or alkoxyalkoxy.

Another embodiment of the present invention are compounds according to formula (I) as described herein, wherein ^R7 is H, halogen, alkyl, cycloalkyl, alkoxy, haloalkoxy, alkylsulfonyl, furanyl or tetrahydropyranyl.

A further particular embodiment of the present invention are compounds according to formula (I) as described herein, wherein ^R7 is H or halogen.

Also an embodiment of the present invention are compounds according to formula (I) as described herein, wherein ^R8 is H or alkyl.

A certain embodiment of the present invention are compounds according to formula (I) as described herein, wherein ^R8 is H.

A more particular embodiment of the present invention are compounds according to formula (I) as described herein, wherein R ¹ is substituted quinolinyl, substituted indolyl, substituted naphthyl or substituted pyridinyl, wherein substituted quinolinyl, substituted indolyl, substituted naphthyl and substituted pyridinyl are substituted with R ⁶ , R ⁷ and R ⁸ , Y is -C(O)- and R ² is ring system A and is of formula (Ib).

A further particular embodiment of the present invention are compounds according to formula (I) as described herein, wherein said compound is of formula (Ic).

Particular examples of compounds of formula (I) as described herein are selected from

[(3aS,3bS,6aR,6bR)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobutadieno[1,2-c;3,4-c′]dipyrrol-2-yl]-(6-chloro-naphthalen-2-yl)-methanone;

1-[(3aS,3bR,6aS,6bR)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobutadien[1,2-c;3,4-c′]dipyrrol-2-yl]-3-(4-trifluoromethoxy-phenyl)-propan-1-one;

[(3aS,3bS,6aR,6bR)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobutadien[1,2-c;3,4-c′]dipyrrol-2-yl]-(4′-fluoro-biphenyl-4-yl)-methanone;

(E)-1-[(3aS,3bR,6aS,6bR)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobutadien[1,2-c;3,4-c′]dipyrrol-2-yl]-3-(4-trifluoromethoxy-phenyl)-propenone;

[(3aS,3bS,6aR,6bR)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobutadieno[1,2-c;3,4-c′]dipyrrol-2-yl]-(6-bromo-naphthalen-2-yl)-methanone;

[(3aS,3bS,6aR,6bR)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobutadieno[1,2-c;3,4-c′]dipyrrol-2-yl]-(6-methoxy-naphthalen-2-yl)-methanone;

(E)-1-[(3aS,3bS,6aR,6bR)-5-((R)-4,5,6,7-tetrahydro-1H-benzotriazole-5-carbonyl)-octahydro-cyclobutadien[1,2-c;3,4-c′]dipyrrol-2-yl]-3-(4-trifluoromethoxy-phenyl)-propenone;

6-[(3aS,3bS,6aR,6bR)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobutadieno[1,2-c;3,4-c′]dipyrrole-2-carbonyl]-naphthalene-2-carbonitrile;

1-[(3aR,3bS,6aR,6bS)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobutadien[1,2-c;3,4-c′]dipyrrol-2-yl]-2-(4-trifluoromethoxy-phenoxy)-ethanone;

1-[(3aR,3bS,6aR,6bS)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobutadien[1,2-c;3,4-c′]dipyrrol-2-yl]-2-(2-isopropyl-phenoxy)-ethanone;

[(3aR,3bS,6aR,6bS)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobutadien[1,2-c;3,4-c′]dipyrrol-2-yl]-(5-trifluoromethoxy-1H-indol-2-yl)-methanone;

[(3aR,3bS,6aR,6bS)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobutadien[1,2-c;3,4-c′]dipyrrol-2-yl]-(6-trifluoromethoxy-1H-indol-2-yl)-methanone;

[(3aS,3bS,6aR,6bR)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobutadieno[1,2-c;3,4-c′]dipyrrol-2-yl]-naphthalen-2-yl-methanone;

[(3aS,3bS,6aR,6bR)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobutadien[1,2-c;3,4-c′]dipyrrol-2-yl]-(6-methyl-naphthalen-2-yl)-methanone;

[(3aS,3bS,6aR,6bR)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobutadieno[1,2-c;3,4-c′]dipyrrol-2-yl]-(7-methyl-naphthalen-2-yl)-methanone;

[(3aS,3bS,6aR,6bR)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobutadieno[1,2-c;3,4-c′]dipyrrol-2-yl]-(6-phenyl-naphthalen-2-yl)-methanone;

(6-Bromo-naphthalen-2-yl)-[(3aR,3bS,6aR,6bS)-5-((R)-4,5,6,7-tetrahydro-1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl]-methanone;

[(3aS,3bS,6aR,6bR)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobutadien[1,2-c;3,4-c′]dipyrrol-2-yl]-(4′-chloro-biphenyl-4-yl)-methanone;

(4′-Chloro-biphenyl-4-yl)-[(3aR,3bS,6aR,6bS)-5-((R)-4,5,6,7-tetrahydro-1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl]-methanone;

[(3aR,3bS,6aR,6bS)-5-((R)-4,5,6,7-tetrahydro-1H-benzotriazole-5-carbonyl)-octahydro-cyclobutadieno[1,2-c;3,4-c′]dipyrrol-2-yl]-(5-trifluoromethoxy-1H-indol-2-yl)-methanone;

[(3aR,3bS,6aR,6bS)-5-((R)-4,5,6,7-tetrahydro-1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl]-(6-trifluoromethoxy-1H-indol-2-yl)-methanone;

[(3aS,3bS,6aR,6bR)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobutadien[1,2-c;3,4-c′]dipyrrol-2-yl]-(3-methoxy-naphthalen-2-yl)-methanone;

[(3aS,3bS,6aR,6bR)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobutadieno[1,2-c;3,4-c′]dipyrrol-2-yl]-(1-methoxy-naphthalen-2-yl)-methanone;

[(3aR,3bS,6aR,6bS)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobutadien[1,2-c;3,4-c′]dipyrrol-2-yl]-(1H-indol-2-yl)-methanone;

[(3aR,3bS,6aR,6bS)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobutadien[1,2-c;3,4-c′]dipyrrol-2-yl]-(1-methyl-1H-indol-2-yl)-methanone;

[(3aS,3bS,6aR,6bR)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobutadien[1,2-c;3,4-c′]dipyrrol-2-yl]-(4-cyclopropylmethoxy-naphthalen-2-yl)-methanone;

[(3aS,3bS,6aR,6bR)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobutadien[1,2-c;3,4-c′]dipyrrol-2-yl]-(4-methoxy-naphthalen-2-yl)-methanone;

2-[(3aR,3bS,6aR,6bS)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobutadien[1,2-c;3,4-c′]dipyrrole-2-carbonyl]-1H-indole-5-carbonitrile;

[(3aS,3bS,6aR,6bR)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobutadien[1,2-c;3,4-c′]dipyrrol-2-yl]-(3-methoxy-phenyl)-methanone;

[(3aR,3bS,6aR,6bS)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobutadien[1,2-c;3,4-c′]dipyrrol-2-yl]-(4-methoxy-quinolin-2-yl)-methanone;

[(3aR,3bS,6aR,6bS)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobutadieno[1,2-c;3,4-c′]dipyrrol-2-yl]-[2-(4-chloro-phenyl)-5-methyl-oxazol-4-yl]-methanone;

[(3aS,3bR,6aS,6bR)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobutadieno[1,2-c;3,4-c′]dipyrrol-2-yl]-(1,2,3,4-tetrahydro-naphthalen-2-yl)-methanone;

[(3aR,3bS,6aR,6bS)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobutadien[1,2-c;3,4-c′]dipyrrol-2-yl]-(1-methyl-5-trifluoromethoxy-1H-indol-2-yl)-methanone;

[(3aR,3bS,6aR,6bS)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobutadien[1,2-c;3,4-c′]dipyrrol-2-yl]-(6-chloro-1H-indol-2-yl)-methanone;

[(3aR,3bS,6aR,6bS)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobutadieno[1,2-c;3,4-c′]dipyrrol-2-yl]-(6-chloro-1-methyl-1H-indol-2-yl)-methanone;

[(3aR,3bS,6aR,6bS)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobutadien[1,2-c;3,4-c′]dipyrrol-2-yl]-(6-methyl-1H-indol-2-yl)-methanone;

{2-[(3aR,3bS,6aR,6bS)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrole-2-carbonyl]-indol-1-yl}-acetonitrile;

[(3aR,3bS,6aR,6bS)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobutadien[1,2-c;3,4-c′]dipyrrol-2-yl]-(1-isobutyl-1H-indol-2-yl)-methanone;

[(3aR,3bS,6aR,6bS)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobutadieno[1,2-c;3,4-c′]dipyrrol-2-yl]-quinolin-2-yl-methanone;

[(3aR,3bS,6aR,6bS)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobutadien[1,2-c;3,4-c′]dipyrrol-2-yl]-isoquinolin-3-yl-methanone;

[(3aS,3bS,6aR,6bR)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobutadien[1,2-c;3,4-c′]dipyrrol-2-yl]-(1H-indol-6-yl)-methanone;

3-[(3aS,3bR,6aS,6bR)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobutadien[1,2-c;3,4-c′]dipyrrole-2-carbonyl]-3,4-dihydro-2H-naphthalen-1-one;

[(3aR,3bS,6aR,6bS)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobutadieno[1,2-c;3,4-c′]dipyrrol-2-yl]-chroman-2-yl-methanone;

[(3aS,3bS,6aR,6bR)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobutadien[1,2-c;3,4-c′]dipyrrol-2-yl]-(1H-indol-5-yl)-methanone;

(4-Methoxy-naphthalen-2-yl)-[(3aR,3bS,6aR,6bS)-5-((R)-4,5,6,7-tetrahydro-1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl]-methanone;

[(3aS,3bS,6aR,6bR)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobutadieno[1,2-c;3,4-c′]dipyrrol-2-yl]-[6-(4-chloro-phenyl)-pyridin-3-yl]-methanone;

[(3aR,3bS,6aR,6bS)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobutadien[1,2-c;3,4-c′]dipyrrol-2-yl]-(1-methoxy-isoquinolin-3-yl)-methanone;

[(3aR,3bS,6aR,6bS)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobutadien[1,2-c;3,4-c′]dipyrrol-2-yl]-(4-methyl-quinolin-2-yl)-methanone;

[(3aR,3bS,6aR,6bS)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobutadien[1,2-c;3,4-c′]dipyrrol-2-yl]-(5-chloro-1H-indol-2-yl)-methanone;

[(3aS,3bS,6aR,6bR)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobutadieno[1,2-c;3,4-c′]dipyrrol-2-yl]-[4-(2-methoxy-ethoxy)-naphthalen-2-yl]-methanone;

[(3aS,3bS,6aR,6bR)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobutadieno[1,2-c;3,4-c′]dipyrrol-2-yl]-(7-phenyl-naphthalen-2-yl)-methanone;

[(3aS,3bS,6aR,6bR)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobutadieno[1,2-c;3,4-c′]dipyrrol-2-yl]-(4-ethoxy-naphthalen-2-yl)-methanone;

[(3aS,3bS,6aR,6bR)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobutadieno[1,2-c;3,4-c′]dipyrrol-2-yl]-(4-isopropoxy-naphthalen-2-yl)-methanone;

[(3aS,3bS,6aR,6bR)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobutadien[1,2-c;3,4-c′]dipyrrol-2-yl]-(4-benzyloxy-1H-indol-6-yl)-methanone;

[(3aS,3bS,6aR,6bR)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobutadieno[1,2-c;3,4-c′]dipyrrol-2-yl]-(5,6,7,8-tetrahydro-naphthalen-2-yl)-methanone;

[(3aS,3bR,6aS,6bR)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobutadieno[1,2-c;3,4-c′]dipyrrol-2-yl]-(4,4-dimethyl-1,2,3,4-tetrahydro-naphthalen-2-yl)-methanone;

[(3aS,3bR,6aS,6bR)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobutadieno[1,2-c;3,4-c′]dipyrrol-2-yl]-[1-(3-methoxy-propyl)-1,2,3,4-tetrahydro-quinolin-3-yl]-methanone;

[(3aR,3bS,6aR,6bS)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobutadien[1,2-c;3,4-c′]dipyrrol-2-yl]-[1-(2-methoxy-ethoxy)-isoquinolin-3-yl]-methanone;

[(3aR,3bS,6aR,6bS)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobutadien[1,2-c;3,4-c′]dipyrrol-2-yl]-(1-cyclopropylmethoxyisoquinolin-3-yl)-methanone;

(4-Isopropoxy-naphthalen-2-yl)-[(3aR,3bS,6aR,6bS)-5-((R)-4,5,6,7-tetrahydro-1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl]-methanone;

[(3aR,3bS,6aR,6bS)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobutadien[1,2-c;3,4-c′]dipyrrol-2-yl]-[1-(2,2,2-trifluoro-ethoxy)-isoquinolin-3-yl]-methanone;

[(3aS,3bS,6aR,6bR)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobutadien[1,2-c;3,4-c′]dipyrrol-2-yl]-(4-isopropoxy-1H-indol-6-yl)-methanone;

4-[(3aS,3bS,6aR,6bR)-5-(4-Isopropoxy-naphthalene-2-carbonyl)-octahydro-cyclobutadieno[1,2-c;3,4-c′]dipyrrole-2-carbonyl]-benzenesulfonamide;

[6-(4-Chloro-phenyl)-pyridin-3-yl]-[(3aR,3bS,6aR,6bS)-5-((R)-4,5,6,7-tetrahydro-1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl]-methanone;

(1-Cyclopropylmethoxy-isoquinolin-3-yl)-[(3aR,3bS,6aR,6bS)-5-((R)-4,5,6,7-tetrahydro-1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl]-methanone;

[(3aS,3bS,6aR,6bR)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobutadieno[1,2-c;3,4-c′]dipyrrol-2-yl]-(4-isopropoxy-1-methyl-1H-indol-6-yl)-methanone;

[(3aR,3bS,6aR,6bS)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobutadien[1,2-c;3,4-c′]dipyrrol-2-yl]-(4-ethoxy-quinolin-2-yl)-methanone;

[(3aR,3bS,6aR,6bS)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobutadien[1,2-c;3,4-c′]dipyrrol-2-yl]-(4-isopropoxy-quinolin-2-yl)-methanone;

[(3aS,3bS,6aR,6bR)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobutadien[1,2-c;3,4-c′]dipyrrol-2-yl]-(6-chloro-9H-carbazol-2-yl)-methanone;

[(3aR,3bS,6aR,6bS)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobutadien[1,2-c;3,4-c′]dipyrrol-2-yl]-[4-(2-methoxy-ethoxy)-quinolin-2-yl]-methanone;

[(3aR,3bS,6aR,6bS)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobutadieno[1,2-c;3,4-c′]dipyrrol-2-yl]-(4-isopropoxy-7-trifluoromethyl-quinolin-2-yl)-methanone;

[(3aR,3bS,6aR,6bS)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobutadien[1,2-c;3,4-c′]dipyrrol-2-yl]-(4-cyclopropylmethoxy-quinolin-2-yl)-methanone;

[(3aR,3bS,6aR,6bS)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobutadieno[1,2-c;3,4-c′]dipyrrol-2-yl]-[5-(4-chloro-phenyl)-pyridin-2-yl]-methanone;

[(3aR,3bS,6aR,6bS)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobutadien[1,2-c;3,4-c′]dipyrrol-2-yl]-(1-ethoxy-isoquinolin-3-yl)-methanone;

[(3aS,3bS,6aR,6bR)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobutadieno[1,2-c;3,4-c′]dipyrrol-2-yl]-(1-ethyl-4-isopropoxy-1H-indol-6-yl)-methanone;

