HK1226403A1

HK1226403A1 - Condensed [1,4]diazepine compounds as autotaxin (atx) and lysophosphatidic acid (lpa) production inhibitors

Info

Publication number: HK1226403A1
Application number: HK16114768.3A
Authority: HK
Inventors: 丹尼尔．洪齐格; 热罗姆．埃尔特; 豪格．屈内; 帕特里齐奥．马太; 马库斯．鲁道夫
Original assignee: 豪夫迈．罗氏有限公司
Priority date: 2014-03-26
Filing date: 2015-03-23
Publication date: 2017-09-29

Description

fused [1,4] diazepine compounds as Autotaxin (ATX) and lysophosphatidic acid (LPA) production inhibitors

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

The present invention provides novel compounds of formula (I)

Wherein

R¹Is alkyl, haloalkyl, substituted cycloalkyl, substituted cycloalkylalkyl, substituted phenyl, substituted phenylalkyl, substituted phenoxyalkyl, substituted phenylalkoxy, substituted phenylcycloalkyl, substituted phenylalkenyl, substituted benzeneAlkynyls, substituted pyridyls, substituted pyridylalkyls, substituted pyridalkenyls, substituted pyridalkynyls, substituted thiophenyls, substituted thienylalkyls, substituted thienylalkenyls, substituted thienylalkynyls, substituted 2, 3-dihydro-1H-isoindol-2-yls, substituted 1H-indol-2-yls, or substituted benzofuran-2-yls, wherein substituted cycloalkyls, substituted cycloalkylalkyls, substituted phenyls, substituted phenylalkyls, substituted phenoxyalkyls, substituted phenylalkoxys, substituted phenylcycloalkyls, substituted phenylalkenyls, substituted phenylalkynyls, substituted pyridyls, substituted pyridylalenyls, substituted pyridalkynyls, substituted thiophenyls, substituted thienylalkyls, substituted pyridylalkyls, substituted thiophenyls, substituted thiophenylalkyls, substituted thiophenyls, substituted thienylalkenyl, substituted thienylalkynyl, substituted 2, 3-dihydro-1H-isoindol-2-yl, substituted 1H-indol-2-yl and substituted benzofuran-2-yl groups substituted by R³、R⁴And R⁵Substitution;

A¹is-N-or-CR⁷-；

A²is-N-or-CR⁸-and A¹And A²At least one of which is-N-;

R²selected from ring systems A, B, C, D, E, F, G, H, I, K and L.

R³、R⁴And R⁵Independently selected from the group consisting of H, alkyl, hydroxyalkyl, haloalkyl, hydroxyhaloalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkoxy, cycloalkoxy, cycloalkoxyalkyl, cycloalkylalkoxyalkyl, alkoxy, alkoxyalkyl, haloalkoxy, alkoxyhaloalkyl, alkoxyalkoxy, alkoxyalkoxyalkyl, heterocycloalkylalkoxy, phenyl, substituted phenyl, pyridyl, substituted pyridyl, halogen, hydroxy, cyano, alkylsulfanyl, haloalkylsulfanyl, cycloalkylsulfanylAlkylsulfinyl, 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 the group consisting of 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 the group consisting of alkyl, halogen, haloalkyl, alkoxy and haloalkoxy;

R⁶is H, alkyl, haloalkyl or cycloalkyl;

R⁷and R⁸Independently selected from H, alkyl, haloalkyl or cycloalkyl;

or a pharmaceutically acceptable salt thereof.

Autotaxin (ATX) is a secreted enzyme also known as exonucleotide pyrophosphatase/phosphodiesterase 2 or lysophospholipase D, which is important for the conversion of Lysophosphatidylcholine (LPC) into the biologically active signal molecule lysophosphatidic acid (LPA). Plasma LPA levels have been shown to correlate well with ATX activity, and thus ATX is believed to be an important source of extracellular LPA. Early experiments with prototype ATX inhibitors have demonstrated that such compounds are capable of inhibiting LAP synthesis activity in mouse plasma. Work carried out in the early 1970 s and 1980 s demonstrated that LPA can elicit a wide variety of cellular responses; including smooth muscle cell contraction, platelet activation, cell proliferation, chemotaxis, and the like. LPA mediates its effects via signaling to several G protein-coupled receptors (GPCRs); the first members were originally designated as Edg (endothelial cell differentiation gene) receptors or ventricular zone gene-1 (vzg-1), but are now referred to as LPA receptors. The prototype population now consisted of LPA1/Edg-2/VZG-1, LPA2/Edg-4 and LPA 3/Edg-7. Recently, three additional LAP receptors have been described, LPA4/p2Y9/GPR23, LPA5/GPR92 and LPA6/p2Y5, which are more closely related to the nucleotide selective purinergic receptor than the prototype LPA1-3 receptor. 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 (obesity) and/or other metabolic diseases such as diabetes (diabetes mellitis). Thus, increased ATX activity and/or increased LPA levels, altered LPA receptor expression and altered response to LPA may contribute to the initiation, progression and/or outcome of a number of different pathophysiological conditions associated with the ATX/LPA axis.

In accordance with the present invention, the compounds of formula (I) or their pharmaceutically acceptable salts and esters may be used for the treatment or prevention of 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 their pharmaceutically acceptable salts and esters inhibit autotaxin activity and, thus, inhibit LPA production and modulate LAP levels and related signals. The autotaxin inhibitors described herein are useful as agents for treating or preventing a disease or disorder: in the disease or disorder, ATX activity and/or LPA signaling is involved in, involved in the etiology or pathology of, or 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.

Objects of the present invention are the compounds of formula (I) and their above-mentioned salts and esters, as well as their use as therapeutically active substances, processes for preparing 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 renal conditions, liver conditions, inflammatory conditions, nervous system conditions, respiratory system conditions, vascular and cardiovascular conditions, fibrotic diseases, cancer, ocular conditions, metabolic conditions, cholestatic and other forms of chronic pruritus and acute and chronic organ transplant rejection, and the use of said compounds, salts or esters for the preparation of medicaments for the treatment or prevention of renal conditions, for the treatment of disorders, Liver disorders, inflammatory disorders, neurological 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 term "alkenyl" denotes a monovalent straight or branched chain hydrocarbon group having 2 to 7 carbon atoms with at least one double bond. In particular embodiments, the alkenyl group has 2 to 4 carbon atoms with at least one double bond. Examples of alkenyl groups include ethenyl, propenyl, prop-2-enyl, isopropenyl, n-butenyl and isobutenyl. A particular alkenyl group is vinyl.

The term "alkoxy" denotes a group of formula-O-R ', wherein R' is alkyl. Examples of alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, and tert-butoxy. Particular alkoxy groups include isopropoxy.

The term "alkoxyalkoxy" denotes an alkoxy group wherein at least one of the hydrogen atoms of the alkoxy group has been replaced by another alkoxy group. Examples of alkoxyalkoxy groups include methoxymethoxy, ethoxymethoxy, methoxyethoxy, ethoxyethoxy, methoxypropoxy and ethoxypropoxy. Particular alkoxyalkoxy groups include methoxymethoxy and methoxyethoxy.

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

The term "alkoxyalkyl" denotes an alkyl group wherein at least one of the hydrogen atoms of the alkyl group has been replaced by an alkoxy group. Exemplary alkoxyalkyl groups include methoxymethyl, ethoxymethyl, methoxyethyl, ethoxyethyl, methoxypropyl, ethoxypropyl, and isopropoxymethyl. Particular alkoxyalkyl groups include methoxymethyl, methoxyethyl, and isopropoxymethyl.

The term "alkoxycarbonyl" denotes a group of formula-C (O) -R ', wherein R' is alkoxy. 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 "alkoxy haloalkyl" denotes a haloalkyl group wherein 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" denotes a monovalent straight or branched chain saturated hydrocarbon group of 1 to 12 carbon atoms. In particular embodiments, the alkyl group has 1 to 7 carbon atoms, and in more particular embodiments 1 to 4 carbon atoms. Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl and pentyl. Particular alkyl groups include methyl, ethyl, propyl and isopropyl. More particular alkyl groups are ethyl and isopropyl.

The term "alkylcarbonyl" denotes a group of formula-c (o) -R ', wherein R' is alkyl. Examples of alkylcarbonyl groups include groups of the formula-c (o) -R ', wherein R' is methyl or ethyl. Particular alkylcarbonyl groups include groups of the formula-c (o) -R ', wherein R' is methyl.

The term "alkylcarbonylamino" denotes a group of formula-NH-c (o) -R ', wherein R' is alkyl. Examples of alkylcarbonylamino include groups 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 groups include groups of the formula-NH-C (O) -R ', wherein R' is tert-butyl.

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

The term "alkylsulfinyl" denotes a group of formula-S (O) -R ', wherein R' is alkyl. Examples of alkylsulfinyl groups include groups of the formula-s (o) -R ', wherein R' is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl. Particular alkylsulfinyl groups include groups of the formula-S (O) -R ', wherein R' is methyl.

The term "alkylsulfonyl" denotes the formula-S (O)₂-a radical of R ', wherein R' is an alkyl radical. Examples of alkylsulfonyl groups include those 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 those of the formula-S (O)₂-the group of R ', wherein R' is methyl.

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

The term "amino" denotes-NH₂A group.

The term "aminoalkyl" denotes an alkyl group wherein 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" denotes-S (O)₂-NH₂A group.

The term "carbonyl" denotes the group-C (O) -.

The term "carboxyl" denotes the-COOH group.

The term "cyano" denotes a-C ≡ N group.

The term "cycloalkoxy" denotes a group of formula-O-R ', wherein R' is cycloalkyl. Examples of the cycloalkoxy group include a cyclopropoxy group, a cyclobutoxy group, a cyclopentoxy group, a cyclohexyloxy group, a cycloheptyloxy group, and a cyclooctyloxy group. A particular cycloalkoxy group is cyclopropoxy.

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

The term "cycloalkyl" denotes a monovalent saturated monocyclic or bicyclic hydrocarbon group of 3 to 10 ring carbon atoms. In a particular embodiment cycloalkyl represents 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 cycloalkyl are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl. Examples of bicycloalkyl are bicyclo [2.2.1] heptyl (heptanyl) or bicyclo [2.2.2] octyl. Particular monocyclic cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. A more particular monocyclic cycloalkyl group is cyclopropyl.

The term "cycloalkylalkoxy" denotes an alkoxy group wherein at least one of the hydrogen atoms of the alkoxy group has been replaced by a cycloalkyl group. Examples of cycloalkylalkoxy groups include cyclopropylmethoxy, cyclobutylmethoxy, cyclopentylmethoxy, cyclohexylmethoxy, cycloheptylmethoxy and cyclooctylmethoxy.

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

The term "cycloalkylalkyl" denotes an alkyl group wherein at least one of the hydrogen atoms of the alkyl group 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. Specific examples of cycloalkylalkyl groups are 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 radicals 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" denotes a group of the formula-S-R ', wherein R' is cycloalkyl. Examples of cycloalkylsulfanyl groups include groups of the formula-S-R ', where R' is cyclopropyl.

The term "cycloalkylsulfinyl" denotes a group of formula-S (O) -R ', wherein R' is cycloalkyl. Examples of cycloalkylsulfinyl groups include groups of the formula-s (o) -R ', wherein R' is cyclopropyl.

