HK1252995B - New bicyclic compounds as dual atx/ca inhibitors - Google Patents

Description

Novel bicyclic compounds as dual ATX/CA inhibitors

The present invention relates to organic compounds useful for treatment or prevention in mammals, and in particular to dual autotaxin (ATX)/carbonic anhydrase inhibitors that are inhibitors of lysophosphatidic acid (LPA) production and, therefore, modulators of LPA levels and related signaling, for the treatment or prevention of inflammatory disorders, neurological disorders, vascular and cardiovascular disorders, cancer, and ocular disorders.

The present invention provides novel compounds of formula (I)

in

^R1 is substituted phenyl, substituted phenyl- _C1-6 -alkyl, substituted phenoxy- _C1-6 -alkyl, substituted phenyl- _{C2-6-alkenyl, substituted phenyl-C2-6} -alkynyl, substituted quinolyl, substituted quinolyl- _C1-6 -alkyl, substituted quinolyl-C1-6-alkenyl, substituted quinolyl- _C1-6 -alkynyl, substituted pyridyl, substituted pyridyl-C1-6-alkyl, substituted pyridyl- _C2-6 -alkenyl, substituted pyridyl-C2-6-alkynyl, substituted thienyl, substituted thienyl- _C1-6 -alkyl, substituted thienyl- _C2-6 -alkenyl or substituted thienyl-C2-6-alkynyl, wherein substituted phenyl, substituted phenyl- _C1-6 -alkyl, substituted phenoxy-C1-6-alkyl, substituted phenyl- _C1-6 -alkyl, substituted phenyl-C1-6-alkyl, substituted phenyl- _C1-6 -alkynyl, substituted quinolyl, substituted quinolyl-C1-6-alkyl, substituted quinolyl-C1-6-alkenyl, substituted quinolyl- _C1-6 -alkynyl, substituted pyridyl, substituted pyridyl- _{C1-6-alkyl, substituted pyridyl-C2-6} -alkenyl, substituted pyridyl- _C2-6 -alkynyl, substituted thienyl, substituted thienyl-C1-6-alkyl, substituted thienyl-C2-6-alkenyl or substituted thienyl- _C2-6 -alkynyl substituted phenyl-C _2-6 -alkynyl, substituted quinolinyl, substituted quinolinyl _- C 1-6 -alkyl, substituted quinolinyl-C _1-6 -alkenyl, substituted quinolinyl-C _1-6 -alkynyl, substituted pyridinyl, substituted pyridinyl-C 1-6 -alkyl, substituted pyridinyl-C _2-6 -alkenyl, substituted pyridinyl-C _2-6 -alkynyl, substituted thienyl, substituted thienyl-C _{1-6 -alkyl} , substituted thienyl-C _2-6 -alkenyl and substituted thienyl-C _2-6 -alkynyl are substituted with R ³ , R ⁴ _and R ³ ;

Y is -OC(O)- or -C(O)-;

W is -C(O)-, -S(O) ₂ - or -CR ⁶ R ⁷ -;

^R2 is substituted phenyl, substituted pyridyl or substituted thienyl, wherein substituted phenyl, substituted pyridyl and substituted thienyl are substituted by ^R6 , ^R7 and ^R8 ;

^R3 is halogen, hydroxy, cyano, _C1-6 -alkyl, _C1-6 -alkoxy, _C1-6 -alkoxy- _C1-6 -alkyl, halo- _C1-6 -alkoxy, halo- _C1-6 -alkyl, hydroxy- _C1-6 -alkyl, _C3-8 -cycloalkyl, _C3-8 -cycloalkyl- _C1-6 -alkyl, _C3-8 -cycloalkyl- _C1-6 -alkoxy, _C3-8 -cycloalkyloxy, _C3-8 -cycloalkyloxy-C1-6-alkyl, _C1-6 -alkylamino, _C1-6 -alkylcarbonylamino, _C3-8 -cycloalkylcarbonylamino, _C1-6 -alkyltetrazolyl, _{C1-6 -alkyltetrazolyl-C1-6 -} alkyl or heterocycloalkyl- _C1-6 -alkoxy;

^R4 and ^R3 are independently selected from H, halogen, hydroxy, cyano, _C1-6 -alkyl, _C1-6 -alkoxy, _C1-6 -alkoxy- _C1-6 -alkyl, halo- _C1-6 -alkoxy, halo- _{C1-6-alkyl, hydroxy-C1-6 -} alkyl, _C3-8 -cycloalkyl, _C3-8 -cycloalkyl- _C1-6 -alkyl, _C3-8 -cycloalkyl- _C1-6 -alkoxy, _C3-8 -cycloalkyloxy, _C3-8 -cycloalkyloxy- _C1-6 -alkyl, _C1-6 -alkylcarbonylamino, _C3-8 -cycloalkylcarbonylamino, _C1-6 -alkyltetrazolyl, _C1-6 -alkyltetrazolyl- _C1-6 -alkyl or heterocycloalkyl- _C1-6 -alkoxy;

^R6 is aminosulfonyl;

R ⁷ and R ⁸ are independently selected from H, halogen, hydroxy, cyano, C _1-6 -alkyl, C _1-6 -alkoxy, C _1-6 -alkoxy-C _1-6 -alkyl, halo-C _1-6 -alkoxy, halo-C _1-6 -alkyl, hydroxy-C _1-6 -alkyl, C _3-8 -cycloalkyl, C _3-8 -cycloalkyl-C _1-6 -alkyl, C _3-8 -cycloalkyl-C _1-6 -alkoxy, C _3-8 -cycloalkyloxy and C _3-8 -cycloalkyloxy-C _1-6 -alkyl;

m, n, p and q are independently selected from 1 or 2;

and pharmaceutically acceptable salts.

Autotaxin (ATX) is a secreted enzyme, also known as ectonucleotide pyrophosphatase/phosphodiesterase 2 or lysophospholipase D, that is important for converting lysophosphatidylcholine (LPC) into the biologically active signaling molecule lysophosphatidic acid (LPA). Plasma LPA levels have been shown to correlate well with ATX activity, and ATX is therefore believed to be an important source of extracellular LPA. Early experiments with prototype ATX inhibitors demonstrated that such compounds were able to inhibit LPA synthesis activity in mouse plasma. Work conducted in the 1970s and early 1980s demonstrated that LPA can elicit a variety of cellular responses, including smooth muscle cell contraction, platelet activation, cell proliferation, chemotaxis, and more. LPA mediates its effects by signaling through several G protein-coupled receptors (GPCRs); the first members were originally described as Edg (endothelial cell differentiation gene) receptor or ventricular zone gene-1 (vzg-1), but are now called LPA receptors. Currently, the prototype group consists of LPA1/Edg-2/VZG-1, LPA2/Edg-4, and LPA3/Edg-7. Recently, three additional LPA receptors, LPA4/p2Y9/GPR23, LPA5/GPR92, and LPA6/p2Y5, have been described that are more closely related to nucleotide-selective purinergic receptors than the prototype LPA1-3 receptors. The ATX-LPA signaling axis is involved in a wide variety of physiological and pathophysiological functions, including, for example, nervous system function, vascular development, cardiovascular physiology, reproduction, immune system function, chronic inflammation, tumor metastasis and progression, organ fibrosis, and obesity and/or other metabolic diseases such as diabetes mellitus. Therefore, increased ATX activity and/or increased LPA levels, altered LPA receptor expression, and altered responses to LPA may contribute to the initiation, progression, and/or outcome of a large number of different pathophysiological conditions associated with the ATX/LPA axis.

Carbonic anhydrases (CAs) are a family of zinc-dependent enzymes that catalyze the equilibrium between carbon dioxide and water with bicarbonate and protons. The CA reaction is involved in a variety of physiological and pathological processes. Carbonic anhydrase inhibition can be used to treat ocular disorders, conditions with reduced blood flow, cancer, edema, and inflammatory conditions including bacterial infections.

Dual-acting ATX/CA inhibitors are believed to lower intraocular pressure by promoting two independent pathways, such as inhibition of aqueous humor (AH) production via CA inhibition at the ciliary body and promotion of AH outflow via ATX inhibition within the AH drainage system. In conditions of intraocular vascular leakage, such as diabetic retinopathy, age-related macular disease, or retinal vein occlusion, CA levels have been shown or expected to increase in the eye and promote an increase in pH. This is expected to activate multiple hydrolases (including ATX) that may contribute to disease progression, suggesting additional ATX inhibition optimized by shifting pH.

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

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

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

The term "C _1-6 -alkoxy" denotes a radical of the formula -OR', wherein R' is C _1-6 -alkyl. Examples of C _1-6 -alkoxy include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy and tert-butoxy. A particular example is methoxy.

The term "C _2-6 -alkenyl" denotes a monovalent straight or branched hydrocarbon radical of 2 to 6 carbon atoms having at least one double bond. A particular example is vinyl.

The term "Ci _-6 -alkoxy-Ci _-6 -alkyl" denotes a Ci _-6 -alkyl group in which at least one of the hydrogen atoms of the Ci _-6 -alkyl group is replaced by a Ci _-6 -alkoxy group. Particular examples are methoxymethyl, methoxyethyl, ethoxymethyl, ethoxyethyl, isopropoxymethyl and isopropoxyethyl.

The term "Ci _-6 -alkyl" refers to a monovalent straight-chain or branched saturated hydrocarbon radical of 1 to 6 carbon atoms. Examples of _Ci-6 -alkyl radicals include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, and pentyl. Particular alkyl radicals include methyl, ethyl, isopropyl, n-butyl, and sec-butyl.

The term "C _1-6 -alkylamino" denotes a group of formula -NH-R', wherein R' is C _1-6 -alkyl. Particular C _1-6 -alkylamino is a group of formula -NH-R', wherein R' is tert-butyl.

The term " _{Ci_6} -alkylcarbonylamino" denotes a radical of the formula -NH-C(O)-R', wherein R' is _{Ci_6} -alkyl. Particular _{Ci_6} -alkylcarbonylamino is a radical of the formula -NH-C(O)-R', wherein R' is tert-butyl.

The term "C _1-6 -alkyltetrazolyl" denotes a tetrazolyl group substituted by one C _1-6 -alkyl group. Particular C _1-6 -alkyltetrazolyl group is methyltetrazolyl.

The term "C _1-6 -alkyltetrazolyl-C _1-6 -alkyl" denotes a C _1-6 -alkyl radical wherein one of the hydrogen atoms of the C _1-6 -alkyl radical is replaced by a C _1-6 -alkyltetrazolyl radical. A particular example is methyltetrazolylmethyl.

The term " _C2-6 -alkynyl" denotes a monovalent straight or branched hydrocarbon radical of 2 to 6 carbon atoms having at least one triple bond.

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

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

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

The term "C _3-8 -cycloalkoxy" denotes a group of formula -OR', wherein R' is C _3-8 -cycloalkyl.

The term "C _3-8 -cycloalkoxy-C _1-6 -alkyl" denotes a C _1-6 -alkyl group, wherein at least one of the hydrogen atoms of the alkyl group is replaced by a C _3-8 -cycloalkoxy group.

The term " _C3-8 -cycloalkyl" refers to a monovalent saturated monocyclic or bicyclic hydrocarbon radical of 3 to 8 ring carbon atoms. Bicyclic refers to a ring system consisting of two saturated carbocyclic rings having two common carbon atoms. Examples of monocyclic cycloalkyls are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl. Examples of bicyclic _C3-8 -cycloalkyls are bicyclo[2.2.1]heptyl or bicyclo[2.2.2]octyl. A particular _C3-8 -cycloalkyl is cyclopropyl.

The term "C _3-8 -cycloalkyl-C _1-6 -alkoxy" denotes a C _1-6 -alkoxy group wherein at least one of the hydrogen atoms of the alkyl group is replaced by a C _3-8 -cycloalkyl group.

The term "C _3-8 -cycloalkyl-C _1-6 -alkyl" denotes a C _1-6 -alkyl group, wherein at least one of the hydrogen atoms of the alkyl group is replaced by a C _3-8 -cycloalkyl group.

The term " _C3-8 -cycloalkylcarbonylamino" denotes a group of formula -NH-C(O)-R', wherein R' is _C3-8 -cycloalkyl.

The term "halo-C _1-6 -alkoxy" denotes a C _1-6 -alkoxy group wherein at least one of the hydrogen atoms of the alkoxy group has been replaced by identical or different halogen atoms. A particular example is trifluoromethoxy.

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

The term "halo-C _1-6 -alkyl" denotes a C _1-6 -alkyl radical wherein at least one of the hydrogen atoms of the C _1-6 -alkyl radical has been replaced by identical or different halogen atoms. A particular example is trifluoromethyl.

The term "heterocycloalkyl" refers to a monovalent saturated or partially unsaturated monocyclic or 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 refers to a ring system consisting of two rings with two common ring atoms, wherein the bridge separating the two rings is a single bond or a chain of one or two ring atoms. Examples of monocyclic saturated heterocycloalkyls are 4,5-dihydro-oxazolyl, oxetanyl, azetidinyl, pyrrolidinyl, 2-oxo-pyrrolidin-3-yl, tetrahydrofuranyl, tetrahydro-thienyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperazinyl, morpholinyl, thiomorpholinyl, 1,1-dioxo-thiomorpholin-4-yl, azepanyl, diazepanyl, homopiperazinyl or oxazepanyl. Examples of bicyclic saturated heterocycloalkyl groups are 8-aza-bicyclo[3.2.1]octyl, quinuclidinyl, 8-oxa-3-aza-bicyclo[3.2.1]octyl, 9-aza-bicyclo[3.3.1]nonyl, 3-oxa-9-aza-bicyclo[3.3.1]nonyl or 3-thia-9-aza-bicyclo[3.3.1]nonyl. Examples of partially unsaturated heterocycloalkyl groups are dihydrofuranyl, imidazolinyl, dihydro-oxazolyl, tetrahydro-pyridyl or dihydropyranyl. A particular example of heterocycloalkyl is tetrahydropyranyl.

The term "heterocycloalkyl-Ci _-6 -alkoxy" denotes a Ci _-6 -alkoxy group in which at least one of the hydrogen atoms of the alkyl group is replaced by a heterocycloalkyl group. A particular example of a heterocycloalkyl-Ci _-6- alkoxy group is tetrahydropyranyl-Ci _-6 -alkoxy, more particular tetrahydropyranylmethoxy.

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

The term "hydroxy-C _1-6 -alkyl" denotes a C _1-6 -alkyl group in which one of the hydrogen atoms of the alkyl group is replaced by a hydroxy group. Particular examples are hydroxymethyl and hydroxyethyl.

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

The term "phenoxy-Ci _-6 -alkyl" denotes a Ci _-6 -alkyl group wherein one of the hydrogen atoms of the alkyl group is replaced by a phenoxy group.

The term "phenyl-C _2-6 -alkenyl" denotes a C _2-6 -alkenyl group wherein one of the hydrogen atoms of the alkyl group is replaced by a phenyl group. A particular example of a phenyl-C _2-6 -alkenyl group is phenylethenyl.

