HK1226403B - Condensed [1,4]diazepine compounds as autotaxin (atx) and lysophosphatidic acid (lpa) production inhibitors - Google Patents

Description

Condensed [1,4]diazepine compounds as inhibitors of autotaxin (ATX) and lysophosphatidic acid (LPA) production

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, inflammatory disorders, 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 alkyl, haloalkyl, substituted cycloalkyl, substituted cycloalkylalkyl, substituted phenyl, substituted phenylalkyl, substituted phenoxyalkyl, substituted phenylalkoxy, substituted phenylcycloalkyl, substituted phenylalkenyl, substituted phenylalkynyl, substituted pyridyl, substituted pyridylalkyl, substituted pyridylalkenyl, substituted pyridylalkynyl, substituted thienyl, substituted thienylalkyl, substituted thienylalkenyl, substituted thienylalkynyl, substituted 2,3-dihydro-1H-isoindol-2-yl, substituted 1H-indol-2-yl, or substituted benzofuran- 2-yl, wherein substituted cycloalkyl, substituted cycloalkylalkyl, substituted phenyl, substituted phenylalkyl, substituted phenoxyalkyl, substituted phenylalkoxy, substituted phenylcycloalkyl, substituted phenylalkenyl, substituted phenylalkynyl, substituted pyridyl, substituted pyridylalkyl, substituted pyridylalkenyl, substituted pyridylalkynyl, substituted thienyl, substituted thienylalkyl, substituted thienylalkenyl, substituted thienylalkynyl, substituted 2,3-dihydro-1H-isoindol-2-yl, substituted 1H-indol-2-yl, and substituted benzofuran-2-yl are substituted with R ³ , R ⁴ , and R ⁵ ;

A ¹ is -N- or -CR ⁷ -;

A ² is -N- or -CR ⁸ - and at least one of A ¹ and A ² is -N-;

^R2 is selected from the ring systems A, B, C, D, E, F, G, H, I, K and L.

R ³ , R ⁴ and R ⁵ are independently selected from H, alkyl, hydroxyalkyl, haloalkyl, hydroxyhaloalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkoxy, cycloalkyloxy, cycloalkyloxyalkyl, cycloalkylalkoxyalkyl, alkoxy, alkoxyalkyl, haloalkoxy, alkoxyhaloalkyl, alkoxyalkoxy, alkoxyalkoxyalkyl, heterocycloalkylalkoxy, phenyl, substituted phenyl, pyridyl, substituted pyridyl, halogen, hydroxy, cyano, alkylsulfanyl, haloalkylsulfanyl, cycloalkylsulfanyl, alkylsulfinyl, haloalkylsulfinyl, cycloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl, cycloalkylsulfonyl, alkylcarbonylamino, substituted aminosulfonyl, substituted amino, and substituted aminoalkyl, wherein substituted aminosulfonyl, substituted amino, and substituted aminoalkyl are substituted on the nitrogen atom with one to two substituents independently selected from H, alkyl, cycloalkyl, cycloalkylalkyl, hydroxyalkyl, alkoxyalkyl, alkylcarbonyl, and cycloalkylcarbonyl, and wherein substituted phenyl and substituted pyridyl are optionally substituted with one to three substituents independently selected from alkyl, halo, haloalkyl, alkoxy, and haloalkoxy;

^R6 is H, alkyl, haloalkyl or cycloalkyl;

R ⁷ and R ⁸ are independently selected from H, alkyl, haloalkyl or cycloalkyl;

or 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 prototype 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 the prototype 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 large number of different 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 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, inflammatory conditions, 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, inflammatory conditions, 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 group of the formula -O-R', wherein R' is an alkyl group. Examples of alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, and tert-butoxy. Particular alkoxy groups include 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. Particular alkoxyalkoxy groups include methoxymethoxy and 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. Particular alkoxyalkyl groups include methoxymethyl, methoxyethyl, and isopropoxymethyl.

The term "alkoxycarbonyl" refers to a group of the formula -C(O)-R', wherein R' is an alkoxy group. Examples of alkoxycarbonyl groups include groups of the formula -C(O)-R', wherein R' is methoxy or ethoxy. Particular alkoxycarbonyl groups include groups of the formula -C(O)-R', wherein R' is methoxy.

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, sec-butyl, tert-butyl, and pentyl. Particular alkyl radicals include methyl, ethyl, propyl, and isopropyl. More particular alkyl radicals are ethyl and isopropyl.

The term "alkylcarbonyl" refers to a group of the formula -C(O)-R', wherein R' is an alkyl group. Examples of alkylcarbonyl groups include groups of the formula -C(O)-R', wherein R' is a methyl group or an ethyl group. Particular alkylcarbonyl groups include groups of the formula -C(O)-R', wherein R' is a methyl group.

The term "alkylcarbonylamino" refers to a radical of the formula -NH-C(O)-R', wherein R' is alkyl. Examples of alkylcarbonylamino radicals include radicals of the formula -NH-C(O)-R', wherein R' is methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, or pentyl. Particular alkylcarbonylamino radicals include radicals of the formula -NH-C(O)-R', wherein R' is tert-butyl.

The term "alkylsulfanyl" refers to a radical of the formula -S-R', wherein R' is an alkyl group. Examples of alkylsulfanyl groups include radicals of the formula -S-R', wherein R' is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or tert-butyl. Particular alkylsulfanyl groups include radicals of the formula -S-R', wherein R' is methyl.

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

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

The term "alkylsulfonylamino" refers to a radical of the formula -NH-S(O) ₂ -R', wherein R' is an alkyl group. Examples of alkylsulfonylamino radicals include radicals of the formula -NH-S(O) ₂ -R', wherein R' is a methyl group or an ethyl group. Particular alkylsulfonylamino radicals include radicals of the formula -NH-S(O) ₂ -R', wherein R' is a methyl group.

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

The term "aminoalkyl" refers to an alkyl group in which at least one of the hydrogen atoms of the alkyl group is replaced by an amino group. Examples of aminoalkyl groups include aminomethyl, aminoethyl, amino-1-methyl-ethyl, aminopropyl, aminomethylpropyl, and aminopropyl. Particular examples are aminomethyl and aminoethyl.

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

The term "carbonyl" refers to a -C(O)- group.

The term "carboxy" refers to a -COOH group.

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

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.

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 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 "cycloalkylcarbonyl" is of the formula -C(O)-R', wherein R' is cycloalkyl. Examples of cycloalkylcarbonyl groups include groups of the formula -C(O)-R', wherein R' is cyclopropyl.

The term "cycloalkylsulfanyl" refers to a radical of the formula -S-R', wherein R' is a cycloalkyl radical. Examples of cycloalkylsulfanyl radicals include radicals of the formula -S-R', wherein R' is a cyclopropyl radical.

The term "cycloalkylsulfinyl" refers to a radical of the formula -S(O)-R', wherein R' is a cycloalkyl radical. Examples of cycloalkylsulfinyl radicals include radicals of the formula -S(O)-R', wherein R' is a cyclopropyl radical.

The term "cycloalkylsulfonyl" denotes a radical of the formula -S(O) ₂ -R', wherein R' is a cycloalkyl. Examples of cycloalkylsulfonyl include radicals of the formula -S(O) ₂ -R', wherein R' is a cyclopropyl.

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. A particular haloalkoxy group is trifluoromethoxy.

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. A particular haloalkyl group is trifluoromethyl.

The term "haloalkylsulfanyl" refers to a radical of the formula -S-R', wherein R' is a haloalkyl radical. Examples of haloalkylsulfanyl radicals include radicals of the formula -S-R', wherein R' is a trifluoromethyl radical.

The term "haloalkylsulfinyl" refers to a group of the formula -S(O)-R', wherein R' is a haloalkyl. Examples of haloalkylsulfinyl groups include groups of the formula -S(O)-R', wherein R' is a trifluoromethyl group.

The term "haloalkylsulfonyl" denotes a radical of the formula -S(O) ₂ -R', wherein R' is a haloalkyl. Examples of haloalkylsulfonyl include radicals of the formula -S(O) ₂ -R', wherein R' is trifluoromethyl.

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

The term "heterocycloalkyl" refers to a monovalent saturated or partially unsaturated mono- or bicyclic ring system of 4 to 9 ring atoms comprising 1, 2 or 3 ring heteroatoms selected from N, O and S, wherein the remaining ring atoms are carbon. Bicyclic means consisting of two rings with two common ring atoms, i.e., the bridge separating the two rings is a single bond or a chain of one or two ring atoms. Examples of monocyclic saturated heterocycloalkyls are 4,5-dihydro-oxazolyls, oxetanes, azetidinyls, pyrrolidinyls, 2-oxo-pyrrolidin-3-yls, tetrahydrofuranyls, tetrahydro-thienyls, pyrazolidinyls, imidazolidinyls, oxazolidinyls, isoxazolidinyls, thiazolidinyls, piperidinyls, tetrahydropyranyls, tetrahydrothiopyranyls, piperazinyls, morpholinyls, thiomorpholinyls, 1,1-dioxo-thiomorpholinyls, azepanyls, diazepanyls, homopiperazinyls or oxazepanyls. Examples of bicyclic saturated heterocycloalkyls are 8-aza-bicyclo[3.2.1]octyl, quinuclidinyl, 8-oxa-3-aza-bicyclo[3.2.1]octyl, 9-aza-bicyclo[3.3.1]nonyl, 3-oxa-9-aza-bicyclo[3.3.1]nonyl, or 3-thia-9-aza-bicyclo[3.3.1]nonyl. Examples of partially unsaturated heterocycloalkyls are dihydrofuranyl, imidazolinyl, dihydro-oxazolyl, tetrahydro-pyridinyl, or dihydropyranyl. A particular example of a heterocycloalkyl is tetrahydropyranyl.

The term "heterocycloalkylalkoxy" refers to an alkoxy group in which at least one of the hydrogen atoms of the alkoxy group is replaced by a heterocycloalkyl group. Examples of heterocycloalkylalkoxy groups include tetrahydropyranylmethoxy, tetrahydrofuranylmethoxy, oxetanylmethoxy, tetrahydropyranylethoxy, tetrahydrofuranylethoxy, and oxetanylethoxy. A particular heterocycloalkylalkoxy group is tetrahydropyranylmethoxy.

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 "naphthylalkenyl" refers to an alkenyl group wherein at least one of the hydrogen atoms of the alkenyl group is replaced by a naphthyl group. A particular naphthylalkenyl group is naphthylethenyl.

The term "naphthylalkyl" denotes an alkyl group wherein at least one of the hydrogen atoms of the alkyl group is replaced by a naphthyl group. Particular naphthylalkyl groups are naphthylmethyl, naphthylethyl and naphthylpropyl.

The term "naphthyloxyalkyl" refers to an alkyl group in which at least one of the hydrogen atoms of the alkyl group is replaced by a naphthyloxy group. Exemplary naphthyloxyalkyl groups include naphthyloxymethyl, naphthyloxyethyl, and naphthyloxypropyl.

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 is 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, phenylethoxy, and phenylpropoxy. 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. Even more particular phenylalkyl group is phenethyl.

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 "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, and the like. Particular pharmaceutically acceptable salts of the compounds of formula (I) are the hydrochloride, methanesulfonate, and citrate 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 as it relates to 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 or Z), 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 μM 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.

Another embodiment of the present invention are compounds according to formula (I) as described above, wherein

^R1 is alkyl, haloalkyl, substituted cycloalkyl, substituted cycloalkylalkyl, substituted phenyl, substituted phenylalkyl, substituted phenoxyalkyl, substituted phenylalkoxy, substituted phenylcycloalkyl, substituted phenylalkenyl, substituted phenylalkynyl, substituted pyridyl, substituted pyridylalkyl, substituted pyridylalkenyl, substituted pyridylalkynyl, substituted thienyl, substituted thienylalkyl, substituted thienylalkenyl, substituted thienylalkynyl, substituted 2,3-dihydro-1H-isoindol-2-yl, substituted 1H-indol-2-yl, or substituted benzofuran- 2-yl, wherein substituted cycloalkyl, substituted cycloalkylalkyl, substituted phenyl, substituted phenylalkyl, substituted phenoxyalkyl, substituted phenylalkoxy, substituted phenylcycloalkyl, substituted phenylalkenyl, substituted phenylalkynyl, substituted pyridyl, substituted pyridylalkyl, substituted pyridylalkenyl, substituted pyridylalkynyl, substituted thienyl, substituted thienylalkyl, substituted thienylalkenyl, substituted thienylalkynyl, substituted 2,3-dihydro-1H-isoindol-2-yl, substituted 1H-indol-2-yl, and substituted benzofuran-2-yl are substituted with R ³ , R ⁴ , and R ⁵ ;

A ¹ is -N- or -CR ⁷ -;

A ² is -N- or -CR ⁸ - and at least one of A ¹ and A ² is -N-;

^R2 is selected from the ring systems A, B, C, D, E, F, G, H, I, K and L.

^R3 , ^R4 and ^R5 are independently selected from H, alkyl, hydroxyalkyl, haloalkyl, hydroxyhaloalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkoxy, cycloalkyloxy, cycloalkyloxyalkyl, cycloalkylalkoxyalkyl, alkoxy, alkoxyalkyl, haloalkoxy, alkoxyhaloalkyl, alkoxyalkoxy, alkoxyalkoxyalkyl, phenyl, substituted phenyl, pyridyl, substituted pyridyl, halogen, hydroxy, cyano, alkylsulfanyl, haloalkylsulfanyl, cycloalkylsulfanyl, alkylsulfinyl, haloalkylsulfinyl, cycloalkylsulfinyl, alkylsulfonyl alkyl, halogenated alkylsulfonyl, cycloalkylsulfonyl, alkylcarbonylamino, substituted aminosulfonyl, substituted amino, and substituted aminoalkyl, wherein the substituted aminosulfonyl, substituted amino, and substituted aminoalkyl are substituted on the nitrogen atom with one to two substituents independently selected from H, alkyl, cycloalkyl, cycloalkylalkyl, hydroxyalkyl, alkoxyalkyl, alkylcarbonyl, and cycloalkylcarbonyl, and wherein substituted phenyl and substituted pyridyl are optionally substituted with one to three substituents independently selected from alkyl, halogen, haloalkyl, alkoxy, and haloalkoxy;

^R6 is H, alkyl, haloalkyl or cycloalkyl;

R ⁷ and R ⁸ are independently selected from H, alkyl, haloalkyl or cycloalkyl;

or pharmaceutically acceptable salts.

Another embodiment of the present invention are compounds according to formula (I) as described herein, wherein ^R1 is substituted phenylalkyl, substituted phenoxyalkyl or substituted phenylalkoxy, wherein substituted phenylalkyl, substituted phenoxyalkyl and substituted phenylalkoxy are substituted with ^R3 , ^R4 and ^R5 .

A particular embodiment of the present invention are compounds according to formula (I) as described herein, wherein ^R1 is substituted phenoxyalkyl or substituted phenylalkoxy, wherein substituted phenoxyalkyl and substituted phenylalkoxy are substituted with ^R3 , ^R4 and ^R5 .

A further particular embodiment of the present invention are compounds according to formula (I) as described herein, wherein ^R1 is phenylalkoxy substituted with ^R3 , ^R4 and ^R5 .

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

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

A further embodiment of the present invention are compounds according to formula (I) as described herein, wherein A ¹ is -N- and A ² is -N- or -CR ⁸ -.

Another further embodiment of the present invention are compounds according to formula (I) as described herein, wherein ^R3 , ^R4 and ^R5 are independently selected from H, alkyl, cycloalkyl, heterocycloalkylalkoxy, haloalkoxy, halogen, cyano and alkylcarbonylamino.

A particular embodiment of the present invention are compounds according to formula (I) as described herein, wherein ^R3 , ^R4 and ^R5 are independently selected from H, alkyl, cycloalkyl, haloalkoxy, halogen, cyano and alkylcarbonylamino.

Another particular embodiment of the present invention are compounds according to formula (I) as described herein, wherein R ³ is heterocycloalkylalkoxy, haloalkoxy or cyano.