6-[(3aR,3bS,6aR,6bS)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobutadien[1,2-c;3,4-c′]dipyrrole-2-carbonyl]-3-(4-chloro-phenyl)-1H-pyridin-2-one;

1-[(3aR,3bS,6aR,6bS)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobutadien[1,2-c;3,4-c′]dipyrrol-2-yl]-(7-chloro-4-ethoxy-quinolin-2-yl)-methanone;

(7-Chloro-4-ethoxy-quinolin-2-yl)-[(3aR,3bS,6aR,6bS)-5-((R)-4,5,6,7-tetrahydro-1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl]methanone;

[(3aS,3bS,6aR,6bR)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobutadieno[1,2-c;3,4-c′]dipyrrol-2-yl]-(4-isopropoxy-5,6,7,8-tetrahydro-naphthalen-2-yl)-methanone;

(1H-Benzotriazol-5-yl)-{(3aS,3bR,6aS,6bR)-5-[4-(2-methoxy-ethoxy)-7-trifluoromethyl-quinoline-2-carbonyl]-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl}-methanone;

(1H-Benzotriazol-5-yl)-[(3aS,3bR,6aS,6bR)-5-(4-ethoxy-6-trifluoromethyl-quinoline-2-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl]-methanone;

[(3aS,3bS,6aR,6bR)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobutadieno[1,2-c;3,4-c′]dipyrrol-2-yl]-(4-ethoxy-1-ethyl-1H-indol-5-yl)-methanone;

[(3aS,3bS,6aR,6bR)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobutadien[1,2-c;3,4-c′]dipyrrol-2-yl]-[1-ethyl-4-(2,2,2-trifluoro-ethoxy)-1H-indol-5-yl]-methanone;

5-[(3aS,3bR,6aS,6bR)-5-(4-ethoxy-quinoline-2-carbonyl)-octahydro-cyclobutadieno[1,2-c;3,4-c′]dipyrrole-2-carbonyl]-pyridine-2-sulfonic acid amide;

(1H-Benzotriazol-5-yl)-{(3aS,3bR,6aS,6bR)-5-[4-(2,2,2-trifluoro-ethoxy)-quinoline-2-carbonyl]-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl}-methanone;

(1H-Benzotriazol-5-yl)-{(3aS,3bS,6aR,6bR)-5-[4-ethoxy-1-(2,2,2-trifluoro-ethyl)-1H-indole-6-carbonyl]-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl}-methanone;

(1H-Benzotriazol-5-yl)-[(3aS,3bR,6aS,6bR)-5-(5-chloro-4-cyclopropylmethoxy-pyridine-2-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl]-methanone;

(1H-Benzotriazol-5-yl)-[(3aS,3bR,6aS,6bR)-5-(5-cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carbonyl)-octahydro-cyclobutadieno[1,2-c;3,4-c′]dipyrrol-2-yl]-methanone;

(3,4-Dimethyl-phenyl)-[(3aS,3bR,6aS,6bR)-5-(4-ethoxy-5,6,7,8-tetrahydro-quinoline-2-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl]-methanone;

(1H-Benzotriazol-5-yl)-[(3aS,3bS,6aR,6bR)-5-(4′-chloro-biphenyl-3-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl]-methanone;

(1H-Benzotriazol-5-yl)-[(3aS,3bR,6aS,6bR)-5-(4-ethoxy-7-methoxy-quinoline-2-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl]-methanone;

[(3aS,3bS,6aR,6bR)-5-(4-Ethoxy-6-trifluoromethyl-quinoline-2-carbonyl)-octahydro-cyclobutadieno[1,2-c;3,4-c′]dipyrrol-2-yl]-(1H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-methanone;

[(3aS,3bS,6aR,6bR)-5-(1-Ethoxy-isoquinoline-3-carbonyl)-octahydro-cyclobutadieno[1,2-c;3,4-c′]dipyrrol-2-yl]-(1H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-methanone;

(1H-Benzotriazol-5-yl)-[(3aS,3bR,6aS,6bR)-5-(6-cyclopropylmethoxy-5-trifluoromethyl-pyridine-2-carbonyl)-octahydro-cyclobutadieno[1,2-c;3,4-c′]dipyrrol-2-yl]-methanone;

(1H-Benzotriazol-5-yl)-{(3aS,3bR,6aS,6bR)-5-[5-cyclopropyl-4-(2,2,2-trifluoro-ethoxy)-pyridine-2-carbonyl]-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl}-methanone;

(1H-Benzotriazol-5-yl)-{(3aS,3bR,6aS,6bR)-5-[6-cyclopropyl-5-(2,2,2-trifluoro-ethoxy)-pyridazine-3-carbonyl]-octahydro-cyclobutadien-[1,2-c;3,4-c′]dipyrrol-2-yl}-methanone′]dipyrrol-2-yl}-methanone;

[(3aR,3bS,6aR,6bS)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobutadien[1,2-c;3,4-c′]dipyrrol-2-yl]-(6-chloro-4-ethoxy-quinolin-2-yl)-methanone;

(1H-Benzotriazol-5-yl)-{(3aS,3bR,6aS,6bR)-5-[6-(2,2,2-trifluoro-ethoxy)-5-trifluoromethyl-pyridine-2-carbonyl]-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl}-methanone;

(1H-Benzotriazol-5-yl)-{(3aS,3bR,6aS,6bR)-5-[6-(2,2,2-trifluoro-ethoxy)-pyridine-2-carbonyl]-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl}-methanone;

(1H-Benzotriazol-5-yl)-{(3aS,3bS,6aR,6bR)-5-[6-(2,2,2-trifluoro-ethoxy)-pyridine-3-carbonyl]-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl}-methanone;

(1H-Benzotriazol-5-yl)-{(3aS,3bS,6aR,6bR)-5-[5-bromo-6-(2,2,2-trifluoro-ethoxy)-pyridine-3-carbonyl]-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl}-methanone;

(1H-Benzotriazol-5-yl)-{(3aS,3bR,6aS,6bR)-5-[5-(2,2,2-trifluoro-ethoxy)-pyridine-2-carbonyl]-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl}-methanone;

[(3aS,3bR,6aS,6bR)-5-(6-Cyclopropylmethoxy-pyridazine-3-carbonyl)-octahydro-cyclobutadieno[1,2-c;3,4-c′]dipyrrol-2-yl]-(3,4-dimethyl-phenyl)-methanone;

(1H-Benzotriazol-5-yl)-{(3aS,3bS,6aR,6bR)-5-[5-bromo-2-methyl-6-(2,2,2-trifluoro-ethoxy)-pyridine-3-carbonyl]-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl}-methanone;

(1H-Benzotriazol-5-yl)-{(3aS,3bS,6aR,6bR)-5-[5-cyclopropyl-6-(2,2,2-trifluoro-ethoxy)-pyridine-3-carbonyl]-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl}-methanone;

(1H-Benzotriazol-5-yl)-{(3aS,3bS,6aR,6bR)-5-[6-(2,2,2-trifluoro-ethoxy)-5-trifluoromethyl-pyridine-3-carbonyl]-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl}-methanone;

(1H-Benzotriazol-5-yl)-{(3aS,3bS,6aR,6bR)-5-[5-(tetrahydro-pyran-4-yl)-6-(2,2,2-trifluoro-ethoxy)-pyridine-3-carbonyl]-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl}-methanone;

(1H-Benzotriazol-5-yl)-{(3aS,3bR,6aS,6bR)-5-[4-(4-chloro-phenyl)-5-(2,2,2-trifluoro-ethoxy)-pyridine-2-carbonyl]-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl}-methanone;

(1H-Benzotriazol-5-yl)-{(3aS,3bS,6aR,6bR)-5-[5-furan-2-yl-6-(2,2,2-trifluoro-ethoxy)-pyridine-3-carbonyl]-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl}-methanone;

(1H-Benzotriazol-5-yl)-{(3aS,3bS,6aR,6bR)-5-[5-chloro-6-(2,2,2-trifluoro-ethoxy)-pyridine-3-carbonyl]-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl}-methanone;

[(3aS,3bR,6aS,6bR)-5-(4-Ethoxy-quinoline-2-carbonyl)-octahydro-cyclobutadieno[1,2-c;3,4-c′]dipyrrol-2-yl]-(4-fluoro-1H-benzotriazol-5-yl)-methanone;

{(3aS,3bS,6aR,6bR)-5-[5-Methanesulfonyl-6-(2,2,2-trifluoro-ethoxy)-pyridine-3-carbonyl]-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl}-phenyl-methanone;

(3aR,3bS,6aR,6bS)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobutadien[1,2-c;3,4-c′]dipyrrole-2-carboxylic acid 4-trifluoromethoxy-benzyl ester;

(3aR,3bS,6aR,6bS)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobutadien[1,2-c;3,4-c′]dipyrrole-2-carboxylic acid 3,5-dichloro-benzyl ester;

(1H-Benzotriazol-5-yl)-[(3aS,3bR,6aS,6bR)-5-(4′-fluoro-biphenyl-4-sulfonyl)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl]-methanone;

(1H-Benzotriazol-5-yl)-[(3aS,3bR,6aS,6bR)-5-(6-chloro-naphthalene-2-sulfonyl)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl]-methanone;

[(3aR,3bS,6aR,6bS)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobutadien[1,2-c;3,4-c′]dipyrrol-2-yl]-(6-trifluoromethyl-3,4-dihydro-1H-isoquinolin-2-yl)-methanone;

and pharmaceutically acceptable salts thereof.

Further particular examples of compounds of formula (I) as described herein are selected from

(E)-1-[(3aS,3bR,6aS,6bR)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobutadien[1,2-c;3,4-c′]dipyrrol-2-yl]-3-(4-trifluoromethoxy-phenyl)-propenone;

(4-Isopropoxy-naphthalen-2-yl)-[(3aR,3bS,6aR,6bS)-5-((R)-4,5,6,7-tetrahydro-1H-benzotriazole-5-carbonyl)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl]-methanone;

4-[(3aS,3bS,6aR,6bR)-5-(4-Isopropoxy-naphthalene-2-carbonyl)-octahydro-cyclobutadieno[1,2-c;3,4-c′]dipyrrole-2-carbonyl]-benzenesulfonamide;

[(3aS,3bS,6aR,6bR)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobutadieno[1,2-c;3,4-c′]dipyrrol-2-yl]-(4-isopropoxy-1-methyl-1H-indol-6-yl)-methanone;

[(3aR,3bS,6aR,6bS)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobutadien[1,2-c;3,4-c′]dipyrrol-2-yl]-[4-(2-methoxy-ethoxy)-quinolin-2-yl]-methanone;

(1H-Benzotriazol-5-yl)-{(3aS,3bS,6aR,6bR)-5-[5-bromo-6-(2,2,2-trifluoro-ethoxy)-pyridine-3-carbonyl]-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl}-methanone;

(3aR,3bS,6aR,6bS)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobutadien[1,2-c;3,4-c′]dipyrrole-2-carboxylic acid 4-trifluoromethoxy-benzyl ester;

and pharmaceutically acceptable salts thereof.

Processes for the preparation of compounds of formula (I) as described herein are an object of the present invention.

The preparation of the compound of formula (I) of the present invention can be carried out in a sequential or convergent synthetic route. The synthesis of the present invention is shown in the following general scheme. The skills required for carrying out the reaction and purification of the resulting product are known to those skilled in the art. In the case of a mixture of enantiomers or diastereomers produced during the reaction, these enantiomers or diastereomers can be separated by methods described herein or methods known to those skilled in the art, such as chiral chromatography or crystallization. The substituents and symbols used in the description of the following methods have the meanings given herein.

Compounds of general formula (I) can be synthesized from amine precursor 1 and appropriate reagents using methods well known in the art.

For example, reaction of amine 1 with an appropriate chloroformate of formula R ¹ —OC(O)—Cl(2) (R ¹ = substituted phenylalkyl), or with an imidazole-1-carboxylate of formula (3A, R ¹ = substituted phenylalkyl), or with a succinimidyl carbonate derivative of formula (3B, R ¹ = phenylalkyl) gives compounds of formula (I) in which R ¹ is substituted phenylalkoxy.

The reaction is carried out in a suitable solvent such as dichloromethane, tetrahydrofuran, N,N-dimethylformamide, acetonitrile, acetone, water or a mixture thereof in the presence or absence of a base such as triethylamine, diisopropylethylamine, pyridine, potassium bicarbonate, potassium carbonate at a temperature between 0°C and the boiling point of the solvent or solvent mixture.

Chloroformates 2 are commercially available or can be synthesized as described in the literature from the corresponding alcohols of formula ^R1 -OH ( ^R1 = substituted phenylalkyl) by reaction with phosgene or a phosgene equivalent (eg diphosgene, triphosgene).

Imidazole-1-carboxylates 3A are synthesized from the corresponding alcohols of formula R ¹ —OH (R ¹ = substituted phenylalkyl) by reaction with 1,1′-carbonyldiimidazole. The reaction is carried out at room temperature in solvents such as dichloromethane, tetrahydrofuran, or acetonitrile. Typically, the imidazole-1-carboxylates 3A are not isolated but are reacted directly with amines 1 as described above.

Succinimidyl carbonate derivatives 3B are synthesized from the corresponding alcohol of formula R ¹ —OH (R ¹ = substituted phenylalkyl) by reaction with N,N′-disuccinimidyl carbonate. The reaction is carried out at room temperature in a solvent such as dichloromethane, tetrahydrofuran, or acetonitrile, optionally in the presence of a base such as triethylamine. Typically, succinimidyl carbonate derivatives 3B are not isolated but are reacted directly with amine 1 as described above.

Alcohols of formula ^R1 -OH are commercially available or can be prepared by methods described herein or known in the art.

Alternatively, amine 1 is reacted with the appropriate N-(chlorocarbonyl)-1,2,3,4-tetrahydroisoquinoline 4 to provide compounds of formula (I) wherein ^R1 is a substituted 1,2,3,4-tetrahydroisoquinolin-2-yl.

As described herein or in the literature, N-(chlorocarbonyl)-1,2,3,4-tetrahydroisoquinoline (4) is synthesized from the corresponding 1,2,3,4-tetrahydroisoquinoline 5 by reaction with phosgene or a phosgene equivalent.

Alternatively, amine 1 is reacted with a suitable carboxylic acid of formula ^R1 -COOH (6) to give compounds of formula (I). The reaction is carried out in the presence of a coupling agent such as 1,1′-carbonyldiimidazole, N,N′-dicyclohexylcarbodiimide, 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride, O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluoro-phosphate, O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluoro-phosphate or bromo-tris-pyrrolidinyl-hexafluorophosphate, in an aprotic solvent such as dichloromethane, tetrahydrofuran, N,N-dimethylformamide, N-methylpyrrolidone 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 a suitable acylating agent such as an acyl chloride of formula ^R1 -COCl(7) to give compounds of formula (I). The reaction is carried out in a solvent such as dichloromethane, tetrahydrofuran, or N,N-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 R ¹ —SO ₂ Cl (8) to give a compound of formula (I) wherein Y is —S(O ₂ )—. The reaction is carried out in a suitable solvent such as dichloromethane, tetrahydrofuran, N,N-dimethylformamide, acetonitrile, acetone, water or a mixture thereof in the presence of a base such as triethylamine, diisopropylethylamine, pyridine, potassium bicarbonate, potassium carbonate at a temperature between 0° C. and the boiling point of the solvent or solvent mixture.

Sulfonyl chlorides (8) are commercially available or can be synthesized as described herein or in the literature.