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

The term "haloalkoxy" denotes an alkoxy group wherein at least one of the hydrogen atoms of the alkoxy group has been replaced by the same or different halogen atom. The term "perhaloalkoxy" denotes an alkoxy group wherein 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" denotes an alkyl group wherein at least one of the hydrogen atoms of the alkyl group has been replaced by the same or different halogen atom. The term "perhaloalkyl" denotes an alkyl group wherein all of the hydrogen atoms of the alkyl group have been replaced by the same or different halogen atoms. Examples of the haloalkyl group include a fluoromethyl group, a difluoromethyl group, a trifluoromethyl group, a trifluoroethyl group, a trifluoromethylethyl group and a pentafluoroethyl group. A particular haloalkyl group is trifluoromethyl.

The term "haloalkylsulfanyl" denotes a group of the formula-S-R ', wherein R' is haloalkyl. Examples of haloalkylsulfanyl include groups of the formula-S-R ', wherein R' is trifluoromethyl.

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

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

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

The term "heterocycloalkyl" denotes a monovalent saturated or partially unsaturated mono-or bicyclic ring system of 4 to 9 ring atoms containing 1,2 or 3 ring heteroatoms selected from N, O and S, the remaining ring atoms being carbon. Bicyclic means consisting of two rings having two ring atoms in common, i.e. the bridge separating the two rings is a single bond or a chain of one or two ring atoms. An example of a monocyclic saturated heterocycloalkyl is 4, 5-dihydro-Azolyl, oxetanyl, azetidinyl, pyrrolidinyl, 2-oxo-pyrrolidin-3-yl, tetrahydrofuranyl, tetrahydro-thienyl, pyrazolidinyl, imidazolidinyl, and the like,Oxazolidinyl, isoOxazolidinyl, thiazolidinyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperazinyl, morpholinyl, thiomorpholinyl, 1-dioxo-thiomorpholin-4-yl, azepanyl, diazepanyl, homopiperazinyl, or oxazepanyl. An example of a bicyclic saturated heterocycloalkyl is 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 radical. Examples of partially unsaturated heterocycloalkyl are dihydrofuranyl, imidazolinyl, dihydro-Oxazolyl, tetrahydro-pyridyl, or dihydropyranyl. A particular example of a heterocycloalkyl group is tetrahydropyranyl.

The term "heterocycloalkylalkoxy" denotes an alkoxy group in which at least one hydrogen atom 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" denotes an-OH group.

The term "hydroxyalkyl" denotes an alkyl group wherein at least one of the hydrogen atoms of the alkyl group has been replaced by a hydroxyl 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" denotes a haloalkyl group wherein at least one hydrogen atom of the haloalkyl group is replaced by a hydroxyl group. Exemplary hydroxyhaloalkyl groups include hydroxytrifluoroethyl and hydroxytrifluoropropyl. Particular hydroxyhaloalkyl groups include hydroxytrifluoroethyl.

The term "naphthylalkenyl" denotes an alkenyl group wherein at least one hydrogen atom of the alkenyl group is replaced by a naphthyl group. A particular naphthylalkenyl group is naphthylvinyl.

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

The term "naphthyloxyalkyl" denotes an alkyl group wherein at least one hydrogen atom of the alkyl group is replaced by a naphthyloxy group. Exemplary naphthyloxyalkyl groups include naphthyloxymethyl, naphthyloxyethyl and naphthyloxypropyl.

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

The term "phenoxyalkyl" denotes an alkyl group wherein at least one hydrogen atom 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" denotes an alkoxy group wherein at least one hydrogen atom 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" denotes an alkyl group wherein 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. A more particular phenylalkyl group is phenethyl.

The term "phenylalkynyl" denotes an alkynyl group in which at least one of the hydrogen atoms of the alkynyl group has been replaced by a phenyl group. A particular phenylalkynyl group is a phenylethynyl group.

The term "phenylcycloalkyl" denotes a cycloalkyl group in which 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 pyridinylalkenyl group is pyridinylvinyl.

The term "pyridylalkyl" denotes an alkyl group wherein 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. A more particular pyridylalkyl group is pyridylethyl.

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

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 thienylvinyl.

The term "thienylalkyl" denotes an alkyl group wherein 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. A more particular thienylalkyl group is 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 "pharmaceutically acceptable salts" refers to those salts that retain the biological utility and properties of the free base or free acid, which are not biologically or otherwise undesirable. The salts are formed with the following acids: inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, particularly hydrochloric acid, and organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, N-acetylcysteine and the like. In addition, these salts can be prepared by adding an inorganic or organic base to the free acid. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium salts, and the like. Salts derived from organic bases include, but are not limited to, the following: 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, mesylate and citrate salts.

By "pharmaceutically acceptable ester" is meant a derivative of a compound of formula (I) which can be derivatised at a functional group to provide a derivative which can be converted 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, any physiologically acceptable equivalent of a compound of formula (I) that is capable of producing the parent compound of formula (I) in vivo, like the metabolically labile ester, is within the scope of the invention.

The term "protecting group" (PG) denotes a group that, in its conventional meaning in relation to synthetic chemistry, selectively blocks a reactive site in a polyfunctional compound so that a chemical reaction can proceed selectively at another unprotected reactive site. The protecting group may be removed at a suitable point. Exemplary protecting groups are amino-protecting groups, carboxy-protecting groups or hydroxy-protecting groups. Particular protecting groups are the tert-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz or Z), fluorenylmethoxycarbonyl (Fmoc) and benzyl (Bn) groups. More particular protecting groups are the tert-butoxycarbonyl (Boc) and fluorenylmethoxycarbonyl (Fmoc) groups. More particular protecting groups are tert-butoxycarbonyl (Boc) groups.

The abbreviation uM denotes micromolar concentration and is equivalent to the symbol μ M.

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

The abbreviation ug denotes microgram and is equivalent to the symbol ug.

The compounds of formula (I) may contain several asymmetric centers and may be present in the form of optically pure enantiomers, mixtures of enantiomers such as, for example, racemates, optically pure diastereoisomers, mixtures of diastereoisomers, diastereoisomeric racemates or mixtures of diastereoisomeric racemates.

According to Cahn-Ingold-Prelog Convention, the asymmetric carbon atoms may be in either the "R" or "S" configuration.

Yet another embodiment of the invention are compounds of formula (I) and pharmaceutically acceptable salts or esters thereof as described herein, particularly compounds of formula (I) and pharmaceutically acceptable salts thereof as described herein, more particularly compounds of formula (I) as described herein.

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

R¹Is 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 pyridalkenyl, substituted pyridynyl, 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 substituted with R³、R⁴And R⁵Substitution;

A¹is-N-or-CR⁷-；

A²is-N-or-CR⁸-and A¹And A²At least one of which is-N-;

R²selected from ring systems A, B, C, D, E, F, G, H, I, K and L.

R³、R⁴And R⁵Independently selected from the group consisting of H, alkyl, hydroxyalkyl, haloalkyl, hydroxyhaloalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkoxy, cycloalkoxy, cycloalkoxyalkyl, cycloalkylalkoxyalkyl, alkoxy, alkoxyalkyl, haloalkoxy, alkoxyhaloalkyl, alkoxyalkoxy, alkoxyalkoxyalkyl, 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 by one to two substituents independently selected from the group consisting of 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;

R⁶is H, alkyl, haloalkyl or cycloalkyl;

R⁷and R⁸Independently selected from H, alkyl, haloalkyl or cycloalkyl;

or a pharmaceutically acceptable salt thereof.

Another embodiment of the present invention are compounds according to formula (I) as described herein, wherein R is¹Is substituted phenylalkyl, substituted phenoxyalkyl or substituted phenylalkoxy, wherein substituted phenylalkyl, substituted phenoxyalkyl and substituted phenylalkoxy are substituted by R³、R⁴And R⁵And (4) substitution.

A particular embodiment of the invention are compounds according to formula (I) as described herein, wherein R is¹Is a substituted phenoxyArylalkyl or substituted phenylalkoxy, wherein substituted phenoxyalkyl and substituted phenylalkoxy are substituted by R³、R⁴And R⁵And (4) substitution.

A further particular embodiment of the invention are compounds according to formula (I) as described herein, wherein R is¹Is by R³、R⁴And R⁵Substituted phenylalkoxy groups.

The invention also relates to compounds according to formula (I) as described herein, wherein R is²Selected from ring systems A and O.

A particular embodiment of the invention are compounds according to formula (I) as described herein, wherein R is²Is cyclic system A and of formula (Ia).

A further embodiment of the invention are compounds according to formula (I) as described herein, wherein a is¹is-N-and A²is-N-or-CR⁸-。

Another further embodiment of the invention are compounds according to formula (I) as described herein, wherein R is³、R⁴And R⁵Independently selected from the group consisting of H, alkyl, cycloalkyl, heterocycloalkylalkoxy, haloalkoxy, halogen, cyano, and alkylcarbonylamino.

A particular embodiment of the invention are compounds according to formula (I) as described herein, wherein R is³、R⁴And R⁵Independently selected from the group consisting of H, alkyl, cycloalkyl, haloalkoxy, halogen, cyano and alkylcarbonylamino.

Another particular embodiment of the invention are compounds according to formula (I) as described herein, wherein R is³Is heterocycloalkylalkoxy, haloalkoxy or cyano.

The invention is advancedA particular embodiment of one step are compounds according to formula (I) as described herein, wherein R is³Is haloalkoxy or cyano.

Another particular embodiment of the invention are compounds according to formula (I) as described herein, wherein R is⁴Is H, alkyl, cycloalkyl or halogen.

A further particular embodiment of the invention are compounds according to formula (I) as described herein, wherein R is⁴Is H, alkyl or halogen.

Furthermore, an embodiment of the invention are compounds according to formula (I) as described herein, wherein R is⁵Is H.

Another embodiment of the present invention are compounds according to formula (I) as described herein, wherein R is⁷Is H.

Another embodiment of the present invention are compounds according to formula (I) as described herein, wherein R is⁸Is H.

A more particular embodiment of the invention are compounds according to formula (I) as described herein, wherein

R¹Is substituted phenylalkoxy which is substituted by R³、R⁴And R⁵Substitution;

A¹is-N-;

A²is-N-or-CR⁸-；

R²Is ring system a.

R³Is haloalkoxy or cyano;

R⁴is H or halogen;

R⁵is H;

R⁸is H;

or a pharmaceutically acceptable salt thereof.

Particular examples of compounds of formula (I) as described herein are 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 derivatives-benzyl 6-carboxylate;

2- (1,4,6, 7-tetrahydrotriazolo [4, 5-c)]Pyridine-5-carbonyl) -5,6,8, 9-tetrahydroimidazo [1,2-d][1,4]Diaza derivatives-benzyl 7-carboxylate;

2- (1,4,6, 7-tetrahydrotriazolo [4, 5-c)]Pyridine-5-carbonyl) -4,5,7, 8-tetrahydropyrazolo [1,5-d][1,4]Diaza derivatives-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 derivatives-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 derivatives-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 derivatives-6(5H) -carboxylic 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 derivatives-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 derivatives-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 derivatives-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 derivatives-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 derivatives-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 derivatives-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 derivatives-7-carboxylic acid [4- (trifluoromethoxy) phenyl]Methyl ester;

1- [2- (1,4,6, 7-tetrahydrotriazolo [4,5-c ]]Pyridine-5-carbonyl) -4,5,7, 8-tetrahydropyrazolo [1,5-d][1,4]Diaza derivatives-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]Diaza derivatives-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]Diaza derivatives-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]Diaza derivatives-6-yl]Ethoxy radical]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]Diaza derivatives-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]Diaza derivatives-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]Diaza derivatives-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]Diaza derivatives-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]Diaza derivatives-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]Diaza derivatives-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]Diaza derivatives-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]Diaza derivatives-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]Diaza derivatives-6-yl]Propan-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 derivatives-6(5H) -carboxylic 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 derivatives-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 derivatives-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 derivatives-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 derivatives-6(5H) -carboxylic 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 derivatives-6(5H) -carboxylic 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 derivatives-6(5H) -carboxylic 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 derivatives-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 derivatives-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 derivatives-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 derivatives-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 derivatives-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 derivatives-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 derivatives-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 derivatives-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 derivatives-7-carboxylic acid [ 3-chloro-4- (trifluoromethoxy) phenyl]Methyl ester;

2- ((3aR,7aR) -2-oxooctahydroAzolo [5,4-c ] s]Pyridine-5-carbonyl) -8, 9-dihydro-5H- [1,2,4]Triazolo [1,5-d][1,4]Diaza derivatives-7(6H) -carboxylic acid 3-fluoro-4- (trifluoromethoxy) benzyl ester;

and pharmaceutically acceptable salts thereof.