A further particular embodiment of the present invention are compounds according to formula (I) as described herein, wherein R ³ is haloalkoxy or cyano.

Another particular embodiment of the present invention are compounds according to formula (I) as described herein, wherein ^R4 is H, alkyl, cycloalkyl or halogen.

A further particular embodiment of the present invention are compounds according to formula (I) as described herein, wherein R ⁴ is H, alkyl or halogen.

Also an embodiment of the present invention are compounds according to formula (I) as described herein, wherein R ⁵ is H.

Another embodiment of the present invention are compounds according to formula (I) as described herein, wherein R ⁷ is H.

Another 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 consisting of

R ¹ is a substituted phenylalkoxy group, which is substituted by R ³ , R ⁴ and R ⁵ ;

A ¹ is -N-;

A ² is -N- or -CR ⁸ -;

^R2 is ring system A.

^R3 is a haloalkoxy group or a cyano group;

^R4 is H or halogen;

^R5 is H;

R ⁸ is H;

or pharmaceutically acceptable salts.

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

Benzyl 2-(1,4,6,7-tetrahydrotriazolo[4,5-c]pyridine-5-carbonyl)-4,5,7,8-tetrahydropyrazolo[1,5-d][1,4]diazepine-6-carboxylate;

Benzyl 2-(1,4,6,7-tetrahydrotriazolo[4,5-c]pyridine-5-carbonyl)-5,6,8,9-tetrahydroimidazo[1,2-d][1,4]diazepine-7-carboxylate;

[3-Fluoro-4-(trifluoromethoxy)phenyl]methyl 2-(1,4,6,7-tetrahydrotriazolo[4,5-c]pyridine-5-carbonyl)-4,5,7,8-tetrahydropyrazolo[1,5-d][1,4]diazepine-6-carboxylate;

2-Fluoro-4-(trifluoromethoxy)benzyl 2-(4,5,6,7-tetrahydro-1H-[1,2,3]triazolo[4,5-c]pyridine-5-carbonyl)-7,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepine-6(5H)-carboxylate;

[4-(trifluoromethoxy)phenyl]methyl 2-(1,4,6,7-tetrahydrotriazolo[4,5-c]pyridine-5-carbonyl)-4,5,7,8-tetrahydropyrazolo[1,5-d][1,4]diazepine-6-carboxylate;

4-Cyanobenzyl 2-(4,5,6,7-tetrahydro-1H-[1,2,3]triazolo[4,5-c]pyridine-5-carbonyl)-7,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepine-6(5H)-carboxylate;

4-Cyano-3-fluorobenzyl 2-(4,5,6,7-tetrahydro-1H-[1,2,3]triazolo[4,5-c]pyridine-5-carbonyl)-7,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepine-6(5H)-carboxylate;

4-Cyano-2-fluorobenzyl 2-(4,5,6,7-tetrahydro-1H-[1,2,3]triazolo[4,5-c]pyridine-5-carbonyl)-7,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepine-6(5H)-carboxylate;

(4-cyano-2-propan-2-ylphenyl)methyl 2-(1,4,6,7-tetrahydrotriazolo[4,5-c]pyridine-5-carbonyl)-4,5,7,8-tetrahydropyrazolo[1,5-d][1,4]diazepine-6-carboxylate;

[4-cyano-2-(2,2-dimethylpropionylamino)phenyl]methyl 2-(1,4,6,7-tetrahydrotriazolo[4,5-c]pyridine-5-carbonyl)-4,5,7,8-tetrahydropyrazolo[1,5-d][1,4]diazepine-6-carboxylate;

[4-(trifluoromethoxy)phenyl]methyl 2-(1,4,6,7-tetrahydrotriazolo[4,5-c]pyridine-5-carbonyl)-5,6,8,9-tetrahydro-[1,2,4]triazolo[1,5-d][1,4]diazepine-7-carboxylate;

2-(1,4,6,7-tetrahydrotriazolo[4,5-c]pyridine-5-carbonyl)-5,6,8,9-tetrahydro-[1,2,4]triazolo[1,5-d][1,4]diazepine-7-carboxylic acid [4-cyano-2-(2,2-dimethylpropionylamino)phenyl]methyl ester;

[4-(trifluoromethoxy)phenyl]methyl 2-(1,4,6,7-tetrahydrotriazolo[4,5-c]pyridine-5-carbonyl)-5,6,8,9-tetrahydroimidazo[1,2-d][1,4]diazepine-7-carboxylate;

1-[2-(1,4,6,7-tetrahydrotriazolo[4,5-c]pyridine-5-carbonyl)-4,5,7,8-tetrahydropyrazolo[1,5-d][1,4]diazepin-6-yl]-3-[4-(trifluoromethoxy)phenyl]propan-1-one;

3-cyclopropyl-4-(2-oxo-2-(2-(4,5,6,7-tetrahydro-1H-[1,2,3]triazolo[4,5-c]pyridine-5-carbonyl)-7,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-6(5H)-yl)ethoxy)benzonitrile;

3-ethyl-4-(2-oxo-2-(2-(4,5,6,7-tetrahydro-1H-[1,2,3]triazolo[4,5-c]pyridine-5-carbonyl)-7,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-6(5H)-yl)ethoxy)benzonitrile;

3-tert-Butyl-4-[2-oxo-2-[2-(1,4,6,7-tetrahydrotriazolo[4,5-c]pyridine-5-carbonyl)-4,5,7,8-tetrahydropyrazolo[1,5-d][1,4]diazepin-6-yl]ethoxy]benzonitrile;

and pharmaceutically acceptable salts thereof.

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

3-[3-Fluoro-4-(trifluoromethoxy)phenyl]-1-[2-(1,4,6,7-tetrahydrotriazolo[4,5-c]pyridine-5-carbonyl)-4,5,7,8-tetrahydropyrazolo[1,5-d][1,4]diazepin-6-yl]propan-1-one;

3-(4-Methoxyphenyl)-1-[2-(1,4,6,7-tetrahydrotriazolo[4,5-c]pyridine-5-carbonyl)-4,5,7,8-tetrahydropyrazolo[1,5-d][1,4]diazepin-6-yl]propan-1-one;

1-[2-(1,4,6,7-tetrahydrotriazolo[4,5-c]pyridine-5-carbonyl)-5,6,8,9-tetrahydro-[1,2,4]triazolo[1,5-d][1,4]diazepin-7-yl]-3-[4-(trifluoromethoxy)phenyl]propan-1-one;

3-[3-Fluoro-4-(trifluoromethoxy)phenyl]-1-[2-(1,4,6,7-tetrahydrotriazolo[4,5-c]pyridine-5-carbonyl)-5,6,8,9-tetrahydro-[1,2,4]triazolo[1,5-d][1,4]diazepin-7-yl]propan-1-one;

3-[3-chloro-4-(trifluoromethoxy)phenyl]-1-[2-(1,4,6,7-tetrahydrotriazolo[4,5-c]pyridine-5-carbonyl)-4,5,7,8-tetrahydropyrazolo[1,5-d][1,4]diazepin-6-yl]propan-1-one;

3-[3-chloro-4-(trifluoromethoxy)phenyl]-1-[2-(1,4,6,7-tetrahydrotriazolo[4,5-c]pyridine-5-carbonyl)-5,6,8,9-tetrahydro-[1,2,4]triazolo[1,5-d][1,4]diazepin-7-yl]propan-1-one;

(6-(2-cyclopropyl-6-((tetrahydro-2H-pyran-4-yl)methoxy)isonicotinoyl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl)(6,7-dihydro-1H-[1,2,3]triazolo[4,5-c]pyridin-5(4H)-yl)methanone;

(E)-3-[4-(difluoromethoxy)-3-fluorophenyl]-1-[2-(1,4,6,7-tetrahydrotriazolo[4,5-c]pyridine-5-carbonyl)-4,5,7,8-tetrahydropyrazolo[1,5-d][1,4]diazepin-6-yl]prop-2-en-1-one;

3-[4-(Difluoromethoxy)-3-fluorophenyl]-1-[2-(1,4,6,7-tetrahydrotriazolo[4,5-c]pyridine-5-carbonyl)-4,5,7,8-tetrahydropyrazolo[1,5-d][1,4]diazepin-6-yl]propan-1-one;

4-Methoxybenzyl 2-(4,5,6,7-tetrahydro-1H-[1,2,3]triazolo[4,5-c]pyridine-5-carbonyl)-7,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepine-6(5H)-carboxylate;

4-Fluorobenzyl 2-(4,5,6,7-tetrahydro-1H-[1,2,3]triazolo[4,5-c]pyridine-5-carbonyl)-7,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepine-6(5H)-carboxylate;

3-Fluorobenzyl 2-(4,5,6,7-tetrahydro-1H-[1,2,3]triazolo[4,5-c]pyridine-5-carbonyl)-7,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepine-6(5H)-carboxylate;

(3,4-difluorophenyl)methyl 2-(1,4,6,7-tetrahydrotriazolo[4,5-c]pyridine-5-carbonyl)-4,5,7,8-tetrahydropyrazolo[1,5-d][1,4]diazepine-6-carboxylate;

4-(Difluoromethoxy)-3-fluorobenzyl 2-(4,5,6,7-tetrahydro-1H-[1,2,3]triazolo[4,5-c]pyridine-5-carbonyl)-7,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepine-6(5H)-carboxylate;

3-Fluoro-4-methoxybenzyl 2-(4,5,6,7-tetrahydro-1H-[1,2,3]triazolo[4,5-c]pyridine-5-carbonyl)-7,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepine-6(5H)-carboxylate;

4-Methoxy-2-methylbenzyl 2-(4,5,6,7-tetrahydro-1H-[1,2,3]triazolo[4,5-c]pyridine-5-carbonyl)-7,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepine-6(5H)-carboxylate;

4-Cyclopropylbenzyl 2-(4,5,6,7-tetrahydro-1H-[1,2,3]triazolo[4,5-c]pyridine-5-carbonyl)-7,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepine-6(5H)-carboxylate;

[2-Fluoro-4-(trifluoromethoxy)phenyl]methyl 2-(1,4,6,7-tetrahydrotriazolo[4,5-c]pyridine-5-carbonyl)-5,6,8,9-tetrahydro-[1,2,4]triazolo[1,5-d][1,4]diazepine-7-carboxylate;

[3-Fluoro-4-(trifluoromethoxy)phenyl]methyl 2-(1,4,6,7-tetrahydrotriazolo[4,5-c]pyridine-5-carbonyl)-5,6,8,9-tetrahydro-[1,2,4]triazolo[1,5-d][1,4]diazepine-7-carboxylate;

3-Chloro-4-(trifluoromethoxy)benzyl 2-(4,5,6,7-tetrahydro-1H-[1,2,3]triazolo[4,5-c]pyridine-5-carbonyl)-7,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepine-6(5H)-carboxylate;

2-Methoxy-4-(trifluoromethoxy)benzyl 2-(4,5,6,7-tetrahydro-1H-[1,2,3]triazolo[4,5-c]pyridine-5-carbonyl)-7,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepine-6(5H)-carboxylate;

2-methyl-4-(trifluoromethoxy)benzyl 2-(4,5,6,7-tetrahydro-1H-[1,2,3]triazolo[4,5-c]pyridine-5-carbonyl)-7,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepine-6(5H)-carboxylate;

4-(2,2,2-trifluoroethoxy)benzyl 2-(4,5,6,7-tetrahydro-1H-[1,2,3]triazolo[4,5-c]pyridine-5-carbonyl)-7,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepine-6(5H)-carboxylate;

[3-chloro-4-(trifluoromethoxy)phenyl]methyl 2-(1,4,6,7-tetrahydrotriazolo[4,5-c]pyridine-5-carbonyl)-5,6,8,9-tetrahydro-[1,2,4]triazolo[1,5-d][1,4]diazepine-7-carboxylate;

[3-chloro-4-(trifluoromethoxy)phenyl]methyl 2-(1,4,6,7-tetrahydrotriazolo[4,5-c]pyridine-5-carbonyl)-5,6,8,9-tetrahydroimidazo[1,2-d][1,4]diazepine-7-carboxylate;

3-Fluoro-4-(trifluoromethoxy)benzyl 2-((3aR,7aR)-2-oxooctahedraloxazolo[5,4-c]pyridine-5-carbonyl)-8,9-dihydro-5H-[1,2,4]triazolo[1,5-d][1,4]diazepine-7(6H)-carboxylate;

and pharmaceutically acceptable salts thereof.

Further

3-Fluoro-4-(trifluoromethoxy)benzyl 2-(4,5,6,7-tetrahydro-1H-[1,2,3]triazolo[4,5-c]pyridine-5-carbonyl)-7,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepine-6(5H)-carboxylate;

[4-(trifluoromethoxy)phenyl]methyl 2-(1,4,6,7-tetrahydrotriazolo[4,5-c]pyridine-5-carbonyl)-4,5,7,8-tetrahydropyrazolo[1,5-d][1,4]diazepine-6-carboxylate;

[4-(trifluoromethoxy)phenyl]methyl 2-(1,4,6,7-tetrahydrotriazolo[4,5-c]pyridine-5-carbonyl)-5,6,8,9-tetrahydro-[1,2,4]triazolo[1,5-d][1,4]diazepine-7-carboxylate;

[4-(trifluoromethoxy)phenyl]methyl 2-(1,4,6,7-tetrahydrotriazolo[4,5-c]pyridine-5-carbonyl)-5,6,8,9-tetrahydroimidazo[1,2-d][1,4]diazepine-7-carboxylate;

3-tert-Butyl-4-[2-oxo-2-[2-(1,4,6,7-tetrahydrotriazolo[4,5-c]pyridine-5-carbonyl)-4,5,7,8-tetrahydropyrazolo[1,5-d][1,4]diazepin-6-yl]ethoxy]benzonitrile;

and pharmaceutically acceptable salts thereof.

Furthermore, further particular examples of compounds of formula (I) as described herein are selected from

(6-(2-cyclopropyl-6-((tetrahydro-2H-pyran-4-yl)methoxy)isonicotinoyl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl)(6,7-dihydro-1H-[1,2,3]triazolo[4,5-c]pyridin-5(4H)-yl)methanone;

(E)-3-[4-(difluoromethoxy)-3-fluorophenyl]-1-[2-(1,4,6,7-tetrahydrotriazolo[4,5-c]pyridine-5-carbonyl)-4,5,7,8-tetrahydropyrazolo[1,5-d][1,4]diazepin-6-yl]prop-2-en-1-one;

4-(Difluoromethoxy)-3-fluorobenzyl 2-(4,5,6,7-tetrahydro-1H-[1,2,3]triazolo[4,5-c]pyridine-5-carbonyl)-7,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepine-6(5H)-carboxylate;

[3-Fluoro-4-(trifluoromethoxy)phenyl]methyl 2-(1,4,6,7-tetrahydrotriazolo[4,5-c]pyridine-5-carbonyl)-5,6,8,9-tetrahydro-[1,2,4]triazolo[1,5-d][1,4]diazepine-7-carboxylate;

3-Chloro-4-(trifluoromethoxy)benzyl 2-(4,5,6,7-tetrahydro-1H-[1,2,3]triazolo[4,5-c]pyridine-5-carbonyl)-7,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepine-6(5H)-carboxylate;

2-methyl-4-(trifluoromethoxy)benzyl 2-(4,5,6,7-tetrahydro-1H-[1,2,3]triazolo[4,5-c]pyridine-5-carbonyl)-7,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepine-6(5H)-carboxylate;

[3-chloro-4-(trifluoromethoxy)phenyl]methyl 2-(1,4,6,7-tetrahydrotriazolo[4,5-c]pyridine-5-carbonyl)-5,6,8,9-tetrahydro-[1,2,4]triazolo[1,5-d][1,4]diazepine-7-carboxylate;

[3-chloro-4-(trifluoromethoxy)phenyl]methyl 2-(1,4,6,7-tetrahydrotriazolo[4,5-c]pyridine-5-carbonyl)-5,6,8,9-tetrahydroimidazo[1,2-d][1,4]diazepine-7-carboxylate;

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 the reaction and purification of the resulting product are well 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 signs used in the description of the following methods have the meanings given herein.

