NZ722157B2 - Bicyclic compounds as autotaxin (atx) and lysophosphatidic acid (lpa) production inhibitors - Google Patents

Abstract

The invention provides novel compounds having the general formula (I) wherein R1, R2, A, W, m, n, p and q are as described herein, compositions including the compounds. The compounds of formula (I) are useful as autotaxin (ATX) inhibitors which are inhibitors of lysophosphatidic acid (LPA) production and thus modulators of LPA levels and associated signaling; in particular they are useful for the treatment or prophylaxis of renal conditions, liver conditions, inflammatory conditions, conditions of the nervous system, conditions of the respiratory system, vascular and cardiovascular conditions, fibrotic diseases, cancer, ocular conditions, metabolic conditions, cholestatic and other forms of chronic pruritus and acute and chronic organ transplant rejection. n and thus modulators of LPA levels and associated signaling; in particular they are useful for the treatment or prophylaxis of renal conditions, liver conditions, inflammatory conditions, conditions of the nervous system, conditions of the respiratory system, vascular and cardiovascular conditions, fibrotic diseases, cancer, ocular conditions, metabolic conditions, cholestatic and other forms of chronic pruritus and acute and chronic organ transplant rejection.

Description

(12) d patent specificaon (19) NZ (11) 722157 (13) B2 (47) Publicaon date: 2021.12.24 (54) BICYCLIC COMPOUNDS AS AUTOTAXIN (ATX) AND LYSOPHOSPHATIDIC ACID (LPA) PRODUCTION INHIBITORS (51) Internaonal Patent Classificaon(s): C07D 487/04 A61K 31/407 A61K 31/55 A61P 3/00 A61P 1/16 (22) Filing date: (73) Owner(s): 2015.03.23 F. HOFFMANN-LA ROCHE AG (23) Complete specificaon filing date: (74) Contact: 3.23 AJ PARK (30) Internaonal Priority Data: (72) Inventor(s): EP 14161760.5 2014.03.26 KUEHNE, Holger HUNZIKER, Daniel (86) Internaonal Applicaon No.: HERT, Jérôme DI GIORGIO, Patrick RUDOLPH, Markus (87) Internaonal Publicaon number: MATTEI, Patrizio WO/2015/144605 (57) Abstract: The on provides novel compounds having the general formula (I) wherein R1, R2, A, W, m, n, p and q are as described herein, composions including the compounds. The nds of formula (I) are useful as autotaxin (ATX) inhibitors which are tors of lysophosphadic acid (LPA) producon and thus modulators of LPA levels and ated signaling; in parcular they are useful for the treatment or prophylaxis of renal ons, liver ons, inflammatory condions, condions of the nervous system, condions of the respiratory system, vascular and cardiovascular condions, fibroc diseases, cancer, ocular condions, metabolic condions, cholestac and other forms of chronic pruritus and acute and chronic organ transplant rejecon. 722157 B2 BICYCLIC COMPOUNDS AS AUTOTAXIN (ATX) AND LYSOPHOSPATIDIC ACID (LPA) PRODUCTION TORS The t invention generally relates to organic compounds useful for therapy or prophylaxis in a mammal, and in particular to autotaxin (ATX) inhibitors which are inhibitors of lysophosphatidic acid (LPA) production and thus modulators of LPA levels and associated signaling, for the treatment or prophylaxis of renal conditions, liver conditions, inflammatory conditions, conditions of the nervous system, conditions of the respiratory system, ar and cardiovascular conditions, fibrotic diseases, cancer, ocular conditions, lic conditions, cholestatic and other forms of chronic pruritus and acute and chronic organ transplant rejection.

In a first aspect, the t invention es novel compounds of formula (I) p( ) ( )m ( )n q( ) (I) wherein R1 is substituted phenyl or substituted pyridinyl, wherein substituted phenyl and substituted pyridinyl are substituted with R3, R4 and R5; A is -N- or -CH-; W is -C(O)-, -C(O)O-, -, -C(O)-NR10- or -CR6R7-; R2 is selected from the ring systems B, C, D, E, F, G, H, I, J, K, L, M, N, O, P, Q, R, S, T, U, V, X, Z, AA, AB, AC, AD, AE, AF, AG, AH, AI, AJ, AK, AL, AM, AN, AO, AP, AQ, AR, AS, AT, AU and AV; B , C , D , E , F , G , H , I , J , K , L , M , N , O , P , Q , R , S , T , U , V , X , Z , AA , AB , AC , AD , AE , AF , AG , AH , AI , AJ , AK , AL , AM , AN , AO , AP , AQ , AR , AS , AT , AU , AV ; R3 is substituted heterocycloalkoxy, substituted heterocycloalkylalkoxy, substituted heterocycloalkylamino or substituted heterocycloalkylalkylamino, wherein substituted heterocycloalkoxy, substituted cycloalkylalkoxy, substituted heterocycloalkylamino and substituted heterocycloalkylalkylamino are substituted with R11, R12 and R13; R4 and R5 are independently selected from H, amino, alkylamino, lamino, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, halogen and cyano; m, n, p and q are independently ed from 1 or 2; R6 and R7 are independently selected from H or alkyl; R8 is H, alkyl, haloalkyl or cycloalkyl; R9 is H, alkyl, halogen, haloalkyl and alkoxy; R10 is H or alkyl; R11, R12 and R13 are independently ed from H, alkyl, , cycloalkyl, cycloalkoxy, halogen, haloalkyl, and cyano; or pharmaceutically acceptable salts.

In a second aspect, the invention provides a process to prepare a compound according to the first aspect comprising the reaction of a compound of formula (II) in the presence of a compound of formula (III), wherein R1, R2, m, n, p and q are as defined above, A is -N- and W is -C(O)-. p( ) ( )m p( ) (III) ( )m ( )n ( )n q( ) q( ) (II) (I) In a third aspect, the invention provides a pharmaceutical composition comprising a compound ing to the first aspect and a therapeutically inert carrier.

In a forth aspect, the invention provides the use of a nd according to the first aspect for the preparation of a medicament for the treatment or prophylaxis of renal conditions, liver conditions, inflammatory conditions, conditions of the s system, fibrotic diseases and acute and chronic organ transplant rejection.

The invention is defined in the claims. However, the disclosure preceding the claims may refer to additional methods and other subject matter e the scope of the present claims. This disclosure is retained for technical purposes.

In this specification where reference has been made to patent specifications, other al documents, or other sources of information, this is generally for the purpose of providing a context for discussing the features of the invention. Unless specifically stated otherwise, reference to such external documents is not to be construed as an admission that such documents, or such s of information, in any jurisdiction, are prior art, or form part of the common general knowledge in the art.

Autotaxin (ATX) is a secreted enzyme also called ectonucleotide pyrophosphatase / phosphodiesterase 2 or lysophospholipase D that is ant for converting lysophosphatidyl e (LPC) to the bioactive signaling molecule lysophosphatidic acid (LPA). It has been shown that plasma LPA levels are well correlated with ATX activity and hence ATX is ed to be an important source of extracellular LPA. Early experiments with a prototype ATX inhibitor have shown that such a compound is able to inhibit the LPA synthesizing activity in mouse plasma. Work conducted in the 1970s and early 1980s has demonstrated that LPA can elicit a wide range of cellular ses; including smooth muscle cell contraction, platelet activation, cell proliferation, chemotaxis and others. LPA mediates its effects via signaling to l G protein coupled receptors (GPCRs); the first s were originally denoted Edg (endothelial cell differentiation gene) receptors or ventricular zone gene-1(vzg-1) but are now called LPA ors. The prototypic group now consists of LPA1/Edg-2/VZG-1, LPA2/Edg-4, and LPA3/Edg-7. Recently, three additional LPA ors LPA4/p2y9/GPR23, LPA5/GPR92 and LPA6/p2Y5 have been described that are more closely related to nucleotide-selective purinergic receptors than to the prototypic LPA1-3 receptors. The ATX-LPA signaling axis is involved in a large range of physiological and pathophysiological functions, including, for example, nervous system on, vascular development, cardiovascular physiology, reproduction, immune system on, chronic inflammation, tumor metastasis and progression, organ fibrosis as well as obesity and/or other metabolic diseases such as diabetes mellitus.

Therefore, increased ty of ATX and/or increased levels of LPA, altered LPA or expression and altered responses to LPA may contribute to the initiation, progression and/or outcome of a number of different pathophysiological conditions related to the ATX/LPA axis.

The nds of a (I) or their pharmaceutically acceptable salts and esters can be used for the treatment or prophylaxis of diseases, ers or conditions that are associated with the activity of autotaxin and/or the biological activity of lysophosphatidic acid (LPA).

The compounds of formula (I) or their pharmaceutically acceptable salts and esters herein inhibit autotaxin activity and therefore inhibit LPA production and modulate LPA levels and associated signaling. Autotaxin inhibitors described herein are useful as agents for the treatment or prevention of diseases or conditions in which ATX activity and/or LPA signaling participates, is involved in the etiology or pathology of the e, or is otherwise ated with at least one symptom of the disease. The ATX-LPA axis has been implicated for example in angiogenesis, chronic inflammation, autoimmune es, fibrotic diseases, cancer and tumor metastasis and ssion, ocular conditions, metabolic ions such as obesity and/or diabetes mellitus, conditions such as cholestatic or other forms of chronic pruritus as well as acute and chronic organ transplant rejection.

Objects of the present invention are the compounds of formula (I) and their aforementioned salts and esters and their use as therapeutically active substances, a process for the manufacture of the said compounds, intermediates, pharmaceutical compositions, medicaments containing the said compounds, their ceutically acceptable salts or esters, the use of the said compounds, salts or esters for the treatment or prophylaxis of disorders or conditions that are associated with the activity of ATX and/or the biological ty of lysophosphatidic acid (LPA), particularly in the treatment or prophylaxis of renal conditions, liver conditions, inflammatory conditions, conditions of the nervous system, conditions of the respiratory system, ar and cardiovascular conditions, fibrotic diseases, , ocular conditions, metabolic conditions, cholestatic and other forms of chronic us and acute andchronic organ transplant rejection, and the use of the said compounds, salts or esters for the production of medicaments for the treatment or prophylaxis of renal conditions, liver conditions, matory conditions, conditions of the s system, conditions of the respiratory system, vascular and cardiovascular conditions, fibrotic diseases, cancer, ocular conditions, metabolic conditions, cholestatic and other forms of chronic us and acute and chronic organ transplant rejection, and/or to at least provide the public with a useful choice.

The term “alkoxy” denotes a group of the formula -O-R’, n R’ is an alkyl group.

Examples of alkoxy group include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy and tert-butoxy.

The term “alkyl” denotes a monovalent linear or branched saturated hydrocarbon group of 1 to 12 carbon atoms. In particular embodiments, alkyl has 1 to 7 carbon atoms, and in more particular embodiments 1 to 4 carbon atoms. es of alkyl include methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, tert-butyl and pentyl. Particular alkyl groups include methyl, ethyl, propyl and isopropyl.

The term “alkylamino” denotes a group of the formula -NH-R’, n R’ is an alkyl group. es of mino group include methylamino, ethylamino, n-propylamino, isopropylamino, n-butylamino, isobutylamino and tert-butylamino.

The term “amino” denotes a -NH2 group.

The term “cyano” denotes a -C≡N group.

The term “cycloalkoxy” denotes a group of the formula -O-R’, wherein R’ is a cycloalkyl group. Examples of cycloalkoxy group include cyclopropoxy, cyclobutoxy, cyclopentyloxy, exyloxy, cycloheptyloxy and cyclooctyloxy. Particular cycloalkoxy group is cyclopropoxy.

The term “cycloalkyl” denotes a monovalent saturated monocyclic or bicyclic hydrocarbon group of 3 to 10 ring carbon atoms. In ular embodiments, cycloalkyl denotes a monovalent saturated monocyclic hydrocarbon group of 3 to 8 ring carbon atoms. Bicyclic means a ring system consisting of two saturated carbocycles having two carbon atoms in common. Examples for clic cycloalkyl are cyclopropyl, cyclobutanyl, cyclopentyl, cyclohexyl or cycloheptyl.

Examples for bicyclic cycloalkyl are bicyclo[2.2.1]heptanyl or bicyclo[2.2.2]octanyl. Particular monocyclic cycloalkyl groups are cyclopropyl, cyclobutanyl, cyclopentyl and cyclohexyl. More particular monocyclic cycloalkyl group is ropyl.

The term “cycloalkylalkyl” denotes an alkyl group wherein at least one of the hydrogen atoms of the alkyl group is replaced by a cycloalkyl group. Examples of cycloalkylalkyl include cyclopropylmethyl, cyclopropylethyl, cyclopropylbutyl, cyclobutylpropyl, 2-cyclopropylbutyl, cyclopentylbutyl, cyclohexylmethyl, cyclohexylethyl, bicyclo[4.1.0]heptanylmethyl, bicyclo[4.1.0]heptanylethyl, bicyclo[2.2.2]octanylmethyl, bicyclo[2.2.2]octanylethyl, adamentanylmethyl and adamantanylethyl. Particular examples of cycloalkylalkyl are exylmethyl, exylethyl, o[4.1.0]heptanylmethyl, bicyclo[4.1.0]heptanylethyl, bicyclo[2.2.2]octanylmethyl, bicyclo[2.2.2]octanylethyl, adamentanylmethyl and tanylethyl. Further particular examples cycloalkylalkyl are cyclohexylmethyl, cyclohexylethyl, o[4.1.0]heptanylmethyl, o[2.2.2]octanylmethyl, adamentanylmethyl and adamantanylethyl.

The term “dialkylamino” denotes a group of the formula -N-R’R’’, wherein R’ and R’’ are independently selected alkyl groups. Particular of dialkylamino group is dimethylamino.

The term “haloalkyl” s an alkyl group n at least one of the hydrogen atoms of the alkyl group has been replaced by the same or different halogen atoms. The term “perhaloalkyl” denotes an alkyl group where all hydrogen atoms of the alkyl group have been replaced by the same or different halogen atoms. Examples of haloalkyl include fluoromethyl, difluoromethyl, trifluoromethyl, trifluoroethyl, oromethylethyl and pentafluoroethyl.

Particular haloalkyl group is trifluoromethyl.

The term “halogen” and “halo” are used interchangeably herein and denote fluoro, chloro, bromo, or iodo. Particular halogen is fluoro.

The term “heterocycloalkyl” denotes a monovalent saturated or partly unsaturated monoor bicyclic ring system of 4 to 9 ring atoms, comprising 1, 2, or 3 ring heteroatoms selected from N, O and S, the remaining ring atoms being carbon. Bicyclic means consisting of two cycles having two ring atoms in common, i.e. the bridge separating the two rings is either a single bond or a chain of one or two ring atoms. Examples for monocyclic saturated heterocycloalkyl are 4,5- dihydro-oxazolyl, oxetanyl, azetidinyl, pyrrolidinyl, 2-oxo-pyrrolidinyl, tetrahydrofuranyl, ydro-thienyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperazinyl, morpholinyl, thiomorpholinyl, oxo-thiomorpholinyl, azepanyl, diazepanyl, homopiperazinyl, or oxazepanyl. Examples for bicyclic saturated heterocycloalkyl are 8-aza-bicyclo[3.2.1]octyl, quinuclidinyl, 8-oxaazabicyclo ]octyl, bicyclo[3.3.1]nonyl, 3-oxaaza-bicyclo[3.3.1]nonyl, or 3-thiaazabicyclo [3.3.1]nonyl. Examples for partly unsaturated cycloalkyl are dihydrofuryl, imidazolinyl, dihydro-oxazolyl, tetrahydro-pyridinyl, or dihydropyranyl. Particular example of cycloalkyl groups are tetrahydropyranyl, tetrahydrofuranyl and yl.

The term ocycloalkoxy” denotes a group of the formula -O-R’, wherein R’ is a heterocycloalkyl group. Examples of heterocycloalkoxy group include tetrahydropyranyloxy, tetrahydrofuranyloxy and oxetanyloxy. Particular heterocycloalkoxy group is tetrahydropyranyloxy.

The term “heterocycloalkylalkoxy” denotes an alkoxy group wherein at least one of the hydrogen atoms of the alkoxy group is replaced by a heterocycloalkyl group. Examples of heterocycloalkylalkoxy include tetrahydropyranylmethoxy, ydrofuranylmethoxy, oxetanylmethoxy, tetrahydropyranylethoxy, tetrahydrofuranylethoxy and ylethoxy.

Particular cycloalkylalkoxy is tetrahydropyranylmethoxy.

The term “heterocycloalkylalkylamino” denotes an alkylamino group wherein at least one of the hydrogen atoms of the alkylamino group is replaced by a heterocycloalkyl group.

