Patent Description:
Galectins are defined as a protein family based on conserved β-galactoside-binding sites found within their characteristic ~<NUM> amino acid (aa) carbohydrate recognition domains (CRDs) (<NPL>). Human, mouse and rat genome sequences reveal the existence of at least <NUM> conserved galectins and galectin-like proteins in one mammalian genome (<NPL>). So far, three galectin subclasses were identified, the prototypical galectins containing one carbohydrate-recognition domain (CRD); the chimaera galectin consisting of unusual tandem repeats of proline- and glycine-rich short stretches fused onto the CRD; and the tandem-repeat-type galectins, containing two distinct CRDs in tandem connected by a linker (<NPL>). As galectins can bind either bivalently or multivalently, they can e.g. cross-link cell surface glycoconjugates to trigger cellular signaling events. Through this mechanism, galectins modulate a wide variety of biological processes (<NPL>).

Galectin-<NUM> (Gal-<NUM>), the only chimaera type in the galectin family, has a molecular weight of <NUM>-<NUM> kDa and consists of <NUM> amino acid residues in humans, a highly conserved CRD and an atypical N- terminal domain (ND). Galectin-<NUM> is monomeric up to high concentrations (<NUM>), but can aggregate with ligands at much lower concentrations, which is promoted by its N-terminal non-CRD region via an oligomerisation mechanism that is not yet completely understood (<NPL>).

Gal-<NUM> is widely distributed in the body, but the expression level varies among different organs. Depending on its extracellular or intracellular localization, it can display a broad diversity of biological functions, including immunomodulation, host-pathogen interactions, angiogenesis, cell migration, wound healing and apoptosis (<NPL>). Gal-<NUM> is highly expressed in many human tumours and cell types, such as myeloid cells, inflammatory cells (macrophages, mast cells, neutrophils, T cells, eosinophils, etc.), fibroblasts and cardiomyocytes (<NPL>), indicating that Gal-<NUM> is involved in the regulation of inflammatory and fibrotic processes (<NPL>; <NPL>). Furthermore, Gal-<NUM> protein expression levels are up-regulated under certain pathological conditions, such as neoplasms and inflammation (<NPL>; <NPL>).

There are multiple lines of evidence supporting functional involvement of Gal-<NUM> in the development of inflammatory / autoimmune diseases, such as asthma (<NPL>;<NPL>), rheumatoid arthritis, multiple sclerosis, diabetes, plaque psoriasis (<NPL>) atopic dermatitis (<NPL>), endometriosis (<NPL>), or viral encephalitis (<NPL>; <NPL>; <NPL>). Recently Gal-<NUM> has emerged as a key player of chronic inflammation and organ fibrogenesis development e.g. liver (<NPL>; <NPL>), kidney (<NPL>;<NPL>), lung (<NPL>; <NPL>), heart (<NPL>; <NPL>), as well as the nervous system (<NPL>), and in corneal neovascularization (<NPL>). Additionally, Gal-<NUM> was found to be associated with dermal thickening of keloid tissues (<NPL>) and systemic sclerosis (SSc) especially with skin fibrosis and proliferative vasculopathy observed in such condition (<NPL>). Gal-<NUM> was found to be up-regulated in patient suffering chronic kidney disease (CKD) associated-kidney failure, and especially in those affected by diabetes. Interestingly, data obtained from this patient population showed correlation between Gal-<NUM> upregulation in glomeruli and the observed urinary protein excretion (<NPL>). Additionally, a recent prospective study from <NUM> demonstrated that higher Gal-<NUM> plasma levels are associated with an elevated risk of developing incident CKD, particularly among hypertension-suffering population (<NPL>). Gal-<NUM> is highly elevated in cardiovascular diseases (<NPL>), such as atherosclerosis (<NPL>), coronary artery disease (<NPL>), heart failure and thrombosis (<NPL>;<NPL>; <NPL>). Gal-<NUM> blood concentration is elevated in obese and diabetic patients and is associated with a higher risk for micro- and macro- vascular complication (such as heart failure, nephropathy/retinopathy, peripheral arterial disease, cerebrovascular event, or myocardial infarction) (<NPL>). Gal-<NUM> influences oncogenesis, cancer progression, and metastasis (<NPL>), and was shown to exert a role as a pro-tumor factor by acting within the micro tumor environment to suppress immune surveillance (<NPL>; <NPL>). Among the cancers that express high level of Gal-<NUM> are found those affecting the thyroid gland, the central nervous system, the tongue, the breast, the gastric cancer, the head and neck squamous cell, the pancreas, the bladder, the kidney, the liver, the parathyroid, the salivary glands, but also lymphoma, carcinoma, non-small cell lung cancer, melanoma and neuroblastoma (<NPL>).

Also, Gal-<NUM> inhibition has been proposed to be beneficial in the treatment of COVID-<NUM> (<NPL>) and influenza H5N1 (<NPL>) possibly due to antiinflammatory effects.

Recently, Gal-<NUM> inhibitors have shown to have positive effects when used in combination immunotherapy (Galectin Therapeutics. Press Release, February <NUM>, <NUM>) and idiopathic pulmonary fibrosis (Galecto Biotech. Press Release, March <NUM>, <NUM>) and in NASH cirrhosis (December <NUM>, <NUM>). <CIT>, <CIT> and <CIT> disclose compounds having binding affinity with galectin proteins for the treatment of systemic insulin resistance disorders. Thus, Gal-<NUM> inhibitors, alone or in combination with other therapies, may be useful for the prevention or treatment of diseases or disorders such as fibrosis of organs, cardiovascular diseases and disorders, acute kidney injury and chronic kidney disease, liver diseases and disorders, interstitial lung diseases and disorders, ocular diseases and disorders, cell proliferative diseases and cancers, inflammatory and autoimmune diseases and disorders, gastrointestinal tract diseases and disorders, pancreatic diseases and disorders, abnormal angiogenesis-associated diseases and disorders, brain-associated diseases and disorders, neuropathic pain and peripheral neuropathy, and / or transplant rejection.

Several publications and patent applications describe synthetic inhibitors of Gal-<NUM> that are being explored as antifibrotic agents (see for example <CIT>, <CIT>, <CIT>, <CIT>, <CIT>, <CIT>, <CIT>, <CIT>, <CIT> and <CIT>).

The present invention provides novel compounds of formula (I) which are Galectin-<NUM> inhibitors. The present compounds may, thus, be useful for the prevention / prophylaxis or treatment of diseases and disorders where modulation of Gal-<NUM> binding to its natural carbohydrate ligands is indicated.

The compounds of Formula (I) contain five stereogenic or asymmetric centers, which are situated on the tetrahydropyran moiety, and two stereogenic or asymmetric centers situated on the cycloalkane moiety which are in the absolute (S,S)-configuration as drawn for Formula (I). In addition, the compounds of Formula (I) may contain one, and possibly more stereogenic or asymmetric centers, such as one or more additional asymmetric carbon atoms. The compounds of Formula (I) may thus be present as mixtures of stereoisomers or preferably as pure stereoisomers. Mixtures of stereoisomers may be separated in a manner known to a person skilled in the art.

In case a particular compound (or generic structure) is designated as being in a certain absolute configuration, e.g. as (R)- or (S)-enantiomer, such designation is to be understood as referring to the respective compound (or generic structure) in enriched, especially essentially pure, enantiomeric form. Likewise, in case a specific asymmetric center in a compound is designated as being in (R)- or (S)-configuration or as being in a certain relative configuration, such designation is to be understood as referring to the compound that is in enriched, especially essentially pure, form with regard to the respective configuration of said asymmetric center. In analogy, two stereogenic centers e. g in a cyclic group may be present in a certain relative configuration. Accordingly, cis- or trans-designations (or (R*,R*) designations as used e.g. for certain intermediates of the present compounds) are to be understood as referring to the respective stereoisomer of the respective relative configuration in enriched form, especially in essentially pure form. Thus, for a given molecule or group, the designation (R*,R*), if not explicitly specified otherwise, includes the respective (R,R)-enantiomer, the (S,S)-enantiomer, and any mixture of these two enantiomers including the racemate.

The term "enriched", when used in the context of stereoisomers, is to be understood in the context of the present invention to mean that the respective stereoisomer is present in a ratio of at least <NUM>:<NUM>, especially of at least <NUM>:<NUM> (i.e., in a purity of at least <NUM>% by weight, especially of at least <NUM>% by weight), with regard to the respective other stereoisomer / the entirety of the respective other stereoisomers.

The term "essentially pure", when used in the context of stereoisomers, is to be understood in the context of the present invention to mean that the respective stereoisomer is present in a purity of at least <NUM>% by weight, especially of at least <NUM>% by weight, with regard to the respective other stereoisomer / the entirety of the respective other stereoisomers.