The term "phenyl-Ci _-6 -alkyl" denotes a Ci _-6 -alkyl group wherein one of the hydrogen atoms of the alkyl group is replaced by a phenyl group. Particular examples of phenyl-Ci- ₆ -alkyl are phenylmethyl and phenylethyl.

The term "phenyl-C _2-6 -alkynyl" denotes a C _2-6 -alkynyl group wherein one of the hydrogen atoms of the alkyl group is replaced by a phenyl group.

The term "pyridinyl-C _2-6 -alkenyl" denotes a C _2-6 -alkenyl group wherein one of the hydrogen atoms of the alkyl group is replaced by a pyridinyl group.

The term "pyridinyl-Ci _-6 -alkyl" denotes a Ci _-6 -alkyl group wherein one of the hydrogen atoms of the alkyl group is replaced by a pyridinyl group. A particular example of a pyridinyl-Ci- ₆ -alkyl group is pyridinylmethyl, more particularly 2-pyridinylmethyl.

The term "pyridinyl-C _2-6 -alkynyl" denotes a C _2-6 -alkynyl group wherein one of the hydrogen atoms of the alkyl group is replaced by a pyridinyl group.

The term "thienyl-C _2-6 -alkenyl" denotes a C _2-6 -alkenyl group wherein one of the hydrogen atoms of the alkyl group is replaced by a thienyl group.

The term "thienyl-Ci- ₆ -alkyl" denotes a Ci _-6 -alkyl group wherein one of the hydrogen atoms of the alkyl group is replaced by a thienyl group.

The term "thienyl-C _2-6 -alkynyl" denotes a C _2-6 -alkynyl group wherein one of the hydrogen atoms of the alkyl group is replaced by a thienyl group.

The term "pharmaceutical salt" refers to those salts that keep the biological effectiveness and property of free alkali or free acid, and they are not biologically or otherwise unsuitable. Said salt adopts following acid to form: inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid etc., particularly hydrochloric acid, and organic acid such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, N-acetylcysteine etc. In addition, these salts can be prepared by adding inorganic base or organic base in free acid. The salt deriving from inorganic base includes but is not limited to sodium salt, potassium salt, lithium salt, ammonium salt, calcium salt, magnesium salt etc. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines, including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, lysine, arginine, N-ethylpiperidine, piperidine, polyimine resins, and the like. Particular pharmaceutically acceptable salts of the compounds of formula (I) are the hydrochloride, methanesulfonate, and citrate salts.

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

The term "protecting group" (PG) refers to a group that, in the sense conventionally associated therewith in synthetic chemistry, selectively blocks a reactive site in a multifunctional compound so that a chemical reaction can proceed selectively at another unprotected reactive site. The protecting group can be removed at an appropriate point in time. Exemplary protecting groups are amino-protecting groups, carboxyl-protecting groups, or hydroxyl-protecting groups. Particular protecting groups are tert-butyloxycarbonyl (Boc), benzyloxycarbonyl (Cbz), fluorenylmethoxycarbonyl (Fmoc), and benzyl (Bn) groups. Further particular protecting groups are tert-butyloxycarbonyl (Boc) and fluorenylmethoxycarbonyl (Fmoc). A more particular protecting group is tert-butyloxycarbonyl (Boc).

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

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

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

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

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

Furthermore, one embodiment of the present invention are compounds according to formula (I) as described herein and pharmaceutically acceptable salts or esters thereof, in particular compounds according to formula (I) as described herein and pharmaceutically acceptable salts thereof, more in particular compounds according to formula (I) as described herein.

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

^R1 is substituted phenyl, substituted phenyl- _C1-6 -alkyl, substituted phenoxy- _C1-6 -alkyl, substituted phenyl- _C2-6 -alkenyl, substituted phenyl- _C2-6 -alkynyl, substituted pyridinyl, substituted pyridinyl- _C1-6 -alkyl, substituted pyridinyl-C2-6-alkenyl, substituted pyridinyl- _C2-6 -alkynyl, substituted thienyl, substituted thienyl- _C1-6 -alkyl, substituted thienyl- _C2-6 -alkenyl or substituted thienyl- _C2-6 -alkynyl, wherein substituted phenyl, substituted phenyl- _C1-6 -alkyl, substituted phenoxy- _C1-6 -alkyl, substituted phenyl- _C2-6 -alkenyl, substituted phenyl- _C2-6 -alkynyl, substituted pyridinyl, substituted pyridinyl- _C1-6 -alkyl, substituted pyridinyl- _{C2-6 -} alkynyl -alkenyl, substituted pyridyl-C _2-6 -alkynyl, substituted thienyl, substituted thienyl-C _1-6 -alkyl, substituted thienyl-C _2-6 -alkenyl and substituted thienyl-C _2-6 -alkynyl are substituted with R ³ , R ⁴ and R ⁵ ;

Y is -OC(O)- or -C(O)-;

W is -C(O)-, -S(O) ₂ - or -CR ⁶ R ⁷ -;

^R2 is substituted phenyl, substituted pyridyl or substituted thienyl, wherein substituted phenyl, substituted pyridyl and substituted thienyl are substituted by ^R6 , ^R7 and ^R8 ;

^R3 is halogen, hydroxy, cyano, _C1-6 -alkyl, _C1-6 -alkoxy, _C1-6 -alkoxy- _C1-6 -alkyl, halo- _C1-6 -alkoxy, halo- _C1-6 -alkyl, hydroxy- _C1-6 -alkyl, _C3-8 -cycloalkyl, _C3-8 -cycloalkyl- _C1-6 -alkyl, _C3-8 -cycloalkyl- _C1-6 -alkoxy, _C3-8 -cycloalkyloxy, _C3-8 -cycloalkyloxy-C1-6-alkyl, _C1-6 -alkylamino, _C1-6 -alkylcarbonylamino, _C3-8 -cycloalkylcarbonylamino, _C1-6 -alkyltetrazolyl, _{C1-6 -alkyltetrazolyl-C1-6 -} alkyl or heterocycloalkyl- _C1-6 -alkoxy;

^R4 and ^R5 are independently selected from H, halogen, hydroxy, cyano, Ci _-6 -alkyl, Ci _-6 -alkoxy, Ci _-6 -alkoxy-Ci _{- 6} -alkyl, halo-Ci _-6 -alkoxy, halo-Ci- ₆ -alkyl, hydroxy-Ci _-6 -alkyl, _C3-8 -cycloalkyl, _C3-8 -cycloalkyl-Ci- _{6 -} alkyl, C3-8-cycloalkyl-Ci _-6 -alkoxy, _C3-8 -cycloalkyloxy, _C3-8 -cycloalkyloxy-Ci _-6 -alkyl, Ci- ₆ -alkylcarbonylamino, C3-8-cycloalkylcarbonylamino, Ci _-6 -alkyltetrazolyl, Ci _-6 -alkyltetrazolyl-Ci- ₆ -alkyl or heterocycloalkyl-Ci- ₆ -alkoxy;

^R6 is aminosulfonyl;

R ⁷ and R ⁸ are independently selected from H, halogen, hydroxy, cyano, C _1-6 -alkyl, C _1-6 -alkoxy, C _1-6 -alkoxy-C _1-6 -alkyl, halo-C _1-6 -alkoxy, halo-C _1-6 -alkyl, hydroxy-C _1-6 -alkyl, C _3-8 -cycloalkyl, C _3-8 -cycloalkyl-C _1-6 -alkyl, C _3-8 -cycloalkyl-C _1-6 -alkoxy, C _3-8 -cycloalkyloxy and C _3-8 -cycloalkyloxy-C _1-6 -alkyl;

m, n, p and q are independently selected from 1 or 2;

and pharmaceutically acceptable salts.

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

R ¹ is substituted phenyl-C _1-6 -alkyl, substituted phenoxy-C _1-6 -alkyl, substituted phenyl-C _2-6 -alkenyl, substituted pyridinyl, or substituted pyridinyl-C _1-6 -alkyl, wherein substituted phenyl-C _1-6 -alkyl, substituted phenoxy-C _1-6 -alkyl, substituted phenyl-C _2-6 -alkenyl, substituted pyridinyl, and substituted pyridinyl-C _1-6 -alkyl are substituted with R ³ , R ⁴ , and R ⁵ ;

Y is -OC(O)- or -C(O)-;

W is -C(O)-;

R ² is substituted phenyl or substituted pyridyl, wherein the substituted phenyl and substituted pyridyl are substituted by R ⁶ , R ⁷ and R ⁸ ;

R ³ is halo-C _1-6 -alkoxy, C _1-6 -alkylamino, C _1-6 -alkylcarbonylamino, C _1-6 -alkyltetrazolyl-C _1-6 -alkyl or tetrahydropyranyl-C _1-6 -alkoxy;

R ⁴ is H, cyano, halogen, C _1-6 -alkyl, halo-C _1-6 -alkyl or C _3-8 -cycloalkyl;

^R5 is H;

^R6 is aminosulfonyl;

R ⁷ and R ⁸ are independently selected from H or halogen;

m and q are 1;

n and p are independently selected from 1 or 2;

and pharmaceutically acceptable salts.

A particular embodiment of the present invention are compounds according to formula (I) as described herein, wherein R ¹ is substituted phenyl-C _1-6 -alkyl, substituted phenoxy-C _1-6 -alkyl, substituted phenyl-C _2-6 -alkenyl, substituted quinolinyl-C _1-6 -alkyl, substituted pyridinyl or substituted pyridinyl-C _1-6 -alkyl, wherein substituted phenyl-C _1-6 -alkyl, substituted phenoxy-C _1-6 -alkyl, substituted phenyl-C _2-6 -alkenyl, substituted quinolinyl-C _1-6 -alkyl, substituted pyridinyl and substituted pyridinyl-C _1-6 -alkyl are substituted with R ³ , R ⁴ and R ⁵ .

A particular embodiment of the present invention are compounds according to formula (I) as described herein, wherein R ¹ is substituted phenyl-C _1-6 -alkyl, substituted phenoxy-C _1-6 -alkyl, substituted phenyl-C _2-6 -alkenyl, substituted pyridinyl or substituted pyridinyl-C _1-6 -alkyl, wherein substituted phenyl-C _1-6 -alkyl, substituted phenoxy-C _1-6 -alkyl, substituted phenyl-C _2-6 -alkenyl, substituted pyridinyl and substituted pyridinyl-C _1-6 -alkyl are substituted with R ³ , R ⁴ and R ⁵ .

Another particular embodiment of the present invention are compounds according to formula (I) as described herein, wherein R ¹ is pyridinyl-C _1-6 -alkyl substituted with R ³ , R ⁴ and R ⁵ .

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

A particular embodiment of the present invention are compounds according to formula (I) as described herein, wherein ^R2 is substituted phenyl or substituted pyridinyl, wherein substituted phenyl and substituted pyridinyl are substituted with ^R6 , ^R7 and ^R8 .

Another particular embodiment of the present invention are compounds according to formula (I) as described herein, wherein ^R2 is phenyl substituted with ^R6 , ^R7 and ^R8 .

A particular embodiment of the present invention are compounds according to formula (I) as described herein, wherein R ³ is halo-C _1-6 -alkoxy, C _1-6 -alkylcarbonylamino, C _1-6 -alkyltetrazolyl-C 1-6 -alkyl, C _1-6 -alkylpiperidinyl-C _{1-6 -alkoxy} or tetrahydropyranyl-C _1-6 -alkoxy.

A particular embodiment of the present invention are compounds according to formula (I) as described herein, wherein R ³ is halo-C _1-6 -alkoxy, C _1-6 -alkylcarbonylamino, C _1-6 -alkyltetrazolyl-C _1-6 -alkyl or tetrahydropyranyl-C _1-6 -alkoxy.

Another particular embodiment of the present invention are compounds according to formula (I) as described herein, wherein R ³ is C _1-6 -alkylcarbonylamino.

A particular embodiment of the present invention are compounds according to formula (I) as described herein, wherein R ⁴ is H, cyano, halogen, C _1-6 -alkyl, halo-C _1-6 -alkyl or C _3-8 -cycloalkyl.

Another particular embodiment of the present invention are compounds according to formula (I) as described herein, wherein R ⁴ is halo-C _1-6 -alkyl.

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

One embodiment of the present invention are compounds according to formula (I) as described herein, wherein R ⁷ and R ⁸ are independently selected from H or halogen.

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

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

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

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

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

R ¹ is pyridinyl-C _1-6 -alkyl substituted by R ³ , R ⁴ and R ⁵ ;

Y is -OC(O)-;

W is -C(O)-;

R ² is phenyl substituted by R ⁶ , R ⁷ and R ⁸ ;

R ³ is C _1-6 -alkylcarbonylamino;

R ⁴ is halo-C _1-6 -alkyl;

^R5 is H;

^R7 is halogen;

R ⁸ is H;

m, n, p, and q are 1

and pharmaceutically acceptable salts.

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

in

R ¹ is substituted phenyl-C _1-6 -alkyl, substituted phenoxy-C _1-6 -alkyl, substituted phenyl-C _2-6 -alkenyl, substituted pyridinyl, or substituted pyridinyl-C _1-6 -alkyl, wherein substituted phenyl-C _1-6 -alkyl, substituted phenoxy-C _1-6 -alkyl, substituted phenyl-C _2-6 -alkenyl, substituted pyridinyl, and substituted pyridinyl-C _1-6 -alkyl are substituted with R ³ , R ⁴ , and R ⁵ ;

Y is -OC(O)- or -C(O)-;

W is -C(O)-;

R ³ is halo-C _1-6 -alkoxy, C _1-6 -alkylcarbonylamino, C _1-6 -alkyltetrazolyl-C _1-6 -alkyl or tetrahydropyranyl-C _1-6 -alkoxy;

R ⁴ is H, cyano, halogen, C _1-6 -alkyl, halo-C _1-6 -alkyl or C _3-8 -cycloalkyl;

^R5 is H;

R ⁷ and R ⁸ are independently selected from H or halogen;

m and q are 1;

n and p are independently selected from 1 or 2;

and pharmaceutically acceptable salts.

Another particular embodiment of the present invention are compounds according to formula I(b) as described herein,

in

R ¹ is pyridinyl-C _1-6 -alkyl substituted by R ³ , R ⁴ and R ⁵ ;

Y is -OC(O)-;

W is -C(O)-;

R ³ is C _1-6 -alkylcarbonylamino;

R ⁴ is halo-C _1-6 -alkyl;

^R5 is H;

^R7 is halogen;

R ⁸ is H;

m, n, p, and q are 1

and pharmaceutically acceptable salts.