A general description of the present invention is given in the following sections and is summarized in Schemes 1-4. To obtain compounds of formula (I), a suitably protected bicyclic carboxylic acid 1A is treated with a suitable cyclic secondary amine 1B in the presence of a suitable coupling agent such as EDC HCl, CDI, HATU, or any other peptide coupling agent in a suitable solvent such as DMF, THF, _CH3CN , etc., at temperatures between -20°C and 100°C to provide the protected amide 1C. In the subsequent step, depending on the nature of the protecting group PG ₁ , various deprotection methods known to those skilled in the art can be applied to provide the intermediate 1D from which PG is removed. For example, the BOC protecting group can be removed by treatment with an organic or aqueous acid or other known methods, while the Z-group is often removed by hydrogenation.

Option 1:

Intermediate 1D can now be treated with an alcohol 1E, wherein _RA is a substituted phenylalkyl group, whereby 1E is suitably activated in the presence of a base such as triethylamine, N-methylmorpholine, Huenig's base, etc., prior to treatment with, for example, CDI or any other type of activated carbonic acid derivative 1F such as N,N'-disuccinimidyl carbonate or phosgene, to provide a first type of embodiments of the present invention having the general structure 1H. The second type of embodiments outlined in the present invention is represented by the general structure 1I and can be prepared by reacting the alcohol 1E in the presence of an activating agent such as CDI, EDC HCl, or any type of peptide coupling agent in the presence of a suitable base such as triethylamine, N-methylmorpholine, Huenig's base, NaOH, _{Na2CO3 ,} etc., in a suitable solvent system such as DMF, _CH3 Intermediate 1D can be prepared by treating intermediate 1D with any type of free carboxylic acid 1G (wherein RB is alkyl, haloalkyl, substituted cycloalkyl, substituted cycloalkylalkyl, substituted phenyl, substituted phenylalkyl, substituted phenoxyalkyl, substituted phenylcycloalkyl, substituted phenylalkenyl, substituted phenylalkynyl, substituted pyridyl, substituted pyridylalkyl, substituted pyridylalkenyl, substituted pyridylalkynyl, substituted thienyl, substituted thienylalkyl, substituted thienylalkenyl, substituted thienylalkynyl, substituted 2,3-dihydro-1H-isoindol-2-yl, substituted 1H-indol-2-yl, or substituted benzofuran-2-yl) in CN, THF, THF/water, etc. Alternatively, any appropriately activated carboxylic acid derivative such as, for example, an acid chloride or acid bromide, a mixed anhydride, or a p-nitrophenolate can also be used in this reaction.

Intermediates of fused bicyclic rings of structure 1A or intermediate precursors thereof are described in the literature or can be prepared analogously to methods in the literature or obtained by syntheses that can be devised by one skilled in the art. As an example of the synthesis of such fused bicyclic ring systems, the synthesis of 6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-d][1,4]diazepine-2-carboxylic acid derivatives 1A (wherein A ¹ and A ² = N (equivalent to the structure of formula 2I) is outlined in Scheme 2. To obtain this material, thioamides 2A, where R _C represents, for example, a small alkyl group, can be treated with, for example, a substituted hydrazine of structure 2B in a solvent such as ethanol or methanol at a temperature ranging from -20°C to the boiling point of the solvent to provide intermediates 2C. Subsequently, intermediates 2C can be reacted with appropriately protected activated β-amino-carboxylic acid derivatives 2D (wherein X ₃ represents a halogen or mixed anhydride or the like, and PG ₂ represents a protecting group), is modified in the presence of an amine base such as triethylamine, Huenig's base, DMAP, etc., in a solvent such as THF, DCM, diethyl ether or the like to give 2E. The hydrazine derivative 2E can be condensed to the triazole 2F by heating in a suitable solvent such as tert-butanol, n-butanol or the like at a temperature ranging up to the boiling point of the solvent or by using a microwave apparatus. The reaction time for such a transformation can range from a few minutes (i.e., at elevated temperature and pressure in a microwave) to several days in a standard reaction flask.

Subsequent elaboration of intermediate 2F includes modification of the primary hydroxyl group of 2F to a better leaving group such as tosylate or mesylate by treatment with an appropriate reagent in the presence of a base such as pyridine, Huenig's base, DMAP or triethylamine or the like, in an appropriate solvent such as THF, DCM or the like (if necessary) at a temperature ranging from -20°C to the boiling point of the solvent. Removal of the protecting group PG ₂ to provide the triazole 2G depends on the nature of PG _2. If PG ₂ is, for example, a BOC group, it can be removed by treatment with an organic or aqueous acid or other known methods; if PG ₂ is a Z-group, it can generally be removed by hydrogenation. In the case where PG ₂ is another N-protecting group, there are other suitable deprotection conditions known to those skilled in the art that need to be applied.

Starting from intermediate 2G, ring closure to the diazepine 2H can be achieved by treatment with _a base such as triethylamine, DMAP, _K₂CO₃ , or the like, in a suitable solvent such as DMF, _CH₃CN , THF, or the like, at temperatures ranging from room temperature to the boiling point of the solvent. If desired, a suitable N-protecting group PG₃, such as a BOC group, a Z-group, or any other suitable protecting group, can now be reintroduced. Compatible groups and conditions for introduction and removal are described, for example, in Green & Wuts., "Protective Groups in Organic Synthesis," John _Wiley & Sons. Finally, if _R₂C is a small alkyl group, the free carboxylic acid 2I is obtained from the ester precursor 2H by hydrolysis, for example, in the presence of a base such as NaOH, KOH, or LiOH, in a solvent such as water, MeOH, EtOH, THF/water, etc., at temperatures ranging from 0°C to the boiling point of the solvent, to provide the desired building block of structure 2I. Other hydrolysis conditions known to those skilled in the art may also be applicable, depending on the nature of the protecting group _PG₃ .

Option 2:

Appropriately substituted benzyl alcohols 3B (wherein _R is R3, R4 and R5) as a subclass of alcohols 1E for subsequent elaboration of the central core of formula 1A are commercially available or can be prepared, for example, from the corresponding carboxylic acids, carboxylates or aldehydes 3A ( _X4 = OH, OR or H, respectively) by reaction with a suitable reducing agent such as LAH, _NaBH4 , _LiBH4 , etc., optionally in the presence of additives such as _CeCl3 , _CaCl2 or the like, in a suitable solvent such as methanol, ethanol, THF, at temperatures ranging from -20 to 100°C (Scheme 3).

Option 3:

Appropriately substituted carboxylic acids of structure 4D (wherein RF is R3, R4, and R5), which are a subclass of carboxylic acids 1G, can be prepared in a variety of ways as shown in Scheme 4. Phenoxyacetic acids 4D with _Y2 =O are obtained, for example, from the corresponding phenols 4A (Scheme 4, upper branch) by alkylation with appropriate acetic acid derivatives 4B (e.g., esters, when _RE is a small alkyl group) (wherein _X1 is a suitable leaving group such as a halogen or p-toluenesulfonate or the like) to afford intermediates 4C. Such transformations are typically carried out in the presence of a base such as potassium carbonate or cesium carbonate, in a suitable solvent such as DMF, acetone, or _CH3CN , at temperatures ranging from room temperature to the boiling point of the solvent. Similar to the conversion of 2H to 2I, esters 4C can be hydrolyzed, for example, in the presence of a base such as NaOH, KOH, or LiOH, to afford the desired building blocks of structure 4D with _Y2 =O.

Appropriately substituted 3-phenylpropionic acids of structure 4D with Y ₂ =C are commercially available or can be prepared as described in Scheme 4 (lower branch). If necessary, they can be prepared using conditions known to those skilled in the art, for example _, from the corresponding aldehyde 4E and the Wittig reagent 4F (which can have phosphorus inner salts of various substituents _RE , _RG , RH, and _RI ) to produce the cinnamic acid derivative 4G. From the cinnamic acid derivative 4G, the corresponding 3-phenylpropionic acid derivative 4H is prepared, for example, by reducing the double bond by hydrogenation in the presence of a catalyst such as, for example, palladium on carbon, whereby various solvents or a variety of other catalysts can be used. Subsequently, the free carboxylic acid of structure 4D with Y ₂ =C is prepared under the hydrolysis conditions described above for the conversion of 4C to 4D.

Option 4:

Other carboxylic acids required as intermediates to prepare some of the autotaxin inhibitors shown in the examples of this application are prepared in different ways. Scheme 5 shows a general route for the synthesis of appropriately substituted oxo-pyridine-4-carboxylic acids 5A:

Option 5:

For example, methyl 6-cyclopropyl-2-oxo-1H-pyridine-4-carboxylate (5B), which is commercially available or prepared from the corresponding carboxylic acid by esterification under conditions known to those skilled in the art, can be alkylated with an appropriate alkyl halide 5C (wherein X is a chlorine, bromine, or iodine atom) in the presence of a suitable base such as sodium hydride, lithium diisopropylamide, potassium carbonate, or cesium carbonate in a suitable solvent such as DMF, THF, or the like to provide the substituted pyridone intermediate 5D. This material is readily converted to the free carboxylic acid 5A under the hydrolysis conditions described above, for example, for the conversion of 4C to 4D.

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

wherein R ¹ is phenylalkoxy substituted by R ³ , R ⁴ and R ⁵ , _RA is phenylalkyl substituted by R ³ , R ⁴ and R ⁵ , and R ² , R ³ , R ⁴ , R ⁵ , A ¹ and A ² are as defined above.

In particular, in the presence of an activating agent such as CDI, N,N'-disuccinimidyl carbonate or phosgene, preferably N,N'-disuccinimidyl, in a solvent such as acetonitrile, in the presence of a base such as triethylamine, N-methylmorpholine or Huenig's base, and at a temperature ranging from -10°C to room temperature.

Another embodiment of the present invention is a process for the preparation of a compound of formula (I) as described above, said process comprising reacting a compound of formula (II) in the presence of a compound of formula (IV):

wherein R ¹ is alkyl, haloalkyl, substituted cycloalkyl, substituted cycloalkylalkyl, substituted phenyl, substituted phenylalkyl, substituted phenoxyalkyl, substituted phenylcycloalkyl, substituted phenylalkenyl, substituted phenylalkynyl, substituted pyridyl, substituted pyridylalkyl, substituted pyridylalkenyl, substituted pyridylalkynyl, substituted thienyl, substituted thienylalkyl, substituted thienylalkenyl, substituted thienylalkynyl, substituted 2,3-dihydro-1H-isoindol-2-yl, substituted 1H-indol-2-yl, or substituted benzofuran- 2-yl, wherein substituted cycloalkyl, substituted cycloalkylalkyl, substituted phenyl, substituted phenylalkyl, substituted phenoxyalkyl, substituted phenylcycloalkyl, substituted phenylalkenyl, substituted phenylalkynyl, substituted pyridyl, substituted pyridylalkyl, substituted pyridylalkenyl, substituted pyridylalkynyl, substituted thienyl, substituted thienylalkyl, substituted thienylalkenyl, substituted thienylalkynyl, substituted 2,3-dihydro-1H-isoindol-2-yl, substituted 1H-indol-2-yl and substituted benzofuran-2-yl are substituted with R ³ , R ⁴ and R ⁵ and R 2 , R ³ , R ⁴ , R ⁵ , A ^{1 and} A ² are as defined above.

In particular, in the presence of an activating agent such as CDI, EDC HCl, in a solvent such as DMF, CH ₃ CN, THF, THF/water, in the presence of a base such as triethylamine, N-methylmorpholine, Huenig's base, NaOH, Na ₂ CO ₃ .

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

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

An object of the present invention is the use of a compound according to formula (I) as described herein for the treatment or prevention of renal disorders, liver disorders, inflammatory disorders, nervous system disorders, respiratory system disorders, vascular and cardiovascular disorders, fibrotic diseases, cancer, eye disorders, metabolic disorders, cholestasis and other forms of chronic pruritus and acute and chronic organ transplant rejection.

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 disorders 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.

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.

Ocular disorders include, but are not limited to, proliferative and non-proliferative (diabetic) retinopathy, dry and wet age-related macular degeneration (AMD), macular edema, central arterial/venous occlusion, traumatic injury, glaucoma, and the like.

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 renal disorders, liver disorders, inflammatory disorders, nervous system disorders, fibrotic diseases and acute and chronic organ transplant rejection.

The present invention also relates to the use of a compound according to formula (I) as described herein for the treatment or prevention of kidney disorders, liver disorders and fibrotic diseases.

A particular embodiment of the present invention are compounds according to formula (I) as described herein for the treatment or prophylaxis of renal disorders, liver disorders, inflammatory disorders, nervous system disorders, fibrotic diseases and acute and chronic organ transplant rejection.

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

The present invention also relates to the use of a compound according to formula (I) as described herein for the preparation of a medicament for the treatment or prevention of renal disorders, liver disorders, inflammatory disorders, nervous system disorders, fibrotic diseases and acute and chronic organ transplant rejection.

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

Furthermore, an object of the present invention is a method for the treatment or prevention of renal disorders, liver disorders, inflammatory disorders, nervous system disorders, fibrotic diseases and acute and chronic organ transplant rejection, which method comprises administering an effective amount of a compound according to formula (I) as described herein.

Furthermore an object of the present invention is a method for the treatment or prevention of kidney disorders, liver disorders and fibrotic diseases, which method comprises administering an effective amount of a compound according to formula (I) as described herein.

In a particular embodiment, the renal 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 autotaxin (ATX) with and without 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 grown in suspension in FreeStyle 293 medium (Invitrogen) and transfected with the above-mentioned plasmid DNAs at approximately 1-1.5×10E6 cells/mL using X-tremeGENE Ro-1539 (trade name, 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 60M02E16 (Cuno) and Sartopore 2 XLG (Sartorius) filter units. The supernatant was stored at 4°C prior to purification.

ATX purification: 20 liters of culture supernatant were adjusted for ultrafiltration by adding Brij35 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 OpenChannel PES filter (Whatman) and then concentrated to 1 liter using an Ultran-Pilot ScreenChannel 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 step-washed 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 elution with a linear gradient to 0.5M imidazoles (15 column volumes).The fraction containing ATX is collected and concentrated using the Amicon pool equipped with a 30kDa PES filter membrane.Then on a 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. The final yield of protein after purification is 5-10mg 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 on the free amine of the ethanolamine side with the 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-) 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 in assay buffer to 1.4-2.5x final concentration;

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 compound solution to the next row until row 0, serial dilution is carried out row by row. Compound and control solution are mixed five times, and 2 μ L are transferred to 384-well assay plates (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 inhibitory activities (IC ₅₀ ) of the examples of the present invention against ATX are given below.

Example IC50 (μM) 1 0.158 2 2.01 3 0.018 4 0.007 5 0.002 6 0.004 7 0.07 8 0.06 9 0.006 10 0.018 11 0.015 12 0.067 13 0.017 14 0.014 15 0.011 16 0.012 17 0.010 18 0.013 19 0.151 20 0.006 twenty one 0.017 twenty two 0.018 twenty three 0.050 twenty four 0.009 25 0.007 26 0.016 27 0.052 28 0.076 29 0.038 30 0.041 31 0.022 32 0.030 33 0.094 34 0.007 35 0.013 36 0.006 37 0.009 38 0.021 39 0.014 40 0.017 41 0.006 42 0.007 43 0.056

The compounds of formula (I) described herein and their pharmaceutically acceptable salts or esters have _IC50 values between 0.00001 μM and 1000 μM, particular compounds have _IC50 values between 0.0005 μM and 500 μM, further particular compounds have _IC50 values between 0.0005 μM and 50 μM, and even more particular compounds have _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 medicaments (e.g. in the form of pharmaceutical preparations). The pharmaceutical preparations can be administered internally, such as orally (e.g. in the form of tablets, coated tablets, dragees, hard and soft gelatin capsules, solutions, emulsions or suspensions), nasally (e.g. in the form of nasal sprays), rectally (e.g. in the form of suppositories) or topically ophthalmically (e.g. in the form of solutions, ointments, gels or water-soluble polymer inserts). However, administration can also be achieved parenterally, such as intramuscularly, intravenously or intraocularly (e.g. in the form of sterile injections).