The present invention also includes isotopically labelled, especially <NUM>H (deuterium) labelled compounds of Formula (I) according to embodiments <NUM>) to <NUM>), which compounds are identical to the compounds of Formula (I) except that one or more atoms have each been replaced by an atom having the same atomic number but an atomic mass different from the atomic mass usually found in nature. Isotopically labelled, especially <NUM>H (deuterium) labelled compounds of formulae (I), (II) and (III) and salts thereof are within the scope of the present invention. Substitution of hydrogen with the heavier isotope <NUM>H (deuterium) may lead to greater metabolic stability, resulting e.g. in increased in-vivo half-life or reduced dosage requirements, or may lead to reduced inhibition of cytochrome P450 enzymes, resulting e.g. in an improved safety profile. In one embodiment of the invention, the compounds of Formula (I) are not isotopically labelled, or they are labelled only with one or more deuterium atoms. In a sub-embodiment, the compounds of Formula (I) are not isotopically labelled at all. Isotopically labelled compounds of Formula (I) may be prepared in analogy to the methods described hereinafter, but using the appropriate isotopic variation of suitable reagents or starting materials.

In this patent application, a bond drawn as a dotted line shows the point of attachment of the radical drawn. For example, the radical drawn below
<CHM>
is a <NUM>-fluorophenyl group.

Where the plural form is used for compounds, salts, pharmaceutical compositions, diseases and the like, this is intended to mean also a single compound, salt, or the like.

Any reference to compounds of Formula (I) according to embodiments <NUM>) to <NUM>) is to be understood as referring also to the salts (and especially the pharmaceutically acceptable salts) of such compounds, as appropriate and expedient.

The term "pharmaceutically acceptable salts" refers to salts that retain the desired biological activity of the subject compound and exhibit minimal undesired toxicological effects. Such salts include inorganic or organic acid and/or base addition salts depending on the presence of basic and/or acidic groups in the subject compound. For reference see for example "<NPL>; and "<NPL>.

Definitions provided herein are intended to apply uniformly to the compounds of Formula (I), as defined in any one of embodiments <NUM>) to <NUM>), and, mutatis mutandis, throughout the description and the claims unless an otherwise expressly set out definition provides a broader or narrower definition. It is well understood that a definition or preferred definition of a term defines and may replace the respective term independently of (and in combination with) any definition or preferred definition of any or all other terms as defined herein.

In this patent application, the compounds are named using IUPAC nomenclature, but can also be named using carbohydrate nomenclature. Thus, the moiety:
<CHM>
can be named (2R,3R,<NUM>,5R,6R)-<NUM>,<NUM>-dihydroxy-<NUM>-(hydroxymethyl)-<NUM>-(<NUM>-phenyl-<NUM>-<NUM>,<NUM>,<NUM>-triazol-<NUM>-yl)tetrahydro-<NUM>-pyran-<NUM>-carbonyl or, alternatively, <NUM>,<NUM>-di-deoxy-<NUM>-[<NUM>-phenyl-<NUM>-<NUM>,<NUM>,<NUM>-triazol-<NUM>-yl]-β-D-galactopyranoside-<NUM>-carbonyl, wherein the absolute configuration of carbon atom carrying the carbonyl group which is the point of attachment to the rest of the molecule is in (2R)- , respectively, beta-configuration. For example, compound (2R,3R,<NUM>,5R,6R)-<NUM>-hydroxy-N-((<NUM>,<NUM>)-<NUM>-hydroxycyclohexyl)-<NUM>-(hydroxymethyl)-<NUM>-methoxy-N-((<NUM>-methyl-<NUM>-pyrrol-<NUM>-yl)methyl)-<NUM>-(<NUM>-(<NUM>,<NUM>,<NUM>-trifluorophenyl)-<NUM>-<NUM>,<NUM>,<NUM>-triazol-<NUM>-yl)tetrahydro-<NUM>-pyran-<NUM>-carboxamide is to be understood as also referring to: <NUM>,<NUM>-di-deoxy-<NUM>-O-methyl-<NUM>-[<NUM>-(<NUM>,<NUM>,<NUM>-trifluorophenyl)-<NUM>-<NUM>,<NUM>,<NUM>-triazol-<NUM>-yl]-(N-((<NUM>-methyl-<NUM>-pyrrol-<NUM>-yl)methyl)-N-((<NUM>,<NUM>)-<NUM>-hydroxycyclohexyl))-β-D-galacto-pyranose-<NUM>-carboxamide.

Whenever a substituent is denoted as optional, it is understood that such substituent may be absent (i.e. the respective residue is unsubstituted with regard to such optional substituent), in which case all positions having a free valency (to which such optional substituent could have been attached to; such as for example in an aromatic ring the ring carbon atoms and / or the ring nitrogen atoms having a free valency) are substituted with hydrogen where appropriate. Likewise, in case the term "optionally" is used in the context of (ring) heteroatom(s), the term means that either the respective optional heteroatom(s), or the like, are absent (i.e. a certain moiety does not contain heteroatom(s) / is a carbocycle / or the like), or the respective optional heteroatom(s), or the like, are present as explicitly defined. If not explicitly defined otherwise in the respective embodiment or claim, groups defined herein are unsubstituted.

The term "halogen" means fluorine, chlorine, or bromine, preferably fluorine or chlorine.

The term "alkyl", used alone or in combination, refers to a saturated straight or branched chain hydrocarbon group containing one to six carbon atoms. The term "Cx-y-alkyl" (x and y each being an integer), refers to an alkyl group as defined before, containing x to y carbon atoms. For example, a C<NUM>-<NUM>-alkyl group contains from one to six carbon atoms. Representative examples of alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert. -butyl, pentyl, <NUM>-methylbutyl, <NUM>,<NUM>-dimethyl-propyl and <NUM>,<NUM>-dimethyl-butyl. Preferred is methyl. For avoidance of any doubt, in case a group is referred to as e.g. propyl or butyl, it is meant to be n-propyl, respectively n-butyl. In case the substituent of Ar<NUM> (being phenyl or <NUM>- or <NUM>-membered heteroaryl) represents "C<NUM>-<NUM>-alkyl", the term especially refers to methyl, ethyl, or isopropyl; in particular to methyl.

The term "-Cx-y-alkylene-", used alone or in combination, refers to bivalently bound alkyl group as defined before containing x to y carbon atoms. The term "-C<NUM>-y-alkylene-" refers to a direct bond, or to a -(C<NUM>-y)alkylene- as defined before. Preferably, the points of attachment of a -C<NUM>-y-alkylene group are in <NUM>,<NUM>-diyl, or in <NUM>,<NUM>-diyl, or in <NUM>,<NUM>-diyl arrangement. Preferably, the points of attachment of a -C<NUM>-y-alkylene group are in <NUM>,<NUM>-diyl or in <NUM>,<NUM>-diyl arrangement. In case a C<NUM> y-alkylene group is used in combination with another substituent, the term means that either said substituent is linked through a C1y-alkylene group to the rest of the molecule, or it is directly attached to the rest of the molecule (i.e. a C<NUM>-alkylene group represents a direct bond linking said substituent to the rest of the molecule). The alkylene group -C<NUM>H<NUM>- (or ethylene) refers to -CH<NUM>-CH<NUM>- if not explicitly indicated otherwise.

The term "alkenyl", used alone or in combination, refers to a straight or branched hydrocarbon chain containing two to five carbon atoms and one carbon-carbon double bond. The term "Cx-y-alkenyl" (x and y each being an integer), refers to an alkenyl group as defined before containing x to y carbon atoms. For example, a C<NUM>-<NUM>-alkenyl group contains from two to five carbon atoms.

The term "fluoroalkyl", used alone or in combination, refers to an alkyl group as defined before containing one to three carbon atoms in which one or more (and possibly all) hydrogen atoms have been replaced with fluorine. The term "Cx-y-fluoroalkyl" (x and y each being an integer) refers to a fluoroalkyl group as defined before containing x to y carbon atoms. For example, a C<NUM>-<NUM>-fluoroalkyl group contains from one to three carbon atoms in which one to seven hydrogen atoms have been replaced with fluorine. Representative examples of fluoroalkyl groups include trifluoromethyl, <NUM>-fluoroethyl, <NUM>,<NUM>-difluoroethyl and <NUM>,<NUM>,<NUM>-trifluoroethyl. Preferred is trifluoromethyl.

The term "fluoroalkoxy", used alone or in combination, refers to an alkoxy group as defined before containing one to three carbon atoms in which one or more (and possibly all) hydrogen atoms have been replaced with fluorine. The term "Cx-y-fluoroalkoxy" (x and y each being an integer) refers to a fluoroalkoxy group as defined before containing x to y carbon atoms. For example, a C<NUM>-<NUM>-fluoroalkoxy group contains from one to three carbon atoms in which one to seven hydrogen atoms have been replaced with fluorine. Representative examples of fluoroalkoxy groups include trifluoromethoxy, difluoromethoxy, <NUM>-fluoroethoxy, <NUM>,<NUM>-difluoroethoxy and <NUM>,<NUM>,<NUM>-trifluoroethoxy.

The term "cycloalkyl", used alone or in combination, refers especially to a saturated monocyclic, or to a fused-, bridged-, or spiro-bicyclic hydrocarbon ring containing three to eight carbon atoms. The term "Cx-y-cycloalkyl" (x and y each being an integer), refers to a cycloalkyl group as defined before containing x to y carbon atoms. For example, a C<NUM>-<NUM>-cycloalkyl group contains from three to six carbon atoms. Examples of cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Preferred is cyclopropyl.