Amines of general formula 1 are synthesized from tert-butyl carbamate precursor 9.

Deprotection of 9 to afford amine 1 can be carried out in the presence of a suitable acid such as hydrochloric acid or trifluoroacetic acid in a solvent such as water, 2-propanol, dichloromethane or 1,4-dioxane at temperatures between 0°C and 30°C.

Amides 9 can be prepared from amines 10 by reaction with appropriate reagents using methods known in the art.

For example, reaction of amine 10 with an appropriate carboxylic acid of formula R ² —COOH (11) affords compounds of formula 9. The reaction is carried out in the presence of a coupling agent such as 1,1′-carbonyldiimidazole, N,N′-dicyclohexylcarbodiimide, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate, O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate or bromo-tris-pyrrolidinyl-hexafluorophosphate, in an aprotic solvent such as dichloromethane, tetrahydrofuran, N,N-dimethylformamide, N-methylpyrrolidone and mixtures thereof, at a temperature 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.

Boc-protected amines 10 can be prepared from diamines 12 using a suitable reagent such as di-tert-butyl dicarbonate. The reaction is carried out in a suitable solvent such as dichloromethane, chloroform, or tetrahydrofuran at a temperature between 0°C and 30°C.

Alternatively, 10 can be prepared in a two-step sequence from 12. In the first step, 12 is reacted with an excess of di-tert-butyl dicarbonate to afford the diprotected intermediate 13. Monodeprotection of dicarbamate 13 under appropriate conditions, for example, with hydrogen chloride in a solvent such as ethyl acetate, diethyl ether, 2-propanol, or a mixture thereof, affords 10 as the hydrochloride salt.

Amines of formula 1 can also be synthesized from diamines 12 by reaction with appropriate reagents using methods known in the art. For example, diamine 12 is reacted with a suitable carboxylic acid of formula R ² —COOH (11) to give compounds of formula 1. The reaction is carried out in the presence of a coupling agent such as 1,1′-carbonyldiimidazole, N,N′-dicyclohexylcarbodiimide, 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride, O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate, O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate or bromo-tris-pyrrolidinyl-hexafluorophosphate, in an aprotic solvent such as dichloromethane, tetrahydrofuran, N,N-dimethylformamide, N-methylpyrrolidone and mixtures thereof, at a temperature 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.

Compounds of formula (I) can also be prepared from amine precursors of formula 14 by reacting with appropriate reagents using methods known in the art.

For example, reaction of amine 14 with an appropriate carboxylic acid of formula ^R2 -COOH (11) provides a compound of formula (I). The reaction is carried out in the presence of a coupling agent such as 1,1′-carbonyldiimidazole, N,N′-dicyclohexylcarbodiimide, 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride, O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluoro-phosphate, O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluoro-phosphate or bromo-tris-pyrrolidinyl-hexafluorophosphate, in an aprotic solvent such as dichloromethane, tetrahydrofuran, N,N-dimethylformamide, N-methylpyrrolidone 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 14 can be synthesized from diamine 12 using methods and reagents known in the art.

For example, diamine 12 is reacted with a suitable chloroformate of formula R ¹ —OC(O)—Cl(2) (R ¹ = substituted phenylalkyl), or with an imidazole-1-carboxylate of formula (3A, R ¹ = substituted phenylalkyl), or with a succinimidyl carbonate derivative of formula (3B, R ¹ = phenylalkyl) to give a compound of formula 14, wherein R ¹ is substituted phenylalkoxy. The reaction is carried out in a suitable solvent such as dichloromethane, tetrahydrofuran, N,N-dimethylformamide, acetonitrile, acetone, water or a mixture thereof, in the presence or absence of a base such as triethylamine, diisopropylethylamine, pyridine, potassium bicarbonate, potassium carbonate, at a temperature between 0° C. and the boiling point of the solvent or solvent mixture.

Alternatively, diamine 12 is reacted with the appropriate N-(chlorocarbonyl)-1,2,3,4-tetrahydroisoquinoline 4 to provide compounds of formula 14, wherein R ^<1> is a substituted 1,2,3,4-tetrahydroisoquinolin-2-yl.

Alternatively, diamine 12 is reacted with a suitable carboxylic acid of formula R ¹ —COOH (6) to give compounds of formula 14 . The reaction is carried out in the presence of a coupling agent such as 1,1′-carbonyldiimidazole, N,N′-dicyclohexylcarbodiimide, 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride, O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluoro-phosphate, O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluoro-phosphate or bromo-tris-pyrrolidinyl-hexafluorophosphate, in an aprotic solvent such as dichloromethane, tetrahydrofuran, N,N-dimethylformamide, N-methylpyrrolidone 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.

Diamine 12 can also be reacted with a suitable acylating agent such as an acyl chloride of formula ^R1 -COCl(7) to give compounds of formula 14. The reaction is carried out in a solvent such as dichloromethane, tetrahydrofuran or N,N-dimethylformamide in the presence of a base such as triethylamine or 4-methylmorpholine at a temperature between 0°C and 80°C.

Alternatively, diamine 12 is reacted with a suitable sulfonyl chloride of formula R ¹ —SO ₂ Cl (8) to give a compound of formula 14, wherein Y is —S(O ₂ )—. The reaction is carried out in a suitable solvent such as dichloromethane, tetrahydrofuran, N,N-dimethylformamide, acetonitrile, acetone, water or a mixture thereof in the presence of a base such as triethylamine, diisopropylethylamine, pyridine, potassium bicarbonate, potassium carbonate at a temperature between 0° C. and the boiling point of the solvent or solvent mixture.

Alternatively, amines 14 can be synthesized by carbamate deprotection from their tert-butyl carbamate derivatives of formula 15. Deprotection can be carried out in the presence of a suitable acid such as hydrochloric acid or trifluoroacetic acid in a solvent such as water, 2-propanol, dichloromethane or 1,4-dioxane at temperatures between 0°C and 30°C.

Intermediates 15 can be prepared from amines 10 by reaction with appropriate reagents using methods known in the art.

For example, amine 10 is reacted with a suitable chloroformate of formula R ¹ —OC(O)—Cl(2) (R ¹ = substituted phenylalkyl), or with an imidazole-1-carboxylate of formula (3A, R ¹ = substituted phenylalkyl), or with a succinimidyl carbonate derivative of formula (3B, R ¹ = phenylalkyl) to give compounds of formula 15 wherein R ¹ is substituted phenylalkoxy. The reaction is carried out in a suitable solvent such as dichloromethane, tetrahydrofuran, N,N-dimethylformamide, acetonitrile, acetone, water or a mixture thereof in the presence or absence of a base such as triethylamine, diisopropylethylamine, pyridine, potassium bicarbonate, potassium carbonate at a temperature between 0° C. and the boiling point of the solvent or solvent mixture.

Alternatively, amine 10 is reacted with the appropriate N-(chlorocarbonyl)-1,2,3,4-tetrahydroisoquinoline 4 to provide compounds of formula 15, wherein ^R1 is a substituted 1,2,3,4-tetrahydroisoquinolin-2-yl.

Alternatively, amine 10 is reacted with a suitable carboxylic acid of formula R ¹ —COOH (6) to give compounds of formula 15 . The reaction is carried out in the presence of a coupling agent such as 1,1′-carbonyldiimidazole, N,N′-dicyclohexylcarbodiimide, 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride, O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluoro-phosphate, O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluoro-phosphate or bromo-tris-pyrrolidinyl-hexafluorophosphate, in an aprotic solvent such as dichloromethane, tetrahydrofuran, N,N-dimethylformamide, N-methylpyrrolidone 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 12 can also be reacted with a suitable acylating agent such as an acyl chloride of formula ^R1 -COCl (7) to give compounds of formula 15. The reaction is carried out in a solvent such as dichloromethane, tetrahydrofuran 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 10 is reacted with a suitable sulfonyl chloride of formula R ¹ —SO ₂ Cl (8) to give a compound of formula 15, wherein Y is —S(O ₂ )—. The reaction is carried out in a suitable solvent such as dichloromethane, tetrahydrofuran, N,N-dimethylformamide, acetonitrile, acetone, water or a mixture thereof in the presence of a base such as triethylamine, diisopropylethylamine, pyridine, potassium bicarbonate, potassium carbonate at a temperature between 0° C. and the boiling point of the solvent or solvent mixture.

Diamine 12 can be synthesized in three steps from N-benzylmaleimide (16) as shown in Scheme 1.

Solution 1

In Scheme 1, step 1, N-benzylmaleimide (16) is photodimerized by irradiation with ultraviolet light (λ = 300 nm) to give imide 17. The reaction is carried out in a suitable solvent, for example, acetonitrile or dichloromethane, at a temperature between -30°C and +40°C. The reaction can be carried out in batch mode or, more preferably, in a continuous flow reactor. A dimer product can be formed as a mixture of stereoisomers (i.e., 3aS, 3bS, 6aR, 6bR-17 and 3aS, 3bR, 6aS, 6bR-17), which can be separated, for example, by crystallization.

In Scheme 1, step 2, imide 17 is reduced to the corresponding diamine 18 using reagents and conditions known in the art. The reaction is carried out, for example, using lithium aluminum hydride in a solvent such as diethyl ether or tetrahydrofuran at a temperature between 0°C and the boiling point of the solvent.

In Scheme 1, step 3, the benzyl group of 18 is removed using reagents and conditions known in the art, for example, by catalytic hydrogenation, to provide diamine 12. The reaction is carried out in a suitable solvent such as methanol or ethanol, at a hydrogen pressure of 1 to 100 bar, at a temperature between 0°C and 100°C, in the presence of a suitable catalyst such as palladium on activated carbon.

Furthermore, an embodiment of the present invention is a method for preparing a compound of formula (I) as described above, said method comprising reacting a compound of formula (II) in the presence of a compound of formula (III);

wherein R ¹ , R ² , A and Y are as defined above.

In particular, in the presence of a coupling agent such as O-(7-azabenzotriazol-1-yl)-N,N,N',N'-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, in particular between -10°C and room temperature.

Furthermore, an object of the present invention are the compounds according to formula (I) as described herein for use as therapeutically active substances.

Yet another object of the present invention is a pharmaceutical composition comprising a compound according to formula (I) as described herein and a therapeutically inert carrier.

Another particular object of the present invention is the use of the compounds according to formula (I) as described herein for the treatment or prevention of fibrotic diseases, cancer and eye diseases.

A further particular object of the present invention is the use of the compounds according to formula (I) as described herein for the treatment or prevention of fibrotic diseases and eye diseases.

Renal disorders include, but are not limited to, acute kidney injury and chronic renal disease, including end-stage renal disease (ESRD), with or without proteinuria. In more detail, this includes decreased creatinine clearance and decreased glomerular filtration rate, micro-albuminuria, albuminuria and proteinuria, glomerulosclerosis with expansion of the reticulated mesangial matrix with or without marked hypercellularity (particularly diabetic nephropathy and amyloidosis), focal thrombosis of the glomerular capillaries (particularly thrombotic microangiopathies), global fibrinoid necrosis, ischemic lesions, malignant nephrosclerosis (such as ischemic retraction), and nephrotic syndromes. retraction), decreased renal blood flow, and renal arteriopathy, such as swelling and proliferation of endocapillary (endothelial and mesangial) and/or extracapillary cells (crescents) in glomerular nephritis entities, focal segmental glomerular sclerosis, IgA nephropathy, vasculitides/systemic diseases, and acute and chronic renal transplant rejection.

Liver disorders include, but are not limited to, liver cirrhosis, hepatic congestion, cholestatic liver disorders including pruritus, nonalcoholic steatohepatitis, and acute and chronic liver transplant rejection.

Inflammatory diseases include, but are not limited to, arthritis, osteoarthritis, multiple sclerosis, systemic lupus erythematodes, inflammatory bowel disease, abnormal evacuation disorder, and inflammatory airway diseases such as idiopathic pulmonary fibrosis (IPF), chronic obstructive pulmonary disease (COPD), or chronic asthma bronchiale.

Other respiratory conditions include, but are not limited to, other diffuse parenchymal lung diseases of various etiologies, including iatrogenic drug-induced fibrosis, occupational and/or environmental fibrosis, systemic diseases and vasculitis, granulomatous diseases (sarcoidosis, hypersensitivity pneumonia), collagen vascular disease, alveolar proteinosis, Langerhans cell granulomatosis, lymphangioleiomyomatosis, genetic diseases (Hermansky-Pudlak Syndrome, tuberous sclerosis, neurofibromatosis), metabolic storage disorders, familial interstitial lung disease, and disease), radiation-induced fibrosis, silicosis, asbestos-induced pulmonary fibrosis, or acute respiratory distress syndrome (ARDS).

Neurological disorders include, but are not limited to, neuropathic pain, schizophrenia, neuro-inflammation (e.g., astrogliosis), extrinsic and/or idiopathic (diabetic) neuropathies, and the like.

Vascular disorders include, but are not limited to, atherosclerosis, thrombotic vascular disease and thrombotic microangiopathies, proliferative arteriopathy (e.g., swollen myoendothelial cells and nodular thickening surrounded by a mucinous extracellular matrix), atherosclerosis, decreased vascular compliance (e.g., stiffness, decreased luminal compliance, and decreased vascular compliance), endothelial dysfunction, and the like.

Cardiovascular disorders 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 injuries.

Fibrotic diseases include, but are not limited to, myocardial and vascular fibrosis, renal fibrosis, hepatic fibrosis, pulmonary fibrosis, cutaneous fibrosis, scleroderma, and encapsulating peritonitis. A particular fibrotic disease is idiopathic pulmonary fibrosis.

In a particular embodiment, the compounds of formula (I) or their pharmaceutically acceptable salts and esters can be used for the treatment or prevention 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 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, liver cancer, gastrointestinal cancer, and their progression and metastatic aggressiveness.

Eye disorders include, but are not limited to, proliferative and non-proliferative (diabetic) retinopathy, dry and wet age-related macular degeneration (AMD), (diabetic) macular edema, central arterial/venous occlusion, traumatic injury, glaucoma, etc. A particular eye disease is glaucoma.

Metabolic disorders 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 prevention 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 prevention of kidney diseases, liver diseases, inflammatory diseases, nervous system diseases, respiratory system diseases, vascular and cardiovascular diseases, fibrotic diseases, cancer, eye diseases, metabolic diseases, cholestasis and other forms of chronic pruritus and acute and chronic organ transplant rejection.

The present invention also relates in particular to the use of compounds according to formula (I) as described herein for the treatment or prevention of fibrotic diseases, cancer and eye diseases.

The present invention also more particularly relates to the use of compounds according to formula (I) as described herein for the treatment or prevention of fibrotic diseases and eye diseases.

Another embodiment of the present invention are compounds according to formula (I) as described herein for the treatment or prophylaxis of kidney diseases, liver diseases, inflammatory diseases, nervous system diseases, respiratory diseases, vascular and cardiovascular diseases, fibrotic diseases, cancer, eye diseases, metabolic diseases, cholestasis and other forms of chronic pruritus and acute and chronic organ transplant rejection.

Another particular embodiment of the present invention are compounds according to formula (I) as described herein for the use in the treatment or prophylaxis of fibrotic diseases, cancer and eye diseases.

Another more particular embodiment of the present invention are compounds according to formula (I) as described herein for use in the treatment or prophylaxis of fibrotic diseases and eye 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 prevention of kidney diseases, liver diseases, inflammatory diseases, nervous system diseases, respiratory diseases, vascular and cardiovascular diseases, fibrotic diseases, cancer, eye diseases, metabolic diseases, cholestasis and other forms of chronic pruritus and acute and chronic organ transplant rejection.