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

2-(4-sulfamoylbenzoyl)-1,3,4,6-tetrahydropyrrolo[3,4-c]pyrrole-5-carboxylic acid [3-(2,2-dimethylpropionylamino)-5-(trifluoromethyl)pyridin-2-yl]methyl ester;

2-(2,5-difluoro-4-sulfamoylbenzoyl)-1,3,4,6-tetrahydropyrrolo[3,4-c]pyrrole-5-carboxylic acid [3-(2,2-dimethylpropionylamino)-5-(trifluoromethyl)pyridin-2-yl]methyl ester;

2-(3-chloro-4-sulfamoylbenzoyl)-1,3,4,6-tetrahydropyrrolo[3,4-c]pyrrole-5-carboxylic acid [3-(2,2-dimethylpropionylamino)-5-(trifluoromethyl)pyridin-2-yl]methyl ester;

2-(3-Fluoro-4-sulfamoylbenzoyl)-1,3,4,6-tetrahydropyrrolo[3,4-c]pyrrole-5-carboxylic acid [3-(2,2-dimethylpropionylamino)-5-(trifluoromethyl)pyridin-2-yl]methyl ester;

2-(2-fluoro-4-sulfamoylbenzoyl)-1,3,4,6-tetrahydropyrrolo[3,4-c]pyrrole-5-carboxylic acid [3-(2,2-dimethylpropionylamino)-5-(trifluoromethyl)pyridin-2-yl]methyl ester;

2-(5-sulfamoylpyridine-2-carbonyl)-1,3,4,6-tetrahydropyrrolo[3,4-c]pyrrole-5-carboxylic acid [3-(2,2-dimethylpropionylamino)-5-(trifluoromethyl)pyridin-2-yl]methyl ester;

4-(trifluoromethoxy)benzyl 5-(4-sulfamoylbenzoyl)-3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate;

6-[5-[2-cyclopropyl-6-(tetrahydropyran-4-ylmethoxy)pyridine-4-carbonyl]-1,3,4,6-tetrahydropyrrolo[3,4-c]pyrrole-2-carbonyl]pyridine-3-sulfonamide;

4-[5-[2-cyclopropyl-6-(tetrahydropyran-4-ylmethoxy)pyridine-4-carbonyl]-1,3,4,6-tetrahydropyrrolo[3,4-c]pyrrole-2-carbonyl]-3-fluorobenzenesulfonamide;

2-(2,3-difluoro-4-sulfamoylbenzoyl)-1,3,4,6-tetrahydropyrrolo[3,4-c]pyrrole-5-carboxylic acid [3-(2,2-dimethylpropionylamino)-5-(trifluoromethyl)pyridin-2-yl]methyl ester;

3-Fluoro-4-(5-(3-(2-((5-methyl-2H-tetrazol-2-yl)methyl)-4-(trifluoromethyl)phenyl)propanoyl)-1,2,3,4,5,6-hexahydropyrrolo[3,4-c]pyrrole-2-carbonyl)benzenesulfonamide;

2-(2,6-difluoro-4-sulfamoylbenzoyl)-1,3,4,6-tetrahydropyrrolo[3,4-c]pyrrole-5-carboxylic acid [3-(2,2-dimethylpropionylamino)-5-(trifluoromethyl)pyridin-2-yl]methyl ester;

[5-chloro-3-(2,2-dimethylpropionylamino)pyridin-2-yl]methyl 2-(2-fluoro-4-sulfamoylbenzoyl)-1,3,4,6-tetrahydropyrrolo[3,4-c]pyrrole-5-carboxylate;

[5-chloro-3-(2,2-dimethylpropionylamino)pyridin-2-yl]methyl 2-(3-fluoro-4-sulfamoylbenzoyl)-1,3,4,6-tetrahydropyrrolo[3,4-c]pyrrole-5-carboxylate;

[5-chloro-3-(2,2-dimethylpropionylamino)pyridin-2-yl]methyl 2-(2,3-difluoro-4-sulfamoylbenzoyl)-1,3,4,6-tetrahydropyrrolo[3,4-c]pyrrole-5-carboxylate;

[5-chloro-3-(2,2-dimethylpropionylamino)pyridin-2-yl]methyl 2-(2,6-difluoro-4-sulfamoylbenzoyl)-1,3,4,6-tetrahydropyrrolo[3,4-c]pyrrole-5-carboxylate;

[5-chloro-3-(2,2-dimethylpropionylamino)pyridin-2-yl]methyl 2-(2,5-difluoro-4-sulfamoylbenzoyl)-1,3,4,6-tetrahydropyrrolo[3,4-c]pyrrole-5-carboxylate;

2-(2-fluoro-4-sulfamoylbenzoyl)-1,3,4,6-tetrahydropyrrolo[3,4-c]pyrrole-5-carboxylic acid [3-(2,2-dimethylpropionylamino)-6-methylpyridin-2-yl]methyl ester;

[6-chloro-3-(2,2-dimethylpropionylamino)pyridin-2-yl]methyl 2-(2-fluoro-4-sulfamoylbenzoyl)-1,3,4,6-tetrahydropyrrolo[3,4-c]pyrrole-5-carboxylate;

2-(2-fluoro-4-sulfamoylbenzoyl)-1,3,4,6-tetrahydropyrrolo[3,4-c]pyrrole-5-carboxylic acid [3-(2,2-dimethylpropionylamino)pyridin-2-yl]methyl ester;

[6-chloro-3-(2,2-dimethylpropionylamino)pyridin-2-yl]methyl 2-(2,5-difluoro-4-sulfamoylbenzoyl)-1,3,4,6-tetrahydropyrrolo[3,4-c]pyrrole-5-carboxylate;

[6-chloro-3-(2,2-dimethylpropionylamino)pyridin-2-yl]methyl 2-(3-fluoro-4-sulfamoylbenzoyl)-1,3,4,6-tetrahydropyrrolo[3,4-c]pyrrole-5-carboxylate;

[6-chloro-3-(2,2-dimethylpropionylamino)pyridin-2-yl]methyl 2-(2,3-difluoro-4-sulfamoylbenzoyl)-1,3,4,6-tetrahydropyrrolo[3,4-c]pyrrole-5-carboxylate;

[6-chloro-3-(2,2-dimethylpropionylamino)pyridin-2-yl]methyl 2-(2,6-difluoro-4-sulfamoylbenzoyl)-1,3,4,6-tetrahydropyrrolo[3,4-c]pyrrole-5-carboxylate;

[5-cyano-3-(2,2-dimethylpropionylamino)pyridin-2-yl]methyl 2-(2-fluoro-4-sulfamoylbenzoyl)-1,3,4,6-tetrahydropyrrolo[3,4-c]pyrrole-5-carboxylate;

2-(2,6-difluoro-4-sulfamoylbenzoyl)-1,3,4,6-tetrahydropyrrolo[3,4-c]pyrrole-5-carboxylic acid [5-cyano-3-(2,2-dimethylpropionylamino)pyridin-2-yl]methyl ester;

[5-cyano-3-(2,2-dimethylpropionylamino)pyridin-2-yl]methyl 2-(2,3-difluoro-4-sulfamoylbenzoyl)-1,3,4,6-tetrahydropyrrolo[3,4-c]pyrrole-5-carboxylate;

[5-cyano-3-(2,2-dimethylpropionylamino)pyridin-2-yl]methyl 2-(2,5-difluoro-4-sulfamoylbenzoyl)-1,3,4,6-tetrahydropyrrolo[3,4-c]pyrrole-5-carboxylate;

6-(2-fluoro-4-sulfamoylbenzoyl)-1,3,4,5,7,8-hexahydro-2,6-naphthyridine-2-carboxylic acid [3-(2,2-dimethylpropionylamino)-5-(trifluoromethyl)pyridin-2-yl]methyl ester;

2-(5-sulfamoylpyridine-2-carbonyl)-1,3,4,6-tetrahydropyrrolo[3,4-c]pyrrole-5-carboxylic acid [5-chloro-4-cyano-2-(2,2-dimethylpropionylamino)phenyl]methyl ester;

[4-(trifluoromethoxy)phenyl]methyl 6-(2-fluoro-4-sulfamoylbenzoyl)-1,3,4,5,7,8-hexahydro-2,6-naphthyridine-2-carboxylate;

[4-(trifluoromethoxy)phenyl]methyl 2-(5-sulfamoylpyridine-2-carbonyl)-1,3,4,6-tetrahydropyrrolo[3,4-c]pyrrole-5-carboxylate;

[4-(trifluoromethoxy)phenyl]methyl 2-(2-fluoro-4-sulfamoylbenzoyl)-1,3,4,6-tetrahydropyrrolo[3,4-c]pyrrole-5-carboxylate;

3-Fluoro-4-[2-[(E)-3-[4-(trifluoromethoxy)phenyl]prop-2-enoyl]-1,3,4,6-tetrahydropyrrolo[3,4-c]pyrrole-5-carbonyl]benzenesulfonamide;

6-[2-[3-[4-(trifluoromethoxy)phenyl]propionyl]-1,3,4,6-tetrahydropyrrolo[3,4-c]pyrrole-5-carbonyl]pyridine-3-sulfonamide;

3-Fluoro-4-[2-[3-[4-(trifluoromethoxy)phenyl]propionyl]-1,3,4,6-tetrahydropyrrolo[3,4-c]pyrrole-5-carbonyl]benzenesulfonamide;

6-[2-[(E)-3-[4-(trifluoromethoxy)phenyl]prop-2-enoyl]-1,3,4,6-tetrahydropyrrolo[3,4-c]pyrrole-5-carbonyl]pyridine-3-sulfonamide;

6-[2-[2-[4-(trifluoromethoxy)phenoxy]acetyl]-1,3,4,6-tetrahydropyrrolo[3,4-c]pyrrole-5-carbonyl]pyridine-3-sulfonamide;

3-Fluoro-4-[2-[2-[4-(trifluoromethoxy)phenoxy]acetyl]-1,3,4,6-tetrahydropyrrolo[3,4-c]pyrrole-5-carbonyl]benzenesulfonamide;

4-[2-[3-[4-cyano-2-[(5-methyltetrazol-2-yl)methyl]phenyl]propionyl]-1,3,4,6-tetrahydropyrrolo[3,4-c]pyrrole-5-carbonyl]-3-fluorobenzenesulfonamide;

4-[2-[3-[4-chloro-2-[(5-methyltetrazol-2-yl)methyl]phenyl]propionyl]-1,3,4,6-tetrahydropyrrolo[3,4-c]pyrrole-5-carbonyl]-3-fluorobenzenesulfonamide;

3-Fluoro-4-[2-[3-[2-[(4-methyltriazol-2-yl)methyl]-4-(trifluoromethyl)phenyl]propanoyl]-1,3,4,6-tetrahydropyrrolo[3,4-c]pyrrole-5-carbonyl]benzenesulfonamide;

3-Fluoro-4-[2-[3-[2-[(4-methyltriazol-1-yl)methyl]-4-(trifluoromethyl)phenyl]propanoyl]-1,3,4,6-tetrahydropyrrolo[3,4-c]pyrrole-5-carbonyl]benzenesulfonamide;

and pharmaceutically acceptable salts thereof.

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

[5,6-dichloro-3-(2,2-dimethylpropionylamino)pyridin-2-yl]methyl 2-(2-fluoro-4-sulfamoylbenzoyl)-1,3,4,6-tetrahydropyrrolo[3,4-c]pyrrole-5-carboxylate;

[5,6-dichloro-3-(2,2-dimethylpropionylamino)pyridin-2-yl]methyl 2-(2,3-difluoro-4-sulfamoylbenzoyl)-1,3,4,6-tetrahydropyrrolo[3,4-c]pyrrole-5-carboxylate;

[5,6-dichloro-3-(2,2-dimethylpropionylamino)pyridin-2-yl]methyl 2-(2,6-difluoro-4-sulfamoylbenzoyl)-1,3,4,6-tetrahydropyrrolo[3,4-c]pyrrole-5-carboxylate;

2-(3-Fluoro-5-sulfamoylpyridine-2-carbonyl)-1,3,4,6-tetrahydropyrrolo[3,4-c]pyrrole-5-carboxylic acid [3-(2,2-dimethylpropionylamino)-5-(trifluoromethyl)pyridin-2-yl]methyl ester;

4-[5-[2-cyclopropyl-6-(tetrahydropyran-4-ylmethoxy)pyridine-4-carbonyl]-1,3,4,6-tetrahydropyrrolo[3,4-c]pyrrole-2-carbonyl]-2,3-difluorobenzenesulfonamide;

4-[5-[2-cyclopropyl-6-[(1-methylpiperidin-4-yl)methoxy]pyridine-4-carbonyl]-1,3,4,6-tetrahydropyrrolo[3,4-c]pyrrole-2-carbonyl]-2,3-difluorobenzenesulfonamide;

[5-chloro-3-[(5-methyltetrazol-2-yl)methyl]pyridin-2-yl]methyl 2-(2-fluoro-4-sulfamoylbenzoyl)-1,3,4,6-tetrahydropyrrolo[3,4-c]pyrrole-5-carboxylate;

3-Fluoro-4-[2-[3-[3-[(5-methyltetrazol-2-yl)methyl]-5-(trifluoromethyl)pyridin-2-yl]propanoyl]-1,3,4,6-tetrahydropyrrolo[3,4-c]pyrrole-5-carbonyl]benzenesulfonamide;

5-Fluoro-6-[2-[3-[2-[(5-methyltetrazol-2-yl)methyl]-4-(trifluoromethyl)phenyl]propanoyl]-1,3,4,6-tetrahydropyrrolo[3,4-c]pyrrole-5-carbonyl]pyridine-3-sulfonamide;

[3-(2,2-dimethylpropionylamino)quinolin-2-yl]methyl 2-(2-fluoro-4-sulfamoylbenzoyl)-1,3,4,6-tetrahydropyrrolo[3,4-c]pyrrole-5-carboxylate;

[3-(2,2-dimethylpropionylamino)-5-(trifluoromethyl)pyridin-2-yl]methyl 5-(2-fluoro-4-sulfamoylphenyl)sulfonyl-1,3,4,6-tetrahydropyrrolo[3,4-c]pyrrole-2-carboxylate;

and pharmaceutically acceptable salts thereof. More particular examples of compounds of formula (I) as described herein are selected from

2-(3-chloro-4-sulfamoylbenzoyl)-1,3,4,6-tetrahydropyrrolo[3,4-c]pyrrole-5-carboxylic acid [3-(2,2-dimethylpropionylamino)-5-(trifluoromethyl)pyridin-2-yl]methyl ester;

2-(3-Fluoro-4-sulfamoylbenzoyl)-1,3,4,6-tetrahydropyrrolo[3,4-c]pyrrole-5-carboxylic acid [3-(2,2-dimethylpropionylamino)-5-(trifluoromethyl)pyridin-2-yl]methyl ester;

2-(2-fluoro-4-sulfamoylbenzoyl)-1,3,4,6-tetrahydropyrrolo[3,4-c]pyrrole-5-carboxylic acid [3-(2,2-dimethylpropionylamino)-5-(trifluoromethyl)pyridin-2-yl]methyl ester;

[5-chloro-3-(2,2-dimethylpropionylamino)pyridin-2-yl]methyl 2-(2,3-difluoro-4-sulfamoylbenzoyl)-1,3,4,6-tetrahydropyrrolo[3,4-c]pyrrole-5-carboxylate;

and pharmaceutically acceptable salts thereof.