The term "alkoxy", used alone or in combination, refers to an alkyl-O- group wherein the alkyl group is as defined before. The term "Cx-y-alkoxy" (x and y each being an integer) refers to an alkoxy group as defined before containing x to y carbon atoms. Preferred are ethoxy and especially methoxy. In case R<NUM> represents "C<NUM>-<NUM>-alkoxy" the term especially refers to methoxy. In case the substituent of Ar<NUM> (being phenyl or <NUM>- or <NUM>-membered heteroaryl) represents "C<NUM>-<NUM>-alkoxy", the term especially refers to methoxy.

The term "heterocyclyl", used alone or in combination, and if not explicitly defined in a broader or more narrow way, refers to a saturated or unsaturated non-aromatic monocyclic hydrocarbon ring containing one or two ring heteroatoms independently selected from nitrogen, sulfur, and oxygen (especially one oxygen atom, one sulfur atom, one nitrogen atom, two nitrogen atoms, two oxygen atoms, one nitrogen atom and one oxygen atom). The term "Cx-y-heterocyclyl" refers to such a heterocycle containing x to y ring atoms. Heterocyclyl groups are unsubstituted or substituted as explicitly defined.

The term "aryl", used alone or in combination, means phenyl or naphthyl, preferably phenyl, wherein said aryl group is unsubstituted or substituted as explicitly defined.

The term "heteroaryl", used alone or in combination, and if not explicitly defined in a broader or more narrow way, means a <NUM>- to <NUM>-membered monocyclic or bicyclic aromatic ring containing one to a maximum of four heteroatoms, each independently selected from oxygen, nitrogen and sulfur. Representative examples of such heteroaryl groups are <NUM>-membered heteroaryl groups such as furanyl, oxazolyl, isoxazolyl, oxadiazolyl, thiophenyl, thiazolyl, isothiazolyl, thiadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl; <NUM>-membered heteroaryl groups such as pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl; and <NUM>- to <NUM>-membered bicyclic heteroaryl groups such as indolyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzothiophenyl, indazolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzoisothiazolyl, benzotriazolyl, benzoxadiazolyl, benzothiadiazolyl, thienopyridinyl, quinolinyl, isoquinolinyl, naphthyridinyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, pyrrolopyridinyl, pyrazolopyridinyl, pyrazolopyrimidinyl, pyrrolopyrazinyl, imidazopyridinyl, imidazopyridazinyl, and imidazothiazolyl. The above-mentioned heteroaryl groups are unsubstituted or substituted as explicitly defined. For the substituent Ar<NUM> representing "<NUM>- or <NUM>-membered heteroaryl", the term especially means furanyl, thiophenyl, pyrrolyl, thiazolyl, isothiazolyl, isoxazolyl, pyrazolyl, imidazolyl, pyridinyl, or pyrimidinyl; notably furan-<NUM>-yl, thiophen-<NUM>-yl, thiophen-<NUM>-yl, <NUM>H-pyrrol-<NUM>-yl, thiazol-<NUM>-yl, thiazol-<NUM>-yl, thiazol-<NUM>-yl, isothiazol-<NUM>-yl, isothiazol-<NUM>-yl, isoxazol-<NUM>-yl, <NUM>-pyrazol-<NUM>-yl, <NUM>-pyrazol-<NUM>-yl, <NUM>-imidazol-<NUM>-yl, <NUM>-imidazol-<NUM>-yl, pyridin-<NUM>-yl, pyridin-<NUM>-yl, pyridin-<NUM>-yl, or pyrimidin-<NUM>-yl. For the substituent Ar<NUM> representing "<NUM>-membered bicyclic heteroaryl", the term especially means indolyl; or, in addition benzothiophenyl, benzothiazolyl, or benzoimidazolyl; notably <NUM>-indol-<NUM>-yl; or, in addition, benzothiophen-<NUM>-yl, benzothiazol-<NUM>-yl, benzothiazol-<NUM>-yl, or benzoimidazol-<NUM>-yl; wherein said <NUM>-membered bicyclic heteroaryl is unsubstituted or substituted as explicitly defined; a particular example is <NUM>-methyl-<NUM>-indol-<NUM>-yl. For the substituent Ar<NUM> representing "<NUM>-membered bicyclic heteroaryl", the term especially means quinolinyl or quinoxalinyl; notably quinoline-<NUM>-yl, or quinoxaline-<NUM>-yl.

Whenever the word "between" is used to describe a numerical range, it is to be understood that the end points of the indicated range are explicitly included in the range. For example: if a temperature range is described to be between <NUM> and <NUM>, this means that the end points <NUM> and <NUM> are included in the range; or if a variable is defined as being an integer between <NUM> and <NUM>, this means that the variable is the integer <NUM>, <NUM>, <NUM>, or <NUM>.

Unless used regarding temperatures, the term "about" placed before a numerical value "X" refers in the current application to an interval extending from X minus <NUM>% of X to X plus <NUM>% of X, and preferably to an interval extending from X minus <NUM>% of X to X plus <NUM>% of X. In the particular case of temperatures, the term "about" placed before a temperature "Y" refers in the current application to an interval extending from the temperature Y minus <NUM> to Y plus <NUM>, and preferably to an interval extending from Y minus <NUM> to Y plus <NUM>. Besides, the term "room temperature" as used herein refers to a temperature of about <NUM>.

Further embodiments of the invention are presented hereinafter:.

In the list above the numbers refer to the embodiments according to their numbering provided hereinabove whereas "+" indicates the dependency from another embodiment. The different individualized embodiments are separated by commas. In other words, "<NUM>+<NUM>+<NUM>+<NUM>" for example refers to embodiment <NUM>) depending on embodiment <NUM>), depending on embodiment <NUM>), depending on embodiment <NUM>), i.e. embodiment "<NUM>+<NUM>+<NUM>+<NUM>" corresponds to the compounds of formula (I) according to embodiment <NUM>) further limited by all the features of the embodiments <NUM>), <NUM>), and <NUM>).

<NUM>) Another embodiment relates to compounds of Formula (I) according to embodiment <NUM>), which are selected from the following compounds:.

<NUM>) In addition to the compounds listed in embodiment <NUM>), further compounds according to embodiment <NUM>) are selected from the following compounds:.

The compounds of Formula (I) according to embodiments <NUM>) to <NUM>) and their pharmaceutically acceptable salts can be used as medicaments, e.g. in the form of pharmaceutical compositions for enteral (such especially oral e.g. in form of a tablet or a capsule) or parenteral administration (including topical application or inhalation).

The production of the pharmaceutical compositions can be effected in a manner which will be familiar to any person skilled in the art (see for example<NPL>]) by bringing the described compounds of Formula (I) or their pharmaceutically acceptable salts, optionally in combination with other therapeutically valuable substances, into a galenical administration form together with suitable, non-toxic, inert, therapeutically compatible solid or liquid carrier materials and, if desired, usual pharmaceutical adjuvants.

The references to methods of treatment in the subsequent paragraphs of this description are to be interpreted as references to the compounds, pharmaceutical compositions and medicaments of present invention for use in a method for treatment of the human (or animal) body by therapy (or for diagnosis).

The present invention also relates to a method for the prevention / prophylaxis or treatment of a disease or disorder mentioned herein comprising administering to a subject a pharmaceutically active amount of a compound of Formula (I) according to embodiments <NUM>) to <NUM>). In a sub- embodiment of the invention, the administered amount is comprised between <NUM> and <NUM> per day.

For avoidance of any doubt, if compounds are described as useful for the prevention / prophylaxis or treatment of certain diseases, such compounds are likewise suitable for use in the preparation of a medicament for the prevention / prophylaxis or treatment of said diseases. Likewise, such compounds are also suitable in a method for the prevention / prophylaxis or treatment of such diseases, comprising administering to a subject (mammal, especially human) in need thereof, an effective amount of such compound.

<NUM>) Another embodiment relates to the compounds of formula (I) as defined in any one of embodiments <NUM>) to <NUM>) which are useful for the prevention / prophylaxis or treatment of diseases and disorders that are related to galectin-<NUM> binding to natural ligands.

Such diseases and disorders that are related to Gal-<NUM> binding to natural ligands are especially diseases and disorders in which inhibition of the physiological activity of Gal-<NUM> is useful, such as diseases in which a Gal-<NUM> receptor participates, is involved in the etiology or pathology of the disease, or is otherwise associated with at least one symptom of the disease.

Diseases or disorders that are related to galectin-<NUM> binding to natural ligands may in particular be defined as including:.

<NUM>) A further embodiment relates to the compounds of formula (I) for use according to embodiment <NUM>) wherein said compounds are for use in the prevention / prophylaxis or treatment of fibrosis of organs including liver / hepatic fibrosis, renal / kidney fibrosis, lung / pulmonary fibrosis ,heart / cardiac fibrosis, eye / corneal fibrosis, and skin fibrosis; as well as gut fibrosis, head and neck fibrosis, hypertrophic scarring and keloids; and fibrosis sequelae of organ transplant.