Further, the method comprises

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 derivatives-6(5H) -carboxylic acid 3-fluoro-4- (trifluoromethoxy) benzyl ester;

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]Diaza derivatives-2-yl) (6, 7-dihydro-1H- [1,2, 3)]Triazolo [4,5-c]Pyridin-5 (4H) -yl) methanone;

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 derivatives-6(5H) -carboxylic acid 3-chloro-4- (trifluoromethoxy)Benzyl ester;

a process for the preparation of a compound of formula (I) as described herein is an object of the present invention.

The preparation of the compounds of formula (I) according to the 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 to carry out the reaction and the purification of the resulting product are known to those skilled in the art. In the case of mixtures of enantiomers or diastereomers which are produced during the course of the reaction, these enantiomers or diastereomers may be separated by the methods described herein or by methods known to those skilled in the art, for example, (chiral) chromatography or crystallization. The substituents and indices used in the description of the following methods have the meanings given herein.

A general description of the invention is given in the following section and is outlined in fig. 1-4. To obtain a compound of formula (I), the appropriately protected bicyclic carboxylic acid 1A is reacted with 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 a temperature of-20 ℃ to 100 ℃ with the appropriate cyclic secondary amine 1B to provide the protected amide 1C. In a subsequent step, according to the protecting group PG₁May be applied to provide intermediate 1D from which PG is removed using a variety of deprotection methods known to those skilled in the art. For example, BOC protecting groups can be removed by treatment with organic or aqueous acids or other known methods, while Z-groups are often removed by hydrogenation.

FIG. 1:

intermediate 1D can now be treated with alcohol 1E, where R_AIs 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, etc., to provide a first type of embodiment of the present invention having the general structure 1H. The second type of embodiment outlined in the present invention is represented by general structure 1I and can be prepared by reaction in the presence of an activating agent such as CDI, EDC HCl or any type of peptide coupling agent, in a suitable base such as triethylamine, N-methylmorpholine, Huenig's base, NaOH, Na₂CO₃Etc. in the presence of a suitable solvent system such as DMF, CH₃CN, THF/water, etc., with any type of free carboxylic acid 1G (wherein R is_BIs alkyl, haloalkyl, substituted cycloalkyl, substituted cycloalkylalkyl, substituted phenyl, substituted phenylalkyl, substituted phenoxyalkyl, substituted phenylcycloalkyl, substituted phenylalkenyl, substituted phenylalkynyl, substituted pyridyl, substituted pyridylalkyl, substituted pyridalkenyl, substituted pyridynyl, 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) intermediate 1D. Alternatively, any suitably activated carboxylic acid derivative such as, for example, an acid chloride or acid bromide, mixed anhydrides or p-nitrophenol esters may also be used in the reaction.

Fused bicyclic intermediates having 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 designable by those skilled in the art. As an example of the synthesis of such fused bicyclic ring systems, 6,7,8, 9-tetrahydro-5H- [1,2, 4] is summarized in FIG. 2]Triazolo [1,5-d][1,4]Diaza derivatives-2-carboxylic acid derivative 1A (wherein A)¹And A²Synthesis of ═ N (corresponding to the structure of formula 2I). In order to obtain this material, R may be_CThioamides 2A representing, for example, small alkyl groups are treated with, for example, substituted hydrazines of structure 2B in a solvent such as ethanol or methanol at temperatures ranging from-20 ℃ to the boiling point of the solvent to provide intermediates 2C intermediate 2C may then be treated with an appropriately protected activated β -amino-carboxylic acid derivative 2D (where X is₃Represents halogen or mixed anhydride or the like, and PG₂Representing a protecting group) 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 afford 2E. The hydrazine derivative 2E can be condensed to triazole 2F by heating in a suitable solvent such as t-butanol, n-butanol or the like at a temperature ranging up to the boiling point of the solvent or by using a microwave device. The reaction time for such conversion can range from minutes (i.e., at elevated temperature and pressure, in microwaves) up to days in a standard reaction flask.

Subsequent processing of intermediate 2F involves modification of the primary hydroxyl group of 2F to a better leaving group such as tosylate or mesylate and the like 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 desired at a temperature ranging from-20 ℃ to the boiling point of the solvent. Removal of the protecting group PG₂To provide triazole 2G is dependent on PG₂The nature of (c). If PG is present₂Are, for example, BOC groups, which can be removed by treatment with organic or aqueous acids or other known methods; if PG is present₂Is a Z-group which can generally be removed by hydrogenation. At PG₂In the case of another N-protecting group, there are other suitable deprotection conditions known to those skilled in the art that may be employed.

From intermediate 2G, ring closure to give diazepine2H, by means of a base such as, for example, triethylamine, DMAP, K₂CO₃Or the like in a suitable solvent such as DMF, CH₃CN, THF or the like, at a temperature from room temperature up to the boiling point of the solvent. If desired, suitable N-protecting groups PG₃Such as a BOC group, a Z-group or any other suitable protecting group may now be reintroduced. Compatible groups and conditions for introduction and removal, e.g. in Green&Wuts.，Protective Groups in Organic Synthesis”，John Wiley&Described in Sons. Finally, if R is_CIs 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 a temperature from 0 ℃ to the boiling point of the solvent, giving the desired building block of structure 2I. According to protecting groups PG₃Other hydrolysis conditions known to those skilled in the art may also be applied.

FIG. 2:

appropriately substituted benzyl alcohols 3B as a subclass of alcohols 1E for subsequent processing of the central nucleus of formula 1A (wherein R is_DAre R3, R4 and R5) are commercially available or can be derived, for example, from the corresponding carboxylic acid, carboxylic ester or aldehyde 3A (X)₄Each of which is equal to OH,OR OR H) by treatment with a suitable reducing agent such as LAH, NaBH₄、LiBH₄Etc., optionally in additives such as CeCl₃、CaCl₂Or the like, in a suitable solvent such as methanol, ethanol, THF, at a temperature ranging from-20 to 100 ℃ (fig. 3).

FIG. 3:

appropriately substituted carboxylic acids of Structure 4D as subclasses of Carboxylic acids 1G (wherein R_FIs R3, R4 and R5) can be prepared in various ways as shown in fig. 4. Y is₂Phenoxyacetic acid 4D of ═ O is for example obtained from the corresponding phenol 4A (fig. 4, branched), by reaction with the appropriate acetic acid derivative 4B (for example an ester, at R_EWhen it is a small alkyl group) (wherein X₁Is a suitable leaving group such as halogen or p-toluenesulfonate or the like) to yield intermediate 4C. Such conversion is usually carried out in the presence of a base such as potassium carbonate or cesium carbonate and the like in a suitable solvent such as DMF, acetone or CH₃CN, at a temperature ranging from room temperature to the boiling point of the solvent. Similar to the conversion of 2H to 2I, the ester 4C can be hydrolyzed, for example, in the presence of a base such as NaOH, KOH, or LiOH, etc., to give the desired Y₂Structural 4D building block of O.

Appropriately substituted Y₂The 3-phenylpropionic acid of structure 4D of ═ C is commercially available or can be prepared as described in fig. 4 (lower branch). If they are to be prepared, they can be prepared using conditions known to the person skilled in the art, for example from the corresponding aldehydes 4E and Wittig reagents 4F (which may have different substituents R)_E、R_G、R_HAnd R_IPhosphonium ylide) to yield the cinnamic acid derivative 4G. From the cinnamic acid derivative 4G, the corresponding 3-phenylpropionic acid derivative 4H is prepared, for example, by reduction of the double bond by hydrogenation in the presence of a catalyst, such as, for example, palladium on carbon, whereby different solvents or many other catalysts can be used. Subsequently, Y₂Free carboxylic acids of structure 4D as ═ C as described abovePrepared under hydrolysis conditions for conversion of 4C to 4D.

FIG. 4:

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

FIG. 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 the appropriate alkyl halide 5C (where 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 and the like in an appropriate solvent such as DMF, THF or the like to provide 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.

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

wherein R is¹Is by R³、R⁴And R⁵Substituted phenylalkoxy, R_AIs by R³、R⁴And R⁵Substituted phenylAlkyl and R²、R³、R⁴、R⁵、A¹And A²As defined above.

In particular, in the presence of an activating agent such as CDI, N ' -disuccinimidyl carbonate or phosgene, preferably N, N ' -disuccinimidyl carbonate, 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 in the range of from-10 ℃ to room temperature.

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

wherein R is¹Is alkyl, haloalkyl, substituted cycloalkyl, substituted cycloalkylalkyl, substituted phenyl, substituted phenylalkyl, substituted phenoxyalkyl, substituted phenylcycloalkyl, substituted phenylalkenyl, substituted phenylalkynyl, substituted pyridyl, substituted pyridylalkyl, substituted pyridalkenyl, substituted pyridynyl, 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 phenyl, substituted phenylalkyl, substituted phenyl-cycloalkyl, substituted phenyl-alkyl, substituted phenyl-alkynyl, substituted phenyl, Substituted phenylalkenyl, substituted phenylalkynyl, substituted pyridyl, substituted pyridylalkyl, substituted pyridenyl, substituted pyridynyl, 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 substituted with R³、R⁴And R⁵Substituted and R²、R³、R⁴、R⁵、A¹And A²As defined above.

In particular, in the presence of an activating agent such as CDI, EDC HCl, in a solvent such as DMF, CH₃CN, THF/water in the presence of a base such as triethylamine, N-methylmorpholine, Huenig's base, NaOH, Na₂CO₃In the presence of (a).

Furthermore, an object of the present invention is a compound according to formula (I) as described herein for use as therapeutically active substance.