The present invention also relates in particular to the use of a compound according to formula (I) as described herein for the preparation of a medicament for the treatment or prevention of fibrotic diseases, cancer and eye diseases.

The present invention furthermore particularly relates to the use of compounds according to formula (I) as described herein for the preparation of medicaments for the treatment or prevention of fibrotic diseases and eye diseases.

Furthermore, the present invention relates to a method for the treatment or prevention of renal diseases, liver diseases, inflammatory diseases, nervous system diseases, respiratory diseases, vascular and cardiovascular diseases, fibrotic diseases, cancer, eye diseases, metabolic diseases, cholestasis and other forms of chronic pruritus, as well as acute and chronic organ transplant rejection, which comprises administering an effective amount of a compound according to formula (I) as described herein.

Furthermore a particular object of the present invention is a method for the treatment or prevention of fibrotic diseases, cancer and eye diseases, said method comprising administering an effective amount of a compound according to formula (I) as described herein.

Furthermore, a more particular object of the present invention is a method for the treatment or prevention of fibrotic diseases and eye diseases, said method comprising administering an effective amount of a compound according to formula (I) as described herein.

In a particular embodiment, the renal disorder is selected from the group consisting of acute kidney injury, chronic kidney disease, diabetic nephropathy, acute renal transplant rejection, or chronic allograft nephropathy.

In another particular embodiment, the renal disorder is acute kidney injury.

In another particular embodiment, the renal disorder is chronic kidney disease.

In a further particular embodiment, the renal disorder is diabetic nephropathy.

In another specific embodiment, the renal disorder is acute renal transplant rejection.

In another specific embodiment, the renal disorder is chronic allograft nephropathy.

In a particular embodiment, the liver disorder is acute and chronic liver transplant rejection.

In a particular embodiment, the inflammatory disease is arthritis.

In a particular embodiment, the neurological disorder is neuropathic pain.

In another embodiment, the fibrotic disease is cystic peritonitis.

In another embodiment, the fibrotic disease is idiopathic pulmonary fibrosis.

In another embodiment, the fibrotic disease is nonalcoholic hepatic steatosis, hepatic fibrosis or cirrhosis.

Furthermore, an embodiment of the present invention is a compound of formula (I) as described herein, prepared according to any of the processes described.

Measurement steps

Preparation of human full-length ATX with and without a HIS tag

Autotaxin (ATX-ENPP2) cloning: cDNA was prepared from commercially available human hematopoietic cell total RNA and used as a template in overlapping PCR to generate the full-length human ENPP2 ORF with or without a 3'-6xHis tag. These full-length inserts were cloned into the pcDNA3.1V5-His TOPO vector (Invitrogen). The DNA sequences of several individual clones were verified. DNA from the correct full-length clones was used to transfect Hek293 cells to test for protein expression. The sequence encoding ENPP2 conforms to Swissprot entry Q13822, with or without an additional C-terminal 6xHis tag.

ATX fermentation: Recombinant protein was produced by large-scale transient transfection in a 20 L controlled stirred tank bioreactor (Sartorius). During cell growth and transfection, temperature, agitation rate, pH, and dissolved oxygen concentration were maintained at 37°C, 120 rpm, 7.1, and 30% DO, respectively. FreeStyle 293-F cells (Invitrogen) were cultured in suspension in FreeStyle 293 medium (Invitrogen) and transfected with the above-mentioned plasmid DNAs at approximately 1-1.5 x 10 cells/mL using X-tremeGENE Ro-1539 (trademark, Roche Diagnostics) as a complexing agent. Cells were fed a concentrated nutrient solution (J Immunol Methods 194 (1996), 19, 1-199 (page 193)) and induced with sodium butyrate (2 mM) 72 h after transfection and harvested 96 h after transfection. Expression was analyzed by Western Blot, enzyme 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 the supernatant were performed by filtration through Zeta Plus 60M02 E16 (Cuno) and Sartopore 2 XLG (Sartorius) filter units. The supernatant was stored at 4°C until purification.

ATX purification: 20 liters of culture supernatant were adjusted for ultrafiltration by adding Brij 35 to a final concentration of 0.02% and by adjusting the pH to 7.0 using 1M HCl. The supernatant was then first microfiltered through a 0.2 μm Ultran-Pilot Open Channel PES filter (Whatman) and then concentrated to 1 liter using an Ultran-Pilot Screen Channel PES filter (Whatman) with a 30 kDa MWCO. Prior to IMAC chromatography, _NiSO₄ was added to a final concentration of 1 mM. The clarified supernatant was then applied to a HisTrap column (GE Healthcare) pre-equilibrated in 50 mM _Na₂HPO₄ pH 7.0, 0.5 _M NaCl, 10% glycerol, _0.3 % CHAPS, 0.02% NaN₃. The column was then washed stepwise with the same buffer containing 20 mM, 40 mM, and 50 mM imidazole, respectively. The protein of the present invention is purified by size exclusion chromatography.The protein of the present invention is purified by size exclusion chromatography.The protein of the present invention is purified by size exclusion chromatography.The protein of the present invention is purified by size exclusion chromatography.Then a linear gradient is used to 0.5M imidazoles, with 15 column volumes of eluted protein.The fraction containing ATX is collected and concentrated using the Amicon pool equipped with a 30kDa PES filter membrane.Subsequently on Superdex S-200 preparation level (XK 26/100) (GE Healthcare), in 20mM BICINE pH 8.5, 0.15M NaCl, 10% glycerol, 0.3% CHAPS, 0.02% NaN ₃ , the protein is further purified by size exclusion chromatography.After purification, the final yield of protein is 5-10 mg ATX/ liters of culture supernatant.Protein is stored at-80 ℃.

Human ATX enzyme inhibition assay

ATX inhibition was measured by fluorescence quenching assay using a specifically labeled substrate mimetic (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, 1-(3-carboxypropyl)-11-ethyl-1,2,3,4,8,9,10,11-octahydro-bipyrido[3,2-b:2',3'-i]phenazine-13-) on the free amine on the ethanolamine side and then, after deprotection, labeled with tryptophan on the aminohexanoic acid side.

The assay working solution was prepared as follows:

Assay buffer (50 mM Tris-HCl, 140 mM NaCl, 5 mM KCl, 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 20 mM bicine, pH 8.5, 0.15 M NaCl, 10% glycerol, 0.3% CHAPS, 0.02% NaN ₃ ), diluted to 1.4-2.5x final concentration in assay buffer;

MR121 substrate solution: MR121 substrate stock solution (800 μM MR121 substrate in DMSO), diluted in assay buffer to 2-5x final concentration.

Test compound (10mM stock, in DMSO, 8 μ L) is obtained in 384-well sample plates (Corning Costar#3655) and diluted with 8 μ L DMSO. By transferring 8 μ L cpd solution to the next column until column 0, serial dilution is performed column by column. Compound and control solution are mixed five times, and 2 μ L are transferred to a 384-well assay plate (Corning Costar#3702). Subsequently, 15 μ L of 41.7 nM ATX solution (30 nM final concentration) is added, mixed five times and then incubated at 30° C. for 15 minutes. 10 μ L of MR121 substrate solution (1 μ M final concentration) is added, mixed 30 times, and then incubated at 30° C. for 15 minutes. Fluorescence was subsequently measured every 2 minutes for 1 hour (Perkin Elmer plate: visual multimodal readout; light intensity: 2.5%; exp. time: 1.4 seconds, filter: Fluo_630/690 nm), and _IC50 values were calculated from these readings.

The _IC50 values of the examples of the present invention are given in the following table:

The compounds of formula (I) described herein and their pharmaceutically acceptable salts or esters have _IC50 values between 0.00001 μM and 1000 μM, with specific compounds having _IC50 values between 0.0005 μM and 500 μM, further specific compounds having _IC50 values between 0.0005 μM and 50 μM, and even more specific compounds having _IC50 values between 0.0005 μM and 5 μM. These results have been obtained using the above-mentioned enzyme assay.

The compounds of formula (I) and their pharmaceutically acceptable salts can be used as medicines (e.g. in the form of pharmaceutical preparations). Pharmaceutical preparations can be administered internally in the following ways: 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, administration can also be achieved parenterally, such as intramuscularly or intravenously (e.g. in the form of injections).

The compound of formula (I) and its pharmaceutically acceptable salts may be treated with pharmaceutically inert, inorganic or organic adjuvants for the preparation of tablets, coated tablets, dragees and hard gelatin capsules. For example, lactose, corn starch or its derivatives, talc, stearic acid or its salts may be used as such adjuvants for tablets, dragees and hard gelatin capsules.

Suitable excipients for soft gelatin capsules are, for example, vegetable oils, waxes, fats, semisolid substances and liquid polyols and the like.

Suitable excipients for the preparation of solutions and syrups are, for example, water, polyols, sucrose, invert sugar, glucose and the like.

Suitable excipients for injection solutions are, for example, water, alcohols, polyols, glycerol, vegetable oils and the like.

Suitable excipients for suppositories are, for example, natural or hardened oils, waxes, fats, semi-liquid or liquid polyols and the like.

In addition, the pharmaceutical preparations may contain preservatives, solubilizers, viscosity-increasing substances, stabilizers, wetting agents, emulsifiers, sweeteners, coloring agents, flavorings, salts for regulating the osmotic pressure, buffers, masking agents or antioxidants. They may also contain other therapeutically valuable substances.

Dosage can vary over a wide range and will certainly be suitable for the individual needs in each particular case. Typically, in the case of oral administration, a daily dose 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), preferably divided into 1-3 individual doses that can, for example, be composed of the same amount, should be suitable. However, it will be clear that, when clearly indicated, the upper limit given herein may be exceeded.

The invention is illustrated below by means of the following non-limiting examples.

In cases where the preparative examples are obtained as mixtures of enantiomers, the pure enantiomers can be obtained by methods described herein or by methods known to those skilled in the art such as, for example, chiral chromatography or crystallization.

Example

Unless otherwise specified, all examples and intermediates were prepared under nitrogen atmosphere.

abbreviation

aq. = aqueous; CAS-RN = Chemical Abstracts Service registration number; e.r. = enantiomeric ratio; HPLC = high performance liquid chromatography; MS = mass spectrometry; NMR = nuclear magnetic resonance; sat. = saturated

Example 1

[(3aS,3bS,6aR,6bR)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobutadien[1,2-c;3,4-c′]dipyrrol-2-yl]-(6-chloro-naphthalen-2-yl)-methanone

To a solution of (3aS,3bS,6aR,6bR)-decahydro-cyclobuta[1,2-c;3,4-c′]dipyrrole (Intermediate 1; 30 mg, 217 μmol) in N,N-dimethylformamide (3.5 ml) were added N-methylmorpholine (110 mg, 1.09 mmol), 6-chloro-naphthalene-2-carboxylic acid (CAS-RN 5042-97-7; 44.9 mg, 217 μmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (82.5 mg, 217 μmol). After stirring at room temperature for 8 h, 1H-benzo[d][1,2,3]triazole-5-carboxylic acid (35.4 mg, 217 μmol, Eq: 1.00) and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (82.5 mg, 217 μmol) were added, and then after 16 h, the reaction mixture was partitioned between saturated aqueous ammonium chloride and ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and evaporated. Chromatography (silica gel; gradient from dichloromethane to dichloromethane/methanol/25% aqueous ammonia solution 90:10:0.25) produced the title compound (51 mg, 50%). Off-white solid, MS: 472.5 (M+H) ⁺ .

The following examples were produced analogously to Example 1, substituting Carboxylic Acid 1 and Carboxylic Acid 2 for 6-chloro-naphthalene-2-carboxylic acid and 1H-benzo[d][1,2,3]triazole-5-carboxylic acid, respectively.

Example 2

(3aR,3bS,6aR,6bS)-5-(1H-Benzotriazole-5-carbonyl)-octahydro-cyclobutadien[1,2-c;3,4-c′]dipyrrole-2-carboxylic acid 4-trifluoromethoxy-benzyl ester

To a solution of (3aS,3bS,6aR,6bR)-decahydro-cyclobuta[1,2-c;3,4-c′]dipyrrole (Intermediate 1; 40 mg, 289 μmol) in N,N-dimethylformamide (2 mL) was added N-methylmorpholine (146 mg, 1.45 mmol), 1H-benzo[d][1,2,3]triazole-5-carboxylic acid (47.2 mg, 289 μmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (110 mg, 289 μmol). In parallel, a second solution of (4-(trifluoromethoxy)phenyl)methanol (CAS-RN 1736-74-9; 55.6 mg, 289 μmol) and 1,1′-carbonyldiimidazole (49.3 mg, 304 μmol) in DMF (2 ml) was prepared. The two reaction mixtures were stirred at room temperature for 4 h, then combined and stirred for another 16 h before being partitioned between saturated aqueous ammonium chloride solution and ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and evaporated. Chromatography (silica gel; gradient from dichloromethane to dichloromethane/methanol/25% aqueous ammonia solution 90:10:0.25) yielded the title compound (38 mg, 26%). White solid, MS: 502.3 (M+H) ⁺ .

Example 2.001

(3aR,3bS,6aR,6bS)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobutadien[1,2-c;3,4-c′]dipyrrole-2-carboxylic acid 3,5-dichloro-benzyl ester

The title compound was produced similarly to Example 2, using (3,5-dichlorophenyl)methanol (CAS-RN 60211-57-6) instead of (4-(trifluoromethoxy)phenyl)methanol. White solid, MS: 486.5 (M+H) ⁺ .

Example 3

(1H-Benzotriazol-5-yl)-[(3aS,3bR,6aS,6bR)-5-(4′-fluoro-biphenyl-4-sulfonyl)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl]-methanone

(3aS,3bR,6aS,6bR)-5-(4′-Fluoro-biphenyl-4-sulfonyl)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrole-2-carboxylic acid tert-butyl ester (Intermediate 12; 26 mg, 55.0 μmol) was combined with a hydrochloric acid solution (5-6 M in 2-propanol; 1 mL) and stirred at room temperature for 18 h. After evaporation of the volatiles, the residue was taken up in N,N-dimethylformamide (1 mL), followed by the addition of N-methylmorpholine (27.8 mg, 275 μmol), 1H-benzo[d][1,2,3]triazole-5-carboxylic acid (9.9 mg, 61 μmol), and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (23 mg, 61 μmol). After 16 h, the reaction mixture was partitioned between saturated aqueous ammonium chloride and ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and evaporated. Chromatography (silica gel; gradient from dichloromethane to dichloromethane/methanol/25% aqueous ammonia 90:10:0.25) yielded the title compound (26 mg, 82%). Pale yellow gum, MS: 516.6 (MH) ⁻ .

Example 3.001

(1H-Benzotriazol-5-yl)-[(3aS,3bR,6aS,6bR)-5-(6-chloro-naphthalene-2-sulfonyl)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl]-methanone

A solution of 6-chloro-naphthalene-2-sulfonyl chloride (CAS-RN 102153-63-9, 33.6 mg, 129 μmol) in dichloromethane (1 mL) was added to a solution of (3aS,3bS,6aR,6bR)-decahydro-cyclobuta[1,2-c;3,4-c′]dipyrrole (Intermediate 1; 11.9 mg, 86 μmol) in dichloromethane (2 mL) and pyridine (33.9 mg, 34.7 μl, 428 μmol, Eq: 5) at room temperature and after 4 h the reaction mixture was evaporated. The residue was taken up in N,N-dimethylformamide, followed by the addition of 1H-benzo[d]-[1,2,3]triazole-5-carboxylic acid (14.0 mg, 86 μmol) and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (35.8 mg, 94 μmol) and 4-methylmorpholine (43.3 mg, 428 μmol). After 16 h, the reaction mixture was partitioned between saturated aqueous ammonium chloride and ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and evaporated. Chromatography (silica gel; dichloromethane/methanol/25% aqueous ammonia solution 90:10:0.25) yielded the title compound (4 mg, 9%). It was a colorless gum, MS: 508.6 (M+H) ⁺ .