<NUM>) A further embodiment relates to the compounds of formula (I) for use according to embodiment <NUM>) wherein said compounds are for use in the prevention / prophylaxis or treatment of cardiovascular diseases and disorders.

<NUM>) A further embodiment relates to the compounds of formula (I) for use according to embodiment <NUM>) wherein said compounds are for use in the prevention / prophylaxis or treatment of acute kidney injury and chronic kidney disease (CKD).

<NUM>) A further embodiment relates to the compounds of formula (I) for use according to embodiment <NUM>) wherein said compounds are for use in the prevention / prophylaxis or treatment of (acute or chronic) liver diseases and disorders.

<NUM>) A further embodiment relates to the compounds of formula (I) for use according to embodiment <NUM>) wherein said compounds are for use in the prevention / prophylaxis or treatment of interstitial lung diseases and disorders.

<NUM>) A further embodiment relates to the compounds of formula (I) for use according to embodiment <NUM>) wherein said compounds are for use in the prevention / prophylaxis or treatment of ocular diseases and disorders.

<NUM>) A further embodiment relates to the compounds of formula (I) for use according to embodiment <NUM>) wherein said compounds are for use in the prevention / prophylaxis or treatment of cell proliferative diseases and cancers.

<NUM>) A further embodiment relates to the compounds of formula (I) for use according to embodiment <NUM>) wherein said compounds are for use in the prevention / prophylaxis or treatment of chronic or acute inflammatory and autoimmune diseases and disorders.

<NUM>) A further embodiment relates to the compounds of formula (I) for use according to embodiment <NUM>) wherein said compounds are for use in the prevention / prophylaxis or treatment of gastrointestinal tract diseases and disorders.

<NUM>) A further embodiment relates to the compounds of formula (I) for use according to embodiment <NUM>) wherein said compounds are for use in the prevention / prophylaxis or treatment of pancreatic diseases and disorders.

<NUM>) A further embodiment relates to the compounds of formula (I) for use according to embodiment <NUM>) wherein said compounds are for use in the prevention / prophylaxis or treatment of abnormal angiogenesis-associated diseases and disorders.

<NUM>) A further embodiment relates to the compounds of formula (I) for use according to embodiment <NUM>) wherein said compounds are for use in the prevention / prophylaxis or treatment of brain-associated diseases and disorders.

<NUM>) A further embodiment relates to the compounds of formula (I) for use according to embodiment <NUM>) wherein said compounds are for use in the prevention / prophylaxis or treatment of neuropathic pain and peripheral neuropathy.

<NUM>) A further embodiment relates to the compounds of formula (I) for use according to embodiment <NUM>) wherein said compounds are for use in the treatment of transplant rejection.

The compounds of Formula (I) can be prepared by well-known literature methods, by the methods given below, by the methods given in the experimental part below or by analogous methods. Optimum reaction conditions may vary with the particular reactants or solvents used, but such conditions can be determined by a person skilled in the art by routine optimisation procedures. In some cases the order of carrying out the following reaction schemes, and/or reaction steps, may be varied to facilitate the reaction or to avoid unwanted by-products. In the general sequence of reactions outlined below, the integer n and the generic groups R<NUM>, L, Ar<NUM>, and Ar<NUM> are as defined for Formula (I). Other abbreviations used herein are explicitly defined, or are as defined in the experimental section. In some instances the generic groups R<NUM>, L, Ar<NUM>, and Ar<NUM> might be incompatible with the assembly illustrated in the schemes below and so will require the use of protecting groups (Pg). The use of protecting groups is well known in the art (see for example "<NPL>). For the purposes of this discussion, it will be assumed that such protecting groups as necessary are in place. In some cases the final product may be further modified, for example, by manipulation of substituents to give a new final product. These manipulations may include, but are not limited to, reduction, oxidation, alkylation, acylation, hydrolysis and transition-metal catalysed cross-coupling reactions which are commonly known to those skilled in the art. The compounds obtained may also be converted into salts, especially pharmaceutically acceptable salts, in a manner known per se.

Compounds of the Formula (I) of the present invention can be prepared according to the general sequence of reactions outlined below. Only a few of the synthetic possibilities leading to compounds of Formula (I) are described.

Compounds of Formula (I) are prepared by coupling a compound of Structure <NUM> where R is either hydrogen, a suitable protective group (Pg) or R<NUM> (as defined in Formula (I)) with a compound of Structure <NUM> to give Structure <NUM>. The coupling reaction is performed using standard peptide coupling conditions such as DCC, HOBT, or T3P in presence of a base such as TEA or DIPEA in a suitable solvent such as DCM or DMF or mixtures thereof. Alternatively, POCl<NUM> can be used with pyridine as a base. In Structure <NUM> and <NUM>, Pg is a suitable protective group such as acetyl, trimethylsilyl (TMS) or tert-butyl dimethylsilyl (TBS), or benzyl, which are well known to the person skilled in the art. The hydroxy groups in position <NUM> and <NUM> of Structure <NUM> can be protected with cyclic protective groups such as isopropylidene, benzylidene or bis-tert-butyl silyl groups. R is either hydrogen, a suitable protective group (Pg) or R<NUM> (as defined in Formula (I)). Compounds of Structure <NUM> are then deprotected to yield compounds of Formula (I).

In the case Pg represents an acyl protective group, such a protective group can be cleaved under standard conditions, e.g. by water or an alcohol in the presence or absence of additional solvents such as THF, dioxane, etc. and in the presence of a base such as K<NUM>CO<NUM>, NaOH, LiOH. In the case wherein such a protective group represents a benzyl group, the protective group can be cleaved e.g. by hydrogen in the presence of a catalyst such as Pd/C, PtO<NUM> in methanol, EA, THF, etc. or mixtures thereof, or by BBr<NUM> in a solvent such as DCM. In the case wherein such a protective group is TMS or TBS, the protective group is cleaved using fluoride ions such as TBAF or HF in pyridine. Alternatively, silyl protective groups are removed under mild acidic conditions such as aqueous acetic acid at temperatures between rt and reflux. In the case where Pg is a cyclic protective group such as isopropylidene, benzylidene and bis-tert-butyl silylene group, the cleavage can be performed under acidic conditions using aqueous acetic acid or TFA.

The compounds of Structure <NUM> are prepared by hydrolysis of the nitrile function in Structure <NUM> to the carboxylic acid using aqueous acidic (conc. HCl) or basic (NaOH) conditions at temperatures between <NUM> and <NUM>, followed by suitable protection or modification of the free hydroxyl groups. Structure <NUM> in turn is obtained e.g. by reacting a compound of Structure <NUM> with a compound of Structure <NUM> in the presence of Cul and DIPEA in solvents such as THF or DMF (<NPL>), alternatively the reaction can be run on a commercial continuous-flow reactor (Vapourtec) using a copper coil in a solvent such as THF. Compounds of Structure <NUM> are either commercially available or can be prepared according to procedures known to a person skilled in the art (<NPL>). Compounds of Structure <NUM> can be prepared from corresponding gulofuranose derivatives through methods well known to a person skilled in the art (<NPL>;<NPL>).

Compounds of Structure <NUM> are obtained by protection of compounds of Structure <NUM> with a suitable silyl-based protective group under standard conditions. Compounds of Structure <NUM> are obtained by functionalization of (<NUM>,<NUM>)-trans-<NUM>-aminocyclohexanol or (<NUM>,<NUM>)-trans-<NUM>-aminocycloheptanol e.g. by reductive amination using a suitable carbonyl component and a reducing agent such as NaB(OAc)<NUM>H or NaCNBH<NUM> in a suitable solvent such as DCM, MeOH , THF, DMF or mixtures thereof. Alternatively, compounds of Structure <NUM> are obtained by reaction of cyclohexene oxide or cycloheptene oxide with an amine. This reaction either yields racemic trans-aminoalcohols or when carried out with a suitable catalyst such as reported in <NPL>, the enantiomerically enriched derivatives. In the case that compounds of Structure <NUM> are used in racemic form, the diastereomers of Structure <NUM> or Formula <NUM> can be separated after the coupling with compounds of Structure <NUM> using techniques which are well known to the person skilled in the art, such as chiral preparative HPLC or column chromatography on SiO<NUM>.

Whenever the compounds of Formula (I) are obtained in the form of mixtures of stereoisomers, the stereoisomers can be separated by preparative HPLC using achiral or chiral stationary phases such as a Waters XBridge C18, <NUM> OBD, 30x75 mm, or Daicel ChiralCel OJ-H (<NUM>-<NUM>) column, a Daicel ChiralPak IH (<NUM>) or AS-H (<NUM>) or IB (<NUM>) column, respectively. Typical conditions of chiral HPLC are an isocratic mixture of eluent A (CO<NUM>) and eluent B (DCM/MeOH, <NUM>% Et<NUM>NH in EtOH, MeOH, EtOH), at a flow rate of <NUM> to <NUM>/min).

The following examples illustrate the invention but do not at all limit the scope thereof.