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

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

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

For example, reaction of amine 1 with an appropriate carboxylic acid of formula ^R1 -COOH (2) affords compounds of formula (I) wherein Y is -C(O)-. The reaction is carried out in the presence of a coupling agent such as 1,1′-carbonyldiimidazole, N,N′-dicyclohexylcarbodiimide, 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride, O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluoro-phosphate, O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluoro-phosphate or bromo-tris-pyrrolidinyl-hexafluorophosphate, in an aprotic solvent such as dichloromethane, tetrahydrofuran, N,N-dimethylformamide, N-methylpyrrolidone and mixtures thereof, at a temperature of -40°C to 80°C in the presence or absence of a base such as triethylamine, diisopropylethylamine, 4-methylmorpholine and/or 4-(dimethylamino)pyridine.

Amine 1 can also be reacted with a suitable acylating agent such as an acyl chloride of formula R ¹ -COCl (3) to give a compound of formula (I) wherein Y is -C(O)-. The reaction is carried out in a solvent such as dichloromethane, tetrahydrofuran or N,N-dimethylformamide in the presence of a base such as triethylamine or 4-methylmorpholine at a temperature of 0°C to 80°C.

Alternatively, amine 1 is reacted with a suitable chloroformate of formula R1 ^- OC(O)-Cl (4) or with an imidazole-1-carboxylate of formula (3) to give compounds of formula (I) wherein Y is -OC(O)-.

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

Chloroformates 4 are commercially available or can be synthesized from the corresponding alcohols of formula ^R1 -OH by reaction with phosgene or a phosgene equivalent (eg diphosgene, triphosgene) as described in the literature.

Imidazole-1-carboxylate 5 is synthesized from the corresponding alcohol of formula R ¹ —OH by reaction with 1,1′-carbonyldiimidazole. The reaction is carried out at room temperature in a solvent such as dichloromethane, tetrahydrofuran, or acetonitrile. Typically, the imidazole-1-carboxylate 5 is not isolated but is reacted directly with amine 1 as described above.

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

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 synthesized from appropriately protected precursors 6.

Suitable protecting groups (PG) are tert-butyloxycarbonyl or benzyloxycarbonyl. Deprotection of intermediate 6 can be carried out using methods and reagents known in the art.

For example, where PG is benzyloxycarbonyl, deprotection can be carried out by hydrogenation at a pressure of 1 to 100 bar in the presence of a suitable catalyst such as palladium on activated carbon at a temperature of 20°C to 150°C in a solvent such as methanol or ethanol.

Alternatively, where PG is tert-butoxycarbonyl, deprotection can be carried out in the presence of a suitable acid, for example, hydrochloric acid or trifluoroacetic acid, in a solvent such as water, 2-propanol, dichloromethane or 1,4-dioxane at a temperature of 0 to 30°C.

Intermediates 6 can be prepared from amine precursors of general formula 7 by reaction with appropriate reagents using methods known in the art.

For example, 7 is reacted with an alkylating agent of the general formula X- ^CR6R7 - ^R2 ( ⁸ ), wherein X is a leaving group such as Cl, Br, I or _OSO2CH3 , to give 6, wherein W is ^-CR6R7- _. The reaction is carried out in a solvent such as tetrahydrofuran or N,N- ^{dimethylformamide} in the presence of a base such as triethylamine or potassium carbonate at a temperature of 0°C to 100°C.

Alternatively, for compounds of formula 6 wherein W is ^-CR6R7- , ^R6 is hydrogen, alkyl ^or cycloalkyl, and ^R7 is H, amine 7 is reacted with an aldehyde or ketone of the general formula ^R6 -C(O) ^-R2 (9) in a reductive amination reaction to afford 6. The reaction is carried out in the presence of a suitable reducing agent such as sodium borohydride or sodium triacetoxyborohydride in a solvent such as methanol, acetic acid, tetrahydrofuran, 1,2-dichloroethane or a mixture thereof at a temperature of 0°C to 50°C.

Alternatively, amine 7 is reacted with a suitable carboxylic acid of formula ^R2 -COOH (10) to provide compounds of formula 6, wherein W is -C(O)-. The reaction is carried out in the presence of a coupling agent such as 1,1′-carbonyldiimidazole, N,N′-dicyclohexylcarbodiimide, 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride, O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluoro-phosphate, O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluoro-phosphate or bromo-tris-pyrrolidinyl-hexafluorophosphate, in an aprotic solvent such as dichloromethane, tetrahydrofuran, N,N-dimethylformamide, N-methylpyrrolidone and mixtures thereof, at a temperature of -40°C to 80°C in the presence or absence of a base such as triethylamine, diisopropylethylamine, 4-methylmorpholine and/or 4-(dimethylamino)pyridine.

Alternatively, amine 7 is reacted with a suitable sulfonyl chloride of formula ^R2 - _SO2Cl (11) to give a compound of formula 6, wherein W is -S( _O2 )-. The reaction is carried out in a suitable solvent such as dichloromethane, tetrahydrofuran, N,N-dimethylformamide, acetonitrile, acetone, water or a mixture thereof in the presence of a base such as triethylamine, diisopropylethylamine, pyridine, potassium bicarbonate, potassium carbonate at a temperature from 0°C to the boiling point of the solvent or solvent mixture.

Amines 7, alkylating agents 8, aldehydes/ketones 9, carboxylic acids 10, and sulfonyl chlorides 11 are commercially available or can be synthesized as described herein or in the literature.

Compounds of formula (I) can be prepared from amine precursors of general formula 12 by reaction with appropriate reagents using methods known in the art.

For example, an amine of formula 12 ^is reacted with an alkylating agent of the general formula X- ^CR6R7 - ^R2 ( ₈ ) (wherein X is a leaving group such as Cl, Br, I or _OSO2CH3 ) to give a compound of formula (I) wherein W is ^-CR6R7- . The reaction is carried out in a solvent such as tetrahydrofuran or N,N- ^{dimethylformamide} in the presence of a base such as triethylamine or potassium carbonate at a temperature of 0°C to 100°C.

Alternatively, an amine of formula 12 is reacted with an aldehyde or ketone of the general formula ^R6 -C(O) ^-R2 ( ⁹ ) in a reductive amination reaction to provide a compound of formula (I) wherein W is ^-CR6R7- , ^R6 is hydrogen, alkyl or cycloalkyl, and ^R7 is H. The reaction is carried out in the presence of a suitable reducing agent such as sodium borohydride or sodium triacetoxyborohydride in a solvent such as methanol, acetic acid, tetrahydrofuran, 1,2-dichloroethane or a mixture thereof at a temperature of 0°C to 50°C.

Alternatively, amine 12 is reacted with a suitable carboxylic acid of formula ^R2 -COOH (10) to provide compounds of formula (I) wherein W is -C(O)-. The reaction is carried out in the presence of a coupling agent such as 1,1′-carbonyldiimidazole, N,N′-dicyclohexylcarbodiimide, 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride, O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluoro-phosphate, O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluoro-phosphate or bromo-tris-pyrrolidinyl-hexafluorophosphate, in an aprotic solvent such as dichloromethane, tetrahydrofuran, N,N-dimethylformamide, N-methylpyrrolidone and mixtures thereof, at a temperature of -40°C to 80°C in the presence or absence of a base such as triethylamine, diisopropylethylamine, 4-methylmorpholine and/or 4-(dimethylamino)pyridine.

Alternatively, amine 12 is reacted with a suitable sulfonyl chloride of formula ^R2 - _SO2Cl (11) to give (I), wherein W is -S( _O2 )-. The reaction is carried out in a suitable solvent such as dichloromethane, tetrahydrofuran, N,N-dimethylformamide, acetonitrile, acetone, water or a mixture thereof in the presence of a base such as triethylamine, diisopropylethylamine, pyridine, potassium bicarbonate, potassium carbonate at a temperature from 0°C to the boiling point of the solvent or solvent mixture.

Amine 12 can be synthesized from its tert-butyl carbamate derivative of formula 13 by carbamate deprotection. The deprotection can be carried out in the presence of a suitable acid such as hydrochloric acid or trifluoroacetic acid in a solvent such as water, 2-propanol, dichloromethane or 1,4-dioxane at a temperature of 0°C to 30°C.

Tert-butyl carbamates 13 can be synthesized from amine precursors of formula 14 and appropriate reagents using methods well known in the art.

For example, reaction of amine 14 with an appropriate carboxylic acid of formula ^R1 -COOH(2) provides a compound of formula 13 wherein Y is -C(O)-. The reaction is carried out in the presence of a coupling agent such as 1,1′-carbonyldiimidazole, N,N′-dicyclohexylcarbodiimide, 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride, O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluoro-phosphate, O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluoro-phosphate or bromo-tris-pyrrolidinyl-hexafluorophosphate, in an aprotic solvent such as dichloromethane, tetrahydrofuran, N,N-dimethylformamide, N-methylpyrrolidone and mixtures thereof, at a temperature of -40°C to 80°C in the presence or absence of a base such as triethylamine, diisopropylethylamine, 4-methylmorpholine and/or 4-(dimethylamino)pyridine.

Amine 14 can also be reacted with a suitable acylating agent such as an acyl chloride of formula R ¹ -COCl (3) to provide compounds of formula 13, wherein Y is -C(O)-. The reaction is carried out in a solvent such as dichloromethane, tetrahydrofuran or N,N-dimethylformamide in the presence of a base such as triethylamine or 4-methylmorpholine at a temperature of 0°C to 80°C.

Alternatively, amine 14 is reacted with a suitable chloroformate of formula R ¹ -OC(O)-Cl(4) or with an imidazole-1-carboxylate of formula 5 to give a compound of formula 13, wherein Y is -OC(O)-. The reaction is carried out in a suitable solvent such as dichloromethane, tetrahydrofuran, N,N-dimethylformamide, acetonitrile, acetone, water or a mixture thereof in the presence of a base such as triethylamine, diisopropylethylamine, pyridine, potassium bicarbonate, potassium carbonate at a temperature from 0°C to the boiling point of the solvent or solvent mixture.

Alternatively, amine 14 can be reacted with phosgene or a phosgene equivalent (e.g., triphosgene) in the presence of a base (e.g., pyridine) in a suitable solvent such as dichloromethane at a temperature of -78°C to +20°C to give the corresponding N-chlorocarbonylamine 14A. N-chlorocarbonylamine 14A is then reacted with an alcohol of formula ^R1- OH to give a compound of formula 13, wherein Y is -OC(O)-. The reaction is carried out in a suitable solvent (e.g., acetonitrile or dichloromethane) in the presence of a suitable base (e.g., sodium hydride, pyridine, or polystyrene-bound 2-tert-butylimino-2-diethylamino-1,3-dimethylperhydro-1,3,2-diazaphosphorine) at a temperature of 20°C to the boiling point of the solvent.

Amines of formula 14 are commercially available or can be prepared as described herein or in the literature.

Additionally, an embodiment of the present invention is a process for the preparation of a compound of formula (I) as defined above, said process comprising the reaction of a compound of formula (II) in the presence of a compound of formula (III);

wherein R ¹ , R ² , m, n, p and q are as defined above and W is -C(O)-.

In particular, the reaction is carried out in the presence of a coupling agent such as 1,1′-carbonyldiimidazole, N,N′-dicyclohexylcarbodiimide, 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride, O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluoro-phosphate, O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluoro-phosphate or bromo-tris-pyrrolidinyl-hexafluorophosphate, in particular O-(7-azabenzotriazol-1-yl)-N, In the presence of N, N', N'-tetramethyluronium hexafluoro-phosphate, in an aprotic solvent such as dichloromethane, tetrahydrofuran, N, N-dimethylformamide, N-methylpyrrolidone and mixtures thereof, in particular in N, N-dimethylformamide, in the presence or absence of a base such as triethylamine, diisopropylethylamine, 4-methylmorpholine and/or 4-(dimethylamino)pyridine, in particular in the presence of 4-methylmorpholine, and at a temperature from -78 ° C to reflux, in particular from -10 ° C to room temperature.

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

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

A particular embodiment of the present invention are compounds according to formula (I) as described herein for use in the treatment or prophylaxis of eye disorders, particularly glaucoma.

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

Furthermore an object of the present invention is a method for the treatment or prevention of eye disorders, in particular glaucoma, which method comprises administering an effective amount of a compound according to formula (I) as described herein.

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

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

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

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

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

Fibrotic diseases include, but are not limited to, myocardial and vascular fibrosis, pulmonary fibrosis, cutaneous fibrosis, scleroderma, and encapsulating peritonitis.

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

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

Metabolic disorders include, but are not limited to, obesity and diabetes.

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

Determination procedure

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

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

ATX fermentation: Recombinant protein was produced by large-scale transient transfection in a 20 L controlled stirred tank bioreactor (Sartorius). During cell growth and transfection, temperature, agitation rate, pH, and dissolved oxygen concentration were maintained at 37° C., 120 rpm, 7.1, and 30% DO, respectively. FreeStyle 293-F cells (Invitrogen) were suspended in FreeStyle 293 medium (Invitrogen) and transfected with the above-mentioned plasmid DNA at approximately 1-1.5×10E6 cells/mL using X-tremeGENE Ro-1539 (trade name, Roche Diagnostics) as a complexing agent. The cells were fed with concentrated nutrient solution (J Immunol Methods 194 (1996), 19, 1-199 (page 193)) and induced with sodium butyrate (2 mM) 72 h after transfection and harvested 96 h after transfection. Expression was analyzed by Western Blot, enzyme assay, and/or analytical IMAC chromatography. After cooling the cell suspension to 4°C in a flow-through heat exchanger, cell separation and sterile filtration of the supernatant were performed by filtration through Zeta Plus 60M02 E16 (Cuno) and Sartopore 2XLG (Sartorius) filter units. The supernatant was stored at 4°C prior to purification.

ATX purification: by adding Brij 35 to a final concentration of 0.02% and by adjusting the pH to 7.0 using 1M HCl, 20 liters of culture supernatant were adjusted for ultrafiltration. Subsequently, the supernatant was first microfiltered through a 0.2 μm Ultran-Pilot Open Channel PES filter (Whatman), then concentrated to 1 liter by an Ultran-Pilot Screen Channel PES filter (Whatman) with a 30kDa MWCO. Before IMAC chromatography, _NiSO was added to a final concentration of 1mM. Subsequently, the supernatant after clarification was applied to a HisTrap _column (GE Healthcare) equilibrated in advance in 50mM Na _HPO pH 7.0, 0.5M NaCl, 10% glycerol, 0.3% CHAPS, 0.02% _NaN . The column was washed stepwise with the same buffer containing 20mM, 40mM, and 50mM imidazoles. The protein of the present invention is purified by size exclusion chromatography (SILC).The protein of the present invention is purified by size exclusion chromatography (SILC).The protein of the present invention is purified by size exclusion chromatography (SILC).The protein of the present invention is purified by size exclusion chromatography (SILC).The protein of the present invention is purified by size exclusion chromatography (SILC).The protein of the present invention is purified by size exclusion chromatography (SILC).The protein of the present invention is purified by size exclusion chromatography (SILC).The protein of the present invention is purified by size exclusion chromatography (SILC).The protein of the present invention is purified by size exclusion chromatography (SILC).The protein of the present invention is purified by size exclusion chromatography (SILC).The protein of the present invention is purified by size exclusion chromatography (SILC).The protein of the present invention is purified by size exclusion chromatography (SILC).The protein of the present invention is purified by size exclusion chromatography (SILC).The protein of the present invention is purified by size exclusion chromatography (SILC ₎ .The protein of the present invention is purified by size exclusion chromatography (SILC).The protein of the present invention is purified by size exclusion chromatography (SILC).The protein of the present invention is purified by size exclusion chromatography (SILC).The protein of the present invention is purified by size exclusion chromatography (SILC).The protein of the present invention is purified by size exclusion chromatography (SILC).The protein of the present invention is purified by size exclusion chromatography (SILC).