Examples of heterocycloalkylalkylamino include tetrahydropyranylmethylamino, tetrahydrofuranylmethylamino, oxetanylmethylamino, tetrahydropyranylethylamino, tetrahydrofuranylethylamino and oxetanylethylamino.

The term “heterocycloalkylamino” denotes a group of the formula -NH-R’, wherein R’ is a heterocycloalkyl group. es of heterocycloalkylamino group include tetrahydropyranylamino, tetrahydrofuranylamino and ylamino. Particular heterocycloalkylamino group is tetrahydropyranylamino.

The term "pharmaceutically able salts" refers to those salts which retain the biological effectiveness and properties of the free bases or free acids, which are not biologically or otherwise undesirable. The salts are formed with inorganic acids such as hloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, in particular hydrochloric acid, and organic acids such as acetic acid, propionic acid, glycolic acid, c acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, ic acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, ptoluenesulfonic acid, salicylic acid, N-acetylcystein and the like. In addition, these salts may be prepared by addition of an inorganic base or an organic base to the free acid. Salts derived from an inorganic base include, but are not d to, the sodium, potassium, lithium, ammonium, calcium, magnesium salts and the like. Salts derived from organic bases include, but are not limited to salts of primary, secondary, and ry amines, substituted amines including lly occurring substituted amines, cyclic amines and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, lysine, arginine, N-ethylpiperidine, piperidine, polyimine resins and the like. Particular pharmaceutically acceptable salts of compounds of formula (I) are the hydrochloride salts, methanesulfonic acid salts and citric acid salts.

"Pharmaceutically acceptable esters" means that compounds of general formula (I) may be derivatised at functional groups to provide derivatives which are capable of sion back to the parent compounds in vivo. es of such nds include physiologically acceptable and metabolically labile ester derivatives, such as methoxymethyl esters, methylthiomethyl esters and pivaloyloxymethyl esters. Additionally, any physiologically acceptable equivalents of the compounds of general formula (I), similar to the metabolically labile esters, which are capable of producing the parent compounds of general formula (I) in vivo, are within the scope of this invention.

The term “protecting group” (PG) denotes a group which selectively blocks a reactive site in a multifunctional compound such that a chemical reaction can be carried out selectively at another unprotected reactive site in the meaning conventionally associated with it in synthetic chemistry. Protecting groups can be removed at the appropriate point. Exemplary protecting groups are amino-protecting groups, carboxy-protecting groups or hydroxy-protecting groups.

Particular protecting groups are the tert-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz), fluorenylmethoxycarbonyl (Fmoc) and benzyl (Bn) groups. Further particular protecting groups are the utoxycarbonyl (Boc) and the fluorenylmethoxycarbonyl (Fmoc) groups. More particular protecting group is the tert-butoxycarbonyl (Boc) group.

The abbreviation uM means microMolar and is equivalent to the symbol µM.

The iation uL means microliter and is equivalent to the symbol µL.

The abbreviation ug means ram and is equivalent to the symbol µg.

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

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

The term “comprising” as used in this ication and claims means “consisting at least in part of”. When interpreting statements in this ication and claims which include the term “comprising”, other es besides the features prefaced by this term in each statement can also be present. Related terms such as “comprise” and “comprises” are to be interpreted in r manner.

Also an embodiment of the t invention are compounds according to formula (I) as described herein and pharmaceutically acceptable salts or esters thereof, in particular compounds according to formula (I) as described herein and pharmaceutically acceptable salts thereof, more particularly compounds according to formula (I) as described herein.

In an embodiment of the present invention are nds according to formula (I) as described herein, wherein R1 is tuted phenyl or tuted pyridinyl, wherein substituted phenyl and substituted pyridinyl are substituted with R3, R4 and R5; A is -N- or -CH-; W is -C(O)-, -S(O)2-, -C(O)-NR10- or -CR6R7-; R2 is selected from the ring systems B, C, D, E, F, G, H, I, J, K, L, M, N, O, P, Q, R, S, T, U, V, X, Z, AA, AB, AC, AD, AE, AF, AG, AH, AI, AJ, AK wherein R9 is H, AL and AM; R3 is substituted heterocycloalkoxy, substituted heterocycloalkylalkoxy, substituted heterocycloalkylamino or substituted heterocycloalkylalkylamino, wherein substituted heterocycloalkoxy, substituted heterocycloalkylalkoxy, substituted cycloalkylamino and tuted heterocycloalkylalkylamino are substituted with R11, R12 and R13; R4 and R5 are independently selected from H, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, halogen and cyano; m, n, p and q are independently selected from 1 or 2; R8 is H, alkyl, haloalkyl or cycloalkyl; R9 is H, alkyl, halogen, haloalkyl and alkoxy; R10 is H or alkyl; R11, R12 and R13 are independently selected from H, alkyl, , cycloalkyl, cycloalkoxy, halogen, haloalkyl, and cyano; or ceutically acceptable salts.

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

Also an embodiment of the present ion are compounds according to formula (I) as described herein, wherein R3 is substituted heterocycloalkoxy, substituted heterocycloalkylalkoxy or substituted heterocycloalkylamino, wherein substituted heterocycloalkoxy, substituted heterocycloalkylalkoxy and substituted heterocycloalkylamino are substituted with R11, R12 and R13.

A particular embodiment of the t invention are compounds ing to formula (I) as described herein, wherein R3 is tetrahydropyranyloxy, tetrahydrofuranyloxy, oxetanyloxy, tetrahydropyranylmethoxy or tetrahydropyranylamino.

In a further particular embodiment of the present invention are compounds according to formula (I) as described herein, wherein R3 is substituted cycloalkoxy or substituted cycloalkylalkoxy, wherein substituted heterocycloalkoxy and substituted heterocycloalkylalkoxy are substituted with R11, R12 and R13.

A more ular embodiment of the present invention are compounds according to formula (I) as described herein, wherein R3 is tetrahydropyranyloxy, tetrahydrofuranyloxy, yloxy or tetrahydropyranylmethoxy.

A further more particular embodiment of the present invention are compounds according to formula (I) as described herein, wherein R3 is heterocycloalkylkoxy substituted with R11, R12 and R13.

A r more particular ment of the present invention are compounds according to formula (I) as described herein, wherein R3 is tetrahydropyranylmethoxy.

The present invention also s to nds according to formula (I) as described herein, wherein R4 is dialkylamino, haloalkyl, cycloalkyl or halogen.

A further particular embodiment of the present invention s to nds according to formula (I) as described herein, wherein R4 is haloalkyl or cycloalkyl.

A more ular embodiment of the present invention are compounds according to formula (I) as described herein, n R4 is cycloalkyl.

Another embodiment of the present invention are compounds according to formula (I) as bed herein, wherein R5 is H.

Also an embodiment of the present invention are compounds according to formula (I) as bed herein, wherein R11, R12 and R13 are H.

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

Another embodiment of the present invention are nds ing to formula (I) as described herein, wherein W is -C(O)-, -, -C(O)-NR10- or -CR6R7-.

A particular embodiment of the present invention are compounds according to formula (I) as described herein, wherein W is -C(O)-.

Another embodiment of the present invention are compounds according to formula (I) as described herein, wherein R2 is selected from the ring systems B, H, M, O, Z, AI, AJ, AK, AL, AM, AN, AO, AQ and AT.

A particular embodiment of the present invention are compounds according to formula (I) as described herein, wherein R2 is selected from the ring systems B, M, O, AJ, AK, AL, AM, AN and AO.

A further particular embodiment of the t invention are compounds according to formula (I) as described herein, wherein R2 is ed from the ring systems M, AJ, AK, AL and A more ular embodiment of the present ion are compounds according to formula (I) as described herein, wherein R2 is selected from the ring systems M, AJ and AL.

A furthermore particular embodiment of the present invention are compounds according to formula (I) as described herein, wherein R2 is the ring system AJ.

A particular embodiment of the present invention are compounds according to a (I) as described herein, wherein m and n are 1 and p and q are 2.

A more particular embodiment of the present invention are compounds according to formula (I) as described herein, wherein R1 is pyridinyl substituted with R3, R4 and R5; A is -N-; W is -C(O)-; R2 is the ring system AJ; R3 is heterocycloalkylalkoxy substituted with R11, R12 and R13; R4 is cycloalkyl; R5 is H; m and n are 1; p and q are 2; R9 is H; R11, R12 and R13 are H; or pharmaceutically able salts.Particular es of compounds of formula (I) as described herein are selected from 5-((3aS,6aS)(5-cyclopropyl(tetrahydro-2H-pyran- 4-yloxy)nicotinoyl)octahydropyrrolo[3,4-c]pyrrolecarbonyl)pyridinesulfonamide; 6-((3aR,6aR)(5-cyclopropyl(tetrahydro-2H-pyran nicotinoyl)octahydropyrrolo[3,4-c]pyrrolecarbonyl)pyridinesulfonamide; 4-((3aS,6aS)(5-cyclopropyl(tetrahydro-2H-pyran yloxy)nicotinoyl)octahydropyrrolo[3,4-c]pyrrolecarbonyl)benzenesulfonamide; 4-((3aR,6aS)(5-cyclopropyl(tetrahydro-2H-pyran yloxy)nicotinoyl)octahydropyrrolo[3,4-c]pyrrolecarbonyl)benzenesulfonamide; ((3aS,6aS)(1H-benzo[d][1,2,3]triazolecarbonyl)hexahydropyrrolo[3,4-c]pyrrol- 2(1H)-yl)(2-cyclopropyl((tetrahydro-2H-pyranyl)methoxy)pyridinyl)methanone; ((3aS,6aS)(3-cyclopropyl(tetrahydrofuranyloxy)benzoyl)hexahydropyrrolo[3,4- c]pyrrol-2(1H)-yl)((R)-4,5,6,7-tetrahydro-1H-benzo[d][1,2,3]triazolyl)methanone; ((3aR,6aR)(1H-benzo[d][1,2,3]triazolecarbonyl)hexahydropyrrolo[3,4-c]pyrrol- yl)(3-cyclopropyl(tetrahydrofuranyloxy)phenyl)methanone; ((3aS,6aS)(1H-benzo[d][1,2,3]triazolecarbonyl)hexahydropyrrolo[3,4-c]pyrrol- 2(1H)-yl)(5-cyclopropyl(tetrahydro-2H-pyranylamino)pyridinyl)methanone; ((3aS,6aS)(1H-benzo[d][1,2,3]triazolecarbonyl)hexahydropyrrolo[3,4-c]pyrrol- 2(1H)-yl)(5-cyclopropyl(tetrahydrofuranyloxy)pyridinyl)methanone; ((3aS,6aS)(1H-benzo[d][1,2,3]triazolecarbonyl)hexahydropyrrolo[3,4-c]pyrrol- 2(1H)-yl)(5-cyclopropyl(tetrahydro-2H-pyranyloxy)pyridinyl)methanone; ((3aS,6aS)(1H-benzo[d][1,2,3]triazolecarbonyl)hexahydropyrrolo[3,4-c]pyrrol- 2(1H)-yl)(5-cyclopropyl(tetrahydro-2H-pyranyloxy)pyridinyl)methanone; ((3aS,6aS)(1H-benzo[d][1,2,3]triazolecarbonyl)hexahydropyrrolo[3,4-c]pyrrol- yl)(6-(oxetanyloxy)(trifluoromethyl)pyridinyl)methanone; ((3aS,6aS)(5-cyclopropyl(tetrahydro-2H-pyran yloxy)nicotinoyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)((R)-4,5,6,7-tetrahydro-1H- benzo[d][1,2,3]triazolyl)methanone; 4-((3aR,6aR)(2-cyclopropyl((tetrahydro-2H-pyran yl)methoxy)isonicotinoyl)octahydropyrrolo[3,4-c]pyrrolecarbonyl) fluorobenzenesulfonamide; 2-chloro((3aR,6aR)(2-cyclopropyl((tetrahydro-2H-pyran yl)methoxy)isonicotinoyl)octahydropyrrolo[3,4-c]pyrrolecarbonyl)benzenesulfonamide; 4-((3aR,6aR)(2-cyclopropyl((tetrahydro-2H-pyran yl)methoxy)isonicotinoyl)octahydropyrrolo[3,4-c]pyrrolecarbonyl) fluorobenzenesulfonamide; ((3aR,8aS)(1H-benzo[d][1,2,3]triazolecarbonyl)octahydropyrrolo[3,4-d]azepin- 6(7H)-yl)(2-cyclopropyl((tetrahydro-2H-pyranyl)methoxy)pyridinyl)methanone; 4-((3aS,6aS)(2-cyclopropyl((tetrahydro-2H-pyran yl)methoxy)isonicotinoyl)octahydropyrrolo[3,4-c]pyrrolecarbonyl)benzenesulfonamide; 4-((3aR,8aS)(2-cyclopropyl((tetrahydro-2H-pyran yl)methoxy)isonicotinoyl)decahydropyrrolo[3,4-d]azepine carbonyl)benzenesulfonamide; ((3aS,6aS)(1H-benzo[d][1,2,3]triazolecarbonyl)hexahydropyrrolo[3,4-c]pyrrol- 2(1H)-yl)(5-cyclopropyl((tetrahydro-2H-pyranyl)methoxy)pyridinyl)methanone; ((3aS,6aS)(5-cyclopropyl((tetrahydro-2H-pyran yl)methoxy)nicotinoyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)((R)-4,5,6,7-tetrahydro- 1H-benzo[d][1,2,3]triazolyl)methanone; 1-((3aS,6aS)(2-cyclopropyl((tetrahydro-2H-pyran yl)methoxy)isonicotinoyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(1H-1,2,3-triazol yl)propanone; ((3aR,8aS)(1H-benzo[d][1,2,3]triazolecarbonyl)octahydropyrrolo[3,4-d]azepin- 6(2H)-yl)(3-cyclopropyl((tetrahydro-2H-pyranyl)methoxy)phenyl)methanone; 1-((3aR,8aS)(3-cyclopropyl((tetrahydro-2H-pyran yl)methoxy)benzoyl)octahydropyrrolo[3,4-d]azepin-2(1H)-yl)(1H-1,2,3-triazol yl)propanone; ((3aS,6aS)(3-cyclopropyl((tetrahydro-2H-pyran yl)methoxy)benzoyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)((R)-4,5,6,7-tetrahydro-1H- benzo[d][1,2,3]triazolyl)methanone; S,6aS)(3-cyclopropyl((tetrahydro-2H-pyran hoxy)benzoyl)octahydropyrrolo[3,4-c]pyrrolecarbonyl)benzenesulfonamide; 4-((3aR,6aR)(3-cyclopropyl((tetrahydro-2H-pyran yl)methoxy)benzoyl)octahydropyrrolo[3,4-c]pyrrolecarbonyl) fluorobenzenesulfonamide; -((3aR,8aS)(2-cyclopropyl((tetrahydro-2H-pyran yl)methoxy)isonicotinoyl)decahydropyrrolo[3,4-d]azepinecarbonyl)-1H- benzo[d]imidazol-2(3H)-one; 6-((3aR,8aS)(2-cyclopropyl((tetrahydro-2H-pyran yl)methoxy)isonicotinoyl)decahydropyrrolo[3,4-d]azepinecarbonyl)methyl-1H- benzo[d]imidazol-2(3H)-one; -(3-((3aR,8aS)(2-cyclopropyl((tetrahydro-2H-pyran yl)methoxy)isonicotinoyl)octahydropyrrolo[3,4-d]azepin-2(1H)-yl)oxopropyl)oxazol- 2(3H)-one; 5-(3-((3aR,8aS)(2-cyclopropyl((tetrahydro-2H-pyran yl)methoxy)isonicotinoyl)octahydropyrrolo[3,4-d]azepin-2(1H)-yl)oxopropyl)thiazol- 2(3H)-one; 1-((3aR,8aS)(2-cyclopropyl((tetrahydro-2H-pyran yl)methoxy)isonicotinoyl)octahydropyrrolo[3,4-d]azepin-2(1H)-yl)(3-hydroxyisoxazol- 5-yl)propanone; ((3aS,6aS)(2-cyclopropyl((tetrahydro-2H-pyran yl)methoxy)isonicotinoyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)((R)-4,5,6,7-tetrahydro- 1H-benzo[d][1,2,3]triazolyl)methanone; ((3aS,6aS)(5-cyclopropyl(tetrahydro-2H-pyran ylamino)nicotinoyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)((R)-4,5,6,7-tetrahydro-1H- benzo[d][1,2,3]triazolyl)methanone; 6aS)(5-cyclopropyl(tetrahydro-2H-pyran yloxy)nicotinoyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)((R)-4,5,6,7-tetrahydro-1H- benzo[d][1,2,3]triazolyl)methanone; 6-((3aR,6aR)(5-cyclopropyl(tetrahydro-2H-pyran yloxy)nicotinoyl)octahydropyrrolo[3,4-c]pyrrolecarbonyl)pyridinesulfonamide; 6-((3aR,6aR)(2-cyclopropyl((tetrahydro-2H-pyran yl)methoxy)isonicotinoyl)octahydropyrrolo[3,4-c]pyrrolecarbonyl)pyridine sulfonamide; ((3aS,6aS)(1H-benzo[d][1,2,3]triazolecarbonyl)hexahydropyrrolo[3,4-c]pyrrol- 2(1H)-yl)(2-cyclopropyl((tetrahydro-2H-pyranyl)methoxy)pyridinyl)methanone; ((3aS,6aS)(2-cyclopropyl((tetrahydro-2H-pyran yl)methoxy)isonicotinoyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)((R)-4,5,6,7-tetrahydro- 1H-benzo[d][1,2,3]triazolyl)methanone; 6-((3aR,6aR)(2-cyclopropyl((tetrahydro-2H-pyran yl)methoxy)isonicotinoyl)octahydropyrrolo[3,4-c]pyrrolecarbonyl)pyridine sulfonamide; ((3aS,6aS)((1H-benzo[d][1,2,3]triazolyl)methyl)hexahydropyrrolo[3,4-c]pyrrol- 2(1H)-yl)(2-cyclopropyl((tetrahydro-2H-pyranyl)methoxy)pyridinyl)methanone; ((3aS,6aS)((1H-benzo[d][1,2,3]triazolyl)methyl)hexahydropyrrolo[3,4-c]pyrrol- 2(1H)-yl)(2-cyclopropyl((tetrahydro-2H-pyranyl)methoxy)pyridinyl)methanone; ((3aR,8aS)(2-cyclopropyl((tetrahydro-2H-pyran yl)methoxy)isonicotinoyl)octahydropyrrolo[3,4-d]azepin-2(1H)-yl)((R)-4,5,6,7-tetrahydro- 1H-benzo[d][1,2,3]triazolyl)methanone; ((3aR,8aS)(1H-benzo[d][1,2,3]triazolecarbonyl)octahydropyrrolo[3,4-d]azepin- 2(1H)-yl)(2-cyclopropyl((tetrahydro-2H-pyranyl)methoxy)pyridinyl)methanone; 6aS)(1H-benzo[d][1,2,3]triazolecarbonyl)hexahydropyrrolo[3,4-c]pyrrol- 2(1H)-yl)(2-(dimethylamino)((tetrahydro-2H-pyranyl)methoxy)pyridin yl)methanone; 6-(((3aS,6aS)(2-cyclopropyl((tetrahydro-2H-pyran yl)methoxy)isonicotinoyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)- yl)methyl)benzo[d]oxazol-2(3H)-one; ((3aS,6aS)(2-(dimethylamino)((tetrahydro-2H-pyran yl)methoxy)isonicotinoyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)((R)-4,5,6,7-tetrahydro- zo[d][1,2,3]triazolyl)methanone; ((3aR,6aS)(1H-benzo[d][1,2,3]triazolecarbonyl)hexahydropyrrolo[3,4-c]pyrrol- 2(1H)-yl)(2-cyclopropyl((tetrahydro-2H-pyranyl)methoxy)pyridinyl)methanone; 4-((3aR,6aS)(2-cyclopropyl((tetrahydro-2H-pyran yl)methoxy)isonicotinoyl)octahydropyrrolo[3,4-c]pyrrolecarbonyl)benzenesulfonamide; ((3aR,8aS)(3-cyclopropyl((tetrahydro-2H-pyran yl)methoxy)benzoyl)octahydropyrrolo[3,4-d]azepin-2(1H)-yl)((R)-4,5,6,7-tetrahydro-1H- benzo[d][1,2,3]triazolyl)methanone; ((3aS,6aS)(1H-benzo[d][1,2,3]triazolecarbonyl)hexahydropyrrolo[3,4-c]pyrrol- 2(1H)-yl)(3-cyclopropyl((tetrahydro-2H-pyranyl)methoxy)phenyl)methanone; R,6aR)(3-cyclopropyl((tetrahydro-2H-pyran yl)methoxy)benzoyl)octahydropyrrolo[3,4-c]pyrrolecarbonyl)pyridinesulfonamide; 6-((3aS,6aS)(5-cyclopropyl(tetrahydro-2H-pyran yloxy)nicotinoyl)octahydropyrrolo[3,4-c]pyrrolecarbonyl)benzo[d]oxazol-2(3H)-one; 6-((3aS,6aS)(2-cyclopropyl((tetrahydro-2H-pyran yl)methoxy)isonicotinoyl)octahydropyrrolo[3,4-c]pyrrolecarbonyl)benzo[d]oxazol- 2(3H)-one; 6-((3aR,8aS)(2-cyclopropyl((tetrahydro-2H-pyran yl)methoxy)isonicotinoyl)decahydropyrrolo[3,4-d]azepinecarbonyl)benzo[d]oxazol- 2(3H)-one; 6-(((3aS,6aS)(5-cyclopropyl(tetrahydro-2H-pyran yloxy)nicotinoyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)methyl)benzo[d]oxazol-2(3H)- one; ((3aS,6aS)((1H-benzo[d][1,2,3]triazolyl)methyl)hexahydropyrrolo[3,4-c]pyrrol- 2(1H)-yl)(5-cyclopropyl(tetrahydro-2H-pyranyloxy)pyridinyl)methanone; ((3aR,6aR)(2-cyclopropyl((tetrahydro-2H-pyran yl)methoxy)isonicotinoyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(6,7-dihydro-1H- [1,2,3]triazolo[4,5-c]pyridin-5(4H)-yl)methanone; 1-((3aR,6aR)(2-cyclopropyl((tetrahydro-2H-pyran hoxy)isonicotinoyl)octahydropyrrolo[3,4-c]pyrrolecarbonyl)piperidine sulfonamide; ((3aR,8aS)(2-cyclopropyl((tetrahydro-2H-pyran yl)methoxy)isonicotinoyl)octahydropyrrolo[3,4-d]azepin-2(1H)-yl)(6,7-dihydro-1H- [1,2,3]triazolo[4,5-c]pyridin-5(4H)-yl)methanone; ((3aR,8aS)(2-cyclopropyl((tetrahydro-2H-pyran hoxy)isonicotinoyl)octahydropyrrolo[3,4-d]azepin-2(1H)-yl)(3-hydroxy-4,5- dihydroisoxazolo[5,4-c]pyridin-6(7H)-yl)methanone; (3aR,8aS)-N-((1H-1,2,3-triazolyl)methyl)(2-cyclopropyl((tetrahydro-2H-pyran yl)methoxy)isonicotinoyl)octahydropyrrolo[3,4-d]azepine-2(1H)-carboxamide; (3aR,8aS)(2-cyclopropyl((tetrahydro-2H-pyranyl)methoxy)isonicotinoyl)-N-((3- hydroxyisoxazolyl)methyl)octahydropyrrolo[3,4-d]azepine-2(1H)-carboxamide; 1H-triazolylmethyl (3aS,8aR)[2-cyclopropyl(oxanylmethoxy)pyridine carbonyl]-1,3,3a,4,5,7,8,8a-octahydropyrrolo[3,4-d]azepinecarboxylate; -((3aR,6aR)(2-cyclopropyl((tetrahydro-2H-pyran yl)methoxy)isonicotinoyl)octahydropyrrolo[3,4-c]pyrrolecarbonyl)pyridine sulfonamide; ((3aR,8aS)(2-cyclopropyl((tetrahydro-2H-pyran yl)methoxy)isonicotinoyl)octahydropyrrolo[3,4-d]azepin-2(1H)-yl)(4,5,6,7-tetrahydro-1H- benzo[d][1,2,3]triazolyl)methanone; ((3aS,6aS)(1H-benzo[d][1,2,3]triazolecarbonyl)hexahydropyrrolo[3,4-c]pyrrol- 2(1H)-yl)(2-chloro((tetrahydro-2H-pyranyl)methoxy)pyridinyl)methanone; ((3aR,8aS)(2-cyclopropyl((tetrahydro-2H-pyran yl)methoxy)isonicotinoyl)octahydropyrrolo[3,4-d]azepin-2(1H)-yl)((S)-4,5,6,7-tetrahydro- 1H-benzo[d][1,2,3]triazolyl)methanone; and pharmaceutically acceptable salts thereof.