Also, 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 prophylaxis of renal disorders, liver disorders, inflammatory disorders, neurological disorders, respiratory disorders, vascular and cardiovascular disorders, fibrotic diseases, cancer, ocular 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 (kidney injury) and chronic kidney disease (renaldisease) with or without proteinuria (proteinuria) including end-stage renal disease (ESRD). In more detail, this includes reduced creatinine clearance and reduced glomerular filtration rate, microalbuminuria (micro-albuminuria), albuminuria (albuminuria) and proteinuria (proteinuria), glomerulosclerosis (globulosclerosis) with reticulal matrix expansion (exaggerated) with or without significant hypercytosis (hypercytology), in particular diabetic nephropathy (diabetic nephropathy) and amyloidosis), focal thrombosis (especially thrombotic microangiopathy), of the glomerular capillaries (ischemic lesions), total fibrin-like necrosis (ischemic necrosis) of the glomerular capillaries (especially thrombotic microangiopathy), ischemic lesions (ischemic swelling), nephrosclerosis (malignant sclerosis) and reduced endothelial blood flow (endothelial cell retraction), and/or renal endothelial cell proliferation (endothelial cell proliferation), such as renal endothelial cell proliferation and renal cell proliferation (endothelial cell proliferation), such as renal cell proliferation and endothelial cell proliferation), renal cell proliferation (endothelial cell proliferation), and renal cell proliferation (endothelial cell), and renal cell (endothelial cell) in the same manner of the renal system, and/or renal cell (endothelial cell), and/or endothelial cell (endothelial cell) in the same manner as the renal cell, and/or the renal cell (endothelial cell, and/or the renal cell, and the method of the treatment of the renal cell, the treatment of the renal cell Genital, focal segmental glomerulosclerosis (focal segmental glomerulosclerosis), IgA nephropathy, vasculitis (vasculitides)/systemic diseases (systemic diseases) and acute and chronic renal transplant rejection.

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

Inflammatory conditions include, but are not limited to, arthritis (arthritis), osteoarthritis (osteo-arthritis), multiple sclerosis (multiple sclerosis), systemic lupus erythematosus (systemic lupus erythematosus), inflammatory bowel disease (inflammatory bowel disease), abnormal voiding disorders (abnormal voiding disorder), and the like, as well as inflammatory airway diseases such as Idiopathic Pulmonary Fibrosis (IPF), Chronic Obstructive Pulmonary Disease (COPD), or chronic bronchial asthma (asthma).

Other respiratory disorders include, but are not limited to, diffuse parenchymal lung diseases of different etiologies (diffuse pathological lung diseases), including iatrogenic drug-induced fibrosis, occupational and/or environmental-induced fibrosis, systemic and vasculitis, granulomatous diseases (granulomatous diseases) (sarcoidosis), hypersensitivity pneumonitis (hypersensitivity pneumonitis), collagen vascular diseases (collagen vascular diseases), alveolar protein deposition (alveolor proteinosis), Langerhans cell granulomatosis (Langerhans interstitial granulomatosis), lymphatic smooth muscle sarcoidosis (lymphoblastomatosis), genetic diseases (herchy-prader-strake Syndrome (hermann-pudly-pulmonary Syndrome), interstitial sclerosis (interstitial sclerosis), neurofibromatosis (neurofibromatosis), fibrotic disorders (neurofibromyalgia disorder), metabolic fibrotic disorders (metabolic fibrosis), inflammatory disorders (inflammatory diseases), silicosis, asbestos-induced pulmonary fibrosis (pulmonnary fibrosis) or Acute Respiratory Distress Syndrome (ARDS).

Neurological disorders include, but are not limited to, neuropathic pain (neuralgia pain), schizophrenia (schizophrenia), neuroinflammation (neuro-inflammation), such as astrocytosis (astrogliosis), external and/or idiopathic (diabetic) neuropathy (neuropathies), and the like.

Vascular disorders include, but are not limited to, atherosclerosis (atherosclerosis), thrombotic vascular disease (thrombotic vasomotor diseases) and thrombotic microangiopathy (thrombotic microangiopathy), proliferative arterial disease (such as swollen endomyocytes and nodular thickening surrounded by mucinous extracellular matrix), atherosclerosis (atherosclerosis), decreased vascular compliance (such as rigidity, decreased luminal compliance and decreased vascular compliance), endothelial dysfunction (endovenous dysfunction), and the like.

Cardiovascular disorders include, but are not limited to, acute coronary syndrome (coronary heart disease), coronary heart disease (coronary heart disease), myocardial infarction (myocardial infarction), arterial and pulmonary hypertension (hypertension), cardiac arrhythmia (cardiac arrhythmia) such as atrial fibrillation, stroke (stroke) and other vascular injuries.

Fibrotic diseases include, but are not limited to, cardiac and vascular fibrosis, renal fibrosis, hepatic fibrosis, pulmonary fibrosis, dermal fibrosis, scleroderma (scleroderma) and cystic peritonitis (encapsulating tissues).

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 tubular interstitial fibrosis (renaltubulo-intestrial fibrosis) or glomerulosclerosis.

In another embodiment, the fibrotic disease is non-alcoholic liver steatosis (non-alcoholic liver fibrosis), liver fibrosis or cirrhosis.

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

Cancers and cancer metastases include, but are not limited to, breast cancer, ovarian cancer, lung cancer, prostate cancer, mesothelioma (mesothelioma), glioma (glioma), liver cancer, gastrointestinal cancer and their progression and metastatic prevalence.

Ocular conditions include, but are not limited to, proliferative and non-proliferative (diabetic) retinopathy (retinopathy), dry and wet age-related macular degeneration (AMD), macular edema (macular edema), aortic/venous occlusion (central aortic/venous occlusion), traumatic injury, glaucoma (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 may be used for the treatment or prevention of cholestatic or non-cholestatic chronic pruritus.

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

The 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 and fibrotic diseases.

A particular embodiment of the invention is a compound according to formula (I) as described herein for use in the treatment or prevention of renal disorders, liver disorders, inflammatory disorders, neurological disorders, fibrotic diseases and acute and chronic organ transplant rejection.

A particular embodiment of the invention is a compound according to formula (I) as described herein for use in the treatment or prevention of renal disorders, liver disorders and fibrotic diseases.

The 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 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 prophylaxis of renal conditions, liver conditions, inflammatory conditions, conditions of the nervous system, fibrotic diseases and acute and chronic organ transplant rejection, which method comprises administering an effective amount of a compound according to formula (I) as described herein.

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

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

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

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

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

In a particular embodiment, the inflammation is arthritis.

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

In another embodiment, the fibrotic disease is cystic peritonitis.

In another embodiment, the fibrotic disease is non-alcoholic liver steatosis, liver fibrosis or cirrhosis.

Further, an embodiment of the invention is a compound of formula (I) as described herein, prepared according to any one of the methods.

Measurement procedure

Preparation of human full-length Autotaxin (ATX) with and without HIS marker:

autotaxin (ATX-ENPP2) clone: cDNA was prepared from commercial human hematopoietic cell total RNA and used as template in overlapping PCR to generate full-length human ENPP2 ORF with or without 3' -6xHis tag. These full-length inserts were cloned into pcDNA3.1V5-HisTOPO (Invitrogen) vectors. Several monoclonal DNA sequences were examined. DNA from the correct full-length clone was used to transfect Hek293 cells to test protein expression. The sequence encoding ENPP2 conforms to Swissprot entry Q13822, with or without an additional C-terminal 6xHis tag.

ATX fermentation: recombinant proteins were prepared by large-scale transient transfection in a 20L controlled stirred tank bioreactor (Sartorius). During cell growth and transfection, temperature, agitation speed, pH and dissolved oxygen concentration were maintained at 37 deg.C, 120rpm, 7.1 and 30% DO, respectively. FreeStyle 293-F cells (Invitrogen) were cultured in suspension in FreeStyle293 medium (Invitrogen) and transfected with the above plasmid DNAs at about 1-1.5X 10E6 cells/mL using X-tremagene Ro-1539 (commercial product, Roche Diagnostics) as a complexing agent. Cells were fed to concentrated nutrient solution (J Immunol Methods 194(1996),19,1-199 (p 193)) and induced by sodium butyrate (2mM) 72h after transfection and harvested 96h after transfection. Expression is analyzed by Western Blot, enzymatic assay and/or analytical IMAC chromatography. After cooling the cell suspension to 4 ℃ in a flow-through heat exchanger, cell separation and sterile filtration of the supernatant was performed by filtration through Zeta Plus 60M 02E 16(Cuno) and Sartopore 2 XLG (Sartorius) filtration units. The supernatant was stored at 4 ℃ prior to purification.

And (3) ATX purification: 20 liters of culture supernatant was adjusted for ultrafiltration by adding Brij 35 to 0.02% final concentration and adjusting the pH to 7.0 by using 1M HCl. The supernatant was then first microfiltered through a 0.2 μm Ultran-Pilot Open Channel PES filter (Whatman) and subsequently concentrated to 1 liter by an Ultran-Pilot Screen Channel PES filter (Whatman) with a 30kDa MWCO. Adding NiSO before IMAC chromatography₄To a final concentration of 1 mM. The clear supernatant was then applied to Na, previously 50mM Na₂HPO₄pH 7.0, 0.5MNaCl, 10% glycerol, 0.3% CHAPS, 0.02% NaN₃Middle equilibrated HisTrap column (GEHealthcare). The column was washed stepwise with the same buffers containing 20mM, 40mM and 50mM imidazole, respectively. The protein was then eluted at 15 column volumes using a linear gradient to 0.5M imidazole. The ATX containing fractions were pooled and concentrated using an Amicon cell equipped with a 30kDa PES filtration membrane. Followed by Superdex S-200 preparative scale (XK 26/100) (GE Healthcare) at 20mM ICINE pH 8.5, 0.15M NaCl, 10% glycerol, 0.3% CHAPS, 0.02% NaN₃The protein is further purified by size exclusion chromatography. The final yield of protein after purification was 5-10mg ATX per liter culture supernatant. The protein was stored at-80 ℃.

Human ATX enzyme inhibition assay

ATX inhibition was measured by fluorescence quenching assay using specially labeled substrate mimetics (MR121 substrates). To obtain this MR121 substrate, MR121 fluorophore (CAS 185308-24-1,1- (3-carboxypropyl) -11-ethyl-1, 2,3,4,8,9,10, 11-octahydro-bipyridino [3,2-b:2 ', 3' -i ] was used]PhenOxazine-13-) BOC and TBS protected 6-amino-hexanoic acid (R) -3- ({2- [3- (2- {2- [2- (2-amino-ethoxy) -was labeled on the free amine on the ethanolamine side]-ethoxy } -ethoxy) -propionylamino]-ethoxy } -hydroxy-phosphoryloxy) -2-hydroxy-propyl ester (Ferguson et al, Org Lett 2006,8(10),2023) and subsequently, after deprotection, followed by labeling with tryptophan on the aminocaproic acid side.

Assay working solutions were prepared as follows:

assay buffer (50mM Tris-HCl, 140mM NaCl, 5mM KCl, 1mM CaCl)₂、1mM MgCl₂、0.01％Triton-X-100、pH 8.0；

ATX solution: ATX (human His-tagged) stock solution (1.08mg/mL in 20mM bicine, pH 8.5, 0.15M NaCl, 10% glycerol, 0.3% CHAPS, 0.02% NaN)₃) Diluted to 1.4-2.5x final concentration in assay buffer;

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

Test compounds (10mM stock in DMSO, 8 μ L) were obtained in 384-well sample plates (Corning Costar #3655) and diluted with 8 μ L DMSO. Serial dilutions were performed row by transferring 8 μ L of compound solution to the next row up to row O. The compound and control solution were mixed five times and 2 μ Ι _ was transferred to a 384 well assay plate (Corning Costar # 3702). Subsequently, 15 μ L of 41.7nM ATX solution (30nM final concentration) was added, mixed five times and subsequently incubated for 15 minutes at 30 ℃. mu.L of MR121 substrate solution (1. mu.M final concentration) was added, mixed 30 times, and then incubated at 30 ℃ for 15 minutes. Fluorescence was then measured every 2 minutes for 1 hour (Perkin Elmer plate: visual multimodal readout); light intensity: 2.5 percent; time: 1.4 seconds, filter: fluo 630/690nm) and calculating IC from these readings₅₀The value is obtained.