The compounds of formula (I) and pharmaceutically acceptable salts thereof may be treated with pharmaceutically inert, inorganic or organic adjuvants for the preparation of tablets, coated tablets, dragees, hard gelatin capsules, injections or topical preparations. 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.

Suitable excipients for ophthalmic topical formulations are, for example, cyclodextrins, mannitol or many other carriers and excipients known in the art.

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, per kg body weight is about 0.1 mg to 20 mg, preferably per kg body weight is about 0.5 mg to 4 mg (e.g., about 300 mg per person) daily dosage, preferably divided into 1-3 single doses that can, for example, be made up of the same amount, which should be suitable for. In the case of topical administration, the preparation can contain 0.001% to 15% medicine by weight, and the required dosage that can be 0.1 to 25 mg can be by daily or weekly single administration, or by daily multiple administration (2 to 4 times), or by weekly multiple administration. However, it will be understood that when displayed as needed, the upper or lower limits given herein can 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.

intermediates

abbreviation

aq. = aqueous; CAS-RN = Chemical Abstracts Service Registry Number; e.r = enantiomeric ratio; HPLC = high performance liquid chromatography; MS = mass spectrometry; NMR = nuclear magnetic resonance spectroscopy; sat. = saturated; rt = room temperature. Other abbreviations, such as those for chemical reagents or solvents, are known to those skilled in the art.

Intermediate 1:

6-phenylmethoxycarbonyl-4,5,7,8-tetrahydropyrazolo[1,5-d][1,4]diazepine-2-carboxylic acid

(6-O-Benzyl 2-O-ethyl 4,5,7,8-tetrahydropyrazolo[1,5-d][1,4]diazepine-2,6-dicarboxylate, CAS: 1080027-19-5; synthesized in steps 1-7 below) has been mentioned in Gerlach et al., PCT Int. Appl. (2008), WO2008135526A1 and synthesized similarly to Venkatesan M.A. et al., J. Med. Chem. 2006, 49, 4623.

Step 1: tert-Butyl 1,4-dibenzyl-1,4-diazepane-5-carboxylate

In a 20 mL round-bottom flask, tert-butyl 2,4-dibromobutyrate (500 mg, [CAS: 77629-96-0]), N,N'-dibenzylethylenediamine (372 mg, [CAS: .140-28-3]) and triethylamine (460 mg) were dissolved in dichloromethane (20 mL) to give a colorless solution. The mixture was heated to 40°C for 15 hours. The reaction mixture was poured into ice/water and basified with saturated _NaHCO3 solution. The aqueous phase was then extracted twice with dichloromethane. The combined organic layers were dried over _Na2SO4 , filtered and the solvent evaporated to dryness. The crude material was purified by flash chromatography (silica gel, gradient of ethyl acetate in heptane) _to give the title compound as a light brown oil (232 mg, 35%). MS (EI): 380.0 [M+].

Step 2: tert-Butyl 1,4-diazepane-5-carboxylate

1,4-Dibenzyl-1,4-diazepane-5-carboxylic acid tert-butyl ester (3.40 g) was dissolved in ethanol (50 mL) to give a light brown solution. Activated carbon-supported palladium (800 mg, 10% Pd) was added and a hydrogen atmosphere was introduced at room temperature. The mixture was stirred at 5 bar under hydrogen for 9 hours. The reaction mixture was filtered through dicalite speed plus (Acros Organics) and the solvent was evaporated to dryness to give the title compound as a light brown oil (1.40 g, 77%). MS (m/e): 201.7 [M+H] ⁺ .

Step 3: 1-O-Benzyl 5-O-tert-butyl 1,4-diazepane-1,5-dicarboxylate

1,4-diazepane-5-carboxylic acid tert-butyl ester (1.055 g) was dissolved in dichloromethane (20 mL) to give a light brown solution at room temperature under an argon atmosphere. The mixture was cooled to 0°C and a solution of dibenzyl dicarbonate (1.51 g) in dichloromethane (10 mL) was added dropwise over 10 minutes. The reaction mixture was stirred at 0°C for 30 minutes and then warmed to room temperature for 1.5 hours. The mixture was directly evaporated to dryness and the residue was purified by flash chromatography (silica gel, methanol gradient in dichloromethane) to give the title compound as a light brown oil (960 mg, 52%). MS (m/e): 335.6 [M+H] ⁺ .

Step 4: 1-phenylmethoxycarbonyl-1,4-diazepane-5-carboxylic acid 2,2,2-trifluoroacetate

1-O-Benzyl 5-O-tert-butyl 1,4-diazepane-1,5-dicarboxylate (9.0 g) was dissolved in dichloromethane (90 mL) at room temperature under an argon atmosphere. 2,2,2-trifluoroacetic acid (30.7 g, 20.70 mL) was then added dropwise over 15 minutes. The mixture was stirred at room temperature for 8 hours. The solvent was directly evaporated and the residue was dried under vacuum to give the title compound as a crude light brown oil (11 g, 100%, 95% purity). MS (m/e): 279.6 [M-TFA+H] ⁺ .

Step 5: 4-Nitroso-1-phenylmethoxycarbonyl-1,4-diazepane-5-carboxylic acid

1-(Benzyloxycarbonyl)-1,4-diazepane-5-carboxylic acid 2,2,2-trifluoroacetic acid (1.448 g) was dissolved in water (11.0 mL) and tetrahydrofuran (4.0 mL) at room temperature. Hydrochloric acid (37%, 337 μL) was then added dropwise over 5 minutes. The light brown solution was cooled to 0°C and sodium nitrite (251 mg) was added. The mixture was warmed to room temperature and stirred for 1 hour. The reaction mixture was poured into ice/water. The aqueous phase was then extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered, and evaporated. The residue was dried under high vacuum to give the title compound as a crude light brown oil (966 mg, 97%, 80% purity). MS (m/e): 308.5 [M+H] ⁺ .

Step 6: 6-phenylmethoxycarbonyl-4,5,7,8-tetrahydro oxadiazolo[3,4-d][1,4]diazepine -9- -3-alkoxide

1-(Benzyloxycarbonyl)-4-nitroso-1,4-diazepane-5-carboxylic acid (936 mg) was dissolved in acetonitrile (15 mL) at room temperature under an argon atmosphere. The mixture was cooled to 0°C and trifluoroacetic anhydride (768 mg) was added dropwise over 10 minutes. The mixture was warmed to room temperature and stirred for 3 hours. Potassium carbonate (505 mg) was then added and the mixture was stirred for 30 minutes. The reaction mixture was poured into ice/water. The aqueous phase was then extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried _{over Na₂SO₄} , filtered, and evaporated. The crude material was purified by flash chromatography (silica gel, gradient of ethyl acetate in heptane) to give the title compound as a light yellow gum (300 mg, 39%). MS (m/e): 290.5 [M+H] ^⁺ .

Step 7: 6-O-Benzyl 2-O-ethyl 4,5,7,8-tetrahydropyrazolo[1,5-d][1,4]diazepine -2,6-dimethyl acid esters

Ethyl propionate (284 mg) was added to a solution of 6-(benzyloxycarbonyl)-5,6,7,8-tetrahydro-4H-[1,2,3]diazolo[3,4-d][1,4]diazepine-9--3-olate (186 mg) in chlorobenzene (4.0 mL) at room temperature under an argon atmosphere. The mixture was heated in a microwave at 150° C. for 2 hours. The reaction mixture was evaporated directly to dryness. The crude material was purified by flash chromatography (silica gel, gradient of ethyl acetate in heptane) to give the title compound as a light yellow gum (131 mg, 53%). MS (m/e): 344.5 [M+H] ⁺ .

The regioisomer 6-O-benzyl 3-O-ethyl 4,5,7,8-tetrahydropyrazolo[1,5-d][1,4]diazepine-3,6-dicarboxylate was also isolated by flash chromatography (silica gel, gradient of ethyl acetate in heptane) as a light yellow gum (36 mg, 16%). MS (m/e): 344.5 [M+H] ⁺ .

Step 8: 6-phenylmethanecarbonyl-4,5,7,8-tetrahydropyrazolo[1,5-d][1,4]diazepine -2-formic acid

1 M lithium hydroxide solution (9.33 mL) was added dropwise over 10 minutes to a solution of 6-benzyl 2-ethyl 7,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepine-2,6(5H)-dicarboxylate (1.78 g) in tetrahydrofuran (20 mL) at room temperature. The mixture was stirred at room temperature for 18 hours. The reaction mixture was poured into ice/water and acidified to pH = 1 with HCl (2 M) solution. The aqueous phase was then extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered, and the solvent was evaporated. The residue was dried in vacuo to give the title compound as a yellow solid (1.64 g, 95%). MS (m/e): 316.5 [M+H] ⁺ .

Intermediate 2:

4,5,7,8-Tetrahydro-1,3,3a,6-tetraaza-azulene-2,6-dicarboxylic acid 6-tert-butyl ester

Step 1: Ethyl (2Z)-2-amino-2-(2-hydroxyethylhydrazono)acetate

To a solution of amino-thio-acetic acid ethyl ester (5.0 g) in ethanol (160 mL) was added 2-hydrazino-ethanol at 0°C and the reaction mixture was stirred at 25°C for 2 h. The volatile components were then removed in vacuo to give the title compound (6.58 g) as a yellow sticky solid, which was used in the next step without further purification. LC-MS: 175.8 [M+H] ⁺ .

Step 2: (2Z)-2-[3-(tert-Butoxycarbonylamino)propionylamino]-2-(2-hydroxyethylhydrazono)ethyl Ethyl acetate

Under nitrogen atmosphere at -10 ℃ to 3-tert-butoxycarbonylamino-propionic acid (7.73g) in THF (100mL) solution, add triethylamine (6.78mL) and ethyl chloroformate (4.64mL) and the reaction mixture is stirred at -10 ℃ for 0.5h.The reaction mixture is filtered and the filtrate is then added to (2Z) -2-amino-2- (2-hydroxyethyl hydrazono) ethyl acetate (6.57g) solution and the mixture is stirred at 25 ℃ for 16h.The solvent is evaporated in vacuo, and the residue is distributed between ethyl acetate (150mL) and water (100mL).The organic layer is separated, and the aqueous layer is extracted again with ethyl acetate (2x100ml).The combined organic layer is washed with brine, dried _over anhydrous Na _SO , filtered, and concentrated in vacuo. The crude material was purified by column chromatography over standard silica gel (20-40% EtOAc/hexanes) to give (3-tert-butoxycarbonylamino-propionylamino)-[(2-hydroxy-ethyl)-hydrazono]-acetic acid ethyl ester (5.81 g) as a yellow sticky solid. LC-MS: 346.9 [M+H] ⁺ .

Step 3: 5-[2-(tert-Butoxycarbonylamino)ethyl]-1-(2-hydroxyethyl)-1,2,4-triazole-3-carboxylic acid ethyl ester

A solution of ethyl (2Z)-2-[3-(tert-butoxycarbonylamino)propionylamino]-2-(2-hydroxyethylhydrazono)acetate (5.8 g) in n-BuOH (400 mL) was refluxed for 18 h. The solvent was removed in vacuo, and the residue was purified by column chromatography over standard silica gel using 0-4% MeOH/DCM as eluent to afford a mixture of ethyl 5-(2-tert-butoxycarbonyl-amino-ethyl)-1-(2-hydroxy-ethyl)-1H-[1,2,4]triazole-3-carboxylate and the corresponding n-butyl ester (4.22 g, impure) as a yellow, sticky solid. LC-MS: 329.2 and 356.9 [M+H] ⁺ .

Step 4: 5-(2-tert-Butoxycarbonylamino-ethyl)-1-[2-(toluene-4-sulfonyloxy)-ethyl]-1H- [1,2,4]triazole-3-carboxylic acid ethyl ester

To a solution of 5-(2-tert-butoxycarbonylamino-ethyl)-1-(2-hydroxy-ethyl)-1H-[1,2,4]triazole-3-carboxylic acid ethyl ester (4.2 g) in DCM (100 mL) was added triethylamine (2.70 mL) and p-toluenesulfonyl chloride (2.92 g) at 0°C and the reaction mixture was stirred at 25°C for 16 h. The reaction mixture was diluted with DCM (50 mL) and washed with saturated aqueous sodium bicarbonate (100 mL). The organic layer was dried over _{anhydrous Na2SO4} , filtered, and concentrated in vacuo. The residue was purified by column chromatography over standard silica gel (10-30% EtOAc/hexanes as eluent) to obtain the title compound as a mixture of the ethyl ester and the corresponding butyl ester (1.98 g) as a yellow sticky solid. LC-MS: 482.9 and 511.1 [M+H] ⁺ .

Step 5: 5-(2-Amino-ethyl)-1-(2-hydroxy-ethyl)-1H-[1,2,4]triazole-3-carboxylic acid ethyl ester

To a solution of 5-(2-tert-butoxycarbonylamino-ethyl)-1-[2-(toluene-4-sulfonyloxy)-ethyl]-1H-[1,2,4]triazole-3-carboxylic acid ethyl ester (5.17 g) in DCM (100 mL) was added 4N HCl in dioxane (40 mL) and the reaction mixture was stirred at 25° C. for 2 h. The volatile components were then removed in vacuo to afford the title compound as a mixture of the ethyl ester and the corresponding butyl ester hydrochloride (4.42 g, crude) as a brown, sticky solid. LC-MS: 383.1 and 410.8 [M+H] ⁺ .

Step 6: 5,6,7,8-Tetrahydro-4H-1,3,3a,6-tetraaza-azulene-2-carboxylic acid ethyl ester

To a suspension of ethyl 5-(2-amino-ethyl)-1-(2-hydroxy-ethyl)-1H-[1,2,4]triazole-3-carboxylate (4.4 g, crude) in THF (200 mL) was added triethylamine (4.44 mL) dropwise at 0° C. and the reaction mixture was stirred at 60° C. for 18 h. The volatiles were removed in vacuo to afford the title compound as a mixture of the ethyl ester and the corresponding butyl ester along with other impurities (2.23 g, crude) as a brown sticky solid, which was used in the next step without further purification. LC-MS: 211.3 and 239.0 [M+H] ⁺ .

Step 7: 4,5,7,8-Tetrahydro-1,3,3a,6-tetraaza-azulene-2,6-dicarboxylic acid 6-tert-butyl ester 2-ethyl ester

To a suspension of 5,6,7,8-tetrahydro-4H-1,3,3a,6-tetraaza-azulene-2-carboxylic acid ethyl ester (2.2 g) in THF (100 mL) were added triethylamine (2.21 mL) and di-tert-butyl carbonate (3.6 mL), and the reaction mixture was stirred at 25° C. for 2 h. The solvent was removed in vacuo, and the residue was purified by column chromatography over standard silica gel (0-5% MaOH/DCM as eluent) to afford the title compound as a mixture of the ethyl ester and the corresponding butyl ester (1.2 g, 53.3% from 5-(2-tert-butoxycarbonylamino-ethyl)-1-[2-(toluene-4-sulfonyloxy)-ethyl]-1H-[1,2,4]triazole-3-carboxylic acid ethyl ester, obtained in Step 4) as a yellow sticky solid. LC-MS: 311.2 and 339.1 [M+H] ⁺ .

Step 8: 4,5,7,8-Tetrahydro-1,3,3a,6-tetraaza-azulene-2,6-dicarboxylic acid 6-tert-butyl ester

To a solution of 6-tert-butyl 2-ethyl 4,5,7,8-tetrahydro-1,3,3a,6-tetraaza-azulene-2,6-dicarboxylate (1.2 g) in THF (16 mL) was added a solution of LiOH H2O (324 mg) in water (4 mL) at 25 ° C, and the reaction mixture was stirred at 25 ° C for 1 h. The solvent was removed in vacuo and the residue was dissolved in water (30 mL) and washed with ethyl acetate. The aqueous layer was acidified with saturated aqueous citric acid and extracted with DCM (3x75 mL). The combined organic layers were dried over _{anhydrous Na2SO4} , filtered, and concentrated in vacuo. The residue was purified by preparative HPLC to obtain the title compound (228 mg, 21%) as an off-white solid. LC-MS: 283.3 [M+H] ⁺ .