Also particular examples of compounds of formula (I) as described herein are selected from -((3aS,6aS)(5-cyclopropyl(tetrahydro-2H-pyran nicotinoyl)octahydropyrrolo[3,4-c]pyrrolecarbonyl)pyridinesulfonamide; 6-((3aR,6aR)(5-cyclopropyl(tetrahydro-2H-pyran yloxy)nicotinoyl)octahydropyrrolo[3,4-c]pyrrolecarbonyl)pyridinesulfonamide; 4-((3aS,6aS)(5-cyclopropyl(tetrahydro-2H-pyran yloxy)nicotinoyl)octahydropyrrolo[3,4-c]pyrrolecarbonyl)benzenesulfonamide; 4-((3aR,6aS)(5-cyclopropyl(tetrahydro-2H-pyran yloxy)nicotinoyl)octahydropyrrolo[3,4-c]pyrrolecarbonyl)benzenesulfonamide; ((3aS,6aS)(1H-benzo[d][1,2,3]triazolecarbonyl)hexahydropyrrolo[3,4-c]pyrrol- 2(1H)-yl)(2-cyclopropyl((tetrahydro-2H-pyranyl)methoxy)pyridinyl)methanone; 6aS)(3-cyclopropyl(tetrahydrofuranyloxy)benzoyl)hexahydropyrrolo[3,4- c]pyrrol-2(1H)-yl)((R)-4,5,6,7-tetrahydro-1H-benzo[d][1,2,3]triazolyl)methanone; ((3aR,6aR)(1H-benzo[d][1,2,3]triazolecarbonyl)hexahydropyrrolo[3,4-c]pyrrol- 2(1H)-yl)(3-cyclopropyl(tetrahydrofuranyloxy)phenyl)methanone; 6aS)(1H-benzo[d][1,2,3]triazolecarbonyl)hexahydropyrrolo[3,4-c]pyrrol- 2(1H)-yl)(5-cyclopropyl(tetrahydro-2H-pyranylamino)pyridinyl)methanone; ((3aS,6aS)(1H-benzo[d][1,2,3]triazolecarbonyl)hexahydropyrrolo[3,4-c]pyrrol- 2(1H)-yl)(5-cyclopropyl(tetrahydrofuranyloxy)pyridinyl)methanone; ((3aS,6aS)(1H-benzo[d][1,2,3]triazolecarbonyl)hexahydropyrrolo[3,4-c]pyrrol- 2(1H)-yl)(5-cyclopropyl(tetrahydro-2H-pyranyloxy)pyridinyl)methanone; ((3aS,6aS)(1H-benzo[d][1,2,3]triazolecarbonyl)hexahydropyrrolo[3,4-c]pyrrol- 2(1H)-yl)(5-cyclopropyl(tetrahydro-2H-pyranyloxy)pyridinyl)methanone; ((3aS,6aS)(1H-benzo[d][1,2,3]triazolecarbonyl)hexahydropyrrolo[3,4-c]pyrrol- 2(1H)-yl)(6-(oxetanyloxy)(trifluoromethyl)pyridinyl)methanone; 6aS)(5-cyclopropyl(tetrahydro-2H-pyran yloxy)nicotinoyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)((R)-4,5,6,7-tetrahydro-1H- d][1,2,3]triazolyl)methanone; and pharmaceutically acceptable salts thereof. r particular examples of compounds of formula (I) as described herein are selected from -((3aS,6aS)(5-cyclopropyl(tetrahydro-2H-pyran yloxy)nicotinoyl)octahydropyrrolo[3,4-c]pyrrolecarbonyl)pyridinesulfonamide; ((3aS,6aS)(1H-benzo[d][1,2,3]triazolecarbonyl)hexahydropyrrolo[3,4-c]pyrrol- 2(1H)-yl)(2-cyclopropyl((tetrahydro-2H-pyranyl)methoxy)pyridinyl)methanone; ((3aS,6aS)(5-cyclopropyl(tetrahydro-2H-pyran yloxy)nicotinoyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)((R)-4,5,6,7-tetrahydro-1H- benzo[d][1,2,3]triazolyl)methanone; 2-chloro((3aR,6aR)(2-cyclopropyl((tetrahydro-2H-pyran yl)methoxy)isonicotinoyl)octahydropyrrolo[3,4-c]pyrrolecarbonyl)benzenesulfonamide; 4-((3aR,6aR)(2-cyclopropyl((tetrahydro-2H-pyran yl)methoxy)isonicotinoyl)octahydropyrrolo[3,4-c]pyrrolecarbonyl) fluorobenzenesulfonamide; ((3aR,8aS)(1H-benzo[d][1,2,3]triazolecarbonyl)octahydropyrrolo[3,4-d]azepin- 6(7H)-yl)(2-cyclopropyl((tetrahydro-2H-pyranyl)methoxy)pyridinyl)methanone; 5-((3aR,8aS)(2-cyclopropyl((tetrahydro-2H-pyran yl)methoxy)isonicotinoyl)decahydropyrrolo[3,4-d]azepinecarbonyl)-1H- benzo[d]imidazol-2(3H)-one; 6-((3aR,8aS)(2-cyclopropyl((tetrahydro-2H-pyran yl)methoxy)isonicotinoyl)decahydropyrrolo[3,4-d]azepinecarbonyl)methyl-1H- benzo[d]imidazol-2(3H)-one; 6-((3aR,6aR)(2-cyclopropyl((tetrahydro-2H-pyran yl)methoxy)isonicotinoyl)octahydropyrrolo[3,4-c]pyrrolecarbonyl)pyridine sulfonamide; ((3aR,8aS)(2-cyclopropyl((tetrahydro-2H-pyran yl)methoxy)isonicotinoyl)octahydropyrrolo[3,4-d]azepin-2(1H)-yl)((R)-4,5,6,7-tetrahydro- 1H-benzo[d][1,2,3]triazolyl)methanone; ((3aR,8aS)(1H-benzo[d][1,2,3]triazolecarbonyl)octahydropyrrolo[3,4-d]azepin- 2(1H)-yl)(2-cyclopropyl((tetrahydro-2H-pyranyl)methoxy)pyridinyl)methanone; 6-((3aR,8aS)(2-cyclopropyl((tetrahydro-2H-pyran yl)methoxy)isonicotinoyl)decahydropyrrolo[3,4-d]azepinecarbonyl)benzo[d]oxazol- 2(3H)-one; ((3aR,8aS)(2-cyclopropyl((tetrahydro-2H-pyran yl)methoxy)isonicotinoyl)octahydropyrrolo[3,4-d]azepin-2(1H)-yl)(6,7-dihydro-1H- ]triazolo[4,5-c]pyridin-5(4H)-yl)methanone; ((3aR,8aS)(2-cyclopropyl((tetrahydro-2H-pyran yl)methoxy)isonicotinoyl)octahydropyrrolo[3,4-d]azepin-2(1H)-yl)(3-hydroxy-4,5- dihydroisoxazolo[5,4-c]pyridin-6(7H)-yl)methanone; and pharmaceutically acceptable salts thereof.

Also r particular examples of compounds of a (I) as described herein are selected from -((3aS,6aS)(5-cyclopropyl(tetrahydro-2H-pyran yloxy)nicotinoyl)octahydropyrrolo[3,4-c]pyrrolecarbonyl)pyridinesulfonamide; ((3aS,6aS)(1H-benzo[d][1,2,3]triazolecarbonyl)hexahydropyrrolo[3,4-c]pyrrol- 2(1H)-yl)(2-cyclopropyl((tetrahydro-2H-pyranyl)methoxy)pyridinyl)methanone; 6aS)(5-cyclopropyl(tetrahydro-2H-pyran yloxy)nicotinoyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)((R)-4,5,6,7-tetrahydro-1H- benzo[d][1,2,3]triazolyl)methanone; and pharmaceutically acceptable salts thereof.

Processes for the manufacture of compounds of formula (I) are described herein.

The preparation of compounds of formula (I) of the present invention may be carried out in sequential or convergent synthetic routes. Syntheses of the invention and/or described herein are shown in the following general schemes. The skills required for carrying out the reactions and purifications of the resulting products are known to those persons skilled in the art. In case a mixture of enantiomers or diastereoisomers is produced during a reaction, these enantiomers or diastereoisomers can be separated by methods bed herein or known to the man skilled in the art such as e.g. l) chromatography or crystallization. The substituents and indices used in the following description of the ses have the significance given herein.