Inhibitory Activity (IC) of the examples of the present invention against ATX₅₀) As given below.

Examples	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
		21	0.017
22	0.018
		23	0.050
24	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) and their pharmaceutically acceptable salts or esters described herein have a value of 0.00IC between 001 mu M and 1000 mu M₅₀Values, particular compounds have an IC between 0.0005. mu.M and 500. mu.M₅₀Values, further particular compounds have an IC between 0.0005. mu.M and 50. mu.M₅₀Values, more particular compounds have an IC of 0.0005. mu.M to 5. mu.M₅₀The value is obtained. These results have been obtained by using the enzyme assays described above.

The compounds of formula (I) and their pharmaceutically acceptable salts can be used as medicaments (e.g. in the form of pharmaceutical preparations). The pharmaceutical formulation may be administered internally in the following manner: such as orally (e.g. in the form of tablets, coated tablets, dragees, hard and soft gelatine capsules, solutions, emulsions or suspensions), nasally (e.g. in the form of nasal sprays), rectally (e.g. in the form of suppositories) or topically ocularly (e.g. in the form of solutions, ointments, gels or water-soluble polymer inserts). However, administration can also be effected parenterally, such as intramuscularly, intravenously or intraocularly (for example in the form of sterile injectable solutions).

The compounds of formula (I) and their pharmaceutically acceptable salts can be processed with pharmaceutically inert, inorganic or organic adjuvants for the preparation of tablets, coated tablets, dragees, hard gelatine capsules, injections or topical preparations. Lactose, corn starch or derivatives thereof, talc, stearic acid or its salts and the like can be used, for example, as such auxiliary materials for tablets, dragees and hard gelatine capsules.

Suitable excipients for soft gelatine capsules are, for example, vegetable oils, waxes, fats, semi-solid substances, liquid polyols and the like.

Suitable adjuvants 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-solid or liquid polyols and the like.

Suitable excipients for topical formulations of the eye 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, colorants, flavorants, salts for regulating the osmotic pressure, buffers, masking agents or antioxidants. They may also contain other therapeutically valuable substances.

The dosage may vary within wide limits and will of course be fitted to the individual requirements in each particular case. Generally, in case of oral administration, a daily dose of about 0.1 to 20mg per kg body weight, preferably about 0.5 to 4mg per kg body weight (e.g. about 300mg per person), is preferably divided into 1-3 individual doses which may e.g. consist of the same amount, which should be suitable. In the case of topical administration, the formulation may contain from 0.001% to 15% by weight of the drug, and may be a desired dose of from 0.1 to 25mg administered by a single daily or weekly administration, or by multiple daily administrations (2 to 4), or by multiple weekly administrations. It will be understood, however, that the upper or lower limits given herein may be exceeded when the indications so indicate.

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

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

Intermediates

Abbreviations

aq. aqueous; CAS-RN is a chemical abstracts service registry number; e.r. ═ enantiomeric ratio; HPLC ═ high performance liquid chromatography; MS ═ mass spectrum; NMR ═ nuclear magnetic resonance spectroscopy; sat. (saturated); rt-room temperature. Other abbreviations, such as for chemical reagents or solvents, are known to those skilled in the art.

Intermediate (II)Body 1:

6-Phenylmethoxycarbonyl-4, 5,7, 8-tetrahydropyrazolo [1,5-d][1,4]Diaza derivatives-2-carboxylic acid

(6-O-benzyl-2-O-ethyl-4, 5,7, 8-tetrahydropyrazolo [1, 5-d)][1,4]Diaza derivatives2, 6-dicarboxylic acid ester, CAS: 1080027-19-5; synthesized in steps 1-7 below) have been mentioned in Gerlach et al, PCT int.appl. (2008), WO 2008135526a1 and synthesized similarly to Venkatesan m.a. et al, j.med.chem.2006, 49, 4623.

Step 1, 4-dibenzyl-1, 4-diazepan-5-carboxylic acid tert-butyl ester

In a 20mL round-bottom flask, tert-butyl 2, 4-dibromobutyrate (500mg, [ CAS: 77629-96-0)]) N, N' -dibenzylethylenediamine (372mg, [ CAS:.140-28-3 ]]) And triethylamine (460mg) were dissolved in dichloromethane (20mL) to give a colorless solution. The mixture was heated to 40 ℃ for 15 hours. The reaction mixture was poured into ice/water and saturated NaHCO₃The solution is basified. The aqueous phase was then extracted twice with dichloromethane. The combined organic layers were passed over Na₂SO₄Dry, filter and evaporate the solvent 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 (232mg, 35%). MS (EI) 380.0[ M ]⁺]。

Step 21, 4-diazepanAlkane-5-carboxylic acid tert-butyl ester

Tert-butyl 1, 4-dibenzyl-1, 4-diazepan-5-carboxylate (3.40g) was dissolved in ethanol (50mL) to give a light brown solution. Palladium on activated carbon (800mg, 10% Pd) was added and an atmosphere of hydrogen was introduced at room temperature. The mixture was stirred under hydrogen at 5 bar for 9 hours. The reaction mixture was filtered through dicalite plus (Acros Organics) and the solvent was evaporated to dryness to give the title compound as a light brown oil (1.40g, 77%). MS (M/e) 201.7[ M + H]⁺。

Step 3 1-O-benzyl 5-O-tert-butyl 1, 4-diazepan-1, 5-dicarboxylate

Tert-butyl 1, 4-diazepan-5-carboxylate (1.055g) was dissolved in dichloromethane (20mL) to give a light brown solution at room temperature under argon. The mixture was cooled to 0 ℃ and a solution of dibenzyl dicarbonate (1.51g) in dichloromethane (10mL) was added dropwise over a period of 10 minutes. The reaction mixture was stirred at 0 ℃ for 30 minutes and then warmed to room temperature for 1.5 hours. The mixture was evaporated directly 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 (960mg, 52%). MS (M/e) 335.6[ M + H]⁺。

Step 4 1-Phenylmethoxycarbonyl-1, 4-diazepan-5-carboxylic acid 2,2, 2-trifluoroacetate salt

At room temperature in an argon atmosphereNext, 1-O-benzyl 5-O-tert-butyl 1, 4-diazepan-1, 5-dicarboxylate (9.0g) was dissolved in methylene chloride (90 mL). Then, 2,2, 2-trifluoroacetic acid (30.7g, 20.70mL) was added dropwise over a period of 15 minutes. The mixture was stirred at room temperature for 8 hours. The solvent was directly evaporated and the residue was dried in vacuo to give the title compound as a crude light brown oil (11g, 100%, 95% purity). MS (M/e) 279.6[ M-TFA + H]⁺。

Step 5-4-nitroso-1-phenylmethoxycarbonyl-1, 4-diazepan-5-carboxylic acid

1- (benzyloxycarbonyl) -1, 4-diazepan-5-carboxylic acid 2,2, 2-trifluoroacetic acid (1.448g) was dissolved in water (11.0mL) and tetrahydrofuran (4.0mL) at room temperature. Then, hydrochloric acid (37%, 337 μ L) was added dropwise over a period of 5 minutes. The light brown solution was cooled to 0 ℃ and sodium nitrite (251mg) was added. The mixture was warmed to room temperature and stirring was continued 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, over Na₂SO₄Dried, filtered and evaporated. The residue was dried under high vacuum to give the title compound as a crude light brown oil (966mg, 97%, purity 80%). MS (M/e) 308.5[ M + H]⁺。

Step 6-6-Phenylmethoxycarbonyl-4, 5,7, 8-tetrahydro Oxadiazole-o [3,4-d][1,4]Diaza derivatives -9- -3-alkoxides

1- (benzyloxycarbonyl) -4-nitroso-1, 4-diazepan-5-carboxylic acid (936mg) was dissolved in acetonitrile (15mL) at room temperature under an argon atmosphere. The mixture was cooled to 0 ℃ and trifluoroacetic anhydride (768mg) was added dropwise over a period of 10 minutes. The mixture was warmed to room temperature and stirring was continued for 3 hours. Then, potassium carbonate (505mg) was 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, over Na₂SO₄Dried, 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 pale yellow gum (300mg, 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]Diaza derivatives 2, 6-dicarboxylic acid esters

Ethyl propionate (284mg) was added to 6- (benzyloxycarbonyl) -5,6,7, 8-tetrahydro-4H- [1,2, 3-d at room temperature under an argon atmosphere]Oxadiazole-o [3,4-d][1,4]Diaza derivatives-9--3-alkoxide (186mg) in chlorobenzene (4.0 mL). Mixing the mixture inHeating in microwave at 150 deg.C for 2 hr. The reaction mixture was directly 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 pale yellow gum (131mg, 53%). MS (M/e) 344.5[ M + H]⁺。

The regioisomer 6-O-benzyl 3-O-ethyl 4,5,7, 8-tetrahydropyrazolo [1,5-d ] is also separated by flash chromatography (silica gel, gradient of ethyl acetate in heptane)][1,4]Diaza derivatives3, 6-dicarboxylic acid ester as pale yellow gum (36mg, 16%). MS (M/e) 344.5[ M + H]⁺。

Step 8 6-Phenylmethoxycarbonyl-4, 5,7, 8-tetrahydropyrazolo [1,5-d][1,4]Diaza derivatives -2- Formic acid

1M lithium hydroxide solution (9.33mL) was added dropwise to 7, 8-dihydro-4H-pyrazolo [1, 5-d) over a period of 10 minutes at room temperature][1,4]Diaza derivatives-6-benzyl 2-ethyl 2,6(5H) -dicarboxylate (1.78g) in tetrahydrofuran (20 mL). 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 (2M) solution. The aqueous phase was then extracted twice with ethyl acetate. The combined organic layers were washed with brine, over Na₂SO₄Dry, filter and evaporate the solvent. The residue was dried in vacuo to give the title compound as a yellow solid (1.64g, 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 (2Z) -2-amino-2- (2-hydroxyethylhydrazono) acetic acid ethyl ester

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

Step 2 (2Z) -2- [3- (tert-butoxycarbonylamino) propionylamino]-2- (2-hydroxyethylhydrazono) Yl) acetic acid ethyl ester

To a solution of 3-tert-butoxycarbonylamino-propionic acid (7.73g) in THF (100mL) was added triethylamine (6.78mL) and ethyl chloroformate (4.64mL) under a nitrogen atmosphere at-10 deg.C and the reaction mixture was stirred at-10 deg.C for 0.5 h. The reaction mixture was filtered and the filtrate was then added to a solution of (2Z) -2-amino-2- (2-hydroxyethylhydrazono) acetic acid ethyl ester (6.57g) and the mixture was stirred at 25 ℃ for 16 h. The solvent was evaporated in vacuo and the residue partitioned between ethyl acetate (150mL) and water (100 mL). The organic layer was separated and the aqueous layer re-extracted with ethyl acetate (2x100 ml). The combined organic layers were washed with brine and dried over anhydrous Na₂SO₄Dried, filtered, and concentrated in vacuo. The rough-made materialPurification of the crude material by column chromatography over standard silica gel (20-40% EtOAc/hexanes) afforded (3-tert-butoxycarbonylamino-propionylamino) - [ (2-hydroxy-ethyl) -hydrazono]-ethyl acetate (5.81g) as a yellow viscous solid. LC-MS 346.9[ M + H ]]⁺。