Example 4

[(3aR,3bS,6aR,6bS)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobutadien[1,2-c;3,4-c′]dipyrrol-2-yl]-(6-trifluoromethyl-3,4-dihydro-1H-isoquinolin-2-yl)-methanone

To a solution of (3aS,3bS,6aR,6bR)-decahydro-cyclobuta[1,2-c;3,4-c′]dipyrrole (Intermediate 1; 30 mg, 217 μmol) and N-methylmorpholine (108 mg, 1.07 mmol) in N,N-dimethylformamide (3 mL) was added dropwise a solution of 6-(trifluoromethyl)-3,4-dihydroisoquinoline-2(1H)-carbonyl chloride (Intermediate 7; 57 mg, 214 μmol) in N,N-dimethylformamide DMF (1 ml) at room temperature, and then after 1 h, 1H-benzo[d][1,2,3]triazole-5-carboxylic acid (34.9 mg, To the reaction mixture was added 1-[4-[ ^...

intermediates

Intermediate 1

(3aS,3bS,6aR,6bR)-Decahydro-cyclobuta[1,2-c;3,4-c′]dipyrrole

Step 1: (3aS,3bS,6aR,6bR)-2,5-dibenzyl-tetrahydro-cyclobuta[1,2-c;3,4-c′]dipyrrolidone Pyrrolidine-1,3,4,6-tetraone

A solution of 1-benzyl-1H-pyrrole-2,5-dione (1.12 g, 5.98 mmol) in acetonitrile (60 mL) was purged with nitrogen for 10 min and then irradiated at 300 nm for 6 h to produce a white suspension. Approximately 30 mL of acetonitrile was distilled off and the product (447 mg, 40%) was collected by filtration. Off-white solid, MS: 375.5 (M+H) ⁺ , ¹ H-NMR (300 MHz, DMSO-d ₆ ): 7.35-7.25 (m, 10H), 4.63 (s, 4H), 3.45 (s, 4H).

Step 2: (3aS,3bS,6aR,6bR)-2,5-dibenzyl-decahydro-cyclobutadien[1,2-c;3,4-c′]dipyrrolidone Slightly

To a suspension of lithium aluminum hydride (3.05 g, 80.3 mmol) in diethyl ether (120 mL) was added (3aS,3bS,6aR,6bR)-2,5-dibenzyl-tetrahydro-cyclobuta[1,2-c;3,4-c′]dipyrrole-1,3,4,6-tetraone (7.52 g, 20.1 mmol) portionwise at room temperature over 10 min. The reaction mixture was stirred at room temperature for 4 h, then cooled to 0° C. and quenched by the slow addition of water (40 mL) and 2M aqueous sodium hydroxide solution. Water (500 mL) and ethyl acetate (500 mL) were added, and after filtration through celite, the organic layer was washed with brine, dried over magnesium sulfate, filtered, and evaporated. The residue was triturated in methanol (40 mL) to yield the title compound (4.60 g, 72%). White solid, MS: 319.6 (M+H) ⁺ , ¹ H-NMR (300 MHz, CDCl ₃ ): 7.4-7.2 (m, 10H), 3.65 (s, 4H), 2.82 (d, J=9.3, 4H), 2.39 (d, J=4.4, 4H), 2.05 (dd, J=9.3, 4.4, 4H).

Step 3: (3aS, 3bS, 6aR, 6bR)-decahydro-cyclobuta[1,2-c; 3,4-c′]dipyrrole

A solution of (3aS,3bS,6aR,6bR)-2,5-dibenzyl-decahydro-cyclobuta[1,2-c;3,4-c′]dipyrrole (4.6 g, 14.4 mmol, Eq: 1.00) was stirred at 50° C. for 4 h under a hydrogen atmosphere (3 bar) in the presence of palladium (10% on activated carbon, 2.08 g). The insoluble material was then removed by filtration through celite. The filtrate was evaporated to yield the title compound (1.72 g, 86%). The product was a white solid. MS: 139.2 (M+H) ⁺ , ¹ H-NMR (300 MHz, CDCl ₃ ): 2.99 (d, J=11.4, 4H), 2.68 (dd, J=11.4, 4.4, 4H), 2.25-2.15 (m, 6H).

Intermediate 2

4-Isopropoxy-7-(trifluoromethyl)quinoline-2-carboxylic acid

Step 1: Methyl 4-isopropoxy-7-(trifluoromethyl)quinoline-2-carboxylate

To a stirred suspension of methyl 4-hydroxy-7-(trifluoromethyl)quinoline-2-carboxylate (300 mg, 1.08 mmol) in acetonitrile (3 mL) was added potassium carbonate (449 mg, 3.25 mmol) and 2-iodopropane (570 mg, 3.25 mmol). The reaction mixture was stirred at 80° C. for 16 h and then partitioned between water and ethyl acetate. 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 (334 mg, 98%) as a white solid.

Step 2: 4-Isopropoxy-7-(trifluoromethyl)quinoline-2-carboxylic acid

A mixture of methyl 4-isopropoxy-7-(trifluoromethyl)quinoline-2-carboxylate (330 mg, 1.05 mmol), potassium hydroxide (209 mg, 3.16 mmol), ethanol (3.5 mL), and water (3.5 mL) was heated at 80°C for 45 min, and most of the ethanol was then distilled off. The remaining aqueous solution was acidified to pH 1 with 1 M hydrochloric acid solution. The precipitate was collected by filtration and dried to yield the title compound (304 mg, 96%). White solid MS: 299.9 (M+H) ⁺ .

Similar to Intermediate 2, the following intermediates were generated by replacing methyl 4-hydroxy-7-(trifluoromethyl)quinoline-2-carboxylate and 2-iodopropane with appropriate starting materials and alkylating agents, respectively.

Intermediate 3

5-Chloro-6-oxo-1-(2,2,2-trifluoroethyl)-1,6-dihydropyridine-3-carboxylic acid

Lithium hydroxide monohydrate (102 mg, 2.4 mmol) was added to a solution of 5-chloro-6-oxo-1-(2,2,2-trifluoroethyl)-1,6-dihydropyridine-3-carboxylic acid methyl ester (328 mg, 1.22 mmol) in tetrahydrofuran (1 mL) and water (1 mL), and then the reaction mixture was partially evaporated after 16 h to remove most of the tetrahydrofuran. The remaining aqueous solution was acidified to pH 1 with 1 M aqueous hydrochloric acid solution. The precipitate was collected by filtration and dried to give the title compound (289 mg, 93%). White solid, MS: 254.2 (MH) ^- .

The following intermediates were prepared similarly to Intermediate 3, substituting appropriate starting materials for methyl 5-chloro-6-oxo-1-(2,2,2-trifluoroethyl)-1,6-dihydropyridine-3-carboxylate.

Intermediate 4

5-Cyclopropyl-4-(2,2,2-trifluoroethoxy)methylpicolinic acid

5-Cyclopropyl-4-(2,2,2-trifluoroethoxy)methylpyridinecarbonitrile (250 mg, 1.03 mmol) was combined with 25% aqueous hydrochloric acid solution (5 mL) and heated at 110° C. for 3 h. After cooling, the reaction mixture was evaporated to dryness. The residue was suspended in water (5 mL), basified with 6 M aqueous sodium hydroxide solution, and the resulting solution was acidified to pH 1. The precipitate was collected by filtration and dried to produce the title compound (159 mg, 59%). White solid, MS: 262.2 (M+H) ⁺ .

Intermediate 5

5-(Methylsulfonyl)-6-(2,2,2-trifluoroethoxy)nicotinic acid

Step 1: Methyl 5-(methylsulfonyl)-6-(2,2,2-trifluoroethoxy)nicotinate

A mixture of L-proline (88 mg, 0.76 mmol, Eq: 0.8) and sodium hydroxide (31 mg, 0.76 mmol) and dimethyl sulfoxide (5 mL) was stirred at room temperature for 30 min, then methyl 5-bromo-6-(2,2,2-trifluoroethoxy)nicotinate (300 mg, 955 μmol), sodium methanesulfonate (804 mg, 7.64 mmol) and copper (I) iodide (146 mg, 764 μmol) were added, and the reaction mixture was heated at 80° C. for 16 h, then partitioned between 1 M aqueous hydrochloric acid solution and ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and evaporated. The residue was purified by chromatography (silica gel; heptane-ethyl acetate gradient) to produce the title compound (80 mg, 27%). White solid, MS: 314 (M+H) ⁺ .

Step 2: 5-(Methylsulfonyl)-6-(2,2,2-trifluoroethoxy)nicotinic acid

The title compound was prepared from methyl 5-(methylsulfonyl)-6-(2,2,2-trifluoroethoxy)nicotinate in analogy to Intermediate 2, Step 2. White solid, MS: 298.1 (MH) ^- .

Intermediate 6

1-(3-Methoxy-propyl)-1,2,3,4-tetrahydro-quinoline-3-carboxylic acid

A mixture of 1,2,3,4-tetrahydroquinoline-3-carboxylic acid methyl ester (CAS-RN 177202-62-9; 300 mg, 1.57 mmol), 1-bromo-3-methoxypropane (735 mg, 4.71 mmol) and sodium bicarbonate (659 mg, 7.84 mmol) in ethanol (3 mL) was heated under reflux. After 18 h, the reaction mixture was evaporated and the residue was chromatographed (silica gel; heptane-ethyl acetate gradient) to give a mixture of 1-(3-methoxy-propyl)-1,2,3,4-tetrahydro-quinoline-3-carboxylic acid methyl ester and 1-(3-methoxy-propyl)-1,2,3,4-tetrahydro-quinoline-3-carboxylic acid ethyl ester (251 mg). This material was combined with ethanol (2.5 mL), water (2.5 mL) and potassium hydroxide (264 mg, 4.71 mmol) and heated at 80° C. for 45 min. The reaction mixture was then partially evaporated to remove most of the ethanol. The remaining aqueous solution was partitioned between ethyl acetate and 1 M aqueous hydrochloric acid. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and evaporated to yield the title compound (190 mg, 49%). Pale yellow oil, MS: 248.5 (MH) ⁻ .

Intermediate 7

6-(Trifluoromethyl)-3,4-dihydroisoquinoline-2(1H)-carbonyl chloride

To a white suspension of 6-(trifluoromethyl)-1,2,3,4-tetrahydroisoquinoline hydrochloride (CAS-RN 215798-14-4; 500 mg, 2.04 mmol) and pyridine (339 mg, 4.29 mmol) in dichloromethane (5 mL) was added dropwise a solution of triphosgene (273 mg, 918 μmol) in dichloromethane (5 mL) at 0°C. After 30 min, the ice bath was removed, and after 16 h, the reaction mixture was partitioned between 1 M aqueous hydrochloric acid and dichloromethane. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and evaporated to yield the title compound (546 mg, equiv.) as a yellow oil.

Intermediate 8

4-Ethoxy-5,6,7,8-tetrahydroquinoline-2-carboxylic acid

Step 1: Methyl 4-hydroxy-5,6,7,8-tetrahydroquinoline-2-carboxylate

A solution of methyl 4-hydroxyquinoline-2-carboxylate (CAS-RN 5965-59-3; 1.0 g, 4.92 mmol) in 37% aqueous hydrochloric acid (36 mL) was stirred in the presence of platinum (IV) oxide (124 mg) under a hydrogen atmosphere (4 bar) at room temperature. After 72 h, insoluble material was removed by filtration through celite, and the filtrate was evaporated to yield the title compound (1.06 g, 69%). The product was a white solid, MS: 208.3 (M+H) ⁺ .

Step 2: Methyl 4-ethoxy-5,6,7,8-tetrahydroquinoline-2-carboxylate

The title compound was prepared from methyl 4-hydroxy-5,6,7,8-tetrahydroquinoline-2-carboxylate in analogy to Intermediate 2, Step 1. White solid, MS: 236.3 (M+H) ⁺ .

Step 3: 4-Ethoxy-5,6,7,8-tetrahydroquinoline-2-carboxylic acid

A mixture of methyl 4-ethoxy-5,6,7,8-tetrahydroquinoline-2-carboxylate (156 mg, 663 μmol, Eq: 1.00) in ethanol (2 mL) and water (2 mL) was heated under reflux for 2 h, after which most of the ethanol was distilled off and the remaining aqueous solution was acidified to pH 1 and then evaporated to dryness. The residue was suspended in dichloromethane and the insoluble material was removed by filtration. The filtrate was evaporated to yield the title compound (172 mg, quantitative). White solid, MS: 222.3 (M+H) ⁺ .

Intermediate 9

4-Isopropoxy-1-methyl-1H-indole-6-carboxylic acid

Step 1: 4-Isopropoxy-1H-indole-6-carboxylic acid methyl ester

Potassium carbonate (651 mg, 4.71 mmol) and 2-iodopropane (275 mg, 1.57 mmol) were added to a solution of methyl 4-hydroxy-1H-indole-6-carboxylate (CAS-RN 77140-48-8; 300 mg, 1.57 mmol) in N,N-dimethylformamide (9 mL) at 0°C. The reaction mixture was stirred at 0°C for 16 h and then partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and evaporated to give a light brown oil. Chromatography (silica gel; heptane-ethyl acetate gradient) produced the title compound (280 mg, 77%). White solid, MS: 232.2 (MH) ^- .

Step 2: Methyl 4-isopropoxy-1-methyl-1H-indole-6-carboxylate

Potassium carbonate (296 mg, 2.14 mmol) and iodomethane (183 mg, 1.29 mmol) were added to a solution of methyl 4-isopropoxy-1H-indole-6-carboxylate (100 mg, 429 μmol) in acetone (2.5 mL). The reaction mixture was heated under reflux for 16 h and then partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, filtered and evaporated to give a light brown oil. Chromatography (silica gel; heptane-ethyl acetate gradient) produced the title compound (102 mg, 96%). Colorless oil, MS: 248.2 (MH) ^- .

Step 3: 4-Isopropoxy-1-methyl-1H-indole-6-carboxylic acid

The title compound was prepared from methyl 4-isopropoxy-1-methyl-1H-indole-6-carboxylate in analogy to Intermediate 2, Step 2. Off-white solid, MS: 232.2 (MH) ⁻ .

Intermediate 10

4-Fluoro-1H-benzo[d][1,2,3]triazole-5-carboxylic acid

Step 1: 5-Bromo-4-fluoro-1H-benzo[d][1,2,3]triazole

To a light brown suspension of 4-bromo-3-fluorobenzene-1,2-diamine (1.50 g, 7.32 mmol) in water (15 mL) and acetic acid (5 mL) was added dropwise a solution of sodium nitrite (555 mg, 8.05 mmol) in water (1.5 mL) at 0°C. After 1 h, the reaction mixture was heated to 85°C at 0°C for 1 h. After cooling, the reaction mixture was 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 (1.53 g, 97%). Brown solid, MS: 214.1 (MH) ^- .