The present invention provides novel compounds of a (I) ( )p ( )m ( )q ( )n (I) Compounds of general formula (I) can be synthesised from amine precursor 1 and appropriate reagents, using methods well known in the art. ( )p ( )m ( )q ( )n For instance, amine 1 is reacted with a suitable carboxylic acid of formula R1–COOH (2) leading to a compound of formula (I). The reaction is performed in the presence of a coupling agent such as arbonyldiimidazole, N,N’-dicyclohexylcarbodiimide, 1-(3- dimethylaminopropyl)ethyl-carbodiimide hydrochloride, O-(benzotriazolyl)-N,N,N’,N’- ethyluronium hexafluoro-phosphate, O-(7-azabenzotriazolyl)-N,N,N’,N’- tetramethyluronium hexafluoro-phosphate or tris-pyrrolidino-phosphonium hexafluorophosphate, in aprotic solvents such as dichloromethane, tetrahydrofuran, N,N- dimethylformamide, N-methylpyrrolidinone and es thereof at temperatures between -40°C and 80°C in the presence or absence of a base such as triethylamine, diisopropylethylamine, 4- morpholine and/or 4-(dimethylamino)pyridine.

Amine 1 can also be reacted with suitable acylating reagents such as acyl des of formula R1–COCl (3) to lead to compounds of formula (I). The reaction is performed in a solvent such as dichloromethane, ydrofuran, or methylformamide, in the ce of a base such as triethylamine or 4-methylmorpholine, at temperatures between 0°C and 80°C.

Carboxylic acids (2) and acyl halides (3) are commercially available or can be prepared as described herein or in the literature.

Amines of general formula 1 are synthesised from suitably protected precursors 4. ( )p ( )m ( )q ( )n Suitable protective groups (PG) are tert-butoxycarbonyl or benzyloxycarbonyl. The deprotection of intermediates 4 can be performed using methods and reagents known in the art.

For ce, in the case where PG is benzyloxycarbonyl, the deprotection may be performed by hydrogenation at pressures between 1 bar and 100 bar, in the presence of a suitable catalyst such as palladium on activated charcoal, at temperatures between 20°C and 150°C in ts such as methanol or ethanol.

Alternatively, in the case where PG is tert-butoxycarbonyl, the deprotection may be performed in the presence of a suitable acid, e. g, hydrochloric acid or trifluoroacetic acid, in a solvent such as water, 2-propanol, dichloromethane, or 1,4-dioxane at temperatures n 0°C and 30°C.

Intermediates 4, wherein A is N are represented by general structure 4A. ( )p ( )m ( )q ( )n PG is a suitable protective group, e. g., tert-butoxycarbonyl or benzyloxycarbonyl.

Intermediates 4A can be produced from amine precursors of general a 5 by reaction with appropriate reagents, using methods known in the art. ( )p ( )m ( )q ( )n For instance, 5 is d with ting agents of general formula X–CR6R7–R2 (6) where X is a leaving group such as Cl, Br, I, or OSO2CH3, leading to 4A, n W is –CR6R7–. This reaction is performed in a solvent such as tetrahydrofuran or N,N- ylformamide, in the presence of a base, e. g. triethylamine or potassium carbonate, at temperatures between 0°C and 100°C.

Alternatively, for compounds of formula 4A, wherein W is –CR6R7–, R6 is hydrogen, alkyl or cycloalkyl, and R7 is H, amine 5 is d with aldehydes or ketones of general formula )–R2 (7) in a reductive amination reaction, leading to 4A. This reaction is performed in the presence of a suitable reducing agent, e. g., sodium borohydride or sodium triacetoxyborohydride , in a solvent such as methanol, acetic acid, tetrahydrofuran, 1,2-dichloroethane or mixtures thereof, at temperatures n 0°C and 50°C.

Alternatively, amine 5 is reacted with a suitable carboxylic acid of formula R2–COOH (8), leading to compounds of formula 4A, wherein W is –C(O)–. The on is performed in the ce of a coupling agent such as 1,1'-carbonyldiimidazole, N,N’-dicyclohexylcarbodiimide, 1-(3-dimethylaminopropyl)ethyl-carbodiimide hydrochloride, O-(benzotriazolyl)- N,N,N’,N’-tetramethyluronium hexafluoro-phosphate, O-(7-azabenzotriazolyl)-N,N,N’,N’- tetramethyluronium hexafluoro-phosphate or bromo-tris-pyrrolidino-phosphonium hexafluorophosphate, in aprotic solvents such as dichloromethane, tetrahydrofuran, N,N- dimethylformamide, ylpyrrolidinone and mixtures thereof at temperatures between -40°C and 80°C in the presence or absence of a base such as triethylamine, diisopropylethylamine, 4- methylmorpholine and/or 4-(dimethylamino)pyridine.

Alternatively, amine 5 is reacted with a suitable sulfonyl chloride of formula R2–SO2Cl (9), leading to compounds of formula 4A, wherein W is –S(O2)–. The reaction is performed in a le solvent such as dichloromethane, tetrahydrofuran, N,N-dimethylformamide , itrile, acetone, water, or mixtures thereof, in the presence of a base, e. g. triethylamine, ropylethylamine, pyridine, potassium hydrogencarbonate, potassium carbonate, at temperatures between 0°C and the boiling point of the solvent or solvent mixture. atively, amine 5 is reacted with a suitable N-(chlorocarbonyl)amine of formula R2–N(R10)–C(O)–Cl (10A) leading to compounds of formula 4A, wherein W is –C(O)–NR10–, or with an isocyanate of formula R2–NCO (11), leading to compounds of formula 4A, wherein W is –C(O)–NR10– and R10 is H.

Alternatively, amine 5 is reacted with phosgene or ne equivalent (diphosgene, triphosgene) in the presence of a base (e. g., pyridine, triethylamine) in a solvent such as romethane or ydrofuran, to provide the corresponding N-(chlorocarbonyl)amine of formula 12, which is then reacted with amine of formula HN(R10)R2 (13), in the presence of a base such as triethylamine or diisopropylethylamine, in a solvent such as dichloromethane, ydrofuran, or N,N-dimethylformamide, leading to nds of formula 4A, wherein W is –C(O)–NR10–. ( )p ( )m ( )q ( )n Alternatively, amine 5 is reacted with phosgene or a phosgene equivalent sgene, triphosgene) in the presence of a base (e. g., pyridine, triethylamine), in a solvent such as romethane or tetrahydrofuran, to the corresponding N-(chlorocarbonyl)amine of formula 12, which is then reacted with amines of formula H–O, H–P, H–Q, H–R, H–T, H–U, H–V, H–X, H–AA, H–AI or H–AO, in the presence of a base such as triethylamine or diisopropylethylamine, in a solvent such as dichloromethane, tetrahydrofuran, or N,N-dimethylformamide, leading to compounds of formula 4A, wherein W is –C(O)– and R2 is O, P, Q, R, T, U, V, X, AA, AI or Alternatively, amine 5 is d with a suitable chloroformate of formula R2–O–C(O)–Cl (10B) or with an imidazolecarboxylate ester (10C), leading to compounds of formula 4A, wherein W is –C(O)–O–. The reaction is performed in a suitable solvent, e. g., acetonitrile or N,N-dimethylformamide, optionally in the presence of a base, e. g., diisopropylethylamine or ylamine, at temperatures between 0°C and 100°C.

Chloroformates 10B are commercially available or can be prepared from the corresponding alcohols of formula R2–OH, by reaction with phosgene or a phosgene equivalent (e. g., diphosgene, sgene) as described herein or in the literature.

Imidazolecarboxylate esters 10C can be prepared from the corresponding alcohols of formula R2–OH, by reaction with 1,1'-carbonyldiimidazole as described herein or in the literature.

N-(Chlorocarbonyl)amines 12 are synthesised from the ponding amines 13 by reaction with phosgene or a phosgene equivalent (diphosgene, triphosgene) as described in the literature.

Isocyanates 11 are commercially available or can be ed from the corresponding amines of formula R2–NH2, by reaction with phosgene or a phosgene equivalent (e. g., diphosgene, triphosgene, 1,1'-carbonyldiimidazole) as described in the ture.

N-(Chlorocarbonyl)amines 10A are commercially available or can be prepared from the corresponding amines of formula HN(R10)R2 (13), by reaction with phosgene or a phosgene equivalent (e. g., diphosgene, triphosgene, 1,1'-carbonyldiimidazole) as described herein or in the literature.

Amines 5, alkylating agents 6, aldehydes/ketones 7, carboxylic acids 8, sulfonyl chlorides 9, nates 11, and amines 13 are commercially available or can be synthesised as described herein or in the literature.

Carbamates 4 wherein A is CH, and W is N(R10), are ented by general formula 4B, wherein R14 is N(R10)R2. Carbamates 4 wherein A is CH, W is –C(O)– and R2 is O, P, Q, R, T, U, V, X, AA, AI or AO are also represented by general formula 4B, wherein R14 is O, P, Q, R, T, U, V, X, AA, AI or AO. ( )p ( )m ( )q ( )n Amide 4B is produced from carboxylic acid 14 by coupling reaction with an amine of formula HN(R10)R2 (13), H–O, H–P, H–Q, H–R, H–T, H–U, H–V, H–X, H–AA, H–AI or H–AO. ( )p ( )m ( )q ( )n The reaction is performed in the presence of a coupling agent such as 1,1'- carbonyldiimidazole, N,N’-dicyclohexylcarbodiimide, 1-(3-dimethylaminopropyl)ethylcarbodiimide hydrochloride, O-(benzotriazolyl)-N,N,N’,N’-tetramethyluronium uorophosphate , O-(7-azabenzotriazolyl)-N,N,N’,N’-tetramethyluronium hexafluoro-phosphate or bromo-tris-pyrrolidino-phosphonium hexafluorophosphate, in c solvents such as romethane, tetrahydrofuran, N,N-dimethylformamide, N-methylpyrrolidinone and mixtures thereof at temperatures between -40°C and 80°C in the presence or e of a base such as ylamine, ropylethylamine, 4-methylmorpholine and/or 4- (dimethylamino)pyridine.

Carboxylic acids 14 are commercially ble or can be produced as described in the literature.

Compounds of formula (I), wherein A is N can be produced from amine precursors of general formula 15 by reaction with appropriate reagents, using methods known in the art. ( )p ( )m ( )q ( )n For instance, an amine of formula 15 is reacted with alkylating agents of general formula X–CR6R7–R2 (6) where X is a leaving group such as Cl, Br, I, or OSO2CH3, leading to compounds of formula (I), n A is N and W is –CR6R7–. This reaction is performed in a solvent such as tetrahydrofuran or N,N-dimethylformamide, in the presence of a base, e. g., triethylamine or potassium carbonate, at temperatures between 0°C and 100°C.

Alternatively, an amine of formula 15 is reacted with aldehydes or ketones of general formula R6–C(O)–R2 (16) in a reductive amination reaction, leading to compounds of formula (I) wherein A is N, W is –CR6R7–, R6 is hydrogen, alkyl or cycloalkyl, and R7 is H. This reaction is performed in the presence of a suitable ng agent, e. g. sodium borohydride or sodium toxyborohydride, in a solvent such as methanol, acetic acid, tetrahydrofuran, 1,2- dichloroethane or mixtures thereof, at temperatures between 0°C and 50°C.

Alternatively, amine 15 is reacted with a suitable carboxylic acid of formula R2–COOH (8), leading to compounds of formula (I) n A is N and W is –C(O)–. The reaction is performed in the presence of a coupling agent such as 1,1'-carbonyldiimidazole, N,N’- dicyclohexylcarbodiimide, 1-(3-dimethylaminopropyl)ethyl-carbodiimide hydrochloride, O- (benzotriazolyl)-N,N,N’,N’-tetramethyluronium hexafluoro-phosphate, O-(7-azabenzotriazol- 1-yl)-N,N,N’,N’-tetramethyluronium hexafluoro-phosphate or bromo-tris-pyrrolidino- phosphonium hexafluorophosphate, in c ts such as romethane, tetrahydrofuran, N,N-dimethylformamide, N-methylpyrrolidinone and mixtures thereof at temperatures between -40°C and 80°C in the presence or absence of a base such as triethylamine, diisopropylethylamine, 4-methylmorpholine and/or 4-(dimethylamino)pyridine.

Alternatively, amine 15 is reacted with a suitable sulfonyl chloride of a R2–SO2Cl (9), leading to (I) wherein A is N and W is –S(O2)–. The reaction is performed in a suitable solvent such as dichloromethane, tetrahydrofuran, N,N-dimethylformamide, acetonitrile, acetone, water, or mixtures f, in the presence of a base, e. g. triethylamine, diisopropylethylamine, ne, potassium hydrogencarbonate, potassium carbonate, at temperatures between 0°C and the boiling point of the solvent or solvent e.

Alternatively, amine 15 is reacted with a suitable N-(chlorocarbonyl)amine of formula R2–N(R10)–C(O)–Cl (10A) leading to nds of formula (I), wherein W is –C(O)–NR10–, or with an isocyanate of formula R2–NCO (11), leading to compounds of formula (I), n W is –C(O)–NR10– and R10 is H. The reaction is performed in a suitable solvent, e. g., acetonitrile or N,N-dimethylformamide, optionally in the presence of a base, e. g., diisopropylethylamine or triethylamine, at temperatures between 0°C and 100°C.

Alternatively, amine 15 is reacted with a suitable chloroformate of formula R2–O–C(O)–Cl (10B) or with an imidazolecarboxylate ester (10C), g to compounds of formula (I), wherein W is –C(O)–O–. The reaction is performed in a suitable solvent, e. g., acetonitrile or methylformamide, optionally in the presence of a base, e. g., diisopropylethylamine or triethylamine, at temperatures between 0°C and 100°C.

Alternatively, amine 15 is reacted with ne or phosgene equivalent (diphosgene, triphosgene) in the presence of a base (e. g., pyridine, triethylamine) in a solvent such as dichloromethane or tetrahydrofuran, to e the corresponding N-(chlorocarbonyl)amine of formula 16, which is then reacted with amine of formula HN(R10)R2 (13), in the presence of a base such as ylamine or diisopropylethylamine, in a solvent such as dichloromethane, tetrahydrofuran, or N,N-dimethylformamide, leading to compounds of formula (I), wherein W is –C(O)–NR10–. ( )p ( )m ( )q ( )n Alternatively, amine 15 is reacted with phosgene or a phosgene equivalent (diphosgene, triphosgene) in the presence of a base (e. g., pyridine, triethylamine), in a solvent such as dichloromethane or tetrahydrofuran, to the corresponding N-(chlorocarbonyl)amine of a 16, which is then reacted with amines of formula H–O, H–P, H–Q, H–R, H–T, H–U, H–V, H–X, H-AA, H-AI or H–AO, in the presence of a base such as triethylamine or diisopropylethylamine, in a solvent such as dichloromethane, tetrahydrofuran, or N,N-dimethylformamide, leading to compounds of formula (I), wherein W is –C(O)– and R2 is O, P, Q, R, T, U, V, X, AA, AI or Amines 15 can be synthesised from their tert-butyl carbamate derivatives of formula 17 by carbamate deprotection. The deprotection may be performed in the presence of a suitable acid, e. g., hydrochloric acid or oroacetic acid, in a solvent such as water, 2-propanol, dichloromethane, or 1,4-dioxane, at atures between 0°C and 30°C. ( )p ( )m O O N N 17 1 ( )q ( )n O tert-Butyl carbamates 17 can be synthesised from amine precursors of formula 18 and appropriate ts, using methods well known in the art. ( )p ( )m ( )q ( )n For instance, amine 18 is reacted with a suitable carboxylic acid of formula R1–COOH (2) leading to compounds of formula 17. The reaction is performed in the presence of a ng agent such as arbonyldiimidazole, N,N’-dicyclohexylcarbodiimide, 1-(3- dimethylaminopropyl)ethyl-carbodiimide hydrochloride, O-(benzotriazolyl)-N,N,N’,N’- tetramethyluronium hexafluoro-phosphate, O-(7-azabenzotriazolyl)-N,N,N’,N’- tetramethyluronium hexafluoro-phosphate or bromo-tris-pyrrolidino-phosphonium hexafluorophosphate, in aprotic solvents such as dichloromethane, tetrahydrofuran, N,N- dimethylformamide, N-methylpyrrolidinone and mixtures thereof at atures between -40°C and 80°C in the presence or absence of a base such as ylamine, diisopropylethylamine, 4- methylmorpholine and/or 4-(dimethylamino)pyridine.