Intermediate 3:

5,6,8,9-Tetrahydro-imidazo[1,2-a][1,4]diazepine-2,7-dicarboxylic acid 7-benzyl ester:

Benzyl 2-formyl-5,6,8,9-tetrahydro-imidazo[1,2-a][1,4]diazepine-7-carboxylate (500 mg), prepared according to the procedure described by Gerlach et al. in PCT Int. Appl. (2008), WO 2008135526A1, was dissolved in acetone (15 mL) and water (15 mL). Then, sulfamic acid (292 mg) and _NaClO₂ (211 mg) were added, and the reaction mixture was stirred at 25° C. for 3 h. The acetone was removed in vacuo, and the aqueous layer was extracted with DCM ( ₃ ×50 mL). The combined organic layers were dried over anhydrous _Na₂SO₄ , filtered, and concentrated in vacuo. The crude material was triturated with _Et2O and provided an off-white solid which was dried to give 5,6,8,9-tetrahydro-imidazo[1,2-a][1,4]diazepine-2,7-dicarboxylic acid 7-benzyl ester (6) (425 mg, 81%). LC-MS: 316.0 [M+H] ⁺ .

Intermediate 4:

4-(Hydroxymethyl)-3-isopropyl-benzonitrile

Step 1: 4-cyano-2-isopropylphenyl trifluoromethanesulfonate

To a solution of pyridine (915 μl) in dichloromethane (70 mL) was added trifluoromethanesulfonic anhydride (1.75 mL) at 0°C. The white suspension was stirred at 0°C for 10 minutes. A solution of 4-hydroxy-3-isopropylbenzonitrile (CAS: 1.52 g) in dichloromethane (40 ml) was added dropwise. The ice bath was removed and the dark brown clear solution was stirred at room temperature. TLC at t = 75 min showed that the reaction was complete. The reaction mixture was diluted with dichloromethane and washed with water and brine. The aqueous layer was back-extracted with dichloromethane, dried over magnesium sulfate, filtered and evaporated. The residue was purified by flash chromatography (100 g, _SiO2 ; gradient from heptane/dichloromethane 9:1 to heptane/dichloromethane 4:6) to obtain the title compound (2.63 g, 95%). Yellow liquid; MS: 292.1 [MH] ^- .

Step 2: Methyl 4-cyano-2-isopropylbenzoate

4-cyano-2-isopropylphenyl trifluoromethanesulfonate (2.30 g) was added to an autoclave and methanol (46 mL) was added. The autoclave was placed under argon and triethylamine (2.73 mL) and 1,1′-bis(diphenylphosphino)ferrocene-dichloropalladium(II) dichloromethane complex (320 mg) were subsequently added. A CO atmosphere was introduced by repeatedly evacuating and introducing 10 bar of CO (3 times). The pressure was then increased to 50 bar, and the autoclave was kept at 110° C. for 20 hours. The reaction mixture was cooled to room temperature and the red solution was evaporated in vacuo. The residue was filtered through a 100 g SiO ₂ column with a solvent of dichloromethane/heptane 1:1 to obtain the title compound (1.23 g, 77%). Pale yellow oil, MS: 218.5 [M+H] ⁺ .

Step 3: 4-(Hydroxymethyl)-3-isopropyl-benzonitrile

To a clear, pale yellow solution of methyl 4-cyano-2-isopropylbenzoate (1.227 g) in tetrahydrofuran (15 mL) was added lithium borohydride (2 M in THF, 9.06 mL). The reaction mixture was heated to reflux. TLC (dichloromethane/heptane 4:1) at t = 1 h indicated the reaction was complete. The reaction was cooled to room temperature and 5 mL of MeOH was added. After 30 min, the reaction was diluted with ethyl acetate and extracted with water and brine. The aqueous layer was back-extracted with ethyl acetate. The combined organic layers were dried over magnesium sulfate, filtered, and evaporated. Chromatography (100 g, _SiO2 ; gradient from dichloromethane to dichloromethane/methanol + 0.25% aqueous _NH4OH 19:1) provided the title compound (802 mg, 76%). A pale yellow oil, MS: 176.2 [M+H] ⁺ .

Intermediate 5:

N-[5-cyano-2-(hydroxymethyl)phenyl]-2,2-dimethyl-propionamide

Step 1: Methyl 4-cyano-2-pivalamidobenzoate

To a clear, red solution of methyl 2-amino-4-cyanobenzoate (CAS: 159847-83-3; 776 mg) in pyridine (6 mL) was added pivaloyl chloride (650 μl) dropwise at 0°C. A solid precipitated. MS at t = 2 h indicated the reaction was complete. The reaction mixture was diluted with 1 M aqueous HCl and extracted twice with _ethyl acetate/2-methyltetrahydrofuran. The combined organic layers were washed with water, 50% _Na₂CO₃ solution, and brine, dried over magnesium sulfate, filtered, and evaporated. The residue was suspended in ethyl acetate to obtain the title compound (819 mg, white solid). The mother liquor was evaporated and the residue was treated with tBME to obtain another batch of the title compound (148 mg, white solid). The products were combined to obtain the title compound (967 mg, 84%) as a white solid. MS: 261.1 [MH] ⁻ .

Step 2: N-[5-cyano-2-(hydroxymethyl)phenyl]-2,2-dimethyl-propionamide

To a white suspension of methyl 4-cyano-2-pivalamidobenzoate (335 mg) in tetrahydrofuran (6.0 mL) under argon was added a solution of calcium chloride (286 mg) in ethanol (6.0 mL). Sodium borohydride (195 mg) was added in three portions over a period of 20 minutes. TLC at t = 4 h indicated the reaction was complete. The reaction mixture was poured onto ice/water and saturated NH ₄ Cl solution. The aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered, and evaporated. Chromatography (50 g, SiO 2 , gradient from dichloromethane to dichloromethane/methanol 9:1) provided the title compound (257 mg, 86%) as a white solid, MS: 233.2 [M+H] ⁺ .

Intermediate 6:

2-(4-Cyano-2-cyclopropylphenoxy)acetic acid

Step 1: Ethyl 2-(4-cyano-2-cyclopropylphenoxy)acetate

3-cyclopropyl-4-hydroxybenzonitrile (140 mg) was dissolved in acetone (5 mL) at room temperature under an argon atmosphere. Potassium carbonate (122 mg) and ethyl 2-bromoacetate (97 μL) were added continuously to the mixture. The reaction mixture was heated to reflux for 3 hours and then cooled to room temperature. The solvent was evaporated and the residue was poured into brine and ethyl acetate and separated. The aqueous layer was extracted twice with additional ethyl acetate. The organic layers were combined, washed once with brine, dried over Na ₂ SO ₄ , filtered, evaporated and dried in a high vacuum to obtain a crude product as a yellow viscous oil, which was used without further purification (210 mg, 88%).

Step 2: 2-(4-cyano-2-cyclopropylphenoxy)acetic acid

1M lithium hydroxide solution (1.47 mL) was added dropwise to a solution of ethyl 2-(4-cyano-2-cyclopropylphenoxy)acetate (200 mg) in THF (4.0 ml) at room temperature over a period of 5 minutes. The mixture was stirred at room temperature for 5 hours. The reaction mixture was poured into ice/water and acidified to pH = 1 with 2M HCl solution. The aqueous phase was then extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered, and the solvent was evaporated. The residue was dried under high vacuum to give the title compound as a yellow solid (170 mg, 96%). MS (m/e): 216.1 [MH] ^- .

Intermediate 7:

2-(4-cyano-2-ethylphenoxy)acetic acid

This material was prepared analogously to Intermediate 6 from 3-ethyl-4-hydroxybenzonitrile (CAS: 4997-55-1).

Intermediate 8:

2-(2-tert-Butyl-4-cyanophenoxy)acetic acid

This material was prepared analogously to Intermediate 7 starting from 3-tert-butyl-4-hydroxybenzonitrile (CAS: 4910-04-7).

Intermediate 9:

5,6,7,8-tetrahydro-4H-pyrazolo[1,5-d][1,4]diazepine -2-yl(1,4,6,7-tetrahydrotriazolo[4, 5-c]pyridin-5-yl)methanone

The synthesis of intermediate 9 is described in Example 3, Step 1.

Intermediate 10:

1,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl(6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5- d][1,4]diazepine -2-yl)methanone hydrochloride

Step 1: 2-(1,4,6,7-tetrahydrotriazolo[4,5-c]pyridine-5-carbonyl)-5,6,8,9-tetrahydro-[1,2,4]triazolo[4,5-c]pyridine-5-carbonyl]- Azo[1,5-d][1,4]diazepine -tert-Butyl 7-formate

In a 20 mL round-bottom flask, 7-(tert-butoxycarbonyl)-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-d][1,4]diazepine-2-carboxylic acid (Intermediate 9, 450 mg) and 4,5,6,7-tetrahydro-1H-[1,2,3]triazolo[4,5-c]pyridine (207 mg) were combined with DMF (12.9 mL) to give a white suspension. N-Ethyldiisopropylamine (587 mg) was added dropwise over 2 minutes at room temperature. HATU (638 mg) was then added and the reaction mixture was stirred at room temperature for 15 h. The mixture was poured into ice/water and the aqueous phase was extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried _{over Na₂SO₄} , filtered and evaporated. The residue was evaporated again with toluene. The crude material was purified by flash chromatography (silica gel, 20 g, 0% to 10% MeOH in _CH2Cl2 ) to give a white foam (310 mg).MS: 389.3 [M+H] ⁺ .

Step 2: 1,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl(6,7,8,9-tetrahydro-5H-[1,2,4]triazole benzo[1,5-d][1,4]diazepine -2-yl)methanone hydrochloride

In a 20 mL round-bottom flask, tert-butyl 2-(4,5,6,7-tetrahydro-1H-[1,2,3]triazolo[4,5-c]pyridine-5-carbonyl)-8,9-dihydro-5H-[1,2,4]triazolo[1,5-d][1,4]diazepine-7(6H)-carboxylate (230 mg) and 5N HCl in 2-propanol (5 mL) were combined to give a white suspension. The reaction mixture was heated to 50° C. and stirred for 2 hours. The reaction mixture was then cooled and concentrated in vacuo to give the crude salt (190 mg), which was used without further purification. MS: 289.1 [M+H] ⁺ .

Intermediate 11:

3-[3-Chloro-4-(trifluoromethoxy)phenyl]propanoic acid

Step 1: (E)-3-[3-chloro-4-(trifluoromethoxy)phenyl]prop-2-enoic acid

In a 20 mL round-bottom flask, 3-chloro-4-(trifluoromethoxy)benzaldehyde (CAS: 83279-39-4, 500 mg), malonic acid (510 mg) and piperidine (22.0 μL) were combined with pyridine (3.0 mL) to give a colorless solution. The mixture was then heated to reflux for 5 h. The reaction mixture was cooled, poured into ice/water and acidified with 2N HCl. The aqueous phase was extracted twice with ethyl acetate and the combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and evaporated. The crude material was purified by flash chromatography (silica gel, 20 g, 0% to 10% MeOH in CH 2 Cl ₂ ) to provide the title compound as a white solid (400 mg). MS: 265.1 [MH] ^- .

Step 2: 3-[3-chloro-4-(trifluoromethoxy)phenyl]propanoic acid

In a 50 mL three-necked flask, (E)-3-[3-chloro-4-(trifluoromethoxy)phenyl]prop-2-enoic acid (300 mg) was combined with ethyl acetate (10 mL) to give a colorless solution. Palladium on carbon (10% Pd, 40 mg) was added and the mixture was hydrogenated for 30 min, with TLC analysis showing no residual starting material. The reaction mixture was filtered through Celite and then concentrated in vacuo to give a light yellow solid (300 mg) which was used without further purification. MS: 267.3 [MH] ⁻ .

Intermediate 12:

2-Cyclopropyl-6-(alkyl-4-ylmethoxy)pyridine-4-carboxylic acid

Step 1: Methyl 6-cyclopropyl-2-oxo-1,2-dihydropyridine-4-carboxylate

A suspension of 6-cyclopropyl-2-oxo-1,2-dihydropyridine-4-carboxylic acid (CAS: 150190-28-6; 400 mg) in methanol (4 mL) and sulfuric acid (12 μL) was heated at 70°C for 48 h. The mixture was then concentrated in vacuo. The residue was suspended in dichloromethane (10 mL), insoluble material was removed by filtration, and the filtrate was evaporated to afford the title compound (427 mg) as a light brown semisolid. MS: 194.1 [M+H] ⁺ .

Step 2: 2-cyclopropyl-6-( Methyl 4-(4-(2 ...alkyl-4-ylmethoxy)pyridine-4-carboxylate)))

To a suspension of methyl 6-cyclopropyl-2-oxo-1,2-dihydropyridine-4-carboxylate (212 mg) in acetonitrile (5 mL) was added potassium carbonate (455 mg) and 4-(iodomethyl)tetrahydro-2H-pyran (CAS: 101691-94-5; 744 mg) and stirred. The reaction mixture was heated at 80°C for 16 h and then evaporated in vacuo. The residue was purified by flash chromatography (silica gel; heptane-ethyl acetate gradient) to give the title compound as a colorless oil (188 mg). MS: 292.2 [M+H] ⁺ .

Step 3: 2-cyclopropyl-6-( (4-Alkylmethoxy)pyridine-4-carboxylic acid

To a solution of methyl 2-cyclopropyl-6-(alkane-4-ylmethoxy)pyridine-4-carboxylate (184 mg) in tetrahydrofuran (2 mL) and water (2 mL) was added lithium hydroxide monohydrate (53.0 mg, 1.26 mmol) and the resulting mixture was stirred at room temperature for 16 h. The mixture was partially evaporated to remove tetrahydrofuran. The aqueous phase was partitioned between 1 M aqueous hydrochloric acid solution and ethyl acetate. The layers were separated and the organic layer was washed with brine, dried over magnesium sulfate, filtered, and evaporated to give the title compound as a colorless oil (218 mg). MS: 276.1 [MH] ^- .

Intermediate 13:

(E)-3-[4-(Difluoromethoxy)-3-fluoro-phenyl]prop-2-enoic acid

This material was prepared in analogy to Intermediate 11, Step 1 from 4-(difluoromethoxy)-3-fluorobenzaldehyde (CAS: 1214379-56-2, 1.54 g). MS: 233.1 [M+H] ⁺ .

Intermediate 14:

6,7,8,9-tetrahydro-5H-imidazo[1,2-d][1,4]diazepine -2-yl(1,4,6,7-tetrahydrotriazolo[4, 5-c]pyridin-5-yl)methanone

This material was prepared similarly to Example 3, Step 1, by hydrogenating benzyl 2-(1,4,6,7-tetrahydrotriazolo[4,5-c]pyridine-5-carbonyl)-5,6,8,9-tetrahydroimidazo[1,2-d][1,4]diazepine-7-carboxylate (obtained in Example 2) to afford the title compound, 6,7,8,9-tetrahydro-5H-imidazo[1,2-d][1,4]diazepine-2-yl(1,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)methanone, as a colorless powder. MS: 288.2 [M+H] ⁺ .