Step 2: 4-Fluoro-1H-benzo[d][1,2,3]triazole-5-carboxylic acid methyl ester

A solution of 5-bromo-4-fluoro-1H-benzo[d][1,2,3]triazole (415 mg, 1.92 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II) dichloromethane complex (63.4 mg, 76.8 μmol), and triethylamine (253 mg, 2.50 mmol) in methanol (5 mL) was stirred at 110° C. for 18 h under a hydrogen atmosphere (70 bar). After cooling, the reaction mixture was evaporated and the residue was purified by chromatography (silica gel; gradient from dichloromethane to dichloromethane/methanol 95:5) to yield the title compound (127 mg, 31%). A red solid, MS: 194.2 (MH) ⁻ .

Step 3: 4-Fluoro-1H-benzo[d][1,2,3]triazole-5-carboxylic acid

The title compound was prepared from methyl 4-fluoro-1H-benzo[d][1,2,3]triazole-5-carboxylate in analogy to Intermediate 3. Brown solid, MS: 180.2 (MH) ^- .

Intermediate 11

(+)-(R)-4,5,6,7-Tetrahydro-1H-benzo[d][1,2,3]triazole-5-carboxylic acid

Racemic 4,5,6,7-tetrahydro-1H-benzo[d][1,2,3]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 yielded the faster eluting (+)-(R)-enantiomer (452 mg, 41%), followed by the slower eluting (-)-(S)-enantiomer (381 mg, 35%). White solid, MS: 166.2 (MH) ⁻ .

Intermediate 12

(3aS,3bR,6aS,6bR)-5-(4′-Fluoro-biphenyl-4-sulfonyl)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrole-2-carboxylic acid tert-butyl ester

A solution of 4′-fluorobiphenyl-4-sulfonyl chloride (CAS-RN 116748-66-4; 42.9 mg, 158 μmol) in dichloromethane (1 mL) was added to a solution of (3aR,3bS,6aR,6bS)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrole-2-carboxylic acid tert-butyl ester hydrochloride (Intermediate 13; 29 mg, 106 μmol) and pyridine (25.0 mg, 317 μmol) in dichloromethane (1 mL) at room temperature. After 2 h, the reaction mixture was concentrated under vacuum, and the residue was purified by chromatography (silica gel; heptane-ethyl acetate gradient) to yield the title compound (30 mg, 60%). The product was obtained as a white solid, MS: 394.6 (M+ _Me₃COCO +Na) ^⁺ .

Intermediate 13

(3aR,3bS,6aR,6bS)-Octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrole-2-carboxylic acid tert-butyl ester hydrochloride

Step 1: (3aS, 3bS, 6aR, 6bR)-octahydro-cyclobutadiene[1,2-c; 3,4-c′]dipyrrole-2,5-dicarbonyl Di-tert-butyl carboxylate

To a solution of (3aS,3bS,6aR,6bR)-decahydro-cyclobuta[1,2-c;3,4-c′]dipyrrole (Intermediate 1; 100 mg, 724 μmol) in chloroform (3 ml) was added dropwise a solution of di-tert-butyl dicarbonate (474 mg, 2.17 mmol) in chloroform (3 ml). After 2 h, the reaction mixture was evaporated and the residue was chromatographed (silica gel; heptane-ethyl acetate gradient) to afford the title compound (222 mg, 91%) as a white solid, MS: 338.6 (M+H) ⁺ .

Step 2: (3aR,3bS,6aR,6bS)-octahydro-cyclobutadieno[1,2-c;3,4-c′]dipyrrole-2-carboxylic acid tert- Butyl ester hydrochloride

A solution of di-tert-butyl (3aS,3bS,6aR,6bR)-octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrole-2,5-dicarboxylate (76 mg, 225 μmol) in ethyl acetate (2 mL) was added with a 5-6 M solution of hydrogen chloride in 2-propanol (90 μL, 0.45 mmol) at 0°C. The reaction mixture was stirred at room temperature for 3 days, after which the precipitate was collected by filtration and dried to afford the title compound (33 mg, 48%). The product was obtained as a white solid, MS: 239.6 (M+H) ⁺ .

Example A

The compound of formula (I) can be used in a manner known per se as active ingredient for the production of tablets of the following composition:

Each tablet

Example B

The compound of formula (I) can be used in a manner known per se as active ingredient for the production of capsules of the following composition:

Each capsule

Claims (20)