Amine 18 can also be reacted with suitable acylating reagents, such as acyl des of formula R1–COCl (3) to provide compounds of formula 17. The reaction is performed in a solvent such as dichloromethane, tetrahydrofuran, or N,N-dimethylformamide, in the presence of a base such as triethylamine or 4-methylmorpholine, at temperatures between 0°C and 80°C.

Amines of formula 18 are commercially available or can be produced as described herein or in the literature.

Compounds of formula (I), wherein A is CH and W is–C(O)–NR10– can be produced from carboxylic acid sors of general a 19 by reaction with appropriate amine reagents of general formula HN(R10)R2. Likewise, compounds of formula (1), wherein A is CH, W is C(O), and R2 is O, P, Q, R, T, U, V, X, AA, AI or AO, can be produced from carboxylic acid precursors of general formula 19 by reaction with appropriate amine reagents of general formula H–O, H–P, H–Q, H–R, H–T, H–U, H–V, H–X, H-AA, H-AI or H–AO, using methods known in the art. ( )p ( )m ( )q ( )n For instance, this reaction is performed in the presence of a coupling agent such as 1,1'- carbonyldiimidazole, N,N’-dicyclohexylcarbodiimide, imethylaminopropyl)ethylcarbodiimide hydrochloride, O-(benzotriazolyl)-N,N,N’,N’-tetramethyluronium hexafluorophosphate , O-(7-azabenzotriazolyl)-N,N,N’,N’-tetramethyluronium hexafluoro-phosphate or tris-pyrrolidino-phosphonium hexafluorophosphate, in aprotic solvents such as romethane, tetrahydrofuran, N,N-dimethylformamide, ylpyrrolidinone and mixtures thereof at temperatures n -40°C and 80°C in the presence or absence of a base such as triethylamine, diisopropylethylamine, 4-methylmorpholine and/or 4- (dimethylamino)pyridine.

Compounds of formula (I), wherein A is CH and W is–C(O)–O– can be produced from carboxylic acid precursors of general formula 19 by reaction with appropriate alcohols of general formula R2–OH, using methods known in the art.

For ce, this reaction is performed in the presence of a coupling agent such as 1,1'- carbonyldiimidazole, N,N’-dicyclohexylcarbodiimide, 1-(3-dimethylaminopropyl)ethyl- carbodiimide hydrochloride, O-(benzotriazolyl)-N,N,N’,N’-tetramethyluronium hexafluorophosphate , O-(7-azabenzotriazolyl)-N,N,N’,N’-tetramethyluronium hexafluoro-phosphate or bromo-tris-pyrrolidino-phosphonium hexafluorophosphate, in aprotic solvents such as dichloromethane, tetrahydrofuran, N,N-dimethylformamide, N-methylpyrrolidinone and mixtures thereof at temperatures between -40°C and 80°C in the presence or absence of a base such as triethylamine, ropylethylamine, ylmorpholine and/or 4- (dimethylamino)pyridine.

Alternatively, the reaction is performed in two steps wherein carboxylic acid 19 is first converted to acid chloride 19A, using methods and reagents known in the art, e. g., thionyl chloride or oxalyl chloride. Acid chloride 19A is then reacted with l R2–OH in a suitable solvent, e. g., dichloromethane or acetonitrile, optionally in the presence of a st, e. g., pyridine or 4-(dimethylamino)pyridine, at temperatures between -40°C and +100°C. ( )p ( )m ( )q ( )n Carboxylic acids 19 can be ed from the corresponding ester precursors 20, wherein Ra is lower alkyl, e. g. methyl or ethyl, using methods and reagents known in the art. For ce, the reaction is med in the presence of a base, e. g., potassium hydroxide, sodium hydroxide, or lithium hydroxide, in solvents such as water, methanol, ethanol, tetrahydrofuran, or mixtures thereof, at temperatures between 20°C and 100°C. ( )p ( )m ( )q ( )n Compounds of formula 20 can be synthesised from amine precursors of formula 21 and appropriate ts, using methods well known in the art. ( )p ( )m ( )q ( )n For instance, amine 21 is d with a suitable carboxylic acid of a R1–COOH (2) g to compounds of a 20. The reaction is performed in the presence of a coupling agent such as 1,1'-carbonyldiimidazole, N,N’-dicyclohexylcarbodiimide, 1-(3- dimethylaminopropyl)ethyl-carbodiimide hydrochloride, O-(benzotriazolyl)-N,N,N’,N’- tetramethyluronium uoro-phosphate, O-(7-azabenzotriazolyl)-N,N,N’,N’- tetramethyluronium hexafluoro-phosphate or bromo-tris-pyrrolidino-phosphonium hexafluorophosphate, in aprotic solvents such as dichloromethane, tetrahydrofuran, N,N- dimethylformamide, N-methylpyrrolidinone and mixtures thereof at temperatures between -40°C and 80°C in the presence or absence of a base such as triethylamine, diisopropylethylamine, 4- morpholine and/or 4-(dimethylamino)pyridine.

Amine 21 can also be reacted with suitable acylating reagents, such as acyl chlorides of formula R1–COCl (3) to lead to compounds of formula 20. The reaction is performed in a solvent such as dichloromethane, tetrahydrofuran, or N,N-dimethylformamide, in the presence of a base such as triethylamine or 4-methylmorpholine, at temperatures between 0°C and 80°C.

Amines of general formula 21 are synthesised from suitably protected precursors 22. ( )p ( )m ( )q ( )n Suitable protective groups (PG) are utoxycarbonyl or oxycarbonyl. The deprotection of intermediates 22 can be performed using methods and reagents known in the art.

For instance, in the case where PG is benzyloxycarbonyl, the deprotection may be performed by hydrogenation at pressures between 1 bar and 100 bar, in the presence of a suitable catalyst such as palladium on ted charcoal, at temperatures between 20°C and 150°C, in solvents such as methanol or ethanol.

Alternatively, in the case where PG is tert-butoxycarbonyl, the deprotection may be performed in the ce of a suitable acid, e. g, hydrochloric acid or trifluoroacetic acid, in a solvent such as water, anol, dichloromethane, or 1,4-dioxane, at temperatures between 0°C and 30°C.

Esters 22, wherein Ra is methyl or ethyl, are ed from carboxylic acids 14, using methods and reagents known in the art. For instance, 14 alkylated with methyl iodide or ethyl bromide, in the presence of a base, e. g., potassium carbonate, in a t such as N,N- dimethylformamide, at –20°C and +30°C, leading to the methyl or ethyl ester 22, respectively. tert-Butyl carbamates 17 wherein R1 is substituted R3–C(3)-phenyl or substituted R3–C(2)- pyridinyl and R3 is O–R15 are represented by general structure 17A. ( )p ( )m ( )q ( )n R15 is heterocycloalkyl or heterocyclyl, X is CH or N, R4, R5, m, n, p, q are as described above.

Compounds of formula 17A can be also produced from phenol or pyridinol 23, using methods and reagents well known in the art. ( )p ( )m ( )q ( )n For instance, compound 23 is alkylated with an appropriate alkylating agent of formula R15–X, n X is a leaving group, e. g., Br or I, leading to compounds 17A. The reaction is performed in the presence of a base, e. g., potassium carbonate, in a solvent such as acetone, acetonitrile, or methylformamide, at temperatures n 20°C and the boiling point of the solvent.

Alkylating agents R15–X are commercially available or can be prepared as bed herein or in the literature.

Compound of formula 23 can be produced from amine 18 and carboxylic acid 24, using methods and ts well known in the art.

For ce, amine 18 is reacted with carboxylic acid 24 leading to compounds of formula 23. The reaction is performed in the presence of a coupling agent such as 1,1'- carbonyldiimidazole, N,N’-dicyclohexylcarbodiimide, 1-(3-dimethylaminopropyl)ethylcarbodiimide hydrochloride, O-(benzotriazolyl)-N,N,N’,N’-tetramethyluronium hexafluoro- phosphate, O-(7-azabenzotriazolyl)-N,N,N’,N’-tetramethyluronium hexafluoro-phosphate or bromo-tris-pyrrolidino-phosphonium hexafluorophosphate, in aprotic solvents such as dichloromethane, ydrofuran, N,N-dimethylformamide, N-methylpyrrolidinone and mixtures thereof at temperatures between -40°C and 80°C in the presence or absence of a base such as triethylamine, diisopropylethylamine, 4-methylmorpholine and/or 4- (dimethylamino)pyridine. ylic acids 24 are commercially available or can be prepared as described herein or in the literature. tert-Butyl carbamates 17 wherein R1 is substituted R3–C(6)-pyridinyl and R3 is O–R15 are represented by general structure 17B. ( )p ( )m 3 ( )q ( )n R15 is heterocycloalkyl or heterocyclyl, R4, R5, m, n, p, q are as described above.

Compounds of a 17B can also be produced from halopyridine 25, using methods and reagents well known in the art. ( )p ( )m ( )q ( )n Y is a halogen, e. g., F, Cl, Br, or I, R4, R5, m, n, p, q are as described above.

For instance, compound 25 is reacted with an appropriate alcohol of formula R15–OH, leading to nds 17B. The reaction is performed in the presence of a base, e. g., potassium hydroxide or potassium carbonate, in a solvent such as or N,N-dimethylformamide or dimethyl sulfoxide, at temperatures between –70°C and +150°C.

Alcohols R15–OH are commercially available or can be prepared as described herein or in the literature. nd of formula 25 can be produced from amine 18 and ylic acid 26, using methods and reagents well known in the art.

For instance, amine 18 is reacted with carboxylic acid 26 leading to compounds of formula . The reaction is performed in the presence of a coupling agent such as 1,1'- carbonyldiimidazole, N,N’-dicyclohexylcarbodiimide, 1-(3-dimethylaminopropyl)ethyl- carbodiimide hydrochloride, O-(benzotriazolyl)-N,N,N’,N’-tetramethyluronium hexafluorophosphate , O-(7-azabenzotriazolyl)-N,N,N’,N’-tetramethyluronium hexafluoro-phosphate or tris-pyrrolidino-phosphonium uorophosphate, in aprotic solvents such as dichloromethane, tetrahydrofuran, methylformamide, N-methylpyrrolidinone and es thereof at atures between -40°C and 80°C in the presence or absence of a base such as triethylamine, diisopropylethylamine, 4-methylmorpholine and/or 4- (dimethylamino)pyridine.

Carboxylic acids 26 are commercially available or can be prepared as described herein or in the literature.

Esters 20 wherein R1 is substituted )-phenyl or substituted )-pyridinyl and R3 is O–R15 are represented by l structure 20A. ( )p ( )m ( )q ( )n R15 is heterocycloalkyl or heterocyclyl, X is CH or N, Ra is lower alkyl, e. g., methyl or ethyl, R4, R5, m, n, p, q are as described above.

Compounds of formula 20A can also be produced from phenol or pyridinol 27, using methods and ts well known in the art.

O ( )p ( )m a R N 27 )q ( )n O X R For instance, compound 27 is ted with an appropriate alkylating agent of formula R15–X, wherein X is a leaving group, e. g., Br or I, leading to nds 20A. The reaction is performed in the presence of a base, e. g., potassium carbonate, in a solvent such as acetone, acetonitrile, or N,N-dimethylformamide, at temperatures between 20°C and the boiling point of the solvent.

Compound of formula 27 can be produced from amine 18, using methods and reagents well known in the art. For instance, amine 18 is reacted with carboxylic acid 24 leading to compounds of formula 27. The reaction is performed in the ce of a coupling agent such as 1,1'-carbonyldiimidazole, N,N’-dicyclohexylcarbodiimide, 1-(3-dimethylaminopropyl)ethylcarbodiimide hydrochloride, O-(benzotriazolyl)-N,N,N’,N’-tetramethyluronium uorophosphate , O-(7-azabenzotriazolyl)-N,N,N’,N’-tetramethyluronium hexafluoro-phosphate or bromo-tris-pyrrolidino-phosphonium hexafluorophosphate, in aprotic solvents such as dichloromethane, tetrahydrofuran, N,N-dimethylformamide, N-methylpyrrolidinone and mixtures thereof at temperatures between -40°C and 80°C in the presence or absence of a base such as triethylamine, diisopropylethylamine, 4-methylmorpholine and/or 4- (dimethylamino)pyridine.

Esters 20 wherein R1 is R3–C(6)-substituted pyridinyl and R3 is O–R15 are represented by general structure 20B. ( )p ( )m ( )q ( )n R15 is heterocycloalkyl or heterocyclyl, Ra is lower alkyl, e. g., methyl or ethyl, R4, R5, m, n, p, q are as described above.

Compounds of formula 20B can also be produced from halopyridine 28, using methods and reagents well known in the art.

O ( )p ( )m O R R N 28 ( )q ( )n O Y is a halogen, e. g., F, Cl, Br, or I, Ra is lower alkyl, e. g., methyl or ethyl, R4, R5, m, n, p, q are as described above.

For instance, compound 28 is reacted with an appropriate alcohol of formula R15–OH, leading to compounds 20B. The reaction is med in the presence of a base, e. g., potassium hydroxide or potassium carbonate, in a solvent such as or N,N-dimethylformamide or dimethyl sulfoxide, at temperatures between –70°C and +150°C.

Compound of formula 28 can be produced from amine 18, using methods and reagents well known in the art. For instance, amine 18 is reacted with carboxylic acid 26 g to compounds of formula 28. The reaction is performed in the presence of a coupling agent such as 1,1'-carbonyldiimidazole, icyclohexylcarbodiimide, 1-(3-dimethylaminopropyl)ethylcarbodiimide hydrochloride, zotriazolyl)-N,N,N’,N’-tetramethyluronium hexafluoro- phosphate, O-(7-azabenzotriazolyl)-N,N,N’,N’-tetramethyluronium hexafluoro-phosphate or bromo-tris-pyrrolidino-phosphonium uorophosphate, in aprotic solvents such as dichloromethane, ydrofuran, N,N-dimethylformamide, N-methylpyrrolidinone and mixtures thereof at temperatures between -40°C and 80°C in the presence or absence of a base such as triethylamine, diisopropylethylamine, 4-methylmorpholine and/or 4- hylamino)pyridine.

Also an embodiment of the present invention is a process to prepare a compound of formula (I) as defined above comprising the reaction of a compound of formula (II) in the presence of a compound of formula (III); p( ) ( )m p( ) (III) ( )m ( )n ( )n q( ) q( ) (II) (I) wherein R1, R2, m, n, p and q are as defined above, A is -N- and W is -C(O)-.

In particular, in the presence of a ng agent such as arbonyldiimidazole, N,N’- ohexylcarbodiimide, 1-(3-dimethylaminopropyl)ethyl-carbodiimide hydrochloride, O- (benzotriazolyl)-N,N,N’,N’-tetramethyluronium hexafluoro-phosphate, O-(7-azabenzotriazol- 1-yl)-N,N,N’,N’-tetramethyluronium hexafluoro-phosphate or bromo-tris-pyrrolidinophosphonium hexafluorophosphate , particularly zabenzotriazolyl)-N,N,N’,N’- ethyluronium hexafluoro-phosphate, in an aprotic solvent such as dichloromethane, tetrahydrofuran, N,N-dimethylformamide, N-methylpyrrolidinone and mixtures thereof , ularly N,N-dimethylformamide, in the presence or absence of a base such as triethylamine, ropylethylamine, 4-methylmorpholine and/or 4-(dimethylamino)pyridine , particularly in the presence of 4-methylmorpholine and at a temperature comprised between -78°C and reflux, particularly between -10°C and room temperature.

Also described herein is a compound according to formula (I) for use as a therapeutically active substance.

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

Described herein is the use of a compound according to formula (I) as described herein for the treatment or prophylaxis of renal conditions, liver conditions, inflammatory conditions, conditions of the nervous system, conditions of the respiratory system, vascular and cardiovascular conditions, fibrotic diseases, cancer, ocular ions, metabolic conditions, cholestatic and other forms of c pruritus and acute and chronic organ transplant rejection, more particularly glaucoma or idiopathic pulmonary formulation Renal conditions include, but are not limited to, acute kidney injury and chronic renal e with and t proteinuria including end-stage renal disease (ESRD). In more detail, this includes decreased creatinine clearance and decreased ular filtration rate, micro- albuminuria, albuminuria and proteinuria, glomerulosclerosis with expansion of reticulated mesangial matrix with or without significant hypercellularity (particularly diabetic pathy and amyloidosis), focal thrombosis of glomerular capillaries (particularly thrombotic microangiopathies), global oid necrosis, ischemic s, malignant nephrosclerosis (such as ischemic retraction, reduced renal blood flow and renal arteriopathy), swelling and proliferation of intracapillary (endothelial and mesangial) and/or extracapillary cells (crescents) like in glomerular nephritis entities, focal segmental glomerular sis, IgA nephropathy, vasculitides / systemic diseases as well as acute and chronic kidney transplant rejection.