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

Reacting (2Z) -2- [3- (tert-butoxycarbonylamino) propionylamino]A solution of ethyl-2- (2-hydroxyethylhydrazono) acetate (5.8g) in n-BuOH (400mL) 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 yield 5- (2-tert-butoxycarbonyl-amino-ethyl) -1- (2-hydroxy-ethyl) -1H- [1,2,4]A mixture of triazole-3-carboxylic acid ethyl ester and the corresponding n-butyl ester (4.22g, impure) was a yellow viscous solid. LC-MS 329.2 and 356.9[ M + H ]]⁺。

Step 4-5- (2-tert-Butoxycarbonylamino-ethyl) -1- [2- (toluene-4-sulfonyloxy) -ethan-yl Base of]-1H-[1,2,4]Triazole-3-carboxylic acid ethyl ester

To 5- (2-tert-butoxycarbonylamino-ethyl) -1- (2-hydroxy-ethyl) -1H- [1,2,4 at 0 deg.C]Triethylamine (2.70mL) and p-toluenesulfonyl chloride (2.92g) were added to a solution of triazole-3-carboxylic acid ethyl ester (4.2g) in DCM (100mL) and the reaction mixture was stirred at 25 ℃ for 16 h. The reaction mixture was diluted with DCM (50mL) and washed with saturated aqueous sodium bicarbonate (100 mL). Subjecting the organic layer to anhydrous Na₂SO₄Dried, filtered, and concentrated in vacuo. The residue was purified by column chromatography over standard silica gel (10-30% EtOAc/hexanes as eluent) to afford the title compoundThe title compound was a mixture of ethyl ester and the corresponding butyl ester (1.98g) as a yellow viscous solid. LC-MS 482.9 and 511.1[ M + H ]]⁺。

Step 5- (2-amino-ethyl) -1- (2-hydroxy-ethyl) -1H- [1,2,4]Triazole-3-carboxylic acid ethyl ester

To 5- (2-tert-butoxycarbonylamino-ethyl) -1- [2- (toluene-4-sulfonyloxy) -ethyl]-1H-[1，2，4]To a solution of triazole-3-carboxylic acid ethyl ester (5.17g) in DCM (100mL) was added bis4N HCl in alkane (40mL) and the reaction mixture was stirred at 25 ℃ for 2 h. The volatiles were then removed in vacuo to give the title compound as a mixture of ethyl ester and the corresponding butyl ester hydrochloride salt (4.42g, crude) as a brown viscous solid. LC-MS 383.1 and 410.8[ M + H ]]⁺。

Step 6 Ethyl 5,6,7, 8-tetrahydro-4H-1, 3,3a, 6-tetraaza-azulene-2-carboxylate

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

Step 7 6-tert-butyl 4,5,7, 8-tetrahydro-1, 3,3a, 6-tetraaza-azulene-2, 6-dicarboxylate 2-ethyl ester

To a suspension of ethyl 5,6,7, 8-tetrahydro-4H-1, 3,3a, 6-tetraaza-azulene-2-carboxylate (2.2g) in THF (100mL) were added triethylamine (2.21mL) and di-tert-butyl carbonate (3.6mL), and the reaction mixture was stirred at 25 ℃ for 2H. 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 give the title compound as a mixture of ethyl ester and the corresponding butyl ester (1.2g, 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 viscous 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 4,5,7, 8-tetrahydro-1, 3,3a, 6-tetraaza-azulene-2, 6-dicarboxylic acid 6-tert-butyl ester 2-ethyl ester (1.2g) in THF (16mL) at 25 ℃ was added LiOH H₂A solution of O (324mg) in water (4mL) was added, and the reaction mixture was stirred at 25 ℃ for 1 h. The solvent was removed in vacuo and the residue was dissolved in water (30mL) and washed with ethyl acetate. The aqueous layer was acidified with saturated aqueous citric acid and extracted with DCM (3 × 75 mL). The combined organic layers were passed over anhydrous Na₂SO₄Dried, filtered, and concentrated in vacuo. The residue was purified by preparative HPLC to give the title compound (228mg, 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]Diaza derivatives-7-benzyl 2, 7-dicarboxylate:

2-formyl-5, 6,8, 9-tetrahydro-imidazo [1,2-a ] prepared according to the procedure described by Gerlach et al, PCT int.appl. (2008), WO 2008135526A1][1,4]Diaza derivativesBenzyl 7-carboxylate (500mg), dissolved in acetone (15mL) and water (15 mL). Then, sulfamic acid (292mg) and NaClO were added₂(211mg), and the reaction mixture was stirred at 25 ℃ 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 passed over anhydrous Na₂SO₄Dried, filtered, and concentrated in vacuo. With Et₂O grinding the crude material and providing an off-white solid which is dried to provide 5,6,8, 9-tetrahydro-imidazo [1,2-a][1,4]Diaza derivatives7-benzyl 2, 7-dicarboxylate (6) (425mg, 81%). LC-MS 316.0[ M + H ]]⁺。

Intermediate 4:

4- (hydroxymethyl) -3-isopropyl-benzonitrile

Step 1-4-cyano-2-isopropylphenyl trifluoromethanesulfonate

Pyridine (915. mu.l) in dichloromethane (70mL) at 0 deg.CTo the solution of (1.75mL) was added trifluoromethanesulfonic anhydride. The white suspension was stirred at 0 ℃ for 10 minutes. A solution of 4-hydroxy-3-isopropylbenzonitrile (CAS:1.52g) in methylene chloride (40ml) was added dropwise. The ice bath was removed and the dark brown clear solution was stirred at room temperature. TLC of 75min indicated completion of the reaction. 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 (100g, SiO)₂(ii) a A gradient of heptane/dichloromethane 9:1 to heptane/dichloromethane 4: 6) to yield the title compound (2.63g, 95%). A yellow liquid; MS 292.1[ M-H ]]^-。

Step 2 methyl 4-cyano-2-isopropylbenzoate

4-cyano-2-isopropylphenyl trifluoromethanesulfonate (2.30g) was added to the autoclave and methanol (46mL) was added. The autoclave was set under argon and then triethylamine (2.73mL) and 1, 1' -bis (diphenylphosphino) ferrocene-palladium (II) dichloride dichloromethane complex (320mg) were added. The CO atmosphere was introduced by repeating (3 times) evacuation and introduction of 10 bar CO. The pressure was then increased to 50 bar and the autoclave was maintained at 110 ℃ for 20 hours. The reaction mixture was cooled to room temperature and the red solution was evaporated in vacuo. Through 100g of SiO₂Column, solvent dichloromethane/heptane 1:1 the residue was filtered to give the title compound (1.23g, 77%). Pale yellow oil, MS:218.5[ M + H]⁺。

Step 3 4- (hydroxymethyl) -3-isopropyl-benzonitrile

To a clear, light yellow solution of methyl 4-cyano-2-isopropylbenzoate (1.227g) in tetrahydrofuran (15mL)To the solution was added lithium borohydride (2M in THF, 9.06 mL). The reaction mixture was heated to reflux. TLC (dichloromethane/heptane 4:1) at t ═ 1h showed the reaction was complete. The reaction was cooled to room temperature and 5mL MeOH was added. After 30min, 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 (100g, SiO)₂(ii) a Dichloromethane to dichloromethane/methanol + 0.25% NH₄Gradient of aqueous OH 19: 1) provided the title compound (802mg, 76%). Light 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-pivaloylamidobenzoate

Pivaloyl chloride (650. mu.l) was added dropwise at 0 ℃ to a clear, red solution of methyl 2-amino-4-cyanobenzoate (CAS: 159847-83-3; 776mg) in pyridine (6 mL). A solid precipitated. MS with t ═ 2h showed the reaction was complete. The reaction mixture was diluted with 1M aqueous HCl and extracted twice with ethyl acetate/2-methyltetrahydrofuran. The combined organic layers were washed with water, 50% Na₂CO₃The solution was washed with brine, dried over magnesium sulfate, filtered and evaporated. The residue was suspended in ethyl acetate to obtain the title compound (819mg, white solid). The mother liquor was evaporated and the residue treated with tBME to give another crop of the title compound (148mg, white solid). The products were combined to give the title compound (967mg, 84%). A white solid. MS 261.1[ M-H ]]^-。

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

To a white suspension of methyl 4-cyano-2-pivaloylamidobenzoate (335mg) in tetrahydrofuran (6.0mL) under argon was added a solution of calcium chloride (286mg) in ethanol (6.0 mL). Sodium borohydride (195mg) was added in 3 portions over 20 minutes. TLC of t ═ 4h showed the reaction was complete. The reaction mixture was poured into ice/water and saturated NH₄And (4) adding 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 (50g, SiO2, gradient of dichloromethane to dichloromethane/methanol 9: 1) afforded the title compound (257mg, 86%). 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 (140mg) was dissolved in acetone (5mL) at room temperature under an argon atmosphere. To the mixture were added potassium carbonate (122mg) and ethyl 2-bromoacetate (97. mu.L) successively. 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 the layers were separated. The aqueous layer was extracted twice with additional ethyl acetate. Combining organic layersWashed once with brine and over Na₂SO₄Dry, filter, evaporate and dry in high vacuum to give the crude product as a yellow viscous oil, which was used without further purification (210mg, 88%).

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

A 1M lithium hydroxide solution (1.47mL) was added dropwise over a period of 5 minutes to a solution of ethyl 2- (4-cyano-2-cyclopropylphenoxy) acetate (200mg) in THF (4.0mL) at room temperature. The mixture was stirred at room temperature for 5 hours. The reaction mixture was poured into ice/water and acidified to pH 1 with HCl 2M solution. The aqueous phase was then extracted twice with ethyl acetate. The combined organic layers were washed with brine, over Na₂SO₄Dry, filter and evaporate the solvent. The residue was dried under high vacuum to give the title compound as a yellow solid (170mg, 96%). MS (M/e) 216.1[ M-H]^-。

Intermediate 7:

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

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

Intermediate 8:

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

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

Intermediate 9:

5,6,7, 8-tetrahydro-4H-pyrazolo [1,5-d][1,4]Diaza derivatives -2-yl (1,4,6, 7-tetrahydrotriazolo) [4,5-c]Pyridin-5-yl) methanones

The synthesis of intermediate 9 is described in example 3, step 1.