1. Compound of formula (I) in R ¹ is a substituted quinolinyl, substituted 1,2,3,4-tetrahydroquinolinyl, substituted isoquinolinyl, substituted 1,2,3,4-tetrahydroisoquinolinyl, substituted 9H-carbazolyl, substituted chromanyl, substituted indoleyl, substituted naphthyl, substituted azole, substituted phenyl, substituted phenyl _C1-7 alkyl, substituted phenyl _C3-8 cycloalkyl, substituted phenoxy C1-7 alkyl, substituted phenyl _C1-7 alkoxy, substituted phenyl _C2-7 alkenyl, substituted phenyl ethynyl, substituted pyridazinyl, substituted pyridazinyl _C1-7 alkyl, substituted pyridazinyl _C2-7 alkenyl, substituted pyridazinyl ethynyl, substituted pyridinyl, substituted pyridinyl _{C1-7 alkyl} , substituted pyridinyl _C2-7 alkenyl, substituted pyridinyl ethynyl, substituted pyridinoneyl, substituted pyridinoneyl C _1-7 alkyl, substituted pyridinone C _2-7 alkenyl, substituted pyridinone ethynyl, substituted thiophene, substituted thiophene C _1-7 alkyl, substituted thiophene C _2-7 alkenyl, substituted thiophene ethynyl, substituted naphthanoyl or substituted naphthanoylone, wherein substituted quinolinyl, substituted 1,2,3,4-tetrahydroquinolinyl, substituted isoquinolinyl, substituted 1,2,3,4-tetrahydroisoquinolinyl, substituted 9H-carbazoyl, substituted chromanyl, substituted indolyl, substituted naphthyl, substituted azole, substituted phenyl, substituted phenyl C _1-7 alkyl, substituted phenyl C _3-8 cycloalkyl, substituted phenoxy C _1-7 alkyl, substituted phenyl C _1-7 alkoxy, substituted phenyl C _2-7 alkenyl, substituted phenyl ethynyl, substituted pyridazinyl, substituted pyridazinyl C _1-7 alkyl, substituted pyridinyl _C2-7 alkenyl, substituted pyridinyl ethynyl, substituted pyridinyl, substituted pyridinyl _C1-7 alkyl, substituted pyridinyl _C2-7 alkenyl, substituted pyridinyl ethynyl, substituted pyridinoneyl, substituted pyridinoneyl _C1-7 alkyl, substituted pyridinoneyl _C2-7 alkenyl, substituted pyridinoneyl ethynyl, substituted thiophenyl, substituted thiophenyl _C1-7 alkyl, substituted thiophenyl _C2-7 alkenyl, substituted thiophenyl ethynyl, substituted naphthyl and substituted naphthylone are substituted by ^R6 , ^R7 and ^R8 ; Y is -C(O)- or -S(O) _2- ; ^R2 is a substituted pyridyl group, a substituted phenyl group, or a group selected from cyclic systems A, B, and C, wherein the substituted pyridyl group and the substituted phenyl group are substituted with a substituted aminosulfonyl group, wherein the substituted aminosulfonyl group is substituted on the nitrogen atom by one or two substituents independently selected from H, _C1-7 alkyl, _C3-8 cycloalkyl, _C3-8 cycloalkyl- _C1-7 alkyl, hydroxy- _C1-7 alkyl, and _C1-7 alkoxy- _C1-7 alkyl; ^R3 , ^R4 and ^R5 are independently selected from H, _C1-7 alkyl, halogen, halogenated _C1-7 alkyl and _C1-7 alkoxy; ^R6 , ^R7 , and ^R8 are independently selected from H, halogen, cyano, _{cyanoC1-7alkyl} , _C1-7alkyl , hydroxyC1-7alkyl, _{halogenatedC1-7alkyl} , _{hydroxyhalogenatedC1-7alkyl} , _{C3-8 cycloalkyl} , _C3-8 cycloalkylC1-7alkyl, _C3-8 cycloalkylC1-7alkoxy, _{C3-8 cycloalkoxy} , _{C3-8 cycloalkoxyC1-7alkyl} , _{C3-8 cycloalkylC1-7alkoxyC1-7alkyl , C1-7alkoxy , C1-7alkoxyC1-7alkyl , halogenatedC1-7alkoxy , C1-7alkoxyhalogenatedC1-7alkyl , C1-7alkoxyC1-7alkoxy , C1-7alkoxyC1-7alkoxyC1-7alkyl ... 1-7} alkylsulfonyl, furanyl, tetrahydropyranyl, phenyl, substituted phenyl, phenyl _C1-7 alkoxy, substituted phenyl _C1-7 alkoxy, pyridyl, substituted pyridyl, pyrrolidinyl, substituted pyrrolidinyl, pyrrolidinyl and substituted pyrrolidinyl, wherein the substituted phenyl, substituted phenyl _C1-7 alkoxy, substituted pyridyl, substituted pyrrolidinyl and substituted pyrrolidinyl are substituted by one to three halogens; Or medicinal salt. 2. The compound according to claim 1, wherein ^R1 is a substituted quinolinyl, a substituted 1,2,3,4-tetrahydroquinolinyl, a substituted isoquinolinyl, a substituted 1,2,3,4-tetrahydroisoquinolinyl, a substituted 9H-carbazoleyl, a substituted chromanyl, a substituted indoleyl, a substituted naphthyl, a substituted azole, a substituted phenyl, a substituted phenyl _C1-7 alkyl, a substituted phenoxy _C1-7 alkyl, a substituted phenyl _C1-7 alkoxy, or a substituted phenyl C1-7 alkyl. _2-7 alkenyl, substituted pyridazinyl, substituted pyridinyl, substituted pyridoneyl, substituted naphthyl or substituted naphthoneyl, wherein the substituted quinolinyl, substituted 1,2,3,4-tetrahydroquinolinyl, substituted isoquinolinyl, substituted 1,2,3,4-tetrahydroisoquinolinyl, substituted 9H-carbazolyl, substituted chromanyl, substituted indolyl, substituted naphthyl, substituted azoleyl, substituted phenyl, substituted phenyl _C1-7 alkyl, substituted phenoxy _C1-7 alkyl, substituted phenyl _C1-7 alkoxy, substituted phenyl _C2-7 alkenyl, substituted pyridazinyl, substituted pyridinyl, substituted pyridoneyl, substituted naphthyl and substituted naphthoneyl are substituted by ^R6 , ^R7 and ^R8 . 3. The compound according to claim 1 or 2, wherein ^R1 is a substituted quinolinyl, a substituted indolyl, a substituted naphthyl, a substituted phenyl _C1-7 alkoxy, a substituted phenyl _C2-7 alkenyl, or a substituted pyridyl, wherein the substituted quinolinyl, the substituted indolyl, the substituted naphthyl, the substituted phenyl _C1-7 alkoxy, the substituted phenyl _C2-7 alkenyl, and the substituted pyridyl are substituted by ^R6 , ^R7 , and ^R8 . 4. The compound according to claim 1 or 2, wherein ^R1 is a substituted quinolinyl, a substituted indolyl, a substituted naphthyl, or a substituted pyridyl, wherein the substituted quinolinyl, the substituted indolyl, the substituted naphthyl, and the substituted pyridyl are substituted by ^R6 , ^R7 , and ^R8 . 5. The compound according to claim 1 or 2, wherein ^R2 is selected from ring systems A and C. 6. The compound according to claim 1 or 2, wherein ^R2 is a cyclic system A. 7. The compound according to claim 1 or 2, wherein Y is -C(O)-. 8. The compound according to claim 1 or 2, wherein ^R3 , ^R4 and ^R5 are independently selected from H and halogens. 9. The compound according to claim 1 or 2, wherein ^R3 , ^R4 and ^R5 are H. 10. The compound according to claim 1 or 2, wherein ^R6 is H, halogen, cyano, cyano _C1-7 alkyl, _C1-7 alkyl, halo- _C1-7 alkyl, _C3-8 cycloalkyl _C1-7 alkoxy, _C1-7 alkoxy, _C1-7 alkoxy- _C1-7 alkyl, halo- _C1-7 alkoxy, _C1-7 alkoxy- _C1-7 alkoxy, phenyl, phenyl- _C1-7 alkoxy, or a phenyl substituted with one to three halogens. 11. The compound according to claim 1 or 2, wherein ^R6 is a _C1-7 alkoxy, a halo- _C1-7 alkoxy, or a _C1-7 alkoxy- _C1-7 alkoxy. 12. The compound according to claim 1 or 2, wherein ^R7 is H, halogen, _C1-7 alkyl, _C3-8 cycloalkyl, _C1-7 alkoxy, halogenated _C1-7 alkoxy, _C1-7 alkylsulfonyl, furanyl, or tetrahydropyranyl. 13. The compound according to claim 1 or 2, wherein R ⁷ is H or a halogen. 14. The compound according to claim 1 or 2, wherein R ⁸ is H or C _1-7 alkyl. 15. The compound according to claim 1 or 2, wherein ^R8 is H. 16. The compound according to claim 1, wherein the compound is selected from... [(3aS,3bS,6aR,6bR)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobutadiene[1,2-c;3,4-c′]dipyrrole-2-yl]-(6-chloro-naphth-2-yl)-methyl ketone; 1-[(3aS,3bR,6aS,6bR)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobutadiene[1,2-c;3,4-c′]dipyrrole-2-yl]-3-(4-trifluoromethoxy-phenyl)-prop-1-one; [(3aS,3bS,6aR,6bR)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobutadiene[1,2-c;3,4-c′]dipyrrole-2-yl]-(4′-fluoro-biphenyl-4-yl)-methyl ketone; (E)-1-[(3aS,3bR,6aS,6bR)-5-(1H-benzotriazol-5-carbonyl)-octahydro-cyclobutadiene[1,2-c;3,4-c′]dipyrrolo-2-yl]-3-(4-trifluoromethoxy-phenyl)-propenone; [(3aS,3bS,6aR,6bR)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobutadiene[1,2-c;3,4-c′]dipyrrole-2-yl]-(6-bromo-naphth-2-yl)-methyl ketone; [(3aS,3bS,6aR,6bR)-5-(1H-benzotriazol-5-carbonyl)-octahydro-cyclobutadiene[1,2-c;3,4-c′]dipyrrole-2-yl]-(6-methoxy-naphth-2-yl)-methyl ketone; (E)-1-[(3aS, 3bS, 6aR, 6bR)-5-((R)-4, 5, 6, 7-tetrahydro-1H-benzotriazole-5-carbonyl)-octahydro-cyclobutadiene[1, 2-c; 3, 4-c′]dipyrrole-2-yl]-3-(4-trifluoromethoxy-phenyl)-propenone; 6-[(3aS, 3bS, 6aR, 6bR)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobutadiene[1,2-c; 3,4-c′]dipyrrole-2-carbonyl]-naphthalene-2-carboxylonitrile; 1-[(3aR,3bS,6aR,6bS)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobutadiene[1,2-c;3,4-c′]dipyrrole-2-yl]-2-(4-trifluoromethoxy-phenoxy)-ethyl ketone; 1-[(3aR,3bS,6aR,6bS)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobutadiene[1,2-c;3,4-c′]dipyrrole-2-yl]-2-(2-isopropyl-phenoxy)-acetone; [(3aR,3bS,6aR,6bS)-5-(1H-benzotriazol-5-carbonyl)-octahydro-cyclobutadiene[1,2-c;3,4-c′]dipyrrole-2-yl]-(5-trifluoromethoxy-1H-indol-2-yl)-methyl ketone; [(3aR,3bS,6aR,6bS)-5-(1H-benzotriazol-5-carbonyl)-octahydro-cyclobutadiene[1,2-c;3,4-c′]dipyrrole-2-yl]-(6-trifluoromethoxy-1H-indol-2-yl)-methyl ketone; [(3aS,3bS,6aR,6bR)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobutadiene[1,2-c;3,4-c′]dipyrrolo-2-yl]-naphth-2-yl-methyl ketone; [(3aS,3bS,6aR,6bR)-5-(1H-benzotriazol-5-carbonyl)-octahydro-cyclobutadiene[1,2-c;3,4-c′]dipyrrolo-2-yl]-(6-methyl-naphth-2-yl)-methyl ketone; [(3aS,3bS,6aR,6bR)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobutadiene[1,2-c;3,4-c′]dipyrrole-2-yl]-(7-methyl-naphth-2-yl)-methyl ketone; [(3aS,3bS,6aR,6bR)-5-(1H-benzotriazol-5-carbonyl)-octahydro-cyclobutadiene[1,2-c;3,4-c′]dipyrrole-2-yl]-(6-phenyl-naphth-2-yl)-methyl ketone; (6-Bromo-naphth-2-yl)-[(3aR,3bS,6aR,6bS)-5-((R)-4,5,6,7-tetrahydro-1H-benzotriazole-5-carbonyl)-octahydro-cyclobutadiene[1,2-c;3,4-c′]dipyrrole-2-yl]-methyl ketone; [(3aS,3bS,6aR,6bR)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobutadiene[1,2-c;3,4-c′]dipyrrole-2-yl]-(4′-chloro-biphenyl-4-yl)-methyl ketone; (4′-Chloro-biphenyl-4-yl)-[(3aR,3bS,6aR,6bS)-5-((R)-4,5,6,7-tetrahydro-1H-benzotriazole-5-carbonyl)-octahydro-cyclobutadiene[1,2-c;3,4-c′]dipyrrole-2-yl]-methyl ketone; [(3aR,3bS,6aR,6bS)-5-((R)-4,5,6,7-tetrahydro-1H-benzotriazole-5-carbonyl)-octahydro-cyclobutadiene[1,2-c;3,4-c′]dipyrrole-2-yl]-(5-trifluoromethoxy-1H-indol-2-yl)-methyl ketone; [(3aR,3bS,6aR,6bS)-5-((R)-4,5,6,7-tetrahydro-1H-benzotriazole-5-carbonyl)-octahydro-cyclobutadiene[1,2-c;3,4-c′]dipyrrole-2-yl]-(6-trifluoromethoxy-1H-indol-2-yl)-methyl ketone; [(3aS,3bS,6aR,6bR)-5-(1H-benzotriazol-5-carbonyl)-octahydro-cyclobutadiene[1,2-c;3,4-c′]dipyrrole-2-yl]-(3-methoxy-naphth-2-yl)-methyl ketone; [(3aS,3bS,6aR,6bR)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobutadiene[1,2-c;3,4-c′]dipyrrole-2-yl]-(1-methoxy-naphth-2-yl)-methyl ketone; [(3aR,3bS,6aR,6bS)-5-(1H-benzotriazol-5-carbonyl)-octahydro-cyclobutadiene[1,2-c;3,4-c′]dipyrrolo-2-yl]-(1H-indol-2-yl)-methyl ketone; [(3aR,3bS,6aR,6bS)-5-(1H-benzotriazol-5-carbonyl)-octahydro-cyclobutadiene[1,2-c;3,4-c′]dipyrrolo-2-yl]-(1-methyl-1H-indol-2-yl)-methyl ketone; [(3aS,3bS,6aR,6bR)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobutadiene[1,2-c;3,4-c′]dipyrrole-2-yl]-(4-cyclopropylmethoxy-naphth-2-yl)-methyl ketone; [(3aS,3bS,6aR,6bR)-5-(1H-benzotriazol-5-carbonyl)-octahydro-cyclobutadiene[1,2-c;3,4-c′]dipyrrole-2-yl]-(4-methoxy-naphth-2-yl)-methyl ketone; 2-[(3aR,3bS,6aR,6bS)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobutadiene[1,2-c;3,4-c′]dipyrrole-2-carbonyl]-1H-indole-5-carboxynitrile; [(3aS,3bS,6aR,6bR)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobutadiene[1,2-c;3,4-c′]dipyrrole-2-yl]-(3-methoxy-phenyl)-methyl ketone; [(3aR,3bS,6aR,6bS)-5-(1H-benzotriazol-5-carbonyl)-octahydro-cyclobutadiene[1,2-c;3,4-c′]dipyrrolo-2-yl]-(4-methoxy-quinolin-2-yl)-methyl ketone; [(3aR,3bS,6aR,6bS)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobutadiene[1,2-c;3,4-c′]dipyrrole-2-yl]-[2-(4-chloro-phenyl)-5-methyl-azol-4-yl]-methyl ketone; [(3aS,3bR,6aS,6bR)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobutadiene[1,2-c;3,4-c′]dipyrrole-2-yl]-(1,2,3,4-tetrahydro-naphth-2-yl)-methyl ketone; [(3aR,3bS,6aR,6bS)-5-(1H-benzotriazol-5-carbonyl)-octahydro-cyclobutadiene[1,2-c;3,4-c′]dipyrrolo-2-yl]-(1-methyl-5-trifluoromethoxy-1H-indol-2-yl)-methyl ketone; [(3aR,3bS,6aR,6bS)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobutadiene[1,2-c;3,4-c′]dipyrrole-2-yl]-(6-chloro-1H-indole-2-yl)-methyl ketone; [(3aR,3bS,6aR,6bS)-5-(1H-benzotriazol-5-carbonyl)-octahydro-cyclobutadiene[1,2-c;3,4-c′]dipyrrole-2-yl]-(6-chloro-1-methyl-1H-indol-2-yl)-methyl ketone; [(3aR,3bS,6aR,6bS)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobutadiene[1,2-c;3,4-c′]dipyrrole-2-yl]-(6-methyl-1H-indol-2-yl)-methyl ketone; {2-[(3aR, 3bS, 6aR, 6bS)-5-(1H-benzotriazol-5-carbonyl)-octahydro-cyclobutadiene[1,2-c; 3,4-c′]dipyrrole-2-carbonyl]-indol-1-yl}-acetonitrile; [(3aR,3bS,6aR,6bS)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobutadiene[1,2-c;3,4-c′]dipyrrole-2-yl]-(1-isobutyl-1H-indole-2-yl)-methyl ketone; [(3aR,3bS,6aR,6bS)-5-(1H-benzotriazol-5-carbonyl)-octahydro-cyclobutadiene[1,2-c;3,4-c′]dipyrrolo-2-yl]-quinoline-2-yl-methyl ketone; [(3aR,3bS,6aR,6bS)-5-(1H-benzotriazol-5-carbonyl)-octahydro-cyclobutadiene[1,2-c;3,4-c′]dipyrrolo-2-yl]-isoquinoline-3-yl-methyl ketone; [(3aS,3bS,6aR,6bR)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobutadiene[1,2-c;3,4-c′]dipyrrole-2-yl]-(1H-indole-6-yl)-methyl ketone; 3-[(3aS, 3bR, 6aS, 6bR)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobutadiene[1,2-c; 3,4-c′]dipyrrole-2-carbonyl]-3,4-dihydro-2H-naphth-1-one; [(3aR,3bS,6aR,6bS)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobutadiene[1,2-c;3,4-c′]dipyrrole-2-yl]-chroman-2-yl-methyl ketone; [(3aS,3bS,6aR,6bR)-5-(1H-benzotriazol-5-carbonyl)-octahydro-cyclobutadiene[1,2-c;3,4-c′]dipyrrole-2-yl]-(1H-indol-5-yl)-methyl ketone; (4-Methoxy-naphth-2-yl)-[(3aR,3bS,6aR,6bS)-5-((R)-4,5,6,7-tetrahydro-1H-benzotriazole-5-carbonyl)-octahydro-cyclobutadiene[1,2-c;3,4-c′]dipyrrole-2-yl]-methyl