Liver conditions e, but are not limited to, liver cirrhosis, hepatic congestion, tatic liver disease including pruritus, nonalcoholic steatohepatitis and acute and chronic liver transplant rejection.

Inflammatory conditions include, but are not limited to, arthritis, rthritis, multiple sclerosis, systemic lupus erythematodes, inflammatory bowel disease, abnormal evacuation disorder and the like as well as inflammatory airways diseases such as idiopathic pulmonary fibrosis (IPF), chronic obstructive pulmonary disease (COPD) or c asthma iale.

Further conditions of the respiratory system include, but are not limited to, other diffuse parenchymal lung diseases of different etiologies including iatrogenic drug-induced fibrosis, occupational and/or environmental induced fibrosis, systemic diseases and vasculitides, granulomatous diseases (sarcoidosis, hypersensitivity pneumonia), collagen vascular e, ar proteinosis, Langerhans cell granulomatosis, lymphangioleiomyomatosis, inherited diseases (Hermansky-Pudlak Syndrome, tuberous sclerosis, ibromatosis, lic storage ers, familial interstitial lung disease), radiation induced fibrosis, silicosis, asbestos induced pulmonary fibrosis or acute respiratory distress syndrome (ARDS).

Conditions of the nervous system include, but are not limited to, neuropathic pain, schizophrenia, neuro-inflammation (e.g. astrogliosis), eral and/or mic (diabetic) neuropathies and the like.

Vascular ions include, but are not limited to, atherosclerosis, otic vascular disease as well as thrombotic microangiopathies, proliferative arteriopathy (such as swollen imal cells surrounded by mucinous extracellular matrix and r thickening), atherosclerosis, decreased vascular compliance (such as stiffness, reduced ventricular compliance and reduced vascular compliance), endothelial dysfunction and the like.

Cardiovascular conditions include, but are not limited to, acute ry syndrome, coronary heart disease, myocardial infarction, al and pulmonary hypertension, cardiac arrhythmia such as atrial fibrillation, stroke and other vascular damage.

Fibrotic diseases include, but are not limited to myocardial and vascular fibrosis, renal fibrosis, liver fibrosis, pulmonary fibrosis, skin fibrosis, derma and encapsulating peritonitis.

In a particular embodiment, the compounds of formula (I) or their ceutically acceptable salts and esters can be used for the treatment or prophylaxis of organ or skin fibrosis.

In another embodiment, the fibrotic disease is renal tubulo-interstitial fibrosis or glomerulosclerosis.

In r embodiment, the fibrotic disease is coholic liver steatosis, liver fibrosis or liver cirrhosis.

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

Cancer and cancer metastasis include, but are not limited to, breast cancer, ovarian cancer, lung cancer, prostate cancer, mesothelioma, glioma, hepatic carcinoma, gastrointestinal cancers and progression and metastatic aggressiveness thereof.

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

In r embodiment, the compounds of formula (I) or their pharmaceutically acceptable salts and esters can be used for the ent or laxis of cholestatic or non-cholestatic chronic us.

Described herein is the use of a compound according to formula (I) as described herein for the treatment or prophylaxis of renal conditions, liver conditions, matory conditions, conditions of the nervous system, fibrotic es and acute and chronic organ lant rejection.

Described herein is the use of a compound according to formula (I) as described herein for the treatment or prophylaxis of renal conditions, liver conditions and fibrotic diseases.

A particular embodiment described herein is a compound according to formula (I) as described herein for the treatment or prophylaxis of renal ions, liver conditions, inflammatory conditions, conditions of the nervous system, fibrotic diseases and acute and chronic organ transplant rejection.

A particular embodiment described herein is a compound according to formula (I) as described herein for the treatment or prophylaxis of renal conditions, liver conditions and fibrotic diseases.

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

The present invention also relates to the use of a compound according to formula (I) as described herein for the preparation of a ment for the treatment or prophylaxis of renal conditions, liver conditions and fibrotic diseases.

Also described herein 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 ion, which method comprises administering an effective amount of a compound according to formula (I) as described herein.

Also described herein is a method for the treatment or prophylaxis of renal conditions, liver conditions and fibrotic es, which method comprises administering an ive amount of a compound according to formula (I) as described herein.

In a particular embodiment, the renal condition is selected from the group consisting of acute kidney , chronic kidney e, diabetic nephropathy, acute kidney transplant rejection and chronic allograft nephropathy.

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

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

In a further particular embodiment, the renal ion is diabetic pathy.

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

In another particular ment, the renal ion is chronic allograft pathy.

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

In a particular embodiment, the condition of the nervous system is neuropathic pain.

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

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

Also described herein are compounds of formula (I) as described herein, when manufactured according to any one of the described processes.

Assay procedures PRODUCTION OF HUMAN FULL LENGTH ATX, WITH AND WITHOUT HIS TAG Autotaxin (ATX - ENPP2) cloning: cDNA was prepared from commercial human hematopoietic cells total RNA and used as template in overlapping PCR to generate a full length human ENPP2 ORF with or without a 3’-6xHis tag. These full length inserts were cloned into the pcDNA3.1V5-His TOPO rogen) vector. The DNA ces of several single clones were verified. The DNA from a correct full length clone was used to transfect Hek293 cells for verification of protein sion. The sequence of the encoded ENPP2 conforms to Swissprot entry Q13822, with or without the additional C-terminal 6xHis tag.

ATX tation: Recombinant protein was produced by large-scale transient transfection in L controlled stirred tank ctors (Sartorius). During cell growth and transfection, temperature, stirrer speed, pH and dissolved oxygen concentration were maintained at 37°C, 120 rpm, 7.1 and 30% DO, tively. FreeStyle 293-F cells rogen) were cultivated in suspension in FreeStyle 293 medium (Invitrogen) and transfected at ca. 1-1.5 x 10E6 cells/mL with above plasmid DNAs using X-tremeGENE Ro-1539 (commercial product, Roche Diagnostics) as complexing agent. Cells were fed a concentrated nutrient solution (J Immunol Methods 194 (1996), 19, 1-199 (page 193)) and induced by sodium butyrate (2 mM) at 72 h post-transfection and harvested at 96 h post-transfection. Expression was analyzed by Western Blot, enzymatic assay and/or analytical IMAC chromatography. After cooling the cell suspension to 4°C in a flow-through heat exchanger, cell separation and sterile filtration of supernatant was performed by filtration through Zeta Plus 60M02 E16 (Cuno) and Sartopore 2 XLG (Sartorius) filter units. The supernatant was stored at 4°C prior to purification.

ATX Purification: 20 liter of culture atant were conditioned for ultrafiltration by adding Brij 35 to a final concentration of 0.02% and by adjusting the pH to 7.0 using 1 M HCl. Then the supernatant was first microfiltred through a 0.2 μm Ultran-Pilot Open Channel PES filter (Whatman) and afterwards concentrated to 1 liter through an Ultran-Pilot Screen Channel PES filter with 30 kDa MWCO an). Prior to IMAC chromatography, NiSO4 was added to a final concentration of 1 mM. The cleared supernatant was then applied to a HisTrap column (GE care) previously brated in 50 mM Na2HPO4 pH 7.0, 0.5 M NaCl, 10% ol, 0.3% CHAPS, 0.02% NaN3. The column was washed stepwise with the same buffer containing mM , 40 mM and 50 mM imidazole, respectively. The protein was subsequently eluted using a linear gradient to 0.5 M imidazole in 15 column volumes. ATX containing fractions were pooled and concentrated using an Amicon cell equipped with a 30 kDa PES filter membrane.

The n was further purified by size exclusion chromatography on Superdex S-200 prep grade (XK ) (GE Healthcare) in 20 mM BICINE pH 8.5, 0.15 M NaCl, 10% ol, 0.3% CHAPS, 0.02% NaN3. Final yield of protein after purification was 5-10 mg ATX per liter of culture supernatant. The protein was stored at -80°C.

HUMAN ATX ENZYME TION ASSAY ATX inhibition was ed by a fluorescence quenching assay using a specifically labeled substrate analogue (MR121 substrate). To obtain this MR121 substrate, BOC and TBS protected 6-amino-hexanoic acid (R)({2-[3-(2-{2-[2-(2-amino-ethoxy)-ethoxy]-ethoxy}-ethoxy)- nylamino]-ethoxy}-hydroxy-phosphoryloxy)hydroxy-propyl ester (Ferguson et al., Org Lett 2006, 8 (10), 2023) was labeled with MR121 fluorophore (CAS 1853081, 1-(3- carboxypropyl)ethyl-1,2,3,4,8,9,10,11-octahydro-dipyrido[3,2-b:2’,3’-i]phenoxazinium) on the free amine of the ethanolamine side and then, after deprotection, subsequently with tryptophan on the side of the aminohexanoic acid.

Assay working solutions were made as follows: Assay buffer (50 mM Tris-HCl, 140 mM NaCl, 5 mM KCl, 1 mM CaCl2, 1 mM MgCl2, 0.01% Triton-X-100, pH 8.0; ATX solution: ATX (human His-tagged) stock solution (1.08 mg/mL in 20mM bicine, pH 8.5, 0.15 M NaCl, 10% glycerol, 0.3% CHAPS, 0.02% NaN3), d to 1.4 – 2.5x final concentration in assay ; MR121 substrate solution: MR121 substrate stock solution (800 µM MR121 substrate in DMSO), diluted to 2 – 5x final concentration in assay buffer.

Test compounds (10 mM stock in DMSO, 8 µL) were obtained in 384 well sample plates (Corning Costar #3655) and diluted with 8 µL DMSO. Row-wise serial dilutions were made by transferring 8 µL cpd solution to the next row up to row O. The compound and control solutions were mixed five times and 2 µL were transferred to 384 well assay plates (Corning Costar # 3702). Then, 15 µL of 41.7 nM ATX solution was added (30 nM final concentration), mixed five times and then incubated for 15 minutes at 30°C. 10 µL of MR121 substrate solution was added (1µM final concentration), mixed 30 times and then incubated for 15 minutes at 30 °C. scence was then measured every 2 minutes for 1 hour (Perkin Elmer plate: vision multimode reader); light intensity: 2.5%; exp. time: 1.4 sec, Filter: Fluo_630/690 nm) and IC50 values were calculated from these ts.

Example IC50 (µM) Example IC50 (µM) Example IC50 (µM) 1 0.029 1.19 0.007 2.14 0.006 1.01 0.017 1.2 0.014 2.15 0.012 1.02 0.022 1.21 0.005 2.16 0.017 1.03 0.009 1.22 0.014 2.17 0.009 1.04 0.008 1.23 0.013 2.18 0.01 1.05 0.006 2 0.091 2.19 0.01 1.06 0.007 2.01 0.003 2.20 0.04 1.07 0.007 2.02 0.017 2.21 0.006 1.08 0.02 2.03 0.01 2.22 0.01 1.09 0.005 2.04 0.04 2.23 0.005 1.10 0.008 2.05 0.0105 2.24 0.011 1.11 0.015 2.06 0.0045 2.25 0.017 1.12 0.009 2.07 0.01 2.26 0.014 1.13 0.003 2.08 0.0685 2.27 0.019 1.14 0.009 2.09 0.02 2.28 0.007 1.15 0.032 2.1 0.003 2.29 0.007 1.16 0.006 2.11 0.009 2.3 0.005 1.17 0.019 2.12 0.011 3 0.025 1.18 0.004 2.13 0.01 3.01 0.012 e IC50 (µM) Example IC50 (µM) Example IC50 (µM) 3.02 0.025 5.01 0.016 5.05 0.006 4 0.019 5.02 0.007 6 0.005 4.01 0.039 5.03 0.01 7 0.006 0.016 5.04 0.007 Compounds of formula (I) and their pharmaceutically acceptable salts or esters thereof as described herein have IC50 values between 0.00001 μM and 1000 μM, particular compounds have IC50 values between 0.0005 μM and 500 μM, further particular compounds have IC50 values n 0.0005 μM and 50 μM, more particular compounds have IC50 values between 0.0005 μM and 5 μM. These results have been obtained by using the enzymatic assay described above.

The compounds of formula (I) and their pharmaceutically acceptable salts can be used as medicaments (e.g. in the form of pharmaceutical preparations). The pharmaceutical preparations can be administered internally, such as orally (e.g. in the form of tablets, coated tablets, dragées, hard and soft gelatin capsules, solutions, emulsions or sions), nasally (e.g. in the form of nasal sprays), rectally (e.g. in the form of suppositories) or l ocularly (e.g. in the form of solutions, ointments, gels or water soluble polymeric inserts). However, the administration can also be effected parenterally, such as intramuscularly, enously, or intraocularly (e.g. in the form of sterile injection solutions).

The compounds of formula (I) and their ceutically acceptable salts can be processed with pharmaceutically inert, inorganic or organic adjuvants for the production of s, coated tablets, dragées,hard gelatin capsules, injection solutions or topical formulations Lactose, corn starch or derivatives thereof, talc, stearic acid or its salts etc. can be used, for e, as such adjuvants for tablets, dragées and hard n capsules.

Suitable adjuvants for soft gelatin capsules, are, for example, vegetable oils, waxes, fats, semi-solid nces and liquid polyols, etc.

Suitable nts for the production of solutions and syrups are, for example, water, s, saccharose, invert sugar, glucose, etc.

Suitable adjuvants for injection ons are, for example, water, alcohols, polyols, glycerol, vegetable oils, etc.

Suitable adjuvants for suppositories are, for example, natural or hardened oils, waxes, fats, semi-solid or liquid s, etc.

Suitable adjuvants for topical ocular formulations are, for example, water, extrins, mannitol or many other carriers and excipients known in the art.

Moreover, the pharmaceutical preparations can contain preservatives, solubilizers, viscosity-increasing substances, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, ants, salts for g the osmotic pressure, buffers, masking agents or antioxidants. They can also contain still other therapeutically valuable nces.

The dosage can vary in wide limits and will, of course, be fitted to the individual requirements in each particular case. In general, in the case of oral administration a daily dosage of about 0.1 mg to 20 mg per kg body weight, preferably about 0.5 mg to 4 mg per kg body weight (e.g. about 300 mg per person), divided into preferably 1-3 individual doses, which can consist, for example, of the same amounts, should it be appropriate. In the case of topical administration, the formulation can contain 0.001% to 15% by weight of ment and the required dose, which can be between 0.001 and 25 mg in can be administered either by single dose per day or per week, or by multiple doses (2 to 4) per day, or by multiple doses per week. It will, however, be clear that the upper or lower limit given herein can be exceeded when this is shown to be indicated.

The invention is illustrated hereinafter by Examples, which have no limiting character.

In case the preparative examples are ed as a mixture of enantiomers, the pure enantiomers can be obtained by methods described herein or by methods known to those skilled in the art, such as e.g. chiral chromatography or crystallization.

Examples All es and intermediates were ed under nitrogen atmosphere if not specified otherwise.

Abbreviations: aq. = aqueous; CAS-RN = Chemical cts Service Registry Number; HPLC = high performance liquid chromatography; MS = mass spectrum; sat. = saturated Example 1 -((3aS,6aS)(5-Cyclopropyl(tetrahydro-2H-pyranyloxy)nicotinoyl)octahydro- pyrrolo[3,4-c]pyrrolecarbonyl)pyridinesulfonamide To a solution of (5-cyclopropyl(tetrahydro-2H-pyranyloxy)pyridinyl)((3aS,6aS)- hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)methanone hydrochloride (intermediate 1; 40 mg, 95.5 µmol) in N,N-dimethylformamide (3 mL) was added ylmorpholine (48.3 mg, 477 µmol), 6-sulfamoylnicotinic acid (20.3 mg, 95.5 µmol) and O-(7-azabenzotriazolyl)-N,N,N’,N’- ethyluronium hexafluoro-phosphate (39.9 mg, 105 µmol) at room temperature, then after 16 h the reaction mixture was partitioned between sat. aq. ammonium chloride solution and ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, filtered and evaporated. Chromatography (silica gel, gradient dichloromethane to romethane/methanol/25% aq. ammonia solution 90:10:0.25) produced the title compound (47 mg, 91%). White solid, MS: 542.2 (M+H)+.

The following examples were prepared according to example 1, replacing (5-cyclopropyl (tetrahydro-2H-pyranyloxy)pyridinyl)((3aS,6aS)-hexahydropyrrolo[3,4-c]pyrrol-2(1H)- yl)methanone hydrochloride by the appropriate amine and 6-sulfamoylnicotinic acid by the appropriate carboxylic acid.