Intermediate 15:

(3aR,7aR)-5-(6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-d][1,4]diazepine -2-Carbonyl 1,3-Hydroxy- Oxazo[5,4-c]pyridin-2(1H)-one 2,2,2-trifluoroacetate

Step 1: (3aR,7aR)-2-oxo-1,3a,4,6,7,7a-hexahydro-[1,3] oxazolo[5,4-c]pyridine-5-carboxylic acid Tert-butyl ester

To a solution of tert-butyl (3R, 4R)-4-amino-3-hydroxypiperidine-1-carboxylate (CAS: 1007596-95-3, 510 mg) in DMF (8.0 mL) was added imidazole (161 mg) and subsequently 1,1'-carbonyldiimidazole (382 mg) at room temperature under an argon atmosphere. The mixture was stirred at room temperature for 18 hours. The reaction mixture was then poured into ice/water and the aqueous layer was extracted twice with ethyl acetate. The organic layer was washed once with brine, dried over Na ₂ SO ₄ , filtered and evaporated. The residue was evaporated again with toluene. The crude material was purified by flash chromatography (silica gel, 20 g cartridge, 0% to 5% methanol in dichloromethane) to give the title compound as a white solid (460 mg). MS: 187.0 [M-56 (isobutylene) + H] ⁺ .

Step 2: (3aR,7aR)-3a,4,5,6,7,7a-hexahydro-iH-[1,3] Azoxazo[5,4-c]pyridin-2-one hydrochloride Salt

(3aR,7aR)-2-oxo-1,3a,4,6,7,7a-hexahydro-[1,3]oxazolo[5,4-c]pyridine-5-carboxylic acid tert-butyl ester (458 mg) was combined with hydrochloric acid (about 5M-6M in isopropanol, 6.87 mL) and the mixture was stirred at room temperature for 19 hours. The reaction mixture was then evaporated directly to dryness. The white residue was combined with ethyl acetate (8 mL) and the suspension was stirred at room temperature for 1 hour. The colorless solid was isolated by filtration, washed with ethyl acetate, and dried under high vacuum to give the title compound (279 mg). MS: 143.0 [M+H] ⁺ (free base).

Step 3: 2-[(3aR,7aR)-2-oxo-1,3a,4,6,7,7a-hexahydro-[1,3] Azo[5,4-c]pyridine- 5-carbonyl]-5,6,8,9-tetrahydro-[1,2,4]triazolo[1,5-d][1,4]diazepine -tert-Butyl 7-formate

In a 50 mL round-bottom flask, (3aR,7aR)-3a,4,5,6,7,7a-hexahydro-1H-[1,3]oxazolo[5,4-c]pyridin-2-one hydrochloride (225 mg), 4-methylmorpholine (382 mg) and 6-tert-butyl 4,5,7,8-tetrahydro-1,3,3a,6-tetraaza-azulene-2,6-dicarboxylate (Intermediate 2, 391 mg) were combined with DMF (10.0 mL) to give a light yellow solution. 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (483 mg) and 1-hydroxybenzotriazole hydrate (340 mg) were added and the reaction mixture was stirred at room temperature for 16 hours. The mixture was poured into ice/water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried _{over Na₂SO₄} , filtered and evaporated. The residue was evaporated again with toluene. The crude material was purified by flash chromatography (silica gel, 50 g cartridge, 0% to 10% methanol in dichloromethane) to afford the title compound as a colorless solid (491 mg).MS: 351.2 [M-56 (isobutylene) + H] ⁺ .

Step 4: (3aR,7aR)-5-(6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-d][1,4]diazepine - 2-carbonyl)hexahydro-[1,3] Oxazo[5,4-c]pyridin-2(1H)-one 2,2,2-trifluoroacetate

2-[(3aR, 7aR)-2-oxo-1,3a,4,6,7,7a-hexahydro-[1,3]oxazolo[5,4-c]pyridine-5-carbonyl]-5,6,8,9-tetrahydro-[1,2,4]triazolo[1,5-d][1,4]diazepine-7-tert-butyl carboxylate (50 mg) was dissolved in dichloromethane (5.0 mL) at room temperature under an argon atmosphere. Then, 2,2,2-trifluoroacetic acid (140 mg) was added dropwise over 5 minutes, and the mixture was stirred at room temperature for 3 hours. More 2,2,2-trifluoroacetic acid (42.1 mg) was slowly added and continued to stir at room temperature for 17 hours. Then, the solvent was removed by evaporation, and residual TFA was removed by adding and evaporating toluene. After evaporation, the residue was dried in a high vacuum to provide a light yellow gum (68 mg), which was used without further purification. MS: 307.2 [M+H] ⁺ (free base).

Example

Example 1

2-(1,4,6,7-tetrahydrotriazolo[4,5-c]pyridine-5-carbonyl)-4,5,7,8-tetrahydropyrazolo[1,5-d][1, 4] Diazepine -6-Benzyl formate

To a suspension of 6-(benzyloxycarbonyl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-d][1,4]diazepine-2-carboxylic acid (Intermediate 1, 1.62 g) and 4,5,6,7-tetrahydro-1H-[1,2,3]triazolo[4,5-c]pyridine (702 mg, [CAS: 706757-05-3]) in dimethylformamide (20 mL) was added dropwise 4-methylmorpholine (1.56 g) at room temperature under an argon atmosphere over a period of 5 minutes. HATU (2.17 g) was then added in four portions. The mixture was stirred at room temperature for 17 hours. The reaction mixture was poured into ice/water. The aqueous phase was then extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried _{over Na₂SO₄} , filtered, and evaporated. The residue was again evaporated with toluene. The crude material was purified by flash chromatography (silica gel, 0% to 100% ethyl acetate in heptane, and then _CH2Cl2 /MeOH = 96/4) to give the title compound as an off-white foam (1.40 g, 62%). MS (m/e): 422.6 [M+H+].

The following Example 2 was synthesized analogously to Example 1 from appropriate building blocks/intermediates:

Example 3

2-(1,4,6,7-tetrahydrotriazolo[4,5-c]pyridine-5-carbonyl)-4,5,7,8-tetrahydropyrazolo[1,5-d][1, 4] Diazepine -6-[3-Fluoro-4-(trifluoromethoxy)phenyl]methylcarboxylate

Step 1: 5,6,7,8-tetrahydro-4H-pyrazolo[1,5-d][1,4]diazepine -2-yl(1,4,6,7-tetrahydrotri oxazolo[4,5-c]pyridin-5-yl)methanone

Benzyl 2-(4,5,6,7-tetrahydro-1H-[1,2,3]triazolo[4,5-c]pyridine-5-carbonyl)-7,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepine-6(5H)-carboxylate (1.40 g, obtained in Example 1) was dissolved in methanol (10 mL) to give a colorless solution. Palladium on activated carbon (140 mg, 10% Pd) was added and a hydrogen atmosphere was introduced at room temperature. The mixture was stirred under hydrogen for 16 hours. The reaction mixture was filtered through dicalite speed plus (Acros Organics) and the solvent was evaporated to dryness to give the title compound as a colorless oil (910 mg, 94%). MS (m/e): 288.2 [M+H+].

Step 2: 2-(1,4,6,7-tetrahydrotriazolo[4,5-c]pyridine-5-carbonyl)-4,5,7,8-tetrahydropyrazolo[1, 5-d][1,4]diazepine -6-[3-Fluoro-4-(trifluoromethoxy)phenyl]methylcarboxylate

Triethylamine (31.7 mg) was added to a solution of (3-fluoro-4-(trifluoromethoxy)phenyl)methanol (CAS: 886498-99-3, 98.7 mg) in acetonitrile (8.0 mL) at room temperature under an argon atmosphere. N,N'-disuccinimidyl carbonate (120 mg) was then added and the colorless solution was stirred at room temperature for 3 hours to give the activated alcohol. (6,7-dihydro-1H-[1,2,3]triazolo[4,5-c]pyridin-5(4H)-yl)(5,6,7,8-tetrahydro-4H-pyrazolo[1,5-d][1,4]diazepine-2-yl)methanone (90 mg) and triethylamine (95.1 mg) were added to the colorless solution and the mixture was stirred at room temperature for 18 hours. The reaction mixture was poured into ice/water and the aqueous phase was extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried _{over Na₂SO₄} , filtered, and evaporated. Toluene was added and the solvent was evaporated again. The crude material was purified by flash chromatography (silica gel, gradient of ethyl acetate in heptane) to afford the title compound as a white solid (53 mg, 32%). MS (m/e): 524.6 [M+H] ^⁺ .

The following Examples 4-13 were synthesized similarly to Example 2, Step 2, from appropriate building blocks and correspondingly substituted benzyl alcohols:

Example 14

1-[2-(1,4,6,7-tetrahydrotriazolo[4,5-c]pyridine-5-carbonyl)-4,5,7,8-tetrahydropyrazolo[1,5-d] [1,4]diazepine -6-yl]-3-[4-(trifluoromethoxy)phenyl]propan-1-one

To a suspension of (6,7-dihydro-1H-[1,2,3]triazolo[4,5-c]pyridin-5(4H)-yl)(5,6,7,8-tetrahydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl)methanone (Intermediate 9, 80 mg) and 3-(4-(trifluoromethoxy)phenyl)propanoic acid (CAS: 886499-74-7; 71.7 mg) in dimethylformamide (4.0 mL) was added dropwise 4-methylmorpholine (84.5 mg) at room temperature under an argon atmosphere over a period of 5 minutes. The mixture was cooled to 0° C. and HATU (117 mg) was added. The mixture was allowed to warm to room temperature for 17 h. The reaction mixture was poured into ice/water and the aqueous phase was subsequently extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and evaporated. Toluene was added and the mixture was evaporated again. The crude material was purified by flash chromatography (silica gel, gradient of ethyl acetate in heptane) to give the title compound as a white solid (13 mg, 10%). MS (m/e): 504.6 [M+H] ⁺

The following Examples 15-17 were synthesized similarly to Example 10 from Intermediate 9 and the corresponding substituted carboxylic acids:

Example 26

3-[4-(difluoromethoxy)-3-fluorophenyl]-1-[2-(1,4,6,7-tetrahydrotriazolo[4,5-c]pyridine-5-carbonyl] yl)-4,5,7,8-tetrahydropyrazolo[1,5-d][1,4]diazepine -6-yl]propan-1-one

In a 25mL three-necked flask, (E)-3-[4-(difluoromethoxy)-3-fluorophenyl]-1-[2-(1,4,6,7-tetrahydrotriazolo[4,5-c]pyridine-5-carbonyl)-4,5,7,8-tetrahydropyrazolo[1,5-d][1,4]diazepine-6-yl]prop-2-ene-1-one (Example 25, 35mg) was combined with EtOH (5mL) to give a colorless solution. The mixture was degassed and Pd/C (10% Pd, 20mg) was added under nitrogen, followed by the introduction of a hydrogen atmosphere. The mixture was then stirred at room temperature overnight. The hydrogen was then removed and the reaction mixture was filtered through Celite. The filtrate was evaporated to give a crude material as a white foam. The residue was purified by flash chromatography (silica gel, 10g, 0% to 50% MeOH in DCM) to give the title compound as a white foam (20mg). MS: 504.2[M+H] ⁺ .

Example 27

2-(4,5,6,7-tetrahydro-1H-[1,2,3]triazolo[4,5-c]pyridine-5-carbonyl)-7,8-dihydro-4H-pyrazole benzo[1,5-d][1,4]diazepine -4-Methoxybenzyl 6(5H)-formate

This material was prepared in analogy to Example 3, Step 2, from 5,6,7,8-tetrahydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl(1,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)methanone (Intermediate 9) and (4-methoxyphenyl)methanol (CAS: 105-13-5). MS: 452.3 [M+H] ⁺ .

The following Examples 28-43 were synthesized analogously to Example 27 from appropriate building blocks and correspondingly substituted benzyl alcohols:

Claims (29)