All temperatures are stated in °C. Commercially available starting materials were used as received without further purification. Unless otherwise specified, all reactions were carried out under an atmosphere of nitrogen or argon. Compounds were purified by flash chromatography on silica gel (Biotage), by prep TLC (TLC-plates from Merck, Silica gel <NUM> F<NUM>) or by preparative HPLC. Compounds described in the invention are characterized by <NUM>H-NMR (Bruker Avance II, <NUM> Ultra ShieldTM or Brooker Avance III HD, Ascend <NUM>); chemical shifts are given in ppm relative to the solvent used; multiplicities: s = singlet, d = doublet, t = triplet, q = quadruplet, quint = quintuplet, hex = hexet, hept = heptet, m = multiplet, br = broad, coupling constants are given in Hz) and/or by LCMS (retention time tR is given in min; molecular weight obtained for the mass spectrum is given in g/mol) using the conditions listed below.

Characterization methods used:
The LC-MS retention times have been obtained using the following elution conditions:.

Zorbax RRHD SB-Aq, <NUM>, <NUM>. 1x50 mm column thermostated at <NUM>. The two elution solvents were as follows: solvent A= water + <NUM>% TFA; solvent B = acetonitrile. The eluent flow rate was <NUM>/min and the characteristics of the eluting mixture proportion in function of the time t from start of the elution are summarized in the table below (a linear gradient being used between two consecutive time points):.

Waters BEH C18, <NUM>, <NUM>*<NUM> column thermostated at <NUM>. The two elution solvents were as follows: solvent A= water + <NUM> NH4OH; solvent B = acetonitrile. The eluent flow rate was <NUM>/min and the characteristics of the eluting mixture proportion in function of the time t from start of the elution are summarized in the table below (a linear gradient being used between two consecutive time points):.

Acquity UPLC CSH C18 <NUM>, <NUM> x <NUM> from Waters column thermostated at <NUM>. The two elution solvents were as follows: solvent A= water + <NUM>% Formic Acid; solvent B = acetonitrile. The eluent flow rate was <NUM>/min and the characteristics of the eluting mixture proportion in function of the time t from start of the elution are summarized in the table below (a linear gradient being used between two consecutive time points):.

Acquity UPLC CSH C18 <NUM>, <NUM> x <NUM> from Waters column thermostated at <NUM>. The two elution solvents were as follows: solvent A= water + <NUM>% Formic acid; solvent B = acetonitrile + <NUM>% Formic acid. The eluent flow rate was <NUM>/min and the characteristics of the eluting mixture proportion in function of the time t from start of the elution are summarized in the table below (a linear gradient being used between two consecutive time points):.

The purifications by preparative LC-MS have been performed using the conditions described hereafter.

A Waters column (Waters XBridge C18, <NUM> OBD, 30x75 mm) was used. The two elution solvents were as follows: solvent A = water + <NUM>% of a solution of <NUM>% NH4OH in water; solvent B = acetonitrile. The eluent flow rate was <NUM>/min and the characteristics of the eluting mixture proportion in function of the time t from start of the elution are summarized in the tables below (a linear gradient being used between two consecutive time points):.

The following precursors have been prepared for the synthesis of the compounds:
<CHM>.

(3R,<NUM>,5R,6R)-<NUM>-(acetoxymethyl)-<NUM>-azidotetrahydro-<NUM>-pyran-<NUM>,<NUM>,<NUM>-triyl triacetate is synthesized from (3aR,<NUM>,<NUM>,6aR)-<NUM>-((R)-<NUM>,<NUM>-dimethyl-<NUM>,<NUM>-dioxolan-<NUM>-yl)-<NUM>,<NUM>-dimethyltetrahydrofuro[<NUM>,<NUM>-d][<NUM>,<NUM>]dioxol-<NUM>-ol following the literature procedures from Ref: <NPL> and references cited therein.

Intermediate <NUM> (<NUM>, <NUM> mmol, <NUM> eq) is dissolved in nitromethane (<NUM> vol. ) (<NUM>) and trimethylsilyl cyanide <NUM>% (<NUM>, <NUM> mmol, <NUM> eq) and boron trifluoride diethyl etherate (<NUM>, <NUM> mmol, <NUM> eq) are added portionwise over <NUM>. Temperature is kept below <NUM> with a water bath. The mixture is stirred at rt for <NUM>. The mixture is partitioned between water (<NUM>), sat aq. bicarbonate (<NUM>) and TBME (<NUM>). The aq phase is extracted once more with TBME (<NUM>) and org. phases washed twice with water/brine (ca. <NUM>:<NUM>) and brine, dried over MgSO<NUM> TBME is evaporated on Rotavap at <NUM>. The crude intermediate is purified by filtration over SiO<NUM> (<NUM> mLcartridge filled <NUM>/<NUM>, DCM/TBME <NUM>:<NUM>). The intermediate is used immediately in the next step.

<NUM> NMR (<NUM>, DMSO) δ: <NUM> (dd, J<NUM> = <NUM>, J<NUM> = <NUM>, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (dd, J<NUM> = <NUM>, J<NUM> = <NUM>, <NUM>), <NUM> (ddd, J<NUM> = <NUM>, J<NUM> = <NUM>, J<NUM> = <NUM>, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (dd, J<NUM> = <NUM>, J<NUM> = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (m, <NUM>), <NUM> (s, <NUM>).

Intermediate <NUM> is dissolved in DMF (<NUM>) and <NUM>-ethynyl-<NUM>,<NUM>,<NUM>-trifluorobenzene (<NUM>, <NUM> mmol, <NUM> eq), DIPEA (<NUM>, <NUM> mmol, <NUM> eq) and Cul (<NUM>, <NUM> mmol, <NUM> eq) are added under N<NUM>. The yellow mixture is stirred at rt for <NUM>. Exothermic. The yellow solution is slowly poured on water (<NUM>) and stirred for <NUM>. The beige precipitate is filtered off and the filtrate discarded. The beige solid is washed with MeOH and then dissolved in EA (<NUM>) and stirred for <NUM>. The fine Cu residues are filtered off and the filtrated is washed with NH4CI solution (half saturated) and brine, dried over MgSO<NUM> and concentrated. The residue is triturated with MeOH (ca <NUM>), filtered and dried at hv to give the desired intermediate 3a as a beige solid.

<NUM>H NMR (<NUM>, DMSO-d6) δ: <NUM> (s, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (m, <NUM>), <NUM> (dd, J1 = <NUM>, J2 = <NUM>, <NUM>), <NUM> (dd, J1 = <NUM>, J2 = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> (m, <NUM>), <NUM> (m, <NUM>). LCMS (A): tR = <NUM>; [M+H]+ = <NUM>.

Prepared in analogy to Intermediate 3a using the appropriate alkyne derivative (commercial). LCMS (A): tR = <NUM>; [M+H]+ = <NUM>.

Prepared in analogy to Intermediate 3a using the appropriate alkyne derivative (commercial). LCMS (A): tR = <NUM>; [M+H]+ = <NUM>
Intermediates <NUM> are further functionalised as shown in the scheme below
<CHM>.

Intermediate 3a (<NUM>, <NUM> mmol, <NUM> eq) is suspended in HCl <NUM>% (<NUM>, <NUM> mmol, <NUM> eq) and heated at reflux for <NUM>. The solution is applied to a MCl ® gel column (ca <NUM> gel) under water. The column is eluted with water until neutral pH (<NUM> fractions a <NUM>). The compound is then eluted with H<NUM>O/MeCN (<NUM>:<NUM>). Fractions of <NUM> are taken. Fractions containing product are first concentrated in vacuo to remove MeCN and then freeze-dried to give the title compound as a colourless solid.

Prepared in analogy to Intermediate 4a. LCMS (A): tR = <NUM>; [M+H]+ = <NUM>.

Intermediate 4a (<NUM>, <NUM> mmol, <NUM> eq) is dissolved in THF (<NUM>) and <NUM>,<NUM>-dimethoxypropane (<NUM>, <NUM> mmol, <NUM> eq) is added followed by PTSA monohydrate (<NUM>, <NUM> mmol, <NUM> eq) at rt.

The mixture is heated to <NUM> for <NUM> and <NUM>-<NUM> solvent are distilled off using a Dean-Stark. The solution is cooled to rt and is then diluted with EA and washed with <NUM>% citric acid solution, water and brine. layer is dried over MgSO<NUM>, filtered and concentrated under reduced pressure to give the title intermediate as a beige solid.

Prepared in analogy to Intermediate 5a. LCMS (A): tR = <NUM>; [M+H]+ = <NUM>.

A solution of Intermediate 5a (<NUM>, <NUM> mmol, <NUM> eq) in DMF (dry) (<NUM>) and THF (dry) (<NUM>) is cooled to <NUM> and dimethyl sulfate* <NUM>% (<NUM>, <NUM> mmol, <NUM> eq) is added followed by NaH (<NUM>% dispersion in mineral oil) (<NUM>, <NUM> mmol, <NUM> eq). The mixture is stirred at <NUM> for <NUM> and then at rt for <NUM>. The mixture is cooled to <NUM> again and quenched by addition of sat. NH<NUM>Cl solution. The mixture is diluted with water and EA and the layers are separated. layer is washed with water and brine and the aq. layer is once re-extracted with EA. The combined org. layers are dried over magnesium sulfate, filtrated and evaporated. The residue is precipitated from TBME/Hept and the colorless solid is filtered off and washed with little TBME and dried at hv. The desired methylester is isolated as a colourless solid.