Ex. Systematic Name Amine / Carboxylic acid MS, m/e 6-((3aR,6aR)(5-cyclopropyl (5-cyclopropyl(tetrahydro-2H- (tetrahydro-2H-pyranyloxy)nicotinoyl)- 4-yloxy)pyridin octahydropyrrolo[3,4-c]pyrrole yl)((3aS,6aS)-hexahydrocarbonyl )pyridinesulfonamide 542.2 1.01 o[3,4-c]pyrrol-2(1H)- (M+H)+ yl)methanonehydrochloride (intermediate 1) / 5- sulfamoylpicolinic acid 4-((3aS,6aS)(5-cyclopropyl (tetrahydro-2H-pyranyloxy)nicotinoyl)- (5-cyclopropyl(tetrahydro-2H- octahydropyrrolo[3,4-c]pyrrole pyranyloxy)pyridin carbonyl)benzenesulfonamide yl)((3aS,6aS)- 541.2 1.02 hexahydropyrrolo[3,4-c]pyrrol- (M+H)+ 2(1H)-yl)methanone hloride (intermediate 1) / 4- sulfamoylbenzoic acid -((3aR,6aR)(2-cyclopropyl ((tetrahydro-2H-pyranyl)methoxy)iso- lopropyl((tetrahydro-2H- nicotinoyl)octahydropyrrolo[3,4-c]pyrrole- pyranyl)methoxy)pyridin 2-carbonyl)pyridinesulfonamide yl)((3aS,6aS)-hexahydropyrrolo [3,4-c]pyrrol-2(1H)- 556.2 1.03 yl)methanone hydrochloride (M+H)+ (intermediate 1.1) / 6-sulfamoylnicotinic acid (CAS-RN 285135- 56-0) Ex. Systematic Name Amine / Carboxylic acid MS, m/e R,6aR)(2-cyclopropyl((tetrahydro-2H-pyranyl )methoxy)iso- (2-cyclopropyl((tetrahydro-2H- nicotinoyl)octahydropyrrolo[3,4-c]pyrrolepyranyl )methoxy)pyridin 2-carbonyl)fluorobenzenesulfonamide yl)((3aS,6aS)- hexahydropyrrolo[3,4-c]pyrrol- 573.2 1.04 2(1H)-yl)methanone (M+H)+ hydrochloride mediate 1.1) / 3-fluorosulfamoylbenzoic acid (CAS-RN 2446069) 2-chloro((3aR,6aR)(2-cyclopropyl ahydro-2H-pyranyl)methoxy)iso- (2-cyclopropyl((tetrahydro-2H- nicotinoyl)octahydropyrrolo[3,4-c]pyrrole- pyranyl)methoxy)pyridin 2-carbonyl)benzenesulfonamide yl)((3aS,6aS)- hexahydropyrrolo[3,4-c]pyrrol- 589.1 1.05 2(1H)-yl)methanone (M+H)+ hydrochloride (intermediate 1.1) / 3-chlorosulfamoylbenzoic acid (CAS-RN 342631) 4-((3aR,6aR)(2-cyclopropyl((tetrahydro-2H-pyranyl )methoxy)iso- (2-cyclopropyl((tetrahydro-2H- nicotinoyl)octahydropyrrolo[3,4-c]pyrrole- pyranyl)methoxy)pyridin 2-carbonyl)fluorobenzenesulfonamide aS,6aS)- hexahydropyrrolo[3,4-c]pyrrol- 573.3 1.06 2(1H)-yl)methanone (M+H)+ hydrochloride (intermediate 1.1) / 2-fluorosulfamoylbenzoic acid (CAS-RN 7149680) Ex. Systematic Name Amine / Carboxylic acid MS, m/e ((3aR,8aS)(1H-benzo[d][1,2,3]triazole- -carbonyl)octahydropyrrolo[3,4-d]azepin- (2-cyclopropyl((tetrahydro-2H- 6(7H)-yl)(2-cyclopropyl((tetrahydro- pyranyl)methoxy)pyridin 2H-pyranyl)methoxy)pyridin yl)((3aR,8aS)- yl)methanone octahydropyrrolo[3,4-d]azepin- 545.3 1.07 6(7H)-yl)methanone (M+H)+ hydrochloride (intermediate 1.2) / 1H-benzo[d]-[1,2,3]triazole carboxylic acid (CAS-RN 23814- 12-2) 4-((3aS,6aS)(2-cyclopropyl((tetrahydro-2H-pyranyl )methoxy)iso- (2-cyclopropyl((tetrahydro-2H- nicotinoyl)octahydropyrrolo[3,4-c]pyrrolepyranyl xy)pyridin 2-carbonyl)benzenesulfonamide yl)((3aS,6aS)- hexahydropyrrolo[3,4-c]pyrrol- 555.3 1.08 2(1H)-yl)methanone (M+H)+ hydrochloride (intermediate 1.1) / 4-sulfamoylbenzoic acid (CASRN 4-((3aR,8aS)(2-cyclopropyl((tetrahydro-2H-pyranyl )methoxy)iso- lopropyl((tetrahydro-2H- nicotinoyl)decahydropyrrolo[3,4- pyranyl)methoxy)pyridin d]azepinecarbonyl)benzenesulfonamide yl)((3aR,8aS)- dropyrrolo[3,4-d]azepin- 583.4 1.09 6(7H)-yl)methanone (M+H)+ hydrochloride (intermediate 1.2) / 4-sulfamoylbenzoic acid (CASRN 1380) Ex. Systematic Name Amine / Carboxylic acid MS, m/e ((3aR,8aS)(2-cyclopropyl ahydro-2H-pyran (2-cyclopropyl((tetrahydro-2H- yl)methoxy)isonicotinoyl)- pyranyl)methoxy)pyridin octahydropyrrolo[3,4-d]azepin-2(1H)- yl)((3aR,8aS)- yl)(4,5,6,7-tetrahydro-1H- dropyrrolo[3,4-d]azepinbenzo [d][1,2,3]triazolyl)methanone 6(7H)-yl)methanone 549.4 1.10 hydrochloride (intermediate 1.2) / (M+H)+ 4,5,6,7-tetrahydro-1H- benzo[d][1,2,3]triazole carboxylic acid (CAS-RN 33062- 47-4) ((3aS,6aS)(1H-benzo[d][1,2,3]triazole- (5-cyclopropyl((tetrahydro-2H- -carbonyl)hexahydropyrrolo[3,4-c]pyrrolpyranyl )methoxy)pyridin 2(1H)-yl)(5-cyclopropyl((tetrahydroyl )((3aS,6aS)-hexahydro- 2H-pyranyl)methoxy)pyridin pyrrolo[3,4-c]pyrrol-2(1H)- 517.4 1.11 yl)methanone hanone hydrochloride (M+H)+ (intermediate 14) / 1H-benzo[d]- ]triazolecarboxylic acid (CAS-RN 238142) ((3aS,6aS)(5-cyclopropyl((tetra- (5-cyclopropyl((tetrahydro-2H- hydro-2H-pyranyl)methoxy)nicotinoyl)- pyranyl)methoxy)pyridin hexahydropyrrolo[3,4-c]pyrrol-2(1H)- yl)((3aS,6aS)-hexahydroyl )((R)-4,5,6,7-tetrahydro-1H- pyrrolo[3,4-c]pyrrol-2(1H)- 521.4 1.12 benzo[d][1,2,3]triazolyl)methanone yl)methanone hydrochloride (M+H)+ (intermediate 14) / (R)-4,5,6,7- ydro-1H-benzo[d]- [1,2,3]triazolecarboxylic acid (intermediate 4) Ex. Systematic Name Amine / Carboxylic acid MS, m/e S,6aS)(2-cyclopropyl((tetrahydro-2H-pyranyl )methoxy)iso- (2-cyclopropyl((tetrahydro-2H- noyl)hexahydropyrrolo[3,4-c]pyrrolpyranyl )methoxy)pyridin 2(1H)-yl)(1H-1,2,3-triazolyl)propanyl )((3aS,6aS)- 1-one hexahydropyrrolo[3,4-c]pyrrol- 1.13 495.4 2(1H)-yl)methanone (M+H)+ hydrochloride (intermediate 1.1) / 3-(1H-1,2,3-triazolyl)propanoic acid (CAS-RN 12254399) ((3aR,8aS)(1H- [(3aS,8aR)-2,3,3a,4,5,7,8,8abenzo [d][1,2,3]triazole octahydro-1H-pyrrolo[3,4- carbonyl)octahydropyrrolo[3,4-d]azepind ]azepinyl]-[3-cyclopropyl 6(2H)-yl)(3-cyclopropyl((tetrahydro- (oxan 2H-pyran 1.14 ylmethoxy)phenyl]methanone 544.3 yl)methoxy)phenyl)methanone (M+H)+ (intermediate 16) / 1H-benzo[d]-[1,2,3]triazole carboxylic acid (CAS-RN 238142) 1-((3aR,8aS)(3-cyclopropyl [(3aS,8aR)-2,3,3a,4,5,7,8,8a- ((tetrahydro-2H-pyran octahydro-1H-pyrrolo[3,4- hoxy)benzoyl)octahydropyrrolo[3, d]azepinyl]-[3-cyclopropyl 4-d]azepin-2(1H)-yl)(1H-1,2,3-triazol- (oxan 1.15 4-yl)propanone ylmethoxy)phenyl]methanone 522.3 (M+H)+ (intermediate 16) / 3-(1H-1,2,3-triazol yl)propanoic acid (CAS-RN 12254399) Ex. atic Name Amine / Carboxylic acid MS, m/e ((3aS,6aS)(3-cyclopropyl [(3aS,6aS)-2,3,3a,4,6,6a- ((tetrahydro-2H-pyran hexahydro-1H-pyrrolo[3,4- yl)methoxy)benzoyl)hexahydropyrrolo[3, c]pyrrolyl]-[3-cyclopropyl 4-c]pyrrol-2(1H)-yl)((R)-4,5,6,7- (oxan tetrahydro-1H-benzo[d][1,2,3]triazol 1.16 ylmethoxy)phenyl]methanone 520.3 yl)methanone (M+H)+ (intermediate 16.1) / (R)-4,5,6,7-tetrahydro-1H- benzo[d][1,2,3]triazole carboxylic acid (intermediate 4) 4-((3aS,6aS)(3-cyclopropyl ((tetrahydro-2H-pyran [(3aS,6aS)-2,3,3a,4,6,6ayl )methoxy)benzoyl)octahydropyrrolo[3, dro-1H-pyrrolo[3,4- 4-c]pyrrole c]pyrrolyl]-[3-cyclopropyl carbonyl)benzenesulfonamide 4- 1.17 554.3 ylmethoxy)phenyl]methanone (M+H)+ (intermediate 16.1) / 4-sulfamoylbenzoic acid (CASRN 1380) 4-((3aR,6aR)(3-cyclopropyl ((tetrahydro-2H-pyran [(3aS,6aS)-2,3,3a,4,6,6ayl )methoxy)benzoyl)octahydropyrrolo[3, hexahydro-1H-pyrrolo[3,4- 4-c]pyrrolecarbonyl) c]pyrrolyl]-[3-cyclopropyl fluorobenzenesulfonamide (oxan 1.18 572.3 oxy)phenyl]methanone (M+H)+ (intermediate 16.1) / 2-fluorosulfamoylbenzoic acid (CAS-RN 7149680) Ex. Systematic Name Amine / Carboxylic acid MS, m/e -((3aR,8aS)(2-cyclopropyl lopropyl((tetrahydro- ((tetrahydro-2H-pyranyl)methoxy)- 2H-pyranyl)methoxy)pyridinisonicotinoyl )decahydropyrrolo[3,4- 4-yl)((3aR,8aS)- d]azepinecarbonyl)-1H- octahydropyrrolo[3,4-d]azepinbenzo dazol-2(3H)-one yl)methanone 1.19 560.3 hydrochloride (intermediate 1.2) (M+H)+ / 2-oxo-1,3- dihydrobenzimidazole carboxylic acid (CAS-RN 238144) 6-((3aR,8aS)(2-cyclopropyl ((tetrahydro-2H-pyranyl)methoxy)- (2-cyclopropyl((tetrahydroisonicotinoyl )decahydropyrrolo[3,4- 2H-pyranyl)methoxy)pyridind ]azepinecarbonyl)methyl-1H- 4-yl)((3aR,8aS)- benzo[d]imidazol-2(3H)-one octahydropyrrolo[3,4-d]azepin- 1.20 6(7H)-yl)methanone 574.3 (M+H)+ hydrochloride (intermediate 1.2) / 3-methyloxo-1H- benzimidazolecarboxylic acid (CAS-RN 8635646) -(3-((3aR,8aS)(2-cyclopropyl ((tetrahydro-2H-pyranyl)methoxy)- (2-cyclopropyl((tetrahydroisonicotinoyl ydropyrrolo[3,4- 2H-pyranyl)methoxy)pyridind ]azepin-2(1H)-yl)oxopropyl)oxazol- 4-yl)((3aR,8aS)- 2(3H)-one octahydropyrrolo[3,4-d]azepin- 1.21 6(7H)-yl)methanone 539.3 (M+H)+ hydrochloride mediate 1.2) / 3-(2-oxo-3H-1,3-oxazol yl)propanoic acid (CAS-RN 15201362) Ex. Systematic Name Amine / Carboxylic acid MS, m/e -(3-((3aR,8aS)(2-cyclopropyl ((tetrahydro-2H-pyranyl)methoxy)- (2-cyclopropyl((tetrahydroisonicotinoyl )octahydropyrrolo[3,4- 2H-pyranyl)methoxy)pyridind ]azepin-2(1H)-yl)oxopropyl)thiazol- 4-yl)((3aR,8aS)- 2(3H)-one octahydropyrrolo[3,4-d]azepin- 1.22 6(7H)-yl)methanone 555.3 (M+H)+ hydrochloride (intermediate 1.2) / 3-(2-oxo-3H-1,3-thiazol yl)propanoic acid N 15536781) 1-((3aR,8aS)(2-cyclopropyl ((tetrahydro-2H-pyranyl)methoxy)- (2-cyclopropyl((tetrahydroisonicotinoyl )octahydropyrrolo[3,4- 2H-pyranyl)methoxy)pyridind ]azepin-2(1H)-yl)(3- 4-yl)((3aR,8aS)- hydroxyisoxazolyl)propanone octahydropyrrolo[3,4-d]azepin- 1.23 6(7H)-yl)methanone 539.3 (M+H)+ hydrochloride (intermediate 1.2) / 3-(3-hydroxy-1,2-oxazol yl)propanoic acid (CAS-RN 19-4) 4-((3aR,6aS)(5-Cyclopropyl(tetrahydro-2H-pyranyloxy)nicotinoyl)octahydropyrrolo [3,4-c]pyrrolecarbonyl)benzenesulfonamide H2N S H O O O To a solution of 4-((3aR,6aS)-octahydropyrrolo[3,4-c]pyrrolecarbonyl)benzenesulfonamide hydrochloride (intermediate 2; 30 mg, 90.4 µmol) in N,N-dimethylformamide (3 mL) was added 4-methylmorpholine (45.7 mg, 452 µmol), 5-cyclopropyl(tetrahydro-2H-pyran yloxy)nicotinic acid (intermediate 6.1; 28.7 mg, 90.4 µmol) and O-(7-azabenzotriazolyl)- N,N,N’,N’-tetramethyluronium hexafluoro-phosphate (37.8 mg, 99.5 µmol) at room temperature, then after 16 h the reaction mixture was partitioned between sat. aq. ammonium chloride on and ethyl e. The organic layer was washed with brine, dried over magnesium sulfate, filtered and evaporated. Chromatography (silica gel, gradient dichloromethane to dichloromethane/methanol/25% aq. ammonia solution 90:10:0.25) produced the title compound (39 mg, 76%). White solid, MS: 541.3 (M+H)+.

The following examples were ed according to example 2, replacing 4-((3aR,6aS)- octahydropyrrolo[3,4-c]pyrrolecarbonyl)benzenesulfonamide hydrochloride by the appropriate amine and 5-cyclopropyl(tetrahydro-2H-pyranyloxy)nicotinic acid by the appropriate carboxylic acid.