Intermediate 10:

1,4,6, 7-tetrahydrotriazolo [4,5-c ] s]Pyridin-5-yl (6,7,8, 9-tetrahydro-5H- [1,2, 4)]Triazolo compounds [1,5-d][1,4]Diaza derivatives -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]III Azolo [1,5-d ] s][1,4]Diaza derivatives -7-Carboxylic acid tert-butyl ester

In a 20mL round-bottom flask, 7- (tert-butoxycarbonyl) -6,7,8, 9-tetrahydro-5H-[1,2,4]Triazolo [1,5-d][1,4]Diaza derivatives-2-carboxylic acid (intermediate 9, 450mg) and 4,5,6, 7-tetrahydro-1H- [1,2,3]Triazolo [4,5-c]Pyridine (207mg) was combined with DMF (12.9mL) to give a white suspension. N-ethyldiisopropylamine (587mg) was added dropwise over a period of 2 minutes at room temperature. Then, HATU (638mg) was 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, over Na₂SO₄Dried, filtered and evaporated. The residue was evaporated again with toluene. The crude material was purified by flash chromatography (silica gel, 20g, CH)₂Cl₂Medium 0% to 10% MeOH) to give a white foam (310 mg). MS 389.3[ M + H ]]⁺。

Step 21, 4,6, 7-Tetrahydrotriazolo [4,5-c ]]Pyridin-5-yl (6,7,8, 9-tetrahydro-5H- [1,2, 4)]III Azolo [1,5-d ] s][1,4]Diaza derivatives -2-yl) methanone hydrochloride

In a 20mL round bottom flask, 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]Diaza derivativesTert-butyl-7 (6H) -carboxylate (230mg) and 5N HCl in 2-propanol (5mL) were combined to give a white suspension. The reaction mixture was heated to 50 ℃ and stirred for 2 hours. The reaction mixture was then cooled and concentrated in vacuo to give the crude salt (190mg), which was used without further purification. MS 289.1[ M + H ]]⁺。

Intermediate 11:

3- [ 3-chloro-4- (trifluoromethoxy) phenyl]Propionic acid

Step 1 (E) -3- [ 3-chloro-4- (trifluoromethoxy) phenyl]2-propenoic acid

In a 20mL round bottom flask, 3-chloro-4- (trifluoromethoxy) benzaldehyde (CAS:83279-39-4, 500mg), malonic acid (510mg) and piperidine (22.0. mu.L) were combined with pyridine (3.0mL) 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 2 times with ethyl acetate and the combined organic layers were washed with brine, over Na₂SO₄Dried, filtered and evaporated. The crude material was purified by flash chromatography (silica gel, 20g, CH)₂Cl₂Medium 0% to 10% MeOH) to afford the title compound as a white solid (400 mg). MS 265.1[ M-H ]]^-。

Step 2 3- [ 3-chloro-4- (trifluoromethoxy) phenyl group]Propionic acid

In a 50mL three-necked flask, (E) -3- [ 3-chloro-4- (trifluoromethoxy) phenyl]Prop-2-enoic acid (300mg) was combined with ethyl acetate (10mL) to give a colorless solution. Palladium on charcoal (10% Pd, 40mg) was added and the mixture was then hydrogenated for 30min, wherein TLC analysis showed no residual starting material. The reaction mixture was filtered through celite, then concentrated in vacuo to give a pale yellow solid (300mg), which was used without further purification. MS 267.3[ M-H ]]^-。

Intermediate 12:

2-cyclopropyl-6-, (Alk-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; 400mg) in methanol (4mL) and sulfuric acid (12. mu.L) was heated at 70 ℃ for 48 h. The mixture was then concentrated in vacuo. The residue was suspended in dichloromethane (10mL), then insoluble material was removed by filtration and the filtrate was evaporated to give the title compound (427mg) as a light brown semisolid. MS 194.1[ M + H ]]⁺。

Step 2-2-cyclopropyl-6-, ( Alk-4-ylmethoxy) pyridine-4-carboxylic acid methyl ester

To a suspension of methyl 6-cyclopropyl-2-oxo-1, 2-dihydropyridine-4-carboxylate (212mg) in acetonitrile (5mL) were added potassium carbonate (455mg) and 4- (iodomethyl) tetrahydro-2H-pyran (CAS: 101691-94-5; 744mg), and stirred. The reaction mixture was heated at 80 ℃ for 16h and then evaporated in vacuo. Will remain behindThe material 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-, ( Alk-4-ylmethoxy) pyridine-4-carboxylic acid

To 2-cyclopropyl-6-, (To a solution of alk-4-ylmethoxy) pyridine-4-carboxylic acid methyl ester (184mg) in tetrahydrofuran (2mL) and water (2mL) was added lithium hydroxide monohydrate (53.0mg, 1.26mmol) 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 1M aqueous hydrochloric acid 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[ M-H ]]^–。

Intermediate 13:

(E) -3- [4- (difluoromethoxy) -3-fluoro-phenyl]2-propenoic 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]Diaza derivatives -2-yl (1,4,6, 7-tetrahydrotriazolo) [4,5-c]Pyridin-5-yl) methanones

In analogy to example 3, step 1, by hydrogenation of 2- (1,4,6, 7-tetrahydrotriazolo [4, 5-c)]Pyridine-5-carbonyl) -5,6,8, 9-tetrahydroimidazo [1,2-d][1,4]Diaza derivatives-benzyl 7-carboxylate (obtained in example 2) this material was prepared to give the title compound 6,7,8, 9-tetrahydro-5H-imidazo [1,2-d][1,4]Diaza derivatives-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]Diaza derivatives -2-carbonyl Radical) hexahydro- [1,3] Azolo [5,4-c ] s]Pyridin-2 (1H) -one 2,2, 2-trifluoroacetate salt

Step 1 (3aR,7aR) -2-oxo-1, 3a,4,6,7,7 a-hexahydro- [1,3] Azolo [5,4-c ] s]Pyridine-5- (iv) Carboxylic acid tert-butyl ester

To a solution of tert-butyl (3R,4R) -4-amino-3-hydroxypiperidine-1-carboxylate (CAS:1007596-95-3, 510mg) in DMF (8.0mL) at room temperature under argon was added imidazole (161mg) and then 1, 1' -carbonyldiimidazole (382 mg). The mixture was stirred at room temperature for 18 hours. Then, the reaction mixture was poured into ice/water and the aqueous layer was extracted twice with ethyl acetate. The organic layer was washed once with brine, over Na₂SO₄Dried, filtered and evaporated. The residue was again evaporated together with toluene. The crude material was purified by flash chromatography (silica gel, 20g 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,4,5,6,7,7 a-hexahydro-1H- [1,3] Azolo [5,4-c ] s]Pyridin-2-ones Hydrochloride salt

Reacting (3aR,7aR) -2-oxo-1, 3a,4,6,7,7 a-hexahydro- [1,3]Azolo [5,4-c ] s]Tert-butyl pyridine-5-carboxylate (458mg) was combined with hydrochloric acid (ca. 5M-6M in isopropanol, 6.87mL) and the mixture was stirred at room temperature for 19 h. The reaction mixture was then directly evaporated to dryness. The white residue was combined with ethyl acetate (8mL) and the suspension was stirred at room temperature for 1 hour. The colorless solid was separated by filtration and extracted with ethyl acetateWashed and dried under high vacuum to give the title compound (279 mg). MS 143.0[ M + H ]]⁺(free base).

Step 3- [ (3aR,7aR) -2-oxo-1, 3a,4,6,7,7 a-hexahydro- [1,3] Azolo [5,4-c ] s]Pyridine compound -5-carbonyl group]-5,6,8, 9-tetrahydro- [1,2,4]Triazolo [1,5-d][1,4]Diaza derivatives -7-Carboxylic acid tert-butyl ester

In a 50mL round-bottom flask, (3aR,7aR) -3a,4,5,6,7,7 a-hexahydro-1H- [1,3]Azolo [5,4-c ] s]Pyridin-2-one hydrochloride (225mg), 4-methylmorpholine (382mg) and 6-tert-butyl 4,5,7, 8-tetrahydro-1, 3,3a, 6-tetraaza-azulene-2, 6-dicarboxylate (intermediate 2, 391mg) were combined with DMF (10.0mL) to give a pale yellow solution. 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (483mg) and 1-hydroxybenzotriazole hydrate (340mg) were added to the solution, 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, over Na₂SO₄Dried, filtered and evaporated. The residue was evaporated again with toluene. The crude material was purified by flash chromatography (silica gel, 50g cartridge, 0% to 10% methanol in dichloromethane) to give the title compound as a colourless 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]Diaza derivatives -2-carbonyl) hexahydro- [1,3] Azolo [5,4-c ] s]Pyridin-2 (1H) -one 2,2, 2-trifluoroacetate salt

2- [ (3aR,7aR) -2-oxo-1, 3a,4,6,7,7 a-hexahydro- [1,3 ] hexahydro-2-carboxylic acid]Azolo [5,4-c ] s]Pyridine-5-carbonyl]-5,6,8, 9-tetrahydro- [1,2,4]Triazolo [1,5-d][1,4]Diaza derivativesTert-butyl-7-carboxylate (50mg) was dissolved in dichloromethane (5.0 mL). Then, 2,2, 2-trifluoroacetic acid (140mg) was added dropwise over a period of 5 minutes, and the mixture was stirred at room temperature for 3 hours. More 2,2, 2-trifluoroacetic acid (42.1mg) was added slowly and stirring was continued at room temperature for 17 hours. Then, the solvent was removed by evaporation, and the residual TFA was removed by addition and evaporation of toluene. After evaporation, the residue was dried in high vacuum to give a light yellow gum (68mg), which was used without further purification. MS 307.2[ M + H ]]⁺(free base).

Examples

Example 1

2- (1,4,6, 7-tetrahydrotriazolo [4, 5-c)]Pyridine-5-carbonyl) -4,5,7, 8-tetrahydropyrazolo [1,5-d][1,4]Diaza derivatives -6-Carboxylic acid benzyl ester

4-methylmorpholine (1.56g) was added dropwise to 6- (benzyloxycarbonyl) -5,6,7, 8-tetrahydro-4H-pyrazolo [1, 5-d) over a period of 5 minutes at room temperature under argon atmosphere][1,4]Diaza derivatives-2-carboxylic acid (intermediate 1, 1.62g) and 4,5,6, 7-tetrahydro-1H- [1,2,3]Triazolo [4,5-c]Pyridine (702mg, [ CAS:706757-05-3 ]]) In suspension in dimethylformamide (20 mL). HATU (2.17g) 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, over Na₂SO₄Dried, filtered and evaporated. The residue was evaporated again with toluene. The crude material was purified by flash chromatography (silica gel, 0% to 100% ethyl acetate in heptane, and then CH₂Cl₂MeOH 96/4) to give the title compound as an off-white foam (1.40g, 62%). MS (M/e) 422.6[ M + H⁺]。

The following example 2 was synthesized analogously to example 1 from suitable 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]Diaza derivatives -6-carboxylic acid [ 3-fluoro-4- (trifluoromethoxy) phenyl]Methyl ester

Step 1:5,6,7, 8-tetrahydro-4H-pyrazolo [1,5-d][1,4]Diaza derivatives -2-yl (1,4,6, 7-tetra Hydrotriazolo [4,5-c ]]Pyridin-5-yl) methanones

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 derivativesBenzyl (6 (5H) -carboxylate (1.40g, obtained in example 1) was dissolved in methanol (10mL) to give a colorless solution. Palladium on activated carbon (140mg, 10% Pd) was added and an atmosphere of hydrogen was introduced at room temperature. The mixture was stirred under hydrogen for 16 hours. The reaction mixture was filtered through dicalite plus (Acros Organics) and the solvent was evaporated to dryness to give the title compound as a colourless oil (910mg, 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]Diaza derivatives -6-carboxylic acid [ 3-fluoro-4- (trifluoromethoxy) phenyl]Methyl ester

At room temperature under argon atmosphereTriethylamine (31.7mg) was added to a solution of (3-fluoro-4- (trifluoromethoxy) phenyl) methanol (CAS:886498-99-3, 98.7mg) in acetonitrile (8.0 mL). Then, N' -disuccinimidyl carbonate (120mg) was added and the colorless solution was stirred at room temperature for 3 hours to give an activated alcohol. Reacting (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]Diaza derivatives-2-yl) methanone (90mg) and triethylamine (95.1mg) were added to the colorless solution, and the mixture was stirred at room temperature for 18 h. 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, over Na₂SO₄Dried, 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 give the title compound as a white solid (53mg, 32%). MS (M/e) 524.6[ M + H]⁺。