Human ATX enzyme inhibition assay

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

The assay working solution was prepared as follows:

Assay buffer (50 mM Tris-HCl, 140 mM NaCl, 5 mM KCl, 1 mM CaCl ₂ , 1 mM MgCl ₂ , 0.01% Triton-X-100, pH 8.0;

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

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

In 384 hole sample plates (Corning Costar#3655), obtain test compound (10mM storage, in DMSO, 8 μ L), and dilute with 8 μ L DMSO.By the cpd compound solution of 8 μ L is transferred to next row until the 0th row, carry out serial dilution line by line.Compound and control solution are mixed five times, and 2 μ L are transferred to 384 hole assay plates (Corning Costar#3702).Subsequently, add the 41.7nM ATX solution (30nM ultimate concentration) of 15 μ L, mix five times and subsequently 30 ℃ of incubations 15 minutes.Add the MR121 substrate solution (1 μ M ultimate concentration) of 10 μ L, mix 30 times, subsequently 30 ℃ of incubations 15 minutes. Fluorescence was subsequently measured every 2 minutes for 1 hour (Perkin Elmer plate: visual multimodal readout; light intensity: 2.5%; exp. time: 1.4 seconds, filter: Fluo_630/690 nm), and _IC50 values were calculated from these readings.

Human carbonic anhydrase-II inhibition assay

Human carbonic anhydrase II (hCA-II) inhibition was measured by absorbance using 4-nitrophenyl acetate (4-NPA) as its substrate. 4-NPA can be catalyzed by active hCA-II via a zinc hydroxide mechanism. The nitrophenolate in the product can be ionized to produce a bright yellow anion with high absorbance at 348 to 400 nm, as reported in the literature (Armstrong et al., J. Biol. Chem. 1966, 241, 5137-5149). OD340 nm was selected for detecting hCA II substrate conversion.

The assay working solution was prepared as follows:

Assay buffer: 50 mM MOPS, 33 mM Na ₂ SO ₄ , 1 mM EDTA, 0.5 mg/ml BSA, pH 7.5:

Enzyme solution: hCA-II (human, full length) stock solution (1.0 mg/mL in 20 mM HEPES, 50 mM NaCl, pH 7.4) diluted to 2133x final concentration in assay buffer;

4-NPA substrate solution: 4-NPA substrate stock solution (250 mM in DMSO, stored at -20°C) diluted in deionized water to 50x final concentration.

Test compounds (10 mM stock, 100 μL in DMSO) were obtained in a 96-well sample plate (Corning Costar #3655) and diluted to 0.5 mM. From column 3 to column 22, serial dilutions were performed column by column by transferring 20 μL of the compound solution to the next column. Thereafter, 1.2 μL was transferred to a 384-well assay plate (Corning Costar #3701). Subsequently, 30 μL of 16 nM hCA II solution (8 nM final concentration) was added and mixed five times. 30 μL of 4-NPA substrate solution (2.5 mM final concentration) was added and mixed five times. The absorbance at 340 nm was then directly measured as time zero. The assay plate was incubated at room temperature for 1 hour and then measured as time 1 hour (Perkin Elmer EnVision 2103; filter: Photometric340; light intensity 60%; number of flashes: 10). IC ₅₀ values and K _i values were calculated from these readouts.

The compounds of formula (I) and pharmaceutically acceptable salts or esters thereof as described herein have IC ₅₀ values of 0.00001 μM to 1000 μM, particular compounds have IC ₅₀ values of 0.0005 μM to 500 μM, further particular compounds have IC ₅₀ values of 0.0005 μM to 50 μM, and even more particular compounds have IC ₅₀ values of 0.0005 μM to 5 μM. These results have been obtained using the above enzyme assay.

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

The compounds of formula (I) and pharmaceutically acceptable salts thereof can be processed together with pharmaceutically inert, inorganic or organic adjuvants for the preparation of tablets, coated tablets, dragees, hard gelatin capsules, injections or topical preparations. For example, lactose, corn starch or derivatives thereof, talcum, stearic acid or salts thereof can be used as such adjuvants for tablets, dragees and hard gelatin capsules.

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

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

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

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

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

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

Dosage can vary over a wide range, and certainly will be suitable for the individual needs in each particular case.Usually, in the case of oral administration, every kg body weight is about 0.1mg to 20mg, preferably every kg body weight is about 0.5mg to 4mg (such as every people's about 300mg) daily dosage, preferably divided into 1-3 can be such as by the single dosage of same amount, this should be suitable for.In the case of topical administration, preparation can include 0.001 % by weight to 15 % by weight of medicine, and required dosage (can be 0.1 to 25mg) can be by every day or weekly single dose administration, or by daily multiple dose (2 to 4) administration, or by weekly multiple dose administration.However, it will be clear that, when clearly indicated, the upper limit or lower limit provided herein can be exceeded.

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

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

Example

If not stated otherwise, all examples and intermediates were prepared under nitrogen atmosphere.

Abbreviations: aq. = aqueous; CAS-RN = Chemical Abstracts Service registration number; HPLC = high performance liquid chromatography; MS = mass spectrometry; sat. = saturated

Example 1

2-(4-sulfamoylbenzoyl)-1,3,4,6-tetrahydropyrrolo[3,4-c]pyrrole-5-carboxylic acid [3-(2,2-dimethylpropionylamino)-5-(trifluoromethyl)pyridin-2-yl]methyl ester

To a solution of (3-pivaloylamino-5-(trifluoromethyl)pyridin-2-yl)methyl 3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate dihydrochloride (Intermediate 4; 50 mg, 92.7 μmol), 4-methylmorpholine (46.9 mg, 464 μmol) and 4-sulfamoylbenzoic acid (CAS-RN 138-41-0; 19.4 mg, 92.7 μmol) in N,N-dimethylformamide (3 mL) was added O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluoro-phosphate (35.3 mg, 92.7 μmol). The clear, dark brown solution was stirred at room temperature for 18 h and then partitioned between saturated aqueous sodium bicarbonate solution and ethyl acetate/2-methyltetrahydrofuran 4:1. The organic layer was washed with saturated aqueous ammonium chloride solution and brine, dried over magnesium sulfate, filtered and evaporated. Chromatography (silica gel; gradient from dichloromethane to dichloromethane/methanol/25% aqueous ammonia solution 90:10:0.25) afforded the title compound (41 mg, 74%). Pale yellow foam, MS: 596.2 (M+H) ⁺ .

The following examples were prepared analogously to Example 1, substituting the appropriate amine for (3-pivaloylamino-5-(trifluoromethyl)pyridin-2-yl)methyl 3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate dihydrochloride (Intermediate 4) and substituting the appropriate carboxylic acid for 4-sulfamoylbenzoic acid.

Example 2

2-(5-sulfamoylpyridine-2-carbonyl)-1,3,4,6-tetrahydropyrrolo[3,4-c]pyrrole-5-carboxylic acid [5-chloro-4-cyano-2-(2,2-dimethylpropionylamino)phenyl]methyl ester

To a clear, colorless solution of N-(4-chloro-5-cyano-2-(hydroxymethyl)phenyl)pivalamide (Intermediate 6; 35 mg, 131 μmol) was added 1,1′-carbonyldiimidazole (21.3 mg, 131 μmol) at room temperature. After 90 min, the reaction mixture was heated at 50° C. for 30 min, then allowed to cool to room temperature, followed by the addition of 6-(1,2,3,4,5,6-hexahydropyrrolo[3,4-c]pyrrole-2-carbonyl)pyridine-3-sulfonamide dihydrochloride (Intermediate 5.01; 48.2 mg, 131 μmol) and triethylamine (66.4 mg, 656 μmol). The reaction was heated at reflux for 18 h, then partitioned between ethyl acetate and saturated aqueous ammonium chloride. The organic layer was washed with saturated aqueous sodium bicarbonate and brine, dried over magnesium sulfate, filtered, and evaporated. The residue was triturated in dichloromethane and the precipitate was collected by filtration to give the title compound (41 mg, 53%) as a white solid, MS: 585.2 (MH) ⁻ .

The following examples were prepared analogously to Example 2, substituting the appropriate amine for 6-(1,2,3,4,5,6-hexahydropyrrolo[3,4-c]pyrrole-2-carbonyl)pyridine-3-sulfonamide dihydrochloride (Intermediate 5.01) and the appropriate alcohol for N-(4-chloro-5-cyano-2-(hydroxymethyl)phenyl)pivalamide (Intermediate 6).

Example 3

3-Fluoro-4-[2-[(E)-3-[4-(trifluoromethoxy)phenyl]prop-2-enoyl]-1,3,4,6-tetrahydropyrrolo[3,4-c]pyrrole-5-carbonyl]benzenesulfonamide

To a clear brown solution of 3-fluoro-4-(1,2,3,4,5,6-hexahydropyrrolo[3,4-c]pyrrole-2-carbonyl)benzenesulfonamide dihydrochloride (Intermediate 5; 51.9 mg, 135 μmol), (E)-3-(4-(trifluoromethoxy)phenyl)acrylic acid (CAS-RN 199679-35-1; 31.4 mg, 135 μmol) and 4-methylmorpholine (68.3 mg, 675 μmol) in N,N-dimethylformamide (4 mL) was added O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluoro-phosphate (51.4 mg, 135 μmol) and after 18 h the reaction mixture was partitioned between saturated aqueous sodium bicarbonate solution and ethyl acetate/2-methyltetrahydrofuran 4:1. The organic layer was washed with saturated aqueous ammonium chloride solution and brine, dried over magnesium sulfate, filtered and evaporated. The residue was triturated with ethyl acetate/heptane and the precipitate was collected by filtration to give the title compound (45 mg, 63%). White solid, MS: 524.2 (MH) ^- .

The following examples were prepared analogously to Example 3, substituting the appropriate amine for 3-fluoro-4-(1,2,3,4,5,6-hexahydropyrrolo[3,4-c]pyrrole-2-carbonyl)benzenesulfonamide dihydrochloride (Intermediate 5) and the appropriate carboxylic acid for (E)-3-(4-(trifluoromethoxy)phenyl)acrylic acid (CAS-RN 199679-35-1).

Example 4

5-Fluoro-6-[2-[3-[2-[(5-methyltetrazol-2-yl)methyl]-4-(trifluoromethyl)phenyl]propionyl]-1,3,4,6-tetrahydropyrrolo[3,4-c]pyrrole-5-carbonyl]pyridine-3-sulfonamide

Trifluoroacetic acid (199 mg, 1.75 mmol) was added to a solution of tert-butyl 5-(3-fluoro-5-sulfamoylpyridinyl)-3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (Intermediate 12; 36 mg, 87.3 μmol) in dichloromethane (3 mL). The reaction mixture was stirred at 40° C. for 2 h. The mixture was then evaporated directly, and the residue was combined with N,N-dimethylformamide (3 mL) and N-methylmorpholine (88.3 mg, 873 μmol), 3-(2-((5-methyl-2H-tetrazol-2-yl)methyl)-4-(trifluoromethyl)phenyl)propanoic acid (Intermediate 8; 27.4 mg, 87.3 μmol), and finally O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluoro-phosphate (36.5 mg, 96 μmol). The mixture was stirred at room temperature for 18 h and then partitioned between saturated aqueous ammonium chloride solution and ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and evaporated. Chromatography (silica gel; gradient from dichloromethane to dichloromethane/methanol/25% aqueous ammonia solution 90:10:0.25) gave the title compound (34 mg, 64%). White solid, MS: 609.2 (M+H) ⁺ .

The following examples were prepared analogously to Example 4, substituting the appropriate carbamate for tert-butyl 5-(3-fluoro-5-sulfamoylpicolinoyl)-3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (Intermediate 12) and substituting the appropriate carboxylic acid for 3-(2-((5-methyl-2H-tetrazol-2-yl)methyl)-4-(trifluoromethyl)phenyl)propanoic acid (Intermediate 8).

Example 5

5-(2-Fluoro-4-sulfamoylphenyl)sulfonyl-1,3,4,6-tetrahydropyrrolo[3,4-c]pyrrole-2-carboxylic acid [3-(2,2-dimethylpropionylamino)-5-(trifluoromethyl)pyridin-2-yl]methyl ester

To a solution of (3-pivaloylamino-5-(trifluoromethyl)pyridin-2-yl)methyl 3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate dihydrochloride (Intermediate 4; 60 mg, 134 μmol) and pyridine (106 mg, 1.34 mmol) in tetrahydrofuran (2 mL) was added a solution of 2-fluoro-4-sulfamoylbenzene-1-sulfonyl chloride (CAS-RN 52295-72-4; 72.3 mg, 240 μmol) in tetrahydrofuran (2 mL). After stirring at 50° C. for 48 h, the reaction mixture was partitioned between saturated aqueous ammonium chloride and ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and evaporated. Chromatography (silica gel; gradient of ethyl acetate/heptane 1:1 to 4:1) afforded the title compound (42 mg, 48%). White solid, MS: 650.2 (M+H) ⁺ .

intermediates

Intermediate 1

4-(Trifluoromethoxy)benzyl 3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate hydrochloride

Step 1: 2-tert-Butyl 4,6-dihydropyrrolo[3,4-c]pyrrole-2,5(1H,3H)-dicarboxylate 5-(4-(trifluoromethyl) 2-(2-(2-oxy)benzyl)ester

To a solution of [4-(trifluoromethoxy)phenyl]methanol (CAS-RN 1736-74-9; 233 mg, 1.21 mmol) in acetonitrile (10 mL) was added 1,1′-carbonyldiimidazole (197 mg, 1.21 mmol). The reaction was heated at 50° C. for 3 h, then triethylamine (736 mg, 7.28 mmol) and tert-butyl 3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate hydrochloride (CAS-RN 1208929-16-1; 315 mg, 1.21 mmol) were added, and the reaction mixture was heated at reflux for an additional 15 h. After cooling, the reaction mixture was partitioned between ethyl acetate and saturated aqueous ammonium chloride. The organic layer was washed with saturated aqueous sodium bicarbonate and brine, dried over magnesium sulfate, filtered, and evaporated. Chromatography (silica gel; gradient dichloromethane to dichloromethane/methanol/25% aqueous ammonia solution 95:5:0.25%) afforded the title compound (458 mg, 88%) as a brown semisolid, MS: 446.1 (M+ _NH4 ) ⁺ .