Ex. atic Name Amine / ylic acid MS, m/e 6aS)(1H-benzo[d][1,2,3]triazole (1H-benzo[d][1,2,3]triazol carbonyl)hexahydropyrrolo[3,4-c]pyrrol- yl)((3aR,6aR)- 2(1H)-yl)(2-cyclopropyl((tetrahydro-2H- hexahydropyrrolo[3,4-c]pyrrolpyranyl )methoxy)pyridinyl)methanone 2(1H)-yl)methanone hydrochloride (intermediate 517.4 2.01 2.2) / 2-cyclopropyl (M+H)+ ((tetrahydro-2H-pyran yl)methoxy)isonicotinic acid (intermediate 5) Ex. Systematic Name Amine / Carboxylic acid MS, m/e ((3aS,6aS)(3-cyclopropyl ((3aR,6aR)-hexahydro- (tetrahydrofuran pyrrolo[3,4-c]pyrrol-2(1H)- yloxy)benzoyl)hexahydropyrrolo[3,4- yl)((R)-4,5,6,7-tetrahydro-1H- c]pyrrol-2(1H)-yl)((R)-4,5,6,7-tetrahydro- benzo[d][1,2,3]triazol 1H-benzo[d][1,2,3]triazolyl)methanone yl)methanone hydrochloride 492.3 2.02 (intermediate 2.1) / 3- (M+H)+ cyclopropyl (tetrahydrofuran yloxy)benzoic acid (intermediate 9) ((3aR,6aR)(1H-benzo[d][1,2,3]triazole (1H-benzo[d][1,2,3]triazol carbonyl)hexahydropyrrolo[3,4-c]pyrrol- yl)((3aR,6aR)- 2(1H)-yl)(3-cyclopropyl(tetrahydrofuran- hexahydropyrrolo[3,4-c]pyrrol- 3-yloxy)phenyl)methanone 2(1H)-yl)methanone 488.3 2.03 hydrochloride (intermediate (M+H)+ 2.2) / 3-cyclopropyl (tetrahydrofuran yloxy)benzoic acid (intermediate 9) 6aS)(1H-benzo[d][1,2,3]triazole (1H-benzo[d][1,2,3]triazol yl)hexahydropyrrolo[3,4-c]pyrrol- yl)((3aR,6aR)- 2(1H)-yl)(5-cyclopropyl(tetrahydro-2H- hexahydropyrrolo[3,4-c]pyrrolpyranylamino )pyridinyl)methanone 2(1H)-yl)methanone 502.3 2.04 hydrochloride (intermediate (M+H)+ 2.2) / opropyl (tetrahydro-2H-pyran o)nicotinic acid (intermediate 7) Ex. Systematic Name Amine / Carboxylic acid MS, m/e ((3aS,6aS)(1H-benzo[d][1,2,3]triazole (1H-benzo[d][1,2,3]triazol carbonyl)hexahydropyrrolo[3,4-c]pyrrol- yl)((3aR,6aR)- 2(1H)-yl)(5-cyclopropyl(tetrahydrofuran- hexahydropyrrolo[3,4-c]pyrrol- 3-yloxy)pyridinyl)methanone yl)methanone 489.2 2.05 hydrochloride (intermediate (M+H)+ 2.2) / 5-cyclopropyl (tetrahydrofuran yloxy)nicotinic acid (intermediate 6) ((3aS,6aS)(1H-benzo[d][1,2,3]triazole (1H-benzo[d][1,2,3]triazol carbonyl)hexahydropyrrolo[3,4-c]pyrrol- yl)((3aR,6aR)- yl)(5-cyclopropyl(tetrahydro-2H- hexahydropyrrolo[3,4-c]pyrrolpyranyloxy )pyridinyl)methanone yl)methanone 503.3 2.06 hydrochloride (intermediate (M+H)+ 2.2) / 5-cyclopropyl (tetrahydro-2H-pyran yloxy)nicotinic acid (intermediate 6.2) ((3aS,6aS)(1H-benzo[d][1,2,3]triazole (1H-benzo[d][1,2,3]triazol carbonyl)hexahydropyrrolo[3,4-c]pyrrol- aR,6aR)- 2(1H)-yl)(5-cyclopropyl(tetrahydro-2H- hexahydropyrrolo[3,4-c]pyrrolpyranyloxy )pyridinyl)methanone 2(1H)-yl)methanone 503.3 2.07 hydrochloride (intermediate (M+H)+ 2.2) / 5-cyclopropyl (tetrahydro-2H-pyran yloxy)nicotinic acid (intermediate 6.1) Ex. Systematic Name Amine / Carboxylic acid MS, m/e ((3aS,6aS)(1H-benzo[d][1,2,3]triazole (1H-benzo[d][1,2,3]triazol carbonyl)hexahydropyrrolo[3,4-c]pyrrol- yl)((3aR,6aR)- 2(1H)-yl)(6-(oxetanyloxy) hexahydropyrrolo[3,4-c]pyrrol- (trifluoromethyl)pyridinyl)methanone 2(1H)-yl)methanone 503.2 2.08 hydrochloride (intermediate (M+H)+ 2.2) / 6-(oxetanyloxy) (trifluoromethyl)nicotinic acid mediate 8) ((3aS,6aS)(5-cyclopropyl(tetrahydro- ((3aR,6aR)- 2H-pyranyloxy)nicotinoyl)hexahydro- hexahydropyrrolo[3,4-c]pyrrolpyrrolo [3,4-c]pyrrol-2(1H)-yl)((R)-4,5,6,7- 2(1H)-yl)((R)-4,5,6,7- tetrahydro-1H-benzo[d][1,2,3]triazol tetrahydro-1H- yl)methanone d][1,2,3]triazol 507.3 2.09 yl)methanone hydrochloride (M+H)+ (intermediate 2.1) / 5- cyclopropyl(tetrahydro-2H- pyranyloxy)nicotinic acid (intermediate 6.1) ((3aS,6aS)(2-cyclopropyl((tetrahydro- ((3aR,6aR)- 2H-pyranyl)methoxy)isonicotinoyl)- hexahydropyrrolo[3,4-c]pyrrolhexahydropyrrolo [3,4-c]pyrrol-2(1H)- 2(1H)-yl)((R)-4,5,6,7- yl)((R)-4,5,6,7-tetrahydro-1H- ydro-1H- benzo[d][1,2,3]triazolyl)methanone benzo[d][1,2,3]triazol 521.3 2.10 yl)methanone hydrochloride (M+H)+ (intermediate 2.1) / 2- cyclopropyl((tetrahydro-2H- pyran hoxy)isonicotinic acid (intermediate 5) Ex. Systematic Name Amine / ylic acid MS, m/e ((3aS,6aS)(5-cyclopropyl(tetrahydro- ((3aR,6aR)- 2H-pyran hexahydropyrrolo[3,4-c]pyrrolylamino )nicotinoyl)hexahydropyrrolo[3,4- 2(1H)-yl)((R)-4,5,6,7- c]pyrrol-2(1H)-yl)((R)-4,5,6,7-tetrahydro- tetrahydro-1H- 1H-benzo[d][1,2,3]triazolyl)methanone d][1,2,3]triazol 506.3 2.11 yl)methanone hydrochloride (M+H)+ (intermediate 2.1) / 5- cyclopropyl(tetrahydro-2H- pyranylamino)nicotinic acid (intermediate 7) ((3aS,6aS)(5-cyclopropyl(tetrahydro- ((3aR,6aR)- 2H-pyran hexahydropyrrolo[3,4-c]pyrrolyloxy )nicotinoyl)hexahydropyrrolo[3,4- 2(1H)-yl)((R)-4,5,6,7- c]pyrrol-2(1H)-yl)((R)-4,5,6,7-tetrahydro- tetrahydro-1H- 1H-benzo[d][1,2,3]triazolyl)methanone benzo[d][1,2,3]triazol 507.3 2.12 yl)methanone hydrochloride (M+H)+ (intermediate 2.1) / 5- cyclopropyl(tetrahydro-2H- pyranyloxy)nicotinic acid (intermediate 6.2) 6-((3aR,6aR)(5-cyclopropyl(tetra- 6-((3aR,6aR)- 2H-pyranyloxy)nicotinoyl)- octahydropyrrolo[3,4- dropyrrolo[3,4-c]pyrrole c]pyrrolecarbonyl)pyridinecarbonyl )pyridinesulfonamide 3-sulfonamide hydrochloride 542.2 2.13 (intermediate 2.3) / 5- (M+H)+ cyclopropyl(tetrahydro-2H- pyranyloxy)nicotinic acid (intermediate 6.2) Ex. Systematic Name Amine / Carboxylic acid MS, m/e 6-((3aR,6aR)(2-cyclopropyl((tetra- 6-((3aR,6aR)- hydro-2H-pyranyl)methoxy)iso- octahydropyrrolo[3,4- nicotinoyl)octahydropyrrolo[3,4-c]pyrrole c]pyrrolecarbonyl)pyridinecarbonyl )pyridinesulfonamide 3-sulfonamide hydrochloride mediate 2.3) / 2- 556.2 2.14 ropyl((tetrahydro-2H- (M+H)+ pyran yl)methoxy)isonicotinic acid (intermediate 5) ((3aS,6aS)(1H-benzo[d][1,2,3]triazole (1H-benzo[d][1,2,3]triazol carbonyl)hexahydropyrrolo[3,4-c]pyrrol- yl)((3aR,6aR)- 2(1H)-yl)(2-cyclopropyl((tetrahydro-2H- hexahydropyrrolo[3,4-c]pyrrolpyranyl )methoxy)pyridinyl)methanone 2(1H)-yl)methanone dihydrochloride (intermediate 517.3 2.15 2.2) / 2-cyclopropyl (M+H)+ ((tetrahydro-2H-pyran yl)methoxy)isonicotinic acid (intermediate 5.1) ((3aS,6aS)(2-cyclopropyl((tetrahydro- ((3aR,6aR)- anyl)methoxy)isonicotinoyl)- hexahydropyrrolo[3,4-c]pyrrolhexahydropyrrolo [3,4-c]pyrrol-2(1H)- 2(1H)-yl)((R)-4,5,6,7- yl)((R)-4,5,6,7-tetrahydro-1H- tetrahydro-1H- benzo[d][1,2,3]triazolyl)methanone benzo[d][1,2,3]triazol 521.4 2.16 yl)methanone hydrochloride (M+H)+ (intermediate 2.1) / 2- ropyl((tetrahydro-2H- pyran yl)methoxy)isonicotinic acid (intermediate 5.1) Ex. Systematic Name Amine / Carboxylic acid MS, m/e 6-((3aR,6aR)(2-cyclopropyl((tetra- 6-((3aR,6aR)- hydro-2H-pyranyl)methoxy)iso- octahydropyrrolo[3,4- nicotinoyl)octahydropyrrolo[3,4-c]pyrrole c]pyrrolecarbonyl)pyridinecarbonyl )pyridinesulfonamide 3-sulfonamide hydrochloride (intermediate 2.3) / 2- 556.3 2.17 cyclopropyl((tetrahydro-2H- (M+H)+ pyran yl)methoxy)isonicotinic acid (intermediate 5.1) ((3aS,6aS)((1H-benzo[d][1,2,3]triazol 5-(((3aR,6aR)- yl)methyl)hexahydropyrrolo[3,4-c]pyrrol- hexahydropyrrolo[3,4-c]pyrrol- 2(1H)-yl)(2-cyclopropyl((tetrahydro-2H- yl)methyl)-1H- pyranyl)methoxy)pyridinyl)methanone d][1,2,3]triazole hydrochloride (intermediate 503.4 2.18 ) / 2-cyclopropyl (M+H)+ ((tetrahydro-2H-pyran hoxy)isonicotinic acid (intermediate 5) 6aS)((1H-benzo[d][1,2,3]triazol 5-(((3aR,6aR)- yl)methyl)hexahydropyrrolo[3,4-c]pyrrol- hexahydropyrrolo[3,4-c]pyrrol- 2(1H)-yl)(2-cyclopropyl((tetrahydro-2H- 2(1H)-yl)methyl)-1H- pyranyl)methoxy)pyridinyl)methanone benzo[d][1,2,3]triazole hydrochloride (intermediate 503.4 2.19 ) / 2-cyclopropyl (M+H)+ ((tetrahydro-2H-pyran yl)methoxy)isonicotinic acid (intermediate 5.1) Ex. Systematic Name Amine / Carboxylic acid MS, m/e ((3aS,6aS)(1H-benzo[d][1,2,3]triazole (1H-benzo[d][1,2,3]triazol carbonyl)hexahydropyrrolo[3,4-c]pyrrol- yl)((3aR,6aR)- 2(1H)-yl)(2-chloro((tetrahydro-2H-pyran- hexahydropyrrolo[3,4-c]pyrrol- ethoxy)pyridinyl)methanone 2(1H)-yl)methanone dihydrochloride (intermediate 511.3 2.20 2.2) / 2-chloro((tetrahydro- (M+H)+ 2H-pyran yl)methoxy)isonicotinic acid (CAS-RN 14562841) 8aS)(2-cyclopropyl((tetrahydro- 8aS)- 2H-pyranyl)methoxy)isonicotinoyl)- octahydropyrrolo[3,4-d]azepinoctahydropyrrolo [3,4-d]azepin-2(1H)- 2(1H)-yl)((R)-4,5,6,7- yl)((R)-4,5,6,7-tetrahydro-1H- tetrahydro-1H- benzo[d][1,2,3]triazolyl)methanone benzo[d][1,2,3]triazol 549.3 2.21 yl)methanone (intermediate 15) (M+H)+ / 2-cyclopropyl((tetrahydro- 2H-pyran yl)methoxy)isonicotinic acid (intermediate 5) 8aS)(1H-benzo[d][1,2,3]triazole (1H-benzo[d][1,2,3]triazol carbonyl)octahydropyrrolo[3,4-d]azepin- yl)((3aR,8aS)- 2(1H)-yl)(2-cyclopropyl((tetrahydro-2H- octahydropyrrolo[3,4-d]azepinpyranyl )methoxy)pyridinyl)methanone 6(7H)-yl)methanone hydrochloride (intermediate 545.3 2.22 2.4) / 2-cyclopropyl (M+H)+ ((tetrahydro-2H-pyran yl)methoxy)isonicotinic acid (intermediate 5) Ex. Systematic Name Amine / Carboxylic acid MS, m/e ((3aS,6aS)(1H-benzo[d][1,2,3]triazole (1H-benzo[d][1,2,3]triazol carbonyl)hexahydropyrrolo[3,4-c]pyrrol- yl)((3aR,6aR)- 2(1H)-yl)(2-(dimethylamino)((tetrahydro- hexahydropyrrolo[3,4-c]pyrrol- 2H-pyranyl)methoxy)pyridin 2(1H)-yl)methanone yl)methanone ochloride (intermediate 520.4 2.23 2.2) / 2-(dimethylamino) (M+H)+ ((tetrahydro-2H-pyran yl)methoxy)isonicotinic acid (intermediate 11) aS,6aS)(2-cyclopropyl((tetra- 6-(((3aR,6aR)-hexahydrohydro-2H-pyranyl )methoxy)iso- pyrrolo[3,4-c]pyrrol-2(1H)- nicotinoyl)hexahydropyrrolo[3,4-c]pyrrol- yl)methyl)benzo[d]oxazol- 2(1H)-yl)methyl)benzo[d]oxazol-2(3H)-one 2(3H)-one hydrochloride (intermediate 12) / 2- 519.3 2.24 cyclopropyl((tetrahydro-2H- (M+H)+ pyran yl)methoxy)isonicotinic acid (intermediate 5) ((3aS,6aS)(2-(dimethylamino)((tetra- ((3aR,6aR)- hydro-2H-pyranyl)methoxy)iso- hexahydropyrrolo[3,4-c]pyrrolnicotinoyl ydropyrrolo[3,4-c]pyrrol- 2(1H)-yl)((R)-4,5,6,7- 2(1H)-yl)((R)-4,5,6,7-tetrahydro-1H- tetrahydro-1H- benzo[d][1,2,3]triazolyl)methanone benzo[d][1,2,3]triazol 524.4 2.25 hanone hydrochloride (M+H)+ (intermediate 2.1) / 2- (dimethylamino) ((tetrahydro-2H-pyran yl)methoxy)isonicotinic acid (intermediate 11) Ex. Systematic Name Amine / Carboxylic acid MS, m/e ((3aR,6aS)(1H-benzo[d][1,2,3]triazole (1H-benzo[d][1,2,3]triazol carbonyl)hexahydropyrrolo[3,4-c]pyrrol- yl)((3aR,6aS)- 2(1H)-yl)(2-cyclopropyl((tetrahydro-2H- hexahydropyrrolo[3,4-c]pyrrolpyranyl )methoxy)pyridinyl)methanone 2(1H)-yl)methanone hydrochloride (intermediate 517.4 2.26 2.5) / 2-cyclopropyl (M+H)+ ((tetrahydro-2H-pyran yl)methoxy)isonicotinic acid (intermediate 5) 4-((3aR,6aS)(2-cyclopropyl R,6aS)- ((tetrahydro-2H-pyran dropyrrolo[3,4- yl)methoxy)isonicotinoyl)octahydropyrrolo[ c]pyrrole 3,4-c]pyrrole carbonyl)benzenesulfonamide carbonyl)benzenesulfonamide hydrochloride (intermediate 2) 2.