The following examples 4-13, analogous to example 2, step 2, were synthesized from the appropriate building blocks and the corresponding 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]Diaza derivatives -6-yl]-3- [4- (trifluoromethoxy) phenyl]Propan-1-ones

4-Methylmorpholine (84.5mg) was added dropwise to (6, 7-dihydro-1H- [1,2, 3) over a period of 5 minutes at room temperature under an argon atmosphere]Triazolo [4,5-c]Pyridin-5 (4H) -yl) (5,6,7, 8-tetrahydro-4H-pyrazolo [1, 5-d)][1,4]Diaza derivatives-2-yl) methanone (intermediate 9, 80mg) and 3- (4- (trifluoromethoxy) phenyl) propanoic acid (CAS: 886499-74-7; 71.7mg,) in dimethylformamide (4.0 mL). The mixture was cooled to 0 ℃ and HATU (117mg) was added. The mixture was warmed to room temperature for 17 h. The reaction mixture was poured into ice/water and the aqueous phase was then extracted twice with ethyl acetate. The combined organic layers were washed with brine, over Na₂SO₄Dried, 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 (13mg, 10%). MS (M/e) 504.6[ M + H]⁺

The following examples 15-17 were synthesized analogously 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]Diaza derivatives -6-yl]Propan-1-ones

In a 25mL three-necked flask, (E) -3- [4- (difluoromethoxy) -3-fluorophenyl ] ester]-1- [2- (1,4,6, 7-tetrahydrotriazolo [4, 5-c)]Pyridine-5-carbonyl) -4,5,7, 8-tetrahydropyrazolo [1,5-d][1,4]Diaza derivatives-6-yl]Prop-2-en-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 introduction of a hydrogen atmosphere. Then, the mixture was stirred at room temperature overnight. The hydrogen was then removed and the reaction mixture was filtered through celite. The filtrate was evaporated to give the 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 (20 mg). 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-pyrazoles And [1,5-d ]][1,4]Diaza derivatives -6(5H) -carboxylic acid 4-methoxybenzyl ester

In analogy to example 3, step 2, from 5,6,7, 8-tetrahydro-4H-pyrazolo [1,5-d][1,4]Diaza derivatives-2-yl (1,4,6, 7-tetrahydrotriazolo [4, 5-c)]Pyridin-5-yl) methanone (intermediate 9) and (4-methoxyphenyl) methanol (CAS:105-13-5) prepared this material. MS 452.3[ M + H ]]⁺。

The following examples 28-43 were synthesized analogously to example 27 from the appropriate building blocks and the corresponding substituted benzyl alcohols:

Claims

1. A compound of formula (I)

Wherein

R¹Is alkyl, haloalkyl, substituted cycloalkyl, substituted cycloalkylalkyl, substituted phenyl, substituted phenylalkyl, substituted phenoxyalkyl, substituted phenylalkoxy, substituted phenylcycloalkyl, substituted phenylalkenyl, substituted phenylalkynylSubstituted 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 pyridylalkynyl, substituted benzothienyl, substituted thiophenylalkynyl, substituted thiophenyl, substituted thiophen, Substituted thienylalkenyl, substituted thienylalkynyl, substituted 2, 3-dihydro-1H-isoindol-2-yl, substituted 1H-indol-2-yl and substituted benzofuran-2-yl groups substituted by R³、R⁴And R⁵Substitution;

A¹is-N-or-CR⁷-；

A²is-N-or-CR⁸-and A¹And A²At least one of which is-N-;

R²selected from the group consisting of ring systems A, B, C, D, E, F, G, H, I, K and L,

R³、R⁴and R⁵Independently selected from the group consisting of H, alkyl, hydroxyalkyl, haloalkyl, hydroxyhaloalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkoxy, cycloalkoxy, cycloalkoxyalkyl, cycloalkylalkoxyalkyl, alkoxy, alkoxyalkyl, haloalkoxy, alkoxyhaloalkyl, alkoxyalkoxy, alkoxyalkoxyalkyl, heterocycloalkylalkoxy, phenyl, substituted phenyl, pyridyl, substituted pyridyl, halogen, hydroxy, cyano, alkylsulfanyl, haloalkylsulfanyl, cycloalkylsulfanyl, alkylsulfinyl, haloalkylsulfinyl, cycloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonylA group, 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 the group consisting of H, alkyl, cycloalkyl, cycloalkylalkyl, hydroxyalkyl, alkoxyalkyl, alkylcarbonyl, and cycloalkylcarbonyl, and wherein substituted phenyl and substituted pyridinyl are optionally substituted with one to three substituents independently selected from the group consisting of alkyl, halo, haloalkyl, alkoxy, and haloalkoxy;

R⁶is H, alkyl, haloalkyl or cycloalkyl;

R⁷and R⁸Independently selected from H, alkyl, haloalkyl or cycloalkyl;

or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1, wherein

R¹Is 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 pyridalkenyl, substituted pyridynyl, 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 groups are substituted withR³、R⁴And R⁵Substitution;

A¹is-N-or-CR⁷-；

A²is-N-or-CR⁸-and A¹And A²At least one of which is-N-;

R⁶is H, alkyl, haloalkyl or cycloalkyl;

R⁷and R⁸Independently selected from H, alkyl, haloalkyl or cycloalkyl;

or a pharmaceutically acceptable salt thereof.

3. The compound of claim 1 or 2, wherein R¹Is substituted phenylalkyl, substituted phenoxyalkyl or substituted phenylalkoxy, whereinSubstituted phenylalkyl, substituted phenoxyalkyl and substituted phenylalkoxy with R³、R⁴And R⁵And (4) substitution.

4. A compound according to any one of claims 1 to 3, wherein R¹Is substituted phenoxyalkyl or substituted phenylalkoxy, wherein substituted phenoxyalkyl and substituted phenylalkoxy are substituted by R³、R⁴And R⁵And (4) substitution.

5. A compound according to any one of claims 1 to 4, wherein R¹Is by R³、R⁴And R⁵Substituted phenylalkoxy groups.

6. A compound according to any one of claims 1 to 5, wherein R²Selected from ring systems A and O.

7. A compound according to any one of claims 1 to 6, wherein R²Is ring system a.

8. The compound according to any one of claims 1 to 7, wherein A¹is-N-and A²is-N-or-CR⁸-。

9. A compound according to any one of claims 1 to 8, wherein R³、R⁴And R⁵Independently selected from the group consisting of H, alkyl, cycloalkyl, heterocycloalkylalkoxy, haloalkoxy, halogen, cyano, and alkylcarbonylamino.

10. According toThe compound of any one of claims 1 to 9, wherein R³、R⁴And R⁵Independently selected from the group consisting of H, alkyl, cycloalkyl, haloalkoxy, halogen, cyano and alkylcarbonylamino.

11. The compound according to any one of claims 1 to 10, wherein R³Is heterocycloalkylalkoxy, haloalkoxy or cyano.

12. The compound according to any one of claims 1 to 11, wherein R³Is haloalkoxy or cyano.

13. The compound according to any one of claims 1 to 12, wherein R⁴Is H, alkyl, cycloalkyl or halogen.

14. The compound according to any one of claims 1 to 13, wherein R⁴Is H, alkyl or halogen.

15. The compound according to any one of claims 1 to 14, wherein R⁵Is H.

16. The compound according to any one of claims 1 to 15, wherein R⁷Is H.

17. The compound according to any one of claims 1 to 16, wherein R⁸Is H.

18. A compound according to any one of claims 1 to 17, wherein

A¹is-N-;

A²is-N-or-CR⁸-；

R²Is ring system a;

R³is haloalkoxy or cyano;

R⁴is H or halogen;

R⁵is H;

R⁸is H;

or a pharmaceutically acceptable salt thereof.

19. A compound according to any one of claims 1 to 18 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 derivatives-6-formic acid (4-cyano-2-prop-2-ylphenyl) methyl ester;

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]Diaza derivatives-6-yl]Propan-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 derivatives-6(5H) -carboxylic acid 4-cyclopropyl groupBenzyl 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 derivatives-7-carboxylic acid [ 3-chloro-4- (trifluoromethoxy) phenyl]Methyl ester;

and pharmaceutically acceptable salts thereof.

20. A compound according to any one of claims 1 to 19 selected from

and pharmaceutically acceptable salts thereof.

21. A compound according to any one of claims 1 to 19 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 derivatives-6(5H) -A4- (difluoromethoxy) -3-fluorobenzyl acid;

and pharmaceutically acceptable salts thereof.

22. A compound according to any one of claims 1 to 20 selected from

and pharmaceutically acceptable salts thereof.

23. A process for the preparation of a compound according to any one of claims 1 to 22, comprising the reaction of a compound of formula (II) in the presence of a compound of formula (III), wherein R¹Is by R³、R⁴And R⁵Substituted phenylalkoxy, R_AIs by R³、R⁴And R⁵Substituted benzenesAlkyl radical, and R²、R³、R⁴、R⁵、A¹And A²As defined in any one of claims 1 to 18.

24. A process for the preparation of a compound according to any one of claims 1 to 22, comprising the reaction of a compound of formula (II) in the presence of a compound of formula (IV), wherein R¹Is alkyl, haloalkyl, substituted cycloalkyl, substituted cycloalkylalkyl, substituted phenyl, substituted phenylalkyl, substituted phenoxyalkyl, substituted phenylcycloalkyl, substituted phenylalkenyl, substituted phenylalkynyl, substituted pyridyl, substituted pyridylalkyl, substituted pyridalkenyl, substituted pyridynyl, 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 phenyl, substituted phenylalkyl, substituted phenyl-cycloalkyl, substituted phenyl-alkyl, substituted phenyl-alkynyl, substituted phenyl, Substituted phenylalkenyl, substituted phenylalkynyl, substituted pyridyl, substituted pyridylalkyl, substituted pyridenyl, substituted pyridynyl, 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 substituted with R³、R⁴And R⁵Substituted and R²、R³、R⁴、R⁵、A¹And A²As defined in any one of claims 1 to 18.

25. A compound according to any one of claims 1 to 22 for use as therapeutically active substance.

26. A pharmaceutical composition comprising a compound according to any one of claims 1 to 22 and a therapeutically inert carrier.

27. Use of a compound according to any one of claims 1 to 22 for the treatment or prophylaxis of renal conditions, liver conditions, inflammatory conditions, conditions of the nervous system, fibrotic diseases and acute and chronic organ transplant rejection.

28. A compound according to any one of claims 1 to 22 for use in the treatment or prophylaxis of renal conditions, liver conditions, inflammatory conditions, conditions of the nervous system, fibrotic diseases and acute and chronic organ transplant rejection.

29. Use of a compound according to any one of claims 1 to 22 for the preparation of a medicament for the treatment or prophylaxis of renal conditions, liver conditions, inflammatory conditions, conditions of the nervous system, fibrotic diseases and acute and chronic organ transplant rejection.

30. A method of treating or preventing a renal disorder selected from the group consisting of renal disorders, liver disorders, inflammatory disorders, neurological disorders, fibrotic diseases and acute and chronic organ transplant rejection, the method comprising administering an effective amount of a compound according to any one of claims 1 to 22.

31. A compound according to any one of claims 1 to 22, when manufactured according to a process of claim 23 or 24.

32. The invention as hereinbefore described.