Step 2: 4-(Trifluoromethoxy)benzyl 3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate hydrochloride Salt

To a brown solution of 2-tert-butyl 4,6-dihydropyrrolo[3,4-c]pyrrole-2,5(1H,3H)-dicarboxylate 5-(4-(trifluoromethoxy)benzyl) ester (452 mg, 1.06 mmol) in 2-propanol (3 mL) was added a solution of hydrochloric acid (5-6 M in 2-propanol, 5.91 mL, 29.5 mmol). The solution was stirred for 16 h and then concentrated in vacuo. The residue was triturated in tert-butyl methyl ether and the precipitate was collected by filtration to yield the title compound (350 mg, 91%). Pale brown solid, MS: 329.1 (M+H) ⁺ .

Intermediate 2

[2-Cyclopropyl-6-(tetrahydropyran-4-ylmethoxy)pyridin-4-yl]-(2,3,4,6-tetrahydro-1H-pyrrolo[3,4-c]pyrrol-5-yl)methanone

Step 1: 5-(6-cyclopropyl-2-oxo-1,2-dihydropyridine-4-carbonyl)-3,4,5,6-tetrahydropyrrolo[3,4- c] tert-Butyl pyrrole-2(1H)-carboxylate

To tert-butyl 3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate hydrochloride (CAS-RN 1208929-16-1; 300 mg, 1.16 mmol) in N,N-dimethylformamide (5 mL) was added 4-methylmorpholine (584 mg, 5.78 mmol), 6-cyclopropyl-2-oxo-1,2-dihydropyridine-4-carboxylic acid (CAS-RN 150190-28-6; 218 mg, 1.16 mmol) and O-(7-azabenzotriazole-1-yl)-N,N,N',N'-tetramethyluronium hexafluoro-phosphate (483 mg, 1.27 mmol). The reaction mixture was stirred for 18 h and then distributed between saturated aqueous ammonium chloride solution and ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, filtered and evaporated. Chromatography (silica gel, gradient dichloromethane to dichloromethane/methanol/25% aqueous ammonia solution 90:10:0.25) gave the title compound (390 mg, 86%) as a white foam, MS: 372.2 (M+H) ^<+ >.

Step 2: 5-(2-cyclopropyl-6-((tetrahydro-2H-pyran-4-yl)methoxy)isonicotinoyl)-3,4,5,6-tetrahydro Tert-Butyl pyrrolo[3,4-c]pyrrole-2(1H)-carboxylate

A mixture of tert-butyl 5-(6-cyclopropyl-2-oxo-1,2-dihydropyridine-4-carbonyl)-3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (385 mg, 985 μmol), potassium carbonate (272 mg, 1.97 mmol), and 4-(iodomethyl)tetrahydro-2H-pyran (459 mg, 1.97 mmol) in acetonitrile (8 mL) was heated at 90° C. for 48 h, then partitioned between saturated aqueous ammonium chloride and ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and evaporated. The residue was chromatographed (silica gel; gradient from dichloromethane to dichloromethane/methanol/25% aqueous ammonia solution 95:5:0.25) to yield the title compound (390 mg, 84%). White foam, MS: 470.3 (M+H) ⁺ .

Step 3: [2-Cyclopropyl-6-(tetrahydropyran-4-ylmethoxy)pyridin-4-yl]-(2,3,4,6-tetrahydro-1H-pyridin- Pyrrol[3,4-c]pyrrol-5-yl)methanone

Trifluoroacetic acid (1.41 g, 12.3 mmol) was added to a solution of tert-butyl 5-(2-cyclopropyl-6-((tetrahydro-2H-pyran-4-yl)methoxy)isonicotinoyl)-3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (386 mg, 822 μmol) in dichloromethane (8 mL) at room temperature. After 5 h, the solution was concentrated and the residue partitioned between dichloromethane and 2 M aqueous sodium hydroxide solution. The organic phase was washed with brine, dried over magnesium sulfate, filtered, and evaporated to yield the title compound (298 mg, 98%). Off-white foam, MS: 370.2 (M+H) ⁺ .

Intermediate 2.01

[2-Cyclopropyl-6-[(1-methylpiperidin-4-yl)methoxy]pyridin-4-yl]-(2,3,4,6-tetrahydro-1H-pyrrolo[3,4-c]pyrrol-5-yl)methanone

The title compound was prepared analogously to Intermediate 2, substituting 4-(bromomethyl)-1-methylpiperidine hydrobromide (CAS-RN 98338-26-2) for 4-(iodomethyl)tetrahydro-2H-pyran. Yellow oil, MS: 383.3 (M+H) ⁺ .

Intermediate 3

3-[2-[(5-methyltetrazol-2-yl)methyl]-4-(trifluoromethyl)phenyl]-1-(2,3,4,6-tetrahydro-1H-pyrrolo[3,4-c]pyrrol-5-yl)propan-1-one

Step 1: 5-(3-(2-((5-methyl-2H-tetrazol-2-yl)methyl)-4-(trifluoromethyl)phenyl)propanoyl)-3-(4-(trifluoromethyl)phenyl)-1-(4-(trifluoromethyl)phenyl)propanoyl)-2-(4-(trifluoromethyl)phenyl)propanoyl)-3-(trifluoromethyl)phenyl)propanoyl)-2 ... tert-Butyl 4,5,6-tetrahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate

The title compound was prepared analogously to Intermediate 2, Step 1, substituting 3-(2-((5-methyl-2H-tetrazol-2-yl)methyl)-4-(trifluoromethyl)phenyl)propanoic acid (Intermediate 8) for 6-cyclopropyl-2-oxo-1,2-dihydropyridine-4-carboxylic acid. Pale yellow gum, MS: 505.4 (MH) ⁻ .

Step 2: 3-[2-[(5-methyltetrazol-2-yl)methyl]-4-(trifluoromethyl)phenyl]-1-(2,3,4,6-tetrahydro- 1H-pyrrolo[3,4-c]pyrrol-5-yl)propan-1-one

Trifluoroacetic acid (1.84 g, 16.1 mmol) was added to a solution of tert-butyl 5-(3-(2-((5-methyl-2H-tetrazol-2-yl)methyl)-4-(trifluoromethyl)phenyl)propanoyl)-3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (573 mg, 1.07 mmol) in dichloromethane (5 mL) at room temperature, and after 4 h the reaction mixture was concentrated in vacuo. The residue was taken up in dichloromethane, washed with 2M aqueous sodium hydroxide solution, dried over magnesium sulfate, filtered and evaporated. Chromatography (silica gel; gradient of dichloromethane/methanol/25% aqueous ammonia solution 95:5:0.25 to 90:10:0.25) gave the title compound (344 mg, 79%). Pale yellow foam, MS: 407.2 (M+H) ⁺ .

Intermediate 4

3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylic acid (3-pivaloylamino-5-(trifluoromethyl)pyridin-2-yl)methyl ester hydrochloride

Step 1: tert-Butyl 5-(chlorocarbonyl)-3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate

To a pale brown mixture of tert-butyl 3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate hydrochloride (CAS-RN 1208929-16-1; 800 mg, 3.08 mmol) and pyridine (1.34 g, 16.9 mmol) in dichloromethane (12 mL) was added dropwise a solution of triphosgene (411 mg, 1.39 mmol) in dichloromethane (7 mL) at 0°C. The ice bath was removed after 30 min, and after 1 h, the reaction mixture was partitioned between 1 M aqueous hydrochloric acid solution and dichloromethane. The organic layer was washed with water and brine, dried over magnesium sulfate, filtered and evaporated to give the title compound (844 mg, 100%). Yellow solid, MS: 217.0 (M+H-isobutylene) ^.

Step 2: 2-tert-Butyl 4,6-dihydropyrrolo[3,4-c]pyrrole-2,5(1H,3H)-dicarboxylate 5-(3-pivaloyl) amino-5-(trifluoromethyl)pyridin-2-yl)methyl)ester

To a solution of tert-butyl 5-(chlorocarbonyl)-3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (834 mg, 3.06 mmol) in acetonitrile (60 mL) was added N-(2-(hydroxymethyl)-5-(trifluoromethyl)pyridin-3-yl)pivalamide (Intermediate 14; 650 mg, 2.35 mmol) and PS-BEMP (CAS-RN 1446424-86-7; 2.58 g). The orange suspension was heated to reflux and stirred for 68 h. The insoluble solid was filtered off and washed with acetonitrile. PS-Trisamine (CAS-RN 1226492-10-9; 860 mg, 2.35 mmol) was added to the filtrate and the reaction mixture was stirred at room temperature for 4 h, after which the insoluble material was removed by filtration and the filtrate was evaporated. Chromatography (silica gel; gradient dichloromethane to dichloromethane/methanol/25% aqueous ammonia solution 95:5:0.25) afforded the title compound (935 mg, 78%) as a pale yellow foam, MS: 513.2 (M+H) ⁺ .

Step 3: 3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylic acid (3-pivaloylamino-5-(trifluoromethyl) 2-Methyl-1,2-pyridin-2-yl)methyl ester hydrochloride

To a pale yellow solution of 2-tert-butyl 4,6-dihydropyrrolo[3,4-c]pyrrole-2,5(1H,3H)-dicarboxylate 5-((3-pivaloylamino-5-(trifluoromethyl)pyridin-2-yl)methyl) ester (925 mg, 1.80 mmol) in 2-propanol (5 mL) was added hydrochloric acid (5-6 M in 2-propanol, 10.1 mL, 50.5 mmol) at room temperature, then after 14 h the solution was evaporated and the residue was triturated in tert-butyl methyl ether. The precipitate was collected by filtration to give the title compound (762 mg, 94%). Pale brown solid, MS: 411.3 (MH) ^- .

The following intermediates were prepared analogously to Intermediate 4, substituting the appropriate amine for tert-butyl 3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate hydrochloride (CAS-RN 1208929-16-1) and the appropriate alcohol for N-(2-(hydroxymethyl)-5-(trifluoromethyl)pyridin-3-yl)pivalamide (Intermediate 14).

Intermediate 5

3-Fluoro-4-(1,2,3,4,5,6-hexahydropyrrolo[3,4-c]pyrrole-2-carbonyl)benzenesulfonamide dihydrochloride

Step 1: 5-(2-Fluoro-4-sulfamoylbenzoyl)-3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrole-2 (1H)-tert-Butyl formate

O-(7-Azatriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluoro-phosphate (623 mg, 1.64 mmol) was added to a solution of tert-butyl 3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate hydrochloride (CAS-RN 1208929-16-1; 404 mg, 1.64 mmol), 2-fluoro-4-sulfamoylbenzoic acid (CAS-RN 714968-42-0; 359 mg, 1.64 mmol) and 4-methylmorpholine (828 mg, 8.19 mmol) in N,N-dimethylformamide (10 mL) at 0° C. The ice bath was removed after 10 min and, after 16 h, the reaction mixture was partitioned between saturated aqueous sodium bicarbonate solution and ethyl acetate/2-methyltetrahydrofuran 4:1. The organic layer was washed with saturated aqueous ammonium chloride and brine, dried over magnesium sulfate, filtered, and evaporated. Chromatography (silica gel; ethyl acetate to methanol gradient) afforded the title compound (555 mg, 82%) as a pale yellow solid. MS: 412.1 (M+H) ⁺ .

Step 2: 3-Fluoro-4-(1,2,3,4,5,6-hexahydropyrrolo[3,4-c]pyrrole-2-carbonyl)benzenesulfonamide dihydrochloride Salt

To a solution of tert-butyl 5-(2-fluoro-4-sulfamoylbenzoyl)-3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (570 mg, 1.39 mmol) in 2-propanol (4 mL) was added hydrochloric acid solution (5M-6M in 2-propanol, 6.1 mL, 30.5 mmol) at room temperature, and after 18 h the reaction mixture was concentrated under vacuum to yield the title compound (448 mg, 84%) as a pale red solid, MS: 310.1 (MH) ⁻ .

The following intermediates were prepared analogously to Intermediate 5, substituting the appropriate amine for tert-butyl 3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate hydrochloride and the appropriate carboxylic acid for 2-fluoro-4-sulfamoylbenzoic acid.

Intermediate 6

N-(4-chloro-5-cyano-2-(hydroxymethyl)phenyl)pivalamide

Step 1: Methyl 4-bromo-5-chloro-2-(2,2-dimethylpropionylamino)benzoate

To a brown solution of methyl 2-amino-4-bromo-5-chlorobenzoate (CAS-RN 1445322-56-4; 311 mg, 1.06 mmol) in pyridine (4 mL) was added pivaloyl chloride (215 mg, 1.74 mmol) at 0°C. The ice bath was removed after 20 min. After stirring for an additional 3 h at 50°C, the reaction mixture was partitioned between 1 M aqueous hydrochloric acid solution and ethyl acetate. The organic layer was washed with water and brine, dried over magnesium sulfate, filtered and evaporated. Chromatography (silica gel; gradient of dichloromethane/heptane 3:7 to 1:1) gave the title compound (279 mg, 76%). White solid, MS: 350.1 (M+H) ⁺ .

Step 2: Methyl 5-chloro-4-cyano-2-(2,2-dimethylpropionylamino)benzoate

A mixture of methyl 4-bromo-5-chloro-2-(2,2-dimethylpropionylamino)benzoate (274 mg, 786 μmol), tris(dibenzylideneacetone)dipalladium(0) (CAS-RN 51364-51-3; 7.2 mg, 7.86 μmol), 1,1′-bis(diphenylphosphino)ferrocene (CAS-RN 12150-46-8; 13.1 mg, 23.6 μmol), zinc cyanide (50.8 mg, 432 μmol), zinc powder (2.06 mg, 31.4 μmol) and zinc acetate (5.77 mg, 31.4 μmol) in N,N-dimethylformamide (8 mL) and water (50 μL) was heated at 130° C. under microwave irradiation for 20 min. After removing the insoluble material under vacuum and concentrating the filtrate, the residue was partitioned between 50% aqueous sodium bicarbonate solution and ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, filtered and evaporated. Chromatography (silica gel; gradient from heptane to dichloromethane) gave the title compound (213 mg, 92%). Pale yellow solid, 295.0 (M+H) ⁺ .

Step 3: N-(4-chloro-5-cyano-2-(hydroxymethyl)phenyl)pivalamide

To a solution of methyl 5-chloro-4-cyano-2-pivalamidobenzoate (204 mg, 692 μmol) in tetrahydrofuran (5 mL) was added a solution of calcium chloride (154 mg, 1.38 mmol) in ethanol (5 mL), followed by the addition of sodium borohydride (105 mg, 2.77 mmol) in three portions over a period of 30 min. The white suspension was stirred at room temperature for 90 min and then partitioned between ethyl acetate and saturated aqueous ammonium chloride. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and evaporated. Chromatography (silica gel; gradient of heptane/ethyl acetate 4:1 to 1:1) afforded the title compound (153 mg, 83%). As a white solid, MS: 267.2 (M+H) ⁺ .

Intermediate 6.01

N-(5-cyano-2-(hydroxymethyl)pyridin-3-yl)pivalamide

The title compound was prepared in analogy to Example 6, substituting methyl 3-amino-5-bromopicolinate (CAS-RN 1072448-08-8) for methyl 2-amino-4-bromo-5-chlorobenzoate (CAS-RN 1445322-56-4). Pale yellow solid, MS: 234.2 (M+H) ⁺ .