1. Compounds of formula (I) in ^R1 is a _C1-7 alkyl, halo _-C1-7 alkyl, substituted _C3-8 cycloalkyl, substituted C3-8 cycloalkyl _C1-7 alkyl, substituted phenyl, substituted phenyl _C1-7 alkyl, substituted phenoxy _C1-7 alkyl, substituted phenyl _C1-7 alkoxy, substituted phenyl _C3-8 cycloalkyl, substituted phenyl _C2-7 alkenyl, substituted phenyl _C2-7 ynyl, substituted pyridyl, substituted pyridyl _C1-7 alkyl, substituted pyridyl _{C2-7 alkenyl} , substituted pyridyl _C2-7 ynyl, substituted thiophene, substituted thiophene _C1-7 alkyl, substituted thiophene _C2-7 alkenyl, substituted thiophene C _2-7 ynyl, substituted 2,3-dihydro-1H-isoindol-2-yl, substituted 1H-indol-2-yl, or substituted benzofuran-2-yl, wherein the substituted _C3-8 cycloalkyl, substituted _C3-8 cycloalkyl- _C1-7 alkyl, substituted phenyl, substituted phenyl- _C1-7 alkyl, substituted phenoxy- _C1-7 alkyl, substituted phenyl _{- C1-7} alkoxy, substituted phenyl- _C3-8 cycloalkyl, substituted phenyl- _C2-7 alkenyl, substituted phenyl-C2-7 ynyl, substituted pyridyl, substituted pyridyl- _C1-7 alkyl, substituted pyridyl _{- C2-7} alkenyl, substituted pyridyl- _C2-7 ynyl, substituted thiophene, substituted thiophene- _C1-7 alkyl, substituted thiophene-C2-7 alkenyl ... _2-7 alkynyl, substituted 2,3-dihydro-1H-isoindol-2-yl, substituted 1H-indol-2-yl and substituted benzofuran-2-yl are substituted by ^R3 , ^R4 and ^R5 ; A ¹ is -N- or -CR ^7- ; ^A2 is -N- or ^-CR8- and at least one of ^A1 and ^A2 is -N-; ^R2 is selected from ring systems A and E. ^R3 , ^R4 , and ^R5 are independently selected from H, _C1-7 alkyl, hydroxy _C1-7 alkyl, halogenated _C1-7 alkyl, hydroxyhalogenated _C1-7 alkyl, _C3-8 cycloalkyl, C3-8 cycloalkyl _C1-7 alkyl, _C3-8 cycloalkyl _C1-7 alkoxy, _C3-8 cycloalkoxy, _C3-8 cycloalkoxy _C1-7 alkyl, _C3-8 cycloalkyl _C1-7 alkoxy _C1-7 alkyl, _C1-7 alkoxy, _C1-7 alkoxy _C1-7 alkyl, halogenated _C1-7 alkoxy, _C1-7 alkoxy halogenated _C1-7 alkyl, _C1-7 alkoxy _C1-7 alkoxy, _C1-7 alkoxy _C1-7 alkoxy _C1-7 alkyl, _heterocyclic alkyl C _1-7 alkoxy, phenyl, substituted phenyl, pyridyl, substituted pyridyl, halogen, hydroxyl, cyano, _C1-7 alkylthioalkyl, halo _-C1-7 alkylthioalkyl, _C3-8 cycloalkylthioalkyl, _C1-7 alkylsulfinyl, halo- _C1-7 alkylsulfinyl, _C3-8 cycloalkylsulfinyl, _C1-7 alkylsulfonyl, halo _-C1-7 alkylsulfonyl, _C3-8 cycloalkylsulfonyl, _C1-7 alkylcarbonylamino, substituted aminosulfonyl, substituted amino and substituted amino _C1-7 alkyl, wherein the substituted aminosulfonyl, substituted amino and substituted amino _C1-7 alkyl are independently selected from H, _C1-7 alkyl, _C3-8 cycloalkyl, _C3-8 cycloalkyl _C1-7 alkyl, hydroxy _C1-7 alkyl, C1-7 alkoxy _C1-7 alkyl, etc. The substituted phenyl group is replaced by a substituent of _{a C1-7} alkyl group, a _C1-7 alkyl carbonyl group, and a _C3-8 cycloalkyl carbonyl group, wherein the substituted phenyl group and the substituted pyridyl group are optionally replaced by one to three substituents independently selected from _C1-7 alkyl, halogen, halo- _C1-7 alkyl, _C1-7 alkoxy, and halo- _C1-7 alkoxy groups; ^R7 and ^R8 are independently selected from H, _C1-7 alkyl, halogenated _C1-7 alkyl, or _C3-8 cycloalkyl; "Heterocyclic alkyl" refers to a monocyclic or bicyclic ring system with 4 to 9 ring atoms, consisting of 1, 2, or 3 ring heteroatoms selected from N, O, and S, with the remaining ring atoms being carbon. " _C1-7 alkylthioalkyl" represents a group of the formula -S-R', where R' is a _C1-7 alkyl group. The term "halogenated _C1-7 alkylthioalkyl" is represented by a group of the formula -S-R', where R' is a halo- _C1-7 alkyl group. "C _3-8 cycloalkylthioalkyl" represents a group of the formula -S-R', where R' is a C _3-8 cycloalkyl group. Or medicinal salt. 2. The compound according to claim 1, wherein... ^R1 is a _C1-7 alkyl, halo _-C1-7 alkyl, substituted _C3-8 cycloalkyl, substituted C3-8 cycloalkyl _C1-7 alkyl, substituted phenyl, substituted phenyl _C1-7 alkyl, substituted phenoxy _C1-7 alkyl, substituted phenyl _C1-7 alkoxy, substituted phenyl _C3-8 cycloalkyl, substituted phenyl _C2-7 alkenyl, substituted phenyl _C2-7 ynyl, substituted pyridyl, substituted pyridyl _C1-7 alkyl, substituted pyridyl _{C2-7 alkenyl} , substituted pyridyl _C2-7 ynyl, substituted thiophene, substituted thiophene _C1-7 alkyl, substituted thiophene _C2-7 alkenyl, substituted thiophene C _2-7 ynyl, substituted 2,3-dihydro-1H-isoindol-2-yl, substituted 1H-indol-2-yl, or substituted benzofuran-2-yl, wherein the substituted _C3-8 cycloalkyl, substituted _C3-8 cycloalkyl- _C1-7 alkyl, substituted phenyl, substituted phenyl- _C1-7 alkyl, substituted phenoxy- _C1-7 alkyl, substituted phenyl _{- C1-7} alkoxy, substituted phenyl- _C3-8 cycloalkyl, substituted phenyl- _C2-7 alkenyl, substituted phenyl-C2-7 ynyl, substituted pyridyl, substituted pyridyl- _C1-7 alkyl, substituted pyridyl _{- C2-7} alkenyl, substituted pyridyl- _C2-7 ynyl, substituted thiophene, substituted thiophene- _C1-7 alkyl, substituted thiophene-C2-7 alkenyl ... _2-7 alkynyl, substituted 2,3-dihydro-1H-isoindol-2-yl, substituted 1H-indol-2-yl and substituted benzofuran-2-yl are substituted by ^R3 , ^R4 and ^R5 ; A ¹ is -N- or -CR ^7- ; ^A2 is -N- or ^-CR8- and at least one of ^A1 and ^A2 is -N-; ^R2 is selected from ring systems A and E. ^R3 , ^R4 , and ^R5 are independently selected from H, _C1-7 alkyl, hydroxy _C1-7 alkyl, halo- _C1-7 alkyl, hydroxy-halo- _C1-7 alkyl, _C3-8 cycloalkyl, _C3-8 cycloalkyl _C1-7 alkyl, _C3-8 cycloalkyl _C1-7 alkoxy, _C3-8 cycloalkoxy _C1-7 alkyl, C3-8 cycloalkyl _C1-7 alkoxy _C1-7 alkyl, _C1-7 alkoxy, _C1-7 alkoxy _C1-7 alkyl, halo- _C1-7 alkoxy, _C1-7 alkoxy-halo- _C1-7 alkyl, _C1-7 alkoxy _C1-7 alkoxy, _C1-7 alkoxy _C1-7 alkoxy _{C1-7 alkyl} , phenyl, substituted phenyl, pyridyl, substituted pyridyl, _halogen , hydroxyl, cyano, C _1-7 alkylthioalkyl, halo- _C1-7 alkylthioalkyl, C3-8 cycloalkylthioalkyl, _C1-7 alkylsulfinyl, halo- _C1-7 alkylsulfinyl, _C3-8 cycloalkylsulfinyl, _C1-7 alkylsulfonyl, halo _-C1-7 alkylsulfonyl, _C3-8 cycloalkylsulfonyl, _C1-7 alkylcarbonylamino, substituted aminosulfonyl, substituted amino, and substituted amino _C1-7 alkyl, wherein the substituted aminosulfonyl, substituted amino, and substituted amino _C1-7 alkyl are independently selected from H, _C1-7 alkyl, _C3-8 cycloalkyl, _C3-8 cycloalkyl _C1-7 alkyl, hydroxy _C1-7 alkyl, _C1-7 alkoxy _C1-7 alkyl, _C1-7 alkylcarbonyl, _and C _{The 3-8} cycloalkyl carbonyl group is substituted with a substituent, wherein the substituted phenyl group and the substituted pyridyl group are optionally substituted with one to three substituents independently selected from _C1-7 alkyl, halogen, halo- _C1-7 alkyl, _C1-7 alkoxy and halo- _C1-7 alkoxy groups; ^R7 and ^R8 are independently selected from H, _C1-7 alkyl, halogenated _C1-7 alkyl, or _C3-8 cycloalkyl; Or medicinal salt. 3. The compound according to claim 1 or 2, wherein ^R1 is a substituted phenyl _C1-7 alkyl, a substituted phenoxy _C1-7 alkyl, or a substituted phenyl _C1-7 alkoxy, wherein the substituted phenyl _C1-7 alkyl, the substituted phenoxy _C1-7 alkyl, and the substituted phenyl _C1-7 alkoxy are substituted by ^R3 , ^R4 , and ^R5 . 4. The compound according to claim 1 or 2, wherein ^R1 is a substituted phenoxy _C1-7 alkyl or a substituted phenyl _C1-7 alkoxy, wherein the substituted phenoxy _C1-7 alkyl and the substituted phenyl _C1-7 alkoxy are substituted by ^R3 , ^R4 and ^R5 . 5. The compound according to claim 1 or 2, wherein ^R1 is a phenyl _C1-7 alkoxy group substituted with ^R3 , ^R4 and ^R5 . 6. The compound according to claim 1 or 2, wherein ^R2 is a ring system E. 7. The compound according to claim 1 or 2, wherein ^R2 is ring system A. 8. The compound according to claim 1 or 2, wherein ^A1 is -N- and ^A2 is -N- or ^-CR8- . 9. The compound according to claim 1 or 2, wherein ^R3 , ^R4 and ^R5 are independently selected from H, _C1-7 alkyl, _C3-8 cycloalkyl, heterocyclic alkyl _C1-7 alkoxy, halogenated _C1-7 alkoxy, halogen, cyano, and _C1-7 alkyl carbonylamino, wherein "heterocyclic alkyl" is as defined in claim 1. 10. The compound according to claim 1 or 2, wherein ^R3 , ^R4 and ^R5 are independently selected from H, _C1-7 alkyl, _C3-8 cycloalkyl, halogenated _C1-7 alkoxy, halogen, cyano and _C1-7 alkylcarbonylamino. 11. The compound according to claim 1 or 2, wherein R ³ is a heterocyclic alkyl _C1-7 alkoxy, halogenated _C1-7 alkoxy, or cyano, wherein "heterocyclic alkyl" is as defined in claim 1. 12. The compound according to claim 1 or 2, wherein ^R3 is a halo- _C1-7 alkoxy or cyano group. 13. The compound according to claim 1 or 2, wherein ^R4 is H, _C1-7 alkyl, _C3-8 cycloalkyl, or halogen. 14. The compound according to claim 1 or 2, wherein ^R4 is H, _C1-7 alkyl or halogen. 15. The compound according to claim 1 or 2, wherein ^R5 is H. 16. The compound according to claim 1 or 2, wherein R ⁷ is H. 17. The compound according to claim 1 or 2, wherein ^R8 is H. 18. The compound according to claim 1 or 2, wherein... ^R1 is a substituted phenyl _C1-7 alkoxy group, which is substituted by ^R3 , ^R4 and ^R5 ; ^A1 is -N-; A ² is -N- or -CR ^8- ; ^R2 is the ring system A; ^R3 is a halogenated _C1-7 alkoxy or cyano group; ^R4 is H or a halogen; R ⁵ is H; R ⁸ is H; Or medicinal salt. 19. The compound according to claim 1 or 2, wherein the compound is selected from... 2-(1,4,6,7-tetrahydrotriazolo[4,5-c]pyridine-5-carbonyl)-4,5,7,8-tetrahydropyrazolo[1,5-d][1,4]diaza-6-carboxylic acid benzyl ester; 2-(1,4,6,7-tetrahydrotriazolo[4,5-c]pyridine-5-carbonyl)-5,6,8,9-tetrahydroimidazo[1,2-d][1,4]diaza-7-carboxylic acid benzyl ester; 2-(1,4,6,7-tetrahydrotriazolo[4,5-c]pyridine-5-carbonyl)-4,5,7,8-tetrahydropyrazolo[1,5-d][1,4]diaza-6-carboxylic acid [3-fluoro-4-(trifluoromethoxy)phenyl]methyl ester; 2-(4,5,6,7-tetrahydro-1H-[1,2,3]triazolo[4,5-c]pyridine-5-carbonyl)-7,8-dihydro-4H-pyrazolo[1,5-d][1,4]diaza-6(5H)-carboxylic acid 2-fluoro-4-(trifluoromethoxy)benzyl ester; 2-(1,4,6,7-tetrahydrotriazolo[4,5-c]pyridine-5-carbonyl)-4,5,7,8-tetrahydropyrazolo[1,5-d][1,4]diaza-6-carboxylic acid[4-(trifluoromethoxy)phenyl]methyl ester; 2-(4,5,6,7-tetrahydro-1H-[1,2,3]triazolo[4,5-c]pyridine-5-carbonyl)-7,8-dihydro-4H-pyrazolo[1,5-d][1,4]diaza-6(5H)-formic acid 4-cyanobenzyl ester; 2-(4,5,6,7-tetrahydro-1H-[1,2,3]triazolo[4,5-c]pyridine-5-carbonyl)-7,8-dihydro-4H-pyrazolo[1,5-d][1,4]diaza-6(5H)-carboxylic acid 4-cyano-3-fluorobenzyl ester; 2-(4,5,6,7-tetrahydro-1H-[1,2,3]triazolo[4,5-c]pyridine-5-carbonyl)-7,8-dihydro-4H-pyrazolo[1,5-d][1,4]diaza-6(5H)-carboxylic acid 4-cyano-2-fluorobenzyl ester; 2-(1,4,6,7-tetrahydrotriazolo[4,5-c]pyridine-5-carbonyl)-4,5,7,8-tetrahydropyrazolo[1,5-d][1,4]diaza-6-carboxylic acid (4-cyano-2-prop-2-ylphenyl) methyl ester; 2-(1,4,6,7-tetrahydrotriazolo[4,5-c]pyridine-5-carbonyl)-4,5,7,8-tetrahydropyrazolo[1,5-d][1,4]diaza-6-carboxylic acid [4-cyano-2-(2,2-dimethylpropionylamino)phenyl]methyl ester; 2-(1,4,6,7-tetrahydrotriazolo[4,5-c]pyridine-5-carbonyl)-5,6,8,9-tetrahydro-[1,2,4]triazolo[1,5-d][1,4]diaza-7-carboxylic acid[4-(trifluoromethoxy)phenyl]methyl ester; 2-(1,4,6,7-tetrahydrotriazolo[4,5-c]pyridine-5-carbonyl)-5,6,8,9-tetrahydro-[1,2,4]triazolo[1,5-d][1,4]diaza-7-carboxylic acid [4-cyano-2-(2,2-dimethylpropionylamino)phenyl]methyl ester; 2-(1,4,6,7-tetrahydrotriazolo[4,5-c]pyridine-5-carbonyl)-5,6,8,9-tetrahydroimidazo[1,2-d][1,4]diaza-7-carboxylic acid[4-(trifluoromethoxy)phenyl]methyl ester; 1-[2-(1,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-carbonyl)-4,5,7,8-tetrahydropyrazolo[1,5-d][1,4]diaza-6-yl]-3-[4-(trifluoromethoxy)phenyl]prop-1-one; 3-Cyclopropyl-4-(2-oxo-2-(2-(4,5,6,7-tetrahydro-1H-[1,2,3]triazolo[4,5-c]pyridin-5-carbonyl)-7,8-dihydro-4H-pyrazolo[1,5-d][1,4]diaza-6(5H)-yl)ethoxy)benzonitrile; 3-Ethyl-4-(2-oxo-2-(2-(4,5,6,7-tetrahydro-1H-[1,2,3]triazolo[4,5-c]pyridin-5-carbonyl)-7,8-dihydro-4H-pyrazolo[1,5-d][1,4]diaza-6(5H)-yl)ethoxy)benzonitrile; 3-tert-butyl-4-[2-oxo-2-[2-(1,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-carbonyl)-4,5,7,8-tetrahydropyrazolo[1,5-d][1,4]diaza-6-yl]ethoxy]benzonitrile; 3-[3-fluoro-4-(trifluoromethoxy)phenyl]-1-[2-(1,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-carbonyl)-4,5,7,8-tetrahydropyrazolo[1,5-d][1,4]diaza-6-yl]prop-1-one; 3-(4-methoxyphenyl)-1-[2-(1,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-carbonyl)-4,5,7,8-tetrahydropyrazolo[1,5-d][1,4]diaza-6-yl]prop-1-one; 