ketone; [(3aS,3bS,6aR,6bR)-5-(1H-benzotriazol-5-carbonyl)-octahydro-cyclobutadiene[1,2-c;3,4-c′]dipyrrolo-2-yl]-[6-(4-chloro-phenyl)-pyridin-3-yl]-methyl ketone; [(3aR,3bS,6aR,6bS)-5-(1H-benzotriazol-5-carbonyl)-octahydro-cyclobutadiene[1,2-c;3,4-c′]dipyrrolo-2-yl]-(1-methoxy-isoquinoline-3-yl)-methyl ketone; [(3aR,3bS,6aR,6bS)-5-(1H-benzotriazol-5-carbonyl)-octahydro-cyclobutadiene[1,2-c;3,4-c′]dipyrrolo-2-yl]-(4-methyl-quinolin-2-yl)-methyl ketone; [(3aR,3bS,6aR,6bS)-5-(1H-benzotriazol-5-carbonyl)-octahydro-cyclobutadiene[1,2-c;3,4-c′]dipyrrole-2-yl]-(5-chloro-1H-indole-2-yl)-methyl ketone; [(3aS,3bS,6aR,6bR)-5-(1H-benzotriazol-5-carbonyl)-octahydro-cyclobutadiene[1,2-c;3,4-c′]dipyrrole-2-yl]-[4-(2-methoxy-ethoxy)-naphth-2-yl]-methyl ketone; [(3aS,3bS,6aR,6bR)-5-(1H-benzotriazol-5-carbonyl)-octahydro-cyclobutadiene[1,2-c;3,4-c′]dipyrrolo-2-yl]-(7-phenyl-naphth-2-yl)-methyl ketone; [(3aS,3bS,6aR,6bR)-5-(1H-benzotriazol-5-carbonyl)-octahydro-cyclobutadiene[1,2-c;3,4-c′]dipyrrole-2-yl]-(4-ethoxy-naphth-2-yl)-methyl ketone; [(3aS,3bS,6aR,6bR)-5-(1H-benzotriazol-5-carbonyl)-octahydro-cyclobutadiene[1,2-c;3,4-c′]dipyrrolo-2-yl]-(4-isopropoxy-naphth-2-yl)-methyl ketone; [(3aS,3bS,6aR,6bR)-5-(1H-benzotriazol-5-carbonyl)-octahydro-cyclobutadiene[1,2-c;3,4-c′]dipyrrole-2-yl]-(4-benzyloxy-1H-indole-6-yl)-methyl ketone; [(3aS,3bS,6aR,6bR)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobutadiene[1,2-c;3,4-c′]dipyrrole-2-yl]-(5,6,7,8-tetrahydro-naphth-2-yl)-methyl ketone; [(3aS,3bR,6aS,6bR)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobutadiene[1,2-c;3,4-c′]dipyrrole-2-yl]-(4,4-dimethyl-1,2,3,4-tetrahydro-naphth-2-yl)-methyl ketone; [(3aS,3bR,6aS,6bR)-5-(1H-benzotriazol-5-carbonyl)-octahydro-cyclobutadiene[1,2-c;3,4-c′]dipyrrole-2-yl]-[1-(3-methoxy-propyl)-1,2,3,4-tetrahydro-quinoline-3-yl]-methyl ketone; [(3aR,3bS,6aR,6bS)-5-(1H-benzotriazol-5-carbonyl)-octahydro-cyclobutadiene[1,2-c;3,4-c′]dipyrrole-2-yl]-[1-(2-methoxy-ethoxy)-isoquinoline-3-yl]-methyl ketone; [(3aR,3bS,6aR,6bS)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobutadiene[1,2-c;3,4-c′]dipyrrole-2-yl]-(1-cyclopropylmethoxy-isoquinoline-3-yl)-methyl ketone; (4-Isopropoxy-naphth-2-yl)-[(3aR,3bS,6aR,6bS)-5-((R)-4,5,6,7-tetrahydro-1H-benzotriazole-5-carbonyl)-octahydro-cyclobutadiene[1,2-c;3,4-c′]dipyrrole-2-yl]-methyl ketone; [(3aR,3bS,6aR,6bS)-5-(1H-benzotriazol-5-carbonyl)-octahydro-cyclobutadiene[1,2-c;3,4-c′]dipyrrole-2-yl]-[1-(2,2,2-trifluoroethoxy)-isoquinoline-3-yl]-methyl ketone; [(3aS,3bS,6aR,6bR)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobutadiene[1,2-c;3,4-c′]dipyrrole-2-yl]-(4-isopropoxy-1H-indole-6-yl)-methyl ketone; 4-[(3aS, 3bS, 6aR, 6bR)-5-(4-isopropoxy-naphthalene-2-carbonyl)-octahydro-cyclobutadiene[1,2-c; 3,4-c′]dipyrrole-2-carbonyl]-benzenesulfonamide; [6-(4-chloro-phenyl)-pyridin-3-yl]-[(3aR,3bS,6aR,6bS)-5-((R)-4,5,6,7-tetrahydro-1H-benzotriazole-5-carbonyl)-octahydro-cyclobutadiene[1,2-c;3,4-c′]dipyrrole-2-yl]-methyl ketone; (1-Cyclopropylmethoxy-isoquinoline-3-yl)-[(3aR,3bS,6aR,6bS)-5-((R)-4,5,6,7-tetrahydro-1H-benzotriazole-5-carbonyl)-octahydro-cyclobutadiene[1,2-c;3,4-c′]dipyrrole-2-yl]-methyl ketone; [(3aS,3bS,6aR,6bR)-5-(1H-benzotriazol-5-carbonyl)-octahydro-cyclobutadiene[1,2-c;3,4-c′]dipyrrolo-2-yl]-(4-isopropoxy-1-methyl-1H-indole-6-yl)-methyl ketone; [(3aR,3bS,6aR,6bS)-5-(1H-benzotriazol-5-carbonyl)-octahydro-cyclobutadiene[1,2-c;3,4-c′]dipyrrolo-2-yl]-(4-ethoxy-quinoline-2-yl)-methyl ketone; [(3aR,3bS,6aR,6bS)-5-(1H-benzotriazol-5-carbonyl)-octahydro-cyclobutadiene[1,2-c;3,4-c′]dipyrrolo-2-yl]-(4-isopropoxy-quinolin-2-yl)-methyl ketone; [(3aS,3bS,6aR,6bR)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobutadiene[1,2-c;3,4-c′]dipyrrole-2-yl]-(6-chloro-9H-carbazole-2-yl)-methyl ketone; [(3aR,3bS,6aR,6bS)-5-(1H-benzotriazol-5-carbonyl)-octahydro-cyclobutadiene[1,2-c;3,4-c′]dipyrrole-2-yl]-[4-(2-methoxy-ethoxy)-quinoline-2-yl]-methyl ketone; [(3aR,3bS,6aR,6bS)-5-(1H-benzotriazol-5-carbonyl)-octahydro-cyclobutadiene[1,2-c;3,4-c′]dipyrrole-2-yl]-(4-isopropoxy-7-trifluoromethyl-quinoline-2-yl)-methyl ketone; [(3aR,3bS,6aR,6bS)-5-(1H-benzotriazol-5-carbonyl)-octahydro-cyclobutadiene[1,2-c;3,4-c′]dipyrrole-2-yl]-(4-cyclopropylmethoxy-quinoline-2-yl)-methyl ketone; [(3aR,3bS,6aR,6bS)-5-(1H-benzotriazol-5-carbonyl)-octahydro-cyclobutadiene[1,2-c;3,4-c′]dipyrrolo-2-yl]-[5-(4-chloro-phenyl)pyridin-2-yl]-methyl ketone; [(3aR,3bS,6aR,6bS)-5-(1H-benzotriazol-5-carbonyl)-octahydro-cyclobutadiene[1,2-c;3,4-c′]dipyrrolo-2-yl]-(1-ethoxy-isoquinoline-3-yl)-methyl ketone; [(3aS,3bS,6aR,6bR)-5-(1H-benzotriazol-5-carbonyl)-octahydro-cyclobutadiene[1,2-c;3,4-c′]dipyrrolo-2-yl]-(1-ethyl-4-isopropoxy-1H-indole-6-yl)-methyl ketone; 6-[(3aR,3bS,6aR,6bS)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobutadiene[1,2-c;3,4-c′]dipyrrole-2-carbonyl]-3-(4-chloro-phenyl)-1H-pyridin-2-one; 1-[(3aR,3bS,6aR,6bS)-5-(1H-benzotriazol-5-carbonyl)-octahydro-cyclobutadiene[1,2-c;3,4-c′]dipyrrole-2-yl]-(7-chloro-4-ethoxy-quinoline-2-yl)-methyl ketone; (7-Chloro-4-ethoxy-quinoline-2-yl)-[(3aR,3bS,6aR,6bS)-5-((R)-4,5,6,7-tetrahydro-1H-benzotriazol-5-carbonyl)-octahydro-cyclobutadiene[1,2-c;3,4-c′]dipyrrole-2-yl] ketone; [(3aS,3bS,6aR,6bR)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobutadiene[1,2-c;3,4-c′]dipyrrole-2-yl]-(4-isopropoxy-5,6,7,8-tetrahydro-naphth-2-yl)-methyl ketone; (1H-benzotriazol-5-yl)-{(3aS,3bR,6aS,6bR)-5-[4-(2-methoxy-ethoxy)-7-trifluoromethyl-quinoline-2-carbonyl]-octahydro-cyclobutadiene[1,2-c;3,4-c″]dipyrrole-2-yl}-methyl ketone; (1H-benzotriazol-5-yl)-[(3aS,3bR,6aS,6bR)-5-(4-ethoxy-6-trifluoromethyl-quinoline-2-carbonyl)-octahydro-cyclobutadiene[1,2-c;3,4-c′]dipyrrole-2-yl]-methyl ketone; [(3aS,3bS,6aR,6bR)-5-(1H-benzotriazol-5-carbonyl)-octahydro-cyclobutadiene[1,2-c;3,4-c′]dipyrrole-2-yl]-(4-ethoxy-1-ethyl-1H-indole-5-yl)-methyl ketone; [(3aS,3bS,6aR,6bR)-5-(1H-benzotriazol-5-carbonyl)-octahydro-cyclobutadiene[1,2-c;3,4-c′]dipyrrole-2-yl]-[1-ethyl-4-(2,2,2-trifluoroethoxy)-1H-indol-5-yl]-methyl ketone; 5-[(3aS, 3bR, 6aS, 6bR)-5-(4-ethoxy-quinoline-2-carbonyl)-octahydro-cyclobutadiene[1,2-c; 3,4-c′]dipyrrole-2-carbonyl]-pyridine-2-sulfonic acid amide; (1H-benzotriazol-5-yl)-{(3aS, 3bR, 6aS, 6bR)-5-[4-(2,2,2-trifluoro-ethoxy)-quinoline-2-carbonyl]-octahydro-cyclobutadiene[1,2-c;3,4-c′]dipyrrole-2-yl}-methyl ketone; (1H-benzotriazol-5-yl)-{(3aS,3bS,6aR,6bR)-5-[4-ethoxy-1-(2,2,2-trifluoro-ethyl)-1H-indole-6-carbonyl]-octahydro-cyclobutadiene[1,2-c;3,4-c′]dipyrrole-2-yl}-methyl ketone; (1H-benzotriazol-5-yl)-[(3aS,3bR,6aS,6bR)-5-(5-chloro-4-cyclopropylmethoxy-pyridine-2-carbonyl)-octahydro-cyclobutadiene[1,2-c;3,4-c′]dipyrrole-2-yl]-methyl ketone; (1H-benzotriazol-5-yl)-[(3aS,3bR,6aS,6bR)-5-(5-cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carbonyl)-octahydro-cyclobutadiene[1,2-c;3,4-c′]dipyrrole-2-yl]-methyl ketone; (1H-benzotriazol-5-yl)-[(3aS,3bR,6aS,6bR)-5-(4-ethoxy-5,6,7,8-tetrahydro-quinoline-2-carbonyl)-octahydro-cyclobutadiene[1,2-c;3,4-c′]dipyrrole-2-yl]-methyl ketone; (1H-benzotriazol-5-yl)-[(3aS,3bS,6aR,6bR)-5-(4′-chloro-biphenyl-3-carbonyl)-octahydro-cyclobutadiene[1,2-c;3,4-c′]dipyrrole-2-yl]-methyl ketone; (1H-benzotriazol-5-yl)-[(3aS,3bR,6aS,6bR)-5-(4-ethoxy-7-methoxy-quinoline-2-carbonyl)-octahydro-cyclobutadiene[1,2-c;3,4-c′]dipyrrole-2-yl]-methyl ketone; [(3aS,3bS,6aR,6bR)-5-(4-ethoxy-6-trifluoromethyl-quinoline-2-carbonyl)-octahydro-cyclobutadiene[1,2-c;3,4-c′]dipyrrolo-2-yl]-(1H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-methyl ketone; [(3aS,3bS,6aR,6bR)-5-(1-ethoxy-isoquinoline-3-carbonyl)-octahydro-cyclobutadiene[1,2-c;3,4-c′]dipyrrolo-2-yl]-(1H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-methyl ketone; (1H-benzotriazol-5-yl)-[(3aS,3bR,6aS,6bR)-5-(6-cyclopropylmethoxy-5-trifluoromethyl-pyridine-2-carbonyl)-octahydro-cyclobutadiene[1,2-c;3,4-c′]dipyrrole-2-yl]-methyl ketone; (1H-benzotriazol-5-yl)-{(3aS, 3bR, 6aS, 6bR)-5-[5-cyclopropyl-4-(2,2,2-trifluoro-ethoxy)-pyridine-2-carbonyl]-octahydro-cyclobutadiene[1,2-c;3,4-c′]dipyrrole-2-yl}-methyl ketone; (1H-benzotriazol-5-yl)-{(3aS,3bR,6aS,6bR)-5-[6-cyclopropyl-5-(2,2,2-trifluoro-ethoxy)-pyridazine-3-carbonyl]-octahydro-cyclobutadiene[1,2-c;3,4-c′]dipyrrolo-2-yl}-methylketone′]dipyrrolo-2-yl}-methylketone; [(3aR,3bS,6aR,6bS)-5-(1H-benzotriazol-5-carbonyl)-octahydro-cyclobutadiene[1,2-c;3,4-c′]dipyrrole-2-yl]-(6-chloro-4-ethoxy-quinoline-2-yl)-methyl ketone; (1H-benzotriazol-5-yl)-{(3aS, 3bR, 6aS, 6bR)-5-[6-(2,2,2-trifluoro-ethoxy)-5-trifluoromethyl-pyridine-2-carbonyl]-octahydro-cyclobutadiene[1,2-c;3,4-c′]dipyrrole-2-yl}-methyl ketone; (1H-benzotriazol-5-yl)-{(3aS, 3bR, 6aS, 6bR)-5-[6-(2,2,2-trifluoro-ethoxy)-pyridin-2-carbonyl]-octahydro-cyclobutadiene[1,2-c;3,4-c′]dipyrrole-2-yl}-methyl ketone; (1H-benzotriazol-5-yl)-{(3aS,3bS,6aR,6bR)-5-[6-(2,2,2-trifluoro-ethoxy)-pyridin-3-carbonyl]-octahydro-cyclobutadiene[1,2-c;3,4-c′]dipyrrole-2-yl}-methyl ketone; (1H-benzotriazol-5-yl)-{(3aS, 3bS, 6aR, 6bR)-5-[5-bromo-6-(2,2,2-trifluoro-ethoxy)-pyridin-3-carbonyl]-octahydro-cyclobutadiene[1,2-c;3,4-c′]dipyrrole-2-yl}-methyl ketone; (1H-benzotriazol-5-yl)-{(3aS, 3bR, 6aS, 6bR)-5-[5-(2,2,2-trifluoro-ethoxy)-pyridin-2-carbonyl]-octahydro-cyclobutadiene[1,2-c;3,4-c′]dipyrrole-2-yl}-methyl ketone; [(3aS,3bR,6aS,6bR)-5-(6-cyclopropylmethoxy-pyridazine-3-carbonyl)-octahydro-cyclobutadiene[1,2-c;3,4-c′]dipyrrole-2-yl]-(1H-benzotriazol-5-yl)-methyl ketone; (1H-benzotriazol-5-yl)-{(3aS, 3bS, 6aR, 6bR)-5-[5-bromo-2-methyl-6-(2,2,2-trifluoro-ethoxy)-pyridine-3-carbonyl]-octahydro-cyclobutadiene[1,2-c;3,4-c′]dipyrrole-2-yl}-methyl ketone; (1H-benzotriazol-5-yl)-{(3aS, 3bS, 6aR, 6bR)-5-[5-cyclopropyl-6-(2,2,2-trifluoro-ethoxy)-pyridine-3-carbonyl]-octahydro-cyclobutadiene[1,2-c;3,4-c′]dipyrrole-2-yl}-methyl ketone; (1H-benzotriazol-5-yl)-{(3aS, 3bS, 6aR, 6bR)-5-[6-(2,2,2-trifluoro-ethoxy)-5-trifluoromethyl-pyridine-3-carbonyl]-octahydro-cyclobutadiene[1,2-c;3,4-c′]dipyrrole-2-yl}-methyl ketone; (1H-benzotriazol-5-yl)-{(3aS, 3bS, 6aR, 6bR)-5-[5-(tetrahydro-pyran-4-yl)-6-(2,2,2-trifluoro-ethoxy)-pyridin-3-carbonyl]-octahydro-cyclobutadiene[1,2-c;3,4-c′]dipyrrole-2-yl}-methyl ketone; (1H-benzotriazol-5-yl)-{(3aS,3bR,6aS,6bR)-5-[4-(4-chloro-phenyl)-5-(2,2,2-trifluoro-ethoxy)-pyridine-2-carbonyl]-octahydro-cyclobutadiene[1,2-c;3,4-c′]dipyrrole-2-yl}-methyl ketone; (1H-benzotriazol-5-yl)-{(3aS,3bS,6aR,6bR)-5-[5-furan-2-yl-6-(2,2,2-trifluoro-ethoxy)-pyridin-3-carbonyl]-octahydro-cyclobutadiene[1,2-c;3,4-c′]dipyrrole-2-yl}-methyl ketone; (1H-benzotriazol-5-yl)-{(3aS,3bS,6aR,6bR)-5-[5-chloro-6-(2,2,2-trifluoro-ethoxy)-pyridin-3-carbonyl]-octahydro-cyclobutadiene[1,2-c;3,4-c′]dipyrrole-2-yl}-methyl ketone; [(3aS,3bR,6aS,6bR)-5-(4-ethoxy-quinoline-2-carbonyl)-octahydro-cyclobutadiene[1,2-c;3,4-c′]dipyrrole-2-yl]-(4-fluoro-1H-benzotriazol-5-yl)-methyl ketone; {(3aS,3bS,6aR,6bR)-5-[5-methanesulfonyl-6-(2,2,2-trifluoro-ethoxy)-pyridine-3-carbonyl]-octahydro-cyclobutadiene[1,2-c;3,4-c′]dipyrrole-2-yl}-(1H-benzotriazol-5-yl)-methyl ketone; (3aR,3bS,6aR,6bS)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobutadiene[1,2-c;3,4-c′]dipyrrole-2-carboxylic acid 4-trifluoromethoxy-benzyl ester; (3aR,3bS,6aR,6bS)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobutadiene[1,2-c;3,4-c′]dipyrrole-2-carboxylic acid 3,5-dichloro-benzyl ester; (1H-benzotriazol-5-yl)-[(3aS,3bR,6aS,6bR)-5-(4′-fluoro-biphenyl-4-sulfonyl)-octahydro-cyclobutadiene[1,2-c;3,4-c′]dipyrrole-2-yl]-methyl ketone; (1H-benzotriazol-5-yl)-[(3aS,3bR,6aS,6bR)-5-(6-chloro-naphthyl-2-sulfonyl)-octahydro-cyclobutadiene[1,2-c;3,4-c′]dipyrrole-2-yl]-methyl ketone; [(3aR,3bS,6aR,6bS)-5-(1H-benzotriazol-5-carbonyl)-octahydro-cyclobutadiene[1,2-c;3,4-c′]dipyrrolo-2-yl]-(6-trifluoromethyl-3,4-dihydro-1H-isoquinoline-2-yl)-methyl ketone; And its medicinal salts. 17. The compound according to claim 1, wherein the compound is selected from... (E)-1-[(3aS,3bR,6aS,6bR)-5-(1H-benzotriazol-5-carbonyl)-octahydro-cyclobutadiene[1,2-c;3,4-c′]dipyrrolo-2-yl]-3-(4-trifluoromethoxy-phenyl)-propenone; (4-Isopropoxy-naphth-2-yl)-[(3aR,3bS,6aR,6bS)-5-((R)-4,5,6,7-tetrahydro-1H-benzotriazole-5-carbonyl)-octahydro-cyclobutadiene[1,2-c;3,4-c′]dipyrrole-2-yl]-methyl ketone; 4-[(3aS, 3bS, 6aR, 6bR)-5-(4-isopropoxy-naphthalene-2-carbonyl)-octahydro-cyclobutadiene[1,2-c; 3,4-c′]dipyrrole-2-carbonyl]-benzenesulfonamide; [(3aS,3bS,6aR,6bR)-5-(1H-benzotriazol-5-carbonyl)-octahydro-cyclobutadiene[1,2-c;3,4-c′]dipyrrolo-2-yl]-(4-isopropoxy-1-methyl-1H-indole-6-yl)-methyl ketone; [(3aR,3bS,6aR,6bS)-5-(1H-benzotriazol-5-carbonyl)-octahydro-cyclobutadiene[1,2-c;3,4-c′]dipyrrole-2-yl]-[4-(2-methoxy-ethoxy)-quinoline-2-yl]-methyl ketone; (1H-benzotriazol-5-yl)-{(3aS,3bS,6aR,6bR)-5-[5-bromo-6-(2,2,2-trifluoro-ethoxy)-pyridine-3-carbonyl]-octahydro-cyclobutadiene[1,2-c;3,4-c′]dipyrrole-2-yl}-methyl ketone; (3aR,3bS,6aR,6bS)-5-(1H-benzotriazole-5-carbonyl)-octahydro-cyclobutadiene[1,2-c;3,4-c′]dipyrrole-2-carboxylic acid 4-trifluoromethoxy-benzyl ester; And its medicinal salts. 18. A method for preparing a compound according to any one of claims 1 to 17, the method comprising a reaction in the presence of a compound of formula (III) and a compound of formula (II), wherein ^R1 , ^R2 and Y are as defined in any one of claims 1 to 17. 19. A pharmaceutical composition comprising the compound according to any one of claims 1 to 17 and a therapeutically inert carrier. 20. Use of the compound according to any one of claims 1 to 17 for the preparation of a medicament for the treatment or prevention of kidney disease, liver disease, inflammatory disease, nervous system disease, respiratory system disease, vascular and cardiovascular disease, fibrotic disease, cancer, eye disease, metabolic disease, cholestasis and other forms of chronic pruritus, and acute and chronic organ transplant rejection.