Intermediate 7

2,5-Difluoro-4-sulfamoylbenzoic acid

To a stirred suspension of 2,5-difluoro-4-methylbenzenesulfonamide (CAS-RN 1204573-30-7; 500 mg, 2.29 mmol) in water (25 mL) was added potassium permanganate (1.63 g, 10.3 mmol) portionwise under reflux over 2 h. The reaction mixture was stirred for another 30 min under reflux, then cooled and stirred for another 24 h at room temperature. After removing insoluble material by filtration, the filtrate was acidified to pH 1 with 37% aqueous hydrochloric acid solution and extracted several times with ethyl acetate. The combined organic layers were dried over magnesium sulfate and evaporated to dryness to obtain the title compound (394 mg, 65%). White solid, MS: 236.0 (MH) ^- .

The following intermediates were prepared analogously to Intermediate 7, substituting the appropriate starting materials for 2,5-difluoro-4-methylbenzenesulfonamide.

Intermediate 8

3-(2-((5-methyl-2H-tetrazol-2-yl)methyl)-4-(trifluoromethyl)phenyl)propanoic acid

Step 1: 2-(2-Bromo-5-(trifluoromethyl)benzyl)-5-methyl-2H-tetrazolyl

A mixture of 5-methyl-2H-tetrazole (CAS-RN 4076-36-2; 1.50 g, 17.5 mmol), potassium carbonate (2.42 g, 17.5 mmol), and 1-bromo-2-(bromomethyl)-4-(trifluoromethyl)benzene (CAS-RN 886496-63-5; 5.73 g, 17.5 mmol) in acetone (75 mL) was heated under reflux for 1 h. After cooling, the reaction mixture was partitioned between ice water and ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and evaporated in vacuo. Chromatography (silica gel; gradient from heptane to ethyl acetate) yielded the title compound (2.62 g, 46%). It was a colorless oil, MS: 321.0 (M+H) ⁺ .

Step 2: Ethyl (E)-3-(2-((5-methyl-2H-tetrazol-2-yl)methyl)-4-(trifluoromethyl)phenyl)acrylate ester

To a colorless solution of 2-(2-bromo-5-(trifluoromethyl)benzyl)-5-methyl-2H-tetrazole (2.62 g, 8.16 mmol) in N,N-dimethylformamide (32 mL) was added triethylamine (2.48 g, 24.5 mmol), ethyl acrylate (990 mg, 9.79 mmol), palladium(II) acetate (36.6 mg, 163 μmol), and tri-o-tolylphosphine (CAS-RN 6163-58-2; 199 mg, 653 μmol). The pale yellow reaction mixture was evacuated and backfilled with argon. After stirring at 120° C. for 17 h, the mixture was partitioned between saturated aqueous ammonium chloride solution and ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and evaporated. Chromatography (silica gel; gradient from heptane to ethyl acetate) produced the title compound (2.48 g, 89%). White solid, MS: 341.1 (M+H) ⁺ .

Step 3: Ethyl 3-(2-((5-methyl-2H-tetrazol-2-yl)methyl)-4-(trifluoromethyl)phenyl)propanoate

A solution of (E)-ethyl 3-(2-((5-methyl-2H-tetrazol-2-yl)methyl)-4-(trifluoromethyl)phenyl)-acrylate (2.60 g, 7.64 mmol) in ethanol (32 mL) was stirred under a hydrogen atmosphere (1 bar) in the presence of palladium (10% on activated carbon; 407 mg, 382 μmol). After 18 h, the insoluble material was removed by filtration through celite, and the filtrate was evaporated to yield the title compound (2.30 g, 88%). Gray oil, MS: 343.1 (M+H) ⁺ .

Step 4: 3-(2-((5-methyl-2H-tetrazol-2-yl)methyl)-4-(trifluoromethyl)phenyl)propanoic acid

To a solution of ethyl 3-(2-((5-methyl-2H-tetrazol-2-yl)methyl)-4-(trifluoromethyl)phenyl)-propionate (2.3 g, 6.72 mmol) in tetrahydrofuran (25 mL) and water (25 mL) was added lithium hydroxide monohydrate (564 mg, 13.4 mmol), and the resulting mixture was stirred at room temperature for 18 h, then partially evaporated to remove tetrahydrofuran. The aqueous phase was acidified to pH 1 with 1 M aqueous hydrochloric acid solution and extracted several times with ethyl acetate. The combined organic layers were dried over magnesium sulfate, filtered, and evaporated to generate the title compound (2.21 g, quantitative). Pale yellow oil, MS: 313.2 (MH) ^- .

The following intermediates were prepared analogously to Intermediate 8, substituting the appropriate halide and oxazole for 1-bromo-2-(bromomethyl)-4-(trifluoromethyl)benzene (CAS-RN 886496-63-5) and 5-methyl-2H-tetrazole, respectively.

Intermediate 9

3-[2-[(4-Methyltriazol-1-yl)methyl]-4-(trifluoromethyl)phenyl]propanoic acid

Step 1: 2-(Azidomethyl)-1-bromo-4-(trifluoromethyl)benzene

To a clear, colorless solution of 1-bromo-2-(bromomethyl)-4-(trifluoromethyl)benzene (CAS-RN 886496-63-5; 1.016 g, 3.20 mmol) in N,N-dimethylformamide (20 mL) was added sodium azide (229 mg, 3.52 mmol). The reaction mixture was stirred at 120° C. for 24 h and then concentrated under vacuum. The residue was partitioned between saturated aqueous sodium bicarbonate solution and ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and evaporated. Chromatography (silica gel; gradient from heptane to dichloromethane) afforded the title compound (520 mg, 58%). Colorless liquid, MS: 281.0 (M+H) ⁺ .

Step 2: 1-[[2-Bromo-5-(trifluoromethyl)phenyl]methyl]-4-methyltriazole

A mixture of 2-(azidomethyl)-1-bromo-4-(trifluoromethyl)benzene (591 mg, 2.11 mmol), 1-(trimethylsilyl)-1-propyne (222 mg, 295 μl, 1.92 mmol), copper (I) bromide (41.3 mg, 288 μmol), and triethylamine (194 mg, 267 μl, 1.92 mmol) in N,N-dimethylformamide (5 mL) was heated at 100° C. under microwave irradiation for 30 min. After cooling, the reaction mixture was partitioned between saturated aqueous ammonium chloride solution and ethyl acetate. The organic layer was washed with water and brine, dried over magnesium sulfate, filtered, and evaporated. Chromatography (silica gel; gradient of dichloromethane/heptane 1:4 to dichloromethane then to dichloromethane/methanol/25% aqueous ammonia solution 90:10:0.25) produced the title compound (214 mg, 35%). Dark brown oil, MS: 322.1 (M+H) ⁺ .

Step 3: Ethyl (E)-3-[2-[(4-methyltriazol-1-yl)methyl]-4-(trifluoromethyl)phenyl]prop-2-enoate

The title compound was prepared in analogy to Intermediate 8, Step 2, from 1-(2-bromo-5-(trifluoromethyl)benzyl)-4-methyl-1H-1,2,3-triazole. Dark brown solid, MS: 340.2 (M+H) ⁺ .

Step 4: Ethyl 3-[2-[(4-methyltriazol-1-yl)methyl]-4-(trifluoromethyl)phenyl]propanoate

The title compound was prepared in analogy to Intermediate 8, Step 3, from ethyl (E)-3-[2-[(4-methyltriazol-1-yl)methyl]-4-(trifluoromethyl)phenyl]prop-2-enoate using methanol. Brown oil, MS: 342.2 (M+H) ⁺ .

Step 5: 3-[2-[(4-Methyltriazol-1-yl)methyl]-4-(trifluoromethyl)phenyl]propanoic acid

The title compound was prepared in analogy to Intermediate 8, Step 4, from ethyl 3-[2-[(4-methyltriazol-1-yl)methyl]-4-(trifluoromethyl)phenyl]propanoate. White solid, MS: 314.2 (M+H) ⁺ .

Intermediate 10

[5-Chloro-3-[(5-methyltetrazol-2-yl)methyl]pyridin-2-yl]methanol

Step 1: Methyl 5-chloro-3-[(5-methyltetrazol-2-yl)methyl]pyridine-2-carboxylate

The title compound was prepared in analogy to Intermediate 8, Step 1, from 3-(bromomethyl)-5-chloro-pyridine-2-carboxylic acid methyl ester (CAS-RN 1260667-62-6). White solid, MS: 268.1 (M+H) ⁺ .

Step 2: [5-Chloro-3-[(5-methyltetrazol-2-yl)methyl]pyridin-2-yl]methanol

The title compound was prepared in analogy to Intermediate 6, Step 3, from methyl 5-chloro-3-[(5-methyltetrazol-2-yl)methyl]pyridine-2-carboxylate. Off-white semisolid, MS: 240.1 (M+H) ⁺ .

Intermediate 11

3-Fluoro-5-sulfamoylpyridine-2-carboxylic acid

Step 1: N′-[(6-chloro-5-fluoro-3-pyridinyl)sulfonyl]-N,N-dimethyl-formamidine

A solution of 1,1-dimethoxy-N,N-dimethyl-methylamine (CAS-RN 4637-24-5; 332 mg, 2.71 mmol) in acetonitrile (1 mL) was added dropwise to a stirred solution of 6-chloro-5-fluoro-pyridine-3-sulfonamide (CAS-RN 1803571-80-3; 500 mg, 2.26 mmol) and acetonitrile (4 mL). The mixture was stirred at room temperature for 1 h and then directly evaporated under high vacuum to give the title compound (600 mg, quantitative). White solid, MS: 266.1 (M+H) ⁺ .

Step 2: 5-[(E)-Dimethylaminomethyleneamino]sulfonyl-3-fluoro-pyridine-2-carboxylic acid ethyl ester

A mixture of N′-[(6-chloro-5-fluoro-3-pyridyl)sulfonyl]-N,N-dimethylformamidine (150 mg, 565 μmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II) dichloromethane complex (CAS-RN 95464-05-4; 55.3 mg, 67.7 μmol), triethylamine (143 mg, 1.41 mmol), and ethanol (3 mL) was stirred at 100° C. under a carbon monoxide atmosphere (7 bar) and then concentrated in vacuo. Chromatography (silica gel, gradient from heptane to heptane/ethyl acetate 1:2) afforded the title compound (118 mg, 62%) as a pale red solid, MS: 304.1 (M+H) ⁺ .

Step 2: 3-Fluoro-5-sulfamoylpyridine-2-carboxylic acid

To a solution of ethyl 5-[(E)-dimethylaminomethyleneamino]sulfonyl-3-fluoro-pyridine-2-carboxylate (114 mg, 338 μmol) in methanol (2 mL) was added 2.5 M aqueous sodium hydroxide solution (2 mL, 5 mmol). The yellow solution was stirred at room temperature for 3 h and then partitioned between 1 M hydrochloric acid solution and ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and evaporated to give the title compound (65 mg, 70%). Pale brown solid, MS: 219.1 (MH) ^- .

Intermediate 12

tert-Butyl 2-(3-fluoro-5-sulfamoylpyridine-2-carbonyl)-1,3,4,6-tetrahydropyrrolo[3,4-c]pyrrole-5-carboxylate

The title compound was prepared in analogy to Intermediate 5, Step 1, substituting 3-fluoro-5-sulfamoylpyridine-2-carboxylic acid (Intermediate 11) for 2-fluoro-4-sulfamoylbenzoic acid (CAS-RN 714968-42-0).White solid, MS: 413.2 (M+H) ⁺ .

Intermediate 13

1,3,4,6-tetrahydropyrrolo[3,4-c]pyrrole-2,5-dicarboxylic acid 5-O-tert-butyl ester 2-O-[[3-(2,2-dimethylpropionylamino)quinolin-2-yl]methyl] ester

The title compound was prepared analogously to Intermediate 4, Steps 1 and 2, substituting N-[2-(hydroxymethyl)-3-quinolinyl]-2,2-dimethyl-propionamide (Intermediate 14.06) for N-(2-(hydroxymethyl)-5-(trifluoromethyl)pyridin-3-yl)pivalamide (Intermediate 14). Pale yellow foam, MS: 495.3 (M+H) ⁺ .

Intermediate 14

N-(2-(Hydroxymethyl)-5-(trifluoromethyl)pyridin-3-yl)pivalamide

Step 1: Methyl 3-pivaloylamino-5-(trifluoromethyl)picolinate

To a brown solution of methyl 3-amino-5-(trifluoromethyl)picolinate (CAS-RN 866775-17-9; 2.00 g, 8.63 mmol) in pyridine (25 mL) was added pivaloyl chloride (2.08 g, 17.3 mmol) at 0°C. The ice bath was removed after 20 min. After stirring at room temperature for 5 h, the reaction mixture was partitioned between 1 M aqueous hydrochloric acid solution and ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, filtered and evaporated. Chromatography (silica gel; gradient from dichloromethane to dichloromethane/methanol/25% aqueous ammonia solution 100:5:0.25) gave the title compound (2.46 g, 92%). Pale yellow solid, MS: 305.1 (M+H) ⁺ .

Step 2: N-(2-(Hydroxymethyl)-5-(trifluoromethyl)pyridin-3-yl)pivalamide

To a clear, pale yellow solution of methyl 3-pivaloylamino-5-(trifluoromethyl)picolinate (2.45 g, 8.05 mmol) in tetrahydrofuran (60 mL) was added a solution of calcium chloride (1.79 g, 16.1 mmol) in ethanol (60 mL), followed by the addition of sodium borohydride (914 mg, 24.2 mmol) in three portions over a period of 30 minutes. The white suspension was stirred at room temperature for 90 minutes and then partitioned between ethyl acetate and saturated aqueous ammonium chloride. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and evaporated. Chromatography (silica gel; heptane/ethyl acetate 4:1 to 1:1 gradient) afforded the title compound (1.97 g, 89%) as a pale yellow, viscous oil, MS: 277.1 (M+H) ⁺ .

The following intermediates were prepared analogously to Intermediate 14, substituting the appropriate starting materials for methyl 3-amino-5-(trifluoromethyl)picolinate (CAS-RN 866775-17-9).