1-[2-(1,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-carbonyl)-5,6,8,9-tetrahydro-[1,2,4]triazolo[1,5-d][1,4]diaza-7-yl]-3-[4-(trifluoromethoxy)phenyl]prop-1-one; 3-[3-fluoro-4-(trifluoromethoxy)phenyl]-1-[2-(1,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-carbonyl)-5,6,8,9-tetrahydro-[1,2,4]triazolo[1,5-d][1,4]diaza-7-yl]prop-1-one; 3-[3-chloro-4-(trifluoromethoxy)phenyl]-1-[2-(1,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-carbonyl)-4,5,7,8-tetrahydropyrazolo[1,5-d][1,4]diaza-6-yl]prop-1-one; 3-[3-chloro-4-(trifluoromethoxy)phenyl]-1-[2-(1,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-carbonyl)-5,6,8,9-tetrahydro-[1,2,4]triazolo[1,5-d][1,4]diaza-7-yl]prop-1-one; (6-(2-cyclopropyl-6-((tetrahydro-2H-pyran-4-yl)methoxy)isonicotinyl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-d][1,4]diaza-2-yl)(6,7-dihydro-1H-[1,2,3]triazolo[4,5-c]pyridin-5(4H)-yl) methyl ketone; (E)-3-[4-(difluoromethoxy)-3-fluorophenyl]-1-[2-(1,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-carbonyl)-4,5,7,8-tetrahydropyrazolo[1,5-d][1,4]diaza-6-yl]propyl-2-en-1-one; 3-[4-(difluoromethoxy)-3-fluorophenyl]-1-[2-(1,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-carbonyl)-4,5,7,8-tetrahydropyrazolo[1,5-d][1,4]diaza-6-yl]prop-1-one; 2-(4,5,6,7-tetrahydro-1H-[1,2,3]triazolo[4,5-c]pyridine-5-carbonyl)-7,8-dihydro-4H-pyrazolo[1,5-d][1,4]diaza-6(5H)-formic acid 4-methoxybenzyl ester; 2-(4,5,6,7-tetrahydro-1H-[1,2,3]triazolo[4,5-c]pyridine-5-carbonyl)-7,8-dihydro-4H-pyrazolo[1,5-d][1,4]diaza-6(5H)-carboxylic acid 4-fluorobenzyl ester; 2-(4,5,6,7-tetrahydro-1H-[1,2,3]triazolo[4,5-c]pyridine-5-carbonyl)-7,8-dihydro-4H-pyrazolo[1,5-d][1,4]diaza-6(5H)-carboxylic acid 3-fluorobenzyl ester; 2-(1,4,6,7-tetrahydrotriazolo[4,5-c]pyridine-5-carbonyl)-4,5,7,8-tetrahydropyrazolo[1,5-d][1,4]diaza-6-carboxylic acid (3,4-difluorophenyl) methyl ester; 2-(4,5,6,7-tetrahydro-1H-[1,2,3]triazolo[4,5-c]pyridine-5-carbonyl)-7,8-dihydro-4H-pyrazolo[1,5-d][1,4]diaza-6(5H)-formic acid 4-(difluoromethoxy)-3-fluorobenzyl ester; 2-(4,5,6,7-tetrahydro-1H-[1,2,3]triazolo[4,5-c]pyridine-5-carbonyl)-7,8-dihydro-4H-pyrazolo[1,5-d][1,4]diaza-6(5H)-formic acid 3-fluoro-4-methoxybenzyl ester; 2-(4,5,6,7-tetrahydro-1H-[1,2,3]triazolo[4,5-c]pyridine-5-carbonyl)-7,8-dihydro-4H-pyrazolo[1,5-d][1,4]diaza-6(5H)-formic acid 4-methoxy-2-methylbenzyl ester; 2-(4,5,6,7-tetrahydro-1H-[1,2,3]triazolo[4,5-c]pyridine-5-carbonyl)-7,8-dihydro-4H-pyrazolo[1,5-d][1,4]diaza-6(5H)-carboxylic acid 4-cyclopropylbenzyl ester; 2-(1,4,6,7-tetrahydrotriazolo[4,5-c]pyridine-5-carbonyl)-5,6,8,9-tetrahydro-[1,2,4]triazolo[1,5-d][1,4]diaza-7-carboxylic acid [2-fluoro-4-(trifluoromethoxy)phenyl]methyl ester; 2-(1,4,6,7-tetrahydrotriazolo[4,5-c]pyridine-5-carbonyl)-5,6,8,9-tetrahydro-[1,2,4]triazolo[1,5-d][1,4]diaza-7-carboxylic acid [3-fluoro-4-(trifluoromethoxy)phenyl]methyl ester; 2-(4,5,6,7-tetrahydro-1H-[1,2,3]triazolo[4,5-c]pyridine-5-carbonyl)-7,8-dihydro-4H-pyrazolo[1,5-d][1,4]diaza-6(5H)-carboxylic acid 3-chloro-4-(trifluoromethoxy)benzyl ester; 2-(4,5,6,7-tetrahydro-1H-[1,2,3]triazolo[4,5-c]pyridine-5-carbonyl)-7,8-dihydro-4H-pyrazolo[1,5-d][1,4]diaza-6(5H)-carboxylic acid 2-methoxy-4-(trifluoromethoxy)benzyl ester; 2-(4,5,6,7-tetrahydro-1H-[1,2,3]triazolo[4,5-c]pyridine-5-carbonyl)-7,8-dihydro-4H-pyrazolo[1,5-d][1,4]diaza-6(5H)-carboxylic acid 2-methyl-4-(trifluoromethoxy)benzyl ester; 2-(4,5,6,7-tetrahydro-1H-[1,2,3]triazolo[4,5-c]pyridine-5-carbonyl)-7,8-dihydro-4H-pyrazolo[1,5-d][1,4]diaza-6(5H)-carboxylic acid 4-(2,2,2-trifluoroethoxy)benzyl ester; 2-(1,4,6,7-tetrahydrotriazolo[4,5-c]pyridine-5-carbonyl)-5,6,8,9-tetrahydro-[1,2,4]triazolo[1,5-d][1,4]diaza-7-carboxylic acid [3-chloro-4-(trifluoromethoxy)phenyl]methyl ester; 2-(1,4,6,7-tetrahydrotriazolo[4,5-c]pyridine-5-carbonyl)-5,6,8,9-tetrahydroimidazo[1,2-d][1,4]diaza-7-carboxylic acid [3-chloro-4-(trifluoromethoxy)phenyl]methyl ester; 2-((3aR,7aR)-2-oxooctahydroazolo[5,4-c]pyridine-5-carbonyl)-8,9-dihydro-5H-[1,2,4]triazolo[1,5-d][1,4]diaza-7(6H)-carboxylic acid 3-fluoro-4-(trifluoromethoxy)benzyl ester; And its medicinal salt. 20. The compound according to claim 1 or 2, wherein the compound is selected from... 2-(1,4,6,7-tetrahydrotriazolo[4,5-c]pyridine-5-carbonyl)-4,5,7,8-tetrahydropyrazolo[1,5-d][1,4]diaza-6-carboxylic acid benzyl ester; 2-(1,4,6,7-tetrahydrotriazolo[4,5-c]pyridine-5-carbonyl)-5,6,8,9-tetrahydroimidazo[1,2-d][1,4]diaza-7-carboxylic acid benzyl ester; 2-(1,4,6,7-tetrahydrotriazolo[4,5-c]pyridine-5-carbonyl)-4,5,7,8-tetrahydropyrazolo[1,5-d][1,4]diaza-6-carboxylic acid [3-fluoro-4-(trifluoromethoxy)phenyl]methyl ester; 2-(4,5,6,7-tetrahydro-1H-[1,2,3]triazolo[4,5-c]pyridine-5-carbonyl)-7,8-dihydro-4H-pyrazolo[1,5-d][1,4]diaza-6(5H)-carboxylic acid 2-fluoro-4-(trifluoromethoxy)benzyl ester; 2-(1,4,6,7-tetrahydrotriazolo[4,5-c]pyridine-5-carbonyl)-4,5,7,8-tetrahydropyrazolo[1,5-d][1,4]diaza-6-carboxylic acid[4-(trifluoromethoxy)phenyl]methyl ester; 2-(4,5,6,7-tetrahydro-1H-[1,2,3]triazolo[4,5-c]pyridine-5-carbonyl)-7,8-dihydro-4H-pyrazolo[1,5-d][1,4]diaza-6(5H)-formic acid 4-cyanobenzyl ester; 2-(4,5,6,7-tetrahydro-1H-[1,2,3]triazolo[4,5-c]pyridine-5-carbonyl)-7,8-dihydro-4H-pyrazolo[1,5-d][1,4]diaza-6(5H)-carboxylic acid 4-cyano-3-fluorobenzyl ester; 2-(4,5,6,7-tetrahydro-1H-[1,2,3]triazolo[4,5-c]pyridine-5-carbonyl)-7,8-dihydro-4H-pyrazolo[1,5-d][1,4]diaza-6(5H)-carboxylic acid 4-cyano-2-fluorobenzyl ester; 2-(1,4,6,7-tetrahydrotriazolo[4,5-c]pyridine-5-carbonyl)-4,5,7,8-tetrahydropyrazolo[1,5-d][1,4]diaza-6-carboxylic acid (4-cyano-2-prop-2-ylphenyl) methyl ester; 2-(1,4,6,7-tetrahydrotriazolo[4,5-c]pyridine-5-carbonyl)-4,5,7,8-tetrahydropyrazolo[1,5-d][1,4]diaza-6-carboxylic acid [4-cyano-2-(2,2-dimethylpropionylamino)phenyl]methyl ester; 2-(1,4,6,7-tetrahydrotriazolo[4,5-c]pyridine-5-carbonyl)-5,6,8,9-tetrahydro-[1,2,4]triazolo[1,5-d][1,4]diaza-7-carboxylic acid[4-(trifluoromethoxy)phenyl]methyl ester; 2-(1,4,6,7-tetrahydrotriazolo[4,5-c]pyridine-5-carbonyl)-5,6,8,9-tetrahydro-[1,2,4]triazolo[1,5-d][1,4]diaza-7-carboxylic acid [4-cyano-2-(2,2-dimethylpropionylamino)phenyl]methyl ester; 2-(1,4,6,7-tetrahydrotriazolo[4,5-c]pyridine-5-carbonyl)-5,6,8,9-tetrahydroimidazo[1,2-d][1,4]diaza-7-carboxylic acid[4-(trifluoromethoxy)phenyl]methyl ester; 1-[2-(1,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-carbonyl)-4,5,7,8-tetrahydropyrazolo[1,5-d][1,4]diaza-6-yl]-3-[4-(trifluoromethoxy)phenyl]prop-1-one; 3-Cyclopropyl-4-(2-oxo-2-(2-(4,5,6,7-tetrahydro-1H-[1,2,3]triazolo[4,5-c]pyridin-5-carbonyl)-7,8-dihydro-4H-pyrazolo[1,5-d][1,4]diaza-6(5H)-yl)ethoxy)benzonitrile; 3-Ethyl-4-(2-oxo-2-(2-(4,5,6,7-tetrahydro-1H-[1,2,3]triazolo[4,5-c]pyridin-5-carbonyl)-7,8-dihydro-4H-pyrazolo[1,5-d][1,4]diaza-6(5H)-yl)ethoxy)benzonitrile; 3-tert-butyl-4-[2-oxo-2-[2-(1,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-carbonyl)-4,5,7,8-tetrahydropyrazolo[1,5-d][1,4]diaza-6-yl]ethoxy]benzonitrile; And its medicinal salt. 21. The compound according to claim 1 or 2, wherein the compound is selected from... (6-(2-cyclopropyl-6-((tetrahydro-2H-pyran-4-yl)methoxy)isonicotinyl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-d][1,4]diaza-2-yl)(6,7-dihydro-1H-[1,2,3]triazolo[4,5-c]pyridin-5(4H)-yl) methyl ketone; (E)-3-[4-(difluoromethoxy)-3-fluorophenyl]-1-[2-(1,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-carbonyl)-4,5,7,8-tetrahydropyrazolo[1,5-d][1,4]diaza-6-yl]propyl-2-en-1-one; 2-(4,5,6,7-tetrahydro-1H-[1,2,3]triazolo[4,5-c]pyridine-5-carbonyl)-7,8-dihydro-4H-pyrazolo[1,5-d][1,4]diaza-6(5H)-formic acid 4-(difluoromethoxy)-3-fluorobenzyl ester; 2-(1,4,6,7-tetrahydrotriazolo[4,5-c]pyridine-5-carbonyl)-5,6,8,9-tetrahydro-[1,2,4]triazolo[1,5-d][1,4]diaza-7-carboxylic acid [3-fluoro-4-(trifluoromethoxy)phenyl]methyl ester; 2-(4,5,6,7-tetrahydro-1H-[1,2,3]triazolo[4,5-c]pyridine-5-carbonyl)-7,8-dihydro-4H-pyrazolo[1,5-d][1,4]diaza-6(5H)-carboxylic acid 3-chloro-4-(trifluoromethoxy)benzyl ester; 2-(4,5,6,7-tetrahydro-1H-[1,2,3]triazolo[4,5-c]pyridine-5-carbonyl)-7,8-dihydro-4H-pyrazolo[1,5-d][1,4]diaza-6(5H)-carboxylic acid 2-methyl-4-(trifluoromethoxy)benzyl ester; 2-(1,4,6,7-tetrahydrotriazolo[4,5-c]pyridine-5-carbonyl)-5,6,8,9-tetrahydro-[1,2,4]triazolo[1,5-d][1,4]diaza-7-carboxylic acid [3-chloro-4-(trifluoromethoxy)phenyl]methyl ester; 2-(1,4,6,7-tetrahydrotriazolo[4,5-c]pyridine-5-carbonyl)-5,6,8,9-tetrahydroimidazo[1,2-d][1,4]diaza-7-carboxylic acid [3-chloro-4-(trifluoromethoxy)phenyl]methyl ester; And its medicinal salt. 22. The compound according to claim 1 or 2, wherein the compound is selected from... 2-(4,5,6,7-tetrahydro-1H-[1,2,3]triazolo[4,5-c]pyridine-5-carbonyl)-7,8-dihydro-4H-pyrazolo[1,5-d][1,4]diaza-6(5H)-formic acid-3-fluoro-4-(trifluoromethoxy)benzyl ester; 2-(1,4,6,7-tetrahydrotriazolo[4,5-c]pyridine-5-carbonyl)-4,5,7,8-tetrahydropyrazolo[1,5-d][1,4]diaza-6-carboxylic acid[4-(trifluoromethoxy)phenyl]methyl ester; 2-(1,4,6,7-tetrahydrotriazolo[4,5-c]pyridine-5-carbonyl)-5,6,8,9-tetrahydro-[1,2,4]triazolo[1,5-d][1,4]diaza-7-carboxylic acid[4-(trifluoromethoxy)phenyl]methyl ester; 2-(1,4,6,7-tetrahydrotriazolo[4,5-c]pyridine-5-carbonyl)-5,6,8,9-tetrahydroimidazo[1,2-d][1,4]diaza-7-carboxylic acid[4-(trifluoromethoxy)phenyl]methyl ester; 3-tert-butyl-4-[2-oxo-2-[2-(1,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-carbonyl)-4,5,7,8-tetrahydropyrazolo[1,5-d][1,4]diaza-6-yl]ethoxy]benzonitrile; And its medicinal salt. 23. A method for preparing a compound according to any one of claims 1 to 22, said method comprising reacting a compound of formula (II) in the presence of a compound of formula (III), wherein ^R1 is a phenyl _C1-7 alkoxy substituted with ^R3 , ^R4 , and ^R5 , _RA is a phenyl _C1-7 alkyl substituted with ^R3 , ^R4 , and ^R5 , and ^R2 , ^R3 , ^R4 , ^R5 , ^A1 , and ^A2 are as defined in any one of claims 1 to 22. 24. A method for preparing a compound according to any one of claims 1 to 22, the method comprising reacting a compound of formula (II) in the presence of a compound of formula (IV), wherein ^R1 is a _C1-7 alkyl, a halo _-C1-7 alkyl, a substituted _C3-8 cycloalkyl, a substituted _C1-7 cycloalkyl _{-C1-7 alkyl} , a substituted phenyl, a substituted phenyl- _C1-7 alkyl, a substituted phenoxy- _C1-7 alkyl, a substituted phenyl- _C3-8 cycloalkyl, a substituted phenyl- _C2-7 alkenyl, a substituted phenyl- _C2-7 ynyl, a substituted pyridyl, a substituted pyridyl- _C1-7 alkyl, a substituted pyridyl- _C2-7 alkenyl, a substituted pyridyl- _C2-7 ynyl, a substituted thiophene, a substituted thiophene-C1-7 alkyl, a substituted thiophene- _C2-7 alkenyl ... _2-7 ynyl, substituted 2,3-dihydro-1H-isoindol-2-yl, substituted 1H-indol-2-yl, or substituted benzofuran-2-yl, wherein the substituted _C3-8 cycloalkyl, substituted _C3-8 cycloalkyl- _C1-7 alkyl, substituted phenyl, substituted phenyl- _C1-7 alkyl, substituted phenoxy _{-C1-7 alkyl} , substituted phenyl- _C3-8 cycloalkyl, substituted phenyl- _C2-7 alkenyl, substituted phenyl- _C2-7 ynyl, substituted pyridyl, substituted pyridyl- _C1-7 alkyl, substituted pyridyl-C2-7 alkenyl, substituted pyridyl- _C2-7 ynyl, substituted thiophenyl, substituted thiophenyl- _C1-7 alkyl, substituted thiophenyl- _C2-7 alkenyl, substituted thiophenyl-C The _2-7 ynyl group, the substituted 2,3-dihydro-1H-isoindol-2-yl group, the substituted 1H-indol-2-yl group, and the substituted benzofuran-2-yl group are substituted by ^R3 , ^R4 , and ^R5 , and ^R2 , ^R3 , ^R4 , ^R5 , ^A1 , and ^A2 are as defined in any one of claims 1 to 22. 25. The compound according to any one of claims 1 to 22, which is used as a therapeutically active substance. 26. A pharmaceutical composition comprising the compound according to any one of claims 1 to 22 and a therapeutically inert carrier. 27. The compound according to any one of claims 1 to 22, for the treatment or prevention of kidney disease, liver disease, inflammatory disease, nervous system disease, fibrotic disease, and acute and chronic organ transplant rejection. 28. Use of the compound according to any one of claims 1 to 22 for the preparation of a medicament for the treatment or prevention of kidney disease, liver disease, inflammatory disease, neurological disease, fibrotic disease, and acute and chronic organ transplant rejection. 29. The compound according to any one of claims 1 to 22, manufactured by the method according to claim 23 or 24.