* lodomethane could be used as reagent as well delivering the same product.

The intermediate from step <NUM> (<NUM>, <NUM> mmol, <NUM> eq) is dissolved in THF/MeOH/H<NUM>O <NUM>:<NUM>:<NUM> (<NUM>) and lithiumhydroxide monohydrate (<NUM>, <NUM> mmol, <NUM> eq) is added at rt.

The mixture is stirred at rt for <NUM>. The mixture is diluted with water, acidified with <NUM>. 1N HCl and two times extracted with EA. layers are washed with brine, combined, dried over magnesium sulfate, filtered and concentrated. The residue is triturated in TBME. The white solid is filtered off and washed with TBME and dried at hv to give the desired intermediate as a colourless solid.

To a solution of Intermediate 5a (<NUM>, <NUM> mmol, <NUM> eq) and <NUM>,<NUM>-lutidine (<NUM>, <NUM> mmol, <NUM> eq) in DCM dry (<NUM>) is dropwise added trimethylsilyl trifluoromethanesulfonate (<NUM>, <NUM> mmol, <NUM> eq) at <NUM>. The mixture is stirred at <NUM> for <NUM>. <NUM>,<NUM>-lutidine (<NUM>, <NUM> mmol, <NUM> eq) and trimethylsilyl trifluoromethanesulfonate (<NUM>, <NUM> mmol, <NUM> eq) are added again at <NUM> and stirring is continued at <NUM>. <NUM>,<NUM>-lutidine (<NUM>, <NUM> mmol, <NUM> eq) and trimethylsilyl trifluoromethanesulfonate (<NUM>, <NUM> mmol, <NUM> eq) are added again and stirring continued for <NUM>. The mixture is diluted with DCM and quenched with water at <NUM>. The layers are separated and the org. one is washed with water and brine. layer is filtered over a phase separator and evaporated. The crude is dried at hv and used without purification due to its instability.

To a solution of Intermediate 5a (<NUM>, <NUM> mmol, <NUM> eq) in DCM dry (<NUM>) under N<NUM> at <NUM> is added <NUM>,<NUM>-lutidine (<NUM>, <NUM> mmol, <NUM> eq), followed by addition of tert-butyldimethylsilyl trifluoromethanesulfonate (<NUM>, <NUM> mmol, <NUM> eq). The orange solution is then stirred at <NUM> for <NUM>. The mixture is stirred at rt o/n. tert-butyldimethylsilyl trifluoromethanesulfonate (<NUM>, <NUM> mmol, <NUM> eq) and <NUM>,<NUM>-lutidine (<NUM>, <NUM> mmol, <NUM> eq) are added again at <NUM> and the mixture is stirred at <NUM> for <NUM>. The mixture is quenched with <NUM>% citric acid and two times extracted with DCM. The combined org. layers are dried using a phase separator and are then concentrated under reduced pressure. The mixture is dissolved in MeCN/water <NUM>/<NUM> (<NUM>) and is treated with HCOOH (<NUM>). The suspension is stirred at rt for <NUM> and is then filtered. The solid is purified by FC using CombiFlash (<NUM> SiO<NUM> column; gradient: hept to hept/EA <NUM>/<NUM> in <NUM>) to give the desired product as a colourless solid.

To a solution of Intermediate 5a (<NUM>, <NUM> mmol, <NUM> eq) in DCM (<NUM>) and TEA (<NUM>, <NUM> mmol, <NUM> eq) is added Ac<NUM>O (<NUM>, <NUM> mmol, <NUM> eq) followed by DMAP (<NUM>, <NUM> mmol, <NUM> eq). The mixture is stirred at rt o/n. The mixture is diluted with water and DCM. The pH is carefully adjusted to <NUM>-<NUM> with <NUM>% citric acid and the layers are separated. layer is once reextracted with DCM and the combined org. layers are dried over MgSO<NUM>, filtered and evaporated. The residue is precipitated from TBME/hept + little MeOH. The colourless solid is filtered off and washed with TBME to give the desired intermediate as a colourless solid.

Prepared form 5b in analogy to Intermediate 6d. LCMS (A): tR = <NUM>; [M+H]+ = <NUM>.

Prepared form 5c in analogy to Intermediate 6d. LCMS (A): tR = <NUM>; [M+H]+ = <NUM>.

Prepared form 5d in analogy to Intermediate 6d. LCMS (A): tR = <NUM>; [M+H]+ = <NUM>.

Prepared form 5e in analogy to Intermediate 6d. LCMS (A): tR = <NUM>; [M+H]+ = <NUM>.

To a suspension of Intermediate 4a (<NUM>, <NUM> mmol, <NUM> eq) in Ac<NUM>O (<NUM>, <NUM> mmol, <NUM> eq) is added perchloric acid <NUM>% in water (<NUM>, <NUM> mmol, <NUM> eq) at <NUM>. The mixture is stirred at <NUM> for <NUM> and then allowed to warm to rt and stirred o/n. The mixture is cooled to <NUM> and diluted with water (<NUM>) and THF (<NUM>). The mixture is allowed to warm to rt (<NUM>, hydrolysis exothermic).

The mixture is cooled to <NUM>-<NUM> and the precipitated product is filtered off, washed with water and dried at hv o/n to afford the product as a white solid.

Intermediate 4a (<NUM>, <NUM> mmol) is dissolved in MeCN (<NUM>). Benzaldehyde dimethylacetal (<NUM>) is added followed by PTSA (<NUM>, <NUM> eq). The mixture is stirred at rt for <NUM>. Volatiles are removed under reduced pressure and the residue partitioned between EA and sat. NH<NUM>Cl solution. The org phase is dried over MgSO<NUM> and concentrated to give the desired intermediate as a colourless solid.

Intermediate 8a (<NUM>, <NUM> mmol, <NUM> eq) is dissolved in DCM (<NUM>) and TEA (<NUM>, <NUM> mmol, <NUM> eq) and acetic anhydride (<NUM>, <NUM> mmol, <NUM> eq) are added. The mixture is stirred at rt o/n. NH<NUM>Cl solution (<NUM>) is added and the resulting mixture is stirred at rt for <NUM>. The resulting precipitate is filtered off and washed with DCM and water. The crude product is dried at hv still containing some salts. The solid is therefore washed with citric acid solution (<NUM>%) and water and dried again at hv.

Intermediates of Structure <NUM> are prepared by a) reductive amination of <NUM>-aminocyclohexanol or <NUM>-aminocycloheptanol with an aldehyde, b) by alkylation with an alkylhalogenide or c) by epoxide opening as shown below
<CHM>.

To a solution of cis-<NUM>-aminocyclohexanol hydrochloride (<NUM>, <NUM> mmol, <NUM> eq) in DCM/MeOH <NUM>/<NUM> (<NUM>) is added <NUM>-chlorobenzaldehyde (<NUM>, <NUM> mmol, <NUM> eq) at rt. To the resulting solution is added sodium cyanoborohydride (<NUM>, <NUM> mmol, <NUM> eq) under nitrogen at rt and the solution is stirred at rt for <NUM>. Sodium cyanoborohydride (<NUM>, <NUM> mmol, <NUM> eq) is added again at rt and the mixture is stirred at rt overnight. The mixture is quenched with water and basified with <NUM>% aq. NH<NUM>OH solution. The mixture is extracted twice with DCM and the combined org. layers are evaporated. The residue is re-dissolved in MeCN and basified with aq. <NUM>% NH<NUM>OH solution. The product is purified by prep LCMS (I). Product containing fractions are freeze-dried to give the desired amino alcohol as a colourless solid.

The following intermediates are prepared in analogy the procedure of Intermediate <NUM>:.

Compounds of Structure <NUM> can be further protected at the hydroxy group following the procedures below:.

To a solution of Intermediate <NUM> (<NUM>, <NUM> mmol, <NUM> eq) and <NUM>,<NUM>-lutidine (<NUM>, <NUM> mmol, <NUM> eq) in dry DCM (<NUM>) at <NUM> is dropwise added trimethylsilyl trifluoromethanesulfonate <NUM>% (<NUM>, <NUM> mmol, <NUM> eq). The mixture is stirred at <NUM> for <NUM> and then allowed to warm to rt. The mixture is quenched with water and extracted twice with DCM. The combined org. layers are dried using a phase separator and are then concentrated under reduced pressure. The crude is absorbed on isolute and purified by FC CombiFlash (<NUM> RediSep column, <NUM>-<NUM>% EA in hept within <NUM>) to give the title intermediate (<NUM>) as a colourless oil.

To a solution of Intermediate <NUM> (<NUM>, <NUM> mmol, <NUM> eq) and <NUM>,<NUM>-lutidine (<NUM>, <NUM> mmol, <NUM> eq) in dry DCM (<NUM>) at <NUM> is dropwise added tert-butyldimethylsilyl trifluoromethanesulphonate (<NUM>, <NUM> mmol, <NUM> eq). The mixture is stirred at <NUM> for <NUM> and then allowed to warm to rt. The mixture is quenched with water and extracted twice with DCM. The combined org. layers are dried using a phase separator and are then concentrated under reduced pressure. The crude is absorbed on isolute and purified by FC CombiFlash (<NUM> RediSep column, <NUM>-<NUM>% EA in hept within <NUM>) to give the title intermediate as a yellowish oil.

The following intermediates are prepared in analogy:.

<NUM>-(Trifluoromethyl)pyrimidine-<NUM>-carboxylic acid (<NUM>, <NUM> mmol, <NUM> eq) is dissolved in THF (<NUM>, <NUM> mmol, <NUM> eq) and cooled to -<NUM> (dry ice bath). <NUM>-Methylmorpholine (<NUM>, <NUM> mmol, <NUM> eq) is added at -<NUM> to -<NUM>, followed by the addition of ethyl chloroformate (<NUM>, <NUM> mmol, <NUM> eq) at an internal temperature of -<NUM> to -<NUM>. THF (<NUM>) is added slowly, keeping the internal temperature below -<NUM> to improve stirring. The mixture kept at -<NUM> for <NUM>. After <NUM>, sodium borohydride (<NUM>, <NUM> mmol, <NUM> eq) is added at -<NUM> and stirring at this temperature is continued for <NUM>. Then, the dry-ice bath is exchanged by an ice-bath and the mixture is stirred at <NUM> for <NUM>. The reaction mixture is quenched with water (<NUM>), acidified with <NUM>% citric acid to pH <NUM>-<NUM>, then extracted with n-butanol (3x). layers are combined, dried over MgSO<NUM>, filtered and evaporated to give a crude orange oil which is still containing some salts. The mixture is suspended in DCM and salts are filtered off. The filtrate is concentrated and the residue is purified by FC CombiFlash (<NUM> RediSep column, <NUM>-<NUM>% EA in hept). The intermediate alcohol is isolated as a yellow oil.

Above alcohol (<NUM>, <NUM> mmol, <NUM> eq) is dissolved in DCM (<NUM>) and activated manganese(IV) oxide, (<NUM>, <NUM> mmol, <NUM> eq) is added at rt. The mixture is stirred at rt o/n. The mixture is filtered over a glass-fibre filter and the filtrate is evaporated to give the title aldehyde as a yellow oil.

(<NUM>,<NUM>)-<NUM>-Aminocyclohexanol (<NUM>, <NUM> mmol, <NUM> eq) and above aldehyde (<NUM>, <NUM> mmol, <NUM> eq) are dissolved in DCM/MeOH <NUM>/<NUM> (<NUM>) and sodium cyanoborohydride (<NUM>, <NUM> mmol, <NUM> eq) is added portionwise at rt. The mixture is stirred at rt for <NUM>. The mixture is diluted with DCM and carefully quenched with water. The mixture is basified with <NUM>% NH<NUM>OH solution and the layers are separated (phase separator). The organic layer is concentrated and the crude is purified by FC (CombiFlash, <NUM> RediSep column, <NUM>-<NUM>% MeOH in EA) to give the title intermediate as a yellow oil.

Cyclohexene oxide (<NUM>, <NUM> mmol, <NUM> eq) and <NUM>,<NUM>-difluoroaniline (<NUM>, <NUM> mmol, <NUM> eq) are mixed with water (<NUM>) and heated at <NUM> o/n. The mixture is diluted with water and EA and the org. phase is dried over MgSO<NUM> and concentrated. The product is purified by FC (hept/EA <NUM>:<NUM>-<NUM>:<NUM>) to give the desired aminoalcohol as a brownish oil.

To a solution of intermediate of step <NUM> (<NUM>, <NUM> mmol, <NUM> eq) and <NUM>,<NUM>-lutidine (<NUM>, <NUM> mmol, <NUM> eq) in DCM dry (<NUM>) is dropwise added tert-butyldimethylsilyl trifluoromethanesulphonate (<NUM>, <NUM> mmol, <NUM> eq) at <NUM> for <NUM>. The mixture is diluted with <NUM> water. The layers are separated (phase separator) and the aq. phase is re-extracted twice with <NUM> DCM. layer is evaporated and dried at hv o/n. The crude is purified by FC (CombiFlash, <NUM> Redi-Sep column, <NUM>-<NUM>% EA in hept) to give the desired intermediate as an orange oil.

Following compounds are prepared in analogy to Intermediate <NUM>, steps <NUM> and <NUM>.

To a solution of the intermediate 5a (<NUM> <NUM> mmol, <NUM> eq) in DMF (<NUM>) is added NaH (<NUM>% dispersion in mineral oil, <NUM>, <NUM> mmol) at <NUM>. The reaction mixture is stirred for <NUM> at rt. Dimethyl sulfate (<NUM>, <NUM> mmol) is added and the reaction mixture is stirred for <NUM> hour at rt. The mixture is cooled and quenched with water, extracted twice with ethyl acetate. The combined org. layers are washed with aq. NaCl solution (<NUM>), dried with MgSO4 and evaporated. The product is purified by CombiFlash, <NUM> RediSep column, <NUM> - <NUM>% ethyl acetate in hexane. The product is isolated as a colourless solid. LCMS (A): tR = <NUM>; [M+H]+ = <NUM>.

To a solution of intermediate <NUM> (<NUM>, <NUM> mmol, <NUM> eq) in DMF (<NUM>) is added at rt tert-butyl bromoacetate (<NUM>, <NUM> mml) and NaH (<NUM>% dispersion in mineral oil,<NUM>, <NUM> mmol). The reaction mixture is stirred for <NUM> at rt. The mixture is cooled and quenched with water, extracted twice with ethyl acetate. The combined org. layers are washed with aq. NaCl solution (<NUM>), dried with MgSO4 and evaporated. The product is purified by CombiFlash, <NUM> RediSep column, <NUM> - <NUM>% ethyl acetate in hexane. The product is isolated as a colourless solid. LCMS (A): tR = <NUM>; [M+H]+ = <NUM>.

To a solution of intermediate <NUM> (<NUM>, <NUM> mmol, <NUM> eq) in THF, MeOH, H<NUM>O (<NUM>, <NUM>:<NUM>:<NUM>) is added at <NUM> LiOH (<NUM>, <NUM> mmol) and the mixture is stirred <NUM>. Additional LiOH (<NUM>, <NUM> mmol) is added and the mixture is stirred for <NUM>. HCl is added to maintain pH <NUM> and the mixture is extracted twice with ethyl acetate. The combined org. layers are washed with aq. NaCl solution (<NUM>), dried with MgSO4 and evaporated. The product is isolated as a colourless solid. LCMS (A): tR = <NUM>; [M+H]+ = <NUM>.

This compound is prepared in analogy to intermediate 100a from the corresponding acid.

The compound is prepared from the intermediate 100a and intermediate <NUM> according to the general procedure B.

To a solution of intermediate <NUM> (<NUM>, <NUM> mmol) in <NUM>,<NUM>-dioxane (<NUM>) and water (<NUM>) is added at <NUM> dropwise TFA (<NUM>). The reaction mixture is stirred at rt for <NUM>. NaHCO<NUM> is added to maintain pH <NUM> and the mixture is extracted twice with ethyl acetate. The combined org. layers are washed with aq. NaCl solution (<NUM>), dried with MgSO4 and evaporated. The product is isolated as a yellowish oil. LCMS (A): tR = <NUM>; [M+H]+ = <NUM>.

The following intermediated are prepared in <NUM> steps procedure from corresponding starting materials in analogy to acid 6a.

To a solution of acid component (<NUM> eq) and amine intermediate (<NUM> eq) in DMF (<NUM>/mmol) is added DIPEA (<NUM> eq) and T3P (<NUM>% solution in EA, <NUM> eq) and the mixture is stirred at rt until complete conversion. After aqueous workup (EA/dil HCl) the products are purified as described in the general methods.

To a solution of acid component (<NUM> eq) and amine intermediate (<NUM> eq) in DCM (<NUM>/mmol) at <NUM> is dropwise added phosphorus(V) oxychloride (<NUM> solution in pyridine, <NUM>, <NUM> mmol, <NUM> eq) within <NUM>-<NUM>. The mixture is stirred at <NUM> for <NUM> and then allowed to slowly warm to rt. After completion of the reaction, the mixture is quenched with <NUM>% citric acid and extracted twice with EA. layers are washed with brine. The combined org. layers are dried over magnesium sulfate, filtered and concentrated. The products are purified as described in the general methods.

The protected intermediate (acetal and/or silyl Pg) (1eq) is refluxed in AcOH/H<NUM>O <NUM>:<NUM> (<NUM>/mmol) until completion of reaction. The products are purified as described in the general methods.

CSA (<NUM> eq) is added to the isopropylidene protected intermediate (<NUM> eq) in MeOH (<NUM>/mmol) and heated at reflux until completion of reaction. The products are purified as described in the general methods.

K<NUM>CO<NUM> (<NUM> eq) is added to the acetate protected intermediate (<NUM> eq) in MeOH (<NUM>/mmol) and stirred at rt until completion of reaction. The products are purified as described in the general methods.

Compounds of Examples listed in Table <NUM> below are prepared by applying either one of the above-mentioned procedures A or B in the coupling with acids <NUM>-<NUM>, <NUM>-<NUM> and amines <NUM>-<NUM>, <NUM>-<NUM>. The final compounds are obtained by deprotection using procedures C, D or E.

To a solution of intermediate <NUM> (<NUM>, <NUM> mmol, <NUM> eq) in DCM (<NUM>) is added at rt <NUM> TFA (<NUM>) and the reaction mixture is stirred at rt for <NUM>. The solvent is evaporated. The product is isolated as a TFA salt. LCMS (A): tR = <NUM>; [M+H]+ = <NUM>.

To a solution of example <NUM> (<NUM>, <NUM> mmol, <NUM> eq) in THF (<NUM>) is added at <NUM> <NUM> solution of BH<NUM>. Me<NUM>S in THF (<NUM>, <NUM> eq) and the reaction mixture is stirred at rt for <NUM>. MeOH (<NUM>) and aq. NH<NUM>Cl solution (<NUM>) is added and the mixture is extracted twice with ethyl acetate. The combined org. layers are washed with aq. NaCl solution (<NUM>) are evaporated. The product is purified by LC-MS (I). The product is isolated as a colourless solid. LCMS (A): tR = <NUM>; [M+H]+ = <NUM>.

To a solution of example <NUM> (<NUM>, <NUM> mmol, <NUM> eq) in DMF (<NUM>) is added at rt HATU (<NUM>, <NUM> eq), morpholine (<NUM>µl, <NUM> eq) and DIPEA (<NUM>µl, <NUM> eq) and the reaction mixture is stirred at rt for <NUM>. The reaction mixture is purified by LC-MS (I). The product is isolated as a colourless solid. LCMS (A): tR = <NUM>; [M+H]+ = <NUM>.

Following compounds are prepared in analogy to example <NUM> from the example <NUM> and the corresponding amine.

Step <NUM> :(2R,3R,<NUM>,5R,6R)-<NUM>-(<NUM>-(<NUM>-((tert-butyldimethylsilyl)oxy)piperidin-<NUM>-yl)-<NUM>-oxoethoxy)-N-(<NUM>,<NUM>-dichlorophenyl)-<NUM>-hydroxy-N-((<NUM>,<NUM>)-<NUM>-hydroxycyclohexyl)-<NUM>-(hydroxymethyl)-<NUM>-(<NUM>-(<NUM>,<NUM>,<NUM>-trifluorophenyl)-<NUM>-<NUM>,<NUM>,<NUM>-triazol-<NUM>-yl)tetrahydro-<NUM>-pyran-<NUM>-carboxamide is prepared from example <NUM> and <NUM>-((tert-butyldimethylsilyl)oxy)piperidine according to the procedure described for example <NUM>.

Step <NUM>:To the solution of the silyl ether described above (<NUM>, <NUM> mmol) in dioxan (<NUM>) and water (<NUM>) is added TFA (<NUM>) and the reaction mixture is stirred at rt for <NUM>. Ethyl acetate (<NUM>) and aq. NaHCO<NUM> solution (<NUM>) is added to maintain the pH <NUM>, the water phase is separated and extracted twice with ethyl acetate. The combined org. layers are evaporated. The product is purified by LC-MS (I). The product is isolated as a colourless solid. LCMS (A): tR = <NUM>; [M+H]+ = <NUM>.

This compound is prepared in <NUM> steps procedure in analogy to example <NUM>. LCMS (A): tR = <NUM>; [M+H]+ = <NUM>.

Step1: To a solution of the intermediate 6a ((<NUM>, <NUM> mmol, <NUM> eq), K2CO3 (<NUM>, <NUM> mmol) in DMSO (<NUM>) is added at rt morpholine (<NUM>, <NUM> mmol) and the reaction mixture is stirred at <NUM> for <NUM>. Morpholine (<NUM>) is added and mixture is stirred for <NUM> days. Ethyl acetate and aq. NaH4Cl solution is added to maintain the pH <NUM>-<NUM>, the water phase is separated and extracted twice with ethyl acetate. The combined org. layers are evaporated. The product is purified by LC-MS (I). The product is isolated as a colourless solid. LCMS (A): tR = <NUM>; [M+H]+= <NUM>.

Step <NUM>: The amide coupling of the acid from step <NUM> with the amine <NUM> is performed according to the procedure B.

Step <NUM>: The product from step <NUM> is deprotected according to the procedure described for example <NUM>, step <NUM>.

Example <NUM> is prepared in analogy to example <NUM> using azetidine instead of morpholine in step <NUM>.

The inhibitory activity of compounds is determined in competitive binding assays. This spectrophotometric assay measures the binding of biotinylated human Gal-<NUM> (hGal-<NUM>) or human Gal-<NUM> (hGal-<NUM>), respectively, to a microplate-adsorbed glycoprotein, asialofetuin (ASF) (<NPL>. Alternatively, and preferably, a human Gal-<NUM> version in which all six cysteines are substituted by serines may be used.

Briefly, compounds are serially diluted in DMSO (working dilutions). ASF-coated 384well plates are supplemented with <NUM>µL/well of biotinylated hGal-<NUM> or hGal-<NUM> in assay buffer (i.e. <NUM>-<NUM> ng/mL biotinylated hGal-<NUM> or hGal-<NUM>) to which <NUM>µL of compound working dilutions are added and mixed.

Plates are incubated for <NUM> hours at <NUM>, then washed with cold assay buffer (3x50uL), incubated for <NUM> hour with <NUM>µL/well of a streptavidin-peroxidase solution (diluted in assay buffer to <NUM> ng/mL) at <NUM>, followed by further washing steps with assay buffer (3x50uL). Finally, <NUM>µL/well of ABTS substrate is added. OD (<NUM>) is recorded after <NUM> to <NUM> and IC<NUM> values are calculated.

The calculated IC<NUM> values may fluctuate depending on the daily assay performance. Fluctuations of this kind are known to those skilled in the art. IC<NUM> values from several measurements are given as mean values.

Claim 1:
A compound of formula (I)
<CHM>
wherein
n represents the integer <NUM> or <NUM>;
Ar<NUM> represents
• aryl which is mono-, di-, tri-, tetra-, or penta-substituted, wherein the substituents are independently selected from halogen; methyl; cyano; methoxy; trifluoromethyl; trifluoromethoxy; NRN11RN12 wherein RN11 represents hydrogen and RN12 represents hydroxy-C<NUM>-<NUM>-alkyl, or RN11 and RN12 together with the nitrogen atom to which they are attached form a <NUM>- to <NUM>-membered heterocyclyl selected from morpholin-<NUM>-yl, azetidine-<NUM>-yl, pyrrolidine-<NUM>-yl, and piperidine-<NUM>-yl, wherein said <NUM>- to <NUM>-membered heterocyclyl is unsubstituted or mono-substituted with hydroxy;
• <NUM>- or <NUM>-membered heteroaryl, wherein said <NUM>- or <NUM>-membered heteroaryl independently is unsubstituted, mono- or di-substituted, wherein the substituents are independently selected from halogen, methyl, cyano, and methoxy; or
• <NUM>- or <NUM>-membered heteroaryl, wherein said <NUM>- or <NUM>-membered heteroaryl independently is unsubstituted, or mono-substituted with methyl;
R<NUM> represents
• hydroxy;
• C<NUM>-<NUM>-alkoxy;
• -O-CO-C<NUM>-<NUM>-alkyl;
• -O-CH<NUM>-CH<NUM>-OH; or
• -O-CH<NUM>-CO-R1Xwherein R1Xrepresents
➢ -hydroxy;
➢ morpholin-<NUM>-yl; or
➢ -NRN21RN22, wherein RN21 and RN22 together with the nitrogen atom to which they are attached form a <NUM>-to <NUM>-membered heterocyclyl selected from azetidine-<NUM>-yl, pyrrolidine-<NUM>-yl, and piperidine-<NUM>-yl, wherein said <NUM>- to <NUM>-membered heterocyclyl is mono-substituted with hydroxy;
L represents a direct bond, methylene, or ethylene; and
Ar<NUM> represents
• phenyl or <NUM>- or <NUM>-membered heteroaryl, wherein said phenyl or <NUM>- or <NUM>-membered heteroaryl independently is unsubstituted, or mono-, di- or tri-substituted; wherein the substituents independently are selected from C<NUM>-<NUM>-alkyl, C<NUM>-<NUM>-cycloalkyl, -CH<NUM>-C<NUM>-<NUM>-cycloalkyl, C<NUM>-<NUM>-fluoroalkyl, C<NUM>-<NUM>-fluoroalkoxy, C<NUM>-<NUM>-alkoxy, halogen, morpholine-<NUM>-yl, amino, ethynyl and cyano;
• <NUM>-membered bicyclic heteroaryl or <NUM>-membered bicyclic heteroaryl, wherein said <NUM>- or <NUM>-membered bicyclic heteroaryl independently is unsubstituted, mono- or di-substituted, wherein the substituents independently are selected from methyl, methoxy, and halogen; or
• naphthyl;
or a pharmaceutically acceptable salt thereof.