Example A

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

Example B

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

Claims (5)

1. A compound, said compound being selected from... 2-(4-aminosulfonylbenzoyl)-1,3,4,6-tetrahydropyrrolo[3,4-c]pyrrolo-5-carboxylic acid [3-(2,2-dimethylpropionylamino)-5-(trifluoromethyl)pyridin-2-yl]methyl ester; 2-(2,5-difluoro-4-aminosulfonylbenzoyl)-1,3,4,6-tetrahydropyrrolo[3,4-c]pyrrolo-5-carboxylic acid [3-(2,2-dimethylpropionylamino)-5-(trifluoromethyl)pyridin-2-yl]methyl ester; 2-(3-chloro-4-aminosulfonylbenzoyl)-1,3,4,6-tetrahydropyrrolo[3,4-c]pyrrolo-5-carboxylic acid [3-(2,2-dimethylpropionylamino)-5-(trifluoromethyl)pyridin-2-yl]methyl ester; 2-(3-fluoro-4-aminosulfonylbenzoyl)-1,3,4,6-tetrahydropyrrolo[3,4-c]pyrrolo-5-carboxylic acid [3-(2,2-dimethylpropionylamino)-5-(trifluoromethyl)pyridin-2-yl]methyl ester; 2-(2-fluoro-4-aminosulfonylbenzoyl)-1,3,4,6-tetrahydropyrrolo[3,4-c]pyrrolo-5-carboxylic acid [3-(2,2-dimethylpropionylamino)-5-(trifluoromethyl)pyridin-2-yl]methyl ester; 2-(5-aminosulfonylpyridine-2-carbonyl)-1,3,4,6-tetrahydropyrrolo[3,4-c]pyrrolo-5-carboxylic acid [3-(2,2-dimethylpropionylamino)-5-(trifluoromethyl)pyridine-2-methyl] methyl ester; 5-(4-aminosulfonylbenzoyl)-3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrolo-2(1H)-carboxylic acid 4-(trifluoromethoxy)benzyl ester; 6-[5-[2-cyclopropyl-6-(tetrahydropyran-4-ylmethoxy)pyridine-4-carbonyl]-1,3,4,6-tetrahydropyrrolo[3,4-c]pyrrolo-2-carbonyl]pyridine-3-sulfonamide; 4-[5-[2-cyclopropyl-6-(tetrahydropyran-4-ylmethoxy)pyridine-4-carbonyl]-1,3,4,6-tetrahydropyrrolo[3,4-c]pyrrolo-2-carbonyl]-3-fluorobenzenesulfonamide; 2-(2,3-difluoro-4-aminosulfonylbenzoyl)-1,3,4,6-tetrahydropyrrolo[3,4-c]pyrrolo-5-carboxylic acid [3-(2,2-dimethylpropionylamino)-5-(trifluoromethyl)pyridin-2-yl]methyl ester; 3-Fluoro-4-(5-(3-(2-((5-methyl-2H-tetrazol-2-yl)methyl)-4-(trifluoromethyl)phenyl)propionyl)-1,2,3,4,5,6-hexahydropyrrolo[3,4-c]pyrrolo-2-carbonyl)benzenesulfonamide; 2-(2,6-difluoro-4-aminosulfonylbenzoyl)-1,3,4,6-tetrahydropyrrolo[3,4-c]pyrrolo-5-carboxylic acid [3-(2,2-dimethylpropionylamino)-5-(trifluoromethyl)pyridin-2-yl]methyl ester; 2-(2-fluoro-4-aminosulfonylbenzoyl)-1,3,4,6-tetrahydropyrrolo[3,4-c]pyrrolo-5-carboxylic acid [5-chloro-3-(2,2-dimethylpropionylamino)pyridin-2-yl]methyl ester; 2-(3-fluoro-4-aminosulfonylbenzoyl)-1,3,4,6-tetrahydropyrrolo[3,4-c]pyrrolo-5-carboxylic acid [5-chloro-3-(2,2-dimethylpropionylamino)pyridin-2-yl]methyl ester; 2-(2,3-difluoro-4-aminosulfonylbenzoyl)-1,3,4,6-tetrahydropyrrolo[3,4-c]pyrrolo-5-carboxylic acid [5-chloro-3-(2,2-dimethylpropionylamino)pyridin-2-yl]methyl ester; 2-(2,6-difluoro-4-aminosulfonylbenzoyl)-1,3,4,6-tetrahydropyrrolo[3,4-c]pyrrolo-5-carboxylic acid [5-chloro-3-(2,2-dimethylpropionylamino)pyridin-2-yl]methyl ester; 2-(2,5-difluoro-4-aminosulfonylbenzoyl)-1,3,4,6-tetrahydropyrrolo[3,4-c]pyrrolo-5-carboxylic acid [5-chloro-3-(2,2-dimethylpropionylamino)pyridin-2-yl]methyl ester; 2-(2-fluoro-4-aminosulfonylbenzoyl)-1,3,4,6-tetrahydropyrrolo[3,4-c]pyrrolo-5-carboxylic acid [3-(2,2-dimethylpropionylamino)-6-methylpyridin-2-yl]methyl ester; 2-(2-fluoro-4-aminosulfonylbenzoyl)-1,3,4,6-tetrahydropyrrolo[3,4-c]pyrrolo-5-carboxylic acid [6-chloro-3-(2,2-dimethylpropionylamino)pyridin-2-yl]methyl ester; 2-(2-fluoro-4-aminosulfonylbenzoyl)-1,3,4,6-tetrahydropyrrolo[3,4-c]pyrrolo-5-carboxylic acid [3-(2,2-dimethylpropionylamino)pyridin-2-yl]methyl ester; 2-(2,5-difluoro-4-aminosulfonylbenzoyl)-1,3,4,6-tetrahydropyrrolo[3,4-c]pyrrolo-5-carboxylic acid [6-chloro-3-(2,2-dimethylpropionylamino)pyridin-2-yl]methyl ester; 2-(3-fluoro-4-aminosulfonylbenzoyl)-1,3,4,6-tetrahydropyrrolo[3,4-c]pyrrolo-5-carboxylic acid [6-chloro-3-(2,2-dimethylpropionylamino)pyridin-2-yl]methyl ester; 2-(2,3-difluoro-4-aminosulfonylbenzoyl)-1,3,4,6-tetrahydropyrrolo[3,4-c]pyrrolo-5-carboxylic acid [6-chloro-3-(2,2-dimethylpropionylamino)pyridin-2-yl]methyl ester; 2-(2,6-difluoro-4-aminosulfonylbenzoyl)-1,3,4,6-tetrahydropyrrolo[3,4-c]pyrrolo-5-carboxylic acid [6-chloro-3-(2,2-dimethylpropionylamino)pyridin-2-yl]methyl ester; 2-(2-fluoro-4-aminosulfonylbenzoyl)-1,3,4,6-tetrahydropyrrolo[3,4-c]pyrrolo-5-carboxylic acid [5-cyano-3-(2,2-dimethylpropionylamino)pyridin-2-yl]methyl ester; 2-(2,6-difluoro-4-aminosulfonylbenzoyl)-1,3,4,6-tetrahydropyrrolo[3,4-c]pyrrolo-5-carboxylic acid [5-cyano-3-(2,2-dimethylpropionylamino)pyridin-2-yl]methyl ester; 2-(2,3-difluoro-4-aminosulfonylbenzoyl)-1,3,4,6-tetrahydropyrrolo[3,4-c]pyrrolo-5-carboxylic acid [5-cyano-3-(2,2-dimethylpropionylamino)pyridin-2-yl]methyl ester; 2-(2,5-difluoro-4-aminosulfonylbenzoyl)-1,3,4,6-tetrahydropyrrolo[3,4-c]pyrrolo-5-carboxylic acid [5-cyano-3-(2,2-dimethylpropionylamino)pyridin-2-yl]methyl ester; 6-(2-fluoro-4-aminosulfonylbenzoyl)-1,3,4,5,7,8-hexahydro-2,6-naphthyl-2-carboxylic acid [3-(2,2-dimethylpropionylamino)-5-(trifluoromethyl)pyridin-2-yl]methyl ester; 2-(5-aminosulfonylpyridine-2-carbonyl)-1,3,4,6-tetrahydropyrrolo[3,4-c]pyrrolo-5-carboxylic acid [5-chloro-4-cyano-2-(2,2-dimethylpropionylamino)phenyl]methyl ester; 6-(2-fluoro-4-aminosulfonylbenzoyl)-1,3,4,5,7,8-hexahydro-2,6-naphthyl-2-carboxylic acid [4-(trifluoromethoxy)phenyl]methyl ester; 2-(5-aminosulfonylpyridine-2-carbonyl)-1,3,4,6-tetrahydropyrrolo[3,4-c]pyrrolo-5-carboxylic acid[4-(trifluoromethoxy)phenyl]methyl ester; 2-(2-fluoro-4-aminosulfonylbenzoyl)-1,3,4,6-tetrahydropyrrolo[3,4-c]pyrrolo-5-carboxylic acid[4-(trifluoromethoxy)phenyl]methyl ester; 3-Fluoro-4-[2-[(E)-3-[4-(trifluoromethoxy)phenyl]prop-2-enoyl]-1,3,4,6-tetrahydropyrrolo[3,4-c]pyrrolo-5-carbonyl]benzenesulfonamide; 6-[2-[3-[4-(trifluoromethoxy)phenyl]propionyl]-1,3,4,6-tetrahydropyrrolo[3,4-c]pyrrolo-5-carbonyl]pyridine-3-sulfonamide; 3-Fluoro-4-[2-[3-[4-(trifluoromethoxy)phenyl]propionyl]-1,3,4,6-tetrahydropyrrolo[3,4-c]pyrrolo-5-carbonyl]benzenesulfonamide; 6-[2-[(E)-3-[4-(trifluoromethoxy)phenyl]prop-2-enoyl]-1,3,4,6-tetrahydropyrrolo[3,4-c]pyrrolo-5-carbonyl]pyridine-3-sulfonamide; 6-[2-[2-[4-(trifluoromethoxy)phenoxy]acetyl]-1,3,4,6-tetrahydropyrrolo[3,4-c]pyrrolo-5-carbonyl]pyridine-3-sulfonamide; 3-Fluoro-4-[2-[2-[4-(trifluoromethoxy)phenoxy]acetyl]-1,3,4,6-tetrahydropyrrolo[3,4-c]pyrrolo-5-carbonyl]benzenesulfonamide; 4-[2-[3-[4-cyano-2-[(5-methyltetrazole-2-yl)methyl]phenyl]propionyl]-1,3,4,6-tetrahydropyrrolo[3,4-c]pyrrolo-5-carbonyl]-3-fluorobenzenesulfonamide; 4-[2-[3-[4-chloro-2-[(5-methyltetrazole-2-yl)methyl]phenyl]propionyl]-1,3,4,6-tetrahydropyrrolo[3,4-c]pyrrolo-5-carbonyl]-3-fluorobenzenesulfonamide; 3-Fluoro-4-[2-[3-[2-[(4-methyltriazol-2-yl)methyl]-4-(trifluoromethyl)phenyl]propionyl]-1,3,4,6-tetrahydropyrrolo[3,4-c]pyrrolo-5-carbonyl]benzenesulfonamide; 3-Fluoro-4-[2-[3-[2-[(4-methyltriazol-1-yl)methyl]-4-(trifluoromethyl)phenyl]propionyl]-1,3,4,6-tetrahydropyrrolo[3,4-c]pyrrolo-5-carbonyl]benzenesulfonamide; And its medicinal salt. 2. A compound, said compound being selected from... 2-(2-fluoro-4-aminosulfonylbenzoyl)-1,3,4,6-tetrahydropyrrolo[3,4-c]pyrrolo-5-carboxylic acid [5,6-dichloro-3-(2,2-dimethylpropionylamino)pyridin-2-yl]methyl ester; 2-(2,3-difluoro-4-aminosulfonylbenzoyl)-1,3,4,6-tetrahydropyrrolo[3,4-c]pyrrolo-5-carboxylic acid [5,6-dichloro-3-(2,2-dimethylpropionylamino)pyridin-2-yl]methyl ester; 2-(2,6-difluoro-4-aminosulfonylbenzoyl)-1,3,4,6-tetrahydropyrrolo[3,4-c]pyrrolo-5-carboxylic acid [5,6-dichloro-3-(2,2-dimethylpropionylamino)pyridin-2-yl]methyl ester; 2-(3-fluoro-5-aminosulfonylpyridin-2-carbonyl)-1,3,4,6-tetrahydropyrrolo[3,4-c]pyrrolo-5-carboxylic acid [3-(2,2-dimethylpropionylamino)-5-(trifluoromethyl)pyridin-2-yl]methyl ester; 4-[5-[2-cyclopropyl-6-(tetrahydropyran-4-ylmethoxy)pyridine-4-carbonyl]-1,3,4,6-tetrahydropyrrolo[3,4-c]pyrrolo-2-carbonyl]-2,3-difluorobenzenesulfonamide; 4-[5-[2-cyclopropyl-6-[(1-methylpiperidin-4-yl)methoxy]pyridine-4-carbonyl]-1,3,4,6-tetrahydropyrrolo[3,4-c]pyrrolo-2-carbonyl]-2,3-difluorobenzenesulfonamide; 2-(2-fluoro-4-aminosulfonylbenzoyl)-1,3,4,6-tetrahydropyrrolo[3,4-c]pyrrolo-5-carboxylic acid [5-chloro-3-[(5-methyltetrazol-2-yl)methyl]pyridin-2-yl]methyl ester; 3-Fluoro-4-[2-[3-[3-[(5-methyltetrazol-2-yl)methyl]-5-(trifluoromethyl)pyridin-2-yl]propionyl]-1,3,4,6-tetrahydropyrrolo[3,4-c]pyrrolo-5-carbonyl]benzenesulfonamide; 5-Fluoro-6-[2-[3-[2-[(5-methyltetrazol-2-yl)methyl]-4-(trifluoromethyl)phenyl]propionyl]-1,3,4,6-tetrahydropyrrolo[3,4-c]pyrrolo-5-carbonyl]pyridine-3-sulfonamide; 2-(2-fluoro-4-aminosulfonylbenzoyl)-1,3,4,6-tetrahydropyrrolo[3,4-c]pyrrolo-5-carboxylic acid [3-(2,2-dimethylpropionylamino)quinoline-2-yl]methyl ester; 5-(2-fluoro-4-aminosulfonylphenyl)sulfonyl-1,3,4,6-tetrahydropyrrolo[3,4-c]pyrrolo-2-carboxylic acid [3-(2,2-dimethylpropionylamino)-5-(trifluoromethyl)pyridin-2-yl]methyl ester; And its medicinal salt. 3. A compound, said compound being selected from... 2-(3-chloro-4-aminosulfonylbenzoyl)-1,3,4,6-tetrahydropyrrolo[3,4-c]pyrrolo-5-carboxylic acid [3-(2,2-dimethylpropionylamino)-5-(trifluoromethyl)pyridin-2-yl]methyl ester; 2-(3-fluoro-4-aminosulfonylbenzoyl)-1,3,4,6-tetrahydropyrrolo[3,4-c]pyrrolo-5-carboxylic acid [3-(2,2-dimethylpropionylamino)-5-(trifluoromethyl)pyridin-2-yl]methyl ester; 2-(2-fluoro-4-aminosulfonylbenzoyl)-1,3,4,6-tetrahydropyrrolo[3,4-c]pyrrolo-5-carboxylic acid [3-(2,2-dimethylpropionylamino)-5-(trifluoromethyl)pyridin-2-yl]methyl ester; 2-(2,3-difluoro-4-aminosulfonylbenzoyl)-1,3,4,6-tetrahydropyrrolo[3,4-c]pyrrolo-5-carboxylic acid [5-chloro-3-(2,2-dimethylpropionylamino)pyridin-2-yl]methyl ester; And its medicinal salt. 4. A pharmaceutical composition comprising a compound according to any one of claims 1 to 3 and a therapeutically inert carrier. 5. Use of the compound according to any one of claims 1 to 3 for the preparation of a medicament for the treatment or prevention